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bam_maqcns.c

#include <math.h>
#include <assert.h>
#include "bam.h"
#include "bam_maqcns.h"
#include "ksort.h"
#include "errmod.h"
#include "kaln.h"
KSORT_INIT_GENERIC(uint32_t)

#define INDEL_WINDOW_SIZE 50
#define INDEL_EXT_DEP 0.9

typedef struct __bmc_aux_t {
      int max;
      uint32_t *info;
      uint16_t *info16;
      errmod_t *em;
} bmc_aux_t;

typedef struct {
      float esum[4], fsum[4];
      uint32_t c[4];
} glf_call_aux_t;

char bam_nt16_nt4_table[] = { 4, 0, 1, 4, 2, 4, 4, 4, 3, 4, 4, 4, 4, 4, 4, 4 };

/*
  P(<b1,b2>) = \theta \sum_{i=1}^{N-1} 1/i
  P(D|<b1,b2>) = \sum_{k=1}^{N-1} p_k 1/2 [(k/N)^n_2(1-k/N)^n_1 + (k/N)^n1(1-k/N)^n_2]
  p_k = 1/k / \sum_{i=1}^{N-1} 1/i
 */
static void cal_het(bam_maqcns_t *aa)
{
      int k, n1, n2;
      double sum_harmo; // harmonic sum
      double poly_rate;

      free(aa->lhet);
      aa->lhet = (double*)calloc(256 * 256, sizeof(double));
      sum_harmo = 0.0;
      for (k = 1; k <= aa->n_hap - 1; ++k)
            sum_harmo += 1.0 / k;
      for (n1 = 0; n1 < 256; ++n1) {
            for (n2 = 0; n2 < 256; ++n2) {
                  long double sum = 0.0;
                  double lC = aa->errmod == BAM_ERRMOD_SOAP? 0 : lgamma(n1+n2+1) - lgamma(n1+1) - lgamma(n2+1);
                  for (k = 1; k <= aa->n_hap - 1; ++k) {
                        double pk = 1.0 / k / sum_harmo;
                        double log1 = log((double)k/aa->n_hap);
                        double log2 = log(1.0 - (double)k/aa->n_hap);
                        sum += pk * 0.5 * (expl(log1*n2) * expl(log2*n1) + expl(log1*n1) * expl(log2*n2));
                  }
                  aa->lhet[n1<<8|n2] = lC + logl(sum);
            }
      }
      poly_rate = aa->het_rate * sum_harmo;
      aa->q_r = -4.343 * log(2.0 * poly_rate / (1.0 - poly_rate));
}

/** initialize the helper structure */
static void cal_coef(bam_maqcns_t *aa)
{
      int k, n, q;
      long double sum_a[257], b[256], q_c[256], tmp[256], fk2[256];
      double *lC;

      if (aa->errmod == BAM_ERRMOD_MAQ2) return; // no need to do the following
      // aa->lhet will be allocated and initialized 
      free(aa->fk); free(aa->coef);
      aa->coef = 0;
      aa->fk = (double*)calloc(256, sizeof(double));
      aa->fk[0] = fk2[0] = 1.0;
      for (n = 1; n != 256; ++n) {
            aa->fk[n] = pow(aa->theta, n) * (1.0 - aa->eta) + aa->eta;
            fk2[n] = aa->fk[n>>1]; // this is an approximation, assuming reads equally likely come from both strands
      }
      if (aa->errmod == BAM_ERRMOD_SOAP) return;
      aa->coef = (double*)calloc(256*256*64, sizeof(double));
      lC = (double*)calloc(256 * 256, sizeof(double));
      for (n = 1; n != 256; ++n)
            for (k = 1; k <= n; ++k)
                  lC[n<<8|k] = lgamma(n+1) - lgamma(k+1) - lgamma(n-k+1);
      for (q = 1; q != 64; ++q) {
            double e = pow(10.0, -q/10.0);
            double le = log(e);
            double le1 = log(1.0-e);
            for (n = 1; n != 256; ++n) {
                  double *coef = aa->coef + (q<<16|n<<8);
                  sum_a[n+1] = 0.0;
                  for (k = n; k >= 0; --k) { // a_k = \sum_{i=k}^n C^n_k \epsilon^k (1-\epsilon)^{n-k}
                        sum_a[k] = sum_a[k+1] + expl(lC[n<<8|k] + k*le + (n-k)*le1);
                        b[k] = sum_a[k+1] / sum_a[k];
                        if (b[k] > 0.99) b[k] = 0.99;
                  }
                  for (k = 0; k != n; ++k) // log(\bar\beta_{nk}(\bar\epsilon)^{f_k})
                        q_c[k] = -4.343 * fk2[k] * logl(b[k] / e);
                  for (k = 1; k != n; ++k) q_c[k] += q_c[k-1]; // \prod_{i=0}^k c_i
                  for (k = 0; k <= n; ++k) { // powl() in 64-bit mode seems broken on my Mac OS X 10.4.9
                        tmp[k] = -4.343 * logl(1.0 - expl(fk2[k] * logl(b[k])));
                        coef[k] = (k? q_c[k-1] : 0) + tmp[k]; // this is the final c_{nk}
                  }
            }
      }
      free(lC);
}

bam_maqcns_t *bam_maqcns_init()
{
      bam_maqcns_t *bm;
      bm = (bam_maqcns_t*)calloc(1, sizeof(bam_maqcns_t));
      bm->aux = (bmc_aux_t*)calloc(1, sizeof(bmc_aux_t));
      bm->het_rate = 0.001;
      bm->theta = 0.83f;
      bm->n_hap = 2;
      bm->eta = 0.03;
      bm->cap_mapQ = 60;
      bm->min_baseQ = 13;
      return bm;
}

void bam_maqcns_prepare(bam_maqcns_t *bm)
{
      if (bm->errmod == BAM_ERRMOD_MAQ2) bm->aux->em = errmod_init(1. - bm->theta);
      cal_coef(bm); cal_het(bm);
}

void bam_maqcns_destroy(bam_maqcns_t *bm)
{
      if (bm == 0) return;
      free(bm->lhet); free(bm->fk); free(bm->coef); free(bm->aux->info); free(bm->aux->info16);
      if (bm->aux->em) errmod_destroy(bm->aux->em);
      free(bm->aux); free(bm);
}

glf1_t *bam_maqcns_glfgen(int _n, const bam_pileup1_t *pl, uint8_t ref_base, bam_maqcns_t *bm)
{
      glf_call_aux_t *b = 0;
      int i, j, k, w[8], c, n;
      glf1_t *g = (glf1_t*)calloc(1, sizeof(glf1_t));
      float p[16], min_p = 1e30;
      uint64_t rms;

      g->ref_base = ref_base;
      if (_n == 0) return g;

      // construct aux array
      if (bm->aux->max < _n) {
            bm->aux->max = _n;
            kroundup32(bm->aux->max);
            bm->aux->info = (uint32_t*)realloc(bm->aux->info, 4 * bm->aux->max);
            bm->aux->info16 = (uint16_t*)realloc(bm->aux->info16, 2 * bm->aux->max);
      }
      for (i = n = 0, rms = 0; i < _n; ++i) {
            const bam_pileup1_t *p = pl + i;
            uint32_t q, x = 0, qq;
            uint16_t y = 0;
            if (p->is_del || p->is_refskip || (p->b->core.flag&BAM_FUNMAP)) continue;
            q = (uint32_t)bam1_qual(p->b)[p->qpos];
            if (q < bm->min_baseQ) continue;
            x |= (uint32_t)bam1_strand(p->b) << 18 | q << 8 | p->b->core.qual;
            y |= bam1_strand(p->b)<<4;
            if (p->b->core.qual < q) q = p->b->core.qual;
            c = p->b->core.qual < bm->cap_mapQ? p->b->core.qual : bm->cap_mapQ;
            rms += c * c;
            x |= q << 24;
            y |= q << 5;
            qq = bam1_seqi(bam1_seq(p->b), p->qpos);
            q = bam_nt16_nt4_table[qq? qq : ref_base];
            if (!p->is_del && !p->is_refskip && q < 4) x |= 1 << 21 | q << 16, y |= q;
            bm->aux->info16[n] = y;
            bm->aux->info[n++] = x;
      }
      rms = (uint8_t)(sqrt((double)rms / n) + .499);
      if (bm->errmod == BAM_ERRMOD_MAQ2) {
            errmod_cal(bm->aux->em, n, 4, bm->aux->info16, p);
            goto goto_glf;
      }
      ks_introsort(uint32_t, n, bm->aux->info);
      // generate esum and fsum
      b = (glf_call_aux_t*)calloc(1, sizeof(glf_call_aux_t));
      for (k = 0; k != 8; ++k) w[k] = 0;
      for (j = n - 1; j >= 0; --j) { // calculate esum and fsum
            uint32_t info = bm->aux->info[j];
            if (info>>24 < 4 && (info>>8&0x3f) != 0) info = 4<<24 | (info&0xffffff);
            k = info>>16&7;
            if (info>>24 > 0) {
                  b->esum[k&3] += bm->fk[w[k]] * (info>>24);
                  b->fsum[k&3] += bm->fk[w[k]];
                  if (w[k] < 0xff) ++w[k];
                  ++b->c[k&3];
            }
      }
      // rescale ->c[]
      for (j = c = 0; j != 4; ++j) c += b->c[j];
      if (c > 255) {
            for (j = 0; j != 4; ++j) b->c[j] = (int)(254.0 * b->c[j] / c + 0.5);
            for (j = c = 0; j != 4; ++j) c += b->c[j];
      }
      if (bm->errmod == BAM_ERRMOD_MAQ) {
            // generate likelihood
            for (j = 0; j != 4; ++j) {
                  // homozygous
                  float tmp1, tmp3;
                  int tmp2, bar_e;
                  for (k = 0, tmp1 = tmp3 = 0.0, tmp2 = 0; k != 4; ++k) {
                        if (j == k) continue;
                        tmp1 += b->esum[k]; tmp2 += b->c[k]; tmp3 += b->fsum[k];
                  }
                  if (tmp2) {
                        bar_e = (int)(tmp1 / tmp3 + 0.5);
                        if (bar_e < 4) bar_e = 4; // should not happen
                        if (bar_e > 63) bar_e = 63;
                        p[j<<2|j] = tmp1 + bm->coef[bar_e<<16|c<<8|tmp2];
                  } else p[j<<2|j] = 0.0; // all the bases are j
                  // heterozygous
                  for (k = j + 1; k < 4; ++k) {
                        for (i = 0, tmp2 = 0, tmp1 = tmp3 = 0.0; i != 4; ++i) {
                              if (i == j || i == k) continue;
                              tmp1 += b->esum[i]; tmp2 += b->c[i]; tmp3 += b->fsum[i];
                        }
                        if (tmp2) {
                              bar_e = (int)(tmp1 / tmp3 + 0.5);
                              if (bar_e < 4) bar_e = 4;
                              if (bar_e > 63) bar_e = 63;
                              p[j<<2|k] = p[k<<2|j] = -4.343 * bm->lhet[b->c[j]<<8|b->c[k]] + tmp1 + bm->coef[bar_e<<16|c<<8|tmp2];
                        } else p[j<<2|k] = p[k<<2|j] = -4.343 * bm->lhet[b->c[j]<<8|b->c[k]]; // all the bases are either j or k
                  }
                  //
                  for (k = 0; k != 4; ++k)
                        if (p[j<<2|k] < 0.0) p[j<<2|k] = 0.0;
            }

            { // fix p[k<<2|k]
                  float max1, max2, min1, min2;
                  int max_k, min_k;
                  max_k = min_k = -1;
                  max1 = max2 = -1.0; min1 = min2 = 1e30;
                  for (k = 0; k < 4; ++k) {
                        if (b->esum[k] > max1) {
                              max2 = max1; max1 = b->esum[k]; max_k = k;
                        } else if (b->esum[k] > max2) max2 = b->esum[k];
                  }
                  for (k = 0; k < 4; ++k) {
                        if (p[k<<2|k] < min1) {
                              min2 = min1; min1 = p[k<<2|k]; min_k = k;
                        } else if (p[k<<2|k] < min2) min2 = p[k<<2|k];
                  }
                  if (max1 > max2 && (min_k != max_k || min1 + 1.0 > min2))
                        p[max_k<<2|max_k] = min1 > 1.0? min1 - 1.0 : 0.0;
            }
      } else if (bm->errmod == BAM_ERRMOD_SOAP) { // apply the SOAP model
            // generate likelihood
            for (j = 0; j != 4; ++j) {
                  float tmp;
                  // homozygous
                  for (k = 0, tmp = 0.0; k != 4; ++k)
                        if (j != k) tmp += b->esum[k];
                  p[j<<2|j] = tmp;
                  // heterozygous
                  for (k = j + 1; k < 4; ++k) {
                        for (i = 0, tmp = 0.0; i != 4; ++i)
                              if (i != j && i != k) tmp += b->esum[i];
                        p[j<<2|k] = p[k<<2|j] = -4.343 * bm->lhet[b->c[j]<<8|b->c[k]] + tmp;
                  }
            }
      }

goto_glf:
      // convert necessary information to glf1_t
      g->ref_base = ref_base; g->max_mapQ = rms;
      g->depth = n > 16777215? 16777215 : n;
      for (j = 0; j != 4; ++j)
            for (k = j; k < 4; ++k)
                  if (p[j<<2|k] < min_p) min_p = p[j<<2|k];
      g->min_lk = min_p > 255.0? 255 : (int)(min_p + 0.5);
      for (j = c = 0; j != 4; ++j)
            for (k = j; k < 4; ++k)
                  g->lk[c++] = p[j<<2|k]-min_p > 255.0? 255 : (int)(p[j<<2|k]-min_p + 0.5);

      free(b);
      return g;
}

uint32_t glf2cns(const glf1_t *g, int q_r)
{
      int i, j, k, p[10], ref4;
      uint32_t x = 0;
      ref4 = bam_nt16_nt4_table[g->ref_base];
      for (i = k = 0; i < 4; ++i)
            for (j = i; j < 4; ++j) {
                  int prior = (i == ref4 && j == ref4? 0 : i == ref4 || j == ref4? q_r : q_r + 3);
                  p[k] = (g->lk[k] + prior)<<4 | i<<2 | j;
                  ++k;
            }
      for (i = 1; i < 10; ++i) // insertion sort
            for (j = i; j > 0 && p[j] < p[j-1]; --j)
                  k = p[j], p[j] = p[j-1], p[j-1] = k;
      x = (1u<<(p[0]&3) | 1u<<(p[0]>>2&3)) << 28; // the best genotype
      x |= (uint32_t)g->max_mapQ << 16; // rms mapQ
      x |= ((p[1]>>4) - (p[0]>>4) < 256? (p[1]>>4) - (p[0]>>4) : 255) << 8; // consensus Q
      for (k = 0; k < 10; ++k)
            if ((p[k]&0xf) == (ref4<<2|ref4)) break;
      if (k == 10) k = 9;
      x |= (p[k]>>4) - (p[0]>>4) < 256? (p[k]>>4) - (p[0]>>4) : 255; // snp Q
      return x;
}

uint32_t bam_maqcns_call(int n, const bam_pileup1_t *pl, bam_maqcns_t *bm)
{
      glf1_t *g;
      uint32_t x;
      if (n) {
            g = bam_maqcns_glfgen(n, pl, 0xf, bm);
            x = g->depth == 0? (0xfU<<28 | 0xfU<<24) : glf2cns(g, (int)(bm->q_r + 0.5));
            free(g);
      } else x = 0xfU<<28 | 0xfU<<24;
      return x;
}

/************** *****************/

bam_maqindel_opt_t *bam_maqindel_opt_init()
{
      bam_maqindel_opt_t *mi = (bam_maqindel_opt_t*)calloc(1, sizeof(bam_maqindel_opt_t));
      mi->q_indel = 40;
      mi->r_indel = 0.00015;
      mi->r_snp = 0.001;
      //
      mi->mm_penalty = 3;
      mi->indel_err = 4;
      mi->ambi_thres = 10;
      return mi;
}

void bam_maqindel_ret_destroy(bam_maqindel_ret_t *mir)
{
      if (mir == 0) return;
      free(mir->s[0]); free(mir->s[1]); free(mir);
}

int bam_tpos2qpos(const bam1_core_t *c, const uint32_t *cigar, int32_t tpos, int is_left, int32_t *_tpos)
{
      int k, x = c->pos, y = 0, last_y = 0;
      *_tpos = c->pos;
      for (k = 0; k < c->n_cigar; ++k) {
            int op = cigar[k] & BAM_CIGAR_MASK;
            int l = cigar[k] >> BAM_CIGAR_SHIFT;
            if (op == BAM_CMATCH) {
                  if (c->pos > tpos) return y;
                  if (x + l > tpos) {
                        *_tpos = tpos;
                        return y + (tpos - x);
                  }
                  x += l; y += l;
                  last_y = y;
            } else if (op == BAM_CINS || op == BAM_CSOFT_CLIP) y += l;
            else if (op == BAM_CDEL || op == BAM_CREF_SKIP) {
                  if (x + l > tpos) {
                        *_tpos = is_left? x : x + l;
                        return y;
                  }
                  x += l;
            }
      }
      *_tpos = x;
      return last_y;
}

#define MINUS_CONST 0x10000000

bam_maqindel_ret_t *bam_maqindel(int n, int pos, const bam_maqindel_opt_t *mi, const bam_pileup1_t *pl, const char *ref,
                                                 int _n_types, int *_types)
{
      int i, j, n_types, *types, left, right, max_rd_len = 0;
      bam_maqindel_ret_t *ret = 0;
      // if there is no proposed indel, check if there is an indel from the alignment
      if (_n_types == 0) {
            for (i = 0; i < n; ++i) {
                  const bam_pileup1_t *p = pl + i;
                  if (!(p->b->core.flag&BAM_FUNMAP) && p->indel != 0) break;
            }
            if (i == n) return 0; // no indel
      }
      { // calculate how many types of indels are available (set n_types and types)
            int m;
            uint32_t *aux;
            aux = (uint32_t*)calloc(n + _n_types + 1, 4);
            m = 0;
            aux[m++] = MINUS_CONST; // zero indel is always a type
            for (i = 0; i < n; ++i) {
                  const bam_pileup1_t *p = pl + i;
                  if (!(p->b->core.flag&BAM_FUNMAP) && p->indel != 0)
                        aux[m++] = MINUS_CONST + p->indel;
                  j = bam_cigar2qlen(&p->b->core, bam1_cigar(p->b));
                  if (j > max_rd_len) max_rd_len = j;
            }
            if (_n_types) // then also add this to aux[]
                  for (i = 0; i < _n_types; ++i)
                        if (_types[i]) aux[m++] = MINUS_CONST + _types[i];
            ks_introsort(uint32_t, m, aux);
            // squeeze out identical types
            for (i = 1, n_types = 1; i < m; ++i)
                  if (aux[i] != aux[i-1]) ++n_types;
            types = (int*)calloc(n_types, sizeof(int));
            j = 0;
            types[j++] = aux[0] - MINUS_CONST; 
            for (i = 1; i < m; ++i) {
                  if (aux[i] != aux[i-1])
                        types[j++] = aux[i] - MINUS_CONST;
            }
            free(aux);
      }
      { // calculate left and right boundary
            left = pos > INDEL_WINDOW_SIZE? pos - INDEL_WINDOW_SIZE : 0;
            right = pos + INDEL_WINDOW_SIZE;
            if (types[0] < 0) right -= types[0];
            // in case the alignments stand out the reference
            for (i = pos; i < right; ++i)
                  if (ref[i] == 0) break;
            right = i;
      }
      { // the core part
            char *ref2, *rs, *inscns = 0;
            int qr_snp, k, l, *score, *pscore, max_ins = types[n_types-1];
            qr_snp = (int)(-4.343 * log(mi->r_snp) + .499);
            if (max_ins > 0) { // get the consensus of inserted sequences
                  int *inscns_aux = (int*)calloc(4 * n_types * max_ins, sizeof(int));
                  // count occurrences
                  for (i = 0; i < n_types; ++i) {
                        if (types[i] <= 0) continue; // not insertion
                        for (j = 0; j < n; ++j) {
                              const bam_pileup1_t *p = pl + j;
                              if (!(p->b->core.flag&BAM_FUNMAP) && p->indel == types[i]) {
                                    for (k = 1; k <= p->indel; ++k) {
                                          int c = bam_nt16_nt4_table[bam1_seqi(bam1_seq(p->b), p->qpos + k)];
                                          if (c < 4) ++inscns_aux[i*max_ins*4 + (k-1)*4 + c];
                                    }
                              }
                        }
                  }
                  // construct the consensus of inserted sequence
                  inscns = (char*)calloc(n_types * max_ins, sizeof(char));
                  for (i = 0; i < n_types; ++i) {
                        for (j = 0; j < types[i]; ++j) {
                              int max = 0, max_k = -1, *ia = inscns_aux + i*max_ins*4 + j*4;
                              for (k = 0; k < 4; ++k) {
                                    if (ia[k] > max) {
                                          max = ia[k];
                                          max_k = k;
                                    }
                              }
                              inscns[i*max_ins + j] = max? 1<<max_k : 15;
                        }
                  }
                  free(inscns_aux);
            }
            // calculate score
            ref2 = (char*)calloc(right - left + types[n_types-1] + 2, 1);
            rs   = (char*)calloc(right - left + max_rd_len + types[n_types-1] + 2, 1);
            score = (int*)calloc(n_types * n, sizeof(int));
            pscore = (int*)calloc(n_types * n, sizeof(int));
            for (i = 0; i < n_types; ++i) {
                  ka_param_t ap = ka_param_blast;
                  ap.band_width = 2 * types[n_types - 1] + 2;
                  ap.gap_end_ext = 0;
                  // write ref2
                  for (k = 0, j = left; j <= pos; ++j)
                        ref2[k++] = bam_nt16_nt4_table[bam_nt16_table[(int)ref[j]]];
                  if (types[i] <= 0) j += -types[i];
                  else for (l = 0; l < types[i]; ++l)
                               ref2[k++] = bam_nt16_nt4_table[(int)inscns[i*max_ins + l]];
                  if (types[0] < 0) { // mask deleted sequences
                        int jj, tmp = types[i] >= 0? -types[0] : -types[0] + types[i];
                        for (jj = 0; jj < tmp && j < right && ref[j]; ++jj, ++j)
                              ref2[k++] = 4;
                  }
                  for (; j < right && ref[j]; ++j)
                        ref2[k++] = bam_nt16_nt4_table[bam_nt16_table[(int)ref[j]]];
                  if (j < right) right = j;
                  // calculate score for each read
                  for (j = 0; j < n; ++j) {
                        const bam_pileup1_t *p = pl + j;
                        int qbeg, qend, tbeg, tend;
                        if (p->b->core.flag & BAM_FUNMAP) continue;
                        qbeg = bam_tpos2qpos(&p->b->core, bam1_cigar(p->b), left,  0, &tbeg);
                        qend = bam_tpos2qpos(&p->b->core, bam1_cigar(p->b), right, 1, &tend);
                        assert(tbeg >= left);
                        for (l = qbeg; l < qend; ++l)
                              rs[l - qbeg] = bam_nt16_nt4_table[bam1_seqi(bam1_seq(p->b), l)];
                        {
                              int x, y, n_acigar, ps;
                              uint32_t *acigar;
                              ps = 0;
                              if (tend - tbeg + types[i] <= 0) {
                                    score[i*n+j] = -(1<<20);
                                    pscore[i*n+j] = 1<<20;
                                    continue;
                              }
                              acigar = ka_global_core((uint8_t*)ref2 + tbeg - left, tend - tbeg + types[i], (uint8_t*)rs, qend - qbeg, &ap, &score[i*n+j], &n_acigar);
                              x = tbeg - left; y = 0;
                              for (l = 0; l < n_acigar; ++l) {
                                    int op = acigar[l]&0xf;
                                    int len = acigar[l]>>4;
                                    if (op == BAM_CMATCH) {
                                          int k;
                                          for (k = 0; k < len; ++k)
                                                if (ref2[x+k] != rs[y+k] && ref2[x+k] < 4)
                                                      ps += bam1_qual(p->b)[y+k] < qr_snp? bam1_qual(p->b)[y+k] : qr_snp;
                                          x += len; y += len;
                                    } else if (op == BAM_CINS || op == BAM_CSOFT_CLIP) {
                                          if (op == BAM_CINS && l > 0 && l < n_acigar - 1) ps += mi->q_indel * len;
                                          y += len;
                                    } else if (op == BAM_CDEL) {
                                          if (l > 0 && l < n_acigar - 1) ps += mi->q_indel * len;
                                          x += len;
                                    }
                              }
                              pscore[i*n+j] = ps;
                              /*if (1) { // for debugging only
                                    fprintf(stderr, "id=%d, pos=%d, type=%d, j=%d, score=%d, psore=%d, %d, %d, %d, %d, %d, ",
                                                j, pos+1, types[i], j, score[i*n+j], pscore[i*n+j], tbeg, tend, qbeg, qend, mi->q_indel);
                                    for (l = 0; l < n_acigar; ++l) fprintf(stderr, "%d%c", acigar[l]>>4, "MIDS"[acigar[l]&0xf]);
                                    fprintf(stderr, "\n");
                                    for (l = 0; l < tend - tbeg + types[i]; ++l) fputc("ACGTN"[ref2[l+tbeg-left]], stderr);
                                    fputc('\n', stderr);
                                    for (l = 0; l < qend - qbeg; ++l) fputc("ACGTN"[rs[l]], stderr);
                                    fputc('\n', stderr);
                                    }*/
                              free(acigar);
                        }
                  }
            }
            { // get final result
                  int *sum, max1, max2, max1_i, max2_i;
                  // pick up the best two score
                  sum = (int*)calloc(n_types, sizeof(int));
                  for (i = 0; i < n_types; ++i)
                        for (j = 0; j < n; ++j)
                              sum[i] += -pscore[i*n+j];
                  max1 = max2 = -0x7fffffff; max1_i = max2_i = -1;
                  for (i = 0; i < n_types; ++i) {
                        if (sum[i] > max1) {
                              max2 = max1; max2_i = max1_i; max1 = sum[i]; max1_i = i;
                        } else if (sum[i] > max2) {
                              max2 = sum[i]; max2_i = i;
                        }
                  }
                  free(sum);
                  // write ret
                  ret = (bam_maqindel_ret_t*)calloc(1, sizeof(bam_maqindel_ret_t));
                  ret->indel1 = types[max1_i]; ret->indel2 = types[max2_i];
                  ret->s[0] = (char*)calloc(abs(ret->indel1) + 2, 1);
                  ret->s[1] = (char*)calloc(abs(ret->indel2) + 2, 1);
                  // write indel sequence
                  if (ret->indel1 > 0) {
                        ret->s[0][0] = '+';
                        for (k = 0; k < ret->indel1; ++k)
                              ret->s[0][k+1] = bam_nt16_rev_table[(int)inscns[max1_i*max_ins + k]];
                  } else if (ret->indel1 < 0) {
                        ret->s[0][0] = '-';
                        for (k = 0; k < -ret->indel1 && ref[pos + k + 1]; ++k)
                              ret->s[0][k+1] = ref[pos + k + 1];
                  } else ret->s[0][0] = '*';
                  if (ret->indel2 > 0) {
                        ret->s[1][0] = '+';
                        for (k = 0; k < ret->indel2; ++k)
                              ret->s[1][k+1] = bam_nt16_rev_table[(int)inscns[max2_i*max_ins + k]];
                  } else if (ret->indel2 < 0) {
                        ret->s[1][0] = '-';
                        for (k = 0; k < -ret->indel2 && ref[pos + k + 1]; ++k)
                              ret->s[1][k+1] = ref[pos + k + 1];
                  } else ret->s[1][0] = '*';
                  // write count
                  for (i = 0; i < n; ++i) {
                        const bam_pileup1_t *p = pl + i;
                        if (p->indel == ret->indel1) ++ret->cnt1;
                        else if (p->indel == ret->indel2) ++ret->cnt2;
                        else ++ret->cnt_anti;
                  }
                  { // write gl[]
                        int tmp, seq_err = 0;
                        double x = 1.0;
                        tmp = max1_i - max2_i;
                        if (tmp < 0) tmp = -tmp;
                        for (j = 0; j < tmp + 1; ++j) x *= INDEL_EXT_DEP;
                        seq_err = mi->q_indel * (1.0 - x) / (1.0 - INDEL_EXT_DEP);
                        ret->gl[0] = ret->gl[1] = 0;
                        for (j = 0; j < n; ++j) {
                              int s1 = pscore[max1_i*n + j], s2 = pscore[max2_i*n + j];
                              //fprintf(stderr, "id=%d, %d, %d, %d, %d, %d\n", j, pl[j].b->core.pos+1, types[max1_i], types[max2_i], s1, s2);
                              if (s1 > s2) ret->gl[0] += s1 - s2 < seq_err? s1 - s2 : seq_err;
                              else ret->gl[1] += s2 - s1 < seq_err? s2 - s1 : seq_err;
                        }
                  }
                  // write cnt_ref and cnt_ambi
                  if (max1_i != 0 && max2_i != 0) {
                        for (j = 0; j < n; ++j) {
                              int diff1 = score[j] - score[max1_i * n + j];
                              int diff2 = score[j] - score[max2_i * n + j];
                              if (diff1 > 0 && diff2 > 0) ++ret->cnt_ref;
                              else if (diff1 == 0 || diff2 == 0) ++ret->cnt_ambi;
                        }
                  }
            }
            free(score); free(pscore); free(ref2); free(rs); free(inscns);
      }
      { // call genotype
            int q[3], qr_indel = (int)(-4.343 * log(mi->r_indel) + 0.5);
            int min1, min2, min1_i;
            q[0] = ret->gl[0] + (ret->s[0][0] != '*'? 0 : 0) * qr_indel;
            q[1] = ret->gl[1] + (ret->s[1][0] != '*'? 0 : 0) * qr_indel;
            q[2] = n * 3 + (ret->s[0][0] == '*' || ret->s[1][0] == '*'? 1 : 1) * qr_indel;
            min1 = min2 = 0x7fffffff; min1_i = -1;
            for (i = 0; i < 3; ++i) {
                  if (q[i] < min1) {
                        min2 = min1; min1 = q[i]; min1_i = i;
                  } else if (q[i] < min2) min2 = q[i];
            }
            ret->gt = min1_i;
            ret->q_cns = min2 - min1;
            // set q_ref
            if (ret->gt < 2) ret->q_ref = (ret->s[ret->gt][0] == '*')? 0 : q[1-ret->gt] - q[ret->gt] - qr_indel - 3;
            else ret->q_ref = (ret->s[0][0] == '*')? q[0] - q[2] : q[1] - q[2];
            if (ret->q_ref < 0) ret->q_ref = 0;
      }
      free(types);
      return ret;
}

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