Table 2.

Summary of Statistical Methods for Rare-Variant Association Testing

	Description	Methods	Advantage	Disadvantage	Software Packagesa
Burden tests	collapse rare variants into genetic scores	ARIEL test,50 CAST,51 CMC method,52 MZ test,53 WSS54	are powerful when a large proportion of variants are causal and effects are in the same direction	lose power in the presence of both trait-increasing and trait-decreasing variants or a small fraction of causal variants	EPACTS, GRANVIL, PLINK/SEQ, Rvtests, SCORE-Seq, SKAT, VAT
Adaptive burden tests	use data-adaptive weights or thresholds	aSum,55 Step-up,56 EREC test,57 VT,58 KBAC method,59 RBT60	are more robust than burden tests using fixed weights or thresholds; some tests can improve result interpretation	are often computationally intensive; VT requires the same assumptions as burden tests	EPACTS, KBAC, PLINK/SEQ, Rvtests, SCORE-Seq, VAT
Variance-component tests	test variance of genetic effects	SKAT,61 SSU test,62 C-alpha test63	are powerful in the presence of both trait-increasing and trait-decreasing variants or a small fraction of causal variants	are less powerful than burden tests when most variants are causal and effects are in the same direction	EPACTS, PLINK/SEQ, SCORE-Seq, SKAT, VAT
Combined tests	combine burden and variance-component tests	SKAT-O,64 Fisher method,65 MiST66	are more robust with respect to the percentage of causal variants and the presence of both trait-increasing and trait-decreasing variants	can be slightly less powerful than burden or variance-component tests if their assumptions are largely held; some methods (e.g., the Fisher method) are computationally intensive	EPACTS, PLINK/SEQ, MiST, SKAT
EC test	exponentially combines score statistics	EC test67	is powerful when a very small proportion of variants are causal	is computationally intensive; is less powerful when a moderate or large proportion of variants are causal	no software is available yet

Abbreviations are as follows: 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 parallelizable 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; and WSS, weighted-sum statistic.

^aMore information is given in Table 3.