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         "errors"
  12         "flag"
  13         "fmt"
  14         "io"
  15         "io/ioutil"
  16         "math"
  17         "net/http"
  18         _ "net/http/pprof"
  19         "os"
  20         "regexp"
  21         "runtime"
  22         "runtime/debug"
  23         "sort"
  24         "strconv"
  25         "strings"
  26         "sync/atomic"
  27         "unsafe"
  28
  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"
  35 )
  36
  37 const annotationMaxTileSpan = 100
  38
  39 type sliceNumpy struct {
  40         filter                filter
  41         threads               int
  42         chi2CaseControlColumn string
  43         chi2CaseControlFile   string
  44         chi2Cases             []bool
  45         chi2PValue            float64
  46         minCoverage           int
  47         cgnames               []string
  48         includeVariant1       bool
  49         debugTag              tagID
  50 }
  51
  52 func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, stdout, stderr io.Writer) int {
  53         var err error
  54         defer func() {
  55                 if err != nil {
  56                         fmt.Fprintf(stderr, "%s\n", err)
  57                 }
  58         }()
  59         flags := flag.NewFlagSet("", flag.ContinueOnError)
  60         flags.SetOutput(stderr)
  61         pprof := flags.String("pprof", "", "serve Go profile data at http://`[addr]:port`")
  62         runlocal := flags.Bool("local", false, "run on local host (default: run in an arvados container)")
  63         projectUUID := flags.String("project", "", "project `UUID` for output data")
  64         priority := flags.Int("priority", 500, "container request priority")
  65         inputDir := flags.String("input-dir", "./in", "input `directory`")
  66         outputDir := flags.String("output-dir", "./out", "output `directory`")
  67         ref := flags.String("ref", "", "reference name (if blank, choose last one that appears in input)")
  68         regionsFilename := flags.String("regions", "", "only output columns/annotations that intersect regions in specified bed `file`")
  69         expandRegions := flags.Int("expand-regions", 0, "expand specified regions by `N` base pairs on each side`")
  70         mergeOutput := flags.Bool("merge-output", false, "merge output into one matrix.npy and one matrix.annotations.csv")
  71         hgvsSingle := flags.Bool("single-hgvs-matrix", false, "also generate hgvs-based matrix")
  72         hgvsChunked := flags.Bool("chunked-hgvs-matrix", false, "also generate hgvs-based matrix per chromosome")
  73         onehotSingle := flags.Bool("single-onehot", false, "generate one-hot tile-based matrix")
  74         onehotChunked := flags.Bool("chunked-onehot", false, "generate one-hot tile-based matrix per input chunk")
  75         onlyPCA := flags.Bool("pca", false, "generate pca matrix")
  76         debugTag := flags.Int("debug-tag", -1, "log debugging details about specified tag")
  77         flags.IntVar(&cmd.threads, "threads", 16, "number of memory-hungry assembly threads")
  78         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)")
  79         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)")
  80         flags.Float64Var(&cmd.chi2PValue, "chi2-p-value", 1, "do Χ² test and omit columns with p-value above this threshold")
  81         flags.BoolVar(&cmd.includeVariant1, "include-variant-1", false, "include most common variant when building one-hot matrix")
  82         cmd.filter.Flags(flags)
  83         err = flags.Parse(args)
  84         if err == flag.ErrHelp {
  85                 err = nil
  86                 return 0
  87         } else if err != nil {
  88                 return 2
  89         }
  90
  91         if *pprof != "" {
  92                 go func() {
  93                         log.Println(http.ListenAndServe(*pprof, nil))
  94                 }()
  95         }
  96
  97         if cmd.chi2PValue != 1 && (cmd.chi2CaseControlFile == "" || cmd.chi2CaseControlColumn == "") {
  98                 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                 return 2
 100         }
 101
 102         cmd.debugTag = tagID(*debugTag)
 103
 104         if !*runlocal {
 105                 runner := arvadosContainerRunner{
 106                         Name:        "lightning slice-numpy",
 107                         Client:      arvados.NewClientFromEnv(),
 108                         ProjectUUID: *projectUUID,
 109                         RAM:         750000000000,
 110                         VCPUs:       96,
 111                         Priority:    *priority,
 112                         KeepCache:   2,
 113                         APIAccess:   true,
 114                 }
 115                 err = runner.TranslatePaths(inputDir, regionsFilename, &cmd.chi2CaseControlFile)
 116                 if err != nil {
 117                         return 1
 118                 }
 119                 runner.Args = []string{"slice-numpy", "-local=true",
 120                         "-pprof=:6060",
 121                         "-input-dir=" + *inputDir,
 122                         "-output-dir=/mnt/output",
 123                         "-threads=" + fmt.Sprintf("%d", cmd.threads),
 124                         "-regions=" + *regionsFilename,
 125                         "-expand-regions=" + fmt.Sprintf("%d", *expandRegions),
 126                         "-merge-output=" + fmt.Sprintf("%v", *mergeOutput),
 127                         "-single-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsSingle),
 128                         "-chunked-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsChunked),
 129                         "-single-onehot=" + fmt.Sprintf("%v", *onehotSingle),
 130                         "-chunked-onehot=" + fmt.Sprintf("%v", *onehotChunked),
 131                         "-pca=" + fmt.Sprintf("%v", *onlyPCA),
 132                         "-chi2-case-control-file=" + cmd.chi2CaseControlFile,
 133                         "-chi2-case-control-column=" + cmd.chi2CaseControlColumn,
 134                         "-chi2-p-value=" + fmt.Sprintf("%f", cmd.chi2PValue),
 135                         "-include-variant-1=" + fmt.Sprintf("%v", cmd.includeVariant1),
 136                         "-debug-tag=" + fmt.Sprintf("%d", cmd.debugTag),
 137                 }
 138                 runner.Args = append(runner.Args, cmd.filter.Args()...)
 139                 var output string
 140                 output, err = runner.Run()
 141                 if err != nil {
 142                         return 1
 143                 }
 144                 fmt.Fprintln(stdout, output)
 145                 return 0
 146         }
 147
 148         infiles, err := allFiles(*inputDir, matchGobFile)
 149         if err != nil {
 150                 return 1
 151         }
 152         if len(infiles) == 0 {
 153                 err = fmt.Errorf("no input files found in %s", *inputDir)
 154                 return 1
 155         }
 156         sort.Strings(infiles)
 157
 158         var refseq map[string][]tileLibRef
 159         var reftiledata = make(map[tileLibRef][]byte, 11000000)
 160         in0, err := open(infiles[0])
 161         if err != nil {
 162                 return 1
 163         }
 164
 165         matchGenome, err := regexp.Compile(cmd.filter.MatchGenome)
 166         if err != nil {
 167                 err = fmt.Errorf("-match-genome: invalid regexp: %q", cmd.filter.MatchGenome)
 168                 return 1
 169         }
 170
 171         cmd.cgnames = nil
 172         var tagset [][]byte
 173         err = DecodeLibrary(in0, strings.HasSuffix(infiles[0], ".gz"), func(ent *LibraryEntry) error {
 174                 if len(ent.TagSet) > 0 {
 175                         tagset = ent.TagSet
 176                 }
 177                 for _, cseq := range ent.CompactSequences {
 178                         if cseq.Name == *ref || *ref == "" {
 179                                 refseq = cseq.TileSequences
 180                         }
 181                 }
 182                 for _, cg := range ent.CompactGenomes {
 183                         if matchGenome.MatchString(cg.Name) {
 184                                 cmd.cgnames = append(cmd.cgnames, cg.Name)
 185                         }
 186                 }
 187                 for _, tv := range ent.TileVariants {
 188                         if tv.Ref {
 189                                 reftiledata[tileLibRef{tv.Tag, tv.Variant}] = tv.Sequence
 190                         }
 191                 }
 192                 return nil
 193         })
 194         if err != nil {
 195                 return 1
 196         }
 197         in0.Close()
 198         if refseq == nil {
 199                 err = fmt.Errorf("%s: reference sequence not found", infiles[0])
 200                 return 1
 201         }
 202         if len(tagset) == 0 {
 203                 err = fmt.Errorf("tagset not found")
 204                 return 1
 205         }
 206
 207         taglib := &tagLibrary{}
 208         err = taglib.setTags(tagset)
 209         if err != nil {
 210                 return 1
 211         }
 212         taglen := taglib.TagLen()
 213
 214         if len(cmd.cgnames) == 0 {
 215                 err = fmt.Errorf("no genomes found matching regexp %q", cmd.filter.MatchGenome)
 216                 return 1
 217         }
 218         sort.Strings(cmd.cgnames)
 219         err = cmd.useCaseControlFiles()
 220         if err != nil {
 221                 return 1
 222         }
 223         if len(cmd.cgnames) == 0 {
 224                 err = fmt.Errorf("fatal: 0 cases, 0 controls, nothing to do")
 225                 return 1
 226         }
 227         if cmd.filter.MinCoverage == 1 {
 228                 // In the generic formula below, floating point
 229                 // arithmetic can effectively push the coverage
 230                 // threshold above 1.0, which is impossible/useless.
 231                 // 1.0 needs to mean exactly 100% coverage.
 232                 cmd.minCoverage = len(cmd.cgnames)
 233         } else {
 234                 cmd.minCoverage = int(math.Ceil(cmd.filter.MinCoverage * float64(len(cmd.cgnames))))
 235         }
 236
 237         {
 238                 labelsFilename := *outputDir + "/samples.csv"
 239                 log.Infof("writing labels to %s", labelsFilename)
 240                 var f *os.File
 241                 f, err = os.Create(labelsFilename)
 242                 if err != nil {
 243                         return 1
 244                 }
 245                 defer f.Close()
 246                 for i, name := range cmd.cgnames {
 247                         cc := 0
 248                         if cmd.chi2Cases != nil && cmd.chi2Cases[i] {
 249                                 cc = 1
 250                         }
 251                         _, err = fmt.Fprintf(f, "%d,%q,%d\n", i, trimFilenameForLabel(name), cc)
 252                         if err != nil {
 253                                 err = fmt.Errorf("write %s: %w", labelsFilename, err)
 254                                 return 1
 255                         }
 256                 }
 257                 err = f.Close()
 258                 if err != nil {
 259                         err = fmt.Errorf("close %s: %w", labelsFilename, err)
 260                         return 1
 261                 }
 262         }
 263
 264         log.Info("indexing reference tiles")
 265         type reftileinfo struct {
 266                 variant  tileVariantID
 267                 seqname  string // chr1
 268                 pos      int    // distance from start of chromosome to starttag
 269                 tiledata []byte // acgtggcaa...
 270                 excluded bool   // true if excluded by regions file
 271                 nexttag  tagID  // tagID of following tile (-1 for last tag of chromosome)
 272         }
 273         isdup := map[tagID]bool{}
 274         reftile := map[tagID]*reftileinfo{}
 275         for seqname, cseq := range refseq {
 276                 pos := 0
 277                 lastreftag := tagID(-1)
 278                 for _, libref := range cseq {
 279                         if cmd.filter.MaxTag >= 0 && libref.Tag > tagID(cmd.filter.MaxTag) {
 280                                 continue
 281                         }
 282                         tiledata := reftiledata[libref]
 283                         if len(tiledata) == 0 {
 284                                 err = fmt.Errorf("missing tiledata for tag %d variant %d in %s in ref", libref.Tag, libref.Variant, seqname)
 285                                 return 1
 286                         }
 287                         foundthistag := false
 288                         taglib.FindAll(tiledata[:len(tiledata)-1], func(tagid tagID, offset, _ int) {
 289                                 if !foundthistag && tagid == libref.Tag {
 290                                         foundthistag = true
 291                                         return
 292                                 }
 293                                 if dupref, ok := reftile[tagid]; ok {
 294                                         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)
 295                                         delete(reftile, tagid)
 296                                 } else {
 297                                         log.Printf("found tag %d at offset %d inside tile variant %+v on %s @ %d", tagid, offset, libref, seqname, pos+offset+1)
 298                                 }
 299                                 isdup[tagid] = true
 300                         })
 301                         if isdup[libref.Tag] {
 302                                 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
 303                         } else if reftile[libref.Tag] != nil {
 304                                 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)
 305                                 delete(reftile, libref.Tag)
 306                                 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
 307                                 isdup[libref.Tag] = true
 308                         } else {
 309                                 reftile[libref.Tag] = &reftileinfo{
 310                                         seqname:  seqname,
 311                                         variant:  libref.Variant,
 312                                         tiledata: tiledata,
 313                                         pos:      pos,
 314                                         nexttag:  -1,
 315                                 }
 316                                 if lastreftag >= 0 {
 317                                         reftile[lastreftag].nexttag = libref.Tag
 318                                 }
 319                                 lastreftag = libref.Tag
 320                         }
 321                         pos += len(tiledata) - taglen
 322                 }
 323                 log.Printf("... %s done, len %d", seqname, pos+taglen)
 324         }
 325
 326         var mask *mask
 327         if *regionsFilename != "" {
 328                 log.Printf("loading regions from %s", *regionsFilename)
 329                 mask, err = makeMask(*regionsFilename, *expandRegions)
 330                 if err != nil {
 331                         return 1
 332                 }
 333                 log.Printf("before applying mask, len(reftile) == %d", len(reftile))
 334                 log.Printf("deleting reftile entries for regions outside %d intervals", mask.Len())
 335                 for _, rt := range reftile {
 336                         if !mask.Check(strings.TrimPrefix(rt.seqname, "chr"), rt.pos, rt.pos+len(rt.tiledata)) {
 337                                 rt.excluded = true
 338                         }
 339                 }
 340                 log.Printf("after applying mask, len(reftile) == %d", len(reftile))
 341         }
 342
 343         type hgvsColSet map[hgvs.Variant][2][]int8
 344         encodeHGVS := throttle{Max: len(refseq)}
 345         encodeHGVSTodo := map[string]chan hgvsColSet{}
 346         tmpHGVSCols := map[string]*os.File{}
 347         if *hgvsChunked {
 348                 for seqname := range refseq {
 349                         var f *os.File
 350                         f, err = os.Create(*outputDir + "/tmp." + seqname + ".gob")
 351                         if err != nil {
 352                                 return 1
 353                         }
 354                         defer os.Remove(f.Name())
 355                         bufw := bufio.NewWriterSize(f, 1<<24)
 356                         enc := gob.NewEncoder(bufw)
 357                         tmpHGVSCols[seqname] = f
 358                         todo := make(chan hgvsColSet, 128)
 359                         encodeHGVSTodo[seqname] = todo
 360                         encodeHGVS.Go(func() error {
 361                                 for colset := range todo {
 362                                         err := enc.Encode(colset)
 363                                         if err != nil {
 364                                                 encodeHGVS.Report(err)
 365                                                 for range todo {
 366                                                 }
 367                                                 return err
 368                                         }
 369                                 }
 370                                 return bufw.Flush()
 371                         })
 372                 }
 373         }
 374
 375         var toMerge [][]int16
 376         if *mergeOutput || *hgvsSingle {
 377                 toMerge = make([][]int16, len(infiles))
 378         }
 379         var onehotIndirect [][2][]uint32 // [chunkIndex][axis][index]
 380         var onehotChunkSize []uint32
 381         var onehotXrefs [][]onehotXref
 382         if *onehotSingle || *onlyPCA {
 383                 onehotIndirect = make([][2][]uint32, len(infiles))
 384                 onehotChunkSize = make([]uint32, len(infiles))
 385                 onehotXrefs = make([][]onehotXref, len(infiles))
 386         }
 387         chunkStartTag := make([]tagID, len(infiles))
 388
 389         throttleMem := throttle{Max: cmd.threads} // TODO: estimate using mem and data size
 390         throttleNumpyMem := throttle{Max: cmd.threads/2 + 1}
 391         log.Info("generating annotations and numpy matrix for each slice")
 392         var errSkip = errors.New("skip infile")
 393         var done int64
 394         for infileIdx, infile := range infiles {
 395                 infileIdx, infile := infileIdx, infile
 396                 throttleMem.Go(func() error {
 397                         seq := make(map[tagID][]TileVariant, 50000)
 398                         cgs := make(map[string]CompactGenome, len(cmd.cgnames))
 399                         f, err := open(infile)
 400                         if err != nil {
 401                                 return err
 402                         }
 403                         defer f.Close()
 404                         log.Infof("%04d: reading %s", infileIdx, infile)
 405                         err = DecodeLibrary(f, strings.HasSuffix(infile, ".gz"), func(ent *LibraryEntry) error {
 406                                 for _, tv := range ent.TileVariants {
 407                                         if tv.Ref {
 408                                                 continue
 409                                         }
 410                                         // Skip tile with no
 411                                         // corresponding ref tile, if
 412                                         // mask is in play (we can't
 413                                         // determine coordinates for
 414                                         // these)
 415                                         if mask != nil && reftile[tv.Tag] == nil {
 416                                                 continue
 417                                         }
 418                                         // Skip tile whose
 419                                         // corresponding ref tile is
 420                                         // outside target regions --
 421                                         // unless it's a potential
 422                                         // spanning tile.
 423                                         if mask != nil && reftile[tv.Tag].excluded &&
 424                                                 (int(tv.Tag+1) >= len(tagset) ||
 425                                                         (bytes.HasSuffix(tv.Sequence, tagset[tv.Tag+1]) && reftile[tv.Tag+1] != nil && !reftile[tv.Tag+1].excluded)) {
 426                                                 continue
 427                                         }
 428                                         if tv.Tag == cmd.debugTag {
 429                                                 log.Printf("infile %d %s tag %d variant %d hash %x", infileIdx, infile, tv.Tag, tv.Variant, tv.Blake2b[:3])
 430                                         }
 431                                         variants := seq[tv.Tag]
 432                                         if len(variants) == 0 {
 433                                                 variants = make([]TileVariant, 100)
 434                                         }
 435                                         for len(variants) <= int(tv.Variant) {
 436                                                 variants = append(variants, TileVariant{})
 437                                         }
 438                                         variants[int(tv.Variant)] = tv
 439                                         seq[tv.Tag] = variants
 440                                 }
 441                                 for _, cg := range ent.CompactGenomes {
 442                                         if cmd.filter.MaxTag >= 0 && cg.StartTag > tagID(cmd.filter.MaxTag) {
 443                                                 return errSkip
 444                                         }
 445                                         if !matchGenome.MatchString(cg.Name) {
 446                                                 continue
 447                                         }
 448                                         // pad to full slice size
 449                                         // to avoid out-of-bounds
 450                                         // checks later
 451                                         if sliceSize := 2 * int(cg.EndTag-cg.StartTag); len(cg.Variants) < sliceSize {
 452                                                 cg.Variants = append(cg.Variants, make([]tileVariantID, sliceSize-len(cg.Variants))...)
 453                                         }
 454                                         cgs[cg.Name] = cg
 455                                 }
 456                                 return nil
 457                         })
 458                         if err == errSkip {
 459                                 return nil
 460                         } else if err != nil {
 461                                 return fmt.Errorf("%04d: DecodeLibrary(%s): err", infileIdx, infile)
 462                         }
 463                         tagstart := cgs[cmd.cgnames[0]].StartTag
 464                         tagend := cgs[cmd.cgnames[0]].EndTag
 465                         chunkStartTag[infileIdx] = tagstart
 466
 467                         // TODO: filters
 468
 469                         log.Infof("%04d: renumber/dedup variants for tags %d-%d", infileIdx, tagstart, tagend)
 470                         variantRemap := make([][]tileVariantID, tagend-tagstart)
 471                         throttleCPU := throttle{Max: runtime.GOMAXPROCS(0)}
 472                         for tag, variants := range seq {
 473                                 tag, variants := tag, variants
 474                                 throttleCPU.Go(func() error {
 475                                         alleleCoverage := 0
 476                                         count := make(map[[blake2b.Size256]byte]int, len(variants))
 477
 478                                         rt := reftile[tag]
 479                                         if rt != nil {
 480                                                 count[blake2b.Sum256(rt.tiledata)] = 0
 481                                         }
 482
 483                                         for cgname, cg := range cgs {
 484                                                 idx := int(tag-tagstart) * 2
 485                                                 for allele := 0; allele < 2; allele++ {
 486                                                         v := cg.Variants[idx+allele]
 487                                                         if v > 0 && len(variants[v].Sequence) > 0 {
 488                                                                 count[variants[v].Blake2b]++
 489                                                                 alleleCoverage++
 490                                                         }
 491                                                         if v > 0 && tag == cmd.debugTag {
 492                                                                 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])
 493                                                         }
 494                                                 }
 495                                         }
 496                                         if alleleCoverage < cmd.minCoverage*2 {
 497                                                 idx := int(tag-tagstart) * 2
 498                                                 for _, cg := range cgs {
 499                                                         cg.Variants[idx] = 0
 500                                                         cg.Variants[idx+1] = 0
 501                                                 }
 502                                                 if tag == cmd.debugTag {
 503                                                         log.Printf("tag %d alleleCoverage %d < min %d, sample data wiped", tag, alleleCoverage, cmd.minCoverage*2)
 504                                                 }
 505                                                 return nil
 506                                         }
 507
 508                                         // hash[i] will be the hash of
 509                                         // the variant(s) that should
 510                                         // be at rank i (0-based).
 511                                         hash := make([][blake2b.Size256]byte, 0, len(count))
 512                                         for b := range count {
 513                                                 hash = append(hash, b)
 514                                         }
 515                                         sort.Slice(hash, func(i, j int) bool {
 516                                                 bi, bj := &hash[i], &hash[j]
 517                                                 if ci, cj := count[*bi], count[*bj]; ci != cj {
 518                                                         return ci > cj
 519                                                 } else {
 520                                                         return bytes.Compare((*bi)[:], (*bj)[:]) < 0
 521                                                 }
 522                                         })
 523                                         // rank[b] will be the 1-based
 524                                         // new variant number for
 525                                         // variants whose hash is b.
 526                                         rank := make(map[[blake2b.Size256]byte]tileVariantID, len(hash))
 527                                         for i, h := range hash {
 528                                                 rank[h] = tileVariantID(i + 1)
 529                                         }
 530                                         if tag == cmd.debugTag {
 531                                                 for h, r := range rank {
 532                                                         log.Printf("tag %d rank(%x) = %v", tag, h[:3], r)
 533                                                 }
 534                                         }
 535                                         // remap[v] will be the new
 536                                         // variant number for original
 537                                         // variant number v.
 538                                         remap := make([]tileVariantID, len(variants))
 539                                         for i, tv := range variants {
 540                                                 remap[i] = rank[tv.Blake2b]
 541                                         }
 542                                         if tag == cmd.debugTag {
 543                                                 for in, out := range remap {
 544                                                         if out > 0 {
 545                                                                 log.Printf("tag %d remap %d => %d", tag, in, out)
 546                                                         }
 547                                                 }
 548                                         }
 549                                         variantRemap[tag-tagstart] = remap
 550                                         if rt != nil {
 551                                                 refrank := rank[blake2b.Sum256(rt.tiledata)]
 552                                                 if tag == cmd.debugTag {
 553                                                         log.Printf("tag %d reftile variant %d => %d", tag, rt.variant, refrank)
 554                                                 }
 555                                                 rt.variant = refrank
 556                                         }
 557                                         return nil
 558                                 })
 559                         }
 560                         throttleCPU.Wait()
 561
 562                         var onehotChunk [][]int8
 563                         var onehotXref []onehotXref
 564
 565                         var annotationsFilename string
 566                         if *onlyPCA {
 567                                 annotationsFilename = "/dev/null"
 568                         } else {
 569                                 annotationsFilename = fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, infileIdx)
 570                                 log.Infof("%04d: writing %s", infileIdx, annotationsFilename)
 571                         }
 572                         annof, err := os.Create(annotationsFilename)
 573                         if err != nil {
 574                                 return err
 575                         }
 576                         annow := bufio.NewWriterSize(annof, 1<<20)
 577                         outcol := 0
 578                         for tag := tagstart; tag < tagend; tag++ {
 579                                 rt := reftile[tag]
 580                                 if rt == nil && mask != nil {
 581                                         // With no ref tile, we don't
 582                                         // have coordinates to say
 583                                         // this is in the desired
 584                                         // regions -- so it's not.
 585                                         // TODO: handle ref spanning
 586                                         // tile case.
 587                                         continue
 588                                 }
 589                                 if rt != nil && rt.excluded {
 590                                         // TODO: don't skip yet --
 591                                         // first check for spanning
 592                                         // tile variants that
 593                                         // intersect non-excluded ref
 594                                         // tiles.
 595                                         continue
 596                                 }
 597                                 if cmd.filter.MaxTag >= 0 && tag > tagID(cmd.filter.MaxTag) {
 598                                         break
 599                                 }
 600                                 remap := variantRemap[tag-tagstart]
 601                                 maxv := tileVariantID(0)
 602                                 for _, v := range remap {
 603                                         if maxv < v {
 604                                                 maxv = v
 605                                         }
 606                                 }
 607                                 if *onehotChunked || *onehotSingle || *onlyPCA {
 608                                         onehot, xrefs := cmd.tv2homhet(cgs, maxv, remap, tag, tagstart, seq)
 609                                         if tag == cmd.debugTag {
 610                                                 log.WithFields(logrus.Fields{
 611                                                         "onehot": onehot,
 612                                                         "xrefs":  xrefs,
 613                                                 }).Info("tv2homhet()")
 614                                         }
 615                                         onehotChunk = append(onehotChunk, onehot...)
 616                                         onehotXref = append(onehotXref, xrefs...)
 617                                 }
 618                                 if *onlyPCA {
 619                                         outcol++
 620                                         continue
 621                                 }
 622                                 if rt == nil {
 623                                         // Reference does not use any
 624                                         // variant of this tile
 625                                         //
 626                                         // TODO: diff against the
 627                                         // relevant portion of the
 628                                         // ref's spanning tile
 629                                         outcol++
 630                                         continue
 631                                 }
 632                                 fmt.Fprintf(annow, "%d,%d,%d,=,%s,%d,,,\n", tag, outcol, rt.variant, rt.seqname, rt.pos)
 633                                 variants := seq[tag]
 634                                 reftilestr := strings.ToUpper(string(rt.tiledata))
 635
 636                                 done := make([]bool, maxv+1)
 637                                 variantDiffs := make([][]hgvs.Variant, maxv+1)
 638                                 for v, tv := range variants {
 639                                         v := remap[v]
 640                                         if v == 0 || v == rt.variant || done[v] {
 641                                                 continue
 642                                         } else {
 643                                                 done[v] = true
 644                                         }
 645                                         if len(tv.Sequence) < taglen {
 646                                                 continue
 647                                         }
 648                                         // if reftilestr doesn't end
 649                                         // in the same tag as tv,
 650                                         // extend reftilestr with
 651                                         // following ref tiles until
 652                                         // it does (up to an arbitrary
 653                                         // sanity-check limit)
 654                                         reftilestr := reftilestr
 655                                         endtagstr := strings.ToUpper(string(tv.Sequence[len(tv.Sequence)-taglen:]))
 656                                         for i, rt := 0, rt; i < annotationMaxTileSpan && !strings.HasSuffix(reftilestr, endtagstr) && rt.nexttag >= 0; i++ {
 657                                                 rt = reftile[rt.nexttag]
 658                                                 if rt == nil {
 659                                                         break
 660                                                 }
 661                                                 reftilestr += strings.ToUpper(string(rt.tiledata[taglen:]))
 662                                         }
 663                                         if mask != nil && !mask.Check(strings.TrimPrefix(rt.seqname, "chr"), rt.pos, rt.pos+len(reftilestr)) {
 664                                                 continue
 665                                         }
 666                                         if !strings.HasSuffix(reftilestr, endtagstr) {
 667                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 668                                                 continue
 669                                         }
 670                                         if lendiff := len(reftilestr) - len(tv.Sequence); lendiff < -1000 || lendiff > 1000 {
 671                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 672                                                 continue
 673                                         }
 674                                         diffs, _ := hgvs.Diff(reftilestr, strings.ToUpper(string(tv.Sequence)), 0)
 675                                         for i := range diffs {
 676                                                 diffs[i].Position += rt.pos
 677                                         }
 678                                         for _, diff := range diffs {
 679                                                 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)
 680                                         }
 681                                         if *hgvsChunked {
 682                                                 variantDiffs[v] = diffs
 683                                         }
 684                                 }
 685                                 if *hgvsChunked {
 686                                         // We can now determine, for each HGVS
 687                                         // variant (diff) in this reftile
 688                                         // region, whether a given genome
 689                                         // phase/allele (1) has the variant, (0) has
 690                                         // =ref or a different variant in that
 691                                         // position, or (-1) is lacking
 692                                         // coverage / couldn't be diffed.
 693                                         hgvsCol := hgvsColSet{}
 694                                         for _, diffs := range variantDiffs {
 695                                                 for _, diff := range diffs {
 696                                                         if _, ok := hgvsCol[diff]; ok {
 697                                                                 continue
 698                                                         }
 699                                                         hgvsCol[diff] = [2][]int8{
 700                                                                 make([]int8, len(cmd.cgnames)),
 701                                                                 make([]int8, len(cmd.cgnames)),
 702                                                         }
 703                                                 }
 704                                         }
 705                                         for row, name := range cmd.cgnames {
 706                                                 variants := cgs[name].Variants[(tag-tagstart)*2:]
 707                                                 for ph := 0; ph < 2; ph++ {
 708                                                         v := variants[ph]
 709                                                         if int(v) >= len(remap) {
 710                                                                 v = 0
 711                                                         } else {
 712                                                                 v = remap[v]
 713                                                         }
 714                                                         if v == rt.variant {
 715                                                                 // hgvsCol[*][ph][row] is already 0
 716                                                         } else if len(variantDiffs[v]) == 0 {
 717                                                                 // lacking coverage / couldn't be diffed
 718                                                                 for _, col := range hgvsCol {
 719                                                                         col[ph][row] = -1
 720                                                                 }
 721                                                         } else {
 722                                                                 for _, diff := range variantDiffs[v] {
 723                                                                         hgvsCol[diff][ph][row] = 1
 724                                                                 }
 725                                                         }
 726                                                 }
 727                                         }
 728                                         for diff, colpair := range hgvsCol {
 729                                                 allele2homhet(colpair)
 730                                                 if !cmd.filterHGVScolpair(colpair) {
 731                                                         delete(hgvsCol, diff)
 732                                                 }
 733                                         }
 734                                         if len(hgvsCol) > 0 {
 735                                                 encodeHGVSTodo[rt.seqname] <- hgvsCol
 736                                         }
 737                                 }
 738                                 outcol++
 739                         }
 740                         err = annow.Flush()
 741                         if err != nil {
 742                                 return err
 743                         }
 744                         err = annof.Close()
 745                         if err != nil {
 746                                 return err
 747                         }
 748
 749                         if *onehotChunked {
 750                                 // transpose onehotChunk[col][row] to numpy[row*ncols+col]
 751                                 rows := len(cmd.cgnames)
 752                                 cols := len(onehotChunk)
 753                                 log.Infof("%04d: preparing onehot numpy (rows=%d, cols=%d, mem=%d)", infileIdx, rows, cols, rows*cols)
 754                                 throttleNumpyMem.Acquire()
 755                                 out := onehotcols2int8(onehotChunk)
 756                                 fnm := fmt.Sprintf("%s/onehot.%04d.npy", *outputDir, infileIdx)
 757                                 err = writeNumpyInt8(fnm, out, rows, cols)
 758                                 if err != nil {
 759                                         return err
 760                                 }
 761                                 fnm = fmt.Sprintf("%s/onehot-columns.%04d.npy", *outputDir, infileIdx)
 762                                 err = writeNumpyInt32(fnm, onehotXref2int32(onehotXref), 4, len(onehotXref))
 763                                 if err != nil {
 764                                         return err
 765                                 }
 766                                 debug.FreeOSMemory()
 767                                 throttleNumpyMem.Release()
 768                         }
 769                         if *onehotSingle || *onlyPCA {
 770                                 onehotIndirect[infileIdx] = onehotChunk2Indirect(onehotChunk)
 771                                 onehotChunkSize[infileIdx] = uint32(len(onehotChunk))
 772                                 onehotXrefs[infileIdx] = onehotXref
 773                                 n := len(onehotIndirect[infileIdx][0])
 774                                 log.Infof("%04d: keeping onehot coordinates in memory (n=%d, mem=%d)", infileIdx, n, n*8*2)
 775                         }
 776                         if !(*onehotSingle || *onehotChunked || *onlyPCA) || *mergeOutput || *hgvsSingle {
 777                                 log.Infof("%04d: preparing numpy (rows=%d, cols=%d)", infileIdx, len(cmd.cgnames), 2*outcol)
 778                                 throttleNumpyMem.Acquire()
 779                                 rows := len(cmd.cgnames)
 780                                 cols := 2 * outcol
 781                                 out := make([]int16, rows*cols)
 782                                 for row, name := range cmd.cgnames {
 783                                         outidx := row * cols
 784                                         for col, v := range cgs[name].Variants {
 785                                                 tag := tagstart + tagID(col/2)
 786                                                 if cmd.filter.MaxTag >= 0 && tag > tagID(cmd.filter.MaxTag) {
 787                                                         break
 788                                                 }
 789                                                 if rt := reftile[tag]; rt == nil || rt.excluded {
 790                                                         continue
 791                                                 }
 792                                                 if v == 0 {
 793                                                         out[outidx] = 0 // tag not found / spanning tile
 794                                                 } else if variants, ok := seq[tag]; ok && int(v) < len(variants) && len(variants[v].Sequence) > 0 {
 795                                                         out[outidx] = int16(variantRemap[tag-tagstart][v])
 796                                                 } else {
 797                                                         out[outidx] = -1 // low quality tile variant
 798                                                 }
 799                                                 if tag == cmd.debugTag {
 800                                                         log.Printf("tag %d row %d col %d outidx %d v %d out %d", tag, row, col, outidx, v, out[outidx])
 801                                                 }
 802                                                 outidx++
 803                                         }
 804                                 }
 805                                 seq = nil
 806                                 cgs = nil
 807                                 debug.FreeOSMemory()
 808                                 throttleNumpyMem.Release()
 809                                 if *mergeOutput || *hgvsSingle {
 810                                         log.Infof("%04d: matrix fragment %d rows x %d cols", infileIdx, rows, cols)
 811                                         toMerge[infileIdx] = out
 812                                 }
 813                                 if !*mergeOutput && !*onehotChunked && !*onehotSingle {
 814                                         fnm := fmt.Sprintf("%s/matrix.%04d.npy", *outputDir, infileIdx)
 815                                         err = writeNumpyInt16(fnm, out, rows, cols)
 816                                         if err != nil {
 817                                                 return err
 818                                         }
 819                                 }
 820                         }
 821                         debug.FreeOSMemory()
 822                         log.Infof("%s: done (%d/%d)", infile, int(atomic.AddInt64(&done, 1)), len(infiles))
 823                         return nil
 824                 })
 825         }
 826         if err = throttleMem.Wait(); err != nil {
 827                 return 1
 828         }
 829
 830         if *hgvsChunked {
 831                 log.Info("flushing hgvsCols temp files")
 832                 for seqname := range refseq {
 833                         close(encodeHGVSTodo[seqname])
 834                 }
 835                 err = encodeHGVS.Wait()
 836                 if err != nil {
 837                         return 1
 838                 }
 839                 for seqname := range refseq {
 840                         log.Infof("%s: reading hgvsCols from temp file", seqname)
 841                         f := tmpHGVSCols[seqname]
 842                         _, err = f.Seek(0, io.SeekStart)
 843                         if err != nil {
 844                                 return 1
 845                         }
 846                         var hgvsCols hgvsColSet
 847                         dec := gob.NewDecoder(bufio.NewReaderSize(f, 1<<24))
 848                         for err == nil {
 849                                 err = dec.Decode(&hgvsCols)
 850                         }
 851                         if err != io.EOF {
 852                                 return 1
 853                         }
 854                         log.Infof("%s: sorting %d hgvs variants", seqname, len(hgvsCols))
 855                         variants := make([]hgvs.Variant, 0, len(hgvsCols))
 856                         for v := range hgvsCols {
 857                                 variants = append(variants, v)
 858                         }
 859                         sort.Slice(variants, func(i, j int) bool {
 860                                 vi, vj := &variants[i], &variants[j]
 861                                 if vi.Position != vj.Position {
 862                                         return vi.Position < vj.Position
 863                                 } else if vi.Ref != vj.Ref {
 864                                         return vi.Ref < vj.Ref
 865                                 } else {
 866                                         return vi.New < vj.New
 867                                 }
 868                         })
 869                         rows := len(cmd.cgnames)
 870                         cols := len(variants) * 2
 871                         log.Infof("%s: building hgvs matrix (rows=%d, cols=%d, mem=%d)", seqname, rows, cols, rows*cols)
 872                         out := make([]int8, rows*cols)
 873                         for varIdx, variant := range variants {
 874                                 hgvsCols := hgvsCols[variant]
 875                                 for row := range cmd.cgnames {
 876                                         for ph := 0; ph < 2; ph++ {
 877                                                 out[row*cols+varIdx+ph] = hgvsCols[ph][row]
 878                                         }
 879                                 }
 880                         }
 881                         err = writeNumpyInt8(fmt.Sprintf("%s/hgvs.%s.npy", *outputDir, seqname), out, rows, cols)
 882                         if err != nil {
 883                                 return 1
 884                         }
 885                         out = nil
 886
 887                         fnm := fmt.Sprintf("%s/hgvs.%s.annotations.csv", *outputDir, seqname)
 888                         log.Infof("%s: writing hgvs column labels to %s", seqname, fnm)
 889                         var hgvsLabels bytes.Buffer
 890                         for varIdx, variant := range variants {
 891                                 fmt.Fprintf(&hgvsLabels, "%d,%s:g.%s\n", varIdx, seqname, variant.String())
 892                         }
 893                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0666)
 894                         if err != nil {
 895                                 return 1
 896                         }
 897                 }
 898         }
 899
 900         if *mergeOutput || *hgvsSingle {
 901                 var annow *bufio.Writer
 902                 var annof *os.File
 903                 if *mergeOutput {
 904                         annoFilename := fmt.Sprintf("%s/matrix.annotations.csv", *outputDir)
 905                         annof, err = os.Create(annoFilename)
 906                         if err != nil {
 907                                 return 1
 908                         }
 909                         annow = bufio.NewWriterSize(annof, 1<<20)
 910                 }
 911
 912                 rows := len(cmd.cgnames)
 913                 cols := 0
 914                 for _, chunk := range toMerge {
 915                         cols += len(chunk) / rows
 916                 }
 917                 log.Infof("merging output matrix (rows=%d, cols=%d, mem=%d) and annotations", rows, cols, rows*cols*2)
 918                 var out []int16
 919                 if *mergeOutput {
 920                         out = make([]int16, rows*cols)
 921                 }
 922                 hgvsCols := map[string][2][]int16{} // hgvs -> [[g0,g1,g2,...], [g0,g1,g2,...]] (slice of genomes for each phase)
 923                 startcol := 0
 924                 for outIdx, chunk := range toMerge {
 925                         chunkcols := len(chunk) / rows
 926                         if *mergeOutput {
 927                                 for row := 0; row < rows; row++ {
 928                                         copy(out[row*cols+startcol:], chunk[row*chunkcols:(row+1)*chunkcols])
 929                                 }
 930                         }
 931                         toMerge[outIdx] = nil
 932
 933                         annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, outIdx)
 934                         log.Infof("reading %s", annotationsFilename)
 935                         buf, err := os.ReadFile(annotationsFilename)
 936                         if err != nil {
 937                                 return 1
 938                         }
 939                         if *mergeOutput {
 940                                 err = os.Remove(annotationsFilename)
 941                                 if err != nil {
 942                                         return 1
 943                                 }
 944                         }
 945                         for _, line := range bytes.Split(buf, []byte{'\n'}) {
 946                                 if len(line) == 0 {
 947                                         continue
 948                                 }
 949                                 fields := bytes.SplitN(line, []byte{','}, 9)
 950                                 tag, _ := strconv.Atoi(string(fields[0]))
 951                                 incol, _ := strconv.Atoi(string(fields[1]))
 952                                 tileVariant, _ := strconv.Atoi(string(fields[2]))
 953                                 hgvsID := string(fields[3])
 954                                 seqname := string(fields[4])
 955                                 pos, _ := strconv.Atoi(string(fields[5]))
 956                                 refseq := fields[6]
 957                                 if hgvsID == "" {
 958                                         // Null entry for un-diffable
 959                                         // tile variant
 960                                         continue
 961                                 }
 962                                 if hgvsID == "=" {
 963                                         // Null entry for ref tile
 964                                         continue
 965                                 }
 966                                 if mask != nil && !mask.Check(strings.TrimPrefix(seqname, "chr"), pos, pos+len(refseq)) {
 967                                         // The tile intersects one of
 968                                         // the selected regions, but
 969                                         // this particular HGVS
 970                                         // variant does not.
 971                                         continue
 972                                 }
 973                                 hgvsColPair := hgvsCols[hgvsID]
 974                                 if hgvsColPair[0] == nil {
 975                                         // values in new columns start
 976                                         // out as -1 ("no data yet")
 977                                         // or 0 ("=ref") here, may
 978                                         // change to 1 ("hgvs variant
 979                                         // present") below, either on
 980                                         // this line or a future line.
 981                                         hgvsColPair = [2][]int16{make([]int16, len(cmd.cgnames)), make([]int16, len(cmd.cgnames))}
 982                                         rt, ok := reftile[tagID(tag)]
 983                                         if !ok {
 984                                                 err = fmt.Errorf("bug: seeing annotations for tag %d, but it has no reftile entry", tag)
 985                                                 return 1
 986                                         }
 987                                         for ph := 0; ph < 2; ph++ {
 988                                                 for row := 0; row < rows; row++ {
 989                                                         v := chunk[row*chunkcols+incol*2+ph]
 990                                                         if tileVariantID(v) == rt.variant {
 991                                                                 hgvsColPair[ph][row] = 0
 992                                                         } else {
 993                                                                 hgvsColPair[ph][row] = -1
 994                                                         }
 995                                                 }
 996                                         }
 997                                         hgvsCols[hgvsID] = hgvsColPair
 998                                         if annow != nil {
 999                                                 hgvsref := hgvs.Variant{
1000                                                         Position: pos,
1001                                                         Ref:      string(refseq),
1002                                                         New:      string(refseq),
1003                                                 }
1004                                                 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])
1005                                         }
1006                                 }
1007                                 if annow != nil {
1008                                         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])
1009                                 }
1010                                 for ph := 0; ph < 2; ph++ {
1011                                         for row := 0; row < rows; row++ {
1012                                                 v := chunk[row*chunkcols+incol*2+ph]
1013                                                 if int(v) == tileVariant {
1014                                                         hgvsColPair[ph][row] = 1
1015                                                 }
1016                                         }
1017                                 }
1018                         }
1019
1020                         startcol += chunkcols
1021                 }
1022                 if *mergeOutput {
1023                         err = annow.Flush()
1024                         if err != nil {
1025                                 return 1
1026                         }
1027                         err = annof.Close()
1028                         if err != nil {
1029                                 return 1
1030                         }
1031                         err = writeNumpyInt16(fmt.Sprintf("%s/matrix.npy", *outputDir), out, rows, cols)
1032                         if err != nil {
1033                                 return 1
1034                         }
1035                 }
1036                 out = nil
1037
1038                 if *hgvsSingle {
1039                         cols = len(hgvsCols) * 2
1040                         log.Printf("building hgvs-based matrix: %d rows x %d cols", rows, cols)
1041                         out = make([]int16, rows*cols)
1042                         hgvsIDs := make([]string, 0, cols/2)
1043                         for hgvsID := range hgvsCols {
1044                                 hgvsIDs = append(hgvsIDs, hgvsID)
1045                         }
1046                         sort.Strings(hgvsIDs)
1047                         var hgvsLabels bytes.Buffer
1048                         for idx, hgvsID := range hgvsIDs {
1049                                 fmt.Fprintf(&hgvsLabels, "%d,%s\n", idx, hgvsID)
1050                                 for ph := 0; ph < 2; ph++ {
1051                                         hgvscol := hgvsCols[hgvsID][ph]
1052                                         for row, val := range hgvscol {
1053                                                 out[row*cols+idx*2+ph] = val
1054                                         }
1055                                 }
1056                         }
1057                         err = writeNumpyInt16(fmt.Sprintf("%s/hgvs.npy", *outputDir), out, rows, cols)
1058                         if err != nil {
1059                                 return 1
1060                         }
1061
1062                         fnm := fmt.Sprintf("%s/hgvs.annotations.csv", *outputDir)
1063                         log.Printf("writing hgvs labels: %s", fnm)
1064                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0777)
1065                         if err != nil {
1066                                 return 1
1067                         }
1068                 }
1069         }
1070         if *onehotSingle {
1071                 nzCount := 0
1072                 for _, part := range onehotIndirect {
1073                         nzCount += len(part[0])
1074                 }
1075                 onehot := make([]uint32, nzCount*2) // [r,r,r,...,c,c,c,...]
1076                 var xrefs []onehotXref
1077                 chunkOffset := uint32(0)
1078                 outcol := 0
1079                 for i, part := range onehotIndirect {
1080                         for i := range part[1] {
1081                                 part[1][i] += chunkOffset
1082                         }
1083                         copy(onehot[outcol:], part[0])
1084                         copy(onehot[outcol+nzCount:], part[1])
1085                         xrefs = append(xrefs, onehotXrefs[i]...)
1086
1087                         outcol += len(part[0])
1088                         chunkOffset += onehotChunkSize[i]
1089
1090                         part[0] = nil
1091                         part[1] = nil
1092                         onehotXrefs[i] = nil
1093                         debug.FreeOSMemory()
1094                 }
1095                 fnm := fmt.Sprintf("%s/onehot.npy", *outputDir)
1096                 err = writeNumpyUint32(fnm, onehot, 2, nzCount)
1097                 if err != nil {
1098                         return 1
1099                 }
1100                 fnm = fmt.Sprintf("%s/onehot-columns.npy", *outputDir)
1101                 err = writeNumpyInt32(fnm, onehotXref2int32(xrefs), 5, len(xrefs))
1102                 if err != nil {
1103                         return 1
1104                 }
1105         }
1106         if *onlyPCA {
1107
1108         }
1109         if !*mergeOutput && !*onehotChunked && !*onehotSingle && !*onlyPCA {
1110                 tagoffsetFilename := *outputDir + "/chunk-tag-offset.csv"
1111                 log.Infof("writing tag offsets to %s", tagoffsetFilename)
1112                 var f *os.File
1113                 f, err = os.Create(tagoffsetFilename)
1114                 if err != nil {
1115                         return 1
1116                 }
1117                 defer f.Close()
1118                 for idx, offset := range chunkStartTag {
1119                         _, err = fmt.Fprintf(f, "%q,%d\n", fmt.Sprintf("matrix.%04d.npy", idx), offset)
1120                         if err != nil {
1121                                 err = fmt.Errorf("write %s: %w", tagoffsetFilename, err)
1122                                 return 1
1123                         }
1124                 }
1125                 err = f.Close()
1126                 if err != nil {
1127                         err = fmt.Errorf("close %s: %w", tagoffsetFilename, err)
1128                         return 1
1129                 }
1130         }
1131         return 0
1132 }
1133
1134 // Read case/control files, remove non-case/control entries from
1135 // cmd.cgnames, and build cmd.chi2Cases.
1136 func (cmd *sliceNumpy) useCaseControlFiles() error {
1137         if cmd.chi2CaseControlFile == "" {
1138                 return nil
1139         }
1140         infiles, err := allFiles(cmd.chi2CaseControlFile, nil)
1141         if err != nil {
1142                 return err
1143         }
1144         // index in cmd.cgnames => case(true) / control(false)
1145         cc := map[int]bool{}
1146         for _, infile := range infiles {
1147                 f, err := open(infile)
1148                 if err != nil {
1149                         return err
1150                 }
1151                 buf, err := io.ReadAll(f)
1152                 f.Close()
1153                 if err != nil {
1154                         return err
1155                 }
1156                 ccCol := -1
1157                 for _, tsv := range bytes.Split(buf, []byte{'\n'}) {
1158                         if len(tsv) == 0 {
1159                                 continue
1160                         }
1161                         split := strings.Split(string(tsv), "\t")
1162                         if ccCol < 0 {
1163                                 // header row
1164                                 for col, name := range split {
1165                                         if name == cmd.chi2CaseControlColumn {
1166                                                 ccCol = col
1167                                                 break
1168                                         }
1169                                 }
1170                                 if ccCol < 0 {
1171                                         return fmt.Errorf("%s: no column named %q in header row %q", infile, cmd.chi2CaseControlColumn, tsv)
1172                                 }
1173                                 continue
1174                         }
1175                         if len(split) <= ccCol {
1176                                 continue
1177                         }
1178                         pattern := split[0]
1179                         found := -1
1180                         for i, name := range cmd.cgnames {
1181                                 if strings.Contains(name, pattern) {
1182                                         if found >= 0 {
1183                                                 log.Warnf("pattern %q in %s matches multiple genome IDs (%qs, %q)", pattern, infile, cmd.cgnames[found], name)
1184                                         }
1185                                         found = i
1186                                 }
1187                         }
1188                         if found < 0 {
1189                                 log.Warnf("pattern %q in %s does not match any genome IDs", pattern, infile)
1190                                 continue
1191                         }
1192                         if split[ccCol] == "0" {
1193                                 cc[found] = false
1194                         }
1195                         if split[ccCol] == "1" {
1196                                 cc[found] = true
1197                         }
1198                 }
1199         }
1200         allnames := cmd.cgnames
1201         cmd.cgnames = nil
1202         cmd.chi2Cases = nil
1203         ncases := 0
1204         for i, name := range allnames {
1205                 if cc, ok := cc[i]; ok {
1206                         cmd.cgnames = append(cmd.cgnames, name)
1207                         cmd.chi2Cases = append(cmd.chi2Cases, cc)
1208                         if cc {
1209                                 ncases++
1210                         }
1211                 }
1212         }
1213         log.Printf("%d cases, %d controls, %d neither (dropped)", ncases, len(cmd.cgnames)-ncases, len(allnames)-len(cmd.cgnames))
1214         return nil
1215 }
1216
1217 func (cmd *sliceNumpy) filterHGVScolpair(colpair [2][]int8) bool {
1218         if cmd.chi2PValue >= 1 {
1219                 return true
1220         }
1221         col0 := make([]bool, 0, len(cmd.chi2Cases))
1222         col1 := make([]bool, 0, len(cmd.chi2Cases))
1223         cases := make([]bool, 0, len(cmd.chi2Cases))
1224         for i, c := range cmd.chi2Cases {
1225                 if colpair[0][i] < 0 {
1226                         continue
1227                 }
1228                 col0 = append(col0, colpair[0][i] != 0)
1229                 col1 = append(col1, colpair[1][i] != 0)
1230                 cases = append(cases, c)
1231         }
1232         return len(cases) >= cmd.minCoverage &&
1233                 (pvalue(col0, cases) <= cmd.chi2PValue || pvalue(col1, cases) <= cmd.chi2PValue)
1234 }
1235
1236 func writeNumpyUint32(fnm string, out []uint32, rows, cols int) error {
1237         output, err := os.Create(fnm)
1238         if err != nil {
1239                 return err
1240         }
1241         defer output.Close()
1242         bufw := bufio.NewWriterSize(output, 1<<26)
1243         npw, err := gonpy.NewWriter(nopCloser{bufw})
1244         if err != nil {
1245                 return err
1246         }
1247         log.WithFields(log.Fields{
1248                 "filename": fnm,
1249                 "rows":     rows,
1250                 "cols":     cols,
1251                 "bytes":    rows * cols * 4,
1252         }).Infof("writing numpy: %s", fnm)
1253         npw.Shape = []int{rows, cols}
1254         npw.WriteUint32(out)
1255         err = bufw.Flush()
1256         if err != nil {
1257                 return err
1258         }
1259         return output.Close()
1260 }
1261
1262 func writeNumpyInt32(fnm string, out []int32, rows, cols int) error {
1263         output, err := os.Create(fnm)
1264         if err != nil {
1265                 return err
1266         }
1267         defer output.Close()
1268         bufw := bufio.NewWriterSize(output, 1<<26)
1269         npw, err := gonpy.NewWriter(nopCloser{bufw})
1270         if err != nil {
1271                 return err
1272         }
1273         log.WithFields(log.Fields{
1274                 "filename": fnm,
1275                 "rows":     rows,
1276                 "cols":     cols,
1277                 "bytes":    rows * cols * 4,
1278         }).Infof("writing numpy: %s", fnm)
1279         npw.Shape = []int{rows, cols}
1280         npw.WriteInt32(out)
1281         err = bufw.Flush()
1282         if err != nil {
1283                 return err
1284         }
1285         return output.Close()
1286 }
1287
1288 func writeNumpyInt16(fnm string, out []int16, rows, cols int) error {
1289         output, err := os.Create(fnm)
1290         if err != nil {
1291                 return err
1292         }
1293         defer output.Close()
1294         bufw := bufio.NewWriterSize(output, 1<<26)
1295         npw, err := gonpy.NewWriter(nopCloser{bufw})
1296         if err != nil {
1297                 return err
1298         }
1299         log.WithFields(log.Fields{
1300                 "filename": fnm,
1301                 "rows":     rows,
1302                 "cols":     cols,
1303                 "bytes":    rows * cols * 2,
1304         }).Infof("writing numpy: %s", fnm)
1305         npw.Shape = []int{rows, cols}
1306         npw.WriteInt16(out)
1307         err = bufw.Flush()
1308         if err != nil {
1309                 return err
1310         }
1311         return output.Close()
1312 }
1313
1314 func writeNumpyInt8(fnm string, out []int8, rows, cols int) error {
1315         output, err := os.Create(fnm)
1316         if err != nil {
1317                 return err
1318         }
1319         defer output.Close()
1320         bufw := bufio.NewWriterSize(output, 1<<26)
1321         npw, err := gonpy.NewWriter(nopCloser{bufw})
1322         if err != nil {
1323                 return err
1324         }
1325         log.WithFields(log.Fields{
1326                 "filename": fnm,
1327                 "rows":     rows,
1328                 "cols":     cols,
1329                 "bytes":    rows * cols,
1330         }).Infof("writing numpy: %s", fnm)
1331         npw.Shape = []int{rows, cols}
1332         npw.WriteInt8(out)
1333         err = bufw.Flush()
1334         if err != nil {
1335                 return err
1336         }
1337         return output.Close()
1338 }
1339
1340 func allele2homhet(colpair [2][]int8) {
1341         a, b := colpair[0], colpair[1]
1342         for i, av := range a {
1343                 bv := b[i]
1344                 if av < 0 || bv < 0 {
1345                         // no-call
1346                         a[i], b[i] = -1, -1
1347                 } else if av > 0 && bv > 0 {
1348                         // hom
1349                         a[i], b[i] = 1, 0
1350                 } else if av > 0 || bv > 0 {
1351                         // het
1352                         a[i], b[i] = 0, 1
1353                 } else {
1354                         // ref (or a different variant in same position)
1355                         // (this is a no-op) a[i], b[i] = 0, 0
1356                 }
1357         }
1358 }
1359
1360 type onehotXref struct {
1361         tag     tagID
1362         variant tileVariantID
1363         hom     bool
1364         pvalue  float64
1365 }
1366
1367 const onehotXrefSize = unsafe.Sizeof(onehotXref{})
1368
1369 // Build onehot matrix (m[tileVariantIndex][genome] == 0 or 1) for all
1370 // variants of a single tile/tag#.
1371 //
1372 // Return nil if no tile variant passes Χ² filter.
1373 func (cmd *sliceNumpy) tv2homhet(cgs map[string]CompactGenome, maxv tileVariantID, remap []tileVariantID, tag, chunkstarttag tagID, seq map[tagID][]TileVariant) ([][]int8, []onehotXref) {
1374         if tag == cmd.debugTag {
1375                 tv := make([]tileVariantID, len(cmd.cgnames)*2)
1376                 for i, name := range cmd.cgnames {
1377                         copy(tv[i*2:(i+1)*2], cgs[name].Variants[(tag-chunkstarttag)*2:])
1378                 }
1379                 log.WithFields(logrus.Fields{
1380                         "cgs[i].Variants[tag*2+j]": tv,
1381                         "maxv":                     maxv,
1382                         "remap":                    remap,
1383                         "tag":                      tag,
1384                         "chunkstarttag":            chunkstarttag,
1385                 }).Info("tv2homhet()")
1386         }
1387         if maxv < 1 || (maxv < 2 && !cmd.includeVariant1) {
1388                 // everyone has the most common variant (of the variants we don't drop)
1389                 return nil, nil
1390         }
1391         tagoffset := tag - chunkstarttag
1392         coverage := 0
1393         for _, cg := range cgs {
1394                 alleles := 0
1395                 for _, v := range cg.Variants[tagoffset*2 : tagoffset*2+2] {
1396                         if v > 0 && int(v) < len(seq[tag]) && len(seq[tag][v].Sequence) > 0 {
1397                                 alleles++
1398                         }
1399                 }
1400                 if alleles == 2 {
1401                         coverage++
1402                 }
1403         }
1404         if coverage < cmd.minCoverage {
1405                 return nil, nil
1406         }
1407         obs := make([][]bool, (maxv+1)*2) // 2 slices (hom + het) for each variant#
1408         for i := range obs {
1409                 obs[i] = make([]bool, len(cmd.cgnames))
1410         }
1411         for cgid, name := range cmd.cgnames {
1412                 cgvars := cgs[name].Variants[tagoffset*2:]
1413                 tv0, tv1 := remap[cgvars[0]], remap[cgvars[1]]
1414                 for v := tileVariantID(1); v <= maxv; v++ {
1415                         if tv0 == v && tv1 == v {
1416                                 obs[v*2][cgid] = true
1417                         } else if tv0 == v || tv1 == v {
1418                                 obs[v*2+1][cgid] = true
1419                         }
1420                 }
1421         }
1422         var onehot [][]int8
1423         var xref []onehotXref
1424         for col := 2; col < len(obs); col++ {
1425                 // col 0,1 correspond to tile variant 0, i.e.,
1426                 // no-call; col 2,3 correspond to the most common
1427                 // variant; so we (normally) start at col 4.
1428                 if col < 4 && !cmd.includeVariant1 {
1429                         continue
1430                 }
1431                 p := pvalue(obs[col], cmd.chi2Cases)
1432                 if cmd.chi2PValue < 1 && !(p < cmd.chi2PValue) {
1433                         continue
1434                 }
1435                 onehot = append(onehot, bool2int8(obs[col]))
1436                 xref = append(xref, onehotXref{
1437                         tag:     tag,
1438                         variant: tileVariantID(col >> 1),
1439                         hom:     col&1 == 0,
1440                         pvalue:  p,
1441                 })
1442         }
1443         return onehot, xref
1444 }
1445
1446 func bool2int8(in []bool) []int8 {
1447         out := make([]int8, len(in))
1448         for i, v := range in {
1449                 if v {
1450                         out[i] = 1
1451                 }
1452         }
1453         return out
1454 }
1455
1456 // convert a []onehotXref with length N to a numpy-style []int32
1457 // matrix with N columns, one row per field of onehotXref struct.
1458 //
1459 // Hom/het row contains hom=0, het=1.
1460 //
1461 // P-value row contains 1000000x actual p-value.
1462 func onehotXref2int32(xrefs []onehotXref) []int32 {
1463         xcols := len(xrefs)
1464         xdata := make([]int32, 5*xcols)
1465         for i, xref := range xrefs {
1466                 xdata[i] = int32(xref.tag)
1467                 xdata[xcols+i] = int32(xref.variant)
1468                 if xref.hom {
1469                         xdata[xcols*2+i] = 1
1470                 }
1471                 xdata[xcols*3+i] = int32(xref.pvalue * 1000000)
1472                 xdata[xcols*4+i] = int32(-math.Log10(xref.pvalue) * 1000000)
1473         }
1474         return xdata
1475 }
1476
1477 // transpose onehot data from in[col][row] to numpy-style
1478 // out[row*cols+col].
1479 func onehotcols2int8(in [][]int8) []int8 {
1480         if len(in) == 0 {
1481                 return nil
1482         }
1483         cols := len(in)
1484         rows := len(in[0])
1485         out := make([]int8, rows*cols)
1486         for row := 0; row < rows; row++ {
1487                 outrow := out[row*cols:]
1488                 for col, incol := range in {
1489                         outrow[col] = incol[row]
1490                 }
1491         }
1492         return out
1493 }
1494
1495 // Return [2][]uint32{rowIndices, colIndices} indicating which
1496 // elements of matrixT[c][r] have non-zero values.
1497 func onehotChunk2Indirect(matrixT [][]int8) [2][]uint32 {
1498         var nz [2][]uint32
1499         for c, col := range matrixT {
1500                 for r, val := range col {
1501                         if val != 0 {
1502                                 nz[0] = append(nz[0], uint32(r))
1503                                 nz[1] = append(nz[1], uint32(c))
1504                         }
1505                 }
1506         }
1507         return nz
1508 }