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/*
* Copyright (C) 2014-2021 Brian L. Browning
*
* This file is part of Beagle
*
* Beagle is free software: you can redistribute it and/or modify
* it under the terms of the GNU General Public License as published by
* the Free Software Foundation, either version 3 of the License, or
* (at your option) any later version.
*
* Beagle is distributed in the hope that it will be useful,
* but WITHOUT ANY WARRANTY; without even the implied warranty of
* MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the
* GNU General Public License for more details.
*
* You should have received a copy of the GNU General Public License
* along with this program. If not, see <http://www.gnu.org/licenses/>.
*/
package phase;
import blbutil.BitArray;
import blbutil.DoubleArray;
import ints.IntArray;
import ints.IntList;
import java.util.Arrays;
import java.util.stream.IntStream;
import java.util.stream.Stream;
import vcf.Markers;
/**
* <p>Each instance of class {@code SamplePhase} stores an estimated haplotype
* pair for a sample.
* </p>
* <p>Instances of class {@code SamplePhase} are not thread-safe.
* </p>
*
* @author Brian L. Browning {@code <browning@uw.edu>}
*/
public final class SamplePhase {
public static enum ClustType {
MISSING_GT,
MASKED_HET,
HOMOZYGOUS_GT,
PHASED_HET,
UNPHASED_HET
}
private static final ClustType[] clustTypes = ClustType.values();
private final int sample;
private final Markers markers;
private final BitArray hap1;
private final BitArray hap2;
private final byte[] clustSize;
private final byte[] clustType;
private final int[] clustTypeCnt = new int[clustTypes.length];
/**
* Constructs a new {@code SamplePhase} instance from the specified data.
* @param sample the sample index
* @param markers the list of markers
* @param genPos the genetic positions of the specifed markers
* @param hap1 the list of alleles on the first haplotype
* @param hap2 the list of alleles on the second haplotype
* @param unphasedHets the indices of markers whose genotype phase with respect
* to the preceding heterozygote is unknown
* @param missingGTs the indices of markers whose genotype is missingGT
* @throws IllegalArgumentException if {@code sample < 0}
* @throws IllegalArgumentException if
* {@code genPos.size() != markers.nMarkers()}
* @throws IllegalArgumentException if
* {@code hap1.length != markers.nMarkers() || hap2.length != markers.nMarkers()}
* @throws IllegalArgumentException if the specified {@code unphasedHet} or
* {@code missingGT} list is not a strictly increasing list of
* marker indices between 0 (inclusive) and {@code markers.nMarkers()}
* (exclusive)
* @throws NullPointerException if any argument is {@code null}
*/
public SamplePhase(int sample, Markers markers, DoubleArray genPos,
int[] hap1, int[] hap2, IntArray unphasedHets, IntArray missingGTs) {
if (sample < 0) {
throw new IllegalArgumentException(String.valueOf(sample));
}
this.sample = sample;
int nMarkers = markers.size();
if (nMarkers!=genPos.size()) {
throw new IllegalArgumentException(String.valueOf(genPos.size()));
}
if (hap1.length!=nMarkers) {
throw new IllegalArgumentException(String.valueOf(hap1.length));
}
if (hap2.length!=nMarkers) {
throw new IllegalArgumentException(String.valueOf(hap2.length));
}
checkIncreasing(unphasedHets, nMarkers);
checkIncreasing(missingGTs, nMarkers);
this.markers = markers;
this.hap1 = new BitArray(markers.sumHapBits());
this.hap2 = new BitArray(markers.sumHapBits());
markers.allelesToBits(hap1, this.hap1);
markers.allelesToBits(hap2, this.hap2);
float maxClusterCM = 0.005f;
IntList clustTypeList = new IntList();
IntList clustSizeList = new IntList();
setClusters(hap1, hap2, missingGTs, unphasedHets, genPos, maxClusterCM,
clustTypeList, clustTypeCnt, clustSizeList);
this.clustType = toByteArray(clustTypeList);
this.clustSize = toByteArray(clustSizeList);
assert clustSize.length==clustType.length;
}
private static void checkIncreasing(IntArray ia, int nMarkers) {
int last = -1;
for (int j=0, n=ia.size(); j<n; ++j) {
if (ia.get(j)<=last) {
throw new IllegalArgumentException(ia.toString());
}
last = ia.get(j);
}
if (last>=nMarkers) {
throw new IllegalArgumentException(ia.toString());
}
}
private static void setClusters(int[] hap1, int[] hap2, IntArray missingGT,
IntArray unphHets, DoubleArray genPos, float maxCM,
IntList clustType, int[] clustTypeCnt, IntList clustSizeList) {
int nMarkers = genPos.size();
double maxClustEnd = genPos.get(0) + maxCM;
boolean prevIsMissingOrHet = false;
int lastEnd = 0;
int missIndex = 0;
int unphIndex = 0;
int nextMiss = missIndex<missingGT.size() ? missingGT.get(missIndex++) : -1;
int nextUnph = unphIndex<unphHets.size() ? unphHets.get(unphIndex++) : -1;
ClustType prevType = ClustType.HOMOZYGOUS_GT;
for (int m=0; m<nMarkers; ++m) {
int size = m - lastEnd;
ClustType type = clustType(m==nextMiss, m==nextUnph, hap1[m], hap2[m]);
if (type==ClustType.MISSING_GT) {
nextMiss = missIndex<missingGT.size() ? missingGT.get(missIndex++) : -1;
}
else if (type==ClustType.UNPHASED_HET) {
nextUnph = unphIndex<unphHets.size() ? unphHets.get(unphIndex++) : -1;
}
boolean isMissingOrHet = type==ClustType.MISSING_GT
|| type==ClustType.UNPHASED_HET
|| type==ClustType.PHASED_HET;
if (isMissingOrHet || prevIsMissingOrHet
|| genPos.get(m)>maxClustEnd || size==255) {
if (m>0) {
clustType.add(prevType.ordinal());
++clustTypeCnt[prevType.ordinal()];
clustSizeList.add(size);
maxClustEnd = genPos.get(m) + maxCM;
lastEnd = m;
}
prevType = type;
}
prevIsMissingOrHet = isMissingOrHet;
}
clustType.add(prevType.ordinal());
++clustTypeCnt[prevType.ordinal()];
clustSizeList.add(nMarkers - lastEnd);
}
private static ClustType clustType(boolean isMissing, boolean isUnphased,
int a1, int a2) {
if (isMissing) {
return ClustType.MISSING_GT;
}
else if (a1==a2) {
return ClustType.HOMOZYGOUS_GT;
}
else if (isUnphased) {
return ClustType.UNPHASED_HET;
}
else {
return ClustType.PHASED_HET;
}
}
private static byte[] toByteArray(IntList intList) {
byte[] ba = new byte[intList.size()];
for (int j=0; j<ba.length; ++j) {
ba[j] = (byte) intList.get(j);
}
return ba;
}
/**
* Returns the sample index.
* @return the sample index
*/
public int sample() {
return sample;
}
/**
* Masks the trailing unphased heterozygote or heterozygotes in any maximal
* sequence of consecutive unphased heterozygotes if the maximal sequence
* has size two or three and spans less than 3000 base pairs.
*/
public void maskTrailingUnphasedHets() {
int maxUnphHetClusters = 3;
int maxMaskedBasePairs = 3000;
IntList unphHetMarkers = new IntList();
IntList unphHetClusters = new IntList();
int startMarker = 0;
for (int c=0; c<clustType.length; ++c) {
ClustType ct = clustType(c);
if (ct==ClustType.PHASED_HET) {
if (2<=unphHetClusters.size() && unphHetClusters.size()<=maxUnphHetClusters) {
maskTrailingUnphasedHets(unphHetClusters, unphHetMarkers, maxMaskedBasePairs);
}
unphHetMarkers.clear();
unphHetClusters.clear();
}
else if (ct==ClustType.UNPHASED_HET) {
unphHetMarkers.add(startMarker);
unphHetClusters.add(c);
}
startMarker += clustSize[c] & 0xff;
}
if (2<=unphHetClusters.size() && unphHetClusters.size()<=maxUnphHetClusters) {
maskTrailingUnphasedHets(unphHetClusters, unphHetMarkers, maxMaskedBasePairs);
}
assert startMarker==markers.size();
}
private void maskTrailingUnphasedHets(IntList unphHetClusters,
IntList unphHetMarkers, int maxMaskedBasePairs) {
int lastMaskedIndex = unphHetClusters.size()-2;
if (lastMaskedIndex==0) {
maskHetCluster(unphHetClusters.get(lastMaskedIndex));
}
else if (lastMaskedIndex>0) {
int startPos = markers.marker(unphHetMarkers.get(0)).pos();
int endPos = markers.marker(unphHetMarkers.get(lastMaskedIndex)).pos();
if ((endPos - startPos)<=maxMaskedBasePairs) {
for (int j=0; j<=lastMaskedIndex; ++j) {
maskHetCluster(unphHetClusters.get(j));
}
}
}
}
/**
* Masks the unphased heterozygote genotype in the specified cluster.
* @param cluster a cluster index
* @throws IllegalArgumentException if
* {@code this.clustType(cluster) != ClustType.UNPHASED_HET}
* @throws IndexOutOfBoundsException if
* {@code (cluster < 0 || cluster >= this.nClusters())}
*/
public void maskHetCluster(int cluster) {
if (clustType[cluster]!=ClustType.UNPHASED_HET.ordinal()) {
throw new IllegalArgumentException(String.valueOf(clustType[cluster]));
}
clustType[cluster] = (byte) ClustType.MASKED_HET.ordinal();
--clustTypeCnt[ClustType.UNPHASED_HET.ordinal()];
++clustTypeCnt[ClustType.MASKED_HET.ordinal()];
}
/**
* Marks the specified unphased heterozygote genotype as phased.
* @param cluster a cluster index
* @throws IllegalArgumentException if
* {@code this.clustType(cluster) != ClustType.UNPHASED_HET}
* @throws IndexOutOfBoundsException if
* {@code (cluster < 0 || cluster >= this.nClusters())}
*/
public void markUnphasedHetClusterAsPhased(int cluster) {
if (clustType[cluster]!=ClustType.UNPHASED_HET.ordinal()) {
throw new IllegalArgumentException(String.valueOf(clustType[cluster]));
}
clustType[cluster] = (byte) ClustType.PHASED_HET.ordinal();
--clustTypeCnt[ClustType.UNPHASED_HET.ordinal()];
++clustTypeCnt[ClustType.PHASED_HET.ordinal()];
}
/**
* Marks the specified masked heterozygote genotype as phased.
* @param cluster a cluster index
* @throws IllegalArgumentException if
* {@code this.clustType(cluster) != ClustType.MASKED_HET}
* @throws IndexOutOfBoundsException if
* {@code (cluster < 0 || cluster >= this.nClusters())}
*/
public void markMaskedHetClusterAsPhased(int cluster) {
if (clustType[cluster]!=ClustType.MASKED_HET.ordinal()) {
throw new IllegalArgumentException(String.valueOf(clustType[cluster]));
}
clustType[cluster] = (byte) ClustType.PHASED_HET.ordinal();
--clustTypeCnt[ClustType.MASKED_HET.ordinal()];
++clustTypeCnt[ClustType.PHASED_HET.ordinal()];
}
/**
* Returns the (exclusive) end marker indices of each marker cluster.
* The returned list is sorted in increasing order.
* @return the (exclusive) end marker indices of each marker cluster
*/
public int[] clustEnds() {
int[] clustEnds = new int[clustSize.length];
int cumSum = 0;
for (int j=0; j<clustSize.length; ++j) {
cumSum += (clustSize[j] & 0xff); // convert unsigned byte to integer
clustEnds[j] = cumSum;
}
return clustEnds;
}
/**
* Returns the list of markers.
* @return the list of markers
*/
public Markers markers() {
return markers;
}
/**
* Returns the number of genotype clusters
* @return the number of genotype clusters
*/
public int nClusters() {
return clustSize.length;
}
/**
* Returns the size of the specified cluster
* @param cluster a cluster index
* @return the size of the specified cluster
* @throws IllegalArgumentException if
* {@code (cluster < 0 || cluster >= this.nClusters())}
*/
public int clustSize(int cluster) {
return clustSize[cluster] & 0xff;
}
/**
* Returns the cluster type
* @param cluster a cluster index
* @return the cluster type
* @throws IndexOutOfBoundsException if
* {@code (cluster < 0 || cluster >= this.clustEnds().length())}
*/
public ClustType clustType(int cluster) {
return clustTypes[clustType[cluster]];
}
/**
* Returns the number of unphased, non-masked heterozygotes.
* @return the number of unphased, non-masked heterozygotes
*/
public int nUnphased() {
return clustTypeCnt[ClustType.UNPHASED_HET.ordinal()];
}
/**
* Returns the number of phased, non-masked heterozygotes.
* @return the number of phased, non-masked heterozygotes
*/
public int nPhased() {
return clustTypeCnt[ClustType.PHASED_HET.ordinal()];
}
/**
* Returns the number of masked heterozygotes.
* @return the number of masked heterozygotes
*/
public int nMasked() {
return clustTypeCnt[ClustType.MASKED_HET.ordinal()];
}
/**
* Returns the number of missing genotypes.
* @return the number of missing genotypes
*/
public int nMissing() {
return clustTypeCnt[ClustType.MISSING_GT.ordinal()];
}
/**
* Returns the number of homozygote clusters.
* @return the number of homozygote clusters
*/
public int nHomClusters() {
return clustTypeCnt[ClustType.HOMOZYGOUS_GT.ordinal()];
}
/**
* Copies the stored haplotypes to the specified {@code BitList} objects
* @param hap1 a {@code BitList} in which the sample's first haplotype's
* alleles will be stored
* @param hap2 a {@code BitList} in which the sample's second haplotype's
* alleles will be stored
* @throws IllegalArgumentException if
* {@code hap1.size() != this.markers().sumHaplotypeBits()}
* @throws IllegalArgumentException if
* {@code hap2.size()!= this.markers().sumHaplotypeBits()}
* @throws NullPointerException if {@code hap1 == null || hap2 == null}
*/
public void getHaps(BitArray hap1, BitArray hap2) {
int nBits = markers.sumHapBits();
if (hap1.size() != nBits || hap2.size() != nBits) {
throw new IllegalArgumentException("inconsistent data");
}
hap1.copyFrom(this.hap1, 0, this.hap1.size());
hap2.copyFrom(this.hap2, 0, this.hap2.size());
}
/**
* Returns the allele on the first haplotype for the specified marker.
* @param marker the marker index
* @return the allele on the first haplotype for the specified marker
* @throws IndexOutOfBoundsException if
* {@code marker < 0 || marker >= this.markers().nMarkers()}
*/
public int allele1(int marker) {
return markers.allele(hap1, marker);
}
/**
* Returns the allele on the second haplotype for the specified marker.
* @param marker the marker index
* @return the allele on the second haplotype for the specified marker
* @throws IndexOutOfBoundsException if
* {@code marker < 0 || marker >= this.markers().nMarkers()}
*/
public int allele2(int marker) {
return markers.allele(hap2, marker);
}
/**
* Sets the allele on the first haplotype for the specified marker
* to the specified allele
* @param marker the marker index
* @param allele the allele
* @throws IndexOutOfBoundsException if
* {@code marker < 0 || marker >= this.markers().nMarkers()}
* @throws IndexOutOfBoundsException if
* {@code allele < 0 || allele >= this.markers().marker(marker).nAlleles()}
*/
public void setAllele1(int marker, int allele) {
markers.setAllele(marker, allele, hap1);
}
/**
* Sets the allele on the second haplotype for the specified marker
* to the specified allele
* @param marker the marker index
* @param allele the allele
* @throws IndexOutOfBoundsException if
* {@code marker < 0 || marker >= this.markers().nMarkers()}
* @throws IndexOutOfBoundsException if
* {@code allele < 0 || allele >= this.markers().marker(marker).nAlleles()}
*/
public void setAllele2(int marker, int allele) {
markers.setAllele(marker, allele, hap2);
}
/**
* Swaps the alleles of the two haplotypes in the specified range of
* markers.
* @param start the start marker index (inclusive)
* @param end the end marker index (exclusive)
* @throws IndexOutOfBoundsException if
* {@code start < 0 || start > end || start >= this.markers().nMarkers()}
*/
public void swapHaps(int start, int end) {
int startBit = markers.sumHapBits(start);
int endBit = markers.sumHapBits(end);
BitArray.swapBits(hap1, hap2, startBit, endBit);
}
/**
* Returns the first haplotype. The haplotype is encoded with the
* {@code this.markers().allelesToBits()} method.
* @return the first haplotype
*/
public BitArray hap1() {
return new BitArray(this.hap1);
}
/**
* Returns the second haplotype. The haplotype is encoded with the
* {@code this.markers().allelesToBits()} method.
* @return the second haplotype
*/
public BitArray hap2() {
return new BitArray(this.hap2);
}
/**
* Returns the current estimated phased genotypes. This method converts
* column-major data into row-major data.
* @param estPhase the current estimated phased genotypes for each target
* sample
* @return the current estimated phased genotypes
* @throws NullPointerException if {@code estPhase == null}
*/
public static BitArray[] toBitLists(EstPhase estPhase) {
int nThreads = estPhase.fpd().par().nthreads();
int nMarkers = estPhase.fpd().stage1TargGT().nMarkers();
int nRecsPerBatch = (nMarkers + nThreads - 1)/nThreads;
while (nRecsPerBatch>4096) {
nRecsPerBatch = (nRecsPerBatch+1) >> 1;
}
int stepSize = nRecsPerBatch;
int nSteps = (nMarkers + (stepSize-1)) / stepSize;
return IntStream.range(0, nSteps)
.parallel()
.boxed()
.flatMap(step -> bitLists(estPhase, step, stepSize))
.toArray(BitArray[]::new);
}
private static Stream<BitArray> bitLists(EstPhase estPhase, int step, int stepSize) {
int nSamples = estPhase.fpd().targGT().nSamples();
int nHaps = nSamples<<1;
Markers markers = estPhase.fpd().stage1TargGT().markers();
int mStart = step*stepSize;
int mEnd = Math.min(mStart + stepSize, markers.size());
BitArray[] bitLists = IntStream.range(mStart, mEnd)
.mapToObj(j -> new BitArray(nHaps*markers.marker(j).bitsPerAllele()))
.toArray(BitArray[]::new);
int[] bitsPerAllele = IntStream.range(mStart, mEnd)
.map(m -> markers.marker(m).bitsPerAllele())
.toArray();
for (int s=0; s<nSamples; ++s) {
SamplePhase sampPhase = estPhase.get(s);
int h1 = s<<1;
int h2 = h1 | 0b1;
int inBit1 = markers.sumHapBits(mStart);
int inBit2 = markers.sumHapBits(mStart);
for (int m=mStart; m<mEnd; ++m) {
int mOffset = m - mStart;
int nBits = bitsPerAllele[mOffset];
int startOutBit1 = h1*nBits;
int startOutBit2 = h2*nBits;
for (int i=0; i<nBits; ++i) {
if (sampPhase.hap1.get(inBit1++)) {
bitLists[mOffset].set(startOutBit1 + i);
}
if (sampPhase.hap2.get(inBit2++)) {
bitLists[mOffset].set(startOutBit2 + i);
}
}
}
}
return Arrays.stream(bitLists);
}
}
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