title: Gene-environment interaction testing in family-based association studies with phenotypically ascertained samples: a causal inference approach.
abstract: We propose a method for testing gene-environment (G × E) interactions on a complex trait in family-based studies in which a phenotypic ascertainment criterion has been imposed. This novel approach employs G-estimation, a semiparametric estimation technique from the causal inference literature, to avoid modeling of the association between the environmental exposure and the phenotype, to gain robustness against unmeasured confounding due to population substructure, and to acknowledge the ascertainment conditions. The proposed test allows for incomplete parental genotypes. It is compared by simulation studies to an analogous conditional likelihood-based approach and to the QBAT-I test, which also invokes the G-estimation principle but ignores ascertainment. We apply our approach to a study of chronic obstructive pulmonary disorder.
authors.affiliation: Department of Biostatistics, Division of Biomedical Informatics, Center for Clinical and Translational Science, University of Kentucky, Lexington, KY 40536, USA. david.fardo@uky.edu
authors.forename: David W
authors.initials: DW
authors.lastname: Fardo
authors.forename: Jinze
authors.initials: J
authors.lastname: Liu
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Demeo
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.forename: Stijn
authors.initials: S
authors.lastname: Vansteelandt
mesh_terms: D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D059647:Gene-Environment Interaction; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics
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