Detecting gene-environment interactions in human birth defects: Study designs and statistical methods

Background: The National Birth Defects Prevention Study (NBDPS) contains a wealth of information on affected and unaffected family triads, and thus provides numerous opportunities to study gene-environment interactions (G×E) in the etiology of birth defect outcomes. Depending on the research objective, several analytic options exist to estimate G×E effects that use varying combinations of individuals drawn from available triads. Methods: In this study, we discuss important considerations in the collection of genetic data and environmental exposures. Results: We will also present several population- and family-based approaches that can be applied to data from the NBDPS including case-control, case-only, family-based trio, and maternal versus fetal effects. For each, we describe the data requirements, applicable statistical methods, advantages, and disadvantages. Conclusion: A range of approaches can be used to evaluate potentially important G×E effects in the NBDPS. Investigators should be aware of the limitations inherent to each approach when choosing a study design and interpreting results.