The mutation weights () can be chosen in an infinite number of ways. We suggest using the estimated standard deviation of the total number of mutations in the sample (including affected and unaffected individuals), under the null hypothesis of no frequency differences between affected and unaffected individuals. This choice of weight ensures that all variants in a group contribute equally to the weighted sum, under the null hypothesis. The weight of each mutation is determined by its frequency in the population of unaffected individuals only. In this way, a mutation which is common among unaffected individuals has lower weight than a mutation which is rare among the unaffected individuals. If further information about the mutations is available, it may be incorporated in the weights. Such information could include the estimated impact of a mutation or a measure of conservation of the surrounding region (as discussed above).
