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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 ints.IntArray;
import java.util.Optional;
import java.util.Random;
import vcf.GT;
import vcf.RefGT;
/**
* <p>Class {@code Stage2Baum} applies the forward and backward algorithms
* for a haploid Li and Stephens hidden Markov model at high-frequency markers,
* and imputes missing genotypes and heterozygote phase at low-frequency
* markers.</p>
*
* <p>Instances of class {@code Stage2Baum} are not thread-safe.</p>
*
* @author Brian L. Browning {@code <browning@uw.edu>}
*/
public class Stage2Baum {
private final FixedPhaseData fpd;
private final PhaseData phaseData;
private final HmmStateProbs stateProbs;
private final int[] nStates = new int[2];
private final int[][][] states;
private final float[][][] probs;
private final GT unphTargGT;
private final Optional<RefGT> refGT;
private final int nTargHaps;
private final int nStage1Markers;
private final Stage2Haps stage2Haps;
private final IntArray stage1To2;
private final Random rand;
/**
* Creates a {@code ImputeBaum} instance from the specified data.
*
* @param phaseIbs the IBS haplotypes
* @param stage2Haps an object for storing phased genotypes
* @throws NullPointerException if
* {@code phaseIbs == null || stage2Haps == null}
*/
public Stage2Baum(LowFreqPhaseIbs phaseIbs, Stage2Haps stage2Haps) {
this.fpd = phaseIbs.phaseData().fpd();
this.phaseData = phaseIbs.phaseData();
this.nStage1Markers = fpd.stage1TargGT().nMarkers();
this.stateProbs = new HmmStateProbs(phaseIbs);
this.states = new int[2][nStage1Markers][stateProbs.maxStates()];
this.probs = new float[2][nStage1Markers][stateProbs.maxStates()];
this.unphTargGT = fpd.targGT();
this.refGT = fpd.restrictedRefGT();
this.nTargHaps = fpd.targGT().nHaps();
this.stage2Haps = stage2Haps;
this.stage1To2 = fpd.stage1To2();
this.rand = new Random(phaseData.seed());
}
/**
* Returns the number of target samples.
* @return the number of target samples
*/
public int nTargSamples() {
return fpd.targGT().nSamples();
}
/**
* Estimates and stores the phased haplotypes for the specified sample.
* @param targSample a sample index
* @throws IndexOutOfBoundsException if
* {@code sample < 0 || sample >= this.nTargSamples()}
*/
public void phase(int targSample) {
rand.setSeed(phaseData.seed() + targSample);
int h1 = (targSample<<1);
int h2 = h1 | 0b1;
nStates[0] = stateProbs.run(h1, states[0], probs[0]);
nStates[1] = stateProbs.run(h2, states[1], probs[1]);
int start = 0;
for (int j=0; j<nStage1Markers; ++j) {
int end = stage1To2.get(j);
imputeInterval(targSample, start, end);
start = end + 1;
}
imputeInterval(targSample, start, unphTargGT.nMarkers());
}
private void imputeInterval(int sample, int start, int end) {
int hap1 = sample << 1;
int hap2 = hap1 | 0b1;
for (int m=start; m<end; ++m) {
int a1 = unphTargGT.allele(m, hap1);
int a2 = unphTargGT.allele(m, hap2);
if (a1>=0 && a2>=0) {
if (a1!=a2) {
float[] alProbs1 = unscaledAlProbs(m, 0, a1, a2);
float[] alProbs2 = unscaledAlProbs(m, 1, a1, a2);
float p1 = alProbs1[a1]*alProbs2[a2];
float p2 = alProbs1[a2]*alProbs2[a1];
boolean switchAlleles = (p1<p2 || (p1==p2 && rand.nextBoolean()));
if (switchAlleles) {
int tmp = a1;
a1 = a2;
a2 = tmp;
}
}
}
else {
a1 = imputeAllele(m, 0);
a2 = imputeAllele(m, 1);
}
stage2Haps.setPhasedGT(m, sample, a1, a2);
}
}
private float[] unscaledAlProbs(int m, int hapBit, int a1, int a2) {
float[] alProbs = new float[unphTargGT.marker(m).nAlleles()];
boolean rare1 = fpd.isLowFreq(m, a1);
boolean rare2 = fpd.isLowFreq(m, a2);
int mkrA = fpd.prevStage1Marker(m);
int mkrB = Math.min(mkrA + 1, nStage1Markers - 1);
int[] statesA = states[hapBit][mkrA];
float[] probsA = probs[hapBit][mkrA];
float[] probsB = probs[hapBit][mkrB];
for (int j=0, n=nStates[hapBit]; j<n; ++j) {
int hap = statesA[j];
int b1 = allele(m, hap);
int b2 = allele(m, (hap ^ 0b1));
if (b1>=0 && b2>=0) {
float wt = fpd.prevStage1Wt(m);
float prob = wt*probsA[j] + (1.0f - wt)*probsB[j];
if (b1==b2) {
alProbs[b1] += prob;
}
else {
boolean match1 = rare1 && (a1==b1 || a1==b2);
boolean match2 = rare2 && (a2==b1 || a2==b2);
if (match1 ^ match2) {
if (match1) {
alProbs[a1] += prob;
}
else {
alProbs[a2] += prob;
}
}
}
}
}
return alProbs;
}
private int imputeAllele(int m, int hapBit) {
float[] alProbs = new float[unphTargGT.marker(m).nAlleles()];
int mkrA = fpd.prevStage1Marker(m);
int mkrB = Math.min(mkrA + 1, nStage1Markers - 1);
int[] statesA = states[hapBit][mkrA];
float[] stateProbsA = probs[hapBit][mkrA];
float[] stateProbsB = probs[hapBit][mkrB];
for (int j=0, n=nStates[hapBit]; j<n; ++j) {
float wt = fpd.prevStage1Wt(m);
float prob = wt*stateProbsA[j] + (1.0f - wt)*stateProbsB[j];
int hap = statesA[j];
int b1 = allele(m, hap);
int b2 = allele(m, hap ^ 0b1);
if (b1>=0 && b2>=0) {
if (b1==b2 || hap>=nTargHaps) {
alProbs[b1] += prob;
}
else {
boolean isRare1 = fpd.isLowFreq(m, b1);
boolean isRare2 = fpd.isLowFreq(m, b2);
if (isRare1^isRare2) {
if (isRare1) {
alProbs[b1] += 0.55*prob;
alProbs[b2] += 0.45*prob;
}
else {
alProbs[b1] += 0.45*prob;
alProbs[b2] += 0.55*prob;
}
}
else {
alProbs[b1] += 0.5*prob;
alProbs[b2] += 0.5*prob;
}
}
}
}
return maxIndex(alProbs);
}
private int allele(int marker, int hap) {
if (hap<nTargHaps) {
return unphTargGT.allele(marker, hap);
}
else {
return refGT.get().allele(marker, hap - nTargHaps);
}
}
private int maxIndex(float[] fa) {
int maxIndex = 0;
for (int j=1; j<fa.length; ++j) {
if (fa[j]>fa[maxIndex]) {
maxIndex = j;
}
}
return maxIndex;
}
}
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