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         "encoding/json"
  12         "errors"
  13         "flag"
  14         "fmt"
  15         "io"
  16         "io/ioutil"
  17         "math"
  18         "net/http"
  19         _ "net/http/pprof"
  20         "os"
  21         "regexp"
  22         "runtime"
  23         "runtime/debug"
  24         "sort"
  25         "strconv"
  26         "strings"
  27         "sync/atomic"
  28         "unsafe"
  29
  30         "git.arvados.org/arvados.git/sdk/go/arvados"
  31         "github.com/arvados/lightning/hgvs"
  32         "github.com/james-bowman/nlp"
  33         "github.com/kshedden/gonpy"
  34         "github.com/sirupsen/logrus"
  35         log "github.com/sirupsen/logrus"
  36         "golang.org/x/crypto/blake2b"
  37         "gonum.org/v1/gonum/mat"
  38 )
  39
  40 const annotationMaxTileSpan = 100
  41
  42 type sliceNumpy struct {
  43         filter             filter
  44         threads            int
  45         chi2Cases          []bool
  46         chi2PValue         float64
  47         pvalueMinFrequency float64
  48         maxFrequency       float64
  49         pcaComponents      int
  50         minCoverage        int
  51         includeVariant1    bool
  52         debugTag           tagID
  53
  54         cgnames         []string
  55         samples         []sampleInfo
  56         trainingSet     []int // samples index => training set index, or -1 if not in training set
  57         trainingSetSize int
  58         pvalue          func(onehot []bool) float64
  59         pvalueCallCount int64
  60 }
  61
  62 func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, stdout, stderr io.Writer) int {
  63         err := cmd.run(prog, args, stdin, stdout, stderr)
  64         if err != nil {
  65                 fmt.Fprintf(stderr, "%s\n", err)
  66                 return 1
  67         }
  68         return 0
  69 }
  70
  71 func (cmd *sliceNumpy) run(prog string, args []string, stdin io.Reader, stdout, stderr io.Writer) error {
  72         flags := flag.NewFlagSet("", flag.ContinueOnError)
  73         flags.SetOutput(stderr)
  74         pprof := flags.String("pprof", "", "serve Go profile data at http://`[addr]:port`")
  75         runlocal := flags.Bool("local", false, "run on local host (default: run in an arvados container)")
  76         arvadosRAM := flags.Int("arvados-ram", 750000000000, "amount of memory to request for arvados container (`bytes`)")
  77         arvadosVCPUs := flags.Int("arvados-vcpus", 96, "number of VCPUs to request for arvados container")
  78         projectUUID := flags.String("project", "", "project `UUID` for output data")
  79         priority := flags.Int("priority", 500, "container request priority")
  80         preemptible := flags.Bool("preemptible", true, "request preemptible instance")
  81         inputDir := flags.String("input-dir", "./in", "input `directory`")
  82         outputDir := flags.String("output-dir", "./out", "output `directory`")
  83         ref := flags.String("ref", "", "reference name (if blank, choose last one that appears in input)")
  84         regionsFilename := flags.String("regions", "", "only output columns/annotations that intersect regions in specified bed `file`")
  85         expandRegions := flags.Int("expand-regions", 0, "expand specified regions by `N` base pairs on each side`")
  86         mergeOutput := flags.Bool("merge-output", false, "merge output into one matrix.npy and one matrix.annotations.csv")
  87         hgvsSingle := flags.Bool("single-hgvs-matrix", false, "also generate hgvs-based matrix")
  88         hgvsChunked := flags.Bool("chunked-hgvs-matrix", false, "also generate hgvs-based matrix per chromosome")
  89         onehotSingle := flags.Bool("single-onehot", false, "generate one-hot tile-based matrix")
  90         onehotChunked := flags.Bool("chunked-onehot", false, "generate one-hot tile-based matrix per input chunk")
  91         samplesFilename := flags.String("samples", "", "`samples.csv` file with training/validation and case/control groups (see 'lightning choose-samples')")
  92         caseControlOnly := flags.Bool("case-control-only", false, "drop samples that are not in case/control groups")
  93         onlyPCA := flags.Bool("pca", false, "run principal component analysis, write components to pca.npy and samples.csv")
  94         flags.IntVar(&cmd.pcaComponents, "pca-components", 4, "number of PCA components to compute / use in logistic regression")
  95         maxPCATiles := flags.Int("max-pca-tiles", 0, "maximum tiles to use as PCA input (filter, then drop every 2nd colum pair until below max)")
  96         debugTag := flags.Int("debug-tag", -1, "log debugging details about specified tag")
  97         flags.IntVar(&cmd.threads, "threads", 16, "number of memory-hungry assembly threads, and number of VCPUs to request for arvados container")
  98         flags.Float64Var(&cmd.chi2PValue, "chi2-p-value", 1, "do Χ² test (or logistic regression if -samples file has PCA components) and omit columns with p-value above this threshold")
  99         flags.Float64Var(&cmd.pvalueMinFrequency, "pvalue-min-frequency", 0.01, "skip p-value calculation on tile variants below this frequency in the training set")
 100         flags.Float64Var(&cmd.maxFrequency, "max-frequency", 1, "do not output variants above this frequency in the training set")
 101         flags.BoolVar(&cmd.includeVariant1, "include-variant-1", false, "include most common variant when building one-hot matrix")
 102         cmd.filter.Flags(flags)
 103         err := flags.Parse(args)
 104         if err == flag.ErrHelp {
 105                 return nil
 106         } else if err != nil {
 107                 return err
 108         } else if flags.NArg() > 0 {
 109                 return fmt.Errorf("errant command line arguments after parsed flags: %v", flags.Args())
 110         }
 111
 112         if *pprof != "" {
 113                 go func() {
 114                         log.Println(http.ListenAndServe(*pprof, nil))
 115                 }()
 116         }
 117
 118         if cmd.chi2PValue != 1 && *samplesFilename == "" {
 119                 return fmt.Errorf("cannot use provided -chi2-p-value=%f because -samples= value is empty", cmd.chi2PValue)
 120         }
 121
 122         cmd.debugTag = tagID(*debugTag)
 123
 124         if !*runlocal {
 125                 runner := arvadosContainerRunner{
 126                         Name:        "lightning slice-numpy",
 127                         Client:      arvados.NewClientFromEnv(),
 128                         ProjectUUID: *projectUUID,
 129                         RAM:         int64(*arvadosRAM),
 130                         VCPUs:       *arvadosVCPUs,
 131                         Priority:    *priority,
 132                         KeepCache:   2,
 133                         APIAccess:   true,
 134                         Preemptible: *preemptible,
 135                 }
 136                 err = runner.TranslatePaths(inputDir, regionsFilename, samplesFilename)
 137                 if err != nil {
 138                         return err
 139                 }
 140                 runner.Args = []string{"slice-numpy", "-local=true",
 141                         "-pprof=:6060",
 142                         "-input-dir=" + *inputDir,
 143                         "-output-dir=/mnt/output",
 144                         "-threads=" + fmt.Sprintf("%d", cmd.threads),
 145                         "-regions=" + *regionsFilename,
 146                         "-expand-regions=" + fmt.Sprintf("%d", *expandRegions),
 147                         "-merge-output=" + fmt.Sprintf("%v", *mergeOutput),
 148                         "-single-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsSingle),
 149                         "-chunked-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsChunked),
 150                         "-single-onehot=" + fmt.Sprintf("%v", *onehotSingle),
 151                         "-chunked-onehot=" + fmt.Sprintf("%v", *onehotChunked),
 152                         "-samples=" + *samplesFilename,
 153                         "-case-control-only=" + fmt.Sprintf("%v", *caseControlOnly),
 154                         "-pca=" + fmt.Sprintf("%v", *onlyPCA),
 155                         "-pca-components=" + fmt.Sprintf("%d", cmd.pcaComponents),
 156                         "-max-pca-tiles=" + fmt.Sprintf("%d", *maxPCATiles),
 157                         "-chi2-p-value=" + fmt.Sprintf("%f", cmd.chi2PValue),
 158                         "-pvalue-min-frequency=" + fmt.Sprintf("%f", cmd.pvalueMinFrequency),
 159                         "-max-frequency=" + fmt.Sprintf("%f", cmd.maxFrequency),
 160                         "-include-variant-1=" + fmt.Sprintf("%v", cmd.includeVariant1),
 161                         "-debug-tag=" + fmt.Sprintf("%d", cmd.debugTag),
 162                 }
 163                 runner.Args = append(runner.Args, cmd.filter.Args()...)
 164                 var output string
 165                 output, err = runner.Run()
 166                 if err != nil {
 167                         return err
 168                 }
 169                 fmt.Fprintln(stdout, output)
 170                 return nil
 171         }
 172
 173         infiles, err := allFiles(*inputDir, matchGobFile)
 174         if err != nil {
 175                 return err
 176         }
 177         if len(infiles) == 0 {
 178                 err = fmt.Errorf("no input files found in %s", *inputDir)
 179                 return err
 180         }
 181         sort.Strings(infiles)
 182
 183         var refseq map[string][]tileLibRef
 184         var reftiledata = make(map[tileLibRef][]byte, 11000000)
 185         in0, err := open(infiles[0])
 186         if err != nil {
 187                 return err
 188         }
 189
 190         matchGenome, err := regexp.Compile(cmd.filter.MatchGenome)
 191         if err != nil {
 192                 err = fmt.Errorf("-match-genome: invalid regexp: %q", cmd.filter.MatchGenome)
 193                 return err
 194         }
 195
 196         if *samplesFilename != "" {
 197                 cmd.samples, err = loadSampleInfo(*samplesFilename)
 198                 if err != nil {
 199                         return err
 200                 }
 201         } else if *caseControlOnly {
 202                 return fmt.Errorf("-case-control-only does not make sense without -samples")
 203         }
 204
 205         cmd.cgnames = nil
 206         var tagset [][]byte
 207         err = DecodeLibrary(in0, strings.HasSuffix(infiles[0], ".gz"), func(ent *LibraryEntry) error {
 208                 if len(ent.TagSet) > 0 {
 209                         tagset = ent.TagSet
 210                 }
 211                 for _, cseq := range ent.CompactSequences {
 212                         if cseq.Name == *ref || *ref == "" {
 213                                 refseq = cseq.TileSequences
 214                         }
 215                 }
 216                 for _, cg := range ent.CompactGenomes {
 217                         if matchGenome.MatchString(cg.Name) {
 218                                 cmd.cgnames = append(cmd.cgnames, cg.Name)
 219                         }
 220                 }
 221                 for _, tv := range ent.TileVariants {
 222                         if tv.Ref {
 223                                 reftiledata[tileLibRef{tv.Tag, tv.Variant}] = tv.Sequence
 224                         }
 225                 }
 226                 return nil
 227         })
 228         if err != nil {
 229                 return err
 230         }
 231         in0.Close()
 232         if refseq == nil {
 233                 err = fmt.Errorf("%s: reference sequence not found", infiles[0])
 234                 return err
 235         }
 236         if len(tagset) == 0 {
 237                 err = fmt.Errorf("tagset not found")
 238                 return err
 239         }
 240
 241         taglib := &tagLibrary{}
 242         err = taglib.setTags(tagset)
 243         if err != nil {
 244                 return err
 245         }
 246         taglen := taglib.TagLen()
 247         sort.Strings(cmd.cgnames)
 248
 249         if len(cmd.cgnames) == 0 {
 250                 return fmt.Errorf("fatal: 0 matching samples in library, nothing to do")
 251         }
 252         cmd.trainingSet = make([]int, len(cmd.cgnames))
 253         if *samplesFilename == "" {
 254                 cmd.trainingSetSize = len(cmd.cgnames)
 255                 for i, name := range cmd.cgnames {
 256                         cmd.samples = append(cmd.samples, sampleInfo{
 257                                 id:         trimFilenameForLabel(name),
 258                                 isTraining: true,
 259                         })
 260                         cmd.trainingSet[i] = i
 261                 }
 262         } else if len(cmd.cgnames) != len(cmd.samples) {
 263                 return fmt.Errorf("mismatched sample list: %d samples in library, %d in %s", len(cmd.cgnames), len(cmd.samples), *samplesFilename)
 264         } else {
 265                 for i, name := range cmd.cgnames {
 266                         if s := trimFilenameForLabel(name); s != cmd.samples[i].id {
 267                                 return fmt.Errorf("mismatched sample list: sample %d is %q in library, %q in %s", i, s, cmd.samples[i].id, *samplesFilename)
 268                         }
 269                 }
 270                 if *caseControlOnly {
 271                         for i := 0; i < len(cmd.samples); i++ {
 272                                 if !cmd.samples[i].isTraining && !cmd.samples[i].isValidation {
 273                                         if i+1 < len(cmd.samples) {
 274                                                 copy(cmd.samples[i:], cmd.samples[i+1:])
 275                                                 copy(cmd.cgnames[i:], cmd.cgnames[i+1:])
 276                                         }
 277                                         cmd.samples = cmd.samples[:len(cmd.samples)-1]
 278                                         cmd.cgnames = cmd.cgnames[:len(cmd.cgnames)-1]
 279                                         i--
 280                                 }
 281                         }
 282                 }
 283                 cmd.chi2Cases = nil
 284                 cmd.trainingSetSize = 0
 285                 for i := range cmd.cgnames {
 286                         if cmd.samples[i].isTraining {
 287                                 cmd.trainingSet[i] = cmd.trainingSetSize
 288                                 cmd.trainingSetSize++
 289                                 cmd.chi2Cases = append(cmd.chi2Cases, cmd.samples[i].isCase)
 290                         } else {
 291                                 cmd.trainingSet[i] = -1
 292                         }
 293                 }
 294                 if cmd.pvalue == nil {
 295                         cmd.pvalue = func(onehot []bool) float64 {
 296                                 return pvalue(onehot, cmd.chi2Cases)
 297                         }
 298                 }
 299         }
 300         if cmd.filter.MinCoverage == 1 {
 301                 // In the generic formula below, floating point
 302                 // arithmetic can effectively push the coverage
 303                 // threshold above 1.0, which is impossible/useless.
 304                 // 1.0 needs to mean exactly 100% coverage.
 305                 cmd.minCoverage = len(cmd.cgnames)
 306         } else {
 307                 cmd.minCoverage = int(math.Ceil(cmd.filter.MinCoverage * float64(len(cmd.cgnames))))
 308         }
 309
 310         if len(cmd.samples[0].pcaComponents) > 0 {
 311                 cmd.pvalue = glmPvalueFunc(cmd.samples, cmd.pcaComponents)
 312                 // Unfortunately, statsmodel/glm lib logs stuff to
 313                 // os.Stdout when it panics on an unsolvable
 314                 // problem. We recover() from the panic in glm.go, but
 315                 // we also need to commandeer os.Stdout to avoid
 316                 // producing large quantities of logs.
 317                 stdoutWas := os.Stdout
 318                 defer func() { os.Stdout = stdoutWas }()
 319                 os.Stdout, err = os.Open(os.DevNull)
 320                 if err != nil {
 321                         return err
 322                 }
 323         }
 324
 325         // cgnamemap[name]==true for samples that we are including in
 326         // output
 327         cgnamemap := map[string]bool{}
 328         for _, name := range cmd.cgnames {
 329                 cgnamemap[name] = true
 330         }
 331
 332         err = writeSampleInfo(cmd.samples, *outputDir)
 333         if err != nil {
 334                 return err
 335         }
 336
 337         log.Info("indexing reference tiles")
 338         type reftileinfo struct {
 339                 variant  tileVariantID
 340                 seqname  string // chr1
 341                 pos      int    // distance from start of chromosome to starttag
 342                 tiledata []byte // acgtggcaa...
 343                 excluded bool   // true if excluded by regions file
 344                 nexttag  tagID  // tagID of following tile (-1 for last tag of chromosome)
 345         }
 346         isdup := map[tagID]bool{}
 347         reftile := map[tagID]*reftileinfo{}
 348         for seqname, cseq := range refseq {
 349                 pos := 0
 350                 lastreftag := tagID(-1)
 351                 for _, libref := range cseq {
 352                         if cmd.filter.MaxTag >= 0 && libref.Tag > tagID(cmd.filter.MaxTag) {
 353                                 continue
 354                         }
 355                         tiledata := reftiledata[libref]
 356                         if len(tiledata) == 0 {
 357                                 err = fmt.Errorf("missing tiledata for tag %d variant %d in %s in ref", libref.Tag, libref.Variant, seqname)
 358                                 return err
 359                         }
 360                         foundthistag := false
 361                         taglib.FindAll(tiledata[:len(tiledata)-1], func(tagid tagID, offset, _ int) {
 362                                 if !foundthistag && tagid == libref.Tag {
 363                                         foundthistag = true
 364                                         return
 365                                 }
 366                                 if dupref, ok := reftile[tagid]; ok {
 367                                         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)
 368                                         delete(reftile, tagid)
 369                                 } else {
 370                                         log.Printf("found tag %d at offset %d inside tile variant %+v on %s @ %d", tagid, offset, libref, seqname, pos+offset+1)
 371                                 }
 372                                 isdup[tagid] = true
 373                         })
 374                         if isdup[libref.Tag] {
 375                                 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
 376                         } else if reftile[libref.Tag] != nil {
 377                                 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)
 378                                 delete(reftile, libref.Tag)
 379                                 log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
 380                                 isdup[libref.Tag] = true
 381                         } else {
 382                                 reftile[libref.Tag] = &reftileinfo{
 383                                         seqname:  seqname,
 384                                         variant:  libref.Variant,
 385                                         tiledata: tiledata,
 386                                         pos:      pos,
 387                                         nexttag:  -1,
 388                                 }
 389                                 if lastreftag >= 0 {
 390                                         reftile[lastreftag].nexttag = libref.Tag
 391                                 }
 392                                 lastreftag = libref.Tag
 393                         }
 394                         pos += len(tiledata) - taglen
 395                 }
 396                 log.Printf("... %s done, len %d", seqname, pos+taglen)
 397         }
 398
 399         var mask *mask
 400         if *regionsFilename != "" {
 401                 log.Printf("loading regions from %s", *regionsFilename)
 402                 mask, err = makeMask(*regionsFilename, *expandRegions)
 403                 if err != nil {
 404                         return err
 405                 }
 406                 log.Printf("before applying mask, len(reftile) == %d", len(reftile))
 407                 log.Printf("deleting reftile entries for regions outside %d intervals", mask.Len())
 408                 for _, rt := range reftile {
 409                         if !mask.Check(strings.TrimPrefix(rt.seqname, "chr"), rt.pos, rt.pos+len(rt.tiledata)) {
 410                                 rt.excluded = true
 411                         }
 412                 }
 413                 log.Printf("after applying mask, len(reftile) == %d", len(reftile))
 414         }
 415
 416         type hgvsColSet map[hgvs.Variant][2][]int8
 417         encodeHGVS := throttle{Max: len(refseq)}
 418         encodeHGVSTodo := map[string]chan hgvsColSet{}
 419         tmpHGVSCols := map[string]*os.File{}
 420         if *hgvsChunked {
 421                 for seqname := range refseq {
 422                         var f *os.File
 423                         f, err = os.Create(*outputDir + "/tmp." + seqname + ".gob")
 424                         if err != nil {
 425                                 return err
 426                         }
 427                         defer os.Remove(f.Name())
 428                         bufw := bufio.NewWriterSize(f, 1<<24)
 429                         enc := gob.NewEncoder(bufw)
 430                         tmpHGVSCols[seqname] = f
 431                         todo := make(chan hgvsColSet, 128)
 432                         encodeHGVSTodo[seqname] = todo
 433                         encodeHGVS.Go(func() error {
 434                                 for colset := range todo {
 435                                         err := enc.Encode(colset)
 436                                         if err != nil {
 437                                                 encodeHGVS.Report(err)
 438                                                 for range todo {
 439                                                 }
 440                                                 return err
 441                                         }
 442                                 }
 443                                 return bufw.Flush()
 444                         })
 445                 }
 446         }
 447
 448         var toMerge [][]int16
 449         if *mergeOutput || *hgvsSingle {
 450                 toMerge = make([][]int16, len(infiles))
 451         }
 452         var onehotIndirect [][2][]uint32 // [chunkIndex][axis][index]
 453         var onehotChunkSize []uint32
 454         var onehotXrefs [][]onehotXref
 455         if *onehotSingle || *onlyPCA {
 456                 onehotIndirect = make([][2][]uint32, len(infiles))
 457                 onehotChunkSize = make([]uint32, len(infiles))
 458                 onehotXrefs = make([][]onehotXref, len(infiles))
 459         }
 460         chunkStartTag := make([]tagID, len(infiles))
 461
 462         throttleMem := throttle{Max: cmd.threads} // TODO: estimate using mem and data size
 463         throttleNumpyMem := throttle{Max: cmd.threads/2 + 1}
 464         log.Info("generating annotations and numpy matrix for each slice")
 465         var errSkip = errors.New("skip infile")
 466         var done int64
 467         for infileIdx, infile := range infiles {
 468                 infileIdx, infile := infileIdx, infile
 469                 throttleMem.Go(func() error {
 470                         seq := make(map[tagID][]TileVariant, 50000)
 471                         cgs := make(map[string]CompactGenome, len(cmd.cgnames))
 472                         f, err := open(infile)
 473                         if err != nil {
 474                                 return err
 475                         }
 476                         defer f.Close()
 477                         log.Infof("%04d: reading %s", infileIdx, infile)
 478                         err = DecodeLibrary(f, strings.HasSuffix(infile, ".gz"), func(ent *LibraryEntry) error {
 479                                 for _, tv := range ent.TileVariants {
 480                                         if tv.Ref {
 481                                                 continue
 482                                         }
 483                                         // Skip tile with no
 484                                         // corresponding ref tile, if
 485                                         // mask is in play (we can't
 486                                         // determine coordinates for
 487                                         // these)
 488                                         if mask != nil && reftile[tv.Tag] == nil {
 489                                                 continue
 490                                         }
 491                                         // Skip tile whose
 492                                         // corresponding ref tile is
 493                                         // outside target regions --
 494                                         // unless it's a potential
 495                                         // spanning tile.
 496                                         if mask != nil && reftile[tv.Tag].excluded &&
 497                                                 (int(tv.Tag+1) >= len(tagset) ||
 498                                                         (bytes.HasSuffix(tv.Sequence, tagset[tv.Tag+1]) && reftile[tv.Tag+1] != nil && !reftile[tv.Tag+1].excluded)) {
 499                                                 continue
 500                                         }
 501                                         if tv.Tag == cmd.debugTag {
 502                                                 log.Printf("infile %d %s tag %d variant %d hash %x", infileIdx, infile, tv.Tag, tv.Variant, tv.Blake2b[:3])
 503                                         }
 504                                         variants := seq[tv.Tag]
 505                                         if len(variants) == 0 {
 506                                                 variants = make([]TileVariant, 100)
 507                                         }
 508                                         for len(variants) <= int(tv.Variant) {
 509                                                 variants = append(variants, TileVariant{})
 510                                         }
 511                                         variants[int(tv.Variant)] = tv
 512                                         seq[tv.Tag] = variants
 513                                 }
 514                                 for _, cg := range ent.CompactGenomes {
 515                                         if cmd.filter.MaxTag >= 0 && cg.StartTag > tagID(cmd.filter.MaxTag) {
 516                                                 return errSkip
 517                                         }
 518                                         if !cgnamemap[cg.Name] {
 519                                                 continue
 520                                         }
 521                                         // pad to full slice size
 522                                         // to avoid out-of-bounds
 523                                         // checks later
 524                                         if sliceSize := 2 * int(cg.EndTag-cg.StartTag); len(cg.Variants) < sliceSize {
 525                                                 cg.Variants = append(cg.Variants, make([]tileVariantID, sliceSize-len(cg.Variants))...)
 526                                         }
 527                                         cgs[cg.Name] = cg
 528                                 }
 529                                 return nil
 530                         })
 531                         if err == errSkip {
 532                                 return nil
 533                         } else if err != nil {
 534                                 return fmt.Errorf("%04d: DecodeLibrary(%s): err", infileIdx, infile)
 535                         }
 536                         tagstart := cgs[cmd.cgnames[0]].StartTag
 537                         tagend := cgs[cmd.cgnames[0]].EndTag
 538                         chunkStartTag[infileIdx] = tagstart
 539
 540                         // TODO: filters
 541
 542                         log.Infof("%04d: renumber/dedup variants for tags %d-%d", infileIdx, tagstart, tagend)
 543                         variantRemap := make([][]tileVariantID, tagend-tagstart)
 544                         throttleCPU := throttle{Max: runtime.GOMAXPROCS(0)}
 545                         for tag, variants := range seq {
 546                                 tag, variants := tag, variants
 547                                 throttleCPU.Go(func() error {
 548                                         alleleCoverage := 0
 549                                         count := make(map[[blake2b.Size256]byte]int, len(variants))
 550
 551                                         rt := reftile[tag]
 552                                         if rt != nil {
 553                                                 count[blake2b.Sum256(rt.tiledata)] = 0
 554                                         }
 555
 556                                         for cgname, cg := range cgs {
 557                                                 idx := int(tag-tagstart) * 2
 558                                                 for allele := 0; allele < 2; allele++ {
 559                                                         v := cg.Variants[idx+allele]
 560                                                         if v > 0 && len(variants[v].Sequence) > 0 {
 561                                                                 count[variants[v].Blake2b]++
 562                                                                 alleleCoverage++
 563                                                         }
 564                                                         if v > 0 && tag == cmd.debugTag {
 565                                                                 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])
 566                                                         }
 567                                                 }
 568                                         }
 569                                         if alleleCoverage < cmd.minCoverage*2 {
 570                                                 idx := int(tag-tagstart) * 2
 571                                                 for _, cg := range cgs {
 572                                                         cg.Variants[idx] = 0
 573                                                         cg.Variants[idx+1] = 0
 574                                                 }
 575                                                 if tag == cmd.debugTag {
 576                                                         log.Printf("tag %d alleleCoverage %d < min %d, sample data wiped", tag, alleleCoverage, cmd.minCoverage*2)
 577                                                 }
 578                                                 return nil
 579                                         }
 580
 581                                         // hash[i] will be the hash of
 582                                         // the variant(s) that should
 583                                         // be at rank i (0-based).
 584                                         hash := make([][blake2b.Size256]byte, 0, len(count))
 585                                         for b := range count {
 586                                                 hash = append(hash, b)
 587                                         }
 588                                         sort.Slice(hash, func(i, j int) bool {
 589                                                 bi, bj := &hash[i], &hash[j]
 590                                                 if ci, cj := count[*bi], count[*bj]; ci != cj {
 591                                                         return ci > cj
 592                                                 } else {
 593                                                         return bytes.Compare((*bi)[:], (*bj)[:]) < 0
 594                                                 }
 595                                         })
 596                                         // rank[b] will be the 1-based
 597                                         // new variant number for
 598                                         // variants whose hash is b.
 599                                         rank := make(map[[blake2b.Size256]byte]tileVariantID, len(hash))
 600                                         for i, h := range hash {
 601                                                 rank[h] = tileVariantID(i + 1)
 602                                         }
 603                                         if tag == cmd.debugTag {
 604                                                 for h, r := range rank {
 605                                                         log.Printf("tag %d rank(%x) = %v", tag, h[:3], r)
 606                                                 }
 607                                         }
 608                                         // remap[v] will be the new
 609                                         // variant number for original
 610                                         // variant number v.
 611                                         remap := make([]tileVariantID, len(variants))
 612                                         for i, tv := range variants {
 613                                                 remap[i] = rank[tv.Blake2b]
 614                                         }
 615                                         if tag == cmd.debugTag {
 616                                                 for in, out := range remap {
 617                                                         if out > 0 {
 618                                                                 log.Printf("tag %d remap %d => %d", tag, in, out)
 619                                                         }
 620                                                 }
 621                                         }
 622                                         variantRemap[tag-tagstart] = remap
 623                                         if rt != nil {
 624                                                 refrank := rank[blake2b.Sum256(rt.tiledata)]
 625                                                 if tag == cmd.debugTag {
 626                                                         log.Printf("tag %d reftile variant %d => %d", tag, rt.variant, refrank)
 627                                                 }
 628                                                 rt.variant = refrank
 629                                         }
 630                                         return nil
 631                                 })
 632                         }
 633                         throttleCPU.Wait()
 634
 635                         var onehotChunk [][]int8
 636                         var onehotXref []onehotXref
 637
 638                         var annotationsFilename string
 639                         if *onlyPCA {
 640                                 annotationsFilename = "/dev/null"
 641                         } else {
 642                                 annotationsFilename = fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, infileIdx)
 643                                 log.Infof("%04d: writing %s", infileIdx, annotationsFilename)
 644                         }
 645                         annof, err := os.Create(annotationsFilename)
 646                         if err != nil {
 647                                 return err
 648                         }
 649                         annow := bufio.NewWriterSize(annof, 1<<20)
 650                         outcol := 0
 651                         for tag := tagstart; tag < tagend; tag++ {
 652                                 rt := reftile[tag]
 653                                 if rt == nil && mask != nil {
 654                                         // With no ref tile, we don't
 655                                         // have coordinates to say
 656                                         // this is in the desired
 657                                         // regions -- so it's not.
 658                                         // TODO: handle ref spanning
 659                                         // tile case.
 660                                         continue
 661                                 }
 662                                 if rt != nil && rt.excluded {
 663                                         // TODO: don't skip yet --
 664                                         // first check for spanning
 665                                         // tile variants that
 666                                         // intersect non-excluded ref
 667                                         // tiles.
 668                                         continue
 669                                 }
 670                                 if cmd.filter.MaxTag >= 0 && tag > tagID(cmd.filter.MaxTag) {
 671                                         break
 672                                 }
 673                                 remap := variantRemap[tag-tagstart]
 674                                 if remap == nil {
 675                                         // was not assigned above,
 676                                         // because minCoverage
 677                                         outcol++
 678                                         continue
 679                                 }
 680                                 maxv := tileVariantID(0)
 681                                 for _, v := range remap {
 682                                         if maxv < v {
 683                                                 maxv = v
 684                                         }
 685                                 }
 686                                 if *onehotChunked || *onehotSingle || *onlyPCA {
 687                                         onehot, xrefs := cmd.tv2homhet(cgs, maxv, remap, tag, tagstart, seq)
 688                                         if tag == cmd.debugTag {
 689                                                 log.WithFields(logrus.Fields{
 690                                                         "onehot": onehot,
 691                                                         "xrefs":  xrefs,
 692                                                 }).Info("tv2homhet()")
 693                                         }
 694                                         onehotChunk = append(onehotChunk, onehot...)
 695                                         onehotXref = append(onehotXref, xrefs...)
 696                                 }
 697                                 if *onlyPCA {
 698                                         outcol++
 699                                         continue
 700                                 }
 701                                 if rt == nil {
 702                                         // Reference does not use any
 703                                         // variant of this tile
 704                                         //
 705                                         // TODO: diff against the
 706                                         // relevant portion of the
 707                                         // ref's spanning tile
 708                                         outcol++
 709                                         continue
 710                                 }
 711                                 fmt.Fprintf(annow, "%d,%d,%d,=,%s,%d,,,\n", tag, outcol, rt.variant, rt.seqname, rt.pos)
 712                                 variants := seq[tag]
 713                                 reftilestr := strings.ToUpper(string(rt.tiledata))
 714
 715                                 done := make([]bool, maxv+1)
 716                                 variantDiffs := make([][]hgvs.Variant, maxv+1)
 717                                 for v, tv := range variants {
 718                                         v := remap[v]
 719                                         if v == 0 || v == rt.variant || done[v] {
 720                                                 continue
 721                                         } else {
 722                                                 done[v] = true
 723                                         }
 724                                         if len(tv.Sequence) < taglen {
 725                                                 continue
 726                                         }
 727                                         // if reftilestr doesn't end
 728                                         // in the same tag as tv,
 729                                         // extend reftilestr with
 730                                         // following ref tiles until
 731                                         // it does (up to an arbitrary
 732                                         // sanity-check limit)
 733                                         reftilestr := reftilestr
 734                                         endtagstr := strings.ToUpper(string(tv.Sequence[len(tv.Sequence)-taglen:]))
 735                                         for i, rt := 0, rt; i < annotationMaxTileSpan && !strings.HasSuffix(reftilestr, endtagstr) && rt.nexttag >= 0; i++ {
 736                                                 rt = reftile[rt.nexttag]
 737                                                 if rt == nil {
 738                                                         break
 739                                                 }
 740                                                 reftilestr += strings.ToUpper(string(rt.tiledata[taglen:]))
 741                                         }
 742                                         if mask != nil && !mask.Check(strings.TrimPrefix(rt.seqname, "chr"), rt.pos, rt.pos+len(reftilestr)) {
 743                                                 continue
 744                                         }
 745                                         if !strings.HasSuffix(reftilestr, endtagstr) {
 746                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 747                                                 continue
 748                                         }
 749                                         if lendiff := len(reftilestr) - len(tv.Sequence); lendiff < -1000 || lendiff > 1000 {
 750                                                 fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 751                                                 continue
 752                                         }
 753                                         diffs, _ := hgvs.Diff(reftilestr, strings.ToUpper(string(tv.Sequence)), 0)
 754                                         for i := range diffs {
 755                                                 diffs[i].Position += rt.pos
 756                                         }
 757                                         for _, diff := range diffs {
 758                                                 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)
 759                                         }
 760                                         if *hgvsChunked {
 761                                                 variantDiffs[v] = diffs
 762                                         }
 763                                 }
 764                                 if *hgvsChunked {
 765                                         // We can now determine, for each HGVS
 766                                         // variant (diff) in this reftile
 767                                         // region, whether a given genome
 768                                         // phase/allele (1) has the variant, (0) has
 769                                         // =ref or a different variant in that
 770                                         // position, or (-1) is lacking
 771                                         // coverage / couldn't be diffed.
 772                                         hgvsCol := hgvsColSet{}
 773                                         for _, diffs := range variantDiffs {
 774                                                 for _, diff := range diffs {
 775                                                         if _, ok := hgvsCol[diff]; ok {
 776                                                                 continue
 777                                                         }
 778                                                         hgvsCol[diff] = [2][]int8{
 779                                                                 make([]int8, len(cmd.cgnames)),
 780                                                                 make([]int8, len(cmd.cgnames)),
 781                                                         }
 782                                                 }
 783                                         }
 784                                         for row, name := range cmd.cgnames {
 785                                                 variants := cgs[name].Variants[(tag-tagstart)*2:]
 786                                                 for ph := 0; ph < 2; ph++ {
 787                                                         v := variants[ph]
 788                                                         if int(v) >= len(remap) {
 789                                                                 v = 0
 790                                                         } else {
 791                                                                 v = remap[v]
 792                                                         }
 793                                                         if v == rt.variant {
 794                                                                 // hgvsCol[*][ph][row] is already 0
 795                                                         } else if len(variantDiffs[v]) == 0 {
 796                                                                 // lacking coverage / couldn't be diffed
 797                                                                 for _, col := range hgvsCol {
 798                                                                         col[ph][row] = -1
 799                                                                 }
 800                                                         } else {
 801                                                                 for _, diff := range variantDiffs[v] {
 802                                                                         hgvsCol[diff][ph][row] = 1
 803                                                                 }
 804                                                         }
 805                                                 }
 806                                         }
 807                                         for diff, colpair := range hgvsCol {
 808                                                 allele2homhet(colpair)
 809                                                 if !cmd.filterHGVScolpair(colpair) {
 810                                                         delete(hgvsCol, diff)
 811                                                 }
 812                                         }
 813                                         if len(hgvsCol) > 0 {
 814                                                 encodeHGVSTodo[rt.seqname] <- hgvsCol
 815                                         }
 816                                 }
 817                                 outcol++
 818                         }
 819                         err = annow.Flush()
 820                         if err != nil {
 821                                 return err
 822                         }
 823                         err = annof.Close()
 824                         if err != nil {
 825                                 return err
 826                         }
 827
 828                         if *onehotChunked {
 829                                 // transpose onehotChunk[col][row] to numpy[row*ncols+col]
 830                                 rows := len(cmd.cgnames)
 831                                 cols := len(onehotChunk)
 832                                 log.Infof("%04d: preparing onehot numpy (rows=%d, cols=%d, mem=%d)", infileIdx, rows, cols, rows*cols)
 833                                 throttleNumpyMem.Acquire()
 834                                 out := onehotcols2int8(onehotChunk)
 835                                 fnm := fmt.Sprintf("%s/onehot.%04d.npy", *outputDir, infileIdx)
 836                                 err = writeNumpyInt8(fnm, out, rows, cols)
 837                                 if err != nil {
 838                                         return err
 839                                 }
 840                                 fnm = fmt.Sprintf("%s/onehot-columns.%04d.npy", *outputDir, infileIdx)
 841                                 err = writeNumpyInt32(fnm, onehotXref2int32(onehotXref), 4, len(onehotXref))
 842                                 if err != nil {
 843                                         return err
 844                                 }
 845                                 debug.FreeOSMemory()
 846                                 throttleNumpyMem.Release()
 847                         }
 848                         if *onehotSingle || *onlyPCA {
 849                                 onehotIndirect[infileIdx] = onehotChunk2Indirect(onehotChunk)
 850                                 onehotChunkSize[infileIdx] = uint32(len(onehotChunk))
 851                                 onehotXrefs[infileIdx] = onehotXref
 852                                 n := len(onehotIndirect[infileIdx][0])
 853                                 log.Infof("%04d: keeping onehot coordinates in memory (n=%d, mem=%d)", infileIdx, n, n*8*2)
 854                         }
 855                         if !(*onehotSingle || *onehotChunked || *onlyPCA) || *mergeOutput || *hgvsSingle {
 856                                 log.Infof("%04d: preparing numpy (rows=%d, cols=%d)", infileIdx, len(cmd.cgnames), 2*outcol)
 857                                 throttleNumpyMem.Acquire()
 858                                 rows := len(cmd.cgnames)
 859                                 cols := 2 * outcol
 860                                 out := make([]int16, rows*cols)
 861                                 for row, name := range cmd.cgnames {
 862                                         outidx := row * cols
 863                                         for col, v := range cgs[name].Variants {
 864                                                 tag := tagstart + tagID(col/2)
 865                                                 if cmd.filter.MaxTag >= 0 && tag > tagID(cmd.filter.MaxTag) {
 866                                                         break
 867                                                 }
 868                                                 if rt := reftile[tag]; rt == nil || rt.excluded {
 869                                                         continue
 870                                                 }
 871                                                 if v == 0 {
 872                                                         out[outidx] = 0 // tag not found / spanning tile
 873                                                 } else if variants, ok := seq[tag]; ok && int(v) < len(variants) && len(variants[v].Sequence) > 0 {
 874                                                         out[outidx] = int16(variantRemap[tag-tagstart][v])
 875                                                 } else {
 876                                                         out[outidx] = -1 // low quality tile variant
 877                                                 }
 878                                                 if tag == cmd.debugTag {
 879                                                         log.Printf("tag %d row %d col %d outidx %d v %d out %d", tag, row, col, outidx, v, out[outidx])
 880                                                 }
 881                                                 outidx++
 882                                         }
 883                                 }
 884                                 seq = nil
 885                                 cgs = nil
 886                                 debug.FreeOSMemory()
 887                                 throttleNumpyMem.Release()
 888                                 if *mergeOutput || *hgvsSingle {
 889                                         log.Infof("%04d: matrix fragment %d rows x %d cols", infileIdx, rows, cols)
 890                                         toMerge[infileIdx] = out
 891                                 }
 892                                 if !*mergeOutput && !*onehotChunked && !*onehotSingle {
 893                                         fnm := fmt.Sprintf("%s/matrix.%04d.npy", *outputDir, infileIdx)
 894                                         err = writeNumpyInt16(fnm, out, rows, cols)
 895                                         if err != nil {
 896                                                 return err
 897                                         }
 898                                 }
 899                         }
 900                         debug.FreeOSMemory()
 901                         log.Infof("%s: done (%d/%d)", infile, int(atomic.AddInt64(&done, 1)), len(infiles))
 902                         return nil
 903                 })
 904         }
 905         if err = throttleMem.Wait(); err != nil {
 906                 return err
 907         }
 908
 909         if *hgvsChunked {
 910                 log.Info("flushing hgvsCols temp files")
 911                 for seqname := range refseq {
 912                         close(encodeHGVSTodo[seqname])
 913                 }
 914                 err = encodeHGVS.Wait()
 915                 if err != nil {
 916                         return err
 917                 }
 918                 for seqname := range refseq {
 919                         log.Infof("%s: reading hgvsCols from temp file", seqname)
 920                         f := tmpHGVSCols[seqname]
 921                         _, err = f.Seek(0, io.SeekStart)
 922                         if err != nil {
 923                                 return err
 924                         }
 925                         var hgvsCols hgvsColSet
 926                         dec := gob.NewDecoder(bufio.NewReaderSize(f, 1<<24))
 927                         for err == nil {
 928                                 err = dec.Decode(&hgvsCols)
 929                         }
 930                         if err != io.EOF {
 931                                 return err
 932                         }
 933                         log.Infof("%s: sorting %d hgvs variants", seqname, len(hgvsCols))
 934                         variants := make([]hgvs.Variant, 0, len(hgvsCols))
 935                         for v := range hgvsCols {
 936                                 variants = append(variants, v)
 937                         }
 938                         sort.Slice(variants, func(i, j int) bool {
 939                                 vi, vj := &variants[i], &variants[j]
 940                                 if vi.Position != vj.Position {
 941                                         return vi.Position < vj.Position
 942                                 } else if vi.Ref != vj.Ref {
 943                                         return vi.Ref < vj.Ref
 944                                 } else {
 945                                         return vi.New < vj.New
 946                                 }
 947                         })
 948                         rows := len(cmd.cgnames)
 949                         cols := len(variants) * 2
 950                         log.Infof("%s: building hgvs matrix (rows=%d, cols=%d, mem=%d)", seqname, rows, cols, rows*cols)
 951                         out := make([]int8, rows*cols)
 952                         for varIdx, variant := range variants {
 953                                 hgvsCols := hgvsCols[variant]
 954                                 for row := range cmd.cgnames {
 955                                         for ph := 0; ph < 2; ph++ {
 956                                                 out[row*cols+varIdx+ph] = hgvsCols[ph][row]
 957                                         }
 958                                 }
 959                         }
 960                         err = writeNumpyInt8(fmt.Sprintf("%s/hgvs.%s.npy", *outputDir, seqname), out, rows, cols)
 961                         if err != nil {
 962                                 return err
 963                         }
 964                         out = nil
 965
 966                         fnm := fmt.Sprintf("%s/hgvs.%s.annotations.csv", *outputDir, seqname)
 967                         log.Infof("%s: writing hgvs column labels to %s", seqname, fnm)
 968                         var hgvsLabels bytes.Buffer
 969                         for varIdx, variant := range variants {
 970                                 fmt.Fprintf(&hgvsLabels, "%d,%s:g.%s\n", varIdx, seqname, variant.String())
 971                         }
 972                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0666)
 973                         if err != nil {
 974                                 return err
 975                         }
 976                 }
 977         }
 978
 979         if *mergeOutput || *hgvsSingle {
 980                 var annow *bufio.Writer
 981                 var annof *os.File
 982                 if *mergeOutput {
 983                         annoFilename := fmt.Sprintf("%s/matrix.annotations.csv", *outputDir)
 984                         annof, err = os.Create(annoFilename)
 985                         if err != nil {
 986                                 return err
 987                         }
 988                         annow = bufio.NewWriterSize(annof, 1<<20)
 989                 }
 990
 991                 rows := len(cmd.cgnames)
 992                 cols := 0
 993                 for _, chunk := range toMerge {
 994                         cols += len(chunk) / rows
 995                 }
 996                 log.Infof("merging output matrix (rows=%d, cols=%d, mem=%d) and annotations", rows, cols, rows*cols*2)
 997                 var out []int16
 998                 if *mergeOutput {
 999                         out = make([]int16, rows*cols)
1000                 }
1001                 hgvsCols := map[string][2][]int16{} // hgvs -> [[g0,g1,g2,...], [g0,g1,g2,...]] (slice of genomes for each phase)
1002                 startcol := 0
1003                 for outIdx, chunk := range toMerge {
1004                         chunkcols := len(chunk) / rows
1005                         if *mergeOutput {
1006                                 for row := 0; row < rows; row++ {
1007                                         copy(out[row*cols+startcol:], chunk[row*chunkcols:(row+1)*chunkcols])
1008                                 }
1009                         }
1010                         toMerge[outIdx] = nil
1011
1012                         annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, outIdx)
1013                         log.Infof("reading %s", annotationsFilename)
1014                         buf, err := os.ReadFile(annotationsFilename)
1015                         if err != nil {
1016                                 return err
1017                         }
1018                         if *mergeOutput {
1019                                 err = os.Remove(annotationsFilename)
1020                                 if err != nil {
1021                                         return err
1022                                 }
1023                         }
1024                         for _, line := range bytes.Split(buf, []byte{'\n'}) {
1025                                 if len(line) == 0 {
1026                                         continue
1027                                 }
1028                                 fields := bytes.SplitN(line, []byte{','}, 9)
1029                                 tag, _ := strconv.Atoi(string(fields[0]))
1030                                 incol, _ := strconv.Atoi(string(fields[1]))
1031                                 tileVariant, _ := strconv.Atoi(string(fields[2]))
1032                                 hgvsID := string(fields[3])
1033                                 seqname := string(fields[4])
1034                                 pos, _ := strconv.Atoi(string(fields[5]))
1035                                 refseq := fields[6]
1036                                 if hgvsID == "" {
1037                                         // Null entry for un-diffable
1038                                         // tile variant
1039                                         continue
1040                                 }
1041                                 if hgvsID == "=" {
1042                                         // Null entry for ref tile
1043                                         continue
1044                                 }
1045                                 if mask != nil && !mask.Check(strings.TrimPrefix(seqname, "chr"), pos, pos+len(refseq)) {
1046                                         // The tile intersects one of
1047                                         // the selected regions, but
1048                                         // this particular HGVS
1049                                         // variant does not.
1050                                         continue
1051                                 }
1052                                 hgvsColPair := hgvsCols[hgvsID]
1053                                 if hgvsColPair[0] == nil {
1054                                         // values in new columns start
1055                                         // out as -1 ("no data yet")
1056                                         // or 0 ("=ref") here, may
1057                                         // change to 1 ("hgvs variant
1058                                         // present") below, either on
1059                                         // this line or a future line.
1060                                         hgvsColPair = [2][]int16{make([]int16, len(cmd.cgnames)), make([]int16, len(cmd.cgnames))}
1061                                         rt, ok := reftile[tagID(tag)]
1062                                         if !ok {
1063                                                 err = fmt.Errorf("bug: seeing annotations for tag %d, but it has no reftile entry", tag)
1064                                                 return err
1065                                         }
1066                                         for ph := 0; ph < 2; ph++ {
1067                                                 for row := 0; row < rows; row++ {
1068                                                         v := chunk[row*chunkcols+incol*2+ph]
1069                                                         if tileVariantID(v) == rt.variant {
1070                                                                 hgvsColPair[ph][row] = 0
1071                                                         } else {
1072                                                                 hgvsColPair[ph][row] = -1
1073                                                         }
1074                                                 }
1075                                         }
1076                                         hgvsCols[hgvsID] = hgvsColPair
1077                                         if annow != nil {
1078                                                 hgvsref := hgvs.Variant{
1079                                                         Position: pos,
1080                                                         Ref:      string(refseq),
1081                                                         New:      string(refseq),
1082                                                 }
1083                                                 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])
1084                                         }
1085                                 }
1086                                 if annow != nil {
1087                                         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])
1088                                 }
1089                                 for ph := 0; ph < 2; ph++ {
1090                                         for row := 0; row < rows; row++ {
1091                                                 v := chunk[row*chunkcols+incol*2+ph]
1092                                                 if int(v) == tileVariant {
1093                                                         hgvsColPair[ph][row] = 1
1094                                                 }
1095                                         }
1096                                 }
1097                         }
1098
1099                         startcol += chunkcols
1100                 }
1101                 if *mergeOutput {
1102                         err = annow.Flush()
1103                         if err != nil {
1104                                 return err
1105                         }
1106                         err = annof.Close()
1107                         if err != nil {
1108                                 return err
1109                         }
1110                         err = writeNumpyInt16(fmt.Sprintf("%s/matrix.npy", *outputDir), out, rows, cols)
1111                         if err != nil {
1112                                 return err
1113                         }
1114                 }
1115                 out = nil
1116
1117                 if *hgvsSingle {
1118                         cols = len(hgvsCols) * 2
1119                         log.Printf("building hgvs-based matrix: %d rows x %d cols", rows, cols)
1120                         out = make([]int16, rows*cols)
1121                         hgvsIDs := make([]string, 0, cols/2)
1122                         for hgvsID := range hgvsCols {
1123                                 hgvsIDs = append(hgvsIDs, hgvsID)
1124                         }
1125                         sort.Strings(hgvsIDs)
1126                         var hgvsLabels bytes.Buffer
1127                         for idx, hgvsID := range hgvsIDs {
1128                                 fmt.Fprintf(&hgvsLabels, "%d,%s\n", idx, hgvsID)
1129                                 for ph := 0; ph < 2; ph++ {
1130                                         hgvscol := hgvsCols[hgvsID][ph]
1131                                         for row, val := range hgvscol {
1132                                                 out[row*cols+idx*2+ph] = val
1133                                         }
1134                                 }
1135                         }
1136                         err = writeNumpyInt16(fmt.Sprintf("%s/hgvs.npy", *outputDir), out, rows, cols)
1137                         if err != nil {
1138                                 return err
1139                         }
1140
1141                         fnm := fmt.Sprintf("%s/hgvs.annotations.csv", *outputDir)
1142                         log.Printf("writing hgvs labels: %s", fnm)
1143                         err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0777)
1144                         if err != nil {
1145                                 return err
1146                         }
1147                 }
1148         }
1149         if *onehotSingle || *onlyPCA {
1150                 nzCount := 0
1151                 for _, part := range onehotIndirect {
1152                         nzCount += len(part[0])
1153                 }
1154                 onehot := make([]uint32, nzCount*2) // [r,r,r,...,c,c,c,...]
1155                 var xrefs []onehotXref
1156                 chunkOffset := uint32(0)
1157                 outcol := 0
1158                 for i, part := range onehotIndirect {
1159                         for i := range part[1] {
1160                                 part[1][i] += chunkOffset
1161                         }
1162                         copy(onehot[outcol:], part[0])
1163                         copy(onehot[outcol+nzCount:], part[1])
1164                         xrefs = append(xrefs, onehotXrefs[i]...)
1165
1166                         outcol += len(part[0])
1167                         chunkOffset += onehotChunkSize[i]
1168
1169                         part[0] = nil
1170                         part[1] = nil
1171                         onehotXrefs[i] = nil
1172                         debug.FreeOSMemory()
1173                 }
1174                 if *onehotSingle {
1175                         fnm := fmt.Sprintf("%s/onehot.npy", *outputDir)
1176                         err = writeNumpyUint32(fnm, onehot, 2, nzCount)
1177                         if err != nil {
1178                                 return err
1179                         }
1180                         fnm = fmt.Sprintf("%s/onehot-columns.npy", *outputDir)
1181                         err = writeNumpyInt32(fnm, onehotXref2int32(xrefs), 5, len(xrefs))
1182                         if err != nil {
1183                                 return err
1184                         }
1185                         fnm = fmt.Sprintf("%s/stats.json", *outputDir)
1186                         j, err := json.Marshal(map[string]interface{}{
1187                                 "pvalueCallCount": cmd.pvalueCallCount,
1188                         })
1189                         if err != nil {
1190                                 return err
1191                         }
1192                         err = os.WriteFile(fnm, j, 0777)
1193                         if err != nil {
1194                                 return err
1195                         }
1196                 }
1197                 if *onlyPCA {
1198                         cols := 0
1199                         for _, c := range onehot[nzCount:] {
1200                                 if int(c) >= cols {
1201                                         cols = int(c) + 1
1202                                 }
1203                         }
1204                         if cols == 0 {
1205                                 return fmt.Errorf("cannot do PCA: one-hot matrix is empty")
1206                         }
1207                         log.Printf("have %d one-hot cols", cols)
1208                         stride := 1
1209                         for *maxPCATiles > 0 && cols > *maxPCATiles*2 {
1210                                 cols = (cols + 1) / 2
1211                                 stride = stride * 2
1212                         }
1213                         if cols%2 == 1 {
1214                                 // we work with pairs of columns
1215                                 cols++
1216                         }
1217                         log.Printf("creating full matrix (%d rows) and training matrix (%d rows) with %d cols, stride %d", len(cmd.cgnames), cmd.trainingSetSize, cols, stride)
1218                         mtxFull := mat.NewDense(len(cmd.cgnames), cols, nil)
1219                         mtxTrain := mat.NewDense(cmd.trainingSetSize, cols, nil)
1220                         for i, c := range onehot[nzCount:] {
1221                                 if int(c/2)%stride == 0 {
1222                                         outcol := int(c/2)/stride*2 + int(c)%2
1223                                         mtxFull.Set(int(onehot[i]), outcol, 1)
1224                                         if trainRow := cmd.trainingSet[int(onehot[i])]; trainRow >= 0 {
1225                                                 mtxTrain.Set(trainRow, outcol, 1)
1226                                         }
1227                                 }
1228                         }
1229                         log.Print("fitting")
1230                         transformer := nlp.NewPCA(cmd.pcaComponents)
1231                         transformer.Fit(mtxTrain.T())
1232                         log.Printf("transforming")
1233                         pca, err := transformer.Transform(mtxFull.T())
1234                         if err != nil {
1235                                 return err
1236                         }
1237                         pca = pca.T()
1238                         outrows, outcols := pca.Dims()
1239                         log.Printf("copying result to numpy output array: %d rows, %d cols", outrows, outcols)
1240                         out := make([]float64, outrows*outcols)
1241                         for i := 0; i < outrows; i++ {
1242                                 for j := 0; j < outcols; j++ {
1243                                         out[i*outcols+j] = pca.At(i, j)
1244                                 }
1245                         }
1246                         fnm := fmt.Sprintf("%s/pca.npy", *outputDir)
1247                         log.Printf("writing numpy: %s", fnm)
1248                         output, err := os.OpenFile(fnm, os.O_CREATE|os.O_TRUNC|os.O_WRONLY, 0777)
1249                         if err != nil {
1250                                 return err
1251                         }
1252                         npw, err := gonpy.NewWriter(nopCloser{output})
1253                         if err != nil {
1254                                 return fmt.Errorf("gonpy.NewWriter: %w", err)
1255                         }
1256                         npw.Shape = []int{outrows, outcols}
1257                         err = npw.WriteFloat64(out)
1258                         if err != nil {
1259                                 return fmt.Errorf("WriteFloat64: %w", err)
1260                         }
1261                         err = output.Close()
1262                         if err != nil {
1263                                 return err
1264                         }
1265                         log.Print("done")
1266
1267                         log.Print("copying pca components to sampleInfo")
1268                         for i := range cmd.samples {
1269                                 cmd.samples[i].pcaComponents = make([]float64, outcols)
1270                                 for c := 0; c < outcols; c++ {
1271                                         cmd.samples[i].pcaComponents[c] = pca.At(i, c)
1272                                 }
1273                         }
1274                         log.Print("done")
1275
1276                         err = writeSampleInfo(cmd.samples, *outputDir)
1277                         if err != nil {
1278                                 return err
1279                         }
1280                 }
1281         }
1282         if !*mergeOutput && !*onehotChunked && !*onehotSingle && !*onlyPCA {
1283                 tagoffsetFilename := *outputDir + "/chunk-tag-offset.csv"
1284                 log.Infof("writing tag offsets to %s", tagoffsetFilename)
1285                 var f *os.File
1286                 f, err = os.Create(tagoffsetFilename)
1287                 if err != nil {
1288                         return err
1289                 }
1290                 defer f.Close()
1291                 for idx, offset := range chunkStartTag {
1292                         _, err = fmt.Fprintf(f, "%q,%d\n", fmt.Sprintf("matrix.%04d.npy", idx), offset)
1293                         if err != nil {
1294                                 err = fmt.Errorf("write %s: %w", tagoffsetFilename, err)
1295                                 return err
1296                         }
1297                 }
1298                 err = f.Close()
1299                 if err != nil {
1300                         err = fmt.Errorf("close %s: %w", tagoffsetFilename, err)
1301                         return err
1302                 }
1303         }
1304
1305         return nil
1306 }
1307
1308 type sampleInfo struct {
1309         id            string
1310         isCase        bool
1311         isControl     bool
1312         isTraining    bool
1313         isValidation  bool
1314         pcaComponents []float64
1315 }
1316
1317 // Read samples.csv file with case/control and training/validation
1318 // flags.
1319 func loadSampleInfo(samplesFilename string) ([]sampleInfo, error) {
1320         var si []sampleInfo
1321         f, err := open(samplesFilename)
1322         if err != nil {
1323                 return nil, err
1324         }
1325         buf, err := io.ReadAll(f)
1326         f.Close()
1327         if err != nil {
1328                 return nil, err
1329         }
1330         lineNum := 0
1331         for _, csv := range bytes.Split(buf, []byte{'\n'}) {
1332                 lineNum++
1333                 if len(csv) == 0 {
1334                         continue
1335                 }
1336                 split := strings.Split(string(csv), ",")
1337                 if len(split) < 4 {
1338                         return nil, fmt.Errorf("%d fields < 4 in %s line %d: %q", len(split), samplesFilename, lineNum, csv)
1339                 }
1340                 if split[0] == "Index" && split[1] == "SampleID" && split[2] == "CaseControl" && split[3] == "TrainingValidation" {
1341                         continue
1342                 }
1343                 idx, err := strconv.Atoi(split[0])
1344                 if err != nil {
1345                         if lineNum == 1 {
1346                                 return nil, fmt.Errorf("header does not look right: %q", csv)
1347                         }
1348                         return nil, fmt.Errorf("%s line %d: index: %s", samplesFilename, lineNum, err)
1349                 }
1350                 if idx != len(si) {
1351                         return nil, fmt.Errorf("%s line %d: index %d out of order", samplesFilename, lineNum, idx)
1352                 }
1353                 var pcaComponents []float64
1354                 if len(split) > 4 {
1355                         for _, s := range split[4:] {
1356                                 f, err := strconv.ParseFloat(s, 64)
1357                                 if err != nil {
1358                                         return nil, fmt.Errorf("%s line %d: cannot parse float %q: %s", samplesFilename, lineNum, s, err)
1359                                 }
1360                                 pcaComponents = append(pcaComponents, f)
1361                         }
1362                 }
1363                 si = append(si, sampleInfo{
1364                         id:            split[1],
1365                         isCase:        split[2] == "1",
1366                         isControl:     split[2] == "0",
1367                         isTraining:    split[3] == "1",
1368                         isValidation:  split[3] == "0" && len(split[2]) > 0, // fix errant 0s in input
1369                         pcaComponents: pcaComponents,
1370                 })
1371         }
1372         return si, nil
1373 }
1374
1375 func writeSampleInfo(samples []sampleInfo, outputDir string) error {
1376         fnm := outputDir + "/samples.csv"
1377         log.Infof("writing sample metadata to %s", fnm)
1378         f, err := os.Create(fnm)
1379         if err != nil {
1380                 return err
1381         }
1382         defer f.Close()
1383         pcaLabels := ""
1384         if len(samples) > 0 {
1385                 for i := range samples[0].pcaComponents {
1386                         pcaLabels += fmt.Sprintf(",PCA%d", i)
1387                 }
1388         }
1389         _, err = fmt.Fprintf(f, "Index,SampleID,CaseControl,TrainingValidation%s\n", pcaLabels)
1390         if err != nil {
1391                 return err
1392         }
1393         for i, si := range samples {
1394                 var cc, tv string
1395                 if si.isCase {
1396                         cc = "1"
1397                 } else if si.isControl {
1398                         cc = "0"
1399                 }
1400                 if si.isTraining {
1401                         tv = "1"
1402                 } else if si.isValidation {
1403                         tv = "0"
1404                 }
1405                 var pcavals string
1406                 for _, pcaval := range si.pcaComponents {
1407                         pcavals += fmt.Sprintf(",%f", pcaval)
1408                 }
1409                 _, err = fmt.Fprintf(f, "%d,%s,%s,%s%s\n", i, si.id, cc, tv, pcavals)
1410                 if err != nil {
1411                         return fmt.Errorf("write %s: %w", fnm, err)
1412                 }
1413         }
1414         err = f.Close()
1415         if err != nil {
1416                 return fmt.Errorf("close %s: %w", fnm, err)
1417         }
1418         log.Print("done")
1419         return nil
1420 }
1421
1422 func (cmd *sliceNumpy) filterHGVScolpair(colpair [2][]int8) bool {
1423         if cmd.chi2PValue >= 1 {
1424                 return true
1425         }
1426         col0 := make([]bool, 0, len(cmd.chi2Cases))
1427         col1 := make([]bool, 0, len(cmd.chi2Cases))
1428         cases := make([]bool, 0, len(cmd.chi2Cases))
1429         for i, c := range cmd.chi2Cases {
1430                 if colpair[0][i] < 0 {
1431                         continue
1432                 }
1433                 col0 = append(col0, colpair[0][i] != 0)
1434                 col1 = append(col1, colpair[1][i] != 0)
1435                 cases = append(cases, c)
1436         }
1437         return len(cases) >= cmd.minCoverage &&
1438                 (pvalue(col0, cases) <= cmd.chi2PValue || pvalue(col1, cases) <= cmd.chi2PValue)
1439 }
1440
1441 func writeNumpyUint32(fnm string, out []uint32, rows, cols int) error {
1442         output, err := os.Create(fnm)
1443         if err != nil {
1444                 return err
1445         }
1446         defer output.Close()
1447         bufw := bufio.NewWriterSize(output, 1<<26)
1448         npw, err := gonpy.NewWriter(nopCloser{bufw})
1449         if err != nil {
1450                 return err
1451         }
1452         log.WithFields(log.Fields{
1453                 "filename": fnm,
1454                 "rows":     rows,
1455                 "cols":     cols,
1456                 "bytes":    rows * cols * 4,
1457         }).Infof("writing numpy: %s", fnm)
1458         npw.Shape = []int{rows, cols}
1459         npw.WriteUint32(out)
1460         err = bufw.Flush()
1461         if err != nil {
1462                 return err
1463         }
1464         return output.Close()
1465 }
1466
1467 func writeNumpyInt32(fnm string, out []int32, rows, cols int) error {
1468         output, err := os.Create(fnm)
1469         if err != nil {
1470                 return err
1471         }
1472         defer output.Close()
1473         bufw := bufio.NewWriterSize(output, 1<<26)
1474         npw, err := gonpy.NewWriter(nopCloser{bufw})
1475         if err != nil {
1476                 return err
1477         }
1478         log.WithFields(log.Fields{
1479                 "filename": fnm,
1480                 "rows":     rows,
1481                 "cols":     cols,
1482                 "bytes":    rows * cols * 4,
1483         }).Infof("writing numpy: %s", fnm)
1484         npw.Shape = []int{rows, cols}
1485         npw.WriteInt32(out)
1486         err = bufw.Flush()
1487         if err != nil {
1488                 return err
1489         }
1490         return output.Close()
1491 }
1492
1493 func writeNumpyInt16(fnm string, out []int16, rows, cols int) error {
1494         output, err := os.Create(fnm)
1495         if err != nil {
1496                 return err
1497         }
1498         defer output.Close()
1499         bufw := bufio.NewWriterSize(output, 1<<26)
1500         npw, err := gonpy.NewWriter(nopCloser{bufw})
1501         if err != nil {
1502                 return err
1503         }
1504         log.WithFields(log.Fields{
1505                 "filename": fnm,
1506                 "rows":     rows,
1507                 "cols":     cols,
1508                 "bytes":    rows * cols * 2,
1509         }).Infof("writing numpy: %s", fnm)
1510         npw.Shape = []int{rows, cols}
1511         npw.WriteInt16(out)
1512         err = bufw.Flush()
1513         if err != nil {
1514                 return err
1515         }
1516         return output.Close()
1517 }
1518
1519 func writeNumpyInt8(fnm string, out []int8, rows, cols int) error {
1520         output, err := os.Create(fnm)
1521         if err != nil {
1522                 return err
1523         }
1524         defer output.Close()
1525         bufw := bufio.NewWriterSize(output, 1<<26)
1526         npw, err := gonpy.NewWriter(nopCloser{bufw})
1527         if err != nil {
1528                 return err
1529         }
1530         log.WithFields(log.Fields{
1531                 "filename": fnm,
1532                 "rows":     rows,
1533                 "cols":     cols,
1534                 "bytes":    rows * cols,
1535         }).Infof("writing numpy: %s", fnm)
1536         npw.Shape = []int{rows, cols}
1537         npw.WriteInt8(out)
1538         err = bufw.Flush()
1539         if err != nil {
1540                 return err
1541         }
1542         return output.Close()
1543 }
1544
1545 func allele2homhet(colpair [2][]int8) {
1546         a, b := colpair[0], colpair[1]
1547         for i, av := range a {
1548                 bv := b[i]
1549                 if av < 0 || bv < 0 {
1550                         // no-call
1551                         a[i], b[i] = -1, -1
1552                 } else if av > 0 && bv > 0 {
1553                         // hom
1554                         a[i], b[i] = 1, 0
1555                 } else if av > 0 || bv > 0 {
1556                         // het
1557                         a[i], b[i] = 0, 1
1558                 } else {
1559                         // ref (or a different variant in same position)
1560                         // (this is a no-op) a[i], b[i] = 0, 0
1561                 }
1562         }
1563 }
1564
1565 type onehotXref struct {
1566         tag     tagID
1567         variant tileVariantID
1568         hom     bool
1569         pvalue  float64
1570         maf     float64
1571 }
1572
1573 const onehotXrefSize = unsafe.Sizeof(onehotXref{})
1574
1575 // Build onehot matrix (m[tileVariantIndex][genome] == 0 or 1) for all
1576 // variants of a single tile/tag#.
1577 //
1578 // Return nil if no tile variant passes Χ² filter.
1579 func (cmd *sliceNumpy) tv2homhet(cgs map[string]CompactGenome, maxv tileVariantID, remap []tileVariantID, tag, chunkstarttag tagID, seq map[tagID][]TileVariant) ([][]int8, []onehotXref) {
1580         if tag == cmd.debugTag {
1581                 tv := make([]tileVariantID, len(cmd.cgnames)*2)
1582                 for i, name := range cmd.cgnames {
1583                         copy(tv[i*2:(i+1)*2], cgs[name].Variants[(tag-chunkstarttag)*2:])
1584                 }
1585                 log.WithFields(logrus.Fields{
1586                         "cgs[i].Variants[tag*2+j]": tv,
1587                         "maxv":                     maxv,
1588                         "remap":                    remap,
1589                         "tag":                      tag,
1590                         "chunkstarttag":            chunkstarttag,
1591                 }).Info("tv2homhet()")
1592         }
1593         if maxv < 1 || (maxv < 2 && !cmd.includeVariant1) {
1594                 // everyone has the most common variant (of the variants we don't drop)
1595                 return nil, nil
1596         }
1597         tagoffset := tag - chunkstarttag
1598         coverage := 0
1599         for _, cg := range cgs {
1600                 alleles := 0
1601                 for _, v := range cg.Variants[tagoffset*2 : tagoffset*2+2] {
1602                         if v > 0 && int(v) < len(seq[tag]) && len(seq[tag][v].Sequence) > 0 {
1603                                 alleles++
1604                         }
1605                 }
1606                 if alleles == 2 {
1607                         coverage++
1608                 }
1609         }
1610         if coverage < cmd.minCoverage {
1611                 return nil, nil
1612         }
1613         // "observed" array for p-value calculation (training set
1614         // only)
1615         obs := make([][]bool, (maxv+1)*2) // 2 slices (hom + het) for each variant#
1616         // one-hot output (all samples)
1617         outcols := make([][]int8, (maxv+1)*2)
1618         for i := range obs {
1619                 obs[i] = make([]bool, cmd.trainingSetSize)
1620                 outcols[i] = make([]int8, len(cmd.cgnames))
1621         }
1622         for cgid, name := range cmd.cgnames {
1623                 tsid := cmd.trainingSet[cgid]
1624                 cgvars := cgs[name].Variants[tagoffset*2:]
1625                 tv0, tv1 := remap[cgvars[0]], remap[cgvars[1]]
1626                 for v := tileVariantID(1); v <= maxv; v++ {
1627                         if tv0 == v && tv1 == v {
1628                                 if tsid >= 0 {
1629                                         obs[v*2][tsid] = true
1630                                 }
1631                                 outcols[v*2][cgid] = 1
1632                         } else if tv0 == v || tv1 == v {
1633                                 if tsid >= 0 {
1634                                         obs[v*2+1][tsid] = true
1635                                 }
1636                                 outcols[v*2+1][cgid] = 1
1637                         }
1638                 }
1639         }
1640         var onehot [][]int8
1641         var xref []onehotXref
1642         var maf float64
1643         for col := 2; col < len(obs); col++ {
1644                 // col 0,1 correspond to tile variant 0, i.e.,
1645                 // no-call; col 2,3 correspond to the most common
1646                 // variant; so we (normally) start at col 4.
1647                 if col < 4 && !cmd.includeVariant1 {
1648                         continue
1649                 }
1650                 if col&1 == 0 {
1651                         maf = homhet2maf(obs[col : col+2])
1652                         if maf < cmd.pvalueMinFrequency {
1653                                 // Skip both columns (hom and het) if
1654                                 // allele frequency is below threshold
1655                                 col++
1656                                 continue
1657                         }
1658                         if maf > cmd.maxFrequency {
1659                                 // Skip both columns if allele
1660                                 // frequency is above threshold
1661                                 col++
1662                                 continue
1663                         }
1664                 }
1665                 atomic.AddInt64(&cmd.pvalueCallCount, 1)
1666                 p := cmd.pvalue(obs[col])
1667                 if cmd.chi2PValue < 1 && !(p < cmd.chi2PValue) {
1668                         continue
1669                 }
1670                 onehot = append(onehot, outcols[col])
1671                 xref = append(xref, onehotXref{
1672                         tag:     tag,
1673                         variant: tileVariantID(col >> 1),
1674                         hom:     col&1 == 0,
1675                         pvalue:  p,
1676                         maf:     maf,
1677                 })
1678         }
1679         return onehot, xref
1680 }
1681
1682 func homhet2maf(onehot [][]bool) float64 {
1683         if len(onehot[0]) == 0 {
1684                 return 0
1685         }
1686         n := 0
1687         for i := range onehot[0] {
1688                 if onehot[0][i] {
1689                         // hom
1690                         n += 2
1691                 } else if onehot[1][i] {
1692                         // het
1693                         n += 1
1694                 }
1695         }
1696         return float64(n) / float64(len(onehot[0])*2)
1697 }
1698
1699 // convert a []onehotXref with length N to a numpy-style []int32
1700 // matrix with N columns, one row per field of onehotXref struct.
1701 //
1702 // Hom/het row contains hom=0, het=1.
1703 //
1704 // P-value row contains 1000000x actual p-value.
1705 func onehotXref2int32(xrefs []onehotXref) []int32 {
1706         xcols := len(xrefs)
1707         xdata := make([]int32, 6*xcols)
1708         for i, xref := range xrefs {
1709                 xdata[i] = int32(xref.tag)
1710                 xdata[xcols+i] = int32(xref.variant)
1711                 if xref.hom {
1712                         xdata[xcols*2+i] = 1
1713                 }
1714                 xdata[xcols*3+i] = int32(xref.pvalue * 1000000)
1715                 xdata[xcols*4+i] = int32(-math.Log10(xref.pvalue) * 1000000)
1716                 xdata[xcols*5+i] = int32(xref.maf * 1000000)
1717         }
1718         return xdata
1719 }
1720
1721 // transpose onehot data from in[col][row] to numpy-style
1722 // out[row*cols+col].
1723 func onehotcols2int8(in [][]int8) []int8 {
1724         if len(in) == 0 {
1725                 return nil
1726         }
1727         cols := len(in)
1728         rows := len(in[0])
1729         out := make([]int8, rows*cols)
1730         for row := 0; row < rows; row++ {
1731                 outrow := out[row*cols:]
1732                 for col, incol := range in {
1733                         outrow[col] = incol[row]
1734                 }
1735         }
1736         return out
1737 }
1738
1739 // Return [2][]uint32{rowIndices, colIndices} indicating which
1740 // elements of matrixT[c][r] have non-zero values.
1741 func onehotChunk2Indirect(matrixT [][]int8) [2][]uint32 {
1742         var nz [2][]uint32
1743         for c, col := range matrixT {
1744                 for r, val := range col {
1745                         if val != 0 {
1746                                 nz[0] = append(nz[0], uint32(r))
1747                                 nz[1] = append(nz[1], uint32(c))
1748                         }
1749                 }
1750         }
1751         return nz
1752 }