# Presentation: 534971

## 	Challenges of an Epidemiologist Working in Genomics

- Wendy Post, MD, MS
- Associate Professor of Medicine
- and Epidemiology
- Cardiology Division
- Johns Hopkins University

##   “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”.

Teri Manolio 5/8/07

- Teri Manolio 5/8/07

- Nature Genetics 2006;38(6):644-51 (epub Apr 30 2006).

## 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

## 	Heritability of Left Ventricular Mass 

- 	**Heritability of Left Ventricular Mass **
**The Framingham Heart Study **
- Wendy S. Post; Martin G. Larson; Richard H. Myers; Maurizio Galderisi; Daniel Levy
*Hypertension.* 1997;30:1025-1028.
- © 1997 American Heart Association, Inc.
- 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.).

## Confusing genetics nomenclature

- Before rs numbers the snp names kept changing
- Makes it hard to compare results to prior studies in PubMed
- rs numbers (RefSNP accession ID- db SNP)
- db SNP- reference database (www.dbsnp.com)
- Forward strand versus reverse strand
- Nucleotide names
- Dominant model versus recessive model
- Relative to major or minor allele?
- AB+AB  vs BB
- Remembering my biochemistry
- Untranslated exon?
- Exon= region of DNA transcribed into the final mRNA

## Complicated authorship issues

- Collaboration is key
- Phenotypers
- Statisticians
- Bioinformatics
- Genotypers
- Collaboration with other cohorts for replication/validation
- Order of authorship on manuscripts is not straightforward
- Decide before the work is done

## What covariates to put in the model?

- Epidemiologists “worry” a lot about confounding.
- Confounders are associated with the outcome (phenotype) and the predictor (genotype).
- most of our traditional confounders are not associated with genotype.
- Might want to add covariates for “precision”
- How much of the variability in the phenotype is explained by genotype after including known predictors in the model?

## Choosing appropriate control groups

- Epidemiology 101
- Cases and controls need to be collected in a similar fashion
- 		similar ancestry
- 		similar environmental exposures

## Dealing with population stratification

- How big of an issue is it really?
- Should we use AIMs or self described race/ethnicity?
- AIM (ancestral informative markers)
- allele frequencies of snps differ based on parental population
- Can estimate the ancestral proportion of an individual
- Self described race/ethnicity
- When can we combine racial/ethnic groups for analyses when there is no statistical interaction?

## Gene-environment and gene-gene interactions

- Complex disorders
- Multiple genes and environmental interactions
- Tests for interactions
- Multiple testing issues
- Power
- How to combine multiple genes/snps into same prediction model

## Multiple testing issues

- Fishing expedition
- Traditionally in epidemiology, seen as “poor science”
- GWAS is a really big, sophisticated, fishing expedition
- Fishing in Alaska for seven different kinds of salmon, instead of fishing on the LI sound.

## What p value do we use?

- Bonferroni adjustment seems overly conservative
- False negatives
- False Discovery Rate
- Need for replication/validation
- What cutpoint do we use to move results forward?

## Other issues

- Lack of reproducibility
- False positives versus
- differences in environmental exposures or haplotype structure
- different study design
- HWE
- Relative frequency of alleles for a snp are stable in the population (not changing over successive generations).
- p2, 2pq, q2
- What genetic model to test
- 2df, additive, dominant, recessive
- Again, issues of multiple testing arise

## To patent or not to patent our results

- Epidemiologists rarely patent findings
- History of new scientific discoveries in genetics acquiring patents
- Could hinder scientific progress?

## Ann. Int. Med. 49:556-567, 1958

**Ann. Int. Med. 49:556-567, ****1958**