Supplemental Tables
Supplemental Table 1. Available statistical methods for analyzing variants discovered in sequencing studies.
Each column indicates if a given feature is available or appropriate (+) for each method. A (-) indicates that
feature is not available or appropriate.
Reference
Software
implementation
available
Appropriate for
quantitative
trait analysis
Allows for
functional
weights
Adjusts for
quantitative
covariates
Description
Incorporates
bi-directional
effects
Uses all variants
(rare and
common)
Method
Single Variant Methods
Combined
single SNP
Combine single-SNP results by Fisher’s Method, Stouffer’s method,
Mantel-Hansel
+
+
+
+
+
+
Penalized
regression
Lasso, ridge, logic regression, logistic, linear regression
+
+
+
+
+
+
Collapsing Methods
CAST
Cohort Allelic Sum Test: compares proportions of cases and controls
carrying variants
+
-
-
-
-
+
[56]
CMC
Combined Multivariate and Collapsing: divide variants into groups,
collapse, run multivariate analysis
-
-
+
+
-
+
[10]
VT
Variable-threshold test: find optimal frequency threshold for inclusion then
collapse rare variants under threshold
+
-
-
+
+
+
[58]
RareCover
Find and collapse best subset of rare variants
-
-
-
-
-
-
[59]
Reference
Software
implementation
available
Appropriate for
quantitative
trait analysis
Allows for
functional
weights
Adjusts for
quantitative
covariates
Incorporates
bi-directional
effects
Uses all variants
(rare and
common)
Method
Description
RVE
Rare Variant Exclusive: test for enrichment of rare variants present only in
cases
-
-
-
-
-
-
[41]
RWAS
Rare variant Weighted Aggregate Statistic: groups rare variants and
computes weighted sum of differences between cases and controls. Aims
to find optimal weights for variants.
-
-
-
+
-
+
[66]
CCRaVAT
Case Control Rare Variant Analysis Tool: collapse variants, analyze
enrichment in cases using 2x2 contingency table
-
-
-
-
-
+
[86]
QuTie
Quantitative Trait: use t-test to analyze differences in quantitative trait
means of carriers and non-carriers of collapsed variants
-
-
-
-
+
+
[86]
CMAT
Cumulative Minor-Allele Test: sum rare-allele counts for cases and
controls, combine in a chi-square-like statistic
+
-
+/-
+
-
+
[87]
HT
Haplotype Test: test for enrichment of rare risk haplotypes in cases
-
-
-
-
-
-
[88]
Aggregation Methods
WSS
Weighted Sum Statistic: weight variants by frequency
+
-
-
-
-
-
[61]
KBAC
Kernel-Based Adaptive Cluster
-
-
+
-
-
+
[62]
Ionita-Laza &
Lange
Test for increased burden of rare variants in cases, weighted by overrepresentation in cases
-
+
-
+
-
+
[63]
Likelihood
Ratio Test
Sum likelihoods for all possible causal states for variants, weigh variants
by estimated effect sizes.
-
-
-
+
-
+
[65]
Reference
Software
implementation
available
Appropriate for
quantitative
trait analysis
Allows for
functional
weights
Adjusts for
quantitative
covariates
Incorporates
bi-directional
effects
Uses all variants
(rare and
common)
Method
Description
RVT1/
RVT2
Linear regression where RVT1 uses phenotype as function of proportion
of rare variants that carry minor allele and RVT2 uses phenotype as
function of presence/absence of minor allele at any rare variant
-
-
+
-
+
-
[89]
Mendel
Penalized regression, group variants by gene
+
-
+
+
+
+
[90]
Bi-directional Effect Methods
C-alpha
Test for over-dispersion of rare alleles
-
+
-
+
-
-
[80]
aSum
Data-Adaptive Sum Test
+
+
-
-
-
-
[55]
KM Test
Logistic Kernel-Machine Test
+
+
+
-
+
+
[91]
Step-Up
Collapsing
Aims to find optimal grouping of variants for regression
+
+
+
+
+
+
[92]
WH
Weighed Haplotype Test: test for burden of rare risk haplotypes in cases,
weighted by haplotype frequency
-
+
-
-
-
+
[93]
IT
Imputation-based Test: test for increased sum of imputation dosages in
cases
-
+
-
-
-
+
[93]
EMMPAT
Evolutionary Mixed Model for Pooled Association Testing: regression
model using estimated fitness effects of variants
+
+
+
-
-
+
[94]