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  1. 1. Challenges of an Epidemiologist Working in Genomics Wendy Post, MD, MS Associate Professor of Medicine and Epidemiology Cardiology Division Johns Hopkins University
  2. 2. <ul><li>“ There is a need to bridge the chasm between geneticists and traditional epidemiologists who are now wondering how they can apply GWAS technology to their studies”. </li></ul><ul><li>Teri Manolio 5/8/07 </li></ul>
  3. 3. Nature Genetics 2006;38(6):644-51 (epub Apr 30 2006).
  4. 4. CAPON Association with adjusted QT interval Results of a genome wide association study in KORA S4 and 2 replication cohorts n n KORA S4 3366 4.9 msec 36% < 10 -7 Cohort N Effect MAF Adjusted p KORA F3 2646 7.9 msec 36% < 10 -11 FHS 1805 4.0 msec 39% 0.004 Arking DE, Pfeufer A, Post W et al. Nature Genetics ; published online Apr 30 2006. *QT- adjusted for age, gender and heart rate
  5. 7. <ul><li>Heritability of Left Ventricular Mass </li></ul><ul><ul><ul><li>The Framingham Heart Study </li></ul></ul></ul><ul><li>Wendy S. Post; Martin G. Larson; Richard H. Myers; Maurizio Galderisi; Daniel Levy </li></ul><ul><li>Hypertension. 1997;30:1025-1028. </li></ul><ul><li>© 1997 American Heart Association, Inc. </li></ul><ul><li>From the National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Mass (W.S.P., M.G.L., R.H.M., M.G., D.L.); the Division of Cardiology, Beth Israel Hospital, Boston, Mass (D.L.); the Department of Neurology (R.H.M.), Division of Epidemiology and Preventive Medicine (M.G.L., D.L.), Boston University School of Medicine; the National Heart, Lung, and Blood Institute, Bethesda, Md (D.L.), University of Naples, Italy (M.G.); and the Division of Cardiology, Johns Hopkins Hospital, Baltimore, Md (W.S.P.). </li></ul>
  6. 8. Confusing genetics nomenclature <ul><li>Before rs numbers the snp names kept changing </li></ul><ul><ul><li>Makes it hard to compare results to prior studies in PubMed </li></ul></ul><ul><ul><li>rs numbers (RefSNP accession ID- db SNP) </li></ul></ul><ul><ul><ul><li>db SNP- reference database ( </li></ul></ul></ul><ul><li>Forward strand versus reverse strand </li></ul><ul><ul><li>Nucleotide names </li></ul></ul><ul><li>Dominant model versus recessive model </li></ul><ul><ul><li>Relative to major or minor allele? </li></ul></ul><ul><ul><ul><li>AB+AB vs BB </li></ul></ul></ul><ul><li>Remembering my biochemistry </li></ul><ul><ul><li>Untranslated exon? </li></ul></ul><ul><ul><ul><li>Exon= region of DNA transcribed into the final mRNA </li></ul></ul></ul>
  7. 9. Complicated authorship issues <ul><li>Collaboration is key </li></ul><ul><ul><li>Phenotypers </li></ul></ul><ul><ul><li>Statisticians </li></ul></ul><ul><ul><li>Bioinformatics </li></ul></ul><ul><ul><li>Genotypers </li></ul></ul><ul><li>Collaboration with other cohorts for replication/validation </li></ul><ul><li>Order of authorship on manuscripts is not straightforward </li></ul><ul><ul><li>Decide before the work is done </li></ul></ul>
  8. 10. What covariates to put in the model? <ul><li>Epidemiologists “worry” a lot about confounding. </li></ul><ul><li>Confounders are associated with the outcome (phenotype) and the predictor (genotype). </li></ul><ul><ul><li>most of our traditional confounders are not associated with genotype. </li></ul></ul><ul><li>Might want to add covariates for “precision” </li></ul><ul><li>How much of the variability in the phenotype is explained by genotype after including known predictors in the model? </li></ul>
  9. 11. Choosing appropriate control groups <ul><li>Epidemiology 101 </li></ul><ul><li>Cases and controls need to be collected in a similar fashion </li></ul><ul><li>similar ancestry </li></ul><ul><li>similar environmental exposures </li></ul>
  10. 12. Dealing with population stratification <ul><li>How big of an issue is it really? </li></ul><ul><li>Should we use AIMs or self described race/ethnicity? </li></ul><ul><ul><li>AIM (ancestral informative markers) </li></ul></ul><ul><ul><ul><li>allele frequencies of snps differ based on parental population </li></ul></ul></ul><ul><ul><ul><li>Can estimate the ancestral proportion of an individual </li></ul></ul></ul><ul><ul><li>Self described race/ethnicity </li></ul></ul><ul><li>When can we combine racial/ethnic groups for analyses when there is no statistical interaction? </li></ul>
  11. 13. Gene-environment and gene-gene interactions <ul><li>Complex disorders </li></ul><ul><ul><li>Multiple genes and environmental interactions </li></ul></ul><ul><li>Tests for interactions </li></ul><ul><ul><li>Multiple testing issues </li></ul></ul><ul><ul><li>Power </li></ul></ul><ul><li>How to combine multiple genes/snps into same prediction model </li></ul>
  12. 14. Multiple testing issues <ul><li>Fishing expedition </li></ul><ul><ul><li>Traditionally in epidemiology, seen as “poor science” </li></ul></ul><ul><ul><li>GWAS is a really big, sophisticated, fishing expedition </li></ul></ul><ul><ul><ul><li>Fishing in Alaska for seven different kinds of salmon, instead of fishing on the LI sound. </li></ul></ul></ul>
  13. 15. What p value do we use? <ul><li>Bonferroni adjustment seems overly conservative </li></ul><ul><ul><li>False negatives </li></ul></ul><ul><li>False Discovery Rate </li></ul><ul><li>Need for replication/validation </li></ul><ul><ul><li>What cutpoint do we use to move results forward? </li></ul></ul>
  14. 16. Other issues <ul><li>Lack of reproducibility </li></ul><ul><ul><li>False positives versus </li></ul></ul><ul><ul><ul><li>differences in environmental exposures or haplotype structure </li></ul></ul></ul><ul><ul><ul><li>different study design </li></ul></ul></ul><ul><li>HWE </li></ul><ul><ul><li>Relative frequency of alleles for a snp are stable in the population (not changing over successive generations). </li></ul></ul><ul><ul><ul><li>p 2 , 2pq, q 2 </li></ul></ul></ul><ul><li>What genetic model to test </li></ul><ul><ul><li>2df, additive, dominant, recessive </li></ul></ul><ul><ul><ul><li>Again, issues of multiple testing arise </li></ul></ul></ul>
  15. 17. To patent or not to patent our results <ul><li>Epidemiologists rarely patent findings </li></ul><ul><li>History of new scientific discoveries in genetics acquiring patents </li></ul><ul><li>Could hinder scientific progress? </li></ul>
  16. 18. Ann. Int. Med. 49:556-567, 1958