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• Privacy Notice for EGA Web user

  Privacy Notice for EGA Public Website 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. 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 , or post at EMBL-EBI, Wellcome Genome Campus, CB10 1SD Hinxton, Cambridgeshire, UK. EMBL’s Data Protection Officer may be contacted by: telephone at +49 6221 387-8590, email at dpo@embl.org , or post at EMBL Heidelberg, Data protection officer, Meyerhofstraße 1, 69117 Heidelberg, Germany. You may contact CRG, whose EGA team is represented by dr. Jordi Rambla de Argila, by: email at jordi.rambla@crg.eu, or post at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), Dr.Aiguader 88, PRBB Building, 08003 Barcelona, Spain. CRG Data protection officer may be contacted by: email at dpo@crg.eu post at Fundació Centre de Regulació Genòmica - Centre for Genomic Regulation (CRG), C/ Dr. Aiguader, 88, PRBB Building, 08003 Barcelona, Spain. 2. Which is the lawful basis for processing personal data? For providing you access to the website and for offering support whilst using the website, we need your consent under Article 5 (2) of the IP 68 (equivalent to Article 6 (1)(a) of the GDPR). 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: IP addressesDate and time of a visit to the service website Operating systemAmount of data transmittedBrowserEmail address (only when support is requested by the user) The data controller will use your personal data for the following purposes: To provide the user access to the serviceTo better understand the needs of the users and guide future improvements of the serviceTo monitor website activities according to and in compliance with the Terms of UseTo better understand the needs of the website visitors and guide future improvements of the serviceTo conduct and monitor website security activitiesTo create anonymous usage statistics 4. Who will have access to your personal data? The personal data will be disclosed to: Authorised staff in the data controller’s institutions acting on data controller`s behalf and instructions. 5. Will your personal data be transferred to third countries (i.e. countries not part of EU/EEA) and/or international organisations? There are no personal data transfers to third countries or international organisations. 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.Object at any time to the processing of your personal data unless we can demonstrate that we have legitimate reasons to process your personal data.Request free of charge and without excessive delay rectification or erasure of your personal data if we have not been processing it respecting the data protection policies of the respective controllers. 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. 9. CookiesWe use cookies and similar technologies that are strictly necessary for the correct functioning and security of the EGA website (for example, to enable core site features and to help protect the service). These cookies do not store information that directly identifies you.You can set your browser to block or delete cookies. Please note that if you disable strictly necessary cookies, parts of the website may not function properly.Published on February 6, 2019

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

• Detection of Colorectal Cancer Susceptibility Loci Using Genome-Wide Sequencing

  The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) is a collaborative effort comprised of a coordinating center and scientific researchers from well-characterized cohort and case-control studies. This international consortium aims to accelerate the discovery of common and rare genetic risk variants for colorectal cancer by conducting large-scale meta-analyses of existing and newly generated genome-wide association study (GWAS) data, whole genome sequencing, replicating and fine-mapping of genetic discoveries, and investigating how genetic risk variants are modified by environmental risk factors. To expand these efforts, we assembled case-control sets or nested case-control sets from 6 different North American or European studies. Summary descriptions and study participant inclusions/exclusion criteria for each of these studies are detailed below. Cancer Prevention Study II (CPS II): The CPS II Nutrition cohort is a prospective study of cancer incidence and mortality in the United States, established in 1992 and described in detail elsewhere (Calle et al., 2002 PMID:12015775; Campbell et al., 2014 PMID:25472679). At enrollment, participants completed a mailed self-administered questionnaire including information on demographic, medical, diet, and lifestyle factors. Follow-up questionnaires to update exposure information and to ascertain newly diagnosed cancers were sent biennially starting in 1997. Reported cancers were verified through medical records, state cancer registry linkage, or death certificates. The Emory University Institutional Review Board approves all aspects of the CPS II Nutrition Cohort. We restricted to samples that had blood DNA source. Controls were matched to cases in a case/control ratio of 2:1 on reference year and sex. Darmkrebs: Chancen der Verhütung durch Screening (DACHS): This German study was initiated as a large population-based case-control study in 2003 in the Rhine-Neckar-Odenwald region (southwest region of Germany) to assess the potential of endoscopic screening for reduction of colorectal cancer risk and to investigate etiologic determinants of disease, particularly lifestyle/environmental factors and genetic factors. Cases with a first diagnosis of invasive colorectal cancer (International Classification of Diseases 10 codes C18-C20) who were at least 30 years of age (no upper age limit), German speaking, a resident in the study region, and mentally and physically able to participate in a one-hour interview, were recruited by their treating physicians either in the hospital a few days after surgery, or by mail after discharge from the hospital. Cases were confirmed based on histologic reports and hospital discharge letters following diagnosis of colorectal cancer. All hospitals treating colorectal cancer patients in the study region participated. Based on estimates from population-based cancer registries, more than 50% of all potentially eligible patients with incident colorectal cancer in the study region were included. Community-based controls were randomly selected from population registries, employing frequency matching with respect to age (5-year groups), sex, and county of residence. Controls with a history of colorectal cancer were excluded. Controls were contacted by mail and follow-up calls. The participation rate was 51%. During an in-person interview, data were collected on demographics, medical history, family history of CRC, and various life-style factors, as were blood and mouthwash samples. Routine formalin-fixed, paraffin-embedded (FFPE) tumor samples from the patients enrolled were requested from the pathology institutes and used for tumor tissue analyses. This analysis includes participants with blood source DNA that were recruited up to 2010 in this ongoing study. Controls were matched to cases on reference age and sex in a case/control ratio of 2:1. Health Professionals Follow-up Study (HPFS): A parallel prospective study to the NHS (Nurses' Health Study). The HPFS cohort comprised 51,529 men aged 40-75 who, in 1986, responded to a mailed questionnaire (Rimm et al., 1990 PMID:2090285). Participants provided information on health related exposures, including current and past smoking history, age, weight, height, diet, physical activity, aspirin use, and family history of colorectal cancer. Colorectal cancer and other outcomes were reported by participants or next-of-kin and were followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical record review. Information was abstracted on histology and primary location. Incident cases were defined as those occurring after the subject provided the blood sample. Prevalent cases were defined as those occurring after enrollment in the study but before the subject provided the blood sample. Follow-up evaluation has been excellent, with 94% of the men responding to date. Colorectal cancer cases were ascertained through January 1, 2008. In 1993-1995, 18,825 men in the HPFS mailed blood samples by overnight courier, which were aliquoted into buffy coat and stored in liquid nitrogen. In 2001-2004, 13,956 men in the HPFS who had not provided a blood sample previously mailed in a swish-and-spit sample of buccal cells. Incident cases were defined as those occurring after the subject provided a blood or buccal sample. Prevalent cases were defined as those occurring after enrollment in the study in 1986, but before the subject provided either a blood or buccal sample. Participants with histories of cancer (except nonmelanoma skin cancer), ulcerative colitis, or familial polyposis, case-control sets were excluded. Control participants were required to be free of invasive colorectal cancer and non-invasive (stage 0 in situ) colorectal cancer. For this study, only European ancestry participants with blood source DNA and incident colorectal cancer cases were eligible for selection. Since enrollment year and sex matched exactly, controls were randomly selected in a case/control ratio of 2:1. Nurses Health Study (NHS): The NHS cohort began in 1976 when 121,700 married female registered nurses age 30-55 years returned the initial questionnaire that ascertained a variety of important health-related exposures (Belanger et al., 1978 PMID:248266). Since 1976, follow-up questionnaires have been mailed every 2 years. Colorectal cancer and other outcomes were reported by participants or next-of-kin and followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical-record review. Information was abstracted on histology and primary location. The rate of follow-up evaluation has been high: as a proportion of the total possible follow-up time, follow-up evaluation has been more than 92%. Colorectal cancer cases were ascertained through June 1, 2008. In 1989-1990, 32,826 women in NHS I mailed blood samples by overnight courier, which were aliquoted into buffy coat and stored in liquid nitrogen. In 2001-2004, 29,684 women in NHS I who did not previously provide a blood sample mailed a swish-and-spit sample of buccal cells. Incident cases were defined as those occurring after the subject provided a blood or buccal sample. Prevalent cases were defined as those occurring after enrollment in the study in 1976 but before the subject provided either a blood or buccal sample. Participants with histories of cancer (except nonmelanoma skin cancer), ulcerative colitis, or familial polyposis, case-control sets were excluded. For this study, only European ancestry participants with blood source DNA and incident colorectal cancer cases were eligible for selection. Since enrollment year and sex matched exactly, controls were randomly selected in a case/control ratio of 2:1. Prostate, Lung, Colorectal and Ovarian Cancer Screening Trail (PLCO): PLCO enrolled 154,934 participants (men and women, aged between 55 and 74 years) at ten centers into a large, randomized, two-arm trial to determine the effectiveness of screening to reduce cancer mortality. Sequential blood samples were collected from participants assigned to the screening arm. Participation was 93% at the baseline blood draw. White colorectal cancer cases with a family history of colorectal cancer (no history of ulcerative colitis, Crohn's Disease, diverticulitis, Gardner's syndrome, Familial Polyposis) and successful genotyping from previous Peters GWAS were selected for this project. Controls were matched to cases on reference age and sex in a case/control ratio of 2:1. Women's Health Initiative (WHI): WHI is a long-term national health study that has focused on strategies for preventing heart disease, breast and colorectal cancer, and osteoporotic fractures in postmenopausal women. The original WHI study included 161,808 postmenopausal women enrolled between 1993 and 1998. The Fred Hutchinson Cancer Research Center in Seattle, WA serves as the WHI Clinical Coordinating Center for data collection, management, and analysis of the WHI. The WHI has two major parts: a partial factorial randomized Clinical Trial (CT) and an Observational Study (OS); both were conducted at 40 Clinical Centers nationwide. The CT enrolled 68,132 postmenopausal women between the ages of 50-79 into trials testing three prevention strategies. If eligible, women could choose to enroll in one, two, or all three of the trial components. The components are: Hormone Therapy Trials (HT): This double-blind component examined the effects of combined hormones or estrogen alone on the prevention of coronary heart disease and osteoporotic fractures, and associated risk for breast cancer. Women participating in this component with an intact uterus were randomized to estrogen plus progestin (conjugated equine estrogens [CEE], 0.625 mg/d plus medroxyprogesterone acetate [MPA] 2.5 mg/d) or a matching placebo. Women with prior hysterectomy were randomized to CEE or placebo. Both trials were stopped early, in July 2002 and March 2004, respectively, based on adverse effects. All HT participants continued to be followed without intervention until close-out. Dietary Modification Trial (DM): The Dietary Modification component evaluated the effect of a low-fat and high fruit, vegetable and grain diet on the prevention of breast and colorectal cancers and coronary heart disease. Study participants were randomized to either their usual eating pattern or a low-fat dietary pattern. Calcium/Vitamin D Trial (CaD): This double-blind component began 1 to 2 years after a woman joined one or both of the other clinical trial components. It evaluated the effect of calcium and vitamin D supplementation on the prevention of osteoporotic fractures and colorectal cancer. Women in this component were randomized to calcium (1000 mg/d) and vitamin D (400 IU/d) supplements or a matching placebo. The Observational Study (OS) examines the relationship between lifestyle, environmental, medical and molecular risk factors and specific measures of health or disease outcomes. This component involves tracking the medical history and health habits of 93,676 women not participating in the CT. Recruitment for the observational study was completed in 1998 and participants were followed annually for 8 to 12 years. All centrally confirmed White cases of invasive colorectal cancer, or death from colorectal cancer were selected as potential cases from the March, 2011 database. Case priory lists are: 1) have positive family history of colorectal cancer; 2) randomly select cases until we get a total of n=800 cases. Control participants were required to be White, free of invasive colorectal cancer and non-invasive (stage 0 in situ) colorectal cancer. Centrally denied cases of colorectal cancer were not allowed into the control pool. Case and control participants were subject to the following exclusion criteria: (1) had prior history of colorectal cancer at baseline; (2) had no available DNA (DNA searching as Nov 15, 2012); (3) cannot be deposited to dbGaP; (4) lost to follow-up after enrollment; (5) selected for WHI study M26 Phase II. Controls were matched to cases in a case/control ratio of 2:1. In order to get 2 cases with 1 control, cases were grouped by enrollment year (a total of 5 groups). For each year group, around 50% cases were selected to match controls. In total, 401 cases were selected to match controls. Matching was done on enrollment year, which was matched exactly. For additional information, see dbGaP: phs000200 and ClinicalTrials: NCT00000611.

  Study phs001554

• eMERGE Network Phase III Clinical Sequencing: eMERGEseq Panel

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

  Study phs001616

• How to upload Crypt4GH files

  Uploading files Users who hold an ega-box-XXX account can upload files using either INBOX or FTP. Users who have a Submitter role associated with their email will only be able to upload files using INBOX. Before uploading your files, please make sure that any files that will be uploaded to EGA do not use special characters in their naming convention, such as # ? ( ) [ ] / \ = + < > : ; " ' , * ^ | &. This can cause issues with the archiving process, leading to problems for end users. The EGA is a shared, public service with limited storage. To manage the available resources, we enforce a limit of 10TB per submission account at any one time. If you exceed this limit, a “permission denied” message will be displayed. This will prevent you from uploading more files, but connecting to your inbox.For submissions larger than 10TB, please perform uploads in 10TB batches: register all the metadata and then finalise the submission. Upload the next batch of files and repeat the same metadata registration and finalisation process until you have completed the file upload. Further information can be found in the SP documentation. INBOX FTP The INBOX is only compatible with files encrypted using the Crypt4gh tool Before uploading If you are not a registered EGA user, you will first need an EGA user account. Please note that it may take a few days for your account to be activated, as it needs to be vouched for by the EGA Helpdesk. Once your account is validated, you will be able to request a submitter role. [Optional] Meanwhile, you can create and add your public key to your EGA account profile. This option is not available for old submission accounts (e.g., ega-box-NNN). As soon as you have been granted a submitter role, you will be able to connect with your username and password to the EGA inbox using the SFTP protocol. If you have also registered a public key in your profile, you can also connect using this key. To upload files to your account, you can use the graphical user interface (GUI) or the command line. Graphical User Interface (GUI)We recommend using FileZilla, a free, open-source FTP client. However, you can use any other GUI that allows connecting over the SFTP protocol. For FileZilla as your GUI, follow these steps to upload files: Create a new connection in Site Manager (File > Site Manager) and select the following options (Figure 1): Protocol: SFTP - SSH File Transfer ProtocolHost: __EGA_INBOX_DOMAIN__Logon Type: Key fileUser: your EGA usernameKey file: Path/to/your/private_keyFigure 1: Process of establishing a new connection to __EGA_INBOX_DOMAIN__ using a key file as the logon method in FileZilla. The figure showcases the FileZilla version 3.52.2 operating on IOS v11.2.3. By following the depicted steps, users can create a secure and efficient connection to the inbox, ensuring seamless data transfers.Click Connect, and you will log in remotely to your home directory. You can think of this folder as a storage "in the EGA cloud" in which you will add your files for the EGA. The uploading area has three folders:To-encrypt: Files uploaded in this folder will be encrypted automatically on the fly.Encrypted: Files uploaded in this folder must already be encrypted with Crypt4gh. Upload your files here if your connection is unstable or you have problems completing the upload into-encrypt.Etc: This folder contains two files that allow the server to show you your username and group instead of some internal numbers. Please do not upload files here; otherwise, you will obtain a permission denied error. Find the files you want to upload by browsing your local storage (left side of your screen in FileZilla). Select all the files you want to upload, then right-click on them and select Upload (Figure 2). Figure 2: Step-by-step process of manually uploading files to __EGA_INBOX_DOMAIN__ using FileZilla, with FileZilla version 3.52.2 operating on IOS v11.2.3. The figure demonstrates how users can transfer data from their local storage to the "EGA cloud" by following the depicted steps Please note that regardless of which folder you upload your files in, both folders (to-encrypt, encrypted) will point to the same path (/) (Figure 3). Therefore, you will see your files in both folders. Figure 3: Both folders, to-encrypt and encrypted, point to the same path (/)" If your connection is unstable, please encrypt your files first using Crypt4gh. Then upload them to the ‘encrypted’ folder. The example above shows how to connect to __EGA_INBOX_DOMAIN__ using the private key. However, if you prefer to log in using your credentials, you can do so. Please go to the Frequently Asked Questions (FAQs)  for more information. SFTP command line To upload files securely to your private area of the EGA, you can use SFTP(Secure File Transfer Protocol) with your favorite FTP client. Here's what you need to know to get started: Connect to the target host __EGA_INBOX_DOMAIN__. This is the new hostname for the EGA SFTP service. Log in with your EGA username and key files (or password). Upload files to your private EGA inbox to ensure that only you can access the files. By following these steps, you can securely upload your files to the EGA for safe storage and sharing. Using the SFTP command line client in Linux/Unix Open a terminal and type sftp username@hostnameEnter your EGA passwordTo see a list of available SFTP commands, type helpsftp> put – Upload filesftp> get – Download filesftp> cd path – Change remote directory to ‘path’sftp> pwd – Display remote working directorysftp> lcd path – Change the local directory to ‘path’sftp> lpwd – Display local working directorysftp> ls – Display the contents of the remote working directorysftp> lls – Display the contents of the local working directoryType the "put" command to upload files. For example: put *.bamUse the bye command to close the connection (SFTP session). After uploading- Once you have uploaded files to the inbox, please bear in mind that the checksum needs to be calculated, which can take up to two days. You will only be able to link your files to a run/analysis once the encrypted checksum has been calculated.- When linking your files to the 'Run' or 'Analysis', ensure that the file name matches the file path '/name' in the INBOX folder.- Please delete the files from your SFTP INBOX after all the runs/analyses have been registered and files are ingested (SP > Files > Files ingested). This will clear your inbox space an allow you to upload more files. This will also prevent the files from reappearing in your Submitter Portal inbox. Frequently Asked Questions Specific to the inbox What username should I use to log in to my inbox? The authentication process for logging in to the EGA website, as well as accessing your inbox and outbox, requires the use of your username.  If you have forgotten your registered username, please contact our Helpdesk team for assistance. How are checksums calculated in your inbox? If you encrypt the file beforehand and upload it to the "encrypted" folder, the unencrypted checksum will not be calculated until the file is ingested (i.e., until it is used in a run/analysis). If the file is uploaded to the "to-encrypt" folder, then both checksums are calculated.Please bear in mind that after files have been uploaded to the inbox, the checksum must be calculated, which can take from a few hours to two days.  Specific to using keys to authenticate Can I access one EGA account from different devices? Yes, you can access your account from different devices by linking several public keys to your EGA account. Each device can generate a unique public-private key pair, and the corresponding public keys can be linked to the same account. This way, you can use different public keys on different devices and still have access to the same account and data. I have several keys and I don't remember which one is which When generating SSH keys, it's a good practice to add a comment using the -C flag. This will allow you to add a descriptive tag to your key, making it easier to identify later on. Here's an example command that generates an SSH key with a comment: ssh-keygen -t ed25519 -C work-pass In this example, we're generating an ed25519 SSH key with the comment work-pass. Once you have multiple keys with different comments, you can use the comments to easily identify each key. To view the comments for your existing SSH keys, you can use the following command: ssh-keygen -l -f /path/to/key This will display the key fingerprint and the associated comment. By checking the comments, you should be able to identify which key is which. What if I can't find my SSH keys for uploading files with a key file, and how can I use new keys? If you can't find your SSH keys, don't worry - you can make new ones. To do this, open your terminal or command prompt and type a command to make a new SSH key. You can pick a name for the key, and choose a password to keep it safe. After making the key, you can add the new key to your account or server where you want to upload files using the key file. This usually involves copying and pasting the key's "public" (e.g. file.pub) part to the right place. If you lose track of the key again, just make a new one and add it again. Keep in mind that SSH keys belong to you and your computer, so if you switch computers or accounts, you'll need to make new keys. I don't want to type the passphrase every time I use the key. What can I do? You can use an ssh-agent to avoid typing the passphrase every time you use the key. An ssh-agent is a program that stores your private keys in memory and provides them to ssh when needed. You can add your key to the ssh-agent using the command ssh-add followed by the path to your key file.Here's an example of the steps to follow: Open a terminal window.Start the ssh-agent by typing the command eval $(ssh-agent).Add your key to the ssh-agent by typing the command ssh-add [key filepath]. For instance, if your key file is located in the home directory with the name mykey, the command will look like this: ssh-add ~/mykey After adding your, key to the ssh-agent, you should be able to use ssh without having to enter your passphrase every time. Can I use my password for authentication (without my private key)? If you prefer to use your username and password for authentication instead of your private key, you can still do so. When using a Graphical User Interface (GUI) such as FileZilla, you can select Ask for password as your Logon Type (Figure 3). This option will prompt you to enter your password when you click Connect, instead of using your private key. Figure 3: This option will prompt you to enter your password when you click "Connect", instead of using your private key. Figure 3: Process of establishing a new connection to __EGA_INBOX_DOMAIN__ using your password as the logon method in FileZilla. The figure showcases the FileZilla version 3.52.2 operating on IOS v11.2.3. By following the depicted steps, users can create a secure and efficient connection to the inbox, ensuring seamless data transfers. It's worth noting that using a password for authentication can be less secure than using an SSH key, as passwords can be more easily compromised through various means. However, if you choose to use your password for authentication, selecting "Ask for password" as your Logon Type is a good way to do so securely via a GUI. Why is it better to use my key and not my password? SSH keys for authentication is generally considered to be more secure and convenient than using passwords. SSH keys are more difficult to crack than passwords, and they can be restricted to specific users and machines, giving you more control over access. Once you set up your SSH keys, you can use them to authenticate quickly and easily, without having to enter a password every time. This makes automation of tasks, such as uploading encrypted files, much simpler. Additionally, SSH keys provide better logging, allowing you to keep track of who is accessing your systems and when. All in all, using SSH keys is a good practice for improving security and convenience in your authentication process.

  Documentation submission/data/uploading-files/inbox

• 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

• Childhood Cancer Survivor Study (CCSS)

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

  Study phs001327

• Molecular Genetic Studies of Developmental Brain Disorders

  Study 1 2R01-NS050375 (PI: DOBYNS, William B.) The genetic basis of mid-hindbrain malformations Our general goal for this project is to advance our understanding of human developmental disorders that involve the brainstem and cerebellum - brain structures derived from the embryonic midbrain and hindbrain - that affect a minimum of 2.4 per 1000 resident births based on data from the CDC. Importantly, this large class of disorders co-occurs with more common developmental disorders such as autism, mental retardation and some forms of infantile epilepsy, and shares some of the same causes. With this renewal, we propose to expand the scope of our work beyond single phenotypes and genes to focus on delineating the critical phenotype spectra to which the most common MHM belong, and defining the underlying biological networks that are disrupted. To pursue these goals, we will use our large and growing cohort of human subjects to map additional MHM loci using SNP microarrays that provide both high-resolution autozygosity and linkage data in informative families as well as detect critical copy number variants in sporadic subjects. The causative genes will be identified using traditional Sanger or new high-throughput sequencing methods as appropriate abased on size of the critical region. We will use these and other known MHM causative genes to construct and revise model biological networks of genes and proteins, and test these genes and networks in additional patients as a candidate gene or more accurately a candidate network approach. These approaches need to be supported by ongoing active subject recruitment, as studies of comparable disorders such as mental retardation and autism have benefited from even larger numbers of subjects that we have so far collected. We need to use new high-throughput sequencing methods to more efficiently test larger critical regions, and to test entire gene networks rather than individual genes in matched cohorts of subjects. At every step; phenotype analysis, CNV analysis, model network construction and high-throughput sequencing, we will need expanded bioinformatics capabilities. Finally, we need to test the biological function of new genes and networks to support our gene identification studies. We expect that these studies will contribute immediately to more accurate diagnosis and counseling, and over time will lead to development of specific treatments for a subset of these disorders. We further expect that studies of mid-hindbrain development will have broad significance for human developmental disorders generally, providing compelling evidence for a connection between cerebellar development and other classes of developmental disorders such as autism, mental retardation and epilepsy. Study 2 R01-NS058721 (PI: DOBYNS, William B.) De novo copy number variation and gene discovery in human brain malformations Project Summary/Abstract The number of recognized brain malformations and syndromes has grown rapidly during the past several decades, yet relatively few causative genes have been identified, especially for three common malformations that have been associated with numerous cytogenetically visible chromosome deletions and duplications, and that often occur together: agenesis of the corpus callosum (ACC), cerebellar vermis hypoplasia (CVH) including Dandy-Walker malformation (DWM), and polymicrogyria (PMG). We propose to perform high-resolution array comparative genome hybridization (aCGH), emerging technology able to detect small copy number variants (CNV), in 700 probands with one or more of these three malformations. Our central hypothesis states that more than 10% of patients with ACC, CVH or PMG will have de novo CNV below the resolution of routine cytogenetic analysis, but detectable by current array platforms. We therefore expect to identify 70-100 patients with small CNV. We will distinguish CNV found in normal individuals from potentially disease-associated changes, and will confirm CNV using fluorescence in situ hybridization (FISH) and microsatellite (STRP) analysis. We will give highest priority to CNV that are de novo and involve 2 or more BACs, and secondary priority to familial and smaller CNV excluding known polymorphisms. After that, we will evaluate and rank candidate genes in the critical regions using information from public databases and our own expression studies, and perform mutation analysis of the best candidate genes from well-defined critical regions by sequencing in a large panel of subjects with phenotypes that match the phenotypes of the patients whose CNV define the critical regions. Here, we will use more refined criteria to supplement our clinical classification, such as the developmental level and presence of epilepsy or other birth defects. Any abnormalities found will be analyzed using existing data regarding polymorphisms (i.e. dbSNP), cross-species comparisons, and functional assays appropriate for the specific sequence change. Study 2A In 1995, we described a novel multiple congenital anomaly syndrome associated with facial dysmorphism (congenital ptosis, high arched eyebrows, shallow orbits, trigonocephaly), colobomas of the eyes, neuronal migration malformation (frontal predominant lissencephaly) and variable hearing loss. We hypothesized from de novo mutations and used trio-based exome sequencing to identify de novo mutations in the ACTB and ACTG1 genes. Study 2B In 1997 and 2004, we and others defined two novel developmental syndromes associated with markedly enlarged brain size, or megalencephaly, and other highly recognizable features. The megalencephaly-capillary malformation syndrome (MCAP) consists of megalencephaly and associated growth dysregulation with variable asymmetry, developmental vascular anomalies, distal limb malformations, variable cortical malformation, and a mild connective tissue dysplasia. The megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) resembles MCAP but lacks vascular malformations and syndactyly. We hypothesized that MCAP and MPPH result from mutations - including postzygotic events - in the same pathway, and studied them together. Using a combination of exome sequencing, Sanger sequencing, restriction-enzyme assays, and targeted ultra-deep sequencing in 50 families with MCAP or MPPH, we identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol-3-kinase/AKT pathway. These include two mutations in AKT3, a recurrent mutation in PIK3R2, and multiple mostly postzygotic mutations in PIK3CA (Rivi&#232;re JB, Mirzaa GM, O&#39;Roak BJ, Beddaoui M, Alcantara D, Conway RL, St-Onge J, Schwartzentruber JA, Gripp KW, Nikkel SM, Worthylake T, Sullivan CT, Ward TR, Butler HE, Kramer NA, Albrecht B, Armour CM, Armstrong L, Caluseriu O, Cytrynbaum C, Drolet BA, Innes AM, Lauzon JL, Lin AE, Mancini GMS, Meschino WS, Reggin JD, Saggar AK, Lerman-Sagie T, Uyanik G, Weksberg R, Zirn B, Beaulieu CL, FORGE Canada Consortium, Majewski J, Bulman DE, O&#39;Driscoll M, Shendure J, Graham Jr. JM, Boycott KM, Dobyns WB. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat. Genet. In press). Study 3 2R01-NS046616 (PI: GOLDEN, Jeffrey A) The role of ARX in normal and abnormal brain development This subcontract from the Children&#39;s Hospital of Philadelphia to the University of Chicago (UC) is intended to support research studies of the ARX and functionally related genes in human subjects with any one of several specific developmental disorders. The Co-investigator at UC (W.B. Dobyns) will identify a series of patients with mental retardation and severe infantile epilepsy, some of whom will have specific brain malformations and others who will have normal brain structure by brain imaging studies, and collect research samples from these subjects with informed consent. The studies to be performed will include mutation analysis of ARX, mutation analysis of specific downstream target genes, X inactivation studies in humans and X inactivation studies in mutant mice. The results will be analyzed to determine the significance of any changes found in the gene.

  Study phs000455

• How to upload GPG files

  Uploading files Users that holds an ega-box-XXX account can upload files using either INBOX or FTP. Users who have a Submitter role associated with their email will only be able to upload files using INBOX. Before uploading your files please make sure that any files that will be uploaded to EGA do not use special characters in their naming convention such as # ? ( ) [ ] / \ = + < > : ; " ' , * ^ | &. This can cause issues with the archiving process, leading to problems for end users. The EGA is a shared, public service with limited storage. In order to manage the available resources, we enforce a limit of 10Tb per submission account at any one time. Please do not exceed this limit. INBOX FTP The FTP is only compatible with files encrypted using the EGACryptor tool Before uploading Once your submission files have been prepared using the EGAryptor, the resulting encrypted files and associated md5sum files can be uploaded to your submission account using Aspera or FTP. The EGA is a shared, public service with limited resources. In order to manage the available resources, EGA submission boxes should not exceed 8Tb in size, and cannot exceed 12Tb. If you are approaching this limit please contact contact EGA Helpdesk so that we can advise on how to register the associated metadata and trigger the archiving of files, so that you can continue with your submission. If we note that your submission account increases above 10Tb on a consistent base your password will be changed until metadata is associated. Aspera Download Aspera Using Aspera FTP FTP windows FTP Linux / Unix FTP client (Filezilla) FTP and TLS Troubleshooting Troubleshooting Aspera Download Aspera is a commercial file transfer protocol that may provide faster transfer speeds than ftp especially over longer distances. The Aspera ascp command line client. Please select Aspera Connect. The ascp command line client is distributed as part of the aspera connect highperformance transfer browser plugin and is free to use, without registration. The minimum required version of the IBM Aspera Cli is V4. Further instructions. Using the Aspera ascp command line program The location of the ascp program in the filesystem: Mac: on the desktop go cd /Applications/Aspera\ Connect.app/Contents/Resources/ there you'll see the command line utilities where you're going to use ascp. Windows: the downloaded files are a bit hidden. For instance, in Windows 7 the ascp.exe is located in the users home directory in: AppData\Local\Programs\Aspera\Aspera Connect\bin\ascp.exe Linux: should be in your user's home directory, cd /home/username/.aspera/connect/bin/ there you'll see the command line utilities where you're going to use ascp. Your command should look similar to this: ascp -P33001 -O33001 -QT -l300M -L- /path/file ega-box-N@fasp.ega.ebi.ac.uk:/path If you wish to upload several files without being requested the password, please use the below command : ASPERA_SCP_PASS=ega-box-password ascp -P33001 -O33001 -QT -l300M /path/file ega-box-N@fasp.ega.ebi.ac.uk:/path/ Explanation of parameters l300M option sets the upload speed limit to 30MB/s. You may wish to lower this value to increase the reliability of the transfer. L option is for printing logs out while transferring files to upload can be a file mask (e.g. '/homes/submitter/*.srf) or a list of files. ega-box-N is your submission account login. Add k2 switch for transfer restarts Check the command line transfer usage for more configuration details. Using FTP to upload your prepared files Use your preferred ftp client. For example, lftp is a popular choice for Linux and Mac users. Use binary mode for file transfers. Use ftp.ega.ebi.ac.uk as the target host. Login with your ega-box username and password. Upload files to your private ega-box upload area. Depending on your network setting you might wish to start FTP in passive or active mode. Using default FTP command line client in Windows Start the command line interpreter: press WinR, type cmd, hit enter Enter ftp ftp.ega.ebi.ac.uk Enter your submission username Enter your submission password Type binary to enter binary mode for transfer To see a list of available ftp commands type help. Type ls command to check the content of your submission account. Type prompt to switch off confirmation for each file uploaded. Use mput command to upload files: mput *.bam* Use bye command to exit the ftp client. Use exit command to exit the command line interpreter. Using default FTP command line client in Linux / Unix Open a terminal and type ftp ftp.ega.ebi.ac.uk Enter your submission username Enter your submission password Type binary to enter binary mode for transfer To see a list of available ftp commands type help. Type ls command to check the content of your submission account. Type prompt to switch off confirmation for each file uploaded. Use mput command to upload files: mput *.bam* Use bye command to exit the ftp client. Using FTP client FileZilla We recommend the use of FileZilla, a free FTP client . FileZilla is open source software distributed free of charge under the terms of the GNU General Public License. Use the following connection details (File - Site Manager) and add yoursubmission account username and password: Using FTP client FileZilla Select the files you wish to upload and then select upload: Using FTP client Filezilla Using LFTP with TLS We recommend the following to force the use of a secure connection. lftp > set ftp:ssl-force yes We also recommend setting the following for not encrypting the bulk data itself for performance reasons (theauthentication will still be encrypted): lftp > ftp:ssl-protect-data no In order to verify the certificate,the recommended way would be to use the CA certificates from your machine. To do that use this command in lftp adjusting the path to your ca-certificates location. lftp > ssl:ca-file "/etc/ssl/certs/ca-certificates.crt" If that is not possible or certificates are old and you can't update them, you can download the certificates needed from Quo Vadis Digital Repository The two certificates to download in PEM format are: QuoVadis Root CA2 G3 QuoVadis EV SSL ICA G3 Then you can concatenate them in a file one after the other and save it as lftp-certificates.pem Once this is done you have to point the ssl:ca-file variable to the path lftp > set ssl:ca-file "/path/to/lftp-certificates.pem" Also note that you can save this configuration at ~/.lftp/rc Another option is to download the certificates and add them to the ca-certificates of your machine. For example: In RHEL7 and cenots and others box the process to add the certificates globally is: Download the two certificates (in PEM or DER format, doesn't matter) and save them to "/etc/pki/ca-trust/source/anchors/" Run "update-ca-trust extract" Another less secure option is to turn off certificate verification with the following command: lftp > set ssl:verify-certificate false Troubleshooting If you are having problems with Aspera connection timeouts, it can be down to either one of the following. Transfers cannot start the connection fails instantly. Ensure that TCP traffic on port 33001 is allowed (open) for outbound connections through your computer's firewall and network's firewall. The connection is made, transfers are started, but 0 bytes (0%) are uploaded for each file. Ensure that UDP traffic on port 33001 is allowed (open) for outbound connections through your computer's firewall and network's firewal

  Documentation submission/data/uploading-files/ftp

• eMERGE Network Imputed GWAS for 41 Phenotypes

  The electronic Medical Records and Genomics (eMERGE) Network is a consortium of ten participating sites (Cincinnati Children&#39;s Hospital Medical Center/Boston Children&#39;s Hospital, Children&#39;s Hospital of Philadelphia, Essentia Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University, Geisinger Clinic, Group Health Cooperative/University of Washington, Mayo Clinic, Icahn School of Medicine at Mount Sinai, Northwestern University, Vanderbilt University Medical Center) funded by the NHGRI to investigate the use of electronic medical record (EMR) systems for genomic research. The goal of eMERGE is to conduct genome-wide association studies in approximately 55,000 individuals using EMR-derived phenotypes and DNA from linked Biorepositories. Using electronic phenotyping methods, the consortium used DNA samples from all participating sites to explore the genetic determinants of over forty phenotypes, including 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, as well as using the phenome-wide association study (PheWAS) paradigm to replicate and discover relationships between targeted genotypes with multiple phenotypes. Sites and participants include: 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 medical records (EMRs). EMRs 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) and Boston Children&#39;s Hospital (BCH) are pediatric institutions dedicated to improving health and welfare of children and to the shared purpose of discovery and practical application of new genomic information to the ordinary care of children. The CCHMC/BCH site has been built on a five-year history of collaboration, particularly in patient electronic record (ERM)-related informatics, the basis of much of eMERGE II. CCHMC and BCH together bring an extraordinary faculty to eMERGE II who are committed to diseases that afflict children, specifically phenotypes that focus upon diseases of children in ways that will leverage the available eMERGE adult GWAS and EMRs to discover meaningful use results. CCHMC/BCH plans to demonstrate real-time execution of phenotypic selection across their two distinct pediatric institutions as a model for ensuring phenotypic standardization and for national scalability. They will also look carefully at parents&#39; responses to results and use of their children&#39;s research results and better understand the factors that influence their decisions about learning incidental findings. In addition to patient and parent perceptions CCHMC/BCH will also explore clinician perceptions of pharmacogenetic research results after EMR integration. 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. Group Health(GH)/University of Washington (UW): GH participants for the PGx project 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~6300.) Participants were eligible if aged 50 - 65 years old at the time of their enrollment into the NWIGM repository, living, enrolled in GH&#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 Group Health: 1. Demographics - participants with self-reported race as Asian or African ancestry were prioritized and selected to enrich for non-European ancestry; 2. Diagnosis and procedure codes - participants were selected if found to have a history of hypertension, atrial fibrillation (AF), or congestive heart failure (CHF). Participants with a history of arrhythmia were added if the entire selection algorithm did not generate 900 individuals. We also enriched for participants with EHR evidence of actionable indications related to PGRNSeq genes. Participants were selected if found to have an ICD9 code for malignant hyperthermia, hypertension, atrial fibrillation, congestive heart failure or long QT syndrome (LQTS); 3. Laboratory values - if participants had any laboratory event of creatine kinase (CK) &#62;1000, and were dispensed statins within 6 months of the event, then they were selected; and 4. Medications - participants were excluded if ever on carbamazepine or had a current regimen of warfarin. 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 biobank 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. 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: BioVU, Vanderbilt&#39;s DNA databank, is an enabling resource for exploration of the relationships among genetic variation, disease susceptibility, and variable drug responses, and represents a key first step in moving the emerging sciences of genomics and pharmacogenomics from research tools to clinical practice. 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.

  Study phs000888

• Uncovering the Genetic Architecture of Colorectal Cancer with Focus of Rare and Less Frequent Variants

  The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) is a collaborative effort comprised of a coordinating center and scientific researchers from well-characterized cohort and case-control studies conducted in North America and Europe. This international consortium aims to accelerate the discovery of common and rare genetic risk variants for colorectal cancer by conducting large-scale meta-analyses of existing and newly generated genome-wide association study (GWAS) data, replicating and fine-mapping of GWAS discoveries, and investigating how genetic risk variants are modified by environmental risk factors. To expand these efforts, we assembled case-control sets or nested case-control sets from 20 different North American or European studies. Summary descriptions and study participant inclusions/exclusion criteria for each of these studies are detailed below. The Black Women&#39;s Health Study (BWHS): Is the largest follow-up study of the health of African-American women (Cozier et al., 2004; Rosenberg et al., 1995) [PMID: 15018884; PMID: 7722208]. The purpose is to identify and evaluate causes and preventives of cancers and other serious illnesses in African-American women. Among the diseases being studied are breast cancer, colorectal cancer, type 2 diabetes, uterine fibroids, systemic lupus erythematosus, and cardiovascular disease. The study began in 1995, when 59,000 black women from all parts of the United States enrolled through postal questionnaires. The women provided demographic and health data on the 1995 baseline questionnaire, including information on weight, height, smoking, drinking, contraceptive use, use of other selected medications, illnesses, reproductive history, physical activity, diet, use of health care, and other factors. The participants are followed through biennial questionnaires to determine the occurrence of cancers and other illnesses and to update information on risk factors. Self-reports of cancer are confirmed through medical records and state cancer registry records. Mouthwash-swish samples, as a source of DNA, were obtained from &#126;26,000 BWHS participants in 2002-2007. DNA was isolated from the mouthwash-swish samples at the Boston University Molecular Core Genetics Laboratory using the QIAAMP DNA Mini Kit (Qiagen). All incident colorectal cancer cases with a DNA sample were included in the present analysis. Two controls per case, selected from among BWHS participants free of colorectal cancer at end of follow-up, were matched to cases on year of birth (&#43;/- 2 years) and geographical region of residence (Northeast, South, Midwest, and West). A total 209 colorectal cancer cases and 423 controls were sent for genotyping. Campaign Against Cancer and Heart Disease (CLUE II): The Campaign Against Cancer and Heart Disease, is a prospective cohort designed to identify biomarkers and other factors associated with risk of cancer, heart disease, and other conditions (Kakourou et al., 2015) [PMID: 26220152]. 32,894 participants were recruited from May through October 1989 from Washington County, Maryland and surrounding communities. Colorectal cancer cases (n &#61; 297) and matched controls (n &#61; 296) were identified between 1989 and 2000 among participants in the CLUE II cohort of Washington County, Maryland. Colorectal Cancer Study of Austria (CORSA): In the ongoing colorectal cancer study of Austria (CORSA), more than 13,000 Caucasian participants have been recruited within the province-wide screening project &#34;Burgenland Prevention Trial of Colorectal Disease with Immunological Testing&#34; (B-PREDICT) since 2003 (Hofer et al., 2011) [PMID: 21422235]. All inhabitants of the Austrian province Burgenland aged between 40 and 80 years are annually invited to participate in fecal immunochemical testing and haemoccult positive screening participants are invited for colonoscopy. CORSA includes genomic DNA and plasma of colorectal cancer cases, low-risk and high-risk adenomas, and colonoscopy-negative controls. Controls received a complete colonoscopy and were free of colorectal cancer or polyps. CORSA participants have been recruited in the four KRAGES hospitals in Burgenland, Austria, and additionally, at the Medical University of Vienna (Department of Surgery), the Viennese hospitals &#34;Rudolfstiftung&#34; and the &#34;Sozialmedizinisches Zentrum Sud&#34;, and at the Medical University of Graz (Department of Internal Medicine). 1403 colorectal cancer and advanced colorectal adenoma cases, and 1404 matched controls were selected for the study. Distribution of factors sex and age (5 year strata) were evenly matched between cases and controls. Cancer Prevention Study II (CPS II): The CPS II Nutrition cohort is a prospective study of cancer incidence and mortality in the United States, established in 1992 and described in detail elsewhere (Calle et al., 2002; Campbell et al., 2014) [PMID: 12015775; PMID: 25472679]. At enrollment, participants completed a mailed self-administered questionnaire including information on demographic, medical, diet, and lifestyle factors. Follow-up questionnaires to update exposure information and to ascertain newly diagnosed cancers were sent biennially starting in 1997. Reported cancers were verified through medical records, state cancer registry linkage, or death certificates. The Emory University Institutional Review Board approves all aspects of the CPS II Nutrition Cohort. A total of 360 cases and 359 controls were selected for this study. Czech Republic Colorectal Cancer Study (Czech Republic CCS): Cases with positive colonoscopy results for malignancy, confirmed by histology as colon or rectal carcinomas, were recruited between September 2003 and May 2012 in several oncological departments in the Czech Republic (Prague, Pilsen, Benesov, Brno, Liberec, Ples, Pribram, Usti and Labem, and Zlin). Two control groups, sampled at the same time of cases recruitment, were included in the study. The first group consisted of hospital-based individuals with a negative colonoscopy result for malignancy or idiopathic bowel diseases. The reasons for the colonoscopy were: i) positive fecal occult blood test, ii) hemorrhoids, iii) abdominal pain of unknown origin, and iv) macroscopic bleeding. The second control group consisted of healthy blood donor volunteers from a blood donor center in Prague. All individuals were subjected to standard examinations to verify the health status for blood donation and were cancer-free at the time of the sampling. Details of CRC cases and controls have been reported previously (Vymetalkova et al., 2014; Naccarati et al., 2016; Vymetalkova et al., 2016) [PMID: 24755277; PMID: 26735576; PMID: 27803053]. All subjects were informed and provided written consent to participate in the study. They approved the use of their biological samples for genetic analyses, according to the Declaration of Helsinki. The design of the study was approved by the Ethics Committee of the Institute of Experimental Medicine, Prague, Czech Republic. All subjects included in the study were Caucasians and comprised 1792 cases and 1764 matched controls. Controls were matched to CRC cases as 1&#58;1 ratio. Matching was done on age and sex. Age was matched on &#43;&#45;5 years, whereas sex was matched exactly. For the cases without matched controls, matching was done only on sex. Early Detection Research Network (EDRN): The aim of the EDRN initiative is to develop and sustain a biorepository for support of translational research (Amin et al., 2010) [PMID: 21031013]. High-quality biospecimens were accrued and annotated with pertinent clinical, epidemiologic, molecular and genomic information. A user-friendly annotation tool and query tool was developed for this purpose. The various components of this annotation tool include: CDEs are developed from the College of American Pathologists (CAP) Cancer Checklists and North American Association of Central Cancer Registries (NAACR) standards. The CDEs provides semantic and syntactic interoperability of the data sets by describing them in the form of metadata or data descriptor. A total of 352 colorectal case samples and 399 controls were selected for this study. Controls were matched to CRC cases based on age and sex. The EPICOLON Consortium (EPICOLON): The EPICOLON Consortium comprises a prospective, multicentre and population-based epidemiology survey of the incidence and features of CRC in the Spanish population (Fernandez-Rozadilla et al., 2013) [PMID: 23350875]. Cases were selected as patients with de novo histologically confirmed diagnosis of colorectal adenocarcinoma. Patients with familial adenomatous polyposis, Lynch syndrome or inflammatory bowel disease-related CRC, and cases where patients or family refused to participate in the study were excluded. Hospital-based controls were recruited through the blood collection unit of each hospital, together with cases. All of the controls were confirmed to have no history of cancer or other neoplasm and no reported family history of CRC. Controls were randomly selected and matched with cases for hospital, sex and age (&#43;&#45; 5 years). A total of 370 cases and 370 controls were selected for genotyping. Hawaii Adenoma Study: For this adenoma study, two flexible-sigmoidoscopy screening clinics were first used to recruit participants on Oahu, Hawaii. Adenoma cases were identified either from the baseline examination at the Hawaii site of the Prostate Lung Colorectal and Ovarian cancer screening trial during 1996-2000 or at the Kaiser Permanente Hawaii&#39;s Gastroenterology Screening Clinic during 1995-2007. In addition, starting in 2002 and up to 2007, we also approached for recruitment all eligible patients who underwent a colonoscopy in the Kaiser Permanente Hawaii Gastroenterology Department. Cases were patients with histologically confirmed first-time adenoma(s) of the colorectum and were of Japanese, Caucasian or Hawaiian race&#47;ethnicity. Controls were selected among patients with a normal colorectum and were individually matched to the cases on age at exam, sex, race/ethnicity, screening date (&#43;&#45;3 months) and clinic and type of examination (colonoscopy or flexible sigmoidoscopy). We recruited 1016 adenoma cases (67.8% of all eligible) and 1355 controls (69.2% of all eligible); 889 cases and 1169 controls agreed to give a blood and 29 cases and 34 controls, a mouthwash sample. A total of 989 cases and 1185 controls were genotyped for this study. Columbus-area HNPCC Study (HNPCC, OSUMC): Patients with colorectal adenocarcinoma diagnosed at six participating hospitals were eligible for this study, regardless of age at diagnosis or family history of cancer. Patients with a clinical diagnosis of familial adenomatous polyposis were not eligible for this study. These six hospitals perform the vast majority of all operations for CRC in the Columbus metropolitan area (population 1.7 million). The institutional review board at all participating hospitals approved the research protocol and consent form in accordance with assurances filed with and approved by the United States Department of Health and Human Services. Briefly, during the period of January 1999 through August 2004, 1,566 eligible patients with CRC were accrued to the study (Hampel et al., 2008) [PMID 18809606]. A total of 1472 colorectal cancer samples had enough blood DNA remaining to be sent for genotyping. Control samples were provided by the Ohio State University Medical Center%#39;s (OSUMC) Human Genetics Sample Bank. The Columbus Area Controls Sample Bank is a collection of control samples for use in human genetics research that includes both donors&#39; anonymized biological specimens and linked phenotypic data. The data and samples are collected under the protocol &#34;Collection and Storage of Controls for Genetics Research Studies&#34;, which is approved by the Biomedical Sciences Institutional Review Board at OSUMC. Recruitment takes place in OSUMC primary care and internal medicine clinics. If individuals agree to participate, they provide written informed consent, complete a questionnaire that includes demographic, medical and family history information, and donate a blood sample. 4-7 ml of blood is drawn into each of 3 ACD Solution A tubes and is used for genomic DNA extraction and the establishment of an EBV-transformed lymphoblastoid cell culture, cell pellet in Trizol, and plasma. Controls were matched to CRC cases as 1&#58;1. Matching was done on age at reference time (age_ref), race, and sex. Age_ref was matched on &#43;&#45;5 years. Sex and race were matched exactly. For the cases without matched controls, matching was done only on sex and race with 1&#58;1 ratio. Since controls are fewer than cases, one control is matched on 2 cases at most. Health Professionals Follow-up Study (HPFS): A parallel prospective study to the NHS (Nurses&#39; Health Study). The HPFS cohort comprised 51,529 men aged 40-75 who, in 1986, responded to a mailed questionnaire (Rimm et al., 1990) [PMID: 2090285]. Participants provided information on health related exposures, including current and past smoking history, age, weight, height, diet, physical activity, aspirin use, and family history of colorectal cancer. Colorectal cancer and other outcomes were reported by participants or next-of-kin and were followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical record review. Information was abstracted on histology and primary location. Incident cases were defined as those occurring after the subject provided the blood sample. Prevalent cases were defined as those occurring after enrollment in the study but before the subject provided the blood sample. Follow-up evaluation has been excellent, with 94% of the men responding to date. Colorectal cancer cases were ascertained through January 1, 2008. In 1993-1995, 18,825 men in the HPFS mailed blood samples by overnight courier, which were aliquoted into buffy coat and stored in liquid nitrogen. In 2001-2004, 13,956 men in the HPFS who had not provided a blood sample previously mailed in a swish-and-spit sample of buccal cells. Incident cases were defined as those occurring after the subject provided a blood or buccal sample. Prevalent cases were defined as those occurring after enrollment in the study in 1986, but before the subject provided either a blood or buccal sample. After excluding participants with histories of cancer (except nonmelanoma skin cancer), ulcerative colitis, or familial polyposis, case-control sets were previously constructed. In addition to colorectal cancer cases and controls, a set of adenoma cases and matched controls with available DNA from buffy coat were selected for genotyping. Over the follow-up period, data were collected on endoscopic screening practices and, if individuals had been diagnosed with a polyp, the polyps were confirmed to be adenomatous by medical record review. Adenoma cases were ascertained through January 1, 2008. A separate case-control set was constructed of participants diagnosed with advanced adenoma matched to control participants who underwent a lower endoscopy in the same time period and did not have an adenoma. Advanced adenoma was defined as an adenoma 1 cm or larger in diameter and&#47;or with tubulovillous, villous, or highgrade dysplasia&#47;carcinoma-in-situ histology. Matching criteria included year of birth (within 1 year) and month&#47; year of blood sampling (within 6 months), the reason for their lower endoscopy (screening, family history, or symptoms), and the time period of any prior endoscopy (within 2 years). Controls matched to cases with a distal adenoma either had a negative sigmoidoscopy or colonoscopy examination, and controls matched to cases with proximal adenoma all had a negative colonoscopy. In total, 159 advanced adenoma cases and 109 controls were selected for genotyping. Leeds Colorectal Cancer Study (LCCS): Following local ethical approval, colorectal cancer cases were recruited from 1997 until 2012 in Leeds, UK through surgical clinics. Initially, funding was provided by the UK Ministry of Agriculture, Farming and Fisheries (subsequently the Food Standards Agency) and Imperial Cancer Research Fund (subsequently Cancer Research UK). Recruitment also occurred similarly in Dundee, Perth and York between the periods of 1997 and 2001 using the same protocol and the data and samples were combined. Pathologically confirmed cases were consented at outpatient clinics, providing information on known and postulated risk factors for colorectal cancer (diet, lifestyle and family history) as well as providing a blood sample for DNA. Exclusion criteria included pre-existing diverticular disease and an inability to complete the questionnaire. The General Practitioners of cases (all UK residents have a nominated General Practitioner to whom to refer initial medical queries) and these GPs were asked to send letters to other persons on their patient list of the same gender and born within 5 years of the case. Subsequently to enhance the number of controls, we systematically invited patients from selected GP practices. Diet was assessed in cases and controls using an extensive dietary and lifestyle questionnaire modified by that produced by the European Prospective Investigation in Cancer (EPIC). The frequency that each specific food items were eaten was recorded and we also obtained average fruit and vegetable consumption as a cross-check. In total, 1591 cases and 739 controls provided a DNA sample. The North Carolina Colon Cancer Studies (NCCCS I/II): The North Carolina Colon Cancer Studies (NCCCS I- colon and NCCCS II-rectal) were population-based case-control studies conducted in 33 counties of North Carolina. Cases were identified using the rapid case ascertainment system of the North Carolina Central Cancer Registry. Patients with a first diagnosis of histologically confirmed invasive adenocarcinoma of the colon (cecum through sigmoid colon) between October 1996 and September 2000 were classified as potential cases in the NCCCS I. The NCCCS II included patients with a first diagnosis of histologically confirmed invasive adenocarcinoma of the sigmoid colon, rectosigmoid, or rectum (hereafter collectively referred to as rectal cancer) between May 2001 and September 2006. Additional eligibility requirements were: aged 40-80 years, residence in one of the 33 counties, ability to give informed consent and complete an interview, had a driver&#39;s license or identification card issued by the North Carolina Department of Motor Vehicles (if under the age of 65), and had no objections from the primary physician in regards to contacting the individual. Controls, identified and sampled during the respective study dates, were selected from two sources. Potential controls under the age of 65 were identified using the North Carolina Department of Motor Vehicles records. For those 65 years and older, records from the Center for Medicare and Medicaid Services were used. Controls were matched to cases using randomized recruitment strategies. Recruitment probabilities were done using strata of 5-year age, sex, and race groups. Dietary information was collected using a modified version of the semiquantitative food frequency questionnaire developed at the National Cancer Institute. In addition, participants were asked about vitamin and mineral supplementation, special diets, restaurant eating, sodium use, and fats used in cooking. In NCCCS I, 515 colorectal cases and 687 matched controls were sent for genotyping. In NCCCS II, 796 colorectal cases and 823 controls were sent from the NCCCS II for genotyping. Controls were matched to CRC cases as 1&#58;1 ratio. Matching was done on age, race, and sex. Age was matched on &#43;&#45;5 years. Race and sex was matched exactly. For the cases without matched controls, matching was done only on sex and race. Nurses Health Study (NHS): The NHS cohort began in 1976 when 121,700 married female registered nurses age 30-55 years returned the initial questionnaire that ascertained a variety of important health-related exposures (Belanger et al., 1978) [PMID: 248266]. Since 1976, follow-up questionnaires have been mailed every 2 years. Colorectal cancer and other outcomes were reported by participants or next-of-kin and followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical-record review. Information was abstracted on histology and primary location. The rate of follow-up evaluation has been high: as a proportion of the total possible follow-up time, follow-up evaluation has been more than 92%. Colorectal cancer cases were ascertained through June 1, 2008. In 1989 -1990, 32,826 women in NHS I mailed blood samples by overnight courier, which were aliquoted into buffy coat and stored in liquid nitrogen. In 2001-2004, 29,684 women in NHS I who did not previously provide a blood sample mailed a swish-and-spit sample of buccal cells. Incident cases were defined as those occurring after the subject provided a blood or buccal sample. Prevalent cases were defined as those occurring after enrollment in the study in 1976 but before the subject provided either a blood or buccal sample. After excluding participants with histories of cancer (except nonmelanoma skin cancer), ulcerative colitis, or familial polyposis, case-control sets were previously constructed from which DNA was isolated from either buffy coat or buccal cells for genotyping. In addition to colorectal cancer cases and controls, a set of advanced adenoma cases and matched controls with available DNA from buffy coat were selected for genotyping. Over the follow-up period, data were collected on endoscopic screening practices and, if individuals had been diagnosed with a polyp, the polyps were confirmed to be adenomatous by medical record review. Adenoma cases were ascertained through June 1, 2011. A separate case-control set was constructed of participants diagnosed with advanced adenoma matched to control participants who underwent a lower endoscopy in the same time period and did not have an adenoma. Advanced adenoma was defined as an adenoma more than 1 cm in diameter and/or with tubulovillous, villous, or high-grade dysplasia/carcinoma-in-situ histology. Matching criteria included year of birth (within 1 year) and month/year of blood sampling (within 6 months), the reason for their lower endoscopy (screening, family history, or symptoms), and the time period of any prior endoscopy (within 2 years). Controls matched to cases with a distal adenoma either had a negative sigmoidoscopy or colonoscopy examination, and controls matched to cases with proximal adenoma all had a negative colonoscopy. A total of 272 cases and 236 matched controls were sent to CIDR for the advanced adenoma case-control set. Northern Swedish Health and Disease Study (NSHDS): Comprises over 110,000 participants, including approximately one third with repeated sampling occasions, from three population-based cohorts (Dahlin et al., 2010; Myte et al., 2016) [PMID: 20197478; PMID: 27367522]. The largest is the ongoing Vasterbotten Intervention Programme, in which all residents of Vasterbotten County are invited to a health examination upon turning 30 (some years), 40, 50 and 60 years of age. Extensive measured and self-reported health and lifestyle data, as well as blood samples for central biobanking in Umea, Sweden, are collected at the health exam. Leucocyte DNA samples for 1&#58;1-matched CRC case-control sets from the NSHDS, of which 878 samples are included in this study, have been selected for genotyping. This is in addition to 354 samples from the NSHDS previously analyzed as part of the multicenter EPIC cohort. Cancer-specific and overall survival data are available for all patients. For at least 425 patients, archival tumor tissue has been analyzed for the BRAF V600E mutation and by sequencing codon 12 and 13 for KRAS mutations, as well as for MSI screening status by immunohistochemistry and for an eight-gene CIMP panel using quantitative real-time PCR (MethyLight). Ohio Colorectal Cancer Prevention Initiative (OCCPI, OSUMC): OCCPI (ClinicalTrials.gov identifier: NCT01850654) is a population-based study of colorectal cancer patients diagnosed in one of 51 hospitals throughout the state of Ohio from January 1, 2013 through December 31, 2016. The OCCPI was created to decrease CRC incidence in Ohio by identifying patients with hereditary predisposition (statewide universal tumor screening for newly diagnosed CRC patients), increase colonoscopy compliance for first-degree relatives of CRC patients, and encourage future research through the creation of a biorepository. The 51 Ohio hospitals participating in the OCCPI were selected to represent a cross-section of clinical centers in the state based on high reported volume of CRC patients, affiliation with a high volume hospital, or interest in participation. Institutional Review Board (IRB) approval was obtained by the individual hospitals, Community Oncology Programs, or by ceding review to the OSU IRB. Written informed consent was obtained. A total of 2139 colorectal cases were genotyped. Patients were considered eligible for this study if they were age 18 or older at the time of enrollment, if they had a surgical resection (or biopsy if unresectable) in the state of Ohio demonstrating an adenocarcinoma of the colorectum from 1&#47;1&#47;13 - 12&#47;31&#47;16. Matched control samples were selected from the Ohio State University Medical Center&#39;s (OSUMC) Human Genetics Sample Bank in an identical way to the selection for the Columbus-area HNPCC Study (please refer to the description for the Columbus-area HNPCC Study). Prostate, Lung, Colorectal and Ovarian Cancer Screening Trail (PLCO): PLCO enrolled 154,934 participants (men and women, aged between 55 and 74 years) at ten centers into a large, randomized, two-arm trial to determine the effectiveness of screening to reduce cancer mortality. Sequential blood samples were collected from participants assigned to the screening arm. Participation was 93% at the baseline blood draw. In the observational (control) arm, buccal cells were collected via mail using the &#34;swish-and-spit&#34; protocol and participation rate was 65%. Details of this study have been previously described (Huang et al., 2016) [PMID&#58; 27673363] and are available online (http://dcp.cancer.gov/plco). For this study 1651 advanced adenoma cases and 1392 controls were selected for genotyping. Selenium and Vitamin E Prevention Trial (SELECT): The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was a double-blind, placebo controlled clinical trial which explored using selenium and vitamin E alone and in combination to prevent prostate cancer in healthy men (Lippman et al., 2009) [PMID&#58; 19066370]. Secondary endpoints included the prevention of colorectal and lung cancers. SELECT was conducted at 427 sites and centers in the United States, Canada and Puerto Rico; 35,533 men 55 years and older (50 or older if African American) were randomized beginning August 22, 2001. Supplementation was discontinued on October 23, 2008 due to futility. 308 colorectal cancer cases and 308 matched controls were selected from the SELECT population and sent for genotyping. Screening Markers For Colorectal Disease Study and Colonoscopy and Health Study (SMS-REACH): Details on this study population were previously reported (Burnett-Hartman et al., 2014) [PMID&#58; 24875374]. Participants were enrollees in an integrated health-care delivery system in western Washington State (Group Health Cooperative, Seattle, Washington) aged 24-79 years who underwent an index colonoscopy for any indication between 1998 and 2007 and donated a buccal-cell or blood sample for genotyping analysis. Study recruitment took place in 2 phases, with phase 1 occurring in 1998-2003 and phase 2 occurring in 2004-2007. Persons who had undergone a colonoscopy less than 1 year prior to the index colonoscopy, persons with inadequate bowel preparation for the index colonoscopy, and persons with a prior or new diagnosis of colorectal cancer, a familial colorectal cancer syndrome (such as familial adenomatous polyposis), or another colorectal disease were ineligible. Patients diagnosed with adenomas or serrated polyps and persons who were polyp-free at the index colonoscopy (controls) were systematically recruited during both phases of recruitment. Approximately 75% agreed to participate and provided written informed consent. Based on medical records, persons who agreed to participate and those who refused study participation were similar with respect to age, sex, and colorectal polyp status. Study protocols were approved by the institutional review boards of the Group Health Cooperative and the Fred Hutchinson Cancer Research Center (Seattle, Washington). A total of 575 cases and 508 matched were selected for the study. Controls were matched to CRC cases as 1&#58;1 ratio. Matching was done on age_ref, race, and sex. Age_ref was matched on &#43;&#45;5 years. The Women&#39;s Health Initiative (WHI): WHI is a long-term national health study that has focused on strategies for preventing heart disease, breast and colorectal cancer, and osteoporotic fractures in postmenopausal women. The original WHI study included 161,808 postmenopausal women enrolled between 1993 and 1998. The Fred Hutchinson Cancer Research Center in Seattle, WA serves as the WHI Clinical Coordinating Center for data collection, management, and analysis of the WHI. The WHI has two major parts&#58; a partial factorial randomized Clinical Trial (CT) and an Observational Study (OS); both were conducted at 40 Clinical Centers nationwide. The CT enrolled 68,132 postmenopausal women between the ages of 50-79 into trials testing three prevention strategies. If eligible, women could choose to enroll in one, two, or all three of the trial components. The components are: Hormone Therapy Trials (HT): This double-blind component examined the effects of combined hormones or estrogen alone on the prevention of coronary heart disease and osteoporotic fractures, and associated risk for breast cancer. Women participating in this component with an intact uterus were randomized to estrogen plus progestin (conjugated equine estrogens [CEE], 0.625 mg&#47;d plus medroxyprogesterone acetate [MPA] 2.5 mg&#47;d] or a matching placebo. Women with prior hysterectomy were randomized to CEE or placebo. Both trials were stopped early, in July 2002 and March 2004, respectively, based on adverse effects. All HT participants continued to be followed without intervention until close-out. Dietary Modification Trial (DM): The Dietary Modification component evaluated the effect of a low-fat and high fruit, vegetable and grain diet on the prevention of breast and colorectal cancers and coronary heart disease. Study participants were randomized to either their usual eating pattern or a low-fat dietary pattern. Calcium/Vitamin D Trial (CaD): This double-blind component began 1 to 2 years after a woman joined one or both of the other clinical trial components. It evaluated the effect of calcium and vitamin D supplementation on the prevention of osteoporotic fractures and colorectal cancer. Women in this component were randomized to calcium (1000 mg&#47;d) and vitamin D (400 IU&#47;d) supplements or a matching placebo. The Observational Study (OS)examines the relationship between lifestyle, environmental, medical and molecular risk factors and specific measures of health or disease outcomes. This component involves tracking the medical history and health habits of 93,676 women not participating in the CT. Recruitment for the observational study was completed in 1998 and participants were followed annually for 8 to 12 years. All centrally confirmed cases of invasive colorectal cancers, or deaths from colorectal cancer were selected as potential cases from September 30, 2015 database. Controls were participants free of colorectal cancer (invasive or in situ) as of September 30, 2015. Potential cases and controls were excluded if they (1) were non-White; (2) had history of colorectal cancers at baseline; (3) lost to follow-up after enrollment; (4) DbGAP ineligible; (5) had &#60;1.25ug of DNA; (6) selected for WHI study M26 Phase I or II; (7) selected for WHI study AS224 and also included in the imputation project. A total of 578 cases and 104,429 controls met the eligibility criteria. Each case was matched with 1 control (1&#58;1) that exactly met the following matching criteria: age (&#43;&#45;5 years), 40 randomization centers (exact), WHI date (&#43;&#45;3 years), CaD date (&#43;&#45;3 years), OS flag (exact), HRT assignments (exact), DM assignments (exact), and CaD assignments (exact). Control selection was done in a time-forward manner, selecting one control for each case from the risk set at the time of the case&#39;s event. The matching algorithm was allowed to select the closest match based on a criteria to minimize an overall distance measure (Bergstralh EJ, Kosanke JL. Computerized matching of cases to controls. Technical Report #56, Department of Health Sciences Research, Mayo Clinic, Rochester MN. April 1995). Each matching factor was given the same weight. When exact matches could not be found, the matching criteria were gradually relaxed among unmatched cases and controls until all cases had found matched controls. Using the matching criteria specified above, 559 of the 578 eligible cases found exact matches. The matching criteria was then relaxed to &#58; Age&#43;&#45;5, randomization centers, WHI date &#43;&#45; 3 years, CaD date &#43;&#45; 3 years, OS flag, HRT flag, DM flag, CaD flag. 17 of the remaining 19 unmatched cases found matched controls. By matching on Age&#43;&#45;5, randomization centers, WHI date &#43;&#45; 3 years, CaD date &#43;&#45; 3 years, OS flag, HRT flag, the remaining 2 unmatched cases found their matches.

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