The weighted-sum method can be adapted to a wide range of study designs, by e.g. the following: (A) Using the posterior probability of each genotype rather than the most probable genotype. (B) Analysing mutations in conserved areas by weighting each mutation according to the measure of conservation; this is an extension of the conservation base selection criterion from [7]. (C) Analysing continuous traits by testing for correlation between genetic ranks (or scores) and the trait measure. Furthermore, the weighted-sum method can be used for other types of data that can be grouped according to function. Such data include for example methylation measures, where multiple regions/sites can be methylated in promotor regions (i.e. the CpG islands). Note that ranking can be omitted in the test procedure, so the test statistic is the sum of the genetic scores (γi) of all affected individuals, rather than the sum of ranks. In the tests performed in this study, the two procedures yield very similar results (results not shown), but we prefer to use the ranking procedure because it is robust to outliers.
