vcfutils.c

/*  vcfutils.c -- allele-related utility functions.

    Copyright (C) 2012-2018, 2020-2022 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 <inttypes.h>

#include "htslib/vcfutils.h"
#include "htslib/kbitset.h"

int bcf_calc_ac(const bcf_hdr_t *header, bcf1_t *line, int *ac, int which)
{
    int i;
    for (i=0; i<line->n_allele; i++) ac[i]=0;

    // Use INFO/AC,AN field only when asked
    if ( which&BCF_UN_INFO )
    {
        bcf_unpack(line, BCF_UN_INFO);
        int an_id = bcf_hdr_id2int(header, BCF_DT_ID, "AN");
        int ac_id = bcf_hdr_id2int(header, BCF_DT_ID, "AC");
        int i, an=-1, ac_len=0, ac_type=0;
        uint8_t *ac_ptr=NULL;
        if ( an_id>=0 && ac_id>=0 )
        {
            for (i=0; i<line->n_info; i++)
            {
                bcf_info_t *z = &line->d.info[i];
                if ( z->key == an_id ) an = z->v1.i;
                else if ( z->key == ac_id ) { ac_ptr = z->vptr; ac_len = z->len; ac_type = z->type; }
            }
        }
        if ( an>=0 && ac_ptr )
        {
            if ( ac_len != line->n_allele - 1 )
            {
                static int warned = 0;
                if ( !warned )
                {
                    hts_log_warning("Incorrect number of AC fields at %s:%"PRIhts_pos". (This message is printed only once.)\n",
                            header->id[BCF_DT_CTG][line->rid].key, line->pos+1);
                    warned = 1;
                }
                return 0;
            }
            int nac = 0;
            #define BRANCH_INT(type_t, convert) {        \
                for (i=0; i<ac_len; i++)        \
                {                               \
                    type_t val = convert(ac_ptr + i * sizeof(type_t)); \
                    ac[i+1] = val;             \
                    nac += val;                \
                }                               \
            }
            switch (ac_type) {
                case BCF_BT_INT8:  BRANCH_INT(int8_t,  le_to_i8); break;
                case BCF_BT_INT16: BRANCH_INT(int16_t, le_to_i16); break;
                case BCF_BT_INT32: BRANCH_INT(int32_t, le_to_i32); break;
                default: hts_log_error("Unexpected type %d at %s:%"PRIhts_pos, ac_type, header->id[BCF_DT_CTG][line->rid].key, line->pos+1); exit(1); break;
            }
            #undef BRANCH_INT
            if ( an<nac )
            {
                hts_log_error("Incorrect AN/AC counts at %s:%"PRIhts_pos, header->id[BCF_DT_CTG][line->rid].key, line->pos+1);
                exit(1);
            }
            ac[0] = an - nac;
            return 1;
        }
    }

    // Split genotype fields only when asked
    if ( which&BCF_UN_FMT )
    {
        int i, gt_id = bcf_hdr_id2int(header,BCF_DT_ID,"GT");
        if ( gt_id<0 ) return 0;
        bcf_unpack(line, BCF_UN_FMT);
        bcf_fmt_t *fmt_gt = NULL;
        for (i=0; i<(int)line->n_fmt; i++)
            if ( line->d.fmt[i].id==gt_id ) { fmt_gt = &line->d.fmt[i]; break; }
        if ( !fmt_gt ) return 0;
        #define BRANCH_INT(type_t, convert, vector_end) { \
            for (i=0; i<line->n_sample; i++) \
            { \
                uint8_t *p = (fmt_gt->p + i*fmt_gt->size); \
                int ial; \
                for (ial=0; ial<fmt_gt->n; ial++) \
                { \
                    int32_t val = convert(&p[ial * sizeof(type_t)]); \
                    if ( val==vector_end ) break; /* smaller ploidy */ \
                    if ( bcf_gt_is_missing(val) ) continue; /* missing allele */ \
                    if ( val>>1 > line->n_allele ) \
                    { \
                        hts_log_error("Incorrect allele (\"%d\") in %s at %s:%"PRIhts_pos, (val>>1)-1, header->samples[i], header->id[BCF_DT_CTG][line->rid].key, line->pos+1); \
                        exit(1); \
                    } \
                    ac[(val>>1)-1]++; \
                } \
            } \
        }
        switch (fmt_gt->type) {
            case BCF_BT_INT8:  BRANCH_INT(int8_t,  le_to_i8,  bcf_int8_vector_end); break;
            case BCF_BT_INT16: BRANCH_INT(int16_t, le_to_i16, bcf_int16_vector_end); break;
            case BCF_BT_INT32: BRANCH_INT(int32_t, le_to_i32, bcf_int32_vector_end); break;
            default: hts_log_error("Unexpected type %d at %s:%"PRIhts_pos, fmt_gt->type, header->id[BCF_DT_CTG][line->rid].key, line->pos+1); exit(1); break;
        }
        #undef BRANCH_INT
        return 1;
    }
    return 0;
}

int bcf_gt_type(bcf_fmt_t *fmt_ptr, int isample, int *_ial, int *_jal)
{
    int i, nals = 0, has_ref = 0, has_alt = 0, ial = 0, jal = 0;
    #define BRANCH_INT(type_t, convert, vector_end) { \
        uint8_t *p = fmt_ptr->p + isample*fmt_ptr->size; \
        for (i=0; i<fmt_ptr->n; i++) \
        { \
            int32_t val = convert(&p[i * sizeof(type_t)]); \
            if ( val == vector_end ) break; /* smaller ploidy */ \
            if ( bcf_gt_is_missing(val) ) return GT_UNKN; /* missing allele */ \
            int tmp = val>>1; \
            if ( tmp>1 ) \
            { \
                if ( !ial ) { ial = tmp; has_alt = 1; } \
                else if ( tmp!=ial ) \
                { \
                    if ( tmp<ial ) \
                    { \
                        jal = ial; \
                        ial = tmp; \
                    } \
                    else \
                    { \
                        jal = tmp; \
                    } \
                    has_alt = 2; \
                } \
            } \
            else has_ref = 1; \
            nals++; \
        } \
    }
    switch (fmt_ptr->type) {
        case BCF_BT_INT8:  BRANCH_INT(int8_t,  le_to_i8,  bcf_int8_vector_end); break;
        case BCF_BT_INT16: BRANCH_INT(int16_t, le_to_i16, bcf_int16_vector_end); break;
        case BCF_BT_INT32: BRANCH_INT(int32_t, le_to_i32, bcf_int32_vector_end); break;
        default: hts_log_error("Unexpected type %d", fmt_ptr->type); exit(1); break;
    }
    #undef BRANCH_INT

    if ( _ial ) *_ial = ial>0 ? ial-1 : ial;
    if ( _jal ) *_jal = jal>0 ? jal-1 : jal;
    if ( !nals ) return GT_UNKN;
    if ( nals==1 )
        return has_ref ? GT_HAPL_R : GT_HAPL_A;
    if ( !has_ref )
        return has_alt==1 ? GT_HOM_AA : GT_HET_AA;
    if ( !has_alt )
        return GT_HOM_RR;
    return GT_HET_RA;
}

int bcf_trim_alleles(const bcf_hdr_t *header, bcf1_t *line)
{
    int i, ret = 0, nrm = 0;
    kbitset_t *rm_set = NULL;
    bcf_fmt_t *gt = bcf_get_fmt(header, line, "GT");
    if ( !gt ) return 0;

    int *ac = (int*) calloc(line->n_allele,sizeof(int));

    // check if all alleles are populated
    #define BRANCH(type_t, convert, vector_end) { \
        for (i=0; i<line->n_sample; i++) \
        { \
            uint8_t *p = gt->p + i*gt->size; \
            int ial; \
            for (ial=0; ial<gt->n; ial++) \
            { \
                int32_t val = convert(&p[ial * sizeof(type_t)]); \
                if ( val==vector_end ) break; /* smaller ploidy */ \
                if ( bcf_gt_is_missing(val) ) continue; /* missing allele */ \
                if ( (val>>1)-1 >= line->n_allele ) { \
                    hts_log_error("Allele index is out of bounds at %s:%"PRIhts_pos, header->id[BCF_DT_CTG][line->rid].key, line->pos+1); \
                    ret = -1; \
                    goto clean; \
                } \
                ac[(val>>1)-1]++; \
            } \
        } \
    }
    switch (gt->type) {
        case BCF_BT_INT8:  BRANCH(int8_t,  le_to_i8,  bcf_int8_vector_end); break;
        case BCF_BT_INT16: BRANCH(int16_t, le_to_i16, bcf_int16_vector_end); break;
        case BCF_BT_INT32: BRANCH(int32_t, le_to_i32, bcf_int32_vector_end); break;
        default: hts_log_error("Unexpected GT %d at %s:%"PRIhts_pos,
            gt->type, header->id[BCF_DT_CTG][line->rid].key, line->pos + 1);
            goto clean;
    }
    #undef BRANCH

    rm_set = kbs_init(line->n_allele);
    for (i=1; i<line->n_allele; i++) {
        if ( !ac[i] ) { kbs_insert(rm_set, i); nrm++; }
    }

    if (nrm) {
        if (bcf_remove_allele_set(header, line, rm_set))
            ret = -2;
    }

clean:
    free(ac);
    if (rm_set) kbs_destroy(rm_set);
    return ret ? ret : nrm;
}

int bcf_remove_alleles(const bcf_hdr_t *header, bcf1_t *line, int rm_mask)
{
    int i;
    kbitset_t *rm_set = kbs_init(line->n_allele);
    for (i=1; i<line->n_allele; i++)
        if ( rm_mask & 1<<i ) kbs_insert(rm_set, i);

    bcf_remove_allele_set(header, line, rm_set);
    kbs_destroy(rm_set);

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

int bcf_remove_allele_set(const bcf_hdr_t *header, bcf1_t *line, const struct kbitset_t *rm_set)
{
    int *map = (int*) calloc(line->n_allele, sizeof(int));
    uint8_t *dat = NULL;

    bcf_unpack(line, BCF_UN_ALL);

    // create map of indexes from old to new ALT numbering and modify ALT
    kstring_t str = {0,0,0};
    kputs(line->d.allele[0], &str);

    int nrm = 0, i,j;  // i: ori alleles, j: new alleles
    for (i=1, j=1; i<line->n_allele; i++)
    {
        if ( kbs_exists(rm_set, i) )
        {
            // remove this allele
            line->d.allele[i] = NULL;
            nrm++;
            continue;
        }
        kputc(',', &str);
        kputs(line->d.allele[i], &str);
        map[i] = j;
        j++;
    }
    if ( !nrm ) goto clean;

    int nR_ori = line->n_allele;
    int nR_new = line->n_allele-nrm;
    if ( nR_new<=0 ) // should not be able to remove reference allele
    {
        hts_log_error("Cannot remove reference allele at %s:%"PRIhts_pos" [%d]",
            bcf_seqname_safe(header,line), line->pos+1, nR_new);
        goto err;
    }
    int nA_ori = nR_ori-1;
    int nA_new = nR_new-1;

    int nG_ori = nR_ori*(nR_ori + 1)/2;
    int nG_new = nR_new*(nR_new + 1)/2;

    bcf_update_alleles_str(header, line, str.s);

    // remove from Number=G, Number=R and Number=A INFO fields.
    int mdat = 0, ndat = 0, mdat_bytes = 0, nret;
    for (i=0; i<line->n_info; i++)
    {
        bcf_info_t *info = &line->d.info[i];
        int vlen = bcf_hdr_id2length(header,BCF_HL_INFO,info->key);

        if ( vlen!=BCF_VL_A && vlen!=BCF_VL_G && vlen!=BCF_VL_R ) continue; // no need to change

        int type = bcf_hdr_id2type(header,BCF_HL_INFO,info->key);
        if ( type==BCF_HT_FLAG ) continue;
        int size = 1;
        if ( type==BCF_HT_REAL || type==BCF_HT_INT ) size = 4;

        mdat = mdat_bytes / size;
        nret = bcf_get_info_values(header, line, bcf_hdr_int2id(header,BCF_DT_ID,info->key), (void**)&dat, &mdat, type);
        mdat_bytes = mdat * size;
        if ( nret<0 )
        {
            hts_log_error("Could not access INFO/%s at %s:%"PRIhts_pos" [%d]",
                bcf_hdr_int2id(header,BCF_DT_ID,info->key), bcf_seqname_safe(header,line), line->pos+1, nret);
            goto err;
        }
        if ( nret==0 ) continue; // no data for this tag

        if ( type==BCF_HT_STR )
        {
            str.l = 0;
            char *ss = (char*) dat, *se = (char*) dat, s = ss[0];
            if ( vlen==BCF_VL_A || vlen==BCF_VL_R )
            {
                int nexp, inc = 0;
                if ( vlen==BCF_VL_A )
                {
                    nexp = nA_ori;
                    inc  = 1;
                }
                else
                    nexp = nR_ori;
                for (j=0; j<nexp; j++)
                {
                    if ( !*se ) break;
                    while ( *se && *se!=',' ) se++;
                    if ( kbs_exists(rm_set, j+inc) )
                    {
                        if ( *se ) se++;
                        ss = se;
                        continue;
                    }
                    if ( str.l ) kputc(',',&str);
                    kputsn(ss,se-ss,&str);
                    if ( *se ) se++;
                    ss = se;
                }
                if ( j==1 && s == '.' ) continue; // missing
                if ( j!=nexp )
                {
                    hts_log_error("Unexpected number of values in INFO/%s at %s:%"PRIhts_pos"; expected Number=%c=%d, but found %d",
                        bcf_hdr_int2id(header,BCF_DT_ID,info->key), bcf_seqname_safe(header,line), line->pos+1, vlen==BCF_VL_A ? 'A' : 'R', nexp, j);
                    goto err;
                }
            }
            else    // Number=G, assuming diploid genotype
            {
                int k = 0, n = 0;
                for (j=0; j<nR_ori; j++)
                {
                    for (k=0; k<=j; k++)
                    {
                        if ( !*se ) break;
                        while ( *se && *se!=',' ) se++;
                        n++;
                        if ( kbs_exists(rm_set, j) || kbs_exists(rm_set, k) )
                        {
                            if ( *se ) se++;
                            ss = se;
                            continue;
                        }
                        if ( str.l ) kputc(',',&str);
                        kputsn(ss,se-ss,&str);
                        if ( *se ) se++;
                        ss = se;
                    }
                    if ( !*se ) break;
                }
                if ( n==1 && s == '.' ) continue; // missing
                if ( n!=nG_ori )
                {
                    hts_log_error("Unexpected number of values in INFO/%s at %s:%"PRIhts_pos"; expected Number=G=%d, but found %d",
                        bcf_hdr_int2id(header,BCF_DT_ID,info->key), bcf_seqname_safe(header,line), line->pos+1, nG_ori, n);
                    goto err;
                }
            }

            nret = bcf_update_info(header, line, bcf_hdr_int2id(header,BCF_DT_ID,info->key), (void*)str.s, str.l, type);
            if ( nret<0 )
            {
                hts_log_error("Could not update INFO/%s at %s:%"PRIhts_pos" [%d]",
                    bcf_hdr_int2id(header,BCF_DT_ID,info->key), bcf_seqname_safe(header,line), line->pos+1, nret);
                goto err;
            }
            continue;
        }

        if (nret==1) // could be missing - check
        {
            int missing = 0;
            #define BRANCH(type_t, convert, is_missing) { \
                type_t val = convert(info->vptr); \
                if ( is_missing ) missing = 1; \
            }
            switch (info->type) {
                case BCF_BT_INT8:  BRANCH(int8_t, le_to_i8,  val==bcf_int8_missing); break;
                case BCF_BT_INT16: BRANCH(int16_t, le_to_i16, val==bcf_int16_missing); break;
                case BCF_BT_INT32: BRANCH(int32_t, le_to_i32, val==bcf_int32_missing); break;
                case BCF_BT_FLOAT: BRANCH(float,   le_to_float, bcf_float_is_missing(val)); break;
                default: hts_log_error("Unexpected type %d", info->type); goto err;
            }
            #undef BRANCH
            if (missing) continue; // could remove this INFO tag?
        }

        if ( vlen==BCF_VL_A || vlen==BCF_VL_R )
        {
            int inc = 0, ntop;
            if ( vlen==BCF_VL_A )
            {
                if ( nret!=nA_ori )
                {
                    hts_log_error("Unexpected number of values in INFO/%s at %s:%"PRIhts_pos"; expected Number=A=%d, but found %d",
                        bcf_hdr_int2id(header,BCF_DT_ID,info->key), bcf_seqname_safe(header,line), line->pos+1, nA_ori, nret);
                    goto err;
                }
                ntop = nA_ori;
                ndat = nA_new;
                inc  = 1;
            }
            else
            {
                if ( nret!=nR_ori )
                {
                    hts_log_error("Unexpected number of values in INFO/%s at %s:%"PRIhts_pos"; expected Number=R=%d, but found %d",
                        bcf_hdr_int2id(header,BCF_DT_ID,info->key), bcf_seqname_safe(header,line), line->pos+1, nR_ori, nret);
                    goto err;
                }
                ntop = nR_ori;
                ndat = nR_new;
            }
            int k = 0;

            #define BRANCH(type_t,is_vector_end) \
            { \
                type_t *ptr = (type_t*) dat; \
                int size = sizeof(type_t); \
                for (j=0; j<ntop; j++) /* j:ori, k:new */ \
                { \
                    if ( is_vector_end ) { memcpy(dat+k*size, dat+j*size, size); break; } \
                    if ( kbs_exists(rm_set, j+inc) ) continue; \
                    if ( j!=k ) memcpy(dat+k*size, dat+j*size, size); \
                    k++; \
                } \
            }
            switch (type)
            {
                case BCF_HT_INT:  BRANCH(int32_t,ptr[j]==bcf_int32_vector_end); break;
                case BCF_HT_REAL: BRANCH(float,bcf_float_is_vector_end(ptr[j])); break;
            }
            #undef BRANCH
        }
        else    // Number=G
        {
            if ( nret!=nG_ori )
            {
                hts_log_error("Unexpected number of values in INFO/%s at %s:%"PRIhts_pos"; expected Number=G=%d, but found %d",
                    bcf_hdr_int2id(header,BCF_DT_ID,info->key), bcf_seqname_safe(header,line), line->pos+1, nG_ori, nret);
                goto err;
            }
            int k, l_ori = -1, l_new = 0;
            ndat = nG_new;

            #define BRANCH(type_t,is_vector_end) \
            { \
                type_t *ptr = (type_t*) dat; \
                int size = sizeof(type_t); \
                for (j=0; j<nR_ori; j++) \
                { \
                    for (k=0; k<=j; k++) \
                    { \
                        l_ori++; \
                        if ( is_vector_end ) { memcpy(dat+l_new*size, dat+l_ori*size, size); break; } \
                        if ( kbs_exists(rm_set, j) || kbs_exists(rm_set, k) ) continue; \
                        if ( l_ori!=l_new ) memcpy(dat+l_new*size, dat+l_ori*size, size); \
                        l_new++; \
                    } \
                } \
            }
            switch (type)
            {
                case BCF_HT_INT:  BRANCH(int32_t,ptr[l_ori]==bcf_int32_vector_end); break;
                case BCF_HT_REAL: BRANCH(float,bcf_float_is_vector_end(ptr[l_ori])); break;
            }
            #undef BRANCH
        }

        nret = bcf_update_info(header, line, bcf_hdr_int2id(header,BCF_DT_ID,info->key), (void*)dat, ndat, type);
        if ( nret<0 )
        {
            hts_log_error("Could not update INFO/%s at %s:%"PRIhts_pos" [%d]",
                bcf_hdr_int2id(header,BCF_DT_ID,info->key), bcf_seqname_safe(header,line), line->pos+1, nret);
            goto err;
        }
    }

    // Update GT fields, the allele indexes might have changed
    for (i=1; i<nR_ori; i++) if ( map[i]!=i ) break;
    if ( i<nR_ori )
    {
        mdat = mdat_bytes / 4;  // sizeof(int32_t)
        nret = bcf_get_genotypes(header,line,(void**)&dat,&mdat);
        mdat_bytes = mdat * 4;
        if ( nret>0 )
        {
            nret /= line->n_sample;
            int32_t *ptr = (int32_t*) dat;
            for (i=0; i<line->n_sample; i++)
            {
                for (j=0; j<nret; j++)
                {
                    if ( bcf_gt_is_missing(ptr[j]) ) continue;
                    if ( ptr[j]==bcf_int32_vector_end ) break;
                    int al = bcf_gt_allele(ptr[j]);
                    if ( !( al<nR_ori && map[al]>=0 ) )
                    {
                        hts_log_error("Problem updating genotypes at %s:%"PRIhts_pos" [ al<nR_ori && map[al]>=0 :: al=%d,nR_ori=%d,map[al]=%d ]",
                            bcf_seqname_safe(header,line), line->pos+1, al, nR_ori, map[al]);
                        goto err;
                    }
                    // if an allele other than the reference is mapped to 0, it has been removed,
                    // so translate it to 'missing', while preserving the phasing bit
                    ptr[j] = ((al>0 && !map[al]) ? bcf_gt_missing : (map[al]+1)<<1) | (ptr[j]&1);
                }
                ptr += nret;
            }
            nret = bcf_update_genotypes(header, line, (void*)dat, nret*line->n_sample);
            if ( nret<0 )
            {
                hts_log_error("Could not update FORMAT/GT at %s:%"PRIhts_pos" [%d]",
                    bcf_seqname_safe(header,line), line->pos+1, nret);
                goto err;
            }
        }
    }

    // Remove from Number=G, Number=R and Number=A FORMAT fields.
    // Assuming haploid or diploid GTs
    for (i=0; i<line->n_fmt; i++)
    {
        bcf_fmt_t *fmt = &line->d.fmt[i];
        int vlen = bcf_hdr_id2length(header,BCF_HL_FMT,fmt->id);

        if ( vlen!=BCF_VL_A && vlen!=BCF_VL_G && vlen!=BCF_VL_R ) continue; // no need to change

        int type = bcf_hdr_id2type(header,BCF_HL_FMT,fmt->id);
        if ( type==BCF_HT_FLAG ) continue;

        int size = 1;
        if ( type==BCF_HT_REAL || type==BCF_HT_INT ) size = 4;

        mdat = mdat_bytes / size;
        nret = bcf_get_format_values(header, line, bcf_hdr_int2id(header,BCF_DT_ID,fmt->id), (void**)&dat, &mdat, type);
        mdat_bytes = mdat * size;
        if ( nret<0 )
        {
            hts_log_error("Could not access FORMAT/%s at %s:%"PRIhts_pos" [%d]",
                bcf_hdr_int2id(header,BCF_DT_ID,fmt->id), bcf_seqname_safe(header,line), line->pos+1, nret);
            goto err;
        }
        if ( nret == 0 ) continue; // no data for this tag

        if ( type==BCF_HT_STR )
        {
            int size = nret/line->n_sample;     // number of bytes per sample
            str.l = 0;
            if ( vlen==BCF_VL_A || vlen==BCF_VL_R )
            {
                int nexp, inc = 0;
                if ( vlen==BCF_VL_A )
                {
                    nexp = nA_ori;
                    inc  = 1;
                }
                else
                    nexp = nR_ori;
                for (j=0; j<line->n_sample; j++)
                {
                    char *ss = ((char*)dat) + j*size, *se = ss + size, *ptr = ss, s = ss[0];
                    int k_src = 0, k_dst = 0, l = str.l;
                    for (k_src=0; k_src<nexp; k_src++)
                    {
                        if ( ptr>=se || !*ptr) break;
                        while ( ptr<se && *ptr && *ptr!=',' ) ptr++;
                        if ( kbs_exists(rm_set, k_src+inc) )
                        {
                            ss = ++ptr;
                            continue;
                        }
                        if ( k_dst ) kputc(',',&str);
                        kputsn(ss,ptr-ss,&str);
                        ss = ++ptr;
                        k_dst++;
                    }
                    if ( k_src==1 && s == '.' ) continue; // missing
                    if ( k_src!=nexp )
                    {
                        hts_log_error("Unexpected number of values in FORMAT/%s at %s:%"PRIhts_pos"; expected Number=%c=%d, but found %d",
                            bcf_hdr_int2id(header,BCF_DT_ID,fmt->id), bcf_seqname_safe(header,line), line->pos+1, vlen==BCF_VL_A ? 'A' : 'R', nexp, k_src);
                        goto err;
                    }
                    l = str.l - l;
                    for (; l<size; l++) kputc(0, &str);
                }
            }
            else    // Number=G, diploid or haploid
            {
                for (j=0; j<line->n_sample; j++)
                {
                    char *ss = ((char*)dat) + j*size, *se = ss + size, *ptr = ss, s = ss[0];
                    int k_src = 0, k_dst = 0, l = str.l;
                    int nexp = 0; // diploid or haploid?
                    while ( ptr<se )
                    {
                        if ( !*ptr ) break;
                        if ( *ptr==',' ) nexp++;
                        ptr++;
                    }
                    if ( ptr!=ss ) nexp++;
                    if ( nexp==1 && s == '.' ) continue; // missing
                    if ( nexp!=nG_ori && nexp!=nR_ori )
                    {
                        hts_log_error("Unexpected number of values in FORMAT/%s at %s:%"PRIhts_pos"; expected Number=G=%d(diploid) or %d(haploid), but found %d",
                            bcf_hdr_int2id(header,BCF_DT_ID,fmt->id), bcf_seqname_safe(header,line), line->pos+1, nG_ori, nR_ori, nexp);
                        goto err;
                    }
                    ptr = ss;
                    if ( nexp==nG_ori ) // diploid
                    {
                        int ia, ib;
                        for (ia=0; ia<nR_ori; ia++)
                        {
                            for (ib=0; ib<=ia; ib++)
                            {
                                if ( ptr>=se || !*ptr ) break;
                                while ( ptr<se && *ptr && *ptr!=',' ) ptr++;
                                if ( kbs_exists(rm_set, ia) || kbs_exists(rm_set, ib) )
                                {
                                    ss = ++ptr;
                                    continue;
                                }
                                if ( k_dst ) kputc(',',&str);
                                kputsn(ss,ptr-ss,&str);
                                ss = ++ptr;
                                k_dst++;
                            }
                            if ( ptr>=se || !*ptr ) break;
                        }
                    }
                    else    // haploid
                    {
                        for (k_src=0; k_src<nR_ori; k_src++)
                        {
                            if ( ptr>=se || !*ptr ) break;
                            while ( ptr<se && *ptr && *ptr!=',' ) ptr++;
                            if ( kbs_exists(rm_set, k_src) )
                            {
                                ss = ++ptr;
                                continue;
                            }
                            if ( k_dst ) kputc(',',&str);
                            kputsn(ss,ptr-ss,&str);
                            ss = ++ptr;
                            k_dst++;
                        }
                        if ( k_src!=nR_ori )
                        {
                            hts_log_error("Unexpected number of values in FORMAT/%s at %s:%"PRIhts_pos"; expected Number=G=%d(haploid), but found %d",
                                bcf_hdr_int2id(header,BCF_DT_ID,fmt->id), bcf_seqname_safe(header,line), line->pos+1, nR_ori, k_src);
                            goto err;
                        }
                        l = str.l - l;
                        for (; l<size; l++) kputc(0, &str);
                    }
                }
            }
            nret = bcf_update_format(header, line, bcf_hdr_int2id(header,BCF_DT_ID,fmt->id), (void*)str.s, str.l, type);
            if ( nret<0 )
            {
                hts_log_error("Could not update FORMAT/%s at %s:%"PRIhts_pos" [%d]",
                    bcf_hdr_int2id(header,BCF_DT_ID,fmt->id), bcf_seqname_safe(header,line), line->pos+1, nret);
                goto err;
            }
            continue;
        }

        int nori = nret / line->n_sample;
        if ( nori==1 && !(vlen==BCF_VL_A && nori==nA_ori) ) // all values may be missing - check
        {
            int all_missing = 1;
            #define BRANCH(type_t, convert, is_missing) { \
                for (j=0; j<line->n_sample; j++) \
                { \
                    type_t val = convert(fmt->p + j*fmt->size); \
                    if ( !(is_missing)) { all_missing = 0; break; } \
                } \
            }
            switch (fmt->type) {
                case BCF_BT_INT8:  BRANCH(int8_t,  le_to_i8, val==bcf_int8_missing); break;
                case BCF_BT_INT16: BRANCH(int16_t, le_to_i16, val==bcf_int16_missing); break;
                case BCF_BT_INT32: BRANCH(int32_t, le_to_i32, val==bcf_int32_missing); break;
                case BCF_BT_FLOAT: BRANCH(float,   le_to_float, bcf_float_is_missing(val)); break;
                default: hts_log_error("Unexpected type %d", fmt->type); goto err;
            }
            #undef BRANCH
            if (all_missing) continue; // could remove this FORMAT tag?
        }

        if ( vlen==BCF_VL_A || vlen==BCF_VL_R || (vlen==BCF_VL_G && nori==nR_ori) ) // Number=A, R or haploid Number=G
        {
            int inc = 0, nnew;
            if ( vlen==BCF_VL_A )
            {
                if ( nori!=nA_ori )
                {
                    hts_log_error("Unexpected number of values in FORMAT/%s at %s:%"PRIhts_pos"; expected Number=A=%d, but found %d",
                        bcf_hdr_int2id(header,BCF_DT_ID,fmt->id), bcf_seqname_safe(header,line), line->pos+1, nA_ori, nori);
                    goto err;
                }
                ndat = nA_new*line->n_sample;
                nnew = nA_new;
                inc  = 1;
            }
            else
            {
                if ( nori!=nR_ori )
                {
                    hts_log_error("Unexpected number of values in FORMAT/%s at %s:%"PRIhts_pos"; expected Number=R=%d, but found %d",
                        bcf_hdr_int2id(header,BCF_DT_ID,fmt->id), bcf_seqname_safe(header,line), line->pos+1, nR_ori, nori);
                    goto err;
                }
                ndat = nR_new*line->n_sample;
                nnew = nR_new;
            }

            #define BRANCH(type_t,is_vector_end,set_missing) \
            { \
                for (j=0; j<line->n_sample; j++) \
                { \
                    type_t *ptr_src = ((type_t*)dat) + j*nori; \
                    type_t *ptr_dst = ((type_t*)dat) + j*nnew; \
                    int size = sizeof(type_t); \
                    int k_src, k_dst = 0; \
                    for (k_src=0; k_src<nori; k_src++) \
                    { \
                        if ( is_vector_end ) \
                        { \
                            if ( k_dst ) memcpy(ptr_dst+k_dst, ptr_src+k_src, size); \
                            else set_missing; \
                            break; \
                        } \
                        if ( kbs_exists(rm_set, k_src+inc) ) continue; \
                        memcpy(ptr_dst+k_dst, ptr_src+k_src, size); \
                        k_dst++; \
                    } \
                } \
            }
            switch (type)
            {
                case BCF_HT_INT:  BRANCH(int32_t,ptr_src[k_src]==bcf_int32_vector_end,ptr_dst[k_dst]=bcf_int32_missing); break;
                case BCF_HT_REAL: BRANCH(float,bcf_float_is_vector_end(ptr_src[k_src]),bcf_float_set_missing(ptr_dst[k_dst])); break;
            }
            #undef BRANCH
        }
        else    // Number=G, diploid or mixture of haploid+diploid
        {
            if ( nori!=nG_ori )
            {
                hts_log_error("Unexpected number of values in FORMAT/%s at %s:%"PRIhts_pos"; expected Number=G=%d, but found %d",
                    bcf_hdr_int2id(header,BCF_DT_ID,fmt->id), bcf_seqname_safe(header,line), line->pos+1, nG_ori, nori);
                goto err;
            }
            ndat = nG_new*line->n_sample;

            #define BRANCH(type_t,is_vector_end) \
            { \
                for (j=0; j<line->n_sample; j++) \
                { \
                    type_t *ptr_src = ((type_t*)dat) + j*nori; \
                    type_t *ptr_dst = ((type_t*)dat) + j*nG_new; \
                    int size = sizeof(type_t); \
                    int ia, ib, k_dst = 0, k_src; \
                    int nset = 0;   /* haploid or diploid? */ \
                    for (k_src=0; k_src<nG_ori; k_src++) { if ( is_vector_end ) break; nset++; } \
                    if ( nset==nR_ori ) /* haploid */ \
                    { \
                        for (k_src=0; k_src<nR_ori; k_src++) \
                        { \
                            if ( kbs_exists(rm_set, k_src) ) continue; \
                            memcpy(ptr_dst+k_dst, ptr_src+k_src, size); \
                            k_dst++; \
                        } \
                        memcpy(ptr_dst+k_dst, ptr_src+k_src, size); \
                    } \
                    else /* diploid */ \
                    { \
                        k_src = -1; \
                        for (ia=0; ia<nR_ori; ia++) \
                        { \
                            for (ib=0; ib<=ia; ib++) \
                            { \
                                k_src++; \
                                if ( is_vector_end ) { memcpy(ptr_dst+k_dst, ptr_src+k_src, size); ia = nR_ori; break; }  \
                                if ( kbs_exists(rm_set, ia) || kbs_exists(rm_set, ib) ) continue; \
                                memcpy(ptr_dst+k_dst, ptr_src+k_src, size); \
                                k_dst++; \
                            } \
                        } \
                    } \
                } \
            }
            switch (type)
            {
                case BCF_HT_INT:  BRANCH(int32_t,ptr_src[k_src]==bcf_int32_vector_end); break;
                case BCF_HT_REAL: BRANCH(float,bcf_float_is_vector_end(ptr_src[k_src])); break;
            }
            #undef BRANCH
        }
        nret = bcf_update_format(header, line, bcf_hdr_int2id(header,BCF_DT_ID,fmt->id), (void*)dat, ndat, type);
        if ( nret<0 )
        {
            hts_log_error("Could not update FORMAT/%s at %s:%"PRIhts_pos" [%d]",
                bcf_hdr_int2id(header,BCF_DT_ID,fmt->id), bcf_seqname_safe(header,line), line->pos+1, nret);
            goto err;
        }
    }

clean:
    free(str.s);
    free(map);
    free(dat);
    return 0;

err:
    free(str.s);
    free(map);
    free(dat);
    return -1;
}