frequencies by purifying selection, and so common variants are most likely neutral and nonfunctional). Therefore, using prediction methods enriches for functional variants and thus boosts the power of association tests. Because such predictions are not perfect, however, they should be used quantitatively by weighing variants, rather than qualitatively by filtering out variants. A number of tests allow including prediction scores into test statistics, e.g., VT test, KBAC, SKAT, Rare variant Weighted Aggregate Statistic (RWAS)72, Likelihood Ratio Test (LRT)73. The PLINK/SEQ suite includes precomputed PolyPhen-246 prediction scores for all possible missense changes in humans, which makes these scores readily applicable.
