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• Privacy Notice for Data Access Committee Account

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

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

• Women's Health Initiative Clinical Trial and Observational Study - Imaging

  Objectives: The clinical trial assessed the safety and efficacy of three interventions. Specifically, it evaluated (1) the major health benefits and risks of estrogen plus progestin and estrogen alone, (2) the effects of a low-fat eating pattern on risk of colorectal cancer, and (3) the efficacy of calcium with vitamin D supplementation for preventing hip and other fractures. The objective of the memory study was to determine whether estrogen plus progestin therapy protects global cognitive function, and evaluate the therapy's effect on the incidence of dementia and mild cognitive impairment.The observational study is examining the relationship between lifestyle, socioeconomic, health, and other risk factors with cardiovascular, breast cancer, colorectal cancer and osteoporotic fracture outcomes. Secondary objectives include providing more reliable estimates of the extent to which known risk factors predict disease, more precise estimates of new occurrences of disease, and to provide a future resource for the identification of new or novel risk factors especially factors found in blood. Background: The Women's Health Initiative (WHI) is a long-term national health study that has focused on strategies for preventing the major causes of death, disability, and frailty in postmenopausal women, specifically heart disease, cancer, and osteoporotic fractures. The WHI is primarily composed of an observational study (OS), as well a clinical trial (CT) with three components: Hormone Replacement Therapy (HT), Dietary Modification, (DM) and Calcium/Vitamin D supplementation (CaD).Prior to the WHI, observational studies suggested that postmenopausal hormone therapy was associated with a decreased risk of coronary heart disease (CHD). Potential cardioprotection was based on generally supportive data on lipid levels in intermediate outcome clinical trials, trials in nonhuman primates, and a large body of observational studies suggesting a 40% to 50% reduction in risk among users of either estrogen alone or, less frequently, combined estrogen and progestin. Observational studies primarily examining unopposed estrogen preparations have suggested a 30% to 50% reduction in coronary events, and an 8% to 30% increase in breast cancer with extended use. Other research findings indicated that hormone therapy was also associated with a decreased risk of osteoporosis and increased bone density. The WHI HT trials were designed to test the effects of postmenopausal hormone therapy on risk for coronary heart disease and assess overall risks and benefits in predominantly healthy women. The Women's Health Initiative Memory Program (WHIMS) consists of a suite of studies which include cohorts of women who participated in the WHI HT trials. Postmenopausal women have a greater risk than men of developing Alzheimer's disease, but studies of the effects of estrogen therapy on Alzheimer's disease have been inconsistent. Additionally, observational studies have suggested that postmenopausal hormone treatment may improve cognitive function, but data from randomized clinical trials have been sparse and inconclusive. International comparisons and migration studies have suggested that countries with 50% lower fat intake than the US population had approximately one third the risk of colorectal cancer. Additionally, fairly consistent evidence existed for an effect of dietary fat, vegetables and fruits, and grains on colorectal cancer risk from within-country observational studies, although the protective effect of lower fat intake was no longer clear after adjusting for energy intake. The WHI DM trial was the first randomized trial to directly address the health effects of a low-fat eating pattern in predominantly healthy postmenopausal women from diverse racial/ethnic, geographic, and socioeconomic backgrounds. Osteoporosis is a major cause of injury, loss of independence, and death, and contributes to hip fractures. Observational evidence and data from previous randomized clinical trials suggest that calcium and/or vitamin D supplements may slow bone loss and reduce the risk of falls in postmenopausal and elderly women. However, evidence from trials, observational studies, and meta-analyses of calcium and vitamin D supplementation with respect to hip and other fractures was limited at the time the WHI was initiated. In two prior randomized trials, calcium plus vitamin D supplements did not reduce the risk of nonvertebral fractures among older women. When the WHI CaD trial was designed, guidelines recommended daily intakes of 800 to 1200 mg of calcium with 400 IU of vitamin D for the prevention of osteoporosis, which was not met by many American women. Therefore, the WHI CaD trial was designed to test the primary hypothesis that postmenopausal women randomly assigned to calcium plus vitamin D supplementation would have a lower risk of hip fracture and, secondarily, of all fractures than women assigned to placebo. Subjects: Postmenopausal women ages 50 to 79 were eligible to participate. A woman was considered postmenopausal if she had experienced no vaginal bleeding for 6 months (12 months for women under 55 years of age), had had a hysterectomy, or had ever used postmenopausal hormones. Recruitment was carried out in 40 US clinical centers in 1993-1998. The clinical trial components had additional specific inclusion or exclusion criteria.A total of 68,132 women were randomized into at least one component of the clinical trial. 27,347 women were enrolled in the hormone therapy component with 16,608 in the estrogen plus progestin trial and 10,739 in the unopposed estrogen trial, 48,835 women were enrolled in the diet modification component, and 36,282 women were enrolled in the calcium/vitamin D component. 7,479 women 65 years of age and older at baseline and that participated in the HT trial component were enrolled in the ancillary memory study. Women who were either ineligible or unwilling to participate in the clinical trial component were enrolled in the observational study. For example, many potential participants to the clinical trial component of the study were already undertaking a low fat diet or were using hormone replacement therapy. The effect of the selection process was that women enrolled in the observational study tended to have healthier lifestyles compared to those enrolled in the clinical trial. In total, 93,676 subjects were enrolled in WHI OS, with over 16% being members of a racial/ethnic minority group. The first WHI Extension Study enrolled 115,407 consenting participants from all components of the original WHI study for an additional five years of follow-up, from 2005 to 2010. In 2010, 93,567 women consented to continued follow-up. Design: The clinical trial component of the WHI included three randomized comparisons: hormone therapy, dietary modification, and calcium/vitamin D supplementation. Women could have been randomized into one, two or all three trials.The hormone therapy trial enrolled women to one of two double-blinded trials: estrogen (0.625 mg of conjugated equine estrogens daily) plus progestin (2.5 mg of medroxyprogesterone acetate daily) or estrogen alone. Women with a prior hysterectomy were eligible for the trial of unopposed estrogen. Women with an intact uterus at screening were initially also eligible for unopposed estrogen, but were reassigned to the trial of combined postmenopausal hormones beginning in 1995. Both trials randomized participants 1:1 to either hormone therapy or placebo. A 3-month washout period was required before baseline evaluation of women using postmenopausal hormones at initial screening. Study participants were contacted by telephone 6 weeks after randomization to assess symptoms and reinforce adherence. Follow-up contacts by telephone or clinic visit occurred every 6 months, with clinic visits required annually. The estrogen plus progestin trial was halted in July 2002 after a mean 5.2 years of follow-up because health risks, including increased risk of breast cancer and cardiovascular disease, exceeded benefits. The estrogen alone trial was stopped early in March 2004, because an increased risk of stroke was found with no benefit for coronary heart disease. The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. The dietary modification trial evaluated the effect of a low-fat, high fruit, vegetable, and grain diet on preventing cardiovascular disease and cancer. Participants were randomly assigned to an intervention or a comparison group in the ratio of 2:3 for cost-efficiency. The intervention was an intensive behavioral modification program, using 18 group sessions in the first year and quarterly sessions thereafter, led by specially trained and certified nutritionists. The program was designed to promote dietary change with the goals of reducing total fat to 20% of energy intake, increasing vegetables and fruits to at least 5 servings daily and grains to at least 6 servings daily. The intervention did not include total energy reduction or weight loss goals. Comparison group participants received a copy of the US Department of Health and Human Services' Dietary Guidelines for Americans and other health-related materials but were not asked to make dietary changes. Dietary intake was monitored using the WHI food frequency questionnaire at 1 year and in a rotating one-third subsample every year thereafter. Women completed a medical update questionnaire every 6 months, and medical records were sought for all women reporting colorectal cancer. The primary outcome was invasive colorectal cancer incidence. Participants in the calcium/vitamin D trial were randomized 1:1 to either supplements or placebo. Active tablets contained 500 mg of elemental calcium (as calcium carbonate) and 200 IU of vitamin D3, to be taken twice daily with meals. The presence and severity of symptoms, safety concerns, and outcomes were ascertained at annual clinic visits and telephone or clinic visits at intervening six-month intervals. Risk factors for fracture were assessed by questionnaire, interview, and clinical examination. The primary outcome was incidence of hip fracture. Participants in the observational study attended a baseline examination and were re-examined three years later. Participants completed annual updates of exposures and clinical outcomes by mail. Final data were collected by mail during the close-out period in April 2004 to March 2005. The major clinical outcomes of interest were coronary heart disease, stroke, breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, osteoporotic fractures, diabetes, and total mortality. Most outcomes were initially ascertained by self-report on an annual questionnaire and documented by hospital and related records. Charts with potential cardiovascular, cancer, and fracture outcomes were sent to the local physician adjudicator for evaluation and classification. Staff at the Clinical Coordinating Center coded and adjudicated all cancers of major interest in the study using standardized SEER guidelines. In 2005, WHI participants were invited to join the Extension Study for an additional five years of follow-up in order to collect long-term outcomes. Participants completed annual data collection forms primarily by mail, similar to the OS follow-up. Women reporting study outcomes were contacted by WHI field center staff to obtain additional details and medical records, which were evaluated by physician adjudicators. In 2010, the woman remaining were invited to join the next Extension Study. In the second extension, women were divided into two groups, one of which would have outcomes documented with medical records (the Medical Records Cohort, MRC), and the other would just be followed by self-report (the Self-Report Cohort, SRC). The MRC consists of women who were in the hormone therapy trials, and all African-American and Hispanic women. In 2012-2013, a subset of the MRC was identified for a potential in-home visit to collect blood and several objective measures of physical functioning. Conclusions: Overall health risks exceeded benefits from use of combined estrogen plus progestin after an average 5.2 year follow-up among healthy postmenopausal US women (Rossouw et al., 2002, PMID:12117397). Among postmenopausal women aged 65 years or older, estrogen plus progestin did not improve cognitive function when compared with placebo (Rapp et al., 2003, PMID: 12771113), increased the risk for probable dementia, and did not prevent mild cognitive impairment (Shumaker, et al., 2003, PMID: 12771112). The use of conjugated equine estrogen increased the risk of stroke, decreased the risk of hip fracture, and did not affect CHD incidence in postmenopausal women with prior hysterectomy after an average of 6.8 years of follow-up (Anderson et al., 2004, PMID: 15082697). Over approximately 8 years of follow-up, a low-fat dietary pattern did not reduce the risk of colorectal cancer (Beresford, et al., PMID: 16467233). Calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density; however, no significant difference was observed in hip fractures (Jackson, et al., 2006, PMID: 16481635). A recent review summarizes the conclusions from the WHI clinical trials with a focus on clinical practice (Manson, et al., 2024, PMID: 38691368).Description of ECG Imaging Data: Electric cardiograms (ECGs) were given to all clinical trial participants at baseline and in years 3, 6, and 9 of the original WHI study.EKG data consist of 12 lead 10 seconds ECGS sampled at 500Hz via GE ECG machines and process via GE MUSE system. The ECG waveform were directly exported from GE MUSE using MUSE export function in XML format, which include EKG waveform data as well as other ECG characteristics. Waveform data is in base64 encoded format, when it is decoded, it is a binary data that can be used to draw waveform graph. Many programming languages and data tools have built in functions to decode base64 strings. All the other necessary information is included in the LeadData section, total byte size, total sample size etc. (usually 1 sample is 2 bytes). See example below: encoded-data (base64 encoded string) JwAoAC0AKAAiACIAJAAkACQAIwAiACIAHgAcABwAGwAZABgAGAAYABcAEwAQABAAEAAL^/AAsADAAM... decoded-binary-data (1 sample is 2 bytes) 270028002D002800220022002400240024002300220022001E001C001C001B00 1900180018001800170013001000100010000B000B000C000C000D000D000D00 0A000A000A0009000600040004000700070005000500020... These binary values are integers (Y axis data of the graph), hence it is a straightforward process to draw the waveform graph. Acquisition dates have been redacted from this ECG data to comply with WHI policy. All acquisition dates within files and in file names have been set to January 1, 1900 (19000101) to comply with this policy.

  Study phs003824

• The Environmental Determinants of Diabetes in the Young Study (TEDDY)

  Study Overview The Environmental Determinants of Diabetes in the Young (TEDDY) Study is a longitudinal study that investigates genetic and genetic-environmental interactions, including gestational events, childhood infections, dietary exposures, and other environmental factors after birth, in relation to the development of islet autoimmunity and type 1 diabetes (T1D). A consortium of six clinical centers assembled to participate in the development and implementation of the study to identify environmental triggers for the development of islet autoimmunity and T1D in genetically susceptible individuals. Beginning in 2004, the TEDDY study screened over 400,000 newborns for high-risk HLA-DR, DQ genotypes from both the general population and families already affected by T1D. The TEDDY study enrolled around 8,676 participants across six clinical centers worldwide (Finland, Germany, Sweden and three in the United States) in the 15-year prospective follow-up. Participants are followed every three months for islet autoantibody (IA) measurements with blood sampling until four years of age and then at least every six months until the age of 15. After the age of four, autoantibody positive participants continue to be followed at three month intervals and autoantibody negative participants are followed at six-month intervals. In addition to the analysis of autoantibodies, additional data and sample collection are performed at each visit. Parents collect monthly stool samples in early childhood. The parents also fill out questionnaires at regular intervals in connection with study visits and record information about diet and health status in the child's TEDDY Book between visits. Continued long-term follow-up of the currently active TEDDY participants will provide important scientific information on early childhood diet, reported and measured infections, vaccinations, and psychosocial stressors that may contribute to the development of type 1 diabetes and islet autoimmunity. Additional information on the TEDDY study is available in the following articles: Rewers et al., 2008, PMID: 19120261 and Hagopian et al., 2006, PMID: 17130573. Details of the TEDDY protocol can be found in Hagopian et al., 2011, PMID: 21564455. TEDDY data currently available in dbGaP include: gene expression, SNPs, exome, microbiome (gut, nasal, and plasma), RNA sequencing, and whole genome sequencing. For more information on TEDDY Study version history please refer to TEDDY Study dbGaP README File. ImmunoChip SNP DNA from whole blood samples on study participants and their family members (mothers, fathers, and siblings) was obtained and used for SNP genotyping. Genotyping was performed by the Center for Public Health Genomics at the University of Virginia using the Illumina ImmunoChip SNP array, which contains around 196,000 SNPs from 186 regions associated with 12 autoimmune diseases (Hadley et al., 2015, PMID: 26010309). Data cleaning and validation included the removal of subjects with a low call rate (< 5% SNPs missing) and differences in reported sex and prior genotyping at the TEDDY HLA laboratory. Additionally, SNPs with a low call rate or Hardy-Weinberg equilibrium P value < 10-6, except for chromosome 6 due to HLA eligibility requirements, were removed from the final dataset (Törn et al., 2015, PMID: 25422107).TEDDY-T1DExome ArrayDNA from whole blood samples on study participants and their family members (mothers, fathers, and siblings) was obtained and used for genotyping. Genotyping was performed by the University of Virginia using the Illumina TEDDY-T1DExome array. The TEDDY-T1DExome array is a custom chip that contains 550,601 markers from the Infinium CoreExome-24 v1.1 BeadChip and an additional 90,214 tagSNPs specifically selected by the TEDDY investigators based on their associations with nutrients, vitamins, type 2 diabetes, autoimmune diseases, body-mass index, or other exposures and phenotypes measured by TEDDY study.The Illumina GenTrain2 algorithm was used for genotype calling. Sample quality control metrics included sample call rate, heterozygosity rate and concordance of gender between the information reported and genotyped. Gene Expression The TEDDY study collected peripheral blood for the extraction of total RNA from enrolled children starting at 3 months of age, and then at 3 month intervals up to 48 months and then biannually. Total RNA was extracted using a high throughput (96-well format) extraction protocol using magnetic (MagMax) beads technology at the TEDDY RNA Laboratory, Jinfiniti Biosciences in Augusta, GA. Purified RNA (200 ng) was further used for cRNA amplification and labeling with biotin using Target Amp cDNA synthesis kit (Epicenter catalog no. TAB1R6924). Labeled cRNA was hybridized to the Illumina HumanHT-12 Expression BeadChips based on the manufacturer's instructions. The HumanHT-12 Expression BeadChip provides coverage for more than 47,000 transcripts and known splice variants across the human transcriptome. Microbiome The TEDDY microbiome study aimed to characterize the longitudinal development of the microbiome, including bacteria, viruses and other microorganisms in the gut, plasma, and nasal cavity of prediabetic and diabetic subjects compared to autoantibody negative non-diabetic subjects. Stool samples used were collected monthly from 3 to 48 months, after which stool samples were collected every 3 months. Nasal swab samples were collected every 3 months starting at 9 months of age until 48 months, after which nasal swabs were collected every 6 months. Plasma samples were collected every 3 months starting at 3 months of age until 48 months, after which plasma samples were collected every 6 months. If the subject was autoantibody positive at 48 months then they remained on the 3 month collection interval for nasal swab and plasma samples. Samples underwent 16s rRNA gene sequencing, DNA and viral RNA metagenomics shotgun sequencing, and sequencing of the internal transcribed spacer (ITS) regions. Additional information on the TEDDY microbiome data is available in the following articles: Vatanen et al., 2018, PMID: 30356183, Stewart et al., 2018, PMID: 30356187, and Vehik et al., 2020, PMID: 31792456. RNA Sequencing The TEDDY study aimed to characterize the transcriptome in subjects with islet autoimmunity and type 1 diabetes compared to matched control subjects. Peripheral blood was collected to extract total RNA from enrolled children starting at 3 months of age, and then at 3 month intervals up to 48 months and then biannually. Total RNA was extracted using a high throughput (96-well format) extraction protocol using magnetic (MagMax) beads technology at the TEDDY RNA Laboratory, Jinfiniti Biosciences in Augusta, GA. Purified RNA was then sent to the Broad Institute for the generation of the TEDDY RNA sequencing (RNA-Seq) data. The RNA samples were prepped using Superscript III reverse transcriptase and Illumina's TruSeq Stranded mRNA Sample Prep Kit. The TruSeq libraries were run on the Illumina HiSeq2500 platform. Whole Genome Sequencing The TEDDY study aimed to conduct deep whole genome sequencing and examine the genomic variations in subjects with islet autoimmunity and type 1 diabetes compared to matched autoantibody negative and non-diabetic children. DNA from whole blood was obtained from TEDDY children for whole genome sequencing. The WGS data were generated on the Illumina HiSeq X Ten system.

  Study phs001442

• GA4GH

  Standards The EGA is a long-standing supporter of the Global Alliance for Genomics & Health (GA4GH) to enhance responsible sharing of human genetic data through the development of interoperable global standards for human data access. The EGA is one of the founding GA4GH Driver Projects and has contributed to the development and implementation of several GA4GH standards and APIs. Below is a list of the GA4GH standards and APIs that are currently available or planned for implementation at EGA. TechnicalStandards Purpose SpecificationVersion SupportedVersion Implementation Large Scale Genomics htsget A protocol for secure, efficient, and reliable access to sequencing read and variation data. V1.3.0 V1.0.0 Specification Documentation Endpoint Read File Formats (SAM/BAM/CRAM) Specifications for storing next-generation sequencing read data. V3.0.0 V3.0.0 Implementation Example of Usage Variation File Formats (VCF/BCF) The specifications for Variant Call Format Files (VCF) and its binary counterpart BCF. V4.0.0 V2.0.0 V4.0.0 V2.0.0 Implementation Example of Usage Crypt4GH v1.0 Enables direct byte-level compatible random access to encrypted genetic data stored in community standards (e.g. CRAM, VCF) V1.0 V1.0 Specification Documentation Endpoint refget API Enables access to reference sequences using an identifier derived from the sequence itself. V1.2.6 NA Specification RNAget API v1 Provides a means of retrieving data from several types of RNA experiments including (i) feature-level expression data from RNA-seq type measurements and (ii) coordinate-based signal/intensity data similar to a bigwig representation via a client/server model. V1.0.0 NA Documentation Discovery Beacon v2 Supports discovery of genomic variants, phenotypes, and individuals V1.0.1 V0.3 Web UI API Source Code Service Info API v1 The Service Info API is an endpoint for describing GA4GH service metadata, designed for extension and inclusion in other APIs. Service info is used to describe a single service, while Service Registry is used to describe multiple services. V1.0.0 NA Documentation Service Registry API v1 provides information about other GA4GH services, primarily for the purpose of organizing services into networks or groups and service discovery across organizational boundaries. V1.0.0 NA Documentation Data Use Researcher Identities Data Use Ontology (DUO) Allow users to semantically tag genomic datasets with usage restrictions, allowing them to become automatically discoverable based on a health, clinical, or biomedical researcher’s authorisation level or intended use. 2021-02-23 2021-02-23 Specification Documentation Endpoint Authentication & Authorization Infrastructure (AAI) The GA4GH AAI specification leverages OpenID Connect (OIDC) Servers for use in authenticating the identity of researchers desiring to access clinical and genomic resources from data holders adhering to GA4GH standards, and to enable data holders to obtain security-related attributes of those researchers. V1.2.0 V1.2.0 API URI: ega.ebi.ac.uk:8443 Documentation Repository Researcher IDs (passport, visa) Specify the collection of researchers that may access a dataset at any given time, and the credentials they must supply. V1.0.1 V1.0.1 Specification Documentation Endpoint Cloud Tool Registry Service API TRS is a standard API for exchanging tools and workflows to analyze, read, and manipulate genomic data. V2.0.1 NA Documentation Repostiory Data Repository Service API ​DRS API is a standard for building data repositories and adapting access tools to work with those repositories, works with other approved APIs from the GA4GH Cloud Work Stream to allow researchers to discover algorithms across different cloud environments and send them to datasets they wish to analyse. V1.0.3 NA Documentation Repostiory Workflow Execution Service API This API lets users run a single workflow (defined using CWL or WDL) on multiple different platforms, clouds, and environments, and be confident that it will work the same way. The API provides methods to request that a workflow be run, pass parameters to that workflow, get information about running workflows, and cancel a running workflow. V1.0.1 NA Documentation Repostiory Genomic Knowledge Standards Variation Representation v1 Provides a flexible framework of computational models, schemas, and algorithms to precisely and consistently exchange genetic variation data across communities. V1.3.0 EGA team is contributing to including it in in Beacon v2 Specification and Elixir Reference Implementation Documentation Repostiory Clin/ Pheno Data Capture Phenopackets Provides information models with different levels of complexity to enable high level clinical phenotype information as well as deep clinical phenotype information to be exchanged. V2.0.0 Included in Ongoing Submissions EGA team is contributing to including it in in Beacon v2 Specification and Elixir Reference Implementation Documentation Repostiory Driver Project The EGA, jointly coordinated by the EBI and the CRG, was announced, in 2017, to be one of the 15 Driver Projects for GA4GH. Driver Projects are international genomic data initiatives, focussed on real projects and challenges that will guide the development efforts in order to accelerate and enable completely responsible and standarised data sharing by 2022. All chosen Driver Projects make a cross-sectional effort by playing an important role across the different workstreams. Thomas Keane, Jordi Rambla, Mallory Freeberg, and Aina Jené have been named Driver Project Champions for the EGA. All Driver Project Champions will be leading this ambitious initiative for the following years.

  Documentation about/projects-and-funders/ga4gh

• The EGA Helpdesk team: 2025 in review and what we are building next

  Behind every dataset submitted, every access request processed, and every technical question answered, there is a team working quietly to keep things moving: the Helpdesk (HD). With the onset of 2026, this feels like the right moment to look back on what 2025 has been like for the HD team: the challenges we faced, how we adapted, and where we're heading next. Why the Helpdesk matters to EGA The EGA Helpdesk is more than a support channel. It plays a key role in maintaining trust in the EGA ecosystem. By supporting data submitters, researchers, Data Access Committees (DACs), and institutional partners, the HD helps ensure that data can flow securely, efficiently, and reliably. When issues arise, the Helpdesk is often the first place where their impact is felt and addressed. In that sense, the HD sits at the intersection of technology, policy, and people. One Helpdesk, two locations, one shared mission The EGA Helpdesk is a joint, distributed team working closely across two locations: CRG (Barcelona, Spain) and EMBL-EBI (Cambridge, UK). Although we are based in different institutions, we operate as a single Helpdesk, with shared workflows, priorities, and responsibility towards users. At CRG, the HD team is formed by: Andrea Max Àlex and me At EMBL-EBI, we work closely with: Silvia Coline Aravind What defines us as a team is simple: we work user-first, even under pressure. In a highly technical environment, clarity, empathy, and consistency matter just as much as tools and processes. A close collaboration across sites is essential to making that happen. What does the EGA Helpdesk do? The HD supports users across the full lifecycle of data in EGA. This includes: Data submissions, uploads, and encryption workflows. Data access requests and permissions. Questions around policies, consent, and data usage. Technical and system-related issues. Coordination between users, internal teams, and external partners. 2025: growth, change, and recalibration 2025 was a year of growth, but not always a predictable one. Early in the year, several technical and system-related challenges required us to adjust our original plans. Priorities shifted, timelines changed, and some improvements had to be rethought. For the HD team, this is often the hardest part of the job: we see delays through the eyes of users and understand the real impact they can have on ongoing research. One of the key lessons from 2025 was that stability is not only a technical challenge, but also an organisational one. Teamwork proved to be essential: anticipating peak periods, sharing context early, and coordinating closely across teams made a tangible difference. When things became complex, working together across roles and locations was what allowed us to keep moving forward. In 2025, the Helpdesk received 5.313 tickets and resolved 5.511 requests, reflecting both increased adoption of EGA and the team’s ability to absorb higher demand. At the same time, demand continued to grow. Compared to 2024, ticket creation increased by over 6%, while resolution capacity grew by more than 11%. The team not only kept up with incoming requests but also resolved part of the accumulated backlog, finishing the year having solved more tickets than were created. The real challenge of 2025 was not overall performance, but how the workload was concentrated during peak months. Seasonality and demand spikes placed pressure on the system, even while overall efficiency remained strong. On a team level, 2025 was also a year of transition. I joined the HD leadership role in January 2025, stepping into a period of change and rapid learning. Later in the year, in October, we said goodbye to Raül, and in January 2026, we welcomed Àlex, strengthening the team for the next phase. What users needed most in 2025 While requests vary widely, some themes stood out throughout the year: Support with data submissions and uploads Data access requests and permissions Technical and system-related issues As EGA matures, day-to-day operations have become more complex. Many long-running tickets are not delayed due to a lack of follow-up, but because they depend on external approvals, cross-institutional coordination, or multi-step processes. Understanding these patterns helps us focus not just on resolving tickets, but on improving how work flows through the system. Looking ahead to 2026 With a reinforced team and clearer insights from 2025, our focus for 2026 shifts from throughput to flow. Key priorities include: Strengthening our web content and documentation Reducing structural backlog Improving cross-team and cross-system coordination Anticipating peak demand earlier and planning capacity accordingly Challenges will continue to arise in 2026, as they always do. However, 2025 reinforced something important: a stable, empathetic, and well-aligned Helpdesk team is essential to supporting EGA's mission at scale. Supporting users well means supporting research, and that remains at the core of what we do.

  Blog ega-helpdesk-team-2025-in-review-and-upcoming-improvements

• Longitudinal Study of Fluoride and Other Factors Related to Dental Fluorosis, Dental Caries, and Bone Health

  This project is a combination of the Iowa Fluoride Study and the Iowa Bone Development Study from 1992 - 2019. The Iowa Fluoride Study (IFS) began in 1992 with recruitment of 1,882 mothers of newborns from eight Iowa hospital post-partum wards from March 1992 to February 1995. The focus of the IFS was to collect detailed fluoride, general dietary intake, and other data several times per year from age 6 weeks on and relate them to dental fluorosis and dental caries (cavities). Data collection occurred 3-5 times per year initially, and then twice per year after ~ age 4. Dental exams of the primary (baby) teeth were initiated at ~ age 5.The Iowa Bone Development Study (IBDS) grew out of the IFS in 1998 when we added a "normal bone development" focus, and soon after the age 5 dental exams, we began to collect genetic samples and accelerometry (motion sensor) data. All then-active parents of IFS-participating children were invited to have their child join the IBDS, and the majority agreed to do so. The majority of participating children received both ~ age 5 dental exams and bone densitometry assessments. The bone densitometry at age 5 was determined by dual-energy X-ray absorptiometry (DXA) of the hip, lumbar spine, and whole body.Dental exams for caries and fluorosis were performed again at age 8-9, along with DXA bone scans and accelerometry. DXA scans and accelerometry were performed again at ages 11 and 15 years, along with peripheral quantitative computed tomography (pQCT) scans of the distal tibia and radius, but no dental exams were performed.At ages 13 and 17, dental exams, DXA and pQCT scans, as well as accelerometry, were obtained.At age 19, no dental exams were conducted, but repeat DXA and pQCT scans and accelerometry were obtained, along with multi-slice detector CT (MDCT) of the distal tibia.At age 23, we conducted the final wave of exams, which included dental, DXA, pQCT, MDCT, and accelerometry assessments.In addition, parents were invited to participate once with DXA bone scans and to also provide limited questionnaire data about their own fluoride and dietary exposures and physical activity.Note: Please refer to the document Iowa Fluoride Study/Iowa Bone Development Study (IFS/IBDS) - dbGaP Data Tables: A User's Guide - Version 2.0 for a detailed reference manual on all of the clinical data submitted for this project.Note: No genetic data or specimens were submitted with this study. However, many of the child/parent participants in the study were genotyped. These genotyping data are linked to dbGaP Study Accession: phs000095 under Dr. Mary Marazita: "Dental Caries: Whole Genome Association and Gene X Environment Studies".<img style="width: 1155px;" 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

  Study phs002203

• eMERGE Network Phase III: HRC SNV and 1000 Genomes SV Imputed Array Data of 105,000 Participants

  The Electronic Medical Records and Genomics (eMERGE) Network is a National Institutes of Health (NIH)-organized and funded consortium of U.S. medical research institutions. The primary goal of the eMERGE Network is to develop, disseminate, and apply approaches to research that combine biorepositories with electronic medical record (EMR) systems for genomic discovery and genomic medicine implementation research. eMERGE was announced in June 2007 and began its third phase in September 2015. eMERGE Phase III (June 2015 - June 2020) consists of 10 study sites, two central sequencing and genotyping facilities, and a coordinating center. Included in this study are: Human Reference Consortium (HRC) single nucleotide variants and 1000 Genomes structural variants imputed array data of 105,108 eMERGE participants from nine Phase III study sites and three Phase II study site collaborators. Corresponding demographics, body mass index measurements. Case/control status for the following phenotypes: Abdominal aortic aneurysm; Ace-Inhibitor/Cough; Attention Deficit Hyperactivity Disorder; Age-related macular disease; Appendicitis; Asthma; Atopic Dermatitis; Autism; Benign Prostatic Hyperplasia; Carotid artery disease as a Quantitative Measure; caMRSA; Cataract; Clostridium difficile colitis; Extreme Obesity; Chronic Kidney Disease; Chronic Kidney Disease and Type 2 Diabetes; Chronic Kidney Disease, Type 2 Diabetes and Hypertension; Colon Polyps; Cardiorespiratory Fitness; Dementia; Diverticulosis; Diabetic retinopathy; Gastroesophageal Reflux Disease; Glaucoma; Height; Heart failure; Hypothyroidism; Lipids; Ocular hypertension; Peripheral Arterial Disease; QRS duration; Red blood cell indices; Remission of Diabetes after ROUX-EN-Y gastric bypass surgery; Resistant hypertension; MACE while on Statins; Type 2 Diabetes; Venous Thromboembolism; White blood cell indices; and Zoster virus infection. Study sites and participants include: Boston Children&#39;s Hospital: The Gene Partnership (TGP) is a prospective longitudinal registry at Boston Children&#39;s Hospital (BCH) to study the genetic and environmental contributions to childhood health and disease, collect genetic information on a large number of children who have been phenotyped, and implement the Informed Cohort and the Informed Cohort Oversight Board (ICOB). The term "The Gene Partnership" reflects a partnership between researchers and participants. Children seen at BCH are offered enrollment, as are their parents and siblings. DNA is collected on all enrollees. BCH has a comprehensive EMR system, and virtually all inpatient and outpatient data are captured electronically. Clinical data in the BCH EMR is loaded in the i2b2 data warehouse which is available to investigators. Cases, phenotypes, and covariates are ascertained using the i2b2 database. Participants at BCH in TGP have consented to receive any research result and/or incidental finding that arises from studies using TGP that is approved by the Informed Cohort Oversight Board (ICOB) and is in accordance with the participants&#39;preferences;results are returned through the Personally Controlled Health Record (PCHR). BCH and Cincinnati Children&#39;s Hospital Medical Center (CCHMC) have partnered as the Pediatric Alliance for Genomic and Electronic Medical Record (EMR) Research (PAGER) site for the eMERGE Phase II network for pediatric institutions, and the cohort for eMERGE at BCH is TGP. Children&#39;s Hospital of Pennsylvania (CHOP): The Center for Applied Genomics (CAG) at the Children&#39;s Hospital of Philadelphia (CHOP) is a high-throughput, highly automated genotyping and sequencing facility equipped with state-of-the-art genotyping and sequencing platforms. Children who are treated at the Children&#39;s Hospital Healthcare Network and their parents may be eligible to take part in a major initiative to collect more than 100,000 blood samples, covering a wide range of pediatric diseases. A large majority of participants consenting to prospective genomic analyses also consent to analysis of their de-identified electronic health records (EHRs). EHRs are longitudinal, with a mean duration of 6.5 years. Cincinnati Children&#39;s Hospital Medical Center/Boston&#39;s Children&#39;s Hospital (CCHMC/BCH): Cincinnati Children&#39;s Hospital Medical Center (CCHMC) is a pediatric institution dedicated to improving health and welfare of children and to the discovery and practical application of new genomic information to the ordinary care of children. CCHMC brings an extraordinary faculty to eMERGE III who are committed to gain a better understanding of the genesis of disease and to elucidate the mechanisms of diseases that afflict children, specifically pediatric disease phenotypes that will leverage the available eMERGE adult genomic data and electronic medical records (EMRs) to discover meaningful use results. Generation of EMR phenotype algorithms, informed by natural language processing, using heuristic and machine learning methods is ongoing. CCHMC has developed tools to evaluate adolescent return of results preferences, examined the ethical and legal obligations and potential to reanalyze results, and developed clinical decision support for phenotyping, test ordering, and returning sequencing results. The success of these eMERGE III studies is enhanced by the ongoing institutional investment made in the CCHMC Biobank, the comprehensive EMR (EPIC), the i2b2 de-identified medical record data warehouse, and hundreds of faculty and senior staff who make genomics or informatics an active focus of their research. Columbia University: Columbia University Medical Center/New York Presbyterian (CUMC/NYP) Hospital system is one of the nation&#39;s largest and most comprehensive hospital systems with over 2 million inpatient and outpatient yearly visits that serves a racially and ethnically diverse urban patient population. The Columbia University GENomic Integration with EHR (GENIE) research study contributed and shared phenotype and genotype data for individuals who were recruited as part of a diverse array of initiatives within the hospital, including Northern Manhattan Study (NOMAS), Pediatric Cardiac Genomic Consortium (PCGC), Caribbean Hispanics with Familial and Sporadic Late Onset Alzheimer&#39;s disease (AD), Alzheimer&#39;s Disease Sequencing Project (ADSP), and Genetics of Chronic Kidney Disease study. Some of these individuals had kidney or neurological problems, some were healthy adult volunteers with self-reported health status information from the medically underserved Northern Manhattan community, and others were pediatric patients with cardiac conditions. For the kidney disease cohort, patients with the diagnosis of Chronic Kidney Disease (CKD) and healthy controls were recruited to the Columbia University CKD biobank. For the NOMAS cohort, eligible participants were stroke-free, were 40 years old, and resided for at least 3 months in a Northern Manhattan household with a telephone. The PCGC study recruited parent-offspring trios with pediatric probands diagnosed with congenital heart defects (CHD). For the Caribbean Hispanics with Alzheimer&#39;s disease project, individuals from families affected by AD and with sporadic AD were recruited, along with unrelated controls. Samples for the ADSP study have been selected from well-characterized cohorts of individuals with AD diagnosis. Geisinger Health System: A research cohort of adult Geisinger Clinic patients was enrolled from community-based primary care clinics of the Geisinger Health System. Patients were eligible for enrollment if they were a primary care patient of a Geisinger Clinic physician and were scheduled for a non-emergent clinic visit. All participants provided written informed consent and HIPAA authorization. Consenting patients agreed to provide blood samples for broad biomedical research use, and permission to access data in their Geisinger electronic medical record for research. The enrollment rate was 90% of patients approached. The demographics of the cohort approximate those of the Geisinger Clinic outpatient population. Research blood samples were collected during an outpatient clinical phlebotomy encounter. Research blood samples are coded and stored in a central biorepository. Samples are linkable to clinical data in a de-identified manner for research via an IRB-approved data broker process. For genomic analysis, DNA is extracted from EDTA-anticoagulated whole blood. Partners Health Care (Harvard): The Partners HealthCare Biobank is a large research program designed to help researchers understand how people&#39;s health is affected by their genes, lifestyle, and environment. This large research data and sample repository provides access to high-quality, consented blood samples to help foster research, advance our understanding of the causes of common diseases, and advance the practice of medicine. For the Partners research community (Massachusetts General Hospital and Brigham and Women&#39;s Hospital), the Biobank provides: Banked samples (plasma, serum, and DNA) collected from consented patients Blood samples that were discarded after clinical testing in the Crimson Cores maintained in the Brigham and Women&#39;s Hospital and Massachusetts General Hospital Pathology Departments Sample handling and preparation services Link to the biobank data to the Partners Research Patient Data Registry (RPDR) a research instance of our electronic clinical chart Data access through our research portal. To date, over 60,000 Partners patients have given their consent to enroll, give a blood sample, receive research results and agreed to be re-contacted for additional research studies. The Biobank has enabled Partners investigators to compete for nationally recognized grants in personalized medicine such as a clinical electronic Medical Records and Genomics network (eMERGE) site and the national All of US program. The Biobank currently supports over 120 Partners investigators and over 100 million dollars in NIH research. Kaiser Permanente Washington with the University of Washington and the Fred Hutchinson Cancer Research Center: KPWA participants were enrolled in the eMERGE Network through the Northwest Institute of Genetic Medicine (NWIGM) biorepository, and provided the appropriate consent to receive clinically relevant genetic results (N~8,073.) NWIGM is based at the University of Washington and co-managed by the University of Washington and KPWA. The purpose of the NWIGM biorepository is to build infrastructure and resources to carry out a broad range of future genetic research. KPWA members enrolled in the biorepository are asked to provide informed consent to providing a DNA sample for storage in the NWIGM biorepository. The consent is purposefully broad to serve the dual purpose of reducing the burden on researchers who wish to use this biorepository and the IRB committees who will be responsible for reviewing these requests in the future. Participants were eligible if aged 50 - 65 years old at the time of their enrollment into the NWIGM repository, living, enrolled in KPWA&#39;s integrated group practice, and had completed an online Health Risk Appraisal. The selection algorithm was based on several data sources from the EHR at KPWA. 1) Demographics - participants with self-reported race as Asian ancestry were prioritized and selected to enrich for non-European ancestry. The KPWA eMERGE cohort includes n=1,245 members of Asian ancestry. 2) Participants were also selected for a history of colorectal cancer (n=1,002), in order to allow us to enrich germline pathogenic variants. Essentia Institute of Rural Health, Marshfield Clinic, Pennsylvania State University (Marshfield): The Marshfield Clinic Personalized Medicine Research Project is a population-based biobank in central Wisconsin with more than 20,000 adult subjects who provided written, informed consent to access their medical records and provided a blood sample from which DNA was extracted and plasma and serum stored. In addition to an average of 30 years of medical history data, a questionnaire about environmental exposures, including a detailed food frequency questionnaire, is available to facilitate gene/environment studies. Mayo Clinic: The Mayo Vascular Disease Biorepository is a disease-specific biobank for vascular diseases including peripheral arterial disease (PAD). PAD patients were identified from individuals referred to the non-invasive vascular laboratory for lower extremity arterial evaluation. Since 1997, laboratory findings have been recorded into an electronic database employing an in-house software package for data archiving and retrieval;this data becomes part of the Mayo EMR. Patients referred to the center with suspected PAD undergo a comprehensive non-invasive evaluation including the ankle-brachial index (ABI) - the ratio of blood pressure measured in the upper arms divided by blood pressure measured at the ankles. Controls subjects are identified from patients referred to the Cardiovascular Health Clinic for stress ECG. The prevalence of PAD in patients with normal exercise capacity who do not have inducible ischemia on the stress ECG , was &#60;1%. Data regarding risk factors for atherosclerosis such as diabetes, dyslipidemia, hypertension, and smoking are ascertained from the EMR. Case control study of venous thromboembolism (PI John Heit) Controls from a case control study of pancreatic cancer (PI Gloria Petersen) Mayo Clinic Biobank. Icahn School of Medicine at Mount Sinai School (Mt. Sinai): The Institute for Personalized Medicine (IPM) Biobank Project is a consented, EMR-linked medical care setting biorepository of the Mount Sinai Medical Center (MSMC) drawing from a population of over 70,000 inpatients and 800,000 outpatient visits annually. MSMC serves diverse local communities of upper Manhattan, including Central Harlem (86% African American), East Harlem (88% Hispanic Latino), and Upper East Side (88% Caucasian/white) with broad health disparities. IPM Biobank populations include 28% African American (AA), 38% Hispanic Latino (HL) predominantly of Caribbean origin, 23% Caucasian/White (CW). IPM Biobank disease burden is reflective of health disparities with broad public health impact: average body mass index of 28.9 and frequencies of hypertension (55%), hypercholesterolemia (32%), diabetes (30%), coronary artery disease (25%), chronic kidney disease (23%), among others. Biobank operations are fully integrated in clinical care processes, including direct recruitment from clinical sites, waiting areas and phlebotomy stations by dedicated Biobank recruiters independent of clinical care providers, prior to or following a clinician standard of care visit. Recruitment currently occurs at a broad spectrum of over 30 clinical care sites. Northwestern University: The NUgene Project is a repository with longitudinal medical information from participating patients at affiliated hospitals and outpatient clinics from the Northwestern University Medical Center. Participants&#39;DNA samples are coupled with data from a self-reported questionnaire and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 2 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators. Vanderbilt University Medical Center: BioVU, Vanderbilt&#39;s DNA databank, was designed as an enabling resource for exploration of the relationships among genetic variation, disease susceptibility, and variable drug responses. BioVU acquires DNA from discarded blood samples collected from routine patient care. The biobank is linked to de-identified clinical data extracted from Vanderbilt&#39;s EMR, which forms the basis for phenotype definitions used in genotype-phenotype correlations. BioVU is currently the largest single site DNA collection world-wide, at &#62;235,000 samples as of spring 2017.

  Study phs001584

• Genome-Wide Association Study of HCC in Non-Asian USA Population

  This GWAS of HCC relied on existing biological and data resources from 7 USA sites and one Canadian site which allows for the integration of genetic and environmental data. Total of 2199 case patients and 1103 non cancer controls were genotyped. Case patients are defined as patients with pathological or radiological diagnosis of HCC with and without chronic hepatitis C virus infection. Study was restricted to Caucasian population without prior infection with chronic HBV infection. All DNA samples were extracted from peripheral blood. Study population of the participated sites are: Site-1: University of Texas MD Anderson Cancer Center A hospital based-case-control study was initiated at UT MD Anderson Cancer Center in 2000 and approved by the Institutional Review Board of The University of Texas M. D. Anderson Cancer Center. Study design was previously described in detailed (1-3). Written informed consent for an interview and for a biological sample was obtained from each participant. At time of diagnosis prior to treatment exposure. Case patients were recruited from the population of patients with newly diagnosed HCC who were evaluated and treated at the institution's gastrointestinal medical and surgical oncology outpatient clinics. Inclusion criteria were as follows: a pathologically confirmed diagnosis of HCC, U.S. residency, and the ability to communicate in English. Patients with concurrent or past history of other types of cancers were excluded. Control subjects were healthy spouses of patients with cancers other than liver, gastrointestinal, lung, or head and neck (smoking-related cancers) undergoing treatment at our institution. Eligibility criteria for control subjects were the same as those for patients, except that control subjects could not have ever had cancer. A short, structured questionnaire was used to screen potential control subjects on the basis of eligibility criteria. Control subjects and patients were recruited simultaneously. Case patients and control subjects were interviewed by well-trained interviewers who followed a written protocol to guide ascertainment and reduce surveillance, interviewer, and recall bias. No proxy interviews were conducted. The interviewers used a structured and validated questionnaire to collect information about demographic characteristics and potential risk factors for HCC such as personal smoking history, alcohol use, medical history, occupational history, and family history of cancer. Blood samples from cases and controls were tested for HBV and HCV. HCV antibodies, hepatitis B surface antigen, and antibodies to hepatitis B core antigen were detected by use of a third-generation enzyme-linked immunosorbent assay (ELISA) (Abbott Laboratories, North Chicago, IL). Important clinical information were retrieved from patients' medical records. Total of 1188 case patients and 278 controls from MD Anderson study were genotyped. Site-2: Mayo Clinic Case patients and controls included in the study from Mayo clinic were recruited as part of Mayo International Hepatobiliary Neoplasia Register and Biorepository. Only USA patients and controls were participated. All cases and controls signed informed consent indicating their willingness to participate in genetic studies. Epidemiological and clinical data were collected from participants and retrieved from medical records. Total of 522 HCC case patients and 182 controls were genotyped in this study. Site-3: Toronto University Molecular Epidemiology of Hepatobiliary Tumors (HBT study, CAPCR 09-0289) is a hospital-based study that includes 1710 patients diagnosed with liver, bile duct or gallbladder adenocarcinoma (Hepatocellular carcinoma - HCC; cholangiocarcinoma - CCA; and gall bladder adenocarcinoma -GBCa) recruited at University Health Network (UHN) between 2009 and 2018. HBT study is a prospective study of cancer patients that collects self-reported demographic and epidemiological data, medical records/clinical information and blood samples for research purposes. Eligible patients recruited between 2009 and March 15 2016 were selected to participate in the Genome-Wide Association Study in Patients with Hepatocellular Carcinoma (GWAS in HCC, CAPCR 15-9943-CE), a sub-study of the HBT study. Eligible prospective patients recruited after March 15 2016 signed the Addendum to the HBT consent form and became eligible to participate in the GWAS in HCC study. Total of 271 cases and 21 controls were genotyped from Toronto University Site-4: University of Pittsburgh The design of the study has been described previously (4-6). Briefly, this population-based study enrolled 120 HCC patients and 230 matched controls from black, Hispanic, and non-Hispanic white residents of Los Angeles County who were between 18 and 74 years of age at diagnosis from January 1995 through December 2001. HCC Cases were identified through the Los Angeles County Cancer Surveillance Program. We sought to recruit up to two control subjects per case from the neighborhoods where HCC patients resided at the time of diagnosis, who were matched to the index case by sex, age (within 5 years), and race (Hispanic white, non-Hispanic white, black). Blood samples (plasma and buffy coat), medical and lifestyle factors were collected from all consenting participants. Total of 65 cases and 60 controls were genotyped in this study Site-5: South Western Dallas Under IRB approval, HCC Cases and controls were prospectively collected since 2015 from the outpatient Liver clinics from Parkland Health and Hospital System and UT Southwestern Medical Center, two large health systems in Dallas TX. A Total of 31 cases and 29 controls were genotyped from site 5. Site-6: Columbia University HCC patients from Columbia are those recruited as part of the Herbert Irving Comprehensive Cancer Center Database Shared Resource which seeks to recruit all cancer patients for potential future studies. The PI is Dr. Katherine Crew AAAL5871. This resource collects sociodemographic, lifestyle and clinical data on patients as well as a blood sample. Those who indicated on their consent form that they would participate in genetic studies were included. Total of 79 case patients with HCC were genotyped from Columbia University. Site-7: University of Michigan The study population included from University of Michigan were included from a prospective study of with chronic HCV infection recruited in Ann Arbor Patients who had under- gone liver transplantation, known coinfection with HIV, life expectancy &lt;12 months due to extra-hepatic illnesses, or were receiving HCV treatment at enrolment, were excluded. Protocol, surveys, and data forms were developed where each enrolled patient completed the same questionnaire All patients provided written informed consent before enrolment in the study. The study was approved by the institutional review board or ethics committee at the University of Michigan. Detailed study description was previously published (7). Total of 44 cases and 347 controls were genotyped Site-8: Veteran Administration Medical Center in Houston This research including written informed consent form was jointly approved by Institutional Review Boards for the Baylor College of Medicine and the Michael E. DeBakey VA Medical Center in Houston, Texas. Study details have been previously published (8). Briefly, we prospectively recruited consecutive HCV-infected veterans prior to their previously scheduled HCV clinic visit at a large tertiary care VA medical center between May 1, 2009 and December 31, 2012. Patients completed a research assistant (RA) administered survey interrogating medical and risk factor history including lifetime alcohol use, had anthropometric measurements taken, and completed a fasting venipuncture for performance of the FibroSure-ActiTest as a measure of hepatic pathology. We restricted our current analysis to individuals who were: (1) White male veterans between 18 and 70 years; (2) had no history of HCC, liver transplant, decompensated liver disease including ascites, dementia, or psychosis; (3) were serologically-confirmed to have chronic HCV and to be negative for both HIV and active HBV infection; (4) were not currently receiving anti-HCV pharmacotherapy; and (5) had FibroSURE testing shown F3/F4 fibrosis consistent with cirrhosis.

  Study phs001744

• A Phase I Study of the Treatment of Recurrent Malignant Glioma with CAN-3110 (AKA rQNestin34.5v.2), a Genetically Engineered HSV-1 Virus

  This study is a "first-in-human" phase 1 trial of recurrent, IDH wild-type glioblastoma (rGBM) patients treated with CAN-3110 (aka rQNestin34.5v.2), a genetically modified oncolytic herpes simplex virus 1 (HSV-1). The study was a 3+3 dose-escalation study starting at a single intra-tumoral injection of 106 PFU CAN-3110 going up to 1010 PFU in half-log increments (cohorts 1-9). An expansion cohort (cohort 10) was treated with 109 PFU injected into up to 5 sites within a single tumor. Principal findings of the study conclude that:CAN-3110 was safe at all tested doses (no dose-limiting toxicities reached)HSV-1 seropositive patients survived significantly longer than HSV-1 seronegative patients in this study - longer than expected based on historical rGBM controlsHSV-1 seropositive patients were significantly more likely to clear CAN-3110 (HSV-1) antigen from their tumors based on immunohistochemical stainingCAN-3110 treatment-induced CD8+/CD4+ T-cell recruitment to injected tumor sites altered TCR beta diversity in both tumor infiltrating leukocytes (TILs) and PBMCs, and initiated changes in specific TCR beta clonotypes and immune gene signatures which were associated with post-treatment survival.Data provided in dbGaP for this study include:Bulk RNA-Seq data for 13 pre/post-treatment pairs of rGBM tumors corresponding to 12 unique patients (patient 28 was treated with CAN-3110 at two different timepoints). This data is provided as raw sequencing reads (.fastq), kallisto pseudoalignment transcript-level read counts (abundance.tsv files), gene-level abundance matrix (Gene_Level_Expression_Matrix.tsv), and immune gene signature scores matrix (Immune_Gene_Signatures_Matrix.tsv). Sequencing was performed as paired 150bp sequencing on NovaSeq6000 S4 Illumina flow cells. Library preparation varied by batch as described in the included RNAseq_Metadata.xlsx table.TCR beta DNA sequencing performed by Adaptive Biotechnologies for 21 pre/post-treatment pairs of rGBM tumors and PBMCs representing 20 unique patients (patient 28 was treated with CAN-3110 at two different timepoints). Note that all tumor pairs with TCR beta sequencing data also have available bulk RNA-Seq data. The TCR beta sequencing data is provided as an excel spreadsheet (TCRbeta_Sample_Overview.xslx), which provides a broad level summary of the sequencing on a per-sample basis (# of TCRbeta templates, T cell fraction, TCR beta diversity metrics, etc.) and as a large tab separated value file (Full_TCRbeta_Rearrangement_Details.tsv), which provides information per sample at the level of each unique TCR beta sequence (amino/nucleic acid sequence, VDJ gene usage, etc.).An excel table of de-identified metadata for the patients involved in this study.

  Study phs003378

• From research to data sharing: exploring EGA user's experiences

  The Cell Plasticity and Regeneration Group at the Bellvitge Biomedical Research Institute-IDIBELL focuses on the process of recruitment of macrophages that takes place in the small intestine during injury and healing. They recently published a paper titled “Mucosal Macrophages Govern Intestinal Regeneration in Response to Injury" in Gastroenterology Journal. As part of the research, some experiments were conducted using human intestinal organoid lines. These cells were processed for RNA sequencing, and the sequencing data were deposited at the EGA to be made available to the scientific community. When dealing with human genomic information, repositories must ensure the availability of the datasets while ensuring data protection. In this context, the European Genome-phenome Archive stands as a service for secure archiving and sharing of genetic, phenotypic and clinical data resulting from biomedical research. Following the recent publication of their paper, we took the opportunity to talk to Ilias Moraitis, first author, and Jordi Guiu, group leader, to find out about their experience with data sharing. Could you explain the focus of your research? In the lab, we study intestinal regeneration and how immune cells participate in this process. We use several techniques: engineered mouse models, image tracing, as well as mouse and human cells intestinal organoids. What challenges do you face regarding data management? We didn’t have a lot of problems. Always the informatic part, the data analysis, can give problems. But everything was smooth and working. We think it’s very important to deposit the data in repositories. For the mouse data it is very straightforward, but for us it was the first time depositing human data, which is sensitive because it comes from patients, and this is legally regulated. That’s why we thought about the EGA, and it was our first time. Why do you think it is important to submit data to repositories such as EGA? Because we think data is important for the science. Nowadays, we are sequencing a lot everywhere worldwide and having these resources shared with the scientific community it’s not only good for science, but it is also saving money and reducing costs. And there is so much data in there that can be used for other projects and for other questions. And it saves time! How was the process of submitting the data to the EGA? The communication worked very well but it was slower than we would like. But I think this is something we learn on the way. People usually wait until the last minute to do this before publication but if you know it in advance, you can start the process earlier. If you had to repeat the process, would you do anything differently? It’s like everything, isn’t it? For the first time you don’t know, you aren’t sure, but for the second time you know the steps, you know what to do and it’s faster. Of course, we would to do it earlier. Also, there were some things related to the control access that we didn’t know how to manage, but it was something more internal to us. Who is going to receive the communications and when, is our ethical committee going to evaluate this? All these technicalities that we didn’t know before starting this process, so we had to think about all these things. Next time it will be faster on our side. Do you have any suggestions for us to improve the submission process? Maybe we’ll need to ask our bioinformatician who did it! He was in charge of this part. Besides that, we think if the process were faster, it would be better for everyone. Also, in science a lot of times you have to do a lot of things at the very last minute, because of the nature of the experiments, or the need to accomplish for submitting a paper. Being faster in the process would be a plus. On your side, we went through the process and were able to find some information, but there were aspects we weren't aware of and weren't sure how to handle. I'm not sure if other institutes have different protocols for managing data requests or how they handle these internally. We believe the main issue lies in how the forms are filled out. Do you have any recommendations for other submitters? The main advice is to do this with enough time. Submit the data when you have the sequences, and don’t wait until the last minute. And then it can be under embargo, so you don’t need to make it public at that moment. As soon as you sequence, upload it and then it will be there for whenever you need to publish. How do you think we could encourage other researchers to submit their data? There are different layers here. One is that it is mandatory. You have to do this. The other is that we belong to a research community, to the same community and sharing this is making our research community stronger and more efficient. And then, also because this gives you visibility. The data is there, other people can analyse your data, and this also will bring citations to your papers. It has many advantages.

  Blog from-research-to-data-sharing