This is the Combined and Multivariate Collapsing (CMC, Li and Leal, 2008) test for rare variants. CMC method considers all variants in a test unit (e.g., a gene). It “collapses” all rare variants in the gene region such that the region is coded “0” if all loci are wildtype, and “1” if any one locus has a minor allele. Then it “combines” this coding with the rest of common variants in the gene region into a multivariate problem that tests for the null hypothesis that the gene region is not associated with a disease or quantitative trait. The statistic for CMC method can be \(\chi^2\) test for collapsed rare variants, Hotelling's \(T^2\) or multivariate regression analysis for joint analysis of common and rare variants. This program implements CMC method for rare variants with Fisher's exact test for evaluating association between rare variants and disease phenotypes (case/ctrl data). The use of Fisher's test results in exact p-value, avoiding the computationally intensive permutation procedure.
This test only works for case control data without covariates. Please refer to CollapseBt and CollapseQt for case control and quantitative traits using the collapsing theme under regression framework that incorporates covariates.
vtools show test CFisher
Name: CFisher
Description: Fisher's exact test on collapsed variant loci, Li & Leal 2008
usage: vtools associate --method CFisher [-h] [--name NAME] [-q1 MAFUPPER]
[-q2 MAFLOWER] [--alternative TAILED]
[--midp]
[--moi {additive,dominant,recessive}]
Collapsing test for case-control data (CMC test, Li & Leal 2008). Different
from the original publication which jointly test for common/rare variants
using Hotelling's t^2 method, this version of CMC will binaries rare variants
(default frequency set to 0.01) within a group defined by "--group_by" and
calculate p-value via Fisher's exact test. A "mid-p" option is available for
one-sided test to obtain a less conservative p-value estimate.
optional arguments:
-h, --help show this help message and exit
--name NAME Name of the test that will be appended to names of
output fields, usually used to differentiate output of
different tests, or the same test with different
parameters. Default set to "CFisher"
-q1 MAFUPPER, --mafupper MAFUPPER
Minor allele frequency upper limit. All variants
having sample MAF<=m1 will be included in analysis.
Default set to 0.01
-q2 MAFLOWER, --maflower MAFLOWER
Minor allele frequency lower limit. All variants
having sample MAF>m2 will be included in analysis.
Default set to 0.0
--alternative TAILED Alternative hypothesis is one-sided ("1") or two-sided
("2"). Default set to 1
--midp This option, if evoked, will use mid-p value
correction for one-sided Fisher's exact test.
--moi {additive,dominant,recessive}
Mode of inheritance. Will code genotypes as 0/1/2/NA
for additive mode, 0/1/NA for dominant or recessive
model. Default set to additive
vtools associate rare status -m "CFisher --name Fisher --alternative 2" --group_by name2 --\
to_db cfisher -j8 > cfisher.txt
INFO: 3180 samples are found
INFO: 2632 groups are found
INFO: Starting 8 processes to load genotypes
Loading genotypes: 100% [======================================] 3,180 32.9/s in 00:01:36
Testing for association: 100% [====================================] 2,632/147 26.5/s in 00:01:39
INFO: Association tests on 2632 groups have completed. 147 failed.
INFO: Using annotation DB cfisher in project test.
INFO: Annotation database used to record results of association tests. Created on Wed, 30 Jan 2013 22:06:07
vtools show fields | grep cfisher
cfisher.name2 name2
cfisher.sample_size_Fisher sample size
cfisher.num_variants_Fisher number of variants in each group (adjusted for specified MAF
cfisher.total_mac_Fisher total minor allele counts in a group (adjusted for MOI)
cfisher.statistic_Fisher test statistic.
cfisher.pvalue_Fisher p-value
head cfisher.txt
name2 sample_size_Fisher num_variants_Fisher total_mac_Fisher statistic_Fisher pvalue_Fisher
AAMP 3180 3 35 1.27335 0.593442
ABCD3 3180 3 42 0.821622 1
ABCB10 3180 6 122 1.33481 0.250852
ABCB6 3180 7 151 0.91265 0.895567
ABHD1 3180 5 29 0.913443 1
ABCG8 3180 12 152 0.641297 0.15483
ABCA12 3180 28 312 0.979172 1
ABI2 3180 1 25 3.00046 0.020062
ACADM 3180 4 103 0.477756 0.0807384
This collapsing test for rare variant is based on an exact test which guarantees to control for type I error yet may be overly conservative. Mid-P values are a reasonable compromise between the conservativeness of the ordinary exact test and the uncertain adequacy of large-sample methods. --midp switch gives Mid-P values for one-sided exact test
vtools associate rare status -m "CFisher --name FisherMidP --alternative 1 --midp" --group_\
by name2 --to_db cfisher -j8 > cfisher-midp.txt
INFO: 3180 samples are found
INFO: 2632 groups are found
Loading genotypes: 100% [==========================] 3,180 33.3/s in 00:01:35
Testing for association: 100% [================================] 2,632/147 25.9/s in 00:01:41
INFO: Association tests on 2632 groups have completed. 147 failed.
INFO: Using annotation DB cfisher in project test.
INFO: Annotation database used to record results of association tests. Created on Wed, 30 Jan 2013 22:14:57
vtools show fields | grep cfisher
cfisher.name2 name2
cfisher.sample_size_FisherMidP sample size
cfisher.num_variants_FisherMidP number of variants in each group (adjusted for specified MAF
cfisher.total_mac_FisherMidP total minor allele counts in a group (adjusted for MOI)
cfisher.statistic_FisherMidP test statistic.
cfisher.pvalue_FisherMidP p-value
head cfisher-midp.txt
name2 sample_size_FisherMidP num_variants_FisherMidP total_mac_FisherMidP statistic_FisherMidP pvalue_FisherMidP
AAMP 3180 3 35 1.27335 0.298742
ABCB6 3180 7 151 0.91265 0.620991
ABCG5 3180 6 87 1.26073 0.228907
ABHD1 3180 5 29 0.913443 0.529454
ABI2 3180 1 25 3.00046 0.0127947
ABL2 3180 4 41 1.05884 0.431808
ABCG8 3180 12 152 0.641297 0.932016
ABCA4 3180 43 492 1.01841 0.448273
ABCA12 3180 28 312 0.979172 0.535912
Bingshan Li and Suzanne M. Leal (2008) Methods for Detecting Associations with Rare Variants for Common Diseases: Application to Analysis of Sequence Data. The American Journal of Human Genetics doi:10.1016/j.ajhg.2008.06.024. http://linkinghub.elsevier.com/retrieve/pii/S0002929708004084