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 onehotChunkSize []uint32
 349         var onehotXrefs [][]onehotXref
 350         if *onehotSingle {
 351                 onehotIndirect = make([][2][]uint32, len(infiles))
 352                 onehotChunkSize = make([]uint32, len(infiles))
 353                 onehotXrefs = make([][]onehotXref, len(infiles))
 354         }
 355
 356         throttleMem := throttle{Max: cmd.threads} // TODO: estimate using mem and data size
 357         throttleNumpyMem := throttle{Max: cmd.threads/2 + 1}
 358         log.Info("generating annotations and numpy matrix for each slice")
 359         var done int64
 360         for infileIdx, infile := range infiles {
 361                 infileIdx, infile := infileIdx, infile
 362                 throttleMem.Go(func() error {
 363                         seq := make(map[tagID][]TileVariant, 50000)
 364                         cgs := make(map[string]CompactGenome, len(cmd.cgnames))
 365                         f, err := open(infile)
 366                         if err != nil {
 367                                 return err
 368                         }
 369                         defer f.Close()
 370                         log.Infof("%04d: reading %s", infileIdx, infile)
 371                         err = DecodeLibrary(f, strings.HasSuffix(infile, ".gz"), func(ent *LibraryEntry) error {
 372                                 for _, tv := range ent.TileVariants {
 373                                         if tv.Ref {
 374                                                 continue
 375                                         }
 376                                         if mask != nil && reftile[tv.Tag] == nil {
 377                                                 // Don't waste
 378                                                 // time/memory on
 379                                                 // masked-out tiles.
 380                                                 continue
 381                                         }
 382                                         variants := seq[tv.Tag]
 383                                         if len(variants) == 0 {
 384                                                 variants = make([]TileVariant, 100)
 385                                         }
 386                                         for len(variants) <= int(tv.Variant) {
 387                                                 variants = append(variants, TileVariant{})
 388                                         }
 389                                         variants[int(tv.Variant)] = tv
 390                                         seq[tv.Tag] = variants
 391                                 }
 392                                 for _, cg := range ent.CompactGenomes {
 393                                         if !matchGenome.MatchString(cg.Name) {
 394                                                 continue
 395                                         }
 396                                         // pad to full slice size
 397                                         // to avoid out-of-bounds
 398                                         // checks later
 399                                         if sliceSize := 2 * int(cg.EndTag-cg.StartTag); len(cg.Variants) < sliceSize {
 400                                                 cg.Variants = append(cg.Variants, make([]tileVariantID, sliceSize-len(cg.Variants))...)
 401                                         }
 402                                         cgs[cg.Name] = cg
 403                                 }
 404                                 return nil
 405                         })
 406                         if err != nil {
 407                                 return err
 408                         }
 409                         tagstart := cgs[cmd.cgnames[0]].StartTag
 410                         tagend := cgs[cmd.cgnames[0]].EndTag
 411
 412                         // TODO: filters
 413
 414                         log.Infof("%04d: renumber/dedup variants for tags %d-%d", infileIdx, tagstart, tagend)
 415                         variantRemap := make([][]tileVariantID, tagend-tagstart)
 416                         throttleCPU := throttle{Max: runtime.GOMAXPROCS(0)}
 417                         for tag, variants := range seq {
 418                                 tag, variants := tag, variants
 419                                 throttleCPU.Acquire()
 420                                 go func() {
 421                                         defer throttleCPU.Release()
 422                                         count := make(map[[blake2b.Size256]byte]int, len(variants))
 423
 424                                         rt := reftile[tag]
 425                                         if rt != nil {
 426                                                 count[blake2b.Sum256(rt.tiledata)] = 0
 427                                         }
 428
 429                                         for _, cg := range cgs {
 430                                                 idx := int(tag-tagstart) * 2
 431                                                 for allele := 0; allele < 2; allele++ {
 432                                                         v := cg.Variants[idx+allele]
 433                                                         if v > 0 && len(variants[v].Sequence) > 0 {
 434                                                                 count[variants[v].Blake2b]++
 435                                                         }
 436                                                 }
 437                                         }
 438                                         // hash[i] will be the hash of
 439                                         // the variant(s) that should
 440                                         // be at rank i (0-based).
 441                                         hash := make([][blake2b.Size256]byte, 0, len(count))
 442                                         for b := range count {
 443                                                 hash = append(hash, b)
 444                                         }
 445                                         sort.Slice(hash, func(i, j int) bool {
 446                                                 bi, bj := &hash[i], &hash[j]
 447                                                 if ci, cj := count[*bi], count[*bj]; ci != cj {
 448                                                         return ci > cj
 449                                                 } else {
 450                                                         return bytes.Compare((*bi)[:], (*bj)[:]) < 0
 451                                                 }
 452                                         })
 453                                         // rank[b] will be the 1-based
 454                                         // new variant number for
 455                                         // variants whose hash is b.
 456                                         rank := make(map[[blake2b.Size256]byte]tileVariantID, len(hash))
 457                                         for i, h := range hash {
 458                                                 rank[h] = tileVariantID(i + 1)
 459                                         }
 460                                         // remap[v] will be the new
 461                                         // variant number for original
 462                                         // variant number v.
 463                                         remap := make([]tileVariantID, len(variants))
 464                                         for i, tv := range variants {
 465                                                 remap[i] = rank[tv.Blake2b]
 466                                         }
 467                                         variantRemap[tag-tagstart] = remap
 468                                         if rt != nil {
 469                                                 rt.variant = rank[blake2b.Sum256(rt.tiledata)]
 470                                         }
 471                                 }()
 472                         }
 473                         throttleCPU.Wait()
 474
 475                         var onehotChunk [][]int8
 476                         var onehotXref []onehotXref
 477
 478                         annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, infileIdx)
 479                         log.Infof("%04d: writing %s", infileIdx, annotationsFilename)
 480                         annof, err := os.Create(annotationsFilename)
 481                         if err != nil {
 482                                 return err
 483                         }
 484                         annow := bufio.NewWriterSize(annof, 1<<20)
 485                         outcol := 0
 486                         for tag := tagstart; tag < tagend; tag++ {
 487                                 rt := reftile[tag]
 488                                 if rt == nil && mask != nil {
 489                                         // Excluded by specified regions
 490                                         continue
 491                                 }
 492                                 if cmd.filter.MaxTag >= 0 && tag > tagID(cmd.filter.MaxTag) {
 493                                         continue
 494                                 }
 495                                 remap := variantRemap[tag-tagstart]
 496                                 maxv := tileVariantID(0)
 497                                 for _, v := range remap {
 498                                         if maxv < v {
 499                                                 maxv = v
 500                                         }
 501                                 }
 502                                 if *onehotChunked || *onehotSingle {
 503                                         onehot, xrefs := cmd.tv2homhet(cgs, maxv, remap, tag, tagstart)
 504                                         onehotChunk = append(onehotChunk, onehot...)
 505                                         onehotXref = append(onehotXref, xrefs...)
 506                                 }
 507                                 if rt == nil {
 508                                         // Reference does not use any
 509                                         // variant of this tile
 510                                         outcol++
 511                                         continue
 512                                 }
 513                                 fmt.Fprintf(annow, "%d,%d,%d,=,%s,%d,,,\n", tag, outcol, rt.variant, rt.seqname, rt.pos)
 514                                 variants := seq[tag]
 515                                 reftilestr := strings.ToUpper(string(rt.tiledata))
 516
 517                                 done := make([]bool, maxv+1)
 518                                 variantDiffs := make([][]hgvs.Variant, maxv+1)
 519                                 for v, tv := range variants {
 520                                         v := remap[v]
 521                                         if v == rt.variant || done[v] {
 522                                                 continue
 523                                         } else {
 524                                                 done[v] = true
 525                                         }
 526                                         if len(tv.Sequence) < taglen || !bytes.HasSuffix(rt.tiledata, tv.Sequence[len(tv.Sequence)-taglen:]) {
 527                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 528                                                 continue
 529                                         }
 530                                         if lendiff := len(rt.tiledata) - len(tv.Sequence); lendiff < -1000 || lendiff > 1000 {
 531                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 532                                                 continue
 533                                         }
 534                                         diffs, _ := hgvs.Diff(reftilestr, strings.ToUpper(string(tv.Sequence)), 0)
 535                                         for i := range diffs {
 536                                                 diffs[i].Position += rt.pos
 537                                         }
 538                                         for _, diff := range diffs {
 539                                                 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)
 540                                         }
 541                                         if *hgvsChunked {
 542                                                 variantDiffs[v] = diffs
 543                                         }
 544                                 }
 545                                 if *hgvsChunked {
 546                                         // We can now determine, for each HGVS
 547                                         // variant (diff) in this reftile
 548                                         // region, whether a given genome
 549                                         // phase/allele (1) has the variant, (0) has
 550                                         // =ref or a different variant in that
 551                                         // position, or (-1) is lacking
 552                                         // coverage / couldn't be diffed.
 553                                         hgvsCol := hgvsColSet{}
 554                                         for _, diffs := range variantDiffs {
 555                                                 for _, diff := range diffs {
 556                                                         if _, ok := hgvsCol[diff]; ok {
 557                                                                 continue
 558                                                         }
 559                                                         hgvsCol[diff] = [2][]int8{
 560                                                                 make([]int8, len(cmd.cgnames)),
 561                                                                 make([]int8, len(cmd.cgnames)),
 562                                                         }
 563                                                 }
 564                                         }
 565                                         for row, name := range cmd.cgnames {
 566                                                 variants := cgs[name].Variants[(tag-tagstart)*2:]
 567                                                 for ph := 0; ph < 2; ph++ {
 568                                                         v := variants[ph]
 569                                                         if int(v) >= len(remap) {
 570                                                                 v = 0
 571                                                         } else {
 572                                                                 v = remap[v]
 573                                                         }
 574                                                         if v == rt.variant {
 575                                                                 // hgvsCol[*][ph][row] is already 0
 576                                                         } else if len(variantDiffs[v]) == 0 {
 577                                                                 // lacking coverage / couldn't be diffed
 578                                                                 for _, col := range hgvsCol {
 579                                                                         col[ph][row] = -1
 580                                                                 }
 581                                                         } else {
 582                                                                 for _, diff := range variantDiffs[v] {
 583                                                                         hgvsCol[diff][ph][row] = 1
 584                                                                 }
 585                                                         }
 586                                                 }
 587                                         }
 588                                         for diff, colpair := range hgvsCol {
 589                                                 allele2homhet(colpair)
 590                                                 if !cmd.filterHGVScolpair(colpair) {
 591                                                         delete(hgvsCol, diff)
 592                                                 }
 593                                         }
 594                                         if len(hgvsCol) > 0 {
 595                                                 encodeHGVSTodo[rt.seqname] <- hgvsCol
 596                                         }
 597                                 }
 598                                 outcol++
 599                         }
 600                         err = annow.Flush()
 601                         if err != nil {
 602                                 return err
 603                         }
 604                         err = annof.Close()
 605                         if err != nil {
 606                                 return err
 607                         }
 608
 609                         if *onehotChunked {
 610                                 // transpose onehotChunk[col][row] to numpy[row*ncols+col]
 611                                 rows := len(cmd.cgnames)
 612                                 cols := len(onehotChunk)
 613                                 log.Infof("%04d: preparing onehot numpy (rows=%d, cols=%d, mem=%d)", infileIdx, len(cmd.cgnames), len(onehotChunk), len(cmd.cgnames)*len(onehotChunk))
 614                                 throttleNumpyMem.Acquire()
 615                                 out := onehotcols2int8(onehotChunk)
 616                                 fnm := fmt.Sprintf("%s/onehot.%04d.npy", *outputDir, infileIdx)
 617                                 err = writeNumpyInt8(fnm, out, rows, cols)
 618                                 if err != nil {
 619                                         return err
 620                                 }
 621                                 fnm = fmt.Sprintf("%s/onehot-columns.%04d.npy", *outputDir, infileIdx)
 622                                 err = writeNumpyInt32(fnm, onehotXref2int32(onehotXref), 4, len(onehotXref))
 623                                 if err != nil {
 624                                         return err
 625                                 }
 626                                 debug.FreeOSMemory()
 627                                 throttleNumpyMem.Release()
 628                         }
 629                         if *onehotSingle {
 630                                 onehotIndirect[infileIdx] = onehotChunk2Indirect(onehotChunk)
 631                                 onehotChunkSize[infileIdx] = uint32(len(onehotChunk))
 632                                 onehotXrefs[infileIdx] = onehotXref
 633                                 n := len(onehotIndirect[infileIdx][0])
 634                                 log.Infof("%04d: keeping onehot coordinates in memory (n=%d, mem=%d)", infileIdx, n, n*8*2)
 635                         }
 636                         if !(*onehotSingle || *onehotChunked) || *mergeOutput || *hgvsSingle {
 637                                 log.Infof("%04d: preparing numpy (rows=%d, cols=%d)", infileIdx, len(cmd.cgnames), 2*outcol)
 638                                 throttleNumpyMem.Acquire()
 639                                 rows := len(cmd.cgnames)
 640                                 cols := 2 * outcol
 641                                 out := make([]int16, rows*cols)
 642                                 for row, name := range cmd.cgnames {
 643                                         out := out[row*cols:]
 644                                         outcol := 0
 645                                         for col, v := range cgs[name].Variants {
 646                                                 tag := tagstart + tagID(col/2)
 647                                                 if mask != nil && reftile[tag] == nil || tag > tagID(cmd.filter.MaxTag) {
 648                                                         continue
 649                                                 }
 650                                                 if variants, ok := seq[tag]; ok && len(variants) > int(v) && len(variants[v].Sequence) > 0 {
 651                                                         out[outcol] = int16(variantRemap[tag-tagstart][v])
 652                                                 } else {
 653                                                         out[outcol] = -1
 654                                                 }
 655                                                 outcol++
 656                                         }
 657                                 }
 658                                 seq = nil
 659                                 cgs = nil
 660                                 debug.FreeOSMemory()
 661                                 throttleNumpyMem.Release()
 662                                 if *mergeOutput || *hgvsSingle {
 663                                         log.Infof("%04d: matrix fragment %d rows x %d cols", infileIdx, rows, cols)
 664                                         toMerge[infileIdx] = out
 665                                 }
 666                                 if !*mergeOutput && !*onehotChunked && !*onehotSingle {
 667                                         fnm := fmt.Sprintf("%s/matrix.%04d.npy", *outputDir, infileIdx)
 668                                         err = writeNumpyInt16(fnm, out, rows, cols)
 669                                         if err != nil {
 670                                                 return err
 671                                         }
 672                                 }
 673                         }
 674                         debug.FreeOSMemory()
 675                         log.Infof("%s: done (%d/%d)", infile, int(atomic.AddInt64(&done, 1)), len(infiles))
 676                         return nil
 677                 })
 678         }
 679         if err = throttleMem.Wait(); err != nil {
 680                 return 1
 681         }
 682
 683         if *hgvsChunked {
 684                 log.Info("flushing hgvsCols temp files")
 685                 for seqname := range refseq {
 686                         close(encodeHGVSTodo[seqname])
 687                 }
 688                 err = encodeHGVS.Wait()
 689                 if err != nil {
 690                         return 1
 691                 }
 692                 for seqname := range refseq {
 693                         log.Infof("%s: reading hgvsCols from temp file", seqname)
 694                         f := tmpHGVSCols[seqname]
 695                         _, err = f.Seek(0, io.SeekStart)
 696                         if err != nil {
 697                                 return 1
 698                         }
 699                         var hgvsCols hgvsColSet
 700                         dec := gob.NewDecoder(bufio.NewReaderSize(f, 1<<24))
 701                         for err == nil {
 702                                 err = dec.Decode(&hgvsCols)
 703                         }
 704                         if err != io.EOF {
 705                                 return 1
 706                         }
 707                         log.Infof("%s: sorting %d hgvs variants", seqname, len(hgvsCols))
 708                         variants := make([]hgvs.Variant, 0, len(hgvsCols))
 709                         for v := range hgvsCols {
 710                                 variants = append(variants, v)
 711                         }
 712                         sort.Slice(variants, func(i, j int) bool {
 713                                 vi, vj := &variants[i], &variants[j]
 714                                 if vi.Position != vj.Position {
 715                                         return vi.Position < vj.Position
 716                                 } else if vi.Ref != vj.Ref {
 717                                         return vi.Ref < vj.Ref
 718                                 } else {
 719                                         return vi.New < vj.New
 720                                 }
 721                         })
 722                         rows := len(cmd.cgnames)
 723                         cols := len(variants) * 2
 724                         log.Infof("%s: building hgvs matrix (rows=%d, cols=%d, mem=%d)", seqname, rows, cols, rows*cols)
 725                         out := make([]int8, rows*cols)
 726                         for varIdx, variant := range variants {
 727                                 hgvsCols := hgvsCols[variant]
 728                                 for row := range cmd.cgnames {
 729                                         for ph := 0; ph < 2; ph++ {
 730                                                 out[row*cols+varIdx+ph] = hgvsCols[ph][row]
 731                                         }
 732                                 }
 733                         }
 734                         err = writeNumpyInt8(fmt.Sprintf("%s/hgvs.%s.npy", *outputDir, seqname), out, rows, cols)
 735                         if err != nil {
 736                                 return 1
 737                         }
 738                         out = nil
 739
 740                         fnm := fmt.Sprintf("%s/hgvs.%s.annotations.csv", *outputDir, seqname)
 741                         log.Infof("%s: writing hgvs column labels to %s", seqname, fnm)
 742                         var hgvsLabels bytes.Buffer
 743                         for varIdx, variant := range variants {
 744                                 fmt.Fprintf(&hgvsLabels, "%d,%s:g.%s\n", varIdx, seqname, variant.String())
 745                         }
 746                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0666)
 747                         if err != nil {
 748                                 return 1
 749                         }
 750                 }
 751         }
 752
 753         if *mergeOutput || *hgvsSingle {
 754                 var annow *bufio.Writer
 755                 var annof *os.File
 756                 if *mergeOutput {
 757                         annoFilename := fmt.Sprintf("%s/matrix.annotations.csv", *outputDir)
 758                         annof, err = os.Create(annoFilename)
 759                         if err != nil {
 760                                 return 1
 761                         }
 762                         annow = bufio.NewWriterSize(annof, 1<<20)
 763                 }
 764
 765                 rows := len(cmd.cgnames)
 766                 cols := 0
 767                 for _, chunk := range toMerge {
 768                         cols += len(chunk) / rows
 769                 }
 770                 log.Infof("merging output matrix (rows=%d, cols=%d, mem=%d) and annotations", rows, cols, rows*cols*2)
 771                 var out []int16
 772                 if *mergeOutput {
 773                         out = make([]int16, rows*cols)
 774                 }
 775                 hgvsCols := map[string][2][]int16{} // hgvs -> [[g0,g1,g2,...], [g0,g1,g2,...]] (slice of genomes for each phase)
 776                 startcol := 0
 777                 for outIdx, chunk := range toMerge {
 778                         chunkcols := len(chunk) / rows
 779                         if *mergeOutput {
 780                                 for row := 0; row < rows; row++ {
 781                                         copy(out[row*cols+startcol:], chunk[row*chunkcols:(row+1)*chunkcols])
 782                                 }
 783                         }
 784                         toMerge[outIdx] = nil
 785
 786                         annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, outIdx)
 787                         log.Infof("reading %s", annotationsFilename)
 788                         buf, err := os.ReadFile(annotationsFilename)
 789                         if err != nil {
 790                                 return 1
 791                         }
 792                         if *mergeOutput {
 793                                 err = os.Remove(annotationsFilename)
 794                                 if err != nil {
 795                                         return 1
 796                                 }
 797                         }
 798                         for _, line := range bytes.Split(buf, []byte{'\n'}) {
 799                                 if len(line) == 0 {
 800                                         continue
 801                                 }
 802                                 fields := bytes.SplitN(line, []byte{','}, 9)
 803                                 tag, _ := strconv.Atoi(string(fields[0]))
 804                                 incol, _ := strconv.Atoi(string(fields[1]))
 805                                 tileVariant, _ := strconv.Atoi(string(fields[2]))
 806                                 hgvsID := string(fields[3])
 807                                 seqname := string(fields[4])
 808                                 pos, _ := strconv.Atoi(string(fields[5]))
 809                                 refseq := fields[6]
 810                                 if hgvsID == "" {
 811                                         // Null entry for un-diffable
 812                                         // tile variant
 813                                         continue
 814                                 }
 815                                 if hgvsID == "=" {
 816                                         // Null entry for ref tile
 817                                         continue
 818                                 }
 819                                 if mask != nil && !mask.Check(strings.TrimPrefix(seqname, "chr"), pos, pos+len(refseq)) {
 820                                         // The tile intersects one of
 821                                         // the selected regions, but
 822                                         // this particular HGVS
 823                                         // variant does not.
 824                                         continue
 825                                 }
 826                                 hgvsColPair := hgvsCols[hgvsID]
 827                                 if hgvsColPair[0] == nil {
 828                                         // values in new columns start
 829                                         // out as -1 ("no data yet")
 830                                         // or 0 ("=ref") here, may
 831                                         // change to 1 ("hgvs variant
 832                                         // present") below, either on
 833                                         // this line or a future line.
 834                                         hgvsColPair = [2][]int16{make([]int16, len(cmd.cgnames)), make([]int16, len(cmd.cgnames))}
 835                                         rt, ok := reftile[tagID(tag)]
 836                                         if !ok {
 837                                                 err = fmt.Errorf("bug: seeing annotations for tag %d, but it has no reftile entry", tag)
 838                                                 return 1
 839                                         }
 840                                         for ph := 0; ph < 2; ph++ {
 841                                                 for row := 0; row < rows; row++ {
 842                                                         v := chunk[row*chunkcols+incol*2+ph]
 843                                                         if tileVariantID(v) == rt.variant {
 844                                                                 hgvsColPair[ph][row] = 0
 845                                                         } else {
 846                                                                 hgvsColPair[ph][row] = -1
 847                                                         }
 848                                                 }
 849                                         }
 850                                         hgvsCols[hgvsID] = hgvsColPair
 851                                         if annow != nil {
 852                                                 hgvsref := hgvs.Variant{
 853                                                         Position: pos,
 854                                                         Ref:      string(refseq),
 855                                                         New:      string(refseq),
 856                                                 }
 857                                                 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])
 858                                         }
 859                                 }
 860                                 if annow != nil {
 861                                         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])
 862                                 }
 863                                 for ph := 0; ph < 2; ph++ {
 864                                         for row := 0; row < rows; row++ {
 865                                                 v := chunk[row*chunkcols+incol*2+ph]
 866                                                 if int(v) == tileVariant {
 867                                                         hgvsColPair[ph][row] = 1
 868                                                 }
 869                                         }
 870                                 }
 871                         }
 872
 873                         startcol += chunkcols
 874                 }
 875                 if *mergeOutput {
 876                         err = annow.Flush()
 877                         if err != nil {
 878                                 return 1
 879                         }
 880                         err = annof.Close()
 881                         if err != nil {
 882                                 return 1
 883                         }
 884                         err = writeNumpyInt16(fmt.Sprintf("%s/matrix.npy", *outputDir), out, rows, cols)
 885                         if err != nil {
 886                                 return 1
 887                         }
 888                 }
 889                 out = nil
 890
 891                 if *hgvsSingle {
 892                         cols = len(hgvsCols) * 2
 893                         log.Printf("building hgvs-based matrix: %d rows x %d cols", rows, cols)
 894                         out = make([]int16, rows*cols)
 895                         hgvsIDs := make([]string, 0, cols/2)
 896                         for hgvsID := range hgvsCols {
 897                                 hgvsIDs = append(hgvsIDs, hgvsID)
 898                         }
 899                         sort.Strings(hgvsIDs)
 900                         var hgvsLabels bytes.Buffer
 901                         for idx, hgvsID := range hgvsIDs {
 902                                 fmt.Fprintf(&hgvsLabels, "%d,%s\n", idx, hgvsID)
 903                                 for ph := 0; ph < 2; ph++ {
 904                                         hgvscol := hgvsCols[hgvsID][ph]
 905                                         for row, val := range hgvscol {
 906                                                 out[row*cols+idx*2+ph] = val
 907                                         }
 908                                 }
 909                         }
 910                         err = writeNumpyInt16(fmt.Sprintf("%s/hgvs.npy", *outputDir), out, rows, cols)
 911                         if err != nil {
 912                                 return 1
 913                         }
 914
 915                         fnm := fmt.Sprintf("%s/hgvs.annotations.csv", *outputDir)
 916                         log.Printf("writing hgvs labels: %s", fnm)
 917                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0777)
 918                         if err != nil {
 919                                 return 1
 920                         }
 921                 }
 922         }
 923         if *onehotSingle {
 924                 nzCount := 0
 925                 for _, part := range onehotIndirect {
 926                         nzCount += len(part[0])
 927                 }
 928                 onehot := make([]uint32, nzCount*2) // [r,r,r,...,c,c,c,...]
 929                 var xrefs []onehotXref
 930                 chunkOffset := uint32(0)
 931                 outcol := 0
 932                 for i, part := range onehotIndirect {
 933                         for i := range part[1] {
 934                                 part[1][i] += chunkOffset
 935                         }
 936                         copy(onehot[outcol:], part[0])
 937                         copy(onehot[outcol+nzCount:], part[1])
 938                         xrefs = append(xrefs, onehotXrefs[i]...)
 939
 940                         outcol += len(part[0])
 941                         chunkOffset += onehotChunkSize[i]
 942
 943                         part[0] = nil
 944                         part[1] = nil
 945                         onehotXrefs[i] = nil
 946                         debug.FreeOSMemory()
 947                 }
 948                 fnm := fmt.Sprintf("%s/onehot.npy", *outputDir)
 949                 err = writeNumpyUint32(fnm, onehot, 2, nzCount)
 950                 if err != nil {
 951                         return 1
 952                 }
 953                 fnm = fmt.Sprintf("%s/onehot-columns.npy", *outputDir)
 954                 err = writeNumpyInt32(fnm, onehotXref2int32(xrefs), 4, len(xrefs))
 955                 if err != nil {
 956                         return 1
 957                 }
 958         }
 959         return 0
 960 }
 961
 962 // Read case/control files, remove non-case/control entries from
 963 // cmd.cgnames, and build cmd.chi2Cases.
 964 func (cmd *sliceNumpy) useCaseControlFiles() error {
 965         if cmd.chi2CaseControlFile == "" {
 966                 return nil
 967         }
 968         infiles, err := allFiles(cmd.chi2CaseControlFile, nil)
 969         if err != nil {
 970                 return err
 971         }
 972         // index in cmd.cgnames => case(true) / control(false)
 973         cc := map[int]bool{}
 974         for _, infile := range infiles {
 975                 f, err := open(infile)
 976                 if err != nil {
 977                         return err
 978                 }
 979                 buf, err := io.ReadAll(f)
 980                 f.Close()
 981                 if err != nil {
 982                         return err
 983                 }
 984                 ccCol := -1
 985                 for _, tsv := range bytes.Split(buf, []byte{'\n'}) {
 986                         if len(tsv) == 0 {
 987                                 continue
 988                         }
 989                         split := strings.Split(string(tsv), "\t")
 990                         if ccCol < 0 {
 991                                 // header row
 992                                 for col, name := range split {
 993                                         if name == cmd.chi2CaseControlColumn {
 994                                                 ccCol = col
 995                                                 break
 996                                         }
 997                                 }
 998                                 if ccCol < 0 {
 999                                         return fmt.Errorf("%s: no column named %q in header row %q", infile, cmd.chi2CaseControlColumn, tsv)
1000                                 }
1001                                 continue
1002                         }
1003                         if len(split) <= ccCol {
1004                                 continue
1005                         }
1006                         pattern := split[0]
1007                         found := -1
1008                         for i, name := range cmd.cgnames {
1009                                 if strings.Contains(name, pattern) {
1010                                         if found >= 0 {
1011                                                 log.Warnf("pattern %q in %s matches multiple genome IDs (%qs, %q)", pattern, infile, cmd.cgnames[found], name)
1012                                         }
1013                                         found = i
1014                                 }
1015                         }
1016                         if found < 0 {
1017                                 log.Warnf("pattern %q in %s does not match any genome IDs", pattern, infile)
1018                                 continue
1019                         }
1020                         if split[ccCol] == "0" {
1021                                 cc[found] = false
1022                         }
1023                         if split[ccCol] == "1" {
1024                                 cc[found] = true
1025                         }
1026                 }
1027         }
1028         allnames := cmd.cgnames
1029         cmd.cgnames = nil
1030         cmd.chi2Cases = nil
1031         ncases := 0
1032         for i, name := range allnames {
1033                 if cc, ok := cc[i]; ok {
1034                         cmd.cgnames = append(cmd.cgnames, name)
1035                         cmd.chi2Cases = append(cmd.chi2Cases, cc)
1036                         if cc {
1037                                 ncases++
1038                         }
1039                 }
1040         }
1041         log.Printf("%d cases, %d controls, %d neither (dropped)", ncases, len(cmd.cgnames)-ncases, len(allnames)-len(cmd.cgnames))
1042         return nil
1043 }
1044
1045 func (cmd *sliceNumpy) filterHGVScolpair(colpair [2][]int8) bool {
1046         if cmd.chi2PValue >= 1 {
1047                 return true
1048         }
1049         col0 := make([]bool, 0, len(cmd.chi2Cases))
1050         col1 := make([]bool, 0, len(cmd.chi2Cases))
1051         cases := make([]bool, 0, len(cmd.chi2Cases))
1052         for i, c := range cmd.chi2Cases {
1053                 if colpair[0][i] < 0 {
1054                         continue
1055                 }
1056                 col0 = append(col0, colpair[0][i] != 0)
1057                 col1 = append(col1, colpair[1][i] != 0)
1058                 cases = append(cases, c)
1059         }
1060         return len(cases) >= cmd.minCoverage &&
1061                 (pvalue(col0, cases) <= cmd.chi2PValue || pvalue(col1, cases) <= cmd.chi2PValue)
1062 }
1063
1064 func writeNumpyUint32(fnm string, out []uint32, rows, cols int) error {
1065         output, err := os.Create(fnm)
1066         if err != nil {
1067                 return err
1068         }
1069         defer output.Close()
1070         bufw := bufio.NewWriterSize(output, 1<<26)
1071         npw, err := gonpy.NewWriter(nopCloser{bufw})
1072         if err != nil {
1073                 return err
1074         }
1075         log.WithFields(log.Fields{
1076                 "filename": fnm,
1077                 "rows":     rows,
1078                 "cols":     cols,
1079                 "bytes":    rows * cols * 4,
1080         }).Infof("writing numpy: %s", fnm)
1081         npw.Shape = []int{rows, cols}
1082         npw.WriteUint32(out)
1083         err = bufw.Flush()
1084         if err != nil {
1085                 return err
1086         }
1087         return output.Close()
1088 }
1089
1090 func writeNumpyInt32(fnm string, out []int32, rows, cols int) error {
1091         output, err := os.Create(fnm)
1092         if err != nil {
1093                 return err
1094         }
1095         defer output.Close()
1096         bufw := bufio.NewWriterSize(output, 1<<26)
1097         npw, err := gonpy.NewWriter(nopCloser{bufw})
1098         if err != nil {
1099                 return err
1100         }
1101         log.WithFields(log.Fields{
1102                 "filename": fnm,
1103                 "rows":     rows,
1104                 "cols":     cols,
1105                 "bytes":    rows * cols * 4,
1106         }).Infof("writing numpy: %s", fnm)
1107         npw.Shape = []int{rows, cols}
1108         npw.WriteInt32(out)
1109         err = bufw.Flush()
1110         if err != nil {
1111                 return err
1112         }
1113         return output.Close()
1114 }
1115
1116 func writeNumpyInt16(fnm string, out []int16, rows, cols int) error {
1117         output, err := os.Create(fnm)
1118         if err != nil {
1119                 return err
1120         }
1121         defer output.Close()
1122         bufw := bufio.NewWriterSize(output, 1<<26)
1123         npw, err := gonpy.NewWriter(nopCloser{bufw})
1124         if err != nil {
1125                 return err
1126         }
1127         log.WithFields(log.Fields{
1128                 "filename": fnm,
1129                 "rows":     rows,
1130                 "cols":     cols,
1131                 "bytes":    rows * cols * 2,
1132         }).Infof("writing numpy: %s", fnm)
1133         npw.Shape = []int{rows, cols}
1134         npw.WriteInt16(out)
1135         err = bufw.Flush()
1136         if err != nil {
1137                 return err
1138         }
1139         return output.Close()
1140 }
1141
1142 func writeNumpyInt8(fnm string, out []int8, rows, cols int) error {
1143         output, err := os.Create(fnm)
1144         if err != nil {
1145                 return err
1146         }
1147         defer output.Close()
1148         bufw := bufio.NewWriterSize(output, 1<<26)
1149         npw, err := gonpy.NewWriter(nopCloser{bufw})
1150         if err != nil {
1151                 return err
1152         }
1153         log.WithFields(log.Fields{
1154                 "filename": fnm,
1155                 "rows":     rows,
1156                 "cols":     cols,
1157                 "bytes":    rows * cols,
1158         }).Infof("writing numpy: %s", fnm)
1159         npw.Shape = []int{rows, cols}
1160         npw.WriteInt8(out)
1161         err = bufw.Flush()
1162         if err != nil {
1163                 return err
1164         }
1165         return output.Close()
1166 }
1167
1168 func allele2homhet(colpair [2][]int8) {
1169         a, b := colpair[0], colpair[1]
1170         for i, av := range a {
1171                 bv := b[i]
1172                 if av < 0 || bv < 0 {
1173                         // no-call
1174                         a[i], b[i] = -1, -1
1175                 } else if av > 0 && bv > 0 {
1176                         // hom
1177                         a[i], b[i] = 1, 0
1178                 } else if av > 0 || bv > 0 {
1179                         // het
1180                         a[i], b[i] = 0, 1
1181                 } else {
1182                         // ref (or a different variant in same position)
1183                         // (this is a no-op) a[i], b[i] = 0, 0
1184                 }
1185         }
1186 }
1187
1188 type onehotXref struct {
1189         tag     tagID
1190         variant tileVariantID
1191         het     bool
1192         pvalue  float64
1193 }
1194
1195 const onehotXrefSize = unsafe.Sizeof(onehotXref{})
1196
1197 // Build onehot matrix (m[variant*2+isHet][genome] == 0 or 1) for all
1198 // variants of a single tile/tag#.
1199 //
1200 // Return nil if no tile variant passes Χ² filter.
1201 func (cmd *sliceNumpy) tv2homhet(cgs map[string]CompactGenome, maxv tileVariantID, remap []tileVariantID, tag, chunkstarttag tagID) ([][]int8, []onehotXref) {
1202         if maxv < 2 {
1203                 // everyone has the most common variant
1204                 return nil, nil
1205         }
1206         tagoffset := tag - chunkstarttag
1207         coverage := 0
1208         for _, cg := range cgs {
1209                 if cg.Variants[tagoffset*2] > 0 && cg.Variants[tagoffset*2+1] > 0 {
1210                         coverage++
1211                 }
1212         }
1213         if coverage < cmd.minCoverage {
1214                 return nil, nil
1215         }
1216         obs := make([][]bool, (maxv+1)*2) // 2 slices (hom + het) for each variant#
1217         for i := range obs {
1218                 obs[i] = make([]bool, len(cmd.cgnames))
1219         }
1220         for cgid, name := range cmd.cgnames {
1221                 cgvars := cgs[name].Variants
1222                 for v := tileVariantID(2); v <= maxv; v++ {
1223                         if remap[cgvars[tagoffset*2]] == v && remap[cgvars[tagoffset*2+1]] == v {
1224                                 obs[v*2][cgid] = true
1225                         } else if remap[cgvars[tagoffset*2]] == v || remap[cgvars[tagoffset*2+1]] == v {
1226                                 obs[v*2+1][cgid] = true
1227                         }
1228                 }
1229         }
1230         var onehot [][]int8
1231         var xref []onehotXref
1232         for homcol := 2; homcol < len(obs); homcol += 2 {
1233                 // homcol 0,1 correspond to tile variant 0, i.e.,
1234                 // no-call; homcol 2,3 correspond to the most common
1235                 // variant; so we (normally) start at homcol 4.
1236                 if homcol < 4 && !cmd.includeVariant1 {
1237                         continue
1238                 }
1239                 for het := 0; het < 2; het++ {
1240                         p := pvalue(obs[homcol+het], cmd.chi2Cases)
1241                         if cmd.chi2PValue < 1 && !(p < cmd.chi2PValue) {
1242                                 continue
1243                         }
1244                         onehot = append(onehot, bool2int8(obs[homcol+het]))
1245                         xref = append(xref, onehotXref{
1246                                 tag:     tag,
1247                                 variant: tileVariantID(homcol / 2),
1248                                 het:     het == 1,
1249                                 pvalue:  p,
1250                         })
1251                 }
1252         }
1253         return onehot, xref
1254 }
1255
1256 func bool2int8(in []bool) []int8 {
1257         out := make([]int8, len(in))
1258         for i, v := range in {
1259                 if v {
1260                         out[i] = 1
1261                 }
1262         }
1263         return out
1264 }
1265
1266 // convert a []onehotXref with length N to a numpy-style []int32
1267 // matrix with N columns, one row per field of onehotXref struct.
1268 //
1269 // Hom/het row contains hom=0, het=1.
1270 //
1271 // P-value row contains 1000000x actual p-value.
1272 func onehotXref2int32(xrefs []onehotXref) []int32 {
1273         xcols := len(xrefs)
1274         xdata := make([]int32, 4*xcols)
1275         for i, xref := range xrefs {
1276                 xdata[i] = int32(xref.tag)
1277                 xdata[xcols+i] = int32(xref.variant)
1278                 if xref.het {
1279                         xdata[xcols*2+i] = 1
1280                 }
1281                 xdata[xcols*3+i] = int32(xref.pvalue * 1000000)
1282         }
1283         return xdata
1284 }
1285
1286 // transpose onehot data from in[col][row] to numpy-style
1287 // out[row*cols+col].
1288 func onehotcols2int8(in [][]int8) []int8 {
1289         if len(in) == 0 {
1290                 return nil
1291         }
1292         cols := len(in)
1293         rows := len(in[0])
1294         out := make([]int8, rows*cols)
1295         for row := 0; row < rows; row++ {
1296                 outrow := out[row*cols:]
1297                 for col, incol := range in {
1298                         outrow[col] = incol[row]
1299                 }
1300         }
1301         return out
1302 }
1303
1304 // Return [2][]uint32{rowIndices, colIndices} indicating which
1305 // elements of matrixT[c][r] have non-zero values.
1306 func onehotChunk2Indirect(matrixT [][]int8) [2][]uint32 {
1307         var nz [2][]uint32
1308         for c, col := range matrixT {
1309                 for r, val := range col {
1310                         if val != 0 {
1311                                 nz[0] = append(nz[0], uint32(r))
1312                                 nz[1] = append(nz[1], uint32(c))
1313                         }
1314                 }
1315         }
1316         return nz
1317 }