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  1. 1. Introduction
  2. 2. Details
    1. 2.1 Command interface
    2. 2.2 Application

1.  Introduction

This implements the variable thresholds version of aggregation methods. Similar to the VT method, the VariableThresholdsBt and VariableThresholdsQt tests use a variable thresholds definition for the rare variants being considered such that multiple test statistics are calculated for an aggregation unit. The final statistic is taken as the one that gives the best result. Type I error is controlled due to the use of permutation testing.

Results from variable thresholds methods have one additional column, i.e., an MAF column reporting the statistic of VT at which it is derived.

2.  Details

2.1  Command interface

vtools show test VariableThresholdsBt
Name:          VariableThresholdsBt
Description:   Variable thresholds method for disease traits, in the spirit of Price
               et al 2010
usage: vtools associate --method VariableThresholdsBt [-h] [--name NAME]
                                                      [-q1 MAFUPPER]
                                                      [-q2 MAFLOWER]
                                                      [--alternative TAILED]
                                                      [-p N] [--permute_by XY]
                                                      [--adaptive C]
                                                      [--NA_adjust]
                                                      [--moi {additive,dominant,recessive}]

Variable thresholds in burden test for disease traits (in the spirit of Price
et al 2010). The burden test statistic of a group of variants will be
maximized over subsets of variants defined by applying different minor allele
frequency thresholds. Significance of the statistic obtained is evaluated via
permutation

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.
  -q1 MAFUPPER, --mafupper MAFUPPER
                        Minor allele frequency upper limit. All variants
                        having sample MAF<=m1 will be included in analysis.
                        Default set to 1.0
  -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
  -p N, --permutations N
                        Number of permutations
  --permute_by XY       Permute phenotypes ("Y") or genotypes ("X"). Default
                        is "Y"
  --adaptive C          Adaptive permutation using Edwin Wilson 95 percent
                        confidence interval for binomial distribution. The
                        program will compute a p-value every 1000 permutations
                        and compare the lower bound of the 95 percent CI of
                        p-value against "C", and quit permutations with the
                        p-value if it is larger than "C". It is recommended to
                        specify a "C" that is slightly larger than the
                        significance level for the study. To disable the
                        adaptive procedure, set C=1. Default is C=0.1
  --NA_adjust           This option, if evoked, will replace missing genotype
                        values with a score relative to sample allele
                        frequencies. The association test will be adjusted to
                        incorporate the information. This is an effective
                        approach to control for type I error due to
                        differential degrees of missing genotypes among
                        samples.
  --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 show test VariableThresholdsQt
Name:          VariableThresholdsQt
Description:   Variable thresholds method for quantitative traits, in the spirit of
               Price et al 2010
usage: vtools associate --method VariableThresholdsQt [-h] [--name NAME]
                                                      [-q1 MAFUPPER]
                                                      [-q2 MAFLOWER]
                                                      [--alternative TAILED]
                                                      [-p N] [--permute_by XY]
                                                      [--adaptive C]
                                                      [--NA_adjust]
                                                      [--moi {additive,dominant,recessive}]

Variable thresholds in burden test for quantitative traits (in the spirit of
Price et al 2010). The burden test statistic of a group of variants will be
maximized over subsets of variants defined by applying different minor allele
frequency thresholds. Significance of the statistic obtained is evaluated via
permutation

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.
  -q1 MAFUPPER, --mafupper MAFUPPER
                        Minor allele frequency upper limit. All variants
                        having sample MAF<=m1 will be included in analysis.
                        Default set to 1.0
  -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
  -p N, --permutations N
                        Number of permutations
  --permute_by XY       Permute phenotypes ("Y") or genotypes ("X"). Default
                        is "Y"
  --adaptive C          Adaptive permutation using Edwin Wilson 95 percent
                        confidence interval for binomial distribution. The
                        program will compute a p-value every 1000 permutations
                        and compare the lower bound of the 95 percent CI of
                        p-value against "C", and quit permutations with the
                        p-value if it is larger than "C". It is recommended to
                        specify a "C" that is slightly larger than the
                        significance level for the study. To disable the
                        adaptive procedure, set C=1. Default is C=0.1
  --NA_adjust           This option, if evoked, will replace missing genotype
                        values with a score relative to sample allele
                        frequencies. The association test will be adjusted to
                        incorporate the information. This is an effective
                        approach to control for type I error due to
                        differential degrees of missing genotypes among
                        samples.
  --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
                        mode. Default set to additive

2.2  Application

Example using snapshot vt_ExomeAssociation

vtools associate rare status --covariates age gender bmi exposure -m "VariableThresholdsBt \
--name VariableThresholdsBt --alternative 2 -p 5000 --permute_by X --adaptive 0.05" --group\
_by name2 --to_db variablethresholdsBt -j8 > variablethresholdsBt.txt

vtools show fields | grep variablethresholdsBt.txt

head variablethresholdsBt.txt

vtools associate rare bmi --covariates age gender exposure -m "VariableThresholdsQt --name \
VariableThresholdsQt --alternative 2 -p 5000 --permute_by X --adaptive 0.05" --group_by nam\
e2 --to_db variablethresholdsQt -j8 > variablethresholdsQt.txt
INFO: 3180 samples are found
INFO: 2632 groups are found
INFO: Starting 8 processes to load genotypes
Loading genotypes: 100% [=========================================================================================================================================] 3,180 34.2/s in 00:01:33
Testing for association: 100% [================================================================================================================================] 2,632/147 2.8/s in 00:15:35
INFO: Association tests on 2632 groups have completed. 147 failed.
INFO: Using annotation DB variablethresholdsQt in project test.
INFO: Annotation database used to record results of association tests. Created on Thu, 31 Jan 2013 22:54:27
vtools show fields | grep variablethresholdsQt.txt
variablethresholdsQt.name2   name2
variablethresholdsQt.sample_size_VariableThresholdsQt sample size
variablethresholdsQt.num_variants_VariableThresholdsQt number of variants in each group (adjusted for specified MAF
                             upper/lower bounds)
variablethresholdsQt.total_mac_VariableThresholdsQt total minor allele counts in a group (adjusted for MOI)
variablethresholdsQt.beta_x_VariableThresholdsQt test statistic. In the context of regression this is estimate of
                             effect size for x
variablethresholdsQt.pvalue_VariableThresholdsQt p-value
variablethresholdsQt.std_error_VariableThresholdsQt Empirical estimate of the standard deviation of statistic under the
                             null
variablethresholdsQt.num_permutations_VariableThresholdsQt number of permutations at which p-value is evaluated
variablethresholdsQt.MAF_threshold_VariableThresholdsQt The minor allele frequency at which the test statistic is maximized
head variablethresholdsQt.txt
name2	sample_size_VariableThresholdsQt	num_variants_VariableThresholdsQt	total_mac_VariableThresholdsQt	beta_x_VariableThresholdsQt	pvalue_VariableThresholdsQt	std_error_VariableThresholdsQt	num_permutations_VariableThresholdsQt	MAF_threshold_VariableThresholdsQt
ABCB10	3180	6	122	5.93777	0.247752	3.68504	1000	0.000157233
ABCD3	3180	3	42	-1.48612	0.301698	0.740477	1000	0.00267296
AADACL4	3180	5	138	-1.70538	0.151848	0.927952	1000	0.00157233
AAMP	3180	3	35	2.352	0.0666445	0.923285	3000	0.00220126
ABCB6	3180	7	151	1.98423	0.655345	3.83344	1000	0.000157233
ABI2	3180	1	25	0	0.993007	0	1000	0.00393082
ABHD1	3180	5	29	-1.81424	0.257742	1.19045	1000	0.000314465
ABCG8	3180	12	152	-3.48381	0.143856	1.26176	1000	0.000786164
ACAP3	3180	3	17	2.70541	0.281718	2.01218	1000	0.000314465