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Study Description

This study is part of the NHLBI Trans-Omics for Precision Medicine (TOPMed) Whole Genome Sequencing Program. TOPMed is part of a broader Precision Medicine Initiative, which aims to provide disease treatments that are tailored to an individual's unique genes and environment. TOPMed will contribute to this initiative through the integration of whole-genome sequencing (WGS) and other -omics (e.g., metabolic profiles, protein and RNA expression patterns) data with molecular, behavioral, imaging, environmental, and clinical data. In doing so, this program aims to uncover factors that increase or decrease the risk of disease, to identify subtypes of disease, and to develop more targeted and personalized treatments. Two genotype call sets derived from WGS are now available, Freeze 9b (GRCh38) and Freeze 10b (GRCh38), with largely overlapping sample sets. Information about how to identify other TOPMed WGS accessions for cross-study analysis, as well as descriptions of TOPMed methods of data acquisition, data processing and quality control, are provided in the accompanying documents, "TOPMed Whole Genome Sequencing Project - Freeze 9b, Phases 1-4" and "TOPMed Whole Genome Sequencing Project - Freeze 10b, Phases 1-8". Please check the study list at the top of each of these methods documents to determine whether it applies to this study accession.

Participants from the Cardiovascular Health Study (CHS), a large population-based longitudinal cohort study (phs000287), have been included in the TOPMed project. Whole genome sequencing will be performed to contribute to multiple analyses, including cardiovascular disease risk factors, subclinical disease measures, the occurrence of myocardial infarction (MI) and stroke, and analyses of venous thromboembolism (VTE).

Comprehensive phenotypic and pedigree data for study participants are available through dbGaP phs000287.

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Study Inclusion/Exclusion Criteria

For TOPMed, CHS participants were initially included if they had appropriate consent, available DNA, and met any of the following criteria:

  1. had an adjudicated idiopathic VTE event during follow-up
  2. were African American
  3. had an incident MI or definite fatal coronary heart disease (CHD) event during follow-up
  4. had a probable fatal CHD event during follow-up
  5. had an incident stroke during follow-up
  6. had a prevalent MI or stroke at baseline, or
  7. were part of a random sample of "healthy elderly" participants who survived free of an MI or stroke.

Selection of participants proceeded in a hierarchical manner from criteria a-g without replacement. Each participant was thus assigned to one, and only one, of the seven groups. Additional CHS participants were included in a second set if they had appropriate consent, had available DNA, and had no TOPMed sequencing. This second set of participants was assigned to an eighth “other” group. Follow-up for MI, stroke, and CHD events occurred from baseline in 1989-1990 or 1992-1993 through June 30, 2014. Follow-up for VTE events occurred from baseline (1989-1990 or 1992-1993) through December 31, 2001.

CHS publications describe the methods for prevalent (PMID: 8520708) and incident events (PMID: 26538580).

VTE includes both deep vein thrombosis (DVT) in which a blood clot forms in a vein deep in the body, and pulmonary embolism (PE) where a blood clot travels to the lungs and blocks blood flow. The objectively diagnosed DVT and PE cases were confirmed by venous or pulmonary imaging, pathology examination of the thrombus removed at surgery, or by autopsy. In addition, many CHS participants have had other cardiovascular events, including atrial fibrillation (AF), angina, and heart failure (HF).

Study History

The Cardiovascular Health Study is an NHLBI-funded observational study of risk factors for cardiovascular disease in adults 65 years of age or older conducted across four US field centers. The original cohort of 5201 persons was recruited in 1989-1990 from random samples of the Medicare eligibility lists. An additional 687 participants, nearly all African Americans, were enrolled in 1992-1993, for a total sample of 5888. Starting in 1989, and continuing through 1999, participants underwent annual extensive clinical examinations. Follow-up for events remains ongoing through the present.

The identification of VTE in CHS was conducted as part of the Longitudinal Investigation of Thromboembolism Etiology (LITE), a collaboration between the Atherosclerosis Risk in Communities (ARIC) Study and CHS.

Selected Publications
Diseases/Traits Related to Study (MeSH terms)
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Study Attribution
  • Principal Investigators
    • Bruce M. Psaty, MD, PhD. TOPMed Cardiovascular Health Study Project (TOPMed-CHS). University of Washington, Seattle, WA, USA.
    • Eric Boerwinkle, PhD. TOPMed Venous Thromboembolism Project (TOPMed-VTE). University of Texas, Houston, TX, USA.
    • Aaron Folsom, MD, MPH. Longitudinal Investigation of Thromboembolism Etiology (LITE). University of Minnesota, Minneapolis, MN, USA.
  • Co-Investigators
    • Russell P Tracy, PhD. Cardiovascular Health Study Project (CHS). University of Vermont, Burlington, VT, USA.
    • Susan R. Heckbert, MD, PhD. Cardiovascular Health Study Project (CHS). University of Washington, Seattle, WA, USA.
    • Mary Cushman, MD, MS. Longitudinal Investigation of Thromboembolism Etiology (LITE). University of Vermont, Burlington, VT, USA.
  • Funding Sources
    • U01 HL130114. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
    • R01 HL059367. Longitudinal Investigation of Thromboembolism Etiology (LITE). National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
    • 75N92021D00006. Cardiovascular Health Study Project (CHS). National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.