cit (version 2.3.2)

fdr.cit: Omnibus FDR Values for CIT

Description

Results including permutation results from cit.cp or cit.bp from multiple tests are used in a permutation-based approach to compute false discovery rates (q-values) for each test. q-values are computed for the omnibus test as well as all component tests. q-values are returned with confidence intervals to quantify uncertainty in the estimate.

Usage

fdr.cit( cit.perm.list, cl=.95, c1=NA )

Value

A dataframe which includes the following columns:

p.raw

CIT (omnibus intersection/union test, IUT) p-value, max of component p-values

q.cit

CIT (omnibus FDR intersection/union test, IUT) q-value, permutation-based FDR, function of component test FDR values

q.ll.cit

Lower 95 percent confidence limit (if cl=.95) for q.cit estimate

q.ul.cit

Upper 95 percent confidence limit (if cl=.95) for q.cit estimate

q.TaL

component q-value (FDR) for the test of association between T and L

q.ll.TaL

Lower 95 percent confidence limit (if cl=.95) for q.TaL estimate

q.ul.TaL

Upper 95 percent confidence limit (if cl=.95) for q.TaL estimate

q.TaGgvL

component q-value (FDR) for the test of association between T and G|L

q.ll.TaGgvL

Lower 95 percent confidence limit (if cl=.95) for q.TaGgvL estimate

q.ul.TaGgvL

Upper 95 percent confidence limit (if cl=.95) for q.TaGgvL estimate

q.GaLgvT

component q-value (FDR) for the test of association between G and L|T

q.ll.GaLgvT

Lower 95 percent confidence limit (if cl=.95) for q.GaLgvT estimate

q.ul.GaLgvT

Upper 95 percent confidence limit (if cl=.95) for q.GaLgvT estimate

q.LiTgvG

component q-value (FDR) for the equivalence test of L ind T|G

q.ll.LiTgvG

Lower 95 percent confidence limit (if cl=.95) for the equivalence test of L ind T|G

q.ul.LiTgvG

Upper 95 percent confidence limit (if cl=.95) for the equivalence test of L ind T|G

Arguments

cit.perm.list

List, where each item is a dataframe output from cit.cp or cit.bp, which must be run with n.perm > 0.

cl

Confidence level for the q-value confidence interval (default is .95).

c1

Over-dispersion parameter. Setting the over-dispersion parameter to one corresponds to the assumption that all tests (referring to multiple omnibus tests conducted using different sets of variables) are independent. The default (c1=NA) is to use an empirically estimated over-dispersion parameter based on the permutation results.

Author

Joshua Millstein

Details

For the initial cit.cp and cit.bp test computations, we suggest setting n.perm to 100 or greater for moderate numbers of tests, say 10s or 100s. Larger numbers of permutations will generate more precise FDR estimates but require substantial computation time. If a large number of tests, say 1000s, have been conducted, then n.perm can be as small as 10 and still generate good FDR estimates and confidence intervals. FDR confidence intervals are especially useful to quantify uncertainty when FDR value > 0.05. The over-dispersion parameter should be set to one if it is known that all tests are independent, however, this is rarely the case in typical multiple testing settings. The fdr.cit function can also be used with simulated data in order to generate power calculations. In this case the over-dispersion parameter may be estimated from pilot data or other datasets and fixed to the prior estimate using the c1 argument. The omnibus CIT FDR value is generated as the maximum FDR across the four component tests, in an intesection-union type of approach analogous to the method used to generate the omnibus CIT p-value in cit.cp and cit.bp.

It is important to be aware that there are certain conditions under which this permutation-based FDR is not stable. This includes the case where all observed tests achieve the significance level and the case where there are zero positive tests among the permuted results. In the latter case, we take the conservative approach of setting the number of positive permutation tests to one. Both these cases produce an NA for the upper confidence limit. The latter problem may be alleviated by increasing the number of permutations conducted.

References

Millstein J, Chen GK, Breton CV. 2016. cit: hypothesis testing software for mediation analysis in genomic applications. Bioinformatics. btw135. PMID: 27153715. Millstein J, Volfson D. 2013. Computationally efficient permutation-based confidence interval estimation for tail-area FDR. Frontiers in Genetics | Statistical Genetics and Methodology 4(179):1-11.

Examples

# Sample Size
ss = 100
n.perm = 20
perm.index = matrix(NA, nrow=ss, ncol=n.perm )
for( j in 1:ncol(perm.index) ) perm.index[, j] = sample( 1:ss )

n.tests = 20
myresults = vector('list', n.tests)

for( tst in 1:n.tests ){

	# Errors
	e1 = matrix(rnorm(ss),ncol=1)
	e2 = matrix(rnorm(ss),ncol=1)

	# Simulate genotypes, gene expression, and clinical traits
	L = matrix(rbinom(ss,2,.5),ncol=1)
	G =  matrix(.5*L + e1,ncol=1)
	T =  matrix(.3*G + e2,ncol=1)
	T = ifelse( T > median(T), 1, 0 )

	myresults[[ tst ]] = cit.bp(L, G, T, perm.index=perm.index, n.perm=n.perm)
}
fdr.cit( myresults )