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• Health Professionals Follow-Up Study

  Health Professionals Follow-up Study (HPFS) is a prospective cohort study of men designed to evaluate hypotheses about men’s health related to diet and lifestyle to the incidence of serious illnesses, such as cancer, heart disease, and other vascular diseases. It consisted of 51,529 U.S. male health professionals who were 40-75 years old at baseline in 1986 and completed a mailed six-page baseline questionnaire. Information on age, height and weight, ancestry, medications, disease history, physical activity, lifestyle factors, and diet were gathered, with follow-up questionnaires sent biennially to update information and record health outcomes with every four years to update their diet. This datafile includes responses to the 2016 questionnaire, which is available at: https://cdn1.sph.harvard.edu/wp-content/uploads/sites/2471/2017/09/16L.pdf

  Study phs002460

• Hereditary Cancer Predisposition Syndromes and Uveal Melanoma

  Uveal melanoma (UM) is a subtype of melanoma characterized by the strong contribution of genetic rather than environmental factors in the pathogenesis of the disease, making it an ideal model disease to study the genetic basis of cancer. The long-term goal of our laboratory is to determine the genes and mechanisms responsible for hereditary cancer predisposition associated with UM. BAP1 has been identified as a candidate gene with definitive association with predisposition to UM. However, pathogenic variants in BAP1 are detected in only a small subset of UM patients even those with strong personal and family history of cancer suggesting the existence of other candidate genes. The goal of this project is to identify novel candidate genes contributing to hereditary predisposition to UM in patients with no detectable germline pathogenic variant in BAP1.

  Study phs001943

• Transcriptomics of Liver and PBMCs in Alcohol-Associated Liver Disease

  This study was designed to characterize the transcriptome of alcohol-associated hepatitis using RNA sequencing (RNA-seq) technology for both liver tissue biopsies and peripheral blood mononuclear cells (PBMCs) extracted from blood samples, in order to identify expressed genes that are markers of the disease. To distinguish genes that differentiate alcohol-associated hepatitis from other inflammatory liver diseases, we compared the RNA-seq data generated from participants with alcohol-associated hepatitis, alcohol-associated cirrhosis, chronic hepatitis C infection, non-alcohol-associated fatty liver disease, and healthy controls. We utilized computational approaches to demonstrate that gene expression data generated from either liver tissue or blood samples can be used to identify a small set of gene biomarkers to distinguish between these liver diseases. The raw RNA-seq data will be available through dbGaP.

  Study phs003112

• MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition

  Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low “variant” subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which combined with chemotherapy strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a novel targeted treatment approach for MYC-driven SCLC.

  Study EGAS00001002115

• XClone for analyzing somatic copy number alterations

  Somatic copy number alterations (CNAs) are major mutations that contribute to the development and progression of various cancers. Despite a few computational methods proposed to detect CNAs from single-cell transcriptomic data, the technical sparsity of such data makes it challenging to identify allele-specific CNAs, particularly in complex clonal structures. In this study, we present a statistical method, XClone, that strengthens the signals of read depth and allelic imbalance by effective smoothing on cell neighborhood and gene coordinate graphs to detect haplotype-aware CNAs from scRNA-seq data. By applying XClone to multiple datasets with challenging compositions, we demonstrated its ability to robustly detect different types of allele-specific CNAs and potentially indicate whole genome duplication, therefore enabling the discovery of corresponding subclones and the dissection of their phenotypic impacts.

  Study EGAS00001007854

• Exome_sequencing_of_thyroid_disease_in_Val_Borbera

  The Val Borbera is a region characterized by low iodine and high prevalence of thyroid disorders, the commonest endocrine disorders in the general population. About 30% of the participants of the Val Borbera Project were affected by such disorders and were characterized by several parameters, TSH level, anti TPO antibodies, echography, family origin. Individuals with extreme phenotypes were identified and could be clustered based on family origin and genotype. We propose to exome sequence 6 of them, affected with true goiter, at high dept (40-60x) to obtain information on exonic rare variants. Due to the family structure and to the availability of whole genome sequence information on 110 individuals from the isolated population we expect to be able to identify putative causative variants for thyroid disorders that may be studied in the remaining affected individuals.

  Study EGAS00001000344

• Molecular sub-classification of hormone receptor-positive breast cancer

  Patients with estrogen and/or progesterone receptor-positive breast cancer benefit from hormonal treatment, yet high global death burdens due to high prevalence and long-term recurrence risk call for biomarkers to guide additional treatment approaches. From a prospective, observational study of postmenopausal early breast cancer patients treated with tamoxifen or aromatase inhibitors gene expression analyses of 612 tumors was performed using the NanoString® Breast Cancer 360 panel. We identified novel gene expression signatures, i.e. BRCAness and Tumor Inflammation Signature (associated with high tumor lymphocyte infiltration), that may aid to select high-risk patients in order to improve adjuvant treatment by targeting DNA repair deficiency or immune-checkpoints in addition to standard chemo-endocrine treatment. The overall goal is to foster novel concepts for a stratified early breast cancer management.

  Study EGAS00001004594

• Gene expression adaptation of metastases to their host tissue

  The adaptation of metastatic cells to their host tissue critically determines the pathogenicity of a cancer and therefore patient survival. Yet, it remains elusive to what extent the host environment drives gene expression programs in metastatic cells. Here we identify adaptive mechanisms that enable metastases to establish themselves in a novel tissue context. We performed single-cell RNA-sequencing on malignant and benign tissue samples from untreated donors with colorectal adenocarcinoma and liver metastasis to deduce tissue adaptive expression patterns. A novel computational approach identified genes and pathways that consistently adapted to the host tissue at the transition from the primary tumor to the paired metastasis across donors. This analysis revealed that the majority of expression changes in the metastasis reflect an expression signature reminiscent of benign liver epithelial cells. Cellular processes adapting to the liver environment include basic cellular functions such as energy metabolism, as well as tissue-specific pathways such as the regulation of lipid metabolism by PPAR-α. These adaptations potentially increase the pathogenicity of the metastatic cells and may provide new therapeutic strategies.

  Study EGAS50000000817

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

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

  Study phs003535

• Therapeutic Resistance to PI3K-alpha Inhibitors

  We have studied the tumor genomic evolution in a patient with metastatic breast cancer bearing an activating PIK3CA mutation. The patient was treated with the PI3Kα inhibitor BYL719 and achieved a lasting clinical response on BYL719, but eventually progressed to treatment and died shortly thereafter. A rapid autopsy was performed and a total of 14 metastatic lesions were collected for further analysis. In order to identify possible genetic determinants of acquired resistance to PI3Kα inhibition, we took a three-step approach. First, we examined both the primary tumor (before BYL719 treatment) and the new lung metastasis by whole genome sequencing (DNA from the spleen was used as a normal control). Then, we analyzed the primary tumor, lung metastasis, and the peri-aortic lesion that remained stable (responding) at the time of progression to BYL719 therapy by whole exome sequencing. Finally, to confirm and expand our findings, we sequenced the primary tumor and all the metastatic lesions to >500-fold coverage using a custom targeted deep-sequencing assay, MSK-IMPACT. Using this 3-step approach, we have demonstrated that patient’s lesion underwent parallel genetic evolution at multiple metastatic sites with different PTEN genomic alterations leading to a convergent PTEN- null phenotype resistant to PI3Kα inhibition. In order to expand our observations, we analyzed paired samples (pre-treatment and at progression) from six additional patients enrolled in the BYL719 trial. Acquired bi-allelic loss of PTEN was found in one additional patient treated with BYL719 whereas in two patients PIK3CA mutations present in the primary tumor were no longer detected at the time of progression. To functionally characterize our findings, inducible PTEN knockdown in sensitive cells resulted in resistance to BYL719, while simultaneous PI3K-p110β blockade reverted this resistance phenotype, both in cell lines and in PTEN-null xenografts derived from our patient. We conclude that parallel genetic evolution of separate sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI3Kα inhibition.

  Study EGAS00001000991

• Target Capture Sequencing of 12 patients

  We perfomed target capture DNA sequencing of 12 patients to assess the detailed biological mechanisms of resistance to immune checkpoint inhibitors.

  Study JGAS000589

• Neoadjuvant_Breast_Cancer_Validations

  This study aims to re-sequence findings from whole genome studies using a bespoke pulldown method to validate mutations in those genomes sequenced.

  Study EGAS00001000428

• CRU-Ukrainian National Research Center for Radiation Medicine Trio Study

  Data on transgenerational effects following nuclear accidents are important for understanding fully the consequences of parental exposure to ionizing radiation. Few studies to date have had adequate statistical power to detect effects of the magnitude expected based on animal data, and most have not been of low-dose, protracted exposures associated with nuclear accidents and their aftermath. Although, to date, scant use has been made of the new genomic technologies, in Chernobyl-exposed areas of Ukraine and Belarus, excess minisatellite mutations have been seen in children born after the accident. We propose a study of parent-child trios in which at least one parent was exposed to Chernobyl radiation as a clean-up worker (mean dose>=100 mGy) and/or evacuee from a contaminated area (mean >=50 mGy). The specific aims are to investigate the transgenerational and de novo mutation rates of the spectrum of genetic variants in trios, in particular looking at effects in children and mapping them to possible parental origin of the chromsoome. Together with long-term collaborators at the Research Center for Radiation Medicine (RCRM) in Kiev, epidemiologic data will be collected for up to 450 trios of parents with preconceptional doses and their unexposed offspring. We will use state-of-the-art genomic technologies to characterize the landscape of the genomes of the trios to determine whether parental radiation exposure is associated with genetic mutations transmitted to the offspring, by examining de novo mutation rates, minisatellite mutations, copy number alterations, and variations in telomere length. The analysis will be conducted in peripheral blood and/or buccal samples (when blood is not available) from complete father-mother-child trios. Doses to the gonads from the time of the accident to the time of conception will be reconstructed for all parents using existing records supplemented by interview data. Trio subjects will be selected from representative populations exposed to radiation from Chernobyl who are under active follow-up in the Clinico-Epidemiologic Registry at RCRM. To help identify specific effects of paternal and maternal radiation exposure, we will initially select sets of trio subjects in five categories: (1) exposed father, unexposed mother; (2) unexposed father, exposed mother; (3) both parents exposed; (4) both parents unexposed; and (5) a group of high dose "emergency workers" with acute radiation syndrome. All trio members will be invited to the RCRM outpatient clinic for collection of a 20 ml blood sample (or buccal cells for those who refuse phlebotomy). Both parents will be asked to complete a general questionnaire to obtain demographic and lifestyle data. Then one or both will complete detailed dosimetry questionnaires, based on forms used in previous collaborations with RCRM and administered by specially trained interviewers. Once 50 trios have been recruited (10 from each of the 5 exposure categories), we will conduct an interim evaluation of participation rates, sample collection and quality, and dose reconstruction in order to modify the protocol as needed. The analytical approach will be to correlate the extent, especially for de novo events of genetic alterations in the offspring with parental pre-conceptional radiation dose overall and by parental origin. The statistical power in relation to de novo mutations is very high, in excess of 90%, but somewhat lower for trends in minisatellite mutations. Study findings will contribute importantly to knowledge of the heritable effects of moderate- and low-dose radiation exposure in humans and to radiation risk projection. Eventually data from the Trio Study may be shared with the international community through dbGap.

  Study phs001163

• Biomarker Screen for Efficacy of Oncolytic Virotherapy in Patient-derived Pancreatic Cancer Cultures

  Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC, different oncolytic viruses (OVs) are currently investigated in clinical trials. However, systematic comparisons of these different OVs in terms of efficacy against PDAC and biomarkers predicting therapeutic response are lacking. We screened fourteen patient-derived PDAC cultures for their sensitivity to five clinically relevant OVs, namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC, measles vaccine strain MV-NIS, reovirus jin-3, and protoparvovirus H 1PV using live cell analysis, quantification of viral genome/gene expression, cell viability as well as cytotoxicity assays. Sensitivity was correlated with transcriptome profiles to identify potential predictive biomarkers for response to OVT. Patient-derived PDAC cultures showed individual response patterns to OV treatment. Twelve of fourteen cultures were responsive to at least one OV, with no single OV proving superior or inferior across all cultures. Known host factors for distinct viruses were retrieved as potential biomarkers. Compared to the basal-like molecular subtype, the quasi-mesenchymal subtype of PDAC was more sensitive to H-1PV, jin-3, and T-VEC. Expression of viral entry receptors did not correlate with sensitivity to OV treatment. Rather, cellular pathways controlling immunological, metabolic, and proliferative signalling appeared to determine outcome. For instance, high baseline expression of interferon-stimulated genes (ISGs) correlated with relative resistance to oncolytic measles virus, whereas cGAS expression was associated with exceptional response. Combination treatment of MV-NIS with a cGAS inhibitor improved tumour cell killing in several PDAC cultures.

  Study EGAS00001007001

• Urethral Microbiome of Adolescent Males

  Urethral microbiome of adolescent males is designed to characterize the microbial communities resident in the urethra of young men, to identify differences in these communities as a function of race/ethnicity, circumcision status, sexual exposures, and uro-genital symptoms. We collect detailed sexual behavior and symptoms data using cellular telephones with Internet access. Specimens are routinely collected at monthly intervals, and intermittently following reported symptoms, specific sexual exposures, or identification of a sexually transmitted infection. We also collect periodic samples from the penile coronal sulcus to better characterize its relationship to the urethral micriobial communities. Participants are ages 14 - 17 at enrollment, and prior history of sexual exposure is not required for participation. Parental permission is obtained for each participant. The planned duration of followup is up to 4 years allowing for prospective observation of both physical and behavioral maturation from middle adolescence into young adulthood. The overall objectives of the project are to better characterize the healthy male urethral microbiome, and to use this information to better understand acquisition of urethritis and sexually transmitted infections, as well as chronic genital pain and prostatitis syndromes that become common among young adults.

  Study phs000259

• Impact of Race and Genetic Factors on Beta Blocker Effectiveness in Heart Failure

  Heart Failure (HF) continues to be an enormous public health problem, despite the many advances in its pharmacotherapy over the past 25 years. The availability of multiple therapeutic options for HF requires individualization of therapy. However, there are currently insufficient tools to guide the optimal selection of therapy. The expansion of human genomic information has led to exciting new opportunities to improve the selection of drug therapy. In order to evaluate whether genetic variation impacts outcomes and drug response in heart failure, we performed a cohort study of patients with heart failure. Our overall plan was to recruit patients who have heart failure and receive treatment through HAP-HFMG. This allowed us to collect clinical outcomes, and quantify medication adherence via electronic pharmacy claims data. We collected whole blood samples for genetic analysis. We then tested whether genetic variants can predict patient outcomes (survival) in the context of their medical therapy (drug exposure). The primary medications of interest were beta blockers. Outcomes were modeled overall, accounting for the amount of exposure to the agent, and adjusting for baseline characteristics.

  Study phs001501

• CIDR Whole Exome Sequencing in Joubert Syndrome

  The purpose of this study is to identify new genetic causes of neurodevelopmental diseases (NDDs) in the Joubert syndrome (JS) spectrum. Joubert syndrome is a recessive disease characterized by cerebellar vermis hypoplasia. Our currently funded NINDS award entitled "Molecular characterization of Joubert syndrome" seeks to identify new genetic causes through a variety of molecular strategies. Although our previous strategies involved whole genome SNP-scans, followed by candidate gene sequencing to arrive at identification of new JS causes, we have recently moved to Whole Exome Sequencing (WES) as a highly efficient methodology that is optimized for recessive disease. In this pilot project, CIDR has sequenced DNA on probands from 20 inbred families with JS spectrum disorders in which known causes have been excluded, that have not previously undergone genome-wide SNP scans. These paired end reads will be subject to our established bioinformatics pipeline including HOMOZGYOSITY, SNP and INDEL callers in our lab to identify potentially deleterious sequence changes (PDSC). This is followed by analysis to include testing each PDSC for segregation in the whole pedigree, for occurrence in a ethnically-matched cohort, as well as a defined patient cohort patients, in order to validate new NDD genes.

  Study phs000382

• Nanobody-Tethered Transposition Allows for Multifactorial Chromatin Profiling at Single-Cell Resolution

  Chromatin states are functionally defined by a complex combination of histone modifications, transcription factor binding, DNA accessibility, and other factors. However, most current single-cell-resolution methods are unable to measure more than one aspect of chromatin state in a single experiment, limiting our ability to accurately measure chromatin states. Here we introduce nanobody-tethered transposition followed by sequencing (NTT-seq), a new assay capable of measuring the genome-wide presence of multiple histone modifications and protein-DNA binding sites at single-cell resolution. NTT-seq utilizes recombinant Tn5 transposase fused to a set of secondary nanobodies (nb). Each nb-Tn5 fusion protein specifically binds to different immunoglobulin-G antibodies, enabling a mixture of primary antibodies binding different epitopes to be used in a single experiment. We apply bulk- and single-cell NTT-seq to generate high-resolution multimodal maps of chromatin states in cell culture and cells of the human immune system, demonstrating the high accuracy and sensitivity of the method. We further extend NTT-seq to enable simultaneous profiling of cell-surface protein expression alongside multimodal chromatin states to study cells of the immune system.

  Study phs003068

• Systems Analysis of Single-Cell Heterogeneity Underlying Glioma Drug Resistance

  This study characterizes the transcriptional regulatory mechanisms that drive responses of two patient-derived glioblastoma multiforme (GBM) stem-like cells (PD-GSCs) that have distinct phenotypes - one sensitive and another resistant to the drug pitavastatin. This study investigates the differing mechanisms driving drug response in the two PD-GSCs at the single-cell level, and provides an approach that can be used to infer transcriptional regulatory network models, which can then be used to identify mechanisms driving cell-state transitions, e.g., proneural-to-mesenchymal transitions (PMT), which has been observed experimentally and clinically in GBM. The use of these network models enabled the identification of transcription factor and gene targets that perturbed drug-induced PMT through 1) simulations of network dynamics network, and 2) characterization of gene program activities over the time-course response to drug treatment. These results enabled the identification of multiple siRNAs and the drug vinflunine as secondary components that potentiate the efficacy of pitavastatin. This work demonstrates an approach to uncover the transcriptional network topology (TRN) topology of PD-GSCs, and use it to rationally predict combinatorial treatments that block treatment escape and acquired resistance to drugs in GBM.

  Study phs003501

• The identification of genetic vulnerabilities in head and neck cancers for the development of novel treatments.

  The global cancer burden is expected to double by the year 2030 and this will disproportionately affect the Asian continent. Head and neck squamous cell carcinoma (HNSCC) is endemic in Asia. It is the sixth most common cancer worldwide and the second most common in Malaysia, with approximately 600,000 new cases per year globally. Longterm survival remains less than 50%, underscoring the need for better therapeutic strategies. In this proposal we aim to bring new technological advancements in the identification of critical genes in HNSCC and the identification of compounds for the development of new therapies in HNSCC. We propose to genomically characterise 16 unique Asian H&N cancer cell lines, to classify sub groups where identification of essential genes that can be targeted for tumor control can be applied in a more rational way. Further, we propose to use zebrafish, an established drug discovery platform to identify promising pathway-specific compounds that could be further studied using CRISPR/Cas9 lethality screens and biological models to better identify novel therapeutic strategies to combat this major health problem in Asia.

  Study EGAS00001002682

• SINGLE_CELL_ANALYSIS_OF_IN_VITRO_ERYTHROPOIESIS

  We are developing a protocol to differentiate mouse and human induced pluripotent stem (IPS) and embryonic stem (ES) cells towards the haematopoietic pathway to generate erythrocytes in vitro. This system has many applications such as the study of the role of specific genes and human polymorphisms in infectious diseases such as malaria, as well as haematological diseases such as myelodysplastic syndrome. The nature of the in vitro differentiation process means that a heterogeneous population of cells is generated. In order to understand the types of cells produced with our protocol, we have performed a single cell analysis, which has the power to reveal the different populations of cells and their characteristics. For this, a cDNA library has been made that needs to be sequenced to obtain the gene expression profiles of the different cells. With this information we will be able to assess the quality of the differentiation protocol and improve it in order to produce better cells for the downstream applications.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/

  Study EGAS00001000764

• About

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

  Documentation about/ega

• Genome-Wide Association Study of Celiac Disease

  Celiac disease (gluten-sensitive enteropathy, celiac sprue) is a common disease with significant morbidity and mortality. It is caused by sensitivity to the dietary protein gluten, resulting in a chronic enteropathy in the small intestine. Celiac disease is now recognized to be a common disease, with reports that the disease frequency is 1:133 in the United States, similar to European estimates. There is recent evidence to suggest that the incidence of the disease is rising. Occult disease is frequently present with minimal classic symptoms or signs. The ratio of symptomatic to asymptomatic celiac disease is estimated to be 1:7. Some complications of celiac disease include lymphoma, osteoporosis, anemia, miscarriages, seizures, vitamin deficiencies, and co-occurrence of other autoimmune diseases. The only treatment is a gluten-free diet, so that recurrence of symptoms and complications may occur after minor dietary indiscretions. Identifying the underlying genetic causes of celiac disease may allow us to identify susceptible individuals, as well as advance new ways to prevent the disease and to treat it once it occurs. Several genome-wide linkage studies and one genome-wide association study of celiac disease have been conducted. Other than the common locus at HLA, few putative celiac disease loci have been replicated between studies, suggesting that the disease is heterogeneous and complex. A portion of the genetic predisposition can be attributed to HLA, but the etiology is likely due to a number of rare, high penetrant genes (as would be identified in linkage analysis) and to more common, low penetrant genes (as would be identified in association studies). The objective of this study is to identify new loci that increase risk to develop celiac disease. We will capitalize on existing North American resources, including three large collections of celiac cases and controls (Aim 1) and an independent set of celiac cases and their families (Aim 3). We propose a comprehensive multi-stage approach, with the following specific aims. In Aim 1, we will conduct a genome-wide association (GWA) study of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). The GWA will include1900 disease cases and 3400 matched controls, genotyped using the Illumina Human 610-quad chip. Statistical analyses will be performed to test for associations with celiac disease. In Aim 2, we will conduct a combined analysis of our GWA dataset from Aim 1 and a previous GWA dataset to identify additional low-penetrance loci. In Aim 3, we will attempt to replicate significant findings from the GWA study in two independent sample sets. At the conclusion of this study, we expect to have validated a number of SNPs and CNPs from regions in the genome that alter the risk of developing celiac disease. These SNPs may prove useful at both the clinical and research level. The data from the study will be shared with the scientific community.

  Study phs000274

• dbGaP Collection: NHLBI Heart Failure Related dbGaP Data (No IRB requirement)

  The National Heart, Lung, and Blood Institute (NHLBI) Big Data Analysis Challenge: Creating New Paradigms for Heart Failure Research has concluded. The NHLBI will continue to make this collection of data available to the research community.Past information regarding the Data Collection for the NHLBI Big Data Analysis Challenge: Creating New Paradigms for Heart Failure Research is below.The National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health (NIH), is inviting novel Solutions for the NHLBI Big Data Analysis Challenge: Creating New Paradigms for Heart Failure Research. The goal of the challenge is to foster innovation in computational analysis and machine learning approaches utilizing large-scale NHLBI-funded datasets to identify new paradigms in heart failure research. The challenge aims to address the need for new open source disease models that can define sub-categorizations of adult heart failure to serve as a springboard for new research hypotheses and tool development in areas of heart failure research from basic to clinical settings. NHLBI has a history of making considerable investments in the creation of deep data resources including: long-standing, deeply-phenotyped epidemiological cohorts, innovative clinical trials, and large-scale precision medicine efforts that have generated whole genome sequencing and "other omics" data for more than one-hundred thousand individuals. To provide challenge participants with streamlined access to data across NHLBI's numerous studies containing heart failure data, the NHLBI has created this dbGaP study collection. Data access for this collection is controlled by NHLBI's Data Access Committee. Challenge participants are required to follow the use restrictions and acknowledgement instructions from the original dataset(s). Please note that the data in this collection are not harmonized across studies or otherwise altered from the original study. The NHLBI Big Data Analysis Challenge: Heart Failure Data Collection contains all NHLBI studies currently in dbGaP that contain data that may be relevant to research on heart failure. The studies in this collection are approved for General Research Use (GRU), Health/Medical/Biomedical Use (HMB), or Disease-Specific Use (DS) that permits research on heart failure. These studies span a variety of study designs, inclusion and exclusion criteria, sample sizes, and provide a wide breadth and depth of phenotype data on study participants. The available genomic data in these studies also varies, including genotyping arrays, sequencing (targeted, exome, whole genome), and additional -omic data (e.g., RNA or metabolite profiles). Please refer to each study's individual accession page to learn more about how study data were collected. Challenge participants are reminded that in addition to dbGaP, NHLBI's Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) contains other studies that have collected data relevant to heart failure and may wish to utilize BioLINCC data in the development of their Solution. Please refer to the individual accession page for each study in this collection to learn more about the history of each study.

  Study phs001991

• INCLUDE Data Hub: NDA GUIDs for Down Syndrome Research

  The INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project is an NIH-wide collaboration that seeks to improve health and quality of life for people with Down syndrome. The INCLUDE Project Data Coordinating Center (DCC) and partners created the INCLUDE Data Hub, a centralized data resource that allows access to large-scale clinical and multi-omics datasets specific to Down syndrome and supports collaborative, cloud-based analysis to accelerate scientific discoveries related to Down syndrome and its co-occurring conditions. The INCLUDE Data Hub includes an innovative researcher data repository, a portal, and a cloud-based platform for data analysis. The portal provides access to de-identified demographics and clinical metadata, as well as multi-omics datasets, including whole genome sequences, transcriptomes, proteomes, and metabolomes. The INCLUDE Data Hub uses a 'registered access' model, whereby users can access the portal and associated data after agreeing to terms of use. From the Data Hub, users can also reach 'controlled access' data (e.g., whole genome sequences) only for those studies for which they have obtained approval by an NIH Data Access Committee through the corresponding dbGaP study. A thoughtful linkage strategy to identify duplicate participants across studies enables researchers to merge multiple datasets and data types to create richer datasets and reduce costly redundancies in large-scale data generation (e.g., -omics) while mitigating potential risks introduced by linkage.Based on recommendations from the NICHD Office of Data Science and Sharing, which completed a comprehensive assessment of existing Privacy Protecting Record Linkage (PPRL) and associated data governance solutions, the INCLUDE DCC and the associated NIH Steering Committee have implemented NIMH Data Archive Global Unique Identifiers (NDA GUIDs) in the INCLUDE Data Hub. The NDA GUID Tool is a government-owned and operated PPRL technology that enables researchers to link data from multiple sources to the same individual without revealing personally identifiable information (PII). With the NDA GUID Tool, the same participant information will return the same GUID whenever or wherever it is entered. The GUID itself is not personally identifiable information or protected health information. Sharing data with NDA GUIDs allows approved researchers to link together data on a single participant, even if the data were collected at different locations or through different studies or are distributed from different data repositories. This dbGaP study enables researchers to access an INCLUDE GUID Mapping File that includes all available NDA GUIDs and their associations to study-specific Participant IDs across studies in the INCLUDE Data Hub. This dbGaP study only distributes NDA GUIDs associated with the INCLUDE Data Hub datasets. To access the associated controlled-access datasets, add the corresponding dbGaP studies to your Data Access Request. A list of these studies is available on the INCLUDE Data Hub Portal: https://portal.includedcc.org/studies.

  Study phs003678

• Submitting array based metadata

  Submitting array based metadata For further information please check our Submission FAQs, submission quickguide as well as submission terms! The submission metadata required for Array-based submission must be submitted using EGA programmatic submission and by completing the Array-based format (AF) template. The guidelines for this workflow are described on this page. Please notice that all files should be encrypted and uploaded prior to the processing of your EGA Array-based-Format (AF) template. You can request a legacy EGA submission account (ega-box-XXXX) by populating this form. Please, allow two business days for our Helpdesk team to contact you after populating this form. Please notice that all files should be encrypted and uploaded prior to the processing of your EGA-Array-based-Format (AF) template. Metadata Model Registering Metadata Use the EGA programmatic submission to register your Study, Samples, Data Access Committee (DAC) and Policy. This online interface enables you to create new and edit existing submissions. Do not use the Submitter Portal to register the metadata objects for array submissions. Please, go to the EGA programmatic submission. Registering Study Go to the EGA programmatic submission Submit an study XML Take a note of your study accession number (EGASXXXXXXXXXXX) To use the study accession number in a publication, we suggest the following format: "Sequence data has been deposited at the European Genome-phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGASXXXXXXXXXXX. Further information about EGA can be found on https://ega-archive.org "The European Genome-phenome Archive of human data consented for biomedical research"(https://doi.org/10.1093/nar/gkab1059 ). Registering Samples Go to the EGA programmatic submission Submit a sample XML Save the list of accession numbers. These will be needed for the AF template. Registering Data Access Committee Further information on the role of your DAC. Go to the EGA programmatic submission Submit a DAC XML Take a note of the DAC accession number (EGACXXXXXXXXXXX) Registering Policy Your Data Access Policy provides the terms and conditions of data use. This is also referred to as the Data Access Agreement (DAA). Completion of a DAA by the applicant/s should form part of the application process to the Data Access Committee (DAA) Go to the EGA programmatic submission Submit a Policy XML Take a note of the Policy accession number (EGAPXXXXXXXXXXX) Complete the Array-based format (AF) spreadsheet Once you have completed the registration of your Study, DAC and Policy using the programmatix submission, you must then complete and return the AF spreadsheet The AF spreadsheet consists on four components: Do not use EGA IDs registered using the Submitter Portal. You can easily identify objects registered in the Submitter Portal by their EGA ID pattern: EGA[A-Z]5{10 more digits} (e.g. for a sample EGAN50000002506). For populating an AF spreadsheet, please exclusively use EGA IDs following this specific pattern: EGA[A-Z]0{10 more digits} (e.g. for a sample EGAN00001691542). Tab1) Webin accessions : Provide the accession numbers for your study, DAC and policy. Please, also add your ega-box number. Tab2) Sample & phenotypes: Please, leave this tab blank. Tab3) Dataset: Describe the dataset to be created Tab4) Data files: Define how your data is going to be organised into datasets and packets for distribution (linkage between samples and files). Should further assistance be required after going through the guide below; please do not hesitate to contact the EGA helpdesk Once the AF spreadsheet is populated, please send it to our EGA helpdesk for further validation. AF spreadsheet Should your submission require multiple DAC's or policies, use ' ; ' to separate the accession numbers. Accessions AF spreadsheet: Samples & phenotypes Samples and phenotypes AF spreadsheet: Datasets We suggest that each dataset consists of a common set of data. The example below consists of two datasets, grouped according to shared data type, technology and by case/control. We also like to capture the number of unique samples that make up the dataset and the Data Access Committee (DAC) responsible for providing the named dataset and their policy (EGAP). Datasets AF spreadsheet: Data files What follows is an example of how to map your samples to the array based files added to your upload account (4th tab). Data Files Please, find below some practical examples on how to register the linkage between samples-files Case 1) 1 sample or list of samples in different datasets: Data Files In case you have a list of samples that belong to different datasets, please, repeat the samples accession number/s in the first column and link the sample to the corresponding dataset each time (each row). Each row is one linkage between sample-file-dataset. Case 2) 1 sample links to several files: Data Files In order to add multiple files to one sample you MUST use “ ; “ between filenames. Example: file1.gpg;file2.gpg;file3.gpg In case that you want to add an extra file to the sample (phenotype or .Rdata), please use “Additional files” column. Important note: You MUST upload the encrypted and unencrypted md5sum values of all files uploaded to your submission account using the filename nomenclature (file.gpg, file.md5,file.md5.gpg). Your submission will not be processed without md5values supplied for all files in the CORRECT format. What happens after the submission of a dataset? All datasets affiliated to unreleased studies are automatically placed on hold until the authorised submitted or DAC contact instructs our EGA helpdesk for the study to be released. Finally, your data is archived within our databases and prepared for encrypted distribution upon the request of permitted EGA account holders. We strongly advise you NOT to delete your data until we confirm that your data has been successfully archived.

  Documentation submission/metadata/submission/array

• Maternal-Fetal Immune Responses in Preterm Labor and Congenital Anomalies

  The purpose of this study is to provide a reference profile of small extracellular RNAs in body fluids. These samples were originally obtained in a study that had a different purpose. The purpose of the original study was to learn and understand more about the causes of preterm labor, how to prevent it, and how to treat it. What the researchers learn by studying tissue, cells, and/or fluid (including blood samples, amniotic fluid, and placental tissue) may help to prevent preterm labor and prevent preterm delivery, which will improve the prenatal care women receive and improve the health of newborns.

  Study phs001693

• Somatic Copy Number Analysis of Endometrial Carcinomas

  Endometrial cancer (EC) is the most commonly diagnosed gynecologic malignancy in the United States and is the sixth leading cause of cancer death amongst American women. The purpose of this study was to identify somatic (tumor-specific) copy number alterations in 7 clear cell ECs, 31 serous ECs, 17 endometrioid ECs, and the clear cell components of 2 endometrioid/clear cell ECs. To this end, DNAs from de-identified primary endometrial tumors and matched non-tumor tissues or blood were hybridized to high-density Illumina Infinium HumanHap650Y Beadchips or to high-density Human660W-Quad Beadchips and the data analyzed to annotate somatic copy number alterations throughout the genome.

  Study phs001690

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Severe Asthma Research Program (SARP)

  Cohort Description The Severe Asthma Research Program (SARP) has been investigating the clinical, physiologic and molecular phenotypes of asthma since 2000. It is currently following ~400 deeply phenotyped asthma patients. Data Being Submitted Wave 1 questionnaire data includes 397 variables for up to 375 SARP participants in C4R.Wave 2 questionnaire data includes 448 variables for up to 289 SARP participants in C4R.Dried Blood Spot/Serosurvey data includes 7 variables for up to 290 SARP participants in C4R.Derived data includes 43 variables for up to 463 SARP participants in C4R.Phenotype data includes 113 variables for up to 463 SARP participants in C4R.

  Study phs002913

• Evolutionary Pressures Shape Undifferentiated Pleomorphic Sarcoma Development and Radiotherapy Response

  To study tumor evolution during tumorigenesis and in response to radiotherapy, we performed whole exome sequencing of 120 spatially distinct tumor regions and matched germline DNA from 20 patients with undifferentiated pleomorphic sarcoma. This data was utilized to generate personalized capture probes for targeted resequencing of the tumor and normal samples along with 17 matched plasma samples for circulating tumor DNA analysis. We found evidence of subclonal selection prior to treatment that was increased after radiotherapy. In addition, circulating tumor DNA analysis was able to measure the abundance of subclones before, during, and after treatment. This dbGaP submission includes whole exome sequencing and targeted resequencing from the study.

  Study phs003830

• Single-Cell Genomic Analysis of Gastrointestinal Cancer

  Our study aimed to define the heterogeneity of gastrointestinal cancers at a single-cell resolution. We subjected single-cell suspensions derived from surgical resections of gastrointestinal cancer tissue, paired normal tissue, peripheral blood mononuclear cells (PBMCs) or their ex vivo cultures to high-throughput microfluidics based single-cell RNA and DNA sequencing. We analyzed the features of the tumor microenvironment including fibroblasts, endothelial cells, macrophages and lymphocytes to determine their contribution to tumor growth and progression. We also characterized the mechanisms of immunosuppression in these tumors. This analysis led to novel insights into the biology of the microenvironment and also enabled the identification of new treatment targets.

  Study phs001818

• Study for establishment for effective screening and diagnosis of Lynch syndrome

  The purpose of this study is to establish efficient diagnostic procedure of the Lynch syndrome in Japan and to determine the MMR gene mutation spectrum and clinicopathologic characteristics.The person who is suspected Lynch Syndrome and gives informed consent for participation in this study .To carry out the project ?Construction of clinical and genetic integral information database to help Lynch syndrome management?, the following three are required. 1) screening for Lynch syndrome-suspected cases, 2) genetic testing to define Lynch syndrome, 3) integration of detailed clinical data of Lynch syndrome, and 4) The case which has not been diagnosed Lynch syndrome, is investigated causing gene.

  Study JGAS000638

• Mapping_regulatory_variation_in_sensory_neurons_using_IPS_lines_from_the_HIPSCI_project

  Sensory neurons are nerve cells that are activated by sensory input such as heat, light and convey information to the brain. Although a key cell type in complex organisms, human sensory neurons are challenging to study because they are impossible to obtain from living donors. We have collaborated with the Neucentis Pharmaceutical Research Unit to differentiate sensory neuron like cells from human induced pluripotent stem cells derived as part of the Human Induced Pluripotent Stem Cells Initiative. We will sequence RNA from 100 IPS lines derived from healthy individuals and perform RNA-seq on the differentiated cells to identify noncoding variants that alter gene expression in human sensory neurons.

  Study EGAS00001001149

• DNTR sequencing data of paediatric acute lymphoblastic leukemia

  This study used the DNTR-seq method in leukaemia samples to profile the whole-genome and mRNA jointly in single cells. Direct tagmentation is used in a collection of single-cell whole genome sequencing (scWGS) methods, including DNTR-seq, which provide high quality data at ultra-low to low coverage. The overall goal was to characterize the genetic and transcriptional heterogeneity of cancer samples. To infer clonal structure and evolutionary history, copy number analysis based workflows were implemented. Bone marrow mononuclear cells from pediatric acute lymphoblastic leukemia samples were FACS sorted into 384 plates to generate the DNA and RNA profiles.

  Study EGAS50000001247

• Genetics and transcriptomes of pediatric B cell precursor leukemia with gain of chromosome 21

  Down syndrome (DS, constitutive trisomy 21) children have a 27-fold increased risk of developing B-ALL (DS-ALL), face a worse outcome due to treatment-related morbidities, and an increased rate of relapses compared to other children. This highlights the need to better understand the mechanisms of DS-associated leukemogenesis to develop more adapted treatment. In this study, we characterized the genetic and transcriptomic landscapes of DS-ALL and found a high incidence of somatic mutations leading to RAS/MAPK pathway activation in DS-ALL, as seen in other pediatric B-ALL presenting somatic gains of the chromosome 21 (B-ALL+21).

  Study EGAS00001003760

• Genomic characterisation of MGUS

  The hematological malignancy multiple myeloma (MM), also called Kahler's disease or plasma cell (PC) myeloma, is characterized by a clonal expansion of PCs originating in the bone marrow (BM). The expansion of these cells leads to an overproduction of antibodies and results in typical symptoms such as anemia, renal failure and bone lesions. All cases of MM are preceded by the asymptomatic, non-malignant pre-stage monoclonal gammopathy of undetermined significance (MGUS). Of all MGUS patients, only 1% per year will progress to MM. Despite efforts to elucidate the molecular mechanisms underlying the MGUS-to-MM progression, its pathogenesis still remains largely unknown. Additionally, the genetic profiles of MGUS patients have only been limitedly investigated due to the only incidental finding of MGUS, the difficulties in BM sampling and isolating a sufficient number of aberrant PCs from the BM aspirates of MGUS patients. Consequently, reliable biomarkers to individually predict which MGUS patients will progress to MM and which will not, are lacking. Therefore, it is highly required to study the molecular pathogenesis of MGUS and the role of genetic events in relation to the malignant transformation to MM.

  Dataset EGAD00001006363

• DNA sequencing of sgRNAs enriched from the CRISPR-Cas9 screened HCC organoids

  Project aims to find enriched or depleted sgRNAs to identify functional genes in HCC progression and lenvatinib resistance

  Study EGAS50000000848

• Use of new methodologies to achieve a thorough molecular characterization in pediatric acute leukemia

  In childhood leukemia, a better genetic characterization is needed to define new clinic-biological entities, refine the risk-stratification of patients and help to reduce the toxicity by applying a risk-directed therapy. This project aims to obtain information that will allow us to personalize the management of pediatric patients with leukemia as much as possible, so that we can offer a complete diagnosis, a sensitive follow-up and a more targeted treatment to the real risk of each case. The use of massive genome analysis technologies such as transcriptome sequencing (RNA-Sequencing) will allow a comprehensive biological characterization of pediatric leukemia patients, especially those cases that we have not been able to characterize by conventional diagnostic techniques. We believe that the RNA-Seq technique will allow us to identify new biomarkers that will be useful for: 1) defining new biological entities with their own clinical behavior; 2) refining the stratification of patients into risk groups; 3) finding targets for a better follow-up of MRD and 4) identifying therapeutic targets for the application of targeted therapies to reduce toxicity. PI: Camós-Guijosa, Mireia; Vega-García, Nerea Funding: PI21/00213 Instituto de Salud Carlos III (ISCIII)

  Study EGAS50000000701

• 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

• Wistar PDX Development and Trial Center

  Overall the outcomes of patients with metastatic melanoma have improved dramatically over the last decade due to an improved understanding of the molecular drivers of this disease. In particular, multiple targeted therapy regimens have been approved for patients with a BRAFV600E/K mutation, which are present in ~50% of cutaneous melanomas. These treatments achieve clinical responses in ~80% of patients with a BRAFV600E/K mutation, thus providing proof-of-concept of the therapeutic potential for personalized therapeutic strategies. However, most of the patients will progress within 2 years of starting those therapies. Further, currently there are no targeted therapies that have been shown to be effective in patients with a wild-type BRAF. Thus, there are unmet clinical needs to develop treatments that prevent or overcome resistance to existing therapies for patients with a BRAFV600E/K mutation, and that are effective in patients without a BRAF mutation. In order to facilitate the development of new therapeutic strategies, over the last 5 years we have led a major effort to develop a broad collection of PDX models to reflect the clinical, histological, and genetic heterogeneity of this disease. Our collection of PDX models represents one of the largest collections for any human malignancy, and our initial testing demonstrates that the collection accurately recapitulates the oncogenic drivers and molecular heterogeneity that is observed in patients. This collection also includes a subset of PDX established from patients with acquired resistance to targeted therapies that have been maintained on those agents in vivo to sustain their resistant phenotype. Together these efforts have generated a robust resource to develop, refine, and prioritize new personalized combinatorial therapies for patients. Thus, we propose to establish a multi-disciplinary and multi-institutional PDTC Program focused on the use and continued expansion of our robust melanoma PDX collection to identify new therapeutic approaches that fill important clinical gaps in this disease.

  Study phs002432

• Phenotypic and Genotypic Study of Keratoconus

  Keratoconus, a disease in which the cornea is abnormally steep and thin, affects approximately 1 in 2000 individuals and usually begins in the second decade of life. Keratoconus is a progressive disorder that results in loss of vision that cannot be alleviated by contact lenses or glasses alone and is a leading indication for corneal transplantation in developed countries (Udar et al., 2006, PMID: 16877401). Keratoconus has a strong genetic component, and while several causative genes are clearly suspected, the underlying pathogenic processes have not yet been identified. The goal of our research is to identify genes that harbor mutations contributing to keratoconus and underlying biochemical processes relevant to keratoconus pathogenesis and to develop a better understanding of the etiology of keratoconus, leading to improved detection, treatment, and management. We will enroll isolated keratoconus along with familial cases and unaffected relatives when available. The subject population will consist of individuals diagnosed with keratoconus and unaffected relatives in families. Individuals/families will be ascertained through support groups and clinical collaborators. The identities of the study participants will be known only to Dr. Chakravarti, the study coordinator, physicians in the team and the post-doctoral fellow(s) working directly on the project. DNA, lymphocytes, and lymphoblastoid cell lines may be prepared from the blood samples for future use. Molecular analyses using markers and sequencing and statistical analyses of these data will be used to identify regions of human chromosomes where putative keratoconus disease genes reside. Analyses of coding DNA sequences within genes from keratoconus subjects will be compared to published control sequences to identify disease specific variants. Additionally, to understand disease pathogenesis, subsets of patients may be asked to provide tear samples. Study subjects will not directly benefit from participation and results will not be disclosed to participants nor their health care providers, unless medically relevant.

  Study phs003168

• Advancing Precision Oncology in a Humanized, Fully Autologous Mouse Model

  Progress in the early detection and treatment of cancer requires accurate model systems to further evaluate new, promising discoveries. Small animal and, in particular, mouse model systems are attractive to researchers for numerous reasons, including their ease of use and well-described platforms. The ability to grow human tumors in immune-deficient mice (so-called patient-derived xenografts, or PDXs) allows researchers to work directly with human cancer tissue in a controlled setting. However, PDX models are limited by their lack of an intact immune system. Immunotherapy has revolutionized clinical oncology, but lacks pre-clinical models of the human immune system and human cancer to investigate new modalities and limitations/toxicities of treatment regimens. The broad objective of this study is to validate an in vivo model to evaluate human tumors in the context of a complete and intact human immune system in a completely personalized and autologous fashion to study cancer immunotherapy. Herein, we will: (1) validate the ability of our humanized system to serve as a model for cancer immunotherapy treatment response and toxicity in patients with melanoma, including immunotherapy checkpoint blockade and vaccine strategies, and (2) extend our current work in melanoma by validating the ability to establish humanized mice and evaluate tumor growth and leukocyte development in autologous human pancreatic and colorectal tumors established in humanized mice. In each of these areas, we will leverage our multi-institutional team's individual expertise along with our institutional infrastructure to maximize the success of the experimental aims. The results from this project will be widely available to the general research community for future, hypothesis-driven research. Taken together, our study will meet multiple goals and address several unmet needs in cancer immunotherapy, thus significantly enhancing the applicability of a fully autologous and immunocompetent precision model system for use in translational oncology research.

  Study phs003090

• Best Practices for DACs

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

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

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

  Study phs003654

• North Carolina Clinical Genomic Evaluation by NextGen Exome Sequencing (NCGENES)

  North Carolina Clinical Genomic Evaluation by Next-generation Exome Sequencing This study is part of a larger consortium project investigating the validity and best use of next-generation sequencing (in particular, whole exome sequencing, or WES) in clinical care. Participants are patients who were either seen in the UNC Cancer and Adult Genetics Clinic or referred to the study by their physician. They will be approached by their physician or a genetic counselor for recruitment. Once enrolled, a clinical geneticist or genetic counselor will obtain consent and collect blood samples to be analyzed using WES. Results may include information related to a diagnosis and incidental information. Medically actionable incidental findings will be CLIA-certified and returned to participants in a routine genetic counseling session, along with diagnostic findings. Eligible adult participants will be randomized to have the opportunity to choose to get certain types of non-medically actionable incidental findings, as well. Their decisions will be investigated, as will psychosocial and behavioral responses to sequencing and receiving sequencing information. This is a longitudinal, mixed methods study (i.e., multiple assessments pre- and post-return of results, with both quantitative and qualitative methods used to gather data). Because only the quantitative component of the study uses randomization, only measures and procedures associated with that component are included here. The third study release includes data of additional n=189 subjects.

  Study phs000827

• GWAS for Genetic Determinants of Bone Fragility in European-American Premenopausal Women

  Osteoporotic fractures are largely due to an increased propensity to fall with aging and a reduction in bone strength. Although skeletal architecture contributes to fracture risk, bone mineral density (BMD) is the most important determinant of bone strength and fracture risk. Between 60 and 80% of the variance of BMD of adult Caucasian women is due to heritable factors. Final BMD is a function of peak bone mass attained during young adulthood and the subsequent rate of bone loss, which occurs as a result of both post-menopausal estrogen loss and aging. The evidence for a genetic contribution to rate of loss in BMD is substantially weaker than that for peak BMD. Therefore, we have focused our sample collection on the recruitment of premenopausal women, in whom we have sought to identify the genes influencing peak BMD at the spine and hip, the two major skeletal sites of osteoporotic fracture. The primary goal of this study is to identify genes that affect peak BMD in premenopausal women. Identification of these genes may: 1) lead to molecular tests that predict risk of osteoporosis and allow institution of early preventive measures; 2) provide insight into basic bone cell biology and other factors that affect peak BMD; and 3) provide molecular targets for therapeutic agents to increase BMD.

  Study phs000138

• MAESTRO-Pool Enables Highly Parallel and Specific Mutation-Enrichment Sequencing for Minimal Residual Disease Detection in Cohort Studies

  MAESTRO-Pool builds upon the technology MAESTRO (Minor Allele Enriched Sequencing Through Recognition Oligonucleotides) by pooling tumor-specific MAESTRO probes from multiple patients and applying these to all samples from all patients. In this study, MAESTRO-Pool was applied to a cohort of 9 melanoma patients where 98 plasma samples were screened for 22,333 mutations. Additionally, a new dynamic minimal residual disease (MRD) caller was used to estimate the likelihood of MRD detection based on the number mutations and cell-free DNA molecules interrogated which allowed each bespoke MRD test to be properly calibrated against false detection. These developments led to sensitive detection in patient-matched samples down to 0.78 parts per million (ppm) while limiting false detection in negative controls to 1/784 (tumor fraction=2.7 ppm). MAESTRO-Pool and the dynamic MRD caller enable a unique blend of sensitivity, specificity, and efficiency, which will improve the ability to detect MRD.The data contained in this repository consists of:Tumor and normal whole genome sequencing data used to call patient-specific tumor mutations and design the MRD Tracker and MAESTRO-Pool fingerprintsMAESTRO-Pool data (enriched duplex sequencing via hybrid capture) of tumor gDNA, normal gDNA and cfDNA MRD Tracker data (duplex sequencing via hybrid capture) of tumor gDNA, normal gDNA and cfDNA

  Study phs003447

• Localised colon cancer WES study contaning WBCs, tissue and plasma samples at different time points

  Decision-making based on circulating tumor DNA (ctDNA) status following curative-intent surgery in stage II-III colon cancer (CC) is where the strongest clinical evidence lies. Commercial or academic assays are predominantly used to detect ctDNA, aiming to reveal minimal residual disease (MRD) and identify patients at high risk of recurrence. However, while current tests demonstrate exceptional specificity in detecting MRD among patients who later experience recurrence, their sensitivity is notably limited, particularly immediately after surgery when decisions regarding ACT are crucial. Additionally, up to 70% of patients with stage II-III colon cancer fail to clear ctDNA after standard adjuvant treatment (ACT) and subsequently experience recurrence. In this study, we performed whole exome sequencing (WES) of ctDNA at different timepoints in relapsed CC patients using two independent cohorts, alongside transcriptomic and proteomic analyses of metastases to gain a deeper understanding of progression mechanisms. An assay based on a tumor-agnostic approach from WES could enhance sensitivity in detecting MRD disease compared to current assays. Immune evasion appears to be the primary driver of progression in the localized CC setting, facilitated by a functional mutational burden at relapse. This suggests that immunotherapy could extend its efficacy to patients with microsatellite stability, broadening treatment options. Moreover, organoid modeling affirms the promising potential of targeted therapy to surpass conventional treatments in eradicating MRD.

  Study EGAS50000000204

• This study generated Oxford Nanopore long read sequencing data of cancer cell line mixtures for validating long-read variant calls in cancer genomics

  Long-read sequencing (LRS) improves genome alignment and facilitates resolving variants in complex genomic regions, making it a promising approach for cancer variant detection and biomarker discovery. Here, we evaluate the performance of LRS to detect somatic variants across different tumour purities and sequencing depths by comparing to somatic variants from short-read sequencing. We generated experimental mixtures of cancer cell lines and matched normal cell lines to simulate 10 tumour purities (ranging from 0 to 100% tumour content). This resulted in 22 samples which were sequenced using whole genome LRS to a targeted depth of 60x and somatic variants were identified. We downsampled sequencing data to explore the optimal read depth for somatic variant detection. Our results show that long-read variant calling tools achieve recall rates comparable to short-read gold standards. While a tumour sequencing depth of 30x to 60× is generally sufficient for detecting common variants, particularly structural variants (SVs), sequencing the matched normal sample at adequate depth is crucial for accuracy. Notably, we found variants unique to LRS that may represent real and previously undetected events. This study highlights key factors for optimising cancer genome sequencing with LRS and provides a comprehensive dataset of cell line mixtures for future research and tool development.

  Study EGAS00001008107

• Cerebrospinal Fluid Analysis of HIV-1 Viral Burden in HIV-1 Infected Subjects: Response to Antiretroviral Therapy

  The purpose of this study is to provide a reference profile of small extracellular RNAs in body fluids. These samples were originally obtained in a study that had a different purpose. The purpose of the original study was to collect information on the changes in cerebrospinal fluid (CSF) related to HIV infection, including the viral burden (amount of virus) and the body responses of the infected individual, such as the number and types of lymphocytes in the CSF. In addition to looking at the number and types of lymphocytes in the CSF, this original study also examined the presence of markers of inflammation and other chemical changes, and the relationship of those changes to nervous system dysfunction in AIDS.

  Study phs001694