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Several improvements to new indel genotyper (more to come soon): 

a) Turns out previous change of centering haplotype around indel was a bad idea. Context to the left of indel is important but not as important as right one, because by definition all alleles start at the same location, so haplotype is the same to the left of indel regardless of allele. So, go back to having a constant size window to the left of event.
b) Expand reference context so we can test larger haplotypes.
c) Optimize computation of read likelihoods by doing them in linear array instead of in a matrix - no difference in biallelic sites but could be significantly faster in multiallelic sites.
d) Bug fix: read alignment wasn't being computed correctly if, a) we were at an insertion, b) read started right at the insertion, c) read CIGAR didn't include insertion - more of these corner conditions are lurking, so a revamped computation of how reads align to candidate haplotypes is in the works.
e) Add debug option not to use prior haplotype likelihoods.
f) Don't hard-code NA12878 for genotyping, now sample name is a required input argument.
g) Bug fix: if there are no reads covering a candidate indel event, just output NO_CALL (didn't notice this in HiSeq, but in P1 data it happens all the time). I need to add a confidence threshold for calling later on.






git-svn-id: file:///humgen/gsa-scr1/gsa-engineering/svn_contents/trunk@4291 348d0f76-0448-11de-a6fe-93d51630548a
This commit is contained in:
delangel 2010-09-15 21:53:08 +00:00
parent fb6d7d19f9
commit c604ed9440
3 changed files with 119 additions and 58 deletions
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9
java/src/org/broadinstitute/sting/gatk/walkers/indels/HaplotypeIndelErrorModel.java
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@ -27,6 +27,7 @@ package org.broadinstitute.sting.gatk.walkers.indels;
import net.sf.samtools.AlignmentBlock;
import net.sf.samtools.SAMRecord;
import org.broad.tribble.util.variantcontext.VariantContext;
import org.broadinstitute.sting.utils.MathUtils;
import org.broadinstitute.sting.utils.QualityUtils;
import org.broadinstitute.sting.utils.Utils;
@ -124,7 +125,8 @@ public class HaplotypeIndelErrorModel {
return -10.0*Math.log10(prob);
}
public double computeReadLikelihoodGivenHaplotype(Haplotype haplotype, SAMRecord read) {
public double computeReadLikelihoodGivenHaplotype(Haplotype haplotype, SAMRecord read,
VariantContext vc, int eventLength) {
long numStartClippedBases = read.getAlignmentStart() - read.getUnclippedStart();
long numEndClippedBases = read.getUnclippedEnd() - read.getAlignmentEnd();
final long readStartPosition = read.getAlignmentStart();
@ -154,6 +156,11 @@ public class HaplotypeIndelErrorModel {
initialIndexInHaplotype = (int)(readStartPosition-haplotypeStartPosition);
}
// special case 1: we're analyzing an insertion and the read starts right at the insertion.
if ((readStartPosition > vc.getStart()-eventLength) && vc.isInsertion() && !haplotype.isReference()) {
initialIndexInHaplotype += eventLength;
}
if (DEBUG) {
System.out.println("READ: "+read.getReadName());

166
java/src/org/broadinstitute/sting/oneoffprojects/walkers/SimpleIndelGenotyperWalker.java
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@ -51,7 +51,7 @@ import org.broadinstitute.sting.gatk.walkers.Reference;
import org.broadinstitute.sting.gatk.walkers.Window;
@Reference(window=@Window(start=-100,stop=100))
@Reference(window=@Window(start=-30,stop=200))
@Allows({DataSource.READS, DataSource.REFERENCE})
public class SimpleIndelGenotyperWalker extends RefWalker<Integer,Integer> {
@Output
@ -76,12 +76,21 @@ public class SimpleIndelGenotyperWalker extends RefWalker<Integer,Integer> {
@Argument(fullName="indelHeterozygozity",shortName="indhet",doc="Indel Heterozygosity (assumed 1/6500 from empirical human data)",required=false)
double indelHeterozygosity = (double)1.0/6500.0;
@Argument(fullName="sampleName",shortName="sample",doc="Sample name to evaluate genotypes in",required=true)
String sampleName;
@Argument(fullName="doSimpleCalculationModel",shortName="simple",doc="Use Simple Calculation Model for Pr(Reads | Haplotype)",required=false)
boolean doSimple = false;
@Argument(fullName="enableDebugOutput",shortName="debugout",doc="Output debug data",required=false)
boolean DEBUG = false;
@Argument(fullName="doTrio",shortName="trio",doc="Output 1KG CEU trio genotype data (sampleName ignored)",required=false)
boolean doTrio = false;
@Argument(fullName="useFlatPriors",shortName="flat",doc="If present, use flat priors on haplotypes",required=false)
boolean useFlatPriors = false;
@Override
public boolean generateExtendedEvents() { return true; }
@ -154,49 +163,62 @@ public class SimpleIndelGenotyperWalker extends RefWalker<Integer,Integer> {
int eventLength = vc.getReference().getBaseString().length() - vc.getAlternateAllele(0).getBaseString().length(); // assume only one alt allele for now
if (eventLength<0)
eventLength = - eventLength;
double lambda = (double)HAPLOTYPE_SIZE * indelHeterozygosity;
double altPrior = HaplotypeIndelErrorModel.probToQual(lambda)-HaplotypeIndelErrorModel.probToQual(eventLength)*1.89 + 0.15*eventLength
+ HaplotypeIndelErrorModel.probToQual(1.5716)+ HaplotypeIndelErrorModel.probToQual(0.5);
haplotypeLikehoodMatrix[0][1] = altPrior;
haplotypeLikehoodMatrix[1][1] = 2*altPrior;
if (!useFlatPriors) {
int bestIndexI =0, bestIndexJ=0;
for (int i=0; i < haplotypesInVC.size(); i++) {
for (int j=i; j < haplotypesInVC.size(); j++){
// combine likelihoods of haplotypeLikelihoods[i], haplotypeLikelihoods[j]
for (SAMRecord read : pileup.getReads()) {
// compute Pr(r | hi, hj) = 1/2*(Pr(r|hi) + Pr(r|hj)
double lambda = (double)HAPLOTYPE_SIZE * indelHeterozygosity;
double altPrior = HaplotypeIndelErrorModel.probToQual(lambda)-HaplotypeIndelErrorModel.probToQual(eventLength)*1.89 + 0.15*eventLength
+ HaplotypeIndelErrorModel.probToQual(1.5716)+ HaplotypeIndelErrorModel.probToQual(0.5);
double readLikelihood[] = new double[2];
double readLikeGivenH;
readLikeGivenH = model.computeReadLikelihoodGivenHaplotype(haplotypesInVC.get(i), read);
readLikelihood[0]= -readLikeGivenH/10.0;
if (i != j){
readLikeGivenH = model.computeReadLikelihoodGivenHaplotype(haplotypesInVC.get(j), read);
readLikelihood[1] = -readLikeGivenH/10.0;
haplotypeLikehoodMatrix[0][1] = altPrior;
haplotypeLikehoodMatrix[1][1] = 2*altPrior;
}
int bestIndexI =-1, bestIndexJ=-1;
double callConfidence = 0.0;
if (pileup.getReads().size() > 0) {
double readLikelihoods[][] = new double[pileup.getReads().size()][haplotypesInVC.size()];
int i=0;
for (SAMRecord read : pileup.getReads()) {
// for each read/haplotype combination, compute likelihoods, ie -10*log10(Pr(R | Hi))
// = sum_j(-10*log10(Pr(R_j | Hi) since reads are assumed to be independent
for (int j=0; j < haplotypesInVC.size(); j++) {
readLikelihoods[i][j]= model.computeReadLikelihoodGivenHaplotype(haplotypesInVC.get(j), read, vc, eventLength);
if (DEBUG) {
System.out.print(read.getReadName()+" ");
System.out.format("%d %d S:%d US:%d E:%d UE:%d C:%s %3.4f\n",i, j, read.getAlignmentStart(),
read.getUnclippedStart(), read.getAlignmentEnd(), read.getUnclippedEnd(),
read.getCigarString(), readLikelihoods[i][j]);
}
else
readLikelihood[1] = readLikelihood[0];
// likelihood is by convention -10*log10(pr(r|h))
// sumlog10 computes 10^x[0]+10^x[1]+...
double probRGivenHPair = MathUtils.sumLog10(readLikelihood)/2;
haplotypeLikehoodMatrix[i][j] += HaplotypeIndelErrorModel.probToQual(probRGivenHPair);
/*System.out.print(read.getReadName()+" ");
System.out.format("%d %d S:%d US:%d E:%d UE:%d C:%s %3.4f %3.4f\n",i, j, read.getAlignmentStart(),
read.getUnclippedStart(), read.getAlignmentEnd(), read.getUnclippedEnd(),
read.getCigarString(), probRGivenHPair, haplotypeLikehoodMatrix[i][j]);
*/
}
i++;
}
for (i=0; i < haplotypesInVC.size(); i++) {
for (int j=i; j < haplotypesInVC.size(); j++){
// combine likelihoods of haplotypeLikelihoods[i], haplotypeLikelihoods[j]
// L(Hi, Hj) = sum_reads ( Pr(R|Hi)/2 + Pr(R|Hj)/2)
//readLikelihoods[k][j] has log10(Pr(R_k) | H[j] )
double[] readLikelihood = new double[2]; // diploid sample
for (int readIdx=0; readIdx < pileup.getReads().size(); readIdx++) {
readLikelihood[0] = -readLikelihoods[readIdx][i]/10;
readLikelihood[1] = -readLikelihoods[readIdx][j]/10;
double probRGivenHPair = MathUtils.sumLog10(readLikelihood)/2;
haplotypeLikehoodMatrix[i][j] += HaplotypeIndelErrorModel.probToQual(probRGivenHPair);
}
if (haplotypeLikehoodMatrix[i][j] < bestLikelihood) {
bestIndexI = i;
bestIndexJ = j;
bestLikelihood = haplotypeLikehoodMatrix[i][j];
if (haplotypeLikehoodMatrix[i][j] < bestLikelihood) {
bestIndexI = i;
bestIndexJ = j;
callConfidence = bestLikelihood - haplotypeLikehoodMatrix[i][j];
bestLikelihood = haplotypeLikehoodMatrix[i][j];
}
}
}
}
@ -215,30 +237,49 @@ public class SimpleIndelGenotyperWalker extends RefWalker<Integer,Integer> {
out.format("%s %d %s ",vc.getChr(), vc.getStart(), type);
Genotype originalGenotype = vc.getGenotype("NA12878");
if (doTrio) {
Genotype originalGenotype = vc.getGenotype("NA12878");
Genotype dadGenotype = vc.getGenotype("NA12891");
Genotype momGenotype = vc.getGenotype("NA12892");
String oldG, newG;
if (originalGenotype.isHomRef())
oldG = "HOMREF";
else if (originalGenotype.isHet())
oldG = "HET";
else if (originalGenotype.isHomVar())
oldG = "HOMVAR";
else
oldG = "OTHER";
String dadG, momG, oldG, newG;
oldG = getGenotypeString(originalGenotype);
dadG = getGenotypeString(dadGenotype);
momG = getGenotypeString(momGenotype);
int x = bestIndexI+bestIndexJ;
if (x == 0)
newG = "HOMREF";
else if (x == 1)
newG = "HET";
else if (x == 2)
newG = "HOMVAR";
else
newG = "OTHER";
int x = bestIndexI+bestIndexJ;
if (x == 0)
newG = "HOMREF";
else if (x == 1)
newG = "HET";
else if (x == 2)
newG = "HOMVAR";
else if (x < 0)
newG = "NOCALL";
else
newG = "OTHER";
out.format("NewG %s OldG %s\n", newG, oldG);
out.format("NewG %s OldG %s DadG %s MomG %s\n", newG, oldG, dadG, momG);
}
else {
Genotype originalGenotype = vc.getGenotype(sampleName);
String oldG, newG;
oldG = getGenotypeString(originalGenotype);
int x = bestIndexI+bestIndexJ;
if (x == 0)
newG = "HOMREF";
else if (x == 1)
newG = "HET";
else if (x == 2)
newG = "HOMVAR";
else if (x < 0)
newG = "NOCALL";
else
newG = "OTHER";
out.format("NewG %s OldG %s\n", newG, oldG);
}
/*
if ( context.hasExtendedEventPileup() ) {
@ -272,6 +313,19 @@ public class SimpleIndelGenotyperWalker extends RefWalker<Integer,Integer> {
return 1; //To change body of implemented methods use File | Settings | File Templates.
}
private String getGenotypeString(Genotype genotype) {
String oldG;
if (genotype.isHomRef())
oldG = "HOMREF";
else if (genotype.isHet())
oldG = "HET";
else if (genotype.isHomVar())
oldG = "HOMVAR";
else
oldG = "OTHER";
return oldG;
}
/**
* Provide an initial value for reduce computations.
*

2
java/src/org/broadinstitute/sting/utils/genotype/Haplotype.java
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@ -111,7 +111,7 @@ public class Haplotype {
byte[] refBases = ref.getBases();
int numPrefBases = haplotypeSize/2;
int numPrefBases = 20;
int startIdxInReference = (int)(1+vc.getStart()-numPrefBases-ref.getWindow().getStart());
//int numPrefBases = (int)(vc.getStart()-ref.getWindow().getStart()+1); // indel vc starts one before event