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, heterogenei ty, and misdiagnosis make mode-of-inheritance determinations even more unreliable. The mode of inheritance can also be determined using a li nkage-based method (maximized maximum lod score or mod score) and asso ciation-based methods, which can overcome many of these problems. In t his 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 penet rance and with varying fractions of linked and unlinked families. We t hen analyzed those data sets, assuming reduced penetrance, both domina nt and recessive inheritance, and no heterogeneity. We investigated th e reliability of two methods for determining the mode of inheritance f rom the linkage data. The first method examined the difference (Delta) between the maximum lod scores calculated under the two mode-of-inher itance assumptions. We found that if Delta was >1.5, then the higher o f 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 correct mode-of-inheritance inference. Furthermore, this reliability appeared to be virtually independent of alpha, the fractio n of linked families in the data set, although the reliability decreas ed slightly as alpha fell below .50. The second method we tested was b ased on choosing the higher of the two maximum lod scores calculated u nder 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.