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incorporating skew check 

git-svn-id: file:///humgen/gsa-scr1/gsa-engineering/svn_contents/trunk@1078 348d0f76-0448-11de-a6fe-93d51630548a
This commit is contained in:
kcibul 2009-06-23 19:51:51 +00:00
parent 1339f3f3e3
commit eb999f880a
1 changed files with 166 additions and 14 deletions
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180
java/src/org/broadinstitute/sting/playground/gatk/walkers/SomaticMutationWalker.java
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@ -23,6 +23,10 @@ import java.util.*;
@By(DataSource.REFERENCE)
public class SomaticMutationWalker extends LocusWalker<Integer, Integer> {
protected enum MutantFailureReason {
StrandImbalance,
Misalignment
}
protected static class QualitySums {
private int a = 0;
private int c = 0;
@ -74,10 +78,11 @@ public class SomaticMutationWalker extends LocusWalker<Integer, Integer> {
@Argument(fullName = "min_mutant_sum", required = false, doc = "threshold for sum of mutant allele quality scores")
public int MIN_MUTANT_SUM = 100;
@Argument(fullName = "mode", required = false, doc="Mode of operation (detect, full)")
public String mode = "full";
public float SKEW_LOD_THRESHOLD = 1.0f;
// @Argument(fullName = "output_failures", required = false, doc="produce output for failed sites")
public boolean OUTPUT_FAILURES = true;
@ -125,9 +130,20 @@ public class SomaticMutationWalker extends LocusWalker<Integer, Integer> {
}
public String getLocusBases() {
return getLocusBases(0);
}
public String getLocusBases(int locusOffset) {
StringBuilder sb = new StringBuilder();
for(int i=0; i<reads.size(); i++) {
sb.append(reads.get(i).getReadString().charAt(offsets.get(i)));
SAMRecord read = reads.get(i);
int readOffset = offsets.get(i);
int offset = readOffset + locusOffset;
if (offset >= 0 && offset < read.getReadString().length()) {
char base = read.getReadString().charAt(offset);
sb.append(base);
}
}
return sb.toString();
}
@ -173,6 +189,71 @@ public class SomaticMutationWalker extends LocusWalker<Integer, Integer> {
return new double[]{refRef, altRef, altAlt};
}
private GenotypeLikelihoods getLikelihood(int locusOffset) {
GenotypeLikelihoods likelihoods = new GenotypeLikelihoods();
for(int i=0; i<reads.size(); i++) {
SAMRecord read = reads.get(i);
int readOffset = offsets.get(i);
int offset = readOffset + locusOffset;
if (offset >= 0 && offset < read.getReadString().length()) {
char base = read.getReadString().charAt(offset);
byte qual = read.getBaseQualities()[offset];
likelihoods.add(refBase, base, qual);
}
}
return likelihoods;
}
public double[] getNormalizedProbs(int locusOffset) {
GenotypeLikelihoods likelihoods = new GenotypeLikelihoods();
for(int i=0; i<reads.size(); i++) {
SAMRecord read = reads.get(i);
int readOffset = offsets.get(i);
int offset = readOffset + locusOffset;
if (offset >= 0 && offset < read.getReadString().length()) {
char base = read.getReadString().charAt(offset);
byte qual = read.getBaseQualities()[offset];
likelihoods.add(refBase, base, qual);
}
}
double[] logLikelihood = likelihoods.likelihoods;
double[] nonLogLikelihood = new double[10];
double sum = 0;
for(int i=0; i<10; i++) {
nonLogLikelihood[i] = Math.pow(10, logLikelihood[i]);
sum += nonLogLikelihood[i];
}
double[] normalizedProbs = new double[10];
for(int i=0; i<10; i++) {
normalizedProbs[i] = nonLogLikelihood[i] / sum;
}
//quick sanity check
// sum=0;
// for(int i=0; i<10; i++) {
// sum += normalizedProbs[i];
// }
// System.out.println("normalized probs = " + sum);
return normalizedProbs;
}
}
public Integer map(RefMetaDataTracker tracker, char ref, LocusContext context) {
@ -272,6 +353,13 @@ public class SomaticMutationWalker extends LocusWalker<Integer, Integer> {
continue;
}
// (ii) the quality score sum for the mutant base in the normal must be < 50 and the
// LOD score for ref:ref vs mutant:ref + mutant:mutant must be at least 2.3.
double normalLod = normalReadPile.getRefVsAlt(altAllele);
if ( normalReadPile.qualitySums.get(altAllele) > 50 || normalLod < NORMAL_LOD_THRESHOLD) {
continue;
}
// make sure we've seen at least 1 obs of the alternate allele within 20bp of the read-middle
boolean failedMidpointCheck = midp.get(altAllele) > 20;
// if (failedMidpointCheck) {
@ -324,14 +412,17 @@ public class SomaticMutationWalker extends LocusWalker<Integer, Integer> {
continue;
}
// TODO: using the original pile here since often these artifacts will be supported
// by those reads that get thrown out! Maybe that means we don't need the noise filter...
boolean shouldDisalign =
disaligner(context.getPosition(), tumorReadPile, StringUtil.bytesToString(refSeq.getBases()), refStart);
// // TODO: using the original pile here since often these artifacts will be supported
// // by those reads that get thrown out! Maybe that means we don't need the noise filter...
// boolean shouldDisalign =
// disaligner(context.getPosition(), tumorReadPile, StringUtil.bytesToString(refSeq.getBases()), refStart);
MutantFailureReason failureReason =
readPileSkew(t2, altAllele, StringUtil.bytesToString(refSeq.getBases()), refStart);
if (mode.equals("full") && shouldDisalign) {
if (mode.equals("full") && failureReason != null) {
if (OUTPUT_FAILURES) {
String msg = "FAILED due to DISALIGNMENT TEST.";
String msg = "FAILED due to " + failureReason.name();
out.println(
context.getContig() + "\t" +
@ -349,12 +440,6 @@ public class SomaticMutationWalker extends LocusWalker<Integer, Integer> {
// (ii) the quality score sum for the mutant base in the normal must be < 50 and the
// LOD score for ref:ref vs mutant:ref + mutant:mutant must be at least 2.3.
double normalLod = normalReadPile.getRefVsAlt(altAllele);
if ( normalReadPile.qualitySums.get(altAllele) > 50 || normalLod < NORMAL_LOD_THRESHOLD) {
continue;
}
// if we're still here... we've got a somatic mutation! Output the results
// and stop looking for mutants!
@ -402,6 +487,73 @@ public class SomaticMutationWalker extends LocusWalker<Integer, Integer> {
private MutantFailureReason readPileSkew(LocusReadPile pile, char mutantAllele, String reference, long leftmostIndex) {
// first split into two piles, those supporting the mutant and those not
LocusReadPile mutantPile = new LocusReadPile(mutantAllele);
LocusReadPile otherPile = new LocusReadPile(mutantAllele);
for (int i=0; i<pile.reads.size(); i++) {
SAMRecord read = pile.reads.get(i);
int offset = pile.offsets.get(i);
if (read.getReadString().charAt(offset) == mutantAllele) {
mutantPile.add(read, offset);
} else {
otherPile.add(read, offset);
}
}
// now we can ask questons abot the two piles.
// e.g. is the mutant allele seen in both strands?
boolean seenOnPositive = false;
boolean seenOnNegative = false;
for(SAMRecord read : mutantPile.reads) {
if (read.getReadNegativeStrandFlag()) { seenOnNegative = true; } else { seenOnPositive = true; }
}
if (!seenOnPositive || !seenOnNegative) {
// return MutantFailureReason.StrandImbalance;
}
//chr17:4979257
// are the two alleles distributed differently
//fixme: calculate this range properly
//fixme: this seems to degrade as you lose reads?
//fixme: what should the threshold be here?
SortedMap<Integer, Double> skewLodOffsets = new TreeMap<Integer, Double>();
for(int offset=-76; offset<76; offset++) {
// allow for doubletons
if (offset >= -1 && offset <= 1 ) { continue; }
double[] mutantNormProbs = mutantPile.getNormalizedProbs(offset);
double[] otherNormProbs = otherPile.getNormalizedProbs(offset);
double J = 0;
for(int i=0; i<10; i++) {
J += mutantNormProbs[i] * otherNormProbs[i];
}
double skewLod = Math.log10( (1-J) / J);
if (skewLod > SKEW_LOD_THRESHOLD) {
// System.out.println( "Offset: " + offset +
// " mutant_reads: " + mutantPile.getLocusBases(offset).length() +
// " other_reads: " + otherPile.getLocusBases(offset).length() +
// " skewLod:" + skewLod );
skewLodOffsets.put(offset, skewLod);
}
}
if (skewLodOffsets.size() > 0) {
return MutantFailureReason.Misalignment;
}
return null;
}
int MAX_READ_MISMATCH_QUALITY_SCORE_SUM = 100;
private LocusReadPile filterHighMismatchScoreReads(LocusReadPile pile, String reference, long leftmostIndex) {
LocusReadPile newPile = new LocusReadPile(pile.refBase);