Using case-parent triads to estimate relative risks associated with a candidate haplotype

Estimating haplotype relative risks in a family-based study is complicated by phase ambiguity and the many parameters needed to quantify relative risks for all possible diplotypes. This problem becomes manageable if a particular haplotype has been implicated previously as relevant to risk. We fit log-linear models to estimate the risks associated with a candidate haplotype relative to the aggregate of other haplotypes. Our approach uses existing haplotype-reconstruction algorithms but requires assumptions about the distribution of haplotypes among triads in the source population. We consider three levels of stringency for those assumptions: Hardy-Weinberg Equilibrium (HWE), random mating, and no assumptions at all. We assessed our method's performance through simulations encompassing a range of risk haplotype frequencies, missing data patterns, and relative risks for either offspring or maternal genetic effects. The unconstrained model provides robustness to bias from population structure but requires excessively large sample sizes unless there are few haplotypes. Assuming HWE accommodates many more haplotypes but sacrifices robustness. The model assuming random mating is intermediate, both in the number of haplotypes it can handle and in robustness. To illustrate, we reanalyze data from a study of orofacial clefts to investigate a 9-SNP candidate haplotype of the IRF6 gene.