Figure 1. Overview of the nsSNP association approaches.

Panel (a) describes key features of the SNP association approaches used. Panel (b) shows, for a single hypothetical SNP, how assignment of affection status for homozygotes for the minor allele (HZMAs) varies by the approaches. The table lists cancer codes present among the HZMAs, the number of HZMAs that have the cancer code and the Fisher's p-value comparing the proportion of affected HZMAs with the cancer to the proportion in the common allele homozygotes. For this example, all of the listed cancers are assumed to be constituents of the mechanistic phenotype. For the standard genetic models, all subjects with any of the cancers are classified as cases. In contrast, the 2 reverse genetics approaches only analyze subsets of these subjects with cancers meeting pre-specified criteria, as designated by the brackets.