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

Abstract

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.

Keywords: National Birth Defects Prevention Study; birth defects; case-only; congenital heart defects; family-based study; gene-environment interaction; genetic epidemiology; neural tube defects; transmission disequilibrium test.

Figure 1. Possible Approaches for Family Trio Data

Required data from individuals indicated by bolded black outline. Affected individuals noted by shaded shapes. Optional or not required individuals noted by dashed outline. Panel A: Case-Control Study Requires genotypes of unrelated affected and unaffected individuals. In a hypothetical sample of 100 case trios and 100 control trios, there would be 200 individuals in the study, 100 affected individuals and 100 unaffected individuals. Panel B: Case-Only Study Requires genotypes of only affected individuals. In a hypothetical sample of 100 case trios and 100 control trios, there would be 100 affected individuals in the study for this approach. Panel C: Family-Based Trio Study Requires genotypes of affected individuals and both their parents. In a hypothetical sample of 100 case trios and 100 control trios, there would be 300 individuals in the study for this approach, 100 affected infants and 200 parents. Panel D: Maternal vs. Fetal Effects Requires genotypes of affected and unaffected individuals and their mothers. In a hypothetical sample of 100 case trios and 100 control trios, there would be 400 individuals in the study, 100 affected individuals their 100 mothers, 100 unaffected individuals, and their 100 mothers.