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Promoting Collaborations Across Studies for Replication and Follow-up Studies. Robert N. Hoover, M.D., Sc.D Director Epidemiology and Biostatistics Program June 22, 2007. Outline. MEETING THE REQUIREMENTS FOR GOOD SCIENCE Extent of Collaboration Leadership Roles Resource Enhancement

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promoting collaborations across studies for replication and follow up studies

Promoting Collaborations Across Studiesfor Replication and Follow-up Studies

Robert N. Hoover, M.D., Sc.D

Director

Epidemiology and Biostatistics Program

June 22, 2007

outline
Outline
  • MEETING THE REQUIREMENTS FOR GOOD SCIENCE
  • Extent of Collaboration
  • Leadership Roles
  • Resource Enhancement
  • Training
  • Institutional Incentives
slide3
GWAS: WHAT WORKS

 Very large studies

 Replication, replication, replication (planned and coordinated)

 Rigorous, high-quality design, conduct, analysis

    • Genomics
    • Epidemiology
    • Statistics
    • Informatics
  • Data sharing
  • Accomplished Through Consortia
review of genetic association studies
Review of Genetic Association Studies
  • 603 associations of polymorphisms and disease
  • 166 studied in at least three populations
  • Only six seen reproducibly (>75% of studies)

Hirschhorn et al., Genetics in Medicine, 2002

slide6
            # of cases         # of SNPs

            Tier 1    443                   198,000

            Tier 2    332                   1800

“We identified 11 SNPs that were associated with PD (P<.01) in both tier 1 and tier 2 samples and had the same direction of effect.” (Maraganore et al)

“In this issue, four investigative teams …have sought to replicate the findings from a GWA study of PD by Maraganore et al.  Taken together these four studies appear to provide substantial evidence that none of the SNPs originally featured as potential PD loci are convincingly replicated and that all may be false positives.”

slide7
Study Size to Detect a Two-Fold Interaction

No. of cases (=No. of controls)

Prevalence of genotype=10%

Exposure specificity=100%

Exposure sensitivity = 60%

Exposure sensitivity = 80%

Exposure sensitivity = 100%

True prevalence of exposure

power of genome wide screen as a function of the number of retained false positive
0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0.01

0.1

1

10

100

1000

10000

100000

Power of genome wide screen as a function of the number of retained false positive

Power

Number of false positives

Model :

One susceptibility allele : MAF = 0.1 , Odds Ratio = 1.4

LD of typed marker with susceptibility marker : r2 = 0.8

Number of cases/control pairs : 1,200

Number of markers types : 500,000

lung cancer risk and cyp2d6
STUDY QUALITY

Lung Cancer Risk and CYP2D6*

* Risk of homozygous extensive metabolizers compared to homozygous poor metabolizers.

slide10
GWAS: WHAT WORKS

 Very large studies

 Replication, replication, replication (planned and coordinated)

 Rigorous, high-quality design, conduct, analysis

    • Genomics
    • Epidemiology
    • Statistics
    • Informatics
  • Data sharing
  • Accomplished Through Consortia
slide11
MEETING THE REQUIREMENTS FOR GOOD SCIENCE
  • Extent of Collaboration
  • Leadership Roles
  • Resource Enhancement
  • Training
  • Institutional Incentives
breast cancer association consortium
Breast Cancer Association Consortium

20 studies:

28,000 cases 30,000 controls

Cases

breast cancer association consortium findings to date
Breast Cancer Association Consortium: Findings to Date

20 candidate SNPs

(published + unpublished)

11SNPs

9 SNPs

Some evidence

No association

ADH1C I350V

AURKA F31I

XRCC1 R399Q

LIG4 D501D

BRCA2 N372H

XRCC3 T241M

XRCC3 5’UTR

XRCC3 IVS5

XRCC2 R188H

ERCC2 D312N

TP53 R72P

BCAC, JNCI (2006)

Follow-up

9-15 studies: 10,783 cases, 18,312 controls

No association

SOD2 V16A

ADH1B 3’UTR

CDK1A S31R

ICAM5 V301I

NUMA1 A794G

Moderate

IGFBP3 -202

(p=0.05)

ATM S49C

(p=0.09)

Reasonable

TGFB1 L10P

(P=0.0001)

(ER-, PR- tumors)

Strong

CASP8 D320H

(P=1x10-7)

Cox A/Dunning AM/Garcia-Closas M for the BCAC

Nat Genet 2007;39:688

slide14
25+ cohorts, over 2.6 million individuals (1.2 million with DNA collected at baseline)

BPC3

CGEMS

PanScan

Scan: ATBC, CLUE II, CPS II, EPIC, HPFS, NHS, NYUWHS, PHS, PLCO, SMWHS, WHI, WHS

Replication: Pancreatic Cancer Case-Control Consortium (PANC4)

Risk Factors: Tobacco, obesity, family history and diabetes

Genes: Genome-wide Association Study (GWAS)

Cancer Sites: Pancreatic cancer

Cases with DNA: ~1,900 pancreatic cases

Website:

http://epi.grants.cancer.gov/PanScan/

Cohorts: ATBC, CPS II, EPIC, HPFS, MEC, NHS, PHS, PLCO, WHS

Risk Factors: Hormone risk factors and hormones

Genes: 53 in steroid hormone and growth factor pathways

Cancer Sites: Breast & Prostate cancer

Cases with DNA:

Website:

http://epi.grants.cancer.gov/BPC3

Scan: PLCO, NHS

Replication: ATBC, CPS II, EPIC, HPFS, MEC, PHS, WHS, WHI

Risk factors: Same as BPC3 plus family history

Genes: Genome-wide Association Study (GWAS)

Cancer Sites: Breast & Prostate cancer

Cases with DNA: 8,850 breast cases, 6,160 prostate cases

Data Portal:

https://caintegrator.nci.nih.gov/cgems/

extent of collaboration
Extent of Collaboration
  • Limited Replication or More
    • Main Effects
    • Fine Mapping
    • Gene X Gene
    • Gene X Environment
    • Candidate Pathways
    • Other Phenotypes and Outcomes
slide17
Data Analysis

Database

Flow of Investigation: From Genome-Wide Association to Clinical Translation

Initial Genome-Wide

Association (GWA) Studies

Replication/Fine Mapping

Sequencing/Genotyping

Functional Studies

Translational Studies

slide18
127.6 M

8q24 Region

Cancer Susceptibility

rs979200

CGEMS region 1

rs1456310

CGEMS region 2

rs6470494

CGEMS region 3

rs1016343

rs132544738

CGEMS region 4

rs6983561

rs13281615

CGEMS region 5

rs16902124

rs10808555

rs6983267

rs10505476

CGEMS region 6

rs7837328

MYC

rs1447295

CGEMS region 7

rs7837688

rs7824074

CGEMS region 8

129.0 M

alcohol consumption and nhl a pooled interlymph analysis
Alcohol Consumption and NHL a Pooled InterLymph Analysis

Morton LM et al. – 2005 Lancet Oncology

leadership roles
Leadership Roles

Leadership

Shared

Complementary Study Conduct

Apportioned Analysis and Publication

interlymph organization
InterLymph Organization

Behavior and Environment Host and Genetics

Executive Committee

Immunity and InfectionPathology and Survival

bpc3 organization
BPC3 Organization

Data Pooling Publications

Steering Committee

Population Genotyping Statistics

Genetics

publication leadership
Publication Leadership

Interlymph Consortium Publications

2005-2007

Number: 17

Number of different 1st authors: 13

Number of different last authors: 14

resource enhancement
Resource Enhancement
  • Infrastructure – extraction, additional specimens or data, biomarkers
  • Additional Genotyping
institutional incentives
Institutional Incentives

Investigator’s Institution

- Promotion/Tenure

- Infrastructure

Funding Institutions

- Support for Consortia

- Targeted funding opportunities

- Base support for contributing studies

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