Make sure inputPriors get used if they are specified
Fix usage of AF prior (i.e. theta) in probability of non-reference calculation Refactored duplicate functions Updated docs for heterozygosity
This commit is contained in:
Laura Gauthier
parent
5fe568c664
commit
53b506a0b8
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@ -70,22 +70,16 @@ public class GenotypeCalculationArgumentCollection implements Cloneable{
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/**
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* The expected heterozygosity value used to compute prior probability that a locus is non-reference.
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*
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* The default priors are for provided for humans:
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* From the heterozygosity we calculate the probability of N samples being hom-ref at a site as 1 - sum_i_2N (hets / i)
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* where hets is this case is analogous to the parameter theta from population genetics. See https://en.wikipedia.org/wiki/Coalescent_theory for more details.
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*
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* het = 1e-3
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* Note that heterozygosity as used here is the population genetics concept. (See http://en.wikipedia.org/wiki/Zygosity#Heterozygosity_in_population_genetics.
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* We also suggest the book "Population Genetics: A Concise Guide" by John H. Gillespie for further details on the theory.) That is, a hets value of 0.001
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* implies that two randomly chosen chromosomes from the population of organisms would differ from each other at a rate of 1 in 1000 bp.
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*
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* which means that the probability of N samples being hom-ref at a site is:
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* The default priors provided for humans (hets = 1e-3)
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*
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* 1 - sum_i_2N (het / i)
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*
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* Note that heterozygosity as used here is the population genetics concept:
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*
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* http://en.wikipedia.org/wiki/Zygosity#Heterozygosity_in_population_genetics
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*
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* That is, a hets value of 0.01 implies that two randomly chosen chromosomes from the population of organisms
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* would differ from each other (one being A and the other B) at a rate of 1 in 100 bp.
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*
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* Note that this quantity has nothing to do with the likelihood of any given sample having a heterozygous genotype,
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* Also note that this quantity has nothing to do with the likelihood of any given sample having a heterozygous genotype,
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* which in the GATK is purely determined by the probability of the observed data P(D | AB) under the model that there
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* may be a AB het genotype. The posterior probability of this AB genotype would use the het prior, but the GATK
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* only uses this posterior probability in determining the prob. that a site is polymorphic. So changing the
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@ -95,13 +89,13 @@ public class GenotypeCalculationArgumentCollection implements Cloneable{
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* The quantity that changes whether the GATK considers the possibility of a het genotype at all is the ploidy,
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* which determines how many chromosomes each individual in the species carries.
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*/
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@Argument(fullName = "heterozygosity", shortName = "hets", doc = "Heterozygosity value used to compute prior likelihoods for any locus. See the GATKDocs for full details on the meaning of this population genetics concept", required = false)
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@Argument(fullName = "heterozygosity", shortName = "hets", doc = "Heterozygosity value used to compute prior likelihoods for any locus", required = false)
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public Double snpHeterozygosity = HomoSapiensConstants.SNP_HETEROZYGOSITY;
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/**
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* This argument informs the prior probability of having an indel at a site.
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*/
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@Argument(fullName = "indel_heterozygosity", shortName = "indelHeterozygosity", doc = "Heterozygosity for indel calling. See the GATKDocs for heterozygosity for full details on the meaning of this population genetics concept", required = false)
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@Argument(fullName = "indel_heterozygosity", shortName = "indelHeterozygosity", doc = "Heterozygosity for indel calling", required = false)
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public double indelHeterozygosity = HomoSapiensConstants.INDEL_HETEROZYGOSITY;
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/**
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@ -135,12 +129,13 @@ public class GenotypeCalculationArgumentCollection implements Cloneable{
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* see e.g. Waterson (1975) or Tajima (1996).
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* This model asserts that the probability of having a population of k variant sites in N chromosomes is proportional to theta/k, for 1=1:N
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*
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* There are instances where using this prior might not be desireable, e.g. for population studies where prior might not be appropriate,
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* There are instances where using this prior might not be desirable, e.g. for population studies where prior might not be appropriate,
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* as for example when the ancestral status of the reference allele is not known.
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* By using this argument, user can manually specify priors to be used for calling as a vector for doubles, with the following restriciotns:
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* By using this argument, the user can manually specify a list of probabilities for each AC>1 to be used as priors for genotyping,
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* with the following restrictions:
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* a) User must specify 2N values, where N is the number of samples.
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* b) Only diploid calls supported.
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* c) Probability values are specified in double format, in linear space.
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* c) Probability values are specified in Double format, in linear space (not log10 space or Phred-scale).
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* d) No negative values allowed.
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* e) Values will be added and Pr(AC=0) will be 1-sum, so that they sum up to one.
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* f) If user-defined values add to more than one, an error will be produced.
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@ -238,10 +238,13 @@ public abstract class GenotypingEngine<Config extends StandardCallerArgumentColl
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final double phredScaledConfidence = (-10.0 * log10Confidence) + 0.0;
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// return a null call if we don't pass the confidence cutoff or the most likely allele frequency is zero
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if ( !passesEmitThreshold(phredScaledConfidence, outputAlternativeAlleles.siteIsMonomorphic) && !forceSiteEmission())
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if ( !passesEmitThreshold(phredScaledConfidence, outputAlternativeAlleles.siteIsMonomorphic) && !forceSiteEmission()) {
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// technically, at this point our confidence in a reference call isn't accurately estimated
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// because it didn't take into account samples with no data, so let's get a better estimate
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return limitedContext ? null : estimateReferenceConfidence(vc, stratifiedContexts, getModelTheta(model), true, PoFGT0);
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double[] AFpriors = getAlleleFrequencyPriors(vc, defaultPloidy, model);
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final int INDEX_FOR_AC_EQUALS_1 = 1;
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return limitedContext ? null : estimateReferenceConfidence(vc, stratifiedContexts, AFpriors[INDEX_FOR_AC_EQUALS_1], true, PoFGT0);
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}
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// start constructing the resulting VC
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final GenomeLocParser genomeLocParser = this.genomeLocParser != null || refContext == null ? this.genomeLocParser : refContext.getGenomeLocParser();
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@ -375,25 +378,6 @@ public abstract class GenotypingEngine<Config extends StandardCallerArgumentColl
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&& QualityUtils.phredScaleErrorRate(PofF) >= configuration.genotypeArgs.STANDARD_CONFIDENCE_FOR_CALLING);
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}
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/**
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* Based in the model used, returns the appropriate heterozygosity argument value.
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* @param model genotyping model.
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*
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* @return a valid heterozygosity in (0,1).
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*/
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private double getModelTheta(final GenotypeLikelihoodsCalculationModel.Model model) {
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switch (model) {
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case SNP:
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case GENERALPLOIDYSNP:
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return configuration.genotypeArgs.snpHeterozygosity;
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case INDEL:
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case GENERALPLOIDYINDEL:
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return configuration.genotypeArgs.indelHeterozygosity;
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default:
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throw new IllegalArgumentException("Unexpected GenotypeCalculationModel " + model);
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}
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}
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/**
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* Checks whether the variant context has too many alternative alleles for progress to genotyping the site.
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@ -473,7 +457,7 @@ public abstract class GenotypingEngine<Config extends StandardCallerArgumentColl
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*/
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protected abstract boolean forceSiteEmission();
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protected final VariantCallContext estimateReferenceConfidence(VariantContext vc, Map<String, AlignmentContext> contexts, double theta, boolean ignoreCoveredSamples, double initialPofRef) {
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protected final VariantCallContext estimateReferenceConfidence(VariantContext vc, Map<String, AlignmentContext> contexts, double log10OfTheta, boolean ignoreCoveredSamples, double initialPofRef) {
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if ( contexts == null )
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return null;
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@ -487,7 +471,7 @@ public abstract class GenotypingEngine<Config extends StandardCallerArgumentColl
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if ( ignoreCoveredSamples && context != null )
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continue;
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final int depth = context == null ? 0 : context.getBasePileup().depthOfCoverage();
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log10POfRef += estimateLog10ReferenceConfidenceForOneSample(depth, theta);
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log10POfRef += estimateLog10ReferenceConfidenceForOneSample(depth, log10OfTheta);
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}
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return new VariantCallContext(vc, QualityUtils.phredScaleLog10CorrectRate(log10POfRef) >= configuration.genotypeArgs.STANDARD_CONFIDENCE_FOR_CALLING, false);
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@ -523,16 +507,13 @@ public abstract class GenotypingEngine<Config extends StandardCallerArgumentColl
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* Assumes the sample is diploid
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*
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* @param depth the depth of the sample
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* @param theta the heterozygosity of this species (between 0 and 1)
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*
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* @throws IllegalArgumentException if {@code depth} is less than 0 or {@code theta} is not in the (0,1) range.
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* @param log10OfTheta the heterozygosity of this species (in log10-space)
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*
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* @return a valid log10 probability of the sample being hom-ref
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*/
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@Ensures("MathUtils.goodLog10Probability(result)")
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protected final double estimateLog10ReferenceConfidenceForOneSample(final int depth, final double theta) {
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if (theta <= 0 || theta >= 1) throw new IllegalArgumentException("theta must be greater than 0 and less than 1");
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final double log10PofNonRef = Math.log10(theta / 2.0) + getRefBinomialProbLog10(depth);
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protected final double estimateLog10ReferenceConfidenceForOneSample(final int depth, final double log10OfTheta) {
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final double log10PofNonRef = log10OfTheta + getRefBinomialProbLog10(depth);
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return MathUtils.log10OneMinusX(Math.pow(10.0, log10PofNonRef));
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}
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@ -558,14 +539,19 @@ public abstract class GenotypingEngine<Config extends StandardCallerArgumentColl
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* @param heterozygosity default heterozygosity to use, if inputPriors is empty
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* @param inputPriors Input priors to use (in which case heterozygosity is ignored)
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*
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* @throws IllegalArgumentException if {@code inputPriors} has size != {@code N} or any entry in {@code inputPriors} is not in the (0,1) range.
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*
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* @return never {@code null}.
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*/
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private static AFPriorProvider composeAlleleFrequencyPriorProvider(final int N, final double heterozygosity, final List<Double> inputPriors) {
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public static AFPriorProvider composeAlleleFrequencyPriorProvider(final int N, final double heterozygosity, final List<Double> inputPriors) {
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if (!inputPriors.isEmpty()) {
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// user-specified priors
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if (inputPriors.size() != N)
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throw new UserException.BadArgumentValue("inputPrior","Invalid length of inputPrior vector: vector length must be equal to # samples +1 ");
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for (final Double prior : inputPriors) {
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if (prior <= 0 || prior >= 1) throw new UserException.BadArgumentValue("inputPrior","inputPrior vector values must be greater than 0 and less than 1");
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}
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return new CustomAFPriorProvider(inputPriors);
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}
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else
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@ -52,7 +52,9 @@
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package org.broadinstitute.gatk.tools.walkers.genotyper.afcalc;
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import org.apache.commons.lang.ArrayUtils;
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import org.broadinstitute.gatk.tools.walkers.genotyper.AFPriorProvider;
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import org.broadinstitute.gatk.tools.walkers.genotyper.GenotypingEngine;
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import org.broadinstitute.gatk.tools.walkers.genotyper.UnifiedGenotypingEngine;
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import org.broadinstitute.gatk.utils.MathUtils;
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import org.broadinstitute.gatk.utils.Utils;
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import htsjdk.variant.variantcontext.*;
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@ -111,6 +113,7 @@ public class AFCalculatorTestBuilder {
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public double[] makePriors() {
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final int nPriorValues = 2*nSamples+1;
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final double human_theta = 0.001;
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switch ( priorType ) {
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case flat:
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@ -118,8 +121,9 @@ public class AFCalculatorTestBuilder {
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//TODO break dependency with human... avoid special reference to this species.
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case human:
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final double[] humanPriors = new double[nPriorValues];
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GenotypingEngine.computeAlleleFrequencyPriors(nPriorValues - 1, humanPriors, 0.001, new ArrayList<Double>());
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final AFPriorProvider log10priorProvider = GenotypingEngine.composeAlleleFrequencyPriorProvider(2*nSamples, human_theta, new ArrayList<Double>());
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final double[] humanPriors = log10priorProvider.forTotalPloidy(2*nSamples);
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return humanPriors;
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default:
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throw new RuntimeException("Unexpected type " + priorType);
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@ -99,12 +99,13 @@ public class UnifiedGenotyperEngineUnitTest extends BaseTest {
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final List<Object[]> tests = new ArrayList<>();
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// this functionality can be adapted to provide input data for whatever you might want in your data
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//Note that this copies code from GenotypingEngine::estimateLog10ReferenceConfidenceForOneSample to provide expected values
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final double p = Math.log10(0.5);
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for ( final double theta : Arrays.asList(0.1, 0.01, 0.001) ) {
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for ( final double log10ofTheta : Arrays.asList(0.0, -1.0, -2.0, -3.0) ) {
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for ( final int depth : Arrays.asList(0, 1, 2, 10, 100, 1000, 10000) ) {
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final double log10PofNonRef = Math.log10(theta / 2.0) + MathUtils.log10BinomialProbability(depth, 0, p);
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final double log10PofNonRef = log10ofTheta + MathUtils.log10BinomialProbability(depth, 0, p);
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final double log10POfRef = MathUtils.log10OneMinusX(Math.pow(10.0, log10PofNonRef));
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tests.add(new Object[]{depth, theta, log10POfRef});
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tests.add(new Object[]{depth, log10ofTheta, log10POfRef});
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}
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}
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@ -112,8 +113,8 @@ public class UnifiedGenotyperEngineUnitTest extends BaseTest {
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}
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@Test(dataProvider = "ReferenceQualityCalculation")
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public void testReferenceQualityCalculation(final int depth, final double theta, final double expected) {
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final double ref = getEngine().estimateLog10ReferenceConfidenceForOneSample(depth, theta);
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public void testReferenceQualityCalculation(final int depth, final double log10ofTheta, final double expected) {
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final double ref = getEngine().estimateLog10ReferenceConfidenceForOneSample(depth, log10ofTheta);
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Assert.assertTrue(MathUtils.goodLog10Probability(ref), "Reference calculation wasn't a well formed log10 prob " + ref);
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Assert.assertEquals(ref, expected, TOLERANCE, "Failed reference confidence for single sample");
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}
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@ -53,6 +53,7 @@ package org.broadinstitute.gatk.tools.walkers.genotyper.afcalc;
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import htsjdk.variant.variantcontext.*;
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import org.apache.commons.lang.ArrayUtils;
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import org.broadinstitute.gatk.tools.walkers.genotyper.AFPriorProvider;
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import org.broadinstitute.gatk.tools.walkers.genotyper.UnifiedGenotypingEngine;
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import org.broadinstitute.gatk.utils.BaseTest;
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import org.broadinstitute.gatk.utils.MathUtils;
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@ -197,10 +198,14 @@ public class AFCalculationUnitTest extends BaseTest {
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for ( final int nSamples : Arrays.asList(1, 2, 3, 4) ) {
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List<AFCalculator> calcs = createAFCalculators(Arrays.asList(AFCalculatorImplementation.values()), MAX_ALT_ALLELES, PLOIDY);
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//number of entries in the priors array, one for AC=[0,2*nSamples]
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final int nPriorValues = 2*nSamples+1;
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//total number of chromosomes in our samples -- here we're assuming diploid
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final int totalPloidy = 2*nSamples;
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final double theta = 0.001;
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final double[] flatPriors = MathUtils.normalizeFromLog10(new double[nPriorValues], true); // flat priors
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final double[] humanPriors = new double[nPriorValues];
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UnifiedGenotypingEngine.computeAlleleFrequencyPriors(nPriorValues - 1, humanPriors, 0.001, new ArrayList<Double>());
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final AFPriorProvider log10priorProvider = UnifiedGenotypingEngine.composeAlleleFrequencyPriorProvider(totalPloidy, theta, new ArrayList<Double>());
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final double[] humanPriors = log10priorProvider.forTotalPloidy(totalPloidy);
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for ( final double[] priors : Arrays.asList(flatPriors, humanPriors) ) { // , humanPriors) ) {
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for ( AFCalculator model : calcs ) {
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@ -609,16 +614,16 @@ public class AFCalculationUnitTest extends BaseTest {
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final Genotype AB = makePL(Arrays.asList(A,C), REF_PL, 0, 10000);
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final double[] flatPriors = new double[]{0.0,0.0,0.0};
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final double[] noPriors = new double[3];
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// test that function computeAlleleFrequency correctly operates when the flat prior option is set
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// computeAlleleFrequencyPriors takes linear priors
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final ArrayList<Double> inputPrior = new ArrayList<Double>();
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inputPrior.add(1.0/3);
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inputPrior.add(1.0/3);
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UnifiedGenotypingEngine.computeAlleleFrequencyPriors(2, noPriors, 0.0, inputPrior);
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final AFPriorProvider log10priorProvider = UnifiedGenotypingEngine.composeAlleleFrequencyPriorProvider(2, 0.0, inputPrior);
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final double[] noPriors = log10priorProvider.forTotalPloidy(2);
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GetGLsTest cfgFlatPrior = new GetGLsTest(model, 1, Arrays.asList(AB), flatPriors, "flatPrior");
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GetGLsTest cfgNoPrior = new GetGLsTest(model, 1, Arrays.asList(AB), flatPriors, "noPrior");
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GetGLsTest cfgNoPrior = new GetGLsTest(model, 1, Arrays.asList(AB), noPriors, "noPrior");
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final AFCalculationResult resultTrackerFlat = cfgFlatPrior.execute();
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final AFCalculationResult resultTrackerNoPrior = cfgNoPrior.execute();
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@ -149,7 +149,7 @@ public class GATKVariantContextUtils {
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}
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/**
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* Calculates the total ploidy of a variant context as the sum of all plodies across genotypes.
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* Calculates the total ploidy of a variant context as the sum of all ploidies across genotypes.
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* @param vc the target variant context.
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* @param defaultPloidy the default ploidy to be assume when there is no ploidy information for a genotype.
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* @return never {@code null}.
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