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         err = 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         chunkStartTag := make([]tagID, len(infiles))
 364
 365         throttleMem := throttle{Max: cmd.threads} // TODO: estimate using mem and data size
 366         throttleNumpyMem := throttle{Max: cmd.threads/2 + 1}
 367         log.Info("generating annotations and numpy matrix for each slice")
 368         var errSkip = errors.New("skip infile")
 369         var done int64
 370         for infileIdx, infile := range infiles {
 371                 infileIdx, infile := infileIdx, infile
 372                 throttleMem.Go(func() error {
 373                         seq := make(map[tagID][]TileVariant, 50000)
 374                         cgs := make(map[string]CompactGenome, len(cmd.cgnames))
 375                         f, err := open(infile)
 376                         if err != nil {
 377                                 return err
 378                         }
 379                         defer f.Close()
 380                         log.Infof("%04d: reading %s", infileIdx, infile)
 381                         err = DecodeLibrary(f, strings.HasSuffix(infile, ".gz"), func(ent *LibraryEntry) error {
 382                                 for _, tv := range ent.TileVariants {
 383                                         if tv.Ref {
 384                                                 continue
 385                                         }
 386                                         if mask != nil && reftile[tv.Tag] == nil {
 387                                                 // Don't waste
 388                                                 // time/memory on
 389                                                 // masked-out tiles.
 390                                                 continue
 391                                         }
 392                                         if tv.Tag == cmd.debugTag {
 393                                                 log.Printf("infile %d %s tag %d variant %d hash %x", infileIdx, infile, tv.Tag, tv.Variant, tv.Blake2b[:3])
 394                                         }
 395                                         variants := seq[tv.Tag]
 396                                         if len(variants) == 0 {
 397                                                 variants = make([]TileVariant, 100)
 398                                         }
 399                                         for len(variants) <= int(tv.Variant) {
 400                                                 variants = append(variants, TileVariant{})
 401                                         }
 402                                         variants[int(tv.Variant)] = tv
 403                                         seq[tv.Tag] = variants
 404                                 }
 405                                 for _, cg := range ent.CompactGenomes {
 406                                         if cmd.filter.MaxTag >= 0 && cg.StartTag > tagID(cmd.filter.MaxTag) {
 407                                                 return errSkip
 408                                         }
 409                                         if !matchGenome.MatchString(cg.Name) {
 410                                                 continue
 411                                         }
 412                                         // pad to full slice size
 413                                         // to avoid out-of-bounds
 414                                         // checks later
 415                                         if sliceSize := 2 * int(cg.EndTag-cg.StartTag); len(cg.Variants) < sliceSize {
 416                                                 cg.Variants = append(cg.Variants, make([]tileVariantID, sliceSize-len(cg.Variants))...)
 417                                         }
 418                                         cgs[cg.Name] = cg
 419                                 }
 420                                 return nil
 421                         })
 422                         if err == errSkip {
 423                                 return nil
 424                         } else if err != nil {
 425                                 return err
 426                         }
 427                         tagstart := cgs[cmd.cgnames[0]].StartTag
 428                         tagend := cgs[cmd.cgnames[0]].EndTag
 429                         chunkStartTag[infileIdx] = tagstart
 430
 431                         // TODO: filters
 432
 433                         log.Infof("%04d: renumber/dedup variants for tags %d-%d", infileIdx, tagstart, tagend)
 434                         variantRemap := make([][]tileVariantID, tagend-tagstart)
 435                         throttleCPU := throttle{Max: runtime.GOMAXPROCS(0)}
 436                         for tag, variants := range seq {
 437                                 tag, variants := tag, variants
 438                                 throttleCPU.Go(func() error {
 439                                         count := make(map[[blake2b.Size256]byte]int, len(variants))
 440
 441                                         rt := reftile[tag]
 442                                         if rt != nil {
 443                                                 count[blake2b.Sum256(rt.tiledata)] = 0
 444                                         }
 445
 446                                         for cgname, cg := range cgs {
 447                                                 idx := int(tag-tagstart) * 2
 448                                                 for allele := 0; allele < 2; allele++ {
 449                                                         v := cg.Variants[idx+allele]
 450                                                         if v > 0 && len(variants[v].Sequence) > 0 {
 451                                                                 count[variants[v].Blake2b]++
 452                                                         }
 453                                                         if v > 0 && tag == cmd.debugTag {
 454                                                                 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])
 455                                                         }
 456                                                 }
 457                                         }
 458                                         // hash[i] will be the hash of
 459                                         // the variant(s) that should
 460                                         // be at rank i (0-based).
 461                                         hash := make([][blake2b.Size256]byte, 0, len(count))
 462                                         for b := range count {
 463                                                 hash = append(hash, b)
 464                                         }
 465                                         sort.Slice(hash, func(i, j int) bool {
 466                                                 bi, bj := &hash[i], &hash[j]
 467                                                 if ci, cj := count[*bi], count[*bj]; ci != cj {
 468                                                         return ci > cj
 469                                                 } else {
 470                                                         return bytes.Compare((*bi)[:], (*bj)[:]) < 0
 471                                                 }
 472                                         })
 473                                         // rank[b] will be the 1-based
 474                                         // new variant number for
 475                                         // variants whose hash is b.
 476                                         rank := make(map[[blake2b.Size256]byte]tileVariantID, len(hash))
 477                                         for i, h := range hash {
 478                                                 rank[h] = tileVariantID(i + 1)
 479                                         }
 480                                         if tag == cmd.debugTag {
 481                                                 for h, r := range rank {
 482                                                         log.Printf("tag %d rank(%x) = %v", tag, h[:3], r)
 483                                                 }
 484                                         }
 485                                         // remap[v] will be the new
 486                                         // variant number for original
 487                                         // variant number v.
 488                                         remap := make([]tileVariantID, len(variants))
 489                                         for i, tv := range variants {
 490                                                 remap[i] = rank[tv.Blake2b]
 491                                         }
 492                                         if tag == cmd.debugTag {
 493                                                 for in, out := range remap {
 494                                                         if out > 0 {
 495                                                                 log.Printf("tag %d remap %d => %d", tag, in, out)
 496                                                         }
 497                                                 }
 498                                         }
 499                                         variantRemap[tag-tagstart] = remap
 500                                         if rt != nil {
 501                                                 refrank := rank[blake2b.Sum256(rt.tiledata)]
 502                                                 if tag == cmd.debugTag {
 503                                                         log.Printf("tag %d reftile variant %d => %d", tag, rt.variant, refrank)
 504                                                 }
 505                                                 rt.variant = refrank
 506                                         }
 507                                         return nil
 508                                 })
 509                         }
 510                         throttleCPU.Wait()
 511
 512                         var onehotChunk [][]int8
 513                         var onehotXref []onehotXref
 514
 515                         annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, infileIdx)
 516                         log.Infof("%04d: writing %s", infileIdx, annotationsFilename)
 517                         annof, err := os.Create(annotationsFilename)
 518                         if err != nil {
 519                                 return err
 520                         }
 521                         annow := bufio.NewWriterSize(annof, 1<<20)
 522                         outcol := 0
 523                         for tag := tagstart; tag < tagend; tag++ {
 524                                 rt := reftile[tag]
 525                                 if rt == nil && mask != nil {
 526                                         // Excluded by specified regions
 527                                         continue
 528                                 }
 529                                 if cmd.filter.MaxTag >= 0 && tag > tagID(cmd.filter.MaxTag) {
 530                                         break
 531                                 }
 532                                 remap := variantRemap[tag-tagstart]
 533                                 maxv := tileVariantID(0)
 534                                 for _, v := range remap {
 535                                         if maxv < v {
 536                                                 maxv = v
 537                                         }
 538                                 }
 539                                 if *onehotChunked || *onehotSingle {
 540                                         onehot, xrefs := cmd.tv2homhet(cgs, maxv, remap, tag, tagstart)
 541                                         if tag == cmd.debugTag {
 542                                                 log.WithFields(logrus.Fields{
 543                                                         "onehot": onehot,
 544                                                         "xrefs":  xrefs,
 545                                                 }).Info("tv2homhet()")
 546                                         }
 547                                         onehotChunk = append(onehotChunk, onehot...)
 548                                         onehotXref = append(onehotXref, xrefs...)
 549                                 }
 550                                 if rt == nil {
 551                                         // Reference does not use any
 552                                         // variant of this tile
 553                                         outcol++
 554                                         continue
 555                                 }
 556                                 fmt.Fprintf(annow, "%d,%d,%d,=,%s,%d,,,\n", tag, outcol, rt.variant, rt.seqname, rt.pos)
 557                                 variants := seq[tag]
 558                                 reftilestr := strings.ToUpper(string(rt.tiledata))
 559
 560                                 done := make([]bool, maxv+1)
 561                                 variantDiffs := make([][]hgvs.Variant, maxv+1)
 562                                 for v, tv := range variants {
 563                                         v := remap[v]
 564                                         if v == rt.variant || done[v] {
 565                                                 continue
 566                                         } else {
 567                                                 done[v] = true
 568                                         }
 569                                         if len(tv.Sequence) < taglen || !bytes.HasSuffix(rt.tiledata, tv.Sequence[len(tv.Sequence)-taglen:]) {
 570                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 571                                                 continue
 572                                         }
 573                                         if lendiff := len(rt.tiledata) - len(tv.Sequence); lendiff < -1000 || lendiff > 1000 {
 574                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 575                                                 continue
 576                                         }
 577                                         diffs, _ := hgvs.Diff(reftilestr, strings.ToUpper(string(tv.Sequence)), 0)
 578                                         for i := range diffs {
 579                                                 diffs[i].Position += rt.pos
 580                                         }
 581                                         for _, diff := range diffs {
 582                                                 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)
 583                                         }
 584                                         if *hgvsChunked {
 585                                                 variantDiffs[v] = diffs
 586                                         }
 587                                 }
 588                                 if *hgvsChunked {
 589                                         // We can now determine, for each HGVS
 590                                         // variant (diff) in this reftile
 591                                         // region, whether a given genome
 592                                         // phase/allele (1) has the variant, (0) has
 593                                         // =ref or a different variant in that
 594                                         // position, or (-1) is lacking
 595                                         // coverage / couldn't be diffed.
 596                                         hgvsCol := hgvsColSet{}
 597                                         for _, diffs := range variantDiffs {
 598                                                 for _, diff := range diffs {
 599                                                         if _, ok := hgvsCol[diff]; ok {
 600                                                                 continue
 601                                                         }
 602                                                         hgvsCol[diff] = [2][]int8{
 603                                                                 make([]int8, len(cmd.cgnames)),
 604                                                                 make([]int8, len(cmd.cgnames)),
 605                                                         }
 606                                                 }
 607                                         }
 608                                         for row, name := range cmd.cgnames {
 609                                                 variants := cgs[name].Variants[(tag-tagstart)*2:]
 610                                                 for ph := 0; ph < 2; ph++ {
 611                                                         v := variants[ph]
 612                                                         if int(v) >= len(remap) {
 613                                                                 v = 0
 614                                                         } else {
 615                                                                 v = remap[v]
 616                                                         }
 617                                                         if v == rt.variant {
 618                                                                 // hgvsCol[*][ph][row] is already 0
 619                                                         } else if len(variantDiffs[v]) == 0 {
 620                                                                 // lacking coverage / couldn't be diffed
 621                                                                 for _, col := range hgvsCol {
 622                                                                         col[ph][row] = -1
 623                                                                 }
 624                                                         } else {
 625                                                                 for _, diff := range variantDiffs[v] {
 626                                                                         hgvsCol[diff][ph][row] = 1
 627                                                                 }
 628                                                         }
 629                                                 }
 630                                         }
 631                                         for diff, colpair := range hgvsCol {
 632                                                 allele2homhet(colpair)
 633                                                 if !cmd.filterHGVScolpair(colpair) {
 634                                                         delete(hgvsCol, diff)
 635                                                 }
 636                                         }
 637                                         if len(hgvsCol) > 0 {
 638                                                 encodeHGVSTodo[rt.seqname] <- hgvsCol
 639                                         }
 640                                 }
 641                                 outcol++
 642                         }
 643                         err = annow.Flush()
 644                         if err != nil {
 645                                 return err
 646                         }
 647                         err = annof.Close()
 648                         if err != nil {
 649                                 return err
 650                         }
 651
 652                         if *onehotChunked {
 653                                 // transpose onehotChunk[col][row] to numpy[row*ncols+col]
 654                                 rows := len(cmd.cgnames)
 655                                 cols := len(onehotChunk)
 656                                 log.Infof("%04d: preparing onehot numpy (rows=%d, cols=%d, mem=%d)", infileIdx, rows, cols, rows*cols)
 657                                 throttleNumpyMem.Acquire()
 658                                 out := onehotcols2int8(onehotChunk)
 659                                 fnm := fmt.Sprintf("%s/onehot.%04d.npy", *outputDir, infileIdx)
 660                                 err = writeNumpyInt8(fnm, out, rows, cols)
 661                                 if err != nil {
 662                                         return err
 663                                 }
 664                                 fnm = fmt.Sprintf("%s/onehot-columns.%04d.npy", *outputDir, infileIdx)
 665                                 err = writeNumpyInt32(fnm, onehotXref2int32(onehotXref), 4, len(onehotXref))
 666                                 if err != nil {
 667                                         return err
 668                                 }
 669                                 debug.FreeOSMemory()
 670                                 throttleNumpyMem.Release()
 671                         }
 672                         if *onehotSingle {
 673                                 onehotIndirect[infileIdx] = onehotChunk2Indirect(onehotChunk)
 674                                 onehotChunkSize[infileIdx] = uint32(len(onehotChunk))
 675                                 onehotXrefs[infileIdx] = onehotXref
 676                                 n := len(onehotIndirect[infileIdx][0])
 677                                 log.Infof("%04d: keeping onehot coordinates in memory (n=%d, mem=%d)", infileIdx, n, n*8*2)
 678                         }
 679                         if !(*onehotSingle || *onehotChunked) || *mergeOutput || *hgvsSingle {
 680                                 log.Infof("%04d: preparing numpy (rows=%d, cols=%d)", infileIdx, len(cmd.cgnames), 2*outcol)
 681                                 throttleNumpyMem.Acquire()
 682                                 rows := len(cmd.cgnames)
 683                                 cols := 2 * outcol
 684                                 out := make([]int16, rows*cols)
 685                                 for row, name := range cmd.cgnames {
 686                                         outidx := row * cols
 687                                         for col, v := range cgs[name].Variants {
 688                                                 tag := tagstart + tagID(col/2)
 689                                                 if cmd.filter.MaxTag >= 0 && tag > tagID(cmd.filter.MaxTag) {
 690                                                         break
 691                                                 }
 692                                                 if mask != nil && reftile[tag] == nil {
 693                                                         continue
 694                                                 }
 695                                                 if v == 0 {
 696                                                         out[outidx] = 0 // tag not found / spanning tile
 697                                                 } else if variants, ok := seq[tag]; ok && int(v) < len(variants) && len(variants[v].Sequence) > 0 {
 698                                                         out[outidx] = int16(variantRemap[tag-tagstart][v])
 699                                                 } else {
 700                                                         out[outidx] = -1 // low quality tile variant
 701                                                 }
 702                                                 if tag == cmd.debugTag {
 703                                                         log.Printf("tag %d row %d col %d outidx %d v %d out %d", tag, row, col, outidx, v, out[outidx])
 704                                                 }
 705                                                 outidx++
 706                                         }
 707                                 }
 708                                 seq = nil
 709                                 cgs = nil
 710                                 debug.FreeOSMemory()
 711                                 throttleNumpyMem.Release()
 712                                 if *mergeOutput || *hgvsSingle {
 713                                         log.Infof("%04d: matrix fragment %d rows x %d cols", infileIdx, rows, cols)
 714                                         toMerge[infileIdx] = out
 715                                 }
 716                                 if !*mergeOutput && !*onehotChunked && !*onehotSingle {
 717                                         fnm := fmt.Sprintf("%s/matrix.%04d.npy", *outputDir, infileIdx)
 718                                         err = writeNumpyInt16(fnm, out, rows, cols)
 719                                         if err != nil {
 720                                                 return err
 721                                         }
 722                                 }
 723                         }
 724                         debug.FreeOSMemory()
 725                         log.Infof("%s: done (%d/%d)", infile, int(atomic.AddInt64(&done, 1)), len(infiles))
 726                         return nil
 727                 })
 728         }
 729         if err = throttleMem.Wait(); err != nil {
 730                 return 1
 731         }
 732
 733         if *hgvsChunked {
 734                 log.Info("flushing hgvsCols temp files")
 735                 for seqname := range refseq {
 736                         close(encodeHGVSTodo[seqname])
 737                 }
 738                 err = encodeHGVS.Wait()
 739                 if err != nil {
 740                         return 1
 741                 }
 742                 for seqname := range refseq {
 743                         log.Infof("%s: reading hgvsCols from temp file", seqname)
 744                         f := tmpHGVSCols[seqname]
 745                         _, err = f.Seek(0, io.SeekStart)
 746                         if err != nil {
 747                                 return 1
 748                         }
 749                         var hgvsCols hgvsColSet
 750                         dec := gob.NewDecoder(bufio.NewReaderSize(f, 1<<24))
 751                         for err == nil {
 752                                 err = dec.Decode(&hgvsCols)
 753                         }
 754                         if err != io.EOF {
 755                                 return 1
 756                         }
 757                         log.Infof("%s: sorting %d hgvs variants", seqname, len(hgvsCols))
 758                         variants := make([]hgvs.Variant, 0, len(hgvsCols))
 759                         for v := range hgvsCols {
 760                                 variants = append(variants, v)
 761                         }
 762                         sort.Slice(variants, func(i, j int) bool {
 763                                 vi, vj := &variants[i], &variants[j]
 764                                 if vi.Position != vj.Position {
 765                                         return vi.Position < vj.Position
 766                                 } else if vi.Ref != vj.Ref {
 767                                         return vi.Ref < vj.Ref
 768                                 } else {
 769                                         return vi.New < vj.New
 770                                 }
 771                         })
 772                         rows := len(cmd.cgnames)
 773                         cols := len(variants) * 2
 774                         log.Infof("%s: building hgvs matrix (rows=%d, cols=%d, mem=%d)", seqname, rows, cols, rows*cols)
 775                         out := make([]int8, rows*cols)
 776                         for varIdx, variant := range variants {
 777                                 hgvsCols := hgvsCols[variant]
 778                                 for row := range cmd.cgnames {
 779                                         for ph := 0; ph < 2; ph++ {
 780                                                 out[row*cols+varIdx+ph] = hgvsCols[ph][row]
 781                                         }
 782                                 }
 783                         }
 784                         err = writeNumpyInt8(fmt.Sprintf("%s/hgvs.%s.npy", *outputDir, seqname), out, rows, cols)
 785                         if err != nil {
 786                                 return 1
 787                         }
 788                         out = nil
 789
 790                         fnm := fmt.Sprintf("%s/hgvs.%s.annotations.csv", *outputDir, seqname)
 791                         log.Infof("%s: writing hgvs column labels to %s", seqname, fnm)
 792                         var hgvsLabels bytes.Buffer
 793                         for varIdx, variant := range variants {
 794                                 fmt.Fprintf(&hgvsLabels, "%d,%s:g.%s\n", varIdx, seqname, variant.String())
 795                         }
 796                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0666)
 797                         if err != nil {
 798                                 return 1
 799                         }
 800                 }
 801         }
 802
 803         if *mergeOutput || *hgvsSingle {
 804                 var annow *bufio.Writer
 805                 var annof *os.File
 806                 if *mergeOutput {
 807                         annoFilename := fmt.Sprintf("%s/matrix.annotations.csv", *outputDir)
 808                         annof, err = os.Create(annoFilename)
 809                         if err != nil {
 810                                 return 1
 811                         }
 812                         annow = bufio.NewWriterSize(annof, 1<<20)
 813                 }
 814
 815                 rows := len(cmd.cgnames)
 816                 cols := 0
 817                 for _, chunk := range toMerge {
 818                         cols += len(chunk) / rows
 819                 }
 820                 log.Infof("merging output matrix (rows=%d, cols=%d, mem=%d) and annotations", rows, cols, rows*cols*2)
 821                 var out []int16
 822                 if *mergeOutput {
 823                         out = make([]int16, rows*cols)
 824                 }
 825                 hgvsCols := map[string][2][]int16{} // hgvs -> [[g0,g1,g2,...], [g0,g1,g2,...]] (slice of genomes for each phase)
 826                 startcol := 0
 827                 for outIdx, chunk := range toMerge {
 828                         chunkcols := len(chunk) / rows
 829                         if *mergeOutput {
 830                                 for row := 0; row < rows; row++ {
 831                                         copy(out[row*cols+startcol:], chunk[row*chunkcols:(row+1)*chunkcols])
 832                                 }
 833                         }
 834                         toMerge[outIdx] = nil
 835
 836                         annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, outIdx)
 837                         log.Infof("reading %s", annotationsFilename)
 838                         buf, err := os.ReadFile(annotationsFilename)
 839                         if err != nil {
 840                                 return 1
 841                         }
 842                         if *mergeOutput {
 843                                 err = os.Remove(annotationsFilename)
 844                                 if err != nil {
 845                                         return 1
 846                                 }
 847                         }
 848                         for _, line := range bytes.Split(buf, []byte{'\n'}) {
 849                                 if len(line) == 0 {
 850                                         continue
 851                                 }
 852                                 fields := bytes.SplitN(line, []byte{','}, 9)
 853                                 tag, _ := strconv.Atoi(string(fields[0]))
 854                                 incol, _ := strconv.Atoi(string(fields[1]))
 855                                 tileVariant, _ := strconv.Atoi(string(fields[2]))
 856                                 hgvsID := string(fields[3])
 857                                 seqname := string(fields[4])
 858                                 pos, _ := strconv.Atoi(string(fields[5]))
 859                                 refseq := fields[6]
 860                                 if hgvsID == "" {
 861                                         // Null entry for un-diffable
 862                                         // tile variant
 863                                         continue
 864                                 }
 865                                 if hgvsID == "=" {
 866                                         // Null entry for ref tile
 867                                         continue
 868                                 }
 869                                 if mask != nil && !mask.Check(strings.TrimPrefix(seqname, "chr"), pos, pos+len(refseq)) {
 870                                         // The tile intersects one of
 871                                         // the selected regions, but
 872                                         // this particular HGVS
 873                                         // variant does not.
 874                                         continue
 875                                 }
 876                                 hgvsColPair := hgvsCols[hgvsID]
 877                                 if hgvsColPair[0] == nil {
 878                                         // values in new columns start
 879                                         // out as -1 ("no data yet")
 880                                         // or 0 ("=ref") here, may
 881                                         // change to 1 ("hgvs variant
 882                                         // present") below, either on
 883                                         // this line or a future line.
 884                                         hgvsColPair = [2][]int16{make([]int16, len(cmd.cgnames)), make([]int16, len(cmd.cgnames))}
 885                                         rt, ok := reftile[tagID(tag)]
 886                                         if !ok {
 887                                                 err = fmt.Errorf("bug: seeing annotations for tag %d, but it has no reftile entry", tag)
 888                                                 return 1
 889                                         }
 890                                         for ph := 0; ph < 2; ph++ {
 891                                                 for row := 0; row < rows; row++ {
 892                                                         v := chunk[row*chunkcols+incol*2+ph]
 893                                                         if tileVariantID(v) == rt.variant {
 894                                                                 hgvsColPair[ph][row] = 0
 895                                                         } else {
 896                                                                 hgvsColPair[ph][row] = -1
 897                                                         }
 898                                                 }
 899                                         }
 900                                         hgvsCols[hgvsID] = hgvsColPair
 901                                         if annow != nil {
 902                                                 hgvsref := hgvs.Variant{
 903                                                         Position: pos,
 904                                                         Ref:      string(refseq),
 905                                                         New:      string(refseq),
 906                                                 }
 907                                                 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])
 908                                         }
 909                                 }
 910                                 if annow != nil {
 911                                         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])
 912                                 }
 913                                 for ph := 0; ph < 2; ph++ {
 914                                         for row := 0; row < rows; row++ {
 915                                                 v := chunk[row*chunkcols+incol*2+ph]
 916                                                 if int(v) == tileVariant {
 917                                                         hgvsColPair[ph][row] = 1
 918                                                 }
 919                                         }
 920                                 }
 921                         }
 922
 923                         startcol += chunkcols
 924                 }
 925                 if *mergeOutput {
 926                         err = annow.Flush()
 927                         if err != nil {
 928                                 return 1
 929                         }
 930                         err = annof.Close()
 931                         if err != nil {
 932                                 return 1
 933                         }
 934                         err = writeNumpyInt16(fmt.Sprintf("%s/matrix.npy", *outputDir), out, rows, cols)
 935                         if err != nil {
 936                                 return 1
 937                         }
 938                 }
 939                 out = nil
 940
 941                 if *hgvsSingle {
 942                         cols = len(hgvsCols) * 2
 943                         log.Printf("building hgvs-based matrix: %d rows x %d cols", rows, cols)
 944                         out = make([]int16, rows*cols)
 945                         hgvsIDs := make([]string, 0, cols/2)
 946                         for hgvsID := range hgvsCols {
 947                                 hgvsIDs = append(hgvsIDs, hgvsID)
 948                         }
 949                         sort.Strings(hgvsIDs)
 950                         var hgvsLabels bytes.Buffer
 951                         for idx, hgvsID := range hgvsIDs {
 952                                 fmt.Fprintf(&hgvsLabels, "%d,%s\n", idx, hgvsID)
 953                                 for ph := 0; ph < 2; ph++ {
 954                                         hgvscol := hgvsCols[hgvsID][ph]
 955                                         for row, val := range hgvscol {
 956                                                 out[row*cols+idx*2+ph] = val
 957                                         }
 958                                 }
 959                         }
 960                         err = writeNumpyInt16(fmt.Sprintf("%s/hgvs.npy", *outputDir), out, rows, cols)
 961                         if err != nil {
 962                                 return 1
 963                         }
 964
 965                         fnm := fmt.Sprintf("%s/hgvs.annotations.csv", *outputDir)
 966                         log.Printf("writing hgvs labels: %s", fnm)
 967                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0777)
 968                         if err != nil {
 969                                 return 1
 970                         }
 971                 }
 972         }
 973         if *onehotSingle {
 974                 nzCount := 0
 975                 for _, part := range onehotIndirect {
 976                         nzCount += len(part[0])
 977                 }
 978                 onehot := make([]uint32, nzCount*2) // [r,r,r,...,c,c,c,...]
 979                 var xrefs []onehotXref
 980                 chunkOffset := uint32(0)
 981                 outcol := 0
 982                 for i, part := range onehotIndirect {
 983                         for i := range part[1] {
 984                                 part[1][i] += chunkOffset
 985                         }
 986                         copy(onehot[outcol:], part[0])
 987                         copy(onehot[outcol+nzCount:], part[1])
 988                         xrefs = append(xrefs, onehotXrefs[i]...)
 989
 990                         outcol += len(part[0])
 991                         chunkOffset += onehotChunkSize[i]
 992
 993                         part[0] = nil
 994                         part[1] = nil
 995                         onehotXrefs[i] = nil
 996                         debug.FreeOSMemory()
 997                 }
 998                 fnm := fmt.Sprintf("%s/onehot.npy", *outputDir)
 999                 err = writeNumpyUint32(fnm, onehot, 2, nzCount)
1000                 if err != nil {
1001                         return 1
1002                 }
1003                 fnm = fmt.Sprintf("%s/onehot-columns.npy", *outputDir)
1004                 err = writeNumpyInt32(fnm, onehotXref2int32(xrefs), 5, len(xrefs))
1005                 if err != nil {
1006                         return 1
1007                 }
1008         }
1009         if !*mergeOutput && !*onehotChunked && !*onehotSingle {
1010                 tagoffsetFilename := *outputDir + "/chunk-tag-offset.csv"
1011                 log.Infof("writing tag offsets to %s", tagoffsetFilename)
1012                 var f *os.File
1013                 f, err = os.Create(tagoffsetFilename)
1014                 if err != nil {
1015                         return 1
1016                 }
1017                 defer f.Close()
1018                 for idx, offset := range chunkStartTag {
1019                         _, err = fmt.Fprintf(f, "%q,%d\n", fmt.Sprintf("matrix.%04d.npy", idx), offset)
1020                         if err != nil {
1021                                 err = fmt.Errorf("write %s: %w", tagoffsetFilename, err)
1022                                 return 1
1023                         }
1024                 }
1025                 err = f.Close()
1026                 if err != nil {
1027                         err = fmt.Errorf("close %s: %w", tagoffsetFilename, err)
1028                         return 1
1029                 }
1030         }
1031         return 0
1032 }
1033
1034 // Read case/control files, remove non-case/control entries from
1035 // cmd.cgnames, and build cmd.chi2Cases.
1036 func (cmd *sliceNumpy) useCaseControlFiles() error {
1037         if cmd.chi2CaseControlFile == "" {
1038                 return nil
1039         }
1040         infiles, err := allFiles(cmd.chi2CaseControlFile, nil)
1041         if err != nil {
1042                 return err
1043         }
1044         // index in cmd.cgnames => case(true) / control(false)
1045         cc := map[int]bool{}
1046         for _, infile := range infiles {
1047                 f, err := open(infile)
1048                 if err != nil {
1049                         return err
1050                 }
1051                 buf, err := io.ReadAll(f)
1052                 f.Close()
1053                 if err != nil {
1054                         return err
1055                 }
1056                 ccCol := -1
1057                 for _, tsv := range bytes.Split(buf, []byte{'\n'}) {
1058                         if len(tsv) == 0 {
1059                                 continue
1060                         }
1061                         split := strings.Split(string(tsv), "\t")
1062                         if ccCol < 0 {
1063                                 // header row
1064                                 for col, name := range split {
1065                                         if name == cmd.chi2CaseControlColumn {
1066                                                 ccCol = col
1067                                                 break
1068                                         }
1069                                 }
1070                                 if ccCol < 0 {
1071                                         return fmt.Errorf("%s: no column named %q in header row %q", infile, cmd.chi2CaseControlColumn, tsv)
1072                                 }
1073                                 continue
1074                         }
1075                         if len(split) <= ccCol {
1076                                 continue
1077                         }
1078                         pattern := split[0]
1079                         found := -1
1080                         for i, name := range cmd.cgnames {
1081                                 if strings.Contains(name, pattern) {
1082                                         if found >= 0 {
1083                                                 log.Warnf("pattern %q in %s matches multiple genome IDs (%qs, %q)", pattern, infile, cmd.cgnames[found], name)
1084                                         }
1085                                         found = i
1086                                 }
1087                         }
1088                         if found < 0 {
1089                                 log.Warnf("pattern %q in %s does not match any genome IDs", pattern, infile)
1090                                 continue
1091                         }
1092                         if split[ccCol] == "0" {
1093                                 cc[found] = false
1094                         }
1095                         if split[ccCol] == "1" {
1096                                 cc[found] = true
1097                         }
1098                 }
1099         }
1100         allnames := cmd.cgnames
1101         cmd.cgnames = nil
1102         cmd.chi2Cases = nil
1103         ncases := 0
1104         for i, name := range allnames {
1105                 if cc, ok := cc[i]; ok {
1106                         cmd.cgnames = append(cmd.cgnames, name)
1107                         cmd.chi2Cases = append(cmd.chi2Cases, cc)
1108                         if cc {
1109                                 ncases++
1110                         }
1111                 }
1112         }
1113         log.Printf("%d cases, %d controls, %d neither (dropped)", ncases, len(cmd.cgnames)-ncases, len(allnames)-len(cmd.cgnames))
1114         return nil
1115 }
1116
1117 func (cmd *sliceNumpy) filterHGVScolpair(colpair [2][]int8) bool {
1118         if cmd.chi2PValue >= 1 {
1119                 return true
1120         }
1121         col0 := make([]bool, 0, len(cmd.chi2Cases))
1122         col1 := make([]bool, 0, len(cmd.chi2Cases))
1123         cases := make([]bool, 0, len(cmd.chi2Cases))
1124         for i, c := range cmd.chi2Cases {
1125                 if colpair[0][i] < 0 {
1126                         continue
1127                 }
1128                 col0 = append(col0, colpair[0][i] != 0)
1129                 col1 = append(col1, colpair[1][i] != 0)
1130                 cases = append(cases, c)
1131         }
1132         return len(cases) >= cmd.minCoverage &&
1133                 (pvalue(col0, cases) <= cmd.chi2PValue || pvalue(col1, cases) <= cmd.chi2PValue)
1134 }
1135
1136 func writeNumpyUint32(fnm string, out []uint32, rows, cols int) error {
1137         output, err := os.Create(fnm)
1138         if err != nil {
1139                 return err
1140         }
1141         defer output.Close()
1142         bufw := bufio.NewWriterSize(output, 1<<26)
1143         npw, err := gonpy.NewWriter(nopCloser{bufw})
1144         if err != nil {
1145                 return err
1146         }
1147         log.WithFields(log.Fields{
1148                 "filename": fnm,
1149                 "rows":     rows,
1150                 "cols":     cols,
1151                 "bytes":    rows * cols * 4,
1152         }).Infof("writing numpy: %s", fnm)
1153         npw.Shape = []int{rows, cols}
1154         npw.WriteUint32(out)
1155         err = bufw.Flush()
1156         if err != nil {
1157                 return err
1158         }
1159         return output.Close()
1160 }
1161
1162 func writeNumpyInt32(fnm string, out []int32, rows, cols int) error {
1163         output, err := os.Create(fnm)
1164         if err != nil {
1165                 return err
1166         }
1167         defer output.Close()
1168         bufw := bufio.NewWriterSize(output, 1<<26)
1169         npw, err := gonpy.NewWriter(nopCloser{bufw})
1170         if err != nil {
1171                 return err
1172         }
1173         log.WithFields(log.Fields{
1174                 "filename": fnm,
1175                 "rows":     rows,
1176                 "cols":     cols,
1177                 "bytes":    rows * cols * 4,
1178         }).Infof("writing numpy: %s", fnm)
1179         npw.Shape = []int{rows, cols}
1180         npw.WriteInt32(out)
1181         err = bufw.Flush()
1182         if err != nil {
1183                 return err
1184         }
1185         return output.Close()
1186 }
1187
1188 func writeNumpyInt16(fnm string, out []int16, rows, cols int) error {
1189         output, err := os.Create(fnm)
1190         if err != nil {
1191                 return err
1192         }
1193         defer output.Close()
1194         bufw := bufio.NewWriterSize(output, 1<<26)
1195         npw, err := gonpy.NewWriter(nopCloser{bufw})
1196         if err != nil {
1197                 return err
1198         }
1199         log.WithFields(log.Fields{
1200                 "filename": fnm,
1201                 "rows":     rows,
1202                 "cols":     cols,
1203                 "bytes":    rows * cols * 2,
1204         }).Infof("writing numpy: %s", fnm)
1205         npw.Shape = []int{rows, cols}
1206         npw.WriteInt16(out)
1207         err = bufw.Flush()
1208         if err != nil {
1209                 return err
1210         }
1211         return output.Close()
1212 }
1213
1214 func writeNumpyInt8(fnm string, out []int8, rows, cols int) error {
1215         output, err := os.Create(fnm)
1216         if err != nil {
1217                 return err
1218         }
1219         defer output.Close()
1220         bufw := bufio.NewWriterSize(output, 1<<26)
1221         npw, err := gonpy.NewWriter(nopCloser{bufw})
1222         if err != nil {
1223                 return err
1224         }
1225         log.WithFields(log.Fields{
1226                 "filename": fnm,
1227                 "rows":     rows,
1228                 "cols":     cols,
1229                 "bytes":    rows * cols,
1230         }).Infof("writing numpy: %s", fnm)
1231         npw.Shape = []int{rows, cols}
1232         npw.WriteInt8(out)
1233         err = bufw.Flush()
1234         if err != nil {
1235                 return err
1236         }
1237         return output.Close()
1238 }
1239
1240 func allele2homhet(colpair [2][]int8) {
1241         a, b := colpair[0], colpair[1]
1242         for i, av := range a {
1243                 bv := b[i]
1244                 if av < 0 || bv < 0 {
1245                         // no-call
1246                         a[i], b[i] = -1, -1
1247                 } else if av > 0 && bv > 0 {
1248                         // hom
1249                         a[i], b[i] = 1, 0
1250                 } else if av > 0 || bv > 0 {
1251                         // het
1252                         a[i], b[i] = 0, 1
1253                 } else {
1254                         // ref (or a different variant in same position)
1255                         // (this is a no-op) a[i], b[i] = 0, 0
1256                 }
1257         }
1258 }
1259
1260 type onehotXref struct {
1261         tag     tagID
1262         variant tileVariantID
1263         hom     bool
1264         pvalue  float64
1265 }
1266
1267 const onehotXrefSize = unsafe.Sizeof(onehotXref{})
1268
1269 // Build onehot matrix (m[tileVariantIndex][genome] == 0 or 1) for all
1270 // variants of a single tile/tag#.
1271 //
1272 // Return nil if no tile variant passes Χ² filter.
1273 func (cmd *sliceNumpy) tv2homhet(cgs map[string]CompactGenome, maxv tileVariantID, remap []tileVariantID, tag, chunkstarttag tagID) ([][]int8, []onehotXref) {
1274         if tag == cmd.debugTag {
1275                 tv := make([]tileVariantID, len(cmd.cgnames)*2)
1276                 for i, name := range cmd.cgnames {
1277                         copy(tv[i*2:(i+1)*2], cgs[name].Variants[(tag-chunkstarttag)*2:])
1278                 }
1279                 log.WithFields(logrus.Fields{
1280                         "cgs[i].Variants[tag*2+j]": tv,
1281                         "maxv":                     maxv,
1282                         "remap":                    remap,
1283                         "tag":                      tag,
1284                         "chunkstarttag":            chunkstarttag,
1285                 }).Info("tv2homhet()")
1286         }
1287         if maxv < 1 || (maxv < 2 && !cmd.includeVariant1) {
1288                 // everyone has the most common variant (of the variants we don't drop)
1289                 return nil, nil
1290         }
1291         tagoffset := tag - chunkstarttag
1292         coverage := 0
1293         for _, cg := range cgs {
1294                 if cg.Variants[tagoffset*2] > 0 && cg.Variants[tagoffset*2+1] > 0 {
1295                         coverage++
1296                 }
1297         }
1298         if coverage < cmd.minCoverage {
1299                 return nil, nil
1300         }
1301         obs := make([][]bool, (maxv+1)*2) // 2 slices (hom + het) for each variant#
1302         for i := range obs {
1303                 obs[i] = make([]bool, len(cmd.cgnames))
1304         }
1305         for cgid, name := range cmd.cgnames {
1306                 cgvars := cgs[name].Variants[tagoffset*2:]
1307                 tv0, tv1 := remap[cgvars[0]], remap[cgvars[1]]
1308                 for v := tileVariantID(1); v <= maxv; v++ {
1309                         if tv0 == v && tv1 == v {
1310                                 obs[v*2][cgid] = true
1311                         } else if tv0 == v || tv1 == v {
1312                                 obs[v*2+1][cgid] = true
1313                         }
1314                 }
1315         }
1316         var onehot [][]int8
1317         var xref []onehotXref
1318         for col := 2; col < len(obs); col++ {
1319                 // col 0,1 correspond to tile variant 0, i.e.,
1320                 // no-call; col 2,3 correspond to the most common
1321                 // variant; so we (normally) start at col 4.
1322                 if col < 4 && !cmd.includeVariant1 {
1323                         continue
1324                 }
1325                 p := pvalue(obs[col], cmd.chi2Cases)
1326                 if cmd.chi2PValue < 1 && !(p < cmd.chi2PValue) {
1327                         continue
1328                 }
1329                 onehot = append(onehot, bool2int8(obs[col]))
1330                 xref = append(xref, onehotXref{
1331                         tag:     tag,
1332                         variant: tileVariantID(col >> 1),
1333                         hom:     col&1 == 0,
1334                         pvalue:  p,
1335                 })
1336         }
1337         return onehot, xref
1338 }
1339
1340 func bool2int8(in []bool) []int8 {
1341         out := make([]int8, len(in))
1342         for i, v := range in {
1343                 if v {
1344                         out[i] = 1
1345                 }
1346         }
1347         return out
1348 }
1349
1350 // convert a []onehotXref with length N to a numpy-style []int32
1351 // matrix with N columns, one row per field of onehotXref struct.
1352 //
1353 // Hom/het row contains hom=0, het=1.
1354 //
1355 // P-value row contains 1000000x actual p-value.
1356 func onehotXref2int32(xrefs []onehotXref) []int32 {
1357         xcols := len(xrefs)
1358         xdata := make([]int32, 5*xcols)
1359         for i, xref := range xrefs {
1360                 xdata[i] = int32(xref.tag)
1361                 xdata[xcols+i] = int32(xref.variant)
1362                 if xref.hom {
1363                         xdata[xcols*2+i] = 1
1364                 }
1365                 xdata[xcols*3+i] = int32(xref.pvalue * 1000000)
1366                 xdata[xcols*4+i] = int32(-math.Log10(xref.pvalue) * 1000000)
1367         }
1368         return xdata
1369 }
1370
1371 // transpose onehot data from in[col][row] to numpy-style
1372 // out[row*cols+col].
1373 func onehotcols2int8(in [][]int8) []int8 {
1374         if len(in) == 0 {
1375                 return nil
1376         }
1377         cols := len(in)
1378         rows := len(in[0])
1379         out := make([]int8, rows*cols)
1380         for row := 0; row < rows; row++ {
1381                 outrow := out[row*cols:]
1382                 for col, incol := range in {
1383                         outrow[col] = incol[row]
1384                 }
1385         }
1386         return out
1387 }
1388
1389 // Return [2][]uint32{rowIndices, colIndices} indicating which
1390 // elements of matrixT[c][r] have non-zero values.
1391 func onehotChunk2Indirect(matrixT [][]int8) [2][]uint32 {
1392         var nz [2][]uint32
1393         for c, col := range matrixT {
1394                 for r, val := range col {
1395                         if val != 0 {
1396                                 nz[0] = append(nz[0], uint32(r))
1397                                 nz[1] = append(nz[1], uint32(c))
1398                         }
1399                 }
1400         }
1401         return nz
1402 }