title: The impact of exposure-biased sampling designs on detection of gene-environment interactions in case-control studies with potential exposure misclassification.
abstract: With limited funding and biological specimen availability, choosing an optimal sampling design to maximize power for detecting gene-by-environment (G-E) interactions is critical. Exposure-enriched sampling is often used to select subjects with rare exposures for genotyping to enhance power for tests of G-E effects. However, exposure misclassification (MC) combined with biased sampling can affect characteristics of tests for G-E interaction and joint tests for marginal association and G-E interaction. Here, we characterize the impact of exposure-biased sampling under conditions of perfect exposure information and exposure MC on properties of several methods for conducting inference. We assess the Type I error, power, bias, and mean squared error properties of case-only, case-control, and empirical Bayes methods for testing/estimating G-E interaction and a joint test for marginal G (or E) effect and G-E interaction across three biased sampling schemes. Properties are evaluated via empirical simulation studies. With perfect exposure information, exposure-enriched sampling schemes enhance power as compared to random selection of subjects irrespective of exposure prevalence but yield bias in estimation of the G-E interaction and marginal E parameters. Exposure MC modifies the relative performance of sampling designs when compared to the case of perfect exposure information. Those conducting G-E interaction studies should be aware of exposure MC properties and the prevalence of exposure when choosing an ideal sampling scheme and method for characterizing G-E interactions and joint effects.
authors.affiliation: Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA, stenzesl@usc.edu.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Stenzel
authors.forename: Jaeil
authors.initials: J
authors.lastname: Ahn
authors.forename: Philip S
authors.initials: PS
authors.lastname: Boonstra
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
authors.forename: Bhramar
authors.initials: B
authors.lastname: Mukherjee
mesh_terms: D001499:Bayes Theorem; D015982:Bias; D016022:Case-Control Studies; D003198:Computer Simulation; D004777:Environment; D004781:Environmental Exposure; D004812:Epidemiologic Methods; D059647:Gene-Environment Interaction; D005796:Genes; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D015983:Selection Bias