The impact of complex informative missingness on the validity of the transmission/disequilibrium test (TDT)

The transmission/disequilibrium test was introduced to test for linkage and association between a marker and a putative disease locus using case-parent triads. Several extensions have been proposed to accommodate incomplete triads. Some strategies assumed that parental genotypes were missing completely at random and some methods allowed informative missingness for parental genotypes. However, the above tests assumed that offspring genotypes were missing completely at random and concluded that the transmission/disequilibrium test remained a valid test by excluding incomplete triads from the analysis. In this article, the conditional distribution of ascertained triads allowing informative missingness for offspring genotypes, as well as their parental genotypes, was derived and several tests under such scenarios were evaluated. In simulations, independent triads from the Genetic Analysis Workshop 15 simulated data (Problem 3) was ascertained. When offspring genotypes were missing informatively, simulation results revealed inflated type I error and/or reduced power for the transmission/disequilibrium test excluding incomplete triads.