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                         if libref.Tag > tagID(cmd.filter.MaxTag) {
 251                                 continue
 252                         }
 253                         tiledata := reftiledata[libref]
 254                         if len(tiledata) == 0 {
 255                                 err = fmt.Errorf("missing tiledata for tag %d variant %d in %s in ref", libref.Tag, libref.Variant, seqname)
 256                                 return 1
 257                         }
 258                         foundthistag := false
 259                         taglib.FindAll(tiledata[:len(tiledata)-1], func(tagid tagID, offset, _ int) {
 260                                 if !foundthistag && tagid == libref.Tag {
 261                                         foundthistag = true
 262                                         return
 263                                 }
 264                                 if dupref, ok := reftile[tagid]; ok {
 265                                         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)
 266                                         delete(reftile, tagid)
 267                                 } else {
 268                                         log.Printf("found tag %d at offset %d inside tile variant %+v on %s @ %d", tagid, offset, libref, seqname, pos+offset+1)
 269                                 }
 270                                 isdup[tagid] = true
 271                         })
 272                         if isdup[libref.Tag] {
 273                                 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
 274                         } else if reftile[libref.Tag] != nil {
 275                                 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)
 276                                 delete(reftile, libref.Tag)
 277                                 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
 278                                 isdup[libref.Tag] = true
 279                         } else {
 280                                 reftile[libref.Tag] = &reftileinfo{
 281                                         seqname:  seqname,
 282                                         variant:  libref.Variant,
 283                                         tiledata: tiledata,
 284                                         pos:      pos,
 285                                 }
 286                         }
 287                         pos += len(tiledata) - taglen
 288                 }
 289                 log.Printf("... %s done, len %d", seqname, pos+taglen)
 290         }
 291
 292         var mask *mask
 293         if *regionsFilename != "" {
 294                 log.Printf("loading regions from %s", *regionsFilename)
 295                 mask, err = makeMask(*regionsFilename, *expandRegions)
 296                 if err != nil {
 297                         return 1
 298                 }
 299                 log.Printf("before applying mask, len(reftile) == %d", len(reftile))
 300                 log.Printf("deleting reftile entries for regions outside %d intervals", mask.Len())
 301                 for tag, rt := range reftile {
 302                         if !mask.Check(strings.TrimPrefix(rt.seqname, "chr"), rt.pos, rt.pos+len(rt.tiledata)) {
 303                                 delete(reftile, tag)
 304                         }
 305                 }
 306                 log.Printf("after applying mask, len(reftile) == %d", len(reftile))
 307         }
 308
 309         type hgvsColSet map[hgvs.Variant][2][]int8
 310         encodeHGVS := throttle{Max: len(refseq)}
 311         encodeHGVSTodo := map[string]chan hgvsColSet{}
 312         tmpHGVSCols := map[string]*os.File{}
 313         if *hgvsChunked {
 314                 for seqname := range refseq {
 315                         var f *os.File
 316                         f, err = os.Create(*outputDir + "/tmp." + seqname + ".gob")
 317                         if err != nil {
 318                                 return 1
 319                         }
 320                         defer os.Remove(f.Name())
 321                         bufw := bufio.NewWriterSize(f, 1<<24)
 322                         enc := gob.NewEncoder(bufw)
 323                         tmpHGVSCols[seqname] = f
 324                         todo := make(chan hgvsColSet, 128)
 325                         encodeHGVSTodo[seqname] = todo
 326                         encodeHGVS.Go(func() error {
 327                                 for colset := range todo {
 328                                         err := enc.Encode(colset)
 329                                         if err != nil {
 330                                                 encodeHGVS.Report(err)
 331                                                 for range todo {
 332                                                 }
 333                                                 return err
 334                                         }
 335                                 }
 336                                 return bufw.Flush()
 337                         })
 338                 }
 339         }
 340
 341         var toMerge [][]int16
 342         if *mergeOutput || *hgvsSingle {
 343                 toMerge = make([][]int16, len(infiles))
 344         }
 345         var onehotIndirect [][2][]uint32 // [chunkIndex][axis][index]
 346         var onehotXrefs [][]onehotXref
 347         if *onehotSingle {
 348                 onehotIndirect = make([][2][]uint32, len(infiles))
 349                 onehotXrefs = make([][]onehotXref, len(infiles))
 350         }
 351
 352         throttleMem := throttle{Max: cmd.threads} // TODO: estimate using mem and data size
 353         throttleNumpyMem := throttle{Max: cmd.threads/2 + 1}
 354         log.Info("generating annotations and numpy matrix for each slice")
 355         var done int64
 356         for infileIdx, infile := range infiles {
 357                 infileIdx, infile := infileIdx, infile
 358                 throttleMem.Go(func() error {
 359                         seq := make(map[tagID][]TileVariant, 50000)
 360                         cgs := make(map[string]CompactGenome, len(cmd.cgnames))
 361                         f, err := open(infile)
 362                         if err != nil {
 363                                 return err
 364                         }
 365                         defer f.Close()
 366                         log.Infof("%04d: reading %s", infileIdx, infile)
 367                         err = DecodeLibrary(f, strings.HasSuffix(infile, ".gz"), func(ent *LibraryEntry) error {
 368                                 for _, tv := range ent.TileVariants {
 369                                         if tv.Ref {
 370                                                 continue
 371                                         }
 372                                         if mask != nil && reftile[tv.Tag] == nil {
 373                                                 // Don't waste
 374                                                 // time/memory on
 375                                                 // masked-out tiles.
 376                                                 continue
 377                                         }
 378                                         variants := seq[tv.Tag]
 379                                         if len(variants) == 0 {
 380                                                 variants = make([]TileVariant, 100)
 381                                         }
 382                                         for len(variants) <= int(tv.Variant) {
 383                                                 variants = append(variants, TileVariant{})
 384                                         }
 385                                         variants[int(tv.Variant)] = tv
 386                                         seq[tv.Tag] = variants
 387                                 }
 388                                 for _, cg := range ent.CompactGenomes {
 389                                         if !matchGenome.MatchString(cg.Name) {
 390                                                 continue
 391                                         }
 392                                         // pad to full slice size
 393                                         // to avoid out-of-bounds
 394                                         // checks later
 395                                         if sliceSize := 2 * int(cg.EndTag-cg.StartTag); len(cg.Variants) < sliceSize {
 396                                                 cg.Variants = append(cg.Variants, make([]tileVariantID, sliceSize-len(cg.Variants))...)
 397                                         }
 398                                         cgs[cg.Name] = cg
 399                                 }
 400                                 return nil
 401                         })
 402                         if err != nil {
 403                                 return err
 404                         }
 405                         tagstart := cgs[cmd.cgnames[0]].StartTag
 406                         tagend := cgs[cmd.cgnames[0]].EndTag
 407
 408                         // TODO: filters
 409
 410                         log.Infof("%04d: renumber/dedup variants for tags %d-%d", infileIdx, tagstart, tagend)
 411                         variantRemap := make([][]tileVariantID, tagend-tagstart)
 412                         throttleCPU := throttle{Max: runtime.GOMAXPROCS(0)}
 413                         for tag, variants := range seq {
 414                                 tag, variants := tag, variants
 415                                 throttleCPU.Acquire()
 416                                 go func() {
 417                                         defer throttleCPU.Release()
 418                                         count := make(map[[blake2b.Size256]byte]int, len(variants))
 419
 420                                         rt := reftile[tag]
 421                                         if rt != nil {
 422                                                 count[blake2b.Sum256(rt.tiledata)] = 0
 423                                         }
 424
 425                                         for _, cg := range cgs {
 426                                                 idx := int(tag-tagstart) * 2
 427                                                 for allele := 0; allele < 2; allele++ {
 428                                                         v := cg.Variants[idx+allele]
 429                                                         if v > 0 && len(variants[v].Sequence) > 0 {
 430                                                                 count[variants[v].Blake2b]++
 431                                                         }
 432                                                 }
 433                                         }
 434                                         // hash[i] will be the hash of
 435                                         // the variant(s) that should
 436                                         // be at rank i (0-based).
 437                                         hash := make([][blake2b.Size256]byte, 0, len(count))
 438                                         for b := range count {
 439                                                 hash = append(hash, b)
 440                                         }
 441                                         sort.Slice(hash, func(i, j int) bool {
 442                                                 bi, bj := &hash[i], &hash[j]
 443                                                 if ci, cj := count[*bi], count[*bj]; ci != cj {
 444                                                         return ci > cj
 445                                                 } else {
 446                                                         return bytes.Compare((*bi)[:], (*bj)[:]) < 0
 447                                                 }
 448                                         })
 449                                         // rank[b] will be the 1-based
 450                                         // new variant number for
 451                                         // variants whose hash is b.
 452                                         rank := make(map[[blake2b.Size256]byte]tileVariantID, len(hash))
 453                                         for i, h := range hash {
 454                                                 rank[h] = tileVariantID(i + 1)
 455                                         }
 456                                         // remap[v] will be the new
 457                                         // variant number for original
 458                                         // variant number v.
 459                                         remap := make([]tileVariantID, len(variants))
 460                                         for i, tv := range variants {
 461                                                 remap[i] = rank[tv.Blake2b]
 462                                         }
 463                                         variantRemap[tag-tagstart] = remap
 464                                         if rt != nil {
 465                                                 rt.variant = rank[blake2b.Sum256(rt.tiledata)]
 466                                         }
 467                                 }()
 468                         }
 469                         throttleCPU.Wait()
 470
 471                         var onehotChunk [][]int8
 472                         var onehotXref []onehotXref
 473
 474                         annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, infileIdx)
 475                         log.Infof("%04d: writing %s", infileIdx, annotationsFilename)
 476                         annof, err := os.Create(annotationsFilename)
 477                         if err != nil {
 478                                 return err
 479                         }
 480                         annow := bufio.NewWriterSize(annof, 1<<20)
 481                         outcol := 0
 482                         for tag := tagstart; tag < tagend; tag++ {
 483                                 rt, ok := reftile[tag]
 484                                 if !ok {
 485                                         if mask == nil {
 486                                                 outcol++
 487                                         }
 488                                         // Excluded by specified
 489                                         // regions, or reference does
 490                                         // not use any variant of this
 491                                         // tile. (TODO: log this?
 492                                         // mention it in annotations?)
 493                                         continue
 494                                 }
 495                                 remap := variantRemap[tag-tagstart]
 496                                 maxv := tileVariantID(0)
 497                                 for _, v := range remap {
 498                                         if maxv < v {
 499                                                 maxv = v
 500                                         }
 501                                 }
 502                                 if *onehotChunked || *onehotSingle {
 503                                         onehot, xrefs := cmd.tv2homhet(cgs, maxv, remap, tag, tagstart)
 504                                         onehotChunk = append(onehotChunk, onehot...)
 505                                         onehotXref = append(onehotXref, xrefs...)
 506                                 }
 507                                 fmt.Fprintf(annow, "%d,%d,%d,=,%s,%d,,,\n", tag, outcol, rt.variant, rt.seqname, rt.pos)
 508                                 variants := seq[tag]
 509                                 reftilestr := strings.ToUpper(string(rt.tiledata))
 510
 511                                 done := make([]bool, maxv+1)
 512                                 variantDiffs := make([][]hgvs.Variant, maxv+1)
 513                                 for v, tv := range variants {
 514                                         v := remap[v]
 515                                         if v == rt.variant || done[v] {
 516                                                 continue
 517                                         } else {
 518                                                 done[v] = true
 519                                         }
 520                                         if len(tv.Sequence) < taglen || !bytes.HasSuffix(rt.tiledata, tv.Sequence[len(tv.Sequence)-taglen:]) {
 521                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 522                                                 continue
 523                                         }
 524                                         if lendiff := len(rt.tiledata) - len(tv.Sequence); lendiff < -1000 || lendiff > 1000 {
 525                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 526                                                 continue
 527                                         }
 528                                         diffs, _ := hgvs.Diff(reftilestr, strings.ToUpper(string(tv.Sequence)), 0)
 529                                         for i := range diffs {
 530                                                 diffs[i].Position += rt.pos
 531                                         }
 532                                         for _, diff := range diffs {
 533                                                 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)
 534                                         }
 535                                         if *hgvsChunked {
 536                                                 variantDiffs[v] = diffs
 537                                         }
 538                                 }
 539                                 if *hgvsChunked {
 540                                         // We can now determine, for each HGVS
 541                                         // variant (diff) in this reftile
 542                                         // region, whether a given genome
 543                                         // phase/allele (1) has the variant, (0) has
 544                                         // =ref or a different variant in that
 545                                         // position, or (-1) is lacking
 546                                         // coverage / couldn't be diffed.
 547                                         hgvsCol := hgvsColSet{}
 548                                         for _, diffs := range variantDiffs {
 549                                                 for _, diff := range diffs {
 550                                                         if _, ok := hgvsCol[diff]; ok {
 551                                                                 continue
 552                                                         }
 553                                                         hgvsCol[diff] = [2][]int8{
 554                                                                 make([]int8, len(cmd.cgnames)),
 555                                                                 make([]int8, len(cmd.cgnames)),
 556                                                         }
 557                                                 }
 558                                         }
 559                                         for row, name := range cmd.cgnames {
 560                                                 variants := cgs[name].Variants[(tag-tagstart)*2:]
 561                                                 for ph := 0; ph < 2; ph++ {
 562                                                         v := variants[ph]
 563                                                         if int(v) >= len(remap) {
 564                                                                 v = 0
 565                                                         } else {
 566                                                                 v = remap[v]
 567                                                         }
 568                                                         if v == rt.variant {
 569                                                                 // hgvsCol[*][ph][row] is already 0
 570                                                         } else if len(variantDiffs[v]) == 0 {
 571                                                                 // lacking coverage / couldn't be diffed
 572                                                                 for _, col := range hgvsCol {
 573                                                                         col[ph][row] = -1
 574                                                                 }
 575                                                         } else {
 576                                                                 for _, diff := range variantDiffs[v] {
 577                                                                         hgvsCol[diff][ph][row] = 1
 578                                                                 }
 579                                                         }
 580                                                 }
 581                                         }
 582                                         for diff, colpair := range hgvsCol {
 583                                                 allele2homhet(colpair)
 584                                                 if !cmd.filterHGVScolpair(colpair) {
 585                                                         delete(hgvsCol, diff)
 586                                                 }
 587                                         }
 588                                         if len(hgvsCol) > 0 {
 589                                                 encodeHGVSTodo[rt.seqname] <- hgvsCol
 590                                         }
 591                                 }
 592                                 outcol++
 593                         }
 594                         err = annow.Flush()
 595                         if err != nil {
 596                                 return err
 597                         }
 598                         err = annof.Close()
 599                         if err != nil {
 600                                 return err
 601                         }
 602
 603                         if *onehotChunked {
 604                                 // transpose onehotChunk[col][row] to numpy[row*ncols+col]
 605                                 rows := len(cmd.cgnames)
 606                                 cols := len(onehotChunk)
 607                                 log.Infof("%04d: preparing onehot numpy (rows=%d, cols=%d, mem=%d)", infileIdx, len(cmd.cgnames), len(onehotChunk), len(cmd.cgnames)*len(onehotChunk))
 608                                 throttleNumpyMem.Acquire()
 609                                 out := onehotcols2int8(onehotChunk)
 610                                 fnm := fmt.Sprintf("%s/onehot.%04d.npy", *outputDir, infileIdx)
 611                                 err = writeNumpyInt8(fnm, out, rows, cols)
 612                                 if err != nil {
 613                                         return err
 614                                 }
 615                                 fnm = fmt.Sprintf("%s/onehot-columns.%04d.npy", *outputDir, infileIdx)
 616                                 err = writeNumpyInt32(fnm, onehotXref2int32(onehotXref), 4, len(onehotXref))
 617                                 if err != nil {
 618                                         return err
 619                                 }
 620                                 debug.FreeOSMemory()
 621                                 throttleNumpyMem.Release()
 622                         }
 623                         if *onehotSingle {
 624                                 onehotIndirect[infileIdx] = onehotChunk2Indirect(onehotChunk)
 625                                 onehotXrefs[infileIdx] = onehotXref
 626                                 n := len(onehotIndirect[infileIdx][0])
 627                                 log.Infof("%04d: keeping onehot coordinates in memory (n=%d, mem=%d)", infileIdx, n, n*8)
 628                         }
 629                         if !(*onehotSingle || *onehotChunked) || *mergeOutput || *hgvsSingle {
 630                                 log.Infof("%04d: preparing numpy", infileIdx)
 631                                 throttleNumpyMem.Acquire()
 632                                 rows := len(cmd.cgnames)
 633                                 cols := 2 * outcol
 634                                 out := make([]int16, rows*cols)
 635                                 for row, name := range cmd.cgnames {
 636                                         out := out[row*cols:]
 637                                         outcol := 0
 638                                         for col, v := range cgs[name].Variants {
 639                                                 tag := tagstart + tagID(col/2)
 640                                                 if mask != nil && reftile[tag] == nil {
 641                                                         continue
 642                                                 }
 643                                                 if variants, ok := seq[tag]; ok && len(variants) > int(v) && len(variants[v].Sequence) > 0 {
 644                                                         out[outcol] = int16(variantRemap[tag-tagstart][v])
 645                                                 } else {
 646                                                         out[outcol] = -1
 647                                                 }
 648                                                 outcol++
 649                                         }
 650                                 }
 651                                 seq = nil
 652                                 cgs = nil
 653                                 debug.FreeOSMemory()
 654                                 throttleNumpyMem.Release()
 655                                 if *mergeOutput || *hgvsSingle {
 656                                         log.Infof("%04d: matrix fragment %d rows x %d cols", infileIdx, rows, cols)
 657                                         toMerge[infileIdx] = out
 658                                 }
 659                                 if !*mergeOutput && !*onehotChunked && !*onehotSingle {
 660                                         fnm := fmt.Sprintf("%s/matrix.%04d.npy", *outputDir, infileIdx)
 661                                         err = writeNumpyInt16(fnm, out, rows, cols)
 662                                         if err != nil {
 663                                                 return err
 664                                         }
 665                                 }
 666                         }
 667                         debug.FreeOSMemory()
 668                         log.Infof("%s: done (%d/%d)", infile, int(atomic.AddInt64(&done, 1)), len(infiles))
 669                         return nil
 670                 })
 671         }
 672         if err = throttleMem.Wait(); err != nil {
 673                 return 1
 674         }
 675
 676         if *hgvsChunked {
 677                 log.Info("flushing hgvsCols temp files")
 678                 for seqname := range refseq {
 679                         close(encodeHGVSTodo[seqname])
 680                 }
 681                 err = encodeHGVS.Wait()
 682                 if err != nil {
 683                         return 1
 684                 }
 685                 for seqname := range refseq {
 686                         log.Infof("%s: reading hgvsCols from temp file", seqname)
 687                         f := tmpHGVSCols[seqname]
 688                         _, err = f.Seek(0, io.SeekStart)
 689                         if err != nil {
 690                                 return 1
 691                         }
 692                         var hgvsCols hgvsColSet
 693                         dec := gob.NewDecoder(bufio.NewReaderSize(f, 1<<24))
 694                         for err == nil {
 695                                 err = dec.Decode(&hgvsCols)
 696                         }
 697                         if err != io.EOF {
 698                                 return 1
 699                         }
 700                         log.Infof("%s: sorting %d hgvs variants", seqname, len(hgvsCols))
 701                         variants := make([]hgvs.Variant, 0, len(hgvsCols))
 702                         for v := range hgvsCols {
 703                                 variants = append(variants, v)
 704                         }
 705                         sort.Slice(variants, func(i, j int) bool {
 706                                 vi, vj := &variants[i], &variants[j]
 707                                 if vi.Position != vj.Position {
 708                                         return vi.Position < vj.Position
 709                                 } else if vi.Ref != vj.Ref {
 710                                         return vi.Ref < vj.Ref
 711                                 } else {
 712                                         return vi.New < vj.New
 713                                 }
 714                         })
 715                         rows := len(cmd.cgnames)
 716                         cols := len(variants) * 2
 717                         log.Infof("%s: building hgvs matrix (rows=%d, cols=%d, mem=%d)", seqname, rows, cols, rows*cols)
 718                         out := make([]int8, rows*cols)
 719                         for varIdx, variant := range variants {
 720                                 hgvsCols := hgvsCols[variant]
 721                                 for row := range cmd.cgnames {
 722                                         for ph := 0; ph < 2; ph++ {
 723                                                 out[row*cols+varIdx+ph] = hgvsCols[ph][row]
 724                                         }
 725                                 }
 726                         }
 727                         err = writeNumpyInt8(fmt.Sprintf("%s/hgvs.%s.npy", *outputDir, seqname), out, rows, cols)
 728                         if err != nil {
 729                                 return 1
 730                         }
 731                         out = nil
 732
 733                         fnm := fmt.Sprintf("%s/hgvs.%s.annotations.csv", *outputDir, seqname)
 734                         log.Infof("%s: writing hgvs column labels to %s", seqname, fnm)
 735                         var hgvsLabels bytes.Buffer
 736                         for varIdx, variant := range variants {
 737                                 fmt.Fprintf(&hgvsLabels, "%d,%s:g.%s\n", varIdx, seqname, variant.String())
 738                         }
 739                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0666)
 740                         if err != nil {
 741                                 return 1
 742                         }
 743                 }
 744         }
 745
 746         if *mergeOutput || *hgvsSingle {
 747                 var annow *bufio.Writer
 748                 var annof *os.File
 749                 if *mergeOutput {
 750                         annoFilename := fmt.Sprintf("%s/matrix.annotations.csv", *outputDir)
 751                         annof, err = os.Create(annoFilename)
 752                         if err != nil {
 753                                 return 1
 754                         }
 755                         annow = bufio.NewWriterSize(annof, 1<<20)
 756                 }
 757
 758                 rows := len(cmd.cgnames)
 759                 cols := 0
 760                 for _, chunk := range toMerge {
 761                         cols += len(chunk) / rows
 762                 }
 763                 log.Infof("merging output matrix (rows=%d, cols=%d, mem=%d) and annotations", rows, cols, rows*cols*2)
 764                 var out []int16
 765                 if *mergeOutput {
 766                         out = make([]int16, rows*cols)
 767                 }
 768                 hgvsCols := map[string][2][]int16{} // hgvs -> [[g0,g1,g2,...], [g0,g1,g2,...]] (slice of genomes for each phase)
 769                 startcol := 0
 770                 for outIdx, chunk := range toMerge {
 771                         chunkcols := len(chunk) / rows
 772                         if *mergeOutput {
 773                                 for row := 0; row < rows; row++ {
 774                                         copy(out[row*cols+startcol:], chunk[row*chunkcols:(row+1)*chunkcols])
 775                                 }
 776                         }
 777                         toMerge[outIdx] = nil
 778
 779                         annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, outIdx)
 780                         log.Infof("reading %s", annotationsFilename)
 781                         buf, err := os.ReadFile(annotationsFilename)
 782                         if err != nil {
 783                                 return 1
 784                         }
 785                         if *mergeOutput {
 786                                 err = os.Remove(annotationsFilename)
 787                                 if err != nil {
 788                                         return 1
 789                                 }
 790                         }
 791                         for _, line := range bytes.Split(buf, []byte{'\n'}) {
 792                                 if len(line) == 0 {
 793                                         continue
 794                                 }
 795                                 fields := bytes.SplitN(line, []byte{','}, 9)
 796                                 tag, _ := strconv.Atoi(string(fields[0]))
 797                                 incol, _ := strconv.Atoi(string(fields[1]))
 798                                 tileVariant, _ := strconv.Atoi(string(fields[2]))
 799                                 hgvsID := string(fields[3])
 800                                 seqname := string(fields[4])
 801                                 pos, _ := strconv.Atoi(string(fields[5]))
 802                                 refseq := fields[6]
 803                                 if hgvsID == "" {
 804                                         // Null entry for un-diffable
 805                                         // tile variant
 806                                         continue
 807                                 }
 808                                 if hgvsID == "=" {
 809                                         // Null entry for ref tile
 810                                         continue
 811                                 }
 812                                 if mask != nil && !mask.Check(strings.TrimPrefix(seqname, "chr"), pos, pos+len(refseq)) {
 813                                         // The tile intersects one of
 814                                         // the selected regions, but
 815                                         // this particular HGVS
 816                                         // variant does not.
 817                                         continue
 818                                 }
 819                                 hgvsColPair := hgvsCols[hgvsID]
 820                                 if hgvsColPair[0] == nil {
 821                                         // values in new columns start
 822                                         // out as -1 ("no data yet")
 823                                         // or 0 ("=ref") here, may
 824                                         // change to 1 ("hgvs variant
 825                                         // present") below, either on
 826                                         // this line or a future line.
 827                                         hgvsColPair = [2][]int16{make([]int16, len(cmd.cgnames)), make([]int16, len(cmd.cgnames))}
 828                                         rt, ok := reftile[tagID(tag)]
 829                                         if !ok {
 830                                                 err = fmt.Errorf("bug: seeing annotations for tag %d, but it has no reftile entry", tag)
 831                                                 return 1
 832                                         }
 833                                         for ph := 0; ph < 2; ph++ {
 834                                                 for row := 0; row < rows; row++ {
 835                                                         v := chunk[row*chunkcols+incol*2+ph]
 836                                                         if tileVariantID(v) == rt.variant {
 837                                                                 hgvsColPair[ph][row] = 0
 838                                                         } else {
 839                                                                 hgvsColPair[ph][row] = -1
 840                                                         }
 841                                                 }
 842                                         }
 843                                         hgvsCols[hgvsID] = hgvsColPair
 844                                         if annow != nil {
 845                                                 hgvsref := hgvs.Variant{
 846                                                         Position: pos,
 847                                                         Ref:      string(refseq),
 848                                                         New:      string(refseq),
 849                                                 }
 850                                                 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])
 851                                         }
 852                                 }
 853                                 if annow != nil {
 854                                         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])
 855                                 }
 856                                 for ph := 0; ph < 2; ph++ {
 857                                         for row := 0; row < rows; row++ {
 858                                                 v := chunk[row*chunkcols+incol*2+ph]
 859                                                 if int(v) == tileVariant {
 860                                                         hgvsColPair[ph][row] = 1
 861                                                 }
 862                                         }
 863                                 }
 864                         }
 865
 866                         startcol += chunkcols
 867                 }
 868                 if *mergeOutput {
 869                         err = annow.Flush()
 870                         if err != nil {
 871                                 return 1
 872                         }
 873                         err = annof.Close()
 874                         if err != nil {
 875                                 return 1
 876                         }
 877                         err = writeNumpyInt16(fmt.Sprintf("%s/matrix.npy", *outputDir), out, rows, cols)
 878                         if err != nil {
 879                                 return 1
 880                         }
 881                 }
 882                 out = nil
 883
 884                 if *hgvsSingle {
 885                         cols = len(hgvsCols) * 2
 886                         log.Printf("building hgvs-based matrix: %d rows x %d cols", rows, cols)
 887                         out = make([]int16, rows*cols)
 888                         hgvsIDs := make([]string, 0, cols/2)
 889                         for hgvsID := range hgvsCols {
 890                                 hgvsIDs = append(hgvsIDs, hgvsID)
 891                         }
 892                         sort.Strings(hgvsIDs)
 893                         var hgvsLabels bytes.Buffer
 894                         for idx, hgvsID := range hgvsIDs {
 895                                 fmt.Fprintf(&hgvsLabels, "%d,%s\n", idx, hgvsID)
 896                                 for ph := 0; ph < 2; ph++ {
 897                                         hgvscol := hgvsCols[hgvsID][ph]
 898                                         for row, val := range hgvscol {
 899                                                 out[row*cols+idx*2+ph] = val
 900                                         }
 901                                 }
 902                         }
 903                         err = writeNumpyInt16(fmt.Sprintf("%s/hgvs.npy", *outputDir), out, rows, cols)
 904                         if err != nil {
 905                                 return 1
 906                         }
 907
 908                         fnm := fmt.Sprintf("%s/hgvs.annotations.csv", *outputDir)
 909                         log.Printf("writing hgvs labels: %s", fnm)
 910                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0777)
 911                         if err != nil {
 912                                 return 1
 913                         }
 914                 }
 915         }
 916         if *onehotSingle {
 917                 nzCount := 0
 918                 for _, part := range onehotIndirect {
 919                         nzCount += len(part[0])
 920                 }
 921                 onehot := make([]uint32, nzCount*2) // [r,r,r,...,c,c,c,...]
 922                 var xrefs []onehotXref
 923                 outcol := 0
 924                 for i, part := range onehotIndirect {
 925                         for i := range part[1] {
 926                                 part[1][i] += uint32(outcol)
 927                         }
 928                         copy(onehot[outcol:], part[0])
 929                         copy(onehot[outcol+nzCount:], part[1])
 930                         outcol += len(part[0])
 931                         xrefs = append(xrefs, onehotXrefs[i]...)
 932
 933                         part[0] = nil
 934                         part[1] = nil
 935                         onehotXrefs[i] = nil
 936                         debug.FreeOSMemory()
 937                 }
 938                 fnm := fmt.Sprintf("%s/onehot.npy", *outputDir)
 939                 err = writeNumpyUint32(fnm, onehot, 2, nzCount)
 940                 if err != nil {
 941                         return 1
 942                 }
 943                 fnm = fmt.Sprintf("%s/onehot-columns.npy", *outputDir)
 944                 err = writeNumpyInt32(fnm, onehotXref2int32(xrefs), 4, len(xrefs))
 945                 if err != nil {
 946                         return 1
 947                 }
 948         }
 949         return 0
 950 }
 951
 952 // Read case/control files, remove non-case/control entries from
 953 // cmd.cgnames, and build cmd.chi2Cases.
 954 func (cmd *sliceNumpy) useCaseControlFiles() error {
 955         if cmd.chi2CaseControlFile == "" {
 956                 return nil
 957         }
 958         infiles, err := allFiles(cmd.chi2CaseControlFile, nil)
 959         if err != nil {
 960                 return err
 961         }
 962         // index in cmd.cgnames => case(true) / control(false)
 963         cc := map[int]bool{}
 964         for _, infile := range infiles {
 965                 f, err := open(infile)
 966                 if err != nil {
 967                         return err
 968                 }
 969                 buf, err := io.ReadAll(f)
 970                 f.Close()
 971                 if err != nil {
 972                         return err
 973                 }
 974                 ccCol := -1
 975                 for _, tsv := range bytes.Split(buf, []byte{'\n'}) {
 976                         if len(tsv) == 0 {
 977                                 continue
 978                         }
 979                         split := strings.Split(string(tsv), "\t")
 980                         if ccCol < 0 {
 981                                 // header row
 982                                 for col, name := range split {
 983                                         if name == cmd.chi2CaseControlColumn {
 984                                                 ccCol = col
 985                                                 break
 986                                         }
 987                                 }
 988                                 if ccCol < 0 {
 989                                         return fmt.Errorf("%s: no column named %q in header row %q", infile, cmd.chi2CaseControlColumn, tsv)
 990                                 }
 991                                 continue
 992                         }
 993                         if len(split) <= ccCol {
 994                                 continue
 995                         }
 996                         pattern := split[0]
 997                         found := -1
 998                         for i, name := range cmd.cgnames {
 999                                 if strings.Contains(name, pattern) {
1000                                         if found >= 0 {
1001                                                 log.Warnf("pattern %q in %s matches multiple genome IDs (%qs, %q)", pattern, infile, cmd.cgnames[found], name)
1002                                         }
1003                                         found = i
1004                                 }
1005                         }
1006                         if found < 0 {
1007                                 log.Warnf("pattern %q in %s does not match any genome IDs", pattern, infile)
1008                                 continue
1009                         }
1010                         if split[ccCol] == "0" {
1011                                 cc[found] = false
1012                         }
1013                         if split[ccCol] == "1" {
1014                                 cc[found] = true
1015                         }
1016                 }
1017         }
1018         allnames := cmd.cgnames
1019         cmd.cgnames = nil
1020         cmd.chi2Cases = nil
1021         ncases := 0
1022         for i, name := range allnames {
1023                 if cc, ok := cc[i]; ok {
1024                         cmd.cgnames = append(cmd.cgnames, name)
1025                         cmd.chi2Cases = append(cmd.chi2Cases, cc)
1026                         if cc {
1027                                 ncases++
1028                         }
1029                 }
1030         }
1031         log.Printf("%d cases, %d controls, %d neither (dropped)", ncases, len(cmd.cgnames)-ncases, len(allnames)-len(cmd.cgnames))
1032         return nil
1033 }
1034
1035 func (cmd *sliceNumpy) filterHGVScolpair(colpair [2][]int8) bool {
1036         if cmd.chi2PValue >= 1 {
1037                 return true
1038         }
1039         col0 := make([]bool, 0, len(cmd.chi2Cases))
1040         col1 := make([]bool, 0, len(cmd.chi2Cases))
1041         cases := make([]bool, 0, len(cmd.chi2Cases))
1042         for i, c := range cmd.chi2Cases {
1043                 if colpair[0][i] < 0 {
1044                         continue
1045                 }
1046                 col0 = append(col0, colpair[0][i] != 0)
1047                 col1 = append(col1, colpair[1][i] != 0)
1048                 cases = append(cases, c)
1049         }
1050         return len(cases) >= cmd.minCoverage &&
1051                 (pvalue(col0, cases) <= cmd.chi2PValue || pvalue(col1, cases) <= cmd.chi2PValue)
1052 }
1053
1054 func writeNumpyUint32(fnm string, out []uint32, rows, cols int) error {
1055         output, err := os.Create(fnm)
1056         if err != nil {
1057                 return err
1058         }
1059         defer output.Close()
1060         bufw := bufio.NewWriterSize(output, 1<<26)
1061         npw, err := gonpy.NewWriter(nopCloser{bufw})
1062         if err != nil {
1063                 return err
1064         }
1065         log.WithFields(log.Fields{
1066                 "filename": fnm,
1067                 "rows":     rows,
1068                 "cols":     cols,
1069                 "bytes":    rows * cols * 4,
1070         }).Infof("writing numpy: %s", fnm)
1071         npw.Shape = []int{rows, cols}
1072         npw.WriteUint32(out)
1073         err = bufw.Flush()
1074         if err != nil {
1075                 return err
1076         }
1077         return output.Close()
1078 }
1079
1080 func writeNumpyInt32(fnm string, out []int32, rows, cols int) error {
1081         output, err := os.Create(fnm)
1082         if err != nil {
1083                 return err
1084         }
1085         defer output.Close()
1086         bufw := bufio.NewWriterSize(output, 1<<26)
1087         npw, err := gonpy.NewWriter(nopCloser{bufw})
1088         if err != nil {
1089                 return err
1090         }
1091         log.WithFields(log.Fields{
1092                 "filename": fnm,
1093                 "rows":     rows,
1094                 "cols":     cols,
1095                 "bytes":    rows * cols * 4,
1096         }).Infof("writing numpy: %s", fnm)
1097         npw.Shape = []int{rows, cols}
1098         npw.WriteInt32(out)
1099         err = bufw.Flush()
1100         if err != nil {
1101                 return err
1102         }
1103         return output.Close()
1104 }
1105
1106 func writeNumpyInt16(fnm string, out []int16, rows, cols int) error {
1107         output, err := os.Create(fnm)
1108         if err != nil {
1109                 return err
1110         }
1111         defer output.Close()
1112         bufw := bufio.NewWriterSize(output, 1<<26)
1113         npw, err := gonpy.NewWriter(nopCloser{bufw})
1114         if err != nil {
1115                 return err
1116         }
1117         log.WithFields(log.Fields{
1118                 "filename": fnm,
1119                 "rows":     rows,
1120                 "cols":     cols,
1121                 "bytes":    rows * cols * 2,
1122         }).Infof("writing numpy: %s", fnm)
1123         npw.Shape = []int{rows, cols}
1124         npw.WriteInt16(out)
1125         err = bufw.Flush()
1126         if err != nil {
1127                 return err
1128         }
1129         return output.Close()
1130 }
1131
1132 func writeNumpyInt8(fnm string, out []int8, rows, cols int) error {
1133         output, err := os.Create(fnm)
1134         if err != nil {
1135                 return err
1136         }
1137         defer output.Close()
1138         bufw := bufio.NewWriterSize(output, 1<<26)
1139         npw, err := gonpy.NewWriter(nopCloser{bufw})
1140         if err != nil {
1141                 return err
1142         }
1143         log.WithFields(log.Fields{
1144                 "filename": fnm,
1145                 "rows":     rows,
1146                 "cols":     cols,
1147                 "bytes":    rows * cols,
1148         }).Infof("writing numpy: %s", fnm)
1149         npw.Shape = []int{rows, cols}
1150         npw.WriteInt8(out)
1151         err = bufw.Flush()
1152         if err != nil {
1153                 return err
1154         }
1155         return output.Close()
1156 }
1157
1158 func allele2homhet(colpair [2][]int8) {
1159         a, b := colpair[0], colpair[1]
1160         for i, av := range a {
1161                 bv := b[i]
1162                 if av < 0 || bv < 0 {
1163                         // no-call
1164                         a[i], b[i] = -1, -1
1165                 } else if av > 0 && bv > 0 {
1166                         // hom
1167                         a[i], b[i] = 1, 0
1168                 } else if av > 0 || bv > 0 {
1169                         // het
1170                         a[i], b[i] = 0, 1
1171                 } else {
1172                         // ref (or a different variant in same position)
1173                         // (this is a no-op) a[i], b[i] = 0, 0
1174                 }
1175         }
1176 }
1177
1178 type onehotXref struct {
1179         tag     tagID
1180         variant tileVariantID
1181         het     bool
1182         pvalue  float64
1183 }
1184
1185 const onehotXrefSize = unsafe.Sizeof(onehotXref{})
1186
1187 // Build onehot matrix (m[variant*2+isHet][genome] == 0 or 1) for all
1188 // variants of a single tile/tag#.
1189 //
1190 // Return nil if no tile variant passes Χ² filter.
1191 func (cmd *sliceNumpy) tv2homhet(cgs map[string]CompactGenome, maxv tileVariantID, remap []tileVariantID, tag, chunkstarttag tagID) ([][]int8, []onehotXref) {
1192         if maxv < 2 {
1193                 // everyone has the most common variant
1194                 return nil, nil
1195         }
1196         tagoffset := tag - chunkstarttag
1197         coverage := 0
1198         for _, cg := range cgs {
1199                 if cg.Variants[tagoffset*2] > 0 && cg.Variants[tagoffset*2+1] > 0 {
1200                         coverage++
1201                 }
1202         }
1203         if coverage < cmd.minCoverage {
1204                 return nil, nil
1205         }
1206         obs := make([][]bool, (maxv+1)*2) // 2 slices (hom + het) for each variant#
1207         for i := range obs {
1208                 obs[i] = make([]bool, len(cmd.cgnames))
1209         }
1210         for cgid, name := range cmd.cgnames {
1211                 cgvars := cgs[name].Variants
1212                 for v := tileVariantID(2); v <= maxv; v++ {
1213                         if remap[cgvars[tagoffset*2]] == v && remap[cgvars[tagoffset*2+1]] == v {
1214                                 obs[v*2][cgid] = true
1215                         } else if remap[cgvars[tagoffset*2]] == v || remap[cgvars[tagoffset*2+1]] == v {
1216                                 obs[v*2+1][cgid] = true
1217                         }
1218                 }
1219         }
1220         var onehot [][]int8
1221         var xref []onehotXref
1222         for homcol := 4; homcol < len(obs); homcol += 2 {
1223                 for het := 0; het < 2; het++ {
1224                         p := pvalue(obs[homcol+het], cmd.chi2Cases)
1225                         if cmd.chi2PValue < 1 && !(p < cmd.chi2PValue) {
1226                                 continue
1227                         }
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,
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 }