slicenumpy.go

   1 // Copyright (C) The Lightning Authors. All rights reserved.
   2 //
   3 // SPDX-License-Identifier: AGPL-3.0
   4
   5 package lightning
   6
   7 import (
   8         "bufio"
   9         "bytes"
  10         "encoding/gob"
  11         "flag"
  12         "fmt"
  13         "io"
  14         "io/ioutil"
  15         "net/http"
  16         _ "net/http/pprof"
  17         "os"
  18         "regexp"
  19         "runtime"
  20         "runtime/debug"
  21         "sort"
  22         "strconv"
  23         "strings"
  24         "sync/atomic"
  25
  26         "git.arvados.org/arvados.git/sdk/go/arvados"
  27         "github.com/arvados/lightning/hgvs"
  28         "github.com/kshedden/gonpy"
  29         log "github.com/sirupsen/logrus"
  30         "golang.org/x/crypto/blake2b"
  31 )
  32
  33 type sliceNumpy struct {
  34         filter  filter
  35         threads int
  36 }
  37
  38 func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, stdout, stderr io.Writer) int {
  39         var err error
  40         defer func() {
  41                 if err != nil {
  42                         fmt.Fprintf(stderr, "%s\n", err)
  43                 }
  44         }()
  45         flags := flag.NewFlagSet("", flag.ContinueOnError)
  46         flags.SetOutput(stderr)
  47         pprof := flags.String("pprof", "", "serve Go profile data at http://`[addr]:port`")
  48         runlocal := flags.Bool("local", false, "run on local host (default: run in an arvados container)")
  49         projectUUID := flags.String("project", "", "project `UUID` for output data")
  50         priority := flags.Int("priority", 500, "container request priority")
  51         inputDir := flags.String("input-dir", "./in", "input `directory`")
  52         outputDir := flags.String("output-dir", "./out", "output `directory`")
  53         ref := flags.String("ref", "", "reference name (if blank, choose last one that appears in input)")
  54         regionsFilename := flags.String("regions", "", "only output columns/annotations that intersect regions in specified bed `file`")
  55         expandRegions := flags.Int("expand-regions", 0, "expand specified regions by `N` base pairs on each side`")
  56         mergeOutput := flags.Bool("merge-output", false, "merge output into one matrix.npy and one matrix.annotations.csv")
  57         hgvsSingle := flags.Bool("single-hgvs-matrix", false, "also generate hgvs-based matrix")
  58         hgvsChunked := flags.Bool("chunked-hgvs-matrix", false, "also generate hgvs-based matrix per chromosome")
  59         flags.IntVar(&cmd.threads, "threads", 16, "number of memory-hungry assembly threads")
  60         cmd.filter.Flags(flags)
  61         err = flags.Parse(args)
  62         if err == flag.ErrHelp {
  63                 err = nil
  64                 return 0
  65         } else if err != nil {
  66                 return 2
  67         }
  68
  69         if *pprof != "" {
  70                 go func() {
  71                         log.Println(http.ListenAndServe(*pprof, nil))
  72                 }()
  73         }
  74
  75         if !*runlocal {
  76                 runner := arvadosContainerRunner{
  77                         Name:        "lightning slice-numpy",
  78                         Client:      arvados.NewClientFromEnv(),
  79                         ProjectUUID: *projectUUID,
  80                         RAM:         750000000000,
  81                         VCPUs:       96,
  82                         Priority:    *priority,
  83                         KeepCache:   2,
  84                         APIAccess:   true,
  85                 }
  86                 err = runner.TranslatePaths(inputDir, regionsFilename)
  87                 if err != nil {
  88                         return 1
  89                 }
  90                 runner.Args = []string{"slice-numpy", "-local=true",
  91                         "-pprof=:6060",
  92                         "-input-dir=" + *inputDir,
  93                         "-output-dir=/mnt/output",
  94                         "-threads=" + fmt.Sprintf("%d", cmd.threads),
  95                         "-regions=" + *regionsFilename,
  96                         "-expand-regions=" + fmt.Sprintf("%d", *expandRegions),
  97                         "-merge-output=" + fmt.Sprintf("%v", *mergeOutput),
  98                         "-single-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsSingle),
  99                         "-chunked-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsChunked),
 100                 }
 101                 runner.Args = append(runner.Args, cmd.filter.Args()...)
 102                 var output string
 103                 output, err = runner.Run()
 104                 if err != nil {
 105                         return 1
 106                 }
 107                 fmt.Fprintln(stdout, output)
 108                 return 0
 109         }
 110
 111         infiles, err := allGobFiles(*inputDir)
 112         if err != nil {
 113                 return 1
 114         }
 115         if len(infiles) == 0 {
 116                 err = fmt.Errorf("no input files found in %s", *inputDir)
 117                 return 1
 118         }
 119         sort.Strings(infiles)
 120
 121         var cgnames []string
 122         var refseq map[string][]tileLibRef
 123         var reftiledata = make(map[tileLibRef][]byte, 11000000)
 124         in0, err := open(infiles[0])
 125         if err != nil {
 126                 return 1
 127         }
 128
 129         matchGenome, err := regexp.Compile(cmd.filter.MatchGenome)
 130         if err != nil {
 131                 err = fmt.Errorf("-match-genome: invalid regexp: %q", cmd.filter.MatchGenome)
 132                 return 1
 133         }
 134
 135         taglen := -1
 136         DecodeLibrary(in0, strings.HasSuffix(infiles[0], ".gz"), func(ent *LibraryEntry) error {
 137                 if len(ent.TagSet) > 0 {
 138                         taglen = len(ent.TagSet[0])
 139                 }
 140                 for _, cseq := range ent.CompactSequences {
 141                         if cseq.Name == *ref || *ref == "" {
 142                                 refseq = cseq.TileSequences
 143                         }
 144                 }
 145                 for _, cg := range ent.CompactGenomes {
 146                         if matchGenome.MatchString(cg.Name) {
 147                                 cgnames = append(cgnames, cg.Name)
 148                         }
 149                 }
 150                 for _, tv := range ent.TileVariants {
 151                         if tv.Ref {
 152                                 reftiledata[tileLibRef{tv.Tag, tv.Variant}] = tv.Sequence
 153                         }
 154                 }
 155                 return nil
 156         })
 157         if err != nil {
 158                 return 1
 159         }
 160         in0.Close()
 161         if refseq == nil {
 162                 err = fmt.Errorf("%s: reference sequence not found", infiles[0])
 163                 return 1
 164         }
 165         if taglen < 0 {
 166                 err = fmt.Errorf("tagset not found")
 167                 return 1
 168         }
 169         if len(cgnames) == 0 {
 170                 err = fmt.Errorf("no genomes found matching regexp %q", cmd.filter.MatchGenome)
 171                 return 1
 172         }
 173         sort.Strings(cgnames)
 174
 175         {
 176                 labelsFilename := *outputDir + "/labels.csv"
 177                 log.Infof("writing labels to %s", labelsFilename)
 178                 var f *os.File
 179                 f, err = os.Create(labelsFilename)
 180                 if err != nil {
 181                         return 1
 182                 }
 183                 defer f.Close()
 184                 for i, name := range cgnames {
 185                         _, err = fmt.Fprintf(f, "%d,%q\n", i, trimFilenameForLabel(name))
 186                         if err != nil {
 187                                 err = fmt.Errorf("write %s: %w", labelsFilename, err)
 188                                 return 1
 189                         }
 190                 }
 191                 err = f.Close()
 192                 if err != nil {
 193                         err = fmt.Errorf("close %s: %w", labelsFilename, err)
 194                         return 1
 195                 }
 196         }
 197
 198         log.Info("indexing reference tiles")
 199         type reftileinfo struct {
 200                 variant  tileVariantID
 201                 seqname  string // chr1
 202                 pos      int    // distance from start of chromosome to starttag
 203                 tiledata []byte // acgtggcaa...
 204         }
 205         isdup := map[tagID]bool{}
 206         reftile := map[tagID]*reftileinfo{}
 207         for seqname, cseq := range refseq {
 208                 pos := 0
 209                 for _, libref := range cseq {
 210                         tiledata := reftiledata[libref]
 211                         if len(tiledata) == 0 {
 212                                 err = fmt.Errorf("missing tiledata for tag %d variant %d in %s in ref", libref.Tag, libref.Variant, seqname)
 213                                 return 1
 214                         }
 215                         if isdup[libref.Tag] {
 216                                 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
 217                         } else if reftile[libref.Tag] != nil {
 218                                 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)
 219                                 delete(reftile, libref.Tag)
 220                                 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
 221                                 isdup[libref.Tag] = true
 222                         } else {
 223                                 reftile[libref.Tag] = &reftileinfo{
 224                                         seqname:  seqname,
 225                                         variant:  libref.Variant,
 226                                         tiledata: tiledata,
 227                                         pos:      pos,
 228                                 }
 229                         }
 230                         pos += len(tiledata) - taglen
 231                 }
 232                 log.Printf("... %s done, len %d", seqname, pos+taglen)
 233         }
 234
 235         var mask *mask
 236         if *regionsFilename != "" {
 237                 log.Printf("loading regions from %s", *regionsFilename)
 238                 mask, err = makeMask(*regionsFilename, *expandRegions)
 239                 if err != nil {
 240                         return 1
 241                 }
 242                 log.Printf("before applying mask, len(reftile) == %d", len(reftile))
 243                 log.Printf("deleting reftile entries for regions outside %d intervals", mask.Len())
 244                 for tag, rt := range reftile {
 245                         if !mask.Check(strings.TrimPrefix(rt.seqname, "chr"), rt.pos, rt.pos+len(rt.tiledata)) {
 246                                 delete(reftile, tag)
 247                         }
 248                 }
 249                 log.Printf("after applying mask, len(reftile) == %d", len(reftile))
 250         }
 251
 252         type hgvsColSet map[hgvs.Variant][2][]int8
 253         encodeHGVS := throttle{Max: len(refseq)}
 254         encodeHGVSTodo := map[string]chan hgvsColSet{}
 255         tmpHGVSCols := map[string]*os.File{}
 256         if *hgvsChunked {
 257                 for seqname := range refseq {
 258                         var f *os.File
 259                         f, err = os.Create(*outputDir + "/tmp." + seqname + ".gob")
 260                         if err != nil {
 261                                 return 1
 262                         }
 263                         defer os.Remove(f.Name())
 264                         bufw := bufio.NewWriterSize(f, 1<<24)
 265                         enc := gob.NewEncoder(bufw)
 266                         tmpHGVSCols[seqname] = f
 267                         todo := make(chan hgvsColSet, 128)
 268                         encodeHGVSTodo[seqname] = todo
 269                         encodeHGVS.Go(func() error {
 270                                 for colset := range todo {
 271                                         err := enc.Encode(colset)
 272                                         if err != nil {
 273                                                 encodeHGVS.Report(err)
 274                                                 for range todo {
 275                                                 }
 276                                                 return err
 277                                         }
 278                                 }
 279                                 return bufw.Flush()
 280                         })
 281                 }
 282         }
 283
 284         var toMerge [][]int16
 285         if *mergeOutput || *hgvsSingle {
 286                 toMerge = make([][]int16, len(infiles))
 287         }
 288
 289         throttleMem := throttle{Max: cmd.threads} // TODO: estimate using mem and data size
 290         throttleNumpyMem := throttle{Max: cmd.threads/2 + 1}
 291         log.Info("generating annotations and numpy matrix for each slice")
 292         var done int64
 293         for infileIdx, infile := range infiles {
 294                 infileIdx, infile := infileIdx, infile
 295                 throttleMem.Go(func() error {
 296                         seq := make(map[tagID][]TileVariant, 50000)
 297                         cgs := make(map[string]CompactGenome, len(cgnames))
 298                         f, err := open(infile)
 299                         if err != nil {
 300                                 return err
 301                         }
 302                         defer f.Close()
 303                         log.Infof("%04d: reading %s", infileIdx, infile)
 304                         err = DecodeLibrary(f, strings.HasSuffix(infile, ".gz"), func(ent *LibraryEntry) error {
 305                                 for _, tv := range ent.TileVariants {
 306                                         if tv.Ref {
 307                                                 continue
 308                                         }
 309                                         if mask != nil && reftile[tv.Tag] == nil {
 310                                                 // Don't waste
 311                                                 // time/memory on
 312                                                 // masked-out tiles.
 313                                                 continue
 314                                         }
 315                                         variants := seq[tv.Tag]
 316                                         if len(variants) == 0 {
 317                                                 variants = make([]TileVariant, 100)
 318                                         }
 319                                         for len(variants) <= int(tv.Variant) {
 320                                                 variants = append(variants, TileVariant{})
 321                                         }
 322                                         variants[int(tv.Variant)] = tv
 323                                         seq[tv.Tag] = variants
 324                                 }
 325                                 for _, cg := range ent.CompactGenomes {
 326                                         if !matchGenome.MatchString(cg.Name) {
 327                                                 continue
 328                                         }
 329                                         // pad to full slice size
 330                                         // to avoid out-of-bounds
 331                                         // checks later
 332                                         if sliceSize := 2 * int(cg.EndTag-cg.StartTag); len(cg.Variants) < sliceSize {
 333                                                 cg.Variants = append(cg.Variants, make([]tileVariantID, sliceSize-len(cg.Variants))...)
 334                                         }
 335                                         cgs[cg.Name] = cg
 336                                 }
 337                                 return nil
 338                         })
 339                         if err != nil {
 340                                 return err
 341                         }
 342                         tagstart := cgs[cgnames[0]].StartTag
 343                         tagend := cgs[cgnames[0]].EndTag
 344
 345                         // TODO: filters
 346
 347                         log.Infof("%04d: renumber/dedup variants for tags %d-%d", infileIdx, tagstart, tagend)
 348                         variantRemap := make([][]tileVariantID, tagend-tagstart)
 349                         throttleCPU := throttle{Max: runtime.GOMAXPROCS(0)}
 350                         for tag, variants := range seq {
 351                                 tag, variants := tag, variants
 352                                 throttleCPU.Acquire()
 353                                 go func() {
 354                                         defer throttleCPU.Release()
 355                                         count := make(map[[blake2b.Size256]byte]int, len(variants))
 356
 357                                         rt := reftile[tag]
 358                                         if rt != nil {
 359                                                 count[blake2b.Sum256(rt.tiledata)] = 0
 360                                         }
 361
 362                                         for _, cg := range cgs {
 363                                                 idx := int(tag-tagstart) * 2
 364                                                 for allele := 0; allele < 2; allele++ {
 365                                                         v := cg.Variants[idx+allele]
 366                                                         if v > 0 && len(variants[v].Sequence) > 0 {
 367                                                                 count[variants[v].Blake2b]++
 368                                                         }
 369                                                 }
 370                                         }
 371                                         // hash[i] will be the hash of
 372                                         // the variant(s) that should
 373                                         // be at rank i (0-based).
 374                                         hash := make([][blake2b.Size256]byte, 0, len(count))
 375                                         for b := range count {
 376                                                 hash = append(hash, b)
 377                                         }
 378                                         sort.Slice(hash, func(i, j int) bool {
 379                                                 bi, bj := &hash[i], &hash[j]
 380                                                 if ci, cj := count[*bi], count[*bj]; ci != cj {
 381                                                         return ci > cj
 382                                                 } else {
 383                                                         return bytes.Compare((*bi)[:], (*bj)[:]) < 0
 384                                                 }
 385                                         })
 386                                         // rank[b] will be the 1-based
 387                                         // new variant number for
 388                                         // variants whose hash is b.
 389                                         rank := make(map[[blake2b.Size256]byte]tileVariantID, len(hash))
 390                                         for i, h := range hash {
 391                                                 rank[h] = tileVariantID(i + 1)
 392                                         }
 393                                         // remap[v] will be the new
 394                                         // variant number for original
 395                                         // variant number v.
 396                                         remap := make([]tileVariantID, len(variants))
 397                                         for i, tv := range variants {
 398                                                 remap[i] = rank[tv.Blake2b]
 399                                         }
 400                                         variantRemap[tag-tagstart] = remap
 401                                         if rt != nil {
 402                                                 rt.variant = rank[blake2b.Sum256(rt.tiledata)]
 403                                         }
 404                                 }()
 405                         }
 406                         throttleCPU.Wait()
 407
 408                         annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, infileIdx)
 409                         log.Infof("%04d: writing %s", infileIdx, annotationsFilename)
 410                         annof, err := os.Create(annotationsFilename)
 411                         if err != nil {
 412                                 return err
 413                         }
 414                         annow := bufio.NewWriterSize(annof, 1<<20)
 415                         outcol := 0
 416                         for tag := tagstart; tag < tagend; tag++ {
 417                                 rt, ok := reftile[tag]
 418                                 if !ok {
 419                                         if mask == nil {
 420                                                 outcol++
 421                                         }
 422                                         // Excluded by specified
 423                                         // regions, or reference does
 424                                         // not use any variant of this
 425                                         // tile. (TODO: log this?
 426                                         // mention it in annotations?)
 427                                         continue
 428                                 }
 429                                 fmt.Fprintf(annow, "%d,%d,%d,=,%s,%d,,,\n", tag, outcol, rt.variant, rt.seqname, rt.pos)
 430                                 variants := seq[tag]
 431                                 reftilestr := strings.ToUpper(string(rt.tiledata))
 432                                 remap := variantRemap[tag-tagstart]
 433                                 maxv := tileVariantID(0)
 434                                 for _, v := range remap {
 435                                         if maxv < v {
 436                                                 maxv = v
 437                                         }
 438                                 }
 439                                 done := make([]bool, maxv+1)
 440                                 variantDiffs := make([][]hgvs.Variant, maxv+1)
 441                                 for v, tv := range variants {
 442                                         v := remap[v]
 443                                         if v == rt.variant || done[v] {
 444                                                 continue
 445                                         } else {
 446                                                 done[v] = true
 447                                         }
 448                                         if len(tv.Sequence) < taglen || !bytes.HasSuffix(rt.tiledata, tv.Sequence[len(tv.Sequence)-taglen:]) {
 449                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 450                                                 continue
 451                                         }
 452                                         if lendiff := len(rt.tiledata) - len(tv.Sequence); lendiff < -1000 || lendiff > 1000 {
 453                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 454                                                 continue
 455                                         }
 456                                         diffs, _ := hgvs.Diff(reftilestr, strings.ToUpper(string(tv.Sequence)), 0)
 457                                         for i := range diffs {
 458                                                 diffs[i].Position += rt.pos
 459                                         }
 460                                         for _, diff := range diffs {
 461                                                 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)
 462                                         }
 463                                         if *hgvsChunked {
 464                                                 variantDiffs[v] = diffs
 465                                         }
 466                                 }
 467                                 if *hgvsChunked {
 468                                         // We can now determine, for each HGVS
 469                                         // variant (diff) in this reftile
 470                                         // region, whether a given genome
 471                                         // phase/allele (1) has the variant, (0) has
 472                                         // =ref or a different variant in that
 473                                         // position, or (-1) is lacking
 474                                         // coverage / couldn't be diffed.
 475                                         hgvsCol := hgvsColSet{}
 476                                         for _, diffs := range variantDiffs {
 477                                                 for _, diff := range diffs {
 478                                                         if _, ok := hgvsCol[diff]; ok {
 479                                                                 continue
 480                                                         }
 481                                                         hgvsCol[diff] = [2][]int8{
 482                                                                 make([]int8, len(cgnames)),
 483                                                                 make([]int8, len(cgnames)),
 484                                                         }
 485                                                 }
 486                                         }
 487                                         for row, name := range cgnames {
 488                                                 variants := cgs[name].Variants[(tag-tagstart)*2:]
 489                                                 for ph := 0; ph < 2; ph++ {
 490                                                         v := variants[ph]
 491                                                         if int(v) >= len(remap) {
 492                                                                 v = 0
 493                                                         } else {
 494                                                                 v = remap[v]
 495                                                         }
 496                                                         if v == rt.variant {
 497                                                                 // hgvsCol[*][ph][row] is already 0
 498                                                         } else if len(variantDiffs[v]) == 0 {
 499                                                                 // lacking coverage / couldn't be diffed
 500                                                                 for _, col := range hgvsCol {
 501                                                                         col[ph][row] = -1
 502                                                                 }
 503                                                         } else {
 504                                                                 for _, diff := range variantDiffs[v] {
 505                                                                         hgvsCol[diff][ph][row] = 1
 506                                                                 }
 507                                                         }
 508                                                 }
 509                                         }
 510                                         encodeHGVSTodo[rt.seqname] <- hgvsCol
 511                                 }
 512                                 outcol++
 513                         }
 514                         err = annow.Flush()
 515                         if err != nil {
 516                                 return err
 517                         }
 518                         err = annof.Close()
 519                         if err != nil {
 520                                 return err
 521                         }
 522
 523                         log.Infof("%04d: preparing numpy", infileIdx)
 524                         throttleNumpyMem.Acquire()
 525                         rows := len(cgnames)
 526                         cols := 2 * outcol
 527                         out := make([]int16, rows*cols)
 528                         for row, name := range cgnames {
 529                                 out := out[row*cols:]
 530                                 outcol := 0
 531                                 for col, v := range cgs[name].Variants {
 532                                         tag := tagstart + tagID(col/2)
 533                                         if mask != nil && reftile[tag] == nil {
 534                                                 continue
 535                                         }
 536                                         if variants, ok := seq[tag]; ok && len(variants) > int(v) && len(variants[v].Sequence) > 0 {
 537                                                 out[outcol] = int16(variantRemap[tag-tagstart][v])
 538                                         } else {
 539                                                 out[outcol] = -1
 540                                         }
 541                                         outcol++
 542                                 }
 543                         }
 544                         seq = nil
 545                         cgs = nil
 546                         debug.FreeOSMemory()
 547                         throttleNumpyMem.Release()
 548
 549                         if *mergeOutput || *hgvsSingle {
 550                                 log.Infof("%04d: matrix fragment %d rows x %d cols", infileIdx, rows, cols)
 551                                 toMerge[infileIdx] = out
 552                         }
 553                         if !*mergeOutput {
 554                                 fnm := fmt.Sprintf("%s/matrix.%04d.npy", *outputDir, infileIdx)
 555                                 err = writeNumpyInt16(fnm, out, rows, cols)
 556                                 if err != nil {
 557                                         return err
 558                                 }
 559                                 debug.FreeOSMemory()
 560                         }
 561                         log.Infof("%s: done (%d/%d)", infile, int(atomic.AddInt64(&done, 1)), len(infiles))
 562                         return nil
 563                 })
 564         }
 565         if err = throttleMem.Wait(); err != nil {
 566                 return 1
 567         }
 568
 569         if *hgvsChunked {
 570                 log.Info("flushing hgvsCols temp files")
 571                 for seqname := range refseq {
 572                         close(encodeHGVSTodo[seqname])
 573                 }
 574                 err = encodeHGVS.Wait()
 575                 if err != nil {
 576                         return 1
 577                 }
 578                 for seqname := range refseq {
 579                         log.Infof("%s: reading hgvsCols from temp file", seqname)
 580                         f := tmpHGVSCols[seqname]
 581                         _, err = f.Seek(0, io.SeekStart)
 582                         if err != nil {
 583                                 return 1
 584                         }
 585                         var hgvsCols hgvsColSet
 586                         dec := gob.NewDecoder(bufio.NewReaderSize(f, 1<<24))
 587                         for err == nil {
 588                                 err = dec.Decode(&hgvsCols)
 589                         }
 590                         if err != io.EOF {
 591                                 return 1
 592                         }
 593                         log.Infof("%s: sorting %d hgvs variants", seqname, len(hgvsCols))
 594                         variants := make([]hgvs.Variant, 0, len(hgvsCols))
 595                         for v := range hgvsCols {
 596                                 variants = append(variants, v)
 597                         }
 598                         sort.Slice(variants, func(i, j int) bool {
 599                                 vi, vj := &variants[i], &variants[j]
 600                                 if vi.Position != vj.Position {
 601                                         return vi.Position < vj.Position
 602                                 } else if vi.Ref != vj.Ref {
 603                                         return vi.Ref < vj.Ref
 604                                 } else {
 605                                         return vi.New < vj.New
 606                                 }
 607                         })
 608                         rows := len(cgnames)
 609                         cols := len(variants) * 2
 610                         log.Infof("%s: building hgvs matrix (rows=%d, cols=%d, mem=%d)", seqname, rows, cols, rows*cols)
 611                         out := make([]int8, rows*cols)
 612                         for varIdx, variant := range variants {
 613                                 hgvsCols := hgvsCols[variant]
 614                                 for row := range cgnames {
 615                                         for ph := 0; ph < 2; ph++ {
 616                                                 out[row*cols+varIdx+ph] = hgvsCols[ph][row]
 617                                         }
 618                                 }
 619                         }
 620                         err = writeNumpyInt8(fmt.Sprintf("%s/hgvs.%s.npy", *outputDir, seqname), out, rows, cols)
 621                         if err != nil {
 622                                 return 1
 623                         }
 624                         out = nil
 625
 626                         fnm := fmt.Sprintf("%s/hgvs.%s.annotations.csv", *outputDir, seqname)
 627                         log.Infof("%s: writing hgvs column labels to %s", seqname, fnm)
 628                         var hgvsLabels bytes.Buffer
 629                         for varIdx, variant := range variants {
 630                                 fmt.Fprintf(&hgvsLabels, "%d,%s:g.%s\n", varIdx, seqname, variant.String())
 631                         }
 632                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0666)
 633                         if err != nil {
 634                                 return 1
 635                         }
 636                 }
 637         }
 638
 639         if *mergeOutput || *hgvsSingle {
 640                 var annow *bufio.Writer
 641                 var annof *os.File
 642                 if *mergeOutput {
 643                         annoFilename := fmt.Sprintf("%s/matrix.annotations.csv", *outputDir)
 644                         annof, err = os.Create(annoFilename)
 645                         if err != nil {
 646                                 return 1
 647                         }
 648                         annow = bufio.NewWriterSize(annof, 1<<20)
 649                 }
 650
 651                 rows := len(cgnames)
 652                 cols := 0
 653                 for _, chunk := range toMerge {
 654                         cols += len(chunk) / rows
 655                 }
 656                 log.Infof("merging output matrix (rows=%d, cols=%d, mem=%d) and annotations", rows, cols, rows*cols*2)
 657                 var out []int16
 658                 if *mergeOutput {
 659                         out = make([]int16, rows*cols)
 660                 }
 661                 hgvsCols := map[string][2][]int16{} // hgvs -> [[g0,g1,g2,...], [g0,g1,g2,...]] (slice of genomes for each phase)
 662                 startcol := 0
 663                 for outIdx, chunk := range toMerge {
 664                         chunkcols := len(chunk) / rows
 665                         if *mergeOutput {
 666                                 for row := 0; row < rows; row++ {
 667                                         copy(out[row*cols+startcol:], chunk[row*chunkcols:(row+1)*chunkcols])
 668                                 }
 669                         }
 670                         toMerge[outIdx] = nil
 671
 672                         annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, outIdx)
 673                         log.Infof("reading %s", annotationsFilename)
 674                         buf, err := os.ReadFile(annotationsFilename)
 675                         if err != nil {
 676                                 return 1
 677                         }
 678                         if *mergeOutput {
 679                                 err = os.Remove(annotationsFilename)
 680                                 if err != nil {
 681                                         return 1
 682                                 }
 683                         }
 684                         for _, line := range bytes.Split(buf, []byte{'\n'}) {
 685                                 if len(line) == 0 {
 686                                         continue
 687                                 }
 688                                 fields := bytes.SplitN(line, []byte{','}, 9)
 689                                 tag, _ := strconv.Atoi(string(fields[0]))
 690                                 incol, _ := strconv.Atoi(string(fields[1]))
 691                                 tileVariant, _ := strconv.Atoi(string(fields[2]))
 692                                 hgvsID := string(fields[3])
 693                                 seqname := string(fields[4])
 694                                 pos, _ := strconv.Atoi(string(fields[5]))
 695                                 refseq := fields[6]
 696                                 if hgvsID == "" {
 697                                         // Null entry for un-diffable
 698                                         // tile variant
 699                                         continue
 700                                 }
 701                                 if hgvsID == "=" {
 702                                         // Null entry for ref tile
 703                                         continue
 704                                 }
 705                                 if mask != nil && !mask.Check(strings.TrimPrefix(seqname, "chr"), pos, pos+len(refseq)) {
 706                                         // The tile intersects one of
 707                                         // the selected regions, but
 708                                         // this particular HGVS
 709                                         // variant does not.
 710                                         continue
 711                                 }
 712                                 hgvsColPair := hgvsCols[hgvsID]
 713                                 if hgvsColPair[0] == nil {
 714                                         // values in new columns start
 715                                         // out as -1 ("no data yet")
 716                                         // or 0 ("=ref") here, may
 717                                         // change to 1 ("hgvs variant
 718                                         // present") below, either on
 719                                         // this line or a future line.
 720                                         hgvsColPair = [2][]int16{make([]int16, len(cgnames)), make([]int16, len(cgnames))}
 721                                         rt, ok := reftile[tagID(tag)]
 722                                         if !ok {
 723                                                 err = fmt.Errorf("bug: seeing annotations for tag %d, but it has no reftile entry", tag)
 724                                                 return 1
 725                                         }
 726                                         for ph := 0; ph < 2; ph++ {
 727                                                 for row := 0; row < rows; row++ {
 728                                                         v := chunk[row*chunkcols+incol*2+ph]
 729                                                         if tileVariantID(v) == rt.variant {
 730                                                                 hgvsColPair[ph][row] = 0
 731                                                         } else {
 732                                                                 hgvsColPair[ph][row] = -1
 733                                                         }
 734                                                 }
 735                                         }
 736                                         hgvsCols[hgvsID] = hgvsColPair
 737                                         if annow != nil {
 738                                                 hgvsref := hgvs.Variant{
 739                                                         Position: pos,
 740                                                         Ref:      string(refseq),
 741                                                         New:      string(refseq),
 742                                                 }
 743                                                 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])
 744                                         }
 745                                 }
 746                                 if annow != nil {
 747                                         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])
 748                                 }
 749                                 for ph := 0; ph < 2; ph++ {
 750                                         for row := 0; row < rows; row++ {
 751                                                 v := chunk[row*chunkcols+incol*2+ph]
 752                                                 if int(v) == tileVariant {
 753                                                         hgvsColPair[ph][row] = 1
 754                                                 }
 755                                         }
 756                                 }
 757                         }
 758
 759                         startcol += chunkcols
 760                 }
 761                 if *mergeOutput {
 762                         err = annow.Flush()
 763                         if err != nil {
 764                                 return 1
 765                         }
 766                         err = annof.Close()
 767                         if err != nil {
 768                                 return 1
 769                         }
 770                         err = writeNumpyInt16(fmt.Sprintf("%s/matrix.npy", *outputDir), out, rows, cols)
 771                         if err != nil {
 772                                 return 1
 773                         }
 774                 }
 775                 out = nil
 776
 777                 if *hgvsSingle {
 778                         cols = len(hgvsCols) * 2
 779                         log.Printf("building hgvs-based matrix: %d rows x %d cols", rows, cols)
 780                         out = make([]int16, rows*cols)
 781                         hgvsIDs := make([]string, 0, cols/2)
 782                         for hgvsID := range hgvsCols {
 783                                 hgvsIDs = append(hgvsIDs, hgvsID)
 784                         }
 785                         sort.Strings(hgvsIDs)
 786                         var hgvsLabels bytes.Buffer
 787                         for idx, hgvsID := range hgvsIDs {
 788                                 fmt.Fprintf(&hgvsLabels, "%d,%s\n", idx, hgvsID)
 789                                 for ph := 0; ph < 2; ph++ {
 790                                         hgvscol := hgvsCols[hgvsID][ph]
 791                                         for row, val := range hgvscol {
 792                                                 out[row*cols+idx*2+ph] = val
 793                                         }
 794                                 }
 795                         }
 796                         err = writeNumpyInt16(fmt.Sprintf("%s/hgvs.npy", *outputDir), out, rows, cols)
 797                         if err != nil {
 798                                 return 1
 799                         }
 800
 801                         fnm := fmt.Sprintf("%s/hgvs.annotations.csv", *outputDir)
 802                         log.Printf("writing hgvs labels: %s", fnm)
 803                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0777)
 804                         if err != nil {
 805                                 return 1
 806                         }
 807                 }
 808         }
 809         return 0
 810 }
 811
 812 func writeNumpyInt16(fnm string, out []int16, rows, cols int) error {
 813         output, err := os.Create(fnm)
 814         if err != nil {
 815                 return err
 816         }
 817         defer output.Close()
 818         bufw := bufio.NewWriterSize(output, 1<<26)
 819         npw, err := gonpy.NewWriter(nopCloser{bufw})
 820         if err != nil {
 821                 return err
 822         }
 823         log.WithFields(log.Fields{
 824                 "filename": fnm,
 825                 "rows":     rows,
 826                 "cols":     cols,
 827         }).Infof("writing numpy: %s", fnm)
 828         npw.Shape = []int{rows, cols}
 829         npw.WriteInt16(out)
 830         err = bufw.Flush()
 831         if err != nil {
 832                 return err
 833         }
 834         return output.Close()
 835 }
 836
 837 func writeNumpyInt8(fnm string, out []int8, rows, cols int) error {
 838         output, err := os.Create(fnm)
 839         if err != nil {
 840                 return err
 841         }
 842         defer output.Close()
 843         bufw := bufio.NewWriterSize(output, 1<<26)
 844         npw, err := gonpy.NewWriter(nopCloser{bufw})
 845         if err != nil {
 846                 return err
 847         }
 848         log.WithFields(log.Fields{
 849                 "filename": fnm,
 850                 "rows":     rows,
 851                 "cols":     cols,
 852         }).Infof("writing numpy: %s", fnm)
 853         npw.Shape = []int{rows, cols}
 854         npw.WriteInt8(out)
 855         err = bufw.Flush()
 856         if err != nil {
 857                 return err
 858         }
 859         return output.Close()
 860 }