Transmission/Disequilibrium test meets measured haplotype analysis: Family-based association analysis guided by evolution of haplotypes

Family data teamed with the transmission/disequilibrium test (TDT), which s imultaneously evaluates linkage and association, is a powerful means of det ecting disease-liability alleles. To increase the information provided by t he test, various researchers have proposed TDT-based methods for haplotype transmission. Haplotypes indeed produce more-definitive transmissions than do the alleles comprising them, and this tends to increase power. However, the larger number of haplotypes, relative to alleles at individual loci, te nds to decrease power, because of the additional degrees of freedom require d for the test. An optimal strategy would focus the test on particular hapl otypes or groups of haplotypes. In this report we develop such an approach by combining the theory of TDT with that of measured haplotype analysis (MH A). MHA uses the evolutionary relationships among haplotypes to produce a l imited set of hypothesis tests and to increase the interpretability of thes e tests. The theory of our approach, called the "evolutionary tree" (ET)-TD T, is developed for two cases: when haplotype transmission is certain and w hen it is not. Simulations show the ET-TDT can be more powerful than other proposed methods under reasonable conditions. More importantly, our results show that, when multiple polymorphisms are found within the gene, the ET-T DT can be useful for determining which polymorphisms affect liability.