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package org.broadinstitute.gatk.tools.walkers.genotyper.afcalc;
import com.google.java.contract.Ensures;
import com.google.java.contract.Requires;
import htsjdk.variant.variantcontext.Allele;
import org.broadinstitute.gatk.utils.MathUtils;
import java.util.Arrays;
import java.util.HashMap;
import java.util.List;
import java.util.Map;
/**
* TODO this class (+AFCalculator) is a bit messy... it seems that it combines "debugging" (unnecessarily adding CPU cost in production)
* TODO but it also contains important part of the AF calculation state... why mix both!!!? It seems that the second
* TODO part could be just blend into AFCalculator ... one one hand you want to reduce classes code size ... but these
* TODO two classes code seems to be quite intertwine and makes it difficult to understand what is going on.
* in the production setting without much need
*
* Keeps track of the state information during the exact model AF calculation.
*
* Tracks things like the MLE and MAP AC values, their corresponding likelihood and posterior
* values, the likelihood of the AF == 0 state, and the number of evaluations needed
* by the calculation to compute the P(AF == 0)
*/
final class StateTracker {
protected static final double VALUE_NOT_CALCULATED = Double.NEGATIVE_INFINITY;
protected final static double MAX_LOG10_ERROR_TO_STOP_EARLY = 6; // we want the calculation to be accurate to 1 / 10^6
/**
* These variables are intended to contain the MLE and MAP (and their corresponding allele counts)
* of the site over all alternate alleles
*/
protected double log10MLE;
protected double log10MAP;
/**
* Returns a vector with maxAltAlleles values containing AC values at the MLE
*
* The values of the ACs for this call are stored in the getAllelesUsedInGenotyping order,
* starting from index 0 (i.e., the first alt allele is at 0). The vector is always
* maxAltAlleles in length, and so only the first getAllelesUsedInGenotyping.size() - 1 values
* are meaningful.
*/
private int[] alleleCountsOfMLE;
private int[] alleleCountsOfMAP;
/**
* A vector of log10 likelihood values seen, for future summation. When the size of the
* vector is exceeed -- because we've pushed more posteriors than there's space to hold
* -- we simply sum up the existing values, make that the first value, and continue.
*/
private final double[] log10LikelihoodsForAFGt0 = new double[LIKELIHOODS_CACHE_SIZE];
private static final int LIKELIHOODS_CACHE_SIZE = 5000;
private int log10LikelihoodsForAFGt0CacheIndex = 0;
/**
* The actual sum of the likelihoods. Null if the sum hasn't been computed yet
*/
protected Double log10LikelihoodsForAFGt0Sum = null;
/**
* Contains the likelihood for the site's being monomorphic (i.e. AF=0 for all alternate alleles)
*/
private double log10LikelihoodOfAFzero = 0.0;
/**
* The number of evaluates we've gone through in the AFCalc
*/
private int nEvaluations = 0;
/**
* The list of alleles actually used in computing the AF
*/
private List<Allele> allelesUsedInGenotyping = null;
/**
* Create a results object capability of storing results for calls with up to maxAltAlleles
*
* @param maxAltAlleles an integer >= 1
*/
public StateTracker(final int maxAltAlleles) {
if ( maxAltAlleles < 0 ) throw new IllegalArgumentException("maxAltAlleles must be >= 0, saw " + maxAltAlleles);
alleleCountsOfMLE = new int[maxAltAlleles];
alleleCountsOfMAP = new int[maxAltAlleles];
reset();
}
/**
* Is the likelihood of configuration K too low to consider, related to the
* maximum likelihood seen already?
*
* @param log10LofK the log10 likelihood of the configuration we're considering analyzing
* @return true if the configuration cannot meaningfully contribute to our likelihood sum
*/
private boolean tooLowLikelihood(final double log10LofK) {
return log10LofK < log10MLE - MAX_LOG10_ERROR_TO_STOP_EARLY;
}
/**
* @return true iff all ACs in this object are less than or equal to their corresponding ACs in the provided set
*/
private boolean isLowerAC(final ExactACcounts otherACs, final boolean otherACsContainsReference) {
final int[] otherACcounts = otherACs.getCounts();
final int firstAltAlleleIndex = otherACsContainsReference ? 1 : 0;
for ( int i = firstAltAlleleIndex; i < otherACcounts.length; i++ ) {
if ( alleleCountsOfMLE[i - firstAltAlleleIndex] > otherACcounts[i] )
return false;
}
return true;
}
/**
* Should we stop exploring paths from ACs, given it's log10LofK
*
* @param log10LofK the log10LofK of these ACs
* @param ACs the ACs of this state
* @param exactACcountsContainReference whether the {@code ACs} contains the reference allele count (index == 0) beside all other alternative alleles.
* @return return true if there's no reason to continue with subpaths of AC, or false otherwise
*/
protected boolean abort(final double log10LofK, final ExactACcounts ACs, final boolean enforceLowerACs, final boolean exactACcountsContainReference) {
return tooLowLikelihood(log10LofK) && (!enforceLowerACs || isLowerAC(ACs,exactACcountsContainReference));
}
@Ensures("result != null")
protected int[] getAlleleCountsOfMAP() {
return alleleCountsOfMAP;
}
@Ensures("result >= 0")
protected int getNEvaluations() {
return nEvaluations;
}
/**
* @return the likelihoods summed across all AC values for AC > 0
*/
private double getLog10LikelihoodOfAFNotZero() {
if ( log10LikelihoodsForAFGt0Sum == null ) {
if ( log10LikelihoodsForAFGt0CacheIndex == 0 ) // there's nothing to sum up, so make the sum equal to the smallest thing we have
log10LikelihoodsForAFGt0Sum = MathUtils.LOG10_P_OF_ZERO;
else
log10LikelihoodsForAFGt0Sum = MathUtils.log10sumLog10(log10LikelihoodsForAFGt0, 0, log10LikelihoodsForAFGt0CacheIndex);
}
return log10LikelihoodsForAFGt0Sum;
}
/**
* @return the log10 likelihood of AF == 0
*/
private double getLog10LikelihoodOfAFzero() {
return log10LikelihoodOfAFzero;
}
/**
* Convert this state to an corresponding AFCalcResult.
*
* Assumes that the values in this state have been filled in with meaningful values during the calculation.
* For example, that the allelesUsedInGenotyping has been set, that the alleleCountsOfMLE contains meaningful
* values, etc.
*
* @param log10PriorsByAC the priors by AC
*
* @return an AFCalcResult summarizing the final results of this calculation
*/
@Requires("allelesUsedInGenotyping != null")
protected AFCalculationResult toAFCalculationResult(final double[] log10PriorsByAC) {
final int [] subACOfMLE = Arrays.copyOf(alleleCountsOfMLE, allelesUsedInGenotyping.size() - 1);
final double[] log10Likelihoods = MathUtils.normalizeFromLog10(new double[]{getLog10LikelihoodOfAFzero(), getLog10LikelihoodOfAFNotZero()}, true);
final double[] log10Priors = MathUtils.normalizeFromLog10(new double[]{log10PriorsByAC[0], MathUtils.log10sumLog10(log10PriorsByAC, 1)}, true);
final Map<Allele, Double> log10pRefByAllele = new HashMap<Allele, Double>(allelesUsedInGenotyping.size());
for ( int i = 0; i < subACOfMLE.length; i++ ) {
final Allele allele = allelesUsedInGenotyping.get(i+1);
final double log10PRef = alleleCountsOfMAP[i] > 0 ? -10000 : 0; // TODO -- a total hack but in effect what the old behavior was
log10pRefByAllele.put(allele, log10PRef);
}
return new AFCalculationResult(subACOfMLE, nEvaluations, allelesUsedInGenotyping, log10Likelihoods, log10Priors, log10pRefByAllele);
}
// --------------------------------------------------------------------------------
//
// Protected mutational methods only for use within the calculation models themselves
//
// --------------------------------------------------------------------------------
/**
* Reset the data in this results object, so that it can be used in a subsequent AF calculation
*
* Resetting of the data is done by the calculation model itself, so shouldn't be done by callers any longer
*
* @param ensureAltAlleleCapacity indicate the minimum number of alt-alleles that should be supported by the
* tracker.
*/
protected void reset(final int ensureAltAlleleCapacity) {
log10MLE = log10MAP = log10LikelihoodOfAFzero = VALUE_NOT_CALCULATED;
log10LikelihoodsForAFGt0CacheIndex = 0;
log10LikelihoodsForAFGt0Sum = null;
allelesUsedInGenotyping = null;
nEvaluations = 0;
if (alleleCountsOfMAP.length < ensureAltAlleleCapacity) {
final int newCapacity = Math.max(ensureAltAlleleCapacity,alleleCountsOfMAP.length << 1);
alleleCountsOfMAP = new int[newCapacity];
alleleCountsOfMLE = new int[newCapacity];
} else {
Arrays.fill(alleleCountsOfMLE, 0);
Arrays.fill(alleleCountsOfMAP, 0);
}
Arrays.fill(log10LikelihoodsForAFGt0, Double.POSITIVE_INFINITY);
}
/**
* Reset the data in this results object, so that it can be used in a subsequent AF calculation
*
* Resetting of the data is done by the calculation model itself, so shouldn't be done by callers any longer
*/
protected void reset() {
log10MLE = log10MAP = log10LikelihoodOfAFzero = VALUE_NOT_CALCULATED;
log10LikelihoodsForAFGt0CacheIndex = 0;
log10LikelihoodsForAFGt0Sum = null;
allelesUsedInGenotyping = null;
nEvaluations = 0;
Arrays.fill(alleleCountsOfMLE, 0);
Arrays.fill(alleleCountsOfMAP, 0);
Arrays.fill(log10LikelihoodsForAFGt0, Double.POSITIVE_INFINITY);
}
/**
* Tell this result we used one more evaluation cycle
*/
protected void incNEvaluations() {
nEvaluations++;
}
/**
* Update the maximum log10 likelihoods seen, if log10LofKs is higher, and the corresponding ACs of this state
*
* @param log10LofK the likelihood of our current configuration state, cannot be the 0 state
* @param alleleCountsForK the allele counts for this state
*/
@Requires({"alleleCountsForK != null", "MathUtils.sum(alleleCountsForK) >= 0"})
@Ensures("log10MLE == Math.max(log10LofK, log10MLE)")
protected void updateMLEifNeeded(final double log10LofK, final int[] alleleCountsForK) {
addToLikelihoodsCache(log10LofK);
if ( log10LofK > log10MLE ) {
log10MLE = log10LofK;
System.arraycopy(alleleCountsForK, 0, alleleCountsOfMLE, 0, alleleCountsForK.length);
}
}
/**
* Update the maximum log10 posterior seen, if log10PofKs is higher, and the corresponding ACs of this state
*
* @param log10PofK the posterior of our current configuration state
* @param alleleCountsForK the allele counts for this state
*/
@Requires({"alleleCountsForK != null", "MathUtils.sum(alleleCountsForK) >= 0"})
@Ensures("log10MAP == Math.max(log10PofK, log10MAP)")
protected void updateMAPifNeeded(final double log10PofK, final int[] alleleCountsForK) {
if ( log10PofK > log10MAP ) {
log10MAP = log10PofK;
System.arraycopy(alleleCountsForK, 0, alleleCountsOfMAP, 0, alleleCountsForK.length);
}
}
private void addToLikelihoodsCache(final double log10LofK) {
// add to the cache
log10LikelihoodsForAFGt0[log10LikelihoodsForAFGt0CacheIndex++] = log10LofK;
// if we've filled up the cache, then condense by summing up all of the values and placing the sum back into the first cell
if ( log10LikelihoodsForAFGt0CacheIndex == LIKELIHOODS_CACHE_SIZE) {
final double temporarySum = MathUtils.log10sumLog10(log10LikelihoodsForAFGt0, 0, log10LikelihoodsForAFGt0CacheIndex);
Arrays.fill(log10LikelihoodsForAFGt0, Double.POSITIVE_INFINITY);
log10LikelihoodsForAFGt0[0] = temporarySum;
log10LikelihoodsForAFGt0CacheIndex = 1;
}
}
protected void setLog10LikelihoodOfAFzero(final double log10LikelihoodOfAFzero) {
this.log10LikelihoodOfAFzero = log10LikelihoodOfAFzero;
if ( log10LikelihoodOfAFzero > log10MLE ) {
log10MLE = log10LikelihoodOfAFzero;
Arrays.fill(alleleCountsOfMLE, 0);
}
}
@Requires({"MathUtils.goodLog10Probability(log10PosteriorOfAFzero)"})
protected void setLog10PosteriorOfAFzero(final double log10PosteriorOfAFzero) {
if ( log10PosteriorOfAFzero > log10MAP ) {
log10MAP = log10PosteriorOfAFzero;
Arrays.fill(alleleCountsOfMAP, 0);
}
}
/**
* Set the list of alleles used in genotyping
*
* @param allelesUsedInGenotyping the list of alleles, where the first allele is reference
*/
@Requires({"allelesUsedInGenotyping != null", "allelesUsedInGenotyping.size() > 1"})
protected void setAllelesUsedInGenotyping(List<Allele> allelesUsedInGenotyping) {
if ( allelesUsedInGenotyping == null || allelesUsedInGenotyping.isEmpty() )
throw new IllegalArgumentException("allelesUsedInGenotyping cannot be null or empty");
if ( allelesUsedInGenotyping.get(0).isNonReference() )
throw new IllegalArgumentException("The first element of allelesUsedInGenotyping must be the reference allele");
this.allelesUsedInGenotyping = allelesUsedInGenotyping;
}
public void ensureMaximumAlleleCapacity(final int capacity) {
if (this.alleleCountsOfMAP.length < capacity)
reset(capacity);
}
}