slicenumpy.go

   1 // Copyright (C) The Lightning Authors. All rights reserved.
   2 //
   3 // SPDX-License-Identifier: AGPL-3.0
   4
   5 package lightning
   6
   7 import (
   8         "bufio"
   9         "bytes"
  10         "encoding/gob"
  11         "flag"
  12         "fmt"
  13         "io"
  14         "io/ioutil"
  15         "math"
  16         "net/http"
  17         _ "net/http/pprof"
  18         "os"
  19         "regexp"
  20         "runtime"
  21         "runtime/debug"
  22         "sort"
  23         "strconv"
  24         "strings"
  25         "sync/atomic"
  26         "unsafe"
  27
  28         "git.arvados.org/arvados.git/sdk/go/arvados"
  29         "github.com/arvados/lightning/hgvs"
  30         "github.com/kshedden/gonpy"
  31         log "github.com/sirupsen/logrus"
  32         "golang.org/x/crypto/blake2b"
  33 )
  34
  35 type sliceNumpy struct {
  36         filter                filter
  37         threads               int
  38         chi2CaseControlColumn string
  39         chi2CaseControlFile   string
  40         chi2Cases             []bool
  41         chi2PValue            float64
  42         minCoverage           int
  43         cgnames               []string
  44 }
  45
  46 func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, stdout, stderr io.Writer) int {
  47         var err error
  48         defer func() {
  49                 if err != nil {
  50                         fmt.Fprintf(stderr, "%s\n", err)
  51                 }
  52         }()
  53         flags := flag.NewFlagSet("", flag.ContinueOnError)
  54         flags.SetOutput(stderr)
  55         pprof := flags.String("pprof", "", "serve Go profile data at http://`[addr]:port`")
  56         runlocal := flags.Bool("local", false, "run on local host (default: run in an arvados container)")
  57         projectUUID := flags.String("project", "", "project `UUID` for output data")
  58         priority := flags.Int("priority", 500, "container request priority")
  59         inputDir := flags.String("input-dir", "./in", "input `directory`")
  60         outputDir := flags.String("output-dir", "./out", "output `directory`")
  61         ref := flags.String("ref", "", "reference name (if blank, choose last one that appears in input)")
  62         regionsFilename := flags.String("regions", "", "only output columns/annotations that intersect regions in specified bed `file`")
  63         expandRegions := flags.Int("expand-regions", 0, "expand specified regions by `N` base pairs on each side`")
  64         mergeOutput := flags.Bool("merge-output", false, "merge output into one matrix.npy and one matrix.annotations.csv")
  65         hgvsSingle := flags.Bool("single-hgvs-matrix", false, "also generate hgvs-based matrix")
  66         hgvsChunked := flags.Bool("chunked-hgvs-matrix", false, "also generate hgvs-based matrix per chromosome")
  67         onehotSingle := flags.Bool("single-onehot", false, "generate one-hot tile-based matrix")
  68         onehotChunked := flags.Bool("chunked-onehot", false, "generate one-hot tile-based matrix per input chunk")
  69         flags.IntVar(&cmd.threads, "threads", 16, "number of memory-hungry assembly threads")
  70         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)")
  71         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)")
  72         flags.Float64Var(&cmd.chi2PValue, "chi2-p-value", 1, "do Χ² test and omit columns with p-value above this threshold")
  73         cmd.filter.Flags(flags)
  74         err = flags.Parse(args)
  75         if err == flag.ErrHelp {
  76                 err = nil
  77                 return 0
  78         } else if err != nil {
  79                 return 2
  80         }
  81
  82         if *pprof != "" {
  83                 go func() {
  84                         log.Println(http.ListenAndServe(*pprof, nil))
  85                 }()
  86         }
  87
  88         if cmd.chi2PValue != 1 && (cmd.chi2CaseControlFile == "" || cmd.chi2CaseControlColumn == "") {
  89                 log.Errorf("cannot use provided -chi2-p-value=%f because -chi2-case-control-file= or -chi2-case-control-column= value is empty", cmd.chi2PValue)
  90                 return 2
  91         }
  92
  93         if !*runlocal {
  94                 runner := arvadosContainerRunner{
  95                         Name:        "lightning slice-numpy",
  96                         Client:      arvados.NewClientFromEnv(),
  97                         ProjectUUID: *projectUUID,
  98                         RAM:         750000000000,
  99                         VCPUs:       96,
 100                         Priority:    *priority,
 101                         KeepCache:   2,
 102                         APIAccess:   true,
 103                 }
 104                 err = runner.TranslatePaths(inputDir, regionsFilename, &cmd.chi2CaseControlFile)
 105                 if err != nil {
 106                         return 1
 107                 }
 108                 runner.Args = []string{"slice-numpy", "-local=true",
 109                         "-pprof=:6060",
 110                         "-input-dir=" + *inputDir,
 111                         "-output-dir=/mnt/output",
 112                         "-threads=" + fmt.Sprintf("%d", cmd.threads),
 113                         "-regions=" + *regionsFilename,
 114                         "-expand-regions=" + fmt.Sprintf("%d", *expandRegions),
 115                         "-merge-output=" + fmt.Sprintf("%v", *mergeOutput),
 116                         "-single-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsSingle),
 117                         "-chunked-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsChunked),
 118                         "-single-onehot=" + fmt.Sprintf("%v", *onehotSingle),
 119                         "-chunked-onehot=" + fmt.Sprintf("%v", *onehotChunked),
 120                         "-chi2-case-control-file=" + cmd.chi2CaseControlFile,
 121                         "-chi2-case-control-column=" + cmd.chi2CaseControlColumn,
 122                         "-chi2-p-value=" + fmt.Sprintf("%f", cmd.chi2PValue),
 123                 }
 124                 runner.Args = append(runner.Args, cmd.filter.Args()...)
 125                 var output string
 126                 output, err = runner.Run()
 127                 if err != nil {
 128                         return 1
 129                 }
 130                 fmt.Fprintln(stdout, output)
 131                 return 0
 132         }
 133
 134         infiles, err := allFiles(*inputDir, matchGobFile)
 135         if err != nil {
 136                 return 1
 137         }
 138         if len(infiles) == 0 {
 139                 err = fmt.Errorf("no input files found in %s", *inputDir)
 140                 return 1
 141         }
 142         sort.Strings(infiles)
 143
 144         var refseq map[string][]tileLibRef
 145         var reftiledata = make(map[tileLibRef][]byte, 11000000)
 146         in0, err := open(infiles[0])
 147         if err != nil {
 148                 return 1
 149         }
 150
 151         matchGenome, err := regexp.Compile(cmd.filter.MatchGenome)
 152         if err != nil {
 153                 err = fmt.Errorf("-match-genome: invalid regexp: %q", cmd.filter.MatchGenome)
 154                 return 1
 155         }
 156
 157         cmd.cgnames = nil
 158         var tagset [][]byte
 159         DecodeLibrary(in0, strings.HasSuffix(infiles[0], ".gz"), func(ent *LibraryEntry) error {
 160                 if len(ent.TagSet) > 0 {
 161                         tagset = ent.TagSet
 162                 }
 163                 for _, cseq := range ent.CompactSequences {
 164                         if cseq.Name == *ref || *ref == "" {
 165                                 refseq = cseq.TileSequences
 166                         }
 167                 }
 168                 for _, cg := range ent.CompactGenomes {
 169                         if matchGenome.MatchString(cg.Name) {
 170                                 cmd.cgnames = append(cmd.cgnames, cg.Name)
 171                         }
 172                 }
 173                 for _, tv := range ent.TileVariants {
 174                         if tv.Ref {
 175                                 reftiledata[tileLibRef{tv.Tag, tv.Variant}] = tv.Sequence
 176                         }
 177                 }
 178                 return nil
 179         })
 180         if err != nil {
 181                 return 1
 182         }
 183         in0.Close()
 184         if refseq == nil {
 185                 err = fmt.Errorf("%s: reference sequence not found", infiles[0])
 186                 return 1
 187         }
 188         if len(tagset) == 0 {
 189                 err = fmt.Errorf("tagset not found")
 190                 return 1
 191         }
 192
 193         taglib := &tagLibrary{}
 194         err = taglib.setTags(tagset)
 195         if err != nil {
 196                 return 1
 197         }
 198         taglen := taglib.TagLen()
 199
 200         if len(cmd.cgnames) == 0 {
 201                 err = fmt.Errorf("no genomes found matching regexp %q", cmd.filter.MatchGenome)
 202                 return 1
 203         }
 204         sort.Strings(cmd.cgnames)
 205         err = cmd.useCaseControlFiles()
 206         if err != nil {
 207                 return 1
 208         }
 209         cmd.minCoverage = int(math.Ceil(cmd.filter.MinCoverage * float64(len(cmd.cgnames))))
 210
 211         {
 212                 labelsFilename := *outputDir + "/samples.csv"
 213                 log.Infof("writing labels to %s", labelsFilename)
 214                 var f *os.File
 215                 f, err = os.Create(labelsFilename)
 216                 if err != nil {
 217                         return 1
 218                 }
 219                 defer f.Close()
 220                 for i, name := range cmd.cgnames {
 221                         cc := 0
 222                         if cmd.chi2Cases != nil && cmd.chi2Cases[i] {
 223                                 cc = 1
 224                         }
 225                         _, err = fmt.Fprintf(f, "%d,%q,%d\n", i, trimFilenameForLabel(name), cc)
 226                         if err != nil {
 227                                 err = fmt.Errorf("write %s: %w", labelsFilename, err)
 228                                 return 1
 229                         }
 230                 }
 231                 err = f.Close()
 232                 if err != nil {
 233                         err = fmt.Errorf("close %s: %w", labelsFilename, err)
 234                         return 1
 235                 }
 236         }
 237
 238         log.Info("indexing reference tiles")
 239         type reftileinfo struct {
 240                 variant  tileVariantID
 241                 seqname  string // chr1
 242                 pos      int    // distance from start of chromosome to starttag
 243                 tiledata []byte // acgtggcaa...
 244         }
 245         isdup := map[tagID]bool{}
 246         reftile := map[tagID]*reftileinfo{}
 247         for seqname, cseq := range refseq {
 248                 pos := 0
 249                 for _, libref := range cseq {
 250                         tiledata := reftiledata[libref]
 251                         if len(tiledata) == 0 {
 252                                 err = fmt.Errorf("missing tiledata for tag %d variant %d in %s in ref", libref.Tag, libref.Variant, seqname)
 253                                 return 1
 254                         }
 255                         foundthistag := false
 256                         taglib.FindAll(tiledata[:len(tiledata)-1], func(tagid tagID, offset, _ int) {
 257                                 if !foundthistag && tagid == libref.Tag {
 258                                         foundthistag = true
 259                                         return
 260                                 }
 261                                 if dupref, ok := reftile[tagid]; ok {
 262                                         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)
 263                                         delete(reftile, tagid)
 264                                 } else {
 265                                         log.Printf("found tag %d at offset %d inside tile variant %+v on %s @ %d", tagid, offset, libref, seqname, pos+offset+1)
 266                                 }
 267                                 isdup[tagid] = true
 268                         })
 269                         if isdup[libref.Tag] {
 270                                 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
 271                         } else if reftile[libref.Tag] != nil {
 272                                 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)
 273                                 delete(reftile, libref.Tag)
 274                                 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
 275                                 isdup[libref.Tag] = true
 276                         } else {
 277                                 reftile[libref.Tag] = &reftileinfo{
 278                                         seqname:  seqname,
 279                                         variant:  libref.Variant,
 280                                         tiledata: tiledata,
 281                                         pos:      pos,
 282                                 }
 283                         }
 284                         pos += len(tiledata) - taglen
 285                 }
 286                 log.Printf("... %s done, len %d", seqname, pos+taglen)
 287         }
 288
 289         var mask *mask
 290         if *regionsFilename != "" {
 291                 log.Printf("loading regions from %s", *regionsFilename)
 292                 mask, err = makeMask(*regionsFilename, *expandRegions)
 293                 if err != nil {
 294                         return 1
 295                 }
 296                 log.Printf("before applying mask, len(reftile) == %d", len(reftile))
 297                 log.Printf("deleting reftile entries for regions outside %d intervals", mask.Len())
 298                 for tag, rt := range reftile {
 299                         if !mask.Check(strings.TrimPrefix(rt.seqname, "chr"), rt.pos, rt.pos+len(rt.tiledata)) {
 300                                 delete(reftile, tag)
 301                         }
 302                 }
 303                 log.Printf("after applying mask, len(reftile) == %d", len(reftile))
 304         }
 305
 306         type hgvsColSet map[hgvs.Variant][2][]int8
 307         encodeHGVS := throttle{Max: len(refseq)}
 308         encodeHGVSTodo := map[string]chan hgvsColSet{}
 309         tmpHGVSCols := map[string]*os.File{}
 310         if *hgvsChunked {
 311                 for seqname := range refseq {
 312                         var f *os.File
 313                         f, err = os.Create(*outputDir + "/tmp." + seqname + ".gob")
 314                         if err != nil {
 315                                 return 1
 316                         }
 317                         defer os.Remove(f.Name())
 318                         bufw := bufio.NewWriterSize(f, 1<<24)
 319                         enc := gob.NewEncoder(bufw)
 320                         tmpHGVSCols[seqname] = f
 321                         todo := make(chan hgvsColSet, 128)
 322                         encodeHGVSTodo[seqname] = todo
 323                         encodeHGVS.Go(func() error {
 324                                 for colset := range todo {
 325                                         err := enc.Encode(colset)
 326                                         if err != nil {
 327                                                 encodeHGVS.Report(err)
 328                                                 for range todo {
 329                                                 }
 330                                                 return err
 331                                         }
 332                                 }
 333                                 return bufw.Flush()
 334                         })
 335                 }
 336         }
 337
 338         var toMerge [][]int16
 339         if *mergeOutput || *hgvsSingle {
 340                 toMerge = make([][]int16, len(infiles))
 341         }
 342         var onehotIndirect [][2][]uint32 // [chunkIndex][axis][index]
 343         var onehotXrefs [][]onehotXref
 344         if *onehotSingle {
 345                 onehotIndirect = make([][2][]uint32, len(infiles))
 346                 onehotXrefs = make([][]onehotXref, len(infiles))
 347         }
 348
 349         throttleMem := throttle{Max: cmd.threads} // TODO: estimate using mem and data size
 350         throttleNumpyMem := throttle{Max: cmd.threads/2 + 1}
 351         log.Info("generating annotations and numpy matrix for each slice")
 352         var done int64
 353         for infileIdx, infile := range infiles {
 354                 infileIdx, infile := infileIdx, infile
 355                 throttleMem.Go(func() error {
 356                         seq := make(map[tagID][]TileVariant, 50000)
 357                         cgs := make(map[string]CompactGenome, len(cmd.cgnames))
 358                         f, err := open(infile)
 359                         if err != nil {
 360                                 return err
 361                         }
 362                         defer f.Close()
 363                         log.Infof("%04d: reading %s", infileIdx, infile)
 364                         err = DecodeLibrary(f, strings.HasSuffix(infile, ".gz"), func(ent *LibraryEntry) error {
 365                                 for _, tv := range ent.TileVariants {
 366                                         if tv.Ref {
 367                                                 continue
 368                                         }
 369                                         if mask != nil && reftile[tv.Tag] == nil {
 370                                                 // Don't waste
 371                                                 // time/memory on
 372                                                 // masked-out tiles.
 373                                                 continue
 374                                         }
 375                                         variants := seq[tv.Tag]
 376                                         if len(variants) == 0 {
 377                                                 variants = make([]TileVariant, 100)
 378                                         }
 379                                         for len(variants) <= int(tv.Variant) {
 380                                                 variants = append(variants, TileVariant{})
 381                                         }
 382                                         variants[int(tv.Variant)] = tv
 383                                         seq[tv.Tag] = variants
 384                                 }
 385                                 for _, cg := range ent.CompactGenomes {
 386                                         if !matchGenome.MatchString(cg.Name) {
 387                                                 continue
 388                                         }
 389                                         // pad to full slice size
 390                                         // to avoid out-of-bounds
 391                                         // checks later
 392                                         if sliceSize := 2 * int(cg.EndTag-cg.StartTag); len(cg.Variants) < sliceSize {
 393                                                 cg.Variants = append(cg.Variants, make([]tileVariantID, sliceSize-len(cg.Variants))...)
 394                                         }
 395                                         cgs[cg.Name] = cg
 396                                 }
 397                                 return nil
 398                         })
 399                         if err != nil {
 400                                 return err
 401                         }
 402                         tagstart := cgs[cmd.cgnames[0]].StartTag
 403                         tagend := cgs[cmd.cgnames[0]].EndTag
 404
 405                         // TODO: filters
 406
 407                         log.Infof("%04d: renumber/dedup variants for tags %d-%d", infileIdx, tagstart, tagend)
 408                         variantRemap := make([][]tileVariantID, tagend-tagstart)
 409                         throttleCPU := throttle{Max: runtime.GOMAXPROCS(0)}
 410                         for tag, variants := range seq {
 411                                 tag, variants := tag, variants
 412                                 throttleCPU.Acquire()
 413                                 go func() {
 414                                         defer throttleCPU.Release()
 415                                         count := make(map[[blake2b.Size256]byte]int, len(variants))
 416
 417                                         rt := reftile[tag]
 418                                         if rt != nil {
 419                                                 count[blake2b.Sum256(rt.tiledata)] = 0
 420                                         }
 421
 422                                         for _, cg := range cgs {
 423                                                 idx := int(tag-tagstart) * 2
 424                                                 for allele := 0; allele < 2; allele++ {
 425                                                         v := cg.Variants[idx+allele]
 426                                                         if v > 0 && len(variants[v].Sequence) > 0 {
 427                                                                 count[variants[v].Blake2b]++
 428                                                         }
 429                                                 }
 430                                         }
 431                                         // hash[i] will be the hash of
 432                                         // the variant(s) that should
 433                                         // be at rank i (0-based).
 434                                         hash := make([][blake2b.Size256]byte, 0, len(count))
 435                                         for b := range count {
 436                                                 hash = append(hash, b)
 437                                         }
 438                                         sort.Slice(hash, func(i, j int) bool {
 439                                                 bi, bj := &hash[i], &hash[j]
 440                                                 if ci, cj := count[*bi], count[*bj]; ci != cj {
 441                                                         return ci > cj
 442                                                 } else {
 443                                                         return bytes.Compare((*bi)[:], (*bj)[:]) < 0
 444                                                 }
 445                                         })
 446                                         // rank[b] will be the 1-based
 447                                         // new variant number for
 448                                         // variants whose hash is b.
 449                                         rank := make(map[[blake2b.Size256]byte]tileVariantID, len(hash))
 450                                         for i, h := range hash {
 451                                                 rank[h] = tileVariantID(i + 1)
 452                                         }
 453                                         // remap[v] will be the new
 454                                         // variant number for original
 455                                         // variant number v.
 456                                         remap := make([]tileVariantID, len(variants))
 457                                         for i, tv := range variants {
 458                                                 remap[i] = rank[tv.Blake2b]
 459                                         }
 460                                         variantRemap[tag-tagstart] = remap
 461                                         if rt != nil {
 462                                                 rt.variant = rank[blake2b.Sum256(rt.tiledata)]
 463                                         }
 464                                 }()
 465                         }
 466                         throttleCPU.Wait()
 467
 468                         var onehotChunk [][]int8
 469                         var onehotXref []onehotXref
 470
 471                         annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, infileIdx)
 472                         log.Infof("%04d: writing %s", infileIdx, annotationsFilename)
 473                         annof, err := os.Create(annotationsFilename)
 474                         if err != nil {
 475                                 return err
 476                         }
 477                         annow := bufio.NewWriterSize(annof, 1<<20)
 478                         outcol := 0
 479                         for tag := tagstart; tag < tagend; tag++ {
 480                                 rt, ok := reftile[tag]
 481                                 if !ok {
 482                                         if mask == nil {
 483                                                 outcol++
 484                                         }
 485                                         // Excluded by specified
 486                                         // regions, or reference does
 487                                         // not use any variant of this
 488                                         // tile. (TODO: log this?
 489                                         // mention it in annotations?)
 490                                         continue
 491                                 }
 492                                 remap := variantRemap[tag-tagstart]
 493                                 maxv := tileVariantID(0)
 494                                 for _, v := range remap {
 495                                         if maxv < v {
 496                                                 maxv = v
 497                                         }
 498                                 }
 499                                 if *onehotChunked || *onehotSingle {
 500                                         onehot, xrefs := cmd.tv2homhet(cgs, maxv, remap, tag, tagstart)
 501                                         onehotChunk = append(onehotChunk, onehot...)
 502                                         onehotXref = append(onehotXref, xrefs...)
 503                                 }
 504                                 fmt.Fprintf(annow, "%d,%d,%d,=,%s,%d,,,\n", tag, outcol, rt.variant, rt.seqname, rt.pos)
 505                                 variants := seq[tag]
 506                                 reftilestr := strings.ToUpper(string(rt.tiledata))
 507
 508                                 done := make([]bool, maxv+1)
 509                                 variantDiffs := make([][]hgvs.Variant, maxv+1)
 510                                 for v, tv := range variants {
 511                                         v := remap[v]
 512                                         if v == rt.variant || done[v] {
 513                                                 continue
 514                                         } else {
 515                                                 done[v] = true
 516                                         }
 517                                         if len(tv.Sequence) < taglen || !bytes.HasSuffix(rt.tiledata, tv.Sequence[len(tv.Sequence)-taglen:]) {
 518                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 519                                                 continue
 520                                         }
 521                                         if lendiff := len(rt.tiledata) - len(tv.Sequence); lendiff < -1000 || lendiff > 1000 {
 522                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 523                                                 continue
 524                                         }
 525                                         diffs, _ := hgvs.Diff(reftilestr, strings.ToUpper(string(tv.Sequence)), 0)
 526                                         for i := range diffs {
 527                                                 diffs[i].Position += rt.pos
 528                                         }
 529                                         for _, diff := range diffs {
 530                                                 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)
 531                                         }
 532                                         if *hgvsChunked {
 533                                                 variantDiffs[v] = diffs
 534                                         }
 535                                 }
 536                                 if *hgvsChunked {
 537                                         // We can now determine, for each HGVS
 538                                         // variant (diff) in this reftile
 539                                         // region, whether a given genome
 540                                         // phase/allele (1) has the variant, (0) has
 541                                         // =ref or a different variant in that
 542                                         // position, or (-1) is lacking
 543                                         // coverage / couldn't be diffed.
 544                                         hgvsCol := hgvsColSet{}
 545                                         for _, diffs := range variantDiffs {
 546                                                 for _, diff := range diffs {
 547                                                         if _, ok := hgvsCol[diff]; ok {
 548                                                                 continue
 549                                                         }
 550                                                         hgvsCol[diff] = [2][]int8{
 551                                                                 make([]int8, len(cmd.cgnames)),
 552                                                                 make([]int8, len(cmd.cgnames)),
 553                                                         }
 554                                                 }
 555                                         }
 556                                         for row, name := range cmd.cgnames {
 557                                                 variants := cgs[name].Variants[(tag-tagstart)*2:]
 558                                                 for ph := 0; ph < 2; ph++ {
 559                                                         v := variants[ph]
 560                                                         if int(v) >= len(remap) {
 561                                                                 v = 0
 562                                                         } else {
 563                                                                 v = remap[v]
 564                                                         }
 565                                                         if v == rt.variant {
 566                                                                 // hgvsCol[*][ph][row] is already 0
 567                                                         } else if len(variantDiffs[v]) == 0 {
 568                                                                 // lacking coverage / couldn't be diffed
 569                                                                 for _, col := range hgvsCol {
 570                                                                         col[ph][row] = -1
 571                                                                 }
 572                                                         } else {
 573                                                                 for _, diff := range variantDiffs[v] {
 574                                                                         hgvsCol[diff][ph][row] = 1
 575                                                                 }
 576                                                         }
 577                                                 }
 578                                         }
 579                                         for diff, colpair := range hgvsCol {
 580                                                 allele2homhet(colpair)
 581                                                 if !cmd.filterHGVScolpair(colpair) {
 582                                                         delete(hgvsCol, diff)
 583                                                 }
 584                                         }
 585                                         if len(hgvsCol) > 0 {
 586                                                 encodeHGVSTodo[rt.seqname] <- hgvsCol
 587                                         }
 588                                 }
 589                                 outcol++
 590                         }
 591                         err = annow.Flush()
 592                         if err != nil {
 593                                 return err
 594                         }
 595                         err = annof.Close()
 596                         if err != nil {
 597                                 return err
 598                         }
 599
 600                         if *onehotChunked {
 601                                 // transpose onehotChunk[col][row] to numpy[row*ncols+col]
 602                                 rows := len(cmd.cgnames)
 603                                 cols := len(onehotChunk)
 604                                 log.Infof("%04d: preparing onehot numpy (rows=%d, cols=%d, mem=%d)", infileIdx, len(cmd.cgnames), len(onehotChunk), len(cmd.cgnames)*len(onehotChunk))
 605                                 throttleNumpyMem.Acquire()
 606                                 out := onehotcols2int8(onehotChunk)
 607                                 fnm := fmt.Sprintf("%s/onehot.%04d.npy", *outputDir, infileIdx)
 608                                 err = writeNumpyInt8(fnm, out, rows, cols)
 609                                 if err != nil {
 610                                         return err
 611                                 }
 612                                 fnm = fmt.Sprintf("%s/onehot-columns.%04d.npy", *outputDir, infileIdx)
 613                                 err = writeNumpyInt32(fnm, onehotXref2int32(onehotXref), 4, len(onehotXref))
 614                                 if err != nil {
 615                                         return err
 616                                 }
 617                                 debug.FreeOSMemory()
 618                                 throttleNumpyMem.Release()
 619                         }
 620                         if *onehotSingle {
 621                                 onehotIndirect[infileIdx] = onehotChunk2Indirect(onehotChunk)
 622                                 onehotXrefs[infileIdx] = onehotXref
 623                                 n := len(onehotIndirect[infileIdx][0])
 624                                 log.Infof("%04d: keeping onehot coordinates in memory (n=%d, mem=%d)", infileIdx, n, n*8)
 625                         }
 626                         if !(*onehotSingle || *onehotChunked) || *mergeOutput || *hgvsSingle {
 627                                 log.Infof("%04d: preparing numpy", infileIdx)
 628                                 throttleNumpyMem.Acquire()
 629                                 rows := len(cmd.cgnames)
 630                                 cols := 2 * outcol
 631                                 out := make([]int16, rows*cols)
 632                                 for row, name := range cmd.cgnames {
 633                                         out := out[row*cols:]
 634                                         outcol := 0
 635                                         for col, v := range cgs[name].Variants {
 636                                                 tag := tagstart + tagID(col/2)
 637                                                 if mask != nil && reftile[tag] == nil {
 638                                                         continue
 639                                                 }
 640                                                 if variants, ok := seq[tag]; ok && len(variants) > int(v) && len(variants[v].Sequence) > 0 {
 641                                                         out[outcol] = int16(variantRemap[tag-tagstart][v])
 642                                                 } else {
 643                                                         out[outcol] = -1
 644                                                 }
 645                                                 outcol++
 646                                         }
 647                                 }
 648                                 seq = nil
 649                                 cgs = nil
 650                                 debug.FreeOSMemory()
 651                                 throttleNumpyMem.Release()
 652                                 if *mergeOutput || *hgvsSingle {
 653                                         log.Infof("%04d: matrix fragment %d rows x %d cols", infileIdx, rows, cols)
 654                                         toMerge[infileIdx] = out
 655                                 }
 656                                 if !*mergeOutput && !*onehotChunked && !*onehotSingle {
 657                                         fnm := fmt.Sprintf("%s/matrix.%04d.npy", *outputDir, infileIdx)
 658                                         err = writeNumpyInt16(fnm, out, rows, cols)
 659                                         if err != nil {
 660                                                 return err
 661                                         }
 662                                 }
 663                         }
 664                         debug.FreeOSMemory()
 665                         log.Infof("%s: done (%d/%d)", infile, int(atomic.AddInt64(&done, 1)), len(infiles))
 666                         return nil
 667                 })
 668         }
 669         if err = throttleMem.Wait(); err != nil {
 670                 return 1
 671         }
 672
 673         if *hgvsChunked {
 674                 log.Info("flushing hgvsCols temp files")
 675                 for seqname := range refseq {
 676                         close(encodeHGVSTodo[seqname])
 677                 }
 678                 err = encodeHGVS.Wait()
 679                 if err != nil {
 680                         return 1
 681                 }
 682                 for seqname := range refseq {
 683                         log.Infof("%s: reading hgvsCols from temp file", seqname)
 684                         f := tmpHGVSCols[seqname]
 685                         _, err = f.Seek(0, io.SeekStart)
 686                         if err != nil {
 687                                 return 1
 688                         }
 689                         var hgvsCols hgvsColSet
 690                         dec := gob.NewDecoder(bufio.NewReaderSize(f, 1<<24))
 691                         for err == nil {
 692                                 err = dec.Decode(&hgvsCols)
 693                         }
 694                         if err != io.EOF {
 695                                 return 1
 696                         }
 697                         log.Infof("%s: sorting %d hgvs variants", seqname, len(hgvsCols))
 698                         variants := make([]hgvs.Variant, 0, len(hgvsCols))
 699                         for v := range hgvsCols {
 700                                 variants = append(variants, v)
 701                         }
 702                         sort.Slice(variants, func(i, j int) bool {
 703                                 vi, vj := &variants[i], &variants[j]
 704                                 if vi.Position != vj.Position {
 705                                         return vi.Position < vj.Position
 706                                 } else if vi.Ref != vj.Ref {
 707                                         return vi.Ref < vj.Ref
 708                                 } else {
 709                                         return vi.New < vj.New
 710                                 }
 711                         })
 712                         rows := len(cmd.cgnames)
 713                         cols := len(variants) * 2
 714                         log.Infof("%s: building hgvs matrix (rows=%d, cols=%d, mem=%d)", seqname, rows, cols, rows*cols)
 715                         out := make([]int8, rows*cols)
 716                         for varIdx, variant := range variants {
 717                                 hgvsCols := hgvsCols[variant]
 718                                 for row := range cmd.cgnames {
 719                                         for ph := 0; ph < 2; ph++ {
 720                                                 out[row*cols+varIdx+ph] = hgvsCols[ph][row]
 721                                         }
 722                                 }
 723                         }
 724                         err = writeNumpyInt8(fmt.Sprintf("%s/hgvs.%s.npy", *outputDir, seqname), out, rows, cols)
 725                         if err != nil {
 726                                 return 1
 727                         }
 728                         out = nil
 729
 730                         fnm := fmt.Sprintf("%s/hgvs.%s.annotations.csv", *outputDir, seqname)
 731                         log.Infof("%s: writing hgvs column labels to %s", seqname, fnm)
 732                         var hgvsLabels bytes.Buffer
 733                         for varIdx, variant := range variants {
 734                                 fmt.Fprintf(&hgvsLabels, "%d,%s:g.%s\n", varIdx, seqname, variant.String())
 735                         }
 736                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0666)
 737                         if err != nil {
 738                                 return 1
 739                         }
 740                 }
 741         }
 742
 743         if *mergeOutput || *hgvsSingle {
 744                 var annow *bufio.Writer
 745                 var annof *os.File
 746                 if *mergeOutput {
 747                         annoFilename := fmt.Sprintf("%s/matrix.annotations.csv", *outputDir)
 748                         annof, err = os.Create(annoFilename)
 749                         if err != nil {
 750                                 return 1
 751                         }
 752                         annow = bufio.NewWriterSize(annof, 1<<20)
 753                 }
 754
 755                 rows := len(cmd.cgnames)
 756                 cols := 0
 757                 for _, chunk := range toMerge {
 758                         cols += len(chunk) / rows
 759                 }
 760                 log.Infof("merging output matrix (rows=%d, cols=%d, mem=%d) and annotations", rows, cols, rows*cols*2)
 761                 var out []int16
 762                 if *mergeOutput {
 763                         out = make([]int16, rows*cols)
 764                 }
 765                 hgvsCols := map[string][2][]int16{} // hgvs -> [[g0,g1,g2,...], [g0,g1,g2,...]] (slice of genomes for each phase)
 766                 startcol := 0
 767                 for outIdx, chunk := range toMerge {
 768                         chunkcols := len(chunk) / rows
 769                         if *mergeOutput {
 770                                 for row := 0; row < rows; row++ {
 771                                         copy(out[row*cols+startcol:], chunk[row*chunkcols:(row+1)*chunkcols])
 772                                 }
 773                         }
 774                         toMerge[outIdx] = nil
 775
 776                         annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, outIdx)
 777                         log.Infof("reading %s", annotationsFilename)
 778                         buf, err := os.ReadFile(annotationsFilename)
 779                         if err != nil {
 780                                 return 1
 781                         }
 782                         if *mergeOutput {
 783                                 err = os.Remove(annotationsFilename)
 784                                 if err != nil {
 785                                         return 1
 786                                 }
 787                         }
 788                         for _, line := range bytes.Split(buf, []byte{'\n'}) {
 789                                 if len(line) == 0 {
 790                                         continue
 791                                 }
 792                                 fields := bytes.SplitN(line, []byte{','}, 9)
 793                                 tag, _ := strconv.Atoi(string(fields[0]))
 794                                 incol, _ := strconv.Atoi(string(fields[1]))
 795                                 tileVariant, _ := strconv.Atoi(string(fields[2]))
 796                                 hgvsID := string(fields[3])
 797                                 seqname := string(fields[4])
 798                                 pos, _ := strconv.Atoi(string(fields[5]))
 799                                 refseq := fields[6]
 800                                 if hgvsID == "" {
 801                                         // Null entry for un-diffable
 802                                         // tile variant
 803                                         continue
 804                                 }
 805                                 if hgvsID == "=" {
 806                                         // Null entry for ref tile
 807                                         continue
 808                                 }
 809                                 if mask != nil && !mask.Check(strings.TrimPrefix(seqname, "chr"), pos, pos+len(refseq)) {
 810                                         // The tile intersects one of
 811                                         // the selected regions, but
 812                                         // this particular HGVS
 813                                         // variant does not.
 814                                         continue
 815                                 }
 816                                 hgvsColPair := hgvsCols[hgvsID]
 817                                 if hgvsColPair[0] == nil {
 818                                         // values in new columns start
 819                                         // out as -1 ("no data yet")
 820                                         // or 0 ("=ref") here, may
 821                                         // change to 1 ("hgvs variant
 822                                         // present") below, either on
 823                                         // this line or a future line.
 824                                         hgvsColPair = [2][]int16{make([]int16, len(cmd.cgnames)), make([]int16, len(cmd.cgnames))}
 825                                         rt, ok := reftile[tagID(tag)]
 826                                         if !ok {
 827                                                 err = fmt.Errorf("bug: seeing annotations for tag %d, but it has no reftile entry", tag)
 828                                                 return 1
 829                                         }
 830                                         for ph := 0; ph < 2; ph++ {
 831                                                 for row := 0; row < rows; row++ {
 832                                                         v := chunk[row*chunkcols+incol*2+ph]
 833                                                         if tileVariantID(v) == rt.variant {
 834                                                                 hgvsColPair[ph][row] = 0
 835                                                         } else {
 836                                                                 hgvsColPair[ph][row] = -1
 837                                                         }
 838                                                 }
 839                                         }
 840                                         hgvsCols[hgvsID] = hgvsColPair
 841                                         if annow != nil {
 842                                                 hgvsref := hgvs.Variant{
 843                                                         Position: pos,
 844                                                         Ref:      string(refseq),
 845                                                         New:      string(refseq),
 846                                                 }
 847                                                 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])
 848                                         }
 849                                 }
 850                                 if annow != nil {
 851                                         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])
 852                                 }
 853                                 for ph := 0; ph < 2; ph++ {
 854                                         for row := 0; row < rows; row++ {
 855                                                 v := chunk[row*chunkcols+incol*2+ph]
 856                                                 if int(v) == tileVariant {
 857                                                         hgvsColPair[ph][row] = 1
 858                                                 }
 859                                         }
 860                                 }
 861                         }
 862
 863                         startcol += chunkcols
 864                 }
 865                 if *mergeOutput {
 866                         err = annow.Flush()
 867                         if err != nil {
 868                                 return 1
 869                         }
 870                         err = annof.Close()
 871                         if err != nil {
 872                                 return 1
 873                         }
 874                         err = writeNumpyInt16(fmt.Sprintf("%s/matrix.npy", *outputDir), out, rows, cols)
 875                         if err != nil {
 876                                 return 1
 877                         }
 878                 }
 879                 out = nil
 880
 881                 if *hgvsSingle {
 882                         cols = len(hgvsCols) * 2
 883                         log.Printf("building hgvs-based matrix: %d rows x %d cols", rows, cols)
 884                         out = make([]int16, rows*cols)
 885                         hgvsIDs := make([]string, 0, cols/2)
 886                         for hgvsID := range hgvsCols {
 887                                 hgvsIDs = append(hgvsIDs, hgvsID)
 888                         }
 889                         sort.Strings(hgvsIDs)
 890                         var hgvsLabels bytes.Buffer
 891                         for idx, hgvsID := range hgvsIDs {
 892                                 fmt.Fprintf(&hgvsLabels, "%d,%s\n", idx, hgvsID)
 893                                 for ph := 0; ph < 2; ph++ {
 894                                         hgvscol := hgvsCols[hgvsID][ph]
 895                                         for row, val := range hgvscol {
 896                                                 out[row*cols+idx*2+ph] = val
 897                                         }
 898                                 }
 899                         }
 900                         err = writeNumpyInt16(fmt.Sprintf("%s/hgvs.npy", *outputDir), out, rows, cols)
 901                         if err != nil {
 902                                 return 1
 903                         }
 904
 905                         fnm := fmt.Sprintf("%s/hgvs.annotations.csv", *outputDir)
 906                         log.Printf("writing hgvs labels: %s", fnm)
 907                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0777)
 908                         if err != nil {
 909                                 return 1
 910                         }
 911                 }
 912         }
 913         if *onehotSingle {
 914                 nzCount := 0
 915                 for _, part := range onehotIndirect {
 916                         nzCount += len(part[0])
 917                 }
 918                 onehot := make([]uint32, nzCount*2) // [r,r,r,...,c,c,c,...]
 919                 var xrefs []onehotXref
 920                 outcol := 0
 921                 for i, part := range onehotIndirect {
 922                         for i := range part[1] {
 923                                 part[1][i] += uint32(outcol)
 924                         }
 925                         copy(onehot[outcol:], part[0])
 926                         copy(onehot[outcol+nzCount:], part[1])
 927                         outcol += len(part[0])
 928                         xrefs = append(xrefs, onehotXrefs[i]...)
 929
 930                         part[0] = nil
 931                         part[1] = nil
 932                         onehotXrefs[i] = nil
 933                         debug.FreeOSMemory()
 934                 }
 935                 fnm := fmt.Sprintf("%s/onehot.npy", *outputDir)
 936                 err = writeNumpyUint32(fnm, onehot, 2, nzCount)
 937                 if err != nil {
 938                         return 1
 939                 }
 940                 fnm = fmt.Sprintf("%s/onehot-columns.npy", *outputDir)
 941                 err = writeNumpyInt32(fnm, onehotXref2int32(xrefs), 4, len(xrefs))
 942                 if err != nil {
 943                         return 1
 944                 }
 945         }
 946         return 0
 947 }
 948
 949 // Read case/control files, remove non-case/control entries from
 950 // cmd.cgnames, and build cmd.chi2Cases.
 951 func (cmd *sliceNumpy) useCaseControlFiles() error {
 952         if cmd.chi2CaseControlFile == "" {
 953                 return nil
 954         }
 955         infiles, err := allFiles(cmd.chi2CaseControlFile, nil)
 956         if err != nil {
 957                 return err
 958         }
 959         // index in cmd.cgnames => case(true) / control(false)
 960         cc := map[int]bool{}
 961         for _, infile := range infiles {
 962                 f, err := open(infile)
 963                 if err != nil {
 964                         return err
 965                 }
 966                 buf, err := io.ReadAll(f)
 967                 f.Close()
 968                 if err != nil {
 969                         return err
 970                 }
 971                 ccCol := -1
 972                 for _, tsv := range bytes.Split(buf, []byte{'\n'}) {
 973                         if len(tsv) == 0 {
 974                                 continue
 975                         }
 976                         split := strings.Split(string(tsv), "\t")
 977                         if ccCol < 0 {
 978                                 // header row
 979                                 for col, name := range split {
 980                                         if name == cmd.chi2CaseControlColumn {
 981                                                 ccCol = col
 982                                                 break
 983                                         }
 984                                 }
 985                                 if ccCol < 0 {
 986                                         return fmt.Errorf("%s: no column named %q in header row %q", infile, cmd.chi2CaseControlColumn, tsv)
 987                                 }
 988                                 continue
 989                         }
 990                         if len(split) <= ccCol {
 991                                 continue
 992                         }
 993                         pattern := split[0]
 994                         found := -1
 995                         for i, name := range cmd.cgnames {
 996                                 if strings.Contains(name, pattern) {
 997                                         if found >= 0 {
 998                                                 log.Warnf("pattern %q in %s matches multiple genome IDs (%qs, %q)", pattern, infile, cmd.cgnames[found], name)
 999                                         }
1000                                         found = i
1001                                 }
1002                         }
1003                         if found < 0 {
1004                                 log.Warnf("pattern %q in %s does not match any genome IDs", pattern, infile)
1005                                 continue
1006                         }
1007                         if split[ccCol] == "0" {
1008                                 cc[found] = false
1009                         }
1010                         if split[ccCol] == "1" {
1011                                 cc[found] = true
1012                         }
1013                 }
1014         }
1015         allnames := cmd.cgnames
1016         cmd.cgnames = nil
1017         cmd.chi2Cases = nil
1018         ncases := 0
1019         for i, name := range allnames {
1020                 if cc, ok := cc[i]; ok {
1021                         cmd.cgnames = append(cmd.cgnames, name)
1022                         cmd.chi2Cases = append(cmd.chi2Cases, cc)
1023                         if cc {
1024                                 ncases++
1025                         }
1026                 }
1027         }
1028         log.Printf("%d cases, %d controls, %d neither (dropped)", ncases, len(cmd.cgnames)-ncases, len(allnames)-len(cmd.cgnames))
1029         return nil
1030 }
1031
1032 func (cmd *sliceNumpy) filterHGVScolpair(colpair [2][]int8) bool {
1033         if cmd.chi2PValue >= 1 {
1034                 return true
1035         }
1036         col0 := make([]bool, 0, len(cmd.chi2Cases))
1037         col1 := make([]bool, 0, len(cmd.chi2Cases))
1038         cases := make([]bool, 0, len(cmd.chi2Cases))
1039         for i, c := range cmd.chi2Cases {
1040                 if colpair[0][i] < 0 {
1041                         continue
1042                 }
1043                 col0 = append(col0, colpair[0][i] != 0)
1044                 col1 = append(col1, colpair[1][i] != 0)
1045                 cases = append(cases, c)
1046         }
1047         return len(cases) >= cmd.minCoverage &&
1048                 (pvalue(col0, cases) <= cmd.chi2PValue || pvalue(col1, cases) <= cmd.chi2PValue)
1049 }
1050
1051 func writeNumpyUint32(fnm string, out []uint32, rows, cols int) error {
1052         output, err := os.Create(fnm)
1053         if err != nil {
1054                 return err
1055         }
1056         defer output.Close()
1057         bufw := bufio.NewWriterSize(output, 1<<26)
1058         npw, err := gonpy.NewWriter(nopCloser{bufw})
1059         if err != nil {
1060                 return err
1061         }
1062         log.WithFields(log.Fields{
1063                 "filename": fnm,
1064                 "rows":     rows,
1065                 "cols":     cols,
1066                 "bytes":    rows * cols * 4,
1067         }).Infof("writing numpy: %s", fnm)
1068         npw.Shape = []int{rows, cols}
1069         npw.WriteUint32(out)
1070         err = bufw.Flush()
1071         if err != nil {
1072                 return err
1073         }
1074         return output.Close()
1075 }
1076
1077 func writeNumpyInt32(fnm string, out []int32, rows, cols int) error {
1078         output, err := os.Create(fnm)
1079         if err != nil {
1080                 return err
1081         }
1082         defer output.Close()
1083         bufw := bufio.NewWriterSize(output, 1<<26)
1084         npw, err := gonpy.NewWriter(nopCloser{bufw})
1085         if err != nil {
1086                 return err
1087         }
1088         log.WithFields(log.Fields{
1089                 "filename": fnm,
1090                 "rows":     rows,
1091                 "cols":     cols,
1092                 "bytes":    rows * cols * 4,
1093         }).Infof("writing numpy: %s", fnm)
1094         npw.Shape = []int{rows, cols}
1095         npw.WriteInt32(out)
1096         err = bufw.Flush()
1097         if err != nil {
1098                 return err
1099         }
1100         return output.Close()
1101 }
1102
1103 func writeNumpyInt16(fnm string, out []int16, rows, cols int) error {
1104         output, err := os.Create(fnm)
1105         if err != nil {
1106                 return err
1107         }
1108         defer output.Close()
1109         bufw := bufio.NewWriterSize(output, 1<<26)
1110         npw, err := gonpy.NewWriter(nopCloser{bufw})
1111         if err != nil {
1112                 return err
1113         }
1114         log.WithFields(log.Fields{
1115                 "filename": fnm,
1116                 "rows":     rows,
1117                 "cols":     cols,
1118                 "bytes":    rows * cols * 2,
1119         }).Infof("writing numpy: %s", fnm)
1120         npw.Shape = []int{rows, cols}
1121         npw.WriteInt16(out)
1122         err = bufw.Flush()
1123         if err != nil {
1124                 return err
1125         }
1126         return output.Close()
1127 }
1128
1129 func writeNumpyInt8(fnm string, out []int8, rows, cols int) error {
1130         output, err := os.Create(fnm)
1131         if err != nil {
1132                 return err
1133         }
1134         defer output.Close()
1135         bufw := bufio.NewWriterSize(output, 1<<26)
1136         npw, err := gonpy.NewWriter(nopCloser{bufw})
1137         if err != nil {
1138                 return err
1139         }
1140         log.WithFields(log.Fields{
1141                 "filename": fnm,
1142                 "rows":     rows,
1143                 "cols":     cols,
1144                 "bytes":    rows * cols,
1145         }).Infof("writing numpy: %s", fnm)
1146         npw.Shape = []int{rows, cols}
1147         npw.WriteInt8(out)
1148         err = bufw.Flush()
1149         if err != nil {
1150                 return err
1151         }
1152         return output.Close()
1153 }
1154
1155 func allele2homhet(colpair [2][]int8) {
1156         a, b := colpair[0], colpair[1]
1157         for i, av := range a {
1158                 bv := b[i]
1159                 if av < 0 || bv < 0 {
1160                         // no-call
1161                         a[i], b[i] = -1, -1
1162                 } else if av > 0 && bv > 0 {
1163                         // hom
1164                         a[i], b[i] = 1, 0
1165                 } else if av > 0 || bv > 0 {
1166                         // het
1167                         a[i], b[i] = 0, 1
1168                 } else {
1169                         // ref (or a different variant in same position)
1170                         // (this is a no-op) a[i], b[i] = 0, 0
1171                 }
1172         }
1173 }
1174
1175 type onehotXref struct {
1176         tag     tagID
1177         variant tileVariantID
1178         het     bool
1179         pvalue  float64
1180 }
1181
1182 const onehotXrefSize = unsafe.Sizeof(onehotXref{})
1183
1184 // Build onehot matrix (m[variant*2+isHet][genome] == 0 or 1) for all
1185 // variants of a single tile/tag#.
1186 //
1187 // Return nil if no tile variant passes Χ² filter.
1188 func (cmd *sliceNumpy) tv2homhet(cgs map[string]CompactGenome, maxv tileVariantID, remap []tileVariantID, tag, chunkstarttag tagID) ([][]int8, []onehotXref) {
1189         if maxv < 2 {
1190                 // everyone has the most common variant
1191                 return nil, nil
1192         }
1193         tagoffset := tag - chunkstarttag
1194         coverage := 0
1195         for _, cg := range cgs {
1196                 if cg.Variants[tagoffset*2] > 0 && cg.Variants[tagoffset*2+1] > 0 {
1197                         coverage++
1198                 }
1199         }
1200         if coverage < cmd.minCoverage {
1201                 return nil, nil
1202         }
1203         obs := make([][]bool, (maxv+1)*2) // 2 slices (hom + het) for each variant#
1204         for i := range obs {
1205                 obs[i] = make([]bool, len(cmd.cgnames))
1206         }
1207         for cgid, name := range cmd.cgnames {
1208                 cgvars := cgs[name].Variants
1209                 for v := tileVariantID(2); v <= maxv; v++ {
1210                         if remap[cgvars[tagoffset*2]] == v && remap[cgvars[tagoffset*2+1]] == v {
1211                                 obs[v*2][cgid] = true
1212                         } else if remap[cgvars[tagoffset*2]] == v || remap[cgvars[tagoffset*2+1]] == v {
1213                                 obs[v*2+1][cgid] = true
1214                         }
1215                 }
1216         }
1217         var onehot [][]int8
1218         var xref []onehotXref
1219         for homcol := 4; homcol < len(obs); homcol += 2 {
1220                 p := [2]float64{
1221                         pvalue(obs[homcol], cmd.chi2Cases),
1222                         pvalue(obs[homcol+1], cmd.chi2Cases),
1223                 }
1224                 if cmd.chi2PValue < 1 && !(p[0] < cmd.chi2PValue || p[1] < cmd.chi2PValue) {
1225                         continue
1226                 }
1227                 for het := 0; het < 2; het++ {
1228                         onehot = append(onehot, bool2int8(obs[homcol+het]))
1229                         xref = append(xref, onehotXref{
1230                                 tag:     tag,
1231                                 variant: tileVariantID(homcol / 2),
1232                                 het:     het == 1,
1233                                 pvalue:  p[het],
1234                         })
1235                 }
1236         }
1237         return onehot, xref
1238 }
1239
1240 func bool2int8(in []bool) []int8 {
1241         out := make([]int8, len(in))
1242         for i, v := range in {
1243                 if v {
1244                         out[i] = 1
1245                 }
1246         }
1247         return out
1248 }
1249
1250 // convert a []onehotXref with length N to a numpy-style []int32
1251 // matrix with N columns, one row per field of onehotXref struct.
1252 //
1253 // Hom/het row contains hom=0, het=1.
1254 //
1255 // P-value row contains 1000000x actual p-value.
1256 func onehotXref2int32(xrefs []onehotXref) []int32 {
1257         xcols := len(xrefs)
1258         xdata := make([]int32, 4*xcols)
1259         for i, xref := range xrefs {
1260                 xdata[i] = int32(xref.tag)
1261                 xdata[xcols+i] = int32(xref.variant)
1262                 if xref.het {
1263                         xdata[xcols*2+i] = 1
1264                 }
1265                 xdata[xcols*3+i] = int32(xref.pvalue * 1000000)
1266         }
1267         return xdata
1268 }
1269
1270 // transpose onehot data from in[col][row] to numpy-style
1271 // out[row*cols+col].
1272 func onehotcols2int8(in [][]int8) []int8 {
1273         if len(in) == 0 {
1274                 return nil
1275         }
1276         cols := len(in)
1277         rows := len(in[0])
1278         out := make([]int8, rows*cols)
1279         for row := 0; row < rows; row++ {
1280                 outrow := out[row*cols:]
1281                 for col, incol := range in {
1282                         outrow[col] = incol[row]
1283                 }
1284         }
1285         return out
1286 }
1287
1288 // Return [2][]uint32{rowIndices, colIndices} indicating which
1289 // elements of matrixT[c][r] have non-zero values.
1290 func onehotChunk2Indirect(matrixT [][]int8) [2][]uint32 {
1291         var nz [2][]uint32
1292         for c, col := range matrixT {
1293                 for r, val := range col {
1294                         if val != 0 {
1295                                 nz[0] = append(nz[0], uint32(r))
1296                                 nz[1] = append(nz[1], uint32(c))
1297                         }
1298                 }
1299         }
1300         return nz
1301 }