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