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• Cancer Moonshot Biobank

  The National Cancer Institute initiated the Cancer Moonshot Biobank to accelerate research through the collection and distribution of biospecimens for key research efforts. The Biobank will engage with over one thousand cancer patients, being treated with standard-of-care therapies, for longitudinal biospecimen and data collection. Cancer patients will be enrolled into the study from a diverse participant population engaged at medical institutions throughout the U.S. The biospecimens will be distributed to qualified scientists to accelerate research progress. The Biobank program, working closely with Leidos Biomedical, Inc. (LBR), will partner with community hospitals and other medical institutions, designated as Biospecimen Source Sites (BSS), to engage and consent eligible participants and collect biospecimens and associated clinical data; work with a central Biospecimen Core Resource (BCR) to support biospecimen collection, processing and storage activities and perform pathology quality control; work with LBR's Molecular Characterization (MoCha) lab to perform clinical tumor molecular characterization assays and return results to patients and their physicians; and make the biospecimens and associated data available to researchers to accelerate cancer research progress. Return of clinical results, a dedicated Patient and Provider Engagement (PPE) website, electronic informed consent, local participant engagement projects, and an embedded ethical, legal and social issues sub-study will together support patient and provider engagement in the program. Cancer Moonshot Biobank imaging data is being made available in The Cancer Imaging Archive (TCIA) on a release schedule that is coordinated with the program releases of data to dbGaP. The imaging data can be found at the following link: Cancer Moonshot Biobank Imaging

  Study phs002192

• Whole exome and transcriptome analysis of UV-exposed epidermis and carcinoma in situ reveals early drivers of carcinogenesis

  Squamous cell carcinoma in situ (SCCIS) is a prevalent precancerous lesion that can progress to cutaneous squamous cell carcinoma (cSCC). Although SCCIS is common, its pathogenesis remains poorly understood. To better understand SCCIS development, we performed laser-captured microdissection of human SCCIS and adjacent epidermis to isolate genomic DNA and RNA for next generation sequencing. Whole exome sequencing (WES) identified UV-signature mutations in multiple genes including Notch 1-3 (GeneID:4851, GeneID:4853, GeneID:4854) in the epidermis and SCCIS and oncogenic TP53 (GeneID:7157) mutations in SCCIS. Novel gene families, including SCHLAFEN genes, contained UV/oxidative-signature disruptive (UVD) epidermal mutations that manifested positive selection in SCCIS. The frequency and distribution of NOTCH and TP53 mutations indicate that NOTCH mutations may precede TP53 mutations. RNA sequencing identified 1166 differentially expressed genes; the top 5 enriched GO biological processes included: 1) immune response, 2) epidermal development, 3) protein phosphorylation, 4) regulation of catalytic activity, and 5) cytoskeletal regulation. The NEURL1 ubiquitin ligase, which targets Notch ligands for degradation, was upregulated in SCCIS. Neuralized 1 protein was found to be elevated in SCCIS suggesting that increased levels could represent a novel mechanism for downregulating Notch during UV-induced carcinogenesis. The data from DNA and RNA sequencing of epidermis and SCCIS provide insights regarding SCCIS formation.

  Study phs002019

• National Heart, Lung, and Blood Institute (NHLBI) Bench to Bassinet Program: The Pediatric Cardiac Genetics Consortium (PCGC) Study

  Multi-center, prospective observational cohort study of individuals with congenital heart defects (CHD). Phenotypic data and source DNA derived from 10,000 probands, parents, and families of interest are being collected to investigate relationships between genetic factors and phenotypic and clinical outcomes in patients with CHD. Phenotype data will be stored at dbGaP, while molecular and sequence data will be stored at BioData Catalyst. The PCGC Cohort is utilized in the following dbGaP substudies. Please click on the following substudies below or in the "Substudies" section of this top-level study page phs001194 PCGC Cohort. phs000571 PCGC: whole exome sequences, whole genome sequences, targeted sequences, MIP sequences, and SNP array data phs001843 PCGC-CMG Collaboration: whole genome sequences The Gabriella Miller Kids First Pediatric Research Program (Kids First) subset of the PCGC project (phs001194) is now accessible through a separate dbGaP study accession: phs001138. To access this dataset, please submit a Data Access Request (DAR) for phs001138. Approval of this DAR will be expedited for approved users of phs001194. To learn about other Kids First datasets visit https://kidsfirstdrc.org/.NHLBI's TOPMed program has provided additional Whole Genome Sequencing for PCGC participants - that data is accessible through a separate dbGaP sudy accession: phs001735. Access to this data set should be requested through a Data Access Request (DAR) for phs001735.

  Study phs001194

• Genetic insights into the biological mechanisms governing human ovarian ageing

  Reproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the underlying biological mechanisms and treatments to preserve it are limited. Here, we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in ~200,000 women of European ancestry. These common alleles influence clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

  Study EGAS00001004947

• POETIC clinical Trial Ki67 Bookend Breast Cancer Targeted Exome and RNAseq Project

  Using RNAseq, we compare the 15% of poorest responders (PRs, n=177) as measured by proportional Ki67 changes after 2 weeks of neoadjuvant aromatase inhibitors to good responders (GRs, n=190) selected from the top 50% responders in the POETIC trial and matched for baseline Ki67 categories. In the POETIC trial, 4,480 postmenopausal women with primary ER+ BC were randomised 2:1 to receive either treatment with a non-steroidal AI (letrozole or anastrozole) for 2 weeks before and 2 weeks after surgery or to no perisurgical treatment. Only AI-treated patients with HER2- tumors, paired baseline and surgery Ki67 available, and baseline Ki67 immunohistochemistry (IHC) >10% (to minimise imprecision in proportional Ki67 falls) were included for selection. Data is baseline RNAseq and targeted exome DNA sequencing analysis of POETIC Good/Poor Responders to aromatase inhibitors based on change in Ki67.

  Dataset EGAD00001010919

• Chromatin accessibility maps of chronic lymphocytic leukemia identify subtype-specific epigenome signatures and transcription regulatory networks

  Chronic lymphocytic leukemia (CLL) is characterized by substantial clinical heterogeneity, despite relatively few genetic alterations. To provide a basis for studying epigenome deregulation in CLL, we established genome-wide chromatin accessibility maps for 88 CLL samples from 55 patients using the ATAC-seq assay, and we also performed ChIPmentation and RNA-seq profiling for ten representative samples. Based on the resulting dataset, we devised and applied a bioinformatic method that links chromatin profiles to clinical annotations. Our analysis identified sample-specific variation on top of a shared core of CLL regulatory regions. IGHV mutation status – which distinguishes the two major subtypes of CLL – was accurately predicted by the chromatin profiles, and gene regulatory networks inferred for IGHV-mutated vs. IGHV-unmutated samples identified characteristic differences between these two disease subtypes. In summary, we discovered widespread heterogeneity in the chromatin landscape of CLL, established a community resource for studying epigenome deregulation in leukemia, and demonstrated the feasibility of chromatin accessibility mapping in cancer cohorts and clinical research.

  Dataset EGAD00001002110

• PAGE: Global Reference Panel

  Stanford contributed samples to the PAGE study that can act as a population reference dataset across the globe. Therefore this dataset includes reference individuals, without phenotypes, chosen to help infer ancestry that will help us understand the diverse samples available in PAGE. The complete dataset comprises individuals of European, African, Asian, Oceanian, and Native American descent, from a total of over 50 populations. A subset of these individuals from Puno, Peru and Easter Island (Rapa Nui), Chile, are included in the PAGE samples that were whole genome sequenced in 2015. Additional details are available in the Study Acknowledgments. The Global Reference Panel comprises 6 sample sets: A population sample of Andean individuals primarily of Quechuan/Aymaran ancestry from Puno, Peru A population sample of Easter Island (Rapa Nui), Chile Individuals of indigenous origin from Oaxaca, Mexico Individuals of indigenous origin from Honduras Individuals of indigenous origin from Colombia Individuals of indigenous origin from the Nama and Khomani KhoeSan populations of the Northern Cape, South Africa In addition, we genotyped publicly available samples that will be hosted on the Bustamante lab website (https://bustamantelab.stanford.edu/). These comprise large public datasets to provide an open reference dataset for the world: The additional related individuals from the Americas in the Human Genome Diversity Panel (H952) plus all additional samples from the Americas A subset of the unrelated individuals from the Maasai in Kinyawa, Kenya (MKK) dataset from the International Hapmap Project hosted at Coriell Additional samples will be available for restricted use with a data access agreement with the Bustamante Lab. This study is part of the Population Architecture using Genomics and Epidemiology (PAGE) study (phs000356).

  Study phs001033

• Genotyping NIGMS CEPH Samples from the United States, Venezuela, and France

  The Human Genetic Cell Repository (HGCR) is sponsored by the National Institute of General Medical Sciences (NIGMS) with the mission of supplying scientists with the materials for accelerating disease gene discovery and functional studies. The resources available include highly-characterized, contaminant-free fibroblast cell lines, transformed lymphoblastoid cell lines (LCLs), and DNA samples derived from these cultures. While the Repository has a major emphasis on inherited diseases, it also contains large collections of cell lines gathered from populations around the world that are intended for use in facilitating the understanding of human variation. Prominent among these resources is the CEPH Reference Family collection contributed by the Centre d'Etude du Polymorphisme Humain (CEPH), Foundation Jean Dausset, Paris, France. The CEPH collection includes families collected by R. White (Utah), J. Dausset (French), J. Gusella (Venezuelan), and J. Egeland (Amish). There are a total of 809 individuals accounting for 832 pedigree positions in the reference families. Family relationships for the 61 reference families were verified at Coriell and approved by CEPH. In an effort to enhance the value of this cell culture resource available from the Repository, the Coriell Genotyping and Microarray Center used the Affymetrix Genome-Wide Human SNP Array 6.0 platform to genotype 181 samples from the NIGMS HGCR CEPH collection. Included are thirteen families from the United States (Amish Pedigree 884 and Utah Pedigrees 1331, 1356, 1400, 1416, 1424, 1427, 1477, and 1582), France (Pedigrees 35 and 66), and Venezuela (Pedigrees 102 and 104). Twelve of the families consist of 3 generations and one family consists of 2 generations. Pedigree charts and sample descriptions are available on the Repository catalog website (see below).

  Study phs000268

• Pediatric Investigation for Genetic Factors Linked with Renal Progression (PediGFR)

  The Pediatric Investigation for Genetic Factors Associated with Renal Progression (PediGFR) (RO1-DK082394) is an international collaborative study among three large prospective cohort studies of children with chronic kidney disease. The participating parent cohort studies are the Chronic Kidney Disease in Children (CKiD), the Effect of Strict Blood Pressure Control and ACE Inhibition on CRF Progression in Pediatric Patients (ESCAPE), and the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study. In these cohorts, pediatric subjects with CKD have been prospectively followed with standardized measurements for renal progression. The dbGaP data upload will utilize the structure of sub-studies to include the genotype and baseline phenotype for the three cohorts, as well as the RBC trait and anemia data for a sub-study under PI Susan Furth: Role of Genetic Variation in the Anemia of Chronic Kidney Disease (K24DK078737). In brief PediGFR is a prospective study of children with chronic kidney disease (CKD) to determine genetic factors associated with kidney function measured by the estimated glomerular filtration rate (eGFR) by Schwartz equation. The PediGFR_v2 Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs000842 PediGFR_v2 Cohort. phs000843 4C phs000650 CKiD phs000844 ESCAPE

  Study phs000842

• Rare Cancer Tumors Project

  A large proportion of common cancers affecting patients around the world have been selected for comprehensive cancer genome studies. Further efforts will be needed to tackle the remaining tumor types, including the rare forms of cancers. Although rare, these cancers tend to be more aggressive and fast growing with an early recurrence following initial chemotherapy and poor prognosis. Besides, patients diagnosed with rare cancers may have difficulty finding a physician knowledgeable in treating their type of cancer. While sample collection is a major challenge, the integrated genomic analyses would identify novel causative genes in these rare cancers, shed new light on the biology of the rare cancers, as well as guide novel targeted cancer therapies. Through efficient collaboration, the Human Genome Sequencing Center (HGSC) at Baylor College of Medicine (BCM) has collected/is expected to collect 20 different types of rare cancers, 15-30 cases each. Whole-exome sequencing and high-resolution SNP array analysis were/will be performed for all cases and whole-genome sequencing was designed for a selected subset of the cases. The Rare Cancer Tumors Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in this sub-study, please click on the following sub-study below or in the "Sub-studies" section of this top-level study page phs000725 Rare Cancer Tumors Cohort. phs000754 Intracranial Germ Cell Tumors phs000861 Craniopharyngioma Tumors phs000859 Sezary Syndrome Genomic Analysis

  Study phs000725

• Single Cell RNA-Seq Reveals Malignant and Stromal Programs Associated with Metastasis in Head and Neck Cancer

  This study of head and neck cancer aimed to profile individual malignant, stromal, and immune cells in treatment-naive oral cavity squamous cell carcinoma, with or without matched metastatic cervical lymph nodes. Clinical and pathologic information was collected on all patients, in addition to a fresh biopsy sample from the primary tumor and/or metastatic lymph node at the time of initial surgery. Biopsy specimens were processed for single cell RNA-seq (scRNA-seq) and/or whole exome sequencing (WES). A total of ~6,000 single cells from 18 participants were included in the final dataset. Stromal and immune cells had consistent expression programs across patients. Conversely, malignant cells varied within and between tumors in their expression of signatures related to cell cycle, stress, hypoxia, epithelial differentiation, and partial epithelial-to-mesenchymal transition (p-EMT). One of the top scoring genes in this program was TGFβ-induced (TGFBI), implicating the classic EMT regulator TGFβ. Cells expressing the p-EMT program spatially localized to the leading edge of primary tumors. By integrating single-cell transcriptomes with bulk expression profiles for hundreds of tumors, we refined Head and Neck Squamous Cell Carcinoma (HNSCC) subtypes by their malignant and stromal composition, and established p-EMT as an independent predictor of nodal metastasis, grade, and adverse pathologic features. Our results provide insight into the HNSCC ecosystem and define stromal interactions and a p-EMT program associated with metastasis.

  Study phs001474

• Copy-Number Analysis of Understudied Black Women Ovarian Cancers

  Two general types of genetic alterations drive cancer progression: mutations and copy number alterations (CNAs). With the exception of p53, single nucleotide variant mutations (here, simply "mutations") are not drivers of 80% of tumors within the most frequent and deadly histotype of ovarian cancer: serous ovarian cancer (SOC). Rather, CNAs are more prevalent in SOC than any other cancer type studied by phs000178 The Cancer Genome Atlas (TCGA). Fully two-thirds of genes are altered by CNAs in the average SOC. Bioinformatic methods have shown that these CNAs modulate specific molecular pathways, such as autophagy, and this finding enabled effective pathway-targeted therapies1. Unfortunately, TCGA ovarian cancer data lacks racial diversity. Only 6% of SOC tumors (n=32) studied are from African origin. Black women diagnosed with ovarian cancer are more likely to die from their disease than white women. Five-year survival after diagnosis is 31% among blacks versus 42% among whites, and this disparity is seen in every age group and tumor stage distribution. Dr. Kelemen examined data from 365 white and 95 black ovarian cancer patients from the Hollings Cancer Center (HCC) Cancer Registry between 2000 and 2015 and found that black women had an 81% higher risk of death after diagnosis compared to white women (HR 1.81, 95% CI 1.35-2.43), independent of diagnosis center (98% were treated at HCC but half were diagnosed elsewhere), tumor stage, histology, extent of residual tumor remaining following surgery, insurance status, smoking, type of treatment for ovarian cancer, and age-adjusted Charlson comorbidity index. This disparity remained even when restricted to women who received the standard of care, surgery-chemotherapy sequence (HR 1.79, 95% CI 1.10-2.89). Despite receiving the same treatment, black race was still associated with inferior survival. A similar disparity has been reported by others, indicating that the HCC experience is representative of national data. Here, an additional set of high-grade serous ovarian cancer primary tumors were acquired from biorepositories with a focus on expanding data originating from African American women. Data were analyzed for copy-number alterations using exome sequencing and control-FREEC software.

  Study phs002313

• German early-onset prostate cancer cohort of the Pan-Prostate Cancer Genome (PPCG) project

  Prostate cancer is the most frequent malignant tumor in males and the second most frequent cause of cancer-related death. Currently, in Germany, more than 60,000 prostate cancers are diagnosed every year. Although most of these patients are treated in a curative attempt, more than 10,000 German men die from prostate cancer annually. Owing to the demographic changes of our society, a further doubling of prostate cancer incidences during the next 20 years is expected. Prostate cancer is generally considered a tumor of elderly men. However, a fraction of prostate cancers are diagnosed at the age of 55 years or less. For several reasons, these “early onset prostate cancers” may represent a key entity for the understanding of prostate cancer biology. First, it is likely that early onset prostate cancers represent a distinct molecular subgroup of prostate cancer (PCa), potentially characterized by relatively small numbers of genetic changes, some of which may be particularly strong driver mutations for PCa development. Second, a fraction of prostate cancers in young individuals could represent classical prostate cancers that are detected at a very early stage and might therefore have accumulated molecular changes/mutations occurring that are most instrumental for prostate cancer early detection. Third, PCa with hereditary backgrounds are likely to accumulate in the age group below 55 years. A comparison with other sample sets (e.g. from other ICGC consortia), a systematic genomic analysis of young men with PCa could therefore lead to the detection of mechanisms for hereditary PCa. Fourth, a better understanding of these tumors is particularly relevant as finding optimal treatment regimens is most critical in young cancer patients. We are analyzing the entire genomic DNA sequences of at least 200 PCas (and matched non-tumorous DNA) of young men (≤ 55y), to at least 30 fold coverage, and integrate single-nucleotide variants and genomic structural variations with differential methylation, mRNA and miRNA expression data.Tissues were collected at the University Medical Center Hamburg-Eppendorf. Sequencing was performed at DKFZ and NCT (Heidelberg), EMBL (Heidelberg), and MPIMG (Berlin). Data management and bioinformatic data analyses is being conducted at DKFZ.

  Study EGAS00001003373

• Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial

  Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements most patients die of their disease. While immune checkpoint blockade has become part of the standard of care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment in the early disease setting remain largely unknown. We hypothesized a higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with non-metastatic G/GEJ cancer. In the phase 2 PANDA trial, patients with previously untreated resectable G/GEJ tumors (n=21) received neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by 4 cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine. Treatment was well-tolerated, and all patients underwent resection without treatment-related delays, meeting the primary endpoint of safety and feasibility. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent PD-L1 blockade and the subsequent combination with chemotherapy on the tumor microenvironment. A total of 21 patients were included, of whom 20 patients underwent surgery and were evaluable for the secondary pathologic response and survival endpoints, while 19 were evaluable for exploratory translational analyses. A major pathologic response (MPR, ≤10% residual viable tumor) was observed in 14/20 (70%; 95% CI 46-88%) patients, including 9 (45%; 95% CI 23-68%) pathologic complete responses. At a median follow-up of 47 months, 13/14 responders were alive and disease-free, while 5/6 nonresponders had died due to disease recurrence. Notably, baseline PD-1+CD8+ T cell infiltration was significantly higher in responders than in nonresponders, and comparison of the tumor microenvironment alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy revealed that increased immune activity was achieved upon single-agent PD-1/L1 axis blockade. Based on these data, anti-PD-L1 plus chemotherapy warrants further exploration in patients with non-metastatic G/GEJ cancer, and these results call for validation in a larger cohort.

  Study EGAS50000000168

• MicroRNAs, Hypertension and End Organ Damage in Humans

  Study 1) Profiling of microRNAs in plasma of patients with hypertension complicated or not by metabolic syndrome or chronic kidney disease Hypertension (HTN) or high blood pressure is associated with subclinical target organ damage such as cardiac, vascular and kidney injury, which may lead to complications and death. In this study, we investigated circulating microRNAs as biomarkers of target organ damage in HTN patients. We profiled circulating microRNAs by RNA sequencing in platelet-poor plasma of normotensive subjects and patients with HTN complicated or not by metabolic syndrome (MetS) or chronic kidney disease (CKD) (n=15 each group). Differentially expressed microRNAs were identified with a threshold of false discovery rate <0.1. Differentially expressed microRNAs were identified uniquely to associate with HTN (8), MetS (1) or CKD (13), and 8 were similarly differentially expressed in different groups. This study identified the association of differentially expressed circulating microRNAs with target organ damage in HTN patients, which could have some pathophysiological and therapeutic implications. Study 2) Profiling of microRNAs in gluteal subcutaneous small arteries of patients with hypertension complicated or not by chronic kidney disease Hypertension (HTN) is associated with vascular damage characterized by endothelial dysfunction and vascular remodeling and stiffening, which contributes to kidney injury leading to chronic kidney disease (CKD). MicroRNAs are short non-coding RNAs which repress/degrade target mRNAs. The microRNA role in vascular injury in HTN remains unclear. In this study, we aimed to identify differentially expressed microRNAs in small arteries of patients with HTN associated or not with CKD, in order to shed light on the pathophysiological molecular mechanisms. Normotensive subjects and HTN patients associated or not with CKD grades 3-4 were studied (n=15-16). Small arteries were isolated from subcutaneous gluteal biopsies, RNAs were extracted, and small and total RNA sequencing was performed by Illumina HiSeq-2500. Differentially expressed genes were identified with a P<0.05 and fold change (FC) >1.3. Differentially expressed microRNAs and mRNAs were identified uniquely to associate with HTN (microRNAs: 10, mRNAs: 68), CKD (microRNAs: 68, mRNAs: 395), and both groups (microRNAs: 2, mRNAs: 32). This study identified differentially expressed microRNAs and mRNAs in small arteries with target organ damage in HTN, which could have some pathophysiological and therapeutic implications.

  Study phs002389

• National Institute of Neurological Disorders and Stroke (NINDS) Parkinson's Disease

  This study utilized the well characterized collection of North American Caucasians with Parkinson's disease, and neurologically normal controls from the sample population which are banked in the National Institute of Neurological Disorders and Stroke (NINDS Repository) collection. Two sub-studies are included, in sub-study NINDS-Genome-Wide Genotyping in Parkinson's Disease, genome-wide, single nucleotide polymorphism (SNP) genotyping of these publicly available samples was originally done in 267 Parkinson's disease patients and 270 controls, and this has been extended to include genome wide genotyping in 939 Parkinson's disease cases and 802 controls; in sub-study NINDS-Exome Sequencing in Parkinson's Disease, genome wide exome DNA sequencing was done in 618 Parkinson's disease samples deposited in Coriell NINDS repository. The DNA comes from a mixture of blood, and from cell lines (lymphoblast cell lines) derived from blood. The GWAS data and exome sequencing data was generated and provided by the laboratory of Neurogenetics lead by Dr. Andrew Singleton, NIA, and Dr. John Hardy, a former chief at NIA, NIH. The NINDS Parkinson's Disease Cohort study is utilized in the following dbGaP individual studies. To view genotypes, whole exome sequencing, and derived variables collected in these individual studies, please click on the following individual studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs001172 NINDS Parkinson's Disease Cohort study. phs000089 PD GWAS phs001103 PD Exome

  Study phs001172

• Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI)

  (Excerpted/paraphrased from original grant application): FOCI seeks to expand our understanding of epithelial ovarian cancer through a coordinated and comprehensive approach. Project 1 will focus on discovery, expansion, and replication. By pooling GWAS, we expect to identify new associations and achieve independent replication, explore whether there are risk variants specific for histologic subtypes, and evaluate structural polymorphisms - copy number variants - as risk factors. Finally, Project 1 will leverage the GWAS data to correlate DNA variants with a new endpoint - survival. Project 2 will focus on biological studies designed to help inform interpretation of findings from Project 1. This will include efforts to identify the functional consequences of variants and improve understanding of biological mechanisms. Project 3 will include epidemiologic studies of gene by gene interaction, gene by environment interaction, and development of risk prediction models. The collective effort builds upon the strengths and history of collaboration inherent in the Ovarian Cancer Association Consortium (OCAC), a multidisciplinary group comprised of epidemiologists, genetic epidemiologists, statistical geneticists, molecular and cell biologists and clinicians that was formed in 2005. The FOCI Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs001133 FOCI Cohort. phs001131 Affymetrix Exome Chip phs001132 GWAS Meta Analysis phs001142 Mayo Omni Express phs001150 Mayo 2 5M

  Study phs001133

• Coding and regulatory somatic profiling of triple-negative breast cancer in Sub-Saharan African patients

  The burden of triple-negative breast cancer (TNBC) may be shaped by genetic factors, particularly inherited and somatic mutation profiles. However, data on this topic remain limited, especially for the African continent, where a higher TNBC incidence is observed. In the age of precision medicine, cataloguing TNBC diversity in African patients becomes imperative. We performed whole exome sequencing, including untranslated regions, on 30 samples from Angola and Cape Verde, which allowed to ascertain on potential regulatory mutations in TNBC for the first time. A high somatic burden was observed for the African cohort, with 86% of variants being so far unreported. Recurring to predictive functional algorithms, 17% of the somatic single nucleotide variants were predicted to be deleterious at the protein level, and 20% overlapped with candidate cis-regulatory elements controlling gene expression. Several of these somatic functionally-impactful mutations and copy number variation (mainly in 1q, 8q, 6 and 10p) occur in known BC- and all cancer-driver genes, enriched for several cancer mechanisms, including response to radiation and related DNA repair mechanisms. TP53 is the top of these known BC-driver genes, but our results identified possible novel TNBC driver genes that may play a main role in the African context, as TTN, CEACAM7, DEFB132, COPZ2 and GAS1. These findings emphasize the need to expand cancer omics screenings across the African continent, the region of the globe with highest genomic diversity, accelerating the discovery of new somatic mutations and cancer-related pathways.

  Study EGAS50000001013

• Targeted and shallow whole genome sequencing identifies therapeutic opportunities in p53abn endometrial cancers

  Purpose: Shallow whole genome sequencing (sWGS) can detect copy number (CN) aberrations. In high-grade serous ovarian (HGSOC) sWGS identified CN signatures such as homologous recombination deficiency (HRD) to direct therapy. We applied sWGS with targeted sequencing to p53abn endometrial cancers (ECs) to identify additional prognostic stratification and therapeutic opportunities. Experimental Design: sWGS and targeted panel sequencing was performed on formalin-fixed paraffin-embedded p53abn ECs. CN alterations, mutational data and CN signatures were derived, and associations to clinicopathologic and outcomes data were assessed. Results: In 187 p53abn ECs, 5 distinct CN signatures were identified. Signature 5 was associated with BRCA1/2 CN loss with features similar to HGSOC HRD signature. 22% potential HRD cases were identified, 35 patients with signature 5, and 8 patients with BRCA1/2 somatic mutations. Signatures 3 and 4 were associated with whole genome duplication, and CCNE1, ERBB2 and MYC amplifications, with mutations in PIK3CA enriched in signature 3. We observed improved overall survival (OS) for patients with signature 2 and worse OS for signatures 1 and 3. 28% of patients had CCNE1 amplification and this subset was enriched with carcinosarcoma histotype. 34% of patients, across all histotypes, had ERBB2 amplification and/or HER2 overexpression on immunohistochemistry, which was associated with worse outcomes. Mutations in PPP2R1A (29%) and FBXW7 (16%) were among the top 5 most common mutations. Conclusions: sWGS and targeted sequencing identified therapeutic opportunities in 75% of p53abn EC patients. Further research is needed to determine the efficacy of treatments targeting these identified pathways within p53abn ECs.

  Study EGAS00001007661

• Beacon v2 and Federated EGA, part of the GDI project Starter Kit to enable access to genomic and phenotypic data across borders

  The European Genomic Data Infrastructure project has released a ‘Starter Kit’ based on the rare disease and cancer proof-of-concepts from the Beyond 1 Million Genomes (B1MG) project. The Starter Kit, freely available to any interested parties, contains a set of software applications and components co-developed by the 20 GDI nodes and based on open community standards from the Global Alliance for Genomics and Health (GA4GH). Products in the Starter Kit give all countries the technical capability to access synthetic genomic and phenotypic data across borders. The image above shows the full workflow of the GDI Starter Kit user journey. The dotted circles are not included in the Starter Kit yet The EGA’s work is represented in the Starter Kit with Beacon v2 and Federated EGA among the software applications and components. About Beacon v2 Beacon is a protocol for data discovery. This API allows the search of genomic variants and associated information without breaching the datasets privacy. The European Genome-phenome Archive (EGA) is a key contributor to the Beacon v2 Protocol, the Beacon v2 Reference Implementation (B2RI) and the EGA Beacon(s). About Federated EGA The Federated EGA network offers a tool for data storage and sharing. Officially launched in 2022, this network of connected resources enables transnational discovery of and access to human omics data for research, while also respecting jurisdictional data protection regulations. The Federated EGA Onboarding Website contains all the information related to the establishment of a Federated Node.

  Blog beacon-v2-and-federated-ega-part-of-the-gdi-project-starter-kit

• European Genome-phenome Archive 15th Anniversary Celebration

  2023 marks the 15th Anniversary of the EGA, jointly managed by the European Bioinformatics Institute (EMBL-EBI) and the Centre for Genomic Regulation (CRG). To mark the occasion, a simultaneous celebration was held in both institutions on the 13th of December 2023. The teams gathered online to play a quiz game and celebrate all the achievements and milestones with two wonderful anniversary cakes. In 2008, the European Genome-phenome Archive was created at the EBI-EMBL in Cambridge to guarantee that human genome and phenome data were available to the international scientific community while data privacy was preserved. The six-person staff at the beginning of the project is now far behind us, with a team that reaches the number of 35 members. Since 2013, the European Bioinformatics Institute and the Centre for Genomic Regulation share responsibility for The European Genome-phenome Archive (EGA). At that time, the EGA had data for about 0,5 petabytes. Currently, the Archive contains more than 12 petabytes. 2023 comes to an end with several good news. The EGA has been renewed as an ELIXIR Core Data Resource. This was announced during the GA4GH 11th Plenary held in San Francisco last September when ELIXIR-Beacon was also confirmed to be a GA4GH Driver Project. Thus, the Beacon API has maintained this title since 2018. What’s more, the first Federated EGA dataset is now live on our website. This year we also launched new services for EGA users in September. By the numbers, in 2023 the EGA counts 2.5 PB archived, 371 studies published, 208 new submitters and 19 active projects in which the team is participating, among others. We look forward to continuing to support your research in 2024!

  Blog 15-anniversary

• Women's Health Initiative Clinical Trial and Observational Study

  The Women's Health Initiative (WHI) is a long-term national health study that has focused on strategies for preventing heart disease, breast and colorectal cancer, and osteoporotic fractures in postmenopausal women. The original WHI study included 161,808 postmenopausal women enrolled between 1993 and 1998. The Fred Hutchinson Cancer Research Center in Seattle, WA serves as the WHI Clinical Coordinating Center for data collection, management, and analysis of the WHI. The WHI has two major parts: a partial factorial randomized Clinical Trial (CT) and an Observational Study (OS); both were conducted at 40 Clinical Centers nationwide. The CT enrolled 68,132 postmenopausal women between the ages of 50-79 into trials testing three prevention strategies. If eligible, women could choose to enroll in one, two, or all three of the trial components. The components are: Hormone Therapy Trials (HT): This double-blind component examined the effects of combined hormones or estrogen alone on the prevention of coronary heart disease and osteoporotic fractures, and associated risk for breast cancer. Women participating in this component with an intact uterus were randomized to estrogen plus progestin (conjugated equine estrogens [CEE], 0.625 mg/d plus medroxyprogesterone acetate [MPA] 2.5 mg/d] or a matching placebo. Women with prior hysterectomy were randomized to CEE or placebo. Both trials were stopped early, in July 2002 and March 2004, respectively, based on adverse effects. All HT participants continued to be followed without intervention until close-out. Dietary Modification Trial (DM): The Dietary Modification component evaluated the effect of a low-fat and high fruit, vegetable and grain diet on the prevention of breast and colorectal cancers and coronary heart disease. Study participants were randomized to either their usual eating pattern or a low-fat dietary pattern. Calcium/Vitamin D Trial (CaD): This double-blind component began 1 to 2 years after a woman joined one or both of the other clinical trial components. It evaluated the effect of calcium and vitamin D supplementation on the prevention of osteoporotic fractures and colorectal cancer. Women in this component were randomized to calcium (1000 mg/d) and vitamin D (400 IU/d) supplements or a matching placebo. The Observational Study (OS) examines the relationship between lifestyle, environmental, medical and molecular risk factors and specific measures of health or disease outcomes. This component involves tracking the medical history and health habits of 93,676 women not participating in the CT. Recruitment for the observational study was completed in 1998 and participants were followed annually for 8 to 12 years. Extension Studies: The original protocol allowed for follow-up until March 2005, after which participants were invited to enroll in the first WHI Extension Study for follow-up through 2010. Participants were invited again to participate in the second WHI Extension Study with continued follow up from 2010 to at least 2015. As of March 31, 2011 there were 93,122 women enrolled in the second extension. In Extension Study 2, the overall WHI study population was divided into two new subsamples, the Medical Records Cohort (MRC) and the Self-Report Cohort (SRC). The MRC consists of all former hormone trial participants and all African American and Hispanic participants from all study components. The SRC consists of the remaining participants. The extent of outcome information collected differs between the two cohorts, with more extensive outcomes information collection on the MRC. As part of Extension Study 2, selected older WHI participants were invited to participate in an In Person Visit (a.k.a., Long Life Study) at their homes during which additional blood samples were collected and various measurements were taken (such as blood pressure, height, weight, waist circumference, grip strength, etc.). In October 2015, Extension Study 2 was renewed with continued follow-up planned through October 2020, pending annual contract review and renewal. Additional Information: The WHI website, https://www.whi.org/about/SitePages/About%20WHI.aspx has much more information about the study. For WHI data collection forms used over the years, please see https://www.whi.org/researchers/studydoc/SitePages/Forms.aspx. For additional dataset documentation, see https://www.whi.org/researchers/data/Pages/Available%20Data.aspx. For data preparation and use, please refer to 'WHI dbGaP Cohort Data Release Data Preparation Guide May 2018' for additional details about the WHI data. The WHI Cohort is utilized in the following dbGaP substudies. To view genotypes, analysis, expression data, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" box located on the right hand side of this top-level study page phs000200 WHI Cohort. phs000386 WHI SHARe phs000281 GO-ESP WHISP phs000315 WHI GARNET phs000503 WHISE phs000227 PAGE WHI phs000675 WHIMS+ phs000746 WHI Harmonized and Imputed GWAS phs001334 WHI Metabolomics of CHD phs001335 WHI BA23 phs001614 WHI LLS Phase III GWAS

  Study phs000200

• National Cancer Institute (NCI) Non-Hodgkin Lymphoma Genome-wide Association Study (GWAS)

  Within the framework of the International Lymphoma Epidemiology Consortium (InterLymph) Consortium and NCI-sponsored Cohort Consortium, investigators from 22 studies came together to conduct a genome-wide association study (GWAS) of non-Hodgkin lymphoma (NHL). The goal of the study was to identify common genetic variants associated with the risk of NHL. As described previously (Berndt SI et al., Nature Genetics, 2013, PMID: 23770605 ), cases and controls from 22 studies, including nine prospective cohort studies, eight population-based case-control studies, and five clinic or hospital-based case-control studies were included in this effort. Cases of NHL were ascertained from cancer registries, clinics or hospitals, or through self-report verified by medical and pathology reports. The phenotype information for all NHL cases was reviewed centrally at the InterLymph Data Coordinating Center and harmonized according to the hierarchical classification proposed by the InterLymph Pathology Working Group based on the World Health Organization (WHO) classification (2008). Controls were frequency matched to cases on age and gender by study, and the study was limited to subjects of European ancestry. Participants were genotyped using the Illumina Omni Express. The NCI Non-Hodgkin Lymphoma GWAS is utilized in the following dbGaP sub-studies. To view genotypes and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs000801 NCI Non-Hodgkin Lymphoma GWAS. phs000802 NCI Non-Hodgkin Lymphoma GWAS: CLL phs000818 NCI Non-Hodgkin Lymphoma GWAS: Controls phs000889 NCI Non-Hodgkin Lymphoma GWAS: DLBCL phs000890 NCI Non-Hodgkin Lymphoma GWAS: FL phs000891 NCI Non-Hodgkin Lymphoma GWAS: MZL

  Study phs000801

• Non-coding RNAs Activated by the Wnt/Beta-catenin Signaling Pathway in Hepatoblastoma

  Hepatoblastoma (HB) is the most common pediatric liver tumor, affecting mostly children under 3 years of age. This rare tumor represents 1% of all pediatric cancers. Genetic studies have shown that HB is characterized by high frequency mutations of the CTNNB1 gene encoding beta-catenin (around 75%) and relative genomic stability. Here we have analyzed the transcriptional profile of 21 HBs compared to matched non-tumor livers by Cap Analysis of Gene Expression (CAGE), which provides accurate and quantitative profiling of all transcripts. CAGE analysis revealed strong upregulation of known Wnt target coding genes in most tumors analyzed, consistent with previous transcriptomic studies. To better define the Wnt-dependent transcriptional landscape of HB, we integrated CAGE data with TCF4 ChIP-seq data from a CTNNB1-mutated cancer cell line and with the FANTOM5 genomic coordinates of TCF/LEF binding motifs. Both TCF/LEF binding motifs and ChIP-seq peaks were strongly enriched in the immediate upstream region, not only for protein-coding genes, but also for non-coding transcripts. Among the selected 112 top Wnt target genes at FDR<1.0E-6 and fold change>8, we found clear over-representation (66%) of distant transcription start sites (TSSs) representing lncRNAs and enhancer RNAs, which raises the question of their role in HB pathogenesis. Analysis of the 112 promoters using CAGEd-oPOSSUM confirmed the predominant involvement of Tcf/Lef transcription factors, together with HNF4G, GATA2, Sox3 and Ets-related genes. Finally, the 112 Wnt target signature defined 3 tumor subclasses, T1, T2 and T3, characterized by progressive alteration of the non-coding part of the transcriptome and significant differences in clinical behavior.

  Study phs001433

• Clinical Sequencing Exploratory Research Consortium: Incorporation of Genomic Sequencing into Pediatric Cancer Care

  This project includes data derived from subjects enrolled in the BASIC3 (Baylor College of Medicine Advancing Sequencing in Childhood Cancer Care) study. BASIC3 is a National Genome Human Research Institute (NHGRI) and National Cancer Institute-funded Clinical Sequencing Exploratory Research (CSER) consortium project that focused on prospective implementation of clinical whole exome sequencing in the pediatric oncology clinic. The primary study objective were to integrate information from CLIA-certified germline and tumor exome sequencing into the care of newly diagnosed solid tumor patients at Texas Children's Cancer Center, and to perform parallel evaluation of the impact of tumor and germline exomes on families and physicians. Blood and frozen tumor (if available) samples were collected from children undergoing surgery or biopsy of newly diagnosed solid tumors and subjected to exome sequencing in a CLIA-certified laboratory. Germline and tumor (if applicable) exome sequencing reports were generated and submitted into the electronic health record and returned to each patient/family by their primary oncologist. In addition to the clinical exome sequencing, specific (optional) consent was requested for research sequencing studies. If this consent was obtained then research studies of some of the children and parents participating in the BASIC3 study (including tumor transcriptome and whole genome sequencing of blood and/or tumor) are performed. The Clinical Sequencing Exploratory Research Consortium Cohort is utilized in the following dbGaP sub-study. To view molecular data, and derived variables collected in this sub-study, please click on the following sub-studies below or in the "Sub-study" section of this top-level study page phs001383 Clinical Sequencing Exploratory Research Consortium Cohort. phs001026 BASIC3 phs001878 GMKF BASIC3

  Study phs001683

• Hispanic Community Health Study /Study of Latinos (HCHS/SOL)

  The Hispanic Community Health Study / Study of Latinos (HCHS/SOL) is a multi-center epidemiologic study in Hispanic/Latino populations to determine the role of acculturation in the prevalence and development of disease, and to identify risk factors playing a protective or harmful role in Hispanics/Latinos. The study is sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and six other institutes, centers, and offices of the National Institutes of Health (NIH). The goals of the HCHS/SOL include studying the prevalence and development of disease in Hispanics/Latinos, including the role of acculturation, and identifying disease risk factors that play protective or harmful roles in Hispanics/Latinos. A total of 16,415 persons of Cuban, Dominican, Mexican, Puerto Rican, Central American, and South American backgrounds were recruited through four Field Centers affiliated with San Diego State University, Northwestern University in Chicago, Albert Einstein College of Medicine in the Bronx area of New York, and the University of Miami. Seven additional academic centers serve as scientific and logistical support centers. Study participants aged 18-74 years took part in an extensive clinic exam and assessments to ascertain socio-demographic, cultural, environmental and biomedical characteristics. Annual follow-up interviews are conducted to determine a range of health outcomes. The HCHS SOL Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" section of this top-level study page phs000810 HCHS SOL Cohort. phs000555 PAGE CALiCo SOL phs000880 HCHS/SOL Omics in Latinos (Ola)

  Study phs000810

• Accurate mutation detection in leukemia by re-sequencing a cancer gene set

  With the advent of whole-genome and whole-exome sequencing, high-quality catalogs of recurrently mutated cancer genes are becoming available for many cancer types. Increasing access to sequencing technology, including bench-top sequencers, provide the opportunity to re-sequence a limited set of cancer genes across a patient cohort with limited processing time. Here, we re-sequenced a set of cancer genes in T-cell acute lymphoblastic leukemia (T-ALL) using the Roche/454 technology coupled with Nimblegen sequence capture. First, we investigated how a maximal sensitivity and specificity of mutation detection can be achieved through a benchmark study. We tested nine combinations of different mapping and variant-calling methods, varied the variant calling parameters, and compared the predicted mutations with a large independent validation set obtained by capillary re-sequencing. We found that the combination of two mapping algorithms, namely BWA-SW and SSAHA2, coupled with the variant calling algorithm Atlas-SNP2 yields the highest sensitivity (95%) and the highest specificity (93%). Next, we applied this analysis pipeline to identify mutations in a set of 58 cancer genes, in a panel of 18 T-ALL cell lines and 15 T-ALL patient samples. We confirmed mutations in known T-ALL drivers, including PHF6, NF1, FBXW7, NOTCH1, KRAS, NRAS, PIK3CA, and PTEN. Interestingly, we also found mutations in several cancer genes that had not been linked to T-ALL before, including JAK3. Finally, we re-sequenced a small set of 39 candidate genes and identified recurrent mutations in TET1, SPRY3 and SPRY4. In conclusion, we established an optimized analysis pipeline for Roche/454 data that can be applied to accurately detect gene mutations in cancer, which led to the identification of several new candidate T-ALL driver mutations.

  Study EGAS00001000268

• Prenatal lead exposure is associated with decreased cord blood DNA methylation of the glycoprotein VI gene involved in platelet activation and thrombus formation

  Early-life lead exposure impairs neurodevelopment and later exposure affects the cardiovascular system. Lead has been associated with reduced global 5-methylcytosine DNA methylation, suggesting that lead toxicity acts through epigenetic mechanisms. The objective of this study is to clarify how early life lead exposure alters DNA methylation of specific genes, using an epigenomic approach. We measured lead concentrations in urine (gestational week, GW, 8) and erythrocytes (GW 14), using ICP-MS, for 127 pregnant mothers recruited in the MINIMat food and supplementation cohort in rural Bangladesh. Cord blood DNA methylation was analyzed with the Infinium HumanMethylation450K BeadChip and top sites were validated by methylation-sensitive high-resolution melt curve analysis. Maternal urinary lead concentrations (divided into quartiles) showed significant (after adjustment for FDR) inverse associations with methylation at nine CpGs. Three of these sites were in the 5’ end, including the promoter, of glycoprotein IV (GP6); cg18355337 (q=0.029, β=-0.30), cg25818583 (q=0.041, β=-0.18) and cg23796967 (q=0.047, β=-0.17). The methylation in another CpG site in GP6 was close to significant (cg05374025, q=0.057, β=-0.23). The erythrocyte lead concentrations (divided into quartiles) were also inversely associated with CpG methylation in GP6, although this was not statistically significant after FDR-adjustments. Eight CpG sites in GP6 constituted a differentially methylated region in relation to urinary lead (p=0.005, q=0.48) and erythrocyte lead (p=0.007, q=0.46). In conclusion, we found that moderate prenatal lead exposure appear to epigenetically affect GP6, a key component of platelet aggregation and thrombus formation, suggesting a novel link between early lead exposure and cardiovascular disease later in life.

  Study EGAS00001001575

• T-cell receptor sequencing of tumor-infiltrating lymphocytes (TIL) in breast cancer

  The spatial distribution of tumor-infiltrating lymphocytes (TIL) predicts breast cancer outcome and response to systemic therapy, highlighting the importance of an intact tissue structure for characterizing patients’ tumors. Here, we present ST-FFPE, a spatial transcriptomics method for the analysis of formalin-fixed paraffin-embedded samples, which opens the possibility of interrogating widely available archival tissue. The method involves extraction, exome capture and sequencing of RNA from different tumor compartments microdissected by laser-capture, and can be used to study the cellular composition of various tumor environments. Focusing on triple-negative breast cancer (TNBC), we characterized T cells, B cells, dendritic cells, fibroblasts and endothelial cells in both stromal and intra-epithelial compartments. We found a highly variable spatial distribution of immune cell subsets among tumors. This analysis revealed that the immune repertoires of intra-epithelial T and B cells were consistently less diverse than those of stromal T and B cells. T-cell receptor (TCR) sequencing confirmed a reduced diversity and revealed higher clonality of intra-epithelial T cells relative to the corresponding stromal T cells. Analysis of the top ten dominant clonotypes in the two compartments showed a majority of shared but also some unique clonotypes both in stromal and intra-epithelial T cells. Hyperexpanded clonotypes were more abundant among intra-epithelial than stromal T cells. These findings validate the ST-FFPE method and suggest an accumulation of antigen-specific T cells within tumor core. Because ST-FFPE is readily applicable for analysis of previously collected tissue samples, it could be useful for rapid assessment of intratumoral cellular heterogeneity in multiple disease and treatment settings.

  Study EGAS00001007125

• H3Africa - Genomic Characterization and Surveillance of Microbial Threats in West Africa

  Viral diseases are remarkably heterogeneous in their presentation and clinical course. Although diseases such as Lassa Fever and Ebola Virus Disease are thought to be severe and rapidly fatal, they can often present with mild symptoms or remain asymptomatic. Host genetic variability is likely an important mediator of this heterogeneity. Complete characterization of the clinical, laboratory, and host genetic features of these illnesses is not only imperative to rapid diagnosis and effective clinical care, but also important for further scientific study. In this project, we propose to address this need through deep characterization of the clinical and laboratory features of viral disease and through study of genetic mediators of resistance to Lassa Fever and Ebola Virus Disease. Will carry out deep clinical characterization and laboratory assessment of viral febrile cases at two West African Collaborative Centers, and will use this data to develop prognostic models using cutting-edge tools in exploratory data visualization and machine learning. Investigate host genetic factors of Lassa Fever and Ebola Virus Disease through genome-wide association studies. We will then develop field-deployable genotyping assays for the top-associated variants, and apply them in new cohorts to replicate our findings and investigate patterns of genetic resistance in clinical subgroups. This project can shed light on the clinical manifestations of viral illness and their host genetic mediators, leading to potential new insights in disease biology and pathophysiology. We will also create a rich resource of clinical, laboratory, and genetic data for these illnesses in two countries in West Africa, which will serve as a foundation for advancing the clinical care and scientific study of viral disease in the region.

  Study EGAS00001007250

• Identifying transcriptional programs underlying anti-EGFR small molecule response and resistance with TraCe-seq

  To QC the TraCe-seq strategy, single-cell RNA-seq libraries were generated from a variety of human cancer cell lines transduced with the TraCe-seq library to validate the TraCe-seq strategy. Specifically, 5 different cell lines (PC9, MCF-10A, MDA-MB-231, NCI-H358, and NCI-H1373) were each transduced with a unique TraCe-seq barcode. The transduced cells were selected with puromycin only, dissociated to single cell suspensions, and then mixed together. The complex mixture of the 5 cell lines was profiled by 10X scRNA-seq. Furthermore, transduced NCI-H1373 cells were sorted by FACS to enrich for the top 50% of eGFP positive cells, and sorted cells were cultured briefly and used to construct scRNA-seq libraries and profiled by 10x scRNA-seq. To carry out the full TraCe-seq experiment, ~600 PC9 cells carrying unique TraCe-seq barcodes were expanded over 12 doublings to establish the barcoded population. A subset of the barcoded PC9 population was used to generate scRNA-seq libraries and profiled by 10x scRNA-seq prior to treatment to establish a baseline transcription profile for each barcoded clone. The rest of the cells were then treated for four days with 1 µM erlotinib, 1 µM GNE-069, or 1 µM GNE-104 respectively. scRNA-seq libraries were then generated form the treated cells and profiled by 10x scRNA-seq.

  Dataset EGAD00001007872

• RNA-seq of high grade serous ovarian tumours

  Somatic RNA for 40 samples matched to the WGS was extracted using the Qiagen Qiasymphony RNA protcol (cat no 931636). The tissue was initially homogenised using a Qiagen Bioruptor, followed by the manufacturers recommended protocol (including DNase digestion). The resulting RNA the underwent quality control as follows: firstly, A260 and A280nm were measured on a Denovix DS-11 Fx to qualitatively illustrate A260/280nm and A260/230nm ratios as measures of RNA purity. A260/280 had to be 2.0 and A260/230 had to be 2.0-2.2. Then RNA was quantified using LifeTechnologies Qubit RNA BR kit (cat no Q10210). RNAseq was carried out by the Edinburgh Clinical Research Facility on an Illumina NExtSeq500. Total RNA samples were assessed on the Agilent Bioanalyser (Agilent Technologies, #G2939AA) with the RNA 6000 Nano Kit (#5067-1512) for quality and integrity of total RNA, and then quantified using the Qubit 2.0 Fluorometer (Thermo Fisher Scientific Inc, #Q32866) and the Qubit RNA HS assay kit (#Q32855). Libraries were prepared from total-RNA sample using the NEBNext Ultra 2 Directional RNA library prep kit for Illumina (#E7760S) with the NEBNext rRNA Depletion kit (#E6310) according to the provided protocol. 400ng of totalRNA was then added to the ribosomal RNA (rRNA) depletion reaction using the NEBNext rRNA depletion kit (Human/mouse/rat) (#E6310). This step uses specific probes that bind to the rRNA in order to cleave it. rRNA-depleted RNA was then DNase treated and purified using Agencourt RNAClean XP beads (Beckman Coulter Inc, #66514). RNA was then fragmented using random primers before undergoing first strand and second strand synthesis to create cDNA. cDNA was end repaired before ligation of sequencing adapters, and libraries were enriched by PCR using the NEBNext Multiplex oligos for Illumina set 1 and 2 (#E7500). Final libraries had an average peak size of 271bp. Libraries were quantified by fluorometry using the Qubit dsDNA HS assay and assessed for quality and fragment size using the Agilent Bioanalyser with the DNA HS Kit (#5067-4626). Sequencing was performed using the NextSeq 500/550 High-Output v2 (150 cycle) Kit (# FC- 404-2002) on the NextSeq 550 platform (Illumina Inc, #SY-415-1002). Libraries were combined in an equimolar pool based on the library quantification results and run across 5 High-Output Flow Cell v2.5.

  Dataset EGAD00001009048

• RNA-seq of high grade serous ovarian tumours

  Somatic RNA for 37 samples was extracted using the Qiagen Qiasymphony RNA protcol (cat no 931636). The tissue was initially homogenised using a Qiagen Bioruptor, followed by the manufacturers recommended protocol (including DNase digestion). The resulting RNA the underwent quality control as follows: firstly, A260 and A280nm were measured on a Denovix DS-11 Fx to qualitatively illustrate A260/280nm and A260/230nm ratios as measures of RNA purity. A260/280 had to be 2.0 and A260/230 had to be 2.0-2.2. Then RNA was quantified using LifeTechnologies Qubit RNA BR kit (cat no Q10210). RNAseq was carried out by the Edinburgh Clinical Research Facility on an Illumina NExtSeq500. Total RNA samples were assessed on the Agilent Bioanalyser (Agilent Technologies, #G2939AA) with the RNA 6000 Nano Kit (#5067-1512) for quality and integrity of total RNA, and then quantified using the Qubit 2.0 Fluorometer (Thermo Fisher Scientific Inc, #Q32866) and the Qubit RNA HS assay kit (#Q32855). Libraries were prepared from total-RNA sample using the NEBNext Ultra 2 Directional RNA library prep kit for Illumina (#E7760S) with the NEBNext rRNA Depletion kit (#E6310) according to the provided protocol. 400ng of totalRNA was then added to the ribosomal RNA (rRNA) depletion reaction using the NEBNext rRNA depletion kit (Human/mouse/rat) (#E6310). This step uses specific probes that bind to the rRNA in order to cleave it. rRNA-depleted RNA was then DNase treated and purified using Agencourt RNAClean XP beads (Beckman Coulter Inc, #66514). RNA was then fragmented using random primers before undergoing first strand and second strand synthesis to create cDNA. cDNA was end repaired before ligation of sequencing adapters, and libraries were enriched by PCR using the NEBNext Multiplex oligos for Illumina set 1 and 2 (#E7500). Final libraries had an average peak size of 271bp. Libraries were quantified by fluorometry using the Qubit dsDNA HS assay and assessed for quality and fragment size using the Agilent Bioanalyser with the DNA HS Kit (#5067-4626). Sequencing was performed using the NextSeq 500/550 High-Output v2 (150 cycle) Kit (# FC- 404-2002) on the NextSeq 550 platform (Illumina Inc, #SY-415-1002). Libraries were combined in an equimolar pool based on the library quantification results and run across 5 High-Output Flow Cell v2.5.

  Dataset EGAD00001010139

• Uncovering RNA Signatures of C9orf72-Linked ALS and Related Disorders

  Substantial clinical and pathological variability has been reported in patients carrying an expanded repeat in C9orf72, who are generally diagnosed with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Emerging evidence suggests that C9orf72 expression, RNA foci, and dipeptide-repeat proteins contribute to C9orf72-related diseases; however, the majority of the clinicopathological variability remains unexplained. We hypothesize that RNA sequencing (RNA-Seq) might reveal individual genes or groups of highly correlated genes (modules) that could account for this variability, which may help to identify much-needed druggable targets and/or biomarkers. Our preliminary studies performed in the frontal cortex, where we compared C9orf72 expansion carriers to (disease) controls, demonstrated that the top differentially expressed gene was C9orf72 itself. We also noticed that differentially expressed genes were enriched for the endocytosis pathway, which is consistent with the reported function of the C9orf72 protein in vesicle trafficking. Furthermore, we detected a module enriched for vesicular pathways, and additionally, we discovered an association with survival after onset for several promising candidates involved in vesicular transport. To find new therapeutic targets and biomarkers, here we have completed RNA-Seq on an increased number of samples to examine another relevant region: the cerebellum. As such, we performed RNA-Seq on a well-characterized cohort of C9orf72 expansion carriers, patients without this expansion, and control subjects without neurological diseases. We used multivariable linear regression models for gene-level analysis, weighted correlation network analysis for module-level analysis, and leafcutter for splicing analysis. Using the cerebellar RNA-Seq data, we found a large number (>6,000) of differentially expressed genes, with a notable increase in expression of homeobox genes in C9orf72 expansion carriers, as well as many gene modules that were associated with C9orf72 expansion status. Additionally, using leafcutter, we detected over 1,000 differential splicing events and an increase in the number of cryptic splicing events in C9orf72 expansion carriers.

  Study phs003065

• ARDSnet and the iSPAAR Consortium: Genomic Basis of Susceptibility and Outcomes in Patients with the Acute Respiratory Distress Syndrome (ARDS)

  Acute Respiratory Distress Syndrome (ARDS)/ Acute Lung Injury (ALI) is a syndrome defined by the presence of acute hypoxemic respiratory failure, bilateral pulmonary infiltrates on chest radiograph, a known clinical risk factor (e.g. sepsis, pneumonia, trauma, gastric fluid aspiration, pancreatitis, massive transfusion), and the absence of physiologic or clinical evidence of congestive heart failure. The Identification of SNPs Predisposing to Altered ALI Risk (iSPAAR) study is a multi-institutional cooperative study, funded through the NHLBI Recovery Act, that assembled samples and phenotype information from existing cohorts. The consortium included samples from patients with ARDS from the NIH NHLBI ARDS Clinical Trials Network (ARDSNet). Samples were obtained from 3 interventional treatment trials in patients with ARDS, including the Fluid and Catheter Treatment Trial (FACTT), the Albuterol to Treat Acute Lung Injury (ALTA) trial, and the Omega-3 Fatty Acid/Antioxidant Supplementation for ALI trial (Omega). In addition to ARDSnet samples, samples from the other cohorts included cases of established ARDS but also controls: critically ill patients who were at-risk for ARDS but who did not develop ARDS during their hospital course. These cohorts included the Molecular Epidemiology of Acute Respiratory Distress (MEA) Study enrolled at the Harvard University/Massachusetts General Hospital, the Systemic Inflammatory Immune Response Syndrome (SIRS) Patient Database and ICU Traumatic Injury cohorts from Harborview Medical Center, and cohorts collected from the ALI research programs at the University of Pennsylvania and the University of California, San Francisco. The Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs000631 ARDSnet iSPAAR Consortium. phs000334 ESP_LungGO_ALI phs000686 ALI_GeneticRisk

  Study phs000631

• Cardiovascular Health Study (CHS) Cohort: an NHLBI-funded observational study of risk factors for cardiovascular disease in adults 65 years or older

  The Cardiovascular Health Study (CHS) is a prospective study of risk factors for development and progression of CHD and stroke in people aged 65 years and older. The 5,888 study participants were recruited from four U.S. communities and have undergone extensive clinic examinations for evaluation of markers of subclinical cardiovascular disease. The original cohort, enrolled in 1989-90, totaled 5,201 participants. A supplemental cohort of 687 predominantly African-American participants was enrolled in 1992-93. Clinic examinations were performed at study baseline and at annual visits through 1998-1999, and again in 2005-2006. Examination components included medical and personal history, medication inventory, ECG, blood pressure, anthropometry, assessment of physical and cognitive function, and depression screening. Other components done less frequently included phlebotomy, spirometry, echocardiography, carotid ultrasound, cerebral magnetic resonance imaging, measurement of ankle-brachial index and retinal exam. Participants were contacted by telephone annually between exams to collect information about hospitalizations and potential cardiovascular events. Since 1999, participants have been contacted every six months by phone, primarily to identify cardiovascular events and to assess physical and cognitive health. Standard protocols for the identification and adjudication of events were implemented during follow-up. The adjudicated events are myocardial infarction, angina, heart failure (HF), stroke, transient ischemic attack (TIA), claudication and mortality. The Cardiovascular Health Study Cohort is utilized in the following dbGaP substudies. To view genotypes, analysis, expression data, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" section of this top-level study page phs000287 Cardiovascular Health Study (CHS) Cohort: an NHLBI-funded observational study of risk factors for cardiovascular disease in adults 65 years or older. phs000226 STAMPEED: Cardiovascular Health Study (CHS) phs000301 PAGE: CaLiCo: Cardiovascular Health Study (CHS) phs000377 CARe: Candidate Gene Association Resource (CARe) phs000400 GO-ESP: Heart Cohorts Exome Sequencing Project (CHS) phs000667 CHARGE: Cardiovascular Health Study (CHS)

  Study phs000287

• National Cancer Institute (NCI) Genome Wide Association Study (GWAS) of Lung Cancer in Never Smokers

  A genomewide study of lung cancer in never smokers Abstract and specific aims In the United States, lung cancer incidence and mortality rates have been steadily declining over the past decade, following decline in the prevalence of tobacco smoking. However, lung cancer remains the leading cause of cancer death, killing more patients than breast, colon, and prostate cancers combined. Although tobacco smoke is the predominant risk factor for development of lung cancer, some patients develop the disease without a history of tobacco smoking. About 10 - 15% of all lung cancers occur in lilfetime never smokers. This figure will increase as the proportion of never smokers increases in the population. Even at present rates, lung cancer in never smokers, if considered a separate disease, is 6th to 8th top cause of cancer death. The growing number of never smokers in the USA and other countries emphasizes the importance of understanding the epidemiology and biology underlying lung cancer in this group. Genetic polymorphisms associated with the risk of lung cancer in never smokers are expected to overlap with those associated with the risk of lung cancer in ever smokers only partially. Epidemiological, molecular and clinical data suggest that molecular mechanisms of LC may differ in smokers and non-smokers, implying that lung cancer in never smokers is a different disease compared to the lung cancer in smokers. One can expect that there should be stronger genetic component in the control lung cancer in never smokers because effects of the genetic factors in never smokers are unmasked by the lack of tobacco smoke exposure. The genetic epidemiology of lung cancer in never smokers has not been well explored, largely because of difficulties in accruing the needed sample size for association studies. We propose a multicenter (total 14 sites from the US and Europe) genomewide association study of lung cancer in never smokers with the following specific aims: Aim 1: To identify candidate SNPs influencing risk for lung cancer in never smokers using Discovery sample. In the Discovery phase we will genotype 1256 Caucasian cases and 1365 age- and gender-matched never smoker controls using the Illumina Human660W-Quad platform. In addition, we will include in the analysis 284 cases and 175 matched controls already genotyped on the 610Quad platform. In this phase we will only include the study sites that have collected blood specimens (MDACC, Mayo Clinic, Karmanos Cancer Institute, The University of Liverpool Cancer research Centre, Institute of Cancer Research in Sutton, and Lunenfeld Research Institute in Toronto, Canada). All the samples will be sent to the independent lab for genotyping, to reduce site-specific technical artifacts. The final sample will consist of 1540 cases and 1540 controls matched by study site. Aim 2: To perform the second phase (validation) analysis of significant SNPs identified in aim 1 using an independent set of cases and controls. SNPs associated with risk at the significance level of 0.01 or below in the discovery set will be included in the replication phase. The proposed threshold guarantees an adequate power to retain SNPs with the typical effect size of 1.3. We plan to carry 6000-7000 SNPs for validation. The independent replication set will include 800 cases and 800 controls, mostly from sites that collected tissue (Mayo Clinic, Karmanos Cancer Institute, UT Southwestern) or buccal specimens (UCLA), but also blood samples (Imperial College London, University of Pennsylvana, German Cancer Research Center, Heidelberg, National Research Center for Environment and Health, Neuherberg, Carmel Medical Center, Haifa). We will then perform a joint analysis to test the significance of the SNPs identified in the first stage using a stringent critical p-value of 10-7. There will be 2340 cases and 2340 controls in the joint set. Based on our experience with GWAS in smokers and assuming that genetic component in lung cancer risk in never smokers can be higher than genetic component in smokers, we expect to identify about 5-10 candidate regions associated with lung cancer risk in never smokers. Aim 3: To identify and explore pathways associated with the risk of lung cancer in never smokers. Results of the number of studies on the molecular mechanisms and drug response suggest that lung cancer in never smokers is a different disease and different pathways will be associated with lung cancer risk in non-smokers and smokers. To identify pathways and molecular functions associated with lung cancer risk in never smokers we will apply Ingenuity and DAVID bioinformatics tools. We will use at least 300 top candidate genes identified in joint and discovery analysis. The reason why we select rather large number of candidate genes for functional annotation is two-fold: 1. Both algorithms are looking for enrichment of pathways and function by most significant genes and they produce statistically robust results only when number of genes is relatively high. 2. Despite the fact that this study will be largest possible for never smokers we still are underpowered to detect SNPs with relatively small effect size. But though those SNPs will not reach genome wide level of significance they will tend to be on the top of the list. In other words genes from the gray zone (significant on individual level and non-significant for genome wide level) are expected to be enriched by true discoveries. True discoveries are likely to be associated with limited number of pathways / functions while false positives are expected to be uniformly distributed across functions and pathways. Therefore significant clustering of the gene to a given function will suggest that that those genes are true discoveries. This is the first GWAS aiming at identifying the genetic control of susceptibility to lung cancer in Caucasian never smokers. We will combine the available resources from the multiple sites to achieve the sample size sufficient for this study. The study will identify genetic architecture of the predisposition to the lung cancer in never smokers.

  Study phs000634

• About

  About What's the EGA? The European Genome-phenome Archive (EGA) is a global network for permanent archiving and sharing of personally identifiable genetic, phenotypic, and clinical data generated for the purposes of biomedical research projects or in the context of research-focused healthcare systems. Jointly managed by the European Bioinformatics Institute (EMBL-EBI) in Cambridge (UK) and the Centre for Genomic Regulation (CRG) in Barcelona, we aim to advance biomedical research and promote personalised medicine worldwide by enabling discovery of and access to human genomic and health research data. The EGA contains data collected from individuals whose consent agreements authorise data release for specific research use to bona fide researchers. We ensure strict security measures to control access to the data and maintain patient confidentiality. With expertise in data management and technical infrastructure, we promote FAIR data reuse and enable researchers to share their data securely. By leveraging public funding and our strategic partnerships, the EGA provides a free service for permanent data storage, data discovery, and secure data access. In addition, we foster a federated network to provide transnational access to human research data in compliance with legal frameworks. For additional information about the EGA, please contact: Helen Parkinson and Mallory Freeberg EMBL European Bioinformatics Institute Arcadi Navarro, Roderic Guigó, and Jordi Rambla Center for Genomic Regulation History The European Genome-phenome Archive was launched in 2008 at the European Bioinformatics Institute (EMBL-EBI), an outstation of the European Molecular Biology Laboratory (EMBL), to address an identified need for archiving and sharing the results of genome-wide association studies from the Wellcome Trust Case Control Consortium. With the signing of a memorandum of understanding in 2013 and a formal agreement in 2016, the EGA became a joint project of EMBL-EBI and the Centre for Genomic Regulation (CRG). The two institutes work together to support the EGA services, including supporting submissions, website, strategic leadership, and data infrastructure developments. In 2022, the Federated EGA was officially launched with the signature of the first five countries: Finland, Germany, Norway, Spain, and Sweden. With more than 20 additional nodes worldwide preparing to join, the Federated EGA aims to become the largest human omics data sharing initiative towards understanding human health and disease. EGA overview If you're a researcher you may need to deposit, manage, or access genomic data in a secure and regulated way. The European Genome-phenome Archive (EGA) is a platform that facilitates these processes, ensuring that sensitive data is stored and shared in accordance with legal and ethical regulations. Submission process To start a submission, you need to become an EGA submitter. For that, you’ll need to sign a Data Processing Agreement (DPA) with us, that defines the terms and conditions under which your data will be processed and shared within the EGA system. The access to each study is controlled by its Data Access Committee (DAC). The DAC is responsible for managing data access requests and ensuring that the release of data is in accordance with the General Data Protection Regulation (GDPR). Please, note that once your data is released, all public metadata related to your study and dataset(s) will be searchable on the EGA website. However, the files are only accessible under controlled access, which means that a DAC has to agree to a previous data access request. Request process It is possible to submit an access request to data stored at the EGA. The DAC assigned to the study will assess the request and, if approved, grant access to the data. Requesters must provide sufficient justification for your request and comply with the intended data usage in order to get access to it. Each dataset is covered by a Data Access Agreement (DAA) that defines the terms and conditions of use for the specified dataset/s. The DAA is created and provided by the DAC, and must be signed by the individual requesting access to the given dataset/s. Download process Once the request for access is approved, the data and metadata can be downloaded. The EGA offers various download options to fit the needs: it is possible to preview files without downloading them, download specific files of interest, or even download terabytes of data. Overall, the EGA provides a secure and regulated environment for depositing, managing, and accessing human data. Regardless of the role - submitter, DAC member, or requester - the EGA provides assistance for each while ensuring that sensitive data is managed in an ethical and responsible manner. More information on how EGA handles data is available in the EGA dataflow.

  Documentation about/ega

• Genome-Wide Association Studies of Prematurity and Its Complications (African American)

  Preterm delivery resulting in the birth of a premature infant is a complex problem with a devastating impact on individuals, families and society. The prevalence of preterm birth has increased steadily in developed countries over the last 20 years and more than three million children die of preterm birth worldwide each year. Despite the importance of the problem and its disproportionate occurrence in poor and minority populations, the underlying causes have been difficult to identify. Spontaneous preterm labor has as its suspected triggers infection, stress, poor nutrition and inherited factors. The single best predictor for preterm delivery is a previous preterm birth. Studies of twins and of recurrences within families provide evidence that genetic factors underlie a substantive component of the risk for prematurity. One major challenge in studying genetic factors in prematurity is that the risk case is not truly established. The genetic risk could reside either in the mother and her uterus or in the infant/placenta. Identification of genetic factors in the mother and/or infant could provide insights into identifying relevant environmental covariates that may be more amenable to rapid interventions but difficult to find using standard epidemiology alone. A comprehensive genome-wide association study (GWAS) is the ideal way to identify those genes that would not be suspected based on our current understanding of the biology of parturition. We are using 2200 African American samples with term or preterm labor. A subset of these (~800) are infant samples recruited by the Neonatal Research Network as part of a study on cytokines and infection in extremely low birth weight infants (Schelonka RL, et al., 2011. PMID: 21145756). Therefore, this group consists of infants <1,000 grams with clinical outcome data for the infant allowing study of the genetic contributors for not only preterm birth but also the complications that often accompany preterm birth. The result will enable a better understanding of the biology of parturition and suggest environmental modifications that can prolong gestations to improve neonatal and adult outcomes. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to preterm birth through large-scale genome-wide association studies of African-American cases and controls from multiple sites in the United States. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000353

• Youth-GEMs, the project using data to define the mental health trajectories of young people

  Mental health trajectories are shaped by genetic, cognitive, social, and environmental factors that are particularly influential during human development. How exactly the interplay between these factors is impacting mental health, however, is yet unknown. The project “Gene Environment interactions in Mental health trajectories of Youth (Youth-GEMs)”, funded by the European Commission under the Horizon Europe programme, aims to help reducing mental suffering among European youth. How do Youth-GEMs contribute to bettering mental health in young people? Youth-GEMs aims to identify specific neurological, (epi)genetic and environmental drivers on mental health trajectories of young people. To do so, the project is working on a public knowledge base on functional genomics of the developing human brain, between birth and 24 years old. Reliable predictive models for trajectories of onset and course of mental illness in young people of the general population in Europe will be developed. Additionally, a secure and FAIR data infrastructure in mental health is being produced. Engaging and empowering young people Youth-GEMs is also working on the engagement of young people in the scientific field of Psychiatry. For that, the project is developing initiatives such as Science Café, intended to create a learning community where ideas and stories are shared. The 10th Science Café will take place today, with the participation of Lauren Fromont from the EGA. How do the EGA contribute to Youth-GEMs? The contributions require careful data management and harmonisation: we are dealing with an extraordinary amount of data types, sources, and time points (since the studies are longitudinal). To analyse them together and to determine which factors and interactions are truly key to account for mental health trajectories, the variables need to be transformed in a common “language”, i.e., harmonised under a common data model. Further, to guarantee FAIRness of data storage and sharing for future projects that will further advance our knowledge in the mental health field, we are ensuring that data are processed securely but can also be discovered easily. Find out more information about the project in the Youth-GEMs website.

  Blog youth-gems-mental-health

• EGA file encryption types

  EGA file encryption The European Genome-Phenome Archive (EGA) stands as a significant initiative in the field of genomics, facilitating the secure storage and sharing of vast amounts of genomic data. Jointly hosted by the Centre for Genomic Regulation (CRG) and the European Bioinformatics Institute (EMBL-EBI), the EGA offers a robust infrastructure for managing encrypted data, ensuring the privacy and integrity of sensitive genomic information. Both CRG and EMBL-EBI play pivotal roles in the EGA, each institution bringing unique expertise in managing different types of encryptions. EMBL-EBI EGACryptor encryption system, while CRG utilises Crypt4GH, resulting in two distinct encryption file types: cip and c4gh, respectively. How can I check the file encryption? To access your dataset of interest on the European Genome-Phenome Archive (EGA) and determine the corresponding encryption file extension, please follow these step-by-step instructions: Utilise the search or navigation features provided on the EGA website to locate the dataset you are interested in. Once you find the dataset webpage, click on the "Files" tab, typically located on the dataset's webpage. Upon reaching the "Files" tab, you will be presented with a table containing comprehensive information about the files associated with the dataset. This table will include various columns, such as "File Name," "Size," and "Location." The "Location" column is particularly relevant for determining the encryption file extension. Figure 1: File table showing all the information available for the files in a dataset. This table is specific for each dataset. To identify the encryption file extension corresponding to a specific file, locate the "Location" column in the table. If the file is archived in Spain, the file will have the .c4gh extension, indicating that it is encrypted using Crypt4gh. Conversely, if the file is archived in the UK, the encrypted file extension will be .cip, indicating the usage of EGACryptor for encryption. It is worth noting that a file can be available in both locations, meaning it will be accessible with both file extensions (.c4gh and .cip). This allows users to choose the encryption method that aligns with their preferred platform or analysis tools.

  Documentation check-encryption-type

• Research Program on Genes, Environment and Health (RPGEH)

  The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) is a resource developed to facilitate research on genetic and environmental factors on common diseases and healthy aging. The RPGEH resource links biospecimens, health surveys, and comprehensive electronic medical records on broadly consented adult members of Kaiser Permanente Medical Care Plan, Northern California Region (KPNC). KPNC is an integrated health care delivery system with a membership of approximately 3.3 million people in northern California. The membership of KPNC is representative of the general population in the 14 county area in which facilities are located, although extremes of income are underrepresented. At the end of 2013, the RPGEH resource included: (1) demographic and behavioral surveys from over 430,000 participants; (2) biospecimens (DNA, serum, plasma, and/or saliva) from over 204,000 participants, including over 13,000 pregnant women; (3) genome-wide genotype data (70 billion SNP genotypes) on over 100,000 participants, including the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort; and (4) the longitudinal electronic medical records of the participants. The RPGEH was developed beginning in 2005 at the Division of Research of Kaiser Permanente Northern California by Catherine Schaefer (Director), Neil Risch (Co-Director), Lisa Croen, Eric Jorgenson, Lawrence Kushi, Charles Quesenberry, Sarah Rowell, Carol Somkin, Stephen Van den Eeden, Larry Walter, and Rachel Whitmer. Funding of the RPGEH was provided to C. Schaefer (PI) and N. Risch (co-PI) by the Wayne and Gladys Valley Foundation, The Ellison Medical Foundation, the Robert Wood Johnson Foundation, Kaiser Permanente Northern California, and the Kaiser Permanente National and Regional Community Benefit Programs. The GERA cohort was funded by a grant from NIH to RPGEH and UCSF (RC2 AG036607; C. Schaefer and N. Risch, PIs). At the time of the award of the RC2 project in late 2009, the RPGEH had established a cohort of about 140,000 individuals who had answered a detailed survey, provided saliva samples for extraction of DNA, and given broad consent for the use of their data in studies of health and disease. Survey and Cohort Recruitment. Initially, the RPGEH developed electronic disease registries to enable identification of phenotypes, using algorithms applied to EMR data. In 2007, the RPGEH mailed a four page survey to 1.9 million adult (≥ 18 years old) members of KPNC who had been members for two years or more, to obtain data on demographic and behavioral factors complementary to the clinical data in the EMR. The survey materials included a cover letter introducing the RPGEH, a two page list of Frequently Asked Questions, and the survey, which included questions on demographic factors such as education, race-ethnicity, income and marital status, dietary factors, physical activity, smoking, and alcohol consumption, as well as reproductive history and reproductive health. Members whose electronic medical records indicated a preference for written communications in Chinese or Spanish received survey materials both in English and a Chinese or Spanish translation. Approximately 400,000 completed surveys were returned. Saliva Sample Collection. Beginning in July 2008, respondents to the survey were asked to sign and return a consent form and authorization for use and disclosure of protected health information. The consent form authorized broad use of biospecimens, survey data, and data from participants' electronic health records for use in studies of genetic and environmental influences on health and disease. Respondents who returned completed consent forms were mailed (Oragene) saliva collection kits; more than 132,000 saliva samples were collected in two years. Completed saliva kits were scanned and archived in a temporary biorepository at the KPNC Division of Research. In late 2009, the RPGEH began collection of saliva samples from the California Men's Health Study (CMHS), a cohort that had been previously assembled in 2002-2003 and had been excluded from the RPGEH survey mailing with the intent of later adding CMHS participants to the assembled RPGEH cohort. The CMHS was developed to facilitate research on prostate cancer and other conditions in older men; the study protocol is described in Enger, et al., 2006. It enrolled and surveyed more than 40,000 men in KPNC, ages 45-69 years, who were members of KPNC during 2002-2003. CMHS men completed two mailed surveys with demographic and behavioral data similar to that of the RPGEH. The data on analogous variables were reconciled and integrated with the data derived from the RPGEH cohort for use in the RPGEH resource. By 2011, RPGEH collected approximately 15,400 saliva samples from men participating in the CMHS. RPGEH Access and Collaborations Website and Procedures. The RPGEH maintains a web portal for inquiries and applications for collaboration and access to data. The url is: https://rpgehportal.kaiser.org/. RPGEH has an application process and an Access Review Committee that reviews applications for collaboration and use. For more information, please contact RPGEH through the website.

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• NIH RECOVER-Pediatric: Understanding the Long-Term Impact of COVID on Children and Families

  The NIH Researching COVID to Enhance Recovery (RECOVER) initiative comprises a set of three combined retrospective and prospective, longitudinal and observational meta-cohort studies with nested case-control studies designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection (PASC or Post-COVID syndrome) in a diverse study population representative of the general COVID-19 population in the US. Enrolled patients, with and without known SARS-CoV-2 infection, will be observed for clinical signs and symptoms of PASC and will be assessed for risk and resiliency factors and potential mediating factors associated with the severity and progression of PASC. The objective of the RECOVER initiative is to enhance knowledge of recovery from SARS-CoV-2 infections in order to support development of novel diagnostic and therapeutic interventions. Overarching scientific objectives are as follows:Characterize the incidence and prevalence of sequelae of SARS-CoV-2 infection.Characterize the spectrum of clinical symptoms, subclinical organ dysfunction, natural history, and distinct phenotypes identified as sequelae of SARS-CoV-2 infection. Define the biological mechanisms underlying pathogenesis of the sequelae of SARS-CoV-2 infection. The RECOVER observational studies comprise three cohorts across the lifespan (adult, pediatric, and tissue pathology (autopsy)). The data collection and data analysis plans for each cohort have been harmonized to use common data elements where feasible. Brief descriptions of each cohort are provided in the following paragraphs: 1) NIH RECOVER: A Multi-site Observational Study of Post-Acute Sequelae of SARS-CoV-2 Infection in Adults (see phs003463)The RECOVER adult cohort study is a combined retrospective and prospective, longitudinal, observational meta-cohort of individuals who will enter the cohort with and without SARS-CoV-2 infection and at varying stages before and after infection. Individuals with and without SARS-CoV-2 infection, and with or without PASC symptoms, will be followed to identify risk factors and occurrence of PASC. This study will be conducted in the United States and subjects will be recruited through inpatient, outpatient, and community-based settings. Study data including age, demographics, social determinants of health, medical history, vaccination history, details of acute SARS-CoV-2 infection, overall health and physical function, and PASC symptom screen will be reported by subjects or collected from the electronic health record using a case report form at specified intervals. Biologic specimens will be collected at specified intervals, with some tests performed in local clinical laboratories and others performed by centralized research centers or banked in the Biospecimen Repository. Advanced clinical examinations and radiologic examinations will be performed at local study sites with cross-site standardization. 2) A Multi-Center Observational Study: The RECOVER Post Acute Sequelae of SARS-CoV-2 (PASC) Pediatric Cohort Study (this study)The RECOVER pediatric study is a combined retrospective and prospective, longitudinal, observational meta-cohort of individuals ages newborn-25 years who will enter the cohort with and without SARS-CoV-2 infection at varying stages before and after infection. Individuals with and without SARS-CoV-2 infection and with or without PASC symptoms will be followed to identify risk factors and occurrence of PASC. This study recruit participants inpatient, outpatient, and community-based settings in the United States. Study data including age, demographics, social determinants of health, medical history, vaccination history, details of acute SARS-CoV-2 infection, overall health and physical function, and PASC symptoms will be reported by participants or collected from the electronic health record using a case report form at specified intervals. Biologic specimens will be collected at specified intervals, with some tests performed in local clinical laboratories and others performed by centralized research centers or banked in the Biospecimen Repository. Advanced clinical and radiologic examinations will be performed at local study sites with cross-site standardization. 3) NIH RECOVER: A Multi-site Pathology Study of Post-Acute Sequelae of SARS-CoV-2 Infection The RECOVER tissue pathology study is a cross-sectional study designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection in a diverse population representative of the general COVID-19 population in the US. The autopsy study will characterize the pathology of PASC in (i) non-hospitalized patients who die 30 days or later from symptom onset of COVID-19, and (ii) hospitalized patients who die 30 days or later after discharge from a hospitalization for COVID-19. The study will include decedents who had previously fully recovered from SARS-CoV-2 infection (i.e., >30 days from onset in non-hospitalized, or >30 days from discharge in hospitalized patients), and decedents who meet clinical criteria of PASC as defined by the recent World Health Organization publication (see Section 5.4 below). The autopsy study will also explore the pathology of acute SARS-CoV-2 infection in a smaller subset of patients who died 15-30 days from symptom onset. This protocol defines the common set of clinical data elements, autopsy procedures for tissue collection, core measures, pathology protocols, shared pathology tissues, data elements, and methodology. Each investigator site is expected to perform autopsies on the decedents to address the pathophysiology of the potential long-term effects of SARS-CoV-2 infection on human health. The Consortium analysis plan aims to address research questions by incorporating: 1) tissue obtained from autopsies performed at each Phase II participant's site; and 2) tissue available from other pathology investigators/autopsy sites within the Consortium.

  Study phs003461

• NIH RECOVER: A Multi-Site Observational Study of Post-Acute Sequelae of SARS-CoV-2 Infection in Adults

  The NIH Researching COVID to Enhance Recovery (RECOVER) initiative comprises a set of three combined retrospective and prospective, longitudinal, observational meta-cohort studies with nested case-control studies designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection (PASC or Post-COVID syndrome) in a diverse study population representative of the general COVID-19 population in the US. Enrolled patients with and without known SARS-CoV-2 infection will be observed for clinical signs and symptoms of PASC and will be assessed for risk and resiliency factors and potential mediating factors associated with the severity and progression of PASC. The objective of the RECOVER initiative is to enhance knowledge of recovery from SARS-CoV-2 infections in order to support development of novel diagnostic and therapeutic interventions. Overarching scientific objectives are as follows: Characterize the incidence and prevalence of sequelae of SARS-CoV-2 infection. Characterize the spectrum of clinical symptoms, subclinical organ dysfunction, natural history, and distinct phenotypes identified as sequelae of SARS-CoV-2 infection.Define the biological mechanisms underlying pathogenesis of the sequelae of SARS-CoV-2 infection. The RECOVER observational studies comprise three cohorts across the lifespan (adult, pediatric, and tissue pathology (autopsy)). The data collection and data analysis plans for each cohort have been harmonized to use common data elements where feasible. Brief descriptions of each cohort are provided in the following paragraphs:1) NIH RECOVER: A Multi-site Observational Study of Post-Acute Sequelae of SARS-CoV-2 Infection in Adults (this study)The RECOVER adult cohort study is a combined retrospective and prospective, longitudinal, observational meta-cohort of individuals who will enter the cohort with and without SARS-CoV-2 infection and at varying stages before and after infection. Individuals with and without SARS-CoV-2 infection and with or without PASC symptoms will be followed to identify risk factors and occurrence of PASC. This study will be conducted in the United States and subjects will be recruited through inpatient, outpatient, and community-based settings. Study data including age, demographics, social determinants of health, medical history, vaccination history, details of acute SARS-CoV-2 infection, overall health and physical function, and PASC symptom screen will be reported by subjects or collected from the electronic health record using a case report form at specified intervals. Biologic specimens will be collected at specified intervals, with some tests performed in local clinical laboratories and others performed by centralized research centers or banked in the Biospecimen Repository. Advanced clinical examinations and radiologic examinations will be performed at local study sites with cross-site standardization. A summary of information available by request in the RECOVER Adult Cohort (this study) can be reviewed via the "Adult Cohort Dataset Release Notes" and the "REDCap Codebook for the Adult Cohort" documents.2) The RECOVER Post Acute Sequelae of SARS-CoV-2 (PASC) Pediatric Cohort Study: A Multi-Center Observational Study (data not yet released)The RECOVER pediatric study is a combined retrospective and prospective, longitudinal, observational meta-cohort of individuals ages newborn-25 years who will enter the cohort with and without SARS-CoV-2 infection at varying stages before and after infection. Individuals with and without SARS-CoV-2 infection and with or without PASC symptoms will be followed to identify risk factors and occurrence of PASC. This study recruit participants inpatient, outpatient, and community-based settings in the United States. Study data including age, demographics, social determinants of health, medical history, vaccination history, details of acute SARS-CoV-2 infection, overall health and physical function, and PASC symptoms will be reported by participants or collected from the electronic health record using a case report form at specified intervals. Biologic specimens will be collected at specified intervals, with some tests performed in local clinical laboratories and others performed by centralized research centers or banked in the Biospecimen Repository. Advanced clinical and radiologic examinations will be performed at local study sites with cross-site standardization.3) NIH RECOVER: A Multi-site Pathology Study of Post-Acute Sequelae of SARS-CoV-2 Infection (data not yet released)The RECOVER tissue pathology study is a cross-sectional study designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection in a diverse population representative of the general COVID-19 population in the US. The autopsy study will characterize the pathology of PASC in (i) non-hospitalized patients who die 30 days or later from symptom onset of COVID-19, and (ii) hospitalized patients who die 30 days or later after discharge from a hospitalization for COVID-19. The study will include decedents who had previously fully recovered from SARS-CoV-2 infection (i.e., >30 days from onset in non-hospitalized, or >30 days from discharge in hospitalized patients), and decedents who meet clinical criteria of PASC as defined by the recent World Health Organization publication (see Section 5.4 below). The autopsy study will also explore the pathology of acute SARS-CoV-2 infection in a smaller subset of patients who died 15-30 days from symptom onset. This protocol defines the common set of clinical data elements, autopsy procedures for tissue collection, core measures, pathology protocols, shared pathology tissues, data elements, and methodology. Each investigator site is expected to perform autopsies on the decedents to address the pathophysiology of the potential long-term effects of SARS-CoV-2 infection on human health. The Consortium analysis plan aims to address research questions by incorporating: 1) tissue obtained from autopsies performed at each Phase II participant's site; and 2) tissue available from other pathology investigators/autopsy sites within the Consortium.

  Study phs003463

• Atherosclerosis Risk in Communities (ARIC) Cohort

  The Atherosclerosis Risk in Communities (ARIC) Study, sponsored by the National Heart, Lung and Blood Institute (NHLBI), is a prospective epidemiologic study conducted in four U.S. communities. The four communities are Forsyth County, NC; Jackson, MS; the northwest suburbs of Minneapolis, MN; and Washington County, MD. ARIC is designed to investigate the etiology and natural history of atherosclerosis, the etiology of clinical atherosclerotic diseases, and variation in cardiovascular risk factors, medical care and disease by race, gender, location, and date. ARIC includes two parts: the Cohort Component and the Community Surveillance Component. The Cohort Component began in 1987, and each ARIC field center randomly selected and recruited a cohort sample of approximately 4,000 individuals aged 45-64 from a defined population in their community. A total of 15,792 participants received an extensive examination, including medical, social, and demographic data. These participants were examined with the baseline visit occurring in 1987-89, the second visit in 1990-92, the third visit in 1993-95, the fourth visit in 1996-98, the fifth visit in 2011-13, the sixth visit 2016-17 and the seventh visit 2018-19. Follow-up occurs yearly by telephone to maintain contact with participants and to assess health status of the cohort. In the Community Surveillance Component, these four communities were investigated to determine the community-wide occurrence of hospitalized myocardial infarction and coronary heart disease deaths in men and women aged 35-84 years. Hospitalized stroke is investigated in cohort participants only. Starting in 2006, the study conducted community surveillance of inpatient (ages 55 years and older) and outpatient heart failure (ages 65 years and older) for heart failure events beginning in 2005. Community Surveillance for non-cohorts ended in event year 2014. ARIC is currently funded through 2028. The ARIC Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" section of this top-level study page phs000280 ARIC Cohort. phs000557 ARIC_CARe phs000090 GENEVA_ARIC phs000223 PAGE_CALiCo_ARIC phs000398 GO-ESP: HeartGo_ARIC phs000668 CHARGE_ARIC phs000860 MICORTEX phs001536 CCDG_ARIC

  Study phs000280

• National Institutes of Health The Cancer Genome Atlas (TCGA)

  The Cancer Genome Atlas (TCGA) is a comprehensive and coordinated effort to accelerate our understanding of the molecular basis of cancer through the application of genome analysis technologies, including large-scale genome sequencing. TCGA is a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), which are both part of the National Institutes of Health, U.S. Department of Health and Human Services. TCGA projects are organized by cancer type or subtype. Click here for a current list of cancer types selected for study in TCGA. Data from TCGA (e.g., gene expression, copy number variation and clinical information), are available via the Genomic Data Commons (GDC). Data from TCGA projects are organized into two tiers: Open Access and Controlled Access. Open Access data tier contains data that cannot be attributed to an individual research participant. The Open Access data tier does not require user certification. Data in Open Access tier are available in the TCGA Data Portal. Controlled Access data tier contains individual-level genotype data that are unique to an individual. Access to data in the Controlled Access data tier requires user certification through dbGaP Authorized Access. Controlled Access data types consist of the following: Individual germline variant data (SNP .cel files) Primary sequence data (.bam files), which are available at GDC Clinical free text fields Exon Array files (for Glioblastoma and Ovarian projects only) NOTE: TCGA strives to release most data in the open access tier. Individual genotype or sequence files are prominent exceptions. Commonly requested files such as descriptions of somatic mutations or clinical data are open access. Please go to this page: https://tcga-data.nci.nih.gov/docs/publications/ to access all data associated with TCGA tumor specific publications. The TCGA study is utilized in the following dbGaP substudies. To view genotypes and other molecular data collected in these substudies, please click on the following substudies below or in the "Substudies" section of this top-level study page phs000178 TCGA study. phs000854 Genome-wide Analysis of Noncoding Regulatory Mutations in Cancer

  Study phs000178

• Integrating Genomic and Transcriptomic Data to Identify Breast Cancer Susceptibility Genes

  Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. Since 2007, common genetic variants in ~200 loci have been identified in genome-wide association studies (GWAS) in relation to breast cancer risk. However, it is often difficult to translate GWAS findings to disease prevention and treatment since causal genes in the large majority of GWAS-identified loci are unknown. Furthermore, a large fraction of breast cancer heritability remains unexplained. Recent studies suggest that nearly 80% of disease heritability can be explained by genetic variants regulating gene expression. Herein, we propose three well-powered transcriptome-wide association studies (TWAS) to systematically investigate the association of breast cancer risk with gene expression across the transcriptome of African, Asian and European descendants. In Aim 1, we will perform RNA sequencing and high-density genotyping assays using normal breast tissue samples, and build race-specific gene expression prediction models using data from 1000 women of African, Asian and European descent. These models will be applied to the GWAS data generated from approximately 320,000 breast cancer patients and controls to impute gene expression for association analyses of predicted gene expression with risk of breast cancer overall, and by estrogen receptor and HER2 status. In Aim 2, we will select the top 50 genes identified in Aim 1 for in vitro functional assays to assess their influence on major cell functions related to cancer biology. In Aim 3, we will evaluate whether TWAS-identified genes may express differently in normal breast tissues and breast cancer tissues collected from African, Asian, and European descendants to assess whether these genes may contribute to racial differences in breast cancer risk by molecular subtypes. With strong methodology and a large sample size, we believe that this proposed study should be able to identify and characterize a large number of novel genes related to breast cancer risk. Uncovering breast cancer susceptibility genes will greatly improve the understanding of the genetic and biological basis for breast cancer and accelerate the translation of genetic findings to disease prevention and patient care.

  Study phs003535

• METSIM (METabolic Syndrome In Men) Study

  The METSIM Study includes 10,197 men, aged from 45 to 73 years, randomly selected from the population register of the town of Kuopio, Eastern Finland, and examined in 2005-2010. The aim of the study is to investigate genetic and non-genetic factors associated with the risk of type 2 diabetes (T2D), cardiovascular disease (CVD), and insulin resistance-related traits in a cross-sectional and longitudinal setting. Study protocol includes collection of data on CVD risk factors (smoking, exercise, diet, history of chronic diseases including coronary heart disease, stroke, cardiac failure, medication, history of diabetes or early onset coronary heart disease in the family), questionnaire on the FINDRISC Score, measurement of height, weight, waist, hip, blood pressure, and bioimpedance for the evaluation of fat percentage. July 2016 - The first study release (v1) included phenotype and whole exome sequencing (WES) data of n=982 participants in substudy: Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples (T2D-GENES) Project 1: Metabolic Syndrome in Men Study (METSIM) - phs001100.v2.p1. The second study release (v2) included phenotype data for the entire METSIM cohort and made two additional substudies available, phs000919.v1.p1 and phs000752.v1.p1. The third study release (v3) made three subcutaneous adipose biopsy substudies available, phs003385.v1.p1, phs003386.v1.p1, and phs003387.v1.p1.The fourth study release (v4) added phenotype data for the subcutaneous adipose biopsies, made two additional substudies available, phs01579.v1.p1 and phs004033.v1.p1, and is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" section of this top-level study page phs000743 METSIM Study. phs000752 METSIM FinMetSeq Exome Sequencing phs000919 METSIM GWAS and Exome Chip phs001100 METSIM T2D-GENES Exome Sequencingphs001579 METSIM CCDG Whole Genome Sequencingphs003385 METSIM Subcutaneous Adipose Needle Biopsy RNA-Seq phs003386 METSIM Subcutaneous Adipose Needle Biopsy ATAC-Seq phs003387 METSIM Subcutaneous Adipose Surgical Biopsy RNA-Seqphs004033 METSIM Metabolomics

  Study phs000743

• Identifying transcriptional programs underlying anti-EGFR small molecule response and resistance with TraCe-seq

  Genetic and non-genetic heterogeneity within cancer cell populations represents a major challenge to anti-cancer therapies. We currently lack robust methods to determine how pre-existing and adaptive features affect cellular responses to therapies. Here, by conducting clonal fitness mapping and transcriptional characterization using expressed barcodes and single-cell RNA-sequencing, we have developed TraCe-seq, a method that captures at clonal resolution the origin, fate, and differential early adaptive transcriptional programs of cells in a complex population in response to distinct treatments. We used TraCe-seq to benchmark how next-generation dual EGFR inhibitors-degraders compare to standard EGFR kinase inhibitors in EGFR-mutant lung cancer cells. To QC the TraCe-seq strategy, single-cell RNA-seq libraries were generated from a variety of human cancer cell lines transduced with the TraCe-seq library to validate the TraCe-seq strategy. Specifically, 5 different cell lines (PC9, MCF-10A, MDA-MB-231, NCI-H358, and NCI-H1373) were each transduced with a unique TraCe-seq barcode. The transduced cells were selected with puromycin only, dissociated to single cell suspensions, and then mixed together. The complex mixture of the 5 cell lines was profiled by 10X scRNA-seq. Furthermore, transduced NCI-H1373 cells were sorted by FACS to enrich for the top 50% of eGFP positive cells, and sorted cells were cultured briefly and used to construct scRNA-seq libraries and profiled by 10x scRNA-seq. To carry out the full TraCe-seq experiment, ~600 PC9 cells carrying unique TraCe-seq barcodes were expanded over 12 doublings to establish the barcoded population. A subset of the barcoded PC9 population was used to generate scRNA-seq libraries and profiled by 10x scRNA-seq prior to treatment to establish a baseline transcription profile for each barcoded clone. The rest of the cells were then treated for four days with 1 µM erlotinib, 1 µM GNE-069, or 1 µM GNE-104 respectively. scRNA-seq libraries were then generated form the treated cells and profiled by 10x scRNA-seq.

  Study EGAS00001005405

• ROCHE PD 92 Multiome dataset

  This dataset contains 10X Multiome data generated on post-mortem brain from 92 individuals (70 PD, 22 controls). For the Roche_PD dataset, nuclei were isolated using Nuclei Pure Prep Nuclei Isolation Kit (Sigma Aldrich) with the following modifications. The tissue was lysed in Nuclei Pure Lysis Solution with 0.1% Triton X, 1mM DTT and 0.4U/ul SUPERase-In™ RNase Inhibitor (ThermoFisher Scientific) freshly added before use and homogenized with the help first of a 23G and then of a 29G syringe. Cold 1.8M Sucrose Cushion Solution, prepared immediately before use with the addition of1mM DTT and 0.4U/ul RNase Inhibitor, was added to the suspensions before they were filtered through a 30μm strainer. The lysates were then carefully and slowly layered on top of 1.8M Sucrose Cushion Solution previously added in new Eppendorf tubes. Samples were centrifuged for 45 minutes at 16000xg at 4°C. Pellets were re-suspended in Nuclei Storage Buffer with RNase Inhibitor, transferred in new Eppendorf tubes and centrifuged twice for 5 minutes at 500xg at 4°C. Finally purified nuclei were re-suspended in Nuclei Storage Buffer with RNase Inhibitor, stained with trypan blue and counted using Countess II (Life technology). After count, nuclei permeabilization was carried out following the demonstrated protocol for single cell multiome ATAC + Gene Expression sequencing from 10x Genomics. A total of 12,000 estimated nuclei from each sample was used for the transposition step and then loaded on the Chromium Next GEM Single Cell Chip J. ATAC library and gene expression library construction was performed using the Chromium Next GEM Single Cell Multiome ATAC + Gene Expression kit according to the manufacturer’s instructions. Libraries were sequenced using Illumina NovaSeq 6000 System and NovaSeq 6000 S2 Reagent Kit v1.5 (100 cycles), aiming at a minimum sequencing depth of 30K reads/nucleus. Genotype was generated as previously described (Bryois et al, Nature Neuroscience, 2022).

  Dataset EGAD50000000964

• National Cancer Institute (NCI) Biospecimen Pre-analytical Variables (BPV) Analysis

  The Biospecimen Pre-analytical Variables (BPV) Program is a National Cancer Institute-sponsored study to systematically assess the effects of pre-analytical factors on the molecular profile of biospecimens. A robust biospecimen collection infrastructure was established to prospectively collect biospecimens using rigorous standard operating procedures to control for most variables while introducing experimental conditions to study specific biospecimen handling issues, including the cold ischemic time (delay to formalin fixation), time in formalin, freezing methods, and storage temperatures and durations. RNA and DNA from biospecimens collected under these conditions was analyzed on multiple molecular platforms. The potential effects of these pre-analytical conditions on protein integrity and detection of metabolites were also examined. Data from this study will be used to develop evidence-based biospecimen standard operating procedures and best practices for fit-for-purpose collection, processing, and storage of biospecimens. The BPV Cohort is utilized in the following dbGaP substudies. To view genotypes, analysis, expression data, other molecular data, and derived variables collected in these substudies, please click on the following sub-studies below or in the "Substudies" box located on the right hand side of this top-level study page phs001304 BPV Cohort. The substudy links will be active once they are released by dbGaP. Preanalytical Impacts on Global Metabolite Profiling - plasma (MassSpec by Metabolon) This study was to evaluate the impact of the storage temperature (s) (-80°C and LN2 vapor) and the length of storage on human plasma quality using LC-MS/MS (liquid-chromatography-mass spectrometry/mass spectrometry) based global metabolite profiling. The study includes 240 plasma samples collected from 40 donors. Investigate the effect of the delay to fixation on the proteome and phosphoproteome -FFPE (MassSpec by Caprion). The study is to do proteome and phosphoproteome analysis on Delay to fixation was carried out using FFPE tumor samples from colon and ovarian cancer patients comparing 2, 3, and 12hr delay to fixation to the 1hr time point. The study includes 100 samples 20 donors. Investigate the effect of storage conditions of tumor specimens on the proteome and phosphoproteome profiling- Frozen tissue and plasma (MassSpec by Caprion). The study was to evaluate the effects of storage conditions on tumor specimens. Plasma samples from 40 cancer patients stored at two different temperatures (-80°C and LN2) for a given period (0-2, 6-8, and 12-14 months) were evaluated. Frozen kidney tumor samples from 20 patients were compared for effects of different snap frozen (dry ice vs. LN2) and storage temperatures (-80°C and LN2). The study includes 100 tissue and 240 plasma samples from 60 donors. Preanalytical Impacts on Genomic Sequencing by Next Generation Sequencing (NGS) technology (mRNA/miRNA and WES by Expression Analysis). The goal of the study is to determine the effects of cold ischemic delay-to-fixation (4 time points) and formalin preservation (FFPE) on the nature and quality of genomic profiles using the matched freshly frozen sample as the gold standard, which including WES, RNAseq. The study includes 395 samples from 37 donors. Preanalytical Impacts on Copy Number Variation (CNV) Detection by aCGH technology (aCGH by Georgetown University). This study was to use aCGH to evaluate the effect of variation in cold ischemia time and time in formalin fixation on CNV in DNA extracted from kidney cancer specimens. The study includes 235 samples from 40 donors. Evaluation of frozen conditions on mRNA profiling by TaqMan assay (mRNA expression by Georgetown University). This study was to utilize gene expression profiling, using custom TaqMan arrays, to compare the molecular profiles of RNA from frozen tumor samples collected using two freezing methods (dry ice or LN2), two storage temperatures (-80°C or LN2 vapor), as well as Optimal Cutting Temperature (OCT) compound and non-OCT embedded. The study includes 100 samples from 20 donors. mRNA signature for stratification by cold ischemia time (mRNA expression by IBBL). The study was to determine the effects of cold ischemic time (delay-to-fixation) and formalin preservation (FFPE) on mRNA detection by Taqman assay using tumor tissue specimens from kidney, colon and ovarian cancer patients. There are160 samples from 40 donors. The Biospecimen PV cohort is utilized in the following dbGaP individual studies. To view molecular data, and derived variables collected in these individual studies, please click on the following individual studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs001304 Biospecimen PV cohort. phs001634 CIT mRNA phs001635 CNV aCGH phs001636 Fixation Delay phs001637 Global Metabolite Profiling phs001638 mRNA TaqMan phs001639 NGS phs001640 Tumor Storage

  Study phs001304

• Coronary Artery Risk Development in Young Adults (CARDIA) Study - Cohort

  CARDIA is a study examining the etiology and natural history of cardiovascular disease beginning in young adulthood. In 1985-1986, a cohort of 5115 healthy black and white men and women aged 18-30 years were selected to have approximately the same number of people in subgroups of age (18-24 and 25-30), sex, race, and education (high school or less and more than high school) within each of four US Field Centers. These same participants were asked to participate in follow-up examinations during 1987-1988 (Year 2), 1990-1991 (Year 5), 1992-1993 (Year 7), 1995-1996 (Year 10), 2000-2001 (Year 15), 2005-2006 (Year 20), and 2010-2011 (Year 25); the proportions of the surviving cohort that have returned for the seven follow-up examinations were 90%, 86%, 81%, 79%, 74%, 72%, and 72%, respectively. In addition to the follow-up examinations, participants are contacted regularly for the ascertainment of information on out-patient procedures and hospitalizations experienced between contacts. Within the past five years, 95% of the original surviving cohort has been contacted. While the specifics of each examination has differed somewhat, data have been collected on a variety of factors believed to be related to heart disease. These include conditions with clear links to heart disease such as blood pressure, cholesterol and other lipids. Data have also been collected on physical measurements such as weight and skinfold fat as well as lifestyle factors such as substance use (tobacco and alcohol), dietary and exercise patterns, behavioral and psychological variables, medical and family history, and other chemistries (e.g., insulin and glucose). In addition, subclinical atherosclerosis was measured via echocardiography during Years 5, 10, and 25, computed tomography during Years 15 and 20, and carotid ultrasound during Year 20. The CARDIA Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs000285 CARDIA Cohort. phs000236 PAGE_CALiCo_CARDIA phs000309 GENEVA_CARDIA phs000399 GO-ESP HeartGO_CARDIA phs000613 CARDIA_CARe

  Study phs000285

• Genetic Modifiers of Huntington's Disease

  Huntington's disease (HD) is a neurodegenerative disorder typically diagnosed in mid-life that is caused by expansion of an otherwise polymorphic CAG trinucleotide repeat. The mutation causes a gain-of-function of the huntingtin protein to trigger a pathogenic process that produces detectable phenotypic differences many years before the traditional diagnosis, which is based upon characteristic motor symptoms. The prediagnosis phase of pathogenesis is now the subject of intense scrutiny by an NINDS-funded longitudinal study, PREDICT-HD, in which undiagnosed gene carriers are followed longitudinally and subjected to detailed phenotyping (PREDICT-HD Huntington Disease Study -- dbGaP Study Accession: phs000222). This powerful approach, which offers the potential for moving the focus of therapeutic development to the decades prior to neurological disease diagnosis, is enabled by the fact that all individuals with HD have the same type of mutation, which can be determined at any time in life by a single HD CAG repeat PCR amplification assay. The precise length of the HD CAG repeat differs between individuals. There is a strong negative correlation between the number of CAG repeats and the age at onset of diagnostic neurological abnormalities in HD, such that the CAG repeat accounts for ~50% of the variation in age at diagnosis. Analysis of the remaining variance not explained by the length of the CAG repeat has shown that it is highly heritable, being due to genetic variation, elsewhere in the genome. The intent of the Genetic Modifiers of Huntington's Disease study is to identify genetic modifiers of HD pathogenesis by using genomewide association techniques in diagnosed HD individuals to identify genetic factors associated with the residual variance in age at onset not explained by the CAG repeat, and to extend these analyses to pre-diagnosis phenotypes, for example, those defined in the PREDICT-HD study. Identification of modifier genes is a top priority for HD research (and an example of an approach that can be applied in other late-onset genetic disorders), as it could provide clues to developing rational treatments that delay or prevent the pathogenic process from causing the ravages of the disease that ensue in the ~15 years of inexorable decline to ultimate death that now follows clinical diagnosis. To further that goal, the release of study version 2 makes available whole exome sequencing data of n=221 study participants.

  Study phs000371

• Genetic Epidemiology of COPD (COPDGene) Funded by the National Heart, Lung, and Blood Institute

  Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and the only leading cause of death that is steadily increasing in frequency. This project will establish a racially diverse cohort that is sufficiently large and appropriately designed for genome-wide association analysis of COPD. A total of 10,000 subjects will be recruited, including control smokers, definite COPD cases (GOLD Stage 2 to 4), and subjects not included in either group (GOLD 1 or GOLD-Unclassified). This cohort will be used for cross-sectional analysis, although long-term longitudinal follow-up will be a future goal. The primary focus of the study will be genome-wide association analysis to identify the genetic risk factors that determine susceptibility for COPD and COPD-related phenotypes. Detailed phenotyping of both cases and controls, including chest CT scan assessment of emphysema and airway disease, will allow identification of genetic determinants for the heterogeneous components of the COPD syndrome. The hypotheses to be studied are: 1) Precise phenotypic characterization of COPD subjects using computed tomography, as well as clinical and physiological measures, will provide data that will enable the broad COPD syndrome to be decomposed into clinically significant subtypes. 2) Genome-wide association studies will identify genetic determinants for COPD susceptibility that will provide insight into clinically relevant COPD subtypes. 3) Distinct genetic determinants influence the development of emphysema and airway disease. The initial phase of genome-wide association analysis included 500 COPD cases and 500 control subjects (all non-Hispanic White) genotyped with the Illumina Omni-1 chip. The second phase genotyped the entire study cohort using the Illumina Omni-Express chip. Unique aspects of the study include: 1) Inclusion of large numbers of African American subjects (approximately 1/3 of the cohort); 2) Obtaining chest CT scans (including inspiratory and expiratory images); and 3) Inclusion of the full range of disease severity. The COPDGene_v6 Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs000179 COPDGene_v6 Cohort. phs000296 ESP LungGO COPDGene phs000765 COPDGene_Geno

  Study phs000179

• Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) was designed to evaluate the hypothesis that amiodarone or a conservatively programmed shock-only, single-lead implantable cardioverter defibrillator (ICD) would decrease the risk of death from any cause in a broad population of patients with mild-to-moderate heart failure. Background Patients with congestive heart failure (CHF) can die suddenly and unpredictably from arrhythmia despite the use of proven medical therapies, such as beta-blockade. Two approaches have been developed to prevent sudden death among patients with CHF: therapy with amiodarone and therapy with an ICD. However, most of the mortality data on amiodarone and ICD therapy at the time of the study had been obtained in clinical trials performed after myocardial infarction in patients without CHF or those with ventricular arrhythmias. Thus, more data was needed to guide these therapies in patients who did not meet these criteria. Participants There were a total of 2521 participants. 847 were randomly assigned to placebo, 845 to amiodarone, and 829 to ICD therapy. Design Before randomization, participants underwent electrocardiography, a 6-minute walk test, 24-hour ambulatory electrocardiography, liver and thyroid function studies, and chest radiography. Participants were required, if clinically reasonable, to receive treatment with a beta-blocker and an angiotensin-converting-enzyme inhibitor, as well as an aldosterone antagonist, aspirin, and statins, when appropriate. Participants were randomly assigned in equal proportions to receive placebo, amiodarone, or a single-chamber ICD programmed to shock-only mode. Participants assigned to amiodarone or matching placebo began therapy as outpatients immediately after randomization. Placebo and amiodarone were administered as a loading dose of 800 mg/day for one week, 400 mg/day for three weeks, and then as a daily maintenance dosage according to weight and bradycardia status. Participants assigned to ICD therapy received their device a median of three days after randomization. The goal of ICD therapy was to treat only rapid, sustained ventricular tachycardia or ventricular fibrillation. Dual-chamber or biventricular devices, or antitachycardia or rate-response pacing therapies were not permitted. The ICD was uniformly programmed to have a detection rate of 187 beats per minute or more. Antibradycardia pacing was initiated only if the intrinsic rate decreased to less than 34 beats per minute. Median follow-up was 45.5 months. The primary end point was death from any cause. Secondary outcome measures included cardiac mortality, arrhythmic mortality, morbidity, quality of life, and incremental cost-effectiveness of the interventions. Each active treatment arm was compared to the placebo drug arm. Conclusions In participants with NYHA class II or III CHF and LVEF of 35% or less, amiodarone had no favorable effect on survival, whereas single-lead, shock-only ICD therapy reduced overall mortality by 23%.

  Study phs003654

• Resuscitation Outcomes Consortium (ROC) Trauma Epidemiologic Registry (Trauma Epistry) (ROC-Trauma Epistry-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions.Available Data: This dataset only includes traumatic injury participants. For ROC cardiac arrest Epistry data please see: ROC-Cardiac Epistry 1 and 2 and ROC-Cardiac Epistry 3.Objectives: To build a prospective population-based registry of participants with out-of-hospital traumatic injury responded to by Emergency Medical Services (EMS). Specific aims included: to establish whether the results of Resuscitation Outcomes Consortium (ROC) trials can be generalized to the larger population of people that experience traumatic injury; to more fully establish the burden of traumatic injury; and to examine the relationships between variation in EMS structure and process, regional and periodic factors, and participant outcomes.Background: Traumatic injury is a major public health problem generating substantial morbidity, mortality, and economic burden on society. The majority of seriously injured persons are initially evaluated and cared for by prehospital providers, however the effect of EMS systems, EMS clinical care, and EMS interventions on trauma patient outcomes is largely unknown. EMS factors such as service level, number of responding providers, use of procedures or drugs in the field, training, quality assurance/feedback, and response time intervals also vary significantly by region.The Resuscitation Outcomes Consortium (ROC) was established in 2004 to conduct clinical research in the areas of cardiopulmonary arrest and life-threatening traumatic injury with the overall goal of improving resuscitation outcomes. Previous trauma registries have generally focused primarily on hospitalized patients with limited prehospital information. Registries may also exclude trauma cases at far ends of the spectrum, such as those who die in the field or in a non-trauma center and/or patients that are treated and released. These limitations do not allow for detailed, outcome-based assessments of EMS system factors necessary to define prehospital resuscitation best practices. Therefore there was a need for standardized data collection of out-of-hospital traumatic injuries matched to hospital-based outcomes in diverse geographic locations in order to identify the independent effects of prognostic or treatment factors accounting for variations in survival. Participants: The registry included 13,830 traumatic events from 264 EMS agencies transporting to 287 acute care hospitals from the following regional centers: Birmingham, Alabama; Dallas, Texas; Iowa City, Iowa; Milwaukee, Wisconsin; Pittsburgh, Pennsylvania; Portland, Oregon; San Diego, California; Seattle/King County, Washington; Ottawa, Ontario; Toronto, Ontario; and Vancouver, British Columbia.Design: ROC Epistry collected standardized data regarding episode-specific factors, participant demographics, clinical information, pre-hospital interventions and disposition, hospital information, and participant outcome for all out-of-hospital traumatic injuries in the ROC regions. Cases were identified through review of emergency response system records including dispatch centers, EMS ground agencies, and air medical services. Out-of-hospital data were extracted from existing databases whenever possible and augmented with targeted review of EMS reports. Hospital data were abstracted directly from the hospital file in most cases. Sites submitted data using a web-based interface or batch uploads (Newgard, et al., 2008, PMID: 18482792).

  Study phs003809

• Privacy Notice for Helpdesk service

  Privacy Notice for EGA Helpdesk service This Privacy Notice explains what personal data is collected by the specific service you are requesting, for what purposes, how it is processed, and how we keep it secure. Note that this service collects personal data directly provided by the user, and also collects personal data from users that is provided by other organisations. 1. Who controls your personal data and how to contact us? European Genome- Phenome Archive - EGA offers a service for permanent archiving and sharing of all types of personally identifiable genetic and phenotypic data resulting from biomedical research projects, jointly managed by European Molecular Biology Laboratory – European Bioinformatics Institute (EMBL-EBI) and Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG). EMBL-EBI and CRG represent joint Data Controllers’ of processing of your personal data. They and their Data protection officers may be contacted for data protection queries and for exercising your rights under Section 8. You may contact EMBL-EBI, represented by dr. Thomas Keane, by: email at: tk2@ebi.ac.uk or post at EMBL-EBI, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridgeshire, UK. EMBL’s Data Protection Officer may be contacted by: telephone at +49 6221 387-8590, email at dpo@embl.org , or post at EMBL Heidelberg, Data protection officer, Meyerhofstraße 1, 69117 Heidelberg, Germany. You may contact CRG, whose EGA team is represented by dr. Jordi Rambla de Argila, by: email at jordi.rambla@crg.eu, or post at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), Dr.Aiguader 88, PRBB Building, 08003 Barcelona, Spain. CRG Data protection officer may be contacted by: email at dpo@crg.eu post at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), C/ Dr. Aiguader, 88, PRBB Building, 08003 Barcelona, Spain. 2. Which is the lawful basis for processing personal data? We process your personal data on the grounds of important public interest. For monitoring your activities on the website, we process your personal data on the grounds of important public interest. Such legal basis is found in Article 5(1)(a) of EMBL Internal Policy No 68 on General Data Protection (hereinafter IP 68), which is equivalent to Article 6 (1)(e) of the EU General Data Protection Regulation (hereinafter GDPR) and upon which personal data are processed for the achievement of the aims laid down in 1973 agreement establishing EMBL, such as the promotion of the cooperation in the fundamental research, in the development of advanced instrumentation and in advanced teaching in molecular biology and dissemination of information. 3. What personal data is collected from users of the service? How do we use this personal data? We collect the following personal data from users of the service: Name Email address Job title Date and time when the support request was sent We will use your personal data for the following purposes: To provide uninterrupted user access to the service To better understand the needs of the users and guide future improvements of the service To create anonymous usage statistics 4. Who will have access to your personal data? The personal data will be disclosed to: Authorised staff in the data controller’s institutions acting on data controller`s behalf and instructions. 5. Will your personal data be transferred to third countries (i.e. countries not part of EU/EEA) and/or international organisations? There are no personal data transfers to third countries or international organizations. 6. How long do we keep your personal data? Any personal data directly obtained from you will be retained as long as the service is live. Such duration serves the purpose of enabling scientific research and ensures legal compliance and facilitates internal and external audits if they arise. By contrast, the log files for the data categories related to anonymous usage statistics (raw web service logs) are processed only for 30 days and thereafter erased. 7. The joint Data Controllers provide these rights regarding your personal data You have the right to: Not be subject to decisions based solely on an automated processing of data (i.e. without human intervention) without you having your views taken into consideration. Request at reasonable intervals and without excessive delay or expense, information about the personal data processed about you. Under your request we will inform you in writing about, for example, the origin of the personal data or the preservation period. Request information to understand data processing activities when the results of these activities are applied to you. It must be clarified that rights under points 4 and 5 are only available whenever you need support whilst using our website. For other processing based on the grounds of important public interest you cannot exercise your rights to object, rectify or erase your personal data according to the Article 13(2)(a)(b) of IP 68 (equivalent to Article 17(3)(b)(d) and Article 21(6) of the GDPR). 8. Supervisory authority If you wish to complain against the processing of your personal data, you may do so by post at: EMBL Heidelberg, Data Protection Committee, Meyerhofstraße 1, 69117 Heidelberg, Germany, or Autoritat Catalana de Protecció de Dades (Catalan Data Protection Authority), C/Rosselló 214, Esc A, 1r 1a, Barcelona 08008, Spain. Published at: February 6, 2019

  Documentation data-protection/privacy-notice/ega-helpdesk

• DAC Portal documentation

  DAC Portal Welcome to the DAC Portal documentation! If you are involved in governance or legal aspects, technical or operational aspects, or serving as a data steward, this page will be helpful for you. By exploring these materials, you can define your own Data Access Committee (DAC) and policies, understand the minimal requirements for a DAC and a policy object, and comprehend how the EGA data access requests are managed. DAC Portal Index Setting up your account DACs and Policies Pending Request table Manage Data Requests History page Audit your DACs, policies, and datasets Deprecation User Preferences DAC API - A programmatic approach Setting up your account Register yourself as an EGA user. The Helpdesk team will validate your account (this could take up to 48 hours). After validation, you will receive an email with a link to verify your email - Make sure you click on the link to verify your account! If you don’t receive the email, please check your spam folder. Once your account is active you can login to the DAC Portal. We recommend you to check out the Take The Tour! DACs and Policies Create a DAC Click on Create a DAC Add the title and description to your DAC. Once ready, click on the ‘Create’ button. You will have to wait until the Helpdesk Team validates the creation of your DAC. Once approved by Helpdesk, your DAC will be assigned with a persistent identifier (EGAC). Edit a DAC Once your DAC is registered and approved, you can edit it and add contacts. Remember, you can add as many contacts as needed. And, you can also remove/add contacts anytime. To add a contact, you must write the username or email of a registered EGA user in the Members field. Once you have typed the whole username or email, a drop-down menu will appear where you can select the contact. Select a contact from the drop-down menu. Make sure you write the full username or email of the contact so it appears as an option. Make sure that you select one main contact. Set up the role you want to grant to the new contact of the DAC. We recommend you to check out the FAQ to learn more about the different roles! After adding all the necessary contacts and assigning roles, click on Update. This will send an email notification to the new DAC member, letting them know about the invitation to managing the DAC. Once they log into the DAC Portal, they will be able to either accept or turn down the invitation. Create a policy First, please note that all information registered in a policy metadata object will be publicly available on the EGA website. For each released dataset, all users will be able to read the policy under the “Data Access” tab. Select Create a Policy from the Policies tab. Select the DAC that you want your policy to depend on. Add the title and terms and conditions for accessing and using your data. If you already have an external website for data access requests, you can add the URL directly here (see example here). You can find a template of a Data Access Agreement (DAA) document in our Policy documentation page. The DAA template is provided for guidance only and should be adapted to suit your own purpose depending on the security policies, terms for publication or embargoes, and restrictions on data use or sharing. You can also add Data Use Ontologies (DUO) to your policy. These DUO codes are used to semantically tag the terms and conditions of using the data linked to the policy (example). For more information, you can refer to the Data Uso Ontology documentation. Once completed, make sure to click the Create button in order to register your policy. A persistent identifier (EGAP) will be assigned automatically. Edit a policy Please, note that you will not be able to edit the policy if it shows in orange. Meaning that you are a member of the DAC linked to that policy. Members don’t have edit rights. Only admins can edit objects. You can check your registered policies on My policies, available at the menu in the top-right corner. Select your policy. It will then display the information of that policy, allowing you to edit the information. Once you are done with the modifications, click Update. Pending Requests Table Table Settings Upon selecting a specific DAC, you will be presented with a customisable table showcasing all pending data access requests. This table allows you to tailor the displayed information according to your preferences by selecting desired columns. Available Columns (Displayed with the Eye Icon): Date: The date when the data access request was submitted. Full Name: Name and surname of the user submitting the request. Email: Email address associated with the user's request. Username: The username linked to the EGA account of the user submitting the request. Organisation: Affiliated organisation of the user submitting the request. Dataset: EGA accession ID for the requested EGA dataset. Dataset Title: Title of the requested dataset. DAC Comment: Space provided for internal comments related to the request. Expiration: Option to specify an expiration date for granted permissions. Check more information on the pending request table here! Table Filters By default, all data access requests are displayed. However, you have the option to apply filters to refine your view. Follow these steps to apply filters: Click on the More button. This action will reveal the different columns available for applying filters. As you select columns, the checked fields will be displayed at the top of the request table. Choose the specific values within the selected columns that you want to filter for. Click the Search button to apply the selected filters. Do you find yourself frequently applying the same filters? You can save multiple combinations of filters for easy access at any time! Here's how: Click the Save button. Provide a descriptive name for the filter combination. Click Save to confirm. To load saved filters, simply select the saved filter from the dropdown menu to apply it automatically. Check more information on filters here! Advanced Search For users requiring more granular control over their data access requests, the DAC Portal offers an Advanced Search feature using JIRA Query Language (JQL). With JQL, you can craft precise and complex queries to filter and retrieve specific data access requests based on various criteria such as date, user details, dataset attributes, and more. Using JQL's flexibility, you can create custom queries to meet your specific needs, allowing for advanced filtering options beyond the standard filters provided. You can find the Advanced Search feature following these steps: Click the … button Select Advanced To view the allowed fields for filtering and explore all available options, simply click on the info icon. Once you have written the filtering values, click the Search button to apply. Check more information on filters here! Manage Data Requests Upon logging into the DAC Portal, you'll notice a sand clock icon next to the DAC ID, indicating the number of pending requests. Click on the DAC to review these requests. Accept requests Click on the right side of the toggle button to grant access to the user. You can manage other requests before proceeding to the next step. After managing the requests, click on the Apply button. A confirmation box will appear summarising the options to be applied. Click on Yes, Confirm to proceed with granting permissions. Deny requests Click on the left side of the toggle button to deny access to the user. Provide a reason for the denial. Note that the user will receive an email with this reason. Click on the Done button. You can manage other requests before proceeding to the next step. After managing the requests, click on the Apply button. A confirmation box will appear summarising the options to be applied. Click on Yes, Confirm to proceed with denying permissions. Tips! Apply a filter to view all requests to be managed at once. Use the toggle in the row with column names to grant or deny permissions for multiple requests simultaneously. You can grant and deny permissions in the same action, simplifying the process. The confirmation box will provide a summary of all actions, including grants, denials, DAC comments, and expiration dates. History Page The History page serves as a dedicated space to view information regarding all requests managed by all DAC members. Here, you can review active permissions and revoke them as needed. Go to the History page by clicking on the "HISTORY" button from a DAC page in the DAC Portal. Here are the different row types you may find: Current permissions: row in green with a toggle button to revoke permissions on the right. Approved requests: row in green, with no toggle button. Request denied: row in red with “request denied” on the right. Permission revoked: row in red with “permission revoked” on the right. Distinctions to Note! Between Request Denied and Permission Revoked: Request Denied: Refers to requests that were rejected from the outset, indicating that access to the dataset was never granted. Permission Revoked: Indicates that permissions were previously granted but have since been revoked. Users with permissions revoked have previously accessed the dataset. Between Approved Request and Current Permissions: Approved Request: Represents an entry when a data access request has been approved in the past. Current Permissions: Denotes ongoing permissions where a user has present access to the dataset. An approved request may now appear as Permission Revoked in the present. By observing these different rows, users can gain insight into the complete history of a user's interactions and permissions regarding a dataset over time. To revoke access to a specific user for a dataset, follow these steps: Go to History page Look for the row with the specific permissions. You can use the filters! Click on the toggle button to revoke access. Add a denial reason. Bear in mind that the requester will receive the denial reason! Click on the Apply button. Check more information on the Hisotry page here! Audit your metadata objects In the DAC Portal, you can efficiently manage and audit various metadata objects pertinent to your role as a Data Controller. Upon accessing the DAC Portal, you will encounter three primary tabs on the homepage: DAC: Contains information about Data Access Committees (DACs). Policies: Provides insights into linked policies. Datasets: Displays datasets and relevant details. Within each tab, you'll find a comprehensive list of the objects you manage, these being grouped by type (DAC, Policies, Datasets), as well as by your role (member/admin). Whilst the lists give you a quick look, to check how things are connected, we've added a table at the bottom DACs and policies. DACs Let’s check which policies are linked to a specific DAC: Go to "My DACs." Select a DAC. Click on "EDIT" to see more details. You are now on this page: Scroll down to see the linked policies. Click on “List of linked policies of this DAC” and you will see a list of all policies linked to your selected DAC. Policies Do you want to view a list of datasets connected to a particular policy? Follow the same steps mentioned earlier, but head to the policy tab this time. In the policy tab, you'll find a list of all your policies. Here, you may notice two different icons next to the policy ID (EGAP): DAC Icon (): This represents the DAC. Hover your mouse over the icon to see the DAC ID. Dataset icon (): This indicates datasets falling under that policy. The number next to the icon tells you how many datasets are linked to the policy. For example, if you see "2" next to the icon, it means there are two datasets linked to that policy. If you want to check the linked datasets and their relevant information, simply click on a specific policy. You'll then find the "List of linked datasets of this policy" at the bottom of the page. Datasets Finally, in the dataset tab, by default you will see a list of all the datasets you can manage with all your DACs and policies. Yet, we've included two handy ways to organise them: DAC vs. policy: You can group by datasets, either by DAC or policy. Released vs. unreleased: You can sort out datasets based on their release status. Feel free to experiment with both options! For instance, if you want to see which DACs have unreleased datasets, simply select DAC and unreleased, and you'll get the details you need! Deprecation Do you have a bunch of metadata objects like DACs and policies that you don’t need anymore? This section shows you how to get rid of them! But what does "deprecation" mean for EGA? It's basically changing the status of a metadata object to "deprecated," which means we won't be using it in the future. In simple terms, it's like saying these objects are no longer useful. However, because we believe in making metadata FAIR, once an object has a persistent identifier, we can't just delete it. So, instead of deleting, we deprecate it. Here's a helpful tip! If you want to make a metadata object disappear from the DAC Portal, deprecate it. You won’t see it in the portal anymore! Let’s say you want to deprecate a DAC. Let’s do it! Go to "My DACs." Select a DAC. Click "EDIT" to see more details. You are now in this page: Click on the Deprecate button It will then appear a message. There are two options here: Your DAC is not linked to any policy, hence it’s ready to be deprecated. Click on “Yes. Confirm” to deprecate your DAC object! Your DAC is linked to at least one policy, and you need to either: Deprecate the linked policy first, or Link the policy to a different DAC Now, let’s say you don’t want to get rid of the policy altogether, but you want to change the DAC it’s linked to. Here's how: Go to the policy tab. Find the policy you want to change (for example, EGAP50000000019). Choose a new DAC to link it to. Click on Update. See the Edit Policy section for more details. After ensuring that the DAC we want to deprecate isn’t linked to any policy, return to the "My DACs" section and follow the steps outlined previously. This will lead you to a confirmation message. You can only deprecate DACs and Policies. To deprecate a dataset, please contact our Helpdesk team. Check more information on how deprecation works here! User Preferences We have implemented email notifications in the DAC Portal. Here’s the complete list: DACs: Pending requests Approved by Helpdesk Rejected by Helpdesk DAC Invitation Requesters: Data access request approved Data access request denied Permissions revoked Upcoming expiration date As a DAC member, you will be able to decide whether you want to receive the DAC notifications or not. For that, go to the top-right corner menu, select User Preference. You will be able to decide whether you want to receive notifications for: Approved by Helpdesk Rejected by Helpdesk DAC Invitation For pending requests, you will be able to select how often do you want to receive the notification: Daily Weekly Fortnightly As a DAC member, you are responsible for managing data access requests. Consequently, you will receive notifications for pending requests. If you prefer not to manage these requests, please arrange to be removed as a contact for your DAC. Here's a tip! Do you have a pending request that you don’t want to receive a notification? Add a DAC comment! The EGA understands that a request resolution can take some time, for this reason, if you add a comment (make sure you save it by clicking the APPLY button!) we will filter those requests at the time of sending the notification! DAC API - A programmatic approach In addition to the new DAC Portal, we are excited to announce the release of the DAC API. This enables users to programmatically manage permissions. If you are interested in learning more about the technical specifications, you can click the button below. Check out the DAC API specification!

  Documentation access/data-access-committee/dac-portal

• Genome-Wide Association Studies of Prematurity and Its Complications

  Preterm labor resulting in the delivery of a premature child is a complex problem with an enormous impact on individuals, families and society. An estimated 500,000 children are born prematurely in the U.S. each year, and 5 million worldwide die annually of prematurity and its complications. Prematurity is also the single largest contributor to disability-adjusted life years, a measure of the lifetime impact of a disease. Despite the importance of the problem and its disproportionate occurrence in poor and minority populations, its underlying etiology (or etiologies) remains unknown; the single best predictor for preterm delivery is a previous preterm birth. The largest single cause of prematurity is spontaneous preterm labor, and suspected triggers for this include infection, stress, poor nutrition and genetic factors. Family and twin studies provide strong evidence that genetic factors underlie about 40% of the risk for prematurity. A major challenge in studying genetic factors in prematurity is maternal/uterine factors, fetal/placental factors, or both may influence risk. Thus, any approach to studying preterm birth should account for both infant and maternal risk, environmental covariates and interactions. The Danish National Birth Cohort (DNBC) is a well-established, prospective cohort that enrolled women early in pregnancy, prior to any adverse pregnancy outcomes, to minimize bias in data collection and sampling. See details at: http://www.ssi.dk/English. The DNBC followed over 100,000 pregnancies beginning in the first trimester and has extensive biological material and epidemiologic data on health outcomes in both mother and child. The current study posted on dbGaP contains data from a genome-wide case/control study using approximately 1,000 preterm mother-child pairs from the DNBC most with spontaneous onset of labor or preterm premature rupture of membranes (PPROM), along with 1,000 control pairs where the child was born at ~40 weeks' gestation. After data cleaning some small changes in case/control status and other variables resulted in minor changes in numbers of cases or controls in certain categories. Environmental variables are being used as covariates in the analysis. To replicate positive findings, we are using additional mother-child pairs from the DNBC and from the general Danish population, as well as 2200 samples coming primarily from an African-American population known to have high rates of preterm labor and delivery. This group includes over 1000 mostly very low birthweight infants, over 500 infant term controls, 326 term mother/baby pairs and 180 preterm mother/baby pairs. The data from these additional cohorts will be available in separate dbGaP postings. The study is expected to yield a better understanding of the biology of parturition, identify common genetic factors that play a role in preterm birth and its complications and suggest environmental modifications that can prolong gestation, with the goal of improving both neonatal and adult outcomes. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to prematurity and its complications through large-scale genome-wide association studies of a well-characterized cohort of Danish mothers and babies. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000103

• Data Quality Control

  Data Quality Control High-throughput sequencing techniques have become the leading method to study, decode and discover the genomic origins of biological phenomenons. EGA provides a secure archival of such identifiable genomics data with the purpose of data-upcycling, i.e. to re-use these data for research. High-quality data standards are essential to ensure the quality and credibility of the research. Moreover, a quality check report can assure a researcher beforehand about the data that they will request access, therefore saving time and effort. The EGA has developed a File Quality Control Report (QC Report) to provide generic quality control reports for Fastq, SAM/BAM/CRAM, and VCF files deposited at EGA. This QC Report will allow users to get information regarding the files submitted within a specific dataset. The data requesters will obtain information such as the quality of reads, mapped reads, number of variants, and other features before starting the requesting process, which will save the efforts and time.Accessing file quality control reportsIn each dataset page, the user can explore the files that it contains by clicking the "files" tab. The Quality Control report of a file has two sections. The first one, contains general information about the file, such as the inferred assembly, total reads, the dataset or study where it comes from, etc. The second section contains plots that summarise interesting information about the file, for example, the base coverage distribution, base quality or mapped reads. The description of each plot is accessible by clicking the "i" button at the top-right corner of each plot box. Technical Description For analysing the fastq, SAM/BAM/CRAM and VCF files, the EGA applies a set of tools widely used in the bioinformatics community. FASTQ: FastQC, recognised as the gold standard tool by the community.Per base sequence quality, per sequence quality scores, per base sequence content, per sequence GC content, sequence duplication levels, etc.SAM/BAM/CRAM: samtools, also the gold standard, generates results plots useful to get an overall idea of the quality of the file.base coverage distribution, base quality, % of mapped reads, % of both mates mapped, singletons, duplicates, etc.VCF: vcftools and bcftools, combined with a custom script to infer the genome assembly.site frequency distribution, Ts/Tv, base changes, indel distribution, etc.

  Documentation access/request-data/quality-control-reports

• Submitters and requesters Statistics

  EGA Statistics Bibliography Growth Community Archive Distribution Catalogue Here, we show the amount and global distribution of submitters and requesters Requester accounts created by country The below figure represents the number of requester accounts by country. In most of the cases cases, country was inferred from the requester email domain. Those requesters whose email domain could not be assigned to a country such as @gmail.com, are not included. Note that a requester is a user that has had a granted permission at some point in time. Requester Accounts Created by Country Download as PNG Download as JPG Download as WEBP Download as CSV map pie mapChart('requester-country', 'https://stats.ega-archive.org/requester/country') pieChart('requester-country-pie-chart', 'https://stats.ega-archive.org/requester/country','Requester accounts created by country') Requester accounts created by year The below figure represents the number of requester accounts by year. Note that a requester is a user that has had a granted permission at some point in time. Requester Accounts Created by Year Download as PNG Download as JPG Download as WEBP Download as CSV barChart('requester-year', 'https://stats.ega-archive.org/requester/year', ['Requester Accounts', 'Years'], true) Industry requester accounts The below figure represents the top 15 industry requesting companies. Industry Requester Accounts Download as PNG Download as JPG Download as WEBP Download as CSV pieChart('industry-requester-accounts', 'https://stats.ega-archive.org/industry/requester/accounts', 'Industry Requester Accounts') Submitter accounts created by country The below figure represents the number of submitter accounts by country. Location was infered from the requester email domain. Submitter Accounts Created by Country Download as PNG Download as JPG Download as WEBP Download as CSV map pie mapChart('submitter-accounts', 'https://stats.ega-archive.org/submitter/accounts/country') pieChart('submitter-accounts-pie-chart', 'https://stats.ega-archive.org/submitter/accounts/country','Submitter accounts created by country') Submitter accounts created by year The below figure represents the number of submitter accounts by year. Submitter Accounts Created by Year Download as PNG Download as JPG Download as WEBP Download as CSV barChart('submitter-users-year', 'https://stats.ega-archive.org/submitter/users/year', ['Submitter Accounts', 'Years'], true) DAC Members by Country The below figure represents the number of DAC members by country. DAC Members by Country Download as PNG Download as JPG Download as WEBP Download as CSV map pie mapChart('dac-members-by-country', 'https://stats.ega-archive.org/dac_member/country') pieChart('dac-members-by-country-pie-chart', 'https://stats.ega-archive.org/dac_member/country','DAC members by country')

  Documentation about/statistics/community

• Sporadic ALS Australia Systems Genomics Consortium (SALSA-SGC)

  In 2016 we established the Sporadic ALS Australia Systems Genomics Consortium (SALSA-SGC) funded by the Ice Bucket Challenge Grant administered by the Motor Neurone Disease Research Institute of Australia. The goals of the SALSA-SGC are to collect biological samples from clinics across Australia with matched in depth clinical and self-report phenotypes and to generate multiple levels of genetic and genomic data. In this first data generation exercise of the SALSA-SGC the majority of the samples were collected prior to the formal establishment of SALSA-SGC from clinics across Australia.Briefly, the cohort includes the University of Sydney’s Australian Motor Neuron Disease DNA Bank (MND Bank) cohort recruited April 2000 to June 2011), with study protocol approved by the Sydney South West Area Health Service Human Research Ethics Committee (HREC). Cases were recruited from around Australia via state-based MND associations with diagnosis verified by a neurologist. The remainder of the cases were recruited from clinics across Australia between 2015 and 2017 under HREC approvals from Royal Brisbane and Women’s Hospital, Macquarie University Multidisciplinary Motor Neurone Disease Clinic,  Calvary Health Care Bethlehem in Melbourne , Fiona Stanley Hospital in Perth, and from 2016 under HREC approvals at each site for the sporadic ALS Australia Systems Genomics Consortium (SALSA-SGC). The ALS cases were diagnosed with definite or probable ALS according to the revised El Escorial criteria. Some controls were recruited as either partners or friends of patients, healthy individuals free of neuromuscular diseases. We are providing GWAS and MWAS data in this dataset. Individual level GWAS data were generated using Illumina Infinium CoreExome-24 version 1.1 chips for N= 846 cases and N=665 controls. Individual MWAS data was generated using the Illumina Human methylation 450K array for N=782 cases and N=613 controls. There 1315 individuals where GWAS and MWAS data has been generated and is available. Further information on these data sets can be found: Paper 1: Restuadi, R, Garton, FC, Benyamin, B, Lin, T, et al. Amyotrophic Lateral Sclerosis Genetic Correlation with Cognitive Performance, educational attainment and schizophrenia: evidence from polygenic risk score analysis. (submitted) Paper 2: Nabais, MF, Lin, T, Benyamin, B et al. Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis. 2020. NPJ genomic medicine. 5(10). Files provided in this submission include: GWAS: This folder contains QCed genotype for the Australian ALS case-control cohort. Contains PLINK files for genotyping data (not imputed yet). The individuals selected here have: good consistency on phenotype data ethics approval registered as part of sporadic ALS studies unrelated by GRM cut-off 0.05 No ancestry QC yet MWAS: This folder contains the IDAT and post-QC normalized DNAm (beta) for the Australian ALS case-control cohort. 2019_AUS_ALS_PCTG_DNAm.tar.gz - IDATS for 1315 individuals analyzed in the MWAS study normalized_beta_values - Binary files (created with the OSCA software) containing information on the individuals, probes and the DNAm (beta) values obtained after QC phenotype_file - contains all the covariates analysed in the MWAS including: case-control status, coded 0 = Control and 1 = ALS, predicted age, predicted cell-type proportions, predicted smoking scores, slide and chip position and sex Important Notes: The DNAm data were normalized together with samples that were not part of this ALS case/control study and thus, the normalization procedure may not be 100% reproducible using only the IDAT files uploaded here. Summary data has been made publicly available and can be accessed directly: Data collection and sample processing were performed at several clinics across Australia. Genotyping and DNA methylation arrays were performed by the Human Studies Unit, at the Institute for Molecular Bioscience (University of Queensland). Quality control of the genotypic, phenotypic and DNA methylation data was done by the Program of Complex Traits Genomics, at the Institute for Molecular Bioscience (University of Queensland).

  Study phs002068

• Brain Arteriovenous Malformation Genetics Study

  The Predictors of Spontaneous Cerebral AVM Hemorrhage study was designed to identify genetic markers that predict adverse outcomes in brain arteriovenous malformation (BAVM) patients, examine race-ethnicity influences on BAVM hemorrhage risk, and use genome-wide association analysis to identify novel genetic predictors of AVM and hemorrhage using the Affymetrix GeneChip. We performed the first genome-wide association study (GWAS) (PMID: 26818729) of sporadic BAVM to investigate association of common single nucleotide polymorphisms (SNPs) with risk of sporadic BAVM in the international, multicenter Genetics of Arteriovenous Malformation (GEN-AVM) consortium. The study included a Caucasian discovery cohort of 515 BAVM cases and 1,191 controls genotyped using Affymetrix genome-wide SNP arrays. The Phase 1 discovery cohort comprised of 338 BAVM cases (154 male) and 504 controls genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0. The molecular data (individual genetic data) for the Phase 1 discovery cohort 338 BAVM cases (self-reported Caucasian) recruited at University of California, San Francisco, or Kaiser Permanente of Northern California (KPNC) are included in the dbGaP Study Report: Brain Arteriovenous Malformation Genetics Study, with the additional BAVM case phenotypic and sample attribute characteristics: sex, race, age at BAVM diagnosis, hemorrhagic presentation, BAVM size. Written informed consent was obtained from all participants and the study was approved by the respective Institutional Review Boards. The molecular dataset for this study in dbGaP is based on the genotypes obtained for the initial set of 906,600 SNPs for cases and controls called together using Birdseed v2 algorithm in Affymetrix Genotyping Console Software. The final QC'd dataset includes 717,335 markers as SNPs with MAF<0.01 or deviating from Hardy-Weinberg equilibrium (P<0.00001) in controls were excluded. After QC, the average genotyping call rate was 99%. The discovery phase GWAS identified 57 top BAVM-associated SNPs which were tested in a replication cohort including 608 BAVM cases and 744 controls. The molecular dataset for these 338 BAVM cases was also included in a report investigating common and rare genome-wide copy number variation for association with BAVM (PMID: 24098321), which included a total sample size of 371 sporadic Caucasian BAVM cases and 563 Caucasian controls. This study identified a CNV region on 1p36.13 (NBPF1 locus) that was significantly enriched with duplications in BAVM cases compared to controls, although this association did not replicate in an independent cohort of 184 sporadic BAVM cases and 182 controls. This resource will help researchers to better understand the genetic risk factors for BAVM and/or hemorrhage. These data may be applied to examine the genetic contributions to arteriovenous malformation, stroke, and related vascular disorders and may help generate hypotheses regarding the genetics of cerebrovascular disease.

  Study phs002069

• GEDI: A Developmental Model of Gene-Environment Interplay in SUDs: Combined Genotype Dataset from the "Great Smoky Mountains Study" and the "Caring for Children in the Community Study".

  1. Great Smoky Mountains Study (GSMS; Costello et al. 1996, 1997) Three cohorts of boys and girls, aged 9, 11, and 13 years at intake in 1993, were selected from a rural population of some 20,000 children using a household equal probability design. A two-phase procedure was used for White and African-American youth to increase power by oversampling children at risk for psychiatric and SUDs. Parents (usually mothers) of the first stage random population sample completed a questionnaire about their child's behavioral problems. Of 4,195 subjects selected, 95% (N=3,896) of parents completed the screen. All children scoring above a predetermined threshold (the top 25% of the total scores), plus a 10% random sample of the remaining 75%, were recruited for detailed interviews. Results can be back-weighted to population levels for analyses. Half of the sample consists of females, and 6% are African Americans, reflecting the population of the study area. The interviewed sample of white and African-American subjects was 1,070 (80% of those recruited). American Indian youth were oversampled (100%) because they are an understudied group known to be at high risk for stressful events, substance disorders, and mood disorders. Of 431 age-eligible children, 350 (81% boys, 49% girls) participated. Thus, the size of total GSMS sample is 1,070 + 350 = 1,420. Data collection is complete for ages 9-26, and age 30 interviews are in progress. By age 26 a total of 9,858 interviews had been completed; the average number of interviews per subject was seven, and by age 26, 97.3% completed two or more interviews. 2. The Caring for Children in the Community Study (CCC; Angold et al., 2002) This representative study of psychiatric illness and service use in African-American and White youth took place in four rural counties in the southeastern USA. The two-stage sampling design and methods are similar to those used in the GSMS. Of 4,500 youth randomly selected from the 17,117 9- to 17-year-olds in the public school's database, 3,613 (80.0%) were successfully contacted and agreed to complete the behavioral screen. Of the 1,302 selected to participate in the study, 920 (70.7%) interviews were completed. Because CCC was also the only study in GEDI to contain more than a very few African-American participants, these were omitted from the multi-site analyses. Reprinted with permission from Cambridge University Press from Costello et al., 2013: PMID: 23461817 References: Costello et al., 1996: PMID: 8956679 Costello et al., 1997: PMID: 9184514 Angold et al., 2002: PMID: 12365876

  Study phs000852

• Privacy Notice for Data Access Committee Account

  Privacy Notice for EGA Data Access Committee Account This Privacy Notice explains what personal data is collected by the specific service you are requesting, for what purposes, how it is processed, and how we keep it secure. Note that this service collects personal data directly provided by the user, and also collects personal data from users that is provided by other organisations. 1. Who controls your personal data and how to contact us? European Genome- Phenome Archive - EGA offers a service for permanent archiving and sharing of all types of personally identifiable genetic and phenotypic data resulting from biomedical research projects, jointly managed by European Molecular Biology Laboratory – European Bioinformatics Institute (EMBL-EBI) and Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG). EMBL-EBI and CRG represent joint Data Controllers’ of processing of your personal data. They and their Data protection officers may be contacted for data protection queries and for exercising your rights under Section 8. You may contact EMBL-EBI, represented by Mallory Freeberg, by: email at mfreeberg@ebi.ac.uk , orpost at EMBL-EBI, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridgeshire, UK. EMBL’s Data Protection Officer may be contacted by: email at dpo@embl.org, orpost at EMBL Heidelberg, Data protection officer, Meyerhofstraße 1, 69117 Heidelberg, Germany. You may contact CRG, whose EGA team is represented by dr. Jordi Rambla de Argila, by: email at jordi.rambla@crg.eu, orpost at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), Dr.Aiguader 88, PRBB Building, 08003 Barcelona, Spain. CRG Data protection officer may be contacted by: email at dpo@crg.eupost at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), C/ Dr. Aiguader, 88, PRBB Building, 08003 Barcelona, Spain. 2. Which is the lawful basis for processing personal data? We process your personal data on the grounds of important public interest. For monitoring your activities on the website, we process your personal data on the grounds of important public interest. Such legal basis is found in Article 5(1)(a) of EMBL Internal Policy No 68 on General Data Protection (hereinafter IP 68), which is equivalent to Article 6 (1)(e) of the EU General Data Protection Regulation (hereinafter GDPR) and upon which personal data are processed for the achievement of the aims laid down in 1973 agreement establishing EMBL, such as the promotion of the cooperation in the fundamental research, in the development of advanced instrumentation and in advanced teaching in molecular biology and dissemination of information. 3. What personal data is collected from users of the service? How do we use this personal data? We collect the following personal data from you: NameEmail addressTitle/PositionOrganisationOrganisational affiliationBusiness addressTelephone numberIP addressesDate and time of a visit to the service websiteOperating systemAmount of data transmittedBrowserUsernamePassword The data controller will use your personal data for the following purposes: To provide DAC user account and authenticated access to the service,To publicly publish some information to facilitate scientific research,To better understand the needs of the data subjects and guide future improvements of the service,To create anonymous usage statistics (from number of DACs, datasets per DAC). 4. Who will have access to your personal data? The personal data will be disclosed to: Authorised staff in the data controller’s institutions acting on data controller`s behalf and instructions (for all user account data),The general public via Internet will get access to your name, email address, business address, telephone number and organisation you belong to. 5. Will your personal data be transferred to third countries (i.e. countries not part of EU/EEA) and/or international organisations? Data categories ‘name`, `email address`, `telephone number`, `business address`; `organisation’ of the DAC user are published on the Internet. They thus become accessible to recipients in countries outside the European Economic Area. Insofar as the second joint controller may be subject to GDPR, data transfer to and from the first joint controller (EMBL-EBI), is necessary for important reasons of public interest embedded in the aims of EMBL and justified in the Article 9(4) of IP 68 (equivalent to Article 49(1)(d) of GDPR) read in conjunction with EMBL`s 1973 establishing agreement and Article 179(2) of the Treaty on the Functioning of the European Union 6. How long do we keep your personal data? Any personal data directly obtained from you will be retained as long as the service is live. Such duration serves the purpose of enabling scientific research and ensures legal compliance and facilitates internal and external audits if they arise. By contrast, the log files for the data categories related to anonymous usage statistics (raw web service logs) are processed only for 30 days and thereafter erased. 7. The joint Data Controllers provide these rights regarding your personal data You have the right to: Not be subject to decisions based solely on an automated processing of data (i.e. without human intervention) without you having your views taken into consideration.Request at reasonable intervals and without excessive delay or expense, information about the personal data processed about you. Under your request we will inform you in writing about, for example, the origin of the personal data or the preservation period.Request information to understand data processing activities when the results of these activities are applied to you. It must be clarified that rights under points 4 and 5 are only available whenever you need support whilst using our website. For other processing based on the grounds of important public interest you cannot exercise your rights to object, rectify or erase your personal data according to the Article 13(2)(a)(b) of IP 68 (equivalent to Article 17(3)(b)(d) and Article 21(6) of the GDPR). 8. Supervisory authority If you wish to complain against the processing of your personal data, you may do so by post at: EMBL Heidelberg, Data Protection Committee, Meyerhofstraße 1, 69117 Heidelberg, Germany, or Autoritat Catalana de Protecció de Dades (Catalan Data Protection Authority), C/Rosselló 214, Esc A, 1r 1a, Barcelona 08008, Spain. Published at: February 6, 2019

  Documentation data-protection/privacy-notice/ega-dac

• Jackson Heart Study (JHS) Cohort

  The Jackson Heart Study (JHS) is a large, community-based, observational study whose participants were recruited from urban and rural areas of the three counties (Hinds, Madison and Rankin) that make up the Jackson, MS metropolitan statistical area (MSA). Participants were enrolled from each of 4 recruitment pools: (1) random, 17%, (2) volunteer, 30%, (3) currently enrolled in the Atherosclerosis Risk in Communities (ARIC) Study, 31%, and (4) secondary family members, 22%. The final cohort of 5,306 participants included 6.59% of all African American Jackson MSA residents, aged 35-84, during the baseline exam (N-76,426, US Census 2000). Among these, approximately 3,600 gave consent that allows genetic research and deposition of data into dbGaP. Major components of three clinic examinations (see study history) include medical history, physical examination, blood/urine analytes, and interview questions on areas such as physical activity, stress, coping and spirituality, racism and discrimination, socioeconomic position, and access to health care. Extensive clinical phenotyping includes anthropometrics, electrocardiography, carotid ultrasound, ankle-brachial blood pressure index, echocardiography, CT chest and abdomen for coronary and aortic calcification, liver fat, and subcutaneous and visceral fat measurements, and cardiac MRI. At 12-month intervals after the baseline clinic visit (Exam 1), participants have been contacted by telephone to update information, confirm vital statistics, document interim medical events, hospitalizations and functional status, and obtain additional sociocultural information. Questions about medical events, symptoms of cardiovascular disease and functional status are repeated annually. Ongoing cohort surveillance includes abstraction of medical records and death certificates for relevant International Classification of Diseases (ICD) codes and adjudication of nonfatal events and deaths. CMS data are currently being incorporated into the dataset. Note: Regarding date variables warehoused in the Jackson Heart Study (JHS) Cohort on dbGaP, the coordinating center has developed an algorithm that will systematically review and de-identify any of the (nearly 100) date-related variable types stored in the data package. To simultaneously minimize (i) de-identifiability of the data and (ii) impact on analyses utilizing sensitive data elements, a participant-level random number was generated to avoid the necessity of sharing any potentially sensitive data. The coordinating center maintains an archived linkage of these data in their raw form and regularly reviews ad hoc requests to utilize the raw data on a project-by-project basis. The JHS Cohort is utilized in the following dbGaP substudies. To view genotypes, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" section of this top-level study page phs000286 JHS Cohort. phs000402 ESP Heart GO JHS phs000498 JHS Allelic Spectrum Seq phs000499 JHS CARephs001069 MI Gen JHS phs001098 T2D GENES Exome Seq phs001356 Exome Chip phs002256 Cardiometabolic Renal Proteomics phs002369 Metabolomics Insulin Resistance

  Study phs000286

• Defining T cell States Associated with Response to Checkpoint Immunotherapy in Melanoma

  Checkpoint blockade therapy using antibodies targeting CTLA4, PD1 or PDL1 have changed the way cancer patients with advanced disease are being treated, as evident by their FDA approval in a wide variety of malignancies, and their ability to induce high response rates when compared to conventional therapies (e.g. chemotherapy). However, even in melanoma, despite the high response rate, most patients are refractory to therapy or acquire resistance in 10-12 months. To identify key immunological elements coupled with response or resistance to checkpoint immunotherapy, we performed an unbiased analysis on 16,291 CD45+ immune cells from 32 patients (48 samples) treated with checkpoint therapy (anti-PD1=37; anti-PD1/CTLA4=11), using single cell transcriptomics. Initial unsupervised clustering of all CD45+ cells identified 11 clusters. When examining the association of these clusters with clinical outcome, we found that two clusters (B-cells, p=0.005; memory T-cells, p=0.03) were significantly enriched in responder lesions while 4 clusters (monocytes/macrophages, p=0.003; dendritic cells, p=0.015; exhausted CD8+ T-cells, p=0.005; and exhausted/cell-cycle lymphocytes, 1.3x10-5) are enriched in non-responder lesions. Next, by leveraging our unbiased single cell approach, we identified not only clusters but also specific markers associated with either responder lesions (PLAC8, LTB, LY9, SELL, TCF7, IGKC and CCR7) or non-responder ones (CCL3, CD38, HAVCR2, ENTPD1 and WARS), many of which were not previously reported to be associated with clinical outcome to checkpoint therapy. Due to the importance of CD8+ T-cells in controlling tumors, the significant association of T-cell states with clinical outcome, and their high abundance in melanoma tumors, we next focused our analysis on CD8+ T-cells and identified 2 main clusters CD8_G (with increased expression of genes linked to memory) and CD8_B (enriched for genes linked to cell dysfunction), that were significantly enriched in responder (CD8_G, p=1.4x10-6) and non-responder (CD8_B, p=0.005) lesions, respectively. Since cells with both states coexist in each of the responder and non-responder lesions, we decided to calculate the ratio between the number of cells in these 2 clusters and observed a significant separation between responders (CD8_G/CD8_B>1) and non-responders (CD8_G/CD8_B<1) when looking at all samples, baseline or post samples separately. Similar results were detected when looking at the expression of a single transcription factor, TCF7, in CD8 T-cells in an independent cohort (n=43) using a simple immunofluorescence assay. Additionally, we validated the identity and function of some of the newly identified cell states as well as their epigenetic landscape, and found that cells expressing the inhibitory molecules CD39 and TIM3, on top of being enriched in non-responder lesions, are likely to play a crucial role in T-cell exhaustion in melanoma. Collectively, our study provides extensive unbiased data in human tumors for discovery of predictors and therapeutic targets to checkpoint immunotherapy.

  Study phs001680

• Angelman, Rett, Prader-Willi Syndrome Consortium (ARP) Rett Syndrome Natural History Protocol

  This observational study will involve the comprehensive assessment of the clinical features of Rett syndrome with this Rare Diseases Clinical Research Network. A clinical database of 1350 individuals with Rett syndrome including MECP2 mutation status for the purpose of elaborating phenotype-genotype correlations will be established. Eligible participants will be enrolled in the natural history study for 11 years from the 4 clinic sites currently involved with Rett syndrome (BCM, GGC, and UAB, CHB) as well as from the several thousand registrants in the International Rett Syndrome Foundation registry who will be invited to the nearest consortium site involved in Rett syndrome. Potential participants are expected to have had determination of their MECP2 mutation status, but will not be excluded should no mutation be present. All individuals who meet criteria and are currently receiving care from study sites will be invited to participate (N>600). Additional participants will be invited through the assistance of the International Rett Syndrome Foundation (IRSF). All individuals with RS registered with IRSF will be invited to participate in this study via the IRSF website and the IRSF newsletter. Potential participants will be apprised of the participating study sites and invited to contact one of the sites based on feasibility of travel. Inasmuch as the enrollment goal of 1350 participants is 40% of the current IRSF registry, we believe this will be a representative sampling. Bias can certainly occur based on travel requirements, level of interest, and other factors. However, inclusion of such a large sample should minimize sampling bias. No travel expenses will be covered, so it is likely that participants will be those with geographic proximity to Houston, Greenwood, Birmingham, or Boston. From the sample pool described above, the aim is to conduct the observational longitudinal (natural history) study on up to 1350 participants with classic Rett syndrome and variant forms of Rett syndrome, that is, participants who fully meet the established clinical criteria for Rett syndrome and those who meet some but not all of these criteria. All participants expressing MECP2 mutations irrespective of phenotype will be eligible for enrollment. For each of the eight common genetic mutations as well as those with large scale deletions, the prevalence of the following RS characteristics will be estimated for each age category and overall: seizure presence and frequency, ambulation status, scoliosis, ECG abnormality, breathing irregularities while awake, feeding difficulties, growth as measured in percentiles from NCHS standards curves, the presence of osteopenia as evidenced by bone fracture, and the presence of gallbladder disease. Both incidence and prevalence estimates will be made using a combination of data obtained at the regularly scheduled clinical visits and that obtained from the medical history. Incidence estimates will be calculated using time-to-event analyses (e.g., Kaplan-Meier survival curves) with appropriate calculations of standard errors and 95% confidence intervals. Cox proportional hazard regression models will be used to allow control for other factors, and t-tests will be calculated on the coefficients themselves. Appropriate transformations on explanatory variables will be used as deemed necessary in Cox models. Prevalence estimates will be calculated from estimates of proportions with exact confidence intervals. For a sample size of 275, the standard error of the estimate will not exceed 0.03 (3%) and for a sample size of 60, the standard error of the estimate will not exceed 0.06 (6%).

  Study phs000574

• Add Health: Longitudinal Study of a Nationally Representative Sample of Adolescents in Grades 7-12 in the United States during the 1994-95 School Year, Followed into Adulthood with Five Interviews/Surveys in 1995, 1996, 2001-02, 2008, and 2016-18

  The National Longitudinal Study of Adolescent to Adult Health [Add Health] is an ongoing longitudinal study of a nationally representative U.S. cohort of more than 20,000 adolescents in grades 7-12 (aged 12-19 years) in 1994 followed into adulthood with five interviews/surveys in 1995, 1996, 2001-02, 2008, and 2016-18. Add Health was designed to understand how social environments and behaviors in adolescence are linked to health and achievement outcomes in young adulthood. Add Health contains unprecedented environmental, behavioral, psychosocial, biological, and genetic data from early adolescence and into adulthood on a large, nationally representative cohort with unprecedented racial, ethnic, socioeconomic, and geographic diversity. Add Health has a large, multidisciplinary user base of over 50,000 researchers around the world who have published over 3,400 research articles. Add Health is housed at the Carolina Population Center of the University of North Carolina at Chapel Hill. Add Health datasets are distributed according to a tiered data disclosure plan designed to protect the data from the risk of direct and indirect disclosure of respondent identity. Add Health's large sample size, population diversity and rich longitudinal database of psychosocial, physical, and contextual data will permit investigation of an exceptionally broad range of phenotypes with known genetic variation. Prospective longitudinal measures are available to document change over time in each of these phenotypes, as well as change in the social environment and life experiences, making the Add Health sample ideal for understanding genetic linkages with health and behavior across the life course. The original design of Add Health included important features for understanding biological processes in health and developmental trajectories across the life course of young people, including an embedded genetic sample with more than 3,000 pairs of adolescents with varying biological resemblance (e.g., twins, full sibs, half sibs, and adolescents who grew up in the same household but have no biological relationship), testing of saliva and urine for sexually transmitted infections and HIV, and biomarkers of cardiovascular health, metabolic processes, immune function, renal function, and inflammation. Add Health therefore has critical objective indicators of health status and disease markers in young adulthood, well before chronic illness or its complications emerge in later adulthood. Because DNA has been collected on the full sample at Wave IV, it is possible to link genetic profiles with social, behavioral, and biological measures over time from adolescence into adulthood. Add Health sampled the multiple environments in which young people live their lives, including the family, peers, school, neighborhood, community, and relationship dyads, and provides independent and direct measurement of these environments over time. Add Health contains extensive longitudinal information on health-related behavior, including life histories of physical activity, involvement in risk behavior, substance use, sexual behavior, civic engagement, education, and multiple indicators of health status based on self-report (e.g., general health, chronic illness), direct measurement (e.g., overweight status and obesity), and biomarkers. No other data resource with this expanse of genotype and phenotype data on a large nationally representative longitudinal sample with race, ethnic, socioeconomic, and geographic diversity exists. A complete reference guide on study design and accomplishments can be found on the Add Health website: https://cdr.lib.unc.edu/concern/articles/6t053j27s.

  Study phs001367

• Privacy Notice for the Account User

  Privacy Notice for EGA User Account This Privacy Notice explains what personal data is collected by the specific service you are requesting, for what purposes, how it is processed, and how we keep it secure. Note that this service collects personal data directly provided by the user, and also collects personal data from users that is provided by other organisations. 1. Who controls your personal data and how to contact us? European Genome- Phenome Archive - EGA offers a service for permanent archiving and sharing of all types of personally identifiable genetic and phenotypic data resulting from biomedical research projects, jointly managed by European Molecular Biology Laboratory – European Bioinformatics Institute (EMBL-EBI) and Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG). EMBL-EBI and CRG represent joint Data Controllers’ of processing of your personal data. They and their Data protection officers may be contacted for data protection queries and for exercising your rights under Section 8. You may contact EMBL-EBI, represented by dr. Thomas Keane, by: email at: tk2@ebi.ac.uk or post at EMBL-EBI, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridgeshire, UK. EMBL’s Data Protection Officer may be contacted by: telephone at +49 6221 387-8590, email at dpo@embl.org, or post at EMBL Heidelberg, Data protection officer, Meyerhofstraße 1, 69117 Heidelberg, Germany. You may contact CRG, whose EGA team is represented by dr. Jordi Rambla de Argila, by: email at jordi.rambla@crg.eu, or post at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), Dr.Aiguader 88, PRBB Building, 08003 Barcelona, Spain. CRG Data protection officer may be contacted by: email at dpo@crg.eu post at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), C/ Dr. Aiguader, 88, PRBB Building, 08003 Barcelona, Spain. 2. Which is the lawful basis for processing personal data? We process your personal data on the grounds of important public interest. For monitoring your activities on the website, we process your personal data on the grounds of important public interest. Such legal basis is found in Article 5(1)(a) of EMBL Internal Policy No 68 on General Data Protection (hereinafter IP 68), which is equivalent to Article 6 (1)(e) of the EU General Data Protection Regulation (hereinafter GDPR) and upon which personal data are processed for the achievement of the aims laid down in 1973 agreement establishing EMBL, such as the promotion of the cooperation in the fundamental research, in the development of advanced instrumentation and in advanced teaching in molecular biology and dissemination of information. 3. What personal data is collected from users of the service? How do we use this personal data? We collect the following personal data from you: Name Email address Title/Position Organisation Organisational affiliation Username and password (to authenticate access to the system) IP Address (for anonymous usage statistics) We process your personal data: to provide you with the authenticated access to the EGA service (opening and managing submission and distribution account), to publicly publish some aggregate data to facilitate scientific research (e.g. number of accounts, geographic distribution), to better understand the needs of the users and to guide future improvements of the service, to create anonymous usage statistics. If you do not provide us with your personal data we will not be able to open the user account and offer you our services or we will only provide you a subset of functionalities available within the service. 4. Who will have access to your personal data? The personal data will be disclosed to: Authorised staff in the data controller’s institutions acting on data controller`s behalf and instructions (for all user account data), Requested dataset Data access committee – DAC will have access to the name, email, organization, affiliation, title/position of the distribution user account, using it for their own purpose of granting access to their datasets. 5. Will your personal data be transferred to third countries (i.e. countries not part of EU/EEA) and/or international organisations? Distribution user account data are in the process of granting access disclosed to dataset(s) DAC, which might be a recipient in countries outside of the European Economic Area. Insofar as the second joint controller may be subject to GDPR, data transfer to and from the first joint controller (EMBL-EBI) is necessary for important reasons of public interest embedded in the aims of the EMBL and justified in the Article 9(4) of IP 68 (equivalent to Article 49(1)(d) of GDPR) read in conjunction with EMBL`s 1973 establishing agreement and Article 179(2) of the Treaty on the Functioning of the European Union. 6. How long do we keep your personal data? All data are stored for as long as you have the account open. Thereafter the storage is prolonged for as long as our service is live, even if you stop using our services. This prolongation is necessary for further scientific research, to ensure legal compliance and security and to facilitate internal and external audits it they arise. By contrast, the log files for the data categories related to anonymous usage statistics (raw web service logs) are processed only for 30 days and thereafter erased. 7. The joint Data Controllers provide these rights regarding your personal data You have the right to: Not be subject to decisions based solely on an automated processing of data (i.e. without human intervention) without you having your views taken into consideration. Request at reasonable intervals and without excessive delay or expense, information about the personal data processed about you. Under your request we will inform you in writing about, for example, the origin of the personal data or the preservation period. Request information to understand data processing activities when the results of these activities are applied to you. It must be clarified that rights under points 4 and 5 are only available whenever you need support whilst using our website. For other processing based on the grounds of important public interest you cannot exercise your rights to object, rectify or erase your personal data according to the Article 13(2)(a)(b) of IP 68 (equivalent to Article 17(3)(b)(d) and Article 21(6) of the GDPR). 8. Supervisory authority If you wish to complain against the processing of your personal data, you may do so by post at: EMBL Heidelberg, Data Protection Committee, Meyerhofstraße 1, 69117 Heidelberg, Germany, or Autoritat Catalana de Protecció de Dades (Catalan Data Protection Authority), C/Rosselló 214, Esc A, 1r 1a, Barcelona 08008, Spain. Published at: February 6, 2019

  Documentation data-protection/privacy-notice/ega-user-account

• Implementation of the GDPR

  Data Protection 1 About the EGA The European Genome-phenome Archive (EGA) was formally launched in 2008 at the European Bioinformatics Institute (EMBL-EBI), an outstation of the European Molecular Biology Laboratory (EMBL), to address an identified need for archiving and sharing the results of genome-wide association studies from the Wellcome Trust Case Control Consortium. In late 2012, with the signing of a memorandum of understanding (and subsequent formal agreement in 2016) between EMBL-EBI and the Centre for Genomic Regulation (CRG), the EGA formally became a joint project of the two institutes. The two institutes work together to support the EGA services, including supporting submissions, web site, strategic leadership, and data infrastructure developments. 2 EMBL-EBI & GDPR The EGA is co-managed by EMBL-EBI and CRG. EMBL-EBI is an international organisation established by treaty and has certain privileges and immunities (e.g. exemptions from the application of national law) and also may self-regulate its activities (e.g. establish its own institutional legal framework) within the framework of its founding act of 1973. The General Data Protection Regulation (GDPR) is a European Union (EU) regulation that legislates how organisations can share and process personal data of EU citizens. EMBL places great value in maintaining collaboration with researchers who are subject to GDPR. For that reason, it is of utmost importance for EMBL to handle data received from those collaborators in a secure and responsible manner. Mindful of its public mandate and the sensitivity of the data it handles, EMBL has always ensured a high level of data protection in its activities. Since the introduction of GDPR in May 2018, EMBL has established its internal policy on General Data Protection (IP68), exercising its right to self-regulate its operations,., IP 68 establishes a robust personal data protection framework that provides for data protection principles, enforceable data subject rights and oversight and redress mechanisms offering a level of protection comparable with GDPR. 3 CRG & GDPR The Centre for Genomic Regulation (CRG) is an international biomedical research institute of excellence, created in July 2000 and mainly participated by the Catalan Government. It is a non-profit foundation and its mission is to discover and advance knowledge for the benefit of society, public health and economic prosperity. The CRG is a CERCA center. CERCA is the collective organisation for all research centres of excellence in Catalonia. CERCA ensures these centres develop successfully by promoting synergies and strategic cooperation improving their visibility and the impact of their research and promoting the dialogue amongst both public and private stakeholders. As a legal entity based in Spain and operating within the EU, the CRG ensures the compliance with the GDPR and the legal regulations on personal data protection applicable at the national level, as well as any other legislation that may replace, modify or supplement the above-mentioned in terms of personal data protection. 4 EGA & GDPR EGA GDPR Schema 4.1 Genetic and phenotypic data Within GDPR, there are two main actors: data controllers and data processors. Data controllers are persons or entities which determine the purposes and means that the personal data may be processed, e.g. companies, researchers, or universities. For EGA, the data controller is ultimately the data producer and the submitter(s) who submit the data to EGA. The data controller also creates a Data Access Committee (DAC) who will decide on data access permissions at EGA. Data processors are the persons or entities which process the data on behalf of a data controller. With regard to GDPR, EGA is a data processor as it processes data as instructed by the data controller. GDPR applies to any organisation which accesses personal data from an individual within the EU. Under GDPR, personal data is defined as any data that is identifiable, including names and email addresses as well as health-related and genetic data. EGA does not accept personally identifiable data except genetic and phenotypic data, so all other data submitted to EGA, such as names and addresses, must be pseudonymised. GDPR requires that data controllers implement data protection principles, such as data minimisation, to minimise the risk of data leakage, and protect the rights of the data subjects. As a data processor, EGA has a set of security policies that are followed to minimise the risk of unauthorised data access or data loss. In its role as a data processor, EGA requires all submitters to sign a Data Processing Agreement (DPA) when the submission account is first created. This agreement is only required to be signed once per submitter, and will remain valid for future submissions to EGA. 4.2 Other personal data The EGA also collects personal data as part of our interactions with submitters, data access committees, and researchers accessing data distributed by EGA. The below privacy notices explain what personal data is collected by the specific service you are requesting, for what purposes, how it is processed, and how we keep it secure. Privacy Notices for EGA Title Version Last Updated EGA Data Access Committee Account Privacy Notice for EGA Data Access Committee Account 1.0 February 6, 2019 EGA User Account Privacy Notice for EGA User Account 1.0 February 6, 2019 EGA Helpdesk Service Privacy Notice for EGA Helpdesk Service 1.0 February 6, 2019 EGA Website Service Privacy Notice for EGA Website Service 1.0 February 6, 2019 Documentation Title Version Description EGA Security Overview Security Document 1.1 The EGA Security Document provides an overview of EGA’s practices in ensuring the security of data stored at EGA. EGA Data Processing Agreement Data Processing Agreement 1.5 The Data Processing Agreement must be completed and returned as part of the submission process. Please note that this document is non-negotiable. Authorised Submitters Authorised Submitters Formulary 1.0 The Authorised Submitters Form must be completed and returned as part of the submission process. Please list all those that should have access to the submission account in order to submit to the EGA should be detailed here. Dispute Resolution Any controversy or claim arising out of, or relating to, the DPA (including the enforceability or breach thereof, any question regarding its existence, validity or termination) or relating to the EGA Service shall be resolved using the internal dispute resolution mechanisms of EGA including those related to Data Protection. The EGA’s internal dispute resolution mechanism has the following procedure: EGA OPERATIONAL PHASE: Meetings between EGA staff and the Data Controller.LEGAL MANAGEMENT PHASE: Meetings between legal teams of EMBL, CRG and the Data Controller. DIRECTION MANAGEMENT PHASE: Negotiation between the legal representatives of EMBL, the CRG and the Data Controller. If the internal dispute resolution mechanism doesn’t resolve the controversy or claim the next phase is:ARBITRATION PHASE: Resolution by arbitration under the WIPO Expedited Arbitration Rules (“Rules”).

  Documentation about/privacy-notice

• The UCSD / O'Connor "TSP" (Twin/Sibling/Pedigree) Resource in Hypertension

  Study Design: The UCSD / O'Connor "TSP" (Twin/Sibling/Pedigree) Resource in Hypertension contains N=797 participants. At the time of recruitment individuals ranged from 15-84 years of age and had varying ethnic backgrounds (Whites, African-Americans and Hispanics). The cohort was developed to study the genetic basis of autonomic dysfunction in human essential hypertension (reviewed in Zhang et al. Curr Hypertens Rep. 2011 13: 36-45. PMID: 21104344) and contains cross-sectionally collected phenotypes related to blood pressure regulation.  Phenotypes: Phenotype data specifically focuses on the sympathetic branch of the autonomic system, which is a key regulator of blood pressure. Data includes circulating concentrations of the secretory "quantum" (catecholamines, neuropeptides, chromogranins) which influence vascular responses to sympatho-adrenal activation resulting in blood pressure. Other measures on the twins and a subset of family members include a standard urine panel with absolute concentrations of potassium, sodium, uric acid, phosphorous; DynaPulse acquired heart rate and blood pressure measures including systolic and diastolic blood pressure, mean arterial pressure, heart rate, Left Ventricular (LV) ejection time, LV contractility, cardiac output, stroke volume data including; and absolute concentrations of plasma aldosterone, endothelin, leptin, and insulin. Phenotype data is included for the 697 individuals sequenced here and 100 family members.  Whole Genome Sequence Data Generation: Whole genome sequencing (20X coverage) was conducted on plasma-derived DNA. The WGS was generated using the Illumina HiSeq X Ten sequencing platform with variants called by Human Longevity, Inc (HLI; Ref 1). Preparation of sample libraries was conducted by mechanical shearing of gDNA (100-800 bp), isolation of DNA fragments 300-500bp in size, followed by library PCR amplification employing high-fidelity, low-bias PCR to amplify library fragments consisting of appropriate adapter sequences on both ends. BAM files were created by alignment of sequence reads to the reference genome (GRCh38) using iSAAC-01.14.02.06 (Python2.7). Note: The user may want to realign the sequence data and recall variants. In total, the WGS dataset contains 30 monozygotic twin pairs represented by one member of the twin pair, 133 monozygotic twin pairs with both individuals sequenced, 7 dizygotic twin pairs represented by one member of the twin pair, 67 dizygotic twin pairs with both individuals sequenced, 8 twin pairs with undetermined zygosity (both individuals sequenced) and 1 triplet with mother (all individuals sequenced). The dataset also contains sequences of 260 family members of twins including their mother, father, non-twin sibling, and offspring. Table 1 describes the composition of families ("sibling" refers to a non-twin sibling in the cohort). Note: We suggest users check gender and family relatedness. Table 1: Description of the families with sequence data                                                                                                               Units with:Twin PairsTwin (no pairs)No twinSibshipsMother and Father511Mother only1222Father only113One or more siblings22133Mother and siblings132Father and siblings(s)211Offspring of twins11Non twin siblings2Sib with unknown relative1Only one member of8The UCSD/O'Connor "TSP" (Twin/Sibling/Pedigree) Resource in Hypertension is now being managed at the UCSD School of Medicine's Institute for Genomic Medicine (IGM). The TSP Resource has collected a wide range of information (phenotypic, genotypic, demographic, metabolomic) and reagents (blood, plasma, urine, DNA, human induced pluripotent stem cells). For additional information about the resource, including other data types available as well as references and links to data from studies with previous collaborators, please go to the resource website at IGM [http://igm.ucsd.edu/research/twins-resource.shtml] or contact Dr. Brinda Rana at UCSD [bkrana@ucsd.edu]. 

  Study phs002230

• How to use EGA Webin?

  EGA Webin EGA Webin serves as a platform for registering metadata for array based submissions, large scale sequence submission as well as for legacy EGA submission accounts (ega-box-XXXX). For large scale submitters of sequence data you have also the option to submit metadata via XMLS programmatic submission, while new submitters are advised to utilise the Submitter Portal for their submissions. You can request a legacy EGA submission account (ega-box-XXXX) by populating this form. Please, allow two business days for our Helpdesk team to contact you after populating this form. WEBIN actions: Register metadata for a sequence submission Register study, samples, experiments, runs, DAC, policy and dataset/s after file upload. Register components for your array-based metadata submission Register study, samples, DAC or policy before uploading files. Edit existing submission metadata Change or update previously submitted metadata. Register metadata for a sequence submission Ensure that all sequence files have been encrypted before uploading them to your submission account using the EgaCryptor. Go to the EGA Webin and log in using your submission account name (ega-box-XXX) and password. Register components of your metadata submission Study Samples Data Access Committee (DAC) Data access policy Dataset For array-base submissions: Study, Samples, Data Access Committee (DAC) and Data access policy may all be registered BEFORE file upload and dataset registration through the array-base template. Register your Study Go to the “Studies (Projects)” box Click on “Register Study” and fill in the information related to your study. Click on “Submit”, this will save the information and generate an EGA study ID. To use the study accession number in a publication, the study has to be previously released on the EGA website, we suggest the following format: "Sequence data has been deposited at the European Genome-phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGASXXXXXXXXXXX.Further information about EGA can be found on https://ega-archive.org and “The European Genome-phenome Archive in 202 "(10.1093/nar/gkab1059)" Register your Samples Go to the “Samples” box Click on “Register Samples” Select “Download spreadsheet to register samples” and customise your template, there is a default EGA template (EGA default checklist) but more attributes can be added if required. For the EGA default checklist, there are mandatory,recommended and optional attributes. As well custom fields which can be added if required. Mandatory attributes Field Name Description tax_id Taxonomy ID of the organism as in the NCBI Taxonomy database. Entries in the NCBI Taxonomy database have integer taxon IDs. See our tips for sample taxonomy here scientific_name Scientific name of the organism as in the NCBI Taxonomy database. Scientific names typically follow the binomial nomenclature. For example, the scientific name for humans is Homo sapiens. sample_alias Unique name of the sample. If not selected system will auto generate an unique alias sample_title Title of the sample sample_description Description of the sample phenotype *** Where possible, please use the Experimental Factor Ontology (EFO) to describe your phenotypes. Recommended attributes Field Name Description subject_id Identifier for the subject where the sample has been derived from gender * Sex Optional attributes Field Name Description sex sex of the organism from which the sample was obtained disease_site Affected organ sample type Affected organ donor_id ** Identifier of the donor where the sample has been derived from *Gender should be described as 'male', 'female' or 'unknown'. If 'unknown' due to a known sex chromosome aneuploidy, please create a user defined attribute called 'Sex chromosome karyotype' and add the appropriate value, for example, 'XXY'. **Donor id (Subject id) should be a de-identified subject handle. If unknown, please add 'unknown' to the field. ***Phenotypes should, where possible, be an Experimental Factor Ontology accession. If a term cannot be found to describe your phenotype please use free text. All sample phenotypes considered important for further analysis of the data should be provided (for example, tumour type), additional phenotype attributes can be created by defining your own attributes; use the notion 'phenotype2', 'phenotype3', etc. After you have customised the fields for the sample submission, download the template and fill in the information. Example of the sample template: Finally upload the sample template to get the EGA accession IDs for the samples. Register your Data Access Committee (DAC) Further information on the role of your DAC Go to the “Data Access” box Click on “Register Dacs” Input the information about the DAC and register at least one main DAC contact. Register your Data Access Policy Your Data Access Policy provides the terms and conditions of data use, this is also referred to as the Data Access Agreement (DAA). Completion of a DAA by the applicant/s should form part of the application process to the Data Access Committee (DAC). Go to the “Data Access” box Click on “Register Policies” Select the DAC to which this policy will be linked to and fill in the policy information. Submitting your Runs and Analyses This section is only for sequence data submission, for array-based submission it can be skipped. Please refer to our Submitting array based metadata Runs Registration Go to the “Raw Reads (Experiments and Runs)” box Click on “Submit Reads” Select “Download spreadsheet template for Read submission” Select the template corresponding to your submission type For the templates you have the option to customise the optional fields. To check their description click on “Show Description “ Download the template and fill in the required information. Example of the runs template: We recommend that Fastq, BAM, and CRAM read files are submitted using Webin-CLI When using this interface instead of Webin-CLI, raw sequences must be uploaded in one of the supported data formats before they can be submitted. The files can be uploaded using FTP or Aspera. The study and the sequenced samples must be pre-registered before the raw reads are submitted. Please note that each individual study and sample should be registered only once. You will be asked to provide information about the sequencing libraries and instruments. Submitting your Dataset This section is only for sequence data submissions, for array based submissions it can be skipped. Please refer to our Submitting array based metadata The dataset describes the data files, defined by the run (EGARXXXXXXXXXXX) and analysis (EGAZXXXXXXXXXXX) accessions that make up the dataset and links the collection of data files to a specified Data Access Committee and Data Access Policy. As a result, you must have registered your Reads and experiments, Data Access Committee (DAC) and Data access policy before submitting your Dataset. Please consider the number of datasets that your submission consists of, for example, a case control study is likely to consist of at least two datasets. In addition, we suggest that multiple datasets should be described for studies using the same samples but different sequence technologies. Please contact EGA Helpdesk for further assistance. Go to the “Data Access” box Click on “Register Dataset” Select the Data Access Committee (DAC) and Data access policy Register your dataset After submitting your dataset you should contact the EGA Helpdesk to provide a release date for your dataset. Datasets are automatically held (i.e. not released) unless they are affiliated to a study that has already been released. Edit/update existing submission metadata Go to the “Report” section of the object you would like to edit. Locate the object and click on the arrow under action. An option menu will be displayed. Objects can be edited through their XML or with the WEBIN menu. After an object has been edited, changes would be available on the website until the submission is released again. Please contact the EGA Helpdesk if you require further assistance.

  Documentation submission/metadata/submission/EGA_webin

• NHLBI Family Heart Study (FamHS-Visit1 and FamHS-Visit2)

  The Family Heart Study (FamHS) was funded by the National Heart, Lung, and Blood Institute (NHLBI). It was begun in 1992 with the ascertainment of 1,200 families, half randomly sampled, and half selected because of an excess of coronary heart disease (CHD) or risk factor abnormalities as compared with age- and sex-specific population rates (Higgins et al. 1996). The families, with approximately 6,000 individuals, were sampled on the basis of information on probands from four population-based parent studies: the Framingham Heart Study, the Utah Family Tree Study, and two Atherosclerosis Risk in Communities (ARIC) centers (Minneapolis, and Forsyth County, NC). A broad range of phenotypes were assessed at a clinic examination in broad domains of CHD, atherosclerosis, cardiac and vascular function, inflammation and hemostasis, lipids and lipoproteins, blood pressure, diabetes and insulin resistance, pulmonary function, and anthropometry (FamHS Visit 1). Approximately 8 years later, study participants belonging to the largest pedigrees were invited for a second clinical exam (FamHS Visit 2). A total of 2,756 Caucasian subjects in 508 extended families were examined. A two-phase design was adopted for the genome wide association (GWA) study. In phase-1, 1007 subjects were chosen, equally distributed between the upper and lower quartile of age- and sex-adjusted values for coronary artery calcification, assessed by CT scan in Visit 2. These subjects were chosen to be largely unrelated; 34% of the subjects were from unique families, while 200 other subjects had 1 or more siblings selected into the sample, yielding a sample of 465 unrelated subjects. The remaining family members (N=1749) were genotyped in the phase-2 for replication of the top hits from the phase-1. The results presented here represent those for the analysis of the phase-1 case-control sample for variables assessed in FamHS Visit 1 (from 1992 to 1995) and for the variables assessed in FamHS Visit 2 (from 2002 to 2003). All subjects were typed on the Illumina HumMap 550 chip (Phase 1 genotype). Of these, 33 (3.3%) were excluded due to technical errors, call rates below 98%, and discrepancies between reported sex and sex-diagnostic markers. The final sample of 974 subjects have Visit 2 phenotypes, approximately 100 of these do not have Visit 1 phenotypes. There was no significant plate-to-plate variation in allele frequencies. The covariate adjustments were performed separately by sex using cubic polynomial age and clinical centers, and retaining the terms in the stepwise regression analysis that were significant at the 5% level. Extreme outliers (>4 SD from the mean) were set aside, temporarily, for the adjustments. The final phenotypes were computed for all individuals using the best mean regression models and standardizing to 0 mean and unit variance. The FamHS has contributed GWA results in many phenotype domains (antropometric and adiposity, atherosclerosis and coronary heart disease, lipid profile, diabetes and glicemic traits, metabolic syndrome etc) to meta-analyses and various consortia, including Heard-Costa et al. 2009, Köttgen et al. 2010, Teslovich et al. 2010, Nettleton et al. 2010, Lango et al. 2010, Heid et al. 2010, Speliotes et al. 2010, Dupuis et al. 2010, Kraja et al. 2011.

  Study phs000221

• All you need to know about our new DAC Portal

  With the DAC Portal, it is possible to streamline the process of managing access to sensitive data, ensuring that researchers have the necessary resources to advance scientific discovery while maintaining the highest standards of data protection and privacy. We know that, as a new tool, its first use can be complex. For this reason, in this article we will try to show all the elements of interest. Enjoy! Credentials: who needs to create a new user to access the DAC Portal and who doesn't? Only new users (since September the 12th) need to create an EGA account to access the DAC Portal. The EGA team went one step ahead by creating EGA accounts for former DAC members to login to the DAC Portal. These accounts are linked to the personal email used in the DAC structure: To check the linked email, DAC members can paste the DAC ID right after this link: https://metadata.ega-archive.org/dacs/ (e.g. https://metadata.ega-archive.org/dacs/EGAC00001002543) In case of password oblivion, it is possible to set a new one. All the process is channelled through the personal email. Some DAC members may be interested in updating the DAC email. This action can be done contacting our Helpdesk team. For the correct functioning of the DAC Portal, users must add the missing information of the DAC Profile. For a deeper dive, check out our documentation. The first step: knowing your workspace on the Portal Once logged in to the platform using the EGA User credentials, note the sections available: DACs and Policies. In the first one it is possible to check all user's registered DACs by default. It provides a comprehensive overview of each DAC, including its EGA accessions (EGAC), title, status, and the number of data access requests associated with each DAC. Whereas the Policies section is where users can manage and view all their registered policies, along with their associated EGA accessions, links, and titles. A drop-down menu is available with shortcuts to the most useful pages in the top right corner. It is possible to check DACs and policies, as well as creating new ones. In this menu, users can also contact the Helpdesk team using the “Need Help?” section to make inquiries about DACs and policies. Comprehending the DACs list & making the most of all the features Colours are crucial in the DAC's section as they will indicate the user role and the status in every committee, namely: Yellow: you are the administrator of the DAC and have full control to add other contacts, modify the content, and manage data access requests. Orange: you are a member of the DAC and have the authority to manage data access requests but cannot make any changes to the content. Blue: you have been invited to join the DAC and need to either accept or decline the invitation. Grey: the DAC is currently pending validation by the EGA Helpdesk team. Red: the DAC has been declined by the EGA Helpdesk team. Discover more information on how to view the message from Helpdesk containing the declination reason or how to validate or reject a DAC invitation by taking the tour of the DAC Portal. How to create, register and edit a DAC Creating a DAC is an easy process that only requires users to complete the necessary information. After that, the EGA Helpdesk team will review the proposal and validate the proposal. Once the DAC is validated it is possible for authorised users with admin role to edit it at any time, ensuring that all information and contacts associated with the committee is accurate and up to date. Membership management is controlled by searching for the EGA user looking for their username, email, or organisation. Please, note that for a person's details to appear in this search engine, they must have registered as a EGA user. Data Access Committee administrators manage two types of permissions that apply to contacts: Main contact and Role. Both can be modified at any time: Main contact refers to the primary person we firstly contact for any inquiry about the DAC (please, note that we can contact all DAC members, and this refers to the person we will contact first). Role defines the actions that can be taken by each contact. There are two possible status, admin and member, details of which can be found in the Take the Tour. Keep in mind that, to save the modifications, it is always necessary to click on “Update”. Moreover, it is also possible to delete any contact in a DAC whenever it is needed. The data request process: how to manage access requests The data request process is now channelled through the EGA website. Once a user sends a request access, the petition will go directly to the DAC Portal profile of the DAC members liked to the requested dataset. Whenever a request is received, a sand clock symbol will be displayed next to the DAC responsible for the dataset involved. By clicking on the DAC, it is possible to discover more information about requester(s). In this section, DAC Portal users will also be able to modify the display of the data access requests. It is possible to group requests by dataset accession or username, depending on the user preferences. Additionally, it is possible to isolate specific requests by user or dataset. To accept a request, users must slide the button to the right. Once the button turns green, it signifies that the request is accepted; the requester will be granted access to the requested dataset. To make lives easier, we have implemented a “Select all” button to easily accept or revoke multiple requests at once. To decline requests, it is necessary to slide the button to the left. A red button means the requester will not be granted access to the dataset. The DAC Portal will always ask to submit the reason why the data access was denied. Please, note that any decision, grant or denial, must be confirmed clicking the "Apply" button. This will update the status of the request and notify the requester accordingly. Taking control of the activity in the DAC Portal: checking the requests history The History button is a useful feature that allows users to access a list of all the requests that have been granted. This is especially useful for auditing purposes, as it enables to keep track of who has been granted access to the data and when. To facilitate control for those users with several requests we have included a filtering option. It allows to filter requests by user, mail, dataset, EGA ID, and date (these are combinable to boost the search). Don't forget about policies: creation, management, and update Similarly to the DACs section, in the Policies one users can manage and view all their registered policies. By clicking on any policy, it is possible to view its details as well as making any necessary updates or modifications. The sheets symbol and its adjacent number indicate the quantity of objects using a policy. By clicking in the location symbol users will go directly to the DAC page on the DAC Portal to see more information about that DAC. DAC Portal users can create new policies. The first step requires to link the policy to a registered DAC. After defining the title, users can either add a link to an external URL containing terms & conditions or write the policy content directly on the DAC Portal. Keep in mind that both options can be included. Data Use Ontology (DUO) codes can be added to new policies. These codes are used to specify the permitted and prohibited uses of the data. Please, note that some of them require a modifier to provide additional specificity. Find out more by checking out this specific content on the DAC Portal Tour. Policies can be modified at any given time by clicking on one registered policy, which will display the current information.

  Blog new-dac-portal

• Best Practices for DACs

  Best Practices Data access committees (DACs) are institutional safeguards responsible for ensuring a balance between data protection and accessibility. However, there are no procedural standards that apply across DACs, which can lead to inconsistencies in their reviews and compromise their quality and effectiveness. Standardising DAC processes can foster trust and mutual recognition, paving the way for greater coordination, collaboration, and delegation between DACs and other oversight bodies to improve the efficiency of data access without sacrificing protection. To provide guidance, the following are suggestions for actions a DAC might take upon receiving a data access request: Aim to respond to all initial requests in less than 2 weeks. Failure to do so may result in follow-up emails from the EGA, journals, and ultimately dataset withdrawal. First, check that the data/EGAD number is consistent with your data submission. In other words, ensure that the requester has contacted the correct DAC. Verify that the user will be using the data within the terms of consent by asking them to sign up to the terms within the DAA. Ensure that data users who are granted access to the data comply with the terms of a Data Access Agreement (DAA) and to use the data only in approved ways. Look for an institutional email address for the requester. Search for evidence that the requester is "appropriately qualified/bona fide" for using the data, for example on PubMed, Research Gate, LinkedIn, etc. Confirm that the affiliated organisation is real and that the requester still works there. Inquire with the requester about who should have accounts created at the EGA under the terms of the agreement. If a negative decision is made, promptly communicate it to the requester and support it with the terms of the Data Access Policy that the requester has not met or cannot meet. Keep the information in the DAC up to date. If you leave your institution and are unable to manage data access requests on their behalf, you should add your replacement as a new contact in the DAC. Assist with data access requests for any further questions related to your data. The EGA can only check information that has been deposited in the repository. If the user has a specific question that the EGA cannot answer, we will redirect the user to the DAC. All the EGA studies and datasets referenced in a publication under your DAC must be publicly searchable on the EGA website before the paper is released. If possible, describe the permitted purposes for subsequent research projects, including associated limits and conditions, for all resources hosted in a repository using a common ontology, such as the GA4GH Data Use Ontology (DUO). It is considered best practice to try and release data only to those with an institutional email address. This gives reassurance to the EGA, research participants, and the general public that an appropriate individual is accessing and using the data. To prevent potential data breaches and ensure adherence to GDPR regulations, it is essential that the European Genome-Phenome Archive (EGA) is informed via the Helpdesk team of any changes to the Data Access Committee (DAC). This should be done in addition to any changes being made on the DAC portal. Data Controllers (as per the definition in the DPA) are also responsible for notifying the previous DAC of any modifications. Without proper notification, changes might not be automatically updated in our system, leading to the risk of incorrect permissions being applied and potential data access issues. Therefore, it is imperative that all Data Controllers follow this protocol to maintain data integrity and security.

  Documentation access/data-access-committee/best-practices

• Framingham Cohort

  Startup of Framingham Heart Study. Cardiovascular disease (CVD) is the leading cause of death and serious illness in the United States. In 1948, the Framingham Heart Study (FHS) -- under the direction of the National Heart Institute (now known as the National Heart, Lung, and Blood Institute, NHLBI) -- embarked on a novel and ambitious project in health research. At the time, little was known about the general causes of heart disease and stroke, but the death rates for CVD had been increasing steadily since the beginning of the century and had become an American epidemic. The objective of the FHS was to identify the common factors or characteristics that contribute to CVD by following its development over a long period of time in a large group of participants who had not yet developed overt symptoms of CVD or suffered a heart attack or stroke. Design of Framingham Heart Study. In 1948, the researchers recruited 5,209 men and women between the ages of 30 and 62 from the town of Framingham, Massachusetts, and began the first round of extensive physical examinations and lifestyle interviews that they would later analyze for common patterns related to CVD development. Since 1948, the subjects have returned to the study every two years for an examination consisting of a detailed medical history, physical examination, and laboratory tests, and in 1971, the study enrolled a second-generation cohort -- 5,124 of the original participants' adult children and their spouses -- to participate in similar examinations. The second examination of the Offspring cohort occurred eight years after the first examination, and subsequent examinations have occurred approximately every four years thereafter. In April 2002 the Study entered a new phase: the enrollment of a third generation of participants, the grandchildren of the original cohort. The first examination of the Third Generation Study was completed in July 2005 and involved 4,095 participants. Thus, the FHS has evolved into a prospective, community-based, three generation family study. The FHS is a joint project of the National Heart, Lung and Blood Institute and Boston University. Research Areas in the Framingham Heart Study. Over the years, careful monitoring of the FHS population has led to the identification of the major CVD risk factors -- high blood pressure, high blood cholesterol, smoking, obesity, diabetes, and physical inactivity -- as well as a great deal of valuable information on the effects of related factors such as blood triglyceride and HDL cholesterol levels, age, gender, and psychosocial issues. Risk factors have been identified for the major components of CVD, including coronary heart disease, stroke, intermittent claudication, and heart failure. It is also clear from research in the FHS and other studies that substantial subclinical vascular disease occurs in the blood vessels, heart and brain that precedes clinical CVD. With recent advances in technology, the FHS has enhanced its research capabilities and capitalized on its inherent resources by the conduct of high resolution imaging to detect and quantify subclinical vascular disease in the major blood vessels, heart and brain. These studies have included ultrasound studies of the heart (echocardiography) and carotid arteries, computed tomography studies of the heart and aorta, and magnetic resonance imaging studies of the brain, heart, and aorta. Although the Framingham cohort is primarily white, the importance of the major CVD risk factors identified in this group have been shown in other studies to apply almost universally among racial and ethnic groups, even though the patterns of distribution may vary from group to group. In the past half century, the Study has produced approximately 1,200 articles in leading medical journals. The concept of CVD risk factors has become an integral part of the modern medical curriculum and has led to the development of effective treatment and preventive strategies in clinical practice. In addition to research studies focused on risk factors, subclinical CVD and clinically apparent CVD, Framingham investigators have also collaborated with leading researchers from around the country and throughout the world on projects involving some of the major chronic illnesses in men and women, including dementia, osteoporosis and arthritis, nutritional deficiencies, eye diseases, hearing disorders, and chronic obstructive lung diseases. Genetic Research in the Framingham Heart Study. While pursuing the Study's established research goals, the NHLBI and the Framingham investigators has expanded its research mission into the study of genetic factors underlying CVD and other disorders. Over the past two decades, DNA has been collected from blood samples and from immortalized cell lines obtained from Original Cohort participants, members of the Offspring Cohort and the Third Generation Cohort. Several large-scale genotyping projects have been conducted in the past decade. Genome-wide linkage analysis has been conducted using genotypes of approximately 400 microsatellite markers that have been completed in over 9,300 subjects in all three generations. Analyses using microsatellite markers completed in the original cohort and offspring cohorts have resulted in over 100 publications, including many publications from the Genetics Analysis Workshop 13. Several other recent collaborative projects have completed thousands of SNP genotypes for candidate gene regions in subsets of FHS subjects with available DNA. These projects include the Cardiogenomics Program of the NHLBI's Programs for Genomics Applications, the genotyping of ~3000 SNPs in inflammation genes, and the completion of a genome-wide scan of 100,000 SNPs using the Affymetrix 100K Genechip. Framingham Cohort Phenotype Data. The phenotype database contains a vast array of phenotype information available in all three generations. These will include the quantitative measures of the major risk factors such as systolic blood pressure, total and HDL cholesterol, fasting glucose, and cigarette use, as well as anthropomorphic measures such as body mass index, biomarkers such as fibrinogen and CRP, and electrocardiography measures such as the QT interval. Many of these measures have been collected repeatedly in the original and offspring cohorts. Also included in the SHARe database will be an array of recently collected biomarkers, subclinical disease imaging measures, clinical CVD outcomes as well as an array of ancillary studies. The phenotype data is located here in the top-level study phs000007 Framingham Cohort. To view the phenotype variables collected from the Framingham Cohort, please click on the "Variables" tab above. The Framingham Cohort is utilized in the following dbGaP substudies. To view genotypes, analysis, expression data, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" section of this top-level study page phs000007 Framingham Cohort. phs000342 Framingham SHARe phs000282 Framingham CARe phs000363 Framingham SABRe phs000307 Framingham Medical Resequencing phs000401 Framingham ESP Heart-GO phs000651 Framingham CHARGE-S phs000724 Framingham DNA Methylation phs001610 Framingham T2D-GENES phs002558 Framingham ADSP phs002559 Framingham BRIDGET phs002560 Framingham Cholesterol phs002611 Framingham Post-Mortem Brain Tissue phs002938 Framingham Molecular QTL The unflagging commitment of the research participants in the NHLBI FHS has made more than a half century of research success possible. For decades, the FHS has made its data and DNA widely available to qualified investigators throughout the world through the Limited Access Datasets and the FHS DNA Committee, and the SHARe database will continue that tradition by allowing access to qualified investigators who agree to the requirements of data access. With the SHARe database, we continue with an ambitious research agenda and look forward to new discoveries in the decades to come.

  Study phs000007

• Security Overview

  Security Overview The European Genome-phenome Archive (EGA) houses consented human data under controlled access. Access decisions are handled by the relevant Data Access Committee (DAC), which autonomously manages requests through the DAC Portal. This document provides an overview of EGA’s practices in ensuring the security of data stored at EGA. As security is a prime concern of the EGA, the EGA is a member of the Global Alliance for Genomics and Health (GA4GH) Data Security work stream. The EGA contributes and helps develop the recommendations outlined the GA4GH Security Technology Infrastructure document, which defines guidelines, best practices, and standards for building and operating an infrastructure that promotes responsible data sharing in accordance with the GA4GH Privacy and Security Policy. Explore the EGA dataflow to gain deeper insights! Accessing data in the EGA involves several steps. First, users need to create an EGA account. Once logged in, they can request access to data controlled by a DAC through the EGA website (see documentation). The DAC oversees these requests through the DAC Portal, and if approved, grants the necessary permissions to the user's EGA account, allowing them to access and download all relevant data and metadata for the requested dataset(s). The key points of EGA security strategy are: 1 Regular Risk Assessment The EGA regularly identifies and assesses risk related to the following: Breach of confidentiality,Breach of privacy or autonomy,Malicious or accidental corruption or destruction of data archived at EGA,Disruption of services provided by the EGA. 2 Risk mitigation The EGA implements and maintains safeguards to minimise the risks identified above in accordance with the 6 control objectives listed in Appendix 1 and outlined in the GA4GH Security and Infrastructure document.If a breach is discovered, the EGA applies a defined protocol to minimise damage. 3 Identity and authorisation management The EGA authenticates the identity of individuals or software accessing controlled access data held at the EGA.The EGA ensures an appropriate level of assurance (LoA) is applied to the identity consistent with the risk associated with that individual, such as multi-factor authentication for DACs.The EGA provides the minimum access rights and privileges consistent with the user’s identity, allowing access consistent with the GA4GH Privacy and Security Policy, as determined by the appropriate DAC. 4 Audit Logs The EGA maintains a set of logs recording: Changes to user access rights,Data access requests,Resource usage. 5 Cryptography, communication security, and data integrity The EGA ensures data transmission integrity using a hash function.All data transmitted to or from the EGA is end-to-end encrypted.All data at EGA is stored using strong encryption.Encryption keys are not stored in the same system as the encrypted data.All data archived at EGA must be accompanied by a signed submission statement ensuring appropriate consent or ethical approval has been obtained, and is in accordance with all applicable laws and regulations. The EGA has a defined protocol defining the response in the event of a security breach, and is continuing to work with the GA4GH Data Security Work Stream to help define best practice and associated standards for breach responses. Appendix 1 GA4GH Control Objectives Control Objective 1: Implement technology safeguards to minimise the risk of unauthorised access, use, or disclosure of confidential and private data.Control Objective 2: Implement technology safeguards to minimise the risk of discovery, access, and use of individuals’ clinical and genomic data, and individual identities, other than as authorised by applicable jurisdictional law, institutional policy, and individual consents.Control Objective 3: Implement technology safeguards to minimise the risk of accidental or malicious corruption or destruction of data.Control Objective 4: Implement technology safeguards to minimise the risk of disruption, degradation, and interruption of services enabling access to data.Control Objective 5: Implement technology safeguards to minimise the risk of potential security attacks and misuse of authorised accesses and privileges.Control Objective 6: Implement technology safeguards to promptly detect the failure to attain the above control objectives and to respond with proper countermeasures.Appendix 2Refer to the document below to learn more about EGA long-term data preservation policy and procedures at EMBL-EBI.Long-term data preservation

  Documentation about/security

• Cincinnati Children's Hospital Medical Center (CCHMC) - eMERGE Phase IIIA Data

  This submission includes genotyping or sequencing data from separate cohorts, each is described in separate paragraphs below. Extreme early onset obesity Obesity is a serious epidemic condition and on the rise in the United States. Today, nearly one out of three children is overweight or obese in this country. According to the Center for Disease Control, 35.7% of American adults and 17% of American children are obese. The medical costs associated with obesity are estimated to be in the billions. Without a doubt, interplay of additive genetic effects and common environmental effects influence this complex disease. However, despite being exposed to so-called "obesogenic environment", a large proportion of the population remains of normal weight. These observations suggest that innate, non-environmental, factors make some individuals more susceptible to obesity providing support for biological mechanisms, and thus genetic factors, to underlie the individual's response to the obesogenic environment. In young children with severe obesity the relative role of genetics and in utero programming are likely to outweigh the short duration of environmental and lifestyle exposures. This group is therefore an ideal one to study as they are likely enriched for variants that influence the risk of developing obesity. The purpose of this project is to further study and understand obesity in childhood and to develop a repository of samples for future studies into obesity. Eosinophilic Esophagitis (EoE) Eosinophilic Esophagitis (EoE) is one of the manifestations of eosinophilic gastrointestinal inflammation which have profound effects on a patient's health and development. Results of epidemiologic studies performed through our center demonstrate that eosinophil-associated gastrointestinal disease is not an uncommon entity. While the epidemiology of eosinophilic esophagitis has not been thoroughly studied until recently, there appears to be a significant increase in the diagnosis of EoE in the last decade. Based on our research, this mainly reflects increased disease recognition, but there is also a bona-fide increase in disease incidence which coincides with the increasing incidence of asthma and allergic diseases in the industrialized world. In addition, many patients with intractable symptoms thought in the past to represent atypical GERD or other disorders are now being recognized as having EoE. Diagnosis of EoE requires endoscopy and biopsies to document the characteristic histologic findings of esophageal eosinophilia. In general, this study proposed to elucidate the mechanisms underlying eosinophil growth, survival, migration, and function, and to investigate and further characterize the pathophysiology of, clinical manifestations of, and spectrum of disease severity of eosinophilic esophagitis in humans. The de-identified genotyping and genome wide association data generated as part of this research will be used for further genome research. Familial Sample Repository (FSR) and Directed Sample Repository (DSR) De novo mutations could cause many diseases, which has been demonstrated in mental retardation, autism and many rare genetic disorders. Family-based studies have a variety of advantages over case/control studies, including the elimination of analysis artifacts related to population stratification, the detection of genes that act through a recessive mechanism of inheritance and validation that the trait is not transmitted from a parent, something not possible using a case/control design. Additionally, DNA from families can be used to identify de novo mutations suggesting strong candidate causal polymorphisms. For this project, samples will be collected from families on an on-going basis. Families may be recruited because the patient either has a disease which is thought to be of genetic origin or from the general patient population to serve as controls or future identified diseases. Some phenotypes under study include fibroblastic rheumatism, diaphragmatic hernia, polymicrogyria, severe congenital neutropenia, primary sclerosing cholangitis and staph infection. CLRR-Cincinnati Lupus Registry and Repository Systemic lupus erythematosus (SLE) is a complex, partially understood autoimmune disorder. Genetic origins for SLE are supported by high heritability (> 66%), familial aggregation, increased monozygotic twin concordance, genetic linkages, and candidate gene genetic association, including HLA genes, Fc receptors, and complement components. Relevant environmental factors likely include infections (Epstein-Barr virus), therapeutics, personal habits (smoking), and diet. To continue a research resource facility for collection of well-characterized pedigrees containing a proband with systemic lupus erythematosus we develop this repository. Juvenile Idiopathic Arthritis (JIA) Juvenile Idiopathic Arthritis (JIA) is a debilitating complex genetic disorder characterized by inflammation of the joints and other tissues and shares histopathological features with other autoimmune diseases. It is considered complex genetic traits. There are more than 50,000 children with JIA in the USA, approximately 1 per 1000 births, which is about the same incidence as juvenile diabetes. It is believed that genes in the major histocompatibility complex (MHC) play a role in defining genetic risk, and it can be hypothesized that loci in other chromosomal regions are involved in conferring risk in JIA. These candidate chromosomal regions can be identified using genome-wide association analyses. The long-term goal is a comprehensive understanding of the genetic basis of these disabling arthropathies for which the molecular basis is not presently understood. These data will contribute to a national resource for the study of autoimmunity in children. Better Outcomes for Children-Cytogenetics Since 2007, more than 4000 samples, enriched with various rare or common genetic diseases as well as specific chromosomal abnormalities such as deletions and duplications have been genotyped for the purpose of subsequent GWAS and Phewas analyses and uncovering main genetic effects.

  Study phs001011

• RNAseq dataset for MALT1 in MCL

  Manuscript Title: Co-targeting of BTK and MALT1 overcomes resistance to BTK inhibitors in mantle cell lymphoma Journal: Journal of Clinical Investigation Authors Vivian Changying Jiang1, Yang Liu1, Junwei Lian1, Shengjian Huang1, Alexa Jordan1, Qingsong Cai1, Fangfang Yan3, Joseph Mitchell McIntosh1, Yijing Li1, Yuxuan Che1, Zhihong Chen1, Jovanny Vargas1, Maria Badillo1, JohnNelson Bigcal1, Heng-Huan Lee1, Wei Wang1, Yixin Yao1, Lei Nie1, Christopher Flowers1, and Michael Wang1, 2* Abstract Bruton’s tyrosine kinase (BTK) is a proven target in mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma. However, resistance to BTK inhibitors is a major clinical challenge. We here report that MALT1 is one of the top overexpressed genes in ibrutinib-resistant MCL cells, while expression of CARD11, which is upstream of MALT1, is decreased. MALT1 genetic knockout or inhibition produced dramatic defects in MCL cell growth regardless of ibrutinib sensitivity. Conversely, CARD11 knockout cells showed anti-tumor effects only in ibrutinib-sensitive cells, suggesting that MALT1 overexpression could drive ibrutinib resistance via bypassing BTK-CARD11 signaling. Additionally, BTK knockdown and MALT1 knockout markedly impaired MCL tumor migration and dissemination, and MALT1 pharmacological inhibition decreased MCL cell viability, adhesion, and migration by suppressing NF-κB, PI3K-ATK-mTOR, and integrin signaling. Importantly, co-targeting MALT1 with safimaltib and BTK with pirtobrutinib induced potent anti-MCL activity in ibrutinib-resistant MCL cell lines and patient-derived xenografts. Therefore, we conclude that MALT1 overexpression associates with resistance to BTK inhibitors in MCL, targeting abnormal MALT1 activity could be a promising therapeutic strategy to overcome BTK inhibitor resistance, and co-targeting of MALT1 and BTK should improve MCL treatment efficacy and durability as well as patient outcomes. Dataset description: The bulk RNA-seq dataset was generated for the cell lines below and used for two major purposes: 1. DEG analysis and GSEA analysis comparing IBN-R and IBN-S cells 2. DEG analysis and GSEA analysis comparing MCL cells with/without MI-2 treatment. sample Cell MI-2 Ibrutinib (IBN) Venetoclax (VEN) Used for IBN-R vs IBN-S comparison Used for MI-2 vs untreated (DMSO) H9 Granta519 - R S yes H21 Granta519 - R S yes H33 Granta519 - R S yes H10 Granta519-VEN-R - R R yes H22 Granta519-VEN-R - R R yes H34 Granta519-VEN-R - R R yes H3 JeKo BTK KD_1 - R R yes yes H15 JeKo BTK KD_1 - R R yes yes H27 JeKo BTK KD_1 - R R yes yes H5 JeKo BTK KD_2 - R R yes yes H17 JeKo BTK KD_2 - R R yes yes H29 JeKo BTK KD_2 - R R yes yes H1 JeKo-1 - S R yes yes H13 JeKo-1 - S R yes yes H25 JeKo-1 - S R yes yes H7 Mino - S S yes H19 Mino - S S yes H31 Mino - S S yes H8 Mino-VEN-R - S R yes H20 Mino-VEN-R - S R yes H32 Mino-VEN-R - S R yes H11 Rec-1 - S S yes H23 Rec-1 - S S yes H12 Rec-VEN-R - S S yes H24 Rec-VEN-R - S R yes H36 Rec-VEN-R - S R yes H35 Rec-1 -- S R yes H4 JeKo BTK KD_1 + MI-2 + yes H16 JeKo BTK KD_1 + MI-2 + yes H28 JeKo BTK KD_1 + MI-2 + yes H6 JeKo BTK KD_2 + MI-2 + yes H18 JeKo BTK KD_2 + MI-2 + yes H30 JeKo BTK KD_2 + MI-2 + yes H2 JeKo-1 + MI-2 + yes H14 JeKo-1 + MI-2 + yes H26 JeKo-1 + MI-2 + yes

  Dataset EGAD00001009771

• Dental Caries: Whole Genome Association and Gene x Environment Studies

  Dental caries (also known as tooth decay) remains the most common chronic disease of childhood, five times more common than asthma and seven times more common than environmental allergies, with more than 40% of children exhibiting caries when they enter kindergarten. In 2005, it was estimated that dental health care costs were approximately $84 billion, of which 60% or about $50 billion were related to treatment of dental caries. Although overall caries prevalence has declined over the last 40 years, dental caries in the primary dentition and mean caries rates in children ages 2-11 has increased markedly over the past 12 years. Childhood caries is a serious public health issue because of associated health problems and because disparities in oral health have led to substantially higher average disease prevalence among children in poverty and in under-served racial and ethnic groups. These issues are of such concern that in 2005, the American Academy of Pediatrics made children's oral health one of their top areas of focus, as it is for the majority of the NIDCR "Disparities Centers". The etiology of dental caries has been studied for many years. Multiple factors contribute to a person's risk for caries, including: 1) environmental factors such as diet, oral hygiene, fluoride exposure and the level of colonization of cariogenic bacteria and 2) host factors such as salivary flow, salivary buffering capacity, position of teeth relative to each other, surface characteristics of tooth enamel and depth of occlusal fissures on posterior teeth. In spite of all that is known about this disease, there are still individuals who appear to be more susceptible to caries and those who are extremely resistant, regardless of the environmental risk factors to which they are exposed, implying that genetic factors also play an important role in caries etiology. This conclusion is supported by studies in both humans and animals, with the most compelling evidence coming from studies of twins reared apart in which investigators found significant resemblance within monozygotic (MZ) but not dizygotic (DZ) twin pairs for percentage of teeth and surfaces restored or carious and estimated the genetic contribution to caries as 40%. Other recent studies of twins reared together estimated the heritability for caries, adjusted for age and gender, as ranging from 45-64%. Despite the strong evidence of a genetic component to risk for dental caries, there have been only a few studies of candidate genes in caries, and no published genome-wide scans. A comprehensive genome wide search is the only approach that will allow us to identify those genetic regions likely to harbor genes increasing the risk for dental caries, and eventually to identify the etiologic genes and to explore the interaction of those genes with microbiological, dietary, fluoride, and behavioral factors that are known to be associated with caries risk and progression. Therefore, the goal of this study is to perform genome-wide association (GWA) studies of dental caries with a large panel of SNP's (610,000) in families and individuals ascertained through multiple US sites (University of Pittsburgh and University of Iowa). The v2 release of this study includes 96 additional individuals who were genotyped with the CCDG: Dental Caries and CL/P in Guatemala project (dbGaP accession number phs000440) to augment the data initially presented here. These subjects were genotyped on the Illumina 610 platform to make their data comparable. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org), which was developed through the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to dental caries through large-scale genome-wide association studies of well-characterized families and individuals at multiple sites in the U.S. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). The study was supported by the National Institute of Dental and Craniofacial Research (NIDCR, U01-DE018903). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington. Samples of some participants in this study were selected for further genomic analysis. These results will be available in the dbGaP CIDR study: Center for Oral Health Research in Appalachia (COHRA) Genomic Studies of Oral Health and Disease (phs001591).

  Study phs000095

• Resource for Genetic Epidemiology Research on Adult Health and Aging (GERA)

  The Resource for Genetic Epidemiology Research on Aging (GERA) Cohort was created by a RC2 "Grand Opportunity" grant that was awarded to the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) and the UCSF Institute for Human Genetics (AG036607; Schaefer/Risch, PIs). The RC2 project enabled genome-wide SNP genotyping (GWAS) to be conducted on a cohort of over 100,000 adults who are members of the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC), and participating in its RPGEH. The purpose of the RPGEH is to facilitate research on the genetic and environmental factors that affect health and disease by linking together clinical data from electronic health records, survey data on demographic and behavioral factors, and environmental data from various sources, with genetic data derived from biospecimens collected from participants. At the time of the award of the RC2 project in late 2009, the RPGEH had established a cohort of about 140,000 individuals who had answered a detailed survey, provided saliva samples for extraction of DNA, and given broad consent for the use of their data in studies of health and disease. To maximize the diversity of the resulting sample, the GERA cohort was formed by including all racial and ethnic minority participants with saliva samples (N = 20,925; 19%); the remaining participants were drawn sequentially and randomly from white non-Hispanic participants (89,341; 81%). A total of 110,266 participant samples were included to ensure that at least 100,000 were successfully assayed. The resulting GERA cohort is 42% male, 58% female, and ranges in age from 18 to over 100 years old with an average age of 63 years at the time of the RPGEH survey (2007). The sample is ethnically diverse, generally well-educated with above average income. Approximately 69% of the participants are married or living with a partner. Length of membership in KPNC averages 23.5 years. UCSF and RPGEH investigators worked with the genomics company Affymetrix to design four custom microarrays for genotyping each of the four major race-ethnicity groups included in the GERA Cohort, described in detail in Hoffmann et al., 2011a and 2011b. Following genotyping and quality control procedures, and after removal of invalid, discordant, or withdrawn samples, about 103,000 participants were successfully genotyped. The resulting genotypic data were linked to survey data and data abstracted from the electronic medical records. As described below, all RPGEH participants were mailed new consent forms with explicit discussion of the placement of data in the NIH-maintained dbGaP. About 77% of participants returned completed consent forms, resulting in a final sample size of 78,486 participants in the GERA Cohort with data for deposit into dbGaP. Origins of the RPGEH GERA Cohort The goal in creating the RPGEH GERA cohort was to create a large, multiethnic, and comprehensive population-based resource for research into the genetic and environmental basis of common age-related diseases and their treatment, and factors influencing healthy aging and longevity. The GERA Cohort consists of a diverse cohort of more than 100,000 adults who are members of the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC), and participating in its Research Program on Genes, Environment and Health (RPGEH). KPNC is an integrated health care delivery system with a population of about 3.3 million people in northern California. The membership of KPNC is representative of the general population in the 14 county area in which facilities are located, although the membership is underrepresented for the extremes of income at both ends of the spectrum. The RPGEH utilizes the longitudinal electronic health records (EHR) of KPNC to obtain clinical, laboratory, imaging and pharmacy information on all cohort members, to which personal demographic, behavioral and health characteristics have been added through member surveys. The GERA Cohort comprises a subsample of the RPGEH participant cohort, and was created through the RC2 award from the NIA, NIMH, and NIH Common Fund as described above. GERA Study Design The GERA Cohort is a subsample, as described above, of the longitudinal cohort enrolled in the Kaiser Permanente RPGEH. The RPGEH cohort includes about 400,000 survey participants of whom about 200,000 have provided broad consent and a sample of saliva or blood for use in studies of genetic and environmental factors in health and disease. The GERA Cohort was developed from a mailed survey sent to all adult members of KPNC who had been members for two years or more in 2007. All survey respondents were contacted and asked to complete a consent form; those who completed consent forms were asked to provide a saliva sample. Additional male participants were added to the RPGEH through inclusion of the Northern California sample of the California Men's Health Study (CMHS) cohort of about 40,000 men from KPNC, ages 45-69 years old at the time of the CMHS survey in 2002-2003. The CMHS participants contributed about 15,400 saliva samples to the RPGEH and were eligible for inclusion in the GERA Cohort. CMHS participants were included according to the same sampling design as for the RPGEH cohort as a whole. Specifically, all minority participants were selected for inclusion in order to maximize representation of minorities in the GERA Cohort, and Non-Hispanic White participants were selected at random to complete the sample of 110,266 GERA Cohort participants. GERA Genotypic Data High-density genotyping was conducted at UCSF using custom designed Affymetrix Axiom arrays, as described in Hoffmann et al. (2011a; 2011b). To maximize genome-wide coverage of common and less common variants, four specific arrays were designed for individuals of Non-Hispanic White (EUR), East Asian (EAS), African-American (AFR), and Latino (LAT) race/ethnicity. There was broad overlap among the SNPs on the arrays, which were designed using a hybrid greedy imputation algorithm (Hoffmann et al., 2011b) applied to genotype information validated by Affymetrix from the 1000 Genomes Project. However, in order to capture low frequency variants specific to particular race-ethnicity groups, SNP content varies between arrays. A more detailed description of the process of genotyping and results is included in Genotyping of DNA Samples. Description of the analyses of population structure and development of principal components for adjustment of population structure is included in Population Structure Analysis. GERA Phenotypic Data RPGEH and CMHS Survey Data. The sources of data on demographic and behavioral factors deposited in dbGaP for the GERA Cohort are the RPGEH and CMHS surveys. Data on common demographic factors such as gender, race/ethnicity, marital status, and education and on behavioral factors such as smoking, alcohol consumption, and body mass index, have been cleaned, edited, reconciled between the two surveys, and compiled into summary indices, where appropriate, for deposition into dbGaP. A more complete description of the survey variables is included in Survey Variables Documentation. Please note that the terms of use of the GERA Cohort Data, as specified in the Data Use Certification (DUC), prohibit the use of survey variables as outcomes in analyses. For example, a genome-wide association study (GWAS) of education or smoking is not permitted as specified by the DUC. Only health conditions can be used as outcome variables in analyses. Health Conditions derived from Kaiser Permanente Electronic Medical Records. Data on the occurrence of health conditions in participants in the GERA Cohort have been derived from summarizing ICD-9 coded diagnoses in Kaiser Permanente's electronic medical records. An algorithm that aggregates specific ICD-9 codes into appropriate diagnostic groups for selected conditions is applied to outpatient and inpatient databases; see Disease and Conditions Definitions Documentation for details. The criterion for including a condition as "present" for a participant is the occurrence of two or more diagnoses within a diagnostic category occurring on separate days. Two or more is used as the criterion in order to reduce false positives due to mistakes or rule-out diagnoses. When compared with validated disease registries, the criterion of 2+ diagnoses yields high specificity and good sensitivity. ICD-9 codes in the electronic records are specified in several ways. For outpatient visits occurring during the period 1995 to 2006, diagnoses were assigned by the treating physician who endorsed specific diagnoses on an optically scanned list that varied by specialty. Beginning in 2006 with the advent of an integrated, fully electronic medical record, outpatient diagnoses are made by physicians/ providers using a pull down menu. Discharge diagnoses from inpatient stays are specified by physicians and coded by specially trained coders. Databases of ICD-9 codes for diagnoses assigned at outpatient visits, or as one of the discharge diagnoses following inpatient stays, are complete and available for all KPNC members dating back to 1995. Although the average length of KPNC membership among GERA cohort members is 23.5 years in 2007, not all have been members since 1995, so the history for some conditions, such as those that are not chronic or recurrent, may not be complete for all cohort members. The year of first membership in KPNC is included as a variable in the list of survey variables, enabling investigators to estimate the number of years of observation of each Cohort member. RPGEH Access and Collaborations Website and Procedures The RPGEH maintains a web portal for inquiries and applications for collaboration and access to data. The url is: https://rpgehportal.kaiser.org/. RPGEH has an application process and an Access Review Committee that reviews applications for collaboration and use. For more details, please contact RPGEH through the website.

  Study phs000674

• Health and Retirement Study (HRS)

  Introduction to V2: This data release comprises data from the V1 release combined with approximately 3,000 additional samples, collected during the HRS 2010 field period. The 2010 data include samples from a random half of the new cohort enrolled in 2010 along with a significant expansion of the minority sample. Description: The University of Michigan Health and Retirement Study (HRS) is a longitudinal panel study that surveys a representative sample of approximately 20,000 people in America over the age of 50 every two years. Supported by the National Institute on Aging (NIA U01AG009740) and the Social Security Administration, the HRS explores the changes in labor force participation and the health transitions that individuals undergo toward the end of their work lives and in the years that follow. The study collects information about income, work, assets, pension plans, health insurance, disability, physical health and functioning, cognitive functioning, and health care expenditures. Through its unique and in-depth interviews, the HRS provides an invaluable and growing body of multidisciplinary data that researchers can use to address important questions about the challenges and opportunities of aging. Because of its innovation and importance, the HRS has become the model and hub for a growing network of harmonized longitudinal aging studies around the world. Origins of the HRS. As the population ages it is increasingly important to obtain reliable data about aging and topics that are relevant to a range of policy issues in aging. To address this need, the National Institutes on Aging (NIA) established a cooperative agreement with the University of Michigan Institute for Social Research to collect such data. The HRS launched data collection in 1992 and has re-interviewed the original sample of respondents every two years since then. By adding new cohorts and refreshing the sample, the HRS has grown to become the largest, most representative longitudinal panel study of Americans 50 years and older. HRS Study Design. The target population for the original HRS cohort includes all adults in the contiguous United States born during the years 1931-1941 who reside in households, with a 2:1 oversample of African-American and Hispanic populations. The original sample is refreshed with new birth cohorts (51-56 years of age) every six years. The sample has been expanded over the years to include a broader range of birth cohorts as well. The target population for the AHEAD survey consists of United States household residents who were born in 1923 or earlier. Children of the Depression (CODA) recruits households born 1924-1930, War Babies 1942-47, Early Boomers 1948-53, and Mid-Boomers 1954-59. Data collection includes a mixed mode design combining in-person, telephone, mail, and Internet. For consenting respondents, HRS data are linked at the individual level to administrative records from Social Security and Medicare claims. Genetic Research in the HRS. The HRS has genotyped 2.5 million single nucleotide polymorphisms (SNPs) on respondents using Illumina's Human Omni2.5-Quad (Omni2.5) BeadChip. The genotyping was performed by the NIH Center for Inherited Disease Research (CIDR). Saliva was collected on half of the HRS sample each wave starting in 2006. In 2006, saliva was collected using a mouthwash collection method. From 2008 onward, the data collection method switched to the Oragene kit. Saliva completion rates were 83% in 2006, 84% in 2008, and 80% in 2010 among new cohort enrollees. HRS Phenotypic data. Phenotypic data are available on a variety of dimensions. Health measures include physical/psychological self-report, various health conditions, disabilities, cognitive performance, health behaviors (smoking, drinking, exercise), physical performance and anthropomorphic measures, and biomarkers (HbA1c, Total Cholesterol, HDL, CRP, Cystatin-C). Data are also available on health services including utilization, insurance and out-of-pocket spending with linkage to Medicare records. Economic measures include employment status/history, earnings, disability, retirement, type of work, income by source, wealth by asset type, capital gains/debt, consumption, linkage to pensions, Social Security earnings/benefit histories. There is also extensive information on family structure, proximity, transfers to/from of money, time, social and psychological characteristics, as well as a wide range of demographics. Performance on a cognitive test combining immediate and delayed word recall was selected as an example trait for the dbGaP data release. In the immediate word recall task the interviewer reads a list of 10 nouns to the respondent and asks the respondent to recall as many words as possible from the list in any order. After approximately five minutes of asking other survey questions, the respondent is asked to recall the nouns previously presented as part of the immediate recall task. The total recall score is the sum of the correct answers to these two tasks, with a range of 0 to 20. Researchers who wish to link to other HRS measures not in dbGaP will be able to apply for access from HRS. A separate Data Use Agreement (DUA) will be required for linkage to the HRS data. See the HRS website (http://hrsonline.isr.umich.edu/gwas) for details.

  Study phs000428

• Better Outcomes for Children: GWAS from Cincinnati Children's Hospital Medical Center (CCHMC) - eMERGE Phase II data - (dbGaP Deposit 1)

  This submission includes genotyping data from 6 separate cohorts (named A-E here), each is described in separate paragraphs below. Cohort A) Autism is a neurodevelopmental disorder that affects 1.5 million people in the United States, at an estimated lifetime cost of $4 million. It is part of Pervasive Developmental Disorder characterized by impairments in communication, language and reciprocal social interaction, and by unusual patterns of restricted and repetitive interests or behaviors. Autism, or autistic disorder, is the most severe form of the disease which has a wide range of symptom severity encompassed by the more inclusive term, Autism Spectrum Disorder (ASD). The prevalence of Autistic Disorder is currently estimated to be 4 per 1000, affecting 4 times more boys than girls. Susceptibility to autism is clearly attributable to genetic factors but the extensive clinical and genetic heterogeneity within the disorder have hindered efforts at genetic dissection. Identifying the genetic variants that contribute to this highly heritable disease is crucial to advancing research on autism. Reported concordance rates among monozygotic twins range from 60% − 90% and heritability of autism has been estimated to be 90% or greater. Identifying genetic variants that contribute to this highly heritable disease is crucial to advancing research on autism. Cohort B) The long-term objective of this research is to determine the molecular genetic basis of Cardiovascular (CV) disease in the young; this study seeks to identify gene mutations that cause "structural heart defects". Every year in the USA, 32,000 individuals are born with CV malformations; approximately 20% die during the first year of life. Another 30,000 young people develop a disturbance of cardiac rhythm or conduction. In addition, the life expectancy of another 40,000 young people is shortened by other forms of CV disease. It is becoming more apparent that in spite of the success in diagnosis and treatment, very little is known about the causes of CV disease in the young; understanding the causes will permit insight into the pathophysiologic basis of disease and allow definition of disease risk - two critical elements for disease prevention. Disease prevention and/or risk modification promises to be the new frontier in the management of CV disease in the young. Cohort C) Eosinophilic Esophagitis (EE) is one of the manifestations of eosinophilic gastrointestinal inflammation which have profound effects on a patient's health and development. Results of epidemiologic studies performed through our center demonstrate that eosinophil-associated gastrointestinal disease is not an uncommon entity. While the epidemiology of eosinophilic esophagitis has not been thoroughly studied until recently, there appears to be a significant increase in the diagnosis of EE in the last decade. Based on our research, this mainly reflects increased disease recognition, but there is also a bona-fide increase in disease incidence which coincides with the increasing incidence of asthma and allergic diseases in the industrialized world. In addition, many patients with intractable symptoms thought in the past to represent atypical GERD or other disorders are now being recognized as having EE. Diagnosis of EE requires endoscopy and biopsies to document the characteristic histologic findings of esophageal eosinophilia. In general, this study proposed to elucidate the mechanisms underlying eosinophil growth, survival, migration, and function, and to investigate and further characterize the pathophysiology of, clinical manifestations of, and spectrum of disease severity of eosinophilic esophagitis in humans. Cohort D) Juvenile idiopathic arthritis (JIA) is a debilitating complex genetic disorder characterized by inflammation of the joints and other tissues and shares histopathological features with other autoimmune diseases. It is considered a complex genetic disorder. There are more than 50,000 children with JIA in the USA, approximately 1 per 1000 births, which is about the same incidence as juvenile diabetes. It is believed that genes in the major histocompatibility complex (MHC) play a role in defining genetic risk, and it can be hypothesized that loci in other chromosomal regions are involved in conferring risk in JIA. These candidate chromosomal regions can be identified using genome wide association analyses. The long-term goal is a comprehensive understanding of the genetic basis of these disabling arthropathies for which the molecular basis is not presently understood. The results of recent GWAS for Caucasian JIA were recently published in Arthritis Rheum. 2012 Feb 21 (Published online, PMID=22354554). Cohort E) Childhood Absence Epilepsy (CAE) is characterized by very frequent (several to many per day) absence seizures in an otherwise normal child with an EEG usually demonstrating 3 Hz bilateral, synchronous, symmetrical spikewaves pattern with normal background activity. CAE occurs in 10% to 15% of all children with epilepsy with an annual incidence of 6.3 to 8/100,000 in children <15 years of age. Females are more affected than males. Epilepsy onset is typically between the ages of 4 to 8 years with a peak incidence of 6 to 7 years. CAE does not start after age 13 years. The primary objective of this study is: To identify the optimal anticonvulsant (i.e. the antiepileptic drug (AED) with highest rate of seizure control and lowest incidence of treatment limiting toxicity) used for the initial treatment of children with Childhood Absence Epilepsy (CAE). The secondary objectives are: To determine the pharmacogenetic and other non-heritable factors underlying the interindividual variation in anticonvulsant response efficacy and toxicity. To define and contrast the effects of ethosuximide, lamotrigine, and valproic acid monotherapy on cognition (attention), behavior and quality of life in children with Childhood Absence Epilepsy. Cohort F) Cincinnati Controls. These are local healthy children selected to be representative of the population of Cincinnati with respect to gender and ancestry. Cohort G) Cytogenetics cases are ascertained by the clinical request to obtain cytogenetic analysis. The platform used included genotyping data which are then available for genome wide association analysis

  Study phs000494

• Field Studies of Human Immunity to Amebiasis in Bangladesh (NIH Birth Cohort) and Exploration of the Biologic Basis for Underperformance of Oral Polio and Rotavirus Vaccines in Bangladesh (PROVIDE)

  NIH birth cohort study Amebiasis is a common cause of diarrhea and is associated with malnutrition in grade-school aged children in an urban slum of Dhaka, Bangladesh. Field Studies of Human Immunity to Amebiasis in Bangladesh was designed to determine the contribution of amebiasis to illness in the first 2 years of life when most deaths due to diarrhea occur, and understand the immunologic and genetic factors that protect children from amebiasis. The hypothesis underlying the study is that susceptibility to amebiasis is determined by host innate and acquired immune responses that vary between individuals in part due to: human genetic polymorphisms; environmental influences including malnutrition and concurrent geohelminth infection; and virulence differences among Entamoeba histolytica genotypes. Specific aims proposed in the design of the study were to: a) Measure the incidence of amebiasis and correlate it with human and parasite genetic polymorphisms, immune responses, and environmental factors such as geohelminth infection and malnutrition; b) Test the hypothesis that protective immunity is mediated both by innate immune responses initiated via TLR stimulation as well as by mucosal IgA against the Gal/GalNAc lectin and systemic IFN-γ; c) Test for the association of common genetic polymorphisms in host innate and acquired immune genes with incidence of amebiasis. 629 newborn babies were enrolled and followed regularly through bi-weekly surveillance for diarrheal episodes, anthropometry at 3-month interval until 60 months of age. The infants that were consented for GWAS analysis were genotyped in 3 separate batches at different times, on 3 different arrays. Quality control was performed on the 3 separate data sets and then jointly after merging. Genetic data available on 447 infants together with their phenotype data is made available in this submission PROVIDE (Performance of Rotavirus and Oral Polio Vaccines in Developing Countries) Study Oral polio and rotavirus vaccines are significantly less effective in children living in the developing world. Environmental enteropathy, which is associated with intestinal inflammation, decreased absorption and increased permeability, may contribute substantially to oral vaccine failure in developing country settings. The primary objective of the study was to determine the association of environmental enteropathy with the efficacy of oral polio and rotavirus vaccines in children in Bangladesh. Secondary and exploratory objectives were designed to address other possible causes of oral vaccine underperformance including malnutrition, interference with maternal or breastmilk antibodies, changes in gut microbiota, and genetic susceptibility. The PROVIDE study was structured as a 2x2 clinical trial with a prospective birth cohort enrollment of 700 infants and their mothers in the urban slum of Mirpur, Dhaka, Bangladesh. All children received the full series of Bangladesh's Expanded Program on Immunization vaccines, including oral polio vaccine (OPV) and followed for their first 2 years of life. Half the children were randomized to receive an inactivated polio vaccine (IPV) for their 4th dose at 39 weeks instead of the standard OPV dose. In the other trial, half the infants received the 2-dose rotavirus vaccine (Rotarix) with delayed dosing at 10 and 17 weeks of age. A detailed description of the study design and procedures can be obtained from PROVIDE methods publication: Kirkpatrick B.D., Colgate R.E., Mychaleckyj J.C., Haque R., Dorothy D.M., Carmolli M.P., et al. (2015) Am J Trop Med Hyg 92, 744-751 The Poliovirus trial and results are described in Mychaleckyj et al, Vaccine 2016 The Rotavirus trial and results are described in Colgate et al, Clin Infect Dis 2016 The PROVIDE infants were genotyped on a custom Affymetrix Axiom array (30K SNPs) at the University of Virginia Center for Public Health Genomics; and on a pre-production version of the Illumina MEGA v2 chip at the Wellcome Trust Sanger Institute, UK. The latter genotyping was performed under the auspices of the VaccGene Consortium. Analyses are ongoing to identify variants associated with the included phenotypes. A manuscript describing the genotyping methods and analysis is in preparation for the initial phenotypes. The Infection Malnutrition Bangladesh Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs001475 Infection Malnutrition Bangladesh Cohort. phs001476 Amebiasis Immunity phs001478 Polio Rotavirus Vaccines phs001665 Cryptosporidiosis Enteropathogens

  Study phs001475

• All you need to know about our new DAC Portal v2

  An updated version to boost the management of DACs (Data Access Committees), policies, and data access requests. In September of 2023, we launched new services for all EGA users, including a DAC Portal. Since then, our team has been working to refine it and improve the user experience. The version 2 of our DAC Portal is now ready, with a range of new features aimed at streamlining your workflow and boosting productivity. If you are interested in learning more about the latest version of our DAC Portal, then you are in the right place! In this post, you will find information about the implemented features and more. The full documentation is available on our website. Moreover, we highly recommend exploring the DAC Portal through the Take the Tour. This said, let's get cracking! Customise your data access requests table This table offers the possibility to tailor information about the data access requests by making visible or hiding different columns regarding the Dataset Persistent Identifier, the Organisation or the requestor's name s, among others. You can choose which columns to see, depending on your needs and interests. Additionally, we have implemented two new features columns with two new functionalities, DAC Comment and Expiration Date. You can find more details in the following sections! In this table, all data access requests are displayed by default. With the latest version of the Portal, you can now apply filters, combine them, and save them for future use. Leave internal comments on pending requests and visible to all the DAC Members We understand that many Data Access Committees (DACs) cannot instantly approve or deny data access requests. Often, there's an intermediary phase where discussions and the signing of legal documents are necessary. To facilitate this process, we've introduced the DAC comment feature! When you navigate to the DAC column, you'll find two tabs: "User" and "DAC". Under "User", you'll see the message provided by the requester at the time of requesting access to the data. As a DAC member/admin, you can then add an internal comment in the "DAC" tab. These comments are visible only to DAC members/admins, ensuring confidentiality. Requesters won't have access to DAC comments. By adding a DAC comment to a pending request, we'll know that you've begun reviewing it. This allows you to filter pending requests without DAC comments to focus on genuinely new requests, and it prevents you from receiving email notifications about ongoing data requests. Set expiration dates for permissions and revoke them automatically The latest update to the DAC Portal introduces a new feature allowing you to set expiration dates for new access requests. For instance, if you anticipate approving a data access request but only wish to grant access for a limited time, you can now specify an expiration date for the granted permissions. Once this date is reached, the permissions will automatically be revoked. By default, permissions are granted indefinitely without an expiration date. However, if you ever need to revoke permissions, you can easily do so from the History page. Audit your metadata objects Managing and auditing your metadata objects will be easier from now on as the new DAC Portal enhances and facilitates your role as a Data Controller. This is possible thanks to the tables available in each of the primary tabs visible on the homepage: DACs, Policies and Datasets. Starting with DACs, this section allows to check the policies linked to a specific DAC. In Policies, you can obtain a list of the datasets connected to a particular policy. In the Dataset tab, it is possible to group datasets by either DAC or Policy, as well as the release status. Now you have the option of deprecating metadata objects that you don’t want to use anymore, or that were created by mistake. You will find the deprecate button on the EDIT page of the DAC, as well as for registered policies. You can find more information here. What's neat about this feature is that once a DAC or policy is deprecated, it becomes hidden within the DAC Portal. This ensures that you only see information that is consistently up to date! Define your preferences regarding email notifications For pending requests, you will be able to decide how often you want to get the notifications: daily, weekly or fortnightly. Remember, you will not receive email notifications for pending requests with a DAC comment! Furthermore, you have the flexibility to decide which notifications you wish to receive, such as invitations to join a new DAC or notifications regarding DAC acceptance by the Helpdesk, among other options. Check the User preference to see the complete list of available notification settings! What’s next: incoming DAC Portal API In addition to the new DAC Portal, we are excited to announce the release of the DAC API! This enables users to programmatically manage permissions. If you are interested in learning more about the technical specifications, you can consult the DAC API specification. This post was written by Aina Jené and Ana T. Alonso.

  Blog new-dac-portal-v2

• T2D-GENES Consortium: San Antonio Mexican American Family Studies (SAMAFS)

  The Type 2 Diabetes (T2D) Genetic Exploration by Next-generation sequencing in Ethnic Samples (T2D-GENES) Consortium is a collaborative international effort to identify genes influencing susceptibility to type 2 diabetes in multiple ethnic groups using next generation sequencing. To fulfill this objective, T2D-GENES Consortium undertook two large sequencing studies, called T2D-GENES Projects 1 and 2. Project 1 has carried out whole exome sequencing of 12,940 individuals, 6,504 with T2D and 6,436 non-diabetic controls, equally divided among five continental ancestry groups: Europeans, East Asians, South Asians, Hispanic Americans, and African Americans. The goal of Project 1 is to identify all genetic variants in the complete coding regions of the genomes (i.e., whole exome) by sequencing, including rare variants. Project 2 (i.e., SAMAFS substudy 2) is a pedigree-based study designed to identify low frequency or rare variants influencing susceptibility to T2D, using whole genome sequence information from approximately 600 individuals in 20 Mexican American T2D-enriched pedigrees from San Antonio, Texas, augmented with family-based imputation into approximately 440 additional family members. The major objectives of Project 2 are to identify low frequency or rare variants in and around known common variant signals for T2D, as well as to find novel low frequency or rare variants influencing susceptibility to T2D. Both T2D-GENES Projects 1 and 2 involve the San Antonio Mexican American Family Studies (SAMAFS), which are composed of four San Antonio, Texas-based family studies: the San Antonio Family Heart Study (SAFHS), San Antonio Family Diabetes/Gallbladder Study (SAFDGS), Veterans Administration Genetic Epidemiology Study (VAGES), and Family Investigation of Nephropathy and Diabetes - San Antonio (FIND-SA) Component and its extension called the Extended FIND [E-FIND]. The SAFHS and SAFDGS began in 1991 and have followed participants with extensive clinical phenotyping related to T2D for over 20 years. The VAGES was initiated in 1994 and a large battery of T2D-related phenotypic data has been obtained from its participants. The FIND-SA began in 2000, a part of the multicenter FIND study which was designed to identify genetic determinants of diabetic kidney disease; data from its participants related to T2D were used for this project. Non-overlapping subsets of SAMAFS participants are part of the T2D-GENES Projects 1 and 2, henceforth referred to as SAMAFS substudies 1 and 2, respectively. The SAMAFS substudies 1 and 2 are part of one of the five awards funded by NIDDK under a cooperative agreement award mechanism, which is governed by the Steering Committee of the T2D-GENES Consortium. Since Project 1 relies on population based subsets of cases and controls, 491 unrelated participants are drawn from the four SAMAFS as part of the T2D-GENES Project 1 Mexican American sample (i.e., SAMAFS substudy 1). The whole exome sequencing was performed at the Broad Institute. For Project 2, 1048 individuals are drawn from two SAMAFS (SAFHS and SAFDGS), representing 20 large families for substudy 2. The substudy 2 strategy is to sequence approximately 600 individuals at an average of 50x coverage across the entire genome, then impute genome wide genotypes for about 440 additional family members. The 600 sequenced individuals are specifically chosen for their value in imputing sequence information into other family members. By studying large pedigrees, we expect to find multiple individuals carrying each genetic variant, even if this variant is very rare in the population at large. Thus, a pedigree-based approach provides an excellent opportunity for identifying rare novel variants influencing risk of T2D and quantitative variation in T2D-related phenotypes. The whole genome sequencing has been done commercially by Complete Genomics, Inc. (CGI). The available sample of 1,048 includes 5 sequenced individuals who do not belong to any of the 20 large pedigrees. The final family data of 1,043 individuals includes whole genome sequence data for 607 individuals. After quality control, 590 sequenced individuals provide data for family based imputation using Merlin linkage analysis software into approximately 440 additional family members for whom chip based genotypes are available to indicate which parental haplotype is transmitted. The complete SAMAFS data including phenotype, genotype, sequence, other T2D-related trait data utilized for Projects 1 and 2 are available. These data can readily be viewed by clicking on the substudy title shown below or in the box: "Substudies", located on the right hand side of this parent or top study page phs000847.v1.p1, titled T2D-GENES Consortium: San Antonio Mexican American Family Studies (SAMAFS). phs000849 T2D-GENES Project 1: San Antonio Mexican American Family Studies (SAMAFS), Substudy 1: Whole Exome Sequencing phs000462 T2D-GENES Project 2: San Antonio Mexican American Family Studies (SAMAFS), Substudy 2: Whole Genome Sequencing in Pedigrees

  Study phs000847

• Submission FAQ

  Submission FAQ Before Submission Is the EGA the right archive for my data? The most suitable archive for your data is dependent on the type of data you are wishing to submit and whether the data require public or controlled access. Public access is defined as complete and open access to all submitted data. On the contrary, controlled access, exerted by the EGA, requires formal applications to be made to access the submitted data files and metadata. EGA only accepts human-derived data subject to controlled access. If your submission contains other types of data, please choose the appropriate repository for it (see image below): ENA, EVA, ArrayExpress, BioSD and GWAS catalog.  Should your submission be subjected to controlled access? Data access conditions are normally defined in the original informed consent agreements signed by the participants involved in your study. All data submitted to the EGA is subject to controlled access. These consents prevent the derived data files, potentially identifiable, from being dispersed by open and public access. Controlled access data often refers to human data derived from medical research and consortium projects. If in doubt, consult the informed consent agreements that apply to your study The EGA enables you to hold a submission before publication. What data types can be submitted to the EGA? Data types accepted by the EGA can be split into three categories: Sequences: both in generic and platform-specific formats. Array-based: from raw signal files to processed matrices. Phenotypes: all possible phenotype formats are accepted. All manufacturer-specific raw data formats derived from major next generation sequencing platforms are accepted. Also generic sequence formats: flat reads in a FASTQ file, aligned sequences (BAM or CRAM files) as well as sequence variation files in VCF format. All array-based technologies are accepted, including raw data, intensity and analysis files, without any restriction on data formats accepted. We also accept and distribute phenotype data (associated to the samples) in almost any format: from an image to a README file. How long does a submission take? Submissions to EGA come in a variety of formats and sizes, thus it is difficult for us to exactly predict how long a submission will take. We, therefore, advise all of our submitters to allow as much time as possible to make a submission. Based on previous records, we anticipate that the submission process may take at least one month. The submitter’s familiarity with the procedures, possible technical issues that may arise during submission and the amount of data that is being submitted are the main factors that will affect the length of the submission process. However, each step of a regular submission should be considered when estimating the time it would take: Encryption of the files Upload of the files Metadata submission Archival of the files Release of the study and datasets to EGA webpage For example, the upload of the files depends on the submission size, while metadata submission mainly relies on each submitter’s expertise. Further, some steps (e.g. answering to inquiries) depend on the EGA Helpdesk team, which may take some days to be processed during busy times Is data deposited in the EGA secure? The EGA set-up consists of a secure computing facility for data processing, a shared EBI set-up for data submissions and distribution of data via data requests made through the EGA website. Data is also copied in the Barcelona Supercomputing Center (BSC) infrastructure, where all stored and distributed data is encrypted Data is encrypted along the submission process and stored securely, granting its access to authorised users exclusively. During the download process, through our Python Client or Aspera, all requested data is downloaded over secure https connections. All data at the EGA is encrypted, and only accessible (for log-in and download) through secure protocols. For further information please, visit our security overview. What documentation do I need to provide? All submissions require policy’s documentation: 'Data Access Agreement (DAA)', 'Data Processing Agreement (DPA)' and 'Authorized Submitters Formulary'. The data processors (EGA) and the data owners will also sign the DPA. Will all metadata be public? Among the submitted metadata we need to make the distinction between identifiable and unidentifiable metadata: (1) the former may allow the identification of the human the sample derived from (e.g. detailed geographical providence, personal name, family ancestry…); (2) while the latter can be used to interpret the data without compromising the anonymity of the patients. The majority of the metadata submitted to the EGA corresponds to the unidentifiable category (e.g. sequencer's model). This type of metadata is publicly available on the EGA website and other EBI resources/partners’ websites. On the other hand, some parts samples’ metadata are subject to being identifiable, and thus only accessible by authorized data requesters, with the exception of: 5 submitter-defined attributes of the sample: alias, title, subject_id, gender and phenotype. It is the submitter’s responsibility not to submit sensitive metadata in these public fields. 3 anonymised fields that pinpoint the sample record in archivals: sample’s EGA stable ID (EGAN…), BioSample ID (SAMEA…) and submitter’s center name. During Submission Are there any sample specific requirements for EGA? All samples submitted to the EGA must include the attributes of biological sex, subject ID (anonymised individual identifier) and phenotype information. These are critical for data findability and its analysis, and we highly recommend using controlled ontology terms where applicable. For example: defining tumour and non-tumour samples and/or defining disease state. The EGA recommends using the Experimental Factor Ontology Database to find ontologized terms that describe your sample phenotypes. How do I get an accession number to use in my publication? You will receive your study accession number (EGAS…) upon complete your submission, either: Programmatically. As soon as the metadata is submitted and validated your study will be assigned an accession number that will be given in the submission’s response. Manually registering your study and relevant metadata using the online metadata submission tool: the EGA submitter Portal. How are files uploaded to the EGA? Data files are uploaded into private submission drop boxes (i.e. environments to which you are granted access and where you can transfer your files) using INBOX or FTP. These spaces are provided as part of the submission procedure. Before uploading any file, you must encrypt your files, . Only encrypted files shall be uploaded to the drop boxes. Why does data need to to encrypted for my submitted files? It is one of the security steps the EGA has implemented. In case of a security breach, people without the proper encryption key will not be able to read or use the information that could have been leaked. This measure is essential when working with sensitive data, such as controlled access human data. All submitters must use crypt4gh to create EGA compliant files prior to uploading them. This encryption is GPG-based, using EGA’s public key. Why are my files not available if I see them in the INBOX? There exists a time window between the data upload and the availability of such files via the Submitter Portal. For this reason, some metadata (run and analysis objects) cannot be registered until at least 24 hours after the files have been uploaded to your box. Why are MD5 sum values generated for my submitted files? We require pre- and post- encryption MD5 (message-digest) checksum values to be provided for all submitted files. These 128-bit values are computed using the content of each file, creating unique sequences that allow us to ensure that file integrity has been maintained during the transfer process. In other words, if the MD5 checksums we generate and those you generated match, we infer that the content of the transferred files is correct (i.e. files are not corrupted or truncated). MD5 checksums are computed automatically using the crypt4gh tool provided. Your submission will not be accepted and may be significantly delayed if you do not provide MD5 checksum values for all data files in the required format. How can I check if my files are correctly uploaded to the inbox? It is important to check the status pf your file so you know whether your files are in the inbox, being processed, or if there is any issue with one of them. In order to check this, you should: Look for the file locally. Drag and drop it to the file table. Then bars will appear on the table, which means that we are processing it. Green: The files checksum are correct and your file will move to “ingested files”. No further actions are needed from your end.. Red: The files checksum does not match and your file needs to be re-uploaded. Please re-upload relevant files to your inbox using the same path. How can I add my dataset to the cBioPortal instance? In order to link your data to the cBioPortal, you must register it as a normal dataset in the Submitter Portal. For more information, please refer to the cBioPortal documentation. After Submission How do I use my accession number in my publication? We suggest the use of the below template, using your study accession ID (EGAS…) : Data has been deposited at the European Genome-phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGASXXXXXXXXXXX. Further information about EGA can be found at https://ega-archive.org and "The European Genome-phenome Archive of human data consented for biomedical research" Your study ID will be the one that groups your whole submission, and thus its usage is recommended as such. Nevertheless, all metadata submitted to EGA hold a unique and persistent identifier (starting with EGA…) that can be used to identify specific records. For example, you could reference a specific dataset (EGAD…) or sample (EGAN…) in your publications (see full list of identifiers). How do I make my data searchable? Once you have finalized your submission, you can schedule the data release. Please take into account that the release process needs time for the files to be archived in our system, and for the Helpdesk team to validate your submission. Can I withdraw (meta)data from the EGA? We have methods in place for the secure removal of deposited (meta)data. Contact EGA-helpdesk for further details. EGA complies with FAIRness of (meta)data, and thus, even when the data is removed we keep an entry for their identifiers in our system. In other words, we execute a soft delete on canceled objects (e.g. a study): metadata is still stored in our systems, but it loses all links, cannot be queried and data files cannot be retrieved anymore. The reason behind this behaviour is so that queries using withdrawn data properly respond back (see example of a canceled study). What happens to the data once it has been submitted to the EGA? When the data is submitted, the submitter can choose either keep their data private or schedule the release of their data.

  Documentation submission/metadata/submission/FAQ

• Transdisciplinary Research Into Cancer of the Lung (TRICL) - Exome Plus Targeted Sequencing

  The study was conducted under the auspices of the Transdisciplinary Research In Cancer of the Lung (TRICL) Research Team, which is a part of the Genetic Associations and MEchanisms in ONcology (GAME-ON) consortium, and associated with the International Lung Cancer Consortium (ILCCO). Ethics All participants provided written informed consent. All studies were reviewed and approved by institutional ethics review committees at the involved institutions. Sequencing data are derived from four sub-studies. The sub-studies that contributed include Harvard, Liverpool, Toronto, and IARC. The IARC and Toronto studies are described above. A description of the Harvard and Liverpool studies is provided below. Liverpool Lung Project: The Liverpool Lung Project (LLP)1 is a case control and cohort study, which has over 11,500 individuals, with detailed epidemiological, clinical and outcome data with associated specimens (i.e. tumour tissue, blood, plasma, sputum, bronchial lavage, EBUS and oral brushings). The participants have completed a detailed lifestyle questionnaire and updated data on clinical outcome and hospital events are collected through the Office of National Statistics, Cancer Registry and from Health Episode Statistics. The project is registered on the UK National Institute for Health Research (NIHR) lung cancer portfolio and has all the required ethical approvals and sponsorship arrangements in place. The LLP has detailed standard operating procedures (SOP) for all aspects of the recruitment, data, specimen collection as well as the data storage. The LLP Cohort study has 8,224 participants with blood and 7,761 with plasma samples. The LLP case-control samples have been incorporated into in a large number of international GWAS and molecular studies 2,3, methylation 4-7, microRNA 8and next generation studies 9-11, resulting in high ranking publications, as well as forming the basis for the LLP risk prediction model 12-14 which has been utilised in the UK lung cancer screening trial (UKLS) 15-17 Patient and control DNAs were derived from EDTA-venous blood samples. Harvard Samples. David Christiani at the Harvard University School of Public Health has been directing research studies to investigate etiological factors influencing lung cancer development since 1983 and has amassed a collection of 2000 controls and 5055 lung cancer cases. He has been actively collecting and storing snap frozen tumor samples since 1992. Around 1500 tumor samples have been collected and the average wet tumor yield is about 30 grams of tumor, of which 631 cases have completely annotated clinical and survival information. Pathology confirmation is provided by two pathologists. At the time of surgery, a minimum of 30 grams of wet lung tumor tissue and 30 grams of non-involved tissue from the same lobe is sectioned, flash frozen and sent to Dr. Christiani's lab for logging and storage. A blood sample for DNA and serum is collected. A structured interview by trained research staff is conducted on each case, and clinical outcomes and treatments is extracted and entered into the molecular epidemiology data base at Harvard. Fresh frozen samples have been collected from 1451 lung cancer and are available for study. Samples from this collaborative study have played key roles in major studies, including the initial finding describing EGFR mutations in lung cancer 22. Participants in this study are patients, > 18 years of age, with newly diagnosed histologically confirmed lung cancer. Samples that are included in the analysis have the following histologies: Adenocarcinoma: 8140/3, 8250/3, 8260/3, 8310/3, 8480/3 8560/3; LCC: 8012/3, 8031/3; squamous carcinoma: 8070/3, 8071/3, 8072/3, 8074/3; and other NSCLC: 8010/3, 8020/3, 8021/3, 8032/3, 8230/3. The Toronto Study: The Toronto study was conducted in the Great Toronto Area between 1997 and 2014. Cases were recruited at the hospitals in the network of University of Toronto and Lunenfeld- Tanenbaum Research Institute. At the time of recruitment in the clinical setting, provisional diagnoses of lung carcinoma were first assigned based on clinical criteria. Diagnoses for all cases included were histologically confirmed by the reference pathologist who is a specialist in pulmonary pathology, based on review of pathology reports from surgery, biopsy or cytology samples in 100% of cases. Diagnostic classification was done initially according to ICD-9, ICD-10, and ICD for oncology-2, and subsequently converted to ICD-O-3. Tumors were grouped into the major categories included in this analysis according to primary cancer type based on the ICD-3 definitions. Controls were randomly selected from individual visiting family medicine clinics and Ministry of Finance Municipal Tax Tapes. All subjects were interviewed using a standard questionnaire and information on lifestyle risk factors, occupational history, medical and family history was collected. Blood samples were collected from more than 85% of the subjects. IARC: The IARC data are derived from case-control studies conducted in Russia and include samples that have available tissue samples. Patient and control DNAs were derived from EDTA-venous blood samples. The lung cancer patients were classified according to ICD-O-3; SQ: 8070/3, 8071/3, 8072/3, 8074/3; AD: 8140/3, 8250/3, 8260/3, 8310/3, 8480/3, 8560/3, 8251/3, 8490/3, 8570/3, 8574/3; with tumous with overlapping histologies classified as mixed. The Lung Cancer Transdisciplinary Research Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" section of this top-level study page phs000876 Lung Cancer Transdisciplinary Research Cohort. phs000877 Meta Analysis phs000878 CIDR Lung Cancer phs001681 Affy Axiom Array

  Study phs000876

• Action to Control Cardiovascular Risk in Diabetes (ACCORD - Imaging)

  Available DataAction to Control Cardiovascular Risk in Diabetes (ACCORD-Imaging), provides access to ECG signals data from the ACCORD clinical trial. The clinical phenotyping and outcomes data from the trial are associated with ACCORD-BioLINCC, phs003551.ObjectivesThe purpose of this study was to determine if intensive glycemic control, multiple lipid management and intensive blood pressure control could prevent major cardiovascular events (myocardial infarction, stroke or cardiovascular death) in adults with type 2 diabetes mellitus. Secondary hypotheses included treatment differences in other cardiovascular outcomes, total mortality, microvascular outcomes, health-related quality of life and cost-effectiveness.BackgroundGlycemia Trial:Patients with type 2 diabetes mellitus die of cardiovascular disease (CVD) at rates two to four times higher than non-diabetic populations of similar demographic characteristics. They also experience increased rates of nonfatal myocardial infarction and stroke. With the growing prevalence of obesity in the United States, CVD associated with type 2 diabetes is expected to become an even greater public health challenge in the coming decades than it is now. Expected increases in event rates will be associated with a concomitant rise in suffering and resource utilization.The ACCORD study investigated whether intensive therapy to target normal glycated hemoglobin (HbA1c) levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors when compared to standard therapy (HbA1c between 7.0% and 7.9%). A separate analysis investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in these patients.Lipid Therapy Trial:Patients with type 2 diabetes mellitus have an increased incidence of atherosclerotic cardiovascular disease attributable, in part, to associated risk factors such as dyslipidemia. This is characterized by elevated plasma triglyceride levels, low levels of high-density lipoprotein (HDL) cholesterol and small, dense low-density lipoprotein (LDL) particles. The ACCORD Lipid Therapy trial was designed to test the effect of a therapeutic strategy that uses a fibrate to raise HDL-C and lower triglyceride levels and uses a statin for treatment of LDL-C reduce the rate of CVD events compared to a strategy that only uses a statin for treatment of LDL-C on cardiovascular outcomes in patients with type 2 diabetes that were at high risk for cardiovascular disease.Blood Pressure Trial:Diabetes mellitus increases the risk of cardiovascular disease at every level of systolic blood pressure. Because cardiovascular risk in patients with diabetes is graded and continuous across the entire range of levels of systolic blood pressure, even at prehypertensive levels, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended beginning drug treatment in patients with diabetes who have systolic blood pressures of 130 mm Hg or higher, with a treatment goal of reducing systolic blood pressure to below 130 mm Hg. There is, however, a paucity of evidence from randomized clinical trials to support these recommendations. The ACCORD Blood Pressure trial tested the effect of a target systolic blood pressure below 120 mm Hg on major cardiovascular events among high-risk persons with type 2 diabetes compared to a strategy that targeted a SBP of EYE Substudy:Diabetic retinopathy, an important microvascular complication of diabetes, is a leading cause of blindness in the United States. Randomized, controlled clinical trials in cohorts of patients with type 1 diabetes and those with type 2 diabetes have shown the beneficial effects of intensive glycemic control and intensive treatment of elevated blood pressure on the progression of diabetic retinopathy. Elevated serum cholesterol and triglyceride levels have been implicated, in observational studies and small trials, as additional risk factors for the development of diabetic retinopathy and visual loss. The ACCORD EYE Substudy evaluated the effects of the ACCORD medical strategies on the progression of diabetic retinopathy in a subgroup of trial patients.MIND Substudy:Studies suggest that older persons with type 2 diabetes have at least twice the likelihood of developing late-life cognitive impairment or dementia compared to those without. The mechanisms underlying these cognitive disorders are increasingly thought to reflect a mixed pathology pattern with contributions from vascular, neurodegenerative and neurovascular processes. Pathophysiological mechanisms that have been described include inflammation, oxidative stress, energy imbalance, protein misfolding, glucocorticoid-mediated effects and differences in genetic susceptibilities. The ACCORD MIND substudy took as a premise that early intervention with the ACCORD therapeutic strategies to improve glycemic control could mitigate the adverse effects of type 2 diabetes on the brain.Subjects10,251 patients with type 2 diabetes and HbA1c concentrations of 7.5% or more participated in the trial. Of these patients, 5518 were assigned to the lipid therapy arm and 4733 to the blood pressure arm. EYE Substudy:A subgroup of 2856 patients was evaluated for the effects of the ACCORD interventions at 4 years on the progression of diabetic retinopathy. Patients who, at baseline, had a history of proliferative diabetic retinopathy that had been treated with laser photocoagulation or vitrectomy were excluded.MIND Substudy:A subgroup of 2977 patients was evaluated for cognitive function and brain volume. The ACCORD MIND substudy excluded patients aged DesignPatients were randomly assigned to undergo either intensive glycemic control (targeting a glycated hemoglobin level EYE Substudy:EYE Substudy patients were evaluated at two standardized and comprehensive eye examinations for the effects of the ACCORD interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy.MIND Substudy:The cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, was assessed at baseline, 20 and 40 months. Total brain volume (TBV), the primary brain structure outcome, was assessed with MRI at baseline and 40 months in a sub-set of 632 patients. All patients with follow-up data were included in the primary analyses.ConclusionsGlycemia Trial:As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. (NEJM. 2008; 358(24): 2545-59).Microvascular Outcomes of the Glycemia Trial:Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Microvascular benefits of intensive therapy should be weighed against the risk of increased total and cardiovascular disease-related mortality, increased weight gain, and higher risk for severe hypoglycemia. (Lancet. 2010; 376(9739): 419-30)Lipid Therapy Trial:The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes (NEJM. 2010; 362(17): 1563–1574).Blood Pressure Trial:In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events (NEJM. 2010; 362: 1575-1585).EYE Substudy:Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy (NEJM. 2010; 363: 233-244).MIND Substudy:Although significant differences in TBV favored the intensive therapy, cognitive outcomes were not different. Combined with the unfavorable effects on other ACCORD outcomes, MIND findings do not support using intensive therapy to reduce the adverse effects of diabetes on the brain in patients similar to MIND patients (Lancet Neurol. 2011; 10(11): 969–977).

  Study phs003562

• Childhood Cancer Survivor Study (CCSS)

  Background and Rationale for the Childhood Cancer Survivor Study (CCSS) Over the last several decades, advances in treatments for childhood and adolescent cancer have substantially improved survival following diagnosis. These improvements gave rise to the responsibility for investigating long-term treatment-associated morbidity and mortality. Early efforts to describe late effects were largely conducted through single-institution and limited consortia studies. However, by the mid-1980s, it became increasingly clear that these approaches had inherent limitations, including small sample size, convenience sampling, incompletely characterized populations, and limited length of follow-up. To overcome these limitations, the CCSS was proposed and funded by the National Cancer Institute (NCI) as a U01 grant in 1994. Subsequently, the strengths of the CCSS, including an efficient and extensive infrastructure, plus expanding database and biorepository, were recognized and appreciated. Thus, in consultation with the NCI, the CCSS was converted to a U24 (resource grant) funding mechanism to serve the scientific community in 2000. The overarching goal of the CCSS resource is to increase the conduct of innovative and high impact research related to pediatric cancer survivorship. CCSS has been used extensively by researchers from a wide range of disciplines to address a broad spectrum of topics. Strengths of the resource include its large size, comprehensive annotation of treatment exposures, ongoing longitudinal follow-up with characterization of a wide array of participant characteristics and outcomes, and an established biorepository. Design of the Childhood Cancer Survivor Study The Childhood Cancer Survivor Study (CCSS) is a multi-institutional, multi-disciplinary collaborative research resource comprised of a retrospective hospital-based cohort of survivors of childhood cancer and a comparison sibling cohort. Eligible survivors from 31 participating institutions were diagnosed between 1970 and 1999, prior to age 21 years, with selected common pediatric cancers (leukemia, central nervous system tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney tumors, neuroblastoma, soft tissue sarcoma, or bone tumors). All patients who survived five years from the date of diagnosis were eligible, regardless of disease or treatment status. The baseline questionnaire was completed by 24,368 survivors and 5,039 siblings recruited to serve as a comparison group. To date, participants have completed three general follow-up surveys, as well as a number of specialized surveys on specific topics (e.g. health care, insurance, screening practices, men's and women's health issues, adolescent health, sleep and fatigue). In addition, biological samples (buccal cells, saliva and/or blood) have been collected for over 11,000 participants. Full descriptions of the design and characteristics of the CCSS have been previously published (Robison et al; Leisenring et al.), and available data and samples are described at https://ccss.stjude.org/develop-a-study/gwas-data-resource.html. Treatment Data in the Childhood Cancer Survivor Study A key feature of CCSS is the availability of detailed treatment data, which were collected by abstraction of medical records for each individual member of the cohort. Detailed abstraction included dates of therapy, protocol information, and specific details regarding surgery, chemotherapy and radiation. Quantitative dose details were collected for 22 specific chemotherapeutic agents, including alkylating agents, anthracyclines, platinum compounds and epipodophyllotoxins. In addition to individual agent doses, algorithms have been created to calculate cumulative doses of all drugs in a specific class, such as anthracyclines (doxorubicin, daunomycin and idarubicin) or platinum agents (cisplatinum and carboplatinum). Data abstracted for surgeries included dates and both the names and corresponding International Classification of Diseases (9th revision) code. For radiation treatment data, all relevant records were sent to the Radiation Physics Center at M.D. Anderson Cancer Center for detailed abstraction and dosimetry. Initial body region dosimetry was performed for all participants, followed by more detailed dosimetry as needed for specific studies. Genomics Data in the Childhood Cancer Survivor StudyThe NCI's Division of Cancer Epidemiology and Genetics and CCSS investigators collaborated to conduct genomics studies (SNP array genotyping and whole exome sequencing) using samples from the CCSS Biorepository. Studies included all cohort participants with available DNA regardless of sex or ancestry when the genomics studies were initiated. Phenotype Data in the Childhood Cancer Survivor Study Vital status and cause of death for both participants and non-participants is determined via linkage with the National Death Index (NDI). Identification of subsequent neoplasms is based on self-report, followed by validation using medical records, or via NDI. A wide array of additional health outcomes have been ascertained via a comprehensive set of questions on the CCSS questionnaires, covering potential adverse events across a range of organ systems (hearing/vision/speech, urinary, hormonal, heart and circulatory, respiratory, digestive, brain and nervous systems). In addition to health outcomes, longitudinal data have been collected on demographics, health behaviors, family history, screening practices, insurance status, and a range of psychosocial and neurocognitive factors. A full listing of available variables and copies of the CCSS questionnaires are available at http://ccss.stjude.org. Research Areas in the Childhood Cancer Survivor Study Extensive use by the research community has resulted in over 265 published manuscripts on a wide range of topics, including associations between treatment factors and mortality, subsequent neoplasms, chronic health conditions, cardiac events, neurocognitive sequelae, psychosocial factors, fertility, and health status. Additional topics have included health behaviors, screening practices, health care access and utilization, statistical and exposure assessment methodology, and development of risk prediction models. A full listing of published manuscripts using CCSS data is available on the CCSS website at https://ccss.stjude.org/published-research/publications.html. The Childhood Cancer Survivor Study as a Resource for Investigators The CCSS is an NCI-funded resource (U24 CA55727) to promote and facilitate research among long-term survivors of cancer diagnosed during childhood and adolescence. Interested investigators are encouraged to develop research ideas and propose projects within CCSS, whether or not they are from a participating CCSS institution. The CCSS is now accepting proposals to collaborate with CCSS and NCI investigators in the use of genomics data and corresponding outcomes-related data to address innovative research questions relating to potential genetic contributions to risk for treatment-related outcomes. Any researcher, or group of researchers, qualified to conduct genetic research can submit a proposal. There are no restrictions relative to country, institution, or prior involvement in CCSS. A full description of the process for developing a proposal for genetic research in CCSS can be found at https://ccss.stjude.org/develop-a-study/gwas-data-resource.html, along with listings of approved proposals.

  Study phs001327

• Characterization_of_individual_foci_of_multicentric_multifocal_breast_cancer_using_targeted_next_generation_sequencing

  Multifocality or multicentricity in breast cancer may be defined as the presence of two or more tumor foci within a single quadrant of the breast or within different quadrants of the same breast, respectively. This original classification of the breast cancer as multicentric or multifocal was based on the assumption that cancers arising in the same quadrant were more likely to arise from the same ductal structures than those occurring in separate areas of the breast. The problem with these definitions is that the “quadrants” of the breast are arbitrary external designations, as no internal boundaries do exist. This project will therefore focus both on synchronous multifocal and multicentric tumors. The incidence of multifocal and multicentric breast cancers was reported to be between 13 and 75% depending on the definition used, the extent of the pathologic sampling of the breast and whether in situ disease is considered evidence of multicentricity (1). Although this incidence is variable, those figures show that it is a frequent phenomenon. Multiple (multifocal/multicentric) breast carcinomas, especially when occurring in the same breast, represent a real challenge for both pathologists and clinicians in terms of identifying the cellular origin and the best therapeutic management of the cancer. Multifocality or multicentricity has been associated with a number of more aggressive features including an increased rate of regional lymph node metastases and adverse patient outcome when compared with unifocal tumors (2-3), and a possible increased risk of local recurrence following breast conserving surgery (4). For the moment, the literature is divided on whether there is a corresponding impact on survival outcomes. Today, the current convention to stage and to treat multifocal and multicentric tumors is the classical tumor-node-metastasis (TNM) staging guidelines with which tumor size is assessed by the largest tumor focus without taking other foci of disease into consideration. If some papers, as the recent one from Lynch and colleagues, support the current staging convention (3), others, however, as Boyages et al. suggested that aggregate size and not the size of the largest lesion should be considered in order to refine the prognostic assessment of those tumors (5). On the top of that, the question whether multifocal/multicentric carcinomas are due to the spread of a single carcinoma throughout the breast or is due to multiple carcinomas arising simultaneously has been a matter of debate. Some studies suggested that multifocal breast cancer may result from either intramammary spread from a single primary tumor or multiple synchronous primary tumors; whereas others suggest that multiple breast carcinomas always arise from the same clone (6-8). Recently, Pietri and colleagues analyzed the biological characterization of a series of 113 multifocal/multicentric breast cancers (8) which were diagnosed over a 5-year period. The expression of estrogen (ER) and progesterone (PgR) receptors, Ki-67 proliferative index, expression of HER2 and tumor grading were prospectively determined in each tumor focus, and mismatches among foci were recorded. Mismatches in ER status were present in 5 (4.4%) cases and PgR in 18 (15.9%) cases. Mismatches in tumor grading were present in 21 cases (18.6%), proliferative index (Ki-67) in 17 (15%) cases and HER2 status in 11 (9.7%) cases. Interestingly, this heterogeneity among foci has led to 14 (12.4%) patients receiving different adjuvant treatments compared with what would have been indicated if we had only taken into account the biologic status of the primary tumor. This study therefore showed that differences in biological characteristics of multifocal/multicentric lesions play a crucial role in the adjuvant treatment decision making process. In this study, we will concentrate on a larger series of patients with multifocal invasive ductal breast cancer lesions. We aim at: 1. Evaluating the incidence of multifocality according to the different breast cancer molecular subtypes (ER-/HER2-, HER2+, ER+/HER2-). 2. Evaluating the incidence of multifocality in patients with hereditary breast cancer disease (presence of germline BRCA1 or BRCA2 mutations). Moreover, we would like to investigate if multifocal lesions with BRCA1 or BRCA2 mutations exhibit a characteristic combination of substitution mutation signatures and a distinctive profile of deletions as demonstrated recently by Nik-Zainal and colleagues (9). 3. Correlating multifocality with clinical information in order to define its influence on patients’ survival (DFS and OS). 4. Carrying high coverage targeted gene sequencing of driver cancer genes and genes whose mutation is of therapeutic importance in order to compare clinically-relevant genetic differences between several multifocal breast cancer lesions. 5. Evaluating the impact of the distance between the different lesions on the clinical outcome but also on the genetic differences. 6. Comparing gene expression patterns between several multifocal breast cancer lesions and correlate them with the results of the targeted genes screen. 7. Characterizing the genomic and transcriptomic status of cancer related genes in metastatic lesions (local recurrence, positive lymph node or distant metastatic sites) from the same multifocal invasive ductal breast cancer patients in order to evaluate the consequence of genomic and transcriptomic heterogeneity of multifocal lesions on metastatic lesions. Multiple (multifocal/multicentric) breast carcinomas, especially when occurring in the same breast, represent a real challenge for both pathologists and clinicians in terms of identifying the cellular origin and the best therapeutic choice. This project has the potential to identify genetic/transcriptomic differences existing between several lesions constituting multifocal breast cancers, which in the routine clinical practice are usually considered to be homogeneous among them. We foresee validating significant results in a larger series of patients and this, in turn, could have a remarkable impact on the treatment and clinical management of multifocal breast cancers. Indeed, we hope to provide some evidence whether or not each focus matters in multifocal and multicentric breast cancer to define the adequate therapeutic approach, especially in the context of targeted therapies. The work to be done at Sanger will be target gene screen pooling of 1400 samples.

  Study EGAS00001000407

• eMERGE Network Phase III Clinical Sequencing: eMERGEseq Panel

  The Electronic Medical Records and Genomics (eMERGE) Network is a National Institutes of Health (NIH)-organized and funded consortium of U.S. medical research institutions. The primary goal of the eMERGE Network is to develop, disseminate, and apply approaches to research that combine biorepositories with electronic medical record (EMR) systems for genomic discovery and genomic medicine implementation research. eMERGE was announced in September 2007 and began its third phase in September 2015. eMERGE III consists of nine study sites, two central sequencing and genotyping facilities, and a coordinating center. eMERGE Phase III aims to: 1) sequence and assess the phenotypic implication of rare variants in a custom designed eMERGEseq panel consisting of 109 genes (including 56 ACMG actionable finding list genes and the top 6 genes from each site relevant to their specific aims), as well as approximately 1400 SNPs; 2) assess the phenotypic implications of these variants by developing, validating and implementing new phenotype algorithms, 3) integrate genetic variants into EMRs to inform clinical care; and 4) create community resources. Included in this study are: ~24,000 eMERGE participants from 10 eMERGE III study sites. Corresponding demographics, body mass index measurements. Top PheWAS codes generated from a collated list of ICD codes from all study sites. Study sites and participants include: Cincinnati Children's Hospital Medical Center (CCHMC): Cincinnati Children's Hospital Medical Center (CCHMC) is a not-for-profit hospital and research center pioneering breakthrough treatments, providing outstanding family-centered patient care and training healthcare professionals for the future, and dedicated to improving health and welfare of children and to the shared purpose of discovery and practical application of new genomic information to the ordinary care of children. We bring a comprehensive electronic health record (EPIC), a deidentified i2b2 data warehouse of 680K patient records, a biobank with >261,000 consents that allow return of results to >84,000 patients and guardians who have provided DNA samples, and hundreds of faculty and senior staff who make genomics or informatics an active focus of their research. CCHMC will help the eMERGE III Steering Committee identify genes for the eMERGE III targeted sequencing panel, provide 3,000 DNA samples from CCHMC patients to be sequenced, review targeted gene panels from clinical care at CCHMC for somatic mosaicism and reinterpretation, and further develop and disseminate a software workflow suite for sequence analysis. We will also extend our work generating phenotype algorithms using heuristic and machine learning methods to many new childhood diseases. We will develop tools to evaluate adolescent return of results preferences, examine the ethical and legal obligations and potential to reanalyze results, and develop clinical decision support for phenotyping, test ordering, and returning sequencing results. Children's Hospital of Philadelphia (CHOP): The Center for Applied Genomics (CAG) is a specialized Center of Emphasis at the Children's Hospital of Philadelphia (CHOP), and one of the world's largest genetics research programs, with to state-of-the-art high-throughput sequencing and genotyping technology. Our primary goal is to translate basic research findings to medical innovations. We aim to develop new and better ways to diagnose and treat children affected by rare and complex medical disorders, including asthma, autism, epilepsy, pediatric cancer, learning disabilities, and a range of rare diseases. Ultimately, our objective is to generate new diagnostic tests and to guide physicians to the most appropriate therapies. Participants were recruited from the CAG biorepository (n>450,000), specifically from >100,000 CHOP pediatric patients and family members, which is enriched for rare-diseases (n>12,000). Center for Applied Genomics, The Children's Hospital of Philadelphia We gratefully thank all the children and their families who enrolled in this study, and all individuals who donated blood samples for research purposes. Genotyping for this project was performed at the Center for Applied Genomics and supported by an Institutional Development Award from The Children's Hospital of Philadelphia. Sequencing was supported by the National Institutes of Health through an award from the National Human Genome Research Institute's Electronic Medical Records and Genomics (eMERGE) program (U01HG008684). Columbia University: The goal of the Columbia eMERGE III project is to develop methods for integrating genomic data in EHRs and to study the impact of such genomic informatics interventions on the health of a diverse, underserved urban adult English- and Spanish-speaking patient population in Northern Manhattan served by Columbia University Medical Center/New York-Presbyterian Hospital system. The study group is 2500 patients recruited from diverse clinics and community outreach centers of self-reported White (~61%), Asian (~11%), African-American (~11%), American Indian/Alaska Native (<1%) racial and Hispanic (~33%) ethnic backgrounds. There are two subgroups in the study cohort - a retrospective group (N=1052) that includes patients from oncology and nephrology clinics, and a prospective one (N=1448) that includes healthy individuals as well as participants with diverse medical conditions. Confirmed pathogenic variants in 70 selected genes will be returned to participants and their healthcare providers through the EHR integration. Participants are able to choose the results they receive and will have the freedom to meet with a genetic counselor and a geneticist to review results. The impact of genetic testing on clinical care is determined by periodic monitoring of EHRs. Geisinger: Samples and phenotype data in this study were provided by the Geisinger MyCode® Community Health Initiative. Participants are recruited across the Geisinger System via online consents or in-person consents at a hospital or clinic visit. Enrollment is ongoing with over 100,000 individuals currently consented. Partners Healthcare (Harvard University): The Partners HealthCare Biobank is a large research program designed to help researchers understand how people's health is affected by their genes, lifestyle, and environment. This large research data and sample repository provides access to high-quality, consented blood samples to help foster research, advance our understanding of the causes of common diseases, and advance the practice of medicine. For the Partners research community (Massachusetts General Hospital and Brigham and Women's Hospital), the Biobank provides: Banked samples (plasma, serum, and DNA) collected from consented patients Blood samples that were discarded after clinical testing in the Crimson Cores maintained in the Brigham and Women's Hospital and Massachusetts General Hospital Pathology Departments Sample handling and preparation services Link to the biobank data to the Partners Research Patient Data Registry (RPDR) a research instance of our electronic clinical chart Data access through our research portal. To date, over 70,000 Partners patients have given their consent to enroll, give a blood sample, receive research results and agreed to be re-contacted for additional research studies. The Biobank has enabled Partners investigators to compete for nationally recognized grants in personalized medicine such as a clinical electronic Medical Records and Genomics network (eMERGE) site and the national All of US program. The Biobank currently supports over 120 Partners investigators and over 130 million dollars in NIH research. Kaiser Permanente Washington/ (KPWA) / University of Washington (UW): KPWA participants were enrolled in the eMERGE Network through the Northwest Institute of Genetic Medicine (NWIGM) biorepository, and provided the appropriate consent to receive clinically relevant genetic results (N=2,500.) NWIGM is based at the University of Washington and co-managed by the University of Washington and KPWA. The purpose of the NWIGM biorepository is to build infrastructure and resources to carry out a broad range of future genetic research. KPWA members enrolled in the biorepository are asked to provide informed consent to providing a DNA sample for storage in the NWIGM biorepository. The consent is purposefully broad to serve the dual purpose of reducing the burden on researchers who wish to use this biorepository and the IRB committees who will be responsible for reviewing these requests in the future. Participants were eligible if aged 50 - 65 years old at the time of their enrollment into the NWIGM repository, living, enrolled in KPWA's integrated group practice, and had completed an online Health Risk Appraisal. The selection algorithm was based on several data sources from the EHR at KPWA. 1) Demographics - participants with self-reported race as Asian ancestry were prioritized and selected to enrich for non-European ancestry. The KPWA eMERGE cohort includes N=1,245 members of Asian ancestry. 2) Participants were also selected for a history of colorectal cancer (N=1,255), in order to allow us to enrich germline pathogenic variants. Mayo Clinic: The Return of Actionable Variants Empirical (RAVE) Study was approved by the Mayo Clinic IRB. We recruited 2537 participants from Mayo Clinic biobanks in Rochester, MN, who had hypercholesterolemia or colon polyps, thereby enriching for Familial hypercholesterolemia (FH) and monogenic causes of colorectal cancer (CRC). Additional eligibility criteria were: 1) residents of Southeast MN who were alive and aged 18-70 years; 2) LDL-C level >155 or >120 mg/dl while on lipid-lowering therapy; 3) no known cause of secondary hyperlipidemia; and 4) no cognitive impairment or dementia that would compromise their ability to give written informed consent. Based on these criteria, we identified 5270 eligible patients and obtained informed consent from 3030 participants. Recruitment was conducted in waves and utilized mailed recruitment packets consisting of a study brochure, a written informed consent form, a baseline psychosocial questionnaire, and a return postage-paid envelope. DNA of 2537 participants was sent for CLIA-certified targeted sequencing of 109 genes including genes associated with FH and CRC. Targeted sequencing and genotyping was performed in a Central Laboratory Improvement Amendment (CLIA)-certified laboratory. Northwestern University: Samples and data used in this study were obtained from patients from Northwestern Medicine, an integrated healthcare system, formed through a partnership of Northwestern Memorial HealthCare and Northwestern University Feinberg School of Medicine. Participants include a retrospective cohort from the Northwestern Pharmacogenomics Study, funded through the eMERGE II project, NHGRI (3U01HG006388-02S1) and a prospective cohort from the Genetic Testing and Your Health Study, funded through the eMERGE III project, NHGRI (U01HG008673). Patients were eligible to participate if they were18 years or older and see a physician at Northwestern Medicine. Patients consented to genetic testing and to allow their results to be placed in their electronic medical record. Vanderbilt University Medical Center: Vanderbilt University Medical Center (VUMC) participants were enrolled in the eMERGE Network through the Vanderbilt Genome-Electronic Records (VGER) project. Patients were provided the appropriate consent to receive clinically relevant genetic results (N=2,700). Participants were eligible if aged 21 or over, had a healthcare provider at VUMC, and visited the provider at least 3 times in the past 3 years. Meharry Medical College: Inclusion of ethnic groups in genomic research is critical to identify possible reasons for health disparities. African-Americans are being enrolled in various outpatient clinics of Nashville General Hospital at Meharry, an inner city hospital primary serving a poorer patient group. A total of 500 African Americans with four cancer types demonstrating health disparities in this population - prostate, colon, breast, lung are identified and approached by clinical research coordinators. The purpose of the study is to determine if any genetic information can be identified from these patients who have or are at high risk of one of these disparate cancers. All participants provide written informed consent and HIPAA authorization to provide blood samples for broad research use and permission to access data in their hospital electronic medical record for research now and in the future. An extensive demographic profile is obtained and entered into a REDCap database. Blood samples are obtained for a panel of alleles from extracted DNA at Baylor. In addition, de-identified coded samples are processed and stored in a central biorepository for further DNA, RNA and proteomic analyses. The survey and phlebotomy are performed at the time of the initial contact and agreement to participate. Nearly all patients approached willingly agree to participate for potential benefit to themselves, family members, or humankind. Little concern is voiced of providing samples for genetic analysis. Study investigators will share results with the participants and providers if testing does not indicate high risk. Results indicating increased risk or actionable alleles for the patient and/or family will be returned by a genetic counselor. Monitoring of the patients' health in this cohort will continue to be followed in the EMR to identify any future associations that might explain health disparities in African Americans. Proposals will be reviewed from investigators to study the genetic or proteomic samples as well as the clinical and demographic information in the repository. Please note that this version of the dataset has a handful of mismatches between genotyped and provided sex. Data with the following IDs should be removed prior to analysis: 420252874213744142412243424569384245694642672223

  Study phs001616

• Action to Control Cardiovascular Risk in Diabetes (ACCORD-BioLINCC)

  Related StudiesWhole genome and whole exome data is available on a subset of participants with phs001411. ECG signal data is available with phs003562.ObjectivesThe purpose of this study was to determine if intensive glycemic control, multiple lipid management and intensive blood pressure control could prevent major cardiovascular events (myocardial infarction, stroke or cardiovascular death) in adults with type 2 diabetes mellitus. Secondary hypotheses included treatment differences in other cardiovascular outcomes, total mortality, microvascular outcomes, health-related quality of life and cost-effectiveness. BackgroundGlycemia Trial:Patients with type 2 diabetes mellitus die of cardiovascular disease (CVD) at rates two to four times higher than non-diabetic populations of similar demographic characteristics. They also experience increased rates of nonfatal myocardial infarction and stroke. With the growing prevalence of obesity in the United States, CVD associated with type 2 diabetes is expected to become an even greater public health challenge in the coming decades than it is now. Expected increases in event rates will be associated with a concomitant rise in suffering and resource utilization.The ACCORD study investigated whether intensive therapy to target normal glycated hemoglobin (HbA1c) levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors when compared to standard therapy (HbA1c between 7.0% and 7.9%). A separate analysis investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in these patients. Lipid Therapy Trial: Patients with type 2 diabetes mellitus have an increased incidence of atherosclerotic cardiovascular disease attributable, in part, to associated risk factors such as dyslipidemia. This is characterized by elevated plasma triglyceride levels, low levels of high-density lipoprotein (HDL) cholesterol and small, dense low-density lipoprotein (LDL) particles. The ACCORD Lipid Therapy trial was designed to test the effect of a therapeutic strategy that uses a fibrate to raise HDL-C and lower triglyceride levels and uses a statin for treatment of LDL-C reduce the rate of CVD events compared to a strategy that only uses a statin for treatment of LDL-C on cardiovascular outcomes in patients with type 2 diabetes that were at high risk for cardiovascular disease. Blood Pressure Trial: Diabetes mellitus increases the risk of cardiovascular disease at every level of systolic blood pressure. Because cardiovascular risk in patients with diabetes is graded and continuous across the entire range of levels of systolic blood pressure, even at prehypertensive levels, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended beginning drug treatment in patients with diabetes who have systolic blood pressures of 130 mm Hg or higher, with a treatment goal of reducing systolic blood pressure to below 130 mm Hg. There is, however, a paucity of evidence from randomized clinical trials to support these recommendations. The ACCORD Blood Pressure trial tested the effect of a target systolic blood pressure below 120 mm Hg on major cardiovascular events among high-risk persons with type 2 diabetes compared to a strategy that targeted a SBP of EYE Substudy: Diabetic retinopathy, an important microvascular complication of diabetes, is a leading cause of blindness in the United States. Randomized, controlled clinical trials in cohorts of patients with type 1 diabetes and those with type 2 diabetes have shown the beneficial effects of intensive glycemic control and intensive treatment of elevated blood pressure on the progression of diabetic retinopathy. Elevated serum cholesterol and triglyceride levels have been implicated, in observational studies and small trials, as additional risk factors for the development of diabetic retinopathy and visual loss. The ACCORD EYE Substudy evaluated the effects of the ACCORD medical strategies on the progression of diabetic retinopathy in a subgroup of trial patients. MIND Substudy: Studies suggest that older persons with type 2 diabetes have at least twice the likelihood of developing late-life cognitive impairment or dementia compared to those without. The mechanisms underlying these cognitive disorders are increasingly thought to reflect a mixed pathology pattern with contributions from vascular, neurodegenerative and neurovascular processes. Pathophysiological mechanisms that have been described include inflammation, oxidative stress, energy imbalance, protein misfolding, glucocorticoid-mediated effects and differences in genetic susceptibilities. The ACCORD MIND substudy took as a premise that early intervention with the ACCORD therapeutic strategies to improve glycemic control could mitigate the adverse effects of type 2 diabetes on the brain. Participants10,251 participants with type 2 diabetes and HbA1c concentrations of 7.5% or more participated in the trial. Of these patients, 5518 were assigned to the lipid therapy arm and 4733 to the blood pressure arm. EYE Substudy: A subgroup of 2856 participants was evaluated for the effects of the ACCORD interventions at 4 years on the progression of diabetic retinopathy. Participants who, at baseline, had a history of proliferative diabetic retinopathy that had been treated with laser photocoagulation or vitrectomy were excluded. MIND Substudy: A subgroup of 2977 participants was evaluated for cognitive function and brain volume. The ACCORD MIND substudy excluded participants aged Design Participants were randomly assigned to undergo either intensive glycemic control (targeting a glycated hemoglobin level EYE Substudy: EYE Substudy participants were evaluated at two standardized and comprehensive eye examinations for the effects of the ACCORD interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy. MIND Substudy: The cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, was assessed at baseline, 20 and 40 months. Total brain volume (TBV), the primary brain structure outcome, was assessed with MRI at baseline and 40 months in a sub-set of 632 patients. All patients with follow-up data were included in the primary analyses. Conclusions Glycemia Trial: As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. (Action to Control Cardiovascular Risk in Diabetes Study Group, et al.,2008, PMID:18539917). Microvascular Outcomes of the Glycemia Trial: Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Microvascular benefits of intensive therapy should be weighed against the risk of increased total and cardiovascular disease-related mortality, increased weight gain, and higher risk for severe hypoglycemia. (Ismail-Beigi et al., 2010, PMID: 20594588) Lipid Therapy Trial: The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes (ACCORD Study Group, et al., 2010, PMID: 20228404). Blood Pressure Trial: In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events (ACCORD Study Group, et al., 2010, PMID: 20228401). EYE Substudy: Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy (ACCORD Study Group, et al., 2010, PMID: 20587587). MIND Substudy: Although significant differences in TBV favored the intensive therapy, cognitive outcomes were not different. Combined with the unfavorable effects on other ACCORD outcomes, MIND findings do not support using intensive therapy to reduce the adverse effects of diabetes on the brain in patients similar to MIND patients (Launer et al., 2011, PMID: 21958949).

  Study phs003551

• Characterization of individual foci of multicentric/multifocal breast cancer using targeted next generation sequencing

  Multifocality or multicentricity in breast cancer may be defined as the presence of two or more tumor foci within a single quadrant of the breast or within different quadrants of the same breast, respectively. This original classification of the breast cancer as multicentric or multifocal was based on the assumption that cancers arising in the same quadrant were more likely to arise from the same ductal structures than those occurring in separate areas of the breast. The problem with these definitions is that the ?quadrants? of the breast are arbitrary external designations, as no internal boundaries do exist. This project will therefore focus both on synchronous multifocal and multicentric tumors. The incidence of multifocal and multicentric breast cancers was reported to be between 13 and 75% depending on the definition used, the extent of the pathologic sampling of the breast and whether in situ disease is considered evidence of multicentricity (1). Although this incidence is variable, those figures show that it is a frequent phenomenon. Multiple (multifocal/multicentric) breast carcinomas, especially when occurring in the same breast, represent a real challenge for both pathologists and clinicians in terms of identifying the cellular origin and the best therapeutic management of the cancer. Multifocality or multicentricity has been associated with a number of more aggressive features including an increased rate of regional lymph node metastases and adverse patient outcome when compared with unifocal tumors (2-3), and a possible increased risk of local recurrence following breast conserving surgery (4). For the moment, the literature is divided on whether there is a corresponding impact on survival outcomes. Today, the current convention to stage and to treat multifocal and multicentric tumors is the classical tumor-node-metastasis (TNM) staging guidelines with which tumor size is assessed by the largest tumor focus without taking other foci of disease into consideration. If some papers, as the recent one from Lynch and colleagues, support the current staging convention (3), others, however, as Boyages et al. suggested that aggregate size and not the size of the largest lesion should be considered in order to refine the prognostic assessment of those tumors (5). On the top of that, the question whether multifocal/multicentric carcinomas are due to the spread of a single carcinoma throughout the breast or is due to multiple carcinomas arising simultaneously has been a matter of debate. Some studies suggested that multifocal breast cancer may result from either intramammary spread from a single primary tumor or multiple synchronous primary tumors; whereas others suggest that multiple breast carcinomas always arise from the same clone (6-8). Recently, Pietri and colleagues analyzed the biological characterization of a series of 113 multifocal/multicentric breast cancers (8) which were diagnosed over a 5-year period. The expression of estrogen (ER) and progesterone (PgR) receptors, Ki-67 proliferative index, expression of HER2 and tumor grading were prospectively determined in each tumor focus, and mismatches among foci were recorded. Mismatches in ER status were present in 5 (4.4%) cases and PgR in 18 (15.9%) cases. Mismatches in tumor grading were present in 21 cases (18.6%), proliferative index (Ki-67) in 17 (15%) cases and HER2 status in 11 (9.7%) cases. Interestingly, this heterogeneity among foci has led to 14 (12.4%) patients receiving different adjuvant treatments compared with what would have been indicated if we had only taken into account the biologic status of the primary tumor. This study therefore showed that differences in biological characteristics of multifocal/multicentric lesions play a crucial role in the adjuvant treatment decision making process. In this study, we will concentrate on a larger series of patients with multifocal invasive ductal breast cancer lesions. We aim at: 1. Evaluating the incidence of multifocality according to the different breast cancer molecular subtypes (ER-/HER2-, HER2+, ER+/HER2-). 2. Evaluating the incidence of multifocality in patients with hereditary breast cancer disease (presence of germline BRCA1 or BRCA2 mutations). Moreover, we would like to investigate if multifocal lesions with BRCA1 or BRCA2 mutations exhibit a characteristic combination of substitution mutation signatures and a distinctive profile of deletions as demonstrated recently by Nik-Zainal and colleagues (9). 3. Correlating multifocality with clinical information in order to define its influence on patients? survival (DFS and OS). 4. Carrying high coverage targeted gene sequencing of driver cancer genes and genes whose mutation is of therapeutic importance in order to compare clinically-relevant genetic differences between several multifocal breast cancer lesions. 5. Evaluating the impact of the distance between the different lesions on the clinical outcome but also on the genetic differences. 6. Comparing gene expression patterns between several multifocal breast cancer lesions and correlate them with the results of the targeted genes screen. 7. Characterizing the genomic and transcriptomic status of cancer related genes in metastatic lesions (local recurrence, positive lymph node or distant metastatic sites) from the same multifocal invasive ductal breast cancer patients in order to evaluate the consequence of genomic and transcriptomic heterogeneity of multifocal lesions on metastatic lesions. Multiple (multifocal/multicentric) breast carcinomas, especially when occurring in the same breast, represent a real challenge for both pathologists and clinicians in terms of identifying the cellular origin and the best therapeutic choice. This project has the potential to identify genetic/transcriptomic differences existing between several lesions constituting multifocal breast cancers, which in the routine clinical practice are usually considered to be homogeneous among them. We foresee validating significant results in a larger series of patients and this, in turn, could have a remarkable impact on the treatment and clinical management of multifocal breast cancers. Indeed, we hope to provide some evidence whether or not each focus matters in multifocal and multicentric breast cancer to define the adequate therapeutic approach, especially in the context of targeted therapies. The work to be done at Sanger will be target gene screen pooling of 1400 samples.

  Dataset EGAD00001000624

• How to encrypt files with EGACryptor

  File preparation Due to the processes used at the EGA for file archival the use of non-alphanumeric characters in a filename will cause issues in archival. By convention whitespaces in filenames are to be avoided and should be replaced with the underscore character (_). Before encrypting your files please make sure that any files that will be uploaded to EGA do not use special characters such as # ? ( ) [ ] / \ = + < > : ; " ' , * ^ | &  Crypt4gh EGACryptor Files encrypted with EGACryptor must be uploaded via FTP EGACryptor The EGACryptor v.2.0.0 is a JAVA-based application which enables submitters to produce EGA compliant encrypted files along with files for the encrypted and unencrypted md5sum for each file to be submitted. The application will generate an output folder that will by default mirror the directory structure containing the original files. This output folder can subsequently be uploaded to the EGA FTP staging area via an FTP or Aspera client. Download EgaCryptor Download EgaCryptor Using the EgaCryptor Using the EgaCryptor Encrypting single file Encrypting multiple files Encrypting all files in folder Points to note Troubleshooting Troubleshooting Download EGACryptor The required jar files can be obtained by downloading EgaCrytptor jar file After the file has been downloaded, extraction of the zipped archive is required. The EGACryptor has been built to work with Java Runtime Environments from version 6 and above and with the OpenJDK Environment. Please refer to the relevant resources for installation guidance. Installing the latest version of the OpenJDK will include the JCE files. If your installation of Java JRE is less than 1.8.0_151 will require the manual installation of the JCE Policy Files. You can verify the version of the Java SE Runtime Environment (JRE) installed by using the command: $ java -version If you need to install the JCE please follow the instructions below: Installing the JCE policy files (due to licensing terms and conditions the required policy files must be downloaded direct from the ORACLE website) : Download the unlimited strength JCE policy files (JRE 6 / JRE 7/ JRE 8) Uncompress and extract the downloaded file. This will create a subdirectory called JCE. This directory contains the following files: README.txt, COPYRIGHT.html, local_policy.jar and US_export_policy.jar Install the two policy JAR files by replacing the existing ones in your java home directory. Install the two policy JAR files by replacing the existing ones in your directory. The standard place for JCE jurisdiction policy JAR files is: /lib/security [Unix] or \lib\security [Win32] Notes: refers to the directory where the Java SE Runtime Environment (JRE) was installed. Additional performance enhancements that have been included in the EGACryptor V2.0.0: The ability to parallelise the processing of datasets through the use of the resources on a system. Multicore systems will allow the user to specify n-1 cores for an n-core system. The use of this feature on clusters may speed up the processing of datasets that have large file numbers but consult your local cluster guide to ensure that there are not monopolising resources that are needed by other system users. The default for this process remains single threaded. 3 levels of system usage can be specified. Full usage within the limits detailed above. A limited mode that will ensure that 50% of the system resources are available for other tasks. Maximum mode is limited to 75% of system resources, this allows encryption to be prioritised but allows for the system to be usable for light alternate tasks. Finally there is a throttling mode that allows you to specify the exact number of computational threads to be used. the EGACryptor is able to ingest a structured directory and will output a directory with the same structure containing the encrypted files along with the md5checksums for the plain and encrypted files. The entire output directory can then be uploaded to the EGA for archival. as with the input path, it is now possible to specify the output path. the options have been updated inline with the upgraded functionality. The tool can only be used via the command line. The EGACryptor is designed to perform a single task, encrypting your data, for upload of these files please refer to our uploading guide Using the EgaCryptor Below are the three ways on how the EGACryptor tool can be used: Encrypting a single file : java -jar ../EGA-Cryptor_2_0_0.jar -i example1.bam Encrypting multiple files : java -jar ../EGA-Cryptor_2_0_0.jar -i "example1.bam,example2.bam" Encrypting all the files within a folder java -jar ../EGA-Cryptor_2_0_0.jar -i path/to/target/directory By default the EGACryptor v2 will create a new output directory containing all encrypted files and the relevant checksums within the target directory. If a specific directory is desired this can be specified by using the -o flag. This can be achieved in a similar manner to the following example: java -jar ../EGA-Cryptor_2_0_0.jar -i /path/to/target/directory -o /path/to/output/directory The tool will output three files per input file: file.gpg ( encrypted file ) file.md5( file md5 sum value file ) file.gpg.md5 ( encrypted file md5 sum value file ) All output files must then be uploaded to your submission account using Aspera or FTP. Further documentation on how to upload files: FTP and Aspera. Points to note Remember to provide the path to EgaCryptor.jar and run the command from within the directory the file/s are located. ECryptor writes files to the source directory of your local file system, as a result you must have write-access permissions for the source directory. Troubleshooting If in doubt about the function of the EGACryptor it is recommended to first consult the built-in documentation. This can be accessessed by using the -h flag as stated in the following table. Built-in Commands Table: list of the command line options built into EGA-Cryptor v2.0.0. Command line Option Action --------------------- ----------- -f Set this option to allow application to create maximum threads to utilise full capacity of cores/processors available on machine -h Use this option to view the bult-in help menu * -i File(s) to encrypt. Provide file/folder path or comma separated file path if multiple files in double quotes -l Set this option to allow application to create maximum threads equals to 50% capacity of cores/processors available on machine -m Set this option to allow application to create maximum threads equals to 75% capacity of cores/processors available on machine -o Path of the output file. This is optional. If not provided then output files will be generated in the same path as that of source file (default: output- files) -t Set this option if user wants to control application to create maximum threads as specified. Application will calculate no. of cores/processors available on machine & will create threads accordingly Encryption Errors UnixFileSystem.createFileExclusively (Native Method) The error is thrown by UNIX ("UnixFileSystem.createFileExclusively(Native Method)"). It appears that the user does not have write-access to the file system where the file to be uploaded is located. EGACryptor always writes MD5 checksums into files before uploading them to the server, and these files are created in the same location where the uploaded file itself resides.Solution: address your directory permission issue and re-run the command. Install JCE Unlimited Strength Jurisdiction Policy files The JCE policy unlimited strength jurisdiction files should be installed according to your current java version If you are still facing difficulty with the EGACryptor v.2 after having consulted the documentation please contact the EGA Helpdesk.

  Documentation submission/data/file-preparation/egacryptor

• Multi-Ethnic Study of Atherosclerosis (MESA) Cohort

  MESA The Multi-Ethnic Study of Atherosclerosis (MESA) is a study of the characteristics of subclinical cardiovascular disease (disease detected non-invasively before it has produced clinical signs and symptoms) and the risk factors that predict progression to clinically overt cardiovascular disease or progression of the subclinical disease. MESA researchers study a diverse, population-based sample of 6,814 asymptomatic men and women aged 45-84. Thirty-eight percent of the recruited participants are white, 28 percent African-American, 22 percent Hispanic, and 12 percent Asian, predominantly of Chinese descent. Participants were recruited from six field centers across the United States: Wake Forest University, Columbia University, Johns Hopkins University, University of Minnesota, Northwestern University and University of California - Los Angeles. Each participant received an extensive physical exam to determine coronary calcification, ventricular mass and function, flow-mediated endothelial vasodilation, carotid intimal-medial wall thickness and presence of echogenic lucencies in the carotid artery, lower extremity vascular insufficiency, arterial wave forms, electrocardiographic (ECG) measures, standard coronary risk factors, sociodemographic factors, lifestyle factors, and psychosocial factors. Selected repetition of subclinical disease measures and risk factors at follow-up visits allows study of the progression of disease. Blood samples have been assayed for putative biochemical risk factors and stored for case-control studies. DNA has been extracted and lymphocytes cryopreserved (for possible immortalization) for study of candidate genes and possibly, genome-wide scanning, expression, and other genetic techniques. Participants are being followed for identification and characterization of cardiovascular disease events, including acute myocardial infarction and other forms of coronary heart disease (CHD), stroke, and congestive heart failure; for cardiovascular disease interventions; and for mortality. In addition to the six Field Centers, MESA involves a Coordinating Center, a Central Laboratory, and Central Reading Centers for Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Ultrasound, and Electrocardiography (ECG). Protocol development, staff training, and pilot testing were performed in the first 18 months of the study. The first examination took place over two years, from July 2000 - July 2002. It was followed by four examination periods that were 17-20 months in length. Participants have been contacted every 9 to 12 months throughout the study to assess clinical morbidity and mortality. MESA Family The general goal of the MESA Family Study, an ancillary study to MESA funded by a grant from NHLBI, is to apply modern genetic analysis and genotyping methodologies to delineate the genetic determinants of early atherosclerosis. This is being accomplished by utilizing all the current organizational structures of the Multi-Ethnic Study of Atherosclerosis (MESA) and Genetic Centers at Cedars-Sinai Medical Center and University of Virginia. In the MESA Family Study, the goal is to locate and identify genes contributing to the genetic risk for cardiovascular disease (CVD), by looking at the early changes of atherosclerosis within families (mainly siblings). 2128 individuals from 594 families, yielding 3,026 sibpairs divided between African Americans and Hispanic-Americans, were recruited by utilizing the existing framework of MESA. MESA Family studied siblings of index subjects from the MESA study and from new sibpair families (with the same demographic characteristics) and is determining the extent of genetic contribution to the variation in coronary calcium (obtained via CT Scan) and carotid artery wall thickness (B-mode ultrasound) in the two largest non-majority U.S. populations. In a small proportion of subjects, parents of MESA index subjects participating in MESA Family were studied but only to have blood drawn for genotyping. The MESA Family cohort was recruited from the six MESA Field Centers. MESA Family participants underwent the same examination as MESA participants during May 2004 - May 2007. DNA was extracted and lymphocytes immortalized for study of candidate genes, genome-wide linkage scanning, and analyzed for linkage with these subclinical cardiovascular traits. While linkage analysis is the primary approach being used, an additional aspect of the MESA Family Study takes advantage of the existing MESA study population for testing a variety of candidate genes for association with the same subclinical traits. Genotyping and data analysis will occur throughout the study. MESA Air The general goal of the Multi-Ethnic Study of Atherosclerosis and Air Pollution (&#39;MESA Air&#39;) is to prospectively examine the relation between an individual level assessment of long-term ambient air pollution exposures (including PM2.5 and the progression of subclinical cardiovascular disease in a multi-city, multi-ethnic cohort. MESA Air will also prospectively examine the relationship between an individual level assessment of long-term ambient air pollution exposures and the incidence of cardiovascular disease, including myocardial infarction and cardiovascular death. MESA AIR is funded by a grant from the United States Environmental Protection Agency to the University of Washington and subcontracts from the UW to other participating institutions. MESA Air will assess if ambient air pollution is associated with changes over time in subclinical measures of atherosclerosis and plasma markers of inflammation, oxidative damage, and endothelial activation in a longitudinal data model, adjusting for age, race/ethnicity, socioeconomic status, and specific cardiovascular risk factors (such as diabetes, hypertension, smoking, and diet). The study will similarly assess if the incidence of cardiovascular events is associated with long-term exposure to ambient air pollution, using a proportional hazards model. The study includes refinement of statistical tools, and explores joint/independent effects of acute and long-term pollutant exposure in the occurrence of cardiovascular disease. The MESA Air study is built on the foundation of the ongoing MESA study. The parent MESA Study cohort is located in six geographic areas (&#39;Field Centers&#39;) that capture tremendous exposure heterogeneity, comparable to or greater than the variability in locations of prior U.S. cohort studies. In addition to the six Field Centers, the study involves a Coordinating Center, a Central Laboratory, and Reading Centers for Computed Tomography (CT), ultrasound and air pollution data. The cohort for the MESA Air study currently includes 6226 subjects: 5479 enrolled in the parent MESA study; 257 recruited specifically for this study, and 490 recruited from the MESA Family study. The entire MESA Air cohort will be followed over a 10-year project period for the occurrence of cardiovascular disease events. On two occasions over the ten-year study period, 3600 subjects from the MESA Air cohort, residing in nine locales, will undergo computed tomography scanning to assess presence and extent of coronary artery calcification (CAC), and ultrasound of the carotid artery to determine intima-media thickness (IMT). We will also repeatedly assess plasma markers of inflammation, oxidative damage, and endothelial function in 720 subjects. MESA Air adds state-of-the-art air pollution exposure assessment information to the MESA cohort study, and introduces new subjects and outcome measures to achieve our aims. The study will assess long-term individual-level exposure to ambient air pollutants for each subject using community-scale monitoring, outdoor spatial variation, subject proximity to pollution sources, pollutants&#39; infiltration efficiency, and personal time-activity information. The exposure models will be validated using detailed monitoring in a subset of subjects. The MESA Cohort is utilized in the following dbGaP substudies. To view genotypes, analysis, expression data, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" box located on the right hand side of this top-level study page phs000209 MESA Cohort. phs000420 MESA SHARe phs000283 MESA CARe phs000403 MESA ESP Heart-GO

  Study phs000209

• GAW16 Framingham and Simulated Data

  Important links to apply for individual-level data Genetic Analysis Workshop Instructions to Request Authorized Access Data Use Certification Requirements (DUC) Apply here for controlled access to individual level data Research Use Statement Questions regarding GAW16 should be directed to Vanessa Olmo at vanessa@business-endeavors.com. Problem 2: Description of the Framingham Heart Study In GAW16, we use data drawn from the Framingham Heart Study. The Framingham Heart Study &#8212; under the direction of National Heart, Lung, and Blood Institute; NHLBI &#8212; began in 1948 with the recruitment of adults from the town of Framingham, Massachusetts. At the time, little was known about the general causes of heart disease and stroke, but the death rates for cardiovascular disease (CVD) had been increasing steadily since the beginning of the 20th century and had become an American epidemic. The Framingham Heart Study is now conducted in collaboration with Boston University. The objective of the Framingham Heart Study was to identify the common factors or characteristics that contribute to CVD by following its development over a long period of time in a large group of participants who had not yet developed overt symptoms of CVD or suffered a heart attack or stroke. Between 1948 and 1953 the researchers recruited 5,209 subjects (2,336 men and 2,873 women) between the ages of 29 and 62 from the town of Framingham, Massachusetts and began the first round of extensive physical examinations and lifestyle interviews that they would later analyze for common patterns related to CVD development. Subjects were recruited from lists of addresses recorded for the town. Two out of every three households were approached for participation in the study. While there was no intention to recruit families for family studies, the plan was to recruit all household members in the ages 30-60 within each house that was selected for study. Hence, many biologically related individuals were recruited, including 1644 spouse pairs. Since 1948, these participants have returned to the study every two years for a detailed medical history, physical examination, and laboratory tests. Now in 2008 at 60 years of follow up, there remain about 500 participants from this cohort. Between 1971 and 1975 the study enrolled a second-generation group &#8212; 5,124 of the original participants&#39; children and the spouses of these children &#8212; to participate in similar examinations. 2,616 subjects are offspring of the original spouse pairs and 34 are stepchildren. A total of 898 offspring are children of cohort members where only one parent was a study participant and 1,576 are spouses of the offspring. The Offspring Cohort has been followed every four years through 2001 (except between Exams 1 and 2 with an intervening 8 years) using protocols similar to those used for study of the Original Cohort. Between 2002 and 2005 the study enrolled the third generation (Gen3) of the Framingham Heart Study - 4095 offspring of the second generation. None of their spouses were recruited. An additional 103 parents of this third generation, who were not recruited between 1971 and 1975, were also recruited at this time. The latter group is not included in the GAW16 data. With the recruitment of this third generation, the study has increasingly focused on genetic factors associated with the development of cardiovascular disease and its associated risk factors. To date, there is only one examination of this generation of participants. A description of the recruitment of this third generation and comparison with the earlier generations at their initial recruitment is presented in Splansky GL et al., 2007. Further information on the Study can be found at http://www.nhlbi.nih.gov/about/framingham/index.html. Genome-wide Dense SNP Scan in Framingham Heart Study Genetic studies did not begin in the FHS until the 1990s. In the late 1980s and through the 1990s DNA was extracted from blood samples of surviving FHS participants. In 2007, the FHS entered a new phase with the conduct of genotyping for the FHS SHARe (SNP Health Association Resource) project, for which dense SNP genotyping was performed using approximately 550,000 SNPs (GeneChip&#174; Human Mapping 500K Array Set and the 50K Human Gene Focused Panel) in 10,775 samples (some duplicates) from the three generations of subjects (including over 900 pedigrees). Affymetrix conducted all genotyping for the FHS SHARe project, using the 250K Sty, 250K Nsp, and the supplemental 50K platforms. Eighty-nine percent of the DNA samples were collected during the 1990s. To maximize the power of the study, we also extracted DNA from 1133 blood samples, drawn from subjects who had no DNA, to include in the SHARe project. These samples had been sitting in our refrigerators for some time, a few as far back as the 1970s. We refer to these DNA samples as the legacy samples. These samples had a higher failure rate in the genotyping process (40%) than the other eighty-nine percent (3%). Affymetrix invoked its own criteria for a sample to succeed in genotyping. All non-legacy samples must succeed on all three platforms, while legacy samples needed to pass on at least one platform. When a sample failed, additional attempts were made. Samples that repeatedly failed 2-4 times were called failures. Other samples failed due to issues of genotyped sex identification not matching our records or low SNP concordance among SNPs common across arrays or contamination. Eighty-nine percent of the legacy samples for which genotyping results are available passed all three platforms. The genotyping data from the 10,043 samples from 9354 subjects that passed the Affymetrix criteria were additionally checked for gender consistency and consistency with family structure, resulting in genotyping data for 9,274 participants in FHS SHARe. Genotype calls were made with the BRLMM algorithm. The SHARe database is housed at the National Center for Biotechnology Information database of genotypes and phenotypes (NCBI dbGaP) and contains all ~550,000 SNPs. This genome-wide dense SNP scan and a subset of phenotypes from the Framingham Heart Study are the focus of the Genetic Analysis Workshop 16. Further information on the specific variables in the Problem 2 dataset can be found by clicking on the Documents tab at the top of the page. Problem 3: Description of the Simulated Data Set The focus of this simulation is gene discovery in genome-wide association scans (GWAS). The Framingham Heart Study data set (distributed as "Problem 2") is the basis for the FHS* simulated data. The pedigree structures are derived from the data distributed for Problem 2, and we distribute an accompanying triplet file (triplet_sim) containing person ID, father ID, mother ID, to ensure the identical subjects, pedigrees, and singletons are used in the simulated data analysis. Consistent with standard practice, founders and singletons are designated as subjects with both fshare and mshare equal to zero (missing). The simulated data includes a total of 6,479 subjects with both phenotype and genotype data, in 942 pedigrees distributed among 3 generations and 188 singletons. Data inclusion is consistent with the subjects&#39; consent for use by both for-profit and not-for-profit researchers. The genotypes for all Problem 3 replicates are fixed as measured and distributed for Problem 2 for both the genomewide scan and the additional candidate gene SNPs, for a total of approximately 550,000 SNPs (GeneChip&#174; Human Mapping 500K Array Set and the 50K Human Gene Focused Panel). Thus, to analyze the Problem 3 simulated data you also will need to download the Problem 2 genotypes. Note that there are slight discrepancies in counts between Problems 2 and 3 due to a change in consents between the two datasets. Several phenotypes that contribute to coronary heart disease (CHD) were simulated for all individuals with genotypes across three different time points, 10 years apart. All genotyped individuals have complete data; the effects of missing values can be investigated by user-specified missing value patterns. There are 200 longitudinal datasets created, based on the generating model, and each replication is found in a separate dataset. We suggest that if only one replication is to be analyzed, that it be replication 1 to enable more precise comparisons among analytical approaches. The &#39;shareid&#39; will allow you to merge the simulated phenotype data with the Problem 2 genotype data, and reconstruction of the pedigrees using the distributed &#39;triplet_sim&#39; file or for larger families&#39; relationships with the triplet distributed with the Problem 2. The simulated data problem is further described in the associated readme file, and a data dictionary is provided defining all the variables. For disclosure of the generating model for these data, please contact Jean MacCluer at jean@sfbrgenetics.org.

  Study phs000128

• Distribution of data using Live Distribution

  Live Distribution Welcome to the documentation for using the Live Distribution feature for distributing data files securely through the EGA platform. This guide will walk you through the process of downloading encrypted files and decrypting them using Crypt4GH. Please follow the steps below to ensure a smooth experience. Before Downloading Create an EGA user. Make sure that you have the permissions to download the dataset of interest. In case you don’t have access, request access to the dataset. Add your Crypt4GH-compatible public key to your EGA account. Please allow a few hours for your public key to be synced with your profile. Afterwards, you will be able to connect to your EGA outbox using the SFTP protocol. Download Graphical User Interface (GUI) You can use any GUI that supports SFTP connections, such as FileZilla, an open-source FTP client. For Filezilla as your GUI, follow these steps to download files: Open FileZilla and access Site Manager (File > Site Manager). Create a new connection with the following settings (Figure 1): Protocol: SFTP - SSH File Transfer Protocol Host: __EGA_OUTBOX_DOMAIN__ Logon Type: Key file User: your EGA username Key file: path/to/your/private_key Figure 1: Process of establishing a new connection to __EGA_OUTBOX_DOMAIN__ using a key file as the logon method in FileZilla. The figure showcases the FileZilla version 3.52.2 operating on IOS v11.2.3. By following the depicted steps, users can create a secure and efficient connection to the EGA outbox, ensuring seamless data transfers. Click Connect to access your Outbox. This folder serves as your storage space within the EGA cloud, containing files accessible for download in a secure way. Browse the remote directory on the right side of the FileZilla screen. Select the files you wish to download, right-click, and choose Download (Figure 2). Figure 2: Step-by-step process of manually downñoad files from __EGA_OUTBOX_DOMAIN__ using FileZilla, with FileZilla version 3.52.2 operating on IOS v11.2.3. The figure demonstrates how users can downñoad data from the EGA outbox to their local storage by following the depicted steps SFTP command line You can also use the SFTP command line to securely download files from the EGA Outbox. Using SFTP command line client in Linux/Unix Open a terminal window Enter the following command to connect: sftp username@hostname Enter your EGA password To see a list of available sftp commands type help sftp> put – Upload file sftp> get – Download file sftp> cd path – Change remote directory to ‘path’ sftp> pwd – Display remote working directory sftp> lcd path – Change the local directory to ‘path’ sftp> lpwd – Display local working directory sftp> ls – Display the contents of the remote working directory sftp> lls – Display the contents of the local working directory Type get command to download files. For example: get encrypted_file.c4gh Use the bye command to close the connection (SFTP session). Convenient SSH settings Include the following settings in your SSH config file, located in ~/.ssh/config Host __EGA_OUTBOX_DOMAIN__ EGA-outbox hostname __EGA_OUTBOX_DOMAIN__ User username IdentityFile path/to/the/private/key Replace username and path/to/the/private/key with the appropriate settings, and you will be able to connect to the __EGA_OUTBOX_DOMAIN__ simply using sftp EGA-outbox. How to decrypt Files archived at the EGA are encrypted based on Crypt4GH. Hence, to decrypt the files you need to install Crypt4GH. You can install a python implementation of it, with pip install crypt4gh or directly from the Github repository pip install git+https://github.com/EGA-archive/crypt4gh.git After installing Crypt4GH, decrypt files using the following command: crypt4gh decrypt --sk /path/private/key < encrypted_file.c4gh > decrypted_filename The command reads the encrypted file from stdin (with <) and output the decrypted version to stdout (with >). Replace encrypted_file.c4gh and decrypted_filename with the appropriate filenames but make sure to not use the same filename for both reading and writing because your SHELL would then truncate both files before you even read or write. Frequently Asked Questions What username should I use to log in to my outbox? The authentication process for logging in to the EGA website, as well as accessing your inbox and outbox, requires the use of your username, not your email address. Therefore, if you registered a username different from your email address when creating your EGA account, you must use that username to log in. If you have forgotten your registered username, please, contact our Helpdesk team for assistance. I see that some files in my dataset have 'unavailable' as extension. What should I do? Within your Outbox, you'll find a list of all the datasets available for download. Occasionally, certain files may be marked as "unavailable". These unavailable files can be identified by the "unavailable" extension added to their filenames (e.g. filename.fastq.gz.unavailable.c4gh). If you encounter an unavailable file that you need, please reach out to our Helpdesk. We'll promptly work on making the file accessible for download as soon as possible. Specific to using keys Can I access one EGA account from different devices? Yes, you can access your account from different devices by linking several public keys to your EGA account. Each device can generate a unique public-private key pair, and the corresponding public keys can be linked to the same account. This way, you can use different public keys on different devices and still have access to the same account and data. I have several keys and I don't remember which one is which When generating SSH keys, it's a good practice to add a comment using the -C flag. This will allow you to add a descriptive tag to your key, making it easier to identify later on. Here's an example command that generates an SSH key with a comment: ssh-keygen -t ed25519 -C work-pass In this example, we're generating an ed25519 SSH key with the comment work-pass. Once you have multiple keys with different comments, you can use the comments to easily identify each key. To view the comments for your existing SSH keys, you can use the following command: ssh-keygen -l -f /path/to/key This will display the key fingerprint and the associated comment. By checking the comments, you should be able to identify which key is which. What if I can't find my SSH keys for uploading files with a key file, and how can I use new keys? If you can't find your SSH keys, don't worry - you can make new ones. To do this, open your terminal or command prompt and type a command to make a new SSH key. You can pick a name for the key, and choose a password to keep it safe. After making the key, you can add the new key to your account or server where you want to upload files using the key file. This usually involves copying and pasting the key's "public" (e.g. file.pub) part to the right place. If you lose track of the key again, just make a new one and add it again. Keep in mind that SSH keys belong to you and your computer, so if you switch computers or accounts, you'll need to make new keys. I don't want to type the passphrase every time I use the key. What can I do? You can use an ssh-agent to avoid typing the passphrase every time you use the key. An ssh-agent is a program that stores your private keys in memory and provides them to ssh when needed. You can add your key to the ssh-agent using the command ssh-add followed by the path to your key file.Here's an example of the steps to follow: Open a terminal window.Start the ssh-agent by typing the command eval $(ssh-agent).Add your key to the ssh-agent by typing the command ssh-add [key filepath]. For instance, if your key file is located in the home directory with the name mykey, the command will look like this: ssh-add ~/mykey After adding your, key to the ssh-agent, you should be able to use ssh without having to enter your passphrase every time. Can I use my password for authentication (without my private key)? If you prefer to use your username and password for authentication instead of your private key, you can still do so. When using a Graphical User Interface (GUI) such as FileZilla, you can select Ask for password as your Logon Type (Figure 3). This option will prompt you to enter your password when you click Connect, instead of using your private key. Figure 3: This option will prompt you to enter your password when you click "Connect", instead of using your private key. Figure 3: Process of establishing a new connection to __EGA_OUTBOX_DOMAIN__ using your password as the logon method in FileZilla. The figure showcases the FileZilla version 3.52.2 operating on IOS v11.2.3. By following the depicted steps, users can create a secure and efficient connection to the inbox, ensuring seamless data transfers. It's worth noting that using a password for authentication can be less secure than using an SSH key, as passwords can be more easily compromised through various means. However, if you choose to use your password for authentication, selecting "Ask for password" as your Logon Type is a good way to do so securely via a GUI. Why is it better to use my key and not my password? SSH keys for authentication is generally considered to be more secure and convenient than using passwords. SSH keys are more difficult to crack than passwords, and they can be restricted to specific users and machines, giving you more control over access. Once you set up your SSH keys, you can use them to authenticate quickly and easily, without having to enter a password every time. This makes automation of tasks, such as uploading encrypted files, much simpler. Additionally, SSH keys provide better logging, allowing you to keep track of who is accessing your systems and when. All in all, using SSH keys is a good practice for improving security and convenience in your authentication process.

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• What is a DAC?

  What is a DAC? Given the complexity, scale, and diversity of global submitters and studies, the EGA operates a distributed data access model in which requests are made to the data controller, not to the EGA. The European Commission defines a data controller, in the General Data Protection Regulation (GDPR), as the person that determines the purposes for which and the means by which personal data is processed. A Data Access Committees, commonly referred to as DACs, comprise on or more individuals (or data controllers) that review data access requests and make decisions on who can access personally identifiable genetic, phenotypic, and clinical data deposited at the EGA. Therefore, the members of a DAC should be individuals who have the authority to approve data access requests. The animation describes how you can authorise access to your sensitive data with the help of Data Access Committee and Authorisation tool. Acknowledgement to CSC - IT Center for Finland, Elixir Finland, Elixir Europe. Frequently Asked Questions How can I create a Data Access Committee? How can I create a Data Access Committee? The members of a DAC can come from different areas of expertise, such as data management, data analysis, information technology, legal and compliance, subject matter experts, privacy and security, and representatives from the organisations or individuals that provide data to the DAC. The specific members of a DAC can vary depending on the needs of the organisation and the type of data being managed. The EGA strongly suggests checking with your organisation to align with its regulations How should a DAC be named? The chosen name must be informative to the applicant.  For example, internal identifiers, such as grant numbers, should not be used. Individual PI names should also not be used. DAC's are often named after the organisation or department of the data source.  Browse the full list of DAC names currently in the EGA. How can I become an EGA DAC contact? To register a DAC at the EGA you must create first as an EGA user. Once your EGA user has been approved by the Helpdesk team, you will be able to log in to the DAC Portal. How can I register a DAC? To register a DAC, follow the DAC Portal instructions.  You will be required to provide a DAC name, name of the individual(s) that make up your DAC and contact details for your DAC including your Institutional email(s). Wherever possible, the DAC should make sure that all points of contact are readily available and able to answer any initial data requests/queries in < 2 weeks.  Once your DAC is registered, you will have to wait upon the validation from our Helpdesk team. As soon as all the validations have been completed, your DAC will be activated. Alternatively, you can also establish a DAC at the EGA during a programmatic submission through Webin API. Which are the possible roles of a DAC contact? There are two possible roles for DAC contacts: member and admin. An admin has additional privileges compared to a member: An “admin” can manage data requests, create and edit policies, edit the content of the DAC, add or remove contacts, and decide the role of each contact. A “member” can manage data requests and create policies. However, a member does not have permission to modify DAC details, edit information from policies where they are not admins, or add/remove contacts. There is no limit to the number of admins in a DAC, and each admin is responsible for deciding who should have editing privileges. This allows for a more decentralised and democratic approach to managing the DAC. How can I modify the information of a DAC? To modify a DAC, follow the instructions here. Keep in mind that only DAC contact with an admin role can modify the information of a DAC. If your DAC was registered before the lauch of the DAC Portal, and its ID is EGAC0 (not EGAC5), you must use the programmatic submission to modify it. Please, do not hesitate to contact our Helpdesk team if you need help with this! To prevent potential data breaches and ensure adherence to GDPR regulations, it is essential that the European Genome-Phenome Archive (EGA) is informed via the Helpdesk team of any changes to the Data Access Committee (DAC). This should be done in addition to any changes being made on the DAC portal. Data Controllers (as per the definition in the DPA) are also responsible for notifying the previous DAC of any modifications. Without proper notification, changes might not be automatically updated in our system, leading to the risk of incorrect permissions being applied and potential data access issues. Therefore, it is imperative that all Data Controllers follow this protocol to maintain data integrity and security. What’s the link between DAC, policy and dataset? A dataset is linked to one single policy. At the same time, one policy has a one to one relationship with a DAC. In this example, you can see that in this dataset page, we are only showing the information of one DAC (1 dataset - 1 DAC). However, the ratio of objects does not work the same in the other direction. One DAC can own multiple policy objects. And each policy object can be reused in several datasets. Thus, one DAC can manage one or more datasets. In this example, you can see that in this DAC page, we are showing all the datasets that are managed by one DAC (1 DAC - >400 datasets). EGA Data Access Committee Best Practices Which are the EGA DAC best practices? Refer to DAC Best Practices What happens if a DAC member changes institutions? EGA is committed to the protection and ownership of the data stored in our systems. We respect the institution's ownership of the data, and as such, if a DAC member changes institutions, the ownership of the data will not be transferred to the new institution. Therefore, before changing institutions, we request that the DAC contact add a new member who will replace them once they no longer work at the institution. This ensures that the data remains protected and is accessible to authorised personnel at the institution. To prevent potential data breaches and ensure adherence to GDPR regulations, it is essential that the European Genome-Phenome Archive (EGA) is informed via the Helpdesk team of any changes to the Data Access Committee (DAC). This should be done in addition to any changes being made on the DAC portal. Data Controllers (as per the definition in the DPA) are also responsible for notifying the previous DAC of any modifications. Without proper notification, changes might not be automatically updated in our system, leading to the risk of incorrect permissions being applied and potential data access issues. Therefore, it is imperative that all Data Controllers follow this protocol to maintain data integrity and security. What happens if EGA detects an unresponsive DAC? EGA defines an unresponsive DAC as a DAC with one or more contacts who do not respond to data access requests. EGA has procedures in place to identify these types of DACs, escalate the issue, and attempt to reassign the DAC to a responsive contact. This is a crucial step in ensuring that data can be accessed and utilised by researchers. If EGA identifies an unresponsive DAC, the organisation will first try to resolve the issue by escalating it to the appropriate parties. This may involve attempting to reassign the DAC to a more responsive contact. Unfortunately, in situations where we cannot reassign the DAC, the dataset will be withdrawn from the public website and the files will be removed from our system. If an EGA ID is referenced in a publication, the EGA will take extra steps to ensure that the public is made aware of the data's unavailability. I don't want to receive an email notification for pending requests. How can I do that? If you are an EGA DAC with pending requests, you will always receive emails for new data access requests. However, the EGA understands that a request resolution can take some time, for this reason, if you add a comment (make sure you save it by clicking the APPLY button!) we will filter those requests at the time of sending the notification! How can I manage data access requests? What documentation does the DAC need to provide? Each dataset that is submitted to the EGA must be linked to a policy object. The policy is a Data Access Agreement (DAA), which defines the terms and conditions of using the dataset, such as how the data files should be stored once downloaded or details of publication embargoes that should be observed by the approved user. As part of the Data Access Agreement, information regarding the application can be captured to help inform the DAC when making its decision. For example, requestors could be asked to provide a proposed title for their research and a proposal of how the data will be used. By asking for provision of such information the DAC can be assured that the requestor fully understands any consents associated with the data. It is important that accounts created at the EGA, are created solely for those individuals that will be downloading the data from the EGA. As part of the data access request, we strongly encourage you to identify individuals that will need an account at the EGA in order to prevent sharing of login details, which is strictly prohibited under EGA user account policy. Such information can easily be captured in the DAA. NOTICE The data access agreement template below is provided for guidance only and should be adapted as you see fit to suit your own purpose. In the interest of promoting data sharing, we suggest that if an agreement cannot be met around clause 19 in this example that both parties should agree to remain silent, and that the clause should be removed from the agreement. Example DAA How can the DAC provide the DAA? The DAC should provide their own DAA when registering a policy. Data requestors will download this document and should fill it in and send it back to the DAC. Data access decisions should be based on such documentation. The DAA can be downloaded through the request data webpage. Once it has been filled in, the signed copy of the DAA can be uploaded back to the request data webpage and sent to the DAC for review. How can I grant access to the data? Once you receive a data access request, you can login to the DAC Portal. In this portal you will see all your pending requests and will be able to grant or decline access to the requestors. I am a member of the Data Access Committee. Could I approve somebody else to deal with the requests on my behalf? If you want to delegate data access decisions to someone else, make sure that the individual's account is officially registered as a member of the DAC. Remember that a DAC contact with an "admin" role can always add new members to an existing DAC, remove members, and modify contact details through the DAC Portal. Can I automatise the process of managing data access requests? The answer is yes! You can use a programmatic approach using our DAC API! Check out the DAC API specification! Data Breach What should a DAC do if they suspect a breach? If a DAC suspects a data breach of one or more of their datasets, they should immediately contact the EGA Helpdesk team at this link. The DAC must provide the following information when contacting the EGA Helpdesk team: A list of affected datasets An estimated date of the data breach (or interval of dates) A list of unauthorised users who accessed the data (if available). Otherwise, they can provide a list of authorised users for the affected datasets Any observations they would like to raise to the EGA team Once the DAC has contacted the EGA team, we will respond within 48 hours (please allow some leeway during peak times) and activate our data breach protocol. What can I expect from the EGA if they detect a breach? Once the EGA determines that a security incident has occurred, we will notify all DAC members that a data breach has been detected, and take steps to contain the incident. Containment approaches may include: Revoking a data provider's access to the EGA resources, such as by changing passwords. Removing affected EGA datasets from distribution, such as by withdrawing a dataset. Disabling certain functions or services, such as the EGA ingestion pipeline. Shutting down the system or disconnecting it from the network. After the incident has been contained, the EGA will determine whether it is necessary to eradicate components related to the incident. Finally, the EGA will enable recovery of the service to normal operation and confirm that all services are functioning normally.

  Documentation access/data-access-committee/what-is-dac