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• 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

• 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

• A Genome-Wide Association Study in Patients Experiencing Musculoskeletal Adverse Events on NCIC CTG Trial MA.27 Evaluating Aromatase Inhibitors as Adjuvant Therapy in Early Breast Cancer. A Collaboration Between the NIH Pharmacogenetics Research Network and the RIKEN Yokohama Institute Center for Genomic Medicine.

  Source of Patients The source of the patients for this genome-wide case control study was MA.27, which was conducted as a multi-cooperative group effort under the auspices of the NCI Breast Cancer Intergroup of North America. The NCIC Clinical Trials Group (CTG) serves as the coordinating group, with participation by the NCI-sponsored North Central Cancer Treatment Group, Eastern Cooperative Oncology Group (ECOG), Southwest Oncology Group, and Cancer and Leukemia Group B (CALGB). MA.27 involved postmenopausal women with histologically confirmed and completely resected invasive breast cancer with surgical margins clear of invasive carcinoma and DCIS in the following TMN categories (AJCC Version 6): pT1, pT2, pT3; pNx, pN0, pN1, pN2, pN3 (only when the sole basis is presence of 10 or more involved axillary nodes); MO. The primary tumor must have been ER and/or progesterone receptor positive. Patients were stratified by lymph node status at diagnosis, prior adjuvant chemotherapy, and trastuzumab use and were randomized to 5 years of adjuvant therapy with anastrozole or exemestane. The trial was activated on May 26, 2003, and reached its accrual objectives on July 31, 2008, after the randomization of 6827 North American patients, with the majority (79%) providing DNA and consent for genetic testing. Non-North American patients were also entered by the International Breast Cancer Study Group but they did not contribute DNA. From 2003 to December 21, 2004, patients also underwent a second randomization to celecoxib 400 mg twice daily or placebo but, after the entry of 1,622 patients, this treatment was discontinued because of reports of increased cardiovascular risk associated with celecoxib. Case Definition for Musculoskeletal Adverse Events Cases were defined to have had at least one of the following six MSAE): 1. pain - joint, 2. pain - muscle, 3. pain - bone, 4. arthritis, 5. joint - function, 6. musculoskeletal - other. Cases were required to have at least grade 3 toxicity, according to the NCI Common Terminology Criteria for Adverse Events v3.0, or go off treatment for any grade of the six MSAEs; and were required to have had an MSAE within the first two years (i.e., a MSAE occurring after 2 years was not be considered a case). Subjects were excluded from the case group who met the case definition while on celecoxib or in the three months after stopping celecoxib but subjects were allowed to be cases if they developed their first MSAE more than three months after stopping celecoxib. Study Design The design was a nested matched case-control study with two controls selected for each case. Random matching from the potential control group (i.e., risk-set sampling such that controls had at least the same length of followup as the timing of the case event) was done by matching the case on the following factors: 1. treatment arm (exemestane vs. anastrozole, blinded), 2. prior adjuvant chemotherapy (yes vs. no), 3. age at start of treatment (+/- 5 years), 4. Celecoxib allocation (yes vs. no). Attempts were made to exactly match each case with two controls according to the above criteria. If, however, controls could not be exactly matched, "close" matching was used to define a distance between each case and all potential controls in an optimal matching algorithm. Race is a potential confounding factor, and 94% of the MA.27 population is Caucasian, 3% are Black, 1% Asian, 1% American Indian, and 1% are of unknown race. Because there are so few non-Caucasian participants, was restricted to only Caucasians. Following identification of cases and controls, the list was sent to the CALGB Pathology Coordinating Office (PCO) at Ohio State University Medical Center for plating of the samples. Other patient factors that might influence the association of SNP genotypes with a MSAE, either as confounding factors or as effect modifiers, were included as investigational covariates. These include 1. body mass index (BMI), 2. bisphosphonate use, 3. fractures in past 10 years, 4. baseline ECOG performance status, 5. prior hormone replacement therapy, 6. prior adjuvant radiotherapy, and 7. prior taxane treatment. An Honest Broker Process was utilized to ensure patient confidentiality. Genotype Assays and Quality Control A GWAS was performed with the Illumina Human610-Quad at the RIKEN Center for Genomic Medicine. The DNA for all of the samples were adjusted to a concentration of 50 to 100 ng/µL in a final volume of 50 µL. The 96-well plates were designed to have a unique distribution pattern with x duplicates per plate to evaluate genotype concordance. Samples with <98% call rate were removed from analyses. SNPs with ambiguous call will be excluded using the following criteria: 1. low signal intensity of each allele, 2. low cluster separation score, 3. SNP call rate <0.98, 4. SNPs with Hardy Weinberg Equilibrium p-value <0.001 were excluded. X-chromosome SNPs were used to validate female sex and quality control measures were examined across the different submitting centers. For all pairs of subjects, the percentage of matching genotypes were computed to screen for unexpected duplicate samples. All SNPs found to be associated with MSAE were subjected to visual inspection of the cluster plots to verify that the genotype clustering was adequate.

  Study phs000210

• Monocyte and macrophage lipid accumulation results in downregulated type-I interferon responses

  Macrophages are critical components of atherosclerotic lesions and their pro- and anti-inflammatory responses influence atherogenesis. Type-I interferons (IFNs) are cytokines that play an essential role in antiviral responses and inflammatory activation and have been shown to promote atherosclerosis. Although the impact of type-I IFNs on macrophage foam cell formation is well-documented, the effect of lipid accumulation in monocytes and macrophages on type-I IFN responses remains unknown. Here we examined IFN stimulated (ISG) and non-ISG inflammatory gene expression in mouse and human macrophages that were loaded with acetylated LDL (acLDL), as a model for foam cell formation. We found that acLDL loading in mouse and human macrophages specifically suppressed expression of ISGs and IFN-β secretion, but not other pro-inflammatory genes. The downregulation of ISGs could be rescued by exogenous IFN-β supplementation. Activation of the cholesterol-sensing nuclear liver X receptor (LXR) recapitulated the cholesterol-initiated type-I IFN suppression. Additional analyses of murine in vitro and in vivo generated foam cells confirmed the suppressed IFN signalling pathways and suggest that this phenotype is mediated via downregulation of interferon regulatory factor binding at gene promoters. Finally, RNA-seq analysis of monocytes of familial hypercholesterolemia (FH) patients also showed type-I IFN suppression which was restored by lipid-lowering therapy and not present in monocytes of healthy donors. Taken together, we define type-I IFN suppression as an athero-protective characteristic of foamy macrophages. These data provide new insights into the mechanisms that control inflammatory responses in hyperlipidaemic settings and can support future therapeutic approaches focusing on reprogramming of macrophages to reduce atherosclerotic plaque progression and improve stability.

  Study EGAS00001005955

• Pseudodiastrophic dysplasia expands the known phenotypic spectrum of defects in proteoglycan biosynthesis

  Pseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a ‘dysplasia with multiple joint dislocations’ however, the molecular aetiology of the disorder is currently unknown. In order to identify the genetic defects underlying PDD, we performed whole exome sequencing (WES) on 3 patients from 2 unrelated families, clinically diagnosed with PDD. WES resulted in the identification of bi-allelic variants in the established skeletal dysplasia genes, B3GAT3 (Family 1) and CANT1 (Family 2). Mutations in these genes have previously been reported to cause ‘multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects’ (B3GAT3) and Desbuquois dysplasia 1 (CANT1); disorders in the same nosological group as PDD. Follow-up of the B3GAT3 variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream in vitro functional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the CANT1 variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate. For the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes B3GAT3 and CANT1, demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3- and CANT1- related skeletal dysplasias to include PDD, and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway.

  Study EGAS00001004145

• Interferon lambda 4 impairs viral antigen presentation and attenuates T cell responses

  Genetic variants of the interferon lambda (IFNL) gene locus are strongly associated with spontaneous and IFN treatment induced clearance of hepatitis C virus (HCV) infections. Individuals with the ancestral IFNL4-dG allele are not able to clear HCV in the acute phase and develop chronic hepatitis C (CHC) with more than 90% probability. Paradoxically, the IFNL4-dG allele encodes a fully functional IFNλ4 protein with antiviral activity against HCV and coronavirus. Here we describe a hitherto unknown effect of IFNλ4 on HCV antigen presentation. Only minor amounts of IFNλ4 are secreted, because the protein is largely retained in the endoplasmic reticulum (ER) where it induces ER stress. Stressed cells were significantly weaker activators of HCV specific CD8+ T cells. This was not due to reduced MHC I surface presentation or extracellular IFNλ4 effects, since T cell responses could be restored by exogenous loading of MHC with HCV antigens. Rather, IFNλ4 induced ER stress impaired HCV antigen processing and/or loading onto the MHC I complex. Our results provide a potential explanation for the IFNλ4 – HCV paradox.

  Study EGAS00001005396

• EstMB cohort participants sequenced with MGISEQ-2000 platform

  Participants collected a fresh stool sample immediately after defecation using a sterile Pasteur pipette and placed it in a 15 mL conical polypropylene tube. They were instructed to collect the sample as close as possible to their study center visit. Samples were transported and stored at −80 °C until DNA extraction. Microbial DNA was extracted from 200 mg of stool using a QIAamp DNA Stool Mini Kit (Qiagen), following manufacturer's instructions, after all samples were collected. DNA was quantified using a Qubit 2.0 Fluorometer with a dsDNA Assay Kit (Thermo Fisher Scientific). Library preparation and circularization of equimolarly pooled libraries were done with MGIEasy FS DNA Library Prep Set (MGI Tech Co, Ltd, Shenzhen, China) according to the standard protocol. The sequencing was performed with MGISEQ-2000 High-throughput Sequencing Set (FCL PE150) according to the manufacturer’s instructions (MGI Tech, Shenzhen, China)

  Dataset EGAD50000002213

• Genetic Heterogeneity of the familial gastric neuroendocrine tumors (2018-06-06)

  Gastric neuroendocrine tumors (gNETs) occur with an estimated frequency of 2 per 100,000 in the general population. Type I gastric neuroendocrine tumors (NETs) represent the 75% of gNTEs and arise from gastric enterochromaffin-like (ECL) cells. They have late age of onset and usually benigh course. Classically, hypergastrinemia in patients who have autoimmune atrophic gastritis, causes hyperplasia of gastric ECL cells that progresses into type I gastric NETs and parietal cell (PC) destruction. The genetic bases in families with this disease are unknown. We performed an exome sequencing study of an atypical aggressive familial gNETs case (with early age onset, nodal infiltrations and gastric adenocarcinomas) that followed a recessive model. We identified a deleterious mutation in homozygosis in the ATP4A gene, which encodes the proton pump responsible for acid secretion by gastric parietal cells. This mutation lead to achlorhydria first, and hypergastrinemia and gNET developing as consequence (Calvete et al. 2014). Recently, two more families with gNETs, classical clinical traits and recessive model have been studies by WES but we didn't find any mutation in the ATP4a gene. However, putative mutations affecting genes that contribute to the development and the integrity of PC have been found suggesting that genetic alterations associated to this disorder target to a unique cell type (parietal cells). In order to cinfirm this hypothesis, it is necessary the search for new genes implicated in the gNETs, more familial cases are needed to be studied. We have identified four more new familial gNETs cases. Here, we propose their study by WES. The first family is formed by thress siblings with gNETs. The other families include two siblings with gNETs. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2018-06-06.

  Dataset EGAD00001004153

• Women's Ischemia Syndrome Evaluation (WISE-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: This is a National Heart, Lung and Blood Institute sponsored, four-center study designed to: 1) optimize symptom evaluation and diagnostic testing for ischemic heart disease; 2) explore mechanisms for symptoms and myocardial ischemia in the absence of epicardial coronary artery stenoses, and 3) evaluate the influence of reproductive hormones on symptoms and diagnostic test response.Background: Women tend to have a higher prevalence of chest pain than men, yet a lower prevalence of epicardial coronary stenoses, and diagnostic tests such as exercise-induced ECG changes tend to have a higher false-positive rate in women than in men. Thus, accurate diagnosis of ischemic heart disease in women is a major challenge to physicians. In addition, prognosis in women with abnormal diagnostic tests is largely unknown and the role reproductive hormones play in this diagnostic uncertainty is unexplored. Moreover, the significance and pathophysiology of ischemia in the absence of significant epicardial coronary stenoses is unknown.Participants: In Phase I (1996-1997), a pilot phase, 256 women were studied. During Phase II (1997-1999) angiographic and baseline data were collected on an additional 680 women to bring total enrollment to 936. Baseline data was also collected on a reference population of 70 women.Conclusions: Among women without CAD, abnormal Magnetic Resonance Spectroscopy (MRS) consistent with myocardial ischemia predicted cardiovascular outcome, notably higher rates of anginal hospitalization, repeat catherization, and greater treatment costs.

  Study phs004310

• Chromosome Segregation Errors Promote a Diverse Spectrum of Simple and Complex Genomic Rearrangements

  Cancer genomes are frequently characterized by numerical and structural karyotypic abnormalities. Here we combined an inducible centromere-specific inactivation approach with selection for a conditionally essential gene, a strategy we term ‘CEN-SELECT’, and show that single-chromosome missegregation during cell division can directly drive a broad spectrum of structural rearrangement types. Cytogenetic profiling revealed that missegregated chromosomes are 120-fold more susceptible to developing seven major categories of structural variants, including translocations, insertions, deletions, and reassembly into chromothriptically rearranged chromosomes. Whole-genome sequencing of clones with genetically propagatable derivative chromosomes identified complex rearrangements and copy-number alterations that can result in gene inactivation or extrachromosomal gene amplification. We conclude that chromosome segregation errors are sufficient to drive extensive structural variation that recapitulates those commonly associated with human cancers.

  Dataset EGAD00001004163

• High-Throughput and High-Dimensional Single Cell Analysis of Antigen-Specific CD8+ T Cells

  We developed a high-dimensional, tetramer associated T cell receptor sequencing (TetTCR-SeqHD) method to simultaneously profile cognate antigen specificities, TCR sequences, targeted gene-expression, and surface protein expression. Cultured antigen-specific CD8+ T cell clones were studied as a proof-of-concept experiment. In addition, both the antigen specific CD8+ T cells from healthy subjects and Type I diabetic patients were investigated. 18 individually consented subjects pooled into four groups for sample processing

  Study phs002441

• Single cell RNA sequencing of peripheral blood HSPC from patients with sickle cell anemia and healthy donors

  Neutrophils and monocytes are critical contributors to the pathophysiology of sickle cell anemia (SCA) and are persistently elevated in patients' circulation. While chronic hemolysis has been implicated in this leukocytosis, the underlying mechanisms remain incompletely understood. Our data show a myeloid-skewed transcriptional signature in early progenitor populations, including multipotent progenitors (MPPs) and hematopoietic stem cells (HSCs). Notably, we identify upregulation of the type I interferon signaling pathway in HSPCs as a key driver of early myeloid programming in SCA.

  Study EGAS50000001046

• Clonal_expansion_of_mutated_cell_population_in_bladder_urothelium_

  1cm biospies of from patients undergoing bladder cystectomy will be collected. The underlying muscle and stroma will be removed and the remaining epithelia dissected into small sequential areas which will be sent for ultra-deep exome sequencing using a panel of known cancer and viral genes. Sequence analysis using similar methods to Martincorena I et al (Science 2015, 348:880) will provide an idea of the somatic mutational landscape in these patient samples. Individual patient muscle samples will also be sequenced as a reference.

  Study EGAS00001001687

• Single-cell and bulk RNA-sequencing of nivolumab-treated glioblastoma

  Glioblastoma is a highly aggressive type of brain tumour for which there is no curative treatment available. Immunotherapies have shown limited responses in unselected glioblastoma patients, and it is currently not well understood what separates the few responders from the non-responders at the cellular and molecular level. Here we investigate the phenotypic and transcriptional evolutionary dynamics at single-cell resolution during nivolumab immune checkpoint treatment of eight glioblastoma patients enrolled in a translational phase I/II clinical trial.

  Study EGAS00001007110

• Cookies

  Cookies https://ega-archive.org does not identify users on this site. It does use cookies, though. What is a cookie? Cookies are text files containing small amounts of information which are downloaded to your device when you visit a website. They allow a website to remember your preferences and are therefore useful to improve your online experience. Find out more information about cookies. Types of cookies we use Functional These cookies record the columns you wish to display or hide in the results page.Performance These cookies are used to analyse trends, administer the website, track visitor movements and gather broad demographic information for aggregate use. We use the information to compile reports and to help us improve our websites. These cookies are not linked to personally identifiable information. Session cookie A session cookie for a website only exists whilst the user is reading or navigating the website. When the user closes their web browser these cookies are usually removed.

  Documentation cookies

• Immunopeptidomics of colorectal cancer organoids reveals a sparse HLA class I neoantigen landscape and no increase in neoantigens with interferon or MEK-inhibitor treatment

  Whole exome sequencing data from a series of 5 patient derived organoids (PDOs) established from metastatic colorectal cancers (CRCs).

  Dataset EGAD00001005357

• Potential Modulatory Role of Osteoprotegerin in Bone Metabolism of Patients with 21-Hydroxylase Deficiency

  21-hydroxylase deficiency (21-OHD) is an inherited disorder that results from a mutation on the CYP21A2 gene. It affects the adrenal glands and is the most common cause of congenital adrenal hyperplasia (CAH). 21-OHD CAH causes the body to produce an insufficient amount of cortisol and an excess of androgen, the type of hormone that produces male characteristics. The primary treatment for 21-OHD CAH, glucocorticoid replacement therapy, has been shown to cause bone loss. However, the elevated hormone levels caused by 21-OHD CAH may increase production of the protein osteoprotegerin (OPG), which in turn may protect against bone loss. This study will compare bone density and OPG levels in women who have 21-OHD CAH and have undergone a lifetime of glucocorticoid replacement therapy to that in women who have neither of these criteria. In doing so, the study will aim to determine the relationship between OPG and bone loss. Because of the excess of androgen caused by 21-OHD CAH, women with CAH may exhibit some male-like characteristics. Glucocorticoids are a member of a class of drugs called corticosteroids, which are used in hormone replacement therapy. In order to counteract the effects of 21-OHD CAH, women with the disease are given hormone replacement therapy with glucocorticoids beginning at infancy. Glucocorticoids are known to cause bone loss. Despite many years of treatment with glucocorticoids, however, young women with 21-OHD CAH seem to be protected against bone loss. Researchers believe that the increased androgen levels in these women lead to increased estrogen levels, which in turn increase OPG production. The increase in OPG levels may protect women against bone loss. This study will evaluate bone density and OPG levels in women with and without 21-OHD CAH to determine the relationship between OPG and bone loss. Participants in this observational study will attend only one study visit. At this visit, they will undergo a blood draw; a scan of their lower spine, hip, and forearm; height and weight measurements; and a body fat analysis test. This last test will entail a weak and painless electrical signal being sent from foot to foot. Participants will not attend any follow-up visits for this study.

  Study phs001314

• Cancer Genomics, ICR, summary data

  DAC for summary level data from the Cancer Genomics group, Division of Genetics and Epidemiology at the Institute of Cancer Research, Sutton, UK.

  Dac EGAC50000000050

• PyEGA3 download client

  PyEGA3 Checks prior to download - Is the dataset available for download? Most datasets are available using the PyEGA3 Download client, except for specific legacy datasets. For these ones, refer to Live Outbox distribution, an alternative way to download these datasets.If the dataset you've been granted access to begins with the ID EGAD5XXXXXXX, please refer to the Live Outbox distribution. If the dataset you have been granted access to contains encrypted data (filename ending in .gpg), contact EGA Helpdesk for detailed information on how to download these files.General Information The PyEGA3 download client is available at its GitHub repository. In its README you will find a step by step guide on how to use it to download files you have been granted access to. PyEGA3 implements the GA4GH-compliant HTSGET protocol supporting requests over genomic ranges. This enables the download of specific regions of interest rather than the entire file. HTSGET is not possible for all the files held by EGA: if the dataset does not contain index files (e.g. filename ending in *.crai), then genomic range requests cannot be performed. The maximum number of connections allowed is 30. If more than 30 connections are used, the download client will encounter 500 errors. The recommended number of connections for maximum output is one. Check out our video tutorial! Frequently Asked Questions General questions How do I download the datasets to which I have been granted access? After setting up your EGA download account, you can proceed to download using the EGA download client – PyEGA3. The pyEGA3 download client is a python-based tool for viewing and downloading files from authorised EGA datasets. This download client is continuously being developed for more user-friendly download experiences. Can I download the dataset’s metadata via the download client? No, the download client cannot be used to download metadata. Registered EGA users can download metadata of an authorised dataset by logging into the EGA webpage and navigating to the dataset of choice. Approximately two thirds down the page you will find the option to download the metadata as a zip file. How do I download large datasets as quickly as possible? The main EGA download client is pyEGA3 download client, a python-based tool for viewing and downloading files from authorised EGA datasets.We could exceptionally consider the option of an Aspera download for users experiencing very slow download rates or facing particular issues.Contact the EGA Helpdesk for further information. Pre-requirement and Installation What are the major requirements for the PyEGA3 download client installation and usage? The PyEGA3 client is compatible with any OS with Python 3.6+ installed. The client requires a connection to the internet, sufficient space on the destination drive, and the EGA download account credentials. Where can I find the PyEGA3 download client installation and download instructions? We strongly recommend checking our video tutorial demonstrating the usage of PyEGA3 from installation to file download. More detailed information is available at PyEGA3 GitHub. What ports are required for the PyEGA3 download client to function? PyEGA3 makes HTTPS calls to the EGA Data API (https://ega.ebi.ac.uk:8443). This port 8443 must be reachable from the location where PyEGA3 is executed to avoid timeouts. PyEGA3 download client How to update the PyEGA3 download client to be on the latest version? Updating the client to the latest version can be achieved by running the following command: pip3 install pyega3 --upgrade I do not have an active EGA account. Can I test the download with the PyEGA3 download client? An EGA download test account (ega-test-data@ebi.ac.uk) has been created for troubleshooting and training purposes. The test account does not require an EGA username and password because it contains publicly accessible files from the 1000 Genomes Project. More information about the use of this account and log in details are available at pyEGA3. I lost my connection while the download was in progress. Does this mean that I have to download the file again from the start? The PyEGA3 download client supports automatic resumption of downloads. To enable quicker download speeds, the API breaks files into up to four segments and downloads them in parallel. With the resume feature, downloads will automatically resume if you encounter any errors or if the connection is interrupted. How can I improve the overall download speed of the PyEGA3 download client? Download speeds can be optimised using the --connections parameter which will parallelise download at the file level. If the --connections parameter is provided, all files >100Mb will be downloaded using the specified number of parallel connections. It is important to note that files are still downloaded sequentially, so using multiple connections does not mean downloading multiple files in parallel. The maximum number of connections allowed is 30. If more than 30 connections are used, the download client will encounter 500 errors. The recommended number of connections for maximum output is one. Why is my file taking a long time to be saved? Please note that when a file is being saved, it goes through two processes. First, the downloaded file "chunks" are pieced back together to reconstruct the original file. Secondly, PyEGA3 calculates the checksum of the file to confirm that the file was downloaded successfully. Larger files will take more time to reconstruct and validate the checksum. Why is the HTSGET protocol not working with my dataset of interest? PyEGA3 implements the GA4GH-compliant htsget protocol for supporting requests over genomic ranges. This exciting new feature means that for data files with accompanying index files (e.g. .crai for CRAM files) users can download specific regions of interest rather than the entire file, saving both time and storage space. Please note that in order for the genomic range requests to work for a BAM, CRAM or VCF file there must be an associated BAI, CRAI or TBI file, respectively. If the dataset does not contain these index files then genomic range requests cannot be performed. After download Do I need to decrypt data files downloaded through the pyEGA3 download client? Files are transferred over secure HTTPS connections and received unencrypted, thus there is no need for decryption after data download. What is the purpose of an MD5 file? After the download completes, file integrity is verified using checksums. The PyEGA3 download client automatically verifies each file’s unencrypted md5 after download to ensure that the file was downloaded correctly from the EGA. Errors Why do I get a “400 Client Error” while trying to access the download client? Ensure that your credentials are formatted correctly. Please contact the EGA Helpdesk if you are unsure about your account’s username (i.e. your email address). Why do I get a “500 Server Error”? It is important to note that files are still downloaded sequentially, so using multiple connections does not mean downloading multiple files in parallel. The maximum number of connections allowed is 30. If more than 30 connections are used, the download client will encounter 500 errors. The recommended number of connections for maximum output is one. Otherwise, 500 server errors are internal server errors from EGA’s end. Retry after some time and, if the 500 error persists: check our homepage or Twitter for any outage information or report it to EGA Helpdesk. Why do I get a “slice error”? This type of error occurs when one slice download was prematurely interrupted. Please re-start the same download. The download client will pick up any partial download and download any missing slices. Why do I get the error “Dataset' EGADXXXXXXXXXXX' is not in the list of your authorised datasets”? Please note that the data access was given to the email (username) provided to the Data Access Committee (DAC) in your official request. Therefore, you shall check that the account that you are using is the same one that you sent to the DAC. Why do I get “ERROR:root:Failed to obtain IP address”? This might mean that the connection ports are blocked. Check that the port 8443 is reachable.In case the port is reachable and the error persists, please try to modify the file pyega3.py on line 44 in the python module installation: Replace endpoint = 'https://ipinfo.io/json' with endpoint = 'https://api.myip.com' Why do I get the error “Invalid username, password or secret key - please check and retry”? Make sure that you are using the correct credentials (username and password) and there is no typo. Contact EGA Helpdesk if the problem persists.

  Documentation access/download/files/pyega3

• Hydroxyurea to Prevent Organ Damage in Children with Sickle Cell Anemia (BABY HUG) Phase III Clinical Trial and Follow-Up Observational Studies I and II

  Sickle cell anemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life. In 1995, the Multicenter Study of Hydroxyurea (MSH) (dbGaP phs002348) demonstrated that, in adults, hydroxyurea is effective in decreasing the frequency of painful crises, hospitalizations for crises, acute chest syndrome, and blood transfusions by 50%. The phase I/II study of hydroxyurea in children (HUG KIDS) demonstrated that children have a response to hydroxyurea similar to that seen in adults in terms of increasing fetal hemoglobin levels and total hemoglobin, and decreasing complications associated with sickle cell anemia. In addition, this study demonstrated that the drug does not adversely affect growth and development between the ages of 5 and 15. A pilot study of hydroxyurea (HUSOFT) given to children between the ages of 6 months and 24 months demonstrated that the drug was well tolerated and that the fetal hemoglobin levels rose and remained elevated compared to baseline with continued hydroxyurea administration. A Special Emphasis Panel (SEP) met on April 12, 1996 to review the results of the MSH trial and the progress to date of the HUG KIDS study. The SEP recommended that NHLBI undertake the BABY HUG trial. The BABY HUG Randomized Controlled Trial concluded that hydroxyurea treatment in very young children seemed to have an acceptable safety profile and to reduce complications of sickle cell anemia. However, more data were needed on the long-term safety of hydroxyurea use in very young children. As a result, follow-up studies were initiated. The Follow-Up Study II provided longer follow-up than Follow-Up Study I, and included more assessment types than Follow-Up Study I.The BABY HUG program consisted of three related studies, each of which has associated datasets and bio-specimens. A randomized controlled trial comparing hydroxyurea to placebo in very young children with sickle cell anemia (BABY HUG Randomized Controlled Trial) The first observational follow-up study of children from the randomized controlled trial (BABY HUG Follow-Up Study I). All children in Follow-Up Study I were offered the option of taking open-label hydroxyurea, with treatment decisions made by the family and the clinical team caring for the child. The second observational follow-up study of children from BABY HUG Follow-Up Study I. All children in Follow-Up Study II were offered the option of taking open-label hydroxyurea, with treatment decisions made by the family and the clinical team caring for the child.The purpose of the Randomized Controlled Trial was to determine if hydroxyurea can safely prevent early end organ damage in very young children with sickle cell anemia. The purpose of the BABY HUG Follow-up Study I was to provide structured follow-up of the children enrolled in the BABY HUG Randomized Controlled Trial, in order to characterize the long-term toxicities and unexpected risks (if any) associated with treatment with hydroxyurea at an early age. The objective of Follow-Up Study II was to obtain additional data about the long-term safety and efficacy of hydroxyurea use in children with Sickle Cell Anemia through at least the first decade of life.Instructions for requesting individual-level data are available on BioData Catalyst at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BioData Catalyst. For questions about availability, you may contact the BioData Catalyst team at https://biodatacatalyst.nhlbi.nih.gov/contact.

  Study phs002415

• The Innate Immune Response as a Therapeutic Target for Cutaneous Leishmaniasis

  The overall goal of the proposed project is to identify innate host functions that contribute to cure or failure during antileishmanial drug therapy, and their related biomarkers. Results from this project enabled the identification of host-specific predictive and prognostic signatures of therapeutic responsiveness, and the bases for rational selection of host-targeted therapeutics that redirect inflammation and revert pathogenicity. Through sequential transcriptomic profiling of blood monocytes (Mo), neutrophils (Nφ), and eosinophils (Eφ) over the course of systemic treatment with meglumine antimoniate, we discovered that a heightened and sustained Type I interferon (IFN) response signature is a hallmark of treatment failure (TF) in Cutaneous Leishmaniasis (CL) patients. The transcriptomes of pre-treatment, mid-treatment and end-of-treatment samples were interrogated to identify predictive and prognostic biomarkers of TF. Results from this study instigate the evaluation of Type-I IFN responses as new immunological targets for host-directed therapies for treatment of CL, and highlight the feasibility of using transcriptional signatures as predictive biomarkers of outcome for therapeutic decision making.

  Study phs003545

• PAGE: The Charles Bronfman Institute for Personalized Medicine (IPM) BioMe BioBank

  The Institute for Personalized Medicine (IPM) BioMe Biobank is a consented, EMR-linked medical care setting biorepository of the Mount Sinai Medical Center (MSMC) drawing from a population of over 70,000 inpatients and 800,000 outpatient visits annually. MSMC serves diverse local communities of upper Manhattan, including Central Harlem (86% African American), East Harlem (88% Hispanic Latino), and Upper East Side (88% Caucasian/white) with broad health disparities. IPM BioMe Biobank populations include 28% African American, 38% Hispanic Latino predominantly of Caribbean origin, 23% Caucasian/White. IPM BioMe Biobank disease burden is reflective of health disparities with broad public health impact. Biobank operations are fully integrated in clinical care processes, including direct recruitment from clinical sites waiting areas and phlebotomy stations by dedicated Biobank recruiters independent of clinical care providers, prior to or following a clinician standard of care visit. Recruitment currently occurs at a broad spectrum of over 30 clinical care sites. This study is part of the Population Architecture using Genomics and Epidemiology (PAGE) study (phs000356).

  Study phs000925

• Gabriella Miller Kids First Pediatric Research Program in Genetics at the Intersection of Childhood Cancer and Birth Defects

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). All of the WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Birth defects and childhood cancer share biological pathways that are important for cell growth and division. We propose that sequencing pediatric patients suffering both conditions will allow us to discover the underlying genes and in turn advance our understanding of the causes of these devastating diseases.

  Study phs001846

• Genomic Characterization CS-MATCH-0007 Arm Z1D

  The CS-MATCH-0007 protocol is a collaboration between the Center for Cancer Genomics (CCG) and the Division of Cancer Treatment and Diagnosis (DCTD) to perform whole-exome sequencing, RNA sequencing and if possible, whole-genome, methylation and miRNA sequencing using pre-and posttreatment tumor biopsy specimens from all patients enrolled on a treatment arm of the NCI-MATCH Clinical Trial (EAY131). The goal of this study is to identify the molecular basis for response and resistance to targeted therapies that are matched to their corresponding genomic alterations. Arm Z1D is one of the treatment sub-protocols within the NCI-MATCH Clinical Trial (EAY131) where patients with MMR deficiency are treated with nivolumab. This subprotocol is one of the treatment arms in the EAY-131 trial included in the CS-MATCH-0007 protocol and will provide specimens for the program including DNA from tumor tissue and whole blood and RNA from tumor tissue. A fuller genomic landscape of tumors from these patients will enable discovery of potential molecular features correlated to clinical outcomes or lay the foundation for future studies leading to new and more effective treatments.

  Study phs001859

• Genomic Characterization CS-MATCH-0007 Arm Y

  The CS-MATCH-0007 protocol is a collaboration between the Center for Cancer Genomics (CCG) and the Division of Cancer Treatment and Diagnosis (DCTD) to perform whole-exome sequencing, RNA sequencing and if possible, whole-genome, methylation and miRNA sequencing using pre-and post-treatment tumor biopsy specimens from all patients enrolled on a treatment arm of the NCI-MATCH Clinical Trial (EAY131). The goal of this study is to identify the molecular basis for response and resistance to targeted therapies that are matched to their corresponding genomic alterations. Arm Y is one of the treatment sub-protocols within the NCI-MATCH Clinical Trial (EAY131) where patients with AKT mutations are treated with AZD5363. This subprotocol is one of the treatment arms in the EAY-131 trial included in the CS-MATCH-0007 protocol and will provide specimens for the program including DNA from tumor tissue and whole blood and RNA from tumor tissue. A fuller genomic landscape of tumors from these patients will enable discovery of potential molecular features correlated to clinical outcomes or lay the foundation for future studies leading to new and more effective treatments.

  Study phs001904

• Genomic Characterization CS-MATCH-0007 Arm H

  The CS-MATCH-0007 protocol is a collaboration between the Center for Cancer Genomics (CCG) and the Division of Cancer Treatment and Diagnosis (DCTD) to perform whole-exome sequencing and RNA sequencing using pre-and post-treatment tumor biopsy specimens from all patients enrolled on a treatment arm of the NCI-MATCH Clinical Trial (EAY131). The goal of this study is to identify the molecular basis for response and resistance to targeted therapies that are matched to their corresponding genomic alterations. Arm H is one of the treatment sub-protocols within the NCI-MATCH Clinical Trial (EAY131) where patients with BRAF V600K/V600E mutations are treated with Dabrafenib and Trametinib. This subprotocol is one of the treatment arms in the EAY-131 trial included in the CS-MATCH-0007 protocol and will provide specimens for the program including DNA from tumor tissue and whole blood and RNA from tumor tissue. A fuller genomic landscape of tumors from these patients will enable discovery of potential molecular features correlated to clinical outcomes or lay the foundation for future studies leading to new and more effective treatments.

  Study phs001888

• GCAT | Genomes for life: cohort study of the genomes of Catalonia

  The GCAT Study have recruited 20 000 participants aged 40–65 years. Participants who agreed to take part in the study completed a self-administered computer-driven questionnaire, and underwent blood pressure, cardiac frequency and anthropometry measurements. For each participant, blood plasma, blood serum and white blood cells are collected at baseline. A total of 5459 genomic profiles have been characterised by comprehensive genotyping. Genome-wide genotypes have been generated using Illumina Infinium SNP-bead array technology. We chose the Multi-Ethnic Global (MEGAEX, V.2) consortium array, a multipurpose, multiethnic genotyping array with two million selected markers (including previously described germline mutations, insertions-deletions (InDels) and SNPs).We have strictly followed the standard manufacturer recommended automated protocol for the Infinium HTS Assay scanned with a HiScan confocal scanner (Illumina, San Diego, California, USA). Genome Studio V.2011.1 has been used for raw data analysis. Genotyping was performed at the Genomics and Bioinformatics Unit of the PMPPC Institute for Health Science Research Germans Trias i Pujol, in Badalona, Spain. Future plans The first follow-up study started in December 2017 and will end by March 2018. Residences of all subjects will be geocoded during the following year. Several genomic analyses are ongoing, and metabolomic and genomic integrations will be performed to identify underlying genetic variants, as well as environmental factors that influence metabolites. http://dx.doi.org/10.1136/bmjopen-2017-018324

  Study EGAS00001003018

• Treatment of genetic screening of hypertriglyceridemia type I, III, and V - HTG Amsterdam

  This is a cohort of patients with extreme hypertriglyceridemia. Patients have been screened for loss of function mutations in LPL, GPIHBP1, APOC2, APOA5 and LMF1.

  Study phs000511

• Cancer Genomics, ICR, cell line data

  DAC for cell line (non patient) data from the Cancer Genomics group, Division of Genetics and Epidemiology at the Institute of Cancer Research, Sutton, UK.

  Dac EGAC50000000023

• CSER: Clinical Implementation of Carrier Testing Using Next Generation Sequencing (NextGen)

  We will investigate the clinical implementation of genome sequencing (GS) for carrier screening to aid reproductive decision-making in adults. The study is organized into three inter-related Projects. The study population will include women and their partners who receive pre-conception testing. In Project 1, we will conduct a Randomized Clinical Trial to test clinical implementation of WGS compared with usual care. We will integrate WGS results with the electronic medical record (EMR), and measure outcomes from patient and physician perspectives. In Project 2, we will perform whole genome sequencing, including validation and interpretation of the identified variants to identify "actionable variants", meaning variants deemed worthy of reporting. This will include a robust approach using a Return of Results Committee (RORC) for determination of reportable results. In Project 3, we will evaluate the ethical and psychosocial implications of expanded carrier screening using WGS for the return of carrier status and secondary findings, and measure the impact on downstream healthcare utilization and cost. Two groups of women are identified through the electronic medical record. The first group has a clinical carrier screening test, usually Cystic Fibrosis (CF), ordered and completed as part of a preconception planning visit. The second group has a carrier screening test, usually CF, performed during pregnancy, they have delivered their baby and are planning a future pregnancy. Eligible women are randomized to either usual care or genome sequencing (GS). Women randomized into the usual care arm have already received their clinical genetic test. These women will not receive genome sequencing. Women in the GS arm will receive their carrier status results for about 700 gene/condition pairs approximately three months after randomization. If there are results to return, women come in for a genetic counseling session. If there are no results, a letter is sent in the mail. Incidental findings (IF) are returned about one month later. As with the carrier status results, all IF are returned in person, and if there are no results a letter is sent in the mail. If a participant is found to be a carrier of an autosomal recessive condition, her male partner is then eligible and invited to participate in the study and receive GS.

  Study phs000927

• Somatic mutations reveal lineage relationships and age-related mutagenesis in human hematopoiesis

  Mutation accumulation during human life can contribute to hematopoietic dysfunction; however, the underlying dynamics are unknown. Somatic mutations in blood progenitors can provide insight into the rate and processes underlying this accumulation, as well as the developmental lineage tree and stem cell division numbers. Here, we catalogue somatic mutations in the genomes of human bone marrow-derived and cord blood-derived hematopoietic stem and multipotent progenitor cells (HSPCs) and find that base substitutions accumulate with approximately 17 base substitutions per year in both populations, while insertions and deletions occur sporadically and at low numbers. The majority of mutations in adult HSPCs were acquired after birth and could be explained by the constant activity of various endogenous processes, which also explains the mutation load in acute myeloid leukemia (AML). We construct a developmental lineage tree revealing a polyclonal architecture of the hematopoietic progenitor compartment and providing evidence that developmental clones exhibit multipotency, though lineage biases can be detected. Our approach highlights novel features of human native hematopoiesis and its implications for leukemogenesis.

  Study EGAS00001003068

• Warfarin Pharmacogenetics: Pharmacogenetic Optimization of Anticoagulant Response (POAT) and Genetic and Environmental Determinants of Warfarin Response (GEDWR)

  Although the efficacy of warfarin in the treatment and prevention of thromboembolic disorders is proven, it is vastly underutilized with difficulties in management and risk of complications being the main deterrents. Recognition of genetic regulation of warfarin response has fueled efforts to quantify this influence, but the focus has been restricted to select genes and outcomes mainly in European Americans. Race appears to influence warfarin dose requirements with African Americans requiring larger and Asians requiring lower doses compared to Europeans. This variation in dose requirement by race may at least partially be explained by genetic differences. The Genetic and Environmental Determinants of Warfarin Response (GEDWR) and the Pharmacogenetic Optimization of Anticoagulation Therapy (POAT) are prospective cohort study aimed at defining the influence of CYP2C9, VKORC1 and other genes. All patients were followed at monthly intervals from initiation of therapy. At each visit factors influencing warfarin response such as warfarin dose, INR, concurrent medications, etc. were documented. Information on concurrent medications was updated at every clinic visit by self-report and verified by medical record review. Concomitant use of drugs such as drugs that alter warfarin pharmacokinetics, including CYP2C9 inhibitors (e.g., amiodarone), and pharmacodynamics such as antiplatelet agents (e.g. aspirin). Although the a priori hypothesis focused on the candidate-gene approach, with the recognition that the candidate-gene approach is bound by the assumption that our knowledge of genetic influences on warfarin response is complete. Among African Americans known variation in candidate genes (CYP2C9 and VKORC1) explain substantially less variability in warfarin dose requirements. Therefore a genome-wide association study (GWAS) was conducted on African American patients to identify novel variants associated with warfarin dose requirements.

  Study phs000708

• UCL Translation Uro-Oncology Data Access Committee will govern access to data generated from the Translation Uro-Oncology groups of the UCL Cancer Institute and UCL Division of Surgery & Interventional Science

  Dac EGAC00001000471

• We evaluate the PGD/PGS including 129 couples with NGS test and 266 couples with SNP-array test for the detection of embryonic chromosomal abnormalities.

  A total of 395 couples were subjected to IVF-PGD treatment, including 129 couples with NGS test and 266 couples with SNP-array test for the detection of embryonic chromosomal abnormalities. The NGS test was performed using low coverage whole genome sequencing with HiSeq 2000 platform. And the SNP array test was using Affymetrix Gene Chip Mapping Nsp I 262K.

  Study EGAS00001000981

• Paired-WGS Sequencing of Primary lymphomas of the central nervous system (PCNSL)

  26 Tumor/Control pairs of WGS data of PCNSL tumors, sequenced on either Illumina HiSeq2000/2500 instruments or HiSeq X Ten. The controls are blood or buffy coat samples in most cases.

  Dataset EGAD00001007806

• 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

• DMET Genes, Nicotine Metabolism and Prospective Abstinence

  This study (DA033813; PI: Andrew W Bergen; PMID:26132489) includes samples from two laboratory studies of nicotine metabolism. The Pharmacokinetics of Nicotine Metabolism in Twins study (PKTWIN; PI: Gary E Swan; PMID: 15527659) was based on recruitment from a twin registry (PMID: 23084148). The Integrated Research Project on Tobacco Use and Dependence (IRP; PI: Gary E Swan; PMID: 14578134) was based on recruitment from a pedigree-based longitudinal study of risk factors for substance use, the Smoking in Families study (SMOFAM; DA03706; PI: Hy Hops). These two laboratory studies (PKTWIN and IRP/SMOFAM) served as the Stage I dataset to interrogate Drug Metabolizing Enzyme and Transporter genes with a targeted SNP array for association with the Nicotine Metabolite Ratio (NMR, ratio of trans-3'-hydroxycotinine and cotinine), an established biomarker of nicotine metabolism. In addition to the laboratory studies, samples from eight RCTs (PMID: 23249876) with the NMR and smoking-related measures used to test SNPs identified in Stage I (PMID: 26132489). In a third stage, a lung cancer meta-analysis database (PMID: 24880342) was used to assess association of SNPs identified in Stage II with lung cancer. The objectives of the study were to identify novel genes and SNPs contributing to nicotine metabolism (Stage I), and to validate PK SNPs associated with the NMR from individuals participating in a clinical laboratory protocol with the NMR obtained from treatment-seeking smokers, and then to investigate association with prospective smoking cessation (Stage II). This study built upon existing studies of nicotine metabolism and randomized trials of smoking cessation therapies. Enhanced knowledge of the genes influencing nicotine metabolism and prospective abstinence may help personalize smoking cessation treatment and risk assessment for smoking-related diseases. For Stage I, both subject [fixed-dose NMR, covariates (age, BMI, ethnicity, sex, smoking status, and hormone use), and pedigree relationships] and sample (common DMET SNP genotype, genotyping quality control) data are available in this accession. The analysis protocol, quality control summaries, summary genotype, summary phenotype, and analysis results are available for Stage I, II and III samples (PMID: 26132489). Extensive discussion of the prior CYP2A6 association literature with the NMR, abstinence, smoking heaviness and lung cancer risk is available (PMID: 26132489). The NMR has previously been associated with CYP2A6 activity, response to smoking cessation treatments, and cigarette consumption. We searched for drug metabolizing enzyme and transporter (DMET) gene variation associated with the NMR and prospective abstinence in 2,946 participants of laboratory studies of nicotine metabolism and of clinical trials of smoking cessation therapies. Stage I was a meta-analysis of the association of 507 common single nucleotide polymorphisms (SNPs) at 173 DMET genes with the NMR in 449 participants of two laboratory studies. Nominally significant associations were identified in ten genes after adjustment for intragenic SNPs; CYP2A6 and two CYP2A6 SNPs attained experiment-wide significance adjusted for correlated SNPs (CYP2A6 PACT=4.1E-7, rs4803381 PACT=4.5E-5, rs1137115, PACT=1.2E-3). Stage II was mega-regression analyses of 10 DMET SNPs with pretreatment NMR and prospective abstinence in up to 2,497 participants from eight trials. rs4803381 and rs1137115 SNPs were associated with pretreatment NMR at genome-wide significance. In post-hoc analyses of CYP2A6 SNPs, we observed nominally significant association with: abstinence in one pharmacotherapy arm; cigarette consumption among all trial participants; and lung cancer in four case:control studies. CYP2A6 minor alleles were associated with reduced NMR, CPD, and lung cancer risk. We confirmed the major role that CYP2A6 plays in nicotine metabolism, and made novel findings with respect to genome-wide significance and associations with CPD, abstinence and lung cancer risk. Additional multivariate analyses with patient variables and genetic modeling will improve prediction of nicotine metabolism, disease risk and smoking cessation treatment prognosis.

  Study phs000931

• A single-cell atlas of the early COPD lung - Nanopore long-read

  Single cell atlas of the human airways from 10 patients suffering of early stage Chronic Obstructive Pulmonary Disease and 12 healthy age matched volunteers. This dataset was sequenced by 10X Genomics 3’ RNA-seq profiling. It is composed of more than 400 000 cells coming from 119 samples total. Sampling was performed by brushings and biopsies from the nose to the 6 th division of the airways. 14 samples were also sequenced using Nanopore long-read sequencing.

  Dataset EGAD50000001002

• Broccoli Sprouts Extracts Trial (BEST-COPD-BioLINCC)

  Data Access NOTE: Please refer to the &#8220;Authorized Access&#8221; section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: To establish a safe and tolerable dose of sulforaphane that effects in vivo antioxidants via Nrf2 for development as a potential novel treatment for participants with Chronic Obstructive Pulmonary Disease (COPD).Background: Chronic Obstructive Pulmonary Disease (COPD), caused primarily by smoking, is the third leading cause of death in the United States and world-wide. Surprisingly, there are few treatments available to address the pathobiology of COPD other than cessation of smoking. The development and progression of COPD are associated with increased inflammatory response(s) and increased oxidative stress in the lung. Thus, one approach to the development of novel therapies is the stimulation of endogenous antioxidant defense mechanisms.Nuclear factor erythroid-2-related factor 2 (NFE2L2/Nrf2) is a transcription factor activated by oxidative stress. Nrf2 activity promotes anti-oxidant enzymes, and anti-oxidant enzymes play key roles in cellular defenses. Sulforaphane, a derivative of broccoli and other cruciferous vegetables, has been shown to stimulate Nrf2 activity in both in vivo and in vitro experiments. For example, activation of Nrf2 protected mice from developing emphysema after chronic smoke exposure and decreased oxidative stress. Similarly, activation of Nrf2 in human COPD lung cells resulted in decreased oxidative stress. Therefore, this study was designed to assess whether daily ingestion of sulforaphane by COPD participants for four weeks increased Nrf2 activity in alveolar macrophages and bronchial epithelial cells. Participants: There were a total of 89 participants randomized to one of three treatment arms. Of these, 31 participants were randomized to the placebo arm, and 29 participants were randomized to the each of the sulforaphane arms. One participant withdrew from the placebo arm, therefore, a total of 88 participants completed the study.Design: Participants were assigned to receive sulforaphane at 25 micromoles (4.4mg), sulforaphane at 150 micromoles (26.6 mg), or placebo (microcellulose) once daily by mouth. Computer-generated treatment assignments were blinded to participants, clinical staff, and study staff. Doses were back-filled with methylcellulose and presented in similar capsules to compensate for appearance and weight differences in sulforaphane and placebo treatments arms.There were a total of five study visits over the six-week study period. Prior to randomization, participants were assessed for eligibility, which included baseline data collection. Participants provided medical histories, underwent a physical examination, pre-and-post bronchodilator spirometry, lung volume measurements, carbon monoxide diffusing capacity (DLCO), and pulse oximetry over the six-week study period. Follow up data and biospecimens were collected at the final visit, which was targeted for four weeks after randomization. Two fiberoptic bronchoscopies were performed under sedation to collect endobronchial brushings and bronchoalveolar lavage used to isolate alveolar macrophages and bronchial epithelial cells. The first bronchoscopy was performed on the day of randomization, and the second bronchoscopy was performed the day after the final visit. In addition, nasal brushings were obtained prior to bronchoscopy to isolate nasal epithelial cells. The primary outcomes were changes in Nrf2 target gene expression at four weeks in alveolar macrophages and bronchial epithelial cells. The target genes for the primary outcome were NQ01, H01, AKR1C1, and AKR1C3. Secondary outcomes included the evaluation of: expression of other genes in the Nrf2/Keap1 pathway (e.g. Nrf2/NFE2L2, KEAP1, and SLPI), markers of oxidative stress (e.g., isoprostane and thiobarbituric acid reactive substances) in plasma and expired breath condensate, and cytokine profiles in bronchoalveolar lavage fluid. Conclusions: Sulforaphane administered at four weeks doses of 25umoles and 150umoles to participants with COPD did not significantly increase Nrf2 target gene expression in alveolar macrophages or bronchial epithelial cells. In addition, changes in oxidative stress markers and the expression of other genes in the Nrf2/Keap1 pathway were not statistically significant between the treatment groups.Wise RA, Holbrook JT, Criner G, et al. Lack of Effect of Oral Sulforaphane Administration on Nrf2 Expression in COPD: A Randomized, Double-Blind, Placebo Controlled Trial. Vij N, ed. PLoS ONE. 2016; 11(11):e0163716. doi:10.1371/journal.pone.0163716 (PMID: 27832073; PMID: 28350841).

  Study phs004022

• The Natural History of Mucolipidosis Type IV

  Mucolipidosis type IV (MLIV) is an autosomal recessive disorder typically characterized by severe psychomotor delay evident by the end of the first year of life and slowly progressive visual impairment during the first decade as a result of a combination of corneal clouding and retinal degeneration. The purpose of this research study is to look at the brain and eye in patients with mucolipidosis type IV (MLIV). MLIV is a lysosomal storage disease that primarily affects the brain and the eyes. The disease is caused by a defect in a gene called MCLON1 that makes a protein called mucolipin-1. Patients with MLIV do not make enough normal mucolipin. The disease begins early in life and the neurological problems seem to stabilize later in life. On the other hand, the eye abnormalities usually progresses over time. The exact course of the disease has not been determined, and until now, no study has addressed this question carefully. The research objectives are: To learn about the natural history of cognitive function for individuals with mucolipidosis type IV. To measure brain volume over time in individuals with mucolipidosis type IV This is an observational study of individuals with MLIV disorder. Those participating in this study will be evaluated annually for five years following a baseline visit.

  Study phs001329

• Gynecology and Lubricant Effects (GALE) Study

  The GALE study is a longitudinal study of the association between lubricant use and the vaginal microbiota in women receiving transvaginal ultrasound (TVUS) at the Diagnostic Radiology and Nuclear Medicine Department at the University of Maryland School of Medicine. Participants undergo a clinical exam at enrollment (at least 5 days prior to TVUS) and self-collect daily, mid-vaginal samples in the week leading up to TVUS, including immediately before the procedure. At the TVUS appointment, the sonographer applies a single-use packet of Glide lubricating jelly to the probe. The product was selected for study as it was currently being used in the TVUS clinic at the University of Maryland Medical Center and is a clinical lubricant which is very similar in composition to many sex lubricants. Participants collect samples the evening after TVUS and present for a follow-up clinical exam within a week of TVUS. Participants continue to sample twice weekly for an additional 8 weeks (returning completed kits each week), complete daily health and behavior diaries, and attend one final clinical exam at week 10. The clinician evaluates participants for bacterial vaginosis (BV) at each clinical visit using Amsel's criteria, and also looks for signs of vulvovaginal candidiasis (VVC) and trichomonas using a wet mount.

  Study phs002211

• Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors

  Large-cell neuroendocrine lung carcinomas (LCNEC) have similarities with other lung cancers, but their precise relationship has remained unclear. We conducted comprehensive genomic (n=60) and transcriptomic (n=69) analyses of 75 LCNECs and identified two molecular subgroups: “type I LCNECs” with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and “type II LCNECs” enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1high/DLL3high/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1low/DLL3low/NOTCHhigh and upregulation of immune-related pathways. In conclusion, LCNECs are comprised of two molecularly defined subgroups, and distinguishing them from SCLC may allow for stratified targeted treatments for high-grade neuroendocrine lung tumors.

  Study EGAS00001000708

• EGA QuickView

  EGA QuickView Secure and Remote Access to EGA Files What is EGA QuickView? EGA QuickView is a FUSE file system that allows secure and remote access to EGA files. It is a hybrid of sshfs and crypt4ghfs, which means it uses ssh to connect to the EGA distribution servers, downloads data in Crypt4GH format, and transparently decrypts those files. It is compatible with Linux and macOS 12. Why use EGA QuickView? EGA QuickView is a highly useful and convenient tool for anyone who needs to access EGA files remotely and securely. The software offers a quick and convenient way to browse through EGA files without the need for complete downloads, thus saving bandwidth and time. Whether you are a medical professional requiring access to sensitive patient data or a research scientist working on a project that involves EGA files, EGA QuickView provides a highly useful solution. The software boasts advanced security features, ensuring that your data is safe and protected at all times. Get started with EGA QuickView To get started with EGA QuickView, visit the EGA QuickView GitHub repository for more information and installation instructions.

  Documentation access/download/visualisation/ega-quickview

• GCAT| ICD Disease Diagnoses

  Disease diagnoses of GCAT Cohort participants obtained from electronic health records (EHR), mainly including the time period from 2012 to 2017. Disease diagnoses are codified in ICD-9, and the position of diagnosis refers to primary/secondary diagnoses (up to 14 secondary diagnoses per visit). The date and origin of the visit are also specified (AP: primary care, UGR: emergency, AH: hospital care, SMA: outpatient medical service, SMH: hospital medical service).

  Dataset EGAD00001007731

• A Phase II Neoadjuvant Study of Palbociclib in Combination with Letrozole and Trastuzumab as Neoadjuvant Treatment of Stage II-III ER+ HER2+ Breast Cancer (PALTAN)

  Women with early stage ER+/HER2+ breast cancer (BC) are less likely to achieve pathological complete response (pCR) after chemotherapy with standard of care dual HER2 blockade than patients with ER-/HER2+ BC. Additionally, the toxicity burden of standard systemic therapy is high. Thus, this single arm phase 2 clinical trial investigated a novel de-escalation regimen with trastuzumab, letrozole, and palbociclib in those with early stage ER+/HER2+ BC. The aim was to determine if this treatment regimen will achieve similar pCR rates as conventional treatment and spare women the toxicity burden of regular treatments. The primary endpoint was pCR after 16 weeks of treatment with trastuzumab, letrozole, and palbociclib. Patients with newly diagnosed ER+ HER2+ invasive BC with clinical stages II and III were eligible for this protocol. Research biopsies were performed during the treatment course for whole exome and RNA sequencing, PAM50 molecular subtyping, and Ki67 assessment using immunohistochemistry for complete cell cycle arrest (CCCA: Ki67 &#8804;2.7%). Results showed a pCR of 7.7% and a rate of residual cancer burden at 0 or I of 38.5%. CCCA was observed in 85% at Cycle 1 day 15 post palbociclib, trastuzumab, and letrozole treatment (C1D15), compared to 27% at surgery after palbociclib was discontinued. PAM50 subtyping identified 31.2% HER2-E, 43.8% Luminal B, 25% Luminal A. 161 genes were differentially expressed comparing C1D15 to baseline. Whole exome and RNA sequencing data will be available through dbGaP.

  Study phs003147

• 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

• Development and Use of Network Infrastructure for High-Throughput GWA Studies

  The "Development and Use of Network Infrastructure for High-Throughput GWA Studies" project is collaboration between Group Health Cooperative (GH), the University of Washington (UW), and the Fred Hutchinson Cancer Research Center (FHCRC). It is one of 5 sites participating in The Electronic Medical Records and Genomics (eMERGE) Network funded by the National Human Genome Research Institute (NHGRI) with additional funding from the National Institute of General Medical Sciences (NIGMS). The overall eMERGE project is designed to assess whether linking biorepositories of patients in healthcare delivery systems with electronic medical records (EMRs) is an efficient strategy for high-throughput genome wide association (GWA) studies and whether information can be pooled across sites. The primary phenotype in the Group Health/UW Aging and Dementia eMERGE study project is dementia. Phenotyped participants originated from four population-based sources. Seattle-area members of GH (a large integrated health care system in Washington State) consented and enrolled in 1) the University of Washington Alzheimer&#39;s Disease Patient Registry (ADPR) and 2) the Adult Changes in Thought (ACT) study, 3) Marshfield Clinic Personalized Medicine Research Project (PMRP), a population-based DNA, plasma and serum biobank of 20,000 adults, 4) Vanderbilt&#39;s BioVU, a de-identified DNA biobank. The ADPR (PI: Eric B. Larson; NIH/NIA U01 AG 006781) is a population-based registry of incident dementia cases designed to identify all new dementia cases within GH from 1987 to 1996. Potential dementia cases were identified through referrals from primary care physicians, mental health services, and neurologists, as well as review of CT scans, neurology, emergency room, geriatrician, and mental health clinic logs, and hospital discharge diagnoses. Medical history, physical, laboratory testing, and neuropsychological testing were performed on all consenting potential cases. These data were reviewed by a consensus conference including a neuropsychologist, study physicians, and an epidemiologist. After discussion of the case, dementia status is assigned using DSM-III-R criteria. Alzheimer&#39;s disease status was assigned using the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer&#39;s Disease and Related Disorders Association (NINCDS-ADRDA) criteria. The study base of the ADPR population was stable with an attrition rate of less than 1%/year. The ACT study (PI: Eric B. Larson; NIH/NIA U01 AG 006781) is an ongoing community-based cohort study designed to determine the incidence of Alzheimer&#39;s Disease (AD), other types of dementia, and cognitive impairment and to determine risk factors for these conditions. The original cohort of 2,581 was enrolled in 1994-1996. An expansion cohort of 811 was enrolled in 2000-2002. Continuous enrollment to keep 2,000 persons enrolled and at-risk for dementia outcomes was begun in 2005. To date the study has accrued more than 4,000 participants. Dementia-free participants are enrolled in this cohort and evaluated every two years by study personnel with many evaluations including an assessment of cognitive functioning using the Cognitive Abilities Screening Instrument (CASI), which is an extended version of the Mini-Mental State Examination that has been widely used in epidemiological studies of the elderly. Persons with CASI scores lower than 86 or in whom interviewers suspect unusual cognitive decline are followed up with dementia diagnostic evaluations which include physical and neurological examinations and neuropsychological tests. Medical records are reviewed, and laboratory tests and neuroimaging are obtained if not available. The dementia diagnoses and dementia subtypes are determined during a consensus conference attended by the examining clinicians and other study physicians, a neuropsychologist, and research nurse. After discussion of the case, dementia status is assigned using DSM-IV criteria. Alzheimer&#39;s disease status was assigned using NINCDS-ADRDA criteria. Individuals diagnosed with dementia are seen again one year following diagnosis using the same procedures. Individuals not diagnosed with dementia are returned to the pool of at-risk individuals and are seen at their next routinely scheduled biennial visit. The ACT sub-sample is stable; for the original cohort, median enrollment in GH was 19 years prior to joining the ACT study, and 85% of the cohort has &#8805; 10 years of GH enrollment. DNA for the ADPR participants were obtained through a companion study, Genetic Differences in Cases and Controls (PI: Walter Kukull; NIH/NIA R01 AG007584). DNA obtained through both studies were extracted from blood using Gentra Systems Puregene methods. DNA concentration is determined by UV optical density. All samples are checked for quality by OD 260/280 ratio. For long-term storage, samples are aliquoted and stored at -70&#176;C. The Marshfield study, Personalized Medicine Research Project (PMRP), a population-based DNA, plasma and serum biobank of 20,000 adults. PMRP was started in 2002 as a 3 Phase project. Completed in April 2004, the objectives of Phase I were to build and develop a large population-based biobank with DNA, plasma and serum samples to facilitate genomics research. Phase 1 was also to educate, inform and consult with the Marshfield Epidemiologic Study Area population and communities concerning potential studies, create the DNA foundation of the personalized medicine database and build the bioinformatics tools to store securely and analyze genotypic and phenotypic data. Phase I tasks included operation of the ethics and security advisory board, scientific advisory board and community advisory group. More than 18,000 residents aged 18 and above from 19 different zip codes surrounding Marshfield, WI were invited to participate in Phase I. After providing written informed consent, participants completed brief questionnaires that included questions about demographics, some environmental exposures, family history of disease, and adverse drug reactions, as well as family members living in the area. Participants provided 50ml of blood from which DNA was extracted and plasma and serum samples were stored. The informed consent process allowed access to electronic medical records and included language about non-disclosure of personal research results. A tick-off box was included so that participants could either allow or decline subsequent recontact for future research studied. The objectives of Phase II are to create the phenotypic database, establish the scientific and administrative infrastructure to support genetic mapping of the DNA and the initial discovery projects and genotype a sufficient portion of the genetic material to support these discovery projects. The objectives of Phase III are to expand the discovery projects, complete the genotyping of the genetic database and expand physician/health care provider education and community consultation. The Vanderbilt BioVU model uses discarded blood leftover from clinical care and de-identified clinical information, both of which are tracked with a Research Unique Identifier that is permanently disconnected from the medical record number used to generate it. The Vanderbilt IRB determined that the project does not qualify as "human subject" research under &#167;46.102(f)(1)(2). The program has been reviewed by OHRP twice (the latest immediately prior to launch), and the determination of the Vanderbilt IRB that the project is consistent with the 8/10/2004 guidance has been validated. The model includes a simple opt out mechanism developed for patients who do not wish to have their samples included. Planning (including community involvement, ethics and IRB discussions, focus groups, development of operating procedures and pilot studies to assess them) began in May 2004, and the resource commenced sample collection in February 2007 and as of May 2009 contains approximately 56,000 samples. The current resource will be available to all Vanderbilt investigators who sign a Data Use Agreement. The resource represents Vanderbilt&#39;s broad patient population and thus provides a potential resource for research in a range of common and rare diseases as well as drug response or medication safety. BioVU patient protection model: There has been extensive involvement by the ethics community and the IRB to put in place procedures to provide privacy protection. The overall protection plan is multifaceted and includes a combination of technology and policy: (1) creation of the SD described above; (2) return of only the specific clinical data items requested by investigators (rather than the complete de-identified chart); (3) submission of any specific proposed project to the IRB and to a separate protocol review committee, both of which must approve; (4) implementing a Data Use Agreement that permits only approved queries and data analyses, specifically prohibits attempts at re-identification (at the risk of institutional sanctions), and mandates redeposit of all genetic information generated in a research study back into a genomic database; and (5) tracking and auditing all use.

  Study phs000234

• Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer

  Mechanisms of acquired resistance to immune checkpoint inhibitors (ICIs) are poorly understood. The purpose of this study was to investigate whether alterations in genes encoding components of the HLA Class I antigen processing and presentation machinery or interferon signaling pathways play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Whole exome sequencing was performed on tumor samples collected from patients with advanced non-small cell lung cancer at the time of resistance to PD-1 axis inhibitors and on available matched pre-treatment and normal samples. Patient-derived xenografts successfully established from the ICI-resistant samples were also exome sequenced. Additionally, RNA sequencing was performed on cases with sufficient tissue.

  Study phs001464

• 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&#39;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&#39;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 (&gt; 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

• Bulk and single-cell RNA-sequencing data from five lines of human iPSC-derived (hiPSC-derived) astrocytes (3 in-house and 2 commercial lines), both alone and in co-culture with neurons, to define the molecular response of astrocytes to misfolded alpha-synuclein

  RNA editing is a post transcriptional mechanism that targets changes in RNA transcripts to modulate innate immune responses. We report the role of astrocyte specific, ADAR1 mediated RNA editing in neuroinflammation in Parkinson’s disease. We generated hiPSC-derived astrocytes, neurons and co-cultures and exposed them to small soluble alpha-synuclein aggregates. Oligomeric alpha-synuclein triggered an inflammatory glial state associated with TLR activation, viral responses, and cytokine secretion. This reactive state resulted in loss of neurosupportive functions, and the induction of neuronal toxicity. Notably, interferon response pathways were activated leading to upregulation, and isoform switching of the RNA deaminase enzyme, ADAR1. ADAR1 mediates A-to-I RNA editing, and increases in RNA editing were observed in inflammatory pathways in cells, as well as in post-mortem human PD brain. Aberrant, or dysregulated, ADAR1 responses and RNA editing may lead to sustained inflammatory reactive states in astrocytes triggered by alpha-synuclein aggregation, and this may drive the neuroinflammatory cascade in Parkinson’s.

  Study EGAS50000000751