The weighted-sum method deviates from the CAST method [5],[27] by weighting the variants differently when determining the genetic load of an individual. By weighting the signals from each mutation, the weighted sum method accentuates mutations that are rare in the unaffected individuals, so that the test is not completely dominated by common mutations. In the CAST method, common variants will have a high impact on the group signal, and if many common mutations are present in a group, almost all individuals will have one or more mutations. To avoid this effect it may be necessary to use a threshold on the mutation-frequencies, as suggested in the CMC method [26]. A drawback of such frequency thresholds is that it can be difficult to select them in a biological meaningful way, and the outcome of the test will depend on the selection of thresholds. In the weighted-sum method we include mutations of all frequencies, but mutations are weighted according to their frequency in the unaffected individuals.
