Testing gene-environment interactions in family-based association studies using trait-based ascertained samples.
The study of gene-environment interactions is an increasingly important aspect of genetic epidemiological investigation. Historically, it has been difficult to study gene-environment interactions using a family-based design for quantitative traits or when parent-offspring trios were incomplete. The QBAT-I provides researchers a tool to estimate and test for a gene-environment interaction in families of arbitrary structure that are sampled without regard to the phenotype of interest, but is vulnerable to inflated type I error if families are ascertained on the basis of the phenotype. In this study, we verified the potential for type I error of the QBAT-I when applied to samples ascertained on a trait of interest. The magnitude of the inflation increases as the main genetic effect increases and as the ascertainment becomes more extreme. We propose an ascertainment-corrected score test that allows the use of the QBAT-I to test for gene-environment interactions in ascertained samples. Our results indicate that the score test and an ad hoc method we propose can often restore the nominal type I error rate, and in cases where complete restoration is not possible, dramatically reduce the inflation of the type I error rate in ascertained samples.
Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, U.S.A.
Weiming
W
Zhang
Carl D
CD
Langefeld
Gary K
GK
Grunwald
Tasha E
TE
Fingerlin
D003627:Data Interpretation, Statistical; D005190:Family; D059647:Gene-Environment Interaction; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D010641:Phenotype; D019655:Quantitative Trait, Heritable
QBAT-I; ascertainment; family-based association study; gene-environment interaction; quantitative trait