The antigen/allele genotype frequencies among patients (AGFAP) method has been powerful in discriminating between modes of inheritance, and detecting heterogeneity effects, for a number of diseases associated with the HLA system. The method is not dependent on the high level of polymorphism seen in the HLA system, but does require a marker allele association with disease. With recent rapid advances in mapping of the human genome, the method is increasingly relevant in all disease studies. Extension of the AGFAP method to ascertainment schemes other than random sampling of patients is presented here. The method is shown to be robust for distinguishing between incompletely penetrant recessive vs. additive or dominant models if affected children are obtained from nuclear families selected on the basis of at least two affected members: two affected sibs, or an affected parent and affected child. The method can lead to false conclusions for data from families ascertained for at least one affected parent and two affected children. A new test, termed the parental contributions test, applicable in families selected for the presence of an affected parent, and one or more affected children, is presented. The test, based on the expected symmetry (recessive) vs. asymmetry (additive and dominant) of parental marker allele contributions to an affected offspring in these pedigrees, is powerful in distinguishing between these modes of inheritance when there is a marker allele association with disease. Sporadic cases of disease are shown to cause deviations from AGFAP expectations for the recessive model, but not for the additive model. These results will aid in study of the genetics, and hence molecular basis, of complex diseases. © 1993 Wiley-Liss, Inc.