On the combination of transmission/disequilibrium test and mean test for linkage detection using affected sib pairs

Abstract

The transmission/disequilibrium test (TDT) and the mean test are the two major nonparametric methods used in linkage analysis. Using case-parent triad data the TDT method tests the equality of the probabilities of a marker allele transmitted or not transmitted with the disease gene of a heterozygous parent. On the other hand, the mean test tests the goodness-of-fit of the observed and expected distributions of the number of alleles shared identical by descent using affected sib-pair data. It has been clarified in the literature that the mean test has higher power than the TDT when linkage disequilibrium (LD) is weak but the TDT has higher power than the mean test when LD is strong. These results indicate that both tests are sensitive to linkage disequilibrium, though their responses are different. The development of a robust method against the interference of linkage disequilibrium is considered. The combination idea is employed to combine the TDT and the mean test to search for such a robust statistic using case-parent tetrad data (two parents and two affected children). Several available combining methods are taken into account in this study. Numerical comparisons of these methods with the published ones are presented.