Gene set analysis

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Description

Determines the significance of pre-defined sets of genes with respect to an outcome variable, such as a group indicator, a quantitative variable or a survival time

Usage

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GSA(x,y, genesets, genenames,
method=c("maxmean","mean","absmean"), resp.type=c("Quantitative","Two class unpaired","Survival","Multiclass", "Two class paired", "tCorr", "taCorr"),
censoring.status=NULL,random.seed=NULL,  knn.neighbors=10,
s0=NULL, s0.perc=NULL,minsize=15,maxsize=500,
restand=TRUE,restand.basis=c("catalog","data"),
 nperms=200, 
xl.mode=c("regular","firsttime","next20","lasttime"), 
xl.time=NULL, xl.prevfit=NULL)

Arguments

x

Data x: p by n matrix of features (expression values), one observation per column (missing values allowed); y: n-vector of outcome measurements

y

Vector of response values: 1,2 for two class problem, or 1,2,3 ... for multiclass problem, or real numbers for quantitative or survival problems

genesets

Gene set collection (a list)

genenames

Vector of genenames in expression dataset

method

Method for summarizing a gene set: "maxmean" (default), "mean" or "absmean"

resp.type

Problem type: "quantitative" for a continuous parameter; "Two class unpaired" ; "Survival" for censored survival outcome; "Multiclass" : more than 2 groups, coded 1,2,3...; "Two class paired" for paired outcomes, coded -1,1 (first pair), -2,2 (second pair), etc

censoring.status

Vector of censoring status values for survival problems, 1 mean death or failure, 0 means censored

random.seed

Optional initial seed for random number generator (integer)

knn.neighbors

Number of nearest neighbors to use for imputation of missing features values

s0

Exchangeability factor for denominator of test statistic; Default is automatic choice

s0.perc

Percentile of standard deviation values to use for s0; default is automatic choice; -1 means s0=0 (different from s0.perc=0, meaning s0=zeroeth percentile of standard deviation values= min of sd values)

minsize

Minimum number of genes in genesets to be considered

maxsize

Maximum number of genes in genesets to be considered

restand

Should restandardization be done? Default TRUE

,

restand.basis

What should be used to do the restandardization? The set of genes in the genesets ("catalog", the default) or the genes in the data set ("data")

nperms

Number of permutations used to estimate false discovery rates

xl.mode

Used by Excel interface

xl.time

Used by Excel interface

xl.prevfit

Used by Excel interface

Details

Carries out a Gene set analysis, as described in the paper by Efron and Tibshirani (2006). It differs from a Gene Set Enrichment Analysis (Subramanian et al 2006) in its use of the "maxmean" statistic: this is the mean of the positive or negative part of gene scores in the gene set, whichever is large in absolute values. Efron and Tibshirani shows that this is often more powerful than the modified KS statistic used in GSEA. GSA also does "restandardization" of the genes (rows), on top of the permutation of columns (done in GSEA). Gene set analysis is applicable to microarray data and other data with a large number of features. This is also the R package that is called by the "official" SAM Excel package v3.0. The format of the response vector y and the calling sequence is illustrated in the examples below. A more complete description is given in the SAM manual at http://www-stat.stanford.edu/~tibs/SAM

Value

A list with components

GSA.scores

Gene set scores for each gene set

GSA.scores.perm

Matrix of Gene set scores from permutions, one column per permutation

fdr.lo

Estimated false discovery rates for negative gene sets (negative means lower expression correlates with class 2 in two sample problems, lower expression correlates with increased y for quantitative problems, lower expression correlates with higher risk for survival problems)

fdr.hi

Estimated false discovery rates for positive gene sets; positive is opposite of negative, as defined above

pvalues.lo

P-values for negative gene sets

pvalues.hi

P-values for positive gene sets

stand.info

Information from restandardization process

stand.info.star

Information from restandardization process in permutations

ngenes

Number of genes in union of gene sets

nperms

Number of permutations used

gene.scores

Individual gene scores (eg t-statistics for two class problem)

s0

Computed exchangeability factor

s0.perc

Computed percentile of standard deviation values. s0= s0.perc percentile of the gene standard deviations

call

The call to GSA

x

For internal use

y

For internal use

genesets

For internal use

genenames

For internal use

r.obs

For internal use

r.star

For internal use

gs.mat

For internal use

gs.ind

For internal use

catalog

For internal use

catalog.unique

For internal use

Author(s)

Robert Tibshirani

References

Efron, B. and Tibshirani, R. On testing the significance of sets of genes. Stanford tech report rep 2006. http://www-stat.stanford.edu/~tibs/ftp/GSA.pdf

Subramanian, A. and Tamayo, P. Mootha, V. K. and Mukherjee, S. and Ebert, B. L. and Gillette, M. A. and Paulovich, A. and Pomeroy, S. L. and Golub, T. R. and Lander, E. S. and Mesirov, J. P. (2005) A knowledge-based approach for interpreting genome-wide expression profiles. PNAS. 102, pg 15545-15550.

Examples

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######### two class unpaired comparison
# y must take values 1,2

set.seed(100)
x<-matrix(rnorm(1000*20),ncol=20)
dd<-sample(1:1000,size=100)

u<-matrix(2*rnorm(100),ncol=10,nrow=100)
x[dd,11:20]<-x[dd,11:20]+u
y<-c(rep(1,10),rep(2,10))


genenames=paste("g",1:1000,sep="")

#create some random gene sets
genesets=vector("list",50)
for(i in 1:50){
 genesets[[i]]=paste("g",sample(1:1000,size=30),sep="")
}
geneset.names=paste("set",as.character(1:50),sep="")

GSA.obj<-GSA(x,y, genenames=genenames, genesets=genesets,  resp.type="Two class unpaired", nperms=100)


GSA.listsets(GSA.obj, geneset.names=geneset.names,FDRcut=.5)



#to use  "real" gene set collection, we read it in from a gmt file:
# 
# geneset.obj<- GSA.read.gmt("file.gmt")
# 
# where file.gmt is a gene set collection from GSEA collection or
#  or the website http://www-stat.stanford.edu/~tibs/GSA, or one
# that you have created yourself. Then

#   GSA.obj<-GSA(x,y, genenames=genenames, genesets=geneset.obj$genesets,  resp.type="Two class unpaired", nperms=100)
#
#