Weighted Transmission Disequilibrium Test for Family Trio Association Design.

BACKGROUND: Family-based design is one of the most popular designs in genetic studies. Transmission disequilibrium test (TDT) for family trio design is optimal only under the additive trait model and may lose power under the other trait models. The TDT-type tests are powerful only when the underlying trait model is correctly specified. Usually, the true trait model is unknown, and the selection of the TDT-type test is problematic. Several methods, which are robust against the mis-specification of the trait model, have been proposed. In this paper, we propose a new efficiency robust procedure for family trio design, namely, the weighted TDT (WTDT) test.

METHODS: We combine information of the largest two TDT-type tests by using weights related to the three TDT-type tests and take the weighted sum as the test statistic.

RESULTS: Simulation results demonstrate that WTDT has power close to, but much more robust than, the optimal TDT-type test based on a single trait model. WTDT also outperforms other efficiency robust methods in terms of power. Applications to real and simulated data from Genetic Analysis Workshop (GAW15) illustrate the practical application of the WTDT method.

CONCLUSION: WTDT is not only efficiency robust to model mis-specifications but also efficiency robust against mis-specifications of risk allele.