Extensions to sib-pair linkage tests applicable to disorders characterized by delayed onset

Extensions of the approach to sib-pair linkage tests developed by Haseman and Elston [Behav Genet 2:3-19, 1972] are proposed which incorporate information on age of onset and age at examination. Alternate sources for the age of onset corrections are described, including models for the estimation of parameters associated with the age of onset distribution. Simulation is used to examine the performance of the approach when applied to a dominant disorder of late onset for a range of recombination fractions ranging from very tight linkage to free recombination. For each set of genetic parameters, 2,000 samples of 50 four-member sibships were generated under a complete ascertainment model to investigate power and Type I error, and to compare variants of the proposed technique. Results with and without age-of-onset correction are compared to each other and to those obtainable if penetrance were complete, i.e., if there were no intervening age-of-onset phenomenon. Results from simulation studies show that significance probabilities are enhanced in the presence of linkage when age-of-onset extensions are used. The proposed methods are associated with acceptable levels of Type I error, and substantive gains in power are obtained when data related to age of onset and age at examination are incorporated into the analysis.