get.post.probs: Main posterior probability calculation

In kdkorthauer/MADGiC: Fits an empirical Bayesian hierarchical model to obtain posterior probabilities that each gene is a driver.

Description

This function reads in an MAF data file, exome annotation, and pre-computed prior information and then fits a hierarchical emprical Bayesian model to obtain posterior probabilities that each gene is a driver.

Usage

  get.post.probs(maf.file,
    exome.file = system.file("data/exome_36.RData", package = "MADGiC"),
    gene.rep.expr.file = system.file("data/gene.rep.expr.RData", package = "MADGiC"),
    gene.names.file = system.file("data/gene_names.txt", package = "MADGiC"),
    prior.file = system.file("data/prior.RData", package = "MADGiC"),
    alpha = 0.2, beta = 6, N = 20, replication.file = NULL,
    expression.file = NULL)

Arguments

maf.file	name of an MAF (Mutation Annotation Format) data file containing the somatic mutations. Currently, NCBI builds 36 and 37 are supported.
exome.file	name of an .RData file that annotates every position of the exome for how many transitions/transversions are possible, whether each change is silent or nonsilent, and the SIFT scores for each possible change
gene.rep.expr.file	name of an .RData file that annotates every gene for its Ensembl name, chromosome, base pair positions, replication timing region, and expression level.
gene.names.file	name of a text file containing the Ensembl names of all genes.
prior.file	name of an .RData file containing a named vector of prior probabilities that each gene is a driver, obtained from positional information in the COSMIC database.
N	integer number of simulated datasets to be used in the estimation of the null distribution of functional impact scores. The default value is 20 (see shuffle.muts).
expression.file	(optional) name of a .txt file containing gene expression data if user wishes to supply one (default is to use an average expression signal of the CCLE). The .txt file should have two columns and no header. The first column should contain the Ensembl Gene ID (using Ensembl 54 for hg18) and the second column should contain the expression measurements. These can be raw or log-scaled but should be normalized if normalization is desired.
replication.file	(optional) name of a .txt file containing replication timing data if user wishes to supply one (default is to use data from Chen et al. (2010)). The .txt file should have two columns and no header. The first column should contain the Ensembl Gene ID (using Ensembl 54 for hg18) and the second column should contain the replication timing measurements.
alpha	numeric value of first shape parameter of the prior Beta distribution on the probability of mutation for driver genes. Default value of 0.2 is chosen as a compromise between a cancer type with a relatively low mutation rate (Ovarian cancer, fitted value from COSMIC of 0.15) and one with a comparatively high mutation rate (Squamous cell lung, fitted value from COSMIC of 0.27), but results are robust to changes in this parameter. Note that intuitively (and empirically), a higher mutation rate overall leads to a higher driver mutation rate overall - and thus less mass is concentrated in the left tail of the distribution.
beta	numeric value of second shape parameter of the prior Beta distribution on the probability of mutation for driver genes. Default value of 6 is chosen as a compromise between a cancer type with a relatively low mutation rate (Ovarian cancer, fitted value from COSMIC of 6.6) and one with a comparatively high mutation rate (Squamous cell lung, fitted value from COSMIC of 5.83), but results are robust to changes in this parameter. Note that intuitively (and empirically), a higher mutation rate overall leads to a higher driver mutation rate overall - and thus less mass is concentrated in the left tail of the distribution.

Details

The typical user only need specify the MAF file they wish to analyze. The other fields (exome annotation, gene annotation, gene names, and prior probabilities) have been precomputed and distributed with this package.

Value

a named vector of posterior probabilities that each gene is a driver

Examples

## Not run: 

# pointer to the MAF file to be analyzed
maf.file <- system.file("data/OV.maf",package="MADGiC")

# calculation of posterior probabilities that each gene is a driver
post.probs <- get.post.probs(maf.file)

# Modify default settings to match TCGA ovarian analysis in paper
post.probs <- get.post.probs(maf.file, N=100, alpha=0.15, beta=6.6)

## End(Not run)

kdkorthauer/MADGiC documentation built on June 13, 2020, 1:35 p.m.