First major update of indel genotyper:
a) Really fix this time strand bias computation for indels, previous version was a partial fix only. b) Change way in which we deal with bad bases at the edge of reads. Even if a base is soft clipped in CIGAR string, there may still be dangling bases with Q=2 that may throw off QUAL computation in some sites. So, we're stricter and we also trim off those bases off read edges even if they are not soft-clipped officially. c) First feeble-minded attempt at runtime optimization - don't compute log and 10^base_qual every time. Rather, cache 10^-k/10 and log(1-10^-k/10) for all k <=60. This speeds up code about 4x. d) Further optimization: don't compute log(10^x+10^y) but rather use softMax function recently put into ExactAFCalculationModel. e) Skip bad reads where all Q=2 (sic) f) Avoid log to lin and back to log conversions of genotype likelihoods - this was legacy code from back when exact model did stuff in linear domain. This improves precision overall. git-svn-id: file:///humgen/gsa-scr1/gsa-engineering/svn_contents/trunk@4802 348d0f76-0448-11de-a6fe-93d51630548a
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@ -45,7 +45,6 @@ public class DindelGenotypeLikelihoodsCalculationModel extends GenotypeLikelihoo
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private final double insertionEndProbability = 0.5;
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private final double alphaDeletionProbability = 1e-3;
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private final int HAPLOTYPE_SIZE = 80;
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private static final double MINUS_LOG_INFINITY = -300;
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// todo - the following need to be exposed for command line argument control
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private final double indelHeterozygosity = 1.0/8000;
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@ -89,11 +88,23 @@ public class DindelGenotypeLikelihoodsCalculationModel extends GenotypeLikelihoo
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if (!vc.isIndel())
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return null;
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if (sitesVisited.contains(new Integer(vc.getStart())) &&
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contextType.equals(StratifiedAlignmentContext.StratifiedContextType.COMPLETE))
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return null;
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boolean visitedBefore = false;
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synchronized (this) {
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if (sitesVisited.contains(new Integer(vc.getStart())) &&
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contextType.equals(StratifiedAlignmentContext.StratifiedContextType.COMPLETE))
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visitedBefore = true;
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else {
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sitesVisited.add(new Integer(vc.getStart()));
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}
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}
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sitesVisited.add(new Integer(vc.getStart()));
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if (visitedBefore)
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return null;
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// protect against having an indel too close to the edge of a contig
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if (vc.getStart() <= HAPLOTYPE_SIZE)
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return null;
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if ( !(priors instanceof DiploidIndelGenotypePriors) )
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throw new StingException("Only diploid-based Indel priors are supported in the DINDEL GL model");
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@ -105,11 +116,9 @@ public class DindelGenotypeLikelihoodsCalculationModel extends GenotypeLikelihoo
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eventLength = - eventLength;
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int currentHaplotypeSize = HAPLOTYPE_SIZE;
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List<Haplotype> haplotypesInVC = new ArrayList<Haplotype>();
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int minHaplotypeSize = Haplotype.LEFT_WINDOW_SIZE + eventLength + 2; // to be safe
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// int numSamples = getNSamples(contexts);
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haplotypesInVC = Haplotype.makeHaplotypeListFromVariantContextAlleles( vc, ref, currentHaplotypeSize);
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List<Haplotype> haplotypesInVC = Haplotype.makeHaplotypeListFromVariantContextAlleles( vc, ref, currentHaplotypeSize);
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// For each sample, get genotype likelihoods based on pileup
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// compute prior likelihoods on haplotypes, and initialize haplotype likelihood matrix with them.
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// initialize the GenotypeLikelihoods
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@ -126,7 +135,7 @@ public class DindelGenotypeLikelihoodsCalculationModel extends GenotypeLikelihoo
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//double[] priorLikelihoods = priors.getPriors();
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for ( Map.Entry<String, StratifiedAlignmentContext> sample : contexts.entrySet() ) {
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AlignmentContext context = sample.getValue().getContext(StratifiedAlignmentContext.StratifiedContextType.COMPLETE);
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AlignmentContext context = sample.getValue().getContext(contextType);
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ReadBackedPileup pileup = null;
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if (context.hasExtendedEventPileup())
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@ -138,14 +147,8 @@ public class DindelGenotypeLikelihoodsCalculationModel extends GenotypeLikelihoo
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haplotypeLikehoodMatrix = model.computeReadHaplotypeLikelihoods( pileup, haplotypesInVC, vc, eventLength);
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double[] genotypeLikelihoods = HaplotypeIndelErrorModel.getPosteriorProbabilitesFromHaplotypeLikelihoods( haplotypeLikehoodMatrix);
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double[] genotypeLikelihoods = HaplotypeIndelErrorModel.getHaplotypeLikelihoods( haplotypeLikehoodMatrix);
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// todo- cleaner solution for case where probability is of form (1,0,0) or similar
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for (int k=0; k < 3; k++) {
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genotypeLikelihoods[k] = Math.log10(genotypeLikelihoods[k]);
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if (Double.isInfinite(genotypeLikelihoods[k]))
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genotypeLikelihoods[k] = MINUS_LOG_INFINITY;
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}
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GLs.put(sample.getKey(), new BiallelicGenotypeLikelihoods(sample.getKey(),
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vc.getReference(),
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vc.getAlternateAllele(0),
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@ -151,7 +151,7 @@ public class ExactAFCalculationModel extends AlleleFrequencyCalculationModel {
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return softMaxPair(a,vec[2]);
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}
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double softMaxPair(double x, double y) {
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static public double softMaxPair(double x, double y) {
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if (Double.isInfinite(x))
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return y;
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@ -28,6 +28,7 @@ package org.broadinstitute.sting.gatk.walkers.indels;
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import net.sf.samtools.AlignmentBlock;
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import net.sf.samtools.SAMRecord;
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import org.broad.tribble.util.variantcontext.VariantContext;
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import org.broadinstitute.sting.gatk.walkers.genotyper.ExactAFCalculationModel;
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import org.broadinstitute.sting.utils.MathUtils;
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import org.broadinstitute.sting.utils.QualityUtils;
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import org.broadinstitute.sting.utils.Utils;
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@ -42,12 +43,13 @@ public class HaplotypeIndelErrorModel {
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private final int maxReadDeletionLength; // maximum length of deletion on a read
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private final double noDeletionProbability; // alpha for geometric distribution for deletion length
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private final int haplotypeSize;
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private final int BASE_QUAL_THRESHOLD = 6;
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private final int PATH_METRIC_TABLE_LENGTH;
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private final int RIGHT_ALIGN_INDEX;
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private final int LEFT_ALIGN_INDEX;
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private static final double INFINITE = 10000000000000.0;
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private double deletionErrorProbabilities[];
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@ -64,6 +66,23 @@ public class HaplotypeIndelErrorModel {
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private static final double QUAL_ONE_HALF = -10*Math.log10(0.5);
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private static final int MAX_CACHED_QUAL = 60;
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private static final double baseMatchArray[];
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private static final double baseMismatchArray[];
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static {
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baseMatchArray = new double[MAX_CACHED_QUAL+1];
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baseMismatchArray = new double[MAX_CACHED_QUAL+1];
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for (int k=1; k <= MAX_CACHED_QUAL; k++) {
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double baseProb = QualityUtils.qualToProb(k);
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baseMatchArray[k] = probToQual(baseProb);
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baseMismatchArray[k] = (double)(k);
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}
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}
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public HaplotypeIndelErrorModel(int mrdl, double insStart, double insEnd, double alpha, int haplotypeSize,
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boolean dosimple, boolean deb) {
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this(mrdl, insStart, insEnd, alpha, haplotypeSize);
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@ -115,17 +134,38 @@ public class HaplotypeIndelErrorModel {
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public double computeReadLikelihoodGivenHaplotype(Haplotype haplotype, SAMRecord read,
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VariantContext vc, int eventLength) {
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long numStartClippedBases = read.getAlignmentStart() - read.getUnclippedStart();
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long numEndClippedBases = read.getUnclippedEnd() - read.getAlignmentEnd();
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final long readStartPosition = read.getAlignmentStart();
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final long haplotypeStartPosition = haplotype.getStartPosition();
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//final long readEndPosition = read.getUnclippedEnd();
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//final long haplotypeEndPosition = haplotype.getStartPosition() + haplotypeSize-1;
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byte[] readBases = Arrays.copyOfRange(read.getReadBases(),(int)numStartClippedBases,
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long numStartClippedBases = 0;
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long numEndClippedBases = 0;
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byte[] unclippedReadQuals = read.getBaseQualities();
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byte[] unclippedReadBases = read.getReadBases();
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// Do a stricter base clipping than provided by CIGAR string, since this one may be too conservative,
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// and may leave a string of Q2 bases still hanging off the reads.
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for (int i=0; i < read.getReadLength(); i++) {
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if (unclippedReadQuals[i] < BASE_QUAL_THRESHOLD)
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numStartClippedBases++;
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else
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break;
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}
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for (int i=read.getReadLength()-1; i >= 0; i-- ){
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if (unclippedReadQuals[i] < BASE_QUAL_THRESHOLD)
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numEndClippedBases++;
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else
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break;
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}
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//System.out.format("numstart: %d numend: %d\n", numStartClippedBases, numEndClippedBases);
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if (numStartClippedBases + numEndClippedBases >= read.getReadLength()) {
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return 0;///Double.POSITIVE_INFINITY;
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}
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byte[] readBases = Arrays.copyOfRange(unclippedReadBases,(int)numStartClippedBases,
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(int)(read.getReadBases().length-numEndClippedBases));
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byte[] readQuals = Arrays.copyOfRange(read.getBaseQualities(),(int)numStartClippedBases,
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byte[] readQuals = Arrays.copyOfRange(unclippedReadQuals,(int)numStartClippedBases,
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(int)(read.getReadBases().length-numEndClippedBases));
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@ -233,8 +273,7 @@ public class HaplotypeIndelErrorModel {
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byte readBase = readBases[indR];
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byte readQual = readQuals[indR];
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for (int indX=LEFT_ALIGN_INDEX; indX <= RIGHT_ALIGN_INDEX; indX++) {
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for (int indX=LEFT_ALIGN_INDEX; indX <= RIGHT_ALIGN_INDEX; indX++) {
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byte haplotypeBase;
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@ -251,17 +290,8 @@ public class HaplotypeIndelErrorModel {
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// for debugging only: compute backtracking to find optimal route through trellis. Since I'm only interested
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// in log-likelihood of best state, this isn't really necessary.
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int[] bestIndexArray = new int[readLength];
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double bestMetric = MathUtils.arrayMin(pathMetricArray[readLength]);
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// start from last position of read, go backwards to find optimal alignment
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int bestIndex = MathUtils.minElementIndex(pathMetricArray[readLength]);
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bestIndexArray[readLength-1] = bestIndex;
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for (int k=readLength-2; k>=0; k--) {
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bestIndex = bestStateIndexArray[k][bestIndex];
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bestIndexArray[k] = bestIndex;
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}
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if (DEBUG) {
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@ -280,6 +310,22 @@ public class HaplotypeIndelErrorModel {
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}
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System.out.println();
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System.out.print("Read quals: ");
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for (int k=0; k <readQuals.length; k++) {
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System.out.format("%d ", (int)readQuals[k]);
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}
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System.out.println();
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// start from last position of read, go backwards to find optimal alignment
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int[] bestIndexArray = new int[readLength];
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int bestIndex = MathUtils.minElementIndex(pathMetricArray[readLength]);
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bestIndexArray[readLength-1] = bestIndex;
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for (int k=readLength-2; k>=0; k--) {
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bestIndex = bestStateIndexArray[k][bestIndex];
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bestIndexArray[k] = bestIndex;
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}
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System.out.print("Alignment: ");
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for (int k=0; k <readBases.length; k++) {
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System.out.format("%d ", bestIndexArray[k]);
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@ -297,7 +343,7 @@ public class HaplotypeIndelErrorModel {
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double bmetric;
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double bestMetric = INFINITE;
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double bestMetric = Double.POSITIVE_INFINITY;
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int bestMetricIndex = -1;
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// compute metric for match/mismatch
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@ -307,11 +353,11 @@ public class HaplotypeIndelErrorModel {
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if (readQual < 1)
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readQual = 1;
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double baseProb = QualityUtils.qualToProb(readQual);
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if (readQual > MAX_CACHED_QUAL)
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readQual = MAX_CACHED_QUAL;
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double pBaseMatch = probToQual(baseProb);
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double pBaseMismatch = (double)(readQual);
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double pBaseMatch = baseMatchArray[(int)readQual];
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double pBaseMismatch = baseMismatchArray[(int)readQual];
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if (haplotypeBase == readBase)
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pBaseRead = pBaseMatch;
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@ -406,8 +452,11 @@ public class HaplotypeIndelErrorModel {
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readLikelihood[0] = -readLikelihoods[readIdx][i]/10;
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readLikelihood[1] = -readLikelihoods[readIdx][j]/10;
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double probRGivenHPair = MathUtils.sumLog10(readLikelihood)/2;
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haplotypeLikehoodMatrix[i][j] += HaplotypeIndelErrorModel.probToQual(probRGivenHPair);
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// Compute log10(10^x1/2 + 10^x2/2) = log10(10^x1+x0^x2)-log10(2)
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// First term is approximated by Jacobian log with table lookup.
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// Second term is a constant added to both likelihoods so will be ignored
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haplotypeLikehoodMatrix[i][j] += ExactAFCalculationModel.softMaxPair(readLikelihood[0],
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readLikelihood[1]);
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}
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@ -419,18 +468,25 @@ public class HaplotypeIndelErrorModel {
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}
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public static double[] getPosteriorProbabilitesFromHaplotypeLikelihoods(double[][] haplotypeLikehoodMatrix) {
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public static double[] getHaplotypeLikelihoods(double[][] haplotypeLikehoodMatrix) {
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int hSize = haplotypeLikehoodMatrix.length;
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double[] genotypeLikelihoods = new double[hSize*(hSize+1)/2];
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int k=0;
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double maxElement = Double.NEGATIVE_INFINITY;
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for (int i=0; i < hSize; i++) {
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for (int j=i; j < hSize; j++){
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genotypeLikelihoods[k++] = -haplotypeLikehoodMatrix[i][j]/10;
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genotypeLikelihoods[k++] = haplotypeLikehoodMatrix[i][j];
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if (haplotypeLikehoodMatrix[i][j] > maxElement)
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maxElement = haplotypeLikehoodMatrix[i][j];
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}
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}
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// normalize likelihoods and pass to linear domain.
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return MathUtils.normalizeFromLog10(genotypeLikelihoods);
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// renormalize
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for (int i=0; i < genotypeLikelihoods.length; i++)
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genotypeLikelihoods[i] -= maxElement;
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return genotypeLikelihoods;
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}
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