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