X-Git-Url: https://git.arvados.org/lightning.git/blobdiff_plain/0bdd658af496fbc2ca2f9e55a5f4ee6c18d06b66..HEAD:/slicenumpy.go

diff --git a/slicenumpy.go b/slicenumpy.go
deleted file mode 100644
index c3d02a99bc..0000000000
--- a/slicenumpy.go
+++ /dev/null
@@ -1,1713 +0,0 @@
-// Copyright (C) The Lightning Authors. All rights reserved.
-//
-// SPDX-License-Identifier: AGPL-3.0
-
-package lightning
-
-import (
-	"bufio"
-	"bytes"
-	"encoding/gob"
-	"encoding/json"
-	"errors"
-	"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/james-bowman/nlp"
-	"github.com/kshedden/gonpy"
-	"github.com/sirupsen/logrus"
-	log "github.com/sirupsen/logrus"
-	"golang.org/x/crypto/blake2b"
-	"gonum.org/v1/gonum/mat"
-)
-
-const annotationMaxTileSpan = 100
-
-type sliceNumpy struct {
-	filter          filter
-	threads         int
-	chi2Cases       []bool
-	chi2PValue      float64
-	glmMinFrequency float64
-	pcaComponents   int
-	minCoverage     int
-	includeVariant1 bool
-	debugTag        tagID
-
-	cgnames         []string
-	samples         []sampleInfo
-	trainingSet     []int // samples index => training set index, or -1 if not in training set
-	trainingSetSize int
-	pvalue          func(onehot []bool) float64
-	pvalueCallCount int64
-}
-
-func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, stdout, stderr io.Writer) int {
-	err := cmd.run(prog, args, stdin, stdout, stderr)
-	if err != nil {
-		fmt.Fprintf(stderr, "%s\n", err)
-		return 1
-	}
-	return 0
-}
-
-func (cmd *sliceNumpy) run(prog string, args []string, stdin io.Reader, stdout, stderr io.Writer) error {
-	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)")
-	arvadosRAM := flags.Int("arvados-ram", 750000000000, "amount of memory to request for arvados container (`bytes`)")
-	arvadosVCPUs := flags.Int("arvados-vcpus", 96, "number of VCPUs to request for arvados container")
-	projectUUID := flags.String("project", "", "project `UUID` for output data")
-	priority := flags.Int("priority", 500, "container request priority")
-	preemptible := flags.Bool("preemptible", true, "request preemptible instance")
-	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")
-	samplesFilename := flags.String("samples", "", "`samples.csv` file with training/validation and case/control groups (see 'lightning choose-samples')")
-	caseControlOnly := flags.Bool("case-control-only", false, "drop samples that are not in case/control groups")
-	onlyPCA := flags.Bool("pca", false, "run principal component analysis, write components to pca.npy and samples.csv")
-	flags.IntVar(&cmd.pcaComponents, "pca-components", 4, "number of PCA components to compute / use in logistic regression")
-	maxPCATiles := flags.Int("max-pca-tiles", 0, "maximum tiles to use as PCA input (filter, then drop every 2nd colum pair until below max)")
-	debugTag := flags.Int("debug-tag", -1, "log debugging details about specified tag")
-	flags.IntVar(&cmd.threads, "threads", 16, "number of memory-hungry assembly threads, and number of VCPUs to request for arvados container")
-	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")
-	flags.Float64Var(&cmd.glmMinFrequency, "glm-min-frequency", 0.01, "skip GLM calculation on tile variants below this frequency in the training set")
-	flags.BoolVar(&cmd.includeVariant1, "include-variant-1", false, "include most common variant when building one-hot matrix")
-	cmd.filter.Flags(flags)
-	err := flags.Parse(args)
-	if err == flag.ErrHelp {
-		return nil
-	} else if err != nil {
-		return err
-	} else if flags.NArg() > 0 {
-		return fmt.Errorf("errant command line arguments after parsed flags: %v", flags.Args())
-	}
-
-	if *pprof != "" {
-		go func() {
-			log.Println(http.ListenAndServe(*pprof, nil))
-		}()
-	}
-
-	if cmd.chi2PValue != 1 && *samplesFilename == "" {
-		return fmt.Errorf("cannot use provided -chi2-p-value=%f because -samples= value is empty", cmd.chi2PValue)
-	}
-
-	cmd.debugTag = tagID(*debugTag)
-
-	if !*runlocal {
-		runner := arvadosContainerRunner{
-			Name:        "lightning slice-numpy",
-			Client:      arvados.NewClientFromEnv(),
-			ProjectUUID: *projectUUID,
-			RAM:         int64(*arvadosRAM),
-			VCPUs:       *arvadosVCPUs,
-			Priority:    *priority,
-			KeepCache:   2,
-			APIAccess:   true,
-			Preemptible: *preemptible,
-		}
-		err = runner.TranslatePaths(inputDir, regionsFilename, samplesFilename)
-		if err != nil {
-			return err
-		}
-		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),
-			"-samples=" + *samplesFilename,
-			"-case-control-only=" + fmt.Sprintf("%v", *caseControlOnly),
-			"-pca=" + fmt.Sprintf("%v", *onlyPCA),
-			"-pca-components=" + fmt.Sprintf("%d", cmd.pcaComponents),
-			"-max-pca-tiles=" + fmt.Sprintf("%d", *maxPCATiles),
-			"-chi2-p-value=" + fmt.Sprintf("%f", cmd.chi2PValue),
-			"-glm-min-frequency=" + fmt.Sprintf("%f", cmd.glmMinFrequency),
-			"-include-variant-1=" + fmt.Sprintf("%v", cmd.includeVariant1),
-			"-debug-tag=" + fmt.Sprintf("%d", cmd.debugTag),
-		}
-		runner.Args = append(runner.Args, cmd.filter.Args()...)
-		var output string
-		output, err = runner.Run()
-		if err != nil {
-			return err
-		}
-		fmt.Fprintln(stdout, output)
-		return nil
-	}
-
-	infiles, err := allFiles(*inputDir, matchGobFile)
-	if err != nil {
-		return err
-	}
-	if len(infiles) == 0 {
-		err = fmt.Errorf("no input files found in %s", *inputDir)
-		return err
-	}
-	sort.Strings(infiles)
-
-	var refseq map[string][]tileLibRef
-	var reftiledata = make(map[tileLibRef][]byte, 11000000)
-	in0, err := open(infiles[0])
-	if err != nil {
-		return err
-	}
-
-	matchGenome, err := regexp.Compile(cmd.filter.MatchGenome)
-	if err != nil {
-		err = fmt.Errorf("-match-genome: invalid regexp: %q", cmd.filter.MatchGenome)
-		return err
-	}
-
-	if *samplesFilename != "" {
-		cmd.samples, err = loadSampleInfo(*samplesFilename)
-		if err != nil {
-			return err
-		}
-	} else if *caseControlOnly {
-		return fmt.Errorf("-case-control-only does not make sense without -samples")
-	}
-
-	cmd.cgnames = nil
-	var tagset [][]byte
-	err = DecodeLibrary(in0, strings.HasSuffix(infiles[0], ".gz"), func(ent *LibraryEntry) error {
-		if len(ent.TagSet) > 0 {
-			tagset = ent.TagSet
-		}
-		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 err
-	}
-	in0.Close()
-	if refseq == nil {
-		err = fmt.Errorf("%s: reference sequence not found", infiles[0])
-		return err
-	}
-	if len(tagset) == 0 {
-		err = fmt.Errorf("tagset not found")
-		return err
-	}
-
-	taglib := &tagLibrary{}
-	err = taglib.setTags(tagset)
-	if err != nil {
-		return err
-	}
-	taglen := taglib.TagLen()
-	sort.Strings(cmd.cgnames)
-
-	if len(cmd.cgnames) == 0 {
-		return fmt.Errorf("fatal: 0 matching samples in library, nothing to do")
-	}
-	cmd.trainingSet = make([]int, len(cmd.cgnames))
-	if *samplesFilename == "" {
-		cmd.trainingSetSize = len(cmd.cgnames)
-		for i, name := range cmd.cgnames {
-			cmd.samples = append(cmd.samples, sampleInfo{
-				id:         trimFilenameForLabel(name),
-				isTraining: true,
-			})
-			cmd.trainingSet[i] = i
-		}
-	} else if len(cmd.cgnames) != len(cmd.samples) {
-		return fmt.Errorf("mismatched sample list: %d samples in library, %d in %s", len(cmd.cgnames), len(cmd.samples), *samplesFilename)
-	} else {
-		for i, name := range cmd.cgnames {
-			if s := trimFilenameForLabel(name); s != cmd.samples[i].id {
-				return fmt.Errorf("mismatched sample list: sample %d is %q in library, %q in %s", i, s, cmd.samples[i].id, *samplesFilename)
-			}
-		}
-		if *caseControlOnly {
-			for i := 0; i < len(cmd.samples); i++ {
-				if !cmd.samples[i].isTraining && !cmd.samples[i].isValidation {
-					if i+1 < len(cmd.samples) {
-						copy(cmd.samples[i:], cmd.samples[i+1:])
-						copy(cmd.cgnames[i:], cmd.cgnames[i+1:])
-					}
-					cmd.samples = cmd.samples[:len(cmd.samples)-1]
-					cmd.cgnames = cmd.cgnames[:len(cmd.cgnames)-1]
-					i--
-				}
-			}
-		}
-		cmd.chi2Cases = nil
-		cmd.trainingSetSize = 0
-		for i := range cmd.cgnames {
-			if cmd.samples[i].isTraining {
-				cmd.trainingSet[i] = cmd.trainingSetSize
-				cmd.trainingSetSize++
-				cmd.chi2Cases = append(cmd.chi2Cases, cmd.samples[i].isCase)
-			} else {
-				cmd.trainingSet[i] = -1
-			}
-		}
-		if cmd.pvalue == nil {
-			cmd.pvalue = func(onehot []bool) float64 {
-				return pvalue(onehot, cmd.chi2Cases)
-			}
-		}
-	}
-	if cmd.filter.MinCoverage == 1 {
-		// In the generic formula below, floating point
-		// arithmetic can effectively push the coverage
-		// threshold above 1.0, which is impossible/useless.
-		// 1.0 needs to mean exactly 100% coverage.
-		cmd.minCoverage = len(cmd.cgnames)
-	} else {
-		cmd.minCoverage = int(math.Ceil(cmd.filter.MinCoverage * float64(len(cmd.cgnames))))
-	}
-
-	if len(cmd.samples[0].pcaComponents) > 0 {
-		cmd.pvalue = glmPvalueFunc(cmd.samples, cmd.pcaComponents, cmd.glmMinFrequency)
-		// Unfortunately, statsmodel/glm lib logs stuff to
-		// os.Stdout when it panics on an unsolvable
-		// problem. We recover() from the panic in glm.go, but
-		// we also need to commandeer os.Stdout to avoid
-		// producing large quantities of logs.
-		stdoutWas := os.Stdout
-		defer func() { os.Stdout = stdoutWas }()
-		os.Stdout, err = os.Open(os.DevNull)
-		if err != nil {
-			return err
-		}
-	}
-
-	// cgnamemap[name]==true for samples that we are including in
-	// output
-	cgnamemap := map[string]bool{}
-	for _, name := range cmd.cgnames {
-		cgnamemap[name] = true
-	}
-
-	err = writeSampleInfo(cmd.samples, *outputDir)
-	if err != nil {
-		return err
-	}
-
-	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...
-		excluded bool   // true if excluded by regions file
-		nexttag  tagID  // tagID of following tile (-1 for last tag of chromosome)
-	}
-	isdup := map[tagID]bool{}
-	reftile := map[tagID]*reftileinfo{}
-	for seqname, cseq := range refseq {
-		pos := 0
-		lastreftag := tagID(-1)
-		for _, libref := range cseq {
-			if cmd.filter.MaxTag >= 0 && libref.Tag > tagID(cmd.filter.MaxTag) {
-				continue
-			}
-			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 err
-			}
-			foundthistag := false
-			taglib.FindAll(tiledata[:len(tiledata)-1], func(tagid tagID, offset, _ int) {
-				if !foundthistag && tagid == libref.Tag {
-					foundthistag = true
-					return
-				}
-				if dupref, ok := reftile[tagid]; ok {
-					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)
-					delete(reftile, tagid)
-				} else {
-					log.Printf("found tag %d at offset %d inside tile variant %+v on %s @ %d", tagid, offset, libref, seqname, pos+offset+1)
-				}
-				isdup[tagid] = true
-			})
-			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,
-					nexttag:  -1,
-				}
-				if lastreftag >= 0 {
-					reftile[lastreftag].nexttag = libref.Tag
-				}
-				lastreftag = libref.Tag
-			}
-			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 err
-		}
-		log.Printf("before applying mask, len(reftile) == %d", len(reftile))
-		log.Printf("deleting reftile entries for regions outside %d intervals", mask.Len())
-		for _, rt := range reftile {
-			if !mask.Check(strings.TrimPrefix(rt.seqname, "chr"), rt.pos, rt.pos+len(rt.tiledata)) {
-				rt.excluded = true
-			}
-		}
-		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 err
-			}
-			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 onehotChunkSize []uint32
-	var onehotXrefs [][]onehotXref
-	if *onehotSingle || *onlyPCA {
-		onehotIndirect = make([][2][]uint32, len(infiles))
-		onehotChunkSize = make([]uint32, len(infiles))
-		onehotXrefs = make([][]onehotXref, len(infiles))
-	}
-	chunkStartTag := make([]tagID, 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 errSkip = errors.New("skip infile")
-	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
-					}
-					// Skip tile with no
-					// corresponding ref tile, if
-					// mask is in play (we can't
-					// determine coordinates for
-					// these)
-					if mask != nil && reftile[tv.Tag] == nil {
-						continue
-					}
-					// Skip tile whose
-					// corresponding ref tile is
-					// outside target regions --
-					// unless it's a potential
-					// spanning tile.
-					if mask != nil && reftile[tv.Tag].excluded &&
-						(int(tv.Tag+1) >= len(tagset) ||
-							(bytes.HasSuffix(tv.Sequence, tagset[tv.Tag+1]) && reftile[tv.Tag+1] != nil && !reftile[tv.Tag+1].excluded)) {
-						continue
-					}
-					if tv.Tag == cmd.debugTag {
-						log.Printf("infile %d %s tag %d variant %d hash %x", infileIdx, infile, tv.Tag, tv.Variant, tv.Blake2b[:3])
-					}
-					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 cmd.filter.MaxTag >= 0 && cg.StartTag > tagID(cmd.filter.MaxTag) {
-						return errSkip
-					}
-					if !cgnamemap[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 == errSkip {
-				return nil
-			} else if err != nil {
-				return fmt.Errorf("%04d: DecodeLibrary(%s): err", infileIdx, infile)
-			}
-			tagstart := cgs[cmd.cgnames[0]].StartTag
-			tagend := cgs[cmd.cgnames[0]].EndTag
-			chunkStartTag[infileIdx] = tagstart
-
-			// 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.Go(func() error {
-					alleleCoverage := 0
-					count := make(map[[blake2b.Size256]byte]int, len(variants))
-
-					rt := reftile[tag]
-					if rt != nil {
-						count[blake2b.Sum256(rt.tiledata)] = 0
-					}
-
-					for cgname, 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]++
-								alleleCoverage++
-							}
-							if v > 0 && tag == cmd.debugTag {
-								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])
-							}
-						}
-					}
-					if alleleCoverage < cmd.minCoverage*2 {
-						idx := int(tag-tagstart) * 2
-						for _, cg := range cgs {
-							cg.Variants[idx] = 0
-							cg.Variants[idx+1] = 0
-						}
-						if tag == cmd.debugTag {
-							log.Printf("tag %d alleleCoverage %d < min %d, sample data wiped", tag, alleleCoverage, cmd.minCoverage*2)
-						}
-						return nil
-					}
-
-					// 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)
-					}
-					if tag == cmd.debugTag {
-						for h, r := range rank {
-							log.Printf("tag %d rank(%x) = %v", tag, h[:3], r)
-						}
-					}
-					// 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]
-					}
-					if tag == cmd.debugTag {
-						for in, out := range remap {
-							if out > 0 {
-								log.Printf("tag %d remap %d => %d", tag, in, out)
-							}
-						}
-					}
-					variantRemap[tag-tagstart] = remap
-					if rt != nil {
-						refrank := rank[blake2b.Sum256(rt.tiledata)]
-						if tag == cmd.debugTag {
-							log.Printf("tag %d reftile variant %d => %d", tag, rt.variant, refrank)
-						}
-						rt.variant = refrank
-					}
-					return nil
-				})
-			}
-			throttleCPU.Wait()
-
-			var onehotChunk [][]int8
-			var onehotXref []onehotXref
-
-			var annotationsFilename string
-			if *onlyPCA {
-				annotationsFilename = "/dev/null"
-			} else {
-				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 := reftile[tag]
-				if rt == nil && mask != nil {
-					// With no ref tile, we don't
-					// have coordinates to say
-					// this is in the desired
-					// regions -- so it's not.
-					// TODO: handle ref spanning
-					// tile case.
-					continue
-				}
-				if rt != nil && rt.excluded {
-					// TODO: don't skip yet --
-					// first check for spanning
-					// tile variants that
-					// intersect non-excluded ref
-					// tiles.
-					continue
-				}
-				if cmd.filter.MaxTag >= 0 && tag > tagID(cmd.filter.MaxTag) {
-					break
-				}
-				remap := variantRemap[tag-tagstart]
-				if remap == nil {
-					// was not assigned above,
-					// because minCoverage
-					outcol++
-					continue
-				}
-				maxv := tileVariantID(0)
-				for _, v := range remap {
-					if maxv < v {
-						maxv = v
-					}
-				}
-				if *onehotChunked || *onehotSingle || *onlyPCA {
-					onehot, xrefs := cmd.tv2homhet(cgs, maxv, remap, tag, tagstart, seq)
-					if tag == cmd.debugTag {
-						log.WithFields(logrus.Fields{
-							"onehot": onehot,
-							"xrefs":  xrefs,
-						}).Info("tv2homhet()")
-					}
-					onehotChunk = append(onehotChunk, onehot...)
-					onehotXref = append(onehotXref, xrefs...)
-				}
-				if *onlyPCA {
-					outcol++
-					continue
-				}
-				if rt == nil {
-					// Reference does not use any
-					// variant of this tile
-					//
-					// TODO: diff against the
-					// relevant portion of the
-					// ref's spanning tile
-					outcol++
-					continue
-				}
-				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 == 0 || v == rt.variant || done[v] {
-						continue
-					} else {
-						done[v] = true
-					}
-					if len(tv.Sequence) < taglen {
-						continue
-					}
-					// if reftilestr doesn't end
-					// in the same tag as tv,
-					// extend reftilestr with
-					// following ref tiles until
-					// it does (up to an arbitrary
-					// sanity-check limit)
-					reftilestr := reftilestr
-					endtagstr := strings.ToUpper(string(tv.Sequence[len(tv.Sequence)-taglen:]))
-					for i, rt := 0, rt; i < annotationMaxTileSpan && !strings.HasSuffix(reftilestr, endtagstr) && rt.nexttag >= 0; i++ {
-						rt = reftile[rt.nexttag]
-						if rt == nil {
-							break
-						}
-						reftilestr += strings.ToUpper(string(rt.tiledata[taglen:]))
-					}
-					if mask != nil && !mask.Check(strings.TrimPrefix(rt.seqname, "chr"), rt.pos, rt.pos+len(reftilestr)) {
-						continue
-					}
-					if !strings.HasSuffix(reftilestr, endtagstr) {
-						fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
-						continue
-					}
-					if lendiff := len(reftilestr) - 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, rows, cols, rows*cols)
-				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 || *onlyPCA {
-				onehotIndirect[infileIdx] = onehotChunk2Indirect(onehotChunk)
-				onehotChunkSize[infileIdx] = uint32(len(onehotChunk))
-				onehotXrefs[infileIdx] = onehotXref
-				n := len(onehotIndirect[infileIdx][0])
-				log.Infof("%04d: keeping onehot coordinates in memory (n=%d, mem=%d)", infileIdx, n, n*8*2)
-			}
-			if !(*onehotSingle || *onehotChunked || *onlyPCA) || *mergeOutput || *hgvsSingle {
-				log.Infof("%04d: preparing numpy (rows=%d, cols=%d)", infileIdx, len(cmd.cgnames), 2*outcol)
-				throttleNumpyMem.Acquire()
-				rows := len(cmd.cgnames)
-				cols := 2 * outcol
-				out := make([]int16, rows*cols)
-				for row, name := range cmd.cgnames {
-					outidx := row * cols
-					for col, v := range cgs[name].Variants {
-						tag := tagstart + tagID(col/2)
-						if cmd.filter.MaxTag >= 0 && tag > tagID(cmd.filter.MaxTag) {
-							break
-						}
-						if rt := reftile[tag]; rt == nil || rt.excluded {
-							continue
-						}
-						if v == 0 {
-							out[outidx] = 0 // tag not found / spanning tile
-						} else if variants, ok := seq[tag]; ok && int(v) < len(variants) && len(variants[v].Sequence) > 0 {
-							out[outidx] = int16(variantRemap[tag-tagstart][v])
-						} else {
-							out[outidx] = -1 // low quality tile variant
-						}
-						if tag == cmd.debugTag {
-							log.Printf("tag %d row %d col %d outidx %d v %d out %d", tag, row, col, outidx, v, out[outidx])
-						}
-						outidx++
-					}
-				}
-				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 err
-	}
-
-	if *hgvsChunked {
-		log.Info("flushing hgvsCols temp files")
-		for seqname := range refseq {
-			close(encodeHGVSTodo[seqname])
-		}
-		err = encodeHGVS.Wait()
-		if err != nil {
-			return err
-		}
-		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 err
-			}
-			var hgvsCols hgvsColSet
-			dec := gob.NewDecoder(bufio.NewReaderSize(f, 1<<24))
-			for err == nil {
-				err = dec.Decode(&hgvsCols)
-			}
-			if err != io.EOF {
-				return err
-			}
-			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 err
-			}
-			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 err
-			}
-		}
-	}
-
-	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 err
-			}
-			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 err
-			}
-			if *mergeOutput {
-				err = os.Remove(annotationsFilename)
-				if err != nil {
-					return err
-				}
-			}
-			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 err
-					}
-					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 err
-			}
-			err = annof.Close()
-			if err != nil {
-				return err
-			}
-			err = writeNumpyInt16(fmt.Sprintf("%s/matrix.npy", *outputDir), out, rows, cols)
-			if err != nil {
-				return err
-			}
-		}
-		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 err
-			}
-
-			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 err
-			}
-		}
-	}
-	if *onehotSingle || *onlyPCA {
-		nzCount := 0
-		for _, part := range onehotIndirect {
-			nzCount += len(part[0])
-		}
-		onehot := make([]uint32, nzCount*2) // [r,r,r,...,c,c,c,...]
-		var xrefs []onehotXref
-		chunkOffset := uint32(0)
-		outcol := 0
-		for i, part := range onehotIndirect {
-			for i := range part[1] {
-				part[1][i] += chunkOffset
-			}
-			copy(onehot[outcol:], part[0])
-			copy(onehot[outcol+nzCount:], part[1])
-			xrefs = append(xrefs, onehotXrefs[i]...)
-
-			outcol += len(part[0])
-			chunkOffset += onehotChunkSize[i]
-
-			part[0] = nil
-			part[1] = nil
-			onehotXrefs[i] = nil
-			debug.FreeOSMemory()
-		}
-		if *onehotSingle {
-			fnm := fmt.Sprintf("%s/onehot.npy", *outputDir)
-			err = writeNumpyUint32(fnm, onehot, 2, nzCount)
-			if err != nil {
-				return err
-			}
-			fnm = fmt.Sprintf("%s/onehot-columns.npy", *outputDir)
-			err = writeNumpyInt32(fnm, onehotXref2int32(xrefs), 5, len(xrefs))
-			if err != nil {
-				return err
-			}
-			fnm = fmt.Sprintf("%s/stats.json", *outputDir)
-			j, err := json.Marshal(map[string]interface{}{
-				"pvalueCallCount": cmd.pvalueCallCount,
-			})
-			if err != nil {
-				return err
-			}
-			err = os.WriteFile(fnm, j, 0777)
-			if err != nil {
-				return err
-			}
-		}
-		if *onlyPCA {
-			cols := 0
-			for _, c := range onehot[nzCount:] {
-				if int(c) >= cols {
-					cols = int(c) + 1
-				}
-			}
-			if cols == 0 {
-				return fmt.Errorf("cannot do PCA: one-hot matrix is empty")
-			}
-			log.Printf("have %d one-hot cols", cols)
-			stride := 1
-			for *maxPCATiles > 0 && cols > *maxPCATiles*2 {
-				cols = (cols + 1) / 2
-				stride = stride * 2
-			}
-			if cols%2 == 1 {
-				// we work with pairs of columns
-				cols++
-			}
-			log.Printf("creating full matrix (%d rows) and training matrix (%d rows) with %d cols, stride %d", len(cmd.cgnames), cmd.trainingSetSize, cols, stride)
-			mtxFull := mat.NewDense(len(cmd.cgnames), cols, nil)
-			mtxTrain := mat.NewDense(cmd.trainingSetSize, cols, nil)
-			for i, c := range onehot[nzCount:] {
-				if int(c/2)%stride == 0 {
-					outcol := int(c/2)/stride*2 + int(c)%2
-					mtxFull.Set(int(onehot[i]), outcol, 1)
-					if trainRow := cmd.trainingSet[int(onehot[i])]; trainRow >= 0 {
-						mtxTrain.Set(trainRow, outcol, 1)
-					}
-				}
-			}
-			log.Print("fitting")
-			transformer := nlp.NewPCA(cmd.pcaComponents)
-			transformer.Fit(mtxTrain.T())
-			log.Printf("transforming")
-			pca, err := transformer.Transform(mtxFull.T())
-			if err != nil {
-				return err
-			}
-			pca = pca.T()
-			outrows, outcols := pca.Dims()
-			log.Printf("copying result to numpy output array: %d rows, %d cols", outrows, outcols)
-			out := make([]float64, outrows*outcols)
-			for i := 0; i < outrows; i++ {
-				for j := 0; j < outcols; j++ {
-					out[i*outcols+j] = pca.At(i, j)
-				}
-			}
-			fnm := fmt.Sprintf("%s/pca.npy", *outputDir)
-			log.Printf("writing numpy: %s", fnm)
-			output, err := os.OpenFile(fnm, os.O_CREATE|os.O_TRUNC|os.O_WRONLY, 0777)
-			if err != nil {
-				return err
-			}
-			npw, err := gonpy.NewWriter(nopCloser{output})
-			if err != nil {
-				return fmt.Errorf("gonpy.NewWriter: %w", err)
-			}
-			npw.Shape = []int{outrows, outcols}
-			err = npw.WriteFloat64(out)
-			if err != nil {
-				return fmt.Errorf("WriteFloat64: %w", err)
-			}
-			err = output.Close()
-			if err != nil {
-				return err
-			}
-			log.Print("done")
-
-			log.Print("copying pca components to sampleInfo")
-			for i := range cmd.samples {
-				cmd.samples[i].pcaComponents = make([]float64, outcols)
-				for c := 0; c < outcols; c++ {
-					cmd.samples[i].pcaComponents[i] = pca.At(i, c)
-				}
-			}
-			log.Print("done")
-
-			err = writeSampleInfo(cmd.samples, *outputDir)
-			if err != nil {
-				return err
-			}
-		}
-	}
-	if !*mergeOutput && !*onehotChunked && !*onehotSingle && !*onlyPCA {
-		tagoffsetFilename := *outputDir + "/chunk-tag-offset.csv"
-		log.Infof("writing tag offsets to %s", tagoffsetFilename)
-		var f *os.File
-		f, err = os.Create(tagoffsetFilename)
-		if err != nil {
-			return err
-		}
-		defer f.Close()
-		for idx, offset := range chunkStartTag {
-			_, err = fmt.Fprintf(f, "%q,%d\n", fmt.Sprintf("matrix.%04d.npy", idx), offset)
-			if err != nil {
-				err = fmt.Errorf("write %s: %w", tagoffsetFilename, err)
-				return err
-			}
-		}
-		err = f.Close()
-		if err != nil {
-			err = fmt.Errorf("close %s: %w", tagoffsetFilename, err)
-			return err
-		}
-	}
-
-	return nil
-}
-
-type sampleInfo struct {
-	id            string
-	isCase        bool
-	isControl     bool
-	isTraining    bool
-	isValidation  bool
-	pcaComponents []float64
-}
-
-// Read samples.csv file with case/control and training/validation
-// flags.
-func loadSampleInfo(samplesFilename string) ([]sampleInfo, error) {
-	var si []sampleInfo
-	f, err := open(samplesFilename)
-	if err != nil {
-		return nil, err
-	}
-	buf, err := io.ReadAll(f)
-	f.Close()
-	if err != nil {
-		return nil, err
-	}
-	lineNum := 0
-	for _, csv := range bytes.Split(buf, []byte{'\n'}) {
-		lineNum++
-		if len(csv) == 0 {
-			continue
-		}
-		split := strings.Split(string(csv), ",")
-		if len(split) < 4 {
-			return nil, fmt.Errorf("%d fields < 4 in %s line %d: %q", len(split), samplesFilename, lineNum, csv)
-		}
-		if split[0] == "Index" && split[1] == "SampleID" && split[2] == "CaseControl" && split[3] == "TrainingValidation" {
-			continue
-		}
-		idx, err := strconv.Atoi(split[0])
-		if err != nil {
-			if lineNum == 1 {
-				return nil, fmt.Errorf("header does not look right: %q", csv)
-			}
-			return nil, fmt.Errorf("%s line %d: index: %s", samplesFilename, lineNum, err)
-		}
-		if idx != len(si) {
-			return nil, fmt.Errorf("%s line %d: index %d out of order", samplesFilename, lineNum, idx)
-		}
-		var pcaComponents []float64
-		if len(split) > 4 {
-			for _, s := range split[4:] {
-				f, err := strconv.ParseFloat(s, 64)
-				if err != nil {
-					return nil, fmt.Errorf("%s line %d: cannot parse float %q: %s", samplesFilename, lineNum, s, err)
-				}
-				pcaComponents = append(pcaComponents, f)
-			}
-		}
-		si = append(si, sampleInfo{
-			id:            split[1],
-			isCase:        split[2] == "1",
-			isControl:     split[2] == "0",
-			isTraining:    split[3] == "1",
-			isValidation:  split[3] == "0" && len(split[2]) > 0, // fix errant 0s in input
-			pcaComponents: pcaComponents,
-		})
-	}
-	return si, nil
-}
-
-func writeSampleInfo(samples []sampleInfo, outputDir string) error {
-	fnm := outputDir + "/samples.csv"
-	log.Infof("writing sample metadata to %s", fnm)
-	f, err := os.Create(fnm)
-	if err != nil {
-		return err
-	}
-	defer f.Close()
-	pcaLabels := ""
-	if len(samples) > 0 {
-		for i := range samples[0].pcaComponents {
-			pcaLabels += fmt.Sprintf(",PCA%d", i)
-		}
-	}
-	_, err = fmt.Fprintf(f, "Index,SampleID,CaseControl,TrainingValidation%s\n", pcaLabels)
-	if err != nil {
-		return err
-	}
-	for i, si := range samples {
-		var cc, tv string
-		if si.isCase {
-			cc = "1"
-		} else if si.isControl {
-			cc = "0"
-		}
-		if si.isTraining {
-			tv = "1"
-		} else if si.isValidation {
-			tv = "0"
-		}
-		var pcavals string
-		for _, pcaval := range si.pcaComponents {
-			pcavals += fmt.Sprintf(",%f", pcaval)
-		}
-		_, err = fmt.Fprintf(f, "%d,%s,%s,%s%s\n", i, si.id, cc, tv, pcavals)
-		if err != nil {
-			return fmt.Errorf("write %s: %w", fnm, err)
-		}
-	}
-	err = f.Close()
-	if err != nil {
-		return fmt.Errorf("close %s: %w", fnm, err)
-	}
-	log.Print("done")
-	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
-	hom     bool
-	pvalue  float64
-}
-
-const onehotXrefSize = unsafe.Sizeof(onehotXref{})
-
-// Build onehot matrix (m[tileVariantIndex][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, seq map[tagID][]TileVariant) ([][]int8, []onehotXref) {
-	if tag == cmd.debugTag {
-		tv := make([]tileVariantID, len(cmd.cgnames)*2)
-		for i, name := range cmd.cgnames {
-			copy(tv[i*2:(i+1)*2], cgs[name].Variants[(tag-chunkstarttag)*2:])
-		}
-		log.WithFields(logrus.Fields{
-			"cgs[i].Variants[tag*2+j]": tv,
-			"maxv":                     maxv,
-			"remap":                    remap,
-			"tag":                      tag,
-			"chunkstarttag":            chunkstarttag,
-		}).Info("tv2homhet()")
-	}
-	if maxv < 1 || (maxv < 2 && !cmd.includeVariant1) {
-		// everyone has the most common variant (of the variants we don't drop)
-		return nil, nil
-	}
-	tagoffset := tag - chunkstarttag
-	coverage := 0
-	for _, cg := range cgs {
-		alleles := 0
-		for _, v := range cg.Variants[tagoffset*2 : tagoffset*2+2] {
-			if v > 0 && int(v) < len(seq[tag]) && len(seq[tag][v].Sequence) > 0 {
-				alleles++
-			}
-		}
-		if alleles == 2 {
-			coverage++
-		}
-	}
-	if coverage < cmd.minCoverage {
-		return nil, nil
-	}
-	// "observed" array for p-value calculation (training set
-	// only)
-	obs := make([][]bool, (maxv+1)*2) // 2 slices (hom + het) for each variant#
-	// one-hot output (all samples)
-	outcols := make([][]int8, (maxv+1)*2)
-	for i := range obs {
-		obs[i] = make([]bool, cmd.trainingSetSize)
-		outcols[i] = make([]int8, len(cmd.cgnames))
-	}
-	for cgid, name := range cmd.cgnames {
-		tsid := cmd.trainingSet[cgid]
-		cgvars := cgs[name].Variants[tagoffset*2:]
-		tv0, tv1 := remap[cgvars[0]], remap[cgvars[1]]
-		for v := tileVariantID(1); v <= maxv; v++ {
-			if tv0 == v && tv1 == v {
-				if tsid >= 0 {
-					obs[v*2][tsid] = true
-				}
-				outcols[v*2][cgid] = 1
-			} else if tv0 == v || tv1 == v {
-				if tsid >= 0 {
-					obs[v*2+1][tsid] = true
-				}
-				outcols[v*2+1][cgid] = 1
-			}
-		}
-	}
-	var onehot [][]int8
-	var xref []onehotXref
-	for col := 2; col < len(obs); col++ {
-		// col 0,1 correspond to tile variant 0, i.e.,
-		// no-call; col 2,3 correspond to the most common
-		// variant; so we (normally) start at col 4.
-		if col < 4 && !cmd.includeVariant1 {
-			continue
-		}
-		atomic.AddInt64(&cmd.pvalueCallCount, 1)
-		p := cmd.pvalue(obs[col])
-		if cmd.chi2PValue < 1 && !(p < cmd.chi2PValue) {
-			continue
-		}
-		onehot = append(onehot, outcols[col])
-		xref = append(xref, onehotXref{
-			tag:     tag,
-			variant: tileVariantID(col >> 1),
-			hom:     col&1 == 0,
-			pvalue:  p,
-		})
-	}
-	return onehot, xref
-}
-
-// 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, 5*xcols)
-	for i, xref := range xrefs {
-		xdata[i] = int32(xref.tag)
-		xdata[xcols+i] = int32(xref.variant)
-		if xref.hom {
-			xdata[xcols*2+i] = 1
-		}
-		xdata[xcols*3+i] = int32(xref.pvalue * 1000000)
-		xdata[xcols*4+i] = int32(-math.Log10(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
-}