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/james-bowman/nlp"
  32         "github.com/kshedden/gonpy"
  33         "github.com/sirupsen/logrus"
  34         log "github.com/sirupsen/logrus"
  35         "golang.org/x/crypto/blake2b"
  36         "gonum.org/v1/gonum/mat"
  37 )
  38
  39 const annotationMaxTileSpan = 100
  40
  41 type sliceNumpy struct {
  42         filter                filter
  43         threads               int
  44         chi2CaseControlColumn string
  45         chi2CaseControlFile   string
  46         chi2Cases             []bool
  47         chi2PValue            float64
  48         minCoverage           int
  49         cgnames               []string
  50         includeVariant1       bool
  51         debugTag              tagID
  52 }
  53
  54 func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, stdout, stderr io.Writer) int {
  55         err := cmd.run(prog, args, stdin, stdout, stderr)
  56         if err != nil {
  57                 fmt.Fprintf(stderr, "%s\n", err)
  58                 return 1
  59         }
  60         return 0
  61 }
  62 func (cmd *sliceNumpy) run(prog string, args []string, stdin io.Reader, stdout, stderr io.Writer) error {
  63         flags := flag.NewFlagSet("", flag.ContinueOnError)
  64         flags.SetOutput(stderr)
  65         pprof := flags.String("pprof", "", "serve Go profile data at http://`[addr]:port`")
  66         runlocal := flags.Bool("local", false, "run on local host (default: run in an arvados container)")
  67         projectUUID := flags.String("project", "", "project `UUID` for output data")
  68         priority := flags.Int("priority", 500, "container request priority")
  69         inputDir := flags.String("input-dir", "./in", "input `directory`")
  70         outputDir := flags.String("output-dir", "./out", "output `directory`")
  71         ref := flags.String("ref", "", "reference name (if blank, choose last one that appears in input)")
  72         regionsFilename := flags.String("regions", "", "only output columns/annotations that intersect regions in specified bed `file`")
  73         expandRegions := flags.Int("expand-regions", 0, "expand specified regions by `N` base pairs on each side`")
  74         mergeOutput := flags.Bool("merge-output", false, "merge output into one matrix.npy and one matrix.annotations.csv")
  75         hgvsSingle := flags.Bool("single-hgvs-matrix", false, "also generate hgvs-based matrix")
  76         hgvsChunked := flags.Bool("chunked-hgvs-matrix", false, "also generate hgvs-based matrix per chromosome")
  77         onehotSingle := flags.Bool("single-onehot", false, "generate one-hot tile-based matrix")
  78         onehotChunked := flags.Bool("chunked-onehot", false, "generate one-hot tile-based matrix per input chunk")
  79         onlyPCA := flags.Bool("pca", false, "generate pca matrix")
  80         pcaComponents := flags.Int("pca-components", 4, "number of PCA components")
  81         debugTag := flags.Int("debug-tag", -1, "log debugging details about specified tag")
  82         flags.IntVar(&cmd.threads, "threads", 16, "number of memory-hungry assembly threads")
  83         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)")
  84         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)")
  85         flags.Float64Var(&cmd.chi2PValue, "chi2-p-value", 1, "do Χ² test and omit columns with p-value above this threshold")
  86         flags.BoolVar(&cmd.includeVariant1, "include-variant-1", false, "include most common variant when building one-hot matrix")
  87         cmd.filter.Flags(flags)
  88         err := flags.Parse(args)
  89         if err == flag.ErrHelp {
  90                 return nil
  91         } else if err != nil {
  92                 return err
  93         }
  94
  95         if *pprof != "" {
  96                 go func() {
  97                         log.Println(http.ListenAndServe(*pprof, nil))
  98                 }()
  99         }
 100
 101         if cmd.chi2PValue != 1 && (cmd.chi2CaseControlFile == "" || cmd.chi2CaseControlColumn == "") {
 102                 return fmt.Errorf("cannot use provided -chi2-p-value=%f because -chi2-case-control-file= or -chi2-case-control-column= value is empty", cmd.chi2PValue)
 103         }
 104
 105         cmd.debugTag = tagID(*debugTag)
 106
 107         if !*runlocal {
 108                 runner := arvadosContainerRunner{
 109                         Name:        "lightning slice-numpy",
 110                         Client:      arvados.NewClientFromEnv(),
 111                         ProjectUUID: *projectUUID,
 112                         RAM:         750000000000,
 113                         VCPUs:       96,
 114                         Priority:    *priority,
 115                         KeepCache:   2,
 116                         APIAccess:   true,
 117                 }
 118                 err = runner.TranslatePaths(inputDir, regionsFilename, &cmd.chi2CaseControlFile)
 119                 if err != nil {
 120                         return err
 121                 }
 122                 runner.Args = []string{"slice-numpy", "-local=true",
 123                         "-pprof=:6060",
 124                         "-input-dir=" + *inputDir,
 125                         "-output-dir=/mnt/output",
 126                         "-threads=" + fmt.Sprintf("%d", cmd.threads),
 127                         "-regions=" + *regionsFilename,
 128                         "-expand-regions=" + fmt.Sprintf("%d", *expandRegions),
 129                         "-merge-output=" + fmt.Sprintf("%v", *mergeOutput),
 130                         "-single-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsSingle),
 131                         "-chunked-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsChunked),
 132                         "-single-onehot=" + fmt.Sprintf("%v", *onehotSingle),
 133                         "-chunked-onehot=" + fmt.Sprintf("%v", *onehotChunked),
 134                         "-pca=" + fmt.Sprintf("%v", *onlyPCA),
 135                         "-pca-components=" + fmt.Sprintf("%d", *pcaComponents),
 136                         "-chi2-case-control-file=" + cmd.chi2CaseControlFile,
 137                         "-chi2-case-control-column=" + cmd.chi2CaseControlColumn,
 138                         "-chi2-p-value=" + fmt.Sprintf("%f", cmd.chi2PValue),
 139                         "-include-variant-1=" + fmt.Sprintf("%v", cmd.includeVariant1),
 140                         "-debug-tag=" + fmt.Sprintf("%d", cmd.debugTag),
 141                 }
 142                 runner.Args = append(runner.Args, cmd.filter.Args()...)
 143                 var output string
 144                 output, err = runner.Run()
 145                 if err != nil {
 146                         return err
 147                 }
 148                 fmt.Fprintln(stdout, output)
 149                 return nil
 150         }
 151
 152         infiles, err := allFiles(*inputDir, matchGobFile)
 153         if err != nil {
 154                 return err
 155         }
 156         if len(infiles) == 0 {
 157                 err = fmt.Errorf("no input files found in %s", *inputDir)
 158                 return err
 159         }
 160         sort.Strings(infiles)
 161
 162         var refseq map[string][]tileLibRef
 163         var reftiledata = make(map[tileLibRef][]byte, 11000000)
 164         in0, err := open(infiles[0])
 165         if err != nil {
 166                 return err
 167         }
 168
 169         matchGenome, err := regexp.Compile(cmd.filter.MatchGenome)
 170         if err != nil {
 171                 err = fmt.Errorf("-match-genome: invalid regexp: %q", cmd.filter.MatchGenome)
 172                 return err
 173         }
 174
 175         cmd.cgnames = nil
 176         var tagset [][]byte
 177         err = DecodeLibrary(in0, strings.HasSuffix(infiles[0], ".gz"), func(ent *LibraryEntry) error {
 178                 if len(ent.TagSet) > 0 {
 179                         tagset = ent.TagSet
 180                 }
 181                 for _, cseq := range ent.CompactSequences {
 182                         if cseq.Name == *ref || *ref == "" {
 183                                 refseq = cseq.TileSequences
 184                         }
 185                 }
 186                 for _, cg := range ent.CompactGenomes {
 187                         if matchGenome.MatchString(cg.Name) {
 188                                 cmd.cgnames = append(cmd.cgnames, cg.Name)
 189                         }
 190                 }
 191                 for _, tv := range ent.TileVariants {
 192                         if tv.Ref {
 193                                 reftiledata[tileLibRef{tv.Tag, tv.Variant}] = tv.Sequence
 194                         }
 195                 }
 196                 return nil
 197         })
 198         if err != nil {
 199                 return err
 200         }
 201         in0.Close()
 202         if refseq == nil {
 203                 err = fmt.Errorf("%s: reference sequence not found", infiles[0])
 204                 return err
 205         }
 206         if len(tagset) == 0 {
 207                 err = fmt.Errorf("tagset not found")
 208                 return err
 209         }
 210
 211         taglib := &tagLibrary{}
 212         err = taglib.setTags(tagset)
 213         if err != nil {
 214                 return err
 215         }
 216         taglen := taglib.TagLen()
 217
 218         if len(cmd.cgnames) == 0 {
 219                 err = fmt.Errorf("no genomes found matching regexp %q", cmd.filter.MatchGenome)
 220                 return err
 221         }
 222         sort.Strings(cmd.cgnames)
 223         err = cmd.useCaseControlFiles()
 224         if err != nil {
 225                 return err
 226         }
 227         if len(cmd.cgnames) == 0 {
 228                 err = fmt.Errorf("fatal: 0 cases, 0 controls, nothing to do")
 229                 return err
 230         }
 231         if cmd.filter.MinCoverage == 1 {
 232                 // In the generic formula below, floating point
 233                 // arithmetic can effectively push the coverage
 234                 // threshold above 1.0, which is impossible/useless.
 235                 // 1.0 needs to mean exactly 100% coverage.
 236                 cmd.minCoverage = len(cmd.cgnames)
 237         } else {
 238                 cmd.minCoverage = int(math.Ceil(cmd.filter.MinCoverage * float64(len(cmd.cgnames))))
 239         }
 240
 241         {
 242                 labelsFilename := *outputDir + "/samples.csv"
 243                 log.Infof("writing labels to %s", labelsFilename)
 244                 var f *os.File
 245                 f, err = os.Create(labelsFilename)
 246                 if err != nil {
 247                         return err
 248                 }
 249                 defer f.Close()
 250                 for i, name := range cmd.cgnames {
 251                         cc := 0
 252                         if cmd.chi2Cases != nil && cmd.chi2Cases[i] {
 253                                 cc = 1
 254                         }
 255                         _, err = fmt.Fprintf(f, "%d,%q,%d\n", i, trimFilenameForLabel(name), cc)
 256                         if err != nil {
 257                                 err = fmt.Errorf("write %s: %w", labelsFilename, err)
 258                                 return err
 259                         }
 260                 }
 261                 err = f.Close()
 262                 if err != nil {
 263                         err = fmt.Errorf("close %s: %w", labelsFilename, err)
 264                         return err
 265                 }
 266         }
 267
 268         log.Info("indexing reference tiles")
 269         type reftileinfo struct {
 270                 variant  tileVariantID
 271                 seqname  string // chr1
 272                 pos      int    // distance from start of chromosome to starttag
 273                 tiledata []byte // acgtggcaa...
 274                 excluded bool   // true if excluded by regions file
 275                 nexttag  tagID  // tagID of following tile (-1 for last tag of chromosome)
 276         }
 277         isdup := map[tagID]bool{}
 278         reftile := map[tagID]*reftileinfo{}
 279         for seqname, cseq := range refseq {
 280                 pos := 0
 281                 lastreftag := tagID(-1)
 282                 for _, libref := range cseq {
 283                         if cmd.filter.MaxTag >= 0 && libref.Tag > tagID(cmd.filter.MaxTag) {
 284                                 continue
 285                         }
 286                         tiledata := reftiledata[libref]
 287                         if len(tiledata) == 0 {
 288                                 err = fmt.Errorf("missing tiledata for tag %d variant %d in %s in ref", libref.Tag, libref.Variant, seqname)
 289                                 return err
 290                         }
 291                         foundthistag := false
 292                         taglib.FindAll(tiledata[:len(tiledata)-1], func(tagid tagID, offset, _ int) {
 293                                 if !foundthistag && tagid == libref.Tag {
 294                                         foundthistag = true
 295                                         return
 296                                 }
 297                                 if dupref, ok := reftile[tagid]; ok {
 298                                         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)
 299                                         delete(reftile, tagid)
 300                                 } else {
 301                                         log.Printf("found tag %d at offset %d inside tile variant %+v on %s @ %d", tagid, offset, libref, seqname, pos+offset+1)
 302                                 }
 303                                 isdup[tagid] = true
 304                         })
 305                         if isdup[libref.Tag] {
 306                                 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
 307                         } else if reftile[libref.Tag] != nil {
 308                                 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)
 309                                 delete(reftile, libref.Tag)
 310                                 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
 311                                 isdup[libref.Tag] = true
 312                         } else {
 313                                 reftile[libref.Tag] = &reftileinfo{
 314                                         seqname:  seqname,
 315                                         variant:  libref.Variant,
 316                                         tiledata: tiledata,
 317                                         pos:      pos,
 318                                         nexttag:  -1,
 319                                 }
 320                                 if lastreftag >= 0 {
 321                                         reftile[lastreftag].nexttag = libref.Tag
 322                                 }
 323                                 lastreftag = libref.Tag
 324                         }
 325                         pos += len(tiledata) - taglen
 326                 }
 327                 log.Printf("... %s done, len %d", seqname, pos+taglen)
 328         }
 329
 330         var mask *mask
 331         if *regionsFilename != "" {
 332                 log.Printf("loading regions from %s", *regionsFilename)
 333                 mask, err = makeMask(*regionsFilename, *expandRegions)
 334                 if err != nil {
 335                         return err
 336                 }
 337                 log.Printf("before applying mask, len(reftile) == %d", len(reftile))
 338                 log.Printf("deleting reftile entries for regions outside %d intervals", mask.Len())
 339                 for _, rt := range reftile {
 340                         if !mask.Check(strings.TrimPrefix(rt.seqname, "chr"), rt.pos, rt.pos+len(rt.tiledata)) {
 341                                 rt.excluded = true
 342                         }
 343                 }
 344                 log.Printf("after applying mask, len(reftile) == %d", len(reftile))
 345         }
 346
 347         type hgvsColSet map[hgvs.Variant][2][]int8
 348         encodeHGVS := throttle{Max: len(refseq)}
 349         encodeHGVSTodo := map[string]chan hgvsColSet{}
 350         tmpHGVSCols := map[string]*os.File{}
 351         if *hgvsChunked {
 352                 for seqname := range refseq {
 353                         var f *os.File
 354                         f, err = os.Create(*outputDir + "/tmp." + seqname + ".gob")
 355                         if err != nil {
 356                                 return err
 357                         }
 358                         defer os.Remove(f.Name())
 359                         bufw := bufio.NewWriterSize(f, 1<<24)
 360                         enc := gob.NewEncoder(bufw)
 361                         tmpHGVSCols[seqname] = f
 362                         todo := make(chan hgvsColSet, 128)
 363                         encodeHGVSTodo[seqname] = todo
 364                         encodeHGVS.Go(func() error {
 365                                 for colset := range todo {
 366                                         err := enc.Encode(colset)
 367                                         if err != nil {
 368                                                 encodeHGVS.Report(err)
 369                                                 for range todo {
 370                                                 }
 371                                                 return err
 372                                         }
 373                                 }
 374                                 return bufw.Flush()
 375                         })
 376                 }
 377         }
 378
 379         var toMerge [][]int16
 380         if *mergeOutput || *hgvsSingle {
 381                 toMerge = make([][]int16, len(infiles))
 382         }
 383         var onehotIndirect [][2][]uint32 // [chunkIndex][axis][index]
 384         var onehotChunkSize []uint32
 385         var onehotXrefs [][]onehotXref
 386         if *onehotSingle || *onlyPCA {
 387                 onehotIndirect = make([][2][]uint32, len(infiles))
 388                 onehotChunkSize = make([]uint32, len(infiles))
 389                 onehotXrefs = make([][]onehotXref, len(infiles))
 390         }
 391         chunkStartTag := make([]tagID, len(infiles))
 392
 393         throttleMem := throttle{Max: cmd.threads} // TODO: estimate using mem and data size
 394         throttleNumpyMem := throttle{Max: cmd.threads/2 + 1}
 395         log.Info("generating annotations and numpy matrix for each slice")
 396         var errSkip = errors.New("skip infile")
 397         var done int64
 398         for infileIdx, infile := range infiles {
 399                 infileIdx, infile := infileIdx, infile
 400                 throttleMem.Go(func() error {
 401                         seq := make(map[tagID][]TileVariant, 50000)
 402                         cgs := make(map[string]CompactGenome, len(cmd.cgnames))
 403                         f, err := open(infile)
 404                         if err != nil {
 405                                 return err
 406                         }
 407                         defer f.Close()
 408                         log.Infof("%04d: reading %s", infileIdx, infile)
 409                         err = DecodeLibrary(f, strings.HasSuffix(infile, ".gz"), func(ent *LibraryEntry) error {
 410                                 for _, tv := range ent.TileVariants {
 411                                         if tv.Ref {
 412                                                 continue
 413                                         }
 414                                         // Skip tile with no
 415                                         // corresponding ref tile, if
 416                                         // mask is in play (we can't
 417                                         // determine coordinates for
 418                                         // these)
 419                                         if mask != nil && reftile[tv.Tag] == nil {
 420                                                 continue
 421                                         }
 422                                         // Skip tile whose
 423                                         // corresponding ref tile is
 424                                         // outside target regions --
 425                                         // unless it's a potential
 426                                         // spanning tile.
 427                                         if mask != nil && reftile[tv.Tag].excluded &&
 428                                                 (int(tv.Tag+1) >= len(tagset) ||
 429                                                         (bytes.HasSuffix(tv.Sequence, tagset[tv.Tag+1]) && reftile[tv.Tag+1] != nil && !reftile[tv.Tag+1].excluded)) {
 430                                                 continue
 431                                         }
 432                                         if tv.Tag == cmd.debugTag {
 433                                                 log.Printf("infile %d %s tag %d variant %d hash %x", infileIdx, infile, tv.Tag, tv.Variant, tv.Blake2b[:3])
 434                                         }
 435                                         variants := seq[tv.Tag]
 436                                         if len(variants) == 0 {
 437                                                 variants = make([]TileVariant, 100)
 438                                         }
 439                                         for len(variants) <= int(tv.Variant) {
 440                                                 variants = append(variants, TileVariant{})
 441                                         }
 442                                         variants[int(tv.Variant)] = tv
 443                                         seq[tv.Tag] = variants
 444                                 }
 445                                 for _, cg := range ent.CompactGenomes {
 446                                         if cmd.filter.MaxTag >= 0 && cg.StartTag > tagID(cmd.filter.MaxTag) {
 447                                                 return errSkip
 448                                         }
 449                                         if !matchGenome.MatchString(cg.Name) {
 450                                                 continue
 451                                         }
 452                                         // pad to full slice size
 453                                         // to avoid out-of-bounds
 454                                         // checks later
 455                                         if sliceSize := 2 * int(cg.EndTag-cg.StartTag); len(cg.Variants) < sliceSize {
 456                                                 cg.Variants = append(cg.Variants, make([]tileVariantID, sliceSize-len(cg.Variants))...)
 457                                         }
 458                                         cgs[cg.Name] = cg
 459                                 }
 460                                 return nil
 461                         })
 462                         if err == errSkip {
 463                                 return nil
 464                         } else if err != nil {
 465                                 return fmt.Errorf("%04d: DecodeLibrary(%s): err", infileIdx, infile)
 466                         }
 467                         tagstart := cgs[cmd.cgnames[0]].StartTag
 468                         tagend := cgs[cmd.cgnames[0]].EndTag
 469                         chunkStartTag[infileIdx] = tagstart
 470
 471                         // TODO: filters
 472
 473                         log.Infof("%04d: renumber/dedup variants for tags %d-%d", infileIdx, tagstart, tagend)
 474                         variantRemap := make([][]tileVariantID, tagend-tagstart)
 475                         throttleCPU := throttle{Max: runtime.GOMAXPROCS(0)}
 476                         for tag, variants := range seq {
 477                                 tag, variants := tag, variants
 478                                 throttleCPU.Go(func() error {
 479                                         alleleCoverage := 0
 480                                         count := make(map[[blake2b.Size256]byte]int, len(variants))
 481
 482                                         rt := reftile[tag]
 483                                         if rt != nil {
 484                                                 count[blake2b.Sum256(rt.tiledata)] = 0
 485                                         }
 486
 487                                         for cgname, cg := range cgs {
 488                                                 idx := int(tag-tagstart) * 2
 489                                                 for allele := 0; allele < 2; allele++ {
 490                                                         v := cg.Variants[idx+allele]
 491                                                         if v > 0 && len(variants[v].Sequence) > 0 {
 492                                                                 count[variants[v].Blake2b]++
 493                                                                 alleleCoverage++
 494                                                         }
 495                                                         if v > 0 && tag == cmd.debugTag {
 496                                                                 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])
 497                                                         }
 498                                                 }
 499                                         }
 500                                         if alleleCoverage < cmd.minCoverage*2 {
 501                                                 idx := int(tag-tagstart) * 2
 502                                                 for _, cg := range cgs {
 503                                                         cg.Variants[idx] = 0
 504                                                         cg.Variants[idx+1] = 0
 505                                                 }
 506                                                 if tag == cmd.debugTag {
 507                                                         log.Printf("tag %d alleleCoverage %d < min %d, sample data wiped", tag, alleleCoverage, cmd.minCoverage*2)
 508                                                 }
 509                                                 return nil
 510                                         }
 511
 512                                         // hash[i] will be the hash of
 513                                         // the variant(s) that should
 514                                         // be at rank i (0-based).
 515                                         hash := make([][blake2b.Size256]byte, 0, len(count))
 516                                         for b := range count {
 517                                                 hash = append(hash, b)
 518                                         }
 519                                         sort.Slice(hash, func(i, j int) bool {
 520                                                 bi, bj := &hash[i], &hash[j]
 521                                                 if ci, cj := count[*bi], count[*bj]; ci != cj {
 522                                                         return ci > cj
 523                                                 } else {
 524                                                         return bytes.Compare((*bi)[:], (*bj)[:]) < 0
 525                                                 }
 526                                         })
 527                                         // rank[b] will be the 1-based
 528                                         // new variant number for
 529                                         // variants whose hash is b.
 530                                         rank := make(map[[blake2b.Size256]byte]tileVariantID, len(hash))
 531                                         for i, h := range hash {
 532                                                 rank[h] = tileVariantID(i + 1)
 533                                         }
 534                                         if tag == cmd.debugTag {
 535                                                 for h, r := range rank {
 536                                                         log.Printf("tag %d rank(%x) = %v", tag, h[:3], r)
 537                                                 }
 538                                         }
 539                                         // remap[v] will be the new
 540                                         // variant number for original
 541                                         // variant number v.
 542                                         remap := make([]tileVariantID, len(variants))
 543                                         for i, tv := range variants {
 544                                                 remap[i] = rank[tv.Blake2b]
 545                                         }
 546                                         if tag == cmd.debugTag {
 547                                                 for in, out := range remap {
 548                                                         if out > 0 {
 549                                                                 log.Printf("tag %d remap %d => %d", tag, in, out)
 550                                                         }
 551                                                 }
 552                                         }
 553                                         variantRemap[tag-tagstart] = remap
 554                                         if rt != nil {
 555                                                 refrank := rank[blake2b.Sum256(rt.tiledata)]
 556                                                 if tag == cmd.debugTag {
 557                                                         log.Printf("tag %d reftile variant %d => %d", tag, rt.variant, refrank)
 558                                                 }
 559                                                 rt.variant = refrank
 560                                         }
 561                                         return nil
 562                                 })
 563                         }
 564                         throttleCPU.Wait()
 565
 566                         var onehotChunk [][]int8
 567                         var onehotXref []onehotXref
 568
 569                         var annotationsFilename string
 570                         if *onlyPCA {
 571                                 annotationsFilename = "/dev/null"
 572                         } else {
 573                                 annotationsFilename = fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, infileIdx)
 574                                 log.Infof("%04d: writing %s", infileIdx, annotationsFilename)
 575                         }
 576                         annof, err := os.Create(annotationsFilename)
 577                         if err != nil {
 578                                 return err
 579                         }
 580                         annow := bufio.NewWriterSize(annof, 1<<20)
 581                         outcol := 0
 582                         for tag := tagstart; tag < tagend; tag++ {
 583                                 rt := reftile[tag]
 584                                 if rt == nil && mask != nil {
 585                                         // With no ref tile, we don't
 586                                         // have coordinates to say
 587                                         // this is in the desired
 588                                         // regions -- so it's not.
 589                                         // TODO: handle ref spanning
 590                                         // tile case.
 591                                         continue
 592                                 }
 593                                 if rt != nil && rt.excluded {
 594                                         // TODO: don't skip yet --
 595                                         // first check for spanning
 596                                         // tile variants that
 597                                         // intersect non-excluded ref
 598                                         // tiles.
 599                                         continue
 600                                 }
 601                                 if cmd.filter.MaxTag >= 0 && tag > tagID(cmd.filter.MaxTag) {
 602                                         break
 603                                 }
 604                                 remap := variantRemap[tag-tagstart]
 605                                 maxv := tileVariantID(0)
 606                                 for _, v := range remap {
 607                                         if maxv < v {
 608                                                 maxv = v
 609                                         }
 610                                 }
 611                                 if *onehotChunked || *onehotSingle || *onlyPCA {
 612                                         onehot, xrefs := cmd.tv2homhet(cgs, maxv, remap, tag, tagstart, seq)
 613                                         if tag == cmd.debugTag {
 614                                                 log.WithFields(logrus.Fields{
 615                                                         "onehot": onehot,
 616                                                         "xrefs":  xrefs,
 617                                                 }).Info("tv2homhet()")
 618                                         }
 619                                         onehotChunk = append(onehotChunk, onehot...)
 620                                         onehotXref = append(onehotXref, xrefs...)
 621                                 }
 622                                 if *onlyPCA {
 623                                         outcol++
 624                                         continue
 625                                 }
 626                                 if rt == nil {
 627                                         // Reference does not use any
 628                                         // variant of this tile
 629                                         //
 630                                         // TODO: diff against the
 631                                         // relevant portion of the
 632                                         // ref's spanning tile
 633                                         outcol++
 634                                         continue
 635                                 }
 636                                 fmt.Fprintf(annow, "%d,%d,%d,=,%s,%d,,,\n", tag, outcol, rt.variant, rt.seqname, rt.pos)
 637                                 variants := seq[tag]
 638                                 reftilestr := strings.ToUpper(string(rt.tiledata))
 639
 640                                 done := make([]bool, maxv+1)
 641                                 variantDiffs := make([][]hgvs.Variant, maxv+1)
 642                                 for v, tv := range variants {
 643                                         v := remap[v]
 644                                         if v == 0 || v == rt.variant || done[v] {
 645                                                 continue
 646                                         } else {
 647                                                 done[v] = true
 648                                         }
 649                                         if len(tv.Sequence) < taglen {
 650                                                 continue
 651                                         }
 652                                         // if reftilestr doesn't end
 653                                         // in the same tag as tv,
 654                                         // extend reftilestr with
 655                                         // following ref tiles until
 656                                         // it does (up to an arbitrary
 657                                         // sanity-check limit)
 658                                         reftilestr := reftilestr
 659                                         endtagstr := strings.ToUpper(string(tv.Sequence[len(tv.Sequence)-taglen:]))
 660                                         for i, rt := 0, rt; i < annotationMaxTileSpan && !strings.HasSuffix(reftilestr, endtagstr) && rt.nexttag >= 0; i++ {
 661                                                 rt = reftile[rt.nexttag]
 662                                                 if rt == nil {
 663                                                         break
 664                                                 }
 665                                                 reftilestr += strings.ToUpper(string(rt.tiledata[taglen:]))
 666                                         }
 667                                         if mask != nil && !mask.Check(strings.TrimPrefix(rt.seqname, "chr"), rt.pos, rt.pos+len(reftilestr)) {
 668                                                 continue
 669                                         }
 670                                         if !strings.HasSuffix(reftilestr, endtagstr) {
 671                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 672                                                 continue
 673                                         }
 674                                         if lendiff := len(reftilestr) - len(tv.Sequence); lendiff < -1000 || lendiff > 1000 {
 675                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 676                                                 continue
 677                                         }
 678                                         diffs, _ := hgvs.Diff(reftilestr, strings.ToUpper(string(tv.Sequence)), 0)
 679                                         for i := range diffs {
 680                                                 diffs[i].Position += rt.pos
 681                                         }
 682                                         for _, diff := range diffs {
 683                                                 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)
 684                                         }
 685                                         if *hgvsChunked {
 686                                                 variantDiffs[v] = diffs
 687                                         }
 688                                 }
 689                                 if *hgvsChunked {
 690                                         // We can now determine, for each HGVS
 691                                         // variant (diff) in this reftile
 692                                         // region, whether a given genome
 693                                         // phase/allele (1) has the variant, (0) has
 694                                         // =ref or a different variant in that
 695                                         // position, or (-1) is lacking
 696                                         // coverage / couldn't be diffed.
 697                                         hgvsCol := hgvsColSet{}
 698                                         for _, diffs := range variantDiffs {
 699                                                 for _, diff := range diffs {
 700                                                         if _, ok := hgvsCol[diff]; ok {
 701                                                                 continue
 702                                                         }
 703                                                         hgvsCol[diff] = [2][]int8{
 704                                                                 make([]int8, len(cmd.cgnames)),
 705                                                                 make([]int8, len(cmd.cgnames)),
 706                                                         }
 707                                                 }
 708                                         }
 709                                         for row, name := range cmd.cgnames {
 710                                                 variants := cgs[name].Variants[(tag-tagstart)*2:]
 711                                                 for ph := 0; ph < 2; ph++ {
 712                                                         v := variants[ph]
 713                                                         if int(v) >= len(remap) {
 714                                                                 v = 0
 715                                                         } else {
 716                                                                 v = remap[v]
 717                                                         }
 718                                                         if v == rt.variant {
 719                                                                 // hgvsCol[*][ph][row] is already 0
 720                                                         } else if len(variantDiffs[v]) == 0 {
 721                                                                 // lacking coverage / couldn't be diffed
 722                                                                 for _, col := range hgvsCol {
 723                                                                         col[ph][row] = -1
 724                                                                 }
 725                                                         } else {
 726                                                                 for _, diff := range variantDiffs[v] {
 727                                                                         hgvsCol[diff][ph][row] = 1
 728                                                                 }
 729                                                         }
 730                                                 }
 731                                         }
 732                                         for diff, colpair := range hgvsCol {
 733                                                 allele2homhet(colpair)
 734                                                 if !cmd.filterHGVScolpair(colpair) {
 735                                                         delete(hgvsCol, diff)
 736                                                 }
 737                                         }
 738                                         if len(hgvsCol) > 0 {
 739                                                 encodeHGVSTodo[rt.seqname] <- hgvsCol
 740                                         }
 741                                 }
 742                                 outcol++
 743                         }
 744                         err = annow.Flush()
 745                         if err != nil {
 746                                 return err
 747                         }
 748                         err = annof.Close()
 749                         if err != nil {
 750                                 return err
 751                         }
 752
 753                         if *onehotChunked {
 754                                 // transpose onehotChunk[col][row] to numpy[row*ncols+col]
 755                                 rows := len(cmd.cgnames)
 756                                 cols := len(onehotChunk)
 757                                 log.Infof("%04d: preparing onehot numpy (rows=%d, cols=%d, mem=%d)", infileIdx, rows, cols, rows*cols)
 758                                 throttleNumpyMem.Acquire()
 759                                 out := onehotcols2int8(onehotChunk)
 760                                 fnm := fmt.Sprintf("%s/onehot.%04d.npy", *outputDir, infileIdx)
 761                                 err = writeNumpyInt8(fnm, out, rows, cols)
 762                                 if err != nil {
 763                                         return err
 764                                 }
 765                                 fnm = fmt.Sprintf("%s/onehot-columns.%04d.npy", *outputDir, infileIdx)
 766                                 err = writeNumpyInt32(fnm, onehotXref2int32(onehotXref), 4, len(onehotXref))
 767                                 if err != nil {
 768                                         return err
 769                                 }
 770                                 debug.FreeOSMemory()
 771                                 throttleNumpyMem.Release()
 772                         }
 773                         if *onehotSingle || *onlyPCA {
 774                                 onehotIndirect[infileIdx] = onehotChunk2Indirect(onehotChunk)
 775                                 onehotChunkSize[infileIdx] = uint32(len(onehotChunk))
 776                                 onehotXrefs[infileIdx] = onehotXref
 777                                 n := len(onehotIndirect[infileIdx][0])
 778                                 log.Infof("%04d: keeping onehot coordinates in memory (n=%d, mem=%d)", infileIdx, n, n*8*2)
 779                         }
 780                         if !(*onehotSingle || *onehotChunked || *onlyPCA) || *mergeOutput || *hgvsSingle {
 781                                 log.Infof("%04d: preparing numpy (rows=%d, cols=%d)", infileIdx, len(cmd.cgnames), 2*outcol)
 782                                 throttleNumpyMem.Acquire()
 783                                 rows := len(cmd.cgnames)
 784                                 cols := 2 * outcol
 785                                 out := make([]int16, rows*cols)
 786                                 for row, name := range cmd.cgnames {
 787                                         outidx := row * cols
 788                                         for col, v := range cgs[name].Variants {
 789                                                 tag := tagstart + tagID(col/2)
 790                                                 if cmd.filter.MaxTag >= 0 && tag > tagID(cmd.filter.MaxTag) {
 791                                                         break
 792                                                 }
 793                                                 if rt := reftile[tag]; rt == nil || rt.excluded {
 794                                                         continue
 795                                                 }
 796                                                 if v == 0 {
 797                                                         out[outidx] = 0 // tag not found / spanning tile
 798                                                 } else if variants, ok := seq[tag]; ok && int(v) < len(variants) && len(variants[v].Sequence) > 0 {
 799                                                         out[outidx] = int16(variantRemap[tag-tagstart][v])
 800                                                 } else {
 801                                                         out[outidx] = -1 // low quality tile variant
 802                                                 }
 803                                                 if tag == cmd.debugTag {
 804                                                         log.Printf("tag %d row %d col %d outidx %d v %d out %d", tag, row, col, outidx, v, out[outidx])
 805                                                 }
 806                                                 outidx++
 807                                         }
 808                                 }
 809                                 seq = nil
 810                                 cgs = nil
 811                                 debug.FreeOSMemory()
 812                                 throttleNumpyMem.Release()
 813                                 if *mergeOutput || *hgvsSingle {
 814                                         log.Infof("%04d: matrix fragment %d rows x %d cols", infileIdx, rows, cols)
 815                                         toMerge[infileIdx] = out
 816                                 }
 817                                 if !*mergeOutput && !*onehotChunked && !*onehotSingle {
 818                                         fnm := fmt.Sprintf("%s/matrix.%04d.npy", *outputDir, infileIdx)
 819                                         err = writeNumpyInt16(fnm, out, rows, cols)
 820                                         if err != nil {
 821                                                 return err
 822                                         }
 823                                 }
 824                         }
 825                         debug.FreeOSMemory()
 826                         log.Infof("%s: done (%d/%d)", infile, int(atomic.AddInt64(&done, 1)), len(infiles))
 827                         return nil
 828                 })
 829         }
 830         if err = throttleMem.Wait(); err != nil {
 831                 return err
 832         }
 833
 834         if *hgvsChunked {
 835                 log.Info("flushing hgvsCols temp files")
 836                 for seqname := range refseq {
 837                         close(encodeHGVSTodo[seqname])
 838                 }
 839                 err = encodeHGVS.Wait()
 840                 if err != nil {
 841                         return err
 842                 }
 843                 for seqname := range refseq {
 844                         log.Infof("%s: reading hgvsCols from temp file", seqname)
 845                         f := tmpHGVSCols[seqname]
 846                         _, err = f.Seek(0, io.SeekStart)
 847                         if err != nil {
 848                                 return err
 849                         }
 850                         var hgvsCols hgvsColSet
 851                         dec := gob.NewDecoder(bufio.NewReaderSize(f, 1<<24))
 852                         for err == nil {
 853                                 err = dec.Decode(&hgvsCols)
 854                         }
 855                         if err != io.EOF {
 856                                 return err
 857                         }
 858                         log.Infof("%s: sorting %d hgvs variants", seqname, len(hgvsCols))
 859                         variants := make([]hgvs.Variant, 0, len(hgvsCols))
 860                         for v := range hgvsCols {
 861                                 variants = append(variants, v)
 862                         }
 863                         sort.Slice(variants, func(i, j int) bool {
 864                                 vi, vj := &variants[i], &variants[j]
 865                                 if vi.Position != vj.Position {
 866                                         return vi.Position < vj.Position
 867                                 } else if vi.Ref != vj.Ref {
 868                                         return vi.Ref < vj.Ref
 869                                 } else {
 870                                         return vi.New < vj.New
 871                                 }
 872                         })
 873                         rows := len(cmd.cgnames)
 874                         cols := len(variants) * 2
 875                         log.Infof("%s: building hgvs matrix (rows=%d, cols=%d, mem=%d)", seqname, rows, cols, rows*cols)
 876                         out := make([]int8, rows*cols)
 877                         for varIdx, variant := range variants {
 878                                 hgvsCols := hgvsCols[variant]
 879                                 for row := range cmd.cgnames {
 880                                         for ph := 0; ph < 2; ph++ {
 881                                                 out[row*cols+varIdx+ph] = hgvsCols[ph][row]
 882                                         }
 883                                 }
 884                         }
 885                         err = writeNumpyInt8(fmt.Sprintf("%s/hgvs.%s.npy", *outputDir, seqname), out, rows, cols)
 886                         if err != nil {
 887                                 return err
 888                         }
 889                         out = nil
 890
 891                         fnm := fmt.Sprintf("%s/hgvs.%s.annotations.csv", *outputDir, seqname)
 892                         log.Infof("%s: writing hgvs column labels to %s", seqname, fnm)
 893                         var hgvsLabels bytes.Buffer
 894                         for varIdx, variant := range variants {
 895                                 fmt.Fprintf(&hgvsLabels, "%d,%s:g.%s\n", varIdx, seqname, variant.String())
 896                         }
 897                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0666)
 898                         if err != nil {
 899                                 return err
 900                         }
 901                 }
 902         }
 903
 904         if *mergeOutput || *hgvsSingle {
 905                 var annow *bufio.Writer
 906                 var annof *os.File
 907                 if *mergeOutput {
 908                         annoFilename := fmt.Sprintf("%s/matrix.annotations.csv", *outputDir)
 909                         annof, err = os.Create(annoFilename)
 910                         if err != nil {
 911                                 return err
 912                         }
 913                         annow = bufio.NewWriterSize(annof, 1<<20)
 914                 }
 915
 916                 rows := len(cmd.cgnames)
 917                 cols := 0
 918                 for _, chunk := range toMerge {
 919                         cols += len(chunk) / rows
 920                 }
 921                 log.Infof("merging output matrix (rows=%d, cols=%d, mem=%d) and annotations", rows, cols, rows*cols*2)
 922                 var out []int16
 923                 if *mergeOutput {
 924                         out = make([]int16, rows*cols)
 925                 }
 926                 hgvsCols := map[string][2][]int16{} // hgvs -> [[g0,g1,g2,...], [g0,g1,g2,...]] (slice of genomes for each phase)
 927                 startcol := 0
 928                 for outIdx, chunk := range toMerge {
 929                         chunkcols := len(chunk) / rows
 930                         if *mergeOutput {
 931                                 for row := 0; row < rows; row++ {
 932                                         copy(out[row*cols+startcol:], chunk[row*chunkcols:(row+1)*chunkcols])
 933                                 }
 934                         }
 935                         toMerge[outIdx] = nil
 936
 937                         annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, outIdx)
 938                         log.Infof("reading %s", annotationsFilename)
 939                         buf, err := os.ReadFile(annotationsFilename)
 940                         if err != nil {
 941                                 return err
 942                         }
 943                         if *mergeOutput {
 944                                 err = os.Remove(annotationsFilename)
 945                                 if err != nil {
 946                                         return err
 947                                 }
 948                         }
 949                         for _, line := range bytes.Split(buf, []byte{'\n'}) {
 950                                 if len(line) == 0 {
 951                                         continue
 952                                 }
 953                                 fields := bytes.SplitN(line, []byte{','}, 9)
 954                                 tag, _ := strconv.Atoi(string(fields[0]))
 955                                 incol, _ := strconv.Atoi(string(fields[1]))
 956                                 tileVariant, _ := strconv.Atoi(string(fields[2]))
 957                                 hgvsID := string(fields[3])
 958                                 seqname := string(fields[4])
 959                                 pos, _ := strconv.Atoi(string(fields[5]))
 960                                 refseq := fields[6]
 961                                 if hgvsID == "" {
 962                                         // Null entry for un-diffable
 963                                         // tile variant
 964                                         continue
 965                                 }
 966                                 if hgvsID == "=" {
 967                                         // Null entry for ref tile
 968                                         continue
 969                                 }
 970                                 if mask != nil && !mask.Check(strings.TrimPrefix(seqname, "chr"), pos, pos+len(refseq)) {
 971                                         // The tile intersects one of
 972                                         // the selected regions, but
 973                                         // this particular HGVS
 974                                         // variant does not.
 975                                         continue
 976                                 }
 977                                 hgvsColPair := hgvsCols[hgvsID]
 978                                 if hgvsColPair[0] == nil {
 979                                         // values in new columns start
 980                                         // out as -1 ("no data yet")
 981                                         // or 0 ("=ref") here, may
 982                                         // change to 1 ("hgvs variant
 983                                         // present") below, either on
 984                                         // this line or a future line.
 985                                         hgvsColPair = [2][]int16{make([]int16, len(cmd.cgnames)), make([]int16, len(cmd.cgnames))}
 986                                         rt, ok := reftile[tagID(tag)]
 987                                         if !ok {
 988                                                 err = fmt.Errorf("bug: seeing annotations for tag %d, but it has no reftile entry", tag)
 989                                                 return err
 990                                         }
 991                                         for ph := 0; ph < 2; ph++ {
 992                                                 for row := 0; row < rows; row++ {
 993                                                         v := chunk[row*chunkcols+incol*2+ph]
 994                                                         if tileVariantID(v) == rt.variant {
 995                                                                 hgvsColPair[ph][row] = 0
 996                                                         } else {
 997                                                                 hgvsColPair[ph][row] = -1
 998                                                         }
 999                                                 }
1000                                         }
1001                                         hgvsCols[hgvsID] = hgvsColPair
1002                                         if annow != nil {
1003                                                 hgvsref := hgvs.Variant{
1004                                                         Position: pos,
1005                                                         Ref:      string(refseq),
1006                                                         New:      string(refseq),
1007                                                 }
1008                                                 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])
1009                                         }
1010                                 }
1011                                 if annow != nil {
1012                                         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])
1013                                 }
1014                                 for ph := 0; ph < 2; ph++ {
1015                                         for row := 0; row < rows; row++ {
1016                                                 v := chunk[row*chunkcols+incol*2+ph]
1017                                                 if int(v) == tileVariant {
1018                                                         hgvsColPair[ph][row] = 1
1019                                                 }
1020                                         }
1021                                 }
1022                         }
1023
1024                         startcol += chunkcols
1025                 }
1026                 if *mergeOutput {
1027                         err = annow.Flush()
1028                         if err != nil {
1029                                 return err
1030                         }
1031                         err = annof.Close()
1032                         if err != nil {
1033                                 return err
1034                         }
1035                         err = writeNumpyInt16(fmt.Sprintf("%s/matrix.npy", *outputDir), out, rows, cols)
1036                         if err != nil {
1037                                 return err
1038                         }
1039                 }
1040                 out = nil
1041
1042                 if *hgvsSingle {
1043                         cols = len(hgvsCols) * 2
1044                         log.Printf("building hgvs-based matrix: %d rows x %d cols", rows, cols)
1045                         out = make([]int16, rows*cols)
1046                         hgvsIDs := make([]string, 0, cols/2)
1047                         for hgvsID := range hgvsCols {
1048                                 hgvsIDs = append(hgvsIDs, hgvsID)
1049                         }
1050                         sort.Strings(hgvsIDs)
1051                         var hgvsLabels bytes.Buffer
1052                         for idx, hgvsID := range hgvsIDs {
1053                                 fmt.Fprintf(&hgvsLabels, "%d,%s\n", idx, hgvsID)
1054                                 for ph := 0; ph < 2; ph++ {
1055                                         hgvscol := hgvsCols[hgvsID][ph]
1056                                         for row, val := range hgvscol {
1057                                                 out[row*cols+idx*2+ph] = val
1058                                         }
1059                                 }
1060                         }
1061                         err = writeNumpyInt16(fmt.Sprintf("%s/hgvs.npy", *outputDir), out, rows, cols)
1062                         if err != nil {
1063                                 return err
1064                         }
1065
1066                         fnm := fmt.Sprintf("%s/hgvs.annotations.csv", *outputDir)
1067                         log.Printf("writing hgvs labels: %s", fnm)
1068                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0777)
1069                         if err != nil {
1070                                 return err
1071                         }
1072                 }
1073         }
1074         if *onehotSingle || *onlyPCA {
1075                 nzCount := 0
1076                 for _, part := range onehotIndirect {
1077                         nzCount += len(part[0])
1078                 }
1079                 onehot := make([]uint32, nzCount*2) // [r,r,r,...,c,c,c,...]
1080                 var xrefs []onehotXref
1081                 chunkOffset := uint32(0)
1082                 outcol := 0
1083                 for i, part := range onehotIndirect {
1084                         for i := range part[1] {
1085                                 part[1][i] += chunkOffset
1086                         }
1087                         copy(onehot[outcol:], part[0])
1088                         copy(onehot[outcol+nzCount:], part[1])
1089                         xrefs = append(xrefs, onehotXrefs[i]...)
1090
1091                         outcol += len(part[0])
1092                         chunkOffset += onehotChunkSize[i]
1093
1094                         part[0] = nil
1095                         part[1] = nil
1096                         onehotXrefs[i] = nil
1097                         debug.FreeOSMemory()
1098                 }
1099                 if *onehotSingle {
1100                         fnm := fmt.Sprintf("%s/onehot.npy", *outputDir)
1101                         err = writeNumpyUint32(fnm, onehot, 2, nzCount)
1102                         if err != nil {
1103                                 return err
1104                         }
1105                         fnm = fmt.Sprintf("%s/onehot-columns.npy", *outputDir)
1106                         err = writeNumpyInt32(fnm, onehotXref2int32(xrefs), 5, len(xrefs))
1107                         if err != nil {
1108                                 return err
1109                         }
1110                 }
1111                 if *onlyPCA {
1112                         cols := 0
1113                         for _, c := range onehot[nzCount:] {
1114                                 if int(c) >= cols {
1115                                         cols = int(c) + 1
1116                                 }
1117                         }
1118                         if cols == 0 {
1119                                 return fmt.Errorf("cannot do PCA: one-hot matrix is empty")
1120                         }
1121                         log.Printf("creating matrix: %d rows, %d cols", len(cmd.cgnames), cols)
1122                         mtx := mat.NewDense(len(cmd.cgnames), cols, nil)
1123                         for i, c := range onehot[nzCount:] {
1124                                 mtx.Set(int(onehot[i]), int(c), 1)
1125                         }
1126                         log.Print("fitting")
1127                         transformer := nlp.NewPCA(*pcaComponents)
1128                         transformer.Fit(mtx.T())
1129                         log.Printf("transforming")
1130                         pca, err := transformer.Transform(mtx.T())
1131                         if err != nil {
1132                                 return err
1133                         }
1134                         pca = pca.T()
1135                         outrows, outcols := pca.Dims()
1136                         log.Printf("copying result to numpy output array: %d rows, %d cols", outrows, outcols)
1137                         out := make([]float64, outrows*outcols)
1138                         for i := 0; i < outrows; i++ {
1139                                 for j := 0; j < outcols; j++ {
1140                                         out[i*outcols+j] = pca.At(i, j)
1141                                 }
1142                         }
1143                         fnm := fmt.Sprintf("%s/pca.npy", *outputDir)
1144                         log.Printf("writing numpy: %s", fnm)
1145                         output, err := os.OpenFile(fnm, os.O_CREATE|os.O_TRUNC|os.O_WRONLY, 0777)
1146                         if err != nil {
1147                                 return err
1148                         }
1149                         npw, err := gonpy.NewWriter(nopCloser{output})
1150                         if err != nil {
1151                                 return fmt.Errorf("gonpy.NewWriter: %w", err)
1152                         }
1153                         npw.Shape = []int{outrows, outcols}
1154                         err = npw.WriteFloat64(out)
1155                         if err != nil {
1156                                 return fmt.Errorf("WriteFloat64: %w", err)
1157                         }
1158                         err = output.Close()
1159                         if err != nil {
1160                                 return err
1161                         }
1162                         log.Print("done")
1163                 }
1164         }
1165         if !*mergeOutput && !*onehotChunked && !*onehotSingle && !*onlyPCA {
1166                 tagoffsetFilename := *outputDir + "/chunk-tag-offset.csv"
1167                 log.Infof("writing tag offsets to %s", tagoffsetFilename)
1168                 var f *os.File
1169                 f, err = os.Create(tagoffsetFilename)
1170                 if err != nil {
1171                         return err
1172                 }
1173                 defer f.Close()
1174                 for idx, offset := range chunkStartTag {
1175                         _, err = fmt.Fprintf(f, "%q,%d\n", fmt.Sprintf("matrix.%04d.npy", idx), offset)
1176                         if err != nil {
1177                                 err = fmt.Errorf("write %s: %w", tagoffsetFilename, err)
1178                                 return err
1179                         }
1180                 }
1181                 err = f.Close()
1182                 if err != nil {
1183                         err = fmt.Errorf("close %s: %w", tagoffsetFilename, err)
1184                         return err
1185                 }
1186         }
1187         return nil
1188 }
1189
1190 // Read case/control files, remove non-case/control entries from
1191 // cmd.cgnames, and build cmd.chi2Cases.
1192 func (cmd *sliceNumpy) useCaseControlFiles() error {
1193         if cmd.chi2CaseControlFile == "" {
1194                 return nil
1195         }
1196         infiles, err := allFiles(cmd.chi2CaseControlFile, nil)
1197         if err != nil {
1198                 return err
1199         }
1200         // index in cmd.cgnames => case(true) / control(false)
1201         cc := map[int]bool{}
1202         for _, infile := range infiles {
1203                 f, err := open(infile)
1204                 if err != nil {
1205                         return err
1206                 }
1207                 buf, err := io.ReadAll(f)
1208                 f.Close()
1209                 if err != nil {
1210                         return err
1211                 }
1212                 ccCol := -1
1213                 for _, tsv := range bytes.Split(buf, []byte{'\n'}) {
1214                         if len(tsv) == 0 {
1215                                 continue
1216                         }
1217                         split := strings.Split(string(tsv), "\t")
1218                         if ccCol < 0 {
1219                                 // header row
1220                                 for col, name := range split {
1221                                         if name == cmd.chi2CaseControlColumn {
1222                                                 ccCol = col
1223                                                 break
1224                                         }
1225                                 }
1226                                 if ccCol < 0 {
1227                                         return fmt.Errorf("%s: no column named %q in header row %q", infile, cmd.chi2CaseControlColumn, tsv)
1228                                 }
1229                                 continue
1230                         }
1231                         if len(split) <= ccCol {
1232                                 continue
1233                         }
1234                         pattern := split[0]
1235                         found := -1
1236                         for i, name := range cmd.cgnames {
1237                                 if strings.Contains(name, pattern) {
1238                                         if found >= 0 {
1239                                                 log.Warnf("pattern %q in %s matches multiple genome IDs (%qs, %q)", pattern, infile, cmd.cgnames[found], name)
1240                                         }
1241                                         found = i
1242                                 }
1243                         }
1244                         if found < 0 {
1245                                 log.Warnf("pattern %q in %s does not match any genome IDs", pattern, infile)
1246                                 continue
1247                         }
1248                         if split[ccCol] == "0" {
1249                                 cc[found] = false
1250                         }
1251                         if split[ccCol] == "1" {
1252                                 cc[found] = true
1253                         }
1254                 }
1255         }
1256         allnames := cmd.cgnames
1257         cmd.cgnames = nil
1258         cmd.chi2Cases = nil
1259         ncases := 0
1260         for i, name := range allnames {
1261                 if cc, ok := cc[i]; ok {
1262                         cmd.cgnames = append(cmd.cgnames, name)
1263                         cmd.chi2Cases = append(cmd.chi2Cases, cc)
1264                         if cc {
1265                                 ncases++
1266                         }
1267                 }
1268         }
1269         log.Printf("%d cases, %d controls, %d neither (dropped)", ncases, len(cmd.cgnames)-ncases, len(allnames)-len(cmd.cgnames))
1270         return nil
1271 }
1272
1273 func (cmd *sliceNumpy) filterHGVScolpair(colpair [2][]int8) bool {
1274         if cmd.chi2PValue >= 1 {
1275                 return true
1276         }
1277         col0 := make([]bool, 0, len(cmd.chi2Cases))
1278         col1 := make([]bool, 0, len(cmd.chi2Cases))
1279         cases := make([]bool, 0, len(cmd.chi2Cases))
1280         for i, c := range cmd.chi2Cases {
1281                 if colpair[0][i] < 0 {
1282                         continue
1283                 }
1284                 col0 = append(col0, colpair[0][i] != 0)
1285                 col1 = append(col1, colpair[1][i] != 0)
1286                 cases = append(cases, c)
1287         }
1288         return len(cases) >= cmd.minCoverage &&
1289                 (pvalue(col0, cases) <= cmd.chi2PValue || pvalue(col1, cases) <= cmd.chi2PValue)
1290 }
1291
1292 func writeNumpyUint32(fnm string, out []uint32, rows, cols int) error {
1293         output, err := os.Create(fnm)
1294         if err != nil {
1295                 return err
1296         }
1297         defer output.Close()
1298         bufw := bufio.NewWriterSize(output, 1<<26)
1299         npw, err := gonpy.NewWriter(nopCloser{bufw})
1300         if err != nil {
1301                 return err
1302         }
1303         log.WithFields(log.Fields{
1304                 "filename": fnm,
1305                 "rows":     rows,
1306                 "cols":     cols,
1307                 "bytes":    rows * cols * 4,
1308         }).Infof("writing numpy: %s", fnm)
1309         npw.Shape = []int{rows, cols}
1310         npw.WriteUint32(out)
1311         err = bufw.Flush()
1312         if err != nil {
1313                 return err
1314         }
1315         return output.Close()
1316 }
1317
1318 func writeNumpyInt32(fnm string, out []int32, rows, cols int) error {
1319         output, err := os.Create(fnm)
1320         if err != nil {
1321                 return err
1322         }
1323         defer output.Close()
1324         bufw := bufio.NewWriterSize(output, 1<<26)
1325         npw, err := gonpy.NewWriter(nopCloser{bufw})
1326         if err != nil {
1327                 return err
1328         }
1329         log.WithFields(log.Fields{
1330                 "filename": fnm,
1331                 "rows":     rows,
1332                 "cols":     cols,
1333                 "bytes":    rows * cols * 4,
1334         }).Infof("writing numpy: %s", fnm)
1335         npw.Shape = []int{rows, cols}
1336         npw.WriteInt32(out)
1337         err = bufw.Flush()
1338         if err != nil {
1339                 return err
1340         }
1341         return output.Close()
1342 }
1343
1344 func writeNumpyInt16(fnm string, out []int16, rows, cols int) error {
1345         output, err := os.Create(fnm)
1346         if err != nil {
1347                 return err
1348         }
1349         defer output.Close()
1350         bufw := bufio.NewWriterSize(output, 1<<26)
1351         npw, err := gonpy.NewWriter(nopCloser{bufw})
1352         if err != nil {
1353                 return err
1354         }
1355         log.WithFields(log.Fields{
1356                 "filename": fnm,
1357                 "rows":     rows,
1358                 "cols":     cols,
1359                 "bytes":    rows * cols * 2,
1360         }).Infof("writing numpy: %s", fnm)
1361         npw.Shape = []int{rows, cols}
1362         npw.WriteInt16(out)
1363         err = bufw.Flush()
1364         if err != nil {
1365                 return err
1366         }
1367         return output.Close()
1368 }
1369
1370 func writeNumpyInt8(fnm string, out []int8, rows, cols int) error {
1371         output, err := os.Create(fnm)
1372         if err != nil {
1373                 return err
1374         }
1375         defer output.Close()
1376         bufw := bufio.NewWriterSize(output, 1<<26)
1377         npw, err := gonpy.NewWriter(nopCloser{bufw})
1378         if err != nil {
1379                 return err
1380         }
1381         log.WithFields(log.Fields{
1382                 "filename": fnm,
1383                 "rows":     rows,
1384                 "cols":     cols,
1385                 "bytes":    rows * cols,
1386         }).Infof("writing numpy: %s", fnm)
1387         npw.Shape = []int{rows, cols}
1388         npw.WriteInt8(out)
1389         err = bufw.Flush()
1390         if err != nil {
1391                 return err
1392         }
1393         return output.Close()
1394 }
1395
1396 func allele2homhet(colpair [2][]int8) {
1397         a, b := colpair[0], colpair[1]
1398         for i, av := range a {
1399                 bv := b[i]
1400                 if av < 0 || bv < 0 {
1401                         // no-call
1402                         a[i], b[i] = -1, -1
1403                 } else if av > 0 && bv > 0 {
1404                         // hom
1405                         a[i], b[i] = 1, 0
1406                 } else if av > 0 || bv > 0 {
1407                         // het
1408                         a[i], b[i] = 0, 1
1409                 } else {
1410                         // ref (or a different variant in same position)
1411                         // (this is a no-op) a[i], b[i] = 0, 0
1412                 }
1413         }
1414 }
1415
1416 type onehotXref struct {
1417         tag     tagID
1418         variant tileVariantID
1419         hom     bool
1420         pvalue  float64
1421 }
1422
1423 const onehotXrefSize = unsafe.Sizeof(onehotXref{})
1424
1425 // Build onehot matrix (m[tileVariantIndex][genome] == 0 or 1) for all
1426 // variants of a single tile/tag#.
1427 //
1428 // Return nil if no tile variant passes Χ² filter.
1429 func (cmd *sliceNumpy) tv2homhet(cgs map[string]CompactGenome, maxv tileVariantID, remap []tileVariantID, tag, chunkstarttag tagID, seq map[tagID][]TileVariant) ([][]int8, []onehotXref) {
1430         if tag == cmd.debugTag {
1431                 tv := make([]tileVariantID, len(cmd.cgnames)*2)
1432                 for i, name := range cmd.cgnames {
1433                         copy(tv[i*2:(i+1)*2], cgs[name].Variants[(tag-chunkstarttag)*2:])
1434                 }
1435                 log.WithFields(logrus.Fields{
1436                         "cgs[i].Variants[tag*2+j]": tv,
1437                         "maxv":                     maxv,
1438                         "remap":                    remap,
1439                         "tag":                      tag,
1440                         "chunkstarttag":            chunkstarttag,
1441                 }).Info("tv2homhet()")
1442         }
1443         if maxv < 1 || (maxv < 2 && !cmd.includeVariant1) {
1444                 // everyone has the most common variant (of the variants we don't drop)
1445                 return nil, nil
1446         }
1447         tagoffset := tag - chunkstarttag
1448         coverage := 0
1449         for _, cg := range cgs {
1450                 alleles := 0
1451                 for _, v := range cg.Variants[tagoffset*2 : tagoffset*2+2] {
1452                         if v > 0 && int(v) < len(seq[tag]) && len(seq[tag][v].Sequence) > 0 {
1453                                 alleles++
1454                         }
1455                 }
1456                 if alleles == 2 {
1457                         coverage++
1458                 }
1459         }
1460         if coverage < cmd.minCoverage {
1461                 return nil, nil
1462         }
1463         obs := make([][]bool, (maxv+1)*2) // 2 slices (hom + het) for each variant#
1464         for i := range obs {
1465                 obs[i] = make([]bool, len(cmd.cgnames))
1466         }
1467         for cgid, name := range cmd.cgnames {
1468                 cgvars := cgs[name].Variants[tagoffset*2:]
1469                 tv0, tv1 := remap[cgvars[0]], remap[cgvars[1]]
1470                 for v := tileVariantID(1); v <= maxv; v++ {
1471                         if tv0 == v && tv1 == v {
1472                                 obs[v*2][cgid] = true
1473                         } else if tv0 == v || tv1 == v {
1474                                 obs[v*2+1][cgid] = true
1475                         }
1476                 }
1477         }
1478         var onehot [][]int8
1479         var xref []onehotXref
1480         for col := 2; col < len(obs); col++ {
1481                 // col 0,1 correspond to tile variant 0, i.e.,
1482                 // no-call; col 2,3 correspond to the most common
1483                 // variant; so we (normally) start at col 4.
1484                 if col < 4 && !cmd.includeVariant1 {
1485                         continue
1486                 }
1487                 p := pvalue(obs[col], cmd.chi2Cases)
1488                 if cmd.chi2PValue < 1 && !(p < cmd.chi2PValue) {
1489                         continue
1490                 }
1491                 onehot = append(onehot, bool2int8(obs[col]))
1492                 xref = append(xref, onehotXref{
1493                         tag:     tag,
1494                         variant: tileVariantID(col >> 1),
1495                         hom:     col&1 == 0,
1496                         pvalue:  p,
1497                 })
1498         }
1499         return onehot, xref
1500 }
1501
1502 func bool2int8(in []bool) []int8 {
1503         out := make([]int8, len(in))
1504         for i, v := range in {
1505                 if v {
1506                         out[i] = 1
1507                 }
1508         }
1509         return out
1510 }
1511
1512 // convert a []onehotXref with length N to a numpy-style []int32
1513 // matrix with N columns, one row per field of onehotXref struct.
1514 //
1515 // Hom/het row contains hom=0, het=1.
1516 //
1517 // P-value row contains 1000000x actual p-value.
1518 func onehotXref2int32(xrefs []onehotXref) []int32 {
1519         xcols := len(xrefs)
1520         xdata := make([]int32, 5*xcols)
1521         for i, xref := range xrefs {
1522                 xdata[i] = int32(xref.tag)
1523                 xdata[xcols+i] = int32(xref.variant)
1524                 if xref.hom {
1525                         xdata[xcols*2+i] = 1
1526                 }
1527                 xdata[xcols*3+i] = int32(xref.pvalue * 1000000)
1528                 xdata[xcols*4+i] = int32(-math.Log10(xref.pvalue) * 1000000)
1529         }
1530         return xdata
1531 }
1532
1533 // transpose onehot data from in[col][row] to numpy-style
1534 // out[row*cols+col].
1535 func onehotcols2int8(in [][]int8) []int8 {
1536         if len(in) == 0 {
1537                 return nil
1538         }
1539         cols := len(in)
1540         rows := len(in[0])
1541         out := make([]int8, rows*cols)
1542         for row := 0; row < rows; row++ {
1543                 outrow := out[row*cols:]
1544                 for col, incol := range in {
1545                         outrow[col] = incol[row]
1546                 }
1547         }
1548         return out
1549 }
1550
1551 // Return [2][]uint32{rowIndices, colIndices} indicating which
1552 // elements of matrixT[c][r] have non-zero values.
1553 func onehotChunk2Indirect(matrixT [][]int8) [2][]uint32 {
1554         var nz [2][]uint32
1555         for c, col := range matrixT {
1556                 for r, val := range col {
1557                         if val != 0 {
1558                                 nz[0] = append(nz[0], uint32(r))
1559                                 nz[1] = append(nz[1], uint32(c))
1560                         }
1561                 }
1562         }
1563         return nz
1564 }