Randomization tests of disease-marker associations.

A powerful test for population association of a disease with alleles at a bi-allelic marker locus is the transmission/disequilibrium test (TDT). A generalization of the test to multi-allelic marker loci is proposed which utilizes the maximal association of individual alleles with the disease, given by the maximum TDT statistic, TDT(max). To overcome the multiple testing problem encountered when using the maximal association to test the null hypothesis of no disease-marker association, a randomization procedure is developed. An investigation of the power of the test suggests that the randomization procedure performs almost as well as a recently proposed likelihood based test of linkage disequilibrium. The advantage of the new test is that it can be applied sequentially, based on a one-sided version of the TDT statistic, for investigating patterns of association of several individual alleles with the disease.