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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 vcf.Steps;
import blbutil.BitArray;
import blbutil.Utilities;
import ints.IntIntMap;
import java.util.Arrays;
import java.util.List;
import java.util.PriorityQueue;
import java.util.Random;
import java.util.stream.IntStream;
import beagleutil.CompHapSegment;
import vcf.Markers;
import vcf.XRefGT;
/**
* <p>Class {@code BasicPhaseStates} has methods for constructing a Li and
* Stephens HMM for a target haplotype or target sample.
* </p>
* <p>Instances of {@code BasicPhaseStates} are not thread-safe.
* </p>
*
* @author Brian L. Browning {@code <browning@uw.edu>}
*/
public final class BasicPhaseStates {
private static final int NIL = -103;
private final PbwtPhaseIbs ibsHaps;
private final PhaseData phaseData;
private final Steps steps;
private final XRefGT allHaps;
private final Markers markers;
private final int nMarkers;
private final int maxStates;
private final int minSteps;
private final IntIntMap hapToLastIbsStep;
private final PriorityQueue<CompHapSegment> q;
private final BitArray[] compHaps;
/**
* Constructs a new {@code BasicPhaseStates} object from the specified data.
* @param ibsHaps the IBS haplotype segments
* @param maxStates the maximum number of composite reference
* haplotypes that will be constructed
* @throws IllegalArgumentException if {@code maxStates < 1}
* @throws NullPointerException if {@code ibsHaps == null}
*/
public BasicPhaseStates(PbwtPhaseIbs ibsHaps, int maxStates) {
if (maxStates < 1) {
throw new IllegalArgumentException(String.valueOf(maxStates));
}
this.ibsHaps = ibsHaps;
this.phaseData = ibsHaps.phaseData();
this.steps = phaseData.fpd().stage1Steps();
this.allHaps = ibsHaps.allHaps();
this.markers = allHaps.markers();
this.nMarkers = allHaps.nMarkers();
this.maxStates = maxStates;
float phaseStep = phaseData.fpd().ibsStep();
this.minSteps = Math.max(200, (int) Math.ceil(1.0f/phaseStep)); // 200 steps and 1 cM
this.hapToLastIbsStep = new IntIntMap(maxStates);
this.q = new PriorityQueue<>(maxStates);
int nBits = markers.sumHapBits();
this.compHaps = IntStream.range(0, maxStates)
.mapToObj(j -> new BitArray(nBits))
.toArray(BitArray[]::new);
}
/**
* Returns the number of target samples.
* @return the number of target samples
*/
public int nTargSamples() {
return phaseData.fpd().targGT().nSamples();
}
/**
* Returns the number of markers.
* @return the number of markers
*/
public int nMarkers() {
return phaseData.fpd().targGT().nMarkers();
}
/**
* Returns the maximum number of HMM states at a marker.
* @return the maximum number of HMM states at a marker
*/
public int maxStates() {
return maxStates;
}
/**
* Stores the Li and Stephens HMM for the specified target sample in
* the specified arrays.The {@code nMismatches} parameter is an array of
* three two-dimensional arrays: {@code nMismatches[0]} stores
* stores the allele mismatch data between the reference haplotypes and
* the haplotype composed of homozygous target genotypes,
* {@code nMismatches[1]} stores the allele mismatch data between
* the reference haplotypes and the first target haplotype, and
* {@code nMismatches[2]} stores the allele mismatch data between
* the reference haplotypes and the first target haplotype. Each
* two-dimensional array must have at least {@code mc.nClusters()}
* rows, and a column for each HMM state. An element of the
* two-dimensional array is 0 if the target and reference allele match
* and is 1 otherwise.
*
* @param mc the marker clusters
* @param refAtMissingGT a list of arrays in which HMM state alleles
* at markers for which one or both target haplotypes have a missing allele
* @param nMismatches arrays for storing present or absence of mismatches
* between target and reference alleles
* @return the number of state alleles at each marker
*
* @throws IndexOutOfBoundsException if
* {@code sample < 0 || sample >= this.nTargSamples()}
* @throws IndexOutOfBoundsException if {@code nMismatches.length < 3}
* @throws IndexOutOfBoundsException if there exists {@code j} such that
* {@code 0 < j && j < 3 && nMismatches[j].length < mc.nClusters()}
* @throws IndexOutOfBoundsException if there exists {@code j, m} such that
* {@code (0 < j && j < 3 && 0 < m && m < mc.nClusters())}, and
* {@code nMismatches[j][m].length} is less than the number of model
* states at marker {@code m}
* @throws IndexOutOfBoundsException if {@code missAlleles.get(j)}
* is less than the number of model states for any {@code j}
* that indexes the missing genotypes
* @throws NullPointerException if
* {@code (samplePhase == null || mc == null || refAtMissingGT == null)}
* or if any array is {@code null}
*/
public int ibsStates(MarkerCluster mc, List<int[]> refAtMissingGT,
byte[][][] nMismatches) {
int nCompHaps = setCompRefHaps(mc.samplePhase().sample());
copyData(mc, nCompHaps, refAtMissingGT, nMismatches);
return nCompHaps;
}
/**
* Stores the Li and Stephens HMM for the specified target sample in
* the specified arrays. The number of allele mismatches (0 or 1)
* between {@code hap1[m]} and {@code hap2[m]} for the {@code j}-th state
* are stored in {@code nMismatchs[0][m][j]} and
* {@code nMismatches[1][m][j]} respectively.
*
* @param sample the target sample index
* @param nMismatches an array of two two-dimensional arrays in which the
* number of allele mismatches with reference haplotypes for the first
* haplotype and the second haplotype will be stored
* @return the number of state alleles at each marker
*
* @throws IndexOutOfBoundsException if
* {@code sample < 0 || sample >= this.nTargSamples()}
* @throws IndexOutOfBoundsException if {@code nMismatches.length < 2}
* @throws IndexOutOfBoundsException if there exists {@code j} such that
* {@code (0 < j && j < 2 && nMismatches[j].length < this.nMarkers())}
* @throws IndexOutOfBoundsException if there exists {@code j, m} such that
* {@code (0 < j && j < 2 && 0 < m && m < this.nMarkers())}, and
* {@code nMismatches[j][m].length} is less than the total number of model
* states
* @throws NullPointerException if any array is {@code null}
*/
public int ibsStates(int sample, byte[][][] nMismatches) {
int nCompHaps = setCompRefHaps(sample);
copyData(sample, nCompHaps, nMismatches);
return nCompHaps;
}
private int setCompRefHaps(int sample) {
int h1 = sample << 1;
int h2 = (h1 | 0b1);
q.clear();
hapToLastIbsStep.clear();
for (int step=0, n=steps.size(); step<n; ++step) {
int ibsHap1 = ibsHaps.ibsHap(h1, step);
if (ibsHap1>=0) {
addIbsHap(ibsHap1, step);
}
int ibsHap2 = ibsHaps.ibsHap(h2, step);
if (ibsHap2>=0) {
addIbsHap(ibsHap2, step);
}
}
if (q.isEmpty()) {
fillQWithRandomHaps(sample);
}
int nCompHaps = copyFinalRefSegs();
return nCompHaps;
}
private void addIbsHap(int ibsHap, int step) {
if (hapToLastIbsStep.get(ibsHap, NIL)==NIL) { // hap not currently in q
updateHeadOfQ();
if (q.size()==maxStates
|| (q.isEmpty()==false && step - q.peek().lastIbsStep() >= minSteps)) {
CompHapSegment head = q.poll();
int index = head.compHapIndex();
int prevHap = head.hap();
int prevStart = head.startMarker();
int nextStart = steps.start((head.lastIbsStep() + step) >>> 1);
hapToLastIbsStep.remove(head.hap());
allHaps.copyTo(prevHap, prevStart, nextStart, compHaps[index]);
head.updateSegment(ibsHap, nextStart, step);
q.offer(head);
}
else {
int index = q.size();
int start = 0;
q.offer(new CompHapSegment(ibsHap, start, step, index));
}
}
hapToLastIbsStep.put(ibsHap, step);
}
private void updateHeadOfQ() {
CompHapSegment head = q.peek();
if (head!=null) {
int lastIbsStep = hapToLastIbsStep.get(head.hap(), NIL);
while (head.lastIbsStep()!=lastIbsStep) {
head = q.poll();
head.setLastIbsStep(lastIbsStep);
q.offer(head);
head = q.peek();
lastIbsStep = hapToLastIbsStep.get(head.hap(), NIL);
}
}
}
private int copyFinalRefSegs() {
int nCompHaps = q.size();
CompHapSegment head = q.poll();
while (head!=null) {
int index = head.compHapIndex();
int hap = head.hap();
int startMarker = head.startMarker();
allHaps.copyTo(hap, startMarker, nMarkers, compHaps[index]);
head = q.poll();
}
return nCompHaps;
}
private void copyData(MarkerCluster mc, int nCompHaps,
List<int[]> refAtMissingGT, byte[][][] nMismatches) {
SamplePhase phase = mc.samplePhase();
BitArray hap1 = phase.hap1();
BitArray hap2 = phase.hap2();
int missIndex = 0;
int nClusters = mc.nClusters();
for (int c=0; c<nClusters; ++c) {
Arrays.fill(nMismatches[0][c], 0, nCompHaps, (byte) 0);
Arrays.fill(nMismatches[1][c], 0, nCompHaps, (byte) 0);
Arrays.fill(nMismatches[2][c], 0, nCompHaps, (byte) 0);
int mStart = mc.clusterStart(c);
int mEnd = mc.clusterEnd(c);
if (mc.isMissingGtOrMaskedHet(c)) {
assert mEnd-mStart==1;
int[] refAlleles = refAtMissingGT.get(missIndex++);
for (int j=0; j<nCompHaps; ++j) {
refAlleles[j] = markers.allele(compHaps[j], mStart);
}
}
else {
int bStart = markers.sumHapBits(mStart);
int bEnd = markers.sumHapBits(mEnd);
if (hap1.equal(hap2, bStart, bEnd)) {
for (int j=0; j<nCompHaps; ++j) {
if (hap1.equal(compHaps[j], bStart, bEnd)==false) {
nMismatches[0][c][j] = 1;
nMismatches[1][c][j] = 1;
nMismatches[2][c][j] = 1;
}
}
}
else {
// cluster contains a heterozygote genotype
for (int j=0; j<nCompHaps; ++j) {
if (hap1.equal(compHaps[j], bStart, bEnd)==false) {
nMismatches[1][c][j] = 1;
}
if (hap2.equal(compHaps[j], bStart, bEnd)==false) {
nMismatches[2][c][j] = 1;
}
}
}
}
}
}
private int copyData(int sample, int nCompHaps, byte[][][] nMismatches) {
byte[][] nMismatches1 = nMismatches[0];
byte[][] nMismatches2 = nMismatches[1];
int h1 = sample << 1;
int h2 = h1 | 0b1;
for (int m=0; m<nMarkers; ++m) {
int a1 = allHaps.allele(m, h1);
int a2 = allHaps.allele(m, h2);
for (int j=0; j<nCompHaps; ++j) {
int refAllele = markers.allele(compHaps[j], m);
nMismatches1[m][j] = (refAllele==a1 ? (byte) 0 : (byte) 1);
nMismatches2[m][j] = (refAllele==a2 ? (byte) 0 : (byte) 1);
}
}
return nCompHaps;
}
private void fillQWithRandomHaps(int sample) {
assert q.isEmpty();
int nHaps = allHaps.nHaps();
int nStates = Math.min(nHaps-2, maxStates);
if (nStates<=0) {
Utilities.exit("ERROR: there is only one sample");
}
else {
Random rand = new Random(phaseData.seed() + sample);
int ibsStep = 0;
int startMarker = 0;
int compHapIndex = 0;
for (int j=0; j<nStates; ++j) {
int h = rand.nextInt(nHaps);
while ((h>>1)==sample) {
h = rand.nextInt(nHaps);
}
if (hapToLastIbsStep.get(h, NIL)==NIL) {
q.add(new CompHapSegment(h, startMarker, ibsStep, compHapIndex++));
hapToLastIbsStep.put(h, startMarker);
}
}
}
}
}
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