Genetic association tests with age at onset

Many diseases or traits exhibit a varying age at onset. Recent data examples of prostate cancer and childhood diabetes show that compared to simply treating the disease outcome as affected vs. unaffected, incorporation of age-at-onset information into the transmission/disequilibrium type of test (TDT) does not appear to change the results much. In this paper, we evaluate the power of TDT as a function of age at onset, and show that age-at-onset information is most useful when the disease is common, or the relative risk associated with the high-risk genotype varies with age. Moreover, an extremely old unaffected subject can contribute substantially to the power of the TDT, sometimes as much as old-onset subjects. We propose a modified test statistic for testing no association between the marker at the candidate locus and age at onset. The simulation study was conducted to evaluate the finite sample properties of proposed and the TDT test statistics under various sampling schemes for trios of parents and offspring, as well as for sibling clusters where unaffected siblings were used as controls.