title: Comparison of 2 models for gene-environment interactions: an example of simulated gene-medication interactions on systolic blood pressure in family-based data.
abstract: BACKGROUND
  Nearly half of adults in the United States who are diagnosed with hypertension use blood-pressure-lowering medications. Yet there is a large interindividual variability in the response to these medications. Two complementary gene-environment interaction methods have been published and incorporated into publicly available software packages to examine interaction effects, including whether genetic variants modify the association between medication use and blood pressure. The first approach uses a gene-environment interaction term to measure the change in outcome when both the genetic marker and medication are present (the "interaction model"). The second approach tests for effect-size differences between strata of an environmental exposure (the "med-diff" approach). However, no studies have quantitatively compared how these methods perform with respect to 1 or 2 degree of freedom (DF) tests or in family-based data sets. We evaluated these 2 approaches using simulated genotype-medication response interactions at 3 single nucleotide polymorphisms (SNPs) across a range of minor allele frequencies (MAFs 0.1-5.4 %) using the Genetic Analysis Workshop 19 family sample.
  
  
  RESULTS
  The estimated interaction effect sizes were on average larger in the interaction model approach compared to the med-diff approach. The true positive proportion was higher for the med-diff approach for SNPs less than 1 % MAF, but higher for the interaction model when common variants were evaluated (MAF >5 %). The interaction model produced lower false-positive proportions than expected (5 %) across a range of MAFs for both the 1DF and 2DF tests. In contrast, the med-diff approach produced higher but stable false-positive proportions around 5 % across MAFs for both tests.
  
  
  CONCLUSIONS
  Although the 1DF tests both performed similarly for common variants, the interaction model estimated true interaction effects with less bias and higher true positive proportions than the med-diff approach. However, if rare variation (MAF <5 %) is of interest, our findings suggest that when convergence is achieved, the med-diff approach may estimate true interaction effects more conservatively and with less variability.
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514 USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Fernández-Rhodes
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514 USA.
authors.forename: Chani J
authors.initials: CJ
authors.lastname: Hodonsky
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514 USA.
authors.forename: Mariaelisa
authors.initials: M
authors.lastname: Graff
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514 USA.
authors.forename: Shelly-Ann M
authors.initials: SM
authors.lastname: Love
authors.affiliation: Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514 USA.
authors.forename: Annie Green
authors.initials: AG
authors.lastname: Howard
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514 USA.
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Seyerle
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514 USA.
authors.forename: Christy L
authors.initials: CL
authors.lastname: Avery
authors.affiliation: Department of Nutrition, and UNC Nutrition Research Institute, University of North Carolina, Kannapolis, NC 28081 USA.
authors.forename: Geetha
authors.initials: G
authors.lastname: Chittoor
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514 USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.affiliation: Department of Nutrition, and UNC Nutrition Research Institute, University of North Carolina, Kannapolis, NC 28081 USA.
authors.forename: V Saroja
authors.initials: VS
authors.lastname: Voruganti
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514 USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Young
authors.affiliation: School of Medicine, University of Maryland, Baltimore, MD 21201 USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: O'Connell
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514 USA.
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514 USA.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Justice