Table 2. Published gene-based rare variant association methods evaluated.

Method name	Citation	Software	Description
Unidirectional rare variant gene-based tests
Collapsing methods
Combined Multivariate and Collapsing (CMC)	Liu & Leal, PLoS Comp. Bio. 2008	EPACTS	All rare variants collapsed into a single variant; individual dosage for the collapsed ‘variant’ is regressed against phenotype.
Weighted and un-weighted sum methods
Variable threshold (VT)	Price et al, AJHG. 2010	PLINK-Seq	Sum of rare allele count in cases vs. controls; allele frequency threshold for inclusion is varied to maximize test statistic.
Weighted Sum Statistic (FRQWGT)	Madsen & Browning, PLoS Gen. 2009	PLINK-Seq	Permutation-based test comparing inverse-frequency-weighted rare variant counts per individual in cases vs. controls.
Weighted Sum Method (WILCOX-WSS)	Madsen & Browning, PLoS Gen. 2009	EPACTS	Wilcoxon Rank Sum test between phenotypes and inverse frequency-weighted rare variant scores.
Kernel-Based Adaptive Cluster (KBAC)	Liu & Leal, PLoS Gen. 2010	PLINK-Seq	Variant weights are determined adaptively, and are based on observed effect sizes; individuals scored by weighted sum of allele counts.
Summary case:control count methods
BURDEN method	Purcell (PLINK-Seq)	PLINK-Seq	Permutation-based test comparing raw allele counts in cases vs. controls.
UNIQ test	Purcell (PLINK-Seq)	PLINK-Seq	Simple count of total case-unique rare alleles; permutations to assess significance.
Bi-directional variance-component gene-based tests
C-ALPHA	Neale et al, PLoS Gen. 2011	PLINK-Seq	Detects deviation of observed case:control variant counts from expected binomial distribution.
Sequence Kernel Association Test (SKAT)	Wu et al, AJHG 2011	EPACTS	Generalized form of C-ALPHA with variants weighted by allele frequency.
Linear combination of unidirectional and variance-component tests
SKAT-O (‘Optimal’ SKAT)	Lee et al, AJHG. 2012	EPACTS	Adaptive linear combination of unidirectional burden test and variance-component SKAT test.
Mixed Effects Score Test (MiST)	Sun et al, Genetic Epi. 2013	Public R package	Hierarchical regression model combining two independent test statistics which quantify variant effect sizes and ‘heterogeneity’.