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vcfroh.c
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/* vcfroh.c -- HMM model for detecting runs of autozygosity.
Copyright (C) 2013-2022 Genome Research Ltd.
Author: Petr Danecek <[email protected]>
Permission is hereby granted, free of charge, to any person obtaining a copy
of this software and associated documentation files (the "Software"), to deal
in the Software without restriction, including without limitation the rights
to use, copy, modify, merge, publish, distribute, sublicense, and/or sell
copies of the Software, and to permit persons to whom the Software is
furnished to do so, subject to the following conditions:
The above copyright notice and this permission notice shall be included in
all copies or substantial portions of the Software.
THE SOFTWARE IS PROVIDED "AS IS", WITHOUT WARRANTY OF ANY KIND, EXPRESS OR
IMPLIED, INCLUDING BUT NOT LIMITED TO THE WARRANTIES OF MERCHANTABILITY,
FITNESS FOR A PARTICULAR PURPOSE AND NONINFRINGEMENT. IN NO EVENT SHALL THE
AUTHORS OR COPYRIGHT HOLDERS BE LIABLE FOR ANY CLAIM, DAMAGES OR OTHER
LIABILITY, WHETHER IN AN ACTION OF CONTRACT, TORT OR OTHERWISE, ARISING FROM,
OUT OF OR IN CONNECTION WITH THE SOFTWARE OR THE USE OR OTHER DEALINGS IN
THE SOFTWARE. */
#include <stdio.h>
#include <unistd.h>
#include <getopt.h>
#include <math.h>
#include <inttypes.h>
#include <htslib/vcf.h>
#include <htslib/synced_bcf_reader.h>
#include <htslib/kstring.h>
#include <htslib/kseq.h>
#include <htslib/bgzf.h>
#include <errno.h>
#include "bcftools.h"
#include "HMM.h"
#include "smpl_ilist.h"
#include "filter.h"
#define STATE_HW 0 // normal state, follows Hardy-Weinberg allele frequencies
#define STATE_AZ 1 // autozygous state
#define OUTPUT_ST (1<<1)
#define OUTPUT_RG (1<<2)
#define OUTPUT_GZ (1<<3)
// Logic of the filters: include or exclude sites which match the filters?
#define FLT_INCLUDE 1
#define FLT_EXCLUDE 2
/** Genetic map */
typedef struct
{
int pos;
double rate;
}
genmap_t;
/** HMM data for each sample */
typedef struct
{
double *eprob; // emission probs [2*nsites,msites]
uint32_t *sites; // positions [nsites,msites]
int nsites, msites;
int igenmap; // current position in genmap
int nused; // some stats to detect if things didn't go wrong
int nrid, *rid, *rid_off; // for viterbi training, keep all chromosomes
void *snapshot; // hmm snapshot
struct {
uint32_t beg,end,nqual;
double qual;
int rid, state;
} rg;
}
smpl_t;
typedef struct _args_t
{
bcf_srs_t *files;
bcf_hdr_t *hdr;
double t2AZ, t2HW; // P(AZ|HW) and P(HW|AZ) parameters
double unseen_PL, dflt_AF;
char *genmap_fname;
genmap_t *genmap;
int ngenmap, mgenmap, igenmap;
double rec_rate; // constant recombination rate if > 0
hmm_t *hmm;
double baum_welch_th;
int nrids, *rids, *rid_offs; // multiple chroms with vi_training
int nbuf_max, nbuf_olap;
float *AFs;
int32_t *itmp;
int mAFs, nitmp, mitmp, pl_hdr_id, gt_hdr_id;
double pl2p[256], *pdg;
int32_t skip_rid, prev_rid, prev_pos;
int ntot; // some stats to detect if things didn't go wrong
int nno_af; // number of sites rejected because AF could not be determined
int nfiltered; // .. because of filters
int nno_alt, nmultiallelic, ndup;
smpl_t *smpl; // HMM data for each sample
smpl_ilist_t *af_smpl; // list of samples to estimate AF from (--estimate-AF)
smpl_ilist_t *roh_smpl; // list of samples to analyze (--samples, --samples-file)
char *estimate_AF; // list of samples for AF estimate and query sample
int af_from_PL; // estimate AF from FMT/PL rather than FMT/GT
char **argv, *targets_list, *regions_list, *af_fname, *af_tag, *samples, *buffer_size, *output_fname;
int argc, fake_PLs, snps_only, vi_training, samples_is_file, output_type, skip_homref, n_threads;
int include_noalt_sites;
BGZF *out;
kstring_t str;
int filter_logic;
filter_t *filter;
char *filter_str;
}
args_t;
void set_tprob_genmap(hmm_t *hmm, uint32_t prev_pos, uint32_t pos, void *data, double *tprob);
void set_tprob_rrate(hmm_t *hmm, uint32_t prev_pos, uint32_t pos, void *data, double *tprob);
void *smalloc(size_t size)
{
void *mem = malloc(size);
if ( !mem ) error("malloc: Could not allocate %d bytes\n", (int)size);
return mem;
}
static inline int max255(int i)
{
return i < 256 ? i : 255;
}
static void init_data(args_t *args)
{
int i;
args->prev_rid = args->skip_rid = -1;
args->hdr = args->files->readers[0].header;
if ( !bcf_hdr_nsamples(args->hdr) ) error("No samples in the VCF?\n");
if ( args->filter_str )
args->filter = filter_init(args->hdr, args->filter_str);
if ( !args->fake_PLs )
{
args->pl_hdr_id = bcf_hdr_id2int(args->hdr, BCF_DT_ID, "PL");
if ( !bcf_hdr_idinfo_exists(args->hdr,BCF_HL_FMT,args->pl_hdr_id) )
error("Error: The FORMAT/PL tag not found in the header, consider running with -G\n");
if ( bcf_hdr_id2type(args->hdr,BCF_HL_FMT,args->pl_hdr_id)!=BCF_HT_INT )
error("Error: The FORMAT/PL tag not defined as Integer in the header\n");
}
if ( args->estimate_AF )
{
if ( !strncmp("GT,",args->estimate_AF,3) ) args->estimate_AF += 3;
else if ( !strncmp("PL,",args->estimate_AF,3) ) { args->estimate_AF += 3; args->af_from_PL = 1; }
if ( strcmp("-",args->estimate_AF) )
args->af_smpl = smpl_ilist_init(args->hdr, args->estimate_AF, 1, SMPL_NONE|SMPL_VERBOSE);
}
if ( args->estimate_AF || args->fake_PLs )
{
if ( args->af_from_PL )
{
args->pl_hdr_id = bcf_hdr_id2int(args->hdr, BCF_DT_ID, "PL");
if ( !bcf_hdr_idinfo_exists(args->hdr,BCF_HL_FMT,args->pl_hdr_id) )
error("Error: The FORMAT/PL tag not found in the header\n");
}
else
{
args->gt_hdr_id = bcf_hdr_id2int(args->hdr, BCF_DT_ID, "GT");
if ( !bcf_hdr_idinfo_exists(args->hdr,BCF_HL_FMT,args->gt_hdr_id) )
error("Error: The FORMAT/GT tag not found in the header\n");
}
}
if ( args->fake_PLs )
{
args->gt_hdr_id = bcf_hdr_id2int(args->hdr, BCF_DT_ID, "GT");
if ( !bcf_hdr_idinfo_exists(args->hdr,BCF_HL_FMT,args->gt_hdr_id) )
error("Error: The FORMAT/GT tag not found in the header\n");
}
args->roh_smpl = smpl_ilist_init(args->hdr, args->samples, args->samples_is_file, SMPL_NONE|SMPL_VERBOSE);
if ( args->samples )
{
// we may be able to subset to a few samples, for a text VCF this can be a major speedup
if ( (bcf_sr_get_reader(args->files,0))->file->format.format==vcf )
{
kstring_t str = {0,0,0};
smpl_ilist_t *tmp = args->roh_smpl, *rmme = NULL;
if ( args->af_smpl )
{
for (i=0; i<args->roh_smpl->n; i++)
{
if ( str.l ) kputc(',', &str);
kputs(args->hdr->samples[args->roh_smpl->idx[i]], &str);
}
for (i=0; i<args->af_smpl->n; i++)
{
kputc(',', &str);
kputs(args->hdr->samples[args->af_smpl->idx[i]], &str);
}
rmme = tmp = smpl_ilist_init(args->hdr, str.s, 0, SMPL_NONE);
}
if ( tmp->n < bcf_hdr_nsamples(args->hdr) )
{
str.l = 0;
for (i=0; i<tmp->n; i++)
{
if ( str.l ) kputc(',', &str);
kputs(args->hdr->samples[tmp->idx[i]], &str);
}
int ret = bcf_hdr_set_samples(args->hdr, str.s, 0);
if ( ret<0 ) error("Error parsing the list of samples: %s\n", str.s);
else if ( ret>0 ) error("The %d-th sample not found in the VCF: %s\n", ret,str.s);
// update sample ids
smpl_ilist_destroy(args->roh_smpl);
args->roh_smpl = smpl_ilist_init(args->hdr, args->samples, args->samples_is_file, SMPL_NONE);
if ( args->af_smpl )
{
smpl_ilist_destroy(args->af_smpl);
args->af_smpl = smpl_ilist_init(args->hdr, args->estimate_AF, 1, SMPL_NONE);
}
}
free(str.s);
if ( rmme )
smpl_ilist_destroy(rmme);
}
}
// check whether all samples are in this list. If so, the lookup will not be needed
if ( args->af_smpl && args->af_smpl->n == bcf_hdr_nsamples(args->hdr) )
{
// all samples are in this list
smpl_ilist_destroy(args->af_smpl);
args->af_smpl = NULL;
}
if ( args->buffer_size )
{
args->nbuf_olap = -1;
char *end;
double tmp = strtod(args->buffer_size,&end);
if ( *end )
{
if ( *end!=',') error("Could not parse: --buffer-size %s\n", args->buffer_size);
args->nbuf_olap = strtol(end+1,&end,10);
if ( *end || args->nbuf_olap<0 ) error("Could not parse: --bufer-size %s\n", args->buffer_size);
}
if ( tmp<0 )
args->nbuf_max = fabs(tmp)*1e6/(4+8*2)/args->roh_smpl->n;
else
args->nbuf_max = tmp;
if ( args->nbuf_olap<0 )
args->nbuf_olap = args->nbuf_max*0.01;
}
fprintf(stderr,"Number of target samples: %d\n", args->roh_smpl->n);
fprintf(stderr,"Number of --estimate-AF samples: %d\n", args->af_smpl ? args->af_smpl->n : (args->estimate_AF ? bcf_hdr_nsamples(args->hdr) : 0));
fprintf(stderr,"Number of sites in the buffer/overlap: ");
if ( args->nbuf_max ) fprintf(stderr,"%d/%d\n", args->nbuf_max,args->nbuf_olap);
else fprintf(stderr,"unlimited\n");
args->smpl = (smpl_t*) calloc(args->roh_smpl->n,sizeof(smpl_t));
for (i=0; i<256; i++) args->pl2p[i] = pow(10., -i/10.);
// Init transition matrix and HMM
double tprob[4];
MAT(tprob,2,STATE_HW,STATE_HW) = 1 - args->t2AZ;
MAT(tprob,2,STATE_HW,STATE_AZ) = args->t2HW;
MAT(tprob,2,STATE_AZ,STATE_HW) = args->t2AZ;
MAT(tprob,2,STATE_AZ,STATE_AZ) = 1 - args->t2HW;
args->hmm = hmm_init(2, tprob, 10000);
if ( args->genmap_fname )
hmm_set_tprob_func(args->hmm, set_tprob_genmap, args);
else if ( args->rec_rate > 0 )
hmm_set_tprob_func(args->hmm, set_tprob_rrate, args);
args->out = bgzf_open(strcmp("stdout",args->output_fname)?args->output_fname:"-", args->output_type&OUTPUT_GZ ? "wg" : "wu");
if ( !args->out ) error("Failed to open %s: %s\n", args->output_fname, strerror(errno));
// print header
args->str.l = 0;
ksprintf(&args->str, "# This file was produced by: bcftools roh(%s+htslib-%s)\n", bcftools_version(),hts_version());
ksprintf(&args->str, "# The command line was:\tbcftools %s", args->argv[0]);
for (i=1; i<args->argc; i++)
ksprintf(&args->str, " %s",args->argv[i]);
ksprintf(&args->str, "\n#\n");
if ( args->output_type & OUTPUT_RG )
{
i = 2;
ksprintf(&args->str, "# RG");
ksprintf(&args->str, "\t[%d]Sample", i++);
ksprintf(&args->str, "\t[%d]Chromosome", i++);
ksprintf(&args->str, "\t[%d]Start", i++);
ksprintf(&args->str, "\t[%d]End", i++);
ksprintf(&args->str, "\t[%d]Length (bp)", i++);
ksprintf(&args->str, "\t[%d]Number of markers", i++);
ksprintf(&args->str, "\t[%d]Quality (average fwd-bwd phred score)", i++);
ksprintf(&args->str, "\n");
}
if ( args->output_type & OUTPUT_ST )
{
i = 2;
ksprintf(&args->str, "# ST");
ksprintf(&args->str, "\t[%d]Sample", i++);
ksprintf(&args->str, "\t[%d]Chromosome", i++);
ksprintf(&args->str, "\t[%d]Position", i++);
ksprintf(&args->str, "\t[%d]State (0:HW, 1:AZ)", i++);
ksprintf(&args->str, "\t[%d]Quality (fwd-bwd phred score)", i++);
ksprintf(&args->str, "\n");
}
if ( args->vi_training)
{
i = 2;
ksprintf(&args->str, "# VT, Viterbi Training");
ksprintf(&args->str, "\t[%d]Sample", i++);
ksprintf(&args->str, "\t[%d]Iteration", i++);
ksprintf(&args->str, "\t[%d]dAZ", i++);
ksprintf(&args->str, "\t[%d]dHW", i++);
ksprintf(&args->str, "\t[%d]1 - P(HW|HW)", i++);
ksprintf(&args->str, "\t[%d]P(AZ|HW)", i++);
ksprintf(&args->str, "\t[%d]1 - P(AZ|AZ)", i++);
ksprintf(&args->str, "\t[%d]P(HW|AZ)", i++);
ksprintf(&args->str, "\n");
}
if ( bgzf_write(args->out, args->str.s, args->str.l) != args->str.l )
error("Error writing %s: %s\n", args->output_fname, strerror(errno));
}
static void destroy_data(args_t *args)
{
if ( args->filter ) filter_destroy(args->filter);
if ( bgzf_close(args->out)!=0 ) error("Error: close failed .. %s\n", args->output_fname);
int i;
for (i=0; i<args->roh_smpl->n; i++)
{
free(args->smpl[i].eprob);
free(args->smpl[i].sites);
free(args->smpl[i].rid);
free(args->smpl[i].rid_off);
free(args->smpl[i].snapshot);
}
free(args->str.s);
free(args->smpl);
if ( args->af_smpl ) smpl_ilist_destroy(args->af_smpl);
smpl_ilist_destroy(args->roh_smpl);
free(args->rids);
free(args->rid_offs);
hmm_destroy(args->hmm);
bcf_sr_destroy(args->files);
free(args->AFs); free(args->pdg);
free(args->genmap);
free(args->itmp);
free(args->samples);
}
static int load_genmap(args_t *args, const char *chr)
{
if ( !args->genmap_fname ) { args->ngenmap = 0; return 0; }
kstring_t str = {0,0,0};
char *fname = strstr(args->genmap_fname,"{CHROM}");
if ( fname )
{
kputsn(args->genmap_fname, fname - args->genmap_fname, &str);
kputs(chr, &str);
kputs(fname+7,&str);
fname = str.s;
}
else
fname = args->genmap_fname;
htsFile *fp = hts_open(fname, "rb");
if ( !fp )
{
args->ngenmap = 0;
return -1;
}
hts_getline(fp, KS_SEP_LINE, &str);
if ( strcmp(str.s,"position COMBINED_rate(cM/Mb) Genetic_Map(cM)") )
error("Unexpected header in %s, found:\n\t[%s], but expected:\n\t[position COMBINED_rate(cM/Mb) Genetic_Map(cM)]\n", fname, str.s);
args->ngenmap = args->igenmap = 0;
while ( hts_getline(fp, KS_SEP_LINE, &str) > 0 )
{
args->ngenmap++;
hts_expand(genmap_t,args->ngenmap,args->mgenmap,args->genmap);
genmap_t *gm = &args->genmap[args->ngenmap-1];
// position, convert to 0-based
char *tmp, *end;
gm->pos = strtol(str.s, &tmp, 10);
if ( str.s==tmp ) error("Could not parse %s: %s\n", fname, str.s);
gm->pos -= 1;
// skip second column
tmp++;
while ( *tmp && !isspace(*tmp) ) tmp++;
// read the genetic map in cM, scale from % to likelihood
gm->rate = strtod(tmp+1, &end);
if ( tmp+1==end ) error("Could not parse %s: %s\n", fname, str.s);
gm->rate *= 0.01;
}
if ( !args->ngenmap ) error("Genetic map empty?\n");
if ( hts_close(fp) ) error("Close failed\n");
free(str.s);
return 0;
}
static double get_genmap_rate(args_t *args, int start, int end)
{
// position i to be equal to or smaller than start
int i = args->igenmap;
if ( args->genmap[i].pos > start )
{
while ( i>0 && args->genmap[i].pos > start ) i--;
}
else
{
while ( i+1<args->ngenmap && args->genmap[i+1].pos < start ) i++;
}
// position j to be equal or larger than end
int j = i;
while ( j+1<args->ngenmap && args->genmap[j].pos < end ) j++;
if ( i==j )
{
args->igenmap = i;
return 0;
}
if ( start < args->genmap[i].pos ) start = args->genmap[i].pos;
if ( end > args->genmap[j].pos ) end = args->genmap[j].pos;
double rate = (args->genmap[j].rate - args->genmap[i].rate)/(args->genmap[j].pos - args->genmap[i].pos) * (end-start);
args->igenmap = j;
return rate;
}
void set_tprob_genmap(hmm_t *hmm, uint32_t prev_pos, uint32_t pos, void *data, double *tprob)
{
args_t *args = (args_t*) data;
double ci = get_genmap_rate(args, prev_pos, pos);
if ( args->rec_rate ) ci *= args->rec_rate;
if ( ci > 1 ) ci = 1;
MAT(tprob,2,STATE_HW,STATE_AZ) *= ci;
MAT(tprob,2,STATE_AZ,STATE_HW) *= ci;
MAT(tprob,2,STATE_AZ,STATE_AZ) = 1 - MAT(tprob,2,STATE_HW,STATE_AZ);
MAT(tprob,2,STATE_HW,STATE_HW) = 1 - MAT(tprob,2,STATE_AZ,STATE_HW);
}
void set_tprob_rrate(hmm_t *hmm, uint32_t prev_pos, uint32_t pos, void *data, double *tprob)
{
args_t *args = (args_t*) data;
double ci = (pos - prev_pos) * args->rec_rate;
if ( ci > 1 ) ci = 1;
MAT(tprob,2,STATE_HW,STATE_AZ) *= ci;
MAT(tprob,2,STATE_AZ,STATE_HW) *= ci;
MAT(tprob,2,STATE_AZ,STATE_AZ) = 1 - MAT(tprob,2,STATE_HW,STATE_AZ);
MAT(tprob,2,STATE_HW,STATE_HW) = 1 - MAT(tprob,2,STATE_AZ,STATE_HW);
}
/**
* This function implements the HMM model:
* D = Data, AZ = autozygosity, HW = Hardy-Weinberg (non-autozygosity),
* f = non-ref allele frequency
*
* Emission probabilities:
* oAZ = P_i(D|AZ) = (1-f)*P(D|RR) + f*P(D|AA)
* oHW = P_i(D|HW) = (1-f)^2 * P(D|RR) + f^2 * P(D|AA) + 2*f*(1-f)*P(D|RA)
*
* Transition probabilities:
* tAZ = P(AZ|HW) .. parameter
* tHW = P(HW|AZ) .. parameter
*
* ci = P_i(C) .. probability of cross-over at site i, from genetic map
*
* AZi = P_i(AZ) .. probability of site i being AZ/non-AZ, scaled so that AZi+HWi = 1
* HWi = P_i(HW)
*
* P_i(AZ|HW) = P(AZ|HW) * ci * HW{i-1} = tAZ * ci * (1 - AZ{i-1})
* P_i(HW|AZ) = P(HW|AZ) * ci * AZ{i-1} = tHW * ci * AZ{i-1}
* P_i(AZ|AZ) = 1 - P_i(HW|AZ)
* P_i(HW|HW) = 1 - P_i(AZ|HW)
*
*/
static void flush_viterbi(args_t *args, int ismpl)
{
smpl_t *smpl = &args->smpl[ismpl];
if ( !smpl->nsites ) return;
const char *name = args->hdr->samples[ args->roh_smpl->idx[ismpl] ];
int i,j,k;
if ( !args->vi_training ) // single viterbi pass
{
hmm_restore(args->hmm, smpl->snapshot);
int end = (args->nbuf_max && smpl->nsites >= args->nbuf_max && smpl->nsites > args->nbuf_olap) ? smpl->nsites - args->nbuf_olap : smpl->nsites;
if ( end < smpl->nsites )
smpl->snapshot = hmm_snapshot(args->hmm, smpl->snapshot, smpl->sites[smpl->nsites - args->nbuf_olap - 1]);
args->igenmap = smpl->igenmap;
hmm_run_viterbi(args->hmm, smpl->nsites, smpl->eprob, smpl->sites);
hmm_run_fwd_bwd(args->hmm, smpl->nsites, smpl->eprob, smpl->sites);
double *fwd = hmm_get_fwd_bwd_prob(args->hmm);
const char *chr = bcf_hdr_id2name(args->hdr,args->prev_rid);
uint8_t *vpath = hmm_get_viterbi_path(args->hmm);
for (i=0; i<end; i++)
{
int state = vpath[i*2]==STATE_AZ ? 1 : 0;
double qual = phred_score(1.0 - fwd[i*2 + state]);
if ( args->output_type & OUTPUT_ST )
{
args->str.l = 0;
ksprintf(&args->str, "ST\t%s\t%s\t%d\t%d\t%.1f\n", name,chr,smpl->sites[i]+1, state, qual);
if ( bgzf_write(args->out, args->str.s, args->str.l) != args->str.l ) error("Error writing %s: %s\n", args->output_fname, strerror(errno));
}
if ( args->output_type & OUTPUT_RG )
{
if ( state!=smpl->rg.state )
{
if ( !state ) // the region ends, flush
{
args->str.l = 0;
ksprintf(&args->str, "RG\t%s\t%s\t%d\t%d\t%d\t%d\t%.1f\n",name,bcf_hdr_id2name(args->hdr,smpl->rg.rid),
smpl->rg.beg+1,smpl->rg.end+1,smpl->rg.end-smpl->rg.beg+1,smpl->rg.nqual,smpl->rg.qual/smpl->rg.nqual);
if ( bgzf_write(args->out, args->str.s, args->str.l) != args->str.l ) error("Error writing %s: %s\n", args->output_fname, strerror(errno));
smpl->rg.state = 0;
}
else
{
smpl->rg.state = 1;
smpl->rg.beg = smpl->sites[i];
smpl->rg.end = smpl->sites[i];
smpl->rg.rid = args->prev_rid;
smpl->rg.qual = qual;
smpl->rg.nqual = 1;
}
}
else if ( state )
{
smpl->rg.nqual++;
smpl->rg.qual += qual;
smpl->rg.end = smpl->sites[i];
}
}
}
if ( end < smpl->nsites )
{
end = smpl->nsites - args->nbuf_olap;
memmove(smpl->sites, smpl->sites + end, sizeof(*smpl->sites)*args->nbuf_olap);
memmove(smpl->eprob, smpl->eprob + end*2, sizeof(*smpl->eprob)*args->nbuf_olap*2);
smpl->nsites = args->nbuf_olap;
smpl->igenmap = args->igenmap;
}
else
{
smpl->nsites = 0;
smpl->igenmap = 0;
if ( smpl->rg.state )
{
args->str.l = 0;
ksprintf(&args->str, "RG\t%s\t%s\t%d\t%d\t%d\t%d\t%.1f\n",name,bcf_hdr_id2name(args->hdr,smpl->rg.rid),
smpl->rg.beg+1,smpl->rg.end+1,smpl->rg.end-smpl->rg.beg+1,smpl->rg.nqual,smpl->rg.qual/smpl->rg.nqual);
if ( bgzf_write(args->out, args->str.s, args->str.l) != args->str.l ) error("Error writing %s: %s\n", args->output_fname, strerror(errno));
smpl->rg.state = 0;
}
}
return;
}
// viterbi training, multiple chromosomes
double t2az_prev, t2hw_prev;
double deltaz, delthw;
double *tprob_arr = hmm_get_tprob(args->hmm);
MAT(tprob_arr,2,STATE_HW,STATE_HW) = 1 - args->t2AZ;
MAT(tprob_arr,2,STATE_HW,STATE_AZ) = args->t2HW;
MAT(tprob_arr,2,STATE_AZ,STATE_HW) = args->t2AZ;
MAT(tprob_arr,2,STATE_AZ,STATE_AZ) = 1 - args->t2HW;
hmm_set_tprob(args->hmm, tprob_arr, 10000);
int niter = 0;
do
{
tprob_arr = hmm_get_tprob(args->hmm);
t2az_prev = MAT(tprob_arr,2,STATE_AZ,STATE_HW); //args->t2AZ;
t2hw_prev = MAT(tprob_arr,2,STATE_HW,STATE_AZ); //args->t2HW;
double tprob_new[] = { 0,0,0,0 };
for (i=0; i<smpl->nrid; i++)
{
int ioff = smpl->rid_off[i];
int nsites = (i+1==smpl->nrid ? smpl->nsites : smpl->rid_off[i+1]) - ioff;
args->igenmap = 0;
tprob_arr = hmm_run_baum_welch(args->hmm, nsites, smpl->eprob+ioff*2, smpl->sites+ioff);
for (j=0; j<2; j++)
for (k=0; k<2; k++) MAT(tprob_new,2,j,k) += MAT(tprob_arr,2,j,k);
}
for (j=0; j<2; j++)
for (k=0; k<2; k++) MAT(tprob_new,2,j,k) /= smpl->nrid;
hmm_set_tprob(args->hmm, tprob_new, 10000);
deltaz = fabs(MAT(tprob_new,2,STATE_AZ,STATE_HW)-t2az_prev);
delthw = fabs(MAT(tprob_new,2,STATE_HW,STATE_AZ)-t2hw_prev);
niter++;
args->str.l = 0;
ksprintf(&args->str, "VT\t%s\t%d\t%e\t%e\t%e\t%e\t%e\t%e\n",
name,niter,deltaz,delthw,
1-MAT(tprob_new,2,STATE_HW,STATE_HW),MAT(tprob_new,2,STATE_AZ,STATE_HW),
1-MAT(tprob_new,2,STATE_AZ,STATE_AZ),MAT(tprob_new,2,STATE_HW,STATE_AZ));
if ( bgzf_write(args->out, args->str.s, args->str.l) != args->str.l ) error("Error writing %s: %s\n", args->output_fname, strerror(errno));
}
while ( deltaz > args->baum_welch_th || delthw > args->baum_welch_th );
// output the results
for (i=0; i<smpl->nrid; i++)
{
int ioff = smpl->rid_off[i];
int nsites = (i+1==smpl->nrid ? smpl->nsites : smpl->rid_off[i+1]) - ioff;
args->igenmap = 0;
hmm_run_viterbi(args->hmm, nsites, smpl->eprob+ioff*2, smpl->sites+ioff);
hmm_run_fwd_bwd(args->hmm, nsites, smpl->eprob+ioff*2, smpl->sites+ioff);
uint8_t *vpath = hmm_get_viterbi_path(args->hmm);
double *fwd = hmm_get_fwd_bwd_prob(args->hmm);
const char *chr = bcf_hdr_id2name(args->hdr,smpl->rid[i]);
for (j=0; j<nsites; j++)
{
int state = vpath[j*2]==STATE_AZ ? 1 : 0;
double *pval = fwd + j*2;
args->str.l = 0;
ksprintf(&args->str, "ROH\t%s\t%s\t%d\t%d\t%.1f\n", name,chr,smpl->sites[ioff+j]+1, state, phred_score(1.0-pval[state]));
if ( bgzf_write(args->out, args->str.s, args->str.l) != args->str.l ) error("Error writing %s: %s\n", args->output_fname, strerror(errno));
}
}
}
int read_AF(bcf_sr_regions_t *tgt, bcf1_t *line, double *alt_freq)
{
if ( tgt->nals < 2 )
error("Expected two comma-separated alleles (REF,ALT) in the third column of %s, found:\n\t%s\n", tgt->fname,tgt->line.s);
if ( tgt->nals != line->n_allele ) return -1; // number of alleles does not match
int i;
for (i=0; i<tgt->nals; i++)
if ( strcmp(line->d.allele[i],tgt->als[i]) ) break; // we could be smarter, see vcmp
if ( i<tgt->nals ) return -1;
char *tmp, *str = tgt->line.s;
i = 0;
while ( *str && i<3 )
{
if ( *str=='\t' ) i++;
str++;
}
*alt_freq = strtod(str, &tmp);
if ( *tmp && !isspace(*tmp) )
{
if ( str[0]=='.' && (!str[1] || isspace(str[1])) ) return -1; // missing value
error("Could not parse: [%s]\n", tgt->line.s);
}
if ( *alt_freq<0 || *alt_freq>1 ) error("Could not parse AF: [%s]\n", tgt->line.s);
return 0;
}
int8_t *get_GT(args_t *args, bcf1_t *line)
{
int i;
for (i=0; i<line->n_fmt; i++)
if ( line->d.fmt[i].id==args->gt_hdr_id ) break;
if ( i==line->n_fmt ) return NULL; // the tag is not present in this record
bcf_fmt_t *fmt = &line->d.fmt[i];
if ( fmt->n!=2 ) return NULL; // not diploid
if ( fmt->type!=BCF_BT_INT8 ) error("This is unexpected, GT type is %d\n", fmt->type);
return (int8_t*) fmt->p;
}
int estimate_AF_from_GT(args_t *args, int8_t *gt, double *alt_freq)
{
int i, nalt = 0, nref = 0;
if ( args->af_smpl ) // subset samples for AF estimate
{
for (i=0; i<args->af_smpl->n; i++)
{
int ismpl = args->af_smpl->idx[i];
if ( bcf_gt_is_missing(gt[2*ismpl]) || bcf_gt_is_missing(gt[2*ismpl+1]) ) continue;
if ( bcf_gt_allele(gt[2*ismpl]) ) nalt++;
else nref++;
if ( bcf_gt_allele(gt[2*ismpl+1]) ) nalt++;
else nref++;
}
}
else // all samples used in AF estimate
{
int8_t *end = gt + 2*bcf_hdr_nsamples(args->hdr);
while ( gt < end )
{
if ( bcf_gt_is_missing(gt[0]) || bcf_gt_is_missing(gt[1]) ) continue;
if ( bcf_gt_allele(gt[0]) ) nalt++;
else nref++;
if ( bcf_gt_allele(gt[1]) ) nalt++;
else nref++;
gt += 2;
}
}
if ( !nalt && !nref ) return -1;
*alt_freq = (double)nalt / (nalt + nref);
return 0;
}
int estimate_AF_from_PL(args_t *args, bcf_fmt_t *fmt_pl, int ial, double *alt_freq)
{
double af = 0;
int i, j, naf = 0;
int irr = bcf_alleles2gt(0,0), ira = bcf_alleles2gt(0,ial), iaa = bcf_alleles2gt(ial,ial);
if ( iaa >= fmt_pl->n ) return -1; // not diploid or wrong number of fields
if ( args->af_smpl ) // subset samples for AF estimate
{
#define BRANCH(type_t) \
{ \
for (i=0; i<args->af_smpl->n; i++) \
{ \
int ismpl = args->af_smpl->idx[i]; \
type_t *p = (type_t*)fmt_pl->p + fmt_pl->n*ismpl; \
if ( p[irr]<0 || p[ira]<0 || p[iaa]<0 ) continue; /* missing value */ \
if ( p[irr]==p[ira] && p[irr]==p[iaa] ) continue; /* all values are the same */ \
double prob[3], norm = 0; \
prob[0] = args->pl2p[ max255(p[irr]) ]; \
prob[1] = args->pl2p[ max255(p[ira]) ]; \
prob[2] = args->pl2p[ max255(p[iaa]) ]; \
for (j=0; j<3; j++) norm += prob[j]; \
for (j=0; j<3; j++) prob[j] /= norm; \
af += 0.5*prob[1] + prob[2]; \
naf++; \
} \
}
switch (fmt_pl->type) {
case BCF_BT_INT8: BRANCH(int8_t); break;
case BCF_BT_INT16: BRANCH(int16_t); break;
case BCF_BT_INT32: BRANCH(int32_t); break;
default: fprintf(stderr,"Unknown format type for PL: %s:%d .. fmt->type=%d\n", __FILE__,__LINE__, fmt_pl->type); exit(1);
}
#undef BRANCH
}
else // all samples used in AF estimate
{
int nsmpl = bcf_hdr_nsamples(args->hdr);
#define BRANCH(type_t) \
{ \
type_t *p = (type_t*)fmt_pl->p; \
p -= fmt_pl->n; \
for (i=0; i<nsmpl; i++) \
{ \
p += fmt_pl->n; \
if ( p[irr]<0 || p[ira]<0 || p[iaa]<0 ) continue; /* missing value */ \
if ( p[irr]==p[ira] && p[irr]==p[iaa] ) continue; /* all values are the same */ \
double prob[3], norm = 0; \
prob[0] = args->pl2p[ max255(p[irr]) ]; \
prob[1] = args->pl2p[ max255(p[ira]) ]; \
prob[2] = args->pl2p[ max255(p[iaa]) ]; \
for (j=0; j<3; j++) norm += prob[j]; \
for (j=0; j<3; j++) prob[j] /= norm; \
af += 0.5*prob[1] + prob[2]; \
naf++; \
} \
}
switch (fmt_pl->type) {
case BCF_BT_INT8: BRANCH(int8_t); break;
case BCF_BT_INT16: BRANCH(int16_t); break;
case BCF_BT_INT32: BRANCH(int32_t); break;
default: fprintf(stderr,"Unknown format type for PL: %s:%d .. fmt->type=%d\n", __FILE__,__LINE__, fmt_pl->type); exit(1);
}
#undef BRANCH
}
if ( !naf ) return -1;
*alt_freq = af / naf;
return 0;
}
bcf_fmt_t *get_PL(args_t *args, bcf1_t *line)
{
int i;
for (i=0; i<line->n_fmt; i++)
if ( line->d.fmt[i].id==args->pl_hdr_id ) return &line->d.fmt[i];
return NULL;
}
int process_line(args_t *args, bcf1_t *line, int ial)
{
if ( !(line->unpacked & BCF_UN_FMT) ) bcf_unpack(line, BCF_UN_FMT);
double alt_freq;
int8_t *GTs = NULL;
bcf_fmt_t *fmt_pl = NULL;
// Set allele frequency
int ret = 0, i,j;
if ( args->af_tag )
{
// Use an INFO tag provided by the user
ret = bcf_get_info_float(args->hdr, line, args->af_tag, &args->AFs, &args->mAFs);
if ( ret>0 )
alt_freq = args->AFs[ial-1];
if ( ret==-2 )
error("Type mismatch for INFO/%s tag at %s:%"PRId64"\n", args->af_tag, bcf_seqname(args->hdr,line), (int64_t) line->pos+1);
}
else if ( args->af_fname )
{
// Read AF from a file
ret = read_AF(args->files->targets, line, &alt_freq);
}
else if ( args->dflt_AF > 0 )
{
alt_freq = args->dflt_AF;
}
else if ( args->estimate_AF )
{
// Estimate AF from GTs or PLs of all samples or samples listed in a file
if ( args->af_from_PL )
{
fmt_pl = get_PL(args, line);
if ( !fmt_pl ) return -1;
ret = estimate_AF_from_PL(args, fmt_pl, ial, &alt_freq);
}
else
{
GTs = get_GT(args, line);
if ( !GTs ) return -1;
ret = estimate_AF_from_GT(args, GTs, &alt_freq);
}
}
else
{
// Use AC/AN
int AC = -1, AN = 0;
ret = bcf_get_info_int32(args->hdr, line, "AN", &args->itmp, &args->mitmp);
if ( ret==1 )
{
AN = args->itmp[0];
ret = bcf_get_info_int32(args->hdr, line, "AC", &args->itmp, &args->mitmp);
if ( ret>0 )
AC = args->itmp[0];
}
if ( AN<=0 || AC<0 )
ret = -1;
else
alt_freq = (double) AC/AN;
}
if ( args->dflt_AF>0 && (ret<0 || alt_freq==0.0) ) alt_freq = args->dflt_AF;
else if ( ret<0 ) { args->nno_af++; return ret; }
else if ( alt_freq==0.0 ) { args->nno_af++; return -1; }
int irr = bcf_alleles2gt(0,0), ira = bcf_alleles2gt(0,ial), iaa = bcf_alleles2gt(ial,ial);
if ( args->fake_PLs )
{
if ( !GTs ) GTs = get_GT(args, line);
}
else
{
fmt_pl = get_PL(args, line);
if ( !fmt_pl ) return -1;
if ( iaa >= fmt_pl->n ) return -1; // not diploid or wrong number of fields
}
for (i=0; i<args->roh_smpl->n; i++)
{
int ismpl = args->roh_smpl->idx[i];
// set P(D|G)
double pdg[3];
if ( args->fake_PLs )
{
int8_t *gt = GTs + 2*ismpl;
if ( bcf_gt_is_missing(gt[0]) || bcf_gt_is_missing(gt[1]) ) continue;
int a = bcf_gt_allele(gt[0]);
int b = bcf_gt_allele(gt[1]);
if ( a!=b )
{
pdg[0] = pdg[2] = args->unseen_PL;
pdg[1] = 1 - 2*args->unseen_PL;
}
else if ( a==0 )
{
pdg[0] = 1 - args->unseen_PL - args->unseen_PL*args->unseen_PL;
pdg[1] = args->unseen_PL;
pdg[2] = args->unseen_PL*args->unseen_PL;
}
else
{
pdg[0] = args->unseen_PL*args->unseen_PL;
pdg[1] = args->unseen_PL;
pdg[2] = 1 - args->unseen_PL - args->unseen_PL*args->unseen_PL;
}
}
else
{
#define BRANCH(type_t) \
{ \
type_t *p = (type_t*)fmt_pl->p + fmt_pl->n*ismpl; \
if ( p[irr]<0 || p[ira]<0 || p[iaa]<0 ) continue; /* missing value */ \
if ( p[irr]==p[ira] && p[irr]==p[iaa] ) continue; /* all values are the same */ \
pdg[0] = args->pl2p[ max255(p[irr]) ]; \
pdg[1] = args->pl2p[ max255(p[ira]) ]; \
pdg[2] = args->pl2p[ max255(p[iaa]) ]; \
}
switch (fmt_pl->type) {
case BCF_BT_INT8: BRANCH(int8_t); break;
case BCF_BT_INT16: BRANCH(int16_t); break;
case BCF_BT_INT32: BRANCH(int32_t); break;
default: fprintf(stderr,"Unknown format type for PL: %s:%d .. fmt->type=%d\n", __FILE__,__LINE__, fmt_pl->type); exit(1);
}
#undef BRANCH
}
double sum = pdg[0] + pdg[1] + pdg[2];
if ( !sum ) continue;
for (j=0; j<3; j++) pdg[j] /= sum;
if ( args->skip_homref && pdg[0]>0.99 ) continue;
smpl_t *smpl = &args->smpl[i];
smpl->nused++;
if ( smpl->nsites >= smpl->msites )
{
hts_expand(uint32_t,smpl->nsites+1,smpl->msites,smpl->sites);
smpl->eprob = (double*) realloc(smpl->eprob,sizeof(*smpl->eprob)*smpl->msites*2);
if ( !smpl->eprob ) error("Error: failed to alloc %"PRIu64" bytes\n", (uint64_t)(sizeof(*smpl->eprob)*smpl->msites*2));
}
// Calculate emission probabilities P(D|AZ) and P(D|HW)
double *eprob = &smpl->eprob[2*smpl->nsites];
eprob[STATE_AZ] = pdg[0]*(1-alt_freq) + pdg[2]*alt_freq;
eprob[STATE_HW] = pdg[0]*(1-alt_freq)*(1-alt_freq) + 2*pdg[1]*(1-alt_freq)*alt_freq + pdg[2]*alt_freq*alt_freq;
smpl->sites[smpl->nsites] = line->pos;
smpl->nsites++;
if ( args->vi_training )
{
if ( !smpl->nrid || line->rid!=smpl->rid[smpl->nrid-1] )
{
smpl->nrid++;
smpl->rid = (int*) realloc(smpl->rid,sizeof(*smpl->rid)*smpl->nrid);
smpl->rid[smpl->nrid-1] = line->rid;
smpl->rid_off = (int*) realloc(smpl->rid_off,sizeof(*smpl->rid_off)*smpl->nrid);
smpl->rid_off[smpl->nrid-1] = smpl->nsites - 1;
}
}
else if ( args->nbuf_max && smpl->nsites >= args->nbuf_max ) flush_viterbi(args, i);
}
return 0;
}
static void vcfroh(args_t *args, bcf1_t *line)
{
int i;
// Are we done?
if ( !line )
{
for (i=0; i<args->roh_smpl->n; i++) flush_viterbi(args, i);
return;
}