Concordance of disease form in kindreds ascertained through affected individuals

When designing or conducting genetic epidemiological studies of a disease with several distinct forms, it is useful to know whether susceptibilities to the different forms are conferred by different genes or whether there are genes that confer susceptibility to multiple forms. A natural approach to exploring these issues is to examine how the disease forms cluster in kindreds. When inclusion in the study is based on the affection status of multiple relatives, however, distorted patterns of familial clustering of disease form can be evident. The purpose here is to present statistical methods for adjusting for this distortion. In particular, approaches to testing two null hypotheses are presented: a null hypothesis that corresponds to all genes acting in the same way on the relative risk of the different disease forms, and a null hypothesis that corresponds to each gene conferring susceptibility to distinct disease forms. The approaches are illustrated through an application to the generalized and localization-related forms of epilepsy.