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Promoting Collaborations Across Studies for Replication and Follow-up Studies

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

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  1. Promoting Collaborations Across Studiesfor Replication and Follow-up Studies Robert N. Hoover, M.D., Sc.D Director Epidemiology and Biostatistics Program June 22, 2007

  2. Outline • MEETING THE REQUIREMENTS FOR GOOD SCIENCE • Extent of Collaboration • Leadership Roles • Resource Enhancement • Training • Institutional Incentives

  3. 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

  4. 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

  5. Interaction of NAT2 and Active Cigarette Smoking in Breast Cancer Risk

  6.             # 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.”

  7. 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

  8. 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

  9. STUDY QUALITY Lung Cancer Risk and CYP2D6* * Risk of homozygous extensive metabolizers compared to homozygous poor metabolizers.

  10. 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

  11. MEETING THE REQUIREMENTS FOR GOOD SCIENCE • Extent of Collaboration • Leadership Roles • Resource Enhancement • Training • Institutional Incentives

  12. Breast Cancer Association Consortium 20 studies: 28,000 cases 30,000 controls Cases

  13. 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

  14. 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/

  15. Results: Overall in BPC3 rs#1447295

  16. Extent of Collaboration • Limited Replication or More • Main Effects • Fine Mapping • Gene X Gene • Gene X Environment • Candidate Pathways • Other Phenotypes and Outcomes

  17. 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

  18. 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

  19. Alcohol Consumption and NHL a Pooled InterLymph Analysis Morton LM et al. – 2005 Lancet Oncology

  20. Leadership Roles Leadership Shared Complementary Study Conduct Apportioned Analysis and Publication

  21. InterLymph Organization Behavior and Environment Host and Genetics Executive Committee Immunity and InfectionPathology and Survival

  22. BPC3 Organization Data Pooling Publications Steering Committee Population Genotyping Statistics Genetics

  23. Publication Leadership Interlymph Consortium Publications 2005-2007 Number: 17 Number of different 1st authors: 13 Number of different last authors: 14

  24. Resource Enhancement • Infrastructure – extraction, additional specimens or data, biomarkers • Additional Genotyping

  25. 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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