1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444
|
/*
* 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 beagleutil.PbwtDivUpdater;
import ints.IndexArray;
import ints.IntArray;
import ints.IntList;
import ints.WrappedIntArray;
import java.util.ArrayList;
import java.util.Arrays;
import java.util.Random;
import java.util.stream.IntStream;
import vcf.Markers;
import vcf.XRefGT;
/**
* <p>Class {@code LowFreqPbwtPhaseIbs} uses the Positional Burrows-Wheeler
* Transform (PBWT) and rare variants to select IBS haplotypes for each
* sample for each specified genomic interval.</p>
*
* <p>Instances of class {@code LowFreqPbwtPhaseIbs} are thread-safe.</p>
*
* <p>Reference: Durbin, R. 2014. Bioinformatics 30(9):1266–1272.
* doi:10.1093/bioinformatics/btu014</p>
*
* @author Brian L. Browning {@code <browning@uw.edu>}
*/
public final class LowFreqPbwtPhaseIbs {
private final PhaseData phaseData;
private final Ibs2 ibs2;
private final XRefGT allHaps;
private final WrappedIntArray[] ibsHaps; //[step][targ hap]
/**
* Constructs a new {@code PbwtPhaseIBS} instance from the
* specified data.
* @param phaseData the current genotype phase estimates and parameter
* values
* @param codedSteps the coded steps
* @param useBwd {@code true} if last-to-first PBWT should be used
* @throws IllegalArgumentException if
* {@code phaseData.fpd().stage1Steps() != codedSteps.steps()}
* @throws IllegalArgumentException if
* {@code phaseData.fpd().stage1XRefGT()!=codedSteps.refHaps()}
* @throws IllegalArgumentException if
* {@code phaseData.fpd().targGT().samples()!=codedSteps.targSamples()}
* @throws NullPointerException if
* {@code phaseData == null || codedSteps == null}
*/
public LowFreqPbwtPhaseIbs(PhaseData phaseData, CodedSteps codedSteps,
boolean useBwd) {
checkConsistency(phaseData, codedSteps);
this.phaseData = phaseData;
this.ibs2 = phaseData.fpd().stage1Ibs2();
this.allHaps = codedSteps.allHaps();
PbwtIbsData data = new PbwtIbsData(phaseData, codedSteps);
this.ibsHaps = IntStream.range(0, data.nBatches())
.parallel()
.mapToObj(j -> useBwd ? bwdIbsHaps(data, j) : fwdIbsHaps(data, j))
.flatMap(a -> Arrays.stream(a))
.toArray(WrappedIntArray[]::new);
}
private static void checkConsistency(PhaseData phaseData,
CodedSteps codedSteps) {
FixedPhaseData fpd = phaseData.fpd();
if (fpd.stage1Steps()!=codedSteps.steps()
|| fpd.stage1XRefGT()!=codedSteps.refHaps()
|| fpd.targGT().samples()!=codedSteps.targSamples()) {
throw new IllegalArgumentException("inconsistent data");
}
}
private WrappedIntArray[] bwdIbsHaps(PbwtIbsData data, int batch) {
int startStep = data.startStep(batch);
int endStep = data.endStep(batch);
int bufferEndStep = data.bufferEndStep(endStep);
WrappedIntArray[] ibsHaps0 = new WrappedIntArray[endStep - startStep];
int nHaps = data.nHaps();
PbwtDivUpdater pbwt = new PbwtDivUpdater(nHaps);
int[] a = IntStream.range(0, nHaps).toArray();
int[] d = IntStream.range(0, nHaps+1).map(j -> (bufferEndStep-1)).toArray(); // last entry is sentinal
int[] aInv = new int[nHaps];
int[] iToPrevI = new int[nHaps];
int[] iToNextI = new int[nHaps];
for (int j=(bufferEndStep-1); j>=endStep; --j) {
IndexArray ia = data.codedSteps().get(j);
pbwt.bwdUpdate(ia, ia.valueSize(), j, a, d);
}
for (int j=(endStep-1); j>=startStep; --j) {
IndexArray ia = data.codedSteps().get(j);
pbwt.bwdUpdate(ia, ia.valueSize(), j, a, d);
setInv(a, aInv);
setIToPrevNextI(data.codedSteps().steps(), j, aInv, iToPrevI, iToNextI);
ibsHaps0[j-startStep] = getBwdIbsHaps(j, a, d, iToPrevI, iToNextI,
data);
}
return ibsHaps0;
}
private WrappedIntArray[] fwdIbsHaps(PbwtIbsData data, int batch) {
int startStep = data.startStep(batch);
int endStep = data.endStep(batch);
int bufferStartStep = data.bufferStartStep(startStep);
WrappedIntArray[] ibsHaps0 = new WrappedIntArray[endStep - startStep];
int nHaps = data.nHaps();
PbwtDivUpdater pbwt = new PbwtDivUpdater(nHaps);
int[] a = IntStream.range(0, nHaps).toArray();
int[] d = IntStream.range(0, nHaps+1).map(j -> bufferStartStep).toArray(); // last entry is sentinal
int[] aInv = new int[nHaps];
int[] iToPrevI = new int[nHaps];
int[] iToNextI = new int[nHaps];
for (int j=bufferStartStep; j<startStep; ++j) {
IndexArray ia = data.codedSteps().get(j);
pbwt.fwdUpdate(ia, ia.valueSize(), j, a, d);
}
for (int j=startStep; j<endStep; ++j) {
IndexArray ia = data.codedSteps().get(j);
pbwt.fwdUpdate(ia, ia.valueSize(), j, a, d);
setInv(a, aInv);
setIToPrevNextI(data.codedSteps().steps(), j, aInv, iToPrevI, iToNextI);
ibsHaps0[j-startStep] = getfwdIbsHaps(j, a, d, iToPrevI, iToNextI,
data);
}
return ibsHaps0;
}
private WrappedIntArray getBwdIbsHaps(int step, int[] a, int[] d,
int[] iToPrevI, int[] iToNextI, PbwtIbsData data) {
Random rand = new Random(phaseData.seed() + step);
int mStart = data.codedSteps().steps().start(step);
int mInclEnd = data.codedSteps().steps().end(step) - 1;
int[] selectedHaps = new int[data.nTargHaps()];
d[a.length] = step - 1; // set sentinal
for (int i=0; i<a.length; ++i) {
if (a[i]<data.nTargHaps()) {
int bestI = bestBwdStage2Index(step, mStart, mInclEnd, i, a, d,
iToPrevI, iToNextI, data);
if (bestI>=0) {
selectedHaps[a[i]] = a[bestI];
}
else {
int u = i; // inclusive start
int v = i + 1; // exclusive end
int uNextMatchEnd = d[u];
int vNextMatchEnd = d[v];
while ((v - u)<data.nCandidates()
&& (step<=uNextMatchEnd || step<=vNextMatchEnd)) {
if (uNextMatchEnd<=vNextMatchEnd) {
vNextMatchEnd = Math.min(d[++v], vNextMatchEnd);
}
else {
uNextMatchEnd = Math.min(d[--u], uNextMatchEnd);
}
}
selectedHaps[a[i]] = getMatch(mStart, mInclEnd, i, u, v, a,
rand);
}
}
}
return new WrappedIntArray(selectedHaps);
}
private WrappedIntArray getfwdIbsHaps(int step, int[] a, int[] d,
int[] iToPrevI, int[] iToNextI, PbwtIbsData data) {
Random rand = new Random(phaseData.seed() + step);
int mStart = data.codedSteps().steps().start(step);
int mInclEnd = data.codedSteps().steps().end(step) - 1;
int[] selectedHaps = new int[data.nTargHaps()];
d[a.length] = step + 1; // set sentinal
for (int i=0; i<a.length; ++i) {
if (a[i]<data.nTargHaps()) {
int bestI = bestFwdStage2Index(step, mStart, mInclEnd, i, a, d,
iToPrevI, iToNextI, data);
if (bestI>=0) {
selectedHaps[a[i]] = a[bestI];
}
else {
int u = i; // inclusive start
int v = i + 1; // exclusive end
int uNextMatchStart = d[u];
int vNextMatchStart = d[v];
while ((v - u)<data.nCandidates()
&& (uNextMatchStart<=step || vNextMatchStart<=step)) {
if (vNextMatchStart<=uNextMatchStart) {
vNextMatchStart = Math.max(d[++v], vNextMatchStart);
}
else {
uNextMatchStart = Math.max(d[--u], uNextMatchStart);
}
}
selectedHaps[a[i]] = getMatch(mStart, mInclEnd, i, u, v, a,
rand);
}
}
}
return new WrappedIntArray(selectedHaps);
}
private int bestFwdStage2Index(int step, int mStart, int mInclEnd,
int i, int[] a, int[] d, int[] iToPrevI, int[] iToNextI, PbwtIbsData tmpData) {
int bestPrevMatch = -1;
int bestNextMatch = -1;
int prevMatchStart = 0;
int nextMatchStart = 0;
int minMatchStart = (i+1)<a.length ? Math.min(d[i], d[i+1]) : d[i];
int dMax = Math.min(minMatchStart + tmpData.maxBackoffSteps(), step);
int prevI = iToPrevI[i];
while (prevI>Integer.MIN_VALUE
&& ibs2.areIbs2(a[i]>>1, a[prevI]>>1, mStart, mInclEnd)) {
prevI = iToPrevI[prevI];
}
if (prevI>Integer.MIN_VALUE) {
assert prevI<i;
int u = i;
while ((u-1)!=prevI && d[u]<=dMax) {
prevMatchStart = Math.max(prevMatchStart, d[u--]);
}
if ((u-1)==prevI && d[u]<=dMax) {
prevMatchStart = Math.max(prevMatchStart, d[u]);
bestPrevMatch = prevI;
}
}
int nextI = iToNextI[i];
while (nextI<Integer.MAX_VALUE
&& ibs2.areIbs2(a[i]>>1, a[nextI]>>1, mStart, mInclEnd)) {
nextI = iToNextI[nextI];
}
if (nextI<Integer.MAX_VALUE) {
assert i<nextI;
int v = i;
while ((v+1)!=nextI && d[v+1]<=dMax) {
nextMatchStart = Math.max(nextMatchStart, d[++v]);
}
if ((v+1)==nextI && d[v+1]<=dMax) {
nextMatchStart = Math.max(nextMatchStart, d[++v]);
bestNextMatch = nextI;
}
}
if (prevMatchStart<nextMatchStart && bestPrevMatch != -1) {
return bestPrevMatch;
}
else {
return bestNextMatch;
}
}
private int bestBwdStage2Index(int step, int mStart, int mInclEnd,
int i, int[] a, int[] d, int[] iToPrevI, int[] iToNextI, PbwtIbsData data) {
int nStepsM1 = data.codedSteps().steps().size()-1;
int bestPrevMatch = -1;
int bestNextMatch = -1;
int prevMatchInclEnd = nStepsM1;
int nextMatchInclEnd = nStepsM1;
int maxMatchStart = (i+1)<a.length ? Math.max(d[i], d[i+1]) : d[i];
int dMin = Math.max(maxMatchStart - data.maxBackoffSteps(), step);
int prevI = iToPrevI[i];
while (prevI>Integer.MIN_VALUE
&& ibs2.areIbs2(a[i]>>1, a[prevI]>>1, mStart, mInclEnd)) {
prevI = iToPrevI[prevI];
}
if (prevI>Integer.MIN_VALUE) {
assert prevI<i;
int u = i;
while ((u-1)!=prevI && d[u]>=dMin) {
prevMatchInclEnd = Math.min(prevMatchInclEnd, d[u--]);
}
if ((u-1)==prevI && d[u]>=dMin) {
prevMatchInclEnd = Math.min(prevMatchInclEnd, d[u]);
bestPrevMatch = prevI;
}
}
int nextI = iToNextI[i];
while (nextI<Integer.MAX_VALUE
&& ibs2.areIbs2(a[i]>>1, a[nextI]>>1, mStart, mInclEnd)) {
nextI = iToNextI[nextI];
}
if (nextI<Integer.MAX_VALUE) {
assert i<nextI;
int v = i;
while ((v+1)!=nextI && d[v+1]>=dMin) {
nextMatchInclEnd = Math.min(nextMatchInclEnd, d[++v]);
}
if ((v+1)==nextI && d[v+1]>=dMin) {
nextMatchInclEnd = Math.min(nextMatchInclEnd, d[++v]);
bestNextMatch = nextI;
}
}
if (prevMatchInclEnd>nextMatchInclEnd && bestPrevMatch != -1) {
return bestPrevMatch;
}
else {
return bestNextMatch;
}
}
private int getMatch(int mStart, int mInclEnd, int i, int iStart,
int iEnd, int[] a, Random rand) {
int iLength = iEnd - iStart;
if (iLength==1) {
return -1;
}
int match = -1;
int index = iStart + rand.nextInt(iLength);
for (int j=0; j<iLength && match==-1; ++j) {
if (ibs2.areIbs2(a[i]>>1, a[index]>>1, mStart, mInclEnd)==false) {
match = a[index];
}
if (++index==iEnd) {
index = iStart;
}
}
return match;
}
/**
* Returns the current genotype phase estimates and parameter values.
* @return the current genotype phase estimates and parameter values
*/
public PhaseData phaseData() {
return phaseData;
}
/**
* Returns the estimated phased genotypes for the target and reference
* samples.
* @return the estimated phased genotypes for the target and reference
* samples
*/
public XRefGT allHaps() {
return allHaps;
}
/**
* Returns the index of a haplotype that is identical by state
* with the specified target haplotype in the specified genomic interval,
* or {@code -1} if there is no identical-by-state haplotype.
* @param hap a target haplotype index
* @param step an index of a genomic interval
* @return the index of a haplotype that is identical by state
* with the specified haplotype int the specified genomic interval
* @throws IndexOutOfBoundsException if
* {@code hap < 0 || hap >= this.phaseData().targGT().nHaps()}
* @throws IndexOutOfBoundsException if
* {@code step < 0 || step >= this.phaseData().fpd().stage1Steps().size()}
*/
public int ibsHap(int hap, int step) {
return ibsHaps[step].get(hap);
}
private void setIToPrevNextI(Steps steps, int step, int[] invA,
int[] iToPrevI, int[] iToNextI) {
Arrays.fill(iToPrevI, Integer.MIN_VALUE);
Arrays.fill(iToNextI, Integer.MAX_VALUE);
ArrayList<IntList> lowFreqHapLists = lowFreqHapLists(steps, step);
for (int j=0, n=lowFreqHapLists.size(); j<n; ++j) {
int[] i = sortedAIndices(lowFreqHapLists.get(j), invA);
for (int k=1; k<i.length; ++k) {
int i0 = i[k-1];
int i1 = i[k];
if (i0>iToPrevI[i1]) {
iToPrevI[i1] = i0;
}
if (i1<iToNextI[i0]) {
iToNextI[i0] = i1;
}
}
}
}
private int[] sortedAIndices(IntList haps, int[] invA) {
return haps.stream()
.map(h -> invA[h])
.sorted()
.toArray();
}
private ArrayList<IntList> lowFreqHapLists(Steps steps, int step) {
FixedPhaseData fpd = phaseData.fpd();
IntArray hiFreqIndices = fpd.stage1To2();
int start = step==0 ? 0 : hiFreqIndices.get(steps.start(step));
int end = (step+1 < steps.size())
? hiFreqIndices.get(steps.start(step+1))
: fpd.targGT().nMarkers();
return lowFreqHapLists(fpd, start, end);
}
private static ArrayList<IntList> lowFreqHapLists(FixedPhaseData fpd,
int start, int end) {
ArrayList<IntList> hapLists = new ArrayList<>();
Markers markers = fpd.targGT().markers();
for (int m=start; m<end; ++m) {
int nAlleles = markers.marker(m).nAlleles();
for (int al=0; al<nAlleles; ++al) {
IntArray carriers = fpd.carriers(m, al);
if (carriers.size()>1) {
hapLists.add(hapList(carriers));
}
}
}
return hapLists;
}
private static IntList hapList(IntArray carriers) {
IntList hapList = new IntList(2*carriers.size());
for (int j=0, n=carriers.size(); j<n; ++j) {
int sample = carriers.get(j);
int h1 = sample<<1;
hapList.add(h1);
hapList.add(h1|0b1);
}
return hapList;
}
private static void setInv(int[] a, int[] aInv) {
for (int j=0; j<a.length; ++j) {
aInv[a[j]] = j;
}
}
}
|