Testing for gene-environment interaction under exposure misspecification.

TitleTesting for gene-environment interaction under exposure misspecification.
Publication TypeJournal Article
Year of Publication2018
AuthorsSun, R, Carroll, RJ, Christiani, DC, Lin, X
JournalBiometrics
Volume74
Issue2
Pagination653-662
Date Published2018 06
ISSN1541-0420
KeywordsBias, Confounding Factors, Epidemiologic, Environmental Exposure, Gene-Environment Interaction, Humans, Linear Models, Models, Genetic, Scientific Experimental Error
Abstract

Complex interplay between genetic and environmental factors characterizes the etiology of many diseases. Modeling gene-environment (GxE) interactions is often challenged by the unknown functional form of the environment term in the true data-generating mechanism. We study the impact of misspecification of the environmental exposure effect on inference for the GxE interaction term in linear and logistic regression models. We first examine the asymptotic bias of the GxE interaction regression coefficient, allowing for confounders as well as arbitrary misspecification of the exposure and confounder effects. For linear regression, we show that under gene-environment independence and some confounder-dependent conditions, when the environment effect is misspecified, the regression coefficient of the GxE interaction can be unbiased. However, inference on the GxE interaction is still often incorrect. In logistic regression, we show that the regression coefficient is generally biased if the genetic factor is associated with the outcome directly or indirectly. Further, we show that the standard robust sandwich variance estimator for the GxE interaction does not perform well in practical GxE studies, and we provide an alternative testing procedure that has better finite sample properties.

DOI10.1111/biom.12813
Alternate JournalBiometrics
PubMed ID29120492
PubMed Central IDPMC5943197
Grant ListU19 CA203654 / CA / NCI NIH HHS / United States
R01 HL113338 / HL / NHLBI NIH HHS / United States
R37 CA057030 / CA / NCI NIH HHS / United States
P01 CA134294 / CA / NCI NIH HHS / United States
U01 CA057030 / CA / NCI NIH HHS / United States
R35 CA197449 / CA / NCI NIH HHS / United States
T32 ES007142 / ES / NIEHS NIH HHS / United States
R01 CA057030 / CA / NCI NIH HHS / United States
U01 HG009088 / HG / NHGRI NIH HHS / United States
P42 ES016454 / ES / NIEHS NIH HHS / United States