Using lod-score differences to determine mode of inheritance: a simple, robust method even in the presence of heterogeneity and reduced penetrance.

Determining the mode of inheritance is often difficult under the best of circumstances, but when segregation analysis is used, the problems of ambiguous ascertainment procedures, reduced penetrance, heterogeneity, and misdiagnosis make mode-of-inheritance determinations even more unreliable. The mode of inheritance can also be determined using a linkage-based method and association-based methods, which can overcome many of these problems. In this work, we determined how much information is necessary to reliably determine the mode of inheritance from linkage data when heterogeneity and reduced penetrance are present in the data set. We generated data sets under both dominant and recessive inheritance with reduced penetrance and with varying fractions of linked and unlinked families. We then analyzed those data sets, assuming reduced penetrance, both dominant and recessive inheritance, and no heterogeneity. We investigated the reliability of two methods for determining the mode of inheritance from the linkage data. The first method examined the difference ({Delta}) between the maximum lod scores calculated under the two mode-of-inheritance assumptions. We found that if {Delta} was >1.5, then the higher of the two maximum lod scores reflected the correct mode of inheritance with high reliability and that a {Delta} of 2.5 appeared to practically guarantee a correctmore » mode-of-inheritance inference. Furthermore, this reliability appeared to be virtually independent of {alpha}, the fraction of linked families in the data set. The second method we tested was based on choosing the higher of the two maximum lod scores calculated under the different mode-of-inheritance assumptions. This method became unreliable as {alpha} decreased. These results suggest that the mode of inheritance can be inferred from linkage data with high reliability, even in the presence of heterogeneity and reduced penetrance. 12 refs., 3 figs., 2 tabs.« less