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MESA CARE Working Group

The CARE Study aims to test a large number of candidate genes in eight NHLBI-funded cohort studies to identify associations between genotypes and HLB phenotypes. This article provides an overview of the study, including the goals, organization, and data management.

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MESA CARE Working Group

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  1. MESA CARE Working Group Jerome I. Rotter Monday Evening Sept. 18, 2006

  2. Overview of CARE Study • To test a large number of candidate genes in NHLBI cohort studies • Goal: 1700 candidate genes (8-10 SNPs per gene); 15,000 markers on ~50,000 participants from eight NHLBI funded-studies • Comparatively smaller sample for genome-wide association

  3. Eight NHLBI CARE Cohorts • ARIC - Atherosclerosis Risk In Communities • CARDIA - Coronary Artery Risk Development in Young Adults • CHS - Cardiovascular Health Study • CSSCD - The Cooperative Study of Sickle Cell Disease • FHS - Framingham Heart Study • JHS - Jackson Heart Study • MESA - Multi-Ethnic Study of Atherosclerosis • SHHS - Sleep Heart Health Study

  4. Organization of CARE Study • RFP to establish a Genotyping/ Coordinating Center • coordination and utilization of genetic and phenotypic data • from well-characterized NHLBI cohorts • Center funded at the Broad Institute Center for Genotyping and Analysis

  5. CARE Genotyping and Analysis Center Goals 1. Receipt and management of DNA samples and phenotypic information to facilitate cross study analysis 2. Design genotyping experiments with software tools integrating sample management, SNP selection, and SNP genotyping platform 3. Support genotyping experiment execution in candidate genes and a set of genome-wide SNPs 4. Manage data and develop and apply statistical methods required to identify associations between genotypes and HLB phenotypes

  6. Larry Atwood, Boston, MAFHS Eric Boerwinkle, Houston, TXARIC Richard Fabsitz, Bethesda, MDNHLBI Myriam Fornage, Houston, TXCARDIA Stacey Gabriel, Cambridge, MABroad Joel Hirschhorn, Cambridge, MABroad Ronald Krauss, Oakland, CAHeart Abdullah Kutlar, August, GABlood Deborah Meyers, Winston-Salem, NCLung Emanual Mignot, Palo Alto, CASleep Dina Paltoo, Bethesda, MDNHLBI Susan Redline, Cleveland, OHSHHS Jerome Rotter, Los Angeles, CAMESA Jeanne Smith, Englewood, NJCSSCD Russell Tracy, Colchester, VTCHS James Wilson, Jackson, MSJHS CARE Steering Committee

  7. Mediawiki-based web pagehttp://www.broad.mit.edu/gen_analysis/care/index.php/Main_Page • Numerous conference calls starting Spring 2006 • Steering Committee Meeting, July 25,2006 • Discussion Items • Define pilot project (phenotypes & SNPs) • Establish principles of data release • Discuss genotyping study design • Select phenotypes to be analyzed

  8. Susan Heckbert Craig Johnson Richard Kronmal Kiang Liu Joe Mychaleckyj James Pankow Wendy Post Bruce Psaty Stephen Rich Jerome Rotter Kent Taylor Russell Tracy Michael Tsai MESA CARE Working Group

  9. Data Release/IRB - James Wilson DNA Transfer/Genotyping - Larry Atwood Analysis/Study Design - Stephen Rich Candidate Gene/SNP Selection - Myriam Fornage Phenotypes - Bruce Psaty- Susan Heckbert Informatics - Joe Mychaleckyj Publications- to be determined CARE Subcommittees & Chair

  10. Data Release/IRB - Rotter, Lui DNA Transfer/Genotyping - Tsai Analysis/Study Design - Rich, Pankow Candidate Gene/SNP Selection - Taylor, Tsai Phenotypes - Heckbert Informatics - Mychaleckyj Publications- Post CARE Subcommittees & MESA Rep

  11. General CARE Timeline • Set up infrastructure at Broad and Steering/ Subcommittees • Determine protocol for Pilot Study • Pilot Study • Candidate Gene Study • Whole Genome Association Study

  12. Proposed for Pilot • Diabetes – yes, no, pre, unknown • Dyslipidemia – Total, HDL, LDL, TG • Hypertension – sitting SPB and DBP, history • Obesity – height, weight • Medications associated with phenotypes • How were phenotypes measured • General covariates – age, sex, race, tobacco • 22 Candidate genes (from prior literature),1-4 SNPs per gene

  13. Proposed Candidate Genes for Pilot

  14. Proposed Candidate Genes for Pilot

  15. CARE Draft Data Distribution Policy and Data Access Agreement • NHLBI goal • Comprehensive genotype and phenotype data set • Broadly accessible to the scientific community • Protect interest of study participants • Promote productivity of CARE Cohort Investigators • Based on Framingham SHARE policy • Will be submitted to each Cohort’s Ancillary Studies Committee and local IRBs for approval

  16. CARE Draft Data Distribution Policy and Data Access Agreement • If approval can not be reached, options include • Re-consent if funding available • Data Enclave model (investigator-driven analysis but not raw genotyping download) • Withdrawal of the study from CARE • CARE will provide final documents and IRB talking points

  17. CARE Draft Data Access Policy Main Points • CARE Database (1) • Limited access, web-based database • Includes genotype and selected phenotype data • Is expandable over time • Includes authentication procedures to ensure: • Compliance with participant informed consent • Protection of participant privacy • Confidentiality of participant data • Stored at secure location at Broad Institute

  18. CARE Draft Data Access Policy Main Points • CARE Database (2) • Genotype data provided by Broad • Phenotype data provided by each cohort • Data will be de-identified • CARE Steering Committee to : • Approve data to be included (to prevent undue threats to privacy and confidentiality) • Calculate and post genotype-phenotype associations • Select other data to post (e.g. allele freq, LD)

  19. CARE Draft Data Access Policy Main Points • CARE Database (3) • Approved user receives a dataset with unique, randomly generated ID numbers • Approved users with access to permanent IDs (i.e. individual cohorts) can use those • Approved users will be provided access to entire CARE database, to be used in accordance with User’s application • Summary genetic information (freqs, LD) will be publicly available; no IDs, no phenotypes • Descriptive info on phenotypes (variables measured, protocols) will be publicly available

  20. CARE Draft Data Access Policy Main Points • Application for Access (1) • Data Access Review Committee (DARC) responsible for • Review of applications • Upon approval of applications, notifying Broad • Track approved users for compliance • Provide annual report of use and publications • Application includes (from all potential users/institutions) • Application • Statement of IRB approval (“exempt” approval is not acceptable) • Signed Data Distribution Agreement

  21. CARE Draft Data Access Policy Main Points • Application for Access (2) • Application composed of • Investigators information (NIH biosketch of PI and associates) • Abstract (~250) addressing scientific question and appropriateness of CARE dataset • Statement (~250) of prior experience of PI and associates including training or scholarly output in genetic research • Assurance of compliance by PI and associates with CARE policies (signed Data Dist. Agrmt)

  22. CARE Draft Data Access Policy Main Points • Application for Access (3) • Access is granted for one year • Renewable for one additional year conditional upon brief (~250 words) progress report • All Approved Users will certify that they: • Will not distribute data contained within CARE database in any form to any third parties other than those research staff who have agreed in writing to the terms of the Data Distribution Agreement • Will comply with all applicable federal, state, local laws and relevant institutional policies • Will not attempt to identify individual participants

  23. CARE Draft Data Access Policy Main Points • Application for Access (4) • Independent collaborating investigators working with CARE investigators will be required to submit a separate Data Distribution Agreement and IRB approval • NHLBI staff, CARE Investigators, and Broad Institute will (not?) be provided advance research access to the combined genotype-phenotype database • Terms and conditions governing access is identical for everyone

  24. CARE Draft Data Access Policy Main Points • Application for Access (5) • Publish at any time: • All CARE Investigators • NonCARE investigators who provide ancillary data • Designees assigned by CARE SC who have applied for and received access • Agree not to submit or show to publishers for pre-review (publications or abstracts) until 12 months after first release of the database • All other approved users

  25. Summary: CARE Discussion Items • Pilot Study • Phenotype List • Candidate Gene List • IRB, Data Distribution Agreement/ Policy • Design/Analysis • Informatics • Publications Policy

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