Fix log message.
[lightning.git] / slicenumpy.go
index 3af4aa04ef51cbc6a0dbefd5fce8c5863d7d3a00..601cb40eacc768df1eb6c27009096f725fb601ed 100644 (file)
@@ -12,15 +12,18 @@ import (
        "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"
@@ -30,8 +33,14 @@ import (
 )
 
 type sliceNumpy struct {
-       filter  filter
-       threads int
+       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 {
@@ -55,7 +64,12 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
        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 {
@@ -71,6 +85,11 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                }()
        }
 
+       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",
@@ -82,7 +101,7 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                        KeepCache:   2,
                        APIAccess:   true,
                }
-               err = runner.TranslatePaths(inputDir, regionsFilename)
+               err = runner.TranslatePaths(inputDir, regionsFilename, &cmd.chi2CaseControlFile)
                if err != nil {
                        return 1
                }
@@ -96,6 +115,11 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                        "-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
@@ -107,7 +131,7 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                return 0
        }
 
-       infiles, err := allGobFiles(*inputDir)
+       infiles, err := allFiles(*inputDir, matchGobFile)
        if err != nil {
                return 1
        }
@@ -117,7 +141,6 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
        }
        sort.Strings(infiles)
 
-       var cgnames []string
        var refseq map[string][]tileLibRef
        var reftiledata = make(map[tileLibRef][]byte, 11000000)
        in0, err := open(infiles[0])
@@ -131,10 +154,11 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                return 1
        }
 
-       taglen := -1
+       cmd.cgnames = nil
+       var tagset [][]byte
        DecodeLibrary(in0, strings.HasSuffix(infiles[0], ".gz"), func(ent *LibraryEntry) error {
                if len(ent.TagSet) > 0 {
-                       taglen = len(ent.TagSet[0])
+                       tagset = ent.TagSet
                }
                for _, cseq := range ent.CompactSequences {
                        if cseq.Name == *ref || *ref == "" {
@@ -143,7 +167,7 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                }
                for _, cg := range ent.CompactGenomes {
                        if matchGenome.MatchString(cg.Name) {
-                               cgnames = append(cgnames, cg.Name)
+                               cmd.cgnames = append(cmd.cgnames, cg.Name)
                        }
                }
                for _, tv := range ent.TileVariants {
@@ -161,18 +185,31 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                err = fmt.Errorf("%s: reference sequence not found", infiles[0])
                return 1
        }
-       if taglen < 0 {
+       if len(tagset) == 0 {
                err = fmt.Errorf("tagset not found")
                return 1
        }
-       if len(cgnames) == 0 {
+
+       taglib := &tagLibrary{}
+       err = taglib.setTags(tagset)
+       if err != nil {
+               return 1
+       }
+       taglen := taglib.TagLen()
+
+       if len(cmd.cgnames) == 0 {
                err = fmt.Errorf("no genomes found matching regexp %q", cmd.filter.MatchGenome)
                return 1
        }
-       sort.Strings(cgnames)
+       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 + "/labels.csv"
+               labelsFilename := *outputDir + "/samples.csv"
                log.Infof("writing labels to %s", labelsFilename)
                var f *os.File
                f, err = os.Create(labelsFilename)
@@ -180,8 +217,12 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                        return 1
                }
                defer f.Close()
-               for i, name := range cgnames {
-                       _, err = fmt.Fprintf(f, "%d,%q\n", i, trimFilenameForLabel(name))
+               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
@@ -211,6 +252,20 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                                err = fmt.Errorf("missing tiledata for tag %d variant %d in %s in ref", libref.Tag, libref.Variant, seqname)
                                return 1
                        }
+                       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 {
@@ -248,9 +303,10 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                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{}
-       bufHGVSCols := map[string]*bufio.Writer{}
-       encodeHGVSCols := map[string]*gob.Encoder{}
        if *hgvsChunked {
                for seqname := range refseq {
                        var f *os.File
@@ -262,8 +318,20 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                        bufw := bufio.NewWriterSize(f, 1<<24)
                        enc := gob.NewEncoder(bufw)
                        tmpHGVSCols[seqname] = f
-                       bufHGVSCols[seqname] = bufw
-                       encodeHGVSCols[seqname] = enc
+                       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()
+                       })
                }
        }
 
@@ -271,6 +339,12 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
        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}
@@ -280,7 +354,7 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                infileIdx, infile := infileIdx, infile
                throttleMem.Go(func() error {
                        seq := make(map[tagID][]TileVariant, 50000)
-                       cgs := make(map[string]CompactGenome, len(cgnames))
+                       cgs := make(map[string]CompactGenome, len(cmd.cgnames))
                        f, err := open(infile)
                        if err != nil {
                                return err
@@ -315,7 +389,7 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                                        // pad to full slice size
                                        // to avoid out-of-bounds
                                        // checks later
-                                       if sliceSize := int(cg.EndTag - cg.StartTag); len(cg.Variants) < sliceSize {
+                                       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
@@ -325,8 +399,8 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                        if err != nil {
                                return err
                        }
-                       tagstart := cgs[cgnames[0]].StartTag
-                       tagend := cgs[cgnames[0]].EndTag
+                       tagstart := cgs[cmd.cgnames[0]].StartTag
+                       tagend := cgs[cmd.cgnames[0]].EndTag
 
                        // TODO: filters
 
@@ -391,6 +465,9 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                        }
                        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)
@@ -412,9 +489,6 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                                        // mention it in annotations?)
                                        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))
                                remap := variantRemap[tag-tagstart]
                                maxv := tileVariantID(0)
                                for _, v := range remap {
@@ -422,6 +496,15 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                                                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 {
@@ -440,8 +523,10 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                                                continue
                                        }
                                        diffs, _ := hgvs.Diff(reftilestr, strings.ToUpper(string(tv.Sequence)), 0)
+                                       for i := range diffs {
+                                               diffs[i].Position += rt.pos
+                                       }
                                        for _, diff := range diffs {
-                                               diff.Position += rt.pos
                                                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 {
@@ -456,19 +541,19 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                                        // =ref or a different variant in that
                                        // position, or (-1) is lacking
                                        // coverage / couldn't be diffed.
-                                       hgvsCol := map[hgvs.Variant][2][]int8{}
+                                       hgvsCol := hgvsColSet{}
                                        for _, diffs := range variantDiffs {
                                                for _, diff := range diffs {
                                                        if _, ok := hgvsCol[diff]; ok {
                                                                continue
                                                        }
                                                        hgvsCol[diff] = [2][]int8{
-                                                               make([]int8, len(cgnames)),
-                                                               make([]int8, len(cgnames)),
+                                                               make([]int8, len(cmd.cgnames)),
+                                                               make([]int8, len(cmd.cgnames)),
                                                        }
                                                }
                                        }
-                                       for row, name := range cgnames {
+                                       for row, name := range cmd.cgnames {
                                                variants := cgs[name].Variants[(tag-tagstart)*2:]
                                                for ph := 0; ph < 2; ph++ {
                                                        v := variants[ph]
@@ -491,7 +576,15 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                                                        }
                                                }
                                        }
-                                       encodeHGVSCols[rt.seqname].Encode(hgvsCol)
+                                       for diff, colpair := range hgvsCol {
+                                               allele2homhet(colpair)
+                                               if !cmd.filterHGVScolpair(colpair) {
+                                                       delete(hgvsCol, diff)
+                                               }
+                                       }
+                                       if len(hgvsCol) > 0 {
+                                               encodeHGVSTodo[rt.seqname] <- hgvsCol
+                                       }
                                }
                                outcol++
                        }
@@ -504,41 +597,71 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                                return err
                        }
 
-                       log.Infof("%04d: preparing numpy", infileIdx)
-                       throttleNumpyMem.Acquire()
-                       rows := len(cgnames)
-                       cols := 2 * outcol
-                       out := make([]int16, rows*cols)
-                       for row, name := range 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++
+                       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
                                }
-                       }
-                       seq = nil
-                       throttleNumpyMem.Release()
-
-                       if *mergeOutput || *hgvsSingle {
-                               log.Infof("%04d: matrix fragment %d rows x %d cols", infileIdx, rows, cols)
-                               toMerge[infileIdx] = out
-                       }
-                       if !*mergeOutput {
-                               fnm := fmt.Sprintf("%s/matrix.%04d.npy", *outputDir, infileIdx)
-                               err = writeNumpyInt16(fnm, out, rows, cols)
+                               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 {
+                               onehotIndirect[infileIdx] = onehotChunk2Indirect(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)
+                       }
+                       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
                })
@@ -550,11 +673,11 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
        if *hgvsChunked {
                log.Info("flushing hgvsCols temp files")
                for seqname := range refseq {
-                       err = bufHGVSCols[seqname].Flush()
-                       if err != nil {
-                               return 1
-                       }
-                       bufHGVSCols[seqname] = nil // free buffer memory
+                       close(encodeHGVSTodo[seqname])
+               }
+               err = encodeHGVS.Wait()
+               if err != nil {
+                       return 1
                }
                for seqname := range refseq {
                        log.Infof("%s: reading hgvsCols from temp file", seqname)
@@ -563,7 +686,7 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                        if err != nil {
                                return 1
                        }
-                       var hgvsCols map[hgvs.Variant][2][]int8
+                       var hgvsCols hgvsColSet
                        dec := gob.NewDecoder(bufio.NewReaderSize(f, 1<<24))
                        for err == nil {
                                err = dec.Decode(&hgvsCols)
@@ -586,13 +709,13 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                                        return vi.New < vj.New
                                }
                        })
-                       rows := len(cgnames)
+                       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 cgnames {
+                               for row := range cmd.cgnames {
                                        for ph := 0; ph < 2; ph++ {
                                                out[row*cols+varIdx+ph] = hgvsCols[ph][row]
                                        }
@@ -629,7 +752,7 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                        annow = bufio.NewWriterSize(annof, 1<<20)
                }
 
-               rows := len(cgnames)
+               rows := len(cmd.cgnames)
                cols := 0
                for _, chunk := range toMerge {
                        cols += len(chunk) / rows
@@ -698,7 +821,7 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                                        // change to 1 ("hgvs variant
                                        // present") below, either on
                                        // this line or a future line.
-                                       hgvsColPair = [2][]int16{make([]int16, len(cgnames)), make([]int16, len(cgnames))}
+                                       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)
@@ -787,9 +910,196 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
                        }
                }
        }
+       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 {
@@ -805,6 +1115,7 @@ func writeNumpyInt16(fnm string, out []int16, rows, cols int) error {
                "filename": fnm,
                "rows":     rows,
                "cols":     cols,
+               "bytes":    rows * cols * 2,
        }).Infof("writing numpy: %s", fnm)
        npw.Shape = []int{rows, cols}
        npw.WriteInt16(out)
@@ -830,6 +1141,7 @@ func writeNumpyInt8(fnm string, out []int8, rows, cols int) error {
                "filename": fnm,
                "rows":     rows,
                "cols":     cols,
+               "bytes":    rows * cols,
        }).Infof("writing numpy: %s", fnm)
        npw.Shape = []int{rows, cols}
        npw.WriteInt8(out)
@@ -839,3 +1151,151 @@ func writeNumpyInt8(fnm string, out []int8, rows, cols int) error {
        }
        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
+}