(rootVC.getNSamples());
+ for ( final Genotype g : rootVC.getGenotypes() )
+ biallelicGenotypes.add(combineGLsPrecise(g, altAlleleIndex, nAlts));
+
+ final VariantContextBuilder vcb = new VariantContextBuilder(rootVC);
+ final Allele altAllele = rootVC.getAlternateAllele(altAlleleIndex - 1);
+ vcb.alleles(Arrays.asList(rootVC.getReference(), altAllele));
+ vcb.genotypes(biallelicGenotypes);
+ return vcb.make();
+ }
+ }
+
+ /**
+ * Returns a new Genotype with the PLs of the multi-allelic original reduced to a bi-allelic case
+ *
+ * This is handled in the following way:
+ *
+ * Suppose we have for a A/B/C site the following GLs:
+ *
+ * AA AB BB AC BC CC
+ *
+ * and we want to get the bi-allelic GLs for X/B, where X is everything not B
+ *
+ * XX = AA + AC + CC (since X = A or C)
+ * XB = AB + BC
+ * BB = BB
+ *
+ * @param original the original multi-allelic genotype
+ * @param altIndex the index of the alt allele we wish to keep in the bialleic case -- with ref == 0
+ * @param nAlts the total number of alt alleles
+ * @return a new biallelic genotype with appropriate PLs
+ */
+ @Requires({"original.hasLikelihoods()"}) // TODO -- add ploidy == 2 test "original.getPLs() == null || original.getPLs().length == 3"})
+ @Ensures({"result.hasLikelihoods()", "result.getPL().length == 3"})
+ @Deprecated
+ protected Genotype combineGLs(final Genotype original, final int altIndex, final int nAlts ) {
+ if ( original.isNonInformative() )
+ return new GenotypeBuilder(original).PL(BIALLELIC_NON_INFORMATIVE_PLS).alleles(BIALLELIC_NOCALL).make();
+
+ if ( altIndex < 1 || altIndex > nAlts ) throw new IllegalStateException("altIndex must be between 1 and nAlts " + nAlts);
+
+ final double[] normalizedPr = MathUtils.normalizeFromLog10(GenotypeLikelihoods.fromPLs(original.getPL()).getAsVector());
+ final double[] biAllelicPr = new double[3];
+
+ for ( int index = 0; index < normalizedPr.length; index++ ) {
+ final GenotypeLikelihoods.GenotypeLikelihoodsAllelePair pair = GenotypeLikelihoods.getAllelePair(index);
+
+ if ( pair.alleleIndex1 == altIndex ) {
+ if ( pair.alleleIndex2 == altIndex )
+ // hom-alt case
+ biAllelicPr[2] = normalizedPr[index];
+ else
+ // het-alt case
+ biAllelicPr[1] += normalizedPr[index];
+ } else {
+ if ( pair.alleleIndex2 == altIndex )
+ // het-alt case
+ biAllelicPr[1] += normalizedPr[index];
+ else
+ // hom-non-alt
+ biAllelicPr[0] += normalizedPr[index];
+ }
+ }
+
+ final double[] GLs = new double[3];
+ for ( int i = 0; i < GLs.length; i++ ) GLs[i] = Math.log10(biAllelicPr[i]);
+
+ return new GenotypeBuilder(original).PL(GLs).alleles(BIALLELIC_NOCALL).make();
+ }
+
+
+ private static final double PHRED_2_LOG10_COEFF = -.1;
+
+ /**
+ * Returns a new Genotype with the PLs of the multi-allelic original reduced to a bi-allelic case.
+ *
+ * Uses the log-sum-exp trick in order to work well with very low PLs
+ *
+ * This is handled in the following way:
+ *
+ * Suppose we have for a A/B/C site the following GLs:
+ *
+ * AA AB BB AC BC CC
+ *
+ * and we want to get the bi-allelic GLs for X/B, where X is everything not B
+ *
+ * XX = AA + AC + CC (since X = A or C)
+ * XB = AB + BC
+ * BB = BB
+ *
+ *
+ * This implementation use the log sum trick in order to avoid numeric inestability.
+ *
+ *
+ * @param original the original multi-allelic genotype
+ * @param altIndex the index of the alt allele we wish to keep in the bialleic case -- with ref == 0
+ * @param nAlts the total number of alt alleles
+ * @return a new biallelic genotype with appropriate PLs
+ */
+ @Requires({"original.hasLikelihoods()"})
+ @Ensures({"result.hasLikelihoods()", "result.getPL().length == 3"})
+ protected Genotype combineGLsPrecise(final Genotype original, final int altIndex, final int nAlts ) {
+
+ if ( original.isNonInformative() )
+ return new GenotypeBuilder(original).PL(BIALLELIC_NON_INFORMATIVE_PLS).alleles(BIALLELIC_NOCALL).make();
+
+ if ( altIndex < 1 || altIndex > nAlts ) throw new IllegalStateException("altIndex must be between 1 and nAlts " + nAlts);
+
+ final int[] pls = original.getPL();
+
+ final int nAlleles = nAlts + 1;
+
+ final int plCount = pls.length;
+
+ double BB = 0;
+ final double[] XBvalues = new double[nAlleles - 1];
+ final double[] XXvalues = new double[plCount - nAlleles];
+
+ int xbOffset = 0;
+ int xxOffset = 0;
+ for ( int index = 0; index < plCount; index++ ) {
+ final GenotypeLikelihoods.GenotypeLikelihoodsAllelePair pair = GenotypeLikelihoods.getAllelePair(index);
+ int i = pair.alleleIndex1;
+ int j = pair.alleleIndex2;
+ if (i == j) {
+ if (i == altIndex) BB = PHRED_2_LOG10_COEFF * pls[index]; else XXvalues[xxOffset++] = PHRED_2_LOG10_COEFF * pls[index];
+ } else if (i == altIndex || j == altIndex)
+ XBvalues[xbOffset++] = PHRED_2_LOG10_COEFF * pls[index];
+ else
+ XXvalues[xxOffset++] = PHRED_2_LOG10_COEFF * pls[index];
+ }
+
+ final double XB = MathUtils.log10sumLog10(XBvalues);
+ final double XX = MathUtils.log10sumLog10(XXvalues);
+
+ final double[] GLs = new double[] { XX, XB, BB};
+ return new GenotypeBuilder(original).PL(GLs).alleles(BIALLELIC_NOCALL).make();
+ }
+
+ protected final List applyMultiAllelicPriors(final List conditionalPNonRefResults) {
+ final ArrayList sorted = new ArrayList(conditionalPNonRefResults);
+
+ // sort the results, so the most likely allele is first
+ Collections.sort(sorted, compareAFCalcResultsByPNonRef);
+
+ double lastPosteriorGt0 = sorted.get(0).getLog10PosteriorOfAFGT0();
+ final double log10SingleAllelePriorOfAFGt0 = conditionalPNonRefResults.get(0).getLog10PriorOfAFGT0();
+
+ for ( int i = 0; i < sorted.size(); i++ ) {
+ if ( sorted.get(i).getLog10PosteriorOfAFGT0() > lastPosteriorGt0 )
+ throw new IllegalStateException("pNonRefResults not sorted: lastPosteriorGt0 " + lastPosteriorGt0 + " but current is " + sorted.get(i).getLog10PosteriorOfAFGT0());
+
+ final double log10PriorAFGt0 = (i + 1) * log10SingleAllelePriorOfAFGt0;
+ final double log10PriorAFEq0 = Math.log10(1 - Math.pow(10, log10PriorAFGt0));
+ final double[] thetaTONPriors = new double[] { log10PriorAFEq0, log10PriorAFGt0 };
+
+ // bind pNonRef for allele to the posterior value of the AF > 0 with the new adjusted prior
+ sorted.set(i, sorted.get(i).withNewPriors(MathUtils.normalizeFromLog10(thetaTONPriors, true)));
+ }
+
+ return sorted;
+ }
+
+ /**
+ * Take the independent estimates of pNonRef for each alt allele and combine them into a single result
+ *
+ * Given n independent calculations for each of n alternate alleles create a single
+ * combined AFCalcResult with:
+ *
+ * priors for AF == 0 equal to theta^N for the nth least likely allele
+ * posteriors that reflect the combined chance that any alleles are segregating and corresponding
+ * likelihoods
+ * combined MLEs in the order of the alt alleles in vc
+ *
+ * @param sortedResultsWithThetaNPriors the pNonRef result for each allele independently
+ */
+ protected AFCalcResult combineIndependentPNonRefs(final VariantContext vc,
+ final List sortedResultsWithThetaNPriors) {
+ int nEvaluations = 0;
+ final int nAltAlleles = sortedResultsWithThetaNPriors.size();
+ final int[] alleleCountsOfMLE = new int[nAltAlleles];
+ final double[] log10PriorsOfAC = new double[2];
+ final Map log10pRefByAllele = new HashMap(nAltAlleles);
+
+ // the sum of the log10 posteriors for AF == 0 and AF > 0 to determine joint probs
+ double log10PosteriorOfACEq0Sum = 0.0;
+ double log10PosteriorOfACGt0Sum = 0.0;
+
+ boolean anyPoly = false;
+ for ( final AFCalcResult sortedResultWithThetaNPriors : sortedResultsWithThetaNPriors ) {
+ final Allele altAllele = sortedResultWithThetaNPriors.getAllelesUsedInGenotyping().get(1);
+ final int altI = vc.getAlleles().indexOf(altAllele) - 1;
+
+ // MLE of altI allele is simply the MLE of this allele in altAlleles
+ alleleCountsOfMLE[altI] = sortedResultWithThetaNPriors.getAlleleCountAtMLE(altAllele);
+
+ // the AF > 0 case requires us to store the normalized likelihood for later summation
+ if ( sortedResultWithThetaNPriors.getLog10PosteriorOfAFGT0() > MIN_LOG10_CONFIDENCE_TO_INCLUDE_ALLELE_IN_POSTERIOR ) {
+ anyPoly = true;
+ log10PosteriorOfACEq0Sum += sortedResultWithThetaNPriors.getLog10PosteriorOfAFEq0();
+ log10PriorsOfAC[0] += sortedResultWithThetaNPriors.getLog10PriorOfAFEq0();
+ log10PriorsOfAC[1] += sortedResultWithThetaNPriors.getLog10PriorOfAFGT0();
+ }
+
+ log10PosteriorOfACGt0Sum += sortedResultWithThetaNPriors.getLog10PosteriorOfAFGT0();
+
+ // bind pNonRef for allele to the posterior value of the AF > 0 with the new adjusted prior
+ log10pRefByAllele.put(altAllele, sortedResultWithThetaNPriors.getLog10PosteriorOfAFEq0());
+
+ // trivial -- update the number of evaluations
+ nEvaluations += sortedResultWithThetaNPriors.nEvaluations;
+ }
+
+ // If no alleles were polymorphic, make sure we have the proper priors (the defaults) for likelihood calculation
+ if ( ! anyPoly ) {
+ log10PriorsOfAC[0] = sortedResultsWithThetaNPriors.get(0).getLog10PriorOfAFEq0();
+ log10PriorsOfAC[1] = sortedResultsWithThetaNPriors.get(0).getLog10PriorOfAFGT0();
+ }
+
+ // In principle, if B_p = x and C_p = y are the probabilities of being poly for alleles B and C,
+ // the probability of being poly is (1 - B_p) * (1 - C_p) = (1 - x) * (1 - y). We want to estimate confidently
+ // log10((1 - x) * (1 - y)) which is log10(1 - x) + log10(1 - y). This sum is log10PosteriorOfACEq0
+ //
+ // note we need to handle the case where the posterior of AF == 0 is 0.0, in which case we
+ // use the summed log10PosteriorOfACGt0Sum directly. This happens in cases where
+ // AF > 0 : 0.0 and AF == 0 : -16, and if you use the inverse calculation you get 0.0 and MathUtils.LOG10_P_OF_ZERO
+ final double log10PosteriorOfACGt0;
+ if ( log10PosteriorOfACEq0Sum == 0.0 )
+ log10PosteriorOfACGt0 = log10PosteriorOfACGt0Sum;
+ else
+ log10PosteriorOfACGt0 = Math.max(Math.log10(1 - Math.pow(10, log10PosteriorOfACEq0Sum)), MathUtils.LOG10_P_OF_ZERO);
+
+ final double[] log10LikelihoodsOfAC = new double[] {
+ // L + prior = posterior => L = poster - prior
+ log10PosteriorOfACEq0Sum - log10PriorsOfAC[0],
+ log10PosteriorOfACGt0 - log10PriorsOfAC[1]
+ };
+
+ return new MyAFCalcResult(alleleCountsOfMLE, nEvaluations, vc.getAlleles(),
+ // necessary to ensure all values < 0
+ MathUtils.normalizeFromLog10(log10LikelihoodsOfAC, true),
+ // priors incorporate multiple alt alleles, must be normalized
+ MathUtils.normalizeFromLog10(log10PriorsOfAC, true),
+ log10pRefByAllele, sortedResultsWithThetaNPriors);
+ }
+}
diff --git a/protected/java/src/org/broadinstitute/sting/gatk/walkers/genotyper/afcalc/OriginalDiploidExactAFCalc.java b/protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/genotyper/afcalc/OriginalDiploidExactAFCalc.java
similarity index 100%
rename from protected/java/src/org/broadinstitute/sting/gatk/walkers/genotyper/afcalc/OriginalDiploidExactAFCalc.java
rename to protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/genotyper/afcalc/OriginalDiploidExactAFCalc.java
diff --git a/protected/java/src/org/broadinstitute/sting/gatk/walkers/genotyper/afcalc/ReferenceDiploidExactAFCalc.java b/protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/genotyper/afcalc/ReferenceDiploidExactAFCalc.java
similarity index 100%
rename from protected/java/src/org/broadinstitute/sting/gatk/walkers/genotyper/afcalc/ReferenceDiploidExactAFCalc.java
rename to protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/genotyper/afcalc/ReferenceDiploidExactAFCalc.java
diff --git a/protected/java/src/org/broadinstitute/sting/gatk/walkers/genotyper/afcalc/StateTracker.java b/protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/genotyper/afcalc/StateTracker.java
similarity index 100%
rename from protected/java/src/org/broadinstitute/sting/gatk/walkers/genotyper/afcalc/StateTracker.java
rename to protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/genotyper/afcalc/StateTracker.java
diff --git a/protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/haplotypecaller/ActiveRegionTrimmer.java b/protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/haplotypecaller/ActiveRegionTrimmer.java
new file mode 100644
index 000000000..b7a646d4e
--- /dev/null
+++ b/protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/haplotypecaller/ActiveRegionTrimmer.java
@@ -0,0 +1,538 @@
+/*
+* By downloading the PROGRAM you agree to the following terms of use:
+*
+* BROAD INSTITUTE - SOFTWARE LICENSE AGREEMENT - FOR ACADEMIC NON-COMMERCIAL RESEARCH PURPOSES ONLY
+*
+* This Agreement is made between the Broad Institute, Inc. with a principal address at 7 Cambridge Center, Cambridge, MA 02142 (BROAD) and the LICENSEE and is effective at the date the downloading is completed (EFFECTIVE DATE).
+*
+* WHEREAS, LICENSEE desires to license the PROGRAM, as defined hereinafter, and BROAD wishes to have this PROGRAM utilized in the public interest, subject only to the royalty-free, nonexclusive, nontransferable license rights of the United States Government pursuant to 48 CFR 52.227-14; and
+* WHEREAS, LICENSEE desires to license the PROGRAM and BROAD desires to grant a license on the following terms and conditions.
+* NOW, THEREFORE, in consideration of the promises and covenants made herein, the parties hereto agree as follows:
+*
+* 1. DEFINITIONS
+* 1.1 PROGRAM shall mean copyright in the object code and source code known as GATK2 and related documentation, if any, as they exist on the EFFECTIVE DATE and can be downloaded from http://www.broadinstitute/GATK on the EFFECTIVE DATE.
+*
+* 2. LICENSE
+* 2.1 Grant. Subject to the terms of this Agreement, BROAD hereby grants to LICENSEE, solely for academic non-commercial research purposes, a non-exclusive, non-transferable license to: (a) download, execute and display the PROGRAM and (b) create bug fixes and modify the PROGRAM.
+* The LICENSEE may apply the PROGRAM in a pipeline to data owned by users other than the LICENSEE and provide these users the results of the PROGRAM provided LICENSEE does so for academic non-commercial purposes only. For clarification purposes, academic sponsored research is not a commercial use under the terms of this Agreement.
+* 2.2 No Sublicensing or Additional Rights. LICENSEE shall not sublicense or distribute the PROGRAM, in whole or in part, without prior written permission from BROAD. LICENSEE shall ensure that all of its users agree to the terms of this Agreement. LICENSEE further agrees that it shall not put the PROGRAM on a network, server, or other similar technology that may be accessed by anyone other than the LICENSEE and its employees and users who have agreed to the terms of this agreement.
+* 2.3 License Limitations. Nothing in this Agreement shall be construed to confer any rights upon LICENSEE by implication, estoppel, or otherwise to any computer software, trademark, intellectual property, or patent rights of BROAD, or of any other entity, except as expressly granted herein. LICENSEE agrees that the PROGRAM, in whole or part, shall not be used for any commercial purpose, including without limitation, as the basis of a commercial software or hardware product or to provide services. LICENSEE further agrees that the PROGRAM shall not be copied or otherwise adapted in order to circumvent the need for obtaining a license for use of the PROGRAM.
+*
+* 3. OWNERSHIP OF INTELLECTUAL PROPERTY
+* LICENSEE acknowledges that title to the PROGRAM shall remain with BROAD. The PROGRAM is marked with the following BROAD copyright notice and notice of attribution to contributors. LICENSEE shall retain such notice on all copies. LICENSEE agrees to include appropriate attribution if any results obtained from use of the PROGRAM are included in any publication.
+* Copyright 2012 Broad Institute, Inc.
+* Notice of attribution: The GATK2 program was made available through the generosity of Medical and Population Genetics program at the Broad Institute, Inc.
+* LICENSEE shall not use any trademark or trade name of BROAD, or any variation, adaptation, or abbreviation, of such marks or trade names, or any names of officers, faculty, students, employees, or agents of BROAD except as states above for attribution purposes.
+*
+* 4. INDEMNIFICATION
+* LICENSEE shall indemnify, defend, and hold harmless BROAD, and their respective officers, faculty, students, employees, associated investigators and agents, and their respective successors, heirs and assigns, (Indemnitees), against any liability, damage, loss, or expense (including reasonable attorneys fees and expenses) incurred by or imposed upon any of the Indemnitees in connection with any claims, suits, actions, demands or judgments arising out of any theory of liability (including, without limitation, actions in the form of tort, warranty, or strict liability and regardless of whether such action has any factual basis) pursuant to any right or license granted under this Agreement.
+*
+* 5. NO REPRESENTATIONS OR WARRANTIES
+* THE PROGRAM IS DELIVERED AS IS. BROAD MAKES NO REPRESENTATIONS OR WARRANTIES OF ANY KIND CONCERNING THE PROGRAM OR THE COPYRIGHT, EXPRESS OR IMPLIED, INCLUDING, WITHOUT LIMITATION, WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, NONINFRINGEMENT, OR THE ABSENCE OF LATENT OR OTHER DEFECTS, WHETHER OR NOT DISCOVERABLE. BROAD EXTENDS NO WARRANTIES OF ANY KIND AS TO PROGRAM CONFORMITY WITH WHATEVER USER MANUALS OR OTHER LITERATURE MAY BE ISSUED FROM TIME TO TIME.
+* IN NO EVENT SHALL BROAD OR ITS RESPECTIVE DIRECTORS, OFFICERS, EMPLOYEES, AFFILIATED INVESTIGATORS AND AFFILIATES BE LIABLE FOR INCIDENTAL OR CONSEQUENTIAL DAMAGES OF ANY KIND, INCLUDING, WITHOUT LIMITATION, ECONOMIC DAMAGES OR INJURY TO PROPERTY AND LOST PROFITS, REGARDLESS OF WHETHER BROAD SHALL BE ADVISED, SHALL HAVE OTHER REASON TO KNOW, OR IN FACT SHALL KNOW OF THE POSSIBILITY OF THE FOREGOING.
+*
+* 6. ASSIGNMENT
+* This Agreement is personal to LICENSEE and any rights or obligations assigned by LICENSEE without the prior written consent of BROAD shall be null and void.
+*
+* 7. MISCELLANEOUS
+* 7.1 Export Control. LICENSEE gives assurance that it will comply with all United States export control laws and regulations controlling the export of the PROGRAM, including, without limitation, all Export Administration Regulations of the United States Department of Commerce. Among other things, these laws and regulations prohibit, or require a license for, the export of certain types of software to specified countries.
+* 7.2 Termination. LICENSEE shall have the right to terminate this Agreement for any reason upon prior written notice to BROAD. If LICENSEE breaches any provision hereunder, and fails to cure such breach within thirty (30) days, BROAD may terminate this Agreement immediately. Upon termination, LICENSEE shall provide BROAD with written assurance that the original and all copies of the PROGRAM have been destroyed, except that, upon prior written authorization from BROAD, LICENSEE may retain a copy for archive purposes.
+* 7.3 Survival. The following provisions shall survive the expiration or termination of this Agreement: Articles 1, 3, 4, 5 and Sections 2.2, 2.3, 7.3, and 7.4.
+* 7.4 Notice. Any notices under this Agreement shall be in writing, shall specifically refer to this Agreement, and shall be sent by hand, recognized national overnight courier, confirmed facsimile transmission, confirmed electronic mail, or registered or certified mail, postage prepaid, return receipt requested. All notices under this Agreement shall be deemed effective upon receipt.
+* 7.5 Amendment and Waiver; Entire Agreement. This Agreement may be amended, supplemented, or otherwise modified only by means of a written instrument signed by all parties. Any waiver of any rights or failure to act in a specific instance shall relate only to such instance and shall not be construed as an agreement to waive any rights or fail to act in any other instance, whether or not similar. This Agreement constitutes the entire agreement among the parties with respect to its subject matter and supersedes prior agreements or understandings between the parties relating to its subject matter.
+* 7.6 Binding Effect; Headings. This Agreement shall be binding upon and inure to the benefit of the parties and their respective permitted successors and assigns. All headings are for convenience only and shall not affect the meaning of any provision of this Agreement.
+* 7.7 Governing Law. This Agreement shall be construed, governed, interpreted and applied in accordance with the internal laws of the Commonwealth of Massachusetts, U.S.A., without regard to conflict of laws principles.
+*/
+package org.broadinstitute.sting.gatk.walkers.haplotypecaller;
+
+import org.apache.log4j.Logger;
+import org.broadinstitute.sting.commandline.Argument;
+import org.broadinstitute.sting.commandline.Hidden;
+import org.broadinstitute.sting.utils.GenomeLoc;
+import org.broadinstitute.sting.utils.GenomeLocParser;
+import org.broadinstitute.sting.utils.activeregion.ActiveRegion;
+import org.broadinstitute.sting.utils.collections.Pair;
+import org.broadinstitute.sting.utils.exceptions.UserException;
+import org.broadinstitute.variant.variantcontext.VariantContext;
+
+import java.util.*;
+
+/**
+ * Helper component to manage active region trimming
+ *
+ *
+ * It receives the user arguments that controls trimming and also performs the trimming region calculation.
+ *
+ * @author Valentin Ruano-Rubio <valentin@broadinstitute.org>
+ */
+class ActiveRegionTrimmer {
+
+ /**
+ * Genome location parser use in order to create and manipulate genomic intervals.
+ */
+ private GenomeLocParser locParser;
+
+ /**
+ * Holds the debug flag. If {@code true} the trimmer will output debugging messages into the log.
+ */
+ private boolean debug;
+
+ /**
+ * Holds the extension to be used based on whether GGA mode is on or off.
+ */
+ private int usableExtension;
+
+ /**
+ * Records whether the trimming intervals are going to be used to emit reference confidence, {@code true},
+ * or regular HC output {@code false}.
+ */
+ private boolean emitReferenceConfidence;
+
+ @Hidden
+ @Argument(fullName="dontTrimActiveRegions", shortName="dontTrimActiveRegions", doc="If specified, we will not trim down the active region from the full region (active + extension) to just the active interval for genotyping", required = false)
+ protected boolean dontTrimActiveRegions = false;
+
+ /**
+ * the maximum extent into the full active region extension that we're willing to go in genotyping our events
+ */
+ @Hidden
+ @Argument(fullName="maxDiscARExtension", shortName="maxDiscARExtension", doc = "the maximum extent into the full active region extension that we're willing to go in genotyping our events for discovery", required=false)
+ protected int discoverExtension = 25;
+
+ @Hidden
+ @Argument(fullName="maxGGAARExtension", shortName="maxGGAARExtension", doc = "the maximum extent into the full active region extension that we're willing to go in genotyping our events for GGA mode", required=false)
+ protected int ggaExtension = 300;
+
+ /**
+ * Include at least this many bases around an event for calling it
+ */
+ @Hidden
+ @Argument(fullName="paddingAroundIndels", shortName="paddingAroundIndels", doc = "Include at least this many bases around an event for calling indels", required=false)
+ protected int indelPadding = 150;
+
+ @Hidden
+ @Argument(fullName="paddingAroundSNPs", shortName="paddingAroundSNPs", doc = "Include at least this many bases around an event for calling snps", required=false)
+ protected int snpPadding = 20;
+
+ /**
+ * Holds a reference the trimmer logger.
+ */
+ private final static Logger logger = Logger.getLogger(ActiveRegionTrimmer.class);
+
+ /**
+ * Initializes the trimmer.
+ *
+ *
+ * This method should be called once and only once before any trimming is performed.
+ *
+ *
+ * @param glp the genome-location-parser to be used when operating with genomic locations.
+ * @param debug whether to show extra debug log messages.
+ * @param isGGA whether the trimming region calculator should act as if we are in GGA mode or not.
+ * @param emitReferenceConfidence indicates whether we plan to use this trimmer to generate trimmed regions
+ * to be used for emitting reference confidence.
+ *
+ * @throws IllegalStateException if this trim calculator has already been initialized.
+ * @throws IllegalArgumentException if the input location parser is {@code null}.
+ * @throws UserException.BadArgumentValue if any of the user argument values is invalid.
+ */
+ void initialize(final GenomeLocParser glp, final boolean debug, final boolean isGGA, final boolean emitReferenceConfidence) {
+ if (locParser != null)
+ throw new IllegalStateException(getClass().getSimpleName() + " instance initialized twice");
+ if (glp == null)
+ throw new IllegalArgumentException("input genome-loc-parser cannot be null");
+ checkUserArguments();
+ locParser = glp;
+ this.debug = debug;
+ usableExtension = isGGA ? ggaExtension : discoverExtension;
+ this.emitReferenceConfidence = emitReferenceConfidence;
+ }
+
+ /**
+ * Checks user trimming argument values
+ *
+ * @throws UserException.BadArgumentValue if there is some problem with any of the arguments values.
+ */
+ private void checkUserArguments() {
+ if ( snpPadding < 0 ) throw new UserException.BadArgumentValue("paddingAroundSNPs","" + snpPadding + "< 0");
+ if ( indelPadding < 0 ) throw new UserException.BadArgumentValue("paddingAroundIndels","" + indelPadding + "< 0");
+ if ( discoverExtension < 0) throw new UserException.BadArgumentValue("maxDiscARExtension","" + discoverExtension + "< 0");
+ if ( ggaExtension < 0) throw new UserException.BadArgumentValue("maxGGAAREExtension","" + ggaExtension + "< 0");
+ }
+
+ /**
+ * Holds the result of trimming.
+ *
+ *
+ *
+ */
+ public static class Result {
+
+ /**
+ * Indicates whether trimming is required per data and user request.
+ */
+ protected final boolean needsTrimming;
+
+ /**
+ * Holds the input active region.
+ */
+ protected final ActiveRegion originalRegion;
+
+ /**
+ * Holds the smaller range that contain all relevant callable variants in the
+ * input active region (not considering the extension).
+ *
+ */
+ protected final GenomeLoc callableSpan;
+
+ /**
+ * Maximum available range for the trimmed variant region.
+ */
+ protected final GenomeLoc maximumSpan;
+
+ /**
+ * The trimmed variant region span including the extension.
+ */
+ protected final GenomeLoc extendedSpan;
+
+
+ /**
+ * The ideal trimmer variant region span including the extension.
+ */
+ protected final GenomeLoc idealSpan;
+
+ /**
+ * Returns the ideal trimming span.
+ *
+ *
+ * The ideal span is the one containing all callable variation overlapping the original active region span
+ * (without extension) and the applicable padding {@link #getPadding()} in both sides.
+ *
+ *
+ * @return never {@code null}.
+ */
+ @SuppressWarnings("unused")
+ public GenomeLoc getIdealSpan() {
+ return idealSpan;
+ }
+
+ /**
+ * Holds the flanking spans that do not contain the callable variants.
+ *
+ * The first element of the pair is the left (up-stream) non-variant flank, whereas the second element is
+ * the right (down-stream) non-variant flank.
+ */
+ protected final Pair nonVariantFlanks;
+
+ /**
+ * Holds the collection of callable events within the variant trimming region.
+ */
+ protected final List callableEvents;
+
+ /**
+ * Required padding around the variant trimming region.
+ */
+ protected final int padding;
+
+
+ /**
+ * Returns the required padding around callable variation.
+ *
+ *
+ * Notice that due to the limiting span of the original active region (including its extension) it
+ * is possible that the resulting final trimmed variant region span does not satisfies the padding. However
+ * that should be rare.
+ *
+ * @return 0 or greater.
+ */
+ @SuppressWarnings("unused")
+ public int getPadding() {
+ return padding;
+ }
+
+ /**
+ * Holds the maximum extension around the original active region span considered for the trimmed
+ * variation region.
+ */
+ protected final int usableExtension;
+
+ /**
+ * Returns the maximum extension around the original active region span considered for the trimmed
+ * variation region.
+ *
+ *
+ * From time to time, the trimmed region may require a span beyond the input original active region's.
+ * For example when there is a callable event close ot one of its ends and the required padding makes it
+ * round beyond that limit.
+ *
+ *
+ * Notice that due to the limiting span of the original active region (including its extended region) it
+ * is possible that the resulting final trimmed variant region span goes beyond this extension including more of
+ * the original active region own extension.
+ *
+ * @return 0 or greater.
+ */
+ @SuppressWarnings("unused")
+ public int getUsableExtension() {
+ return usableExtension;
+ }
+
+ /**
+ * Holds variant-containing callable region.
+ *
+ * This is lazy-initialized using {@link #callableSpan}.
+ */
+ protected ActiveRegion callableRegion;
+
+
+ /**
+ * Non-variant left flank region.
+ *
+ * This is lazy-initialized using
+ * {@link #nonVariantFlanks}.{@link Pair#getFirst() getFirst()}.
+ */
+ private ActiveRegion leftFlankRegion;
+
+ /**
+ * Non-variant right flank region.
+ *
+ * This is lazy-initialized using
+ * {@link #nonVariantFlanks}.{@link Pair#getFirst() getSecond()}.
+ */
+ private ActiveRegion rightFlankRegion;
+
+ /**
+ * Whether the variant trimmed region is going to be used for emitting reference confidence records.
+ */
+ private final boolean emitReferenceConfidence;
+
+ /**
+ * Creates a trimming result given all its properties.
+ *
+ * @param emitReferenceConfidence whether reference confidence output modes are on.
+ * @param needsTrimming whether there is any trimming needed at all.
+ * @param originalRegion the original active region.
+ * @param padding padding around contained callable variation events.
+ * @param extension the extension applied to the trimmed variant span.
+ * @param overlappingEvents contained callable variation events.
+ * @param nonVariantFlanks pair of non-variant flank spans around the variant containing span.
+ * @param extendedSpan final trimmed variant span including the extension.
+ * @param idealSpan the ideal span, that contains.
+ * @param maximumSpan maximum possible trimmed span based on the input original active region extended span.
+ * @param callableSpan variant containing span without padding.
+ */
+ protected Result(final boolean emitReferenceConfidence, final boolean needsTrimming, final ActiveRegion originalRegion,
+ final int padding, final int extension,
+ final List overlappingEvents, final Pair nonVariantFlanks,
+ final GenomeLoc extendedSpan,
+ final GenomeLoc idealSpan,
+ final GenomeLoc maximumSpan,
+ final GenomeLoc callableSpan) {
+ this.emitReferenceConfidence = emitReferenceConfidence;
+ this.needsTrimming = needsTrimming;
+ this.originalRegion = originalRegion;
+ this.nonVariantFlanks = nonVariantFlanks;
+ this.padding = padding;
+ this.usableExtension = extension;
+ this.callableEvents = overlappingEvents;
+ this.callableSpan = callableSpan;
+ this.idealSpan = idealSpan;
+ this.maximumSpan = maximumSpan;
+ this.extendedSpan = extendedSpan;
+
+ if (!extendedSpan.isUnmapped() && !callableSpan.isUnmapped() && !extendedSpan.containsP(callableSpan))
+ throw new IllegalArgumentException("the extended callable span must include the callable span");
+ }
+
+
+ /**
+ * Checks whether there is any variation present in the target region.
+ *
+ * @return {@code true} if there is any variant, {@code false} otherwise.
+ */
+ public boolean isVariationPresent() {
+ return ! callableEvents.isEmpty();
+ }
+
+ /**
+ * Checks whether the active region needs trimming.
+ */
+ public boolean needsTrimming() {
+ return needsTrimming;
+ }
+
+ /**
+ * Returns the trimmed variant containing region
+ *
+ * @throws IllegalStateException if there is no variation detected.
+ *
+ * @return never {@code null}.
+ */
+ public ActiveRegion getCallableRegion() {
+ if (callableRegion == null && !extendedSpan.isUnmapped())
+ //TODO this conditional is a patch to retain the current standard HC run behaviour
+ //TODO we should simply remove this difference between trimming with or without GVCF
+ //TODO embracing slight changes in the standard HC output
+ callableRegion = emitReferenceConfidence ? originalRegion.trim(callableSpan, extendedSpan) : originalRegion.trim(extendedSpan);
+ else if (extendedSpan.isUnmapped())
+ throw new IllegalStateException("there is no variation thus no variant region");
+ return callableRegion;
+ }
+
+ /**
+ * Checks whether there is a non-empty left flanking non-variant trimmed out region.
+ * @return {@code true} if there is a non-trivial left flank region, {@code false} otherwise.
+ */
+ public boolean hasLeftFlankingRegion() {
+ return ! nonVariantFlanks.getFirst().isUnmapped();
+ }
+
+ /**
+ * Checks whether there is a non-empty right flanking non-variant trimmed out region.
+ * @return {@code true} if there is a non-trivial right flank region, {@code false} otherwise.
+ */
+ public boolean hasRightFlankingRegion() {
+ return ! nonVariantFlanks.getSecond().isUnmapped();
+ }
+
+ /**
+ * Returns the trimmed out left non-variant region.
+ *
+ * Notice that in case of no variation, the whole original region is considered the left flanking region.
+ *
+ * @throws IllegalStateException if there is not such as left flanking region.
+ */
+ public ActiveRegion nonVariantLeftFlankRegion() {
+ if (leftFlankRegion == null && ! nonVariantFlanks.getFirst().isUnmapped())
+ leftFlankRegion = originalRegion.trim(nonVariantFlanks.getFirst(),originalRegion.getExtension());
+ else if (nonVariantFlanks.getFirst().isUnmapped())
+ throw new IllegalStateException("there is no left flank non-variant trimmed out region");
+ return leftFlankRegion;
+ }
+
+ /**
+ * Returns the trimmed out right non-variant region.
+ */
+ public ActiveRegion nonVariantRightFlankRegion() {
+ if (rightFlankRegion == null && ! nonVariantFlanks.getSecond().isUnmapped())
+ rightFlankRegion = originalRegion.trim(nonVariantFlanks.getSecond(),originalRegion.getExtension());
+ else if (nonVariantFlanks.getSecond().isUnmapped())
+ throw new IllegalStateException("there is no right flank non-variant trimmed out region");
+ return rightFlankRegion;
+ }
+
+ /**
+ * Creates a result indicating that there was no trimming to be done.
+ */
+ protected static Result noTrimming(final boolean emitReferenceConfidence,
+ final ActiveRegion targetRegion, final int padding,
+ final int usableExtension,final List events) {
+ final GenomeLoc targetRegionLoc = targetRegion.getLocation();
+ final Result result = new Result(emitReferenceConfidence,false,targetRegion,padding,usableExtension,events,new Pair<>(GenomeLoc.UNMAPPED,GenomeLoc.UNMAPPED),
+ targetRegionLoc,targetRegionLoc,targetRegionLoc,targetRegionLoc);
+ result.callableRegion = targetRegion;
+ return result;
+ }
+
+ /**
+ * Creates a result indicating that no variation was found.
+ */
+ protected static Result noVariation(final boolean emitReferenceConfidence, final ActiveRegion targetRegion,
+ final int padding, final int usableExtension) {
+ final Result result = new Result(emitReferenceConfidence,false,targetRegion,padding,usableExtension,
+ Collections.emptyList(),new Pair<>(targetRegion.getLocation(),GenomeLoc.UNMAPPED),
+ GenomeLoc.UNMAPPED,GenomeLoc.UNMAPPED,GenomeLoc.UNMAPPED,GenomeLoc.UNMAPPED);
+ result.leftFlankRegion = targetRegion;
+ return result;
+ }
+ }
+
+ /**
+ * Returns a trimming result object from which the variant trimmed region and flanking non-variant sections
+ * can be recovered latter.
+ *
+ * @param originalRegion the genome location range to trim.
+ * @param allVariantsWithinExtendedRegion list of variants contained in the trimming location. Variants therein
+ * not overlapping with {@code originalRegion} are simply ignored.
+ * @return never {@code null}.
+ */
+ public Result trim(final ActiveRegion originalRegion,
+ final TreeSet allVariantsWithinExtendedRegion) {
+
+
+ if ( allVariantsWithinExtendedRegion.isEmpty() ) // no variants,
+ return Result.noVariation(emitReferenceConfidence,originalRegion,snpPadding, usableExtension);
+
+ final List withinActiveRegion = new LinkedList<>();
+ final GenomeLoc originalRegionRange = originalRegion.getLocation();
+ boolean foundNonSnp = false;
+ GenomeLoc variantSpan = null;
+ for ( final VariantContext vc : allVariantsWithinExtendedRegion ) {
+ final GenomeLoc vcLoc = locParser.createGenomeLoc(vc);
+ if ( originalRegionRange.overlapsP(vcLoc) ) {
+ foundNonSnp = foundNonSnp || ! vc.isSNP();
+ variantSpan = variantSpan == null ? vcLoc : variantSpan.endpointSpan(vcLoc);
+ withinActiveRegion.add(vc);
+ }
+ }
+ final int padding = foundNonSnp ? indelPadding : snpPadding;
+
+ // we don't actually have anything in the region after skipping out variants that don't overlap
+ // the region's full location
+ if ( variantSpan == null )
+ return Result.noVariation(emitReferenceConfidence,originalRegion,padding, usableExtension);
+
+ if ( dontTrimActiveRegions)
+ return Result.noTrimming(emitReferenceConfidence,originalRegion, padding, usableExtension, withinActiveRegion);
+
+ final GenomeLoc maximumSpan = locParser.createPaddedGenomeLoc(originalRegionRange, usableExtension);
+ final GenomeLoc idealSpan = locParser.createPaddedGenomeLoc(variantSpan, padding);
+ final GenomeLoc finalSpan = maximumSpan.intersect(idealSpan).union(variantSpan);
+
+ // Make double sure that, if we are emitting GVCF we won't call non-variable positions beyond the target active region span.
+ // In regular call we don't do so so we don't care and we want to maintain behavior, so the conditional.
+ final GenomeLoc callableSpan = emitReferenceConfidence ? variantSpan.intersect(originalRegionRange) : variantSpan;
+
+ final Pair nonVariantRegions = nonVariantTargetRegions(originalRegion, callableSpan);
+
+ if ( debug ) {
+ logger.info("events : " + withinActiveRegion);
+ logger.info("region : " + originalRegion);
+ logger.info("callableSpan : " + callableSpan);
+ logger.info("padding : " + padding);
+ logger.info("idealSpan : " + idealSpan);
+ logger.info("maximumSpan : " + maximumSpan);
+ logger.info("finalSpan : " + finalSpan);
+ }
+
+ return new Result(emitReferenceConfidence,true,originalRegion,padding, usableExtension,withinActiveRegion,nonVariantRegions,finalSpan,idealSpan,maximumSpan,variantSpan);
+ }
+
+ /**
+ * Calculates the list of region to trim away.
+ * @param targetRegion region for which to generate the flanking regions.
+ * @param variantSpan the span of the core region containing relevant variation and required padding.
+ * @return never {@code null}; 0, 1 or 2 element list.
+ */
+ private Pair nonVariantTargetRegions(final ActiveRegion targetRegion, final GenomeLoc variantSpan) {
+ final GenomeLoc targetRegionRange = targetRegion.getLocation();
+ final int finalStart = variantSpan.getStart();
+ final int finalStop = variantSpan.getStop();
+
+ final int targetStart = targetRegionRange.getStart();
+ final int targetStop = targetRegionRange.getStop();
+
+ final boolean preTrimmingRequired = targetStart < finalStart;
+ final boolean postTrimmingRequired = targetStop > finalStop;
+ if (preTrimmingRequired) {
+ final String contig = targetRegionRange.getContig();
+ return postTrimmingRequired ? new Pair<>(
+ locParser.createGenomeLoc(contig, targetStart, finalStart - 1),
+ locParser.createGenomeLoc(contig, finalStop + 1, targetStop)) :
+ new Pair<>(locParser.createGenomeLoc(contig, targetStart, finalStart - 1),GenomeLoc.UNMAPPED);
+ } else if (postTrimmingRequired)
+ return new Pair<>(GenomeLoc.UNMAPPED,locParser.createGenomeLoc(targetRegionRange.getContig(), finalStop + 1, targetStop));
+ else
+ return new Pair<>(GenomeLoc.UNMAPPED,GenomeLoc.UNMAPPED);
+ }
+}
\ No newline at end of file
diff --git a/protected/java/src/org/broadinstitute/sting/gatk/walkers/haplotypecaller/AssemblyResult.java b/protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/haplotypecaller/AssemblyResult.java
similarity index 100%
rename from protected/java/src/org/broadinstitute/sting/gatk/walkers/haplotypecaller/AssemblyResult.java
rename to protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/haplotypecaller/AssemblyResult.java
diff --git a/protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/haplotypecaller/AssemblyResultSet.java b/protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/haplotypecaller/AssemblyResultSet.java
new file mode 100644
index 000000000..8cadea6ec
--- /dev/null
+++ b/protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/haplotypecaller/AssemblyResultSet.java
@@ -0,0 +1,543 @@
+/*
+* By downloading the PROGRAM you agree to the following terms of use:
+*
+* BROAD INSTITUTE - SOFTWARE LICENSE AGREEMENT - FOR ACADEMIC NON-COMMERCIAL RESEARCH PURPOSES ONLY
+*
+* This Agreement is made between the Broad Institute, Inc. with a principal address at 7 Cambridge Center, Cambridge, MA 02142 (BROAD) and the LICENSEE and is effective at the date the downloading is completed (EFFECTIVE DATE).
+*
+* WHEREAS, LICENSEE desires to license the PROGRAM, as defined hereinafter, and BROAD wishes to have this PROGRAM utilized in the public interest, subject only to the royalty-free, nonexclusive, nontransferable license rights of the United States Government pursuant to 48 CFR 52.227-14; and
+* WHEREAS, LICENSEE desires to license the PROGRAM and BROAD desires to grant a license on the following terms and conditions.
+* NOW, THEREFORE, in consideration of the promises and covenants made herein, the parties hereto agree as follows:
+*
+* 1. DEFINITIONS
+* 1.1 PROGRAM shall mean copyright in the object code and source code known as GATK2 and related documentation, if any, as they exist on the EFFECTIVE DATE and can be downloaded from http://www.broadinstitute/GATK on the EFFECTIVE DATE.
+*
+* 2. LICENSE
+* 2.1 Grant. Subject to the terms of this Agreement, BROAD hereby grants to LICENSEE, solely for academic non-commercial research purposes, a non-exclusive, non-transferable license to: (a) download, execute and display the PROGRAM and (b) create bug fixes and modify the PROGRAM.
+* The LICENSEE may apply the PROGRAM in a pipeline to data owned by users other than the LICENSEE and provide these users the results of the PROGRAM provided LICENSEE does so for academic non-commercial purposes only. For clarification purposes, academic sponsored research is not a commercial use under the terms of this Agreement.
+* 2.2 No Sublicensing or Additional Rights. LICENSEE shall not sublicense or distribute the PROGRAM, in whole or in part, without prior written permission from BROAD. LICENSEE shall ensure that all of its users agree to the terms of this Agreement. LICENSEE further agrees that it shall not put the PROGRAM on a network, server, or other similar technology that may be accessed by anyone other than the LICENSEE and its employees and users who have agreed to the terms of this agreement.
+* 2.3 License Limitations. Nothing in this Agreement shall be construed to confer any rights upon LICENSEE by implication, estoppel, or otherwise to any computer software, trademark, intellectual property, or patent rights of BROAD, or of any other entity, except as expressly granted herein. LICENSEE agrees that the PROGRAM, in whole or part, shall not be used for any commercial purpose, including without limitation, as the basis of a commercial software or hardware product or to provide services. LICENSEE further agrees that the PROGRAM shall not be copied or otherwise adapted in order to circumvent the need for obtaining a license for use of the PROGRAM.
+*
+* 3. OWNERSHIP OF INTELLECTUAL PROPERTY
+* LICENSEE acknowledges that title to the PROGRAM shall remain with BROAD. The PROGRAM is marked with the following BROAD copyright notice and notice of attribution to contributors. LICENSEE shall retain such notice on all copies. LICENSEE agrees to include appropriate attribution if any results obtained from use of the PROGRAM are included in any publication.
+* Copyright 2012 Broad Institute, Inc.
+* Notice of attribution: The GATK2 program was made available through the generosity of Medical and Population Genetics program at the Broad Institute, Inc.
+* LICENSEE shall not use any trademark or trade name of BROAD, or any variation, adaptation, or abbreviation, of such marks or trade names, or any names of officers, faculty, students, employees, or agents of BROAD except as states above for attribution purposes.
+*
+* 4. INDEMNIFICATION
+* LICENSEE shall indemnify, defend, and hold harmless BROAD, and their respective officers, faculty, students, employees, associated investigators and agents, and their respective successors, heirs and assigns, (Indemnitees), against any liability, damage, loss, or expense (including reasonable attorneys fees and expenses) incurred by or imposed upon any of the Indemnitees in connection with any claims, suits, actions, demands or judgments arising out of any theory of liability (including, without limitation, actions in the form of tort, warranty, or strict liability and regardless of whether such action has any factual basis) pursuant to any right or license granted under this Agreement.
+*
+* 5. NO REPRESENTATIONS OR WARRANTIES
+* THE PROGRAM IS DELIVERED AS IS. BROAD MAKES NO REPRESENTATIONS OR WARRANTIES OF ANY KIND CONCERNING THE PROGRAM OR THE COPYRIGHT, EXPRESS OR IMPLIED, INCLUDING, WITHOUT LIMITATION, WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, NONINFRINGEMENT, OR THE ABSENCE OF LATENT OR OTHER DEFECTS, WHETHER OR NOT DISCOVERABLE. BROAD EXTENDS NO WARRANTIES OF ANY KIND AS TO PROGRAM CONFORMITY WITH WHATEVER USER MANUALS OR OTHER LITERATURE MAY BE ISSUED FROM TIME TO TIME.
+* IN NO EVENT SHALL BROAD OR ITS RESPECTIVE DIRECTORS, OFFICERS, EMPLOYEES, AFFILIATED INVESTIGATORS AND AFFILIATES BE LIABLE FOR INCIDENTAL OR CONSEQUENTIAL DAMAGES OF ANY KIND, INCLUDING, WITHOUT LIMITATION, ECONOMIC DAMAGES OR INJURY TO PROPERTY AND LOST PROFITS, REGARDLESS OF WHETHER BROAD SHALL BE ADVISED, SHALL HAVE OTHER REASON TO KNOW, OR IN FACT SHALL KNOW OF THE POSSIBILITY OF THE FOREGOING.
+*
+* 6. ASSIGNMENT
+* This Agreement is personal to LICENSEE and any rights or obligations assigned by LICENSEE without the prior written consent of BROAD shall be null and void.
+*
+* 7. MISCELLANEOUS
+* 7.1 Export Control. LICENSEE gives assurance that it will comply with all United States export control laws and regulations controlling the export of the PROGRAM, including, without limitation, all Export Administration Regulations of the United States Department of Commerce. Among other things, these laws and regulations prohibit, or require a license for, the export of certain types of software to specified countries.
+* 7.2 Termination. LICENSEE shall have the right to terminate this Agreement for any reason upon prior written notice to BROAD. If LICENSEE breaches any provision hereunder, and fails to cure such breach within thirty (30) days, BROAD may terminate this Agreement immediately. Upon termination, LICENSEE shall provide BROAD with written assurance that the original and all copies of the PROGRAM have been destroyed, except that, upon prior written authorization from BROAD, LICENSEE may retain a copy for archive purposes.
+* 7.3 Survival. The following provisions shall survive the expiration or termination of this Agreement: Articles 1, 3, 4, 5 and Sections 2.2, 2.3, 7.3, and 7.4.
+* 7.4 Notice. Any notices under this Agreement shall be in writing, shall specifically refer to this Agreement, and shall be sent by hand, recognized national overnight courier, confirmed facsimile transmission, confirmed electronic mail, or registered or certified mail, postage prepaid, return receipt requested. All notices under this Agreement shall be deemed effective upon receipt.
+* 7.5 Amendment and Waiver; Entire Agreement. This Agreement may be amended, supplemented, or otherwise modified only by means of a written instrument signed by all parties. Any waiver of any rights or failure to act in a specific instance shall relate only to such instance and shall not be construed as an agreement to waive any rights or fail to act in any other instance, whether or not similar. This Agreement constitutes the entire agreement among the parties with respect to its subject matter and supersedes prior agreements or understandings between the parties relating to its subject matter.
+* 7.6 Binding Effect; Headings. This Agreement shall be binding upon and inure to the benefit of the parties and their respective permitted successors and assigns. All headings are for convenience only and shall not affect the meaning of any provision of this Agreement.
+* 7.7 Governing Law. This Agreement shall be construed, governed, interpreted and applied in accordance with the internal laws of the Commonwealth of Massachusetts, U.S.A., without regard to conflict of laws principles.
+*/
+
+package org.broadinstitute.sting.gatk.walkers.haplotypecaller;
+
+import org.apache.log4j.Logger;
+import org.broadinstitute.sting.gatk.walkers.haplotypecaller.readthreading.ReadThreadingGraph;
+import org.broadinstitute.sting.utils.GenomeLoc;
+import org.broadinstitute.sting.utils.activeregion.ActiveRegion;
+import org.broadinstitute.sting.utils.collections.CountSet;
+import org.broadinstitute.sting.utils.haplotype.EventMap;
+import org.broadinstitute.sting.utils.haplotype.Haplotype;
+import org.broadinstitute.sting.utils.haplotype.HaplotypeSizeAndBaseComparator;
+import org.broadinstitute.variant.variantcontext.VariantContext;
+
+import java.io.PrintWriter;
+import java.io.StringWriter;
+import java.util.*;
+
+/**
+ * Collection of read assembly using several kmerSizes.
+ *
+ *
+ * There could be a different assembly per each kmerSize. In turn, haplotypes are result of one of those
+ * assemblies.
+ *
+ *
+ *
+ * Where there is more than one possible kmerSize that generates a haplotype we consider the smaller one.
+ *
+ *
+ * @author Valentin Ruano-Rubio <valentin@broadinstitute.com>
+ */
+public class AssemblyResultSet {
+
+ private final Map assemblyResultByKmerSize;
+ private final Set haplotypes;
+ private final Map assemblyResultByHaplotype;
+ private ActiveRegion regionForGenotyping;
+ private byte[] fullReferenceWithPadding;
+ private GenomeLoc paddedReferenceLoc;
+ private boolean variationPresent;
+ private Haplotype refHaplotype;
+ private boolean wasTrimmed = false;
+ private final CountSet kmerSizes;
+ private TreeSet variationEvents;
+ private boolean debug;
+ private static Logger logger = Logger.getLogger(AssemblyResultSet.class);
+
+ /**
+ * Constructs a new empty assembly result set.
+ */
+ public AssemblyResultSet() {
+ assemblyResultByKmerSize = new LinkedHashMap<>(4);
+ haplotypes = new LinkedHashSet<>(10);
+ assemblyResultByHaplotype = new LinkedHashMap<>(10);
+ kmerSizes = new CountSet(4);
+ }
+
+
+ /**
+ * Change the debug status for this assembly-result-set.
+ * @param newValue new value for the debug status.
+ */
+ void setDebug(final boolean newValue) {
+ debug = newValue;
+ }
+
+ /**
+ * Trims an assembly result set down based on a new set of trimmed haplotypes.
+ *
+ * @param trimmedActiveRegion the trimmed down active region.
+ *
+ * @throws NullPointerException if any argument in {@code null} or
+ * if there are {@code null} entries in {@code originalByTrimmedHaplotypes} for trimmed haplotype keys.
+ * @throws IllegalArgumentException if there is no reference haplotype amongst the trimmed ones.
+ *
+ * @return never {@code null}, a new trimmed assembly result set.
+ */
+ public AssemblyResultSet trimTo(final ActiveRegion trimmedActiveRegion) {
+
+ final Map originalByTrimmedHaplotypes = calculateOriginalByTrimmedHaplotypes(trimmedActiveRegion);
+ if (refHaplotype == null) throw new IllegalStateException();
+ if (trimmedActiveRegion == null) throw new NullPointerException();
+ final AssemblyResultSet result = new AssemblyResultSet();
+
+ for (final Haplotype trimmed : originalByTrimmedHaplotypes.keySet()) {
+ final Haplotype original = originalByTrimmedHaplotypes.get(trimmed);
+ if (original == null)
+ throw new NullPointerException("all trimmed haplotypes must have an original one");
+ final AssemblyResult as = assemblyResultByHaplotype.get(original);
+ if (as == null) result.add(trimmed); else result.add(trimmed, as);
+ }
+
+ result.setRegionForGenotyping(trimmedActiveRegion);
+ result.setFullReferenceWithPadding(this.fullReferenceWithPadding);
+ result.setPaddedReferenceLoc(this.paddedReferenceLoc);
+ if (result.refHaplotype == null)
+ throw new IllegalStateException("missing reference haplotype in the trimmed set");
+ result.wasTrimmed = true;
+ return result;
+ }
+
+ private Map calculateOriginalByTrimmedHaplotypes(final ActiveRegion trimmedActiveRegion) {
+ if ( debug ) logger.info("Trimming active region " + getRegionForGenotyping() + " with " + getHaplotypeCount() + " haplotypes");
+
+ final List haplotypeList = getHaplotypeList();
+
+ // trim down the haplotypes
+ final Map originalByTrimmedHaplotypes = new HashMap<>();
+
+ for ( final Haplotype h : haplotypeList ) {
+ final Haplotype trimmed = h.trim(trimmedActiveRegion.getExtendedLoc());
+
+ if ( trimmed != null ) {
+ if (originalByTrimmedHaplotypes.containsKey(trimmed)) {
+ if (trimmed.isReference()) {
+ originalByTrimmedHaplotypes.remove(trimmed);
+ originalByTrimmedHaplotypes.put(trimmed, h);
+ }
+ } else
+ originalByTrimmedHaplotypes.put(trimmed,h);
+ } else if (h.isReference())
+ throw new IllegalStateException("trimming eliminates the reference haplotype");
+ else if ( debug ) {
+ logger.info("Throwing out haplotype " + h + " with cigar " + h.getCigar() +
+ " because it starts with or ends with an insertion or deletion when trimmed to " +
+ trimmedActiveRegion.getExtendedLoc());
+ }
+ }
+
+ // create the final list of trimmed haplotypes
+ final List trimmedHaplotypes = new ArrayList<>(originalByTrimmedHaplotypes.keySet());
+
+ // resort the trimmed haplotypes.
+ Collections.sort(trimmedHaplotypes,new HaplotypeSizeAndBaseComparator());
+ final Map sortedOriginalByTrimmedHaplotypes = new LinkedHashMap<>(trimmedHaplotypes.size());
+ for (final Haplotype trimmed : trimmedHaplotypes)
+ sortedOriginalByTrimmedHaplotypes.put(trimmed,originalByTrimmedHaplotypes.get(trimmed));
+
+
+ if ( debug ) logger.info("Trimmed region to " + trimmedActiveRegion.getLocation() + " size " +
+ trimmedActiveRegion.getLocation().size() + " reduced number of haplotypes from " +
+ haplotypeList.size() + " to only " + trimmedHaplotypes.size());
+ if ( debug )
+ for ( final Haplotype remaining: trimmedHaplotypes )
+ logger.info("Remains: " + remaining + " cigar " + remaining.getCigar());
+ return sortedOriginalByTrimmedHaplotypes;
+ }
+
+ /**
+ * Query the reference haplotype in the result set.
+ * @return {@code null} if none wasn't yet added, otherwise a reference haplotype.
+ */
+ public Haplotype getReferenceHaplotype() {
+ return refHaplotype;
+ }
+
+ /**
+ * Checks whether there is any variation present in the assembly result set.
+ *
+ *
+ * This is equivalent to whether there is more than one haplotype.
+ *
+ *
+ * @return {@code true} if there is variation present, {@code false} otherwise.
+ */
+ public boolean isVariationPresent() {
+ return variationPresent && haplotypes.size() > 1;
+ }
+
+ /**
+ * Dumps debugging information into a print-writer.
+ *
+ * @param pw where to dump the information.
+ *
+ * @throws NullPointerException if {@code pw} is {@code null}.
+ */
+ public void debugDump(final PrintWriter pw) {
+ if (getHaplotypeList().size() == 0) {
+ return;
+ }
+ pw.println("Active Region " + this.regionForGenotyping.getLocation());
+ pw.println("Extended Act Region " + this.getRegionForGenotyping().getExtendedLoc());
+ pw.println("Ref haplotype coords " + getHaplotypeList().get(0).getGenomeLocation());
+ pw.println("Haplotype count " + haplotypes.size());
+ final Map kmerSizeToCount = new HashMap<>();
+
+ for (final Map.Entry e : assemblyResultByHaplotype.entrySet()) {
+ final AssemblyResult as = e.getValue();
+ final int kmerSize = as.getGraph().getKmerSize();
+ if (kmerSizeToCount.containsKey(kmerSize)) {
+ kmerSizeToCount.put(kmerSize,kmerSizeToCount.get(kmerSize) + 1);
+ } else {
+ kmerSizeToCount.put(kmerSize,1);
+ }
+ }
+ pw.println("Kmer sizes count " + kmerSizeToCount.entrySet().size() );
+ Integer[] kmerSizes = new Integer[kmerSizeToCount.size()];
+ kmerSizes = kmerSizeToCount.keySet().toArray(kmerSizes);
+ Arrays.sort(kmerSizes);
+ pw.println("Kmer sizes values " + Arrays.toString(kmerSizes));
+ for (int size : kmerSizes) {
+ pw.println("Kmer size " + size + " count " + kmerSizeToCount.get(size));
+ }
+ }
+
+ /**
+ * Adds a haplotype to the result set without indicating a generating assembly result.
+ *
+ *
+ * It is possible to call this method with the same haplotype several times. In that the second and further
+ * calls won't have any effect (thus returning {@code false}).
+ *
+ *
+ * @param h the haplotype to add to the assembly result set.
+ *
+ * @throws NullPointerException if {@code h} is {@code null}
+ * @throws IllegalArgumentException if {@code h} does not have a genome location.
+ *
+ * @return {@code true} if the assembly result set has been modified as a result of this call.
+ */
+ public boolean add(final Haplotype h) {
+ if (h == null) throw new NullPointerException("input haplotype cannot be null");
+ if (h.getGenomeLocation() == null)
+ throw new IllegalArgumentException("the haplotype provided must have a genomic location");
+ if (haplotypes.contains(h))
+ return false;
+ haplotypes.add(h);
+ updateReferenceHaplotype(h);
+ return true;
+ }
+
+ /**
+ * Adds simultaneously a haplotype and the generating assembly-result.
+ *
+ *
+ * Haplotypes and their assembly-result can be added multiple times although just the first call will have
+ * any effect (return value is {@code true}).
+ *
+ *
+ *
+ * @param h haplotype to add.
+ * @param ar assembly-result that is assumed to have given rise to that haplotype.
+ *
+ * @throws NullPointerException if {@code h} or {@code ar} is {@code null}.
+ * @throws IllegalArgumentException if {@code h} has not defined genome location.
+ *
+ * @return {@code true} iff this called changes the assembly result set.
+ */
+ public boolean add(final Haplotype h, final AssemblyResult ar) {
+ if (h == null) throw new NullPointerException("input haplotype cannot be null");
+ if (ar == null) throw new NullPointerException("input assembly-result cannot be null");
+ if (h.getGenomeLocation() == null)
+ throw new IllegalArgumentException("the haplotype provided must have a genomic location");
+
+ final boolean assemblyResultAdditionReturn = add(ar);
+
+ if (haplotypes.contains(h)) {
+ final AssemblyResult previousAr = assemblyResultByHaplotype.get(h);
+ if (previousAr == null) {
+ assemblyResultByHaplotype.put(h, ar);
+ return true;
+ } else if (!previousAr.equals(ar))
+ throw new IllegalStateException("there is already a different assembly result for the input haplotype");
+ else
+ return assemblyResultAdditionReturn;
+ } else {
+ haplotypes.add(h);
+ assemblyResultByHaplotype.put(h,ar);
+ updateReferenceHaplotype(h);
+ if (h.isNonReference()) variationPresent = true;
+ return true;
+ }
+ }
+
+ /**
+ * Add a assembly-result object.
+ *
+ * @param ar the assembly result to add.
+ *
+ * @throws NullPointerException if {@code ar} is {@code null}.
+ * @throws IllegalStateException if there is an assembly result with the same kmerSize.
+ * @return {@code true} iff this addition changed the assembly result set.
+ */
+ public boolean add(final AssemblyResult ar) {
+ if (ar == null)
+ throw new NullPointerException();
+ final int kmerSize = ar.getKmerSize();
+ if (assemblyResultByKmerSize.containsKey(kmerSize)) {
+ if (!assemblyResultByKmerSize.get(kmerSize).equals(ar))
+ throw new IllegalStateException("a different assembly result with the same kmerSize was already added");
+ return false;
+ } else {
+ assemblyResultByKmerSize.put(kmerSize, ar);
+ kmerSizes.add(kmerSize);
+ return true;
+ }
+ }
+
+ /**
+ * Returns the current region for genotyping.
+ *
+ * @return might be {@code null}.
+ */
+ public ActiveRegion getRegionForGenotyping() {
+ return regionForGenotyping;
+ }
+
+ /**
+ * Sets the region for genotyping.
+ *
+ * @param regionForGenotyping the new value.
+ */
+ public void setRegionForGenotyping(final ActiveRegion regionForGenotyping) {
+ this.regionForGenotyping = regionForGenotyping;
+ }
+
+ /**
+ * Returns the current full reference with padding.
+ *
+ * @return might be {@code null}.
+ */
+ public byte[] getFullReferenceWithPadding() {
+ return fullReferenceWithPadding;
+ }
+
+ /**
+ * Sets the full reference with padding base sequence.
+ *
+ * @param fullReferenceWithPadding the new value.
+ */
+ public void setFullReferenceWithPadding(final byte[] fullReferenceWithPadding) {
+ this.fullReferenceWithPadding = fullReferenceWithPadding;
+ }
+
+ /**
+ * Returns the padded reference location.
+ *
+ * @return might be {@code null}
+ */
+ public GenomeLoc getPaddedReferenceLoc() {
+ return paddedReferenceLoc;
+ }
+
+ /**
+ * Changes the padded reference location.
+ * @param paddedReferenceLoc the new value.
+ */
+ public void setPaddedReferenceLoc(final GenomeLoc paddedReferenceLoc) {
+ this.paddedReferenceLoc = paddedReferenceLoc;
+ }
+
+ /**
+ * Returns the number of haplotypes in the assembly result set.
+ * @return {@code 0} or greater.
+ */
+ public int getHaplotypeCount() {
+ return haplotypes.size();
+ }
+
+ /**
+ * Returns the haplotypes as a list.
+ *
+ *
+ * The result is unmodifiable.
+ *
+ *
+ * @return never {@code null}, but perhaps a empty list if no haplotype was generated during assembly.
+ */
+ public List getHaplotypeList() {
+ return Arrays.asList(haplotypes.toArray(new Haplotype[haplotypes.size()]));
+ }
+
+ /**
+ * Returns the maximum kmerSize available.
+ *
+ * @throws IllegalStateException if no assembly-result was added to the set, thus there is no kmerSize.
+ *
+ * @return greater than 0.
+ */
+ public int getMaximumKmerSize() {
+ if (kmerSizes.size() == 0)
+ throw new IllegalStateException("there is yet no kmerSize in this assembly result set");
+ return kmerSizes.max();
+ }
+
+ /**
+ * Indicates whether there are more than one kmerSize in the set.
+ *
+ * @return {@code true} iff there is more than one kmerSize assembly in the set.
+ */
+ public boolean hasMultipleKmerSizes() {
+ return kmerSizes.size() > 1;
+ }
+
+ /**
+ * Returns the minimum kmerSize available.
+ *
+ * @throws IllegalStateException if no assembly-result was added to the set, thus there is no kmerSize.
+ *
+ * @return greater than 0.
+ */
+ public int getMinimumKmerSize() {
+ if (kmerSizes.size() == 0)
+ throw new IllegalStateException("there is yet no kmerSize in this assembly result set");
+ return kmerSizes.min();
+ }
+
+ /**
+ * Returns a read-threading graph in the assembly set that has a particular kmerSize.
+ *
+ * @param kmerSize the requested kmerSize.
+ *
+ * @return {@code null} if there is no read-threading-graph amongst assembly results with that kmerSize.
+ */
+ public ReadThreadingGraph getUniqueReadThreadingGraph(final int kmerSize) {
+ final AssemblyResult assemblyResult = assemblyResultByKmerSize.get(kmerSize);
+ if (assemblyResult == null) return null;
+ return assemblyResult.getThreadingGraph();
+ }
+
+ /**
+ * Checks whether this assembly result set was trimmed.
+ *
+ * @return {@code true} iff this assembly result set was trimmed.
+ */
+ public boolean wasTrimmed() {
+ return wasTrimmed;
+ }
+
+ /**
+ * Marks the assembly as not having variation even if it has more than one haplotype.
+ */
+ public void resetVariationPresent() {
+ variationPresent = false;
+ }
+
+ /**
+ * Dumps debugging information into a logger.
+ *
+ * @param logger where to dump the information.
+ *
+ * @throws NullPointerException if {@code logger} is {@code null}.
+ */
+ public void debugDump(final Logger logger) {
+ final StringWriter sw = new StringWriter();
+ final PrintWriter pw = new PrintWriter(sw);
+ debugDump(pw);
+ final String str = sw.toString();
+ final String[] lines = str.split("\n");
+ for (final String line : lines) {
+ if (line.isEmpty()) {
+ continue;
+ }
+ logger.debug(line);
+ }
+ }
+
+ /**
+ * Given whether a new haplotype that has been already added to {@link #haplotypes} collection is the
+ * reference haplotype and updates {@link #refHaplotype} accordingly.
+ *
+ *
+ * This method assumes that the colling code has verified that the haplotype was not already in {@link #haplotypes}
+ * I.e. that it is really a new one. Otherwise it will result in an exception if it happen to be a reference
+ * haplotype and this has already be set. This is the case even if the new haplotypes and the current reference
+ * are equal.
+ *
+ *
+ * @param newHaplotype the new haplotype.
+ * @throws NullPointerException if {@code newHaplotype} is {@code null}.
+ * @throws IllegalStateException if there is already a reference haplotype.
+ */
+ private void updateReferenceHaplotype(final Haplotype newHaplotype) {
+ if (!newHaplotype.isReference()) return;
+ if (refHaplotype == null)
+ refHaplotype = newHaplotype;
+ else // assumes that we have checked wether the haplotype is already in the collection and so is no need to check equality.
+ throw new IllegalStateException("the assembly-result-set already have a reference haplotype that is different");
+ }
+
+ /**
+ * Returns a sorted set of variant events that best explain the haplotypes found by the assembly
+ * across kmerSizes.
+ *
+ *
+ * The result is sorted incrementally by location.
+ *
+ * @return never {@code null}, but perhaps an empty collection.
+ */
+ public TreeSet getVariationEvents() {
+ if (variationEvents == null) {
+ final List haplotypeList = getHaplotypeList();
+ EventMap.buildEventMapsForHaplotypes(haplotypeList,fullReferenceWithPadding,paddedReferenceLoc,debug);
+ variationEvents = EventMap.getAllVariantContexts(haplotypeList);
+ }
+ return variationEvents;
+ }
+}
diff --git a/protected/java/src/org/broadinstitute/sting/gatk/walkers/haplotypecaller/EventBlock.java b/protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/haplotypecaller/EventBlock.java
similarity index 100%
rename from protected/java/src/org/broadinstitute/sting/gatk/walkers/haplotypecaller/EventBlock.java
rename to protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/haplotypecaller/EventBlock.java
diff --git a/protected/java/src/org/broadinstitute/sting/gatk/walkers/haplotypecaller/EventBlockFinder.java b/protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/haplotypecaller/EventBlockFinder.java
similarity index 100%
rename from protected/java/src/org/broadinstitute/sting/gatk/walkers/haplotypecaller/EventBlockFinder.java
rename to protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/haplotypecaller/EventBlockFinder.java
diff --git a/protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/haplotypecaller/GenotypingEngine.java b/protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/haplotypecaller/GenotypingEngine.java
new file mode 100644
index 000000000..d65251e58
--- /dev/null
+++ b/protected/gatk-protected/src/main/java/org/broadinstitute/sting/gatk/walkers/haplotypecaller/GenotypingEngine.java
@@ -0,0 +1,566 @@
+/*
+* By downloading the PROGRAM you agree to the following terms of use:
+*
+* BROAD INSTITUTE - SOFTWARE LICENSE AGREEMENT - FOR ACADEMIC NON-COMMERCIAL RESEARCH PURPOSES ONLY
+*
+* This Agreement is made between the Broad Institute, Inc. with a principal address at 7 Cambridge Center, Cambridge, MA 02142 (BROAD) and the LICENSEE and is effective at the date the downloading is completed (EFFECTIVE DATE).
+*
+* WHEREAS, LICENSEE desires to license the PROGRAM, as defined hereinafter, and BROAD wishes to have this PROGRAM utilized in the public interest, subject only to the royalty-free, nonexclusive, nontransferable license rights of the United States Government pursuant to 48 CFR 52.227-14; and
+* WHEREAS, LICENSEE desires to license the PROGRAM and BROAD desires to grant a license on the following terms and conditions.
+* NOW, THEREFORE, in consideration of the promises and covenants made herein, the parties hereto agree as follows:
+*
+* 1. DEFINITIONS
+* 1.1 PROGRAM shall mean copyright in the object code and source code known as GATK2 and related documentation, if any, as they exist on the EFFECTIVE DATE and can be downloaded from http://www.broadinstitute/GATK on the EFFECTIVE DATE.
+*
+* 2. LICENSE
+* 2.1 Grant. Subject to the terms of this Agreement, BROAD hereby grants to LICENSEE, solely for academic non-commercial research purposes, a non-exclusive, non-transferable license to: (a) download, execute and display the PROGRAM and (b) create bug fixes and modify the PROGRAM.
+* The LICENSEE may apply the PROGRAM in a pipeline to data owned by users other than the LICENSEE and provide these users the results of the PROGRAM provided LICENSEE does so for academic non-commercial purposes only. For clarification purposes, academic sponsored research is not a commercial use under the terms of this Agreement.
+* 2.2 No Sublicensing or Additional Rights. LICENSEE shall not sublicense or distribute the PROGRAM, in whole or in part, without prior written permission from BROAD. LICENSEE shall ensure that all of its users agree to the terms of this Agreement. LICENSEE further agrees that it shall not put the PROGRAM on a network, server, or other similar technology that may be accessed by anyone other than the LICENSEE and its employees and users who have agreed to the terms of this agreement.
+* 2.3 License Limitations. Nothing in this Agreement shall be construed to confer any rights upon LICENSEE by implication, estoppel, or otherwise to any computer software, trademark, intellectual property, or patent rights of BROAD, or of any other entity, except as expressly granted herein. LICENSEE agrees that the PROGRAM, in whole or part, shall not be used for any commercial purpose, including without limitation, as the basis of a commercial software or hardware product or to provide services. LICENSEE further agrees that the PROGRAM shall not be copied or otherwise adapted in order to circumvent the need for obtaining a license for use of the PROGRAM.
+*
+* 3. OWNERSHIP OF INTELLECTUAL PROPERTY
+* LICENSEE acknowledges that title to the PROGRAM shall remain with BROAD. The PROGRAM is marked with the following BROAD copyright notice and notice of attribution to contributors. LICENSEE shall retain such notice on all copies. LICENSEE agrees to include appropriate attribution if any results obtained from use of the PROGRAM are included in any publication.
+* Copyright 2012 Broad Institute, Inc.
+* Notice of attribution: The GATK2 program was made available through the generosity of Medical and Population Genetics program at the Broad Institute, Inc.
+* LICENSEE shall not use any trademark or trade name of BROAD, or any variation, adaptation, or abbreviation, of such marks or trade names, or any names of officers, faculty, students, employees, or agents of BROAD except as states above for attribution purposes.
+*
+* 4. INDEMNIFICATION
+* LICENSEE shall indemnify, defend, and hold harmless BROAD, and their respective officers, faculty, students, employees, associated investigators and agents, and their respective successors, heirs and assigns, (Indemnitees), against any liability, damage, loss, or expense (including reasonable attorneys fees and expenses) incurred by or imposed upon any of the Indemnitees in connection with any claims, suits, actions, demands or judgments arising out of any theory of liability (including, without limitation, actions in the form of tort, warranty, or strict liability and regardless of whether such action has any factual basis) pursuant to any right or license granted under this Agreement.
+*
+* 5. NO REPRESENTATIONS OR WARRANTIES
+* THE PROGRAM IS DELIVERED AS IS. BROAD MAKES NO REPRESENTATIONS OR WARRANTIES OF ANY KIND CONCERNING THE PROGRAM OR THE COPYRIGHT, EXPRESS OR IMPLIED, INCLUDING, WITHOUT LIMITATION, WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, NONINFRINGEMENT, OR THE ABSENCE OF LATENT OR OTHER DEFECTS, WHETHER OR NOT DISCOVERABLE. BROAD EXTENDS NO WARRANTIES OF ANY KIND AS TO PROGRAM CONFORMITY WITH WHATEVER USER MANUALS OR OTHER LITERATURE MAY BE ISSUED FROM TIME TO TIME.
+* IN NO EVENT SHALL BROAD OR ITS RESPECTIVE DIRECTORS, OFFICERS, EMPLOYEES, AFFILIATED INVESTIGATORS AND AFFILIATES BE LIABLE FOR INCIDENTAL OR CONSEQUENTIAL DAMAGES OF ANY KIND, INCLUDING, WITHOUT LIMITATION, ECONOMIC DAMAGES OR INJURY TO PROPERTY AND LOST PROFITS, REGARDLESS OF WHETHER BROAD SHALL BE ADVISED, SHALL HAVE OTHER REASON TO KNOW, OR IN FACT SHALL KNOW OF THE POSSIBILITY OF THE FOREGOING.
+*
+* 6. ASSIGNMENT
+* This Agreement is personal to LICENSEE and any rights or obligations assigned by LICENSEE without the prior written consent of BROAD shall be null and void.
+*
+* 7. MISCELLANEOUS
+* 7.1 Export Control. LICENSEE gives assurance that it will comply with all United States export control laws and regulations controlling the export of the PROGRAM, including, without limitation, all Export Administration Regulations of the United States Department of Commerce. Among other things, these laws and regulations prohibit, or require a license for, the export of certain types of software to specified countries.
+* 7.2 Termination. LICENSEE shall have the right to terminate this Agreement for any reason upon prior written notice to BROAD. If LICENSEE breaches any provision hereunder, and fails to cure such breach within thirty (30) days, BROAD may terminate this Agreement immediately. Upon termination, LICENSEE shall provide BROAD with written assurance that the original and all copies of the PROGRAM have been destroyed, except that, upon prior written authorization from BROAD, LICENSEE may retain a copy for archive purposes.
+* 7.3 Survival. The following provisions shall survive the expiration or termination of this Agreement: Articles 1, 3, 4, 5 and Sections 2.2, 2.3, 7.3, and 7.4.
+* 7.4 Notice. Any notices under this Agreement shall be in writing, shall specifically refer to this Agreement, and shall be sent by hand, recognized national overnight courier, confirmed facsimile transmission, confirmed electronic mail, or registered or certified mail, postage prepaid, return receipt requested. All notices under this Agreement shall be deemed effective upon receipt.
+* 7.5 Amendment and Waiver; Entire Agreement. This Agreement may be amended, supplemented, or otherwise modified only by means of a written instrument signed by all parties. Any waiver of any rights or failure to act in a specific instance shall relate only to such instance and shall not be construed as an agreement to waive any rights or fail to act in any other instance, whether or not similar. This Agreement constitutes the entire agreement among the parties with respect to its subject matter and supersedes prior agreements or understandings between the parties relating to its subject matter.
+* 7.6 Binding Effect; Headings. This Agreement shall be binding upon and inure to the benefit of the parties and their respective permitted successors and assigns. All headings are for convenience only and shall not affect the meaning of any provision of this Agreement.
+* 7.7 Governing Law. This Agreement shall be construed, governed, interpreted and applied in accordance with the internal laws of the Commonwealth of Massachusetts, U.S.A., without regard to conflict of laws principles.
+*/
+
+package org.broadinstitute.sting.gatk.walkers.haplotypecaller;
+
+import com.google.java.contract.Ensures;
+import com.google.java.contract.Requires;
+import org.apache.log4j.Logger;
+import org.broadinstitute.sting.gatk.refdata.RefMetaDataTracker;
+import org.broadinstitute.sting.gatk.walkers.annotator.VariantAnnotatorEngine;
+import org.broadinstitute.sting.gatk.walkers.genotyper.GenotypeLikelihoodsCalculationModel;
+import org.broadinstitute.sting.gatk.walkers.genotyper.UnifiedGenotyperEngine;
+import org.broadinstitute.sting.utils.GenomeLoc;
+import org.broadinstitute.sting.utils.GenomeLocParser;
+import org.broadinstitute.sting.utils.Utils;
+import org.broadinstitute.sting.utils.collections.DefaultHashMap;
+import org.broadinstitute.sting.utils.genotyper.PerReadAlleleLikelihoodMap;
+import org.broadinstitute.sting.utils.haplotype.EventMap;
+import org.broadinstitute.sting.utils.haplotype.Haplotype;
+import org.broadinstitute.sting.utils.haplotype.MergeVariantsAcrossHaplotypes;
+import org.broadinstitute.sting.utils.sam.GATKSAMRecord;
+import org.broadinstitute.sting.utils.variant.GATKVariantContextUtils;
+import org.broadinstitute.variant.variantcontext.*;
+
+import java.util.*;
+
+public class GenotypingEngine {
+ private final static Logger logger = Logger.getLogger(GenotypingEngine.class);
+
+ private final boolean DEBUG;
+ private final boolean USE_FILTERED_READ_MAP_FOR_ANNOTATIONS;
+ private final static List noCall = new ArrayList<>(); // used to noCall all genotypes until the exact model is applied
+ private final VariantAnnotatorEngine annotationEngine;
+ private final MergeVariantsAcrossHaplotypes crossHaplotypeEventMerger;
+
+ public GenotypingEngine( final boolean DEBUG, final VariantAnnotatorEngine annotationEngine,
+ final boolean USE_FILTERED_READ_MAP_FOR_ANNOTATIONS,
+ final MergeVariantsAcrossHaplotypes crossHaplotypeEventMerger) {
+ this.DEBUG = DEBUG;
+ this.annotationEngine = annotationEngine;
+ this.USE_FILTERED_READ_MAP_FOR_ANNOTATIONS = USE_FILTERED_READ_MAP_FOR_ANNOTATIONS;
+ noCall.add(Allele.NO_CALL);
+ this.crossHaplotypeEventMerger = crossHaplotypeEventMerger;
+ }
+
+ /**
+ * Carries the result of a call to #assignGenotypeLikelihoods
+ */
+ public static class CalledHaplotypes {
+ private final List calls;
+ private final Set calledHaplotypes;
+
+ protected CalledHaplotypes(final List calls, final Set calledHaplotypes) {
+ if ( calls == null ) throw new IllegalArgumentException("calls cannot be null");
+ if ( calledHaplotypes == null ) throw new IllegalArgumentException("calledHaplotypes cannot be null");
+ if ( Utils.xor(calls.isEmpty(), calledHaplotypes.isEmpty()) )
+ throw new IllegalArgumentException("Calls and calledHaplotypes should both be empty or both not but got calls=" + calls + " calledHaplotypes=" + calledHaplotypes);
+ this.calls = calls;
+ this.calledHaplotypes = calledHaplotypes;
+ }
+
+ /**
+ * Get the list of calls made at this location
+ * @return a non-null (but potentially empty) list of calls
+ */
+ public List getCalls() {
+ return calls;
+ }
+
+ /**
+ * Get the set of haplotypes that we actually called (i.e., underlying one of the VCs in getCalls().
+ * @return a non-null set of haplotypes
+ */
+ public Set getCalledHaplotypes() {
+ return calledHaplotypes;
+ }
+ }
+
+ /**
+ * Main entry point of class - given a particular set of haplotypes, samples and reference context, compute
+ * genotype likelihoods and assemble into a list of variant contexts and genomic events ready for calling
+ *
+ * The list of samples we're working with is obtained from the haplotypeReadMap
+ *
+ * @param UG_engine UG Engine with basic input parameters
+ * @param haplotypes Haplotypes to assign likelihoods to
+ * @param haplotypeReadMap Map from reads->(haplotypes,likelihoods)
+ * @param perSampleFilteredReadList
+ * @param ref Reference bytes at active region
+ * @param refLoc Corresponding active region genome location
+ * @param activeRegionWindow Active window
+ * @param genomeLocParser GenomeLocParser
+ * @param activeAllelesToGenotype Alleles to genotype
+ * @param emitReferenceConfidence whether we should add a <NON_REF> alternative allele to the result variation contexts.
+ *
+ * @return A CalledHaplotypes object containing a list of VC's with genotyped events and called haplotypes
+ *
+ */
+ @Requires({"refLoc.containsP(activeRegionWindow)", "haplotypes.size() > 0"})
+ @Ensures("result != null")
+ // TODO - can this be refactored? this is hard to follow!
+ public CalledHaplotypes assignGenotypeLikelihoods( final UnifiedGenotyperEngine UG_engine,
+ final List haplotypes,
+ final Map haplotypeReadMap,
+ final Map> perSampleFilteredReadList,
+ final byte[] ref,
+ final GenomeLoc refLoc,
+ final GenomeLoc activeRegionWindow,
+ final GenomeLocParser genomeLocParser,
+ final RefMetaDataTracker tracker,
+ final List activeAllelesToGenotype,
+ final boolean emitReferenceConfidence) {
+ // sanity check input arguments
+ if (UG_engine == null) throw new IllegalArgumentException("UG_Engine input can't be null, got "+UG_engine);
+ if (haplotypes == null || haplotypes.isEmpty()) throw new IllegalArgumentException("haplotypes input should be non-empty and non-null, got "+haplotypes);
+ if (haplotypeReadMap == null || haplotypeReadMap.isEmpty()) throw new IllegalArgumentException("haplotypeReadMap input should be non-empty and non-null, got "+haplotypeReadMap);
+ if (ref == null || ref.length == 0 ) throw new IllegalArgumentException("ref bytes input should be non-empty and non-null, got "+ref);
+ if (refLoc == null || refLoc.size() != ref.length) throw new IllegalArgumentException(" refLoc must be non-null and length must match ref bytes, got "+refLoc);
+ if (activeRegionWindow == null ) throw new IllegalArgumentException("activeRegionWindow must be non-null, got "+activeRegionWindow);
+ if (activeAllelesToGenotype == null ) throw new IllegalArgumentException("activeAllelesToGenotype must be non-null, got "+activeAllelesToGenotype);
+ if (genomeLocParser == null ) throw new IllegalArgumentException("genomeLocParser must be non-null, got "+genomeLocParser);
+
+ // update the haplotypes so we're ready to call, getting the ordered list of positions on the reference
+ // that carry events among the haplotypes
+ final TreeSet startPosKeySet = decomposeHaplotypesIntoVariantContexts(haplotypes, haplotypeReadMap, ref, refLoc, activeAllelesToGenotype);
+
+ // Walk along each position in the key set and create each event to be outputted
+ final Set calledHaplotypes = new HashSet<>();
+ final List returnCalls = new ArrayList<>();
+ final Map emptyDownSamplingMap = new DefaultHashMap<>(0.0);
+
+ for( final int loc : startPosKeySet ) {
+ if( loc >= activeRegionWindow.getStart() && loc <= activeRegionWindow.getStop() ) { // genotyping an event inside this active region
+ final List eventsAtThisLoc = getVCsAtThisLocation(haplotypes, loc, activeAllelesToGenotype);
+
+ if( eventsAtThisLoc.isEmpty() ) { continue; }
+
+ // Create the event mapping object which maps the original haplotype events to the events present at just this locus
+ final Map> eventMapper = createEventMapper(loc, eventsAtThisLoc, haplotypes);
+
+ // Sanity check the priority list for mistakes
+ final List priorityList = makePriorityList(eventsAtThisLoc);
+
+ // Merge the event to find a common reference representation
+
+ VariantContext mergedVC = GATKVariantContextUtils.simpleMerge(eventsAtThisLoc, priorityList, GATKVariantContextUtils.FilteredRecordMergeType.KEEP_IF_ANY_UNFILTERED, GATKVariantContextUtils.GenotypeMergeType.PRIORITIZE, false, false, null, false, false);
+
+ final VariantContextBuilder vcb = new VariantContextBuilder(mergedVC);
+
+ if( mergedVC == null ) { continue; }
+
+ final GenotypeLikelihoodsCalculationModel.Model calculationModel = mergedVC.isSNP()
+ ? GenotypeLikelihoodsCalculationModel.Model.SNP : GenotypeLikelihoodsCalculationModel.Model.INDEL;
+
+ if (emitReferenceConfidence) {
+ final List alleleList = new ArrayList<>();
+ alleleList.addAll(mergedVC.getAlleles());
+ alleleList.add(GATKVariantContextUtils.NON_REF_SYMBOLIC_ALLELE);
+ vcb.alleles(alleleList);
+ mergedVC = vcb.make();
+ }
+
+ final Map mergeMap = new LinkedHashMap<>();
+ mergeMap.put(null, mergedVC.getReference()); // the reference event (null) --> the reference allele
+ for(int iii = 0; iii < eventsAtThisLoc.size(); iii++) {
+ mergeMap.put(eventsAtThisLoc.get(iii), mergedVC.getAlternateAllele(iii)); // BUGBUG: This is assuming that the order of alleles is the same as the priority list given to simpleMerge function
+ }
+
+ final Map> alleleMapper = createAlleleMapper(mergeMap, eventMapper);
+
+ if( DEBUG ) {
+ logger.info("Genotyping event at " + loc + " with alleles = " + mergedVC.getAlleles());
+ }
+
+ final Map alleleReadMap = convertHaplotypeReadMapToAlleleReadMap( haplotypeReadMap, alleleMapper, UG_engine.getUAC().getSampleContamination() );
+
+ if (emitReferenceConfidence) addMiscellaneousAllele(alleleReadMap);
+
+ final GenotypesContext genotypes = calculateGLsForThisEvent( alleleReadMap, mergedVC );
+ VariantContext call = UG_engine.calculateGenotypes(new VariantContextBuilder(mergedVC).genotypes(genotypes).make(), calculationModel);
+ if( call != null ) {
+ final Map alleleReadMap_annotations = ( USE_FILTERED_READ_MAP_FOR_ANNOTATIONS ? alleleReadMap :
+ convertHaplotypeReadMapToAlleleReadMap( haplotypeReadMap, alleleMapper, emptyDownSamplingMap ) );
+ if (emitReferenceConfidence) addMiscellaneousAllele(alleleReadMap_annotations);
+ final Map stratifiedReadMap = filterToOnlyOverlappingReads( genomeLocParser, alleleReadMap_annotations, perSampleFilteredReadList, call );
+
+ VariantContext annotatedCall = annotationEngine.annotateContextForActiveRegion(tracker, stratifiedReadMap, call);
+
+ if( call.getAlleles().size() != mergedVC.getAlleles().size() )
+ annotatedCall = GATKVariantContextUtils.reverseTrimAlleles(annotatedCall);
+
+ // maintain the set of all called haplotypes
+ for ( final Allele calledAllele : call.getAlleles() ) {
+ final List haplotypeList = alleleMapper.get(calledAllele);
+ if (haplotypeList == null) continue;
+ calledHaplotypes.addAll(haplotypeList);
+ }
+
+ returnCalls.add( annotatedCall );
+ }
+ }
+ }
+
+ return new CalledHaplotypes(returnCalls, calledHaplotypes);
+ }
+
+ /**
+ * Add the allele
+ * @param stratifiedReadMap target per-read-allele-likelihood-map.
+ */
+ public static Map addMiscellaneousAllele(final Map stratifiedReadMap) {
+ final Allele miscellanoeusAllele = GATKVariantContextUtils.NON_REF_SYMBOLIC_ALLELE;
+ for (Map.Entry perSample : stratifiedReadMap.entrySet()) {
+ for (Map.Entry> perRead : perSample.getValue().getLikelihoodReadMap().entrySet()) {
+ double bestLikelihood = Double.NEGATIVE_INFINITY;
+ double secondBestLikelihood = Double.NEGATIVE_INFINITY;
+ for (Map.Entry perAllele : perRead.getValue().entrySet()) {
+ final double value = perAllele.getValue();
+ if (value > bestLikelihood) {
+ secondBestLikelihood = bestLikelihood;
+ bestLikelihood = value;
+ } else if (value < bestLikelihood && value > secondBestLikelihood) {
+ secondBestLikelihood = value;
+ }
+ }
+ final double miscellanousLikelihood = Double.isInfinite(secondBestLikelihood) ? bestLikelihood : secondBestLikelihood;
+ perSample.getValue().add(perRead.getKey(),miscellanoeusAllele,miscellanousLikelihood);
+ }
+ }
+ return stratifiedReadMap;
+ }
+
+ /**
+ * Go through the haplotypes we assembled, and decompose them into their constituent variant contexts
+ *
+ * @param haplotypes the list of haplotypes we're working with
+ * @param haplotypeReadMap map from samples -> the per read allele likelihoods
+ * @param ref the reference bases (over the same interval as the haplotypes)
+ * @param refLoc the span of the reference bases
+ * @param activeAllelesToGenotype alleles we want to ensure are scheduled for genotyping (GGA mode)
+ * @return
+ */
+ private TreeSet decomposeHaplotypesIntoVariantContexts(final List haplotypes,
+ final Map haplotypeReadMap,
+ final byte[] ref,
+ final GenomeLoc refLoc,
+ final List activeAllelesToGenotype) {
+ final boolean in_GGA_mode = !activeAllelesToGenotype.isEmpty();
+
+ // Using the cigar from each called haplotype figure out what events need to be written out in a VCF file
+ final TreeSet startPosKeySet = EventMap.buildEventMapsForHaplotypes(haplotypes, ref, refLoc, DEBUG);
+
+ if ( in_GGA_mode ) startPosKeySet.clear();
+
+ //cleanUpSymbolicUnassembledEvents( haplotypes ); // We don't make symbolic alleles so this isn't needed currently
+ if ( !in_GGA_mode ) {
+ // run the event merger if we're not in GGA mode
+ final boolean mergedAnything = crossHaplotypeEventMerger.merge(haplotypes, haplotypeReadMap, startPosKeySet, ref, refLoc);
+ if ( mergedAnything )
+ cleanUpSymbolicUnassembledEvents( haplotypes ); // the newly created merged events could be overlapping the unassembled events
+ }
+
+ if ( in_GGA_mode ) {
+ for( final VariantContext compVC : activeAllelesToGenotype ) {
+ startPosKeySet.add( compVC.getStart() );
+ }
+ }
+
+ return startPosKeySet;
+ }
+
+ /**
+ * Get the priority list (just the list of sources for these variant context) used to merge overlapping events into common reference view
+ * @param vcs a list of variant contexts
+ * @return the list of the sources of vcs in the same order
+ */
+ private List makePriorityList(final List vcs) {
+ final List priorityList = new LinkedList<>();
+ for ( final VariantContext vc : vcs ) priorityList.add(vc.getSource());
+ return priorityList;
+ }
+
+ private List getVCsAtThisLocation(final List haplotypes,
+ final int loc,
+ final List activeAllelesToGenotype) {
+ // the overlapping events to merge into a common reference view
+ final List eventsAtThisLoc = new ArrayList<>();
+
+ if( activeAllelesToGenotype.isEmpty() ) {
+ for( final Haplotype h : haplotypes ) {
+ final EventMap eventMap = h.getEventMap();
+ final VariantContext vc = eventMap.get(loc);
+ if( vc != null && !containsVCWithMatchingAlleles(eventsAtThisLoc, vc) ) {
+ eventsAtThisLoc.add(vc);
+ }
+ }
+ } else { // we are in GGA mode!
+ int compCount = 0;
+ for( final VariantContext compVC : activeAllelesToGenotype ) {
+ if( compVC.getStart() == loc ) {
+ int alleleCount = 0;
+ for( final Allele compAltAllele : compVC.getAlternateAlleles() ) {
+ List alleleSet = new ArrayList<>(2);
+ alleleSet.add(compVC.getReference());
+ alleleSet.add(compAltAllele);
+ final String vcSourceName = "Comp" + compCount + "Allele" + alleleCount;
+ // check if this event is already in the list of events due to a repeat in the input alleles track
+ final VariantContext candidateEventToAdd = new VariantContextBuilder(compVC).alleles(alleleSet).source(vcSourceName).make();
+ boolean alreadyExists = false;
+ for( final VariantContext eventToTest : eventsAtThisLoc ) {
+ if( eventToTest.hasSameAllelesAs(candidateEventToAdd) ) {
+ alreadyExists = true;
+ }
+ }
+ if( !alreadyExists ) {
+ eventsAtThisLoc.add(candidateEventToAdd);
+ }
+ alleleCount++;
+ }
+ }
+ compCount++;
+ }
+ }
+
+ return eventsAtThisLoc;
+ }
+
+ /**
+ * For a particular event described in inputVC, form PL vector for each sample by looking into allele read map and filling likelihood matrix for each allele
+ * @param alleleReadMap Allele map describing mapping from reads to alleles and corresponding likelihoods
+ * @param mergedVC Input VC with event to genotype
+ * @return GenotypesContext object wrapping genotype objects with PLs
+ */
+ @Requires({"alleleReadMap!= null", "mergedVC != null"})
+ @Ensures("result != null")
+ private GenotypesContext calculateGLsForThisEvent( final Map alleleReadMap, final VariantContext mergedVC ) {
+ final GenotypesContext genotypes = GenotypesContext.create(alleleReadMap.size());
+ // Grab the genotype likelihoods from the appropriate places in the haplotype likelihood matrix -- calculation performed independently per sample
+ for( final String sample : alleleReadMap.keySet() ) {
+ final int numHaplotypes = mergedVC.getAlleles().size();
+ final double[] genotypeLikelihoods = new double[numHaplotypes * (numHaplotypes+1) / 2];
+ final double[][] haplotypeLikelihoodMatrix = PairHMMLikelihoodCalculationEngine.computeDiploidHaplotypeLikelihoods(sample, alleleReadMap, mergedVC.getAlleles(), true);
+ int glIndex = 0;
+ for( int iii = 0; iii < numHaplotypes; iii++ ) {
+ for( int jjj = 0; jjj <= iii; jjj++ ) {
+ genotypeLikelihoods[glIndex++] = haplotypeLikelihoodMatrix[iii][jjj]; // for example: AA,AB,BB,AC,BC,CC
+ }
+ }
+ genotypes.add(new GenotypeBuilder(sample).alleles(noCall).PL(genotypeLikelihoods).make());
+ }
+ return genotypes;
+ }
+
+ private static Map filterToOnlyOverlappingReads( final GenomeLocParser parser,
+ final Map perSampleReadMap,
+ final Map> perSampleFilteredReadList,
+ final VariantContext call ) {
+
+ final Map returnMap = new LinkedHashMap<>();
+ final GenomeLoc callLoc = parser.createGenomeLoc(call);
+ for( final Map.Entry sample : perSampleReadMap.entrySet() ) {
+ final PerReadAlleleLikelihoodMap likelihoodMap = new PerReadAlleleLikelihoodMap();
+
+ for( final Map.Entry> mapEntry : sample.getValue().getLikelihoodReadMap().entrySet() ) {
+ // only count the read if it overlaps the event, otherwise it is not added to the output read list at all
+ if( callLoc.overlapsP(parser.createGenomeLoc(mapEntry.getKey())) ) { // BUGBUG: This uses alignment start and stop, NOT soft start and soft end...
+ for( final Map.Entry alleleDoubleEntry : mapEntry.getValue().entrySet() ) {
+ likelihoodMap.add(mapEntry.getKey(), alleleDoubleEntry.getKey(), alleleDoubleEntry.getValue());
+ }
+ }
+ }
+
+ // add all filtered reads to the NO_CALL list because they weren't given any likelihoods
+ for( final GATKSAMRecord read : perSampleFilteredReadList.get(sample.getKey()) ) {
+ // only count the read if it overlaps the event, otherwise it is not added to the output read list at all
+ if( callLoc.overlapsP(parser.createGenomeLoc(read)) ) {
+ for( final Allele allele : call.getAlleles() ) {
+ likelihoodMap.add(read, allele, 0.0);
+ }
+ }
+ }
+
+ returnMap.put(sample.getKey(), likelihoodMap);
+ }
+ return returnMap;
+ }
+
+ /**
+ * Removes symbolic events from list of haplotypes
+ * @param haplotypes Input/output list of haplotypes, before/after removal
+ */
+ // TODO - split into input haplotypes and output haplotypes as not to share I/O arguments
+ @Requires("haplotypes != null")
+ protected static void cleanUpSymbolicUnassembledEvents( final List haplotypes ) {
+ final List haplotypesToRemove = new ArrayList<>();
+ for( final Haplotype h : haplotypes ) {
+ for( final VariantContext vc : h.getEventMap().getVariantContexts() ) {
+ if( vc.isSymbolic() ) {
+ for( final Haplotype h2 : haplotypes ) {
+ for( final VariantContext vc2 : h2.getEventMap().getVariantContexts() ) {
+ if( vc.getStart() == vc2.getStart() && (vc2.isIndel() || vc2.isMNP()) ) { // unfortunately symbolic alleles can't currently be combined with non-point events
+ haplotypesToRemove.add(h);
+ break;
+ }
+ }
+ }
+ }
+ }
+ }
+ haplotypes.removeAll(haplotypesToRemove);
+ }
+
+ // BUGBUG: ugh, too complicated
+ protected Map convertHaplotypeReadMapToAlleleReadMap( final Map haplotypeReadMap,
+ final Map> alleleMapper,
+ final Map perSampleDownsamplingFraction ) {
+
+ final Map alleleReadMap = new LinkedHashMap<>();
+ for( final Map.Entry haplotypeReadMapEntry : haplotypeReadMap.entrySet() ) { // for each sample
+ final PerReadAlleleLikelihoodMap perReadAlleleLikelihoodMap = new PerReadAlleleLikelihoodMap();
+ for( final Map.Entry> alleleMapperEntry : alleleMapper.entrySet() ) { // for each output allele
+ final List mappedHaplotypes = alleleMapperEntry.getValue();
+ for( final Map.Entry> readEntry : haplotypeReadMapEntry.getValue().getLikelihoodReadMap().entrySet() ) { // for each read
+ double maxLikelihood = Double.NEGATIVE_INFINITY;
+ for( final Map.Entry alleleDoubleEntry : readEntry.getValue().entrySet() ) { // for each input allele
+ if( mappedHaplotypes.contains( new Haplotype(alleleDoubleEntry.getKey())) ) { // exact match of haplotype base string
+ maxLikelihood = Math.max( maxLikelihood, alleleDoubleEntry.getValue() );
+ }
+ }
+ perReadAlleleLikelihoodMap.add(readEntry.getKey(), alleleMapperEntry.getKey(), maxLikelihood);
+ }
+ }
+ perReadAlleleLikelihoodMap.performPerAlleleDownsampling(perSampleDownsamplingFraction.get(haplotypeReadMapEntry.getKey())); // perform contamination downsampling
+ alleleReadMap.put(haplotypeReadMapEntry.getKey(), perReadAlleleLikelihoodMap);
+ }
+
+ return alleleReadMap;
+ }
+
+ protected static Map> createAlleleMapper( final Map mergeMap, final Map> eventMap ) {
+ final Map> alleleMapper = new LinkedHashMap<>();
+ for( final Map.Entry entry : mergeMap.entrySet() ) {
+ alleleMapper.put(entry.getValue(), eventMap.get(new Event(entry.getKey())));
+ }
+ return alleleMapper;
+ }
+
+ @Requires({"haplotypes.size() >= eventsAtThisLoc.size() + 1"})
+ @Ensures({"result.size() == eventsAtThisLoc.size() + 1"})
+ protected static Map> createEventMapper( final int loc, final List eventsAtThisLoc, final List haplotypes ) {
+
+ final Map> eventMapper = new LinkedHashMap<>(eventsAtThisLoc.size()+1);
+ final Event refEvent = new Event(null);
+ eventMapper.put(refEvent, new ArrayList());
+ for( final VariantContext vc : eventsAtThisLoc ) {
+ eventMapper.put(new Event(vc), new ArrayList());
+ }
+
+ for( final Haplotype h : haplotypes ) {
+ if( h.getEventMap().get(loc) == null ) {
+ eventMapper.get(refEvent).add(h);
+ } else {
+ for( final VariantContext vcAtThisLoc : eventsAtThisLoc ) {
+ if( h.getEventMap().get(loc).hasSameAllelesAs(vcAtThisLoc) ) {
+ eventMapper.get(new Event(vcAtThisLoc)).add(h);
+ break;
+ }
+ }
+ }
+ }
+
+ return eventMapper;
+ }
+
+ @Ensures({"result.size() == haplotypeAllelesForSample.size()"})
+ protected static List findEventAllelesInSample( final List eventAlleles, final List