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         "errors"
  12         "flag"
  13         "fmt"
  14         "io"
  15         "io/ioutil"
  16         "math"
  17         "net/http"
  18         _ "net/http/pprof"
  19         "os"
  20         "regexp"
  21         "runtime"
  22         "runtime/debug"
  23         "sort"
  24         "strconv"
  25         "strings"
  26         "sync/atomic"
  27         "unsafe"
  28
  29         "git.arvados.org/arvados.git/sdk/go/arvados"
  30         "github.com/arvados/lightning/hgvs"
  31         "github.com/kshedden/gonpy"
  32         "github.com/sirupsen/logrus"
  33         log "github.com/sirupsen/logrus"
  34         "golang.org/x/crypto/blake2b"
  35 )
  36
  37 type sliceNumpy struct {
  38         filter                filter
  39         threads               int
  40         chi2CaseControlColumn string
  41         chi2CaseControlFile   string
  42         chi2Cases             []bool
  43         chi2PValue            float64
  44         minCoverage           int
  45         cgnames               []string
  46         includeVariant1       bool
  47         debugTag              tagID
  48 }
  49
  50 func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, stdout, stderr io.Writer) int {
  51         var err error
  52         defer func() {
  53                 if err != nil {
  54                         fmt.Fprintf(stderr, "%s\n", err)
  55                 }
  56         }()
  57         flags := flag.NewFlagSet("", flag.ContinueOnError)
  58         flags.SetOutput(stderr)
  59         pprof := flags.String("pprof", "", "serve Go profile data at http://`[addr]:port`")
  60         runlocal := flags.Bool("local", false, "run on local host (default: run in an arvados container)")
  61         projectUUID := flags.String("project", "", "project `UUID` for output data")
  62         priority := flags.Int("priority", 500, "container request priority")
  63         inputDir := flags.String("input-dir", "./in", "input `directory`")
  64         outputDir := flags.String("output-dir", "./out", "output `directory`")
  65         ref := flags.String("ref", "", "reference name (if blank, choose last one that appears in input)")
  66         regionsFilename := flags.String("regions", "", "only output columns/annotations that intersect regions in specified bed `file`")
  67         expandRegions := flags.Int("expand-regions", 0, "expand specified regions by `N` base pairs on each side`")
  68         mergeOutput := flags.Bool("merge-output", false, "merge output into one matrix.npy and one matrix.annotations.csv")
  69         hgvsSingle := flags.Bool("single-hgvs-matrix", false, "also generate hgvs-based matrix")
  70         hgvsChunked := flags.Bool("chunked-hgvs-matrix", false, "also generate hgvs-based matrix per chromosome")
  71         onehotSingle := flags.Bool("single-onehot", false, "generate one-hot tile-based matrix")
  72         onehotChunked := flags.Bool("chunked-onehot", false, "generate one-hot tile-based matrix per input chunk")
  73         debugTag := flags.Int("debug-tag", -1, "log debugging details about specified tag")
  74         flags.IntVar(&cmd.threads, "threads", 16, "number of memory-hungry assembly threads")
  75         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)")
  76         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)")
  77         flags.Float64Var(&cmd.chi2PValue, "chi2-p-value", 1, "do Χ² test and omit columns with p-value above this threshold")
  78         flags.BoolVar(&cmd.includeVariant1, "include-variant-1", false, "include most common variant when building one-hot matrix")
  79         cmd.filter.Flags(flags)
  80         err = flags.Parse(args)
  81         if err == flag.ErrHelp {
  82                 err = nil
  83                 return 0
  84         } else if err != nil {
  85                 return 2
  86         }
  87
  88         if *pprof != "" {
  89                 go func() {
  90                         log.Println(http.ListenAndServe(*pprof, nil))
  91                 }()
  92         }
  93
  94         if cmd.chi2PValue != 1 && (cmd.chi2CaseControlFile == "" || cmd.chi2CaseControlColumn == "") {
  95                 log.Errorf("cannot use provided -chi2-p-value=%f because -chi2-case-control-file= or -chi2-case-control-column= value is empty", cmd.chi2PValue)
  96                 return 2
  97         }
  98
  99         cmd.debugTag = tagID(*debugTag)
 100
 101         if !*runlocal {
 102                 runner := arvadosContainerRunner{
 103                         Name:        "lightning slice-numpy",
 104                         Client:      arvados.NewClientFromEnv(),
 105                         ProjectUUID: *projectUUID,
 106                         RAM:         750000000000,
 107                         VCPUs:       96,
 108                         Priority:    *priority,
 109                         KeepCache:   2,
 110                         APIAccess:   true,
 111                 }
 112                 err = runner.TranslatePaths(inputDir, regionsFilename, &cmd.chi2CaseControlFile)
 113                 if err != nil {
 114                         return 1
 115                 }
 116                 runner.Args = []string{"slice-numpy", "-local=true",
 117                         "-pprof=:6060",
 118                         "-input-dir=" + *inputDir,
 119                         "-output-dir=/mnt/output",
 120                         "-threads=" + fmt.Sprintf("%d", cmd.threads),
 121                         "-regions=" + *regionsFilename,
 122                         "-expand-regions=" + fmt.Sprintf("%d", *expandRegions),
 123                         "-merge-output=" + fmt.Sprintf("%v", *mergeOutput),
 124                         "-single-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsSingle),
 125                         "-chunked-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsChunked),
 126                         "-single-onehot=" + fmt.Sprintf("%v", *onehotSingle),
 127                         "-chunked-onehot=" + fmt.Sprintf("%v", *onehotChunked),
 128                         "-chi2-case-control-file=" + cmd.chi2CaseControlFile,
 129                         "-chi2-case-control-column=" + cmd.chi2CaseControlColumn,
 130                         "-chi2-p-value=" + fmt.Sprintf("%f", cmd.chi2PValue),
 131                         "-include-variant-1=" + fmt.Sprintf("%v", cmd.includeVariant1),
 132                         "-debug-tag=" + fmt.Sprintf("%d", cmd.debugTag),
 133                 }
 134                 runner.Args = append(runner.Args, cmd.filter.Args()...)
 135                 var output string
 136                 output, err = runner.Run()
 137                 if err != nil {
 138                         return 1
 139                 }
 140                 fmt.Fprintln(stdout, output)
 141                 return 0
 142         }
 143
 144         infiles, err := allFiles(*inputDir, matchGobFile)
 145         if err != nil {
 146                 return 1
 147         }
 148         if len(infiles) == 0 {
 149                 err = fmt.Errorf("no input files found in %s", *inputDir)
 150                 return 1
 151         }
 152         sort.Strings(infiles)
 153
 154         var refseq map[string][]tileLibRef
 155         var reftiledata = make(map[tileLibRef][]byte, 11000000)
 156         in0, err := open(infiles[0])
 157         if err != nil {
 158                 return 1
 159         }
 160
 161         matchGenome, err := regexp.Compile(cmd.filter.MatchGenome)
 162         if err != nil {
 163                 err = fmt.Errorf("-match-genome: invalid regexp: %q", cmd.filter.MatchGenome)
 164                 return 1
 165         }
 166
 167         cmd.cgnames = nil
 168         var tagset [][]byte
 169         DecodeLibrary(in0, strings.HasSuffix(infiles[0], ".gz"), func(ent *LibraryEntry) error {
 170                 if len(ent.TagSet) > 0 {
 171                         tagset = ent.TagSet
 172                 }
 173                 for _, cseq := range ent.CompactSequences {
 174                         if cseq.Name == *ref || *ref == "" {
 175                                 refseq = cseq.TileSequences
 176                         }
 177                 }
 178                 for _, cg := range ent.CompactGenomes {
 179                         if matchGenome.MatchString(cg.Name) {
 180                                 cmd.cgnames = append(cmd.cgnames, cg.Name)
 181                         }
 182                 }
 183                 for _, tv := range ent.TileVariants {
 184                         if tv.Ref {
 185                                 reftiledata[tileLibRef{tv.Tag, tv.Variant}] = tv.Sequence
 186                         }
 187                 }
 188                 return nil
 189         })
 190         if err != nil {
 191                 return 1
 192         }
 193         in0.Close()
 194         if refseq == nil {
 195                 err = fmt.Errorf("%s: reference sequence not found", infiles[0])
 196                 return 1
 197         }
 198         if len(tagset) == 0 {
 199                 err = fmt.Errorf("tagset not found")
 200                 return 1
 201         }
 202
 203         taglib := &tagLibrary{}
 204         err = taglib.setTags(tagset)
 205         if err != nil {
 206                 return 1
 207         }
 208         taglen := taglib.TagLen()
 209
 210         if len(cmd.cgnames) == 0 {
 211                 err = fmt.Errorf("no genomes found matching regexp %q", cmd.filter.MatchGenome)
 212                 return 1
 213         }
 214         sort.Strings(cmd.cgnames)
 215         err = cmd.useCaseControlFiles()
 216         if err != nil {
 217                 return 1
 218         }
 219         cmd.minCoverage = int(math.Ceil(cmd.filter.MinCoverage * float64(len(cmd.cgnames))))
 220
 221         {
 222                 labelsFilename := *outputDir + "/samples.csv"
 223                 log.Infof("writing labels to %s", labelsFilename)
 224                 var f *os.File
 225                 f, err = os.Create(labelsFilename)
 226                 if err != nil {
 227                         return 1
 228                 }
 229                 defer f.Close()
 230                 for i, name := range cmd.cgnames {
 231                         cc := 0
 232                         if cmd.chi2Cases != nil && cmd.chi2Cases[i] {
 233                                 cc = 1
 234                         }
 235                         _, err = fmt.Fprintf(f, "%d,%q,%d\n", i, trimFilenameForLabel(name), cc)
 236                         if err != nil {
 237                                 err = fmt.Errorf("write %s: %w", labelsFilename, err)
 238                                 return 1
 239                         }
 240                 }
 241                 err = f.Close()
 242                 if err != nil {
 243                         err = fmt.Errorf("close %s: %w", labelsFilename, err)
 244                         return 1
 245                 }
 246         }
 247
 248         log.Info("indexing reference tiles")
 249         type reftileinfo struct {
 250                 variant  tileVariantID
 251                 seqname  string // chr1
 252                 pos      int    // distance from start of chromosome to starttag
 253                 tiledata []byte // acgtggcaa...
 254         }
 255         isdup := map[tagID]bool{}
 256         reftile := map[tagID]*reftileinfo{}
 257         for seqname, cseq := range refseq {
 258                 pos := 0
 259                 for _, libref := range cseq {
 260                         if cmd.filter.MaxTag >= 0 && libref.Tag > tagID(cmd.filter.MaxTag) {
 261                                 continue
 262                         }
 263                         tiledata := reftiledata[libref]
 264                         if len(tiledata) == 0 {
 265                                 err = fmt.Errorf("missing tiledata for tag %d variant %d in %s in ref", libref.Tag, libref.Variant, seqname)
 266                                 return 1
 267                         }
 268                         foundthistag := false
 269                         taglib.FindAll(tiledata[:len(tiledata)-1], func(tagid tagID, offset, _ int) {
 270                                 if !foundthistag && tagid == libref.Tag {
 271                                         foundthistag = true
 272                                         return
 273                                 }
 274                                 if dupref, ok := reftile[tagid]; ok {
 275                                         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)
 276                                         delete(reftile, tagid)
 277                                 } else {
 278                                         log.Printf("found tag %d at offset %d inside tile variant %+v on %s @ %d", tagid, offset, libref, seqname, pos+offset+1)
 279                                 }
 280                                 isdup[tagid] = true
 281                         })
 282                         if isdup[libref.Tag] {
 283                                 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
 284                         } else if reftile[libref.Tag] != nil {
 285                                 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)
 286                                 delete(reftile, libref.Tag)
 287                                 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
 288                                 isdup[libref.Tag] = true
 289                         } else {
 290                                 reftile[libref.Tag] = &reftileinfo{
 291                                         seqname:  seqname,
 292                                         variant:  libref.Variant,
 293                                         tiledata: tiledata,
 294                                         pos:      pos,
 295                                 }
 296                         }
 297                         pos += len(tiledata) - taglen
 298                 }
 299                 log.Printf("... %s done, len %d", seqname, pos+taglen)
 300         }
 301
 302         var mask *mask
 303         if *regionsFilename != "" {
 304                 log.Printf("loading regions from %s", *regionsFilename)
 305                 mask, err = makeMask(*regionsFilename, *expandRegions)
 306                 if err != nil {
 307                         return 1
 308                 }
 309                 log.Printf("before applying mask, len(reftile) == %d", len(reftile))
 310                 log.Printf("deleting reftile entries for regions outside %d intervals", mask.Len())
 311                 for tag, rt := range reftile {
 312                         if !mask.Check(strings.TrimPrefix(rt.seqname, "chr"), rt.pos, rt.pos+len(rt.tiledata)) {
 313                                 delete(reftile, tag)
 314                         }
 315                 }
 316                 log.Printf("after applying mask, len(reftile) == %d", len(reftile))
 317         }
 318
 319         type hgvsColSet map[hgvs.Variant][2][]int8
 320         encodeHGVS := throttle{Max: len(refseq)}
 321         encodeHGVSTodo := map[string]chan hgvsColSet{}
 322         tmpHGVSCols := map[string]*os.File{}
 323         if *hgvsChunked {
 324                 for seqname := range refseq {
 325                         var f *os.File
 326                         f, err = os.Create(*outputDir + "/tmp." + seqname + ".gob")
 327                         if err != nil {
 328                                 return 1
 329                         }
 330                         defer os.Remove(f.Name())
 331                         bufw := bufio.NewWriterSize(f, 1<<24)
 332                         enc := gob.NewEncoder(bufw)
 333                         tmpHGVSCols[seqname] = f
 334                         todo := make(chan hgvsColSet, 128)
 335                         encodeHGVSTodo[seqname] = todo
 336                         encodeHGVS.Go(func() error {
 337                                 for colset := range todo {
 338                                         err := enc.Encode(colset)
 339                                         if err != nil {
 340                                                 encodeHGVS.Report(err)
 341                                                 for range todo {
 342                                                 }
 343                                                 return err
 344                                         }
 345                                 }
 346                                 return bufw.Flush()
 347                         })
 348                 }
 349         }
 350
 351         var toMerge [][]int16
 352         if *mergeOutput || *hgvsSingle {
 353                 toMerge = make([][]int16, len(infiles))
 354         }
 355         var onehotIndirect [][2][]uint32 // [chunkIndex][axis][index]
 356         var onehotChunkSize []uint32
 357         var onehotXrefs [][]onehotXref
 358         if *onehotSingle {
 359                 onehotIndirect = make([][2][]uint32, len(infiles))
 360                 onehotChunkSize = make([]uint32, len(infiles))
 361                 onehotXrefs = make([][]onehotXref, len(infiles))
 362         }
 363
 364         throttleMem := throttle{Max: cmd.threads} // TODO: estimate using mem and data size
 365         throttleNumpyMem := throttle{Max: cmd.threads/2 + 1}
 366         log.Info("generating annotations and numpy matrix for each slice")
 367         var errSkip = errors.New("skip infile")
 368         var done int64
 369         for infileIdx, infile := range infiles {
 370                 infileIdx, infile := infileIdx, infile
 371                 throttleMem.Go(func() error {
 372                         seq := make(map[tagID][]TileVariant, 50000)
 373                         cgs := make(map[string]CompactGenome, len(cmd.cgnames))
 374                         f, err := open(infile)
 375                         if err != nil {
 376                                 return err
 377                         }
 378                         defer f.Close()
 379                         log.Infof("%04d: reading %s", infileIdx, infile)
 380                         err = DecodeLibrary(f, strings.HasSuffix(infile, ".gz"), func(ent *LibraryEntry) error {
 381                                 for _, tv := range ent.TileVariants {
 382                                         if tv.Ref {
 383                                                 continue
 384                                         }
 385                                         if mask != nil && reftile[tv.Tag] == nil {
 386                                                 // Don't waste
 387                                                 // time/memory on
 388                                                 // masked-out tiles.
 389                                                 continue
 390                                         }
 391                                         if tv.Tag == cmd.debugTag {
 392                                                 log.Printf("infile %d %s tag %d variant %d hash %x", infileIdx, infile, tv.Tag, tv.Variant, tv.Blake2b[:3])
 393                                         }
 394                                         variants := seq[tv.Tag]
 395                                         if len(variants) == 0 {
 396                                                 variants = make([]TileVariant, 100)
 397                                         }
 398                                         for len(variants) <= int(tv.Variant) {
 399                                                 variants = append(variants, TileVariant{})
 400                                         }
 401                                         variants[int(tv.Variant)] = tv
 402                                         seq[tv.Tag] = variants
 403                                 }
 404                                 for _, cg := range ent.CompactGenomes {
 405                                         if cmd.filter.MaxTag >= 0 && cg.StartTag > tagID(cmd.filter.MaxTag) {
 406                                                 return errSkip
 407                                         }
 408                                         if !matchGenome.MatchString(cg.Name) {
 409                                                 continue
 410                                         }
 411                                         // pad to full slice size
 412                                         // to avoid out-of-bounds
 413                                         // checks later
 414                                         if sliceSize := 2 * int(cg.EndTag-cg.StartTag); len(cg.Variants) < sliceSize {
 415                                                 cg.Variants = append(cg.Variants, make([]tileVariantID, sliceSize-len(cg.Variants))...)
 416                                         }
 417                                         cgs[cg.Name] = cg
 418                                 }
 419                                 return nil
 420                         })
 421                         if err == errSkip {
 422                                 return nil
 423                         } else if err != nil {
 424                                 return err
 425                         }
 426                         tagstart := cgs[cmd.cgnames[0]].StartTag
 427                         tagend := cgs[cmd.cgnames[0]].EndTag
 428
 429                         // TODO: filters
 430
 431                         log.Infof("%04d: renumber/dedup variants for tags %d-%d", infileIdx, tagstart, tagend)
 432                         variantRemap := make([][]tileVariantID, tagend-tagstart)
 433                         throttleCPU := throttle{Max: runtime.GOMAXPROCS(0)}
 434                         for tag, variants := range seq {
 435                                 tag, variants := tag, variants
 436                                 throttleCPU.Go(func() error {
 437                                         count := make(map[[blake2b.Size256]byte]int, len(variants))
 438
 439                                         rt := reftile[tag]
 440                                         if rt != nil {
 441                                                 count[blake2b.Sum256(rt.tiledata)] = 0
 442                                         }
 443
 444                                         for cgname, cg := range cgs {
 445                                                 idx := int(tag-tagstart) * 2
 446                                                 for allele := 0; allele < 2; allele++ {
 447                                                         v := cg.Variants[idx+allele]
 448                                                         if v > 0 && len(variants[v].Sequence) > 0 {
 449                                                                 count[variants[v].Blake2b]++
 450                                                         }
 451                                                         if v > 0 && tag == cmd.debugTag {
 452                                                                 log.Printf("tag %d cg %s allele %d tv %d hash %x count is now %d", tag, cgname, allele, v, variants[v].Blake2b[:3], count[variants[v].Blake2b])
 453                                                         }
 454                                                 }
 455                                         }
 456                                         // hash[i] will be the hash of
 457                                         // the variant(s) that should
 458                                         // be at rank i (0-based).
 459                                         hash := make([][blake2b.Size256]byte, 0, len(count))
 460                                         for b := range count {
 461                                                 hash = append(hash, b)
 462                                         }
 463                                         sort.Slice(hash, func(i, j int) bool {
 464                                                 bi, bj := &hash[i], &hash[j]
 465                                                 if ci, cj := count[*bi], count[*bj]; ci != cj {
 466                                                         return ci > cj
 467                                                 } else {
 468                                                         return bytes.Compare((*bi)[:], (*bj)[:]) < 0
 469                                                 }
 470                                         })
 471                                         // rank[b] will be the 1-based
 472                                         // new variant number for
 473                                         // variants whose hash is b.
 474                                         rank := make(map[[blake2b.Size256]byte]tileVariantID, len(hash))
 475                                         for i, h := range hash {
 476                                                 rank[h] = tileVariantID(i + 1)
 477                                         }
 478                                         if tag == cmd.debugTag {
 479                                                 for h, r := range rank {
 480                                                         log.Printf("tag %d rank(%x) = %v", tag, h[:3], r)
 481                                                 }
 482                                         }
 483                                         // remap[v] will be the new
 484                                         // variant number for original
 485                                         // variant number v.
 486                                         remap := make([]tileVariantID, len(variants))
 487                                         for i, tv := range variants {
 488                                                 remap[i] = rank[tv.Blake2b]
 489                                         }
 490                                         if tag == cmd.debugTag {
 491                                                 for in, out := range remap {
 492                                                         if out > 0 {
 493                                                                 log.Printf("tag %d remap %d => %d", tag, in, out)
 494                                                         }
 495                                                 }
 496                                         }
 497                                         variantRemap[tag-tagstart] = remap
 498                                         if rt != nil {
 499                                                 refrank := rank[blake2b.Sum256(rt.tiledata)]
 500                                                 if tag == cmd.debugTag {
 501                                                         log.Printf("tag %d reftile variant %d => %d", tag, rt.variant, refrank)
 502                                                 }
 503                                                 rt.variant = refrank
 504                                         }
 505                                         return nil
 506                                 })
 507                         }
 508                         throttleCPU.Wait()
 509
 510                         var onehotChunk [][]int8
 511                         var onehotXref []onehotXref
 512
 513                         annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, infileIdx)
 514                         log.Infof("%04d: writing %s", infileIdx, annotationsFilename)
 515                         annof, err := os.Create(annotationsFilename)
 516                         if err != nil {
 517                                 return err
 518                         }
 519                         annow := bufio.NewWriterSize(annof, 1<<20)
 520                         outcol := 0
 521                         for tag := tagstart; tag < tagend; tag++ {
 522                                 rt := reftile[tag]
 523                                 if rt == nil && mask != nil {
 524                                         // Excluded by specified regions
 525                                         continue
 526                                 }
 527                                 if cmd.filter.MaxTag >= 0 && tag > tagID(cmd.filter.MaxTag) {
 528                                         break
 529                                 }
 530                                 remap := variantRemap[tag-tagstart]
 531                                 maxv := tileVariantID(0)
 532                                 for _, v := range remap {
 533                                         if maxv < v {
 534                                                 maxv = v
 535                                         }
 536                                 }
 537                                 if *onehotChunked || *onehotSingle {
 538                                         onehot, xrefs := cmd.tv2homhet(cgs, maxv, remap, tag, tagstart)
 539                                         if tag == cmd.debugTag {
 540                                                 log.WithFields(logrus.Fields{
 541                                                         "onehot": onehot,
 542                                                         "xrefs":  xrefs,
 543                                                 }).Info("tv2homhet()")
 544                                         }
 545                                         onehotChunk = append(onehotChunk, onehot...)
 546                                         onehotXref = append(onehotXref, xrefs...)
 547                                 }
 548                                 if rt == nil {
 549                                         // Reference does not use any
 550                                         // variant of this tile
 551                                         outcol++
 552                                         continue
 553                                 }
 554                                 fmt.Fprintf(annow, "%d,%d,%d,=,%s,%d,,,\n", tag, outcol, rt.variant, rt.seqname, rt.pos)
 555                                 variants := seq[tag]
 556                                 reftilestr := strings.ToUpper(string(rt.tiledata))
 557
 558                                 done := make([]bool, maxv+1)
 559                                 variantDiffs := make([][]hgvs.Variant, maxv+1)
 560                                 for v, tv := range variants {
 561                                         v := remap[v]
 562                                         if v == rt.variant || done[v] {
 563                                                 continue
 564                                         } else {
 565                                                 done[v] = true
 566                                         }
 567                                         if len(tv.Sequence) < taglen || !bytes.HasSuffix(rt.tiledata, tv.Sequence[len(tv.Sequence)-taglen:]) {
 568                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 569                                                 continue
 570                                         }
 571                                         if lendiff := len(rt.tiledata) - len(tv.Sequence); lendiff < -1000 || lendiff > 1000 {
 572                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 573                                                 continue
 574                                         }
 575                                         diffs, _ := hgvs.Diff(reftilestr, strings.ToUpper(string(tv.Sequence)), 0)
 576                                         for i := range diffs {
 577                                                 diffs[i].Position += rt.pos
 578                                         }
 579                                         for _, diff := range diffs {
 580                                                 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)
 581                                         }
 582                                         if *hgvsChunked {
 583                                                 variantDiffs[v] = diffs
 584                                         }
 585                                 }
 586                                 if *hgvsChunked {
 587                                         // We can now determine, for each HGVS
 588                                         // variant (diff) in this reftile
 589                                         // region, whether a given genome
 590                                         // phase/allele (1) has the variant, (0) has
 591                                         // =ref or a different variant in that
 592                                         // position, or (-1) is lacking
 593                                         // coverage / couldn't be diffed.
 594                                         hgvsCol := hgvsColSet{}
 595                                         for _, diffs := range variantDiffs {
 596                                                 for _, diff := range diffs {
 597                                                         if _, ok := hgvsCol[diff]; ok {
 598                                                                 continue
 599                                                         }
 600                                                         hgvsCol[diff] = [2][]int8{
 601                                                                 make([]int8, len(cmd.cgnames)),
 602                                                                 make([]int8, len(cmd.cgnames)),
 603                                                         }
 604                                                 }
 605                                         }
 606                                         for row, name := range cmd.cgnames {
 607                                                 variants := cgs[name].Variants[(tag-tagstart)*2:]
 608                                                 for ph := 0; ph < 2; ph++ {
 609                                                         v := variants[ph]
 610                                                         if int(v) >= len(remap) {
 611                                                                 v = 0
 612                                                         } else {
 613                                                                 v = remap[v]
 614                                                         }
 615                                                         if v == rt.variant {
 616                                                                 // hgvsCol[*][ph][row] is already 0
 617                                                         } else if len(variantDiffs[v]) == 0 {
 618                                                                 // lacking coverage / couldn't be diffed
 619                                                                 for _, col := range hgvsCol {
 620                                                                         col[ph][row] = -1
 621                                                                 }
 622                                                         } else {
 623                                                                 for _, diff := range variantDiffs[v] {
 624                                                                         hgvsCol[diff][ph][row] = 1
 625                                                                 }
 626                                                         }
 627                                                 }
 628                                         }
 629                                         for diff, colpair := range hgvsCol {
 630                                                 allele2homhet(colpair)
 631                                                 if !cmd.filterHGVScolpair(colpair) {
 632                                                         delete(hgvsCol, diff)
 633                                                 }
 634                                         }
 635                                         if len(hgvsCol) > 0 {
 636                                                 encodeHGVSTodo[rt.seqname] <- hgvsCol
 637                                         }
 638                                 }
 639                                 outcol++
 640                         }
 641                         err = annow.Flush()
 642                         if err != nil {
 643                                 return err
 644                         }
 645                         err = annof.Close()
 646                         if err != nil {
 647                                 return err
 648                         }
 649
 650                         if *onehotChunked {
 651                                 // transpose onehotChunk[col][row] to numpy[row*ncols+col]
 652                                 rows := len(cmd.cgnames)
 653                                 cols := len(onehotChunk)
 654                                 log.Infof("%04d: preparing onehot numpy (rows=%d, cols=%d, mem=%d)", infileIdx, rows, cols, rows*cols)
 655                                 throttleNumpyMem.Acquire()
 656                                 out := onehotcols2int8(onehotChunk)
 657                                 fnm := fmt.Sprintf("%s/onehot.%04d.npy", *outputDir, infileIdx)
 658                                 err = writeNumpyInt8(fnm, out, rows, cols)
 659                                 if err != nil {
 660                                         return err
 661                                 }
 662                                 fnm = fmt.Sprintf("%s/onehot-columns.%04d.npy", *outputDir, infileIdx)
 663                                 err = writeNumpyInt32(fnm, onehotXref2int32(onehotXref), 4, len(onehotXref))
 664                                 if err != nil {
 665                                         return err
 666                                 }
 667                                 debug.FreeOSMemory()
 668                                 throttleNumpyMem.Release()
 669                         }
 670                         if *onehotSingle {
 671                                 onehotIndirect[infileIdx] = onehotChunk2Indirect(onehotChunk)
 672                                 onehotChunkSize[infileIdx] = uint32(len(onehotChunk))
 673                                 onehotXrefs[infileIdx] = onehotXref
 674                                 n := len(onehotIndirect[infileIdx][0])
 675                                 log.Infof("%04d: keeping onehot coordinates in memory (n=%d, mem=%d)", infileIdx, n, n*8*2)
 676                         }
 677                         if !(*onehotSingle || *onehotChunked) || *mergeOutput || *hgvsSingle {
 678                                 log.Infof("%04d: preparing numpy (rows=%d, cols=%d)", infileIdx, len(cmd.cgnames), 2*outcol)
 679                                 throttleNumpyMem.Acquire()
 680                                 rows := len(cmd.cgnames)
 681                                 cols := 2 * outcol
 682                                 out := make([]int16, rows*cols)
 683                                 for row, name := range cmd.cgnames {
 684                                         outidx := row * cols
 685                                         for col, v := range cgs[name].Variants {
 686                                                 tag := tagstart + tagID(col/2)
 687                                                 if cmd.filter.MaxTag >= 0 && tag > tagID(cmd.filter.MaxTag) {
 688                                                         break
 689                                                 }
 690                                                 if mask != nil && reftile[tag] == nil {
 691                                                         continue
 692                                                 }
 693                                                 if v == 0 {
 694                                                         out[outidx] = 0 // tag not found / spanning tile
 695                                                 } else if variants, ok := seq[tag]; ok && int(v) < len(variants) && len(variants[v].Sequence) > 0 {
 696                                                         out[outidx] = int16(variantRemap[tag-tagstart][v])
 697                                                 } else {
 698                                                         out[outidx] = -1 // low quality tile variant
 699                                                 }
 700                                                 if tag == cmd.debugTag {
 701                                                         log.Printf("tag %d row %d col %d outidx %d v %d out %d", tag, row, col, outidx, v, out[outidx])
 702                                                 }
 703                                                 outidx++
 704                                         }
 705                                 }
 706                                 seq = nil
 707                                 cgs = nil
 708                                 debug.FreeOSMemory()
 709                                 throttleNumpyMem.Release()
 710                                 if *mergeOutput || *hgvsSingle {
 711                                         log.Infof("%04d: matrix fragment %d rows x %d cols", infileIdx, rows, cols)
 712                                         toMerge[infileIdx] = out
 713                                 }
 714                                 if !*mergeOutput && !*onehotChunked && !*onehotSingle {
 715                                         fnm := fmt.Sprintf("%s/matrix.%04d.npy", *outputDir, infileIdx)
 716                                         err = writeNumpyInt16(fnm, out, rows, cols)
 717                                         if err != nil {
 718                                                 return err
 719                                         }
 720                                 }
 721                         }
 722                         debug.FreeOSMemory()
 723                         log.Infof("%s: done (%d/%d)", infile, int(atomic.AddInt64(&done, 1)), len(infiles))
 724                         return nil
 725                 })
 726         }
 727         if err = throttleMem.Wait(); err != nil {
 728                 return 1
 729         }
 730
 731         if *hgvsChunked {
 732                 log.Info("flushing hgvsCols temp files")
 733                 for seqname := range refseq {
 734                         close(encodeHGVSTodo[seqname])
 735                 }
 736                 err = encodeHGVS.Wait()
 737                 if err != nil {
 738                         return 1
 739                 }
 740                 for seqname := range refseq {
 741                         log.Infof("%s: reading hgvsCols from temp file", seqname)
 742                         f := tmpHGVSCols[seqname]
 743                         _, err = f.Seek(0, io.SeekStart)
 744                         if err != nil {
 745                                 return 1
 746                         }
 747                         var hgvsCols hgvsColSet
 748                         dec := gob.NewDecoder(bufio.NewReaderSize(f, 1<<24))
 749                         for err == nil {
 750                                 err = dec.Decode(&hgvsCols)
 751                         }
 752                         if err != io.EOF {
 753                                 return 1
 754                         }
 755                         log.Infof("%s: sorting %d hgvs variants", seqname, len(hgvsCols))
 756                         variants := make([]hgvs.Variant, 0, len(hgvsCols))
 757                         for v := range hgvsCols {
 758                                 variants = append(variants, v)
 759                         }
 760                         sort.Slice(variants, func(i, j int) bool {
 761                                 vi, vj := &variants[i], &variants[j]
 762                                 if vi.Position != vj.Position {
 763                                         return vi.Position < vj.Position
 764                                 } else if vi.Ref != vj.Ref {
 765                                         return vi.Ref < vj.Ref
 766                                 } else {
 767                                         return vi.New < vj.New
 768                                 }
 769                         })
 770                         rows := len(cmd.cgnames)
 771                         cols := len(variants) * 2
 772                         log.Infof("%s: building hgvs matrix (rows=%d, cols=%d, mem=%d)", seqname, rows, cols, rows*cols)
 773                         out := make([]int8, rows*cols)
 774                         for varIdx, variant := range variants {
 775                                 hgvsCols := hgvsCols[variant]
 776                                 for row := range cmd.cgnames {
 777                                         for ph := 0; ph < 2; ph++ {
 778                                                 out[row*cols+varIdx+ph] = hgvsCols[ph][row]
 779                                         }
 780                                 }
 781                         }
 782                         err = writeNumpyInt8(fmt.Sprintf("%s/hgvs.%s.npy", *outputDir, seqname), out, rows, cols)
 783                         if err != nil {
 784                                 return 1
 785                         }
 786                         out = nil
 787
 788                         fnm := fmt.Sprintf("%s/hgvs.%s.annotations.csv", *outputDir, seqname)
 789                         log.Infof("%s: writing hgvs column labels to %s", seqname, fnm)
 790                         var hgvsLabels bytes.Buffer
 791                         for varIdx, variant := range variants {
 792                                 fmt.Fprintf(&hgvsLabels, "%d,%s:g.%s\n", varIdx, seqname, variant.String())
 793                         }
 794                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0666)
 795                         if err != nil {
 796                                 return 1
 797                         }
 798                 }
 799         }
 800
 801         if *mergeOutput || *hgvsSingle {
 802                 var annow *bufio.Writer
 803                 var annof *os.File
 804                 if *mergeOutput {
 805                         annoFilename := fmt.Sprintf("%s/matrix.annotations.csv", *outputDir)
 806                         annof, err = os.Create(annoFilename)
 807                         if err != nil {
 808                                 return 1
 809                         }
 810                         annow = bufio.NewWriterSize(annof, 1<<20)
 811                 }
 812
 813                 rows := len(cmd.cgnames)
 814                 cols := 0
 815                 for _, chunk := range toMerge {
 816                         cols += len(chunk) / rows
 817                 }
 818                 log.Infof("merging output matrix (rows=%d, cols=%d, mem=%d) and annotations", rows, cols, rows*cols*2)
 819                 var out []int16
 820                 if *mergeOutput {
 821                         out = make([]int16, rows*cols)
 822                 }
 823                 hgvsCols := map[string][2][]int16{} // hgvs -> [[g0,g1,g2,...], [g0,g1,g2,...]] (slice of genomes for each phase)
 824                 startcol := 0
 825                 for outIdx, chunk := range toMerge {
 826                         chunkcols := len(chunk) / rows
 827                         if *mergeOutput {
 828                                 for row := 0; row < rows; row++ {
 829                                         copy(out[row*cols+startcol:], chunk[row*chunkcols:(row+1)*chunkcols])
 830                                 }
 831                         }
 832                         toMerge[outIdx] = nil
 833
 834                         annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, outIdx)
 835                         log.Infof("reading %s", annotationsFilename)
 836                         buf, err := os.ReadFile(annotationsFilename)
 837                         if err != nil {
 838                                 return 1
 839                         }
 840                         if *mergeOutput {
 841                                 err = os.Remove(annotationsFilename)
 842                                 if err != nil {
 843                                         return 1
 844                                 }
 845                         }
 846                         for _, line := range bytes.Split(buf, []byte{'\n'}) {
 847                                 if len(line) == 0 {
 848                                         continue
 849                                 }
 850                                 fields := bytes.SplitN(line, []byte{','}, 9)
 851                                 tag, _ := strconv.Atoi(string(fields[0]))
 852                                 incol, _ := strconv.Atoi(string(fields[1]))
 853                                 tileVariant, _ := strconv.Atoi(string(fields[2]))
 854                                 hgvsID := string(fields[3])
 855                                 seqname := string(fields[4])
 856                                 pos, _ := strconv.Atoi(string(fields[5]))
 857                                 refseq := fields[6]
 858                                 if hgvsID == "" {
 859                                         // Null entry for un-diffable
 860                                         // tile variant
 861                                         continue
 862                                 }
 863                                 if hgvsID == "=" {
 864                                         // Null entry for ref tile
 865                                         continue
 866                                 }
 867                                 if mask != nil && !mask.Check(strings.TrimPrefix(seqname, "chr"), pos, pos+len(refseq)) {
 868                                         // The tile intersects one of
 869                                         // the selected regions, but
 870                                         // this particular HGVS
 871                                         // variant does not.
 872                                         continue
 873                                 }
 874                                 hgvsColPair := hgvsCols[hgvsID]
 875                                 if hgvsColPair[0] == nil {
 876                                         // values in new columns start
 877                                         // out as -1 ("no data yet")
 878                                         // or 0 ("=ref") here, may
 879                                         // change to 1 ("hgvs variant
 880                                         // present") below, either on
 881                                         // this line or a future line.
 882                                         hgvsColPair = [2][]int16{make([]int16, len(cmd.cgnames)), make([]int16, len(cmd.cgnames))}
 883                                         rt, ok := reftile[tagID(tag)]
 884                                         if !ok {
 885                                                 err = fmt.Errorf("bug: seeing annotations for tag %d, but it has no reftile entry", tag)
 886                                                 return 1
 887                                         }
 888                                         for ph := 0; ph < 2; ph++ {
 889                                                 for row := 0; row < rows; row++ {
 890                                                         v := chunk[row*chunkcols+incol*2+ph]
 891                                                         if tileVariantID(v) == rt.variant {
 892                                                                 hgvsColPair[ph][row] = 0
 893                                                         } else {
 894                                                                 hgvsColPair[ph][row] = -1
 895                                                         }
 896                                                 }
 897                                         }
 898                                         hgvsCols[hgvsID] = hgvsColPair
 899                                         if annow != nil {
 900                                                 hgvsref := hgvs.Variant{
 901                                                         Position: pos,
 902                                                         Ref:      string(refseq),
 903                                                         New:      string(refseq),
 904                                                 }
 905                                                 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])
 906                                         }
 907                                 }
 908                                 if annow != nil {
 909                                         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])
 910                                 }
 911                                 for ph := 0; ph < 2; ph++ {
 912                                         for row := 0; row < rows; row++ {
 913                                                 v := chunk[row*chunkcols+incol*2+ph]
 914                                                 if int(v) == tileVariant {
 915                                                         hgvsColPair[ph][row] = 1
 916                                                 }
 917                                         }
 918                                 }
 919                         }
 920
 921                         startcol += chunkcols
 922                 }
 923                 if *mergeOutput {
 924                         err = annow.Flush()
 925                         if err != nil {
 926                                 return 1
 927                         }
 928                         err = annof.Close()
 929                         if err != nil {
 930                                 return 1
 931                         }
 932                         err = writeNumpyInt16(fmt.Sprintf("%s/matrix.npy", *outputDir), out, rows, cols)
 933                         if err != nil {
 934                                 return 1
 935                         }
 936                 }
 937                 out = nil
 938
 939                 if *hgvsSingle {
 940                         cols = len(hgvsCols) * 2
 941                         log.Printf("building hgvs-based matrix: %d rows x %d cols", rows, cols)
 942                         out = make([]int16, rows*cols)
 943                         hgvsIDs := make([]string, 0, cols/2)
 944                         for hgvsID := range hgvsCols {
 945                                 hgvsIDs = append(hgvsIDs, hgvsID)
 946                         }
 947                         sort.Strings(hgvsIDs)
 948                         var hgvsLabels bytes.Buffer
 949                         for idx, hgvsID := range hgvsIDs {
 950                                 fmt.Fprintf(&hgvsLabels, "%d,%s\n", idx, hgvsID)
 951                                 for ph := 0; ph < 2; ph++ {
 952                                         hgvscol := hgvsCols[hgvsID][ph]
 953                                         for row, val := range hgvscol {
 954                                                 out[row*cols+idx*2+ph] = val
 955                                         }
 956                                 }
 957                         }
 958                         err = writeNumpyInt16(fmt.Sprintf("%s/hgvs.npy", *outputDir), out, rows, cols)
 959                         if err != nil {
 960                                 return 1
 961                         }
 962
 963                         fnm := fmt.Sprintf("%s/hgvs.annotations.csv", *outputDir)
 964                         log.Printf("writing hgvs labels: %s", fnm)
 965                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0777)
 966                         if err != nil {
 967                                 return 1
 968                         }
 969                 }
 970         }
 971         if *onehotSingle {
 972                 nzCount := 0
 973                 for _, part := range onehotIndirect {
 974                         nzCount += len(part[0])
 975                 }
 976                 onehot := make([]uint32, nzCount*2) // [r,r,r,...,c,c,c,...]
 977                 var xrefs []onehotXref
 978                 chunkOffset := uint32(0)
 979                 outcol := 0
 980                 for i, part := range onehotIndirect {
 981                         for i := range part[1] {
 982                                 part[1][i] += chunkOffset
 983                         }
 984                         copy(onehot[outcol:], part[0])
 985                         copy(onehot[outcol+nzCount:], part[1])
 986                         xrefs = append(xrefs, onehotXrefs[i]...)
 987
 988                         outcol += len(part[0])
 989                         chunkOffset += onehotChunkSize[i]
 990
 991                         part[0] = nil
 992                         part[1] = nil
 993                         onehotXrefs[i] = nil
 994                         debug.FreeOSMemory()
 995                 }
 996                 fnm := fmt.Sprintf("%s/onehot.npy", *outputDir)
 997                 err = writeNumpyUint32(fnm, onehot, 2, nzCount)
 998                 if err != nil {
 999                         return 1
1000                 }
1001                 fnm = fmt.Sprintf("%s/onehot-columns.npy", *outputDir)
1002                 err = writeNumpyInt32(fnm, onehotXref2int32(xrefs), 4, len(xrefs))
1003                 if err != nil {
1004                         return 1
1005                 }
1006         }
1007         return 0
1008 }
1009
1010 // Read case/control files, remove non-case/control entries from
1011 // cmd.cgnames, and build cmd.chi2Cases.
1012 func (cmd *sliceNumpy) useCaseControlFiles() error {
1013         if cmd.chi2CaseControlFile == "" {
1014                 return nil
1015         }
1016         infiles, err := allFiles(cmd.chi2CaseControlFile, nil)
1017         if err != nil {
1018                 return err
1019         }
1020         // index in cmd.cgnames => case(true) / control(false)
1021         cc := map[int]bool{}
1022         for _, infile := range infiles {
1023                 f, err := open(infile)
1024                 if err != nil {
1025                         return err
1026                 }
1027                 buf, err := io.ReadAll(f)
1028                 f.Close()
1029                 if err != nil {
1030                         return err
1031                 }
1032                 ccCol := -1
1033                 for _, tsv := range bytes.Split(buf, []byte{'\n'}) {
1034                         if len(tsv) == 0 {
1035                                 continue
1036                         }
1037                         split := strings.Split(string(tsv), "\t")
1038                         if ccCol < 0 {
1039                                 // header row
1040                                 for col, name := range split {
1041                                         if name == cmd.chi2CaseControlColumn {
1042                                                 ccCol = col
1043                                                 break
1044                                         }
1045                                 }
1046                                 if ccCol < 0 {
1047                                         return fmt.Errorf("%s: no column named %q in header row %q", infile, cmd.chi2CaseControlColumn, tsv)
1048                                 }
1049                                 continue
1050                         }
1051                         if len(split) <= ccCol {
1052                                 continue
1053                         }
1054                         pattern := split[0]
1055                         found := -1
1056                         for i, name := range cmd.cgnames {
1057                                 if strings.Contains(name, pattern) {
1058                                         if found >= 0 {
1059                                                 log.Warnf("pattern %q in %s matches multiple genome IDs (%qs, %q)", pattern, infile, cmd.cgnames[found], name)
1060                                         }
1061                                         found = i
1062                                 }
1063                         }
1064                         if found < 0 {
1065                                 log.Warnf("pattern %q in %s does not match any genome IDs", pattern, infile)
1066                                 continue
1067                         }
1068                         if split[ccCol] == "0" {
1069                                 cc[found] = false
1070                         }
1071                         if split[ccCol] == "1" {
1072                                 cc[found] = true
1073                         }
1074                 }
1075         }
1076         allnames := cmd.cgnames
1077         cmd.cgnames = nil
1078         cmd.chi2Cases = nil
1079         ncases := 0
1080         for i, name := range allnames {
1081                 if cc, ok := cc[i]; ok {
1082                         cmd.cgnames = append(cmd.cgnames, name)
1083                         cmd.chi2Cases = append(cmd.chi2Cases, cc)
1084                         if cc {
1085                                 ncases++
1086                         }
1087                 }
1088         }
1089         log.Printf("%d cases, %d controls, %d neither (dropped)", ncases, len(cmd.cgnames)-ncases, len(allnames)-len(cmd.cgnames))
1090         return nil
1091 }
1092
1093 func (cmd *sliceNumpy) filterHGVScolpair(colpair [2][]int8) bool {
1094         if cmd.chi2PValue >= 1 {
1095                 return true
1096         }
1097         col0 := make([]bool, 0, len(cmd.chi2Cases))
1098         col1 := make([]bool, 0, len(cmd.chi2Cases))
1099         cases := make([]bool, 0, len(cmd.chi2Cases))
1100         for i, c := range cmd.chi2Cases {
1101                 if colpair[0][i] < 0 {
1102                         continue
1103                 }
1104                 col0 = append(col0, colpair[0][i] != 0)
1105                 col1 = append(col1, colpair[1][i] != 0)
1106                 cases = append(cases, c)
1107         }
1108         return len(cases) >= cmd.minCoverage &&
1109                 (pvalue(col0, cases) <= cmd.chi2PValue || pvalue(col1, cases) <= cmd.chi2PValue)
1110 }
1111
1112 func writeNumpyUint32(fnm string, out []uint32, rows, cols int) error {
1113         output, err := os.Create(fnm)
1114         if err != nil {
1115                 return err
1116         }
1117         defer output.Close()
1118         bufw := bufio.NewWriterSize(output, 1<<26)
1119         npw, err := gonpy.NewWriter(nopCloser{bufw})
1120         if err != nil {
1121                 return err
1122         }
1123         log.WithFields(log.Fields{
1124                 "filename": fnm,
1125                 "rows":     rows,
1126                 "cols":     cols,
1127                 "bytes":    rows * cols * 4,
1128         }).Infof("writing numpy: %s", fnm)
1129         npw.Shape = []int{rows, cols}
1130         npw.WriteUint32(out)
1131         err = bufw.Flush()
1132         if err != nil {
1133                 return err
1134         }
1135         return output.Close()
1136 }
1137
1138 func writeNumpyInt32(fnm string, out []int32, rows, cols int) error {
1139         output, err := os.Create(fnm)
1140         if err != nil {
1141                 return err
1142         }
1143         defer output.Close()
1144         bufw := bufio.NewWriterSize(output, 1<<26)
1145         npw, err := gonpy.NewWriter(nopCloser{bufw})
1146         if err != nil {
1147                 return err
1148         }
1149         log.WithFields(log.Fields{
1150                 "filename": fnm,
1151                 "rows":     rows,
1152                 "cols":     cols,
1153                 "bytes":    rows * cols * 4,
1154         }).Infof("writing numpy: %s", fnm)
1155         npw.Shape = []int{rows, cols}
1156         npw.WriteInt32(out)
1157         err = bufw.Flush()
1158         if err != nil {
1159                 return err
1160         }
1161         return output.Close()
1162 }
1163
1164 func writeNumpyInt16(fnm string, out []int16, rows, cols int) error {
1165         output, err := os.Create(fnm)
1166         if err != nil {
1167                 return err
1168         }
1169         defer output.Close()
1170         bufw := bufio.NewWriterSize(output, 1<<26)
1171         npw, err := gonpy.NewWriter(nopCloser{bufw})
1172         if err != nil {
1173                 return err
1174         }
1175         log.WithFields(log.Fields{
1176                 "filename": fnm,
1177                 "rows":     rows,
1178                 "cols":     cols,
1179                 "bytes":    rows * cols * 2,
1180         }).Infof("writing numpy: %s", fnm)
1181         npw.Shape = []int{rows, cols}
1182         npw.WriteInt16(out)
1183         err = bufw.Flush()
1184         if err != nil {
1185                 return err
1186         }
1187         return output.Close()
1188 }
1189
1190 func writeNumpyInt8(fnm string, out []int8, rows, cols int) error {
1191         output, err := os.Create(fnm)
1192         if err != nil {
1193                 return err
1194         }
1195         defer output.Close()
1196         bufw := bufio.NewWriterSize(output, 1<<26)
1197         npw, err := gonpy.NewWriter(nopCloser{bufw})
1198         if err != nil {
1199                 return err
1200         }
1201         log.WithFields(log.Fields{
1202                 "filename": fnm,
1203                 "rows":     rows,
1204                 "cols":     cols,
1205                 "bytes":    rows * cols,
1206         }).Infof("writing numpy: %s", fnm)
1207         npw.Shape = []int{rows, cols}
1208         npw.WriteInt8(out)
1209         err = bufw.Flush()
1210         if err != nil {
1211                 return err
1212         }
1213         return output.Close()
1214 }
1215
1216 func allele2homhet(colpair [2][]int8) {
1217         a, b := colpair[0], colpair[1]
1218         for i, av := range a {
1219                 bv := b[i]
1220                 if av < 0 || bv < 0 {
1221                         // no-call
1222                         a[i], b[i] = -1, -1
1223                 } else if av > 0 && bv > 0 {
1224                         // hom
1225                         a[i], b[i] = 1, 0
1226                 } else if av > 0 || bv > 0 {
1227                         // het
1228                         a[i], b[i] = 0, 1
1229                 } else {
1230                         // ref (or a different variant in same position)
1231                         // (this is a no-op) a[i], b[i] = 0, 0
1232                 }
1233         }
1234 }
1235
1236 type onehotXref struct {
1237         tag     tagID
1238         variant tileVariantID
1239         het     bool
1240         pvalue  float64
1241 }
1242
1243 const onehotXrefSize = unsafe.Sizeof(onehotXref{})
1244
1245 // Build onehot matrix (m[tileVariantIndex][genome] == 0 or 1) for all
1246 // variants of a single tile/tag#.
1247 //
1248 // Return nil if no tile variant passes Χ² filter.
1249 func (cmd *sliceNumpy) tv2homhet(cgs map[string]CompactGenome, maxv tileVariantID, remap []tileVariantID, tag, chunkstarttag tagID) ([][]int8, []onehotXref) {
1250         if tag == cmd.debugTag {
1251                 tv := make([]tileVariantID, len(cmd.cgnames)*2)
1252                 for i, name := range cmd.cgnames {
1253                         copy(tv[i*2:(i+1)*2], cgs[name].Variants[(tag-chunkstarttag)*2:])
1254                 }
1255                 log.WithFields(logrus.Fields{
1256                         "cgs[i].Variants[tag*2+j]": tv,
1257                         "maxv":                     maxv,
1258                         "remap":                    remap,
1259                         "tag":                      tag,
1260                         "chunkstarttag":            chunkstarttag,
1261                 }).Info("tv2homhet()")
1262         }
1263         if maxv < 1 || (maxv < 2 && !cmd.includeVariant1) {
1264                 // everyone has the most common variant (of the variants we don't drop)
1265                 return nil, nil
1266         }
1267         tagoffset := tag - chunkstarttag
1268         coverage := 0
1269         for _, cg := range cgs {
1270                 if cg.Variants[tagoffset*2] > 0 && cg.Variants[tagoffset*2+1] > 0 {
1271                         coverage++
1272                 }
1273         }
1274         if coverage < cmd.minCoverage {
1275                 return nil, nil
1276         }
1277         obs := make([][]bool, (maxv+1)*2) // 2 slices (hom + het) for each variant#
1278         for i := range obs {
1279                 obs[i] = make([]bool, len(cmd.cgnames))
1280         }
1281         for cgid, name := range cmd.cgnames {
1282                 cgvars := cgs[name].Variants[tagoffset*2:]
1283                 tv0, tv1 := remap[cgvars[0]], remap[cgvars[1]]
1284                 for v := tileVariantID(1); v <= maxv; v++ {
1285                         if tv0 == v && tv1 == v {
1286                                 obs[v*2][cgid] = true
1287                         } else if tv0 == v || tv1 == v {
1288                                 obs[v*2+1][cgid] = true
1289                         }
1290                 }
1291         }
1292         var onehot [][]int8
1293         var xref []onehotXref
1294         for col := 2; col < len(obs); col++ {
1295                 // col 0,1 correspond to tile variant 0, i.e.,
1296                 // no-call; col 2,3 correspond to the most common
1297                 // variant; so we (normally) start at col 4.
1298                 if col < 4 && !cmd.includeVariant1 {
1299                         continue
1300                 }
1301                 p := pvalue(obs[col], cmd.chi2Cases)
1302                 if cmd.chi2PValue < 1 && !(p < cmd.chi2PValue) {
1303                         continue
1304                 }
1305                 onehot = append(onehot, bool2int8(obs[col]))
1306                 xref = append(xref, onehotXref{
1307                         tag:     tag,
1308                         variant: tileVariantID(col >> 1),
1309                         het:     col&1 == 1,
1310                         pvalue:  p,
1311                 })
1312         }
1313         return onehot, xref
1314 }
1315
1316 func bool2int8(in []bool) []int8 {
1317         out := make([]int8, len(in))
1318         for i, v := range in {
1319                 if v {
1320                         out[i] = 1
1321                 }
1322         }
1323         return out
1324 }
1325
1326 // convert a []onehotXref with length N to a numpy-style []int32
1327 // matrix with N columns, one row per field of onehotXref struct.
1328 //
1329 // Hom/het row contains hom=0, het=1.
1330 //
1331 // P-value row contains 1000000x actual p-value.
1332 func onehotXref2int32(xrefs []onehotXref) []int32 {
1333         xcols := len(xrefs)
1334         xdata := make([]int32, 4*xcols)
1335         for i, xref := range xrefs {
1336                 xdata[i] = int32(xref.tag)
1337                 xdata[xcols+i] = int32(xref.variant)
1338                 if xref.het {
1339                         xdata[xcols*2+i] = 1
1340                 }
1341                 xdata[xcols*3+i] = int32(xref.pvalue * 1000000)
1342         }
1343         return xdata
1344 }
1345
1346 // transpose onehot data from in[col][row] to numpy-style
1347 // out[row*cols+col].
1348 func onehotcols2int8(in [][]int8) []int8 {
1349         if len(in) == 0 {
1350                 return nil
1351         }
1352         cols := len(in)
1353         rows := len(in[0])
1354         out := make([]int8, rows*cols)
1355         for row := 0; row < rows; row++ {
1356                 outrow := out[row*cols:]
1357                 for col, incol := range in {
1358                         outrow[col] = incol[row]
1359                 }
1360         }
1361         return out
1362 }
1363
1364 // Return [2][]uint32{rowIndices, colIndices} indicating which
1365 // elements of matrixT[c][r] have non-zero values.
1366 func onehotChunk2Indirect(matrixT [][]int8) [2][]uint32 {
1367         var nz [2][]uint32
1368         for c, col := range matrixT {
1369                 for r, val := range col {
1370                         if val != 0 {
1371                                 nz[0] = append(nz[0], uint32(r))
1372                                 nz[1] = append(nz[1], uint32(c))
1373                         }
1374                 }
1375         }
1376         return nz
1377 }