R/anomSegStats.R
In amstilp/GWASTools: Tools for Genome Wide Association Studies
#####
# Function to calculate LRR and BAF stats for anomalous segments
#####
anomSegStats <- function(intenData, genoData,
snp.ids, # vector of "int.id"s for 'eligible' snps (usually missing.n1<1 and excluding HLA and XTR regions)
anom, # data.frame with "scanID", "chromosome", "left.index","right.index","sex"
centromere, # data.frame with centromere positions, with variables "chromosome", "left.base", "right.base"
lrr.cut= -2, # the function counts the number of eligible LRR values less than this lrr.cut
verbose=TRUE)
{
# modified from anom.seg.stats.baf.lrr.v3.r
# v2 adds calculation of the length of each anomaly
# v3 adds several new stats and renames some of the old ones; rename some of the input variables in anom
# use 'eligible' instead of separate snp.exclude baf and lrr;
# calculate 'nmark.baf' and 'nmark.lrr' for each anomaly regardless of 'method'
# allow for missing value codes other than -1 for genotypes
# v4 adds stats to distiguish wide splits from heterozygous deletions using LOH detection
# for each snp, calculate y = min of absolute value of BAF deviations from 0 and 1
# then yh = y>0 and genotype call = 0 or 2 (i.e. homozygous)
# and ya = y>0 and y<0.25 and genotype call = 0, 2 or missing
# for the anom and non-anom regions, get mean of ya and yh and mean of sqrt(ya) and sqrt(yh)
# mean of yh called "anom.homo.dev" and "non.anom.homo.dev"
# mean of ya called "anom.homo.na.dev" and "non.anom.homo.na.dev"
# mean of sqrt(yh) called "anom.homo.sqrt" and "non.anom.homo.sqrt"
# mean of sqrt(ya) called "anom.homo.na.sqrt" and non.anom.homo.na.sqrt"
# v5 make calculation of homo stats optional
# v6 add MAD for non-anom LRR
# v7 add stats for detecting terminal anomalies
# v8 more on terminal anoms
# v9 add stats for analysis anoms that span the centromere - number of elig markers on each side of centromere and distance they span
# v10 stats for Cooper metric
# v11 add check for chromosome matching in anom and cent
# v12 remove the restriction that any variables calculated by anom stats be excluded from the input data set (they will just be replaced anyway)
# v13 allows centromere stats for chr 24 (pseudo-autosomal)
# v14 require "method" and "anom.id", variables in anom
# v15 adds a count of the number of eligible LRR markers with value < lrr.cut
# v16 adds SD and MAD for BAF and LRR for eligible markers within the anomaly
# v17 adds mean for BAF for eligible markers within the anomaly
# NOTE: WHEN REVISING THIS FUNCTION TO CREATE A NEW VARIABLE IN THE ANOM DATA.FRAME, DEFINE IT AS NA IN THE SECTION BELOW ("results will be added...")
# check that intenData has BAF/LRR
if (!hasBAlleleFreq(intenData)) stop("BAlleleFreq not found in intenData")
if (!hasLogRRatio(intenData)) stop("LogRRatio not found in intenData")
# check that dimensions of intenData and genoData are equal
intenSnpID <- getSnpID(intenData)
genoSnpID <- getSnpID(genoData)
if (!all(intenSnpID == genoSnpID)) stop("snp dimensions of intenData and genoData differ")
intenScanID <- getScanID(intenData)
genoScanID <- getScanID(genoData)
if (!all(intenScanID == genoScanID)) stop("scan dimensions of intenData and genoData differ")
intid <- intenSnpID
sid <- intenScanID
indices <- 1:length(intid)
chrom <- getChromosome(intenData)
pos <- getPosition(intenData)
nsnp <- nsnp(intenData)
# check and supplement centromere
if(class(centromere)!="data.frame") stop("centromere should be a data.frame")
if(!all(is.element(c("chrom","left.base","right.base"), names(centromere)))) stop("names of centromere must include chrom, left.base, right.base")
centromere$chrom[is.element(centromere$chrom, "X")] <- XchromCode(intenData)
centromere$chrom[is.element(centromere$chrom, "Y")] <- YchromCode(intenData)
centromere$chrom[is.element(centromere$chrom, "XY")] <- XYchromCode(intenData)
centromere$chrom <- as.integer(centromere$chrom)
centromere <- centromere[, c("chrom","left.base","right.base")]
if(!all(is.element(anom$chromosome, centromere$chrom))) stop("centromere must include all 'chromosome' values in anom")
centromere <- centromere[order(centromere$chrom),]
if(sum(duplicated(centromere$chrom))!=0) stop("chromosome in centromere must not be duplicated")
if(!all(is.element(anom$chromosome, centromere$chrom))) stop("chromosome in centromere does not include all those in anom")
# get indices of markers adjacent to centromere
centromere$left.index <- NA
centromere$right.index <- NA
for(i in 1:nrow(centromere)){
left <- centromere$left.base[i] - pos
right <- pos - centromere$right.base[i]
chr.sel <- chrom==centromere$chrom[i]
left.sel <- chr.sel & left>0
right.sel <- chr.sel & right>0
if(sum(left.sel)>0) { # this is needed for the acrocentric chroms with no markers left of the centromere
lmin <- min(left[chr.sel & left>0])
lind <- indices[chr.sel & left==lmin]
centromere$left.index[i] <- lind[length(lind)]
}
if(sum(right.sel)>0) { # for symmetry even though all chroms should have markers right of the centromere
rmin <- min(right[chr.sel & right>0])
rind <- indices[chr.sel & right==rmin]
centromere$right.index[i] <- rind[length(rind)]
}
}
setw <- which(!is.na(centromere$left.index) & !is.na(centromere$right.index))
for(i in setw){
tmpind <- indices[indices>centromere$left.index[i] & indices<centromere$right.index[i]]
tmpid <- intid[tmpind]
if(any(is.element(tmpid,snp.ids))) stop("eligible snps in centromere gap")
}
# check anom
if(class(anom)!="data.frame") stop("anom should be a data.frame")
if(!all(is.element(c("scanID", "chromosome", "left.index","right.index","sex","method","anom.id"),names(anom)))) stop("anom does not have required variable names")
if(!all(is.element(c(anom$left.index,anom$right.index),indices))) stop("left.index and/or right.index are not within range of snp indices")
ok.chrom <- c(autosomeCode(intenData), XchromCode(intenData), XYchromCode(intenData))
if(!all(anom$chromosome %in% ok.chrom)) stop("chromosome must be integer code for autosomes, X, or XY")
# check eligible and get selection vector
eligible <- snp.ids
if(!all(is.element(eligible,intid))) stop("eligible values must be snpIDs")
elig <- is.element(intid, eligible)
# unique samples with anoms
anom <- anom[order(anom$scanID),]
snum <- unique(anom$scanID)
n <- length(snum)
# results will be added on to the anom data.frame
m <- nrow(anom)
anom$left.method <- rep(NA,m) # first letter of method (for BAF-LOH merges)
anom$right.method <- rep(NA,m) # last letter of method
anom$nmark.all <- rep(NA,m) # total number of probes on the array from left.index to right.index inclusive
anom$nmark.elig <- rep(NA,m) # total number of eligible probes on the array from left.index to right.index, inclusive
anom$left.base <- rep(NA,m) # base position corresponding to left.index
anom$right.base <- rep(NA,m) # base position corresponding to right.index
anom$nbase <- rep(NA,m) # number of bases from left.index to right.index, inclusive
anom$non.anom.baf.med <- rep(NA, m) # BAF median of non-anomalous segments on all autosomes, using (eligible & is.element(geno,c(1,-1))
anom$non.anom.lrr.med <- rep(NA, m) # LRR median of non-anomalous segments on all autosomes, using eligible snps
anom$non.anom.lrr.mad <- rep(NA,m) # MAD for LRR of non-anomalous segments on all autosomes
anom$anom.baf.dev.med <- rep(NA,m) # BAF median of deviations of points used to detect anomaly(eligible & is.element(geno,c(1,-1)) from non.anom.baf.med
anom$anom.baf.dev.5 <- rep(NA,m) # BAF median of deviations of points used to detect anomaly(eligible & is.element(geno,c(1,-1)) from 0.5
anom$anom.baf.dev.mean <- rep(NA,m) # BAF mean of deviations of points used to detect anomaly(eligible & is.element(geno,c(1,-1)) from non.anom.baf.med
anom$anom.baf.sd <- rep(NA,m) # SD of BAF deviations from non.anom.baf.med for points used to detect anomaly
anom$anom.baf.mad <- rep(NA,m) # MAD of BAF deviations from non.anom.baf.med for points used to detect anomaly
anom$anom.lrr.med <- rep(NA,m) # LRR median of eligible markers in the anomaly
anom$anom.lrr.sd <- rep(NA,m) # SD of LRR for eligible points within the anomaly
anom$anom.lrr.mad <- rep(NA,m) # MAD of LRR for eligible points within the anomaly
anom$nmark.baf <- rep(NA,m) # number of markers eligible for baf detection
anom$nmark.lrr <- rep(NA,m) # number of markers eligible for lrr detection
# for detecting terminal anomalies
anom$cent.rel <- rep(NA,m) # position relative to centromere - left, right, span
anom$left.most <- rep(NA,m) # T/F is this the left-most anomaly for this sample-chrom
anom$right.most <- rep(NA,m) # T/F is this the right-most anomaly for this sample-chrom
anom$left.last.elig <- rep(NA,m) # T/F if it contains the last eligible marker going to the left
anom$right.last.elig <- rep(NA,m) # T/F if it contains the last eligible marker going to the right
anom$left.term.lrr.med <- rep(NA,m) # median of LRR for all markers from leftmost eligible marker to the left telomere (only calculated for the most distal anom)
anom$right.term.lrr.med <- rep(NA,m) # median of LRR for all markers from rightmost eligible marker to the right telomere
anom$left.term.lrr.n <- rep(NA,m) # sample size for calculating median LRR
anom$right.term.lrr.n <- rep(NA,m)
# for analyzing centromere-spanning anomalies
anom$cent.span.left.elig.n <- rep(NA,m) # number of eligible markers on the left side of centromere-spanning anomalies
anom$cent.span.right.elig.n <- rep(NA,m) # number of eligible markers on the right side of centromere-spanning anomalies
anom$cent.span.left.bases <- rep(NA,m) # length of anomaly covered by eligible markers on the left side of the centromere
anom$cent.span.right.bases <- rep(NA,m) # length of anomaly covered by eligible markers on the right side of the centromere
anom$cent.span.left.index <- rep(NA,m) # index of elig marker left-adjacent to centromere
anom$cent.span.right.index <- rep(NA,m) # index of elig marker right-adjacent to centromere
# Cooper metric = sqrt(min(BAF,1-BAF,abs(BAF-M))) for eligible markers, where M is the median BAF over non-anomalous autosomal segments
anom$bafmetric.anom.mean <- rep(NA,m)
anom$bafmetric.non.anom.mean <- rep(NA,m)
anom$bafmetric.non.anom.sd <- rep(NA,m)
# number of eligible lrr markers with value less than lrr.cut
anom$nmark.lrr.low <- rep(NA,m)
# check method values
anom$left.method <- substr(anom$method,1,1)
tmp<- nchar(anom$method)
anom$right.method <- substr(anom$method, tmp, tmp)
if(!all(is.element(anom$left.method,c("B","L")) & is.element(anom$right.method,c("F","H","B","L")))) stop("method values should begin with B or L and end with F,H,B,L")
r <- 1 # counter for row number in anom
for(i in 1:n) { # for each sample 1:n
# get all data for the ith sample
dat <- anom[is.element(anom$scanID, snum[i]),]
sind <- which(is.element(sid, snum[i]))
geno <- getGenotype(genoData, snp=c(1,-1), scan=c(sind,1))
baf <- getBAlleleFreq(intenData, snp=c(1,-1), scan=c(sind,1))
lrr <- getLogRRatio(intenData, snp=c(1,-1), scan=c(sind,1))
# make missing genotype calls equal -1 (regardless of missing value code)
geno[is.na(geno)] <- -1
# get vector to select eligible markers not in anomalies
k <- nrow(dat)
ai <- NULL #indices included in anomalies
for(j in 1:k) ai <- c(ai, dat$left.index[j]:dat$right.index[j])
non.baf <- is.element(chrom, autosomeCode(intenData)) & is.element(intid, eligible) & !is.element(indices, ai) & is.element(geno, c(1,-1))
non.lrr <- is.element(chrom, autosomeCode(intenData)) & is.element(intid, eligible) & !is.element(indices, ai)
# calculate median of baf and lrr in non-anomalous regions
baf.non.med <- median(baf[non.baf], na.rm=TRUE)
lrr.non.med <- median(lrr[non.lrr], na.rm=TRUE)
# calculate MAD of lrr in non-anomalous regions
lrr.non.mad <- mad(lrr[non.lrr], na.rm=TRUE)
# calculate stats in anomalous segments
# eligible points used for anomaly detection
ebaf <- is.element(intid, eligible) & is.element(geno, c(1,-1))
elrr <- is.element(intid, eligible)
# Cooper metric
coop <- sqrt(pmin( (baf-0), (1-baf), abs(baf-baf.non.med) ))
coop.non.mean <- mean(coop[non.baf], na.rm=TRUE)
coop.non.sd <- sd(coop[non.baf], na.rm=TRUE)
# loop through anomalies within sample
for(j in 1:k){ # for each anomaly within a sample
# MARKER NUMBERS
anom$nmark.all[r] <- dat$right.index[j] - dat$left.index[j] + 1
anom$nmark.elig[r] <- sum(is.element(intid,eligible)[dat$left.index[j]:dat$right.index[j]])
# BAF
baf.sel <- ebaf & indices>=dat$left.index[j] & indices<=dat$right.index[j] & !is.na(baf)
baf.dev <- abs(baf[baf.sel]-baf.non.med)
anom$anom.baf.dev.med[r] <- median(baf.dev)
anom$anom.baf.dev.mean[r] <- mean(baf.dev)
baf.dev <- abs(baf[baf.sel]- 0.5)
anom$anom.baf.dev.5[r] <- median(baf.dev)
anom$non.anom.baf.med[r] <- baf.non.med
anom$nmark.baf[r] <- sum(baf.sel)
anom$anom.baf.sd[r] <- sd(baf.dev)
anom$anom.baf.mad[r] <- mad(baf.dev)
# COOPER METRIC
anom$bafmetric.anom.mean[r] <- mean(coop[baf.sel])
anom$bafmetric.non.anom.mean[r] <- coop.non.mean
anom$bafmetric.non.anom.sd[r] <- coop.non.sd
# LRR
lrr.sel <- elrr & indices>=dat$left.index[j] & indices<=dat$right.index[j] & !is.na(lrr)
anom$anom.lrr.med[r] <- median(lrr[lrr.sel])
anom$non.anom.lrr.med[r] <- lrr.non.med
anom$non.anom.lrr.mad[r] <- lrr.non.mad
anom$nmark.lrr[r] <- sum(lrr.sel)
anom$nmark.lrr.low[r] <- sum(lrr[lrr.sel] < lrr.cut)
anom$anom.lrr.sd[r] <- sd(lrr[lrr.sel])
anom$anom.lrr.mad[r] <- mad(lrr[lrr.sel])
# BASES
anom$left.base[r] <- pos[dat$left.index[j]]
anom$right.base[r] <- pos[dat$right.index[j]]
anom$nbase[r] <- anom$right.base[r] - anom$left.base[r] + 1
# CENTROMERE
# find relation to centromere
chrj <- anom$chromosome[r]
left <- anom$right.base[r] <= centromere$left.base[centromere$chrom==chrj]
right <- anom$left.base[r] >= centromere$right.base[centromere$chrom==chrj]
span <- anom$left.base[r] <= centromere$left.base[centromere$chrom==chrj] &
anom$right.base[r] >= centromere$right.base[centromere$chrom==chrj]
if(left) anom$cent.rel[r] <- "left"
if(right) anom$cent.rel[r] <- "right"
if(span) anom$cent.rel[r] <- "span"
if(is.na(anom$cent.rel[r])) { stop(paste("i=",i,"j=",j,"\ncent.rel is missing")) }
# for centromere-spanning, find number of eligible markers (method dependent) and length spanned by elig markers on each side
if(anom$cent.rel[r]=="span" & !is.element(anom$method[r], c("BAF","LOH")) ) {
warning(paste("sample",anom$scanID[r],"chromosome", anom$chromosome[r],"spans centromere and has non-standard method", anom$method[r],
"so centromere check will not be done"))
}
if(anom$cent.rel[r]=="span" & is.element(anom$method[r],c("BAF","LOH"))){
if(is.element(anom$method[r],"LOH")) { elog <- elrr } else { elog <- ebaf }
left.elig <- which(elog & indices >= anom$left.index[r] & indices <= centromere$left.index[centromere$chrom==chrj])
right.elig <- which(elog & indices >= centromere$right.index[centromere$chrom==chrj] & indices <= anom$right.index[r])
nle <- length(left.elig)
nre <- length(right.elig)
anom$cent.span.left.elig.n[r] <- nle # number of eligible markers in anom left of the centromere
anom$cent.span.right.elig.n[r] <- nre
anom$cent.span.left.bases[r] <- pos[left.elig[nle]] - pos[left.elig[1]]+ 1 # number of bases covered by eligible markers in the anom left of the centromere *
anom$cent.span.right.bases[r] <- pos[right.elig[nre]] - pos[right.elig[1]] + 1
anom$cent.span.left.index[r] <- left.elig[nle] # index of eligible marker just left of the centromere (for splitting if necessary)
anom$cent.span.right.index[r] <- right.elig[1]
}
# TERMINAL
# is it the most distal anomaly in this sample-chrom?
datc <- dat[dat$chromosome==anom$chromosome[r],c("left.index","right.index")]
anom$left.most[r] <- anom$left.index[r]==min(datc$left.index)
anom$right.most[r] <- anom$right.index[r]==max(datc$right.index)
# check whether all markers distal to the breakpoint are ineligible, which depends on method
# method will be BAF, LOH (for original anoms) or BL, LB for merged anoms (corresponding to BAF left end and LOH right end or vice versa)
sel.chrom <- chrom==anom$chromosome[r]
if(anom$left.most[r]){
anom$left.last.elig[r] <- FALSE
if(is.element(anom$left.method[r],"L")){
chk.left <- all(!elrr[ sel.chrom & indices < anom$left.index[r] ]) # all distal markers not elig
}
if(is.element(anom$left.method[r],"B")){
chk.left <- all(!ebaf[ sel.chrom & indices < anom$left.index[r] ]) # all distal markers not elig
}
if(chk.left){ # get median lrr for left-distal markers
anom$left.last.elig[r] <- TRUE
chr.ind <- indices[sel.chrom]
left <- chr.ind[1]; right <- anom$left.index[r]-1
anom$left.term.lrr.n[r] <- right-left+1
if(right>=left) anom$left.term.lrr.med[r] <- median(lrr[left:right], na.rm=TRUE)
}
}
if(anom$right.most[r]){
anom$right.last.elig[r] <- FALSE
if(is.element(anom$left.method[r],c("L","H"))){
chk.right <- all(!elrr[ sel.chrom & indices > anom$right.index[r] ]) # all distal markers not elig
}
if(is.element(anom$left.method[r],c("B","F"))){
chk.right <- all(!ebaf[ sel.chrom & indices > anom$right.index[r] ]) # all distal markers not elig
}
if(chk.right){ # get median lrr for right-distal markers
anom$right.last.elig[r] <- TRUE
chr.ind <- indices[sel.chrom]; ni <- length(chr.ind)
left <- anom$right.index[r]+1; right <- chr.ind[ni]
anom$right.term.lrr.n[r] <- right-left+1
if(right>=left) anom$right.term.lrr.med[r] <- median(lrr[left:right], na.rm=TRUE)
}
}
# increment counter
#message(paste("r=",r))
r <- r+1
} # end loop over anomalies within a sample
# print status
if(verbose & i %% 100 == 0) message(paste("sample", i, "of", n))
} # end loop over samples
# remove "left.method" and "right.method"
anom$left.method <- NULL
anom$right.method <- NULL
return(anom)
}
amstilp/GWASTools documentation built on May 10, 2019, 1:08 a.m.
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#####
# Function to calculate LRR and BAF stats for anomalous segments
#####
anomSegStats <- function(intenData, genoData,
snp.ids, # vector of "int.id"s for 'eligible' snps (usually missing.n1<1 and excluding HLA and XTR regions)
anom, # data.frame with "scanID", "chromosome", "left.index","right.index","sex"
centromere, # data.frame with centromere positions, with variables "chromosome", "left.base", "right.base"
lrr.cut= -2, # the function counts the number of eligible LRR values less than this lrr.cut
verbose=TRUE)
{
# modified from anom.seg.stats.baf.lrr.v3.r
# v2 adds calculation of the length of each anomaly
# v3 adds several new stats and renames some of the old ones; rename some of the input variables in anom
# use 'eligible' instead of separate snp.exclude baf and lrr;
# calculate 'nmark.baf' and 'nmark.lrr' for each anomaly regardless of 'method'
# allow for missing value codes other than -1 for genotypes
# v4 adds stats to distiguish wide splits from heterozygous deletions using LOH detection
# for each snp, calculate y = min of absolute value of BAF deviations from 0 and 1
# then yh = y>0 and genotype call = 0 or 2 (i.e. homozygous)
# and ya = y>0 and y<0.25 and genotype call = 0, 2 or missing
# for the anom and non-anom regions, get mean of ya and yh and mean of sqrt(ya) and sqrt(yh)
# mean of yh called "anom.homo.dev" and "non.anom.homo.dev"
# mean of ya called "anom.homo.na.dev" and "non.anom.homo.na.dev"
# mean of sqrt(yh) called "anom.homo.sqrt" and "non.anom.homo.sqrt"
# mean of sqrt(ya) called "anom.homo.na.sqrt" and non.anom.homo.na.sqrt"
# v5 make calculation of homo stats optional
# v6 add MAD for non-anom LRR
# v7 add stats for detecting terminal anomalies
# v8 more on terminal anoms
# v9 add stats for analysis anoms that span the centromere - number of elig markers on each side of centromere and distance they span
# v10 stats for Cooper metric
# v11 add check for chromosome matching in anom and cent
# v12 remove the restriction that any variables calculated by anom stats be excluded from the input data set (they will just be replaced anyway)
# v13 allows centromere stats for chr 24 (pseudo-autosomal)
# v14 require "method" and "anom.id", variables in anom
# v15 adds a count of the number of eligible LRR markers with value < lrr.cut
# v16 adds SD and MAD for BAF and LRR for eligible markers within the anomaly
# v17 adds mean for BAF for eligible markers within the anomaly
# NOTE: WHEN REVISING THIS FUNCTION TO CREATE A NEW VARIABLE IN THE ANOM DATA.FRAME, DEFINE IT AS NA IN THE SECTION BELOW ("results will be added...")
# check that intenData has BAF/LRR
if (!hasBAlleleFreq(intenData)) stop("BAlleleFreq not found in intenData")
if (!hasLogRRatio(intenData)) stop("LogRRatio not found in intenData")
# check that dimensions of intenData and genoData are equal
intenSnpID <- getSnpID(intenData)
genoSnpID <- getSnpID(genoData)
if (!all(intenSnpID == genoSnpID)) stop("snp dimensions of intenData and genoData differ")
intenScanID <- getScanID(intenData)
genoScanID <- getScanID(genoData)
if (!all(intenScanID == genoScanID)) stop("scan dimensions of intenData and genoData differ")
intid <- intenSnpID
sid <- intenScanID
indices <- 1:length(intid)
chrom <- getChromosome(intenData)
pos <- getPosition(intenData)
nsnp <- nsnp(intenData)
# check and supplement centromere
if(class(centromere)!="data.frame") stop("centromere should be a data.frame")
if(!all(is.element(c("chrom","left.base","right.base"), names(centromere)))) stop("names of centromere must include chrom, left.base, right.base")
centromere$chrom[is.element(centromere$chrom, "X")] <- XchromCode(intenData)
centromere$chrom[is.element(centromere$chrom, "Y")] <- YchromCode(intenData)
centromere$chrom[is.element(centromere$chrom, "XY")] <- XYchromCode(intenData)
centromere$chrom <- as.integer(centromere$chrom)
centromere <- centromere[, c("chrom","left.base","right.base")]
if(!all(is.element(anom$chromosome, centromere$chrom))) stop("centromere must include all 'chromosome' values in anom")
centromere <- centromere[order(centromere$chrom),]
if(sum(duplicated(centromere$chrom))!=0) stop("chromosome in centromere must not be duplicated")
if(!all(is.element(anom$chromosome, centromere$chrom))) stop("chromosome in centromere does not include all those in anom")
# get indices of markers adjacent to centromere
centromere$left.index <- NA
centromere$right.index <- NA
for(i in 1:nrow(centromere)){
left <- centromere$left.base[i] - pos
right <- pos - centromere$right.base[i]
chr.sel <- chrom==centromere$chrom[i]
left.sel <- chr.sel & left>0
right.sel <- chr.sel & right>0
if(sum(left.sel)>0) { # this is needed for the acrocentric chroms with no markers left of the centromere
lmin <- min(left[chr.sel & left>0])
lind <- indices[chr.sel & left==lmin]
centromere$left.index[i] <- lind[length(lind)]
}
if(sum(right.sel)>0) { # for symmetry even though all chroms should have markers right of the centromere
rmin <- min(right[chr.sel & right>0])
rind <- indices[chr.sel & right==rmin]
centromere$right.index[i] <- rind[length(rind)]
}
}
setw <- which(!is.na(centromere$left.index) & !is.na(centromere$right.index))
for(i in setw){
tmpind <- indices[indices>centromere$left.index[i] & indices<centromere$right.index[i]]
tmpid <- intid[tmpind]
if(any(is.element(tmpid,snp.ids))) stop("eligible snps in centromere gap")
}
# check anom
if(class(anom)!="data.frame") stop("anom should be a data.frame")
if(!all(is.element(c("scanID", "chromosome", "left.index","right.index","sex","method","anom.id"),names(anom)))) stop("anom does not have required variable names")
if(!all(is.element(c(anom$left.index,anom$right.index),indices))) stop("left.index and/or right.index are not within range of snp indices")
ok.chrom <- c(autosomeCode(intenData), XchromCode(intenData), XYchromCode(intenData))
if(!all(anom$chromosome %in% ok.chrom)) stop("chromosome must be integer code for autosomes, X, or XY")
# check eligible and get selection vector
eligible <- snp.ids
if(!all(is.element(eligible,intid))) stop("eligible values must be snpIDs")
elig <- is.element(intid, eligible)
# unique samples with anoms
anom <- anom[order(anom$scanID),]
snum <- unique(anom$scanID)
n <- length(snum)
# results will be added on to the anom data.frame
m <- nrow(anom)
anom$left.method <- rep(NA,m) # first letter of method (for BAF-LOH merges)
anom$right.method <- rep(NA,m) # last letter of method
anom$nmark.all <- rep(NA,m) # total number of probes on the array from left.index to right.index inclusive
anom$nmark.elig <- rep(NA,m) # total number of eligible probes on the array from left.index to right.index, inclusive
anom$left.base <- rep(NA,m) # base position corresponding to left.index
anom$right.base <- rep(NA,m) # base position corresponding to right.index
anom$nbase <- rep(NA,m) # number of bases from left.index to right.index, inclusive
anom$non.anom.baf.med <- rep(NA, m) # BAF median of non-anomalous segments on all autosomes, using (eligible & is.element(geno,c(1,-1))
anom$non.anom.lrr.med <- rep(NA, m) # LRR median of non-anomalous segments on all autosomes, using eligible snps
anom$non.anom.lrr.mad <- rep(NA,m) # MAD for LRR of non-anomalous segments on all autosomes
anom$anom.baf.dev.med <- rep(NA,m) # BAF median of deviations of points used to detect anomaly(eligible & is.element(geno,c(1,-1)) from non.anom.baf.med
anom$anom.baf.dev.5 <- rep(NA,m) # BAF median of deviations of points used to detect anomaly(eligible & is.element(geno,c(1,-1)) from 0.5
anom$anom.baf.dev.mean <- rep(NA,m) # BAF mean of deviations of points used to detect anomaly(eligible & is.element(geno,c(1,-1)) from non.anom.baf.med
anom$anom.baf.sd <- rep(NA,m) # SD of BAF deviations from non.anom.baf.med for points used to detect anomaly
anom$anom.baf.mad <- rep(NA,m) # MAD of BAF deviations from non.anom.baf.med for points used to detect anomaly
anom$anom.lrr.med <- rep(NA,m) # LRR median of eligible markers in the anomaly
anom$anom.lrr.sd <- rep(NA,m) # SD of LRR for eligible points within the anomaly
anom$anom.lrr.mad <- rep(NA,m) # MAD of LRR for eligible points within the anomaly
anom$nmark.baf <- rep(NA,m) # number of markers eligible for baf detection
anom$nmark.lrr <- rep(NA,m) # number of markers eligible for lrr detection
# for detecting terminal anomalies
anom$cent.rel <- rep(NA,m) # position relative to centromere - left, right, span
anom$left.most <- rep(NA,m) # T/F is this the left-most anomaly for this sample-chrom
anom$right.most <- rep(NA,m) # T/F is this the right-most anomaly for this sample-chrom
anom$left.last.elig <- rep(NA,m) # T/F if it contains the last eligible marker going to the left
anom$right.last.elig <- rep(NA,m) # T/F if it contains the last eligible marker going to the right
anom$left.term.lrr.med <- rep(NA,m) # median of LRR for all markers from leftmost eligible marker to the left telomere (only calculated for the most distal anom)
anom$right.term.lrr.med <- rep(NA,m) # median of LRR for all markers from rightmost eligible marker to the right telomere
anom$left.term.lrr.n <- rep(NA,m) # sample size for calculating median LRR
anom$right.term.lrr.n <- rep(NA,m)
# for analyzing centromere-spanning anomalies
anom$cent.span.left.elig.n <- rep(NA,m) # number of eligible markers on the left side of centromere-spanning anomalies
anom$cent.span.right.elig.n <- rep(NA,m) # number of eligible markers on the right side of centromere-spanning anomalies
anom$cent.span.left.bases <- rep(NA,m) # length of anomaly covered by eligible markers on the left side of the centromere
anom$cent.span.right.bases <- rep(NA,m) # length of anomaly covered by eligible markers on the right side of the centromere
anom$cent.span.left.index <- rep(NA,m) # index of elig marker left-adjacent to centromere
anom$cent.span.right.index <- rep(NA,m) # index of elig marker right-adjacent to centromere
# Cooper metric = sqrt(min(BAF,1-BAF,abs(BAF-M))) for eligible markers, where M is the median BAF over non-anomalous autosomal segments
anom$bafmetric.anom.mean <- rep(NA,m)
anom$bafmetric.non.anom.mean <- rep(NA,m)
anom$bafmetric.non.anom.sd <- rep(NA,m)
# number of eligible lrr markers with value less than lrr.cut
anom$nmark.lrr.low <- rep(NA,m)
# check method values
anom$left.method <- substr(anom$method,1,1)
tmp<- nchar(anom$method)
anom$right.method <- substr(anom$method, tmp, tmp)
if(!all(is.element(anom$left.method,c("B","L")) & is.element(anom$right.method,c("F","H","B","L")))) stop("method values should begin with B or L and end with F,H,B,L")
r <- 1 # counter for row number in anom
for(i in 1:n) { # for each sample 1:n
# get all data for the ith sample
dat <- anom[is.element(anom$scanID, snum[i]),]
sind <- which(is.element(sid, snum[i]))
geno <- getGenotype(genoData, snp=c(1,-1), scan=c(sind,1))
baf <- getBAlleleFreq(intenData, snp=c(1,-1), scan=c(sind,1))
lrr <- getLogRRatio(intenData, snp=c(1,-1), scan=c(sind,1))
# make missing genotype calls equal -1 (regardless of missing value code)
geno[is.na(geno)] <- -1
# get vector to select eligible markers not in anomalies
k <- nrow(dat)
ai <- NULL #indices included in anomalies
for(j in 1:k) ai <- c(ai, dat$left.index[j]:dat$right.index[j])
non.baf <- is.element(chrom, autosomeCode(intenData)) & is.element(intid, eligible) & !is.element(indices, ai) & is.element(geno, c(1,-1))
non.lrr <- is.element(chrom, autosomeCode(intenData)) & is.element(intid, eligible) & !is.element(indices, ai)
# calculate median of baf and lrr in non-anomalous regions
baf.non.med <- median(baf[non.baf], na.rm=TRUE)
lrr.non.med <- median(lrr[non.lrr], na.rm=TRUE)
# calculate MAD of lrr in non-anomalous regions
lrr.non.mad <- mad(lrr[non.lrr], na.rm=TRUE)
# calculate stats in anomalous segments
# eligible points used for anomaly detection
ebaf <- is.element(intid, eligible) & is.element(geno, c(1,-1))
elrr <- is.element(intid, eligible)
# Cooper metric
coop <- sqrt(pmin( (baf-0), (1-baf), abs(baf-baf.non.med) ))
coop.non.mean <- mean(coop[non.baf], na.rm=TRUE)
coop.non.sd <- sd(coop[non.baf], na.rm=TRUE)
# loop through anomalies within sample
for(j in 1:k){ # for each anomaly within a sample
# MARKER NUMBERS
anom$nmark.all[r] <- dat$right.index[j] - dat$left.index[j] + 1
anom$nmark.elig[r] <- sum(is.element(intid,eligible)[dat$left.index[j]:dat$right.index[j]])
# BAF
baf.sel <- ebaf & indices>=dat$left.index[j] & indices<=dat$right.index[j] & !is.na(baf)
baf.dev <- abs(baf[baf.sel]-baf.non.med)
anom$anom.baf.dev.med[r] <- median(baf.dev)
anom$anom.baf.dev.mean[r] <- mean(baf.dev)
baf.dev <- abs(baf[baf.sel]- 0.5)
anom$anom.baf.dev.5[r] <- median(baf.dev)
anom$non.anom.baf.med[r] <- baf.non.med
anom$nmark.baf[r] <- sum(baf.sel)
anom$anom.baf.sd[r] <- sd(baf.dev)
anom$anom.baf.mad[r] <- mad(baf.dev)
# COOPER METRIC
anom$bafmetric.anom.mean[r] <- mean(coop[baf.sel])
anom$bafmetric.non.anom.mean[r] <- coop.non.mean
anom$bafmetric.non.anom.sd[r] <- coop.non.sd
# LRR
lrr.sel <- elrr & indices>=dat$left.index[j] & indices<=dat$right.index[j] & !is.na(lrr)
anom$anom.lrr.med[r] <- median(lrr[lrr.sel])
anom$non.anom.lrr.med[r] <- lrr.non.med
anom$non.anom.lrr.mad[r] <- lrr.non.mad
anom$nmark.lrr[r] <- sum(lrr.sel)
anom$nmark.lrr.low[r] <- sum(lrr[lrr.sel] < lrr.cut)
anom$anom.lrr.sd[r] <- sd(lrr[lrr.sel])
anom$anom.lrr.mad[r] <- mad(lrr[lrr.sel])
# BASES
anom$left.base[r] <- pos[dat$left.index[j]]
anom$right.base[r] <- pos[dat$right.index[j]]
anom$nbase[r] <- anom$right.base[r] - anom$left.base[r] + 1
# CENTROMERE
# find relation to centromere
chrj <- anom$chromosome[r]
left <- anom$right.base[r] <= centromere$left.base[centromere$chrom==chrj]
right <- anom$left.base[r] >= centromere$right.base[centromere$chrom==chrj]
span <- anom$left.base[r] <= centromere$left.base[centromere$chrom==chrj] &
anom$right.base[r] >= centromere$right.base[centromere$chrom==chrj]
if(left) anom$cent.rel[r] <- "left"
if(right) anom$cent.rel[r] <- "right"
if(span) anom$cent.rel[r] <- "span"
if(is.na(anom$cent.rel[r])) { stop(paste("i=",i,"j=",j,"\ncent.rel is missing")) }
# for centromere-spanning, find number of eligible markers (method dependent) and length spanned by elig markers on each side
if(anom$cent.rel[r]=="span" & !is.element(anom$method[r], c("BAF","LOH")) ) {
warning(paste("sample",anom$scanID[r],"chromosome", anom$chromosome[r],"spans centromere and has non-standard method", anom$method[r],
"so centromere check will not be done"))
}
if(anom$cent.rel[r]=="span" & is.element(anom$method[r],c("BAF","LOH"))){
if(is.element(anom$method[r],"LOH")) { elog <- elrr } else { elog <- ebaf }
left.elig <- which(elog & indices >= anom$left.index[r] & indices <= centromere$left.index[centromere$chrom==chrj])
right.elig <- which(elog & indices >= centromere$right.index[centromere$chrom==chrj] & indices <= anom$right.index[r])
nle <- length(left.elig)
nre <- length(right.elig)
anom$cent.span.left.elig.n[r] <- nle # number of eligible markers in anom left of the centromere
anom$cent.span.right.elig.n[r] <- nre
anom$cent.span.left.bases[r] <- pos[left.elig[nle]] - pos[left.elig[1]]+ 1 # number of bases covered by eligible markers in the anom left of the centromere *
anom$cent.span.right.bases[r] <- pos[right.elig[nre]] - pos[right.elig[1]] + 1
anom$cent.span.left.index[r] <- left.elig[nle] # index of eligible marker just left of the centromere (for splitting if necessary)
anom$cent.span.right.index[r] <- right.elig[1]
}
# TERMINAL
# is it the most distal anomaly in this sample-chrom?
datc <- dat[dat$chromosome==anom$chromosome[r],c("left.index","right.index")]
anom$left.most[r] <- anom$left.index[r]==min(datc$left.index)
anom$right.most[r] <- anom$right.index[r]==max(datc$right.index)
# check whether all markers distal to the breakpoint are ineligible, which depends on method
# method will be BAF, LOH (for original anoms) or BL, LB for merged anoms (corresponding to BAF left end and LOH right end or vice versa)
sel.chrom <- chrom==anom$chromosome[r]
if(anom$left.most[r]){
anom$left.last.elig[r] <- FALSE
if(is.element(anom$left.method[r],"L")){
chk.left <- all(!elrr[ sel.chrom & indices < anom$left.index[r] ]) # all distal markers not elig
}
if(is.element(anom$left.method[r],"B")){
chk.left <- all(!ebaf[ sel.chrom & indices < anom$left.index[r] ]) # all distal markers not elig
}
if(chk.left){ # get median lrr for left-distal markers
anom$left.last.elig[r] <- TRUE
chr.ind <- indices[sel.chrom]
left <- chr.ind[1]; right <- anom$left.index[r]-1
anom$left.term.lrr.n[r] <- right-left+1
if(right>=left) anom$left.term.lrr.med[r] <- median(lrr[left:right], na.rm=TRUE)
}
}
if(anom$right.most[r]){
anom$right.last.elig[r] <- FALSE
if(is.element(anom$left.method[r],c("L","H"))){
chk.right <- all(!elrr[ sel.chrom & indices > anom$right.index[r] ]) # all distal markers not elig
}
if(is.element(anom$left.method[r],c("B","F"))){
chk.right <- all(!ebaf[ sel.chrom & indices > anom$right.index[r] ]) # all distal markers not elig
}
if(chk.right){ # get median lrr for right-distal markers
anom$right.last.elig[r] <- TRUE
chr.ind <- indices[sel.chrom]; ni <- length(chr.ind)
left <- anom$right.index[r]+1; right <- chr.ind[ni]
anom$right.term.lrr.n[r] <- right-left+1
if(right>=left) anom$right.term.lrr.med[r] <- median(lrr[left:right], na.rm=TRUE)
}
}
# increment counter
#message(paste("r=",r))
r <- r+1
} # end loop over anomalies within a sample
# print status
if(verbose & i %% 100 == 0) message(paste("sample", i, "of", n))
} # end loop over samples
# remove "left.method" and "right.method"
anom$left.method <- NULL
anom$right.method <- NULL
return(anom)
}
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