1 // Copyright (C) The Lightning Authors. All rights reserved.
3 // SPDX-License-Identifier: AGPL-3.0
29 "git.arvados.org/arvados.git/sdk/go/arvados"
30 "github.com/arvados/lightning/hgvs"
31 "github.com/kshedden/gonpy"
32 "github.com/sirupsen/logrus"
33 log "github.com/sirupsen/logrus"
34 "golang.org/x/crypto/blake2b"
37 type sliceNumpy struct {
40 chi2CaseControlColumn string
41 chi2CaseControlFile string
50 func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, stdout, stderr io.Writer) int {
54 fmt.Fprintf(stderr, "%s\n", err)
57 flags := flag.NewFlagSet("", flag.ContinueOnError)
58 flags.SetOutput(stderr)
59 pprof := flags.String("pprof", "", "serve Go profile data at http://`[addr]:port`")
60 runlocal := flags.Bool("local", false, "run on local host (default: run in an arvados container)")
61 projectUUID := flags.String("project", "", "project `UUID` for output data")
62 priority := flags.Int("priority", 500, "container request priority")
63 inputDir := flags.String("input-dir", "./in", "input `directory`")
64 outputDir := flags.String("output-dir", "./out", "output `directory`")
65 ref := flags.String("ref", "", "reference name (if blank, choose last one that appears in input)")
66 regionsFilename := flags.String("regions", "", "only output columns/annotations that intersect regions in specified bed `file`")
67 expandRegions := flags.Int("expand-regions", 0, "expand specified regions by `N` base pairs on each side`")
68 mergeOutput := flags.Bool("merge-output", false, "merge output into one matrix.npy and one matrix.annotations.csv")
69 hgvsSingle := flags.Bool("single-hgvs-matrix", false, "also generate hgvs-based matrix")
70 hgvsChunked := flags.Bool("chunked-hgvs-matrix", false, "also generate hgvs-based matrix per chromosome")
71 onehotSingle := flags.Bool("single-onehot", false, "generate one-hot tile-based matrix")
72 onehotChunked := flags.Bool("chunked-onehot", false, "generate one-hot tile-based matrix per input chunk")
73 debugTag := flags.Int("debug-tag", -1, "log debugging details about specified tag")
74 flags.IntVar(&cmd.threads, "threads", 16, "number of memory-hungry assembly threads")
75 flags.StringVar(&cmd.chi2CaseControlFile, "chi2-case-control-file", "", "tsv file or directory indicating cases and controls for Χ² test (if directory, all .tsv files will be read)")
76 flags.StringVar(&cmd.chi2CaseControlColumn, "chi2-case-control-column", "", "name of case/control column in case-control files for Χ² test (value must be 0 for control, 1 for case)")
77 flags.Float64Var(&cmd.chi2PValue, "chi2-p-value", 1, "do Χ² test and omit columns with p-value above this threshold")
78 flags.BoolVar(&cmd.includeVariant1, "include-variant-1", false, "include most common variant when building one-hot matrix")
79 cmd.filter.Flags(flags)
80 err = flags.Parse(args)
81 if err == flag.ErrHelp {
84 } else if err != nil {
90 log.Println(http.ListenAndServe(*pprof, nil))
94 if cmd.chi2PValue != 1 && (cmd.chi2CaseControlFile == "" || cmd.chi2CaseControlColumn == "") {
95 log.Errorf("cannot use provided -chi2-p-value=%f because -chi2-case-control-file= or -chi2-case-control-column= value is empty", cmd.chi2PValue)
99 cmd.debugTag = tagID(*debugTag)
102 runner := arvadosContainerRunner{
103 Name: "lightning slice-numpy",
104 Client: arvados.NewClientFromEnv(),
105 ProjectUUID: *projectUUID,
112 err = runner.TranslatePaths(inputDir, regionsFilename, &cmd.chi2CaseControlFile)
116 runner.Args = []string{"slice-numpy", "-local=true",
118 "-input-dir=" + *inputDir,
119 "-output-dir=/mnt/output",
120 "-threads=" + fmt.Sprintf("%d", cmd.threads),
121 "-regions=" + *regionsFilename,
122 "-expand-regions=" + fmt.Sprintf("%d", *expandRegions),
123 "-merge-output=" + fmt.Sprintf("%v", *mergeOutput),
124 "-single-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsSingle),
125 "-chunked-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsChunked),
126 "-single-onehot=" + fmt.Sprintf("%v", *onehotSingle),
127 "-chunked-onehot=" + fmt.Sprintf("%v", *onehotChunked),
128 "-chi2-case-control-file=" + cmd.chi2CaseControlFile,
129 "-chi2-case-control-column=" + cmd.chi2CaseControlColumn,
130 "-chi2-p-value=" + fmt.Sprintf("%f", cmd.chi2PValue),
131 "-include-variant-1=" + fmt.Sprintf("%v", cmd.includeVariant1),
132 "-debug-tag=" + fmt.Sprintf("%d", cmd.debugTag),
134 runner.Args = append(runner.Args, cmd.filter.Args()...)
136 output, err = runner.Run()
140 fmt.Fprintln(stdout, output)
144 infiles, err := allFiles(*inputDir, matchGobFile)
148 if len(infiles) == 0 {
149 err = fmt.Errorf("no input files found in %s", *inputDir)
152 sort.Strings(infiles)
154 var refseq map[string][]tileLibRef
155 var reftiledata = make(map[tileLibRef][]byte, 11000000)
156 in0, err := open(infiles[0])
161 matchGenome, err := regexp.Compile(cmd.filter.MatchGenome)
163 err = fmt.Errorf("-match-genome: invalid regexp: %q", cmd.filter.MatchGenome)
169 DecodeLibrary(in0, strings.HasSuffix(infiles[0], ".gz"), func(ent *LibraryEntry) error {
170 if len(ent.TagSet) > 0 {
173 for _, cseq := range ent.CompactSequences {
174 if cseq.Name == *ref || *ref == "" {
175 refseq = cseq.TileSequences
178 for _, cg := range ent.CompactGenomes {
179 if matchGenome.MatchString(cg.Name) {
180 cmd.cgnames = append(cmd.cgnames, cg.Name)
183 for _, tv := range ent.TileVariants {
185 reftiledata[tileLibRef{tv.Tag, tv.Variant}] = tv.Sequence
195 err = fmt.Errorf("%s: reference sequence not found", infiles[0])
198 if len(tagset) == 0 {
199 err = fmt.Errorf("tagset not found")
203 taglib := &tagLibrary{}
204 err = taglib.setTags(tagset)
208 taglen := taglib.TagLen()
210 if len(cmd.cgnames) == 0 {
211 err = fmt.Errorf("no genomes found matching regexp %q", cmd.filter.MatchGenome)
214 sort.Strings(cmd.cgnames)
215 err = cmd.useCaseControlFiles()
219 cmd.minCoverage = int(math.Ceil(cmd.filter.MinCoverage * float64(len(cmd.cgnames))))
222 labelsFilename := *outputDir + "/samples.csv"
223 log.Infof("writing labels to %s", labelsFilename)
225 f, err = os.Create(labelsFilename)
230 for i, name := range cmd.cgnames {
232 if cmd.chi2Cases != nil && cmd.chi2Cases[i] {
235 _, err = fmt.Fprintf(f, "%d,%q,%d\n", i, trimFilenameForLabel(name), cc)
237 err = fmt.Errorf("write %s: %w", labelsFilename, err)
243 err = fmt.Errorf("close %s: %w", labelsFilename, err)
248 log.Info("indexing reference tiles")
249 type reftileinfo struct {
250 variant tileVariantID
251 seqname string // chr1
252 pos int // distance from start of chromosome to starttag
253 tiledata []byte // acgtggcaa...
255 isdup := map[tagID]bool{}
256 reftile := map[tagID]*reftileinfo{}
257 for seqname, cseq := range refseq {
259 for _, libref := range cseq {
260 if cmd.filter.MaxTag >= 0 && libref.Tag > tagID(cmd.filter.MaxTag) {
263 tiledata := reftiledata[libref]
264 if len(tiledata) == 0 {
265 err = fmt.Errorf("missing tiledata for tag %d variant %d in %s in ref", libref.Tag, libref.Variant, seqname)
268 foundthistag := false
269 taglib.FindAll(tiledata[:len(tiledata)-1], func(tagid tagID, offset, _ int) {
270 if !foundthistag && tagid == libref.Tag {
274 if dupref, ok := reftile[tagid]; ok {
275 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique, also found inside %+v from %s @ %d", tileLibRef{Tag: tagid, Variant: dupref.variant}, dupref.seqname, dupref.pos, libref, seqname, pos+offset+1)
276 delete(reftile, tagid)
278 log.Printf("found tag %d at offset %d inside tile variant %+v on %s @ %d", tagid, offset, libref, seqname, pos+offset+1)
282 if isdup[libref.Tag] {
283 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
284 } else if reftile[libref.Tag] != nil {
285 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", tileLibRef{Tag: libref.Tag, Variant: reftile[libref.Tag].variant}, reftile[libref.Tag].seqname, reftile[libref.Tag].pos)
286 delete(reftile, libref.Tag)
287 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
288 isdup[libref.Tag] = true
290 reftile[libref.Tag] = &reftileinfo{
292 variant: libref.Variant,
297 pos += len(tiledata) - taglen
299 log.Printf("... %s done, len %d", seqname, pos+taglen)
303 if *regionsFilename != "" {
304 log.Printf("loading regions from %s", *regionsFilename)
305 mask, err = makeMask(*regionsFilename, *expandRegions)
309 log.Printf("before applying mask, len(reftile) == %d", len(reftile))
310 log.Printf("deleting reftile entries for regions outside %d intervals", mask.Len())
311 for tag, rt := range reftile {
312 if !mask.Check(strings.TrimPrefix(rt.seqname, "chr"), rt.pos, rt.pos+len(rt.tiledata)) {
316 log.Printf("after applying mask, len(reftile) == %d", len(reftile))
319 type hgvsColSet map[hgvs.Variant][2][]int8
320 encodeHGVS := throttle{Max: len(refseq)}
321 encodeHGVSTodo := map[string]chan hgvsColSet{}
322 tmpHGVSCols := map[string]*os.File{}
324 for seqname := range refseq {
326 f, err = os.Create(*outputDir + "/tmp." + seqname + ".gob")
330 defer os.Remove(f.Name())
331 bufw := bufio.NewWriterSize(f, 1<<24)
332 enc := gob.NewEncoder(bufw)
333 tmpHGVSCols[seqname] = f
334 todo := make(chan hgvsColSet, 128)
335 encodeHGVSTodo[seqname] = todo
336 encodeHGVS.Go(func() error {
337 for colset := range todo {
338 err := enc.Encode(colset)
340 encodeHGVS.Report(err)
351 var toMerge [][]int16
352 if *mergeOutput || *hgvsSingle {
353 toMerge = make([][]int16, len(infiles))
355 var onehotIndirect [][2][]uint32 // [chunkIndex][axis][index]
356 var onehotChunkSize []uint32
357 var onehotXrefs [][]onehotXref
359 onehotIndirect = make([][2][]uint32, len(infiles))
360 onehotChunkSize = make([]uint32, len(infiles))
361 onehotXrefs = make([][]onehotXref, len(infiles))
364 throttleMem := throttle{Max: cmd.threads} // TODO: estimate using mem and data size
365 throttleNumpyMem := throttle{Max: cmd.threads/2 + 1}
366 log.Info("generating annotations and numpy matrix for each slice")
367 var errSkip = errors.New("skip infile")
369 for infileIdx, infile := range infiles {
370 infileIdx, infile := infileIdx, infile
371 throttleMem.Go(func() error {
372 seq := make(map[tagID][]TileVariant, 50000)
373 cgs := make(map[string]CompactGenome, len(cmd.cgnames))
374 f, err := open(infile)
379 log.Infof("%04d: reading %s", infileIdx, infile)
380 err = DecodeLibrary(f, strings.HasSuffix(infile, ".gz"), func(ent *LibraryEntry) error {
381 for _, tv := range ent.TileVariants {
385 if mask != nil && reftile[tv.Tag] == nil {
391 if tv.Tag == cmd.debugTag {
392 log.Printf("infile %d %s tag %d variant %d hash %x", infileIdx, infile, tv.Tag, tv.Variant, tv.Blake2b[:3])
394 variants := seq[tv.Tag]
395 if len(variants) == 0 {
396 variants = make([]TileVariant, 100)
398 for len(variants) <= int(tv.Variant) {
399 variants = append(variants, TileVariant{})
401 variants[int(tv.Variant)] = tv
402 seq[tv.Tag] = variants
404 for _, cg := range ent.CompactGenomes {
405 if cmd.filter.MaxTag >= 0 && cg.StartTag > tagID(cmd.filter.MaxTag) {
408 if !matchGenome.MatchString(cg.Name) {
411 // pad to full slice size
412 // to avoid out-of-bounds
414 if sliceSize := 2 * int(cg.EndTag-cg.StartTag); len(cg.Variants) < sliceSize {
415 cg.Variants = append(cg.Variants, make([]tileVariantID, sliceSize-len(cg.Variants))...)
423 } else if err != nil {
426 tagstart := cgs[cmd.cgnames[0]].StartTag
427 tagend := cgs[cmd.cgnames[0]].EndTag
431 log.Infof("%04d: renumber/dedup variants for tags %d-%d", infileIdx, tagstart, tagend)
432 variantRemap := make([][]tileVariantID, tagend-tagstart)
433 throttleCPU := throttle{Max: runtime.GOMAXPROCS(0)}
434 for tag, variants := range seq {
435 tag, variants := tag, variants
436 throttleCPU.Acquire()
438 defer throttleCPU.Release()
439 count := make(map[[blake2b.Size256]byte]int, len(variants))
443 count[blake2b.Sum256(rt.tiledata)] = 0
446 for cgname, cg := range cgs {
447 idx := int(tag-tagstart) * 2
448 for allele := 0; allele < 2; allele++ {
449 v := cg.Variants[idx+allele]
450 if v > 0 && len(variants[v].Sequence) > 0 {
451 count[variants[v].Blake2b]++
452 if tag == cmd.debugTag {
453 log.Printf("tag %d cg %s allele %d tv %d hash %x count is now %d", tag, cgname, allele, v, variants[v].Blake2b[:3], count[variants[v].Blake2b])
458 // hash[i] will be the hash of
459 // the variant(s) that should
460 // be at rank i (0-based).
461 hash := make([][blake2b.Size256]byte, 0, len(count))
462 for b := range count {
463 hash = append(hash, b)
465 sort.Slice(hash, func(i, j int) bool {
466 bi, bj := &hash[i], &hash[j]
467 if ci, cj := count[*bi], count[*bj]; ci != cj {
470 return bytes.Compare((*bi)[:], (*bj)[:]) < 0
473 // rank[b] will be the 1-based
474 // new variant number for
475 // variants whose hash is b.
476 rank := make(map[[blake2b.Size256]byte]tileVariantID, len(hash))
477 for i, h := range hash {
478 rank[h] = tileVariantID(i + 1)
480 if tag == cmd.debugTag {
481 for h, r := range rank {
482 log.Printf("tag %d rank(%x) = %v", tag, h[:3], r)
485 // remap[v] will be the new
486 // variant number for original
488 remap := make([]tileVariantID, len(variants))
489 for i, tv := range variants {
490 remap[i] = rank[tv.Blake2b]
492 if tag == cmd.debugTag {
493 log.Printf("tag %d remap %+v", tag, remap)
495 variantRemap[tag-tagstart] = remap
497 refrank := rank[blake2b.Sum256(rt.tiledata)]
498 if tag == cmd.debugTag {
499 log.Printf("tag %d reftile variant %d => %d", tag, rt.variant, refrank)
507 var onehotChunk [][]int8
508 var onehotXref []onehotXref
510 annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, infileIdx)
511 log.Infof("%04d: writing %s", infileIdx, annotationsFilename)
512 annof, err := os.Create(annotationsFilename)
516 annow := bufio.NewWriterSize(annof, 1<<20)
518 for tag := tagstart; tag < tagend; tag++ {
520 if rt == nil && mask != nil {
521 // Excluded by specified regions
524 if cmd.filter.MaxTag >= 0 && tag > tagID(cmd.filter.MaxTag) {
527 remap := variantRemap[tag-tagstart]
528 maxv := tileVariantID(0)
529 for _, v := range remap {
534 if *onehotChunked || *onehotSingle {
535 if tag == cmd.debugTag {
536 log.WithFields(logrus.Fields{
537 "cgs[2].Variants[tag*2:(tag+1)*2]": cgs[cmd.cgnames[2]].Variants[(tag-tagstart)*2 : (tag-tagstart+1)*2],
538 }).Info("before tv2homhet")
540 onehot, xrefs := cmd.tv2homhet(cgs, maxv, remap, tag, tagstart)
541 if tag == cmd.debugTag {
542 log.WithFields(logrus.Fields{
545 }).Info("tv2homhet()")
547 onehotChunk = append(onehotChunk, onehot...)
548 onehotXref = append(onehotXref, xrefs...)
551 // Reference does not use any
552 // variant of this tile
556 fmt.Fprintf(annow, "%d,%d,%d,=,%s,%d,,,\n", tag, outcol, rt.variant, rt.seqname, rt.pos)
558 reftilestr := strings.ToUpper(string(rt.tiledata))
560 done := make([]bool, maxv+1)
561 variantDiffs := make([][]hgvs.Variant, maxv+1)
562 for v, tv := range variants {
564 if v == rt.variant || done[v] {
569 if len(tv.Sequence) < taglen || !bytes.HasSuffix(rt.tiledata, tv.Sequence[len(tv.Sequence)-taglen:]) {
570 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
573 if lendiff := len(rt.tiledata) - len(tv.Sequence); lendiff < -1000 || lendiff > 1000 {
574 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
577 diffs, _ := hgvs.Diff(reftilestr, strings.ToUpper(string(tv.Sequence)), 0)
578 for i := range diffs {
579 diffs[i].Position += rt.pos
581 for _, diff := range diffs {
582 fmt.Fprintf(annow, "%d,%d,%d,%s:g.%s,%s,%d,%s,%s,%s\n", tag, outcol, v, rt.seqname, diff.String(), rt.seqname, diff.Position, diff.Ref, diff.New, diff.Left)
585 variantDiffs[v] = diffs
589 // We can now determine, for each HGVS
590 // variant (diff) in this reftile
591 // region, whether a given genome
592 // phase/allele (1) has the variant, (0) has
593 // =ref or a different variant in that
594 // position, or (-1) is lacking
595 // coverage / couldn't be diffed.
596 hgvsCol := hgvsColSet{}
597 for _, diffs := range variantDiffs {
598 for _, diff := range diffs {
599 if _, ok := hgvsCol[diff]; ok {
602 hgvsCol[diff] = [2][]int8{
603 make([]int8, len(cmd.cgnames)),
604 make([]int8, len(cmd.cgnames)),
608 for row, name := range cmd.cgnames {
609 variants := cgs[name].Variants[(tag-tagstart)*2:]
610 for ph := 0; ph < 2; ph++ {
612 if int(v) >= len(remap) {
618 // hgvsCol[*][ph][row] is already 0
619 } else if len(variantDiffs[v]) == 0 {
620 // lacking coverage / couldn't be diffed
621 for _, col := range hgvsCol {
625 for _, diff := range variantDiffs[v] {
626 hgvsCol[diff][ph][row] = 1
631 for diff, colpair := range hgvsCol {
632 allele2homhet(colpair)
633 if !cmd.filterHGVScolpair(colpair) {
634 delete(hgvsCol, diff)
637 if len(hgvsCol) > 0 {
638 encodeHGVSTodo[rt.seqname] <- hgvsCol
653 // transpose onehotChunk[col][row] to numpy[row*ncols+col]
654 rows := len(cmd.cgnames)
655 cols := len(onehotChunk)
656 log.Infof("%04d: preparing onehot numpy (rows=%d, cols=%d, mem=%d)", infileIdx, rows, cols, rows*cols)
657 throttleNumpyMem.Acquire()
658 out := onehotcols2int8(onehotChunk)
659 fnm := fmt.Sprintf("%s/onehot.%04d.npy", *outputDir, infileIdx)
660 err = writeNumpyInt8(fnm, out, rows, cols)
664 fnm = fmt.Sprintf("%s/onehot-columns.%04d.npy", *outputDir, infileIdx)
665 err = writeNumpyInt32(fnm, onehotXref2int32(onehotXref), 4, len(onehotXref))
670 throttleNumpyMem.Release()
673 onehotIndirect[infileIdx] = onehotChunk2Indirect(onehotChunk)
674 onehotChunkSize[infileIdx] = uint32(len(onehotChunk))
675 onehotXrefs[infileIdx] = onehotXref
676 n := len(onehotIndirect[infileIdx][0])
677 log.Infof("%04d: keeping onehot coordinates in memory (n=%d, mem=%d)", infileIdx, n, n*8*2)
679 if !(*onehotSingle || *onehotChunked) || *mergeOutput || *hgvsSingle {
680 log.Infof("%04d: preparing numpy (rows=%d, cols=%d)", infileIdx, len(cmd.cgnames), 2*outcol)
681 throttleNumpyMem.Acquire()
682 rows := len(cmd.cgnames)
684 out := make([]int16, rows*cols)
685 for row, name := range cmd.cgnames {
686 out := out[row*cols:]
688 for col, v := range cgs[name].Variants {
689 tag := tagstart + tagID(col/2)
690 if mask != nil && reftile[tag] == nil || (cmd.filter.MaxTag >= 0 && tag > tagID(cmd.filter.MaxTag)) {
693 if variants, ok := seq[tag]; ok && len(variants) > int(v) && len(variants[v].Sequence) > 0 {
694 out[outcol] = int16(variantRemap[tag-tagstart][v])
704 throttleNumpyMem.Release()
705 if *mergeOutput || *hgvsSingle {
706 log.Infof("%04d: matrix fragment %d rows x %d cols", infileIdx, rows, cols)
707 toMerge[infileIdx] = out
709 if !*mergeOutput && !*onehotChunked && !*onehotSingle {
710 fnm := fmt.Sprintf("%s/matrix.%04d.npy", *outputDir, infileIdx)
711 err = writeNumpyInt16(fnm, out, rows, cols)
718 log.Infof("%s: done (%d/%d)", infile, int(atomic.AddInt64(&done, 1)), len(infiles))
722 if err = throttleMem.Wait(); err != nil {
727 log.Info("flushing hgvsCols temp files")
728 for seqname := range refseq {
729 close(encodeHGVSTodo[seqname])
731 err = encodeHGVS.Wait()
735 for seqname := range refseq {
736 log.Infof("%s: reading hgvsCols from temp file", seqname)
737 f := tmpHGVSCols[seqname]
738 _, err = f.Seek(0, io.SeekStart)
742 var hgvsCols hgvsColSet
743 dec := gob.NewDecoder(bufio.NewReaderSize(f, 1<<24))
745 err = dec.Decode(&hgvsCols)
750 log.Infof("%s: sorting %d hgvs variants", seqname, len(hgvsCols))
751 variants := make([]hgvs.Variant, 0, len(hgvsCols))
752 for v := range hgvsCols {
753 variants = append(variants, v)
755 sort.Slice(variants, func(i, j int) bool {
756 vi, vj := &variants[i], &variants[j]
757 if vi.Position != vj.Position {
758 return vi.Position < vj.Position
759 } else if vi.Ref != vj.Ref {
760 return vi.Ref < vj.Ref
762 return vi.New < vj.New
765 rows := len(cmd.cgnames)
766 cols := len(variants) * 2
767 log.Infof("%s: building hgvs matrix (rows=%d, cols=%d, mem=%d)", seqname, rows, cols, rows*cols)
768 out := make([]int8, rows*cols)
769 for varIdx, variant := range variants {
770 hgvsCols := hgvsCols[variant]
771 for row := range cmd.cgnames {
772 for ph := 0; ph < 2; ph++ {
773 out[row*cols+varIdx+ph] = hgvsCols[ph][row]
777 err = writeNumpyInt8(fmt.Sprintf("%s/hgvs.%s.npy", *outputDir, seqname), out, rows, cols)
783 fnm := fmt.Sprintf("%s/hgvs.%s.annotations.csv", *outputDir, seqname)
784 log.Infof("%s: writing hgvs column labels to %s", seqname, fnm)
785 var hgvsLabels bytes.Buffer
786 for varIdx, variant := range variants {
787 fmt.Fprintf(&hgvsLabels, "%d,%s:g.%s\n", varIdx, seqname, variant.String())
789 err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0666)
796 if *mergeOutput || *hgvsSingle {
797 var annow *bufio.Writer
800 annoFilename := fmt.Sprintf("%s/matrix.annotations.csv", *outputDir)
801 annof, err = os.Create(annoFilename)
805 annow = bufio.NewWriterSize(annof, 1<<20)
808 rows := len(cmd.cgnames)
810 for _, chunk := range toMerge {
811 cols += len(chunk) / rows
813 log.Infof("merging output matrix (rows=%d, cols=%d, mem=%d) and annotations", rows, cols, rows*cols*2)
816 out = make([]int16, rows*cols)
818 hgvsCols := map[string][2][]int16{} // hgvs -> [[g0,g1,g2,...], [g0,g1,g2,...]] (slice of genomes for each phase)
820 for outIdx, chunk := range toMerge {
821 chunkcols := len(chunk) / rows
823 for row := 0; row < rows; row++ {
824 copy(out[row*cols+startcol:], chunk[row*chunkcols:(row+1)*chunkcols])
827 toMerge[outIdx] = nil
829 annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, outIdx)
830 log.Infof("reading %s", annotationsFilename)
831 buf, err := os.ReadFile(annotationsFilename)
836 err = os.Remove(annotationsFilename)
841 for _, line := range bytes.Split(buf, []byte{'\n'}) {
845 fields := bytes.SplitN(line, []byte{','}, 9)
846 tag, _ := strconv.Atoi(string(fields[0]))
847 incol, _ := strconv.Atoi(string(fields[1]))
848 tileVariant, _ := strconv.Atoi(string(fields[2]))
849 hgvsID := string(fields[3])
850 seqname := string(fields[4])
851 pos, _ := strconv.Atoi(string(fields[5]))
854 // Null entry for un-diffable
859 // Null entry for ref tile
862 if mask != nil && !mask.Check(strings.TrimPrefix(seqname, "chr"), pos, pos+len(refseq)) {
863 // The tile intersects one of
864 // the selected regions, but
865 // this particular HGVS
869 hgvsColPair := hgvsCols[hgvsID]
870 if hgvsColPair[0] == nil {
871 // values in new columns start
872 // out as -1 ("no data yet")
873 // or 0 ("=ref") here, may
874 // change to 1 ("hgvs variant
875 // present") below, either on
876 // this line or a future line.
877 hgvsColPair = [2][]int16{make([]int16, len(cmd.cgnames)), make([]int16, len(cmd.cgnames))}
878 rt, ok := reftile[tagID(tag)]
880 err = fmt.Errorf("bug: seeing annotations for tag %d, but it has no reftile entry", tag)
883 for ph := 0; ph < 2; ph++ {
884 for row := 0; row < rows; row++ {
885 v := chunk[row*chunkcols+incol*2+ph]
886 if tileVariantID(v) == rt.variant {
887 hgvsColPair[ph][row] = 0
889 hgvsColPair[ph][row] = -1
893 hgvsCols[hgvsID] = hgvsColPair
895 hgvsref := hgvs.Variant{
900 fmt.Fprintf(annow, "%d,%d,%d,%s:g.%s,%s,%d,%s,%s,%s\n", tag, incol+startcol/2, rt.variant, seqname, hgvsref.String(), seqname, pos, refseq, refseq, fields[8])
904 fmt.Fprintf(annow, "%d,%d,%d,%s,%s,%d,%s,%s,%s\n", tag, incol+startcol/2, tileVariant, hgvsID, seqname, pos, refseq, fields[7], fields[8])
906 for ph := 0; ph < 2; ph++ {
907 for row := 0; row < rows; row++ {
908 v := chunk[row*chunkcols+incol*2+ph]
909 if int(v) == tileVariant {
910 hgvsColPair[ph][row] = 1
916 startcol += chunkcols
927 err = writeNumpyInt16(fmt.Sprintf("%s/matrix.npy", *outputDir), out, rows, cols)
935 cols = len(hgvsCols) * 2
936 log.Printf("building hgvs-based matrix: %d rows x %d cols", rows, cols)
937 out = make([]int16, rows*cols)
938 hgvsIDs := make([]string, 0, cols/2)
939 for hgvsID := range hgvsCols {
940 hgvsIDs = append(hgvsIDs, hgvsID)
942 sort.Strings(hgvsIDs)
943 var hgvsLabels bytes.Buffer
944 for idx, hgvsID := range hgvsIDs {
945 fmt.Fprintf(&hgvsLabels, "%d,%s\n", idx, hgvsID)
946 for ph := 0; ph < 2; ph++ {
947 hgvscol := hgvsCols[hgvsID][ph]
948 for row, val := range hgvscol {
949 out[row*cols+idx*2+ph] = val
953 err = writeNumpyInt16(fmt.Sprintf("%s/hgvs.npy", *outputDir), out, rows, cols)
958 fnm := fmt.Sprintf("%s/hgvs.annotations.csv", *outputDir)
959 log.Printf("writing hgvs labels: %s", fnm)
960 err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0777)
968 for _, part := range onehotIndirect {
969 nzCount += len(part[0])
971 onehot := make([]uint32, nzCount*2) // [r,r,r,...,c,c,c,...]
972 var xrefs []onehotXref
973 chunkOffset := uint32(0)
975 for i, part := range onehotIndirect {
976 for i := range part[1] {
977 part[1][i] += chunkOffset
979 copy(onehot[outcol:], part[0])
980 copy(onehot[outcol+nzCount:], part[1])
981 xrefs = append(xrefs, onehotXrefs[i]...)
983 outcol += len(part[0])
984 chunkOffset += onehotChunkSize[i]
991 fnm := fmt.Sprintf("%s/onehot.npy", *outputDir)
992 err = writeNumpyUint32(fnm, onehot, 2, nzCount)
996 fnm = fmt.Sprintf("%s/onehot-columns.npy", *outputDir)
997 err = writeNumpyInt32(fnm, onehotXref2int32(xrefs), 4, len(xrefs))
1005 // Read case/control files, remove non-case/control entries from
1006 // cmd.cgnames, and build cmd.chi2Cases.
1007 func (cmd *sliceNumpy) useCaseControlFiles() error {
1008 if cmd.chi2CaseControlFile == "" {
1011 infiles, err := allFiles(cmd.chi2CaseControlFile, nil)
1015 // index in cmd.cgnames => case(true) / control(false)
1016 cc := map[int]bool{}
1017 for _, infile := range infiles {
1018 f, err := open(infile)
1022 buf, err := io.ReadAll(f)
1028 for _, tsv := range bytes.Split(buf, []byte{'\n'}) {
1032 split := strings.Split(string(tsv), "\t")
1035 for col, name := range split {
1036 if name == cmd.chi2CaseControlColumn {
1042 return fmt.Errorf("%s: no column named %q in header row %q", infile, cmd.chi2CaseControlColumn, tsv)
1046 if len(split) <= ccCol {
1051 for i, name := range cmd.cgnames {
1052 if strings.Contains(name, pattern) {
1054 log.Warnf("pattern %q in %s matches multiple genome IDs (%qs, %q)", pattern, infile, cmd.cgnames[found], name)
1060 log.Warnf("pattern %q in %s does not match any genome IDs", pattern, infile)
1063 if split[ccCol] == "0" {
1066 if split[ccCol] == "1" {
1071 allnames := cmd.cgnames
1075 for i, name := range allnames {
1076 if cc, ok := cc[i]; ok {
1077 cmd.cgnames = append(cmd.cgnames, name)
1078 cmd.chi2Cases = append(cmd.chi2Cases, cc)
1084 log.Printf("%d cases, %d controls, %d neither (dropped)", ncases, len(cmd.cgnames)-ncases, len(allnames)-len(cmd.cgnames))
1088 func (cmd *sliceNumpy) filterHGVScolpair(colpair [2][]int8) bool {
1089 if cmd.chi2PValue >= 1 {
1092 col0 := make([]bool, 0, len(cmd.chi2Cases))
1093 col1 := make([]bool, 0, len(cmd.chi2Cases))
1094 cases := make([]bool, 0, len(cmd.chi2Cases))
1095 for i, c := range cmd.chi2Cases {
1096 if colpair[0][i] < 0 {
1099 col0 = append(col0, colpair[0][i] != 0)
1100 col1 = append(col1, colpair[1][i] != 0)
1101 cases = append(cases, c)
1103 return len(cases) >= cmd.minCoverage &&
1104 (pvalue(col0, cases) <= cmd.chi2PValue || pvalue(col1, cases) <= cmd.chi2PValue)
1107 func writeNumpyUint32(fnm string, out []uint32, rows, cols int) error {
1108 output, err := os.Create(fnm)
1112 defer output.Close()
1113 bufw := bufio.NewWriterSize(output, 1<<26)
1114 npw, err := gonpy.NewWriter(nopCloser{bufw})
1118 log.WithFields(log.Fields{
1122 "bytes": rows * cols * 4,
1123 }).Infof("writing numpy: %s", fnm)
1124 npw.Shape = []int{rows, cols}
1125 npw.WriteUint32(out)
1130 return output.Close()
1133 func writeNumpyInt32(fnm string, out []int32, rows, cols int) error {
1134 output, err := os.Create(fnm)
1138 defer output.Close()
1139 bufw := bufio.NewWriterSize(output, 1<<26)
1140 npw, err := gonpy.NewWriter(nopCloser{bufw})
1144 log.WithFields(log.Fields{
1148 "bytes": rows * cols * 4,
1149 }).Infof("writing numpy: %s", fnm)
1150 npw.Shape = []int{rows, cols}
1156 return output.Close()
1159 func writeNumpyInt16(fnm string, out []int16, rows, cols int) error {
1160 output, err := os.Create(fnm)
1164 defer output.Close()
1165 bufw := bufio.NewWriterSize(output, 1<<26)
1166 npw, err := gonpy.NewWriter(nopCloser{bufw})
1170 log.WithFields(log.Fields{
1174 "bytes": rows * cols * 2,
1175 }).Infof("writing numpy: %s", fnm)
1176 npw.Shape = []int{rows, cols}
1182 return output.Close()
1185 func writeNumpyInt8(fnm string, out []int8, rows, cols int) error {
1186 output, err := os.Create(fnm)
1190 defer output.Close()
1191 bufw := bufio.NewWriterSize(output, 1<<26)
1192 npw, err := gonpy.NewWriter(nopCloser{bufw})
1196 log.WithFields(log.Fields{
1200 "bytes": rows * cols,
1201 }).Infof("writing numpy: %s", fnm)
1202 npw.Shape = []int{rows, cols}
1208 return output.Close()
1211 func allele2homhet(colpair [2][]int8) {
1212 a, b := colpair[0], colpair[1]
1213 for i, av := range a {
1215 if av < 0 || bv < 0 {
1218 } else if av > 0 && bv > 0 {
1221 } else if av > 0 || bv > 0 {
1225 // ref (or a different variant in same position)
1226 // (this is a no-op) a[i], b[i] = 0, 0
1231 type onehotXref struct {
1233 variant tileVariantID
1238 const onehotXrefSize = unsafe.Sizeof(onehotXref{})
1240 // Build onehot matrix (m[tileVariantIndex][genome] == 0 or 1) for all
1241 // variants of a single tile/tag#.
1243 // Return nil if no tile variant passes Χ² filter.
1244 func (cmd *sliceNumpy) tv2homhet(cgs map[string]CompactGenome, maxv tileVariantID, remap []tileVariantID, tag, chunkstarttag tagID) ([][]int8, []onehotXref) {
1245 if tag == cmd.debugTag {
1246 tv := make([]tileVariantID, len(cmd.cgnames)*2)
1247 for i, name := range cmd.cgnames {
1248 copy(tv[i*2:(i+1)*2], cgs[name].Variants[(tag-chunkstarttag)*2:])
1250 log.WithFields(logrus.Fields{
1251 "cgs[i].Variants[tag*2+j]": tv,
1255 "chunkstarttag": chunkstarttag,
1256 }).Info("tv2homhet()")
1258 if maxv < 1 || (maxv < 2 && !cmd.includeVariant1) {
1259 // everyone has the most common variant (of the variants we don't drop)
1262 tagoffset := tag - chunkstarttag
1264 for _, cg := range cgs {
1265 if cg.Variants[tagoffset*2] > 0 && cg.Variants[tagoffset*2+1] > 0 {
1269 if coverage < cmd.minCoverage {
1272 obs := make([][]bool, (maxv+1)*2) // 2 slices (hom + het) for each variant#
1273 for i := range obs {
1274 obs[i] = make([]bool, len(cmd.cgnames))
1276 for cgid, name := range cmd.cgnames {
1277 cgvars := cgs[name].Variants[tagoffset*2:]
1278 tv0, tv1 := remap[cgvars[0]], remap[cgvars[1]]
1279 for v := tileVariantID(1); v <= maxv; v++ {
1280 if tv0 == v && tv1 == v {
1281 obs[v*2][cgid] = true
1282 } else if tv0 == v || tv1 == v {
1283 obs[v*2+1][cgid] = true
1288 var xref []onehotXref
1289 for col := 2; col < len(obs); col++ {
1290 // col 0,1 correspond to tile variant 0, i.e.,
1291 // no-call; col 2,3 correspond to the most common
1292 // variant; so we (normally) start at col 4.
1293 if col < 4 && !cmd.includeVariant1 {
1296 p := pvalue(obs[col], cmd.chi2Cases)
1297 if cmd.chi2PValue < 1 && !(p < cmd.chi2PValue) {
1300 onehot = append(onehot, bool2int8(obs[col]))
1301 xref = append(xref, onehotXref{
1303 variant: tileVariantID(col >> 1),
1311 func bool2int8(in []bool) []int8 {
1312 out := make([]int8, len(in))
1313 for i, v := range in {
1321 // convert a []onehotXref with length N to a numpy-style []int32
1322 // matrix with N columns, one row per field of onehotXref struct.
1324 // Hom/het row contains hom=0, het=1.
1326 // P-value row contains 1000000x actual p-value.
1327 func onehotXref2int32(xrefs []onehotXref) []int32 {
1329 xdata := make([]int32, 4*xcols)
1330 for i, xref := range xrefs {
1331 xdata[i] = int32(xref.tag)
1332 xdata[xcols+i] = int32(xref.variant)
1334 xdata[xcols*2+i] = 1
1336 xdata[xcols*3+i] = int32(xref.pvalue * 1000000)
1341 // transpose onehot data from in[col][row] to numpy-style
1342 // out[row*cols+col].
1343 func onehotcols2int8(in [][]int8) []int8 {
1349 out := make([]int8, rows*cols)
1350 for row := 0; row < rows; row++ {
1351 outrow := out[row*cols:]
1352 for col, incol := range in {
1353 outrow[col] = incol[row]
1359 // Return [2][]uint32{rowIndices, colIndices} indicating which
1360 // elements of matrixT[c][r] have non-zero values.
1361 func onehotChunk2Indirect(matrixT [][]int8) [2][]uint32 {
1363 for c, col := range matrixT {
1364 for r, val := range col {
1366 nz[0] = append(nz[0], uint32(r))
1367 nz[1] = append(nz[1], uint32(c))