title: Tests for Gene-Environment Interactions and Joint Effects With Exposure Misclassification.
abstract: The number of methods for genome-wide testing of gene-environment (G-E) interactions continues to increase, with the aim of discovering new genetic risk factors and obtaining insight into the disease-gene-environment relationship. The relative performance of these methods, assessed on the basis of family-wise type I error rate and power, depends on underlying disease-gene-environment associations, estimates of which may be biased in the presence of exposure misclassification. This simulation study expands on a previously published simulation study of methods for detecting G-E interactions by evaluating the impact of exposure misclassification. We consider 7 single-step and modular screening methods for identifying G-E interaction at a genome-wide level and 7 joint tests for genetic association and G-E interaction, for which the goal is to discover new genetic susceptibility loci by leveraging G-E interaction when present. In terms of statistical power, modular methods that screen on the basis of the marginal disease-gene relationship are more robust to exposure misclassification. Joint tests that include main/marginal effects of a gene display a similar robustness, which confirms results from earlier studies. Our results offer an increased understanding of the strengths and limitations of methods for genome-wide searches for G-E interaction and joint tests in the presence of exposure misclassification.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Boonstra
authors.forename: Bhramar
authors.initials: B
authors.lastname: Mukherjee
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
authors.forename: Jaeil
authors.initials: J
authors.lastname: Ahn
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Schmit
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Chatterjee
mesh_terms: D003198:Computer Simulation; D059647:Gene-Environment Interaction; D023281:Genomics / Q000379:methods*
keywords: case-control; gene discovery; gene-environment independence; genome-wide association; modular methods; multiple testing; screening test; weighted hypothesis test