X-Git-Url: https://git.arvados.org/lightning.git/blobdiff_plain/c95b337f14e5d6bed6afa9fb03eb15a5b121904f..5d939b4ccdab73d0729db56219ba674fb9995c26:/slicenumpy.go

diff --git a/slicenumpy.go b/slicenumpy.go
index c5e48f0983..1dcf4cb61c 100644
--- a/slicenumpy.go
+++ b/slicenumpy.go
@@ -7,19 +7,23 @@ package lightning
 import (
 	"bufio"
 	"bytes"
+	"encoding/gob"
 	"flag"
 	"fmt"
 	"io"
 	"io/ioutil"
+	"math"
 	"net/http"
 	_ "net/http/pprof"
 	"os"
 	"regexp"
 	"runtime"
+	"runtime/debug"
 	"sort"
 	"strconv"
 	"strings"
 	"sync/atomic"
+	"unsafe"
 
 	"git.arvados.org/arvados.git/sdk/go/arvados"
 	"github.com/arvados/lightning/hgvs"
@@ -29,8 +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 {
@@ -52,7 +62,14 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
 	regionsFilename := flags.String("regions", "", "only output columns/annotations that intersect regions in specified bed `file`")
 	expandRegions := flags.Int("expand-regions", 0, "expand specified regions by `N` base pairs on each side`")
 	mergeOutput := flags.Bool("merge-output", false, "merge output into one matrix.npy and one matrix.annotations.csv")
+	hgvsSingle := flags.Bool("single-hgvs-matrix", false, "also generate hgvs-based matrix")
+	hgvsChunked := flags.Bool("chunked-hgvs-matrix", false, "also generate hgvs-based matrix per chromosome")
+	onehotSingle := flags.Bool("single-onehot", false, "generate one-hot tile-based matrix")
+	onehotChunked := flags.Bool("chunked-onehot", false, "generate one-hot tile-based matrix per input chunk")
 	flags.IntVar(&cmd.threads, "threads", 16, "number of memory-hungry assembly threads")
+	flags.StringVar(&cmd.chi2CaseControlFile, "chi2-case-control-file", "", "tsv file or directory indicating cases and controls for Χ² test (if directory, all .tsv files will be read)")
+	flags.StringVar(&cmd.chi2CaseControlColumn, "chi2-case-control-column", "", "name of case/control column in case-control files for Χ² test (value must be 0 for control, 1 for case)")
+	flags.Float64Var(&cmd.chi2PValue, "chi2-p-value", 1, "do Χ² test and omit columns with p-value above this threshold")
 	cmd.filter.Flags(flags)
 	err = flags.Parse(args)
 	if err == flag.ErrHelp {
@@ -68,18 +85,23 @@ 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",
 			Client:      arvados.NewClientFromEnv(),
 			ProjectUUID: *projectUUID,
-			RAM:         650000000000,
+			RAM:         750000000000,
 			VCPUs:       96,
 			Priority:    *priority,
 			KeepCache:   2,
 			APIAccess:   true,
 		}
-		err = runner.TranslatePaths(inputDir, regionsFilename)
+		err = runner.TranslatePaths(inputDir, regionsFilename, &cmd.chi2CaseControlFile)
 		if err != nil {
 			return 1
 		}
@@ -91,6 +113,13 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
 			"-regions=" + *regionsFilename,
 			"-expand-regions=" + fmt.Sprintf("%d", *expandRegions),
 			"-merge-output=" + fmt.Sprintf("%v", *mergeOutput),
+			"-single-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsSingle),
+			"-chunked-hgvs-matrix=" + fmt.Sprintf("%v", *hgvsChunked),
+			"-single-onehot=" + fmt.Sprintf("%v", *onehotSingle),
+			"-chunked-onehot=" + fmt.Sprintf("%v", *onehotChunked),
+			"-chi2-case-control-file=" + cmd.chi2CaseControlFile,
+			"-chi2-case-control-column=" + cmd.chi2CaseControlColumn,
+			"-chi2-p-value=" + fmt.Sprintf("%f", cmd.chi2PValue),
 		}
 		runner.Args = append(runner.Args, cmd.filter.Args()...)
 		var output string
@@ -102,7 +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
 	}
@@ -112,7 +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])
@@ -126,10 +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 == "" {
@@ -138,7 +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 {
@@ -156,18 +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)
@@ -175,8 +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
@@ -206,6 +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, tag not unique, also found inside %+v from %s @ %d", dupref, 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 {
@@ -243,10 +303,48 @@ 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{}
+	if *hgvsChunked {
+		for seqname := range refseq {
+			var f *os.File
+			f, err = os.Create(*outputDir + "/tmp." + seqname + ".gob")
+			if err != nil {
+				return 1
+			}
+			defer os.Remove(f.Name())
+			bufw := bufio.NewWriterSize(f, 1<<24)
+			enc := gob.NewEncoder(bufw)
+			tmpHGVSCols[seqname] = f
+			todo := make(chan hgvsColSet, 128)
+			encodeHGVSTodo[seqname] = todo
+			encodeHGVS.Go(func() error {
+				for colset := range todo {
+					err := enc.Encode(colset)
+					if err != nil {
+						encodeHGVS.Report(err)
+						for range todo {
+						}
+						return err
+					}
+				}
+				return bufw.Flush()
+			})
+		}
+	}
+
 	var toMerge [][]int16
-	if *mergeOutput {
+	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}
@@ -256,7 +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
@@ -285,17 +383,24 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
 					seq[tv.Tag] = variants
 				}
 				for _, cg := range ent.CompactGenomes {
-					if matchGenome.MatchString(cg.Name) {
-						cgs[cg.Name] = cg
+					if !matchGenome.MatchString(cg.Name) {
+						continue
 					}
+					// pad to full slice size
+					// to avoid out-of-bounds
+					// checks later
+					if sliceSize := 2 * int(cg.EndTag-cg.StartTag); len(cg.Variants) < sliceSize {
+						cg.Variants = append(cg.Variants, make([]tileVariantID, sliceSize-len(cg.Variants))...)
+					}
+					cgs[cg.Name] = cg
 				}
 				return nil
 			})
 			if err != nil {
 				return err
 			}
-			tagstart := cgs[cgnames[0]].StartTag
-			tagend := cgs[cgnames[0]].EndTag
+			tagstart := cgs[cmd.cgnames[0]].StartTag
+			tagend := cgs[cmd.cgnames[0]].EndTag
 
 			// TODO: filters
 
@@ -308,14 +413,18 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
 				go func() {
 					defer throttleCPU.Release()
 					count := make(map[[blake2b.Size256]byte]int, len(variants))
+
+					rt := reftile[tag]
+					if rt != nil {
+						count[blake2b.Sum256(rt.tiledata)] = 0
+					}
+
 					for _, cg := range cgs {
 						idx := int(tag-tagstart) * 2
-						if idx < len(cg.Variants) {
-							for allele := 0; allele < 2; allele++ {
-								v := cg.Variants[idx+allele]
-								if v > 0 && len(variants[v].Sequence) > 0 {
-									count[variants[v].Blake2b]++
-								}
+						for allele := 0; allele < 2; allele++ {
+							v := cg.Variants[idx+allele]
+							if v > 0 && len(variants[v].Sequence) > 0 {
+								count[variants[v].Blake2b]++
 							}
 						}
 					}
@@ -349,10 +458,16 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
 						remap[i] = rank[tv.Blake2b]
 					}
 					variantRemap[tag-tagstart] = remap
+					if rt != nil {
+						rt.variant = rank[blake2b.Sum256(rt.tiledata)]
+					}
 				}()
 			}
 			throttleCPU.Wait()
 
+			var onehotChunk [][]int8
+			var onehotXref []onehotXref
+
 			annotationsFilename := fmt.Sprintf("%s/matrix.%04d.annotations.csv", *outputDir, infileIdx)
 			log.Infof("%04d: writing %s", infileIdx, annotationsFilename)
 			annof, err := os.Create(annotationsFilename)
@@ -374,32 +489,102 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
 					// mention it in annotations?)
 					continue
 				}
-				variants, ok := seq[tag]
-				if !ok {
-					outcol++
-					continue
+				remap := variantRemap[tag-tagstart]
+				maxv := tileVariantID(0)
+				for _, v := range remap {
+					if maxv < v {
+						maxv = v
+					}
 				}
+				if *onehotChunked || *onehotSingle {
+					onehot, xrefs := cmd.tv2homhet(cgs, maxv, remap, tag, tagstart)
+					onehotChunk = append(onehotChunk, onehot...)
+					onehotXref = append(onehotXref, xrefs...)
+				}
+				fmt.Fprintf(annow, "%d,%d,%d,=,%s,%d,,,\n", tag, outcol, rt.variant, rt.seqname, rt.pos)
+				variants := seq[tag]
 				reftilestr := strings.ToUpper(string(rt.tiledata))
-				remap := variantRemap[tag-tagstart]
-				done := make([]bool, len(variants))
+
+				done := make([]bool, maxv+1)
+				variantDiffs := make([][]hgvs.Variant, maxv+1)
 				for v, tv := range variants {
 					v := remap[v]
-					if done[v] {
+					if v == rt.variant || done[v] {
 						continue
 					} else {
 						done[v] = true
 					}
 					if len(tv.Sequence) < taglen || !bytes.HasSuffix(rt.tiledata, tv.Sequence[len(tv.Sequence)-taglen:]) {
+						fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 						continue
 					}
 					if lendiff := len(rt.tiledata) - len(tv.Sequence); lendiff < -1000 || lendiff > 1000 {
+						fmt.Fprintf(annow, "%d,%d,%d,,%s,%d,,,\n", tag, outcol, v, rt.seqname, rt.pos)
 						continue
 					}
 					diffs, _ := hgvs.Diff(reftilestr, strings.ToUpper(string(tv.Sequence)), 0)
+					for i := range diffs {
+						diffs[i].Position += rt.pos
+					}
 					for _, diff := range diffs {
-						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 {
+						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++
 			}
@@ -412,40 +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 {
-				log.Infof("%04d: matrix fragment %d rows x %d cols", infileIdx, rows, cols)
-				toMerge[infileIdx] = out
-			} else {
-				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
 		})
@@ -453,28 +669,107 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
 	if err = throttleMem.Wait(); err != nil {
 		return 1
 	}
-	if *mergeOutput {
-		log.Info("merging output matrix and annotations")
 
-		annoFilename := fmt.Sprintf("%s/matrix.annotations.csv", *outputDir)
-		annof, err := os.Create(annoFilename)
+	if *hgvsChunked {
+		log.Info("flushing hgvsCols temp files")
+		for seqname := range refseq {
+			close(encodeHGVSTodo[seqname])
+		}
+		err = encodeHGVS.Wait()
 		if err != nil {
 			return 1
 		}
-		annow := bufio.NewWriterSize(annof, 1<<20)
+		for seqname := range refseq {
+			log.Infof("%s: reading hgvsCols from temp file", seqname)
+			f := tmpHGVSCols[seqname]
+			_, err = f.Seek(0, io.SeekStart)
+			if err != nil {
+				return 1
+			}
+			var hgvsCols hgvsColSet
+			dec := gob.NewDecoder(bufio.NewReaderSize(f, 1<<24))
+			for err == nil {
+				err = dec.Decode(&hgvsCols)
+			}
+			if err != io.EOF {
+				return 1
+			}
+			log.Infof("%s: sorting %d hgvs variants", seqname, len(hgvsCols))
+			variants := make([]hgvs.Variant, 0, len(hgvsCols))
+			for v := range hgvsCols {
+				variants = append(variants, v)
+			}
+			sort.Slice(variants, func(i, j int) bool {
+				vi, vj := &variants[i], &variants[j]
+				if vi.Position != vj.Position {
+					return vi.Position < vj.Position
+				} else if vi.Ref != vj.Ref {
+					return vi.Ref < vj.Ref
+				} else {
+					return vi.New < vj.New
+				}
+			})
+			rows := len(cmd.cgnames)
+			cols := len(variants) * 2
+			log.Infof("%s: building hgvs matrix (rows=%d, cols=%d, mem=%d)", seqname, rows, cols, rows*cols)
+			out := make([]int8, rows*cols)
+			for varIdx, variant := range variants {
+				hgvsCols := hgvsCols[variant]
+				for row := range cmd.cgnames {
+					for ph := 0; ph < 2; ph++ {
+						out[row*cols+varIdx+ph] = hgvsCols[ph][row]
+					}
+				}
+			}
+			err = writeNumpyInt8(fmt.Sprintf("%s/hgvs.%s.npy", *outputDir, seqname), out, rows, cols)
+			if err != nil {
+				return 1
+			}
+			out = nil
+
+			fnm := fmt.Sprintf("%s/hgvs.%s.annotations.csv", *outputDir, seqname)
+			log.Infof("%s: writing hgvs column labels to %s", seqname, fnm)
+			var hgvsLabels bytes.Buffer
+			for varIdx, variant := range variants {
+				fmt.Fprintf(&hgvsLabels, "%d,%s:g.%s\n", varIdx, seqname, variant.String())
+			}
+			err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0666)
+			if err != nil {
+				return 1
+			}
+		}
+	}
 
-		rows := len(cgnames)
+	if *mergeOutput || *hgvsSingle {
+		var annow *bufio.Writer
+		var annof *os.File
+		if *mergeOutput {
+			annoFilename := fmt.Sprintf("%s/matrix.annotations.csv", *outputDir)
+			annof, err = os.Create(annoFilename)
+			if err != nil {
+				return 1
+			}
+			annow = bufio.NewWriterSize(annof, 1<<20)
+		}
+
+		rows := len(cmd.cgnames)
 		cols := 0
 		for _, chunk := range toMerge {
 			cols += len(chunk) / rows
 		}
-		out := make([]int16, rows*cols)
-		hgvs := map[string][2][]int16{} // hgvs -> [[g0,g1,g2,...], [g0,g1,g2,...]] (slice of genomes for each phase)
+		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
-			for row := 0; row < rows; row++ {
-				copy(out[row*cols+startcol:], chunk[row*chunkcols:(row+1)*chunkcols])
+			if *mergeOutput {
+				for row := 0; row < rows; row++ {
+					copy(out[row*cols+startcol:], chunk[row*chunkcols:(row+1)*chunkcols])
+				}
 			}
 			toMerge[outIdx] = nil
 
@@ -484,21 +779,33 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
 			if err != nil {
 				return 1
 			}
-			err = os.Remove(annotationsFilename)
-			if err != nil {
-				return 1
+			if *mergeOutput {
+				err = os.Remove(annotationsFilename)
+				if err != nil {
+					return 1
+				}
 			}
 			for _, line := range bytes.Split(buf, []byte{'\n'}) {
 				if len(line) == 0 {
 					continue
 				}
-				fields := bytes.SplitN(line, []byte{','}, 8)
+				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
@@ -506,18 +813,48 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
 					// variant does not.
 					continue
 				}
-				fmt.Fprintf(annow, "%s,%d,%d,%s,%s,%d,%s,%s\n", fields[0], incol+startcol/2, tileVariant, hgvsID, seqname, pos, refseq, fields[7])
-				hgvscols := hgvs[hgvsID]
-				if hgvscols[0] == nil {
-					hgvscols = [2][]int16{make([]int16, len(cgnames)), make([]int16, len(cgnames))}
-					hgvs[hgvsID] = hgvscols
+				hgvsColPair := hgvsCols[hgvsID]
+				if hgvsColPair[0] == nil {
+					// values in new columns start
+					// out as -1 ("no data yet")
+					// or 0 ("=ref") here, may
+					// change to 1 ("hgvs variant
+					// present") below, either on
+					// this line or a future line.
+					hgvsColPair = [2][]int16{make([]int16, len(cmd.cgnames)), make([]int16, len(cmd.cgnames))}
+					rt, ok := reftile[tagID(tag)]
+					if !ok {
+						err = fmt.Errorf("bug: seeing annotations for tag %d, but it has no reftile entry", tag)
+						return 1
+					}
+					for ph := 0; ph < 2; ph++ {
+						for row := 0; row < rows; row++ {
+							v := chunk[row*chunkcols+incol*2+ph]
+							if tileVariantID(v) == rt.variant {
+								hgvsColPair[ph][row] = 0
+							} else {
+								hgvsColPair[ph][row] = -1
+							}
+						}
+					}
+					hgvsCols[hgvsID] = hgvsColPair
+					if annow != nil {
+						hgvsref := hgvs.Variant{
+							Position: pos,
+							Ref:      string(refseq),
+							New:      string(refseq),
+						}
+						fmt.Fprintf(annow, "%d,%d,%d,%s:g.%s,%s,%d,%s,%s,%s\n", tag, incol+startcol/2, rt.variant, seqname, hgvsref.String(), seqname, pos, refseq, refseq, fields[8])
+					}
+				}
+				if annow != nil {
+					fmt.Fprintf(annow, "%d,%d,%d,%s,%s,%d,%s,%s,%s\n", tag, incol+startcol/2, tileVariant, hgvsID, seqname, pos, refseq, fields[7], fields[8])
 				}
 				for ph := 0; ph < 2; ph++ {
 					for row := 0; row < rows; row++ {
-						if v := chunk[row*chunkcols+incol*2+ph]; int(v) == tileVariant {
-							hgvscols[ph][row] = 1
-						} else if v < 0 {
-							hgvscols[ph][row] = -1
+						v := chunk[row*chunkcols+incol*2+ph]
+						if int(v) == tileVariant {
+							hgvsColPair[ph][row] = 1
 						}
 					}
 				}
@@ -525,51 +862,242 @@ func (cmd *sliceNumpy) RunCommand(prog string, args []string, stdin io.Reader, s
 
 			startcol += chunkcols
 		}
-		err = annow.Flush()
-		if err != nil {
-			return 1
+		if *mergeOutput {
+			err = annow.Flush()
+			if err != nil {
+				return 1
+			}
+			err = annof.Close()
+			if err != nil {
+				return 1
+			}
+			err = writeNumpyInt16(fmt.Sprintf("%s/matrix.npy", *outputDir), out, rows, cols)
+			if err != nil {
+				return 1
+			}
+		}
+		out = nil
+
+		if *hgvsSingle {
+			cols = len(hgvsCols) * 2
+			log.Printf("building hgvs-based matrix: %d rows x %d cols", rows, cols)
+			out = make([]int16, rows*cols)
+			hgvsIDs := make([]string, 0, cols/2)
+			for hgvsID := range hgvsCols {
+				hgvsIDs = append(hgvsIDs, hgvsID)
+			}
+			sort.Strings(hgvsIDs)
+			var hgvsLabels bytes.Buffer
+			for idx, hgvsID := range hgvsIDs {
+				fmt.Fprintf(&hgvsLabels, "%d,%s\n", idx, hgvsID)
+				for ph := 0; ph < 2; ph++ {
+					hgvscol := hgvsCols[hgvsID][ph]
+					for row, val := range hgvscol {
+						out[row*cols+idx*2+ph] = val
+					}
+				}
+			}
+			err = writeNumpyInt16(fmt.Sprintf("%s/hgvs.npy", *outputDir), out, rows, cols)
+			if err != nil {
+				return 1
+			}
+
+			fnm := fmt.Sprintf("%s/hgvs.annotations.csv", *outputDir)
+			log.Printf("writing hgvs labels: %s", fnm)
+			err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0777)
+			if err != nil {
+				return 1
+			}
+		}
+	}
+	if *onehotSingle {
+		nzCount := 0
+		for _, part := range onehotIndirect {
+			nzCount += len(part[0])
+		}
+		onehot := make([]uint32, nzCount*2) // [r,r,r,...,c,c,c,...]
+		var xrefs []onehotXref
+		outcol := 0
+		for i, part := range onehotIndirect {
+			for i := range part[1] {
+				part[1][i] += uint32(outcol)
+			}
+			copy(onehot[outcol:], part[0])
+			copy(onehot[outcol+nzCount:], part[1])
+			outcol += len(part[0])
+			xrefs = append(xrefs, onehotXrefs[i]...)
+
+			part[0] = nil
+			part[1] = nil
+			onehotXrefs[i] = nil
+			debug.FreeOSMemory()
 		}
-		err = annof.Close()
+		fnm := fmt.Sprintf("%s/onehot.npy", *outputDir)
+		err = writeNumpyUint32(fnm, onehot, 2, nzCount)
 		if err != nil {
 			return 1
 		}
-		err = writeNumpyInt16(fmt.Sprintf("%s/matrix.npy", *outputDir), out, rows, cols)
+		fnm = fmt.Sprintf("%s/onehot-columns.npy", *outputDir)
+		err = writeNumpyInt32(fnm, onehotXref2int32(xrefs), 4, len(xrefs))
 		if err != nil {
 			return 1
 		}
-		out = nil
+	}
+	return 0
+}
 
-		cols = len(hgvs) * 2
-		log.Printf("building hgvs-based matrix: %d rows x %d cols", rows, cols)
-		out = make([]int16, rows*cols)
-		hgvsIDs := make([]string, 0, len(hgvs))
-		for hgvsID := range hgvs {
-			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 := hgvs[hgvsID][ph]
-				for row, val := range hgvscol {
-					out[row*cols+idx*2+ph] = val
+// 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
+			}
 		}
-		err = writeNumpyInt16(fmt.Sprintf("%s/hgvs.npy", *outputDir), out, rows, cols)
-		if err != nil {
-			return 1
+	}
+	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
+}
 
-		fnm := fmt.Sprintf("%s/hgvs.annotations.csv", *outputDir)
-		log.Printf("writing hgvs labels: %s", fnm)
-		err = ioutil.WriteFile(fnm, hgvsLabels.Bytes(), 0777)
-		if err != nil {
-			return 1
+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 0
+	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 {
@@ -587,6 +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)
@@ -596,3 +1125,177 @@ func writeNumpyInt16(fnm string, out []int16, rows, cols int) error {
 	}
 	return output.Close()
 }
+
+func writeNumpyInt8(fnm string, out []int8, rows, cols int) error {
+	output, err := os.Create(fnm)
+	if err != nil {
+		return err
+	}
+	defer output.Close()
+	bufw := bufio.NewWriterSize(output, 1<<26)
+	npw, err := gonpy.NewWriter(nopCloser{bufw})
+	if err != nil {
+		return err
+	}
+	log.WithFields(log.Fields{
+		"filename": fnm,
+		"rows":     rows,
+		"cols":     cols,
+		"bytes":    rows * cols,
+	}).Infof("writing numpy: %s", fnm)
+	npw.Shape = []int{rows, cols}
+	npw.WriteInt8(out)
+	err = bufw.Flush()
+	if err != nil {
+		return err
+	}
+	return output.Close()
+}
+
+func allele2homhet(colpair [2][]int8) {
+	a, b := colpair[0], colpair[1]
+	for i, av := range a {
+		bv := b[i]
+		if av < 0 || bv < 0 {
+			// no-call
+			a[i], b[i] = -1, -1
+		} else if av > 0 && bv > 0 {
+			// hom
+			a[i], b[i] = 1, 0
+		} else if av > 0 || bv > 0 {
+			// het
+			a[i], b[i] = 0, 1
+		} else {
+			// ref (or a different variant in same position)
+			// (this is a no-op) a[i], b[i] = 0, 0
+		}
+	}
+}
+
+type onehotXref struct {
+	tag     tagID
+	variant tileVariantID
+	het     bool
+	pvalue  float64
+}
+
+const onehotXrefSize = unsafe.Sizeof(onehotXref{})
+
+// Build onehot matrix (m[variant*2+isHet][genome] == 0 or 1) for all
+// variants of a single tile/tag#.
+//
+// Return nil if no tile variant passes Χ² filter.
+func (cmd *sliceNumpy) tv2homhet(cgs map[string]CompactGenome, maxv tileVariantID, remap []tileVariantID, tag, chunkstarttag tagID) ([][]int8, []onehotXref) {
+	if maxv < 2 {
+		// everyone has the most common variant
+		return nil, nil
+	}
+	tagoffset := tag - chunkstarttag
+	coverage := 0
+	for _, cg := range cgs {
+		if cg.Variants[tagoffset*2] > 0 && cg.Variants[tagoffset*2+1] > 0 {
+			coverage++
+		}
+	}
+	if coverage < cmd.minCoverage {
+		return nil, nil
+	}
+	obs := make([][]bool, (maxv+1)*2) // 2 slices (hom + het) for each variant#
+	for i := range obs {
+		obs[i] = make([]bool, len(cmd.cgnames))
+	}
+	for cgid, name := range cmd.cgnames {
+		cgvars := cgs[name].Variants
+		for v := tileVariantID(2); v <= maxv; v++ {
+			if remap[cgvars[tagoffset*2]] == v && remap[cgvars[tagoffset*2+1]] == v {
+				obs[v*2][cgid] = true
+			} else if remap[cgvars[tagoffset*2]] == v || remap[cgvars[tagoffset*2+1]] == v {
+				obs[v*2+1][cgid] = true
+			}
+		}
+	}
+	var onehot [][]int8
+	var xref []onehotXref
+	for homcol := 4; homcol < len(obs); homcol += 2 {
+		p := [2]float64{
+			pvalue(obs[homcol], cmd.chi2Cases),
+			pvalue(obs[homcol+1], cmd.chi2Cases),
+		}
+		if cmd.chi2PValue < 1 && !(p[0] < cmd.chi2PValue || p[1] < cmd.chi2PValue) {
+			continue
+		}
+		for het := 0; het < 2; het++ {
+			onehot = append(onehot, bool2int8(obs[homcol+het]))
+			xref = append(xref, onehotXref{
+				tag:     tag,
+				variant: tileVariantID(homcol / 2),
+				het:     het == 1,
+				pvalue:  p[het],
+			})
+		}
+	}
+	return onehot, xref
+}
+
+func bool2int8(in []bool) []int8 {
+	out := make([]int8, len(in))
+	for i, v := range in {
+		if v {
+			out[i] = 1
+		}
+	}
+	return out
+}
+
+// convert a []onehotXref with length N to a numpy-style []int32
+// matrix with N columns, one row per field of onehotXref struct.
+//
+// Hom/het row contains hom=0, het=1.
+//
+// P-value row contains 1000000x actual p-value.
+func onehotXref2int32(xrefs []onehotXref) []int32 {
+	xcols := len(xrefs)
+	xdata := make([]int32, 4*xcols)
+	for i, xref := range xrefs {
+		xdata[i] = int32(xref.tag)
+		xdata[xcols+i] = int32(xref.variant)
+		if xref.het {
+			xdata[xcols*2+i] = 1
+		}
+		xdata[xcols*3+i] = int32(xref.pvalue * 1000000)
+	}
+	return xdata
+}
+
+// transpose onehot data from in[col][row] to numpy-style
+// out[row*cols+col].
+func onehotcols2int8(in [][]int8) []int8 {
+	if len(in) == 0 {
+		return nil
+	}
+	cols := len(in)
+	rows := len(in[0])
+	out := make([]int8, rows*cols)
+	for row := 0; row < rows; row++ {
+		outrow := out[row*cols:]
+		for col, incol := range in {
+			outrow[col] = incol[row]
+		}
+	}
+	return out
+}
+
+// Return [2][]uint32{rowIndices, colIndices} indicating which
+// elements of matrixT[c][r] have non-zero values.
+func onehotChunk2Indirect(matrixT [][]int8) [2][]uint32 {
+	var nz [2][]uint32
+	for c, col := range matrixT {
+		for r, val := range col {
+			if val != 0 {
+				nz[0] = append(nz[0], uint32(r))
+				nz[1] = append(nz[1], uint32(c))
+			}
+		}
+	}
+	return nz
+}