synced_bcf_reader.c

/*  synced_bcf_reader.c -- stream through multiple VCF files.

    Copyright (C) 2012-2020 Genome Research Ltd.

    Author: Petr Danecek <pd3@sanger.ac.uk>

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.  */

#define HTS_BUILDING_LIBRARY // Enables HTSLIB_EXPORT, see htslib/hts_defs.h
#include <config.h>

#include <assert.h>
#include <stdio.h>
#include <unistd.h>
#include <string.h>
#include <strings.h>
#include <limits.h>
#include <inttypes.h>
#include <errno.h>
#include <sys/stat.h>
#include "htslib/synced_bcf_reader.h"
#include "htslib/kseq.h"
#include "htslib/khash_str2int.h"
#include "htslib/bgzf.h"
#include "htslib/thread_pool.h"
#include "bcf_sr_sort.h"

#define REQUIRE_IDX_      1
#define ALLOW_NO_IDX_     2

// Maximum indexable coordinate of .csi, for default min_shift of 14.
// This comes out to about 17 Tbp.  Limiting factor is the bin number,
// which is a uint32_t in CSI.  The highest number of levels compatible
// with this is 10 (needs 31 bits).
#define MAX_CSI_COOR ((1LL << (14 + 30)) - 1)

typedef struct
{
    hts_pos_t start, end;   // records are marked for skipping have start>end
}
region1_t;

typedef struct bcf_sr_region_t
{
    region1_t *regs;            // regions will sorted and merged, redundant records marked for skipping have start>end
    int nregs, mregs, creg;     // creg: the current active region
}
region_t;

#define BCF_SR_AUX(x) ((aux_t*)((x)->aux))
typedef struct
{
    sr_sort_t sort;
}
aux_t;

static int _regions_add(bcf_sr_regions_t *reg, const char *chr, hts_pos_t start, hts_pos_t end);
static bcf_sr_regions_t *_regions_init_string(const char *str);
static int _regions_match_alleles(bcf_sr_regions_t *reg, int als_idx, bcf1_t *rec);
static void _regions_sort_and_merge(bcf_sr_regions_t *reg);

char *bcf_sr_strerror(int errnum)
{
    switch (errnum)
    {
        case open_failed:
            return strerror(errno);
        case not_bgzf:
            return "not compressed with bgzip";
        case idx_load_failed:
            return "could not load index";
        case file_type_error:
            return "unknown file type";
        case api_usage_error:
            return "API usage error";
        case header_error:
            return "could not parse header";
        case no_eof:
            return "no BGZF EOF marker; file may be truncated";
        case no_memory:
            return "Out of memory";
        case vcf_parse_error:
            return "VCF parse error";
        case bcf_read_error:
            return "BCF read error";
        case noidx_error:
            return "merge of unindexed files failed";
        default: return "";
    }
}

int bcf_sr_set_opt(bcf_srs_t *readers, bcf_sr_opt_t opt, ...)
{
    va_list args;
    switch (opt)
    {
        case BCF_SR_REQUIRE_IDX:
            readers->require_index = REQUIRE_IDX_;
            return 0;

        case BCF_SR_ALLOW_NO_IDX:
            readers->require_index = ALLOW_NO_IDX_;
            return 0;

        case BCF_SR_PAIR_LOGIC:
            va_start(args, opt);
            BCF_SR_AUX(readers)->sort.pair = va_arg(args, int);
            return 0;

        default:
            break;
    }
    return 1;
}

static int *init_filters(bcf_hdr_t *hdr, const char *filters, int *nfilters)
{
    kstring_t str = {0,0,0};
    const char *tmp = filters, *prev = filters;
    int nout = 0, *out = NULL;
    while ( 1 )
    {
        if ( *tmp==',' || !*tmp )
        {
            int *otmp = (int*) realloc(out, (nout+1)*sizeof(int));
            if (!otmp)
                goto err;
            out = otmp;
            if ( tmp-prev==1 && *prev=='.' )
            {
                out[nout] = -1;
                nout++;
            }
            else
            {
                str.l = 0;
                kputsn(prev, tmp-prev, &str);
                out[nout] = bcf_hdr_id2int(hdr, BCF_DT_ID, str.s);
                if ( out[nout]>=0 ) nout++;
            }
            if ( !*tmp ) break;
            prev = tmp+1;
        }
        tmp++;
    }
    if ( str.m ) free(str.s);
    *nfilters = nout;
    return out;

 err:
    if (str.m) free(str.s);
    free(out);
    return NULL;
}

int bcf_sr_set_regions(bcf_srs_t *readers, const char *regions, int is_file)
{
    assert( !readers->regions );
    if ( readers->nreaders )
    {
        hts_log_error("Must call bcf_sr_set_regions() before bcf_sr_add_reader()");
        return -1;
    }
    readers->regions = bcf_sr_regions_init(regions,is_file,0,1,-2);
    if ( !readers->regions ) return -1;
    readers->explicit_regs = 1;
    readers->require_index = REQUIRE_IDX_;
    return 0;
}
int bcf_sr_set_targets(bcf_srs_t *readers, const char *targets, int is_file, int alleles)
{
    assert( !readers->targets );
    if ( targets[0]=='^' )
    {
        readers->targets_exclude = 1;
        targets++;
    }
    readers->targets = bcf_sr_regions_init(targets,is_file,0,1,-2);
    if ( !readers->targets ) return -1;
    readers->targets_als = alleles;
    return 0;
}

int bcf_sr_set_threads(bcf_srs_t *files, int n_threads)
{
    if (!(files->n_threads = n_threads))
        return 0;

    files->p = calloc(1, sizeof(*files->p));
    if (!files->p) {
        files->errnum = no_memory;
        return -1;
    }
    if (!(files->p->pool = hts_tpool_init(n_threads)))
        return -1;

    return 0;
}

void bcf_sr_destroy_threads(bcf_srs_t *files) {
    if (!files->p)
        return;

    if (files->p->pool)
        hts_tpool_destroy(files->p->pool);
    free(files->p);
}

int bcf_sr_add_reader(bcf_srs_t *files, const char *fname)
{
    char fmode[5];
    strcpy(fmode, "r");
    vcf_open_mode(fmode+1, fname, NULL);
    htsFile* file_ptr = hts_open(fname, fmode);
    if ( ! file_ptr ) {
        files->errnum = open_failed;
        return 0;
    }

    files->has_line = (int*) realloc(files->has_line, sizeof(int)*(files->nreaders+1));
    files->has_line[files->nreaders] = 0;
    files->readers  = (bcf_sr_t*) realloc(files->readers, sizeof(bcf_sr_t)*(files->nreaders+1));
    bcf_sr_t *reader = &files->readers[files->nreaders++];
    memset(reader,0,sizeof(bcf_sr_t));

    reader->file = file_ptr;

    files->errnum = 0;

    if ( reader->file->format.compression==bgzf )
    {
        BGZF *bgzf = hts_get_bgzfp(reader->file);
        if ( bgzf && bgzf_check_EOF(bgzf) == 0 ) {
            files->errnum = no_eof;
            hts_log_warning("No BGZF EOF marker; file '%s' may be truncated", fname);
        }
        if (files->p)
            bgzf_thread_pool(bgzf, files->p->pool, files->p->qsize);
    }

    if ( files->require_index==REQUIRE_IDX_ )
    {
        if ( reader->file->format.format==vcf )
        {
            if ( reader->file->format.compression!=bgzf )
            {
                files->errnum = not_bgzf;
                return 0;
            }

            reader->tbx_idx = tbx_index_load(fname);
            if ( !reader->tbx_idx )
            {
                files->errnum = idx_load_failed;
                return 0;
            }

            reader->header = bcf_hdr_read(reader->file);
        }
        else if ( reader->file->format.format==bcf )
        {
            if ( reader->file->format.compression!=bgzf )
            {
                files->errnum = not_bgzf;
                return 0;
            }

            reader->header = bcf_hdr_read(reader->file);

            reader->bcf_idx = bcf_index_load(fname);
            if ( !reader->bcf_idx )
            {
                files->errnum = idx_load_failed;
                return 0;
            }
        }
        else
        {
            files->errnum = file_type_error;
            return 0;
        }
    }
    else
    {
        if ( reader->file->format.format==bcf || reader->file->format.format==vcf )
        {
            reader->header = bcf_hdr_read(reader->file);
        }
        else
        {
            files->errnum = file_type_error;
            return 0;
        }
        files->streaming = 1;
    }
    if ( files->streaming && files->nreaders>1 )
    {
        static int no_index_warned = 0;
        if ( files->require_index==ALLOW_NO_IDX_ && !no_index_warned )
        {
            hts_log_warning("Using multiple unindexed files may produce errors, make sure chromosomes are in the same order!");
            no_index_warned = 1;
        }
        if ( files->require_index!=ALLOW_NO_IDX_ )
        {
            files->errnum = api_usage_error;
            hts_log_error("Must set require_index when the number of readers is greater than one");
            return 0;
        }
    }
    if ( files->streaming && files->regions )
    {
        files->errnum = api_usage_error;
        hts_log_error("Cannot tabix-jump in streaming mode");
        return 0;
    }
    if ( !reader->header )
    {
        files->errnum = header_error;
        return 0;
    }

    reader->fname = strdup(fname);
    if ( files->apply_filters )
        reader->filter_ids = init_filters(reader->header, files->apply_filters, &reader->nfilter_ids);

    // Update list of chromosomes
    if ( !files->explicit_regs && !files->streaming )
    {
        int n = 0, i;
        const char **names = reader->tbx_idx ? tbx_seqnames(reader->tbx_idx, &n) : bcf_hdr_seqnames(reader->header, &n);
        for (i=0; i<n; i++)
        {
            if ( !files->regions )
                files->regions = _regions_init_string(names[i]);
            else
                _regions_add(files->regions, names[i], -1, -1);
        }
        free(names);
        _regions_sort_and_merge(files->regions);
    }

    if ( files->require_index==ALLOW_NO_IDX_ && files->nreaders > 1 )
    {
        bcf_hdr_t *hdr0 = files->readers[0].header;
        bcf_hdr_t *hdr1 = reader->header;
        if ( hdr0->n[BCF_DT_CTG]!=hdr1->n[BCF_DT_CTG] )
        {
            files->errnum = noidx_error;
            hts_log_error("Different number of sequences in the header, refusing to stream multiple unindexed files");
            return 0;
        }
        int i;
        for (i=0; i<hdr0->n[BCF_DT_CTG]; i++)
        {
            if ( strcmp(bcf_hdr_id2name(hdr0,i),bcf_hdr_id2name(hdr1,i)) )
            {
                files->errnum = noidx_error;
                hts_log_error("Sequences in the header appear in different order, refusing to stream multiple unindexed files");
                return 0;
            }
        }
    }

    return 1;
}

bcf_srs_t *bcf_sr_init(void)
{
    bcf_srs_t *files = (bcf_srs_t*) calloc(1,sizeof(bcf_srs_t));
    files->aux = (aux_t*) calloc(1,sizeof(aux_t));
    bcf_sr_sort_init(&BCF_SR_AUX(files)->sort);
    return files;
}

static void bcf_sr_destroy1(bcf_sr_t *reader)
{
    free(reader->fname);
    if ( reader->tbx_idx ) tbx_destroy(reader->tbx_idx);
    if ( reader->bcf_idx ) hts_idx_destroy(reader->bcf_idx);
    bcf_hdr_destroy(reader->header);
    hts_close(reader->file);
    if ( reader->itr ) tbx_itr_destroy(reader->itr);
    int j;
    for (j=0; j<reader->mbuffer; j++)
        bcf_destroy1(reader->buffer[j]);
    free(reader->buffer);
    free(reader->samples);
    free(reader->filter_ids);
}

void bcf_sr_destroy(bcf_srs_t *files)
{
    int i;
    for (i=0; i<files->nreaders; i++)
        bcf_sr_destroy1(&files->readers[i]);
    free(files->has_line);
    free(files->readers);
    for (i=0; i<files->n_smpl; i++) free(files->samples[i]);
    free(files->samples);
    if (files->targets) bcf_sr_regions_destroy(files->targets);
    if (files->regions) bcf_sr_regions_destroy(files->regions);
    if (files->tmps.m) free(files->tmps.s);
    if (files->n_threads) bcf_sr_destroy_threads(files);
    bcf_sr_sort_destroy(&BCF_SR_AUX(files)->sort);
    free(files->aux);
    free(files);
}

void bcf_sr_remove_reader(bcf_srs_t *files, int i)
{
    assert( !files->samples );  // not ready for this yet
    bcf_sr_sort_remove_reader(files, &BCF_SR_AUX(files)->sort, i);
    bcf_sr_destroy1(&files->readers[i]);
    if ( i+1 < files->nreaders )
    {
        memmove(&files->readers[i], &files->readers[i+1], (files->nreaders-i-1)*sizeof(bcf_sr_t));
        memmove(&files->has_line[i], &files->has_line[i+1], (files->nreaders-i-1)*sizeof(int));
    }
    files->nreaders--;
}

#if DEBUG_SYNCED_READER
void debug_buffer(FILE *fp, bcf_sr_t *reader)
{
    int j;
    for (j=0; j<=reader->nbuffer; j++)
    {
        bcf1_t *line = reader->buffer[j];
        fprintf(fp,"\t%p\t%s%s\t%s:%"PRIhts_pos"\t%s ", (void*)line,reader->fname,j==0?"*":" ",reader->header->id[BCF_DT_CTG][line->rid].key,line->pos+1,line->n_allele?line->d.allele[0]:"");
        int k;
        for (k=1; k<line->n_allele; k++) fprintf(fp," %s", line->d.allele[k]);
        fprintf(fp,"\n");
    }
}

void debug_buffers(FILE *fp, bcf_srs_t *files)
{
    int i;
    for (i=0; i<files->nreaders; i++)
    {
        fprintf(fp, "has_line: %d\t%s\n", bcf_sr_has_line(files,i),files->readers[i].fname);
        debug_buffer(fp, &files->readers[i]);
    }
    fprintf(fp,"\n");
}
#endif

static inline int has_filter(bcf_sr_t *reader, bcf1_t *line)
{
    int i, j;
    if ( !line->d.n_flt )
    {
        for (j=0; j<reader->nfilter_ids; j++)
            if ( reader->filter_ids[j]<0 ) return 1;
        return 0;
    }
    for (i=0; i<line->d.n_flt; i++)
    {
        for (j=0; j<reader->nfilter_ids; j++)
            if ( line->d.flt[i]==reader->filter_ids[j] ) return 1;
    }
    return 0;
}

static int _reader_seek(bcf_sr_t *reader, const char *seq, hts_pos_t start, hts_pos_t end)
{
    if ( end>=MAX_CSI_COOR )
    {
        hts_log_error("The coordinate is out of csi index limit: %"PRIhts_pos, end+1);
        exit(1);
    }
    if ( reader->itr )
    {
        hts_itr_destroy(reader->itr);
        reader->itr = NULL;
    }
    reader->nbuffer = 0;
    if ( reader->tbx_idx )
    {
        int tid = tbx_name2id(reader->tbx_idx, seq);
        if ( tid==-1 ) return -1;    // the sequence not present in this file
        reader->itr = tbx_itr_queryi(reader->tbx_idx,tid,start,end+1);
    }
    else
    {
        int tid = bcf_hdr_name2id(reader->header, seq);
        if ( tid==-1 ) return -1;    // the sequence not present in this file
        reader->itr = bcf_itr_queryi(reader->bcf_idx,tid,start,end+1);
    }
    if (!reader->itr) {
        hts_log_error("Could not seek: %s:%"PRIhts_pos"-%"PRIhts_pos, seq, start + 1, end + 1);
        assert(0);
    }
    return 0;
}

/*
 *  _readers_next_region() - jumps to next region if necessary
 *  Returns 0 on success or -1 when there are no more regions left
 */
static int _readers_next_region(bcf_srs_t *files)
{
    // Need to open new chromosome? Check number of lines in all readers' buffers
    int i, eos = 0;
    for (i=0; i<files->nreaders; i++)
        if ( !files->readers[i].itr && !files->readers[i].nbuffer ) eos++;

    if ( eos!=files->nreaders )
    {
        // Some of the readers still has buffered lines
        return 0;
    }

    // No lines in the buffer, need to open new region or quit.
    int prev_iseq = files->regions->iseq;
    hts_pos_t prev_end = files->regions->end;
    if ( bcf_sr_regions_next(files->regions)<0 ) return -1;
    files->regions->prev_end = prev_iseq==files->regions->iseq ? prev_end : -1;

    for (i=0; i<files->nreaders; i++)
        _reader_seek(&files->readers[i],files->regions->seq_names[files->regions->iseq],files->regions->start,files->regions->end);

    return 0;
}

/*
 *  _reader_fill_buffer() - buffers all records with the same coordinate
 */
static int _reader_fill_buffer(bcf_srs_t *files, bcf_sr_t *reader)
{
    // Return if the buffer is full: the coordinate of the last buffered record differs
    if ( reader->nbuffer && reader->buffer[reader->nbuffer]->pos != reader->buffer[1]->pos ) return 0;

    // No iterator (sequence not present in this file) and not streaming
    if ( !reader->itr && !files->streaming ) return 0;

    // Fill the buffer with records starting at the same position
    int i, ret = 0;
    while (1)
    {
        if ( reader->nbuffer+1 >= reader->mbuffer )
        {
            // Increase buffer size
            reader->mbuffer += 8;
            reader->buffer = (bcf1_t**) realloc(reader->buffer, sizeof(bcf1_t*)*reader->mbuffer);
            for (i=8; i>0; i--)     // initialize
            {
                reader->buffer[reader->mbuffer-i] = bcf_init1();
                reader->buffer[reader->mbuffer-i]->max_unpack = files->max_unpack;
                reader->buffer[reader->mbuffer-i]->pos = -1;    // for rare cases when VCF starts from 1
            }
        }
        if ( files->streaming )
        {
            if ( reader->file->format.format==vcf )
            {
                if ( (ret=hts_getline(reader->file, KS_SEP_LINE, &files->tmps)) < 0 ) break;   // no more lines
                ret = vcf_parse1(&files->tmps, reader->header, reader->buffer[reader->nbuffer+1]);
                if ( ret<0 ) { files->errnum = vcf_parse_error; break; }
            }
            else if ( reader->file->format.format==bcf )
            {
                ret = bcf_read1(reader->file, reader->header, reader->buffer[reader->nbuffer+1]);
                if ( ret < -1 ) files->errnum = bcf_read_error;
                if ( ret < 0 ) break; // no more lines or an error
            }
            else
            {
                hts_log_error("Fixme: not ready for this");
                exit(1);
            }
        }
        else if ( reader->tbx_idx )
        {
            if ( (ret=tbx_itr_next(reader->file, reader->tbx_idx, reader->itr, &files->tmps)) < 0 ) break;  // no more lines
            ret = vcf_parse1(&files->tmps, reader->header, reader->buffer[reader->nbuffer+1]);
            if ( ret<0 ) { files->errnum = vcf_parse_error; break; }
        }
        else
        {
            ret = bcf_itr_next(reader->file, reader->itr, reader->buffer[reader->nbuffer+1]);
            if ( ret < -1 ) files->errnum = bcf_read_error;
            if ( ret < 0 ) break; // no more lines or an error
            bcf_subset_format(reader->header,reader->buffer[reader->nbuffer+1]);
        }

        // prevent creation of duplicates from records overlapping multiple regions
        if ( files->regions && reader->buffer[reader->nbuffer+1]->pos <= files->regions->prev_end ) continue;

        // apply filter
        if ( !reader->nfilter_ids )
            bcf_unpack(reader->buffer[reader->nbuffer+1], BCF_UN_STR);
        else
        {
            bcf_unpack(reader->buffer[reader->nbuffer+1], BCF_UN_STR|BCF_UN_FLT);
            if ( !has_filter(reader, reader->buffer[reader->nbuffer+1]) ) continue;
        }
        reader->nbuffer++;

        if ( files->require_index==ALLOW_NO_IDX_ && reader->buffer[reader->nbuffer]->rid != reader->buffer[1]->rid ) break;
        if ( reader->buffer[reader->nbuffer]->pos != reader->buffer[1]->pos ) break;    // the buffer is full
    }
    if ( ret<0 )
    {
        // done for this region
        tbx_itr_destroy(reader->itr);
        reader->itr = NULL;
    }
    if ( files->require_index==ALLOW_NO_IDX_ && reader->buffer[reader->nbuffer]->rid < reader->buffer[1]->rid )
    {
         hts_log_error("Sequences out of order, cannot stream multiple unindexed files: %s", reader->fname);
         exit(1);
    }
    return 0; // FIXME: Check for more errs in this function
}

/*
 *  _readers_shift_buffer() - removes the first line and all subsequent lines with the same position
 */
static void _reader_shift_buffer(bcf_sr_t *reader)
{
    int i;
    for (i=2; i<=reader->nbuffer; i++)
        if ( reader->buffer[i]->pos!=reader->buffer[1]->pos ) break;
    if ( i<=reader->nbuffer )
    {
        // A record with a different position follows, swap it. Because of the reader's logic,
        // only one such line can be present.
        bcf1_t *tmp = reader->buffer[1]; reader->buffer[1] = reader->buffer[i]; reader->buffer[i] = tmp;
        reader->nbuffer = 1;
    }
    else
        reader->nbuffer = 0;    // no other line
}

static int next_line(bcf_srs_t *files)
{
    const char *chr = NULL;
    hts_pos_t min_pos = HTS_POS_MAX;

    // Loop until next suitable line is found or all readers have finished
    while ( 1 )
    {
        // Get all readers ready for the next region.
        if ( files->regions && _readers_next_region(files)<0 ) break;

        // Fill buffers and find the minimum chromosome
        int i, min_rid = INT32_MAX;
        for (i=0; i<files->nreaders; i++)
        {
            _reader_fill_buffer(files, &files->readers[i]);
            if ( files->require_index==ALLOW_NO_IDX_ )
            {
                if ( !files->readers[i].nbuffer ) continue;
                if ( min_rid > files->readers[i].buffer[1]->rid ) min_rid = files->readers[i].buffer[1]->rid;
            }
        }

        for (i=0; i<files->nreaders; i++)
        {
            if ( !files->readers[i].nbuffer ) continue;
            if ( files->require_index==ALLOW_NO_IDX_ && min_rid != files->readers[i].buffer[1]->rid ) continue;

            // Update the minimum coordinate
            if ( min_pos > files->readers[i].buffer[1]->pos )
            {
                min_pos = files->readers[i].buffer[1]->pos;
                chr = bcf_seqname(files->readers[i].header, files->readers[i].buffer[1]);
                assert(chr);
                bcf_sr_sort_set_active(&BCF_SR_AUX(files)->sort, i);
            }
            else if ( min_pos==files->readers[i].buffer[1]->pos )
                bcf_sr_sort_add_active(&BCF_SR_AUX(files)->sort, i);
        }
        if ( min_pos==HTS_POS_MAX )
        {
            if ( !files->regions ) break;
            continue;
        }

        // Skip this position if not present in targets
        if ( files->targets )
        {
            int ret = bcf_sr_regions_overlap(files->targets, chr, min_pos, min_pos);
            if ( (!files->targets_exclude && ret<0) || (files->targets_exclude && !ret) )
            {
                // Remove all lines with this position from the buffer
                for (i=0; i<files->nreaders; i++)
                    if ( files->readers[i].nbuffer && files->readers[i].buffer[1]->pos==min_pos )
                        _reader_shift_buffer(&files->readers[i]);
                min_pos = HTS_POS_MAX;
                chr = NULL;
                continue;
            }
        }

        break;  // done: chr and min_pos are set
    }
    if ( !chr ) return 0;

    return bcf_sr_sort_next(files, &BCF_SR_AUX(files)->sort, chr, min_pos);
}

int bcf_sr_next_line(bcf_srs_t *files)
{
    if ( !files->targets_als )
        return next_line(files);

    while (1)
    {
        int i, ret = next_line(files);
        if ( !ret ) return ret;

        for (i=0; i<files->nreaders; i++)
            if ( files->has_line[i] ) break;

        if ( _regions_match_alleles(files->targets, files->targets_als-1, files->readers[i].buffer[0]) ) return ret;

        // Check if there are more duplicate lines in the buffers. If not, return this line as if it
        // matched the targets, even if there is a type mismatch
        for (i=0; i<files->nreaders; i++)
        {
            if ( !files->has_line[i] ) continue;
            if ( files->readers[i].nbuffer==0 || files->readers[i].buffer[1]->pos!=files->readers[i].buffer[0]->pos ) continue;
            break;
        }
        if ( i==files->nreaders ) return ret;   // no more lines left, output even if target alleles are not of the same type
    }
}

static void bcf_sr_seek_start(bcf_srs_t *readers)
{
    bcf_sr_regions_t *reg = readers->regions;
    int i;
    for (i=0; i<reg->nseqs; i++)
        reg->regs[i].creg = -1;
    reg->iseq = 0;
}


int bcf_sr_seek(bcf_srs_t *readers, const char *seq, hts_pos_t pos)
{
    if ( !readers->regions ) return 0;
    bcf_sr_sort_reset(&BCF_SR_AUX(readers)->sort);
    if ( !seq && !pos )
    {
        // seek to start
        bcf_sr_seek_start(readers);
        return 0;
    }
    bcf_sr_regions_overlap(readers->regions, seq, pos, pos);
    int i, nret = 0;
    for (i=0; i<readers->nreaders; i++)
    {
        nret += _reader_seek(&readers->readers[i],seq,pos,MAX_CSI_COOR-1);
    }
    return nret;
}

int bcf_sr_set_samples(bcf_srs_t *files, const char *fname, int is_file)
{
    int i, j, nsmpl, free_smpl = 0;
    char **smpl = NULL;

    void *exclude = (fname[0]=='^') ? khash_str2int_init() : NULL;
    if ( exclude || strcmp("-",fname) ) // "-" stands for all samples
    {
        smpl = hts_readlist(fname, is_file, &nsmpl);
        if ( !smpl )
        {
            hts_log_error("Could not read the file: \"%s\"", fname);
            return 0;
        }
        if ( exclude )
        {
            for (i=0; i<nsmpl; i++)
                khash_str2int_inc(exclude, smpl[i]);
        }
        free_smpl = 1;
    }
    if ( !smpl )
    {
        smpl  = files->readers[0].header->samples;   // intersection of all samples
        nsmpl = bcf_hdr_nsamples(files->readers[0].header);
    }

    files->samples = NULL;
    files->n_smpl  = 0;
    for (i=0; i<nsmpl; i++)
    {
        if ( exclude && khash_str2int_has_key(exclude,smpl[i])  ) continue;

        int n_isec = 0;
        for (j=0; j<files->nreaders; j++)
        {
            if ( bcf_hdr_id2int(files->readers[j].header, BCF_DT_SAMPLE, smpl[i])<0 ) break;
            n_isec++;
        }
        if ( n_isec!=files->nreaders )
        {
            hts_log_warning("The sample \"%s\" was not found in %s, skipping",
                smpl[i], files->readers[n_isec].fname);
            continue;
        }

        files->samples = (char**) realloc(files->samples, (files->n_smpl+1)*sizeof(const char*));
        files->samples[files->n_smpl++] = strdup(smpl[i]);
    }

    if ( exclude ) khash_str2int_destroy(exclude);
    if ( free_smpl )
    {
        for (i=0; i<nsmpl; i++) free(smpl[i]);
        free(smpl);
    }

    if ( !files->n_smpl )
    {
        if ( files->nreaders>1 )
            hts_log_warning("No samples in common");
        return 0;
    }
    for (i=0; i<files->nreaders; i++)
    {
        bcf_sr_t *reader = &files->readers[i];
        reader->samples  = (int*) malloc(sizeof(int)*files->n_smpl);
        reader->n_smpl   = files->n_smpl;
        for (j=0; j<files->n_smpl; j++)
            reader->samples[j] = bcf_hdr_id2int(reader->header, BCF_DT_SAMPLE, files->samples[j]);
    }
    return 1;
}

// Add a new region into a list. On input the coordinates are 1-based, inclusive, then stored 0-based,
// inclusive. Sorting and merging step needed afterwards: qsort(..,cmp_regions) and merge_regions().
static int _regions_add(bcf_sr_regions_t *reg, const char *chr, hts_pos_t start, hts_pos_t end)
{
    if ( start==-1 && end==-1 )
    {
        start = 0; end = MAX_CSI_COOR-1;
    }
    else
    {
        start--; end--; // store 0-based coordinates
    }

    if ( !reg->seq_hash )
         reg->seq_hash = khash_str2int_init();

    int iseq;
    if ( khash_str2int_get(reg->seq_hash, chr, &iseq)<0 )
    {
        // the chromosome block does not exist
        iseq = reg->nseqs++;
        reg->seq_names = (char**) realloc(reg->seq_names,sizeof(char*)*reg->nseqs);
        reg->regs = (region_t*) realloc(reg->regs,sizeof(region_t)*reg->nseqs);
        memset(&reg->regs[reg->nseqs-1],0,sizeof(region_t));
        reg->seq_names[iseq] = strdup(chr);
        reg->regs[iseq].creg = -1;
        khash_str2int_set(reg->seq_hash,reg->seq_names[iseq],iseq);
    }

    region_t *creg = &reg->regs[iseq];
    hts_expand(region1_t,creg->nregs+1,creg->mregs,creg->regs);
    creg->regs[creg->nregs].start = start;
    creg->regs[creg->nregs].end   = end;
    creg->nregs++;

    return 0; // FIXME: check for errs in this function
}

static int regions_cmp(const void *aptr, const void *bptr)
{
    region1_t *a = (region1_t*)aptr;
    region1_t *b = (region1_t*)bptr;
    if ( a->start < b->start ) return -1;
    if ( a->start > b->start ) return 1;
    if ( a->end < b->end ) return -1;
    if ( a->end > b->end ) return 1;
    return 0;
}
static void regions_merge(region_t *reg)
{
    int i = 0, j;
    while ( i<reg->nregs )
    {
        j = i + 1;
        while ( j<reg->nregs && reg->regs[i].end >= reg->regs[j].start )
        {
            if ( reg->regs[i].end < reg->regs[j].end ) reg->regs[i].end = reg->regs[j].end;
            reg->regs[j].start = 1;  reg->regs[j].end = 0;  // if beg>end, this region marked for skipping
            j++;
        }
        i = j;
    }
}
void _regions_sort_and_merge(bcf_sr_regions_t *reg)
{
    if ( !reg ) return;

    int i;
    for (i=0; i<reg->nseqs; i++)
    {
        qsort(reg->regs[i].regs, reg->regs[i].nregs, sizeof(*reg->regs[i].regs), regions_cmp);
        regions_merge(&reg->regs[i]);
    }
}

// File name or a list of genomic locations. If file name, NULL is returned.
static bcf_sr_regions_t *_regions_init_string(const char *str)
{
    bcf_sr_regions_t *reg = (bcf_sr_regions_t *) calloc(1, sizeof(bcf_sr_regions_t));
    reg->start = reg->end = -1;
    reg->prev_start = reg->prev_end = reg->prev_seq = -1;

    kstring_t tmp = {0,0,0};
    const char *sp = str, *ep = str;
    hts_pos_t from, to;
    while ( 1 )
    {
        while ( *ep && *ep!=',' && *ep!=':' ) ep++;
        tmp.l = 0;
        kputsn(sp,ep-sp,&tmp);
        if ( *ep==':' )
        {
            sp = ep+1;
            from = hts_parse_decimal(sp,(char**)&ep,0);
            if ( sp==ep )
            {
                hts_log_error("Could not parse the region(s): %s", str);
                free(reg); free(tmp.s); return NULL;
            }
            if ( !*ep || *ep==',' )
            {
                _regions_add(reg, tmp.s, from, from);
                sp = ep;
                continue;
            }
            if ( *ep!='-' )
            {
                hts_log_error("Could not parse the region(s): %s", str);
                free(reg); free(tmp.s); return NULL;
            }
            ep++;
            sp = ep;
            to = hts_parse_decimal(sp,(char**)&ep,0);
            if ( *ep && *ep!=',' )
            {
                hts_log_error("Could not parse the region(s): %s", str);
                free(reg); free(tmp.s); return NULL;
            }
            if ( sp==ep ) to = MAX_CSI_COOR-1;
            _regions_add(reg, tmp.s, from, to);
            if ( !*ep ) break;
            sp = ep;
        }
        else
        {
            if ( tmp.l ) _regions_add(reg, tmp.s, -1, -1);
            if ( !*ep ) break;
            sp = ++ep;
        }
    }
    free(tmp.s);
    return reg;
}

// ichr,ifrom,ito are 0-based;
// returns -1 on error, 0 if the line is a comment line, 1 on success
static int _regions_parse_line(char *line, int ichr, int ifrom, int ito, char **chr, char **chr_end, hts_pos_t *from, hts_pos_t *to)
{
    if (ifrom < 0 || ito < 0) return -1;
    *chr_end = NULL;

    if ( line[0]=='#' ) return 0;

    int k,l;    // index of the start and end column of the tab-delimited file
    if ( ifrom <= ito )
        k = ifrom, l = ito;
    else
        l = ifrom, k = ito;

    int i;
    char *se = line, *ss = NULL; // start and end
    char *tmp;
    for (i=0; i<=k && *se; i++)
    {
        ss = i==0 ? se++ : ++se;
        while (*se && *se!='\t') se++;
    }
    if ( i<=k ) return -1;
    if ( k==l )
    {
        *from = *to = hts_parse_decimal(ss, &tmp, 0);
        if ( tmp==ss ) return -1;
    }
    else
    {
        if ( k==ifrom )
            *from = hts_parse_decimal(ss, &tmp, 0);
        else
            *to = hts_parse_decimal(ss, &tmp, 0);
        if ( ss==tmp ) return -1;

        for (i=k; i<l && *se; i++)
        {
            ss = ++se;
            while (*se && *se!='\t') se++;
        }
        if ( i<l ) return -1;
        if ( k==ifrom )
            *to = hts_parse_decimal(ss, &tmp, 0);
        else
            *from = hts_parse_decimal(ss, &tmp, 0);
        if ( ss==tmp ) return -1;
    }

    ss = se = line;
    for (i=0; i<=ichr && *se; i++)
    {
        if ( i>0 ) ss = ++se;
        while (*se && *se!='\t') se++;
    }
    if ( i<=ichr ) return -1;
    *chr_end = se;
    *chr = ss;
    return 1;
}

bcf_sr_regions_t *bcf_sr_regions_init(const char *regions, int is_file, int ichr, int ifrom, int ito)
{
    bcf_sr_regions_t *reg;
    if ( !is_file )
    {
        reg = _regions_init_string(regions);
        _regions_sort_and_merge(reg);
        return reg;
    }

    reg = (bcf_sr_regions_t *) calloc(1, sizeof(bcf_sr_regions_t));
    reg->start = reg->end = -1;
    reg->prev_start = reg->prev_end = reg->prev_seq = -1;

    reg->file = hts_open(regions, "rb");
    if ( !reg->file )
    {
        hts_log_error("Could not open file: %s", regions);
        free(reg);
        return NULL;
    }

    reg->tbx = tbx_index_load3(regions, NULL, HTS_IDX_SAVE_REMOTE|HTS_IDX_SILENT_FAIL);
    if ( !reg->tbx )
    {
        size_t iline = 0;
        int len = strlen(regions);
        int is_bed  = strcasecmp(".bed",regions+len-4) ? 0 : 1;
        if ( !is_bed && !strcasecmp(".bed.gz",regions+len-7) ) is_bed = 1;

        if ( reg->file->format.format==vcf ) ito = 1;

        // read the whole file, tabix index is not present
        while ( hts_getline(reg->file, KS_SEP_LINE, &reg->line) > 0 )
        {
            iline++;
            char *chr, *chr_end;
            hts_pos_t from, to;
            int ret;
            ret = _regions_parse_line(reg->line.s, ichr,ifrom,abs(ito), &chr,&chr_end,&from,&to);
            if ( ret < 0 )
            {
                if ( ito<0 )
                    ret = _regions_parse_line(reg->line.s, ichr,ifrom,ifrom, &chr,&chr_end,&from,&to);
                if ( ret<0 )
                {
                    hts_log_error("Could not parse %zu-th line of file %s, using the columns %d,%d[,%d]",
                        iline, regions,ichr+1,ifrom+1,ito+1);
                    hts_close(reg->file); reg->file = NULL; free(reg);
                    return NULL;
                }
            }
            if ( !ret ) continue;
            if ( is_bed ) from++;
            *chr_end = 0;
            _regions_add(reg, chr, from, to);
            *chr_end = '\t';
        }
        hts_close(reg->file); reg->file = NULL;
        if ( !reg->nseqs ) { free(reg); return NULL; }
        _regions_sort_and_merge(reg);
        return reg;
    }

    reg->seq_names = (char**) tbx_seqnames(reg->tbx, &reg->nseqs);
    if ( !reg->seq_hash )
        reg->seq_hash = khash_str2int_init();
    int i;
    for (i=0; i<reg->nseqs; i++)
    {
        khash_str2int_set(reg->seq_hash,reg->seq_names[i],i);
    }
    reg->fname  = strdup(regions);
    reg->is_bin = 1;
    return reg;
}

void bcf_sr_regions_destroy(bcf_sr_regions_t *reg)
{
    int i;
    free(reg->fname);
    if ( reg->itr ) tbx_itr_destroy(reg->itr);
    if ( reg->tbx ) tbx_destroy(reg->tbx);
    if ( reg->file ) hts_close(reg->file);
    if ( reg->als ) free(reg->als);
    if ( reg->als_str.s ) free(reg->als_str.s);
    free(reg->line.s);
    if ( reg->regs )
    {
         // free only in-memory names, tbx names are const
        for (i=0; i<reg->nseqs; i++)
        {
            free(reg->seq_names[i]);
            free(reg->regs[i].regs);
        }
    }
    free(reg->regs);
    free(reg->seq_names);
    khash_str2int_destroy(reg->seq_hash);
    free(reg);
}

int bcf_sr_regions_seek(bcf_sr_regions_t *reg, const char *seq)
{
    reg->iseq = reg->start = reg->end = -1;
    if ( khash_str2int_get(reg->seq_hash, seq, &reg->iseq) < 0 ) return -1;  // sequence seq not in regions

    // using in-memory regions
    if ( reg->regs )
    {
        reg->regs[reg->iseq].creg = -1;
        return 0;
    }

    // reading regions from tabix
    if ( reg->itr ) tbx_itr_destroy(reg->itr);
    reg->itr = tbx_itr_querys(reg->tbx, seq);
    if ( reg->itr ) return 0;

    return -1;
}

// Returns 0 on success, -1 when done
static int advance_creg(region_t *reg)
{
    int i = reg->creg + 1;
    while ( i<reg->nregs && reg->regs[i].start > reg->regs[i].end ) i++;    // regions with start>end are marked to skip by merge_regions()
    reg->creg = i;
    if ( i>=reg->nregs ) return -1;
    return 0;
}

int bcf_sr_regions_next(bcf_sr_regions_t *reg)
{
    if ( reg->iseq<0 ) return -1;
    reg->start = reg->end = -1;
    reg->nals = 0;

    // using in-memory regions
    if ( reg->regs )
    {
        while ( reg->iseq < reg->nseqs )
        {
            if ( advance_creg(&reg->regs[reg->iseq])==0 ) break;    // a valid record was found
            reg->iseq++;
        }
        if ( reg->iseq >= reg->nseqs ) { reg->iseq = -1; return -1; } // no more regions left
        region1_t *creg = &reg->regs[reg->iseq].regs[reg->regs[reg->iseq].creg];
        reg->start = creg->start;
        reg->end   = creg->end;
        return 0;
    }

    // reading from tabix
    char *chr, *chr_end;
    int ichr = 0, ifrom = 1, ito = 2, is_bed = 0;
    hts_pos_t from, to;
    if ( reg->tbx )
    {
        ichr   = reg->tbx->conf.sc-1;
        ifrom  = reg->tbx->conf.bc-1;
        ito    = reg->tbx->conf.ec-1;
        if ( ito<0 ) ito = ifrom;
        is_bed = reg->tbx->conf.preset==TBX_UCSC ? 1 : 0;
    }

    int ret = 0;
    while ( !ret )
    {
        if ( reg->itr )
        {
            // tabix index present, reading a chromosome block
            ret = tbx_itr_next(reg->file, reg->tbx, reg->itr, &reg->line);
            if ( ret<0 ) { reg->iseq = -1; return -1; }
        }
        else
        {
            if ( reg->is_bin )
            {
                // Waited for seek which never came. Reopen in text mode and stream
                // through the regions, otherwise hts_getline would fail
                hts_close(reg->file);
                reg->file = hts_open(reg->fname, "r");
                if ( !reg->file )
                {
                    hts_log_error("Could not open file: %s", reg->fname);
                    reg->file = NULL;
                    bcf_sr_regions_destroy(reg);
                    return -1;
                }
                reg->is_bin = 0;
            }

            // tabix index absent, reading the whole file
            ret = hts_getline(reg->file, KS_SEP_LINE, &reg->line);
            if ( ret<0 ) { reg->iseq = -1; return -1; }
        }
        ret = _regions_parse_line(reg->line.s, ichr,ifrom,ito, &chr,&chr_end,&from,&to);
        if ( ret<0 )
        {
            hts_log_error("Could not parse the file %s, using the columns %d,%d,%d",
                reg->fname,ichr+1,ifrom+1,ito+1);
            return -1;
        }
    }
    if ( is_bed ) from++;

    *chr_end = 0;
    if ( khash_str2int_get(reg->seq_hash, chr, &reg->iseq)<0 )
    {
        hts_log_error("Broken tabix index? The sequence \"%s\" not in dictionary [%s]",
            chr, reg->line.s);
        exit(1);
    }
    *chr_end = '\t';

    reg->start = from - 1;
    reg->end   = to - 1;
    return 0;
}

static int _regions_match_alleles(bcf_sr_regions_t *reg, int als_idx, bcf1_t *rec)
{
    if ( reg->regs )
    {
        // payload is not supported for in-memory regions, switch to regidx instead in future
        hts_log_error("Compressed and indexed targets file is required");
        exit(1);
    }

    int i = 0, max_len = 0;
    if ( !reg->nals )
    {
        char *ss = reg->line.s;
        while ( i<als_idx && *ss )
        {
            if ( *ss=='\t' ) i++;
            ss++;
        }
        char *se = ss;
        reg->nals = 1;
        while ( *se && *se!='\t' )
        {
            if ( *se==',' ) reg->nals++;
            se++;
        }
        ks_resize(&reg->als_str, se-ss+1+reg->nals);
        reg->als_str.l = 0;
        hts_expand(char*,reg->nals,reg->mals,reg->als);
        reg->nals = 0;

        se = ss;
        while ( *(++se) )
        {
            if ( *se=='\t' ) break;
            if ( *se!=',' ) continue;
            reg->als[reg->nals] = &reg->als_str.s[reg->als_str.l];
            kputsn(ss,se-ss,&reg->als_str);
            if ( &reg->als_str.s[reg->als_str.l] - reg->als[reg->nals] > max_len ) max_len = &reg->als_str.s[reg->als_str.l] - reg->als[reg->nals];
            reg->als_str.l++;
            reg->nals++;
            ss = ++se;
        }
        reg->als[reg->nals] = &reg->als_str.s[reg->als_str.l];
        kputsn(ss,se-ss,&reg->als_str);
        if ( &reg->als_str.s[reg->als_str.l] - reg->als[reg->nals] > max_len ) max_len = &reg->als_str.s[reg->als_str.l] - reg->als[reg->nals];
        reg->nals++;
        reg->als_type = max_len > 1 ? VCF_INDEL : VCF_SNP;  // this is a simplified check, see vcf.c:bcf_set_variant_types
    }
    int type = bcf_get_variant_types(rec);
    if ( reg->als_type & VCF_INDEL )
        return type & VCF_INDEL ? 1 : 0;
    return !(type & VCF_INDEL) ? 1 : 0;
}

int bcf_sr_regions_overlap(bcf_sr_regions_t *reg, const char *seq, hts_pos_t start, hts_pos_t end)
{
    int iseq;
    if ( khash_str2int_get(reg->seq_hash, seq, &iseq)<0 ) return -1;    // no such sequence

    if ( reg->prev_seq==-1 || iseq!=reg->prev_seq || reg->prev_start > start ) // new chromosome or after a seek
    {
        // flush regions left on previous chromosome
        if ( reg->missed_reg_handler && reg->prev_seq!=-1 && reg->iseq!=-1 )
            bcf_sr_regions_flush(reg);

        bcf_sr_regions_seek(reg, seq);
        reg->start = reg->end = -1;
    }
    if ( reg->prev_seq==iseq && reg->iseq!=iseq ) return -2;    // no more regions on this chromosome
    reg->prev_seq = reg->iseq;
    reg->prev_start = start;

    while ( iseq==reg->iseq && reg->end < start )
    {
        if ( bcf_sr_regions_next(reg) < 0 ) return -2;  // no more regions left
        if ( reg->iseq != iseq ) return -1; // does not overlap any regions
        if ( reg->missed_reg_handler && reg->end < start ) reg->missed_reg_handler(reg, reg->missed_reg_data);
    }
    if ( reg->start <= end ) return 0;    // region overlap
    return -1;  // no overlap
}

int bcf_sr_regions_flush(bcf_sr_regions_t *reg)
{
    if ( !reg->missed_reg_handler || reg->prev_seq==-1 ) return 0;
    while ( !bcf_sr_regions_next(reg) ) reg->missed_reg_handler(reg, reg->missed_reg_data);
    return 0; // FIXME: check for errs in this function
}