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A semiparametric efficient estimator in case-control studies for gene-environment independent models.

ABSTRACT: Case-controls studies are popular epidemiological designs for detecting gene-environment interactions in the etiology of complex diseases, where the genetic susceptibility and environmental exposures may often be reasonably assumed independent in the source population. Various papers have presented analytical methods exploiting gene-environment independence to achieve better efficiency, all of which require either a rare disease assumption or a distributional assumption on the genetic variables. We relax both assumptions. We construct a semiparametric estimator in case-control studies exploiting gene-environment independence, while the distributions of genetic susceptibility and environmental exposures are both unspecified and the disease rate is assumed unknown and is not required to be close to zero. The resulting estimator is semiparametric efficient and its superiority over prospective logistic regression, the usual analysis in case-control studies, is demonstrated in various numerical illustrations.

SUBMITTER: Liang L

PROVIDER: S-EPMC6824552 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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A semiparametric efficient estimator in case-control studies for gene-environment independent models.

Liang Liang L Ma Yanyuan Y Carroll Raymond J RJ

Journal of multivariate analysis 20190208

Case-controls studies are popular epidemiological designs for detecting gene-environment interactions in the etiology of complex diseases, where the genetic susceptibility and environmental exposures may often be reasonably assumed independent in the source population. Various papers have presented analytical methods exploiting gene-environment independence to achieve better efficiency, all of which require either a rare disease assumption or a distributional assumption on the genetic variables. ...[more]

PMID: 31680705

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Project description:The two-phase sampling design is a cost-efficient way of collecting expensive covariate information on a judiciously selected sub-sample. It is natural to apply such a strategy for collecting genetic data in a sub-sample enriched for exposure to environmental factors for gene-environment interaction (G × E) analysis. In this paper, we consider two-phase studies of G × E interaction where phase I data are available on exposure, covariates and disease status. Stratified sampling is done to prioritize individuals for genotyping at phase II conditional on disease and exposure. We consider a Bayesian analysis based on the joint retrospective likelihood of phase I and phase II data. We address several important statistical issues: (i) we consider a model with multiple genes, environmental factors and their pairwise interactions. We employ a Bayesian variable selection algorithm to reduce the dimensionality of this potentially high-dimensional model; (ii) we use the assumption of gene-gene and gene-environment independence to trade-off between bias and efficiency for estimating the interaction parameters through use of hierarchical priors reflecting this assumption; (iii) we posit a flexible model for the joint distribution of the phase I categorical variables using the non-parametric Bayes construction of Dunson and Xing (2009). We carry out a small-scale simulation study to compare the proposed Bayesian method with weighted likelihood and pseudo likelihood methods that are standard choices for analyzing two-phase data. The motivating example originates from an ongoing case-control study of colorectal cancer, where the goal is to explore the interaction between the use of statins (a drug used for lowering lipid levels) and 294 genetic markers in the lipid metabolism/cholesterol synthesis pathway. The sub-sample of cases and controls on which these genetic markers were measured is enriched in terms of statin users. The example and simulation results illustrate that the proposed Bayesian approach has a number of advantages for characterizing joint effects of genotype and exposure over existing alternatives and makes efficient use of all available data in both phases.

Dataset Information

A semiparametric efficient estimator in case-control studies for gene-environment independent models.

Publications

A semiparametric efficient estimator in case-control studies for gene-environment independent models.

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