X-Git-Url: https://git.arvados.org/lightning.git/blobdiff_plain/cf6bba16548ea76aef580fce9fdd04abebcd7d3f..HEAD:/slicenumpy.go

diff --git a/slicenumpy.go b/slicenumpy.go
deleted file mode 100644
index 9e5e315c50..0000000000
--- a/slicenumpy.go
+++ /dev/null
@@ -1,1278 +0,0 @@
-// Copyright (C) The Lightning Authors. All rights reserved.
-//
-// SPDX-License-Identifier: AGPL-3.0
-
-package lightning
-
-import (
-	"bufio"
-	"bytes"
-	"encoding/gob"
-	"flag"
-	"fmt"
-	"io"
-	"io/ioutil"
-	"math"
-	"net/http"
-	_ "net/http/pprof"
-	"os"
-	"regexp"
-	"runtime"
-	"runtime/debug"
-	"sort"
-	"strconv"
-	"strings"
-	"sync/atomic"
-	"unsafe"
-
-	"git.arvados.org/arvados.git/sdk/go/arvados"
-	"github.com/arvados/lightning/hgvs"
-	"github.com/kshedden/gonpy"
-	log "github.com/sirupsen/logrus"
-	"golang.org/x/crypto/blake2b"
-)
-
-type sliceNumpy struct {
-	filter                filter
-	threads               int
-	chi2CaseControlColumn string
-	chi2CaseControlFile   string
-	chi2Cases             []bool
-	chi2PValue            float64
-	minCoverage           int
-	cgnames               []string
-}
-
-func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, stdout, stderr io.Writer) int {
-	var err error
-	defer func() {
-		if err != nil {
-			fmt.Fprintf(stderr, "%s\n", err)
-		}
-	}()
-	flags := flag.NewFlagSet("", flag.ContinueOnError)
-	flags.SetOutput(stderr)
-	pprof := flags.String("pprof", "", "serve Go profile data at http://`[addr]:port`")
-	runlocal := flags.Bool("local", false, "run on local host (default: run in an arvados container)")
-	projectUUID := flags.String("project", "", "project `UUID` for output data")
-	priority := flags.Int("priority", 500, "container request priority")
-	inputDir := flags.String("input-dir", "./in", "input `directory`")
-	outputDir := flags.String("output-dir", "./out", "output `directory`")
-	ref := flags.String("ref", "", "reference name (if blank, choose last one that appears in input)")
-	regionsFilename := flags.String("regions", "", "only output columns/annotations that intersect regions in specified bed `file`")
-	expandRegions := flags.Int("expand-regions", 0, "expand specified regions by `N` base pairs on each side`")
-	mergeOutput := flags.Bool("merge-output", false, "merge output into one matrix.npy and one matrix.annotations.csv")
-	hgvsSingle := flags.Bool("single-hgvs-matrix", false, "also generate hgvs-based matrix")
-	hgvsChunked := flags.Bool("chunked-hgvs-matrix", false, "also generate hgvs-based matrix per chromosome")
-	onehotSingle := flags.Bool("single-onehot", false, "generate one-hot tile-based matrix")
-	onehotChunked := flags.Bool("chunked-onehot", false, "generate one-hot tile-based matrix per input chunk")
-	flags.IntVar(&cmd.threads, "threads", 16, "number of memory-hungry assembly threads")
-	flags.StringVar(&cmd.chi2CaseControlFile, "chi2-case-control-file", "", "tsv file or directory indicating cases and controls for Χ² test (if directory, all .tsv files will be read)")
-	flags.StringVar(&cmd.chi2CaseControlColumn, "chi2-case-control-column", "", "name of case/control column in case-control files for Χ² test (value must be 0 for control, 1 for case)")
-	flags.Float64Var(&cmd.chi2PValue, "chi2-p-value", 1, "do Χ² test and omit columns with p-value above this threshold")
-	cmd.filter.Flags(flags)
-	err = flags.Parse(args)
-	if err == flag.ErrHelp {
-		err = nil
-		return 0
-	} else if err != nil {
-		return 2
-	}
-
-	if *pprof != "" {
-		go func() {
-			log.Println(http.ListenAndServe(*pprof, nil))
-		}()
-	}
-
-	if cmd.chi2PValue != 1 && (cmd.chi2CaseControlFile == "" || cmd.chi2CaseControlColumn == "") {
-		log.Errorf("cannot use provided -chi2-p-value=%f because -chi2-case-control-file= or -chi2-case-control-column= value is empty", cmd.chi2PValue)
-		return 2
-	}
-
-	if !*runlocal {
-		runner := arvadosContainerRunner{
-			Name:        "lightning slice-numpy",
-			Client:      arvados.NewClientFromEnv(),
-			ProjectUUID: *projectUUID,
-			RAM:         750000000000,
-			VCPUs:       96,
-			Priority:    *priority,
-			KeepCache:   2,
-			APIAccess:   true,
-		}
-		err = runner.TranslatePaths(inputDir, regionsFilename, &cmd.chi2CaseControlFile)
-		if err != nil {
-			return 1
-		}
-		runner.Args = []string{"slice-numpy", "-local=true",
-			"-pprof=:6060",
-			"-input-dir=" + *inputDir,
-			"-output-dir=/mnt/output",
-			"-threads=" + fmt.Sprintf("%d", cmd.threads),
-			"-regions=" + *regionsFilename,
-			"-expand-regions=" + fmt.Sprintf("%d", *expandRegions),
-			"-merge-output=" + fmt.Sprintf("%v", *mergeOutput),
-			"-single-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsSingle),
-			"-chunked-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsChunked),
-			"-single-onehot=" + fmt.Sprintf("%v", *onehotSingle),
-			"-chunked-onehot=" + fmt.Sprintf("%v", *onehotChunked),
-			"-chi2-case-control-file=" + cmd.chi2CaseControlFile,
-			"-chi2-case-control-column=" + cmd.chi2CaseControlColumn,
-			"-chi2-p-value=" + fmt.Sprintf("%f", cmd.chi2PValue),
-		}
-		runner.Args = append(runner.Args, cmd.filter.Args()...)
-		var output string
-		output, err = runner.Run()
-		if err != nil {
-			return 1
-		}
-		fmt.Fprintln(stdout, output)
-		return 0
-	}
-
-	infiles, err := allFiles(*inputDir, matchGobFile)
-	if err != nil {
-		return 1
-	}
-	if len(infiles) == 0 {
-		err = fmt.Errorf("no input files found in %s", *inputDir)
-		return 1
-	}
-	sort.Strings(infiles)
-
-	var refseq map[string][]tileLibRef
-	var reftiledata = make(map[tileLibRef][]byte, 11000000)
-	in0, err := open(infiles[0])
-	if err != nil {
-		return 1
-	}
-
-	matchGenome, err := regexp.Compile(cmd.filter.MatchGenome)
-	if err != nil {
-		err = fmt.Errorf("-match-genome: invalid regexp: %q", cmd.filter.MatchGenome)
-		return 1
-	}
-
-	cmd.cgnames = nil
-	taglen := -1
-	DecodeLibrary(in0, strings.HasSuffix(infiles[0], ".gz"), func(ent *LibraryEntry) error {
-		if len(ent.TagSet) > 0 {
-			taglen = len(ent.TagSet[0])
-		}
-		for _, cseq := range ent.CompactSequences {
-			if cseq.Name == *ref || *ref == "" {
-				refseq = cseq.TileSequences
-			}
-		}
-		for _, cg := range ent.CompactGenomes {
-			if matchGenome.MatchString(cg.Name) {
-				cmd.cgnames = append(cmd.cgnames, cg.Name)
-			}
-		}
-		for _, tv := range ent.TileVariants {
-			if tv.Ref {
-				reftiledata[tileLibRef{tv.Tag, tv.Variant}] = tv.Sequence
-			}
-		}
-		return nil
-	})
-	if err != nil {
-		return 1
-	}
-	in0.Close()
-	if refseq == nil {
-		err = fmt.Errorf("%s: reference sequence not found", infiles[0])
-		return 1
-	}
-	if taglen < 0 {
-		err = fmt.Errorf("tagset not found")
-		return 1
-	}
-	if len(cmd.cgnames) == 0 {
-		err = fmt.Errorf("no genomes found matching regexp %q", cmd.filter.MatchGenome)
-		return 1
-	}
-	sort.Strings(cmd.cgnames)
-	err = cmd.useCaseControlFiles()
-	if err != nil {
-		return 1
-	}
-	cmd.minCoverage = int(math.Ceil(cmd.filter.MinCoverage * float64(len(cmd.cgnames))))
-
-	{
-		labelsFilename := *outputDir + "/samples.csv"
-		log.Infof("writing labels to %s", labelsFilename)
-		var f *os.File
-		f, err = os.Create(labelsFilename)
-		if err != nil {
-			return 1
-		}
-		defer f.Close()
-		for i, name := range cmd.cgnames {
-			cc := 0
-			if cmd.chi2Cases != nil && cmd.chi2Cases[i] {
-				cc = 1
-			}
-			_, err = fmt.Fprintf(f, "%d,%q,%d\n", i, trimFilenameForLabel(name), cc)
-			if err != nil {
-				err = fmt.Errorf("write %s: %w", labelsFilename, err)
-				return 1
-			}
-		}
-		err = f.Close()
-		if err != nil {
-			err = fmt.Errorf("close %s: %w", labelsFilename, err)
-			return 1
-		}
-	}
-
-	log.Info("indexing reference tiles")
-	type reftileinfo struct {
-		variant  tileVariantID
-		seqname  string // chr1
-		pos      int    // distance from start of chromosome to starttag
-		tiledata []byte // acgtggcaa...
-	}
-	isdup := map[tagID]bool{}
-	reftile := map[tagID]*reftileinfo{}
-	for seqname, cseq := range refseq {
-		pos := 0
-		for _, libref := range cseq {
-			tiledata := reftiledata[libref]
-			if len(tiledata) == 0 {
-				err = fmt.Errorf("missing tiledata for tag %d variant %d in %s in ref", libref.Tag, libref.Variant, seqname)
-				return 1
-			}
-			if isdup[libref.Tag] {
-				log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
-			} else if reftile[libref.Tag] != nil {
-				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)
-				delete(reftile, libref.Tag)
-				log.Printf("dropping reference tile %+v from %s @ %d, tag not unique", libref, seqname, pos)
-				isdup[libref.Tag] = true
-			} else {
-				reftile[libref.Tag] = &reftileinfo{
-					seqname:  seqname,
-					variant:  libref.Variant,
-					tiledata: tiledata,
-					pos:      pos,
-				}
-			}
-			pos += len(tiledata) - taglen
-		}
-		log.Printf("... %s done, len %d", seqname, pos+taglen)
-	}
-
-	var mask *mask
-	if *regionsFilename != "" {
-		log.Printf("loading regions from %s", *regionsFilename)
-		mask, err = makeMask(*regionsFilename, *expandRegions)
-		if err != nil {
-			return 1
-		}
-		log.Printf("before applying mask, len(reftile) == %d", len(reftile))
-		log.Printf("deleting reftile entries for regions outside %d intervals", mask.Len())
-		for tag, rt := range reftile {
-			if !mask.Check(strings.TrimPrefix(rt.seqname, "chr"), rt.pos, rt.pos+len(rt.tiledata)) {
-				delete(reftile, tag)
-			}
-		}
-		log.Printf("after applying mask, len(reftile) == %d", len(reftile))
-	}
-
-	type hgvsColSet map[hgvs.Variant][2][]int8
-	encodeHGVS := throttle{Max: len(refseq)}
-	encodeHGVSTodo := map[string]chan hgvsColSet{}
-	tmpHGVSCols := map[string]*os.File{}
-	if *hgvsChunked {
-		for seqname := range refseq {
-			var f *os.File
-			f, err = os.Create(*outputDir + "/tmp." + seqname + ".gob")
-			if err != nil {
-				return 1
-			}
-			defer os.Remove(f.Name())
-			bufw := bufio.NewWriterSize(f, 1<<24)
-			enc := gob.NewEncoder(bufw)
-			tmpHGVSCols[seqname] = f
-			todo := make(chan hgvsColSet, 128)
-			encodeHGVSTodo[seqname] = todo
-			encodeHGVS.Go(func() error {
-				for colset := range todo {
-					err := enc.Encode(colset)
-					if err != nil {
-						encodeHGVS.Report(err)
-						for range todo {
-						}
-						return err
-					}
-				}
-				return bufw.Flush()
-			})
-		}
-	}
-
-	var toMerge [][]int16
-	if *mergeOutput || *hgvsSingle {
-		toMerge = make([][]int16, len(infiles))
-	}
-	var onehotIndirect [][2][]uint32 // [chunkIndex][axis][index]
-	var onehotXrefs [][]onehotXref
-	if *onehotSingle {
-		onehotIndirect = make([][2][]uint32, len(infiles))
-		onehotXrefs = make([][]onehotXref, len(infiles))
-	}
-
-	throttleMem := throttle{Max: cmd.threads} // TODO: estimate using mem and data size
-	throttleNumpyMem := throttle{Max: cmd.threads/2 + 1}
-	log.Info("generating annotations and numpy matrix for each slice")
-	var done int64
-	for infileIdx, infile := range infiles {
-		infileIdx, infile := infileIdx, infile
-		throttleMem.Go(func() error {
-			seq := make(map[tagID][]TileVariant, 50000)
-			cgs := make(map[string]CompactGenome, len(cmd.cgnames))
-			f, err := open(infile)
-			if err != nil {
-				return err
-			}
-			defer f.Close()
-			log.Infof("%04d: reading %s", infileIdx, infile)
-			err = DecodeLibrary(f, strings.HasSuffix(infile, ".gz"), func(ent *LibraryEntry) error {
-				for _, tv := range ent.TileVariants {
-					if tv.Ref {
-						continue
-					}
-					if mask != nil && reftile[tv.Tag] == nil {
-						// Don't waste
-						// time/memory on
-						// masked-out tiles.
-						continue
-					}
-					variants := seq[tv.Tag]
-					if len(variants) == 0 {
-						variants = make([]TileVariant, 100)
-					}
-					for len(variants) <= int(tv.Variant) {
-						variants = append(variants, TileVariant{})
-					}
-					variants[int(tv.Variant)] = tv
-					seq[tv.Tag] = variants
-				}
-				for _, cg := range ent.CompactGenomes {
-					if !matchGenome.MatchString(cg.Name) {
-						continue
-					}
-					// pad to full slice size
-					// to avoid out-of-bounds
-					// checks later
-					if sliceSize := 2 * int(cg.EndTag-cg.StartTag); len(cg.Variants) < sliceSize {
-						cg.Variants = append(cg.Variants, make([]tileVariantID, sliceSize-len(cg.Variants))...)
-					}
-					cgs[cg.Name] = cg
-				}
-				return nil
-			})
-			if err != nil {
-				return err
-			}
-			tagstart := cgs[cmd.cgnames[0]].StartTag
-			tagend := cgs[cmd.cgnames[0]].EndTag
-
-			// TODO: filters
-
-			log.Infof("%04d: renumber/dedup variants for tags %d-%d", infileIdx, tagstart, tagend)
-			variantRemap := make([][]tileVariantID, tagend-tagstart)
-			throttleCPU := throttle{Max: runtime.GOMAXPROCS(0)}
-			for tag, variants := range seq {
-				tag, variants := tag, variants
-				throttleCPU.Acquire()
-				go func() {
-					defer throttleCPU.Release()
-					count := make(map[[blake2b.Size256]byte]int, len(variants))
-
-					rt := reftile[tag]
-					if rt != nil {
-						count[blake2b.Sum256(rt.tiledata)] = 0
-					}
-
-					for _, cg := range cgs {
-						idx := int(tag-tagstart) * 2
-						for allele := 0; allele < 2; allele++ {
-							v := cg.Variants[idx+allele]
-							if v > 0 && len(variants[v].Sequence) > 0 {
-								count[variants[v].Blake2b]++
-							}
-						}
-					}
-					// hash[i] will be the hash of
-					// the variant(s) that should
-					// be at rank i (0-based).
-					hash := make([][blake2b.Size256]byte, 0, len(count))
-					for b := range count {
-						hash = append(hash, b)
-					}
-					sort.Slice(hash, func(i, j int) bool {
-						bi, bj := &hash[i], &hash[j]
-						if ci, cj := count[*bi], count[*bj]; ci != cj {
-							return ci > cj
-						} else {
-							return bytes.Compare((*bi)[:], (*bj)[:]) < 0
-						}
-					})
-					// rank[b] will be the 1-based
-					// new variant number for
-					// variants whose hash is b.
-					rank := make(map[[blake2b.Size256]byte]tileVariantID, len(hash))
-					for i, h := range hash {
-						rank[h] = tileVariantID(i + 1)
-					}
-					// remap[v] will be the new
-					// variant number for original
-					// variant number v.
-					remap := make([]tileVariantID, len(variants))
-					for i, tv := range variants {
-						remap[i] = rank[tv.Blake2b]
-					}
-					variantRemap[tag-tagstart] = remap
-					if rt != nil {
-						rt.variant = rank[blake2b.Sum256(rt.tiledata)]
-					}
-				}()
-			}
-			throttleCPU.Wait()
-
-			var onehotChunk [][]int8
-			var onehotXref []onehotXref
-
-			annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, infileIdx)
-			log.Infof("%04d: writing %s", infileIdx, annotationsFilename)
-			annof, err := os.Create(annotationsFilename)
-			if err != nil {
-				return err
-			}
-			annow := bufio.NewWriterSize(annof, 1<<20)
-			outcol := 0
-			for tag := tagstart; tag < tagend; tag++ {
-				rt, ok := reftile[tag]
-				if !ok {
-					if mask == nil {
-						outcol++
-					}
-					// Excluded by specified
-					// regions, or reference does
-					// not use any variant of this
-					// tile. (TODO: log this?
-					// mention it in annotations?)
-					continue
-				}
-				remap := variantRemap[tag-tagstart]
-				maxv := tileVariantID(0)
-				for _, v := range remap {
-					if maxv < v {
-						maxv = v
-					}
-				}
-				if *onehotChunked || *onehotSingle {
-					onehot, xrefs := cmd.tv2homhet(cgs, maxv, remap, tag, tagstart)
-					onehotChunk = append(onehotChunk, onehot...)
-					onehotXref = append(onehotXref, xrefs...)
-				}
-				fmt.Fprintf(annow, "%d,%d,%d,=,%s,%d,,,\n", tag, outcol, rt.variant, rt.seqname, rt.pos)
-				variants := seq[tag]
-				reftilestr := strings.ToUpper(string(rt.tiledata))
-
-				done := make([]bool, maxv+1)
-				variantDiffs := make([][]hgvs.Variant, maxv+1)
-				for v, tv := range variants {
-					v := remap[v]
-					if v == rt.variant || done[v] {
-						continue
-					} else {
-						done[v] = true
-					}
-					if len(tv.Sequence) < taglen || !bytes.HasSuffix(rt.tiledata, tv.Sequence[len(tv.Sequence)-taglen:]) {
-						fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
-						continue
-					}
-					if lendiff := len(rt.tiledata) - len(tv.Sequence); lendiff < -1000 || lendiff > 1000 {
-						fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
-						continue
-					}
-					diffs, _ := hgvs.Diff(reftilestr, strings.ToUpper(string(tv.Sequence)), 0)
-					for i := range diffs {
-						diffs[i].Position += rt.pos
-					}
-					for _, diff := range diffs {
-						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)
-					}
-					if *hgvsChunked {
-						variantDiffs[v] = diffs
-					}
-				}
-				if *hgvsChunked {
-					// We can now determine, for each HGVS
-					// variant (diff) in this reftile
-					// region, whether a given genome
-					// phase/allele (1) has the variant, (0) has
-					// =ref or a different variant in that
-					// position, or (-1) is lacking
-					// coverage / couldn't be diffed.
-					hgvsCol := hgvsColSet{}
-					for _, diffs := range variantDiffs {
-						for _, diff := range diffs {
-							if _, ok := hgvsCol[diff]; ok {
-								continue
-							}
-							hgvsCol[diff] = [2][]int8{
-								make([]int8, len(cmd.cgnames)),
-								make([]int8, len(cmd.cgnames)),
-							}
-						}
-					}
-					for row, name := range cmd.cgnames {
-						variants := cgs[name].Variants[(tag-tagstart)*2:]
-						for ph := 0; ph < 2; ph++ {
-							v := variants[ph]
-							if int(v) >= len(remap) {
-								v = 0
-							} else {
-								v = remap[v]
-							}
-							if v == rt.variant {
-								// hgvsCol[*][ph][row] is already 0
-							} else if len(variantDiffs[v]) == 0 {
-								// lacking coverage / couldn't be diffed
-								for _, col := range hgvsCol {
-									col[ph][row] = -1
-								}
-							} else {
-								for _, diff := range variantDiffs[v] {
-									hgvsCol[diff][ph][row] = 1
-								}
-							}
-						}
-					}
-					for diff, colpair := range hgvsCol {
-						allele2homhet(colpair)
-						if !cmd.filterHGVScolpair(colpair) {
-							delete(hgvsCol, diff)
-						}
-					}
-					if len(hgvsCol) > 0 {
-						encodeHGVSTodo[rt.seqname] <- hgvsCol
-					}
-				}
-				outcol++
-			}
-			err = annow.Flush()
-			if err != nil {
-				return err
-			}
-			err = annof.Close()
-			if err != nil {
-				return err
-			}
-
-			if *onehotChunked {
-				// transpose onehotChunk[col][row] to numpy[row*ncols+col]
-				rows := len(cmd.cgnames)
-				cols := len(onehotChunk)
-				log.Infof("%04d: preparing onehot numpy (rows=%d, cols=%d, mem=%d)", infileIdx, len(cmd.cgnames), len(onehotChunk), len(cmd.cgnames)*len(onehotChunk))
-				throttleNumpyMem.Acquire()
-				out := onehotcols2int8(onehotChunk)
-				fnm := fmt.Sprintf("%s/onehot.%04d.npy", *outputDir, infileIdx)
-				err = writeNumpyInt8(fnm, out, rows, cols)
-				if err != nil {
-					return err
-				}
-				fnm = fmt.Sprintf("%s/onehot-columns.%04d.npy", *outputDir, infileIdx)
-				err = writeNumpyInt32(fnm, onehotXref2int32(onehotXref), 4, len(onehotXref))
-				if err != nil {
-					return err
-				}
-				debug.FreeOSMemory()
-				throttleNumpyMem.Release()
-			}
-			if *onehotSingle {
-				log.Infof("%04d: keeping onehot chunk in memory (rows=%d, cols=%d, mem=%d)", infileIdx, len(cmd.cgnames), len(onehotChunk), (len(cmd.cgnames)+int(onehotXrefSize))*len(onehotChunk))
-				onehotIndirect[infileIdx] = onehotChunk2Indirect(onehotChunk)
-				onehotXrefs[infileIdx] = onehotXref
-			}
-			if !(*onehotSingle || *onehotChunked) || *mergeOutput || *hgvsSingle {
-				log.Infof("%04d: preparing numpy", infileIdx)
-				throttleNumpyMem.Acquire()
-				rows := len(cmd.cgnames)
-				cols := 2 * outcol
-				out := make([]int16, rows*cols)
-				for row, name := range cmd.cgnames {
-					out := out[row*cols:]
-					outcol := 0
-					for col, v := range cgs[name].Variants {
-						tag := tagstart + tagID(col/2)
-						if mask != nil && reftile[tag] == nil {
-							continue
-						}
-						if variants, ok := seq[tag]; ok && len(variants) > int(v) && len(variants[v].Sequence) > 0 {
-							out[outcol] = int16(variantRemap[tag-tagstart][v])
-						} else {
-							out[outcol] = -1
-						}
-						outcol++
-					}
-				}
-				seq = nil
-				cgs = nil
-				debug.FreeOSMemory()
-				throttleNumpyMem.Release()
-				if *mergeOutput || *hgvsSingle {
-					log.Infof("%04d: matrix fragment %d rows x %d cols", infileIdx, rows, cols)
-					toMerge[infileIdx] = out
-				}
-				if !*mergeOutput && !*onehotChunked && !*onehotSingle {
-					fnm := fmt.Sprintf("%s/matrix.%04d.npy", *outputDir, infileIdx)
-					err = writeNumpyInt16(fnm, out, rows, cols)
-					if err != nil {
-						return err
-					}
-				}
-			}
-			debug.FreeOSMemory()
-			log.Infof("%s: done (%d/%d)", infile, int(atomic.AddInt64(&done, 1)), len(infiles))
-			return nil
-		})
-	}
-	if err = throttleMem.Wait(); err != nil {
-		return 1
-	}
-
-	if *hgvsChunked {
-		log.Info("flushing hgvsCols temp files")
-		for seqname := range refseq {
-			close(encodeHGVSTodo[seqname])
-		}
-		err = encodeHGVS.Wait()
-		if err != nil {
-			return 1
-		}
-		for seqname := range refseq {
-			log.Infof("%s: reading hgvsCols from temp file", seqname)
-			f := tmpHGVSCols[seqname]
-			_, err = f.Seek(0, io.SeekStart)
-			if err != nil {
-				return 1
-			}
-			var hgvsCols hgvsColSet
-			dec := gob.NewDecoder(bufio.NewReaderSize(f, 1<<24))
-			for err == nil {
-				err = dec.Decode(&hgvsCols)
-			}
-			if err != io.EOF {
-				return 1
-			}
-			log.Infof("%s: sorting %d hgvs variants", seqname, len(hgvsCols))
-			variants := make([]hgvs.Variant, 0, len(hgvsCols))
-			for v := range hgvsCols {
-				variants = append(variants, v)
-			}
-			sort.Slice(variants, func(i, j int) bool {
-				vi, vj := &variants[i], &variants[j]
-				if vi.Position != vj.Position {
-					return vi.Position < vj.Position
-				} else if vi.Ref != vj.Ref {
-					return vi.Ref < vj.Ref
-				} else {
-					return vi.New < vj.New
-				}
-			})
-			rows := len(cmd.cgnames)
-			cols := len(variants) * 2
-			log.Infof("%s: building hgvs matrix (rows=%d, cols=%d, mem=%d)", seqname, rows, cols, rows*cols)
-			out := make([]int8, rows*cols)
-			for varIdx, variant := range variants {
-				hgvsCols := hgvsCols[variant]
-				for row := range cmd.cgnames {
-					for ph := 0; ph < 2; ph++ {
-						out[row*cols+varIdx+ph] = hgvsCols[ph][row]
-					}
-				}
-			}
-			err = writeNumpyInt8(fmt.Sprintf("%s/hgvs.%s.npy", *outputDir, seqname), out, rows, cols)
-			if err != nil {
-				return 1
-			}
-			out = nil
-
-			fnm := fmt.Sprintf("%s/hgvs.%s.annotations.csv", *outputDir, seqname)
-			log.Infof("%s: writing hgvs column labels to %s", seqname, fnm)
-			var hgvsLabels bytes.Buffer
-			for varIdx, variant := range variants {
-				fmt.Fprintf(&hgvsLabels, "%d,%s:g.%s\n", varIdx, seqname, variant.String())
-			}
-			err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0666)
-			if err != nil {
-				return 1
-			}
-		}
-	}
-
-	if *mergeOutput || *hgvsSingle {
-		var annow *bufio.Writer
-		var annof *os.File
-		if *mergeOutput {
-			annoFilename := fmt.Sprintf("%s/matrix.annotations.csv", *outputDir)
-			annof, err = os.Create(annoFilename)
-			if err != nil {
-				return 1
-			}
-			annow = bufio.NewWriterSize(annof, 1<<20)
-		}
-
-		rows := len(cmd.cgnames)
-		cols := 0
-		for _, chunk := range toMerge {
-			cols += len(chunk) / rows
-		}
-		log.Infof("merging output matrix (rows=%d, cols=%d, mem=%d) and annotations", rows, cols, rows*cols*2)
-		var out []int16
-		if *mergeOutput {
-			out = make([]int16, rows*cols)
-		}
-		hgvsCols := map[string][2][]int16{} // hgvs -> [[g0,g1,g2,...], [g0,g1,g2,...]] (slice of genomes for each phase)
-		startcol := 0
-		for outIdx, chunk := range toMerge {
-			chunkcols := len(chunk) / rows
-			if *mergeOutput {
-				for row := 0; row < rows; row++ {
-					copy(out[row*cols+startcol:], chunk[row*chunkcols:(row+1)*chunkcols])
-				}
-			}
-			toMerge[outIdx] = nil
-
-			annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, outIdx)
-			log.Infof("reading %s", annotationsFilename)
-			buf, err := os.ReadFile(annotationsFilename)
-			if err != nil {
-				return 1
-			}
-			if *mergeOutput {
-				err = os.Remove(annotationsFilename)
-				if err != nil {
-					return 1
-				}
-			}
-			for _, line := range bytes.Split(buf, []byte{'\n'}) {
-				if len(line) == 0 {
-					continue
-				}
-				fields := bytes.SplitN(line, []byte{','}, 9)
-				tag, _ := strconv.Atoi(string(fields[0]))
-				incol, _ := strconv.Atoi(string(fields[1]))
-				tileVariant, _ := strconv.Atoi(string(fields[2]))
-				hgvsID := string(fields[3])
-				seqname := string(fields[4])
-				pos, _ := strconv.Atoi(string(fields[5]))
-				refseq := fields[6]
-				if hgvsID == "" {
-					// Null entry for un-diffable
-					// tile variant
-					continue
-				}
-				if hgvsID == "=" {
-					// Null entry for ref tile
-					continue
-				}
-				if mask != nil && !mask.Check(strings.TrimPrefix(seqname, "chr"), pos, pos+len(refseq)) {
-					// The tile intersects one of
-					// the selected regions, but
-					// this particular HGVS
-					// variant does not.
-					continue
-				}
-				hgvsColPair := hgvsCols[hgvsID]
-				if hgvsColPair[0] == nil {
-					// values in new columns start
-					// out as -1 ("no data yet")
-					// or 0 ("=ref") here, may
-					// change to 1 ("hgvs variant
-					// present") below, either on
-					// this line or a future line.
-					hgvsColPair = [2][]int16{make([]int16, len(cmd.cgnames)), make([]int16, len(cmd.cgnames))}
-					rt, ok := reftile[tagID(tag)]
-					if !ok {
-						err = fmt.Errorf("bug: seeing annotations for tag %d, but it has no reftile entry", tag)
-						return 1
-					}
-					for ph := 0; ph < 2; ph++ {
-						for row := 0; row < rows; row++ {
-							v := chunk[row*chunkcols+incol*2+ph]
-							if tileVariantID(v) == rt.variant {
-								hgvsColPair[ph][row] = 0
-							} else {
-								hgvsColPair[ph][row] = -1
-							}
-						}
-					}
-					hgvsCols[hgvsID] = hgvsColPair
-					if annow != nil {
-						hgvsref := hgvs.Variant{
-							Position: pos,
-							Ref:      string(refseq),
-							New:      string(refseq),
-						}
-						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])
-					}
-				}
-				if annow != nil {
-					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])
-				}
-				for ph := 0; ph < 2; ph++ {
-					for row := 0; row < rows; row++ {
-						v := chunk[row*chunkcols+incol*2+ph]
-						if int(v) == tileVariant {
-							hgvsColPair[ph][row] = 1
-						}
-					}
-				}
-			}
-
-			startcol += chunkcols
-		}
-		if *mergeOutput {
-			err = annow.Flush()
-			if err != nil {
-				return 1
-			}
-			err = annof.Close()
-			if err != nil {
-				return 1
-			}
-			err = writeNumpyInt16(fmt.Sprintf("%s/matrix.npy", *outputDir), out, rows, cols)
-			if err != nil {
-				return 1
-			}
-		}
-		out = nil
-
-		if *hgvsSingle {
-			cols = len(hgvsCols) * 2
-			log.Printf("building hgvs-based matrix: %d rows x %d cols", rows, cols)
-			out = make([]int16, rows*cols)
-			hgvsIDs := make([]string, 0, cols/2)
-			for hgvsID := range hgvsCols {
-				hgvsIDs = append(hgvsIDs, hgvsID)
-			}
-			sort.Strings(hgvsIDs)
-			var hgvsLabels bytes.Buffer
-			for idx, hgvsID := range hgvsIDs {
-				fmt.Fprintf(&hgvsLabels, "%d,%s\n", idx, hgvsID)
-				for ph := 0; ph < 2; ph++ {
-					hgvscol := hgvsCols[hgvsID][ph]
-					for row, val := range hgvscol {
-						out[row*cols+idx*2+ph] = val
-					}
-				}
-			}
-			err = writeNumpyInt16(fmt.Sprintf("%s/hgvs.npy", *outputDir), out, rows, cols)
-			if err != nil {
-				return 1
-			}
-
-			fnm := fmt.Sprintf("%s/hgvs.annotations.csv", *outputDir)
-			log.Printf("writing hgvs labels: %s", fnm)
-			err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0777)
-			if err != nil {
-				return 1
-			}
-		}
-	}
-	if *onehotSingle {
-		nzCount := 0
-		for _, part := range onehotIndirect {
-			nzCount += len(part[0])
-		}
-		onehot := make([]uint32, nzCount*2) // [r,r,r,...,c,c,c,...]
-		var xrefs []onehotXref
-		outcol := 0
-		for i, part := range onehotIndirect {
-			for i := range part[1] {
-				part[1][i] += uint32(outcol)
-			}
-			copy(onehot[outcol:], part[0])
-			copy(onehot[outcol+nzCount:], part[1])
-			outcol += len(part[0])
-			xrefs = append(xrefs, onehotXrefs[i]...)
-
-			part[0] = nil
-			part[1] = nil
-			onehotXrefs[i] = nil
-			debug.FreeOSMemory()
-		}
-		fnm := fmt.Sprintf("%s/onehot.npy", *outputDir)
-		err = writeNumpyUint32(fnm, onehot, 2, nzCount)
-		if err != nil {
-			return 1
-		}
-		fnm = fmt.Sprintf("%s/onehot-columns.npy", *outputDir)
-		err = writeNumpyInt32(fnm, onehotXref2int32(xrefs), 4, len(xrefs))
-		if err != nil {
-			return 1
-		}
-	}
-	return 0
-}
-
-// Read case/control files, remove non-case/control entries from
-// cmd.cgnames, and build cmd.chi2Cases.
-func (cmd *sliceNumpy) useCaseControlFiles() error {
-	if cmd.chi2CaseControlFile == "" {
-		return nil
-	}
-	infiles, err := allFiles(cmd.chi2CaseControlFile, nil)
-	if err != nil {
-		return err
-	}
-	// index in cmd.cgnames => case(true) / control(false)
-	cc := map[int]bool{}
-	for _, infile := range infiles {
-		f, err := open(infile)
-		if err != nil {
-			return err
-		}
-		buf, err := io.ReadAll(f)
-		f.Close()
-		if err != nil {
-			return err
-		}
-		ccCol := -1
-		for _, tsv := range bytes.Split(buf, []byte{'\n'}) {
-			if len(tsv) == 0 {
-				continue
-			}
-			split := strings.Split(string(tsv), "\t")
-			if ccCol < 0 {
-				// header row
-				for col, name := range split {
-					if name == cmd.chi2CaseControlColumn {
-						ccCol = col
-						break
-					}
-				}
-				if ccCol < 0 {
-					return fmt.Errorf("%s: no column named %q in header row %q", infile, cmd.chi2CaseControlColumn, tsv)
-				}
-				continue
-			}
-			if len(split) <= ccCol {
-				continue
-			}
-			pattern := split[0]
-			found := -1
-			for i, name := range cmd.cgnames {
-				if strings.Contains(name, pattern) {
-					if found >= 0 {
-						log.Warnf("pattern %q in %s matches multiple genome IDs (%qs, %q)", pattern, infile, cmd.cgnames[found], name)
-					}
-					found = i
-				}
-			}
-			if found < 0 {
-				log.Warnf("pattern %q in %s does not match any genome IDs", pattern, infile)
-				continue
-			}
-			if split[ccCol] == "0" {
-				cc[found] = false
-			}
-			if split[ccCol] == "1" {
-				cc[found] = true
-			}
-		}
-	}
-	allnames := cmd.cgnames
-	cmd.cgnames = nil
-	cmd.chi2Cases = nil
-	ncases := 0
-	for i, name := range allnames {
-		if cc, ok := cc[i]; ok {
-			cmd.cgnames = append(cmd.cgnames, name)
-			cmd.chi2Cases = append(cmd.chi2Cases, cc)
-			if cc {
-				ncases++
-			}
-		}
-	}
-	log.Printf("%d cases, %d controls, %d neither (dropped)", ncases, len(cmd.cgnames)-ncases, len(allnames)-len(cmd.cgnames))
-	return nil
-}
-
-func (cmd *sliceNumpy) filterHGVScolpair(colpair [2][]int8) bool {
-	if cmd.chi2PValue >= 1 {
-		return true
-	}
-	col0 := make([]bool, 0, len(cmd.chi2Cases))
-	col1 := make([]bool, 0, len(cmd.chi2Cases))
-	cases := make([]bool, 0, len(cmd.chi2Cases))
-	for i, c := range cmd.chi2Cases {
-		if colpair[0][i] < 0 {
-			continue
-		}
-		col0 = append(col0, colpair[0][i] != 0)
-		col1 = append(col1, colpair[1][i] != 0)
-		cases = append(cases, c)
-	}
-	return len(cases) >= cmd.minCoverage &&
-		(pvalue(col0, cases) <= cmd.chi2PValue || pvalue(col1, cases) <= cmd.chi2PValue)
-}
-
-func writeNumpyUint32(fnm string, out []uint32, rows, cols int) error {
-	output, err := os.Create(fnm)
-	if err != nil {
-		return err
-	}
-	defer output.Close()
-	bufw := bufio.NewWriterSize(output, 1<<26)
-	npw, err := gonpy.NewWriter(nopCloser{bufw})
-	if err != nil {
-		return err
-	}
-	log.WithFields(log.Fields{
-		"filename": fnm,
-		"rows":     rows,
-		"cols":     cols,
-		"bytes":    rows * cols * 4,
-	}).Infof("writing numpy: %s", fnm)
-	npw.Shape = []int{rows, cols}
-	npw.WriteUint32(out)
-	err = bufw.Flush()
-	if err != nil {
-		return err
-	}
-	return output.Close()
-}
-
-func writeNumpyInt32(fnm string, out []int32, rows, cols int) error {
-	output, err := os.Create(fnm)
-	if err != nil {
-		return err
-	}
-	defer output.Close()
-	bufw := bufio.NewWriterSize(output, 1<<26)
-	npw, err := gonpy.NewWriter(nopCloser{bufw})
-	if err != nil {
-		return err
-	}
-	log.WithFields(log.Fields{
-		"filename": fnm,
-		"rows":     rows,
-		"cols":     cols,
-		"bytes":    rows * cols * 4,
-	}).Infof("writing numpy: %s", fnm)
-	npw.Shape = []int{rows, cols}
-	npw.WriteInt32(out)
-	err = bufw.Flush()
-	if err != nil {
-		return err
-	}
-	return output.Close()
-}
-
-func writeNumpyInt16(fnm string, out []int16, rows, cols int) error {
-	output, err := os.Create(fnm)
-	if err != nil {
-		return err
-	}
-	defer output.Close()
-	bufw := bufio.NewWriterSize(output, 1<<26)
-	npw, err := gonpy.NewWriter(nopCloser{bufw})
-	if err != nil {
-		return err
-	}
-	log.WithFields(log.Fields{
-		"filename": fnm,
-		"rows":     rows,
-		"cols":     cols,
-		"bytes":    rows * cols * 2,
-	}).Infof("writing numpy: %s", fnm)
-	npw.Shape = []int{rows, cols}
-	npw.WriteInt16(out)
-	err = bufw.Flush()
-	if err != nil {
-		return err
-	}
-	return output.Close()
-}
-
-func writeNumpyInt8(fnm string, out []int8, rows, cols int) error {
-	output, err := os.Create(fnm)
-	if err != nil {
-		return err
-	}
-	defer output.Close()
-	bufw := bufio.NewWriterSize(output, 1<<26)
-	npw, err := gonpy.NewWriter(nopCloser{bufw})
-	if err != nil {
-		return err
-	}
-	log.WithFields(log.Fields{
-		"filename": fnm,
-		"rows":     rows,
-		"cols":     cols,
-		"bytes":    rows * cols,
-	}).Infof("writing numpy: %s", fnm)
-	npw.Shape = []int{rows, cols}
-	npw.WriteInt8(out)
-	err = bufw.Flush()
-	if err != nil {
-		return err
-	}
-	return output.Close()
-}
-
-func allele2homhet(colpair [2][]int8) {
-	a, b := colpair[0], colpair[1]
-	for i, av := range a {
-		bv := b[i]
-		if av < 0 || bv < 0 {
-			// no-call
-			a[i], b[i] = -1, -1
-		} else if av > 0 && bv > 0 {
-			// hom
-			a[i], b[i] = 1, 0
-		} else if av > 0 || bv > 0 {
-			// het
-			a[i], b[i] = 0, 1
-		} else {
-			// ref (or a different variant in same position)
-			// (this is a no-op) a[i], b[i] = 0, 0
-		}
-	}
-}
-
-type onehotXref struct {
-	tag     tagID
-	variant tileVariantID
-	het     bool
-	pvalue  float64
-}
-
-const onehotXrefSize = unsafe.Sizeof(onehotXref{})
-
-// Build onehot matrix (m[variant*2+isHet][genome] == 0 or 1) for all
-// variants of a single tile/tag#.
-//
-// Return nil if no tile variant passes Χ² filter.
-func (cmd *sliceNumpy) tv2homhet(cgs map[string]CompactGenome, maxv tileVariantID, remap []tileVariantID, tag, chunkstarttag tagID) ([][]int8, []onehotXref) {
-	if maxv < 2 {
-		// everyone has the most common variant
-		return nil, nil
-	}
-	tagoffset := tag - chunkstarttag
-	coverage := 0
-	for _, cg := range cgs {
-		if cg.Variants[tagoffset*2] > 0 && cg.Variants[tagoffset*2+1] > 0 {
-			coverage++
-		}
-	}
-	if coverage < cmd.minCoverage {
-		return nil, nil
-	}
-	obs := make([][]bool, (maxv+1)*2) // 2 slices (hom + het) for each variant#
-	for i := range obs {
-		obs[i] = make([]bool, len(cmd.cgnames))
-	}
-	for cgid, name := range cmd.cgnames {
-		cgvars := cgs[name].Variants
-		for v := tileVariantID(2); v <= maxv; v++ {
-			if remap[cgvars[tagoffset*2]] == v && remap[cgvars[tagoffset*2+1]] == v {
-				obs[v*2][cgid] = true
-			} else if remap[cgvars[tagoffset*2]] == v || remap[cgvars[tagoffset*2+1]] == v {
-				obs[v*2+1][cgid] = true
-			}
-		}
-	}
-	var onehot [][]int8
-	var xref []onehotXref
-	for homcol := 4; homcol < len(obs); homcol += 2 {
-		p := [2]float64{
-			pvalue(obs[homcol], cmd.chi2Cases),
-			pvalue(obs[homcol+1], cmd.chi2Cases),
-		}
-		if cmd.chi2PValue < 1 && !(p[0] < cmd.chi2PValue || p[1] < cmd.chi2PValue) {
-			continue
-		}
-		for het := 0; het < 2; het++ {
-			onehot = append(onehot, bool2int8(obs[homcol+het]))
-			xref = append(xref, onehotXref{
-				tag:     tag,
-				variant: tileVariantID(homcol / 2),
-				het:     het == 1,
-				pvalue:  p[het],
-			})
-		}
-	}
-	return onehot, xref
-}
-
-func bool2int8(in []bool) []int8 {
-	out := make([]int8, len(in))
-	for i, v := range in {
-		if v {
-			out[i] = 1
-		}
-	}
-	return out
-}
-
-// convert a []onehotXref with length N to a numpy-style []int32
-// matrix with N columns, one row per field of onehotXref struct.
-//
-// Hom/het row contains hom=0, het=1.
-//
-// P-value row contains 1000000x actual p-value.
-func onehotXref2int32(xrefs []onehotXref) []int32 {
-	xcols := len(xrefs)
-	xdata := make([]int32, 4*xcols)
-	for i, xref := range xrefs {
-		xdata[i] = int32(xref.tag)
-		xdata[xcols+i] = int32(xref.variant)
-		if xref.het {
-			xdata[xcols*2+i] = 1
-		}
-		xdata[xcols*3+i] = int32(xref.pvalue * 1000000)
-	}
-	return xdata
-}
-
-// transpose onehot data from in[col][row] to numpy-style
-// out[row*cols+col].
-func onehotcols2int8(in [][]int8) []int8 {
-	if len(in) == 0 {
-		return nil
-	}
-	cols := len(in)
-	rows := len(in[0])
-	out := make([]int8, rows*cols)
-	for row := 0; row < rows; row++ {
-		outrow := out[row*cols:]
-		for col, incol := range in {
-			outrow[col] = incol[row]
-		}
-	}
-	return out
-}
-
-// Return [2][]uint32{rowIndices, colIndices} indicating which
-// elements of matrixT[c][r] have non-zero values.
-func onehotChunk2Indirect(matrixT [][]int8) [2][]uint32 {
-	var nz [2][]uint32
-	for c, col := range matrixT {
-		for r, val := range col {
-			if val != 0 {
-				nz[0] = append(nz[0], uint32(r))
-				nz[1] = append(nz[1], uint32(c))
-			}
-		}
-	}
-	return nz
-}