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Robust Age at Onset Linkage Analysis in Nuclear Families

Objective: Standard methods for linkage analysis ignore the phenotype of the parents when they are not genotyped. However, this information can be useful for gene mapping. In this paper we propose methods for age at onset genetic linkage analysis in sibling pairs, taking into account parental age at onset. Methods:Two new score statistics are derived, one from an additive gamma frailty model and one from a log-normal frailty model. The score statistics are classical non-parametric linkage (NPL) statistics weighted by a function of the age at onset of the four family members. The weight depends on information from registries (age-specific incidences) and family studies (sib-sib and father-mother correlation). Results:In order to investigate how age at onset of sibs and their parents affect the information for linkage analysis the weight functions were studied for rare and common disease models, realistic models for breast cancer and human lifespan. We studied the performance of the weighted NPL methods by simulations. As illustration, the score statistics were applied to the GAW12 data. The results show that it is useful to include parental age at onset information in genetic linkage analysis.