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 const annotationMaxTileSpan = 100
  38
  39 type sliceNumpy struct {
  40         filter                filter
  41         threads               int
  42         chi2CaseControlColumn string
  43         chi2CaseControlFile   string
  44         chi2Cases             []bool
  45         chi2PValue            float64
  46         minCoverage           int
  47         cgnames               []string
  48         includeVariant1       bool
  49         debugTag              tagID
  50 }
  51
  52 func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, stdout, stderr io.Writer) int {
  53         var err error
  54         defer func() {
  55                 if err != nil {
  56                         fmt.Fprintf(stderr, "%s\n", err)
  57                 }
  58         }()
  59         flags := flag.NewFlagSet("", flag.ContinueOnError)
  60         flags.SetOutput(stderr)
  61         pprof := flags.String("pprof", "", "serve Go profile data at http://`[addr]:port`")
  62         runlocal := flags.Bool("local", false, "run on local host (default: run in an arvados container)")
  63         projectUUID := flags.String("project", "", "project `UUID` for output data")
  64         priority := flags.Int("priority", 500, "container request priority")
  65         inputDir := flags.String("input-dir", "./in", "input `directory`")
  66         outputDir := flags.String("output-dir", "./out", "output `directory`")
  67         ref := flags.String("ref", "", "reference name (if blank, choose last one that appears in input)")
  68         regionsFilename := flags.String("regions", "", "only output columns/annotations that intersect regions in specified bed `file`")
  69         expandRegions := flags.Int("expand-regions", 0, "expand specified regions by `N` base pairs on each side`")
  70         mergeOutput := flags.Bool("merge-output", false, "merge output into one matrix.npy and one matrix.annotations.csv")
  71         hgvsSingle := flags.Bool("single-hgvs-matrix", false, "also generate hgvs-based matrix")
  72         hgvsChunked := flags.Bool("chunked-hgvs-matrix", false, "also generate hgvs-based matrix per chromosome")
  73         onehotSingle := flags.Bool("single-onehot", false, "generate one-hot tile-based matrix")
  74         onehotChunked := flags.Bool("chunked-onehot", false, "generate one-hot tile-based matrix per input chunk")
  75         debugTag := flags.Int("debug-tag", -1, "log debugging details about specified tag")
  76         flags.IntVar(&cmd.threads, "threads", 16, "number of memory-hungry assembly threads")
  77         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)")
  78         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)")
  79         flags.Float64Var(&cmd.chi2PValue, "chi2-p-value", 1, "do Χ² test and omit columns with p-value above this threshold")
  80         flags.BoolVar(&cmd.includeVariant1, "include-variant-1", false, "include most common variant when building one-hot matrix")
  81         cmd.filter.Flags(flags)
  82         err = flags.Parse(args)
  83         if err == flag.ErrHelp {
  84                 err = nil
  85                 return 0
  86         } else if err != nil {
  87                 return 2
  88         }
  89
  90         if *pprof != "" {
  91                 go func() {
  92                         log.Println(http.ListenAndServe(*pprof, nil))
  93                 }()
  94         }
  95
  96         if cmd.chi2PValue != 1 && (cmd.chi2CaseControlFile == "" || cmd.chi2CaseControlColumn == "") {
  97                 log.Errorf("cannot use provided -chi2-p-value=%f because -chi2-case-control-file= or -chi2-case-control-column= value is empty", cmd.chi2PValue)
  98                 return 2
  99         }
 100
 101         cmd.debugTag = tagID(*debugTag)
 102
 103         if !*runlocal {
 104                 runner := arvadosContainerRunner{
 105                         Name:        "lightning slice-numpy",
 106                         Client:      arvados.NewClientFromEnv(),
 107                         ProjectUUID: *projectUUID,
 108                         RAM:         750000000000,
 109                         VCPUs:       96,
 110                         Priority:    *priority,
 111                         KeepCache:   2,
 112                         APIAccess:   true,
 113                 }
 114                 err = runner.TranslatePaths(inputDir, regionsFilename, &cmd.chi2CaseControlFile)
 115                 if err != nil {
 116                         return 1
 117                 }
 118                 runner.Args = []string{"slice-numpy", "-local=true",
 119                         "-pprof=:6060",
 120                         "-input-dir=" + *inputDir,
 121                         "-output-dir=/mnt/output",
 122                         "-threads=" + fmt.Sprintf("%d", cmd.threads),
 123                         "-regions=" + *regionsFilename,
 124                         "-expand-regions=" + fmt.Sprintf("%d", *expandRegions),
 125                         "-merge-output=" + fmt.Sprintf("%v", *mergeOutput),
 126                         "-single-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsSingle),
 127                         "-chunked-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsChunked),
 128                         "-single-onehot=" + fmt.Sprintf("%v", *onehotSingle),
 129                         "-chunked-onehot=" + fmt.Sprintf("%v", *onehotChunked),
 130                         "-chi2-case-control-file=" + cmd.chi2CaseControlFile,
 131                         "-chi2-case-control-column=" + cmd.chi2CaseControlColumn,
 132                         "-chi2-p-value=" + fmt.Sprintf("%f", cmd.chi2PValue),
 133                         "-include-variant-1=" + fmt.Sprintf("%v", cmd.includeVariant1),
 134                         "-debug-tag=" + fmt.Sprintf("%d", cmd.debugTag),
 135                 }
 136                 runner.Args = append(runner.Args, cmd.filter.Args()...)
 137                 var output string
 138                 output, err = runner.Run()
 139                 if err != nil {
 140                         return 1
 141                 }
 142                 fmt.Fprintln(stdout, output)
 143                 return 0
 144         }
 145
 146         infiles, err := allFiles(*inputDir, matchGobFile)
 147         if err != nil {
 148                 return 1
 149         }
 150         if len(infiles) == 0 {
 151                 err = fmt.Errorf("no input files found in %s", *inputDir)
 152                 return 1
 153         }
 154         sort.Strings(infiles)
 155
 156         var refseq map[string][]tileLibRef
 157         var reftiledata = make(map[tileLibRef][]byte, 11000000)
 158         in0, err := open(infiles[0])
 159         if err != nil {
 160                 return 1
 161         }
 162
 163         matchGenome, err := regexp.Compile(cmd.filter.MatchGenome)
 164         if err != nil {
 165                 err = fmt.Errorf("-match-genome: invalid regexp: %q", cmd.filter.MatchGenome)
 166                 return 1
 167         }
 168
 169         cmd.cgnames = nil
 170         var tagset [][]byte
 171         err = DecodeLibrary(in0, strings.HasSuffix(infiles[0], ".gz"), func(ent *LibraryEntry) error {
 172                 if len(ent.TagSet) > 0 {
 173                         tagset = ent.TagSet
 174                 }
 175                 for _, cseq := range ent.CompactSequences {
 176                         if cseq.Name == *ref || *ref == "" {
 177                                 refseq = cseq.TileSequences
 178                         }
 179                 }
 180                 for _, cg := range ent.CompactGenomes {
 181                         if matchGenome.MatchString(cg.Name) {
 182                                 cmd.cgnames = append(cmd.cgnames, cg.Name)
 183                         }
 184                 }
 185                 for _, tv := range ent.TileVariants {
 186                         if tv.Ref {
 187                                 reftiledata[tileLibRef{tv.Tag, tv.Variant}] = tv.Sequence
 188                         }
 189                 }
 190                 return nil
 191         })
 192         if err != nil {
 193                 return 1
 194         }
 195         in0.Close()
 196         if refseq == nil {
 197                 err = fmt.Errorf("%s: reference sequence not found", infiles[0])
 198                 return 1
 199         }
 200         if len(tagset) == 0 {
 201                 err = fmt.Errorf("tagset not found")
 202                 return 1
 203         }
 204
 205         taglib := &tagLibrary{}
 206         err = taglib.setTags(tagset)
 207         if err != nil {
 208                 return 1
 209         }
 210         taglen := taglib.TagLen()
 211
 212         if len(cmd.cgnames) == 0 {
 213                 err = fmt.Errorf("no genomes found matching regexp %q", cmd.filter.MatchGenome)
 214                 return 1
 215         }
 216         sort.Strings(cmd.cgnames)
 217         err = cmd.useCaseControlFiles()
 218         if err != nil {
 219                 return 1
 220         }
 221         if len(cmd.cgnames) == 0 {
 222                 err = fmt.Errorf("fatal: 0 cases, 0 controls, nothing to do")
 223                 return 1
 224         }
 225         cmd.minCoverage = int(math.Ceil(cmd.filter.MinCoverage * float64(len(cmd.cgnames))))
 226
 227         {
 228                 labelsFilename := *outputDir + "/samples.csv"
 229                 log.Infof("writing labels to %s", labelsFilename)
 230                 var f *os.File
 231                 f, err = os.Create(labelsFilename)
 232                 if err != nil {
 233                         return 1
 234                 }
 235                 defer f.Close()
 236                 for i, name := range cmd.cgnames {
 237                         cc := 0
 238                         if cmd.chi2Cases != nil && cmd.chi2Cases[i] {
 239                                 cc = 1
 240                         }
 241                         _, err = fmt.Fprintf(f, "%d,%q,%d\n", i, trimFilenameForLabel(name), cc)
 242                         if err != nil {
 243                                 err = fmt.Errorf("write %s: %w", labelsFilename, err)
 244                                 return 1
 245                         }
 246                 }
 247                 err = f.Close()
 248                 if err != nil {
 249                         err = fmt.Errorf("close %s: %w", labelsFilename, err)
 250                         return 1
 251                 }
 252         }
 253
 254         log.Info("indexing reference tiles")
 255         type reftileinfo struct {
 256                 variant  tileVariantID
 257                 seqname  string // chr1
 258                 pos      int    // distance from start of chromosome to starttag
 259                 tiledata []byte // acgtggcaa...
 260                 excluded bool   // true if excluded by regions file
 261                 nexttag  tagID  // tagID of following tile (-1 for last tag of chromosome)
 262         }
 263         isdup := map[tagID]bool{}
 264         reftile := map[tagID]*reftileinfo{}
 265         for seqname, cseq := range refseq {
 266                 pos := 0
 267                 lastreftag := tagID(-1)
 268                 for _, libref := range cseq {
 269                         if cmd.filter.MaxTag >= 0 && libref.Tag > tagID(cmd.filter.MaxTag) {
 270                                 continue
 271                         }
 272                         tiledata := reftiledata[libref]
 273                         if len(tiledata) == 0 {
 274                                 err = fmt.Errorf("missing tiledata for tag %d variant %d in %s in ref", libref.Tag, libref.Variant, seqname)
 275                                 return 1
 276                         }
 277                         foundthistag := false
 278                         taglib.FindAll(tiledata[:len(tiledata)-1], func(tagid tagID, offset, _ int) {
 279                                 if !foundthistag && tagid == libref.Tag {
 280                                         foundthistag = true
 281                                         return
 282                                 }
 283                                 if dupref, ok := reftile[tagid]; ok {
 284                                         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)
 285                                         delete(reftile, tagid)
 286                                 } else {
 287                                         log.Printf("found tag %d at offset %d inside tile variant %+v on %s @ %d", tagid, offset, libref, seqname, pos+offset+1)
 288                                 }
 289                                 isdup[tagid] = true
 290                         })
 291                         if isdup[libref.Tag] {
 292                                 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
 293                         } else if reftile[libref.Tag] != nil {
 294                                 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)
 295                                 delete(reftile, libref.Tag)
 296                                 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
 297                                 isdup[libref.Tag] = true
 298                         } else {
 299                                 reftile[libref.Tag] = &reftileinfo{
 300                                         seqname:  seqname,
 301                                         variant:  libref.Variant,
 302                                         tiledata: tiledata,
 303                                         pos:      pos,
 304                                         nexttag:  -1,
 305                                 }
 306                                 if lastreftag >= 0 {
 307                                         reftile[lastreftag].nexttag = libref.Tag
 308                                 }
 309                                 lastreftag = libref.Tag
 310                         }
 311                         pos += len(tiledata) - taglen
 312                 }
 313                 log.Printf("... %s done, len %d", seqname, pos+taglen)
 314         }
 315
 316         var mask *mask
 317         if *regionsFilename != "" {
 318                 log.Printf("loading regions from %s", *regionsFilename)
 319                 mask, err = makeMask(*regionsFilename, *expandRegions)
 320                 if err != nil {
 321                         return 1
 322                 }
 323                 log.Printf("before applying mask, len(reftile) == %d", len(reftile))
 324                 log.Printf("deleting reftile entries for regions outside %d intervals", mask.Len())
 325                 for _, rt := range reftile {
 326                         if !mask.Check(strings.TrimPrefix(rt.seqname, "chr"), rt.pos, rt.pos+len(rt.tiledata)) {
 327                                 rt.excluded = true
 328                         }
 329                 }
 330                 log.Printf("after applying mask, len(reftile) == %d", len(reftile))
 331         }
 332
 333         type hgvsColSet map[hgvs.Variant][2][]int8
 334         encodeHGVS := throttle{Max: len(refseq)}
 335         encodeHGVSTodo := map[string]chan hgvsColSet{}
 336         tmpHGVSCols := map[string]*os.File{}
 337         if *hgvsChunked {
 338                 for seqname := range refseq {
 339                         var f *os.File
 340                         f, err = os.Create(*outputDir + "/tmp." + seqname + ".gob")
 341                         if err != nil {
 342                                 return 1
 343                         }
 344                         defer os.Remove(f.Name())
 345                         bufw := bufio.NewWriterSize(f, 1<<24)
 346                         enc := gob.NewEncoder(bufw)
 347                         tmpHGVSCols[seqname] = f
 348                         todo := make(chan hgvsColSet, 128)
 349                         encodeHGVSTodo[seqname] = todo
 350                         encodeHGVS.Go(func() error {
 351                                 for colset := range todo {
 352                                         err := enc.Encode(colset)
 353                                         if err != nil {
 354                                                 encodeHGVS.Report(err)
 355                                                 for range todo {
 356                                                 }
 357                                                 return err
 358                                         }
 359                                 }
 360                                 return bufw.Flush()
 361                         })
 362                 }
 363         }
 364
 365         var toMerge [][]int16
 366         if *mergeOutput || *hgvsSingle {
 367                 toMerge = make([][]int16, len(infiles))
 368         }
 369         var onehotIndirect [][2][]uint32 // [chunkIndex][axis][index]
 370         var onehotChunkSize []uint32
 371         var onehotXrefs [][]onehotXref
 372         if *onehotSingle {
 373                 onehotIndirect = make([][2][]uint32, len(infiles))
 374                 onehotChunkSize = make([]uint32, len(infiles))
 375                 onehotXrefs = make([][]onehotXref, len(infiles))
 376         }
 377         chunkStartTag := make([]tagID, len(infiles))
 378
 379         throttleMem := throttle{Max: cmd.threads} // TODO: estimate using mem and data size
 380         throttleNumpyMem := throttle{Max: cmd.threads/2 + 1}
 381         log.Info("generating annotations and numpy matrix for each slice")
 382         var errSkip = errors.New("skip infile")
 383         var done int64
 384         for infileIdx, infile := range infiles {
 385                 infileIdx, infile := infileIdx, infile
 386                 throttleMem.Go(func() error {
 387                         seq := make(map[tagID][]TileVariant, 50000)
 388                         cgs := make(map[string]CompactGenome, len(cmd.cgnames))
 389                         f, err := open(infile)
 390                         if err != nil {
 391                                 return err
 392                         }
 393                         defer f.Close()
 394                         log.Infof("%04d: reading %s", infileIdx, infile)
 395                         err = DecodeLibrary(f, strings.HasSuffix(infile, ".gz"), func(ent *LibraryEntry) error {
 396                                 for _, tv := range ent.TileVariants {
 397                                         if tv.Ref {
 398                                                 continue
 399                                         }
 400                                         // Skip tile with no
 401                                         // corresponding ref tile, if
 402                                         // mask is in play (we can't
 403                                         // determine coordinates for
 404                                         // these)
 405                                         if mask != nil && reftile[tv.Tag] == nil {
 406                                                 continue
 407                                         }
 408                                         // Skip tile whose
 409                                         // corresponding ref tile is
 410                                         // outside target regions --
 411                                         // unless it's a potential
 412                                         // spanning tile.
 413                                         if mask != nil && reftile[tv.Tag].excluded &&
 414                                                 (int(tv.Tag+1) >= len(tagset) ||
 415                                                         (bytes.HasSuffix(tv.Sequence, tagset[tv.Tag+1]) && reftile[tv.Tag+1] != nil && !reftile[tv.Tag+1].excluded)) {
 416                                                 continue
 417                                         }
 418                                         if tv.Tag == cmd.debugTag {
 419                                                 log.Printf("infile %d %s tag %d variant %d hash %x", infileIdx, infile, tv.Tag, tv.Variant, tv.Blake2b[:3])
 420                                         }
 421                                         variants := seq[tv.Tag]
 422                                         if len(variants) == 0 {
 423                                                 variants = make([]TileVariant, 100)
 424                                         }
 425                                         for len(variants) <= int(tv.Variant) {
 426                                                 variants = append(variants, TileVariant{})
 427                                         }
 428                                         variants[int(tv.Variant)] = tv
 429                                         seq[tv.Tag] = variants
 430                                 }
 431                                 for _, cg := range ent.CompactGenomes {
 432                                         if cmd.filter.MaxTag >= 0 && cg.StartTag > tagID(cmd.filter.MaxTag) {
 433                                                 return errSkip
 434                                         }
 435                                         if !matchGenome.MatchString(cg.Name) {
 436                                                 continue
 437                                         }
 438                                         // pad to full slice size
 439                                         // to avoid out-of-bounds
 440                                         // checks later
 441                                         if sliceSize := 2 * int(cg.EndTag-cg.StartTag); len(cg.Variants) < sliceSize {
 442                                                 cg.Variants = append(cg.Variants, make([]tileVariantID, sliceSize-len(cg.Variants))...)
 443                                         }
 444                                         cgs[cg.Name] = cg
 445                                 }
 446                                 return nil
 447                         })
 448                         if err == errSkip {
 449                                 return nil
 450                         } else if err != nil {
 451                                 return err
 452                         }
 453                         tagstart := cgs[cmd.cgnames[0]].StartTag
 454                         tagend := cgs[cmd.cgnames[0]].EndTag
 455                         chunkStartTag[infileIdx] = tagstart
 456
 457                         // TODO: filters
 458
 459                         log.Infof("%04d: renumber/dedup variants for tags %d-%d", infileIdx, tagstart, tagend)
 460                         variantRemap := make([][]tileVariantID, tagend-tagstart)
 461                         throttleCPU := throttle{Max: runtime.GOMAXPROCS(0)}
 462                         for tag, variants := range seq {
 463                                 tag, variants := tag, variants
 464                                 throttleCPU.Go(func() error {
 465                                         count := make(map[[blake2b.Size256]byte]int, len(variants))
 466
 467                                         rt := reftile[tag]
 468                                         if rt != nil {
 469                                                 count[blake2b.Sum256(rt.tiledata)] = 0
 470                                         }
 471
 472                                         for cgname, cg := range cgs {
 473                                                 idx := int(tag-tagstart) * 2
 474                                                 for allele := 0; allele < 2; allele++ {
 475                                                         v := cg.Variants[idx+allele]
 476                                                         if v > 0 && len(variants[v].Sequence) > 0 {
 477                                                                 count[variants[v].Blake2b]++
 478                                                         }
 479                                                         if v > 0 && tag == cmd.debugTag {
 480                                                                 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])
 481                                                         }
 482                                                 }
 483                                         }
 484                                         // hash[i] will be the hash of
 485                                         // the variant(s) that should
 486                                         // be at rank i (0-based).
 487                                         hash := make([][blake2b.Size256]byte, 0, len(count))
 488                                         for b := range count {
 489                                                 hash = append(hash, b)
 490                                         }
 491                                         sort.Slice(hash, func(i, j int) bool {
 492                                                 bi, bj := &hash[i], &hash[j]
 493                                                 if ci, cj := count[*bi], count[*bj]; ci != cj {
 494                                                         return ci > cj
 495                                                 } else {
 496                                                         return bytes.Compare((*bi)[:], (*bj)[:]) < 0
 497                                                 }
 498                                         })
 499                                         // rank[b] will be the 1-based
 500                                         // new variant number for
 501                                         // variants whose hash is b.
 502                                         rank := make(map[[blake2b.Size256]byte]tileVariantID, len(hash))
 503                                         for i, h := range hash {
 504                                                 rank[h] = tileVariantID(i + 1)
 505                                         }
 506                                         if tag == cmd.debugTag {
 507                                                 for h, r := range rank {
 508                                                         log.Printf("tag %d rank(%x) = %v", tag, h[:3], r)
 509                                                 }
 510                                         }
 511                                         // remap[v] will be the new
 512                                         // variant number for original
 513                                         // variant number v.
 514                                         remap := make([]tileVariantID, len(variants))
 515                                         for i, tv := range variants {
 516                                                 remap[i] = rank[tv.Blake2b]
 517                                         }
 518                                         if tag == cmd.debugTag {
 519                                                 for in, out := range remap {
 520                                                         if out > 0 {
 521                                                                 log.Printf("tag %d remap %d => %d", tag, in, out)
 522                                                         }
 523                                                 }
 524                                         }
 525                                         variantRemap[tag-tagstart] = remap
 526                                         if rt != nil {
 527                                                 refrank := rank[blake2b.Sum256(rt.tiledata)]
 528                                                 if tag == cmd.debugTag {
 529                                                         log.Printf("tag %d reftile variant %d => %d", tag, rt.variant, refrank)
 530                                                 }
 531                                                 rt.variant = refrank
 532                                         }
 533                                         return nil
 534                                 })
 535                         }
 536                         throttleCPU.Wait()
 537
 538                         var onehotChunk [][]int8
 539                         var onehotXref []onehotXref
 540
 541                         annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, infileIdx)
 542                         log.Infof("%04d: writing %s", infileIdx, annotationsFilename)
 543                         annof, err := os.Create(annotationsFilename)
 544                         if err != nil {
 545                                 return err
 546                         }
 547                         annow := bufio.NewWriterSize(annof, 1<<20)
 548                         outcol := 0
 549                         for tag := tagstart; tag < tagend; tag++ {
 550                                 rt := reftile[tag]
 551                                 if rt == nil && mask != nil {
 552                                         // With no ref tile, we don't
 553                                         // have coordinates to say
 554                                         // this is in the desired
 555                                         // regions -- so it's not.
 556                                         // TODO: handle ref spanning
 557                                         // tile case.
 558                                         continue
 559                                 }
 560                                 if rt != nil && rt.excluded {
 561                                         // TODO: don't skip yet --
 562                                         // first check for spanning
 563                                         // tile variants that
 564                                         // intersect non-excluded ref
 565                                         // tiles.
 566                                         continue
 567                                 }
 568                                 if cmd.filter.MaxTag >= 0 && tag > tagID(cmd.filter.MaxTag) {
 569                                         break
 570                                 }
 571                                 remap := variantRemap[tag-tagstart]
 572                                 maxv := tileVariantID(0)
 573                                 for _, v := range remap {
 574                                         if maxv < v {
 575                                                 maxv = v
 576                                         }
 577                                 }
 578                                 if *onehotChunked || *onehotSingle {
 579                                         onehot, xrefs := cmd.tv2homhet(cgs, maxv, remap, tag, tagstart, seq)
 580                                         if tag == cmd.debugTag {
 581                                                 log.WithFields(logrus.Fields{
 582                                                         "onehot": onehot,
 583                                                         "xrefs":  xrefs,
 584                                                 }).Info("tv2homhet()")
 585                                         }
 586                                         onehotChunk = append(onehotChunk, onehot...)
 587                                         onehotXref = append(onehotXref, xrefs...)
 588                                 }
 589                                 if rt == nil {
 590                                         // Reference does not use any
 591                                         // variant of this tile
 592                                         //
 593                                         // TODO: diff against the
 594                                         // relevant portion of the
 595                                         // ref's spanning tile
 596                                         outcol++
 597                                         continue
 598                                 }
 599                                 fmt.Fprintf(annow, "%d,%d,%d,=,%s,%d,,,\n", tag, outcol, rt.variant, rt.seqname, rt.pos)
 600                                 variants := seq[tag]
 601                                 reftilestr := strings.ToUpper(string(rt.tiledata))
 602
 603                                 done := make([]bool, maxv+1)
 604                                 variantDiffs := make([][]hgvs.Variant, maxv+1)
 605                                 for v, tv := range variants {
 606                                         v := remap[v]
 607                                         if v == rt.variant || done[v] {
 608                                                 continue
 609                                         } else {
 610                                                 done[v] = true
 611                                         }
 612                                         if len(tv.Sequence) < taglen {
 613                                                 continue
 614                                         }
 615                                         // if reftilestr doesn't end
 616                                         // in the same tag as tv,
 617                                         // extend reftilestr with
 618                                         // following ref tiles until
 619                                         // it does (up to an arbitrary
 620                                         // sanity-check limit)
 621                                         reftilestr := reftilestr
 622                                         endtagstr := strings.ToUpper(string(tv.Sequence[len(tv.Sequence)-taglen:]))
 623                                         for i, rt := 0, rt; i < annotationMaxTileSpan && !strings.HasSuffix(reftilestr, endtagstr) && rt.nexttag >= 0; i++ {
 624                                                 rt = reftile[rt.nexttag]
 625                                                 reftilestr += strings.ToUpper(string(rt.tiledata[taglen:]))
 626                                         }
 627                                         if mask != nil && !mask.Check(strings.TrimPrefix(rt.seqname, "chr"), rt.pos, rt.pos+len(reftilestr)) {
 628                                                 continue
 629                                         }
 630                                         if !strings.HasSuffix(reftilestr, endtagstr) {
 631                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 632                                                 continue
 633                                         }
 634                                         if lendiff := len(reftilestr) - len(tv.Sequence); lendiff < -1000 || lendiff > 1000 {
 635                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 636                                                 continue
 637                                         }
 638                                         diffs, _ := hgvs.Diff(reftilestr, strings.ToUpper(string(tv.Sequence)), 0)
 639                                         for i := range diffs {
 640                                                 diffs[i].Position += rt.pos
 641                                         }
 642                                         for _, diff := range diffs {
 643                                                 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)
 644                                         }
 645                                         if *hgvsChunked {
 646                                                 variantDiffs[v] = diffs
 647                                         }
 648                                 }
 649                                 if *hgvsChunked {
 650                                         // We can now determine, for each HGVS
 651                                         // variant (diff) in this reftile
 652                                         // region, whether a given genome
 653                                         // phase/allele (1) has the variant, (0) has
 654                                         // =ref or a different variant in that
 655                                         // position, or (-1) is lacking
 656                                         // coverage / couldn't be diffed.
 657                                         hgvsCol := hgvsColSet{}
 658                                         for _, diffs := range variantDiffs {
 659                                                 for _, diff := range diffs {
 660                                                         if _, ok := hgvsCol[diff]; ok {
 661                                                                 continue
 662                                                         }
 663                                                         hgvsCol[diff] = [2][]int8{
 664                                                                 make([]int8, len(cmd.cgnames)),
 665                                                                 make([]int8, len(cmd.cgnames)),
 666                                                         }
 667                                                 }
 668                                         }
 669                                         for row, name := range cmd.cgnames {
 670                                                 variants := cgs[name].Variants[(tag-tagstart)*2:]
 671                                                 for ph := 0; ph < 2; ph++ {
 672                                                         v := variants[ph]
 673                                                         if int(v) >= len(remap) {
 674                                                                 v = 0
 675                                                         } else {
 676                                                                 v = remap[v]
 677                                                         }
 678                                                         if v == rt.variant {
 679                                                                 // hgvsCol[*][ph][row] is already 0
 680                                                         } else if len(variantDiffs[v]) == 0 {
 681                                                                 // lacking coverage / couldn't be diffed
 682                                                                 for _, col := range hgvsCol {
 683                                                                         col[ph][row] = -1
 684                                                                 }
 685                                                         } else {
 686                                                                 for _, diff := range variantDiffs[v] {
 687                                                                         hgvsCol[diff][ph][row] = 1
 688                                                                 }
 689                                                         }
 690                                                 }
 691                                         }
 692                                         for diff, colpair := range hgvsCol {
 693                                                 allele2homhet(colpair)
 694                                                 if !cmd.filterHGVScolpair(colpair) {
 695                                                         delete(hgvsCol, diff)
 696                                                 }
 697                                         }
 698                                         if len(hgvsCol) > 0 {
 699                                                 encodeHGVSTodo[rt.seqname] <- hgvsCol
 700                                         }
 701                                 }
 702                                 outcol++
 703                         }
 704                         err = annow.Flush()
 705                         if err != nil {
 706                                 return err
 707                         }
 708                         err = annof.Close()
 709                         if err != nil {
 710                                 return err
 711                         }
 712
 713                         if *onehotChunked {
 714                                 // transpose onehotChunk[col][row] to numpy[row*ncols+col]
 715                                 rows := len(cmd.cgnames)
 716                                 cols := len(onehotChunk)
 717                                 log.Infof("%04d: preparing onehot numpy (rows=%d, cols=%d, mem=%d)", infileIdx, rows, cols, rows*cols)
 718                                 throttleNumpyMem.Acquire()
 719                                 out := onehotcols2int8(onehotChunk)
 720                                 fnm := fmt.Sprintf("%s/onehot.%04d.npy", *outputDir, infileIdx)
 721                                 err = writeNumpyInt8(fnm, out, rows, cols)
 722                                 if err != nil {
 723                                         return err
 724                                 }
 725                                 fnm = fmt.Sprintf("%s/onehot-columns.%04d.npy", *outputDir, infileIdx)
 726                                 err = writeNumpyInt32(fnm, onehotXref2int32(onehotXref), 4, len(onehotXref))
 727                                 if err != nil {
 728                                         return err
 729                                 }
 730                                 debug.FreeOSMemory()
 731                                 throttleNumpyMem.Release()
 732                         }
 733                         if *onehotSingle {
 734                                 onehotIndirect[infileIdx] = onehotChunk2Indirect(onehotChunk)
 735                                 onehotChunkSize[infileIdx] = uint32(len(onehotChunk))
 736                                 onehotXrefs[infileIdx] = onehotXref
 737                                 n := len(onehotIndirect[infileIdx][0])
 738                                 log.Infof("%04d: keeping onehot coordinates in memory (n=%d, mem=%d)", infileIdx, n, n*8*2)
 739                         }
 740                         if !(*onehotSingle || *onehotChunked) || *mergeOutput || *hgvsSingle {
 741                                 log.Infof("%04d: preparing numpy (rows=%d, cols=%d)", infileIdx, len(cmd.cgnames), 2*outcol)
 742                                 throttleNumpyMem.Acquire()
 743                                 rows := len(cmd.cgnames)
 744                                 cols := 2 * outcol
 745                                 out := make([]int16, rows*cols)
 746                                 for row, name := range cmd.cgnames {
 747                                         outidx := row * cols
 748                                         for col, v := range cgs[name].Variants {
 749                                                 tag := tagstart + tagID(col/2)
 750                                                 if cmd.filter.MaxTag >= 0 && tag > tagID(cmd.filter.MaxTag) {
 751                                                         break
 752                                                 }
 753                                                 if rt := reftile[tag]; rt == nil || rt.excluded {
 754                                                         continue
 755                                                 }
 756                                                 if v == 0 {
 757                                                         out[outidx] = 0 // tag not found / spanning tile
 758                                                 } else if variants, ok := seq[tag]; ok && int(v) < len(variants) && len(variants[v].Sequence) > 0 {
 759                                                         out[outidx] = int16(variantRemap[tag-tagstart][v])
 760                                                 } else {
 761                                                         out[outidx] = -1 // low quality tile variant
 762                                                 }
 763                                                 if tag == cmd.debugTag {
 764                                                         log.Printf("tag %d row %d col %d outidx %d v %d out %d", tag, row, col, outidx, v, out[outidx])
 765                                                 }
 766                                                 outidx++
 767                                         }
 768                                 }
 769                                 seq = nil
 770                                 cgs = nil
 771                                 debug.FreeOSMemory()
 772                                 throttleNumpyMem.Release()
 773                                 if *mergeOutput || *hgvsSingle {
 774                                         log.Infof("%04d: matrix fragment %d rows x %d cols", infileIdx, rows, cols)
 775                                         toMerge[infileIdx] = out
 776                                 }
 777                                 if !*mergeOutput && !*onehotChunked && !*onehotSingle {
 778                                         fnm := fmt.Sprintf("%s/matrix.%04d.npy", *outputDir, infileIdx)
 779                                         err = writeNumpyInt16(fnm, out, rows, cols)
 780                                         if err != nil {
 781                                                 return err
 782                                         }
 783                                 }
 784                         }
 785                         debug.FreeOSMemory()
 786                         log.Infof("%s: done (%d/%d)", infile, int(atomic.AddInt64(&done, 1)), len(infiles))
 787                         return nil
 788                 })
 789         }
 790         if err = throttleMem.Wait(); err != nil {
 791                 return 1
 792         }
 793
 794         if *hgvsChunked {
 795                 log.Info("flushing hgvsCols temp files")
 796                 for seqname := range refseq {
 797                         close(encodeHGVSTodo[seqname])
 798                 }
 799                 err = encodeHGVS.Wait()
 800                 if err != nil {
 801                         return 1
 802                 }
 803                 for seqname := range refseq {
 804                         log.Infof("%s: reading hgvsCols from temp file", seqname)
 805                         f := tmpHGVSCols[seqname]
 806                         _, err = f.Seek(0, io.SeekStart)
 807                         if err != nil {
 808                                 return 1
 809                         }
 810                         var hgvsCols hgvsColSet
 811                         dec := gob.NewDecoder(bufio.NewReaderSize(f, 1<<24))
 812                         for err == nil {
 813                                 err = dec.Decode(&hgvsCols)
 814                         }
 815                         if err != io.EOF {
 816                                 return 1
 817                         }
 818                         log.Infof("%s: sorting %d hgvs variants", seqname, len(hgvsCols))
 819                         variants := make([]hgvs.Variant, 0, len(hgvsCols))
 820                         for v := range hgvsCols {
 821                                 variants = append(variants, v)
 822                         }
 823                         sort.Slice(variants, func(i, j int) bool {
 824                                 vi, vj := &variants[i], &variants[j]
 825                                 if vi.Position != vj.Position {
 826                                         return vi.Position < vj.Position
 827                                 } else if vi.Ref != vj.Ref {
 828                                         return vi.Ref < vj.Ref
 829                                 } else {
 830                                         return vi.New < vj.New
 831                                 }
 832                         })
 833                         rows := len(cmd.cgnames)
 834                         cols := len(variants) * 2
 835                         log.Infof("%s: building hgvs matrix (rows=%d, cols=%d, mem=%d)", seqname, rows, cols, rows*cols)
 836                         out := make([]int8, rows*cols)
 837                         for varIdx, variant := range variants {
 838                                 hgvsCols := hgvsCols[variant]
 839                                 for row := range cmd.cgnames {
 840                                         for ph := 0; ph < 2; ph++ {
 841                                                 out[row*cols+varIdx+ph] = hgvsCols[ph][row]
 842                                         }
 843                                 }
 844                         }
 845                         err = writeNumpyInt8(fmt.Sprintf("%s/hgvs.%s.npy", *outputDir, seqname), out, rows, cols)
 846                         if err != nil {
 847                                 return 1
 848                         }
 849                         out = nil
 850
 851                         fnm := fmt.Sprintf("%s/hgvs.%s.annotations.csv", *outputDir, seqname)
 852                         log.Infof("%s: writing hgvs column labels to %s", seqname, fnm)
 853                         var hgvsLabels bytes.Buffer
 854                         for varIdx, variant := range variants {
 855                                 fmt.Fprintf(&hgvsLabels, "%d,%s:g.%s\n", varIdx, seqname, variant.String())
 856                         }
 857                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0666)
 858                         if err != nil {
 859                                 return 1
 860                         }
 861                 }
 862         }
 863
 864         if *mergeOutput || *hgvsSingle {
 865                 var annow *bufio.Writer
 866                 var annof *os.File
 867                 if *mergeOutput {
 868                         annoFilename := fmt.Sprintf("%s/matrix.annotations.csv", *outputDir)
 869                         annof, err = os.Create(annoFilename)
 870                         if err != nil {
 871                                 return 1
 872                         }
 873                         annow = bufio.NewWriterSize(annof, 1<<20)
 874                 }
 875
 876                 rows := len(cmd.cgnames)
 877                 cols := 0
 878                 for _, chunk := range toMerge {
 879                         cols += len(chunk) / rows
 880                 }
 881                 log.Infof("merging output matrix (rows=%d, cols=%d, mem=%d) and annotations", rows, cols, rows*cols*2)
 882                 var out []int16
 883                 if *mergeOutput {
 884                         out = make([]int16, rows*cols)
 885                 }
 886                 hgvsCols := map[string][2][]int16{} // hgvs -> [[g0,g1,g2,...], [g0,g1,g2,...]] (slice of genomes for each phase)
 887                 startcol := 0
 888                 for outIdx, chunk := range toMerge {
 889                         chunkcols := len(chunk) / rows
 890                         if *mergeOutput {
 891                                 for row := 0; row < rows; row++ {
 892                                         copy(out[row*cols+startcol:], chunk[row*chunkcols:(row+1)*chunkcols])
 893                                 }
 894                         }
 895                         toMerge[outIdx] = nil
 896
 897                         annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, outIdx)
 898                         log.Infof("reading %s", annotationsFilename)
 899                         buf, err := os.ReadFile(annotationsFilename)
 900                         if err != nil {
 901                                 return 1
 902                         }
 903                         if *mergeOutput {
 904                                 err = os.Remove(annotationsFilename)
 905                                 if err != nil {
 906                                         return 1
 907                                 }
 908                         }
 909                         for _, line := range bytes.Split(buf, []byte{'\n'}) {
 910                                 if len(line) == 0 {
 911                                         continue
 912                                 }
 913                                 fields := bytes.SplitN(line, []byte{','}, 9)
 914                                 tag, _ := strconv.Atoi(string(fields[0]))
 915                                 incol, _ := strconv.Atoi(string(fields[1]))
 916                                 tileVariant, _ := strconv.Atoi(string(fields[2]))
 917                                 hgvsID := string(fields[3])
 918                                 seqname := string(fields[4])
 919                                 pos, _ := strconv.Atoi(string(fields[5]))
 920                                 refseq := fields[6]
 921                                 if hgvsID == "" {
 922                                         // Null entry for un-diffable
 923                                         // tile variant
 924                                         continue
 925                                 }
 926                                 if hgvsID == "=" {
 927                                         // Null entry for ref tile
 928                                         continue
 929                                 }
 930                                 if mask != nil && !mask.Check(strings.TrimPrefix(seqname, "chr"), pos, pos+len(refseq)) {
 931                                         // The tile intersects one of
 932                                         // the selected regions, but
 933                                         // this particular HGVS
 934                                         // variant does not.
 935                                         continue
 936                                 }
 937                                 hgvsColPair := hgvsCols[hgvsID]
 938                                 if hgvsColPair[0] == nil {
 939                                         // values in new columns start
 940                                         // out as -1 ("no data yet")
 941                                         // or 0 ("=ref") here, may
 942                                         // change to 1 ("hgvs variant
 943                                         // present") below, either on
 944                                         // this line or a future line.
 945                                         hgvsColPair = [2][]int16{make([]int16, len(cmd.cgnames)), make([]int16, len(cmd.cgnames))}
 946                                         rt, ok := reftile[tagID(tag)]
 947                                         if !ok {
 948                                                 err = fmt.Errorf("bug: seeing annotations for tag %d, but it has no reftile entry", tag)
 949                                                 return 1
 950                                         }
 951                                         for ph := 0; ph < 2; ph++ {
 952                                                 for row := 0; row < rows; row++ {
 953                                                         v := chunk[row*chunkcols+incol*2+ph]
 954                                                         if tileVariantID(v) == rt.variant {
 955                                                                 hgvsColPair[ph][row] = 0
 956                                                         } else {
 957                                                                 hgvsColPair[ph][row] = -1
 958                                                         }
 959                                                 }
 960                                         }
 961                                         hgvsCols[hgvsID] = hgvsColPair
 962                                         if annow != nil {
 963                                                 hgvsref := hgvs.Variant{
 964                                                         Position: pos,
 965                                                         Ref:      string(refseq),
 966                                                         New:      string(refseq),
 967                                                 }
 968                                                 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])
 969                                         }
 970                                 }
 971                                 if annow != nil {
 972                                         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])
 973                                 }
 974                                 for ph := 0; ph < 2; ph++ {
 975                                         for row := 0; row < rows; row++ {
 976                                                 v := chunk[row*chunkcols+incol*2+ph]
 977                                                 if int(v) == tileVariant {
 978                                                         hgvsColPair[ph][row] = 1
 979                                                 }
 980                                         }
 981                                 }
 982                         }
 983
 984                         startcol += chunkcols
 985                 }
 986                 if *mergeOutput {
 987                         err = annow.Flush()
 988                         if err != nil {
 989                                 return 1
 990                         }
 991                         err = annof.Close()
 992                         if err != nil {
 993                                 return 1
 994                         }
 995                         err = writeNumpyInt16(fmt.Sprintf("%s/matrix.npy", *outputDir), out, rows, cols)
 996                         if err != nil {
 997                                 return 1
 998                         }
 999                 }
1000                 out = nil
1001
1002                 if *hgvsSingle {
1003                         cols = len(hgvsCols) * 2
1004                         log.Printf("building hgvs-based matrix: %d rows x %d cols", rows, cols)
1005                         out = make([]int16, rows*cols)
1006                         hgvsIDs := make([]string, 0, cols/2)
1007                         for hgvsID := range hgvsCols {
1008                                 hgvsIDs = append(hgvsIDs, hgvsID)
1009                         }
1010                         sort.Strings(hgvsIDs)
1011                         var hgvsLabels bytes.Buffer
1012                         for idx, hgvsID := range hgvsIDs {
1013                                 fmt.Fprintf(&hgvsLabels, "%d,%s\n", idx, hgvsID)
1014                                 for ph := 0; ph < 2; ph++ {
1015                                         hgvscol := hgvsCols[hgvsID][ph]
1016                                         for row, val := range hgvscol {
1017                                                 out[row*cols+idx*2+ph] = val
1018                                         }
1019                                 }
1020                         }
1021                         err = writeNumpyInt16(fmt.Sprintf("%s/hgvs.npy", *outputDir), out, rows, cols)
1022                         if err != nil {
1023                                 return 1
1024                         }
1025
1026                         fnm := fmt.Sprintf("%s/hgvs.annotations.csv", *outputDir)
1027                         log.Printf("writing hgvs labels: %s", fnm)
1028                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0777)
1029                         if err != nil {
1030                                 return 1
1031                         }
1032                 }
1033         }
1034         if *onehotSingle {
1035                 nzCount := 0
1036                 for _, part := range onehotIndirect {
1037                         nzCount += len(part[0])
1038                 }
1039                 onehot := make([]uint32, nzCount*2) // [r,r,r,...,c,c,c,...]
1040                 var xrefs []onehotXref
1041                 chunkOffset := uint32(0)
1042                 outcol := 0
1043                 for i, part := range onehotIndirect {
1044                         for i := range part[1] {
1045                                 part[1][i] += chunkOffset
1046                         }
1047                         copy(onehot[outcol:], part[0])
1048                         copy(onehot[outcol+nzCount:], part[1])
1049                         xrefs = append(xrefs, onehotXrefs[i]...)
1050
1051                         outcol += len(part[0])
1052                         chunkOffset += onehotChunkSize[i]
1053
1054                         part[0] = nil
1055                         part[1] = nil
1056                         onehotXrefs[i] = nil
1057                         debug.FreeOSMemory()
1058                 }
1059                 fnm := fmt.Sprintf("%s/onehot.npy", *outputDir)
1060                 err = writeNumpyUint32(fnm, onehot, 2, nzCount)
1061                 if err != nil {
1062                         return 1
1063                 }
1064                 fnm = fmt.Sprintf("%s/onehot-columns.npy", *outputDir)
1065                 err = writeNumpyInt32(fnm, onehotXref2int32(xrefs), 5, len(xrefs))
1066                 if err != nil {
1067                         return 1
1068                 }
1069         }
1070         if !*mergeOutput && !*onehotChunked && !*onehotSingle {
1071                 tagoffsetFilename := *outputDir + "/chunk-tag-offset.csv"
1072                 log.Infof("writing tag offsets to %s", tagoffsetFilename)
1073                 var f *os.File
1074                 f, err = os.Create(tagoffsetFilename)
1075                 if err != nil {
1076                         return 1
1077                 }
1078                 defer f.Close()
1079                 for idx, offset := range chunkStartTag {
1080                         _, err = fmt.Fprintf(f, "%q,%d\n", fmt.Sprintf("matrix.%04d.npy", idx), offset)
1081                         if err != nil {
1082                                 err = fmt.Errorf("write %s: %w", tagoffsetFilename, err)
1083                                 return 1
1084                         }
1085                 }
1086                 err = f.Close()
1087                 if err != nil {
1088                         err = fmt.Errorf("close %s: %w", tagoffsetFilename, err)
1089                         return 1
1090                 }
1091         }
1092         return 0
1093 }
1094
1095 // Read case/control files, remove non-case/control entries from
1096 // cmd.cgnames, and build cmd.chi2Cases.
1097 func (cmd *sliceNumpy) useCaseControlFiles() error {
1098         if cmd.chi2CaseControlFile == "" {
1099                 return nil
1100         }
1101         infiles, err := allFiles(cmd.chi2CaseControlFile, nil)
1102         if err != nil {
1103                 return err
1104         }
1105         // index in cmd.cgnames => case(true) / control(false)
1106         cc := map[int]bool{}
1107         for _, infile := range infiles {
1108                 f, err := open(infile)
1109                 if err != nil {
1110                         return err
1111                 }
1112                 buf, err := io.ReadAll(f)
1113                 f.Close()
1114                 if err != nil {
1115                         return err
1116                 }
1117                 ccCol := -1
1118                 for _, tsv := range bytes.Split(buf, []byte{'\n'}) {
1119                         if len(tsv) == 0 {
1120                                 continue
1121                         }
1122                         split := strings.Split(string(tsv), "\t")
1123                         if ccCol < 0 {
1124                                 // header row
1125                                 for col, name := range split {
1126                                         if name == cmd.chi2CaseControlColumn {
1127                                                 ccCol = col
1128                                                 break
1129                                         }
1130                                 }
1131                                 if ccCol < 0 {
1132                                         return fmt.Errorf("%s: no column named %q in header row %q", infile, cmd.chi2CaseControlColumn, tsv)
1133                                 }
1134                                 continue
1135                         }
1136                         if len(split) <= ccCol {
1137                                 continue
1138                         }
1139                         pattern := split[0]
1140                         found := -1
1141                         for i, name := range cmd.cgnames {
1142                                 if strings.Contains(name, pattern) {
1143                                         if found >= 0 {
1144                                                 log.Warnf("pattern %q in %s matches multiple genome IDs (%qs, %q)", pattern, infile, cmd.cgnames[found], name)
1145                                         }
1146                                         found = i
1147                                 }
1148                         }
1149                         if found < 0 {
1150                                 log.Warnf("pattern %q in %s does not match any genome IDs", pattern, infile)
1151                                 continue
1152                         }
1153                         if split[ccCol] == "0" {
1154                                 cc[found] = false
1155                         }
1156                         if split[ccCol] == "1" {
1157                                 cc[found] = true
1158                         }
1159                 }
1160         }
1161         allnames := cmd.cgnames
1162         cmd.cgnames = nil
1163         cmd.chi2Cases = nil
1164         ncases := 0
1165         for i, name := range allnames {
1166                 if cc, ok := cc[i]; ok {
1167                         cmd.cgnames = append(cmd.cgnames, name)
1168                         cmd.chi2Cases = append(cmd.chi2Cases, cc)
1169                         if cc {
1170                                 ncases++
1171                         }
1172                 }
1173         }
1174         log.Printf("%d cases, %d controls, %d neither (dropped)", ncases, len(cmd.cgnames)-ncases, len(allnames)-len(cmd.cgnames))
1175         return nil
1176 }
1177
1178 func (cmd *sliceNumpy) filterHGVScolpair(colpair [2][]int8) bool {
1179         if cmd.chi2PValue >= 1 {
1180                 return true
1181         }
1182         col0 := make([]bool, 0, len(cmd.chi2Cases))
1183         col1 := make([]bool, 0, len(cmd.chi2Cases))
1184         cases := make([]bool, 0, len(cmd.chi2Cases))
1185         for i, c := range cmd.chi2Cases {
1186                 if colpair[0][i] < 0 {
1187                         continue
1188                 }
1189                 col0 = append(col0, colpair[0][i] != 0)
1190                 col1 = append(col1, colpair[1][i] != 0)
1191                 cases = append(cases, c)
1192         }
1193         return len(cases) >= cmd.minCoverage &&
1194                 (pvalue(col0, cases) <= cmd.chi2PValue || pvalue(col1, cases) <= cmd.chi2PValue)
1195 }
1196
1197 func writeNumpyUint32(fnm string, out []uint32, rows, cols int) error {
1198         output, err := os.Create(fnm)
1199         if err != nil {
1200                 return err
1201         }
1202         defer output.Close()
1203         bufw := bufio.NewWriterSize(output, 1<<26)
1204         npw, err := gonpy.NewWriter(nopCloser{bufw})
1205         if err != nil {
1206                 return err
1207         }
1208         log.WithFields(log.Fields{
1209                 "filename": fnm,
1210                 "rows":     rows,
1211                 "cols":     cols,
1212                 "bytes":    rows * cols * 4,
1213         }).Infof("writing numpy: %s", fnm)
1214         npw.Shape = []int{rows, cols}
1215         npw.WriteUint32(out)
1216         err = bufw.Flush()
1217         if err != nil {
1218                 return err
1219         }
1220         return output.Close()
1221 }
1222
1223 func writeNumpyInt32(fnm string, out []int32, rows, cols int) error {
1224         output, err := os.Create(fnm)
1225         if err != nil {
1226                 return err
1227         }
1228         defer output.Close()
1229         bufw := bufio.NewWriterSize(output, 1<<26)
1230         npw, err := gonpy.NewWriter(nopCloser{bufw})
1231         if err != nil {
1232                 return err
1233         }
1234         log.WithFields(log.Fields{
1235                 "filename": fnm,
1236                 "rows":     rows,
1237                 "cols":     cols,
1238                 "bytes":    rows * cols * 4,
1239         }).Infof("writing numpy: %s", fnm)
1240         npw.Shape = []int{rows, cols}
1241         npw.WriteInt32(out)
1242         err = bufw.Flush()
1243         if err != nil {
1244                 return err
1245         }
1246         return output.Close()
1247 }
1248
1249 func writeNumpyInt16(fnm string, out []int16, rows, cols int) error {
1250         output, err := os.Create(fnm)
1251         if err != nil {
1252                 return err
1253         }
1254         defer output.Close()
1255         bufw := bufio.NewWriterSize(output, 1<<26)
1256         npw, err := gonpy.NewWriter(nopCloser{bufw})
1257         if err != nil {
1258                 return err
1259         }
1260         log.WithFields(log.Fields{
1261                 "filename": fnm,
1262                 "rows":     rows,
1263                 "cols":     cols,
1264                 "bytes":    rows * cols * 2,
1265         }).Infof("writing numpy: %s", fnm)
1266         npw.Shape = []int{rows, cols}
1267         npw.WriteInt16(out)
1268         err = bufw.Flush()
1269         if err != nil {
1270                 return err
1271         }
1272         return output.Close()
1273 }
1274
1275 func writeNumpyInt8(fnm string, out []int8, rows, cols int) error {
1276         output, err := os.Create(fnm)
1277         if err != nil {
1278                 return err
1279         }
1280         defer output.Close()
1281         bufw := bufio.NewWriterSize(output, 1<<26)
1282         npw, err := gonpy.NewWriter(nopCloser{bufw})
1283         if err != nil {
1284                 return err
1285         }
1286         log.WithFields(log.Fields{
1287                 "filename": fnm,
1288                 "rows":     rows,
1289                 "cols":     cols,
1290                 "bytes":    rows * cols,
1291         }).Infof("writing numpy: %s", fnm)
1292         npw.Shape = []int{rows, cols}
1293         npw.WriteInt8(out)
1294         err = bufw.Flush()
1295         if err != nil {
1296                 return err
1297         }
1298         return output.Close()
1299 }
1300
1301 func allele2homhet(colpair [2][]int8) {
1302         a, b := colpair[0], colpair[1]
1303         for i, av := range a {
1304                 bv := b[i]
1305                 if av < 0 || bv < 0 {
1306                         // no-call
1307                         a[i], b[i] = -1, -1
1308                 } else if av > 0 && bv > 0 {
1309                         // hom
1310                         a[i], b[i] = 1, 0
1311                 } else if av > 0 || bv > 0 {
1312                         // het
1313                         a[i], b[i] = 0, 1
1314                 } else {
1315                         // ref (or a different variant in same position)
1316                         // (this is a no-op) a[i], b[i] = 0, 0
1317                 }
1318         }
1319 }
1320
1321 type onehotXref struct {
1322         tag     tagID
1323         variant tileVariantID
1324         hom     bool
1325         pvalue  float64
1326 }
1327
1328 const onehotXrefSize = unsafe.Sizeof(onehotXref{})
1329
1330 // Build onehot matrix (m[tileVariantIndex][genome] == 0 or 1) for all
1331 // variants of a single tile/tag#.
1332 //
1333 // Return nil if no tile variant passes Χ² filter.
1334 func (cmd *sliceNumpy) tv2homhet(cgs map[string]CompactGenome, maxv tileVariantID, remap []tileVariantID, tag, chunkstarttag tagID, seq map[tagID][]TileVariant) ([][]int8, []onehotXref) {
1335         if tag == cmd.debugTag {
1336                 tv := make([]tileVariantID, len(cmd.cgnames)*2)
1337                 for i, name := range cmd.cgnames {
1338                         copy(tv[i*2:(i+1)*2], cgs[name].Variants[(tag-chunkstarttag)*2:])
1339                 }
1340                 log.WithFields(logrus.Fields{
1341                         "cgs[i].Variants[tag*2+j]": tv,
1342                         "maxv":                     maxv,
1343                         "remap":                    remap,
1344                         "tag":                      tag,
1345                         "chunkstarttag":            chunkstarttag,
1346                 }).Info("tv2homhet()")
1347         }
1348         if maxv < 1 || (maxv < 2 && !cmd.includeVariant1) {
1349                 // everyone has the most common variant (of the variants we don't drop)
1350                 return nil, nil
1351         }
1352         tagoffset := tag - chunkstarttag
1353         coverage := 0
1354         for _, cg := range cgs {
1355                 alleles := 0
1356                 for _, v := range cg.Variants[tagoffset*2 : tagoffset*2+2] {
1357                         if v > 0 && int(v) < len(seq[tag]) && len(seq[tag][v].Sequence) > 0 {
1358                                 alleles++
1359                         }
1360                 }
1361                 if alleles == 2 {
1362                         coverage++
1363                 }
1364         }
1365         if coverage < cmd.minCoverage {
1366                 return nil, nil
1367         }
1368         obs := make([][]bool, (maxv+1)*2) // 2 slices (hom + het) for each variant#
1369         for i := range obs {
1370                 obs[i] = make([]bool, len(cmd.cgnames))
1371         }
1372         for cgid, name := range cmd.cgnames {
1373                 cgvars := cgs[name].Variants[tagoffset*2:]
1374                 tv0, tv1 := remap[cgvars[0]], remap[cgvars[1]]
1375                 for v := tileVariantID(1); v <= maxv; v++ {
1376                         if tv0 == v && tv1 == v {
1377                                 obs[v*2][cgid] = true
1378                         } else if tv0 == v || tv1 == v {
1379                                 obs[v*2+1][cgid] = true
1380                         }
1381                 }
1382         }
1383         var onehot [][]int8
1384         var xref []onehotXref
1385         for col := 2; col < len(obs); col++ {
1386                 // col 0,1 correspond to tile variant 0, i.e.,
1387                 // no-call; col 2,3 correspond to the most common
1388                 // variant; so we (normally) start at col 4.
1389                 if col < 4 && !cmd.includeVariant1 {
1390                         continue
1391                 }
1392                 p := pvalue(obs[col], cmd.chi2Cases)
1393                 if cmd.chi2PValue < 1 && !(p < cmd.chi2PValue) {
1394                         continue
1395                 }
1396                 onehot = append(onehot, bool2int8(obs[col]))
1397                 xref = append(xref, onehotXref{
1398                         tag:     tag,
1399                         variant: tileVariantID(col >> 1),
1400                         hom:     col&1 == 0,
1401                         pvalue:  p,
1402                 })
1403         }
1404         return onehot, xref
1405 }
1406
1407 func bool2int8(in []bool) []int8 {
1408         out := make([]int8, len(in))
1409         for i, v := range in {
1410                 if v {
1411                         out[i] = 1
1412                 }
1413         }
1414         return out
1415 }
1416
1417 // convert a []onehotXref with length N to a numpy-style []int32
1418 // matrix with N columns, one row per field of onehotXref struct.
1419 //
1420 // Hom/het row contains hom=0, het=1.
1421 //
1422 // P-value row contains 1000000x actual p-value.
1423 func onehotXref2int32(xrefs []onehotXref) []int32 {
1424         xcols := len(xrefs)
1425         xdata := make([]int32, 5*xcols)
1426         for i, xref := range xrefs {
1427                 xdata[i] = int32(xref.tag)
1428                 xdata[xcols+i] = int32(xref.variant)
1429                 if xref.hom {
1430                         xdata[xcols*2+i] = 1
1431                 }
1432                 xdata[xcols*3+i] = int32(xref.pvalue * 1000000)
1433                 xdata[xcols*4+i] = int32(-math.Log10(xref.pvalue) * 1000000)
1434         }
1435         return xdata
1436 }
1437
1438 // transpose onehot data from in[col][row] to numpy-style
1439 // out[row*cols+col].
1440 func onehotcols2int8(in [][]int8) []int8 {
1441         if len(in) == 0 {
1442                 return nil
1443         }
1444         cols := len(in)
1445         rows := len(in[0])
1446         out := make([]int8, rows*cols)
1447         for row := 0; row < rows; row++ {
1448                 outrow := out[row*cols:]
1449                 for col, incol := range in {
1450                         outrow[col] = incol[row]
1451                 }
1452         }
1453         return out
1454 }
1455
1456 // Return [2][]uint32{rowIndices, colIndices} indicating which
1457 // elements of matrixT[c][r] have non-zero values.
1458 func onehotChunk2Indirect(matrixT [][]int8) [2][]uint32 {
1459         var nz [2][]uint32
1460         for c, col := range matrixT {
1461                 for r, val := range col {
1462                         if val != 0 {
1463                                 nz[0] = append(nz[0], uint32(r))
1464                                 nz[1] = append(nz[1], uint32(c))
1465                         }
1466                 }
1467         }
1468         return nz
1469 }