Genelevel Empirical Bayes (EB) false discovery rate (FDR) analysis for somatic mutations in cancer
Description
Empirical Bayes estimates of the False Discovery Rate (FDR) and passenger probabilities in the analysis of somatic mutations in cancer.
Usage
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26  cma.fdr(cma.alter,
cma.cov,
cma.samp,
scores = c("CaMP", "logLRT"),
passenger.rates = t(data.frame(.55*rep(1.0e6,25))),
allgenes=TRUE,
estimate.p0=FALSE,
p0.step=1,
p0=1,
eliminate.noval=FALSE,
filter.threshold=0,
filter.above=0,
filter.below=0,
filter.mutations=0,
aa=1e10,
bb=1e10,
priorH0=1500/13020,
prior.a0=100,
prior.a1=5,
prior.fold=10,
M=2,
DiscOnly=FALSE,
PrevSamp="Sjoeblom06",
KnownCANGenes=NULL,
showFigure=FALSE,
cutoffFdr=0.1)

Arguments
cma.alter 
Data frame with somatic mutation information, broken down by
gene, sample, screen, and mutation type.
See 
cma.cov 
Data frame with the total number of nucleotides "at
risk" ("coverage"), broken down by gene, screen, and mutation type.
See 
cma.samp 
Data frame with the number of samples analyzed,
broken down by gene and screen.
See 
scores 
Vector with the scores which are to be computed.
It can include: 
passenger.rates 
Data frame of passenger mutation rates per nucleotide, by type, or "context". If two rows are present, the first refers to the Discovery screen and the second to the Prevalence screen. 
allgenes 
If TRUE, genes where no mutations were found are considered in the analysis. 
estimate.p0 
If TRUE, estimates the percent of genes with only
passenger mutations. Requires 
p0.step 
Size of bins of histograms in the distribution of scores, to use in estimating p0 if estimate.p0 = TRUE. All scores are in the log 10 scale. 
p0 
Proportion of genes with only
passenger mutations. Only used if 
eliminate.noval 
If 
filter.threshold 
This and the following three input control filtering of genes, allowing to exclude genes from analysis, by size and number of mutations. Different criteria can be set above and below this threshold. The threshold is a gene size in base pairs. 
filter.above 
Minimum number of mutations per
Mb, applied to genes of size greater than 
filter.below 
Minimum number of mutations per
Mb, applied to genes of size lower than 
filter.mutations 
Only consider genes
whose total number of mutations is greater than or equal to

aa 
Hyperparameter of beta prior used in compute.binomial.posterior. 
bb 
Hyperparameter of beta prior used in compute.binomial.posterior. 
priorH0 
Prior probability of the null hypothesis, used to convert the BF in compute.poisson.BF to a posterior probability 
prior.a0 
Shape hyperparameter of gamma prior on passenger rates used in compute.poisson.BF 
prior.a1 
Shape hyperparameter of gamma prior on nonpassenger rates used in compute.poisson.BF 
prior.fold 
Hyperparameter of gamma prior on nonpassenger
rates used compute.poisson.BF. The mean of the gamma is set so that
the ratio of the mean to the passenger rate is the specified

M 
The number of null datasets generated to get the false discovery rates. Numbers on the order of 100 are recommended, but this will cause the function to run very slowly. 
DiscOnly 
If TRUE, only considers data from Discovery screen. 
PrevSamp 
If "Sjoeblom06", then the experimental design from Sjoeblom et al. or Wood et al. is used, namely, genes "pass" from the Discovery into the Prevalence (or Validation) screens if they are mutated at least once in the Discovery samples. If "Parsons11", the experimental design from Parsons et al. 2011 is approximated, namely, in the null datasets, a gene passes into the Prevalence screen if it is mutated at least once, and is found on a specified list of known cancer candidate (CAN) genes, or if it is mutated at least twice. 
KnownCANGenes 
Vector of known CAN genes, to be used if PrevSamp is not set to "Sjoeblom07". 
showFigure 
If TRUE, displays a figure for each score in

cutoffFdr 
If 
Value
A list of data frames. Each gives a gene genebygene significance for one of the score requested. The columns in each data frame are:
score 
The score requested (e.g. the LRT). 
F 
Number of genes experimentally observed to give a larger score than the gene in question. 
F0 
Number of genes giving a larger score than the gene in question in datasets simulated from passenger mutation rates. 
Fdr 
The Empirical Bayes False Discovery Rate, as defined in Efron and Tibshirani 2002. 
fdr 
The Empirical Bayes Local False Discovery Rate, as defined in Efron and Tibshirani 2002. 
p0 
Scalar, Proportion of genes with only
passenger mutations. Estimated or passed on from input (depending on
whether estimate.p0 is 
Author(s)
Giovanni Parmigiani, Simina M. Boca
References
Efron B, Tibshirani R. Empirical Bayes methods and false discovery rates for microarrays. Genetic Epidemiology. DOI: 10.1002/gepi.1124
Parmigiani G, Lin J, Boca S, Sjoeblom T, Kinzler KW, Velculescu VE, Vogelstein B. Statistical methods for the analysis of cancer genome sequencing data, 2007. http://www.bepress.com/jhubiostat/paper126/
Sjoeblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber T, Mandelker D, Leary R, Ptak J, Silliman N, et al. The consensus coding sequences of breast and colorectal cancers. Science. DOI: 10.1126/science.1133427
Wood LD, Parsons DW, Jones S, Lin J, Sjoeblom, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, et al. The Genomic Landscapes of Human Breast and Colorectal Cancer. Science. DOI: 10.1126/science.1145720
Parsons DW, Jones S, Zhang X, Lin JCH, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu I, et al. An Integrated Genomic Analysis of Human Glioblastoma Multiforme. Science. DOI: 10.1126/science.1164382
Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. DOI: 10.1126/science.1164368
Parsons DW, Li M, Zhang X, Jones S, Leary RJ, Lin J, Boca SM, Carter H, Samayoa J, Bettegowda C, et al. The genetic landscape of the childhood cancer medulloblastoma. Science. DOI: 10.1126/science.1198056
See Also
GeneCov
, GeneSamp
, GeneAlter
,
BackRates
,cma.scores
Examples
1 2 3 4 5 6 7 8 9 10 11  data(ParsonsMB11)
set.seed(188310)
cma.fdr.out < cma.fdr(cma.alter = GeneAlterMB,
cma.cov = GeneCovMB,
cma.samp = GeneSampMB,
allgenes = TRUE,
estimate.p0=FALSE,
eliminate.noval=FALSE,
filter.mutations=0,
M = 2)
names(cma.fdr.out)
