Gene Sets Net Correlations Analysis

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Description

Performs Gene Sets Net Correlation Analysis (GSNCA) test to detect differentially coexpressed gene sets.

Usage

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GSNCAtest(object, group, nperm=1000, cor.method="pearson", check.sd=TRUE, 
min.sd=1e-3, max.skip=10, pvalue.only=TRUE)

Arguments

object

a numeric matrix with columns and rows respectively corresponding to samples and features.

group

a numeric vector indicating group associations for samples. Possible values are 1 and 2.

nperm

number of permutations used to estimate the null distribution of the test statistic. If not given, a default value 1000 is used.

cor.method

a character string indicating which correlation coefficient is to be computed. Possible values are “pearson” (default), “spearman” and “kendall”.

check.sd

logical. Should the standard deviations of features checked for small values before the intergene correlations are computed? Default is TRUE (recommended).

min.sd

the minimum allowed standard deviation for any feature. If any feature has a standard deviation smaller than min.sd the execution stops and an error message is returned.

max.skip

maximum number of skipped random permutations which yield any feature with a standard deviation less than min.sd.

pvalue.only

logical. If TRUE (default), the p-value is returned. If FALSE a list of length three containing the observed statistic, the vector of permuted statistics, and the p-value is returned.

Details

This function performs the Gene Sets Net Correlations Analysis (GSNCA), a two-sample nonparametric multivariate differential coexpression test that accounts for the correlation structure between features (genes). The test assigns weight factors to features under one condition and adjust these weights simultaneously such that equality is achieved between each feature's weight and the sum of its weighted absolute correlations with other features in the feature set. The problem is solved as an eigenvector problem with a unique solution (see Rahmatallah et. al. 2014 for details). The test statistic w_{GSNCA} is given by the first norm between the scaled weight vectors w^{(1)} and w^{(2)} (each vector is multiplied by its norm) between two conditions

w = ∑_{i=1}^{p} | w_{i}^{(1)} - w_{i}^{(2)} |

This test statistic tests the null hypothesis that w=0 against the alternative that w does not equal to zero. The performance of this test was thoroughly examind in Rahmatallah et. al. (2014). The null distribution of the test statistic is estimated by permuting sample labels nperm times and calculating the test statistic for each. P-value is calculated as

p.value = \frac{∑_{k=1}^{nperm} I ≤ft[ W_{k} ≥q W_{obs} \right] + 1}{nperm+1}

where W_{k} is the test statistic for permutation k, W_{obs} is the observed test statistic, and I is the indicator function.

In the case of RNA-seq count data, some non-expressed genes may have zero counts across the samples under one or two conditions. Such situation results in zero or tiny standard deviation for one or more features. Such case produces an error in command cor used to compute the correlation coefficients between features. To avoid this situation, standard deviations are checked in advance when check.sd is TRUE (default) and if any is found below the minimum limit min.sd (default is 1e-3), the execution stops and an error message is returned indicating the number of feature causing the problem (if only one the index of that feature is given too). If a feature has nearly a constant level for some samples under both conditions, permuting sample labels may group such samples under one condition and produce a standard deviation smaller than min.sd. To allow the test to skip such permutations without causing excessive delay, we set an upper limit for the number of allowed skips by the argument max.skip (default is 10). If the upper limit is exceeded, an error message is returned. Allowing this skipping may or may not solve the issue depending on the proportion of samples causing the problem in the feature set.

If the user is certain that the tested feature sets contain no feature with nearly equal levels over many samples (such as the case with microarrays), the checking stage for tiny standard deviations can be skipped by setting check.sd to FALSE in order to reduce the execution time.

Value

When pvalue.only=TRUE (default), function GSNCAtest returns the p-value indicating the attained significance level. When pvalue.only=FALSE, function GSNCAtest produces a list of length 3 with the following components:

statistic

the value of the observed test statistic.

perm.stat

numeric vector of the resulting test statistic for nperm random permutations of sample labels.

p.value

p-value indicating the attained significance level.

Author(s)

Yasir Rahmatallah and Galina Glazko

References

Rahmatallah Y., Emmert-Streib F. and Glazko G. (2014) Gene sets net correlations analysis (GSNCA): a multivariate differential coexpression test for gene sets. Bioinformatics 30, 360–368.

See Also

findMST2, plotMST2.pathway.

Examples

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## generate a feature set of length 20 in two conditions
## each condition has 20 samples
## use multivariate normal distribution with different covariance matrices
library(MASS)
ngenes <- 20
nsamples <- 40
zero_vector <- array(0,c(1,ngenes))
## create a covariance matrix with low off-diagonal elements
cov_mtrx1 <- diag(ngenes)
cov_mtrx1[!diag(ngenes)] <- 0.1
## create a covariance matrix with high off-diagonal elements
## for the first 5 features and low for the rest 15 features
cov_mtrx2 <- diag(ngenes)
cov_mtrx2[!diag(ngenes)] <- 0.1
mask <- diag(ngenes/4)
mask[!diag(ngenes/4)] <- 0.6
cov_mtrx2[1:(ngenes/4),1:(ngenes/4)] <- mask
gp1 <- mvrnorm((nsamples/2), zero_vector, cov_mtrx1)
gp2 <- mvrnorm((nsamples/2), zero_vector, cov_mtrx2)
gp <- rbind(gp1,gp2)
dataset <- aperm(gp, c(2,1))
## first 20 samples belong to group 1
## second 20 samples belong to group 2
pvalue <- GSNCAtest(object=dataset, group=c(rep(1,20),rep(2,20)))