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Table 1 Summary of the features, the pros and cons of the different type of methods described in this review and the software currently available

From: The impact of rare and low-frequency genetic variants in common disease

Type of method Methods Main features Ability to discriminate risk and protective alleles Range of study designs they can be applied to Allelic architecture scenarios the method is compatible with Available software
Burden test ARIEL test [53], RWAS [54], CAST [55], CMC method [56], MZ Test [57], WSS [58], aSum [59], Step-up [60], EREC test [61], VT [62], KBAC method [63], RBT [64] Collapsing genetic variants into a single score, assumption that tested variants are all causal and associated with the trait with the same direction and magnitude of effect No Causal variants, e.g. loss of function (LoF) variants All variants have the same direction and magnitude of effect ARIEL, EPACTS, GRANVIL, PLINK/SEQ, Rvtests, SCORE-Seq, SKAT, VAT, KBAC, RAREMETAL
Variance-component test C-Alpha test [67], SKAT [68], SSU test [69], KBAT [70] Allowing for both risk and protective alleles, i.e. tested variants can have different directions of effect Yes Applicable to all available variants, possibly using some weighting strategy Variants can have opposing directions of effect EPACTS, PLINK/SEQ, SCORE-Seq, SKAT, VAT, RAREMETAL
Combined test SKAT-O [71], EMMPAT [72], Fisher method [73], MiST [74] Combining results from two or more complementary tests Yes Applicable to all available variants, possibly using some weighting strategy Variants can have both opposing or same direction of effect EPACTS, PLINK/SEQ, MiST, SKAT, RAREMETAL
Other tests LASSO [75], EC [76] Accounting for signal sparsity No Applicable to all available variants, possibly using some weighting strategy Variants are sparse MENDEL
  1. ARIEL accumulation of rare variants integrated and extended locus-specific, aSum data-adaptive sum test, CAST cohort allelic sums test, CMC combined multivariate and collapsing, EC exponential combination, EPACTS efficient and parallelisable association container toolbox, EREC estimated regression coefficient, GRANVIL gene- or region-based analysis of variants of intermediate and low-frequency, KBAC kernel-based adaptive cluster, MiST mixed-effects score test for continuous outcomes, MZ Morris and Zeggini, RBT replication-based test, Rvtests rare-variant tests, SKAT sequence kernel association test, SSU sum of squared score, VAT variant association tools, VT variable threshold, WSS weighted-sum statistic