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• Identification of genes involved in congenital disorders of glycosylation and 3-methylglutaconic aciduria (2018-03-14)

  Identification of genes involved in congenital disorders of glycosylation and 3-methylglutaconic aciduria. There are more than 100 genes known for congenital disorders of glycosylation and new disorders are discovered each year. WE included patients with a so far unsolved glycosylation disease. The diagnostic group 3-methyglutaconic aciduria is a heterogenous group of disorders mostly caused by abnormal phospholipid synthesis or in association with mitochondrial dysfunction. We included patients with a so far unsolved disease and 3-methylglutaconic aciduria. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2018-03-14.

  Dataset EGAD00001004038

• Influence of culture media on airway differentiation at the Air-Liquid Interface

  Single-cell dataset of human airways after in vitro regeneration at the Air-Liquid Interface. Samples from 2 donors were used for the establishment of Human Bronchial Epithelial Cell cultures (HBECs) and were analyzed during proliferation, at the onset of differentiation (ALI0) and after full differentiation (ALI28), in 4 distinct culture media. Single-cell RNAseq was performed with 10x Genomics 3’ v2 RNA-seq using hashtag antibodies for multiplexing, and sequenced on a NextSeq 500. Samples from 3 additional donors were used for the establishment of Human Nasal Epithelial Cell cultures (HNECs) and were analyzed during proliferation in three distinct culture media. Single-cell RNAseq was performed with 10x Genomics 3’ v3 RNA-seq without multiplexing, and sequenced on a NextSeq 2000.

  Dataset EGAD00001011362

• Genetic scoring guide for personalized risk assessment in pediatric B-cell precursor Acute Lymphoblastic Leukemia

  In this study a next-generation sequencing based method was applied to comprehensively screen for recurrent, disease-relevant copy number aberrations in a cohort of Hungarian patients. Diagnostic bone marrow samples from 260 children with B-cell acute lymphoblastic leukemia and were investigated by digital multiplex ligation-dependent probe amplification using the disease-specific D007 probemix. Whole chromosome gains and losses, as well as subchromosomal copy number aberrations were simultaneously profiled.

  Study EGAS00001007239

• Data Access Commitee for the project : Methylome profiling of human mesenchymal chondrosarcoma

  Dac EGAC00001003217

• Quantitative analysis of a novel DNA hypermethylation panel for lung cancer diagnosis

  Study EGAS00001007008

• Data Access Commitee for single-cell analysis of multiple myeloma and precursors

  Dac EGAC00001002920

• Data Access Committee for the Metastatic Breast Cancer Whole-exome sequencing study

  Dac EGAC00001000434

• DAC for patient-derived cell line samples

  Dac EGAC00001000594

• DAC for Direct Detection of Early-stage Cancers Using Circulating Tumor DNA

  Dac EGAC00001000701

• Data Access Committee for desmoplastic small round cell tumor (DSRCT) RNAseq data.

  Dac EGAC00001000851

• DAC for Oncogenic fate conversion by PRDM16s causes acute myeloid leukemia

  Dac EGAC00001001023

• EMBL genome biology research group for structural variation (Strand-seq application)

  Dac EGAC00001001091

• DAC for Integrated Genomic, Epigenetic, and Expression Analyses of Ovarian Cancer Cell Lines

  Dac EGAC00001001101

• Stanford Data Access Committee for Multi-Region WES of Metastatic Colorectal Cancer

  Dac EGAC00001001164

• DAC for the study of tumor-derived somatic mutation detection in cfDNA

  Dac EGAC00001001569

• Nicola Murray Centre for Ovarian Cancer Research Data Access Committee

  Dac EGAC00001001588

• Cancer Clinical Research Trust DAC for WES of HER2+ metastatic cancer samples

  Dac EGAC00001001632

• Data Access Commitee of the Princess Maxima Center for Pediatric Oncology

  Dac EGAC00001001948

• Data access committee for Gut microbiome of BA patients and normal controls

  Dac EGAC00001002146

• "DAC for RNAseq from regions of insitu and invasive human mammary ductal disease"

  Dac EGAC00001002538

• Chromatin Profiles in PRAD - Englander Institute for Precision Medicine - Weill Cornell Medicine

  Dac EGAC00001002559

• Single cell multi-omics group for somatic structural variation in human blood lineages

  Dac EGAC00001002852

• EGAD00010000831

  BLUEPRINT EpiMatch: harnessing epigenetics for haematopoietic stem cell transplantation

  Dataset EGAD00010000831

• irish_fineSTRUCTURE

  SNP data for 991 Irish individuals

  Dataset EGAD00010001479

• DNA Methylation data for EGAS00001002592

  Islet_HumanMethylation450K_ThurnerEtAl

  Dataset EGAD00010001695

• DAC for Tuebingen-Stuttgart cohort

  Dac EGAC00001000317

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Jackson Heart Study (JHS)

  Study phs002907

• A multi-center genome-wide association study for nasopharyngeal carcinoma

  Study EGAS00001006062

• DAC for Clonal driver neoantigen loss under EGFR TKI and immune selection pressures

  Dac EGAC00001003522

• Validation of cfDNA fragmentome analyses for early detection of liver cancer

  Study EGAS00001008111

• Prevention and Early Treatment of Acute Lung Injury (PETAL) Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) (PETAL CLOVERS-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL CLOVERS include plasma, and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Available Data: The data available for request now include Long Term Outcome data.Objectives: To compare the effects of a restrictive fluid strategy (with early use of vasopressors) to a liberal fluid strategy in participants with sepsis-induced hypotension.Background: Intravenous fluid resuscitation is a common therapy used in the initial treatment of participants with septic shock and sepsis-induced hypotension. The goal of initial fluid therapy is to increase depleted or functionally reduced intravascular volume that occurs in sepsis due to a vasodilated vascular network. However, intravenous fluid resuscitation can create dilutional coagulopathy, fluid overload, and pathogenic edema in the lungs and other organs. Vasopressor agents are also commonly used to treat hypoperfusion by inducing constriction of arterioles and venules and increasing cardiac contractility. Vasopressor therapy also comes with risks that include vasoconstriction resulting in tissue ischemia, increased cardiac workload, and arrhythmias. Clinicians have used these strategies, typically in combination, to provide supportive care for participants with sepsis-induced hypoperfusion. However, at the time of the CLOVERS study, there was limited data to guide specific use of these therapies, including fluid volumes, in the early care of participants with sepsis-induced hypotension. The CLOVERS study hypothesized that a restrictive fluid strategy used during the first 24-hours of resuscitation for sepsis-induced hypotension would lead to lower mortality before discharge home by day 90 than a liberal fluid strategy.Participants: A total of 1,563 participants, from 60 medical centers, of the planned 2,230 participants were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Enrollment in the trial was ended after the second interim analysis due to a lack of significant difference observed between the two 24-hour strategies.Design: This study was a multi-center, prospective, phase 3 randomized non-blinded interventional trial of fluid treatment strategies in the first 24 hours for participants with sepsis-induced hypotension. Participants were randomly assigned in a 1:1 ratio to either a restrictive fluid strategy (with early vasopressor use) or a liberal fluid strategy. In each group, the assigned protocol was followed for a period of 24 hours. The restrictive fluid protocol prioritized vasopressors as the primary treatment for sepsis-induced hypotension, with 'rescue fluids' being permitted for prespecified indications that suggested severe intravascular volume depletion. The liberal fluid protocol consisted of a recommended initial 2000-ml intravenous infusion of isotonic crystalloid, followed by fluid boluses administered on the basis of clinical triggers (e.g., tachycardia) with 'rescue vasopressors' permitted for prespecified indications. A protocol amendment implemented in October, 2019, allowed for limiting the initial infusion to 1,000 ml if the participant's blood pressure and heart rate had stabilized and the clinical assessment was that the participant was unlikely to benefit from additional intravenous fluid administration. The clinical team could override the protocol-specified care instructions at any time if it was judged to be in the best interest of the participant.The primary outcome was death from any cause before discharge home by day 90. Secondary outcomes included 28-day measures of the number of days free from ventilator use, days free from renal-replacement therapy, days free from vasopressor use, days out of the ICU, and days out of the hospital. Conclusions: Among participants with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality, or other measures of recovery such as length of hospital stay, before discharge home by day 90 than the liberal fluid strategy.

  Study phs004080

• Rapid Acceleration of Diagnostics - Underserved Populations (RADx-UP): COVID-19 Testing and Prevention in Correctional Settings

  This study will work with diverse correctional facilities across MN, RI, WA, and FL to characterize the incidence of COVID-19 disease progression and related outcomes. The goal is to identify barriers and facilitators to develop strategies to improve testing in these under-served populations by: Increasing the reach, access, uptake, and impact of COVID-19 testing among incarcerated people and staff in prison and jails. Individuals in congregate settings have been disproportionately affected by COVID-19, with correctional settings accounting for 39 of the 50 largest cluster outbreaks in the country to date. Schema of Correctional Facilities: Correctional facilities are amplifiers of infectious diseases for structural reasons: 1) Dormitory-style living and overcrowded conditions make social distancing nearly impossible 2) They have a focus primarily on security not health 3) Their medical departments are under-resourced and often disconnected from local public health agencies. Correctional facilities must be the focus of urgent intervention to understand the incidence of COVID-19, how it spreads in correctional facilities, and durable long-term strategies to reduce transmission, including testing and vaccines. However, our work from the COVID Prison Project shows that correctional systems have implemented a range of testing strategies, without coordination, such that synthesizing the information on COVID-19 incidence, outcomes and optimal testing strategies (including repeat testing and contact tracing) has been challenging. Incarcerated people decline testing due to concerns about confidentiality, implications for release, and fear of placement in solitary confinement. Through interviews we will identify ethical concerns and potential solutions for COVID-19 testing and vaccine strategies in correctional facilities using a community-engaged strategy. The project's work from the COVID Prison Project shows that correctional systems have implemented a range of testing strategies, without coordination, such that synthesizing the information on COVID-19 incidence, outcomes and optimal testing strategies (including repeat testing and contact tracing) has been challenging. Incarcerated people decline testing due to concerns about confidentiality, implications for release, and fear of placement in solitary confinement. Through interviews we will Identify ethical concerns and potential solutions for COVID-19 testing and vaccine strategies in correctional facilities using a community-engaged strategy. Goals: 1. Identify ethical concerns and potential solutions for COVID-19 testing and vaccine strategies in correctional facilities using a community-engaged strategy. 2. Characterize incidence of COVID-19, disease progression, and related-outcomes and effectiveness of testing and contact tracing in correctional facilities. Participant Selection: a. Potential subjects must be currently incarcerated at key facilities in Washington, Rhode Island, Minnesota, and Florida. These facilities are Everglades Correctional Institution and Homestead Correctional Institution in Florida, Shakopee and Stillwater correctional facilities in Minnesota, the Rhode Island Department of Corrections, and Yakima County Jail in Washington. b. Participating correctional facilities in Florida, Minnesota, Rhode Island, and Washington will provide de-identified data on approximately 16,859 incarcerated adults and correctional staff. Data sources include deidentified data from medical records, administrative data, and policy documents pertaining to COVID-19. c. 3 series of focus groups (6, 12, 18 months) x 3 distinct groups (incarcerated people, medical providers, and correctional leaders) x 4 sites=36 total focus groups over the study period. d. Will utilize 74,812 COVID-19 tests to test and re-test a total of 16,859 incarcerated people and correctional staff for active infection over a six-month period in the FL, MN, and RI state prison systems and the Yakima County Jail in WA.

  Study phs003361

• Resuscitation Outcomes Consortium (ROC) Cardiac Epidemiologic Registry (Cardiac Epistry) Version 3 (ROC-Cardiac Epistry 3-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Available Data The ROC Cardiac Epistry version 3 include all cardiac arrest cases entered into the ROC database from April 1, 2011 to June 30, 2015. This is separate from versions 1 and 2 because of the major changes in how and which data were collected. Version 3 represents the following major changes to the structure and data collection: separate ED Arrival and Hospital Admits forms, mandatory ED and Hospital elements and a revamped CPR Process form. For ROC traumatic injury Epistry data please see: ROC-Trauma Epistry Objectives To build a prospective population-based registry of participants with out-of-hospital cardiac arrest responded to by Emergency Medical Services (EMS). Specific aims included: to establish whether the results of Resuscitation Outcomes Consortium (ROC) trials can be generalized to the larger population of participants that experience cardiac arrest; to more fully establish the burden of cardiac arrest; and to examine the relationships between variation in EMS structure and process, regional and periodic factors, and participant outcomes. Background Cardiac arrest is a common, serious, debilitating and costly public health problem. Although there has been a steady decline in morbidity and mortality from most cardiovascular diseases, high mortality rates for out-of-hospital cardiac arrests continue to pose a challenge for healthcare providers and a significant public health burden. The Resuscitation Outcomes Consortium (ROC) was established in 2004 to conduct clinical research in the areas of cardiopulmonary arrest and life-threatening traumatic injury with the overall goal of improving resuscitation outcomes. Participant and care characteristics can predict favorable outcomes in cardiac arrests, but there is still a wide variation in outcomes that is not well understood. EMS factors such as service level, number of responding providers, use of procedures or drugs in the field, training, quality assurance/feedback, and response time intervals also vary significantly by region. Variations in geographic, socioeconomic and periodic factors may also be associated with differences in outcomes. Prior to ROC Cardiac Epistry, there were no North American population-based registries for out-of-hospital cardiac arrests. Therefore there was a need for standardized data collection of out-of-hospital cardiac arrests in diverse geographic locations in order to identify the independent effects of prognostic or treatment factors accounting for variations in survival. Participants There were 120,306 participants. Design ROC Epistry collected standardized data regarding episode-specific factors, participant demographics, clinical information, pre-hospital interventions and disposition, hospital information, and participant outcome for all out-of-hospital cardiac arrests in the ROC regions. Each ROC site had to ensure capture of all eligible cases within the EMS service areas. Out-of-hospital data were extracted from existing databases whenever possible and augmented with targeted review of EMS reports. Hospital data were abstracted directly from the hospital file in most cases. Alternative methods included linkage to death registries and obituaries if the death occurred within 30 days. Sites submitted data using a web-based interface or batch uploads. Participants were not contacted directly.

  Study phs003726

• Prevention and Early Treatment of Acute Lung Injury Network - Reevaluation of Systemic Early Neuromuscular Blockade (PETAL ROSE-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP. Available Data: The data available for request now include Long Term Outcome data.Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL ROSE include Plasma, DNA, Whole Blood, and Urine. Please note that use of biospecimens in genetic research is subject to a tiered consent.Objectives: To determine the efficacy and safety of early neuromuscular blockade with concomitant heavy sedation as compared with a strategy of usual care with lighter sedation targets in patients with moderate-to-severe ARDS.Background: It has been well established that the approaches used for the application of mechanical ventilation in patients with acute respiratory distress syndrome (ARDS) can affect survival and outcomes after discharge from the intensive care unit (ICU). A large, multicenter trial conducted a decade before this study reported that the early administration of a 48-hour infusion of neuromuscular blockade in patients with moderate-to-severe ARDS (defined by a ratio of the partial pressure of arterial oxygen [Pao2] to the fraction of inspired oxygen [Fio2] of Participants: There were 1006 participants.Design: PETAL-ROSE was a multicenter, unblinded, randomized trial of patients with moderate-to-severe ARDS. Participants were randomly assigned in a 1:1 ratio to receive 48 hours of continuous neuromuscular blockade with concomitant deep sedation (intervention group) or to receive usual care without routine neuromuscular blockade and with lighter sedation targets (control group).Patients in the intervention group who were not under deep sedation at baseline were deeply sedated within 4 hours after randomization. Subsequently, patients in this group received an intravenous bolus of 15 mg of cisatracurium, followed by a continuous infusion of 37.5 mg per hour for 48 hours. After the 48-hour trial intervention period, decisions regarding further use of neuromuscular blockade, including the choice of agent, were left to the discretion of the treating clinician. Neuromuscular blockade could be stopped early if the patient met the criteria for freedom from mechanical ventilation (Fio2 ≤0.40 and PEEP ≤8 cm of water) for at least 12 hours. All patients were treated with a strategy of low tidal volume ventilation within 2 hours after randomization and a high PEEP strategy for up to 5 days after randomization. Assessors who were unaware of the group assignment interviewed surviving patients or their proxies at 3, 6, and 12 months after randomization. The primary end point was in-hospital death from any cause at 90 days (in-hospital was defined as the time in the trial hospital plus transfer to another hospital, including the time in long-term acute care facilities). Conclusions: After the second interim analysis, the decision to stop the trial for futility was made independently by the data and safety monitoring board.In critically ill patients identified shortly after the diagnosis of moderate-to-severe ARDS, the addition of early continuous neuromuscular blockade with concomitant deep sedation did not result in lower mortality than a usual-care approach to mechanical ventilation that included lighter sedation targets.

  Study phs003878

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

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.Related Studies: Other CARDIA data available include:phs000236.v2.p2 PAGE: CALiCo: Coronary Artery Risk Development in Young Adults(CARDIA) phs000309.v3.p2 The CARDIA-GENEVA Study phs000399.v1.p2 NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (CARDIA) phs000613.v1.p2 NHLBI CARDIA Candidate Gene Association Resource (CARe) phs003675.v1.p1 CARDIA Multi-omics Obesity & CVD Substudy – Year 20 Untargeted Metabolomics Data phs001612.v3.p2 NHLBI TOPMed: CARDIA (Coronary Artery Risk Development in Young Adults) phs003045.v1.p1 Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Coronary Artery Risk Development in Young Adults Study (CARDIA) phs000285.v4.p3 CARDIA_Cohort Available Data: Available data for request include exam data through Year 30 and outcomes and death data through 2022. Additionally, data from 28 ancillary studies are available for request.Objectives: The original objectives of CARDIA were to document levels of risk factors for coronary artery disease and potential determinants of these risk factors in young adults; to study the interrelationships of risk factors and lifestyles and to document behavioral and environmental changes during the transition from young adulthood to middle age; to compare cross-sectional and longitudinal data on age-related trends in cardiovascular disease risk factors; and to compare levels and evolution of risk factors between men and women, blacks and whites, and in groups of differing socioeconomic status. Goals of the study have evolved to emphasize understanding determinants of left ventricular mass, emerging obesity and hypertension, and sequelae of hypertension in pregnancy.Background: CARDIA is designed to increase understanding of contributors to changes in cardiovascular disease (CVD) risk factors during the critical years of transition from young adulthood to middle age. CARDIA was funded initially in 1983 for a five-year cycle that included two rounds of examinations. Contract renewals have allowed for subsequent re-examinations.Participants: Black and white men and women; ages 18-30 years at entry with a range of attained education; original sample size: 5,115.Design: CARDIA is a population-based observational study of 5,115 participants aged 18-30 years recruited in 1985-1986. The sample was designed to achieve approximately balanced subgroups of race, gender, education (high school or less and more than high school) and age (18-24 and 25-30). Forty percent of the cohort had no more than a high school education. A total of nine examinations have been completed in the cohort with examination cycles at year 2 of the project and years 5, 7, 10 , 15, 20, 25, and 30.In addition to standard measurements of blood pressure, anthropometry, blood lipids, smoking behavior, physical activity, diet, pulmonary function, and many psychological factors, CARDIA has other included measurements (in subsets or in the full cohort) to obtain unique information on other aspects of risk factor development and early morbidity. These have included: graded exercise treadmill testing; echocardiography, particularly for measurement of left ventricular mass; cardiovascular reactivity; serum cotinine; Lp(a), apoE phenotype, apolipoprotein A1 and B; homocysteine; skin reflectance; body composition by dual X-ray absorptiometry; glucose tolerance testing; vascular resistance and compliance; and plasma renin activity and sympathetic nervous system activity.

  Study phs003739

• Implementation of the GDPR

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

  Documentation about/privacy-notice

• Targeted_sequencing_of_genes_recurrently_mutated_in_AML

  Background Massively parallel sequencing technology has transformed cancer genomics. It is now feasible, in a clinically relevant time-frame, for a clinically manageable cost, to screen DNA from patient tumours for mutations essentially genome-wide. The challenge for personalised medicine will be to increase the sample size to thousands or tens of thousands of well-characterised cases in order to attain sufficient statistical power to stratify patients accurately across the complexity and genomic heterogeneity expected for most of the common tumour types. Currently, whole genome sequencing on this scale is not feasible, and targeted sequencing of relevant portions of the genome will be required. Pilot data We have developed protocols for large-scale, multiplexed sequencing of 100-200 genes in thousands of samples. Essentially, using robotic technology, genomic DNA from the cancer specimen is processed into sequencing libraries with unique DNA barcodes, thereby allowing sequencing reads to be attributed to the sample they derive from. Currently, these sequencing libraries can be generated in a 96-well format using fully automated protocols, and we are exploring methods to expand this to a 384-well format. The sequencing libraries are pooled and hybridized to custom sets of RNA baits representing the genomic regions of interest. Sequencing of the pulled-down libraries is done in pools of 48-96 samples per lane of an Illumina Hi-Seq. This protocol is already implemented at the Sanger Institute. We have published proof that somatic mutations in novel cancer genes can be identified from exome-wide sequencing. In unpublished pilot data, we have established the feasibility of robotic library production, custom pull-down, and multiplexed sequencing of barcoded libraries for 100 known myeloid cancer genes across 760 myelodysplasia samples. Highlights of the data thus far analysed reveal that the coverage is remarkably even between samples; when 96 samples are run, average coverage per lane of sequencing is ~250, with 90-95% of targeted exons covered by >25 reads; known mutations can be discovered in the data set; and the protocol is amenable to whole genome amplified DNA. The bioinformatic algorithms for identification of substitutions and indels in pull-down data are well-established; we have pilot data proving that copy number changes, LOH and genomic rearrangements in specific regions of interest can also be identified by tiling of baits across the relevant loci. Proposal We propose to apply this methodology to 10000 samples from patients with AML enrolled in clinical trials over the last 10-20 years. Oncogenic point mutations and potentially genomic rearrangements will be identified, and linked to clinical outcome data, with a view to undertaking the following sorts of analyses: • Identification of co-occurrence, mutual exclusivity and clusters of driver mutations. • Correlation of prognosis with driver mutations and potentially gene-gene interactions • Exploration of genomic markers of drug response Ultimately, we would like to be in a position to release the mutation data together with matched clinical outcome data to genuine medical researchers via a controlled access approach, possibly within the COSMIC framework (www.sanger.ac.uk/genetics/CGP/cosmic/). The vision here is to generate a portal whereby a clinician faced with an AML patient and his / her mutational profile can obtain a ‘personalised’ prediction of outcome, together with a fair assessment of the uncertainty of the estimate. With a sufficient sample size, there would also be the potential to develop decision support algorithms for therapeutic choices based on such data.

  Study EGAS00001000408

• Berlin Institute for Medical Systems Biology - ccfDNA Methylation Data Access Commitee

  Dac EGAC00001003283

• The data access committee for Detecting Liver Cancer Using Cell-Free DNA Fragmentomes

  Dac EGAC00001003279

• DAC for the study of response to EGFR Blockade in Colorectal Cancer

  Dac EGAC00001000360

• DAC for Dependency of Transcriptional circuit of glioblastoma-associated macrophages that drive mesenchymal differentiation

  Dac EGAC00001000441

• Wellcome Trust Sanger Institute Data Sharing Policy for Trachoma GWAS

  Dac EGAC00001000489

• Agreement for accessing data of NGS based ctDNA tests

  Dac EGAC00001000598

• Data Access Committee for the Centre National de Recherche en Génomique Humaine (CNRGH)

  Dac EGAC00001000723

• RNA Seq fastq files generated for the "Proteogenomic landscape of medulloblastoma subgroups"

  Dac EGAC00001000792

• DAC for the Canadian Biobank on Respiratory and Allergic diseases (CoBRA)

  Dac EGAC00001000901

• DAC: Whole transcriptome RNA sequencing as comprehensive diagnostic tool for acute myeloid leukemia.

  Dac EGAC00001000956

• DAC for study: Frequent mutation of the FOXA1 untranslated region in prostate cancer

  Dac EGAC00001000962

• DAC for project: Subcutaneous panniculitis-like T-cell lymphomas (SPTCL) with hemophagocytic lymphohistiocytic syndrome.

  Dac EGAC00001000992

• DAC for study: Evaluation of commercial Guardant360 ctDNA test in metastatic prostate cancer

  Dac EGAC00001001082

• FORTH-BRFAA DAC for Systemic Lupus Erythematosus (SLE)

  Dac EGAC00001001213

• DAC for Enhancer-gene rewiring in the pathogenesis of Quebec Platelet Disorder

  Dac EGAC00001001529

• RNA-seq from FFPE - Englander Institute for Precision Medicine - Weill Cornell Medicine DAC

  Dac EGAC00001002098

• Cancer Clinical Research Trust DAC for the 23 WES samples of melanoma subtypes

  Dac EGAC00001002402

• COVID-19 Severity of First Wave of Infection for Severe Patients in Madrid

  Dac EGAC00001002480

• DAC for ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA

  Dac EGAC00001003141

• PopArg94_raw

  Raw data files for 94 Argentinean samples

  Dataset EGAD00010001913

• GermlineSNP

  SNP data for 473 germline samples

  Dataset EGAD00010002039

• COVID-19 Severity of First Wave of Infection for Severe Patients in Madrid

  Dac EGAC00001003435

• Data Access Committee for study Positive Selection in Peruvians from Three Ecological Regions

  Dac EGAC00001002414

• Coloured Project - Lankheet et al

  The data is for non-commercial use only.

  Dac EGAC50000000240

• The Data Access Committee for Human Olfactory Mucosa Cells (DAC HOM) at UEF

  Dac EGAC00001003404

• DAC for scRNA-seq and scp-MS data on human bone marrow

  Dac EGAC00001003505

• A machine learning classifier for DNA repair defects using plasma DNA

  Study EGAS00001007006

• Initial cohort of 500 solid tumors screened for Basket of Baskets

  Study EGAS00001005893

• Searching for genetic modulators of the phenotypic heterogeneity in Brugada Syndrome

  Study EGAS00001005848

• DAC_MATCH-R molecular driver

  Data access committee for MATCH-R molecular driver study

  Dac EGAC50000000335

• human HYPOMAP

  Data access for HYPOMAP raw sequence data and result data objects

  Dac EGAC50000000410

• This DAC will review all requests for data related to the dataset: EGAD00001015613.

  Dac EGAC00001003562

• CITE-seq for peripheral blood samples of 5 breast cancer patients

  Study EGAS00001006241

• DAC for DNA methylation data (iMED, BCG prime, and 500FG)

  Dac EGAC00001003534

• human biopsies

  DAC for human samples derived from biopsies from patients with hydrocephaly.

  Dac EGAC50000000625

• Validation study of genome-wide polygenic score for body mass index in South Asians

  Dac EGAC00001003593

• CoV2 challenge data

  Repository containing the transcriptomic data for the CoV2 challenge study

  Dac EGAC50000000391

• H3N2 challenge data

  Repository containing the transcriptomic data for the H3N3 challenge study

  Dac EGAC50000000379

• Exome

  Exome Seq for EGAS00001001845

  Dataset EGAD00001002160

• The Institute for Genomic Medicine at Nationwide Children's Hospital Pediatric Cancer and Blood Disorder Project

  The aim of this study is to enable the unification of the clinical and research arms of comprehensive genomic profiling in the setting of cancer and hematologic disease. Increasingly, studies of the genomic etiology of cancer and hematologic diseases are being utilized for patient management, including prognostication, informing diagnosis, and evaluating eligibility for targeted therapeutics and clinical trials. Clinically available testing can be limited in scope and follow-up, and thus assessment of the impact on patient outcomes is difficult to ascertain. N-of-1 studies have the ability to more broadly impact our understanding of the mechanisms of cancer and hematologic disease, and can have benefit for the individual as well as the larger population of patients with these diseases. Thus, we seek to study and characterize the genomic underpinnings of cancer and hematologic disease through genomic profiling studies bridging both clinical and research components. We will rigorously perform and vet research sequencing and genomic studies protocols for the purpose of transitioning these assays to clinically valid testing for use in clinical patient care. We have been enrolling patients onto this comprehensive genomic profiling study since January 2018. As part of the genomic workup for these patients, we have been performing tumor and normal whole genome sequencing, whole exome sequencing and RNA-Seq. The project is largely supported by the Nationwide Children's Foundation, and we anticipate adding another 50-70 cases per year. This protocol is significant in that it expands our understanding of the etiology of cancer and hematologic disease through a comprehensive analysis aimed at detecting a broad scope of genomic aberrations. Additionally, it improves our understanding of the clinical utility of genomic profiling and has the potential to ultimately improve patient management and surveillance at both level of an individual and general populations of patients affected by these diseases. Primary Objectives: Aim 1: Use diagnostic, relapse, and/or germline samples for augmented whole exome sequencing to characterize the spectrum of germline and somatic genomic alterations in pediatric malignancies and hematologic disease. Aim 2: Examine gene expression and fusion events using whole RNA-seq "transcriptome" analysis or targeted RNA-seq analysis such as the Archer FusionPlex technology. Aim 3: Compare the results of our enhanced molecular profiling vs. that which is detectable by traditional methods as related to cytogenetic, molecular, and minimal residual disease analyses performed as part of standard of care. Aim 4: Examine the utility of comprehensive genomic profiling by collection and evaluation of outcomes data as related to enhancement/alteration in diagnosis, prognosis, treatment management, and clinical benefit. Secondary Objective: Aim 1: Use and clinically validate expanded laboratory methodologies and bioinformatic approaches to more broadly assess genomic complexity (e.g. whole genome sequencing, transcriptome sequencing, in vitro analyses, minimal residual disease testing, clonality assays, proteomics) in the setting of hematologic and oncologic disease. In so doing, we aspire to make novel discoveries and associations, as related to disease phenotypes and subtypes, variant causality, therapeutic targeting, and cancer biology.

  Study phs001820

• Whole-Genome Sequencing in Multiplex Epilepsy Families

  Epilepsy is one of the most common neurologic disorders, affecting approximately 4% of individuals at some time in their lives. More than 30% of people with epilepsy continue to have seizures despite treatment, and improved approaches to treatment and prevention are sorely needed. In the search for new strategies to reduce the burden of disease, the discovery of specific genes that influence risk offers a novel opportunity to clarify pathogenic mechanisms, identify susceptible individuals prior to seizure onset, and treat and prevent seizures in people at risk. Despite clear evidence of the importance of genetics in susceptibility to epilepsy, only limited progress has been made in identifying the specific genes that influence risk. One of the greatest challenges for genetic research on this disorder is its extreme clinical and genetic heterogeneity. Although epilepsy is broadly defined by recurrent unprovoked seizures, it is so variable in its clinical manifestations, natural history, and treatment response that most epileptologists view it as a collection of different syndromes ("epilepsies") with distinct etiologies. The genetic effects on susceptibility are also likely to be extremely variable, ranging from rare variants with high penetrance (some of which produce Mendelian patterns of inheritance) to common variants with low penetrance. Recent findings strongly suggest that rare gene variants play a major role in the genetic architecture of the epilepsies. The purpose of this study was to discover new genetic risk factors for epilepsy. The primary approach was to use whole-genome sequencing to interrogate classes of genetic variants, including very rare variants, in multiplex families. Our main hypothesis was that, in at least some proportion of these families, a single variant would explain all instances of epilepsy. Variants identified within the families could then be tested for cosegregation within the family and also validated by seeing enrichment in sporadic epilepsy cases. Furthermore, understanding the impact of rare variation in epilepsy also has the potential to provide insight into the genetic architecture of other complex human diseases. Our analysis focused on families containing multiple individuals with non-acquired (idiopathic or unknown cause) epilepsy under the hypothesis that these would be enriched for genetic control. The families studied had been previously collected and phenotyped in detail, and contain an average of 3.8 individuals per family with a range of different types of epilepsy. We selected one or two affected individuals from each family for sequencing. This work has generated NGS data on 60 samples from 29 multiplex epilepsy families. We have established that, under a monogenic model of inheritance, sequencing pairs of distantly related relatives is an effective method for reducing the number of candidate variants. Critically, we have found that no single variant can explain a large proportion of these epilepsy families. This work emphasizes that identifying causal variants among the many genetic candidates found in this work will require very large sample sizes and gene-based analyses.

  Study phs000690

• Center for Common Disease Genomics [CCDG] - Neuropsychiatric: SPARK Simons Foundation Powering Autism Research for Knowledge

  In this study, we address the enormous challenges common complex diseases pose for genomic analysis and the enormous opportunities surmounting them offers for advancing healthcare. The common genetic disorders proposed for study here are believed to have extreme locus heterogeneity, requiring the analysis of large numbers of samples to comprehensively identify the genomic variants underlying them. We propose that a combination of deep population studies and joint analysis of SNPs, indels, and structural variants, both in coding and noncoding regions, will provide the next level of understanding of common genetic disorders. Whole genome sequencing (WGS) will be critical to this next-generation approach to the genomics of complex disease. WGS will need to be accompanied by the technical ability to generate and handle very large data sets, a particular focus and strength of New York Genome Center (NYGC). WGS will also need to be accompanied by new statistical tools and algorithms, which will be developed by the strong core group committed to this proposal.An overarching goal of this proposal, one that capitalizes on the power of WGS, is to identify disease-associated variants at the individual nucleotide level. In many cases, pathogenic mutations fall in noncoding regions of the genome, which can only be fruitfully explored with WGS. A major effort was put into building new computational strategies to functionally annotate noncoding transcribed sequences, and to build new datasets to enable such strategies, opening new frontiers of understanding of disease-related regulatory variants.

  Study phs002511

• National Heart Lung and Blood Institute Exome sequencing in SCID

  Analysis of the molecular etiologies of severe combined immunodeficiency (SCID) has led to important insights into the control of immune cell development. Most cases of SCID result from either X-linked or autosomal recessive inheritance of mutations in a known causative gene. However, in some cases, the molecular etiology remains unclear. To identify the cause of SCID in a patient known to lack the protein tyrosine phosphatase CD45, we utilized single nucleotide polymorphisms (SNP) arrays and whole exome sequencing. The patient's mother was heterozygous for an inactivating mutation in CD45, while the paternal alleles lacked mutations. The patient exhibited a single CD45 mutation identical to the maternal allele. Patient SNP array analysis revealed no change in copy number but loss of heterozygosity for the entire length of chromosome 1 (Chr1), indicating that disease was caused by uniparental disomy (UPD) with isodisomy of the entire maternal Chr1 bearing the CD45 mutation. Non-lymphoid blood cells and other mesoderm and ectoderm-derived tissues retained UPD of the entire maternal Chr1 in this patient who had undergone successful bone marrow transplantation. Exome sequencing revealed mutations in 7 additional genes bearing nonsynonymous SNPs predicted to have deleterious effects. These findings represent the first reported case of SCID caused by UPD and suggest UPD should be considered in SCID and other recessive disorders, especially when the patient appears homozygous for an abnormal gene found in only one parent. Evaluation for alterations in other genes affected by UPD should also be considered in such cases.

  Study phs000479

• Genetic Markers of Lipids in Indians: A Validation Study of Most Relevant Findings of Genome-Wide Association Studies

  We aimed to validate the GWAS loci (identified in European populations) related to serum lipid levels (total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and very low-density lipoprotein cholesterol (VLDL-C)) in the Indian population originally recruited to examine the 20-year trend of cardiometabolic risk factors in rural and urban areas around National Capital region in India. Isolated DNA was processed for genotyping of 12 established GWAS variants using multiplex Sequenom Mass ARRAY technology. We examined the association of these genetic variants with different lipid levels and found association of eight variants for lipid levels. We also derived weighted genetic risk scores (wGRAS) using the validated variants. The wGRS for triglycerides and VLDL-C was derived based on four associated variants (rs174546 at FADS1, rs17482753 at LPL, rs2293889 at TRPS1, rs4148005 at ABCA8, rs4420638 at APOC1) which was associated with 36.31 mg/dL elevated triglycerides and VLDL-C (β=0.95, SE=0.16, pTRPS1 and rs4147536 at ADH1B) was associated with 40.62 mg/dL higher total cholesterol (β=1.01, SE=0.23, pTRPS1, rs4147536 at ADH1B, rs4420638 at APOC1 and rs660240 at CELSR2). The wGRS derived from five associated variants (rs174546 and FADS1, rs17482753 at LPL, rs4148005 at ABCA8, rs4420638 at APOC1 and rs7832643 at PLEC) was associated with 10.64 mg/dL lower HDL-C (β= -0.87, SE =0.14, pThe phenotypic and genotypic data will be made available on the dbGaP portal for access.

  Study phs003469

• ILyAD (Indolent Lymphoma And vitamin D)

  Indolent non-Hodgkin lymphomas are incurable diseases, and require intermittent and often morbid and expensive therapy during their prolonged natural history. Lower intensity and better-tolerated, cost-effective treatment strategies are needed for these patients. Low vitamin D levels at diagnosis of indolent lymphomas are strongly associated with inferior outcomes to treatment. Standard therapy for low tumor burden, indolent lymphoma includes a single agent monoclonal antibody (rituximab). In our double-blind, placebo-controlled, randomized trial we evaluated if vitamin D supplementation with 2000IU oral cholecalciferol daily for three years improved the progression-free survival of patients with indolent lymphoma treated with single agent rituximab. Stratification factors for randomization included histology and Follicular Lymphoma International Prognostic Index (FL-IPI) prognostic score. The primary endpoint of the trial was progression-free survival over three years; secondary endpoints included response at 13 weeks, and overall survival. Eligible participants were adults with biopsy proven follicular lymphoma (grades 1-3a), small lymphocytic lymphoma, marginal zone lymphoma and mucosal-associated lymphoid tissue with no prior anti-lymphoma systemic therapy. Participants had Ann Arbor stage II or greater, measurable disease defined by Lugano criteria. Participants with osteoporosis requiring prescription treatment, symptomatic primary hyperthyroidism, hypercalcemia, creatinine greater than 1.5 times the upper limit of normal or a history of calcium-related kidney stones were excluded. Germline DNA was isolated from saliva samples obtained from participants at baseline. Whole exome sequencing was performed and SNPs were analyzed using the Agilent SureSelectXT Human All Exon V6 +UTR array. SNP data from 185 participants are available through dbGaP.

  Study phs003503

• Multiple Myeloma Clinical Targeted Sequencing of Patient Samples

  Purpose: Molecular diagnostics for the risk stratification of patients with multiple myeloma (MM) have languished in the area of cytogenetics and fluorescence in situ hybidization (FISH). However, here we present the case for next generation sequencing of MM patient samples to not only identify high-risk markers, but also mutations and deletions relating to immunomodulatory drugs (IMiDs), and more importantly to guide the sequencing of immunotherapy regimens in response to intrinsic antigen escape as a means of treatment resistance and relapse. Experimental design: CD138+ cell selected samples (n=134) from bone marrow aspirates from patients with multiple myeloma were sequenced using a targeted panel in a clinical diagnostics laboratory. Data were analyzed for high-risk markers, treatment-related resistance mechanisms, and precision medicine targets to guide the future treatment of patients in the clinic. Results: High-risk markers including t(4;14), t(14;16), t(14;20), gain or amplification 1q, deletion of CDKN2C, and deletion or mutation of TP53 were identified in 15% of newly diagnosed myeloma patient samples. At relapse, alterations in the cereblon degradation pathway were found in 24.3% of IMiD treated patients. Deletions of 4p (CD38) were also enriched in patients who received anti-CD38 treatment (P=0.03) which were mostly monoallelic. Deletions and mutations were detected in TNFRSF17 encoding BCMA in patients treated with anti-BCMA regimens, and the information was used to change the treatment of the patients. Conclusions: Targeted sequencing of multiple myeloma patient diagnostic samples can be used for risk stratification, and also to monitor and adjust treatments as resistance mechanisms evolve.

  Study phs003908

• Nanopore sequencing of blood, saliva, buccal mucosa samples of patients with inherited retinal disorders

  X-linked genetic disorders typically affect females less severely than males due to the presence of a second X chromosome not carrying the deleterious variant. However, the phenotypic expression in females is highly variable, which may be explained by an allelic skew in X chromosome inactivation. Accurate measurement of X inactivation skew is crucial to understand and predict disease phenotype in carrier females, with prediction especially relevant for degenerative conditions. We propose a novel approach using nanopore sequencing to quantify skewed X inactivation accurately. By phasing sequence variants and methylation patterns, this single assay reveals the disease variant, X inactivation skew, its directionality, and is applicable to all patients and X-linked variants. Enrichment of X-chromosome reads through adaptive sampling enhances cost-efficiency. Our study includes a cohort of 16 X-linked variant carrier females affected by two X-linked inherited retinal diseases: choroideremia and RPGR-associated retinitis pigmentosa. As retinal DNA cannot be readily obtained, we instead determine the skew from peripheral samples (blood, saliva and buccal mucosa), and correlate it to phenotypic outcomes. This revealed a strong correlation between X inactivation skew and disease presentation, confirming the value in performing this assay and its potential as a way to prioritise patients for early intervention, such as gene therapy currently in clinical trials for these conditions. Our method of assessing skewed X inactivation is applicable to all long-read genomic datasets, providing insights into disease risk and severity and aiding in the development of individualised strategies for X-linked variant carrier females.

  Study EGAS50000000440

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

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

  Study EGAS50000001013

• Analysis of mutational and proteomic heterogeneity of gastric cancer to monitor post-treatment tumor burden using circulating tumor DNA

  It remains unclear whether complete spectrum of tumor heterogeneity is reflected in circulating tumor DNA (ctDNA). Here, we performed multi-regional target sequencing of primary tumors from 10 patients who underwent surgical resection for gastric cancer. A total of 126 non-synonymous mutations were identified from 30 samples from 10 tumors. Of these, 16 (12.7%) were likely mutations that occurred early in tumor development (i.e., present in all three regions) and were designated founder mutations. Among those validated with highly sensitive digital PCR (dPCR), 93% of non-founder mutations were found in all three regions. Variant allele frequencies (VAFs) of founder mutations were significantly higher than those of non-founder mutations. Phylogenetic analysis demonstrated that five of eight tumors (62.5%, excluding two hypermutator) had at least one identifiable truncal/founder mutation. These findings led us to prioritize founder mutations for ctDNA detection with individually-designed primer/probe sets for dPCR. Marked proteomic diversity was present across the tumor regions both within and between patients independent of mutational status. In preoperative plasma, the average ctDNA VAF of founder mutations was significantly higher than that of non-founder mutations (p = 0.039). Our present data demonstrated that high VAF mutations in the tumor likely represent founder or truncal mutations. However, mutation patterns alone appear insufficient to predict protein heterogeneity. These results suggest that, in practice, mutations having high VAF identified without multi-regional sequencing may be useful for ctDNA monitoring but are inadequate to fully predict proteomic heterogeneity of the tumor.

  Study JGAS000231

• Sequencing and analysis of a South Asian-Indian personal genome

  India with over 1.3 billion people is estimated to carry three times more genetic diversity compared to Europe. Next-generation sequencing technologies have facilitated the understanding of diversity by enabling whole genome sequencing at greater speed and lower cost. While multiple genomes from people of European and a few of Asian descent have been sequenced, only recently a single male genome from the Indian subcontinent at sufficient depth and coverage was published. We have in this study sequenced and analyzed the genome of a South Asian Indian female (SAIF) from the Indian state of Kerala. We identified over 3.4 million SNPs in this genome including over 89,873 private variations. Comparison of the SAIF genome with several published personal genomes revealed that this individual shared ~50% of the SNPs with each of these genomes. Analysis of the SAIF mitochondrial genome showed that it is closely related to the U1a3 haplogroup which has been previously observed in Kerala. We assessed the SAIF genome for SNPs with health and disease consequences and found that the individual was at a higher risk for multiple sclerosis and a few other diseases. In assessing SNPs that modulate drug response we found a variation that predicts a favorable response to metformin used for treating diabetes. SNPs predictive of adverse reaction to warfarin indicated that the SAIF individual is not at risk for bleeding if treated with typical doses of warfarin. In addition to these, we report the presence of several other SNPs of medical relevance.

  Study EGAS00001000328

• Analysis of recent shared ancestry in a familial cohort identifies coding and noncoding autism spectrum disorder variants

  Autism spectrum disorder (ASD) is a collection of neurodevelopmental disorders characterized by deficits in social communication and restricted, repetitive patterns of behavior or interests. ASD is highly heritable, but genetically and phenotypically heterogeneous, reducing the power to identify causative genes. We performed whole genome sequencing (WGS) in an ASD cohort of 68 individuals from 22 families enriched for recent shared ancestry. We identified an average of 3.07 million variants per genome, of which an average of 112,512 were rare. We mapped runs of homozygosity (ROHs) in affected individuals and found an average genomic homozygosity of 9.65%, consistent with expectations for multiple generations of consanguineous unions. We identified potentially pathogenic rare exonic or splice site variants in 12 known (including KMT2C, SCN1A, SPTBN1, SYNE1, ZNF292) and 12 candidate (including CHD5, GRB10, PPP1R13B) ASD genes. Furthermore, we annotated noncoding variants in ROHs with brain-specific regulatory elements and identified putative disease-causing variants within brain-specific promoters and enhancers for 5 known ASD and neurodevelopmental disease genes (ACTG1, AUTS2, CTNND2, CNTNAP4, SPTBN4). We also identified copy number variants in two known ASD and neurodevelopmental disease loci in two affected individuals. In total we identified potentially etiological variants in known ASD or neurodevelopmental disease genes for ~61% (14/23) of affected individuals. We combined WGS with homozygosity mapping and regulatory element annotations to identify candidate ASD variants. Our analyses add to the growing number of ASD genes and variants and emphasize the importance of leveraging recent shared ancestry to map disease variants in complex neurodevelopmental disorders.

  Study EGAS00001006058

• Microsatellite data show recent demographic expansions in sedentary but not in nomadic human populations in Africa and Eurasia.

  The transition from hunting and gathering to plant and animal domestication was one of the most important cultural and technological revolutions in human history. According to archeologists and paleoanthropologists, this transition triggered major demographic expansions. However, few genetic studies have found traces of Neolithic expansions in the current repartition of genetic polymorphism, pointing rather toward Paleolithic expansions. Here, we used microsatellite autosomal data to investigate the past demographic history of 87 African and Eurasian human populations with contrasted lifestyles (nomadic hunter-gatherers, semi-nomadic herders and sedentary farmers). Likely due to the combination of a higher mutation rate and the possibility to analyze several loci as independent replicates of the coalescent process, the analysis of microsatellite data allowed us to infer more recent expansions than previous genetic studies, potentially resulting from the Neolithic transition. Despite the variability in their location and environment, we found consistent expansions for all sedentary farmers, while we inferred constant population sizes for all hunter-gatherers and most herders, which could result from constraints linked to a nomadic or semi-nomadic lifestyle and/or competition for land between herders and farmers. As an exception, we inferred expansions for Central Asian herders. This might be linked with the arid environment of this area, which may have been more favorable to nomadic herders than to sedentary farmers. Alternatively, current Central Asian herders may descent from populations who have first experienced a transition from hunter-gathering to sedentary agropastoralism, and then a second transition to nomadic herding.

  Study EGAS00001000652

• Genome-Wide Association Study of aspirin-induced PUD in a UK cohort

  Aspirin is a widely prescribed non-steroidal anti-inflammatory drug used as an effective analgesic and at low doses as anti-platelet drug for the prevention of cardiovascular diseases. However, aspirin is associated with a significant incidence of upper gastrointestinal (GI) complications, notably peptic ulceration. This study aims to identify genetic risk factors associated with the pathogenesis of aspirin-induced upper GI ulceration.A cohort of 248 patients with aspirin-induced, endoscopiclly confirmed GI ulceration and 491 controls (ulcer, without aspirin or aspirin without ulcer) were genotyped for 1.524,956 SNPs using the Illumina Omni 2.5 SNP array. A replication cohort (206 NSAID-induced ulcer cases [of which 87 were aspirin] and 309 controls) was subsequently genotyped for identified SNP association signals using Sequenom iPLEX Massarry. Logistic regression analysis of identified two SNP signal with suggestive association with aspirin-induced GI ulceration. A SNP within the EYA1 locus (rs12678747) was found to be associated with aspirin GI ulceration in both the discovery cohort (p=3.79x10-7, OR=2.06 ([1.55-2.73]) and, to a lesser extent, in the replication cohort (p=.0005, OR=1.71[1.17-2.50]. Combined analysis of both cohorts yielded a genome wide significant association (p=1.46x10-8). The rs12678747 genotype was found to be associated with significantly higher EYA1 transcript in ulcer biopsy tissue (p<0.05).Data suggest that EYA1 may represent a risk locus for aspirin-induced GI ulceration. Though it is thought that EYA1 may play a key role in mediating cell death/ survival

  Study EGAS00001002052

• Sequencing-based counting and size profiling of plasma Epstein-Barr virus DNA enhance population screening of nasopharyngeal carcinoma.

  Circulating tumor-derived DNA testing for cancer screening has recently been demonstrated in a prospective study on identification of nasopharyngeal carcinoma (NPC) among 20,174 asymptomatic individuals. Plasma EBV DNA, a marker for NPC, was detected using real-time PCR. While plasma EBV DNA was persistently detectable in 97.1% of the NPCs identified, ∼5% of the general population had transiently detectable plasma EBV DNA. We hypothesized that EBV DNA in plasma of subjects with or without NPC may have different molecular characteristics. We performed target-capture sequencing of plasma EBV DNA and identified differences in the abundance and size profiles of EBV DNA molecules within plasma of NPC and non-NPC subjects. NPC patients had significantly higher amounts of plasma EBV DNA, which showed longer fragment lengths. Cutoff values were established from an exploratory dataset and tested in a validation sample set. Adopting an algorithm that required a sample to concurrently pass cutoffs for EBV DNA counting and size measurements, NPCs were detected at a positive predictive value (PPV) of 19.6%. This represented superior performance compared with the PPV of 11.0% in the prospective screening study, which required participants with an initially detectable plasma EBV DNA result to be retested within 4 weeks. The observed differences in the molecular nature of EBV DNA molecules in plasma of subjects with or without NPC were successfully translated into a sequencing-based test that had a high PPV for NPC screening and achievable through single time-point testing.

  Study EGAS00001002707

• Open_Targets_020_Epigenomes_of_Cell_Lines

  There is currently a drive to establish cell based assay systems of greater human biological and disease relevance through the use of well characterised transformed cell lines, primary cells and complex cellular models (e.g. co-culture, 3D models). However, although the field is gaining valuable experience in running more non-standard & complex cell assays for target validation and compound pharmacology studies, there is the lack of a systematic approach to determine if this expansion in cell assay models is reflected in increased human biological and disease relevance. The increasing wealth of publically available transcriptomic, and epigenome (ENCODE and Epigenome Roadmap) data represents an ideal reference mechanism for determining the relationship between cell types used for target & compound studies to primary human cells and tissues from both healthy volunteers & patients. The CTTV020 epigenomes of cell line project aims to generate epigenetic and transcriptomic profiles of cell lines and compare these with existing and newly generated reference data sets from human tissue and cell types. The aim is to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. Multiple cell types commonly used within research have been grouped according to biology. Examples include erythroid, lung epithelial, hepatocyte cell types and immortalised models of monocyte / macrophage biology. 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 EGAS00001003136

• Quantification of chromosomal copy number aberrations by shallow whole-genome sequencing

  Detection of DNA copy number aberrations by shallow whole-genome sequencing (WGS) faces many challenges including lack of completion and errors in the human reference genome, repetitive sequences, polymorphisms, variable sample quality, and biases in the sequencing procedures.Formalin-fixed paraffin-embedded (FFPE) archival material, the analysis of which is important for studies of cancer, presents particular analytical difficulties due to degradation of the DNA and frequent lack of matched reference samples. We present a robust, cost-effective WGS method for DNA copy number analysis that addresses these challenges more successfully than currently available procedures. In practice very useful profiles can be obtained with 0.1 fold genome coverage. We improve on previous methods by; first, implementing a combined correction for sequence mappability and GC content, and second, applying this procedure to sequence data from the 1000 Genomes Project in order to develop a blacklist of problematic genome regions. A small subset of these blacklisted regions were previously identified by ENCODE, but the vast majority are novel unappreciated problematic regions. Our procedures are implemented in a pipeline called QDNAseq. We have analyzed over 1,000 samples, most of which were obtained from the fixed tissue archives of over 25 institutions.We demonstrate that for most samples our sequencing and analysis procedures yield genome profiles with noise levels near the statistical limit imposed by read counting. The described procedures also provide better correction of artifacts introduced by low DNA quality than prior approaches, and better copy number data than high-resolution microarrays at substantially lower cost.

  Study EGAS00001000642

• Prediction of pigmentation phenotypes by SNP typing in a Northern German population

  Human pigmentation traits are of great interest to many research areas, from ancient DNA analysis to forensic science. We aimed to develop a gene-based predictive model for pigmentation phenotypes in a realistic target population for forensic case work from Northern Germany. Our aim was to determine whether better prediction accuracy can be achieved, or fewer genetic markers may suffice, than in previously studied, genetically more heterogeneous populations. We investigated the association between eye, hair and skin colour, and 12 candidate single nucleotide polymorphisms (SNPs) from six genes. Our study comprised two samples of 300 and 100 individuals from Northern Germany who were carefully characterized with regard to pigmentation phenotypes. The first sample was used to select trait-associated SNPs whereas the second sample served to estimate odds ratios (ORs) and to quantify the predictive capability of the respective SNP genotypes. SNP rs12913832 in HERC2 was found to be strongly associated with blue eye colour (OR=15.6, p<1.2•10-4) and to yield reasonable predictive power (90% sensitivity, 63% specificity). SNP associations with hair and skin colour were weaker and genotypes less predictive. A comparison to two recently published sets of markers to predict eye and hair colour revealed that the consideration of additional SNPs with weak to moderate effect increases the predictive power in Northern Germans for eye colour, but not for hair colour. In addition, fine phenotyping and differentiation of hair colour (light / dark and red tint / no red tint) were found to increase the number of significant genotype-phenotype associations.

  Study EGAS00001001174

• The Dutch Microbiome Project: Defining the (un)healthy gut microbiome

  The Dutch Microbiome Project (DMP) data includes raw data generated by shotgun metagenomic sequencing of faecal samples of 8,208 Dutch individuals, processed microbiome data analysed using Biobakery2 tools (including taxonomy, pathway, virulence factors and antibiotic resistance gene profiles), and basic phenotypes (age and sex, BMI). Data is made available in two randomly assigned batches to facilitate the data access and maintenance. Access to this dataset requires a minimal access procedure (data access form at https://forms.gle/eHeBdXJMXbVvCJRc8 or email request to the data access committee (DAC) of this study, listed at DAC EGAC00001001996, https://ega-archive.org/dacs/EGAC00001001996). This access procedure is to ensure that the data is being requested for research/scientific purposes only and thus complies with the informed consent signed by Lifelines participants, which specifies that the collected data will not be used for commercial purposes. Submitted data access forms will be evaluated by the DAC and Lifelines, and a response to requests will be given within two weeks. For requests from verified academic parties, access will be given without further delay. For requests from commercial parties, Lifelines will perform a pre-DPIA (Data Privacy Impact Assessment) to assess the risks of the proposed processing of personal data (e.g. purpose, storage, access, archiving, etc.) with respect to the GDPR (EU privacy laws) subject rights. Based on the outcome of the pre-DPIA, Lifelines will decide whether sharing data with the commercial entity is allowed and/or whether additional measures have to be taken.

  Study EGAS00001005027

• Open_Targets_020_Epigenomes_of_Cell_Lines

  There is currently a drive to establish cell based assay systems of greater human biological and disease relevance through the use of well characterised transformed cell lines, primary cells and complex cellular models (e.g. co-culture, 3D models). However, although the field is gaining valuable experience in running more non-standard & complex cell assays for target validation and compound pharmacology studies, there is the lack of a systematic approach to determine if this expansion in cell assay models is reflected in increased human biological and disease relevance. The increasing wealth of publically available transcriptomic, and epigenome (ENCODE and Epigenome Roadmap) data represents an ideal reference mechanism for determining the relationship between cell types used for target & compound studies to primary human cells and tissues from both healthy volunteers & patients. The CTTV020 epigenomes of cell line project aims to generate epigenetic and transcriptomic profiles of cell lines and compare these with existing and newly generated reference data sets from human tissue and cell types. The aim is to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. Multiple cell types commonly used within research have been grouped according to biology. Examples include erythroid, lung epithelial, hepatocyte cell types and immortalised models of monocyte / macrophage biology. 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 EGAS00001003137

• Open_Targets_020_Epigenomes_of_Cell_Lines

  There is currently a drive to establish cell based assay systems of greater human biological and disease relevance through the use of well characterised transformed cell lines, primary cells and complex cellular models (e.g. co-culture, 3D models). However, although the field is gaining valuable experience in running more non-standard & complex cell assays for target validation and compound pharmacology studies, there is the lack of a systematic approach to determine if this expansion in cell assay models is reflected in increased human biological and disease relevance. The increasing wealth of publically available transcriptomic, and epigenome (ENCODE and Epigenome Roadmap) data represents an ideal reference mechanism for determining the relationship between cell types used for target & compound studies to primary human cells and tissues from both healthy volunteers & patients. The CTTV020 epigenomes of cell line project aims to generate epigenetic and transcriptomic profiles of cell lines and compare these with existing and newly generated reference data sets from human tissue and cell types. The aim is to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. Multiple cell types commonly used within research have been grouped according to biology. Examples include erythroid, lung epithelial, hepatocyte cell types and immortalised models of monocyte / macrophage biology. 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 EGAS00001003139

• Healthy_ageing_thymus

  Single cell RNA sequencing of immune and non-immune cells from healthy ageing thymus Thymus is a primary lymphoid organ that creates an environment for the T lymphocyte precursors differentiation into the naive T cells, which involves TCR gene rearrangement, negative and positive selection. Despite thymus critical function for the recognition of the pathogens it starts to atrophy very early in life. Thymic Epithelial Space (TES), where thymocyte education occurs, starts to decline rapidly just after birth, while with the onset of puberty thymus is also progressively replaced with adipose tissue. This leads to a reduced naive T cell output,which decreases an organism's ability to recognize pathogens. In our lab, we have already collected and characterized cell type composition and gene regulatory networks of the fetal tand adult human thymus (Park et al, Science 2020). In the current project we plan to expand the number of paediatric and adult samples in the study with the aim to understand how the process of thymic involution happens. We will use single-cell transcriptomics to zoom on changes that occur in immune and non-immune cell types in different phases of thymic involution with the hope to understand which gene expression changes are causal for the thymic involution process and how naïve T cell production can be increased in elderly. 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 EGAS00001004311

• Robust methylation-based classification of brain tumours using nanopore sequencing

  Background: DNA methylation-based classification of cancer provides a comprehensive molecular approach to diagnose tumours. In fact, DNA methylation profiling of human brain tumours already profoundly impacts clinical neuro-oncology. However, current implementations using hybridization microarrays are time-consuming and costly. We recently reported on shallow nanopore whole-genome sequencing for rapid and cost-effective generation of genome-wide 5-methylcytosine profiles as input to supervised classification. Here, we demonstrate that this approach allows to discriminate a wide spectrum of primary brain tumours. Results: Using public reference data of 82 distinct tumour entities, we performed nanopore genome sequencing on N=382 tissue samples covering 46 brain tumour (sub)types. Using bootstrap sampling in a cohort of N = 56 cases, we find that a minimum set of 1,000 random CpG features is sufficient for high-confidence classification by ad hoc random forests. We implemented score recalibration as confidence measure for interpretation in a clinical context and empirically determined a platform-specific threshold in a randomly sampled discovery cohort (N = 185). Applying this cut-off to an independent validation series (N = 184) yielded 148 classifiable cases (sensitivity 80.4%) and demonstrated 100 % specificity. Cross-lab validation demonstrated robustness with concordant results across four laboratories in 10/11 (90.9%) cases. In a prospective benchmarking (N = 15), median time to results was 21.1 hours. Conclusions: In conclusion, nanopore sequencing allows robust and rapid methylation-based classification across the full spectrum of brain tumours. Platform-specific confidence scores facilitate clinical implementation for which prospective evaluation is warranted and ongoing.

  Study EGAS00001006540

• Treatment stratification and biomarker validation using patient-derived head and neck cancer organoids

  Background Organoids are three-dimensional structures that can be grown from patient-derived material including carcinomas. These in vitro models can be cryopreserved to generate “living” biobanks that reflect patient heterogeneity. Head and neck cancer (HNC) is a collective term used for tumors arising in the head and neck area, including squamous cell carcinomas (HNSCC) and adenocarcinoma of the salivary gland. Methods to culture patient-derived HNC organoids have previously been described. Methods Organoids were derived from resection or biopsy material of patients included between 2016 and 2022. Organoids were characterised with immunohistochemistry and whole exome sequencing (WES) and exposed to chemo-, radio- and targeted-therapies. CRISPR/Cas9-based gene editing was applied to validate proposed biomarkers. Results We have extended our previously published organoid biobank to a total of 110 organoid models, some of which were characterised by histology and WES. Organoids recapitulated both single nucleotide variants and copy number alterations as found in patient HNSCC samples. Organoid and patient response to radiotherapy (RT; primary (n=6) and adjuvant (n=15)) could be compared in 21 HNC cases. In the adjuvant RT group, organoids derived from patients that relapsed were more resistant to RT in vitro, showing potential for guiding treatment options in this subset of patients. Conclusion Taken together, these results indicate illustrate the potential of organoids as a diagnostic tool in personalised medicine for HNC and indicate the potential of this technology for biomarker discovery and validation within the context of relevant patient heterogeneity.

  Study EGAS00001007076