Eric Boerwinkle; February, 2015 Precision Medicine Workshop · CHARGE (Cohorts for Heart & Aging Research in Genome Epidemiology) Consortium, N>>100,000 FHS N~9,400 ARIC N~16,000

Building a National Cohort

Eric Boerwinkle; February, 2015Precision Medicine Workshop

What is a Cohort?

• Sample of people

• Who share some characteristic (e.g. a place) and time frame

• Cohort study– Longitudinal

– Measure/monitor/estimate some things

– Assess outcomes (usually in the future)

• Does not have to be a representative sample, but clear eligibility criteria allow making generalizable inferences.

Prospective, longitudinal follow-up.Deep phenotyping for RFs and outcomes. Similar methods and QC for phenotyping.Available DNA, RNA, blood, imaging.

CHARGE (Cohorts for Heart & Aging Research in Genome Epidemiology) Consortium, N>>100,000

FHSN~9,400

ARICN~16,000

Jackson Heart Studyn~5,300

Study of LatinosN~16,000

Deeply PhenotypedRisk Factors and Disease

Array Genotypes andSequence

CHSN~5,000

>600 Investigators, >80 Cohorts>60 Phenotype Working GroupsPublished Collaboration Principles >370 Publications since 2008

*Psaty BM, O’Donnell CJ, et al. Circulation CV Genetics 2009.

MESA, FamHeart, JHS, CARDIAn~20,000

CHARGE (Cohorts for Heart & Aging Research in Genome Epidemiology) Consortium, N>>100,000

FHSN~9,400

ARICN~16,000

Jackson Heart Studyn~5,300

Study of LatinosN~16,000

Deeply PhenotypedRisk Factors and Disease

Array Genotypes andSequence

CHSN~5,000

>600 Investigators, >80 Cohorts>60 Phenotype Working GroupsPublished Collaboration Principles >140 Publications since 2008

MESA, FamHeart, JHS, CARDIAn~20,000

Sequencing in Cohorts

• Update

– WES (N=11,500)(F4)

– WGS (N=5,700)

– Collaborations (ESP) (N=23,000)

– Strong analytic infrastructure

5

Morrison A. Nat Genet 2013; 45: 899-901.

FHS: phs000651.v4.p9; CHS: phs000667.v1.p1; ARIC phs000668.v1.p1

Building a National Cohort

ConsortiumOf Cohorts A National Cohort

Artist: Chuck Close

Building A National Cohort

• Harmonization • Big Data Challenges

• Storage• Analytics• Connectivity

The CHARGE Data Commons

Technical ChallengesEnhanced Opportunities• Participatory• Enhanced phenotyping• Platform for clinical trials• Pilot for national health/EMRs• Enhanced community resources• Virtuous cycle of health care and research

HAL

histidine

Incident HF

Incident CHD

Incident CKD

p = 1.2×10-13

p = 2.6×10-6

p = 1.9×10-5

p = 1.4×10-4

splice (n =1) R322X (n = 22)

154 16123

splice (n =1)

Gene

Metabolite

Clinical

Endpoints

8

Clinical and Biologic Continuum of Simple/Complex and Rare/Common

PCSK9, Cohen, 2006; PMID: 16554528APOC3, Crosby, 2013; PMID: 24941081NPC1L1, Stitziel, 2014; PMID: 25390462PLA2G7, Polfus, 2015;

Few Actionable AllelesMissing ‘Heritability’

Rare Mendelian……….. ‘Oligogenic’ ……………. Common Complex

Low frequency/High impactNot related to sporadic cases

in a simple way

Jim Lupski Richard Gibbs Eric Boerwinkle

Clinical and Biologic Continuum of Simple/Complex and Rare/Common

Building a National Cohort

A National CohortVirtuous Cycle of

Health Care and Research