#include <string.h>
#include <stdio.h>
#include <errno.h>
+#include <assert.h>
+#include <limits.h>
#include "prob1.h"
+#include "kstring.h"
#include "kseq.h"
KSTREAM_INIT(gzFile, gzread, 16384)
-#define MC_AVG_ERR 0.007
#define MC_MAX_EM_ITER 16
-#define MC_EM_EPS 1e-4
+#define MC_EM_EPS 1e-5
+#define MC_DEF_INDEL 0.15
unsigned char seq_nt4_table[256] = {
4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
};
struct __bcf_p1aux_t {
- int n, M, n1;
+ int n, M, n1, is_indel;
+ uint8_t *ploidy; // haploid or diploid ONLY
double *q2p, *pdg; // pdg -> P(D|g)
- double *phi;
+ double *phi, *phi_indel;
double *z, *zswap; // aux for afs
double *z1, *z2, *phi1, *phi2; // only calculated when n1 is set
+ double **hg; // hypergeometric distribution
+ double *lf; // log factorial
double t, t1, t2;
double *afs, *afs1; // afs: accumulative AFS; afs1: site posterior distribution
const uint8_t *PL; // point to PL
int PL_len;
};
+void bcf_p1_indel_prior(bcf_p1aux_t *ma, double x)
+{
+ int i;
+ for (i = 0; i < ma->M; ++i)
+ ma->phi_indel[i] = ma->phi[i] * x;
+ ma->phi_indel[ma->M] = 1. - ma->phi[ma->M] * x;
+}
+
static void init_prior(int type, double theta, int M, double *phi)
{
int i;
void bcf_p1_init_prior(bcf_p1aux_t *ma, int type, double theta)
{
init_prior(type, theta, ma->M, ma->phi);
+ bcf_p1_indel_prior(ma, MC_DEF_INDEL);
}
void bcf_p1_init_subprior(bcf_p1aux_t *ma, int type, double theta)
for (k = 0; k <= ma->M; ++k) ma->phi[k] /= sum;
for (k = 0; k <= ma->M; ++k) fprintf(stderr, " %d:%.3lg", k, ma->phi[ma->M - k]);
fputc('\n', stderr);
- for (sum = 0., k = 1; k <= ma->M; ++k) sum += k * ma->phi[ma->M - k];
- fprintf(stderr, "[heterozygosity] %lf\n", (double)sum / ma->M);
+ for (sum = 0., k = 1; k < ma->M; ++k) sum += ma->phi[ma->M - k] * (2.* k * (ma->M - k) / ma->M / (ma->M - 1));
+ fprintf(stderr, "[%s] heterozygosity=%lf, ", __func__, (double)sum);
+ for (sum = 0., k = 1; k <= ma->M; ++k) sum += k * ma->phi[ma->M - k] / ma->M;
+ fprintf(stderr, "theta=%lf\n", (double)sum);
+ bcf_p1_indel_prior(ma, MC_DEF_INDEL);
return 0;
}
-bcf_p1aux_t *bcf_p1_init(int n)
+bcf_p1aux_t *bcf_p1_init(int n, uint8_t *ploidy)
{
bcf_p1aux_t *ma;
int i;
ma = calloc(1, sizeof(bcf_p1aux_t));
ma->n1 = -1;
ma->n = n; ma->M = 2 * n;
+ if (ploidy) {
+ ma->ploidy = malloc(n);
+ memcpy(ma->ploidy, ploidy, n);
+ for (i = 0, ma->M = 0; i < n; ++i) ma->M += ploidy[i];
+ if (ma->M == 2 * n) {
+ free(ma->ploidy);
+ ma->ploidy = 0;
+ }
+ }
ma->q2p = calloc(256, sizeof(double));
ma->pdg = calloc(3 * ma->n, sizeof(double));
ma->phi = calloc(ma->M + 1, sizeof(double));
+ ma->phi_indel = calloc(ma->M + 1, sizeof(double));
ma->phi1 = calloc(ma->M + 1, sizeof(double));
ma->phi2 = calloc(ma->M + 1, sizeof(double));
- ma->z = calloc(2 * ma->n + 1, sizeof(double));
- ma->zswap = calloc(2 * ma->n + 1, sizeof(double));
+ ma->z = calloc(ma->M + 1, sizeof(double));
+ ma->zswap = calloc(ma->M + 1, sizeof(double));
ma->z1 = calloc(ma->M + 1, sizeof(double)); // actually we do not need this large
ma->z2 = calloc(ma->M + 1, sizeof(double));
- ma->afs = calloc(2 * ma->n + 1, sizeof(double));
- ma->afs1 = calloc(2 * ma->n + 1, sizeof(double));
+ ma->afs = calloc(ma->M + 1, sizeof(double));
+ ma->afs1 = calloc(ma->M + 1, sizeof(double));
+ ma->lf = calloc(ma->M + 1, sizeof(double));
for (i = 0; i < 256; ++i)
ma->q2p[i] = pow(10., -i / 10.);
+ for (i = 0; i <= ma->M; ++i) ma->lf[i] = lgamma(i + 1);
bcf_p1_init_prior(ma, MC_PTYPE_FULL, 1e-3); // the simplest prior
return ma;
}
int bcf_p1_set_n1(bcf_p1aux_t *b, int n1)
{
if (n1 == 0 || n1 >= b->n) return -1;
+ if (b->M != b->n * 2) {
+ fprintf(stderr, "[%s] unable to set `n1' when there are haploid samples.\n", __func__);
+ return -1;
+ }
b->n1 = n1;
return 0;
}
+void bcf_p1_set_ploidy(bcf1_t *b, bcf_p1aux_t *ma)
+{
+ // bcf_p1aux_t fields are not visible outside of prob1.c, hence this wrapper.
+ // Ideally, this should set ploidy per site to allow pseudo-autosomal regions
+ b->ploidy = ma->ploidy;
+}
+
void bcf_p1_destroy(bcf_p1aux_t *ma)
{
if (ma) {
- free(ma->q2p); free(ma->pdg);
- free(ma->phi); free(ma->phi1); free(ma->phi2);
+ int k;
+ free(ma->lf);
+ if (ma->hg && ma->n1 > 0) {
+ for (k = 0; k <= 2*ma->n1; ++k) free(ma->hg[k]);
+ free(ma->hg);
+ }
+ free(ma->ploidy); free(ma->q2p); free(ma->pdg);
+ free(ma->phi); free(ma->phi_indel); free(ma->phi1); free(ma->phi2);
free(ma->z); free(ma->zswap); free(ma->z1); free(ma->z2);
free(ma->afs); free(ma->afs1);
free(ma);
}
}
-#define char2int(s) (((int)s[0])<<8|s[1])
+extern double kf_gammap(double s, double z);
+int test16(bcf1_t *b, anno16_t *a);
-static int cal_pdg(const bcf1_t *b, bcf_p1aux_t *ma)
+int call_multiallelic_gt(bcf1_t *b, bcf_p1aux_t *ma, double threshold)
{
- int i, j, k;
- long *p, tmp;
- p = alloca(b->n_alleles * sizeof(long));
- memset(p, 0, sizeof(long) * b->n_alleles);
- for (j = 0; j < ma->n; ++j) {
- const uint8_t *pi = ma->PL + j * ma->PL_len;
- double *pdg = ma->pdg + j * 3;
- pdg[0] = ma->q2p[pi[b->n_alleles]]; pdg[1] = ma->q2p[pi[1]]; pdg[2] = ma->q2p[pi[0]];
- for (i = k = 0; i < b->n_alleles; ++i) {
- p[i] += (int)pi[k];
- k += b->n_alleles - i;
- }
- }
- for (i = 0; i < b->n_alleles; ++i) p[i] = p[i]<<4 | i;
- for (i = 1; i < b->n_alleles; ++i) // insertion sort
- for (j = i; j > 0 && p[j] < p[j-1]; --j)
- tmp = p[j], p[j] = p[j-1], p[j-1] = tmp;
- for (i = b->n_alleles - 1; i >= 0; --i)
- if ((p[i]&0xf) == 0) break;
- return i;
+ int nals = 1;
+ char *p;
+ for (p=b->alt; *p; p++)
+ {
+ if ( *p=='X' || p[0]=='.' ) break;
+ if ( p[0]==',' ) nals++;
+ }
+ if ( b->alt[0] && !*p ) nals++;
+
+ if ( nals==1 ) return 1;
+
+ if ( nals>4 )
+ {
+ if ( *b->ref=='N' ) return 0;
+ fprintf(stderr,"Not ready for this, more than 4 alleles at %d: %s, %s\n", b->pos+1, b->ref,b->alt);
+ exit(1);
+ }
+
+ // find PL and DP FORMAT indexes
+ uint8_t *pl = NULL;
+ int npl = 0, idp=-1;
+ int i;
+ for (i = 0; i < b->n_gi; ++i)
+ {
+ if (b->gi[i].fmt == bcf_str2int("PL", 2))
+ {
+ pl = (uint8_t*)b->gi[i].data;
+ npl = b->gi[i].len;
+ }
+ if (b->gi[i].fmt == bcf_str2int("DP", 2)) idp=i;
+ }
+ if ( !pl ) return -1;
+
+ assert(ma->q2p[0] == 1);
+
+ // Init P(D|G)
+ int npdg = nals*(nals+1)/2;
+ double *pdg,*_pdg;
+ _pdg = pdg = malloc(sizeof(double)*ma->n*npdg);
+ for (i=0; i<ma->n; i++)
+ {
+ int j;
+ double sum = 0;
+ for (j=0; j<npdg; j++)
+ {
+ //_pdg[j] = pow(10,-0.1*pl[j]);
+ _pdg[j] = ma->q2p[pl[j]];
+ sum += _pdg[j];
+ }
+ if ( sum )
+ for (j=0; j<npdg; j++) _pdg[j] /= sum;
+ _pdg += npdg;
+ pl += npl;
+ }
+
+ if ((p = strstr(b->info, "QS=")) == 0) { fprintf(stderr,"INFO/QS is required with -m, exiting\n"); exit(1); }
+ double qsum[4];
+ if ( sscanf(p+3,"%lf,%lf,%lf,%lf",&qsum[0],&qsum[1],&qsum[2],&qsum[3])!=4 ) { fprintf(stderr,"Could not parse %s\n",p); exit(1); }
+
+
+ // Calculate the most likely combination of alleles
+ int ia,ib,ic, max_als=0, max_als2=0;
+ double ref_lk = 0, max_lk = INT_MIN, max_lk2 = INT_MIN, lk_sum = INT_MIN;
+ for (ia=0; ia<nals; ia++)
+ {
+ double lk_tot = 0;
+ int iaa = (ia+1)*(ia+2)/2-1;
+ int isample;
+ for (isample=0; isample<ma->n; isample++)
+ {
+ double *p = pdg + isample*npdg;
+ // assert( log(p[iaa]) <= 0 );
+ lk_tot += log(p[iaa]);
+ }
+ if ( ia==0 ) ref_lk = lk_tot;
+ if ( max_lk<lk_tot ) { max_lk2 = max_lk; max_als2 = max_als; max_lk = lk_tot; max_als = 1<<ia; }
+ else if ( max_lk2<lk_tot ) { max_lk2 = lk_tot; max_als2 = 1<<ia; }
+ lk_sum = lk_tot>lk_sum ? lk_tot + log(1+exp(lk_sum-lk_tot)) : lk_sum + log(1+exp(lk_tot-lk_sum));
+ }
+ if ( nals>1 )
+ {
+ for (ia=0; ia<nals; ia++)
+ {
+ if ( qsum[ia]==0 ) continue;
+ int iaa = (ia+1)*(ia+2)/2-1;
+ for (ib=0; ib<ia; ib++)
+ {
+ if ( qsum[ib]==0 ) continue;
+ double lk_tot = 0;
+ double fa = qsum[ia]/(qsum[ia]+qsum[ib]);
+ double fb = qsum[ib]/(qsum[ia]+qsum[ib]);
+ double fab = 2*fa*fb; fa *= fa; fb *= fb;
+ int isample, ibb = (ib+1)*(ib+2)/2-1, iab = iaa - ia + ib;
+ for (isample=0; isample<ma->n; isample++)
+ {
+ if ( b->ploidy && b->ploidy[isample]==1 ) continue;
+ double *p = pdg + isample*npdg;
+ //assert( log(fa*p[iaa] + fb*p[ibb] + fab*p[iab]) <= 0 );
+ lk_tot += log(fa*p[iaa] + fb*p[ibb] + fab*p[iab]);
+ }
+ if ( max_lk<lk_tot ) { max_lk2 = max_lk; max_als2 = max_als; max_lk = lk_tot; max_als = 1<<ia|1<<ib; }
+ else if ( max_lk2<lk_tot ) { max_lk2 = lk_tot; max_als2 = 1<<ia|1<<ib; }
+ lk_sum = lk_tot>lk_sum ? lk_tot + log(1+exp(lk_sum-lk_tot)) : lk_sum + log(1+exp(lk_tot-lk_sum));
+ }
+ }
+ }
+ if ( nals>2 )
+ {
+ for (ia=0; ia<nals; ia++)
+ {
+ if ( qsum[ia]==0 ) continue;
+ int iaa = (ia+1)*(ia+2)/2-1;
+ for (ib=0; ib<ia; ib++)
+ {
+ if ( qsum[ib]==0 ) continue;
+ int ibb = (ib+1)*(ib+2)/2-1;
+ int iab = iaa - ia + ib;
+ for (ic=0; ic<ib; ic++)
+ {
+ if ( qsum[ic]==0 ) continue;
+ double lk_tot = 0;
+ double fa = qsum[ia]/(qsum[ia]+qsum[ib]+qsum[ic]);
+ double fb = qsum[ib]/(qsum[ia]+qsum[ib]+qsum[ic]);
+ double fc = qsum[ic]/(qsum[ia]+qsum[ib]+qsum[ic]);
+ double fab = 2*fa*fb, fac = 2*fa*fc, fbc = 2*fb*fc; fa *= fa; fb *= fb; fc *= fc;
+ int isample, icc = (ic+1)*(ic+2)/2-1;
+ int iac = iaa - ia + ic, ibc = ibb - ib + ic;
+ for (isample=0; isample<ma->n; isample++)
+ {
+ if ( b->ploidy && b->ploidy[isample]==1 ) continue;
+ double *p = pdg + isample*npdg;
+ //assert( log(fa*p[iaa] + fb*p[ibb] + fc*p[icc] + fab*p[iab] + fac*p[iac] + fbc*p[ibc]) <= 0 );
+ lk_tot += log(fa*p[iaa] + fb*p[ibb] + fc*p[icc] + fab*p[iab] + fac*p[iac] + fbc*p[ibc]);
+ }
+ if ( max_lk<lk_tot ) { max_lk2 = max_lk; max_als2 = max_als; max_lk = lk_tot; max_als = 1<<ia|1<<ib|1<<ic; }
+ else if ( max_lk2<lk_tot ) { max_lk2 = lk_tot; max_als2 = 1<<ia|1<<ib|1<<ic; }
+ lk_sum = lk_tot>lk_sum ? lk_tot + log(1+exp(lk_sum-lk_tot)) : lk_sum + log(1+exp(lk_tot-lk_sum));
+ }
+ }
+ }
+ }
+
+
+ // Should we add another allele, does it increase the likelihood significantly?
+ int n1=0, n2=0;
+ for (i=0; i<nals; i++) if ( max_als&1<<i) n1++;
+ for (i=0; i<nals; i++) if ( max_als2&1<<i) n2++;
+ if ( n2<n1 && kf_gammap(1,2.0*(max_lk-max_lk2))<threshold )
+ {
+ max_lk = max_lk2;
+ max_als = max_als2;
+ }
+
+ // Get the BCF record ready for GT and GQ
+ kstring_t s;
+ int old_n_gi = b->n_gi;
+ s.m = b->m_str; s.l = b->l_str - 1; s.s = b->str;
+ kputs(":GT:GQ", &s); kputc('\0', &s);
+ b->m_str = s.m; b->l_str = s.l; b->str = s.s;
+ bcf_sync(b);
+
+ // Call GTs
+ int isample, gts=0, ac[4] = {0,0,0,0};
+ for (isample = 0; isample < b->n_smpl; isample++)
+ {
+ int ploidy = b->ploidy ? b->ploidy[isample] : 2;
+ double *p = pdg + isample*npdg;
+ int ia, als = 0;
+ double lk = 0, lk_sum=0;
+ for (ia=0; ia<nals; ia++)
+ {
+ if ( !(max_als&1<<ia) ) continue;
+ int iaa = (ia+1)*(ia+2)/2-1;
+ double _lk = p[iaa]*qsum[ia]*qsum[ia];
+ if ( _lk > lk ) { lk = _lk; als = ia<<3 | ia; }
+ lk_sum += _lk;
+ }
+ if ( ploidy==2 )
+ {
+ for (ia=0; ia<nals; ia++)
+ {
+ if ( !(max_als&1<<ia) ) continue;
+ int iaa = (ia+1)*(ia+2)/2-1;
+ for (ib=0; ib<ia; ib++)
+ {
+ if ( !(max_als&1<<ib) ) continue;
+ int iab = iaa - ia + ib;
+ double _lk = 2*qsum[ia]*qsum[ib]*p[iab];
+ if ( _lk > lk ) { lk = _lk; als = ib<<3 | ia; }
+ lk_sum += _lk;
+ }
+ }
+ }
+ lk = -log(1-lk/lk_sum)/0.2302585;
+ if ( idp>=0 && ((uint16_t*)b->gi[idp].data)[isample]==0 )
+ {
+ ((uint8_t*)b->gi[old_n_gi].data)[isample] = 1<<7;
+ ((uint8_t*)b->gi[old_n_gi+1].data)[isample] = 0;
+ continue;
+ }
+ ((uint8_t*)b->gi[old_n_gi].data)[isample] = als;
+ ((uint8_t*)b->gi[old_n_gi+1].data)[isample] = lk<100 ? (int)lk : 99;
+
+ gts |= 1<<(als>>3&7) | 1<<(als&7);
+ ac[ als>>3&7 ]++;
+ ac[ als&7 ]++;
+ }
+ bcf_fit_alt(b,max_als);
+
+
+ // Prepare BCF for output: ref, alt, filter, info, format
+ memset(&s, 0, sizeof(kstring_t)); kputc('\0', &s);
+ kputs(b->ref, &s); kputc('\0', &s);
+ kputs(b->alt, &s); kputc('\0', &s); kputc('\0', &s);
+ {
+ int an=0, nalts=0;
+ for (i=0; i<nals; i++)
+ {
+ an += ac[i];
+ if ( i>0 && ac[i] ) nalts++;
+ }
+ ksprintf(&s, "AN=%d;", an);
+ if ( nalts )
+ {
+ kputs("AC=", &s);
+ for (i=1; i<nals; i++)
+ {
+ if ( !(gts&1<<i) ) continue;
+ nalts--;
+ ksprintf(&s,"%d", ac[i]);
+ if ( nalts>0 ) kputc(',', &s);
+ }
+ kputc(';', &s);
+ }
+ kputs(b->info, &s);
+ anno16_t a;
+ int has_I16 = test16(b, &a) >= 0? 1 : 0;
+ if (has_I16 )
+ {
+ if ( a.is_tested) ksprintf(&s, ";PV4=%.2g,%.2g,%.2g,%.2g", a.p[0], a.p[1], a.p[2], a.p[3]);
+ ksprintf(&s, ";DP4=%d,%d,%d,%d;MQ=%d", a.d[0], a.d[1], a.d[2], a.d[3], a.mq);
+ }
+ kputc('\0', &s);
+ rm_info(&s, "I16=");
+ rm_info(&s, "QS=");
+ }
+ kputs(b->fmt, &s); kputc('\0', &s);
+ free(b->str);
+ b->m_str = s.m; b->l_str = s.l; b->str = s.s;
+ b->qual = gts>1 ? -4.343*(ref_lk - lk_sum) : -4.343*(max_lk - lk_sum);
+ if ( b->qual>999 ) b->qual = 999;
+ bcf_sync(b);
+
+
+ free(pdg);
+ return gts;
}
-// f0 is the reference allele frequency
-static double mc_freq_iter(double f0, const bcf_p1aux_t *ma)
+
+static int cal_pdg(const bcf1_t *b, bcf_p1aux_t *ma)
{
- double f, f3[3];
- int i;
- f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
- for (i = 0, f = 0.; i < ma->n; ++i) {
- double *pdg;
- pdg = ma->pdg + i * 3;
- f += (pdg[1] * f3[1] + 2. * pdg[2] * f3[2])
- / (pdg[0] * f3[0] + pdg[1] * f3[1] + pdg[2] * f3[2]);
- }
- f /= ma->n * 2.;
- return f;
+ int i, j;
+ long *p, tmp;
+ p = alloca(b->n_alleles * sizeof(long));
+ memset(p, 0, sizeof(long) * b->n_alleles);
+ for (j = 0; j < ma->n; ++j) {
+ const uint8_t *pi = ma->PL + j * ma->PL_len;
+ double *pdg = ma->pdg + j * 3;
+ pdg[0] = ma->q2p[pi[2]]; pdg[1] = ma->q2p[pi[1]]; pdg[2] = ma->q2p[pi[0]];
+ for (i = 0; i < b->n_alleles; ++i)
+ p[i] += (int)pi[(i+1)*(i+2)/2-1];
+ }
+ for (i = 0; i < b->n_alleles; ++i) p[i] = p[i]<<4 | i;
+ for (i = 1; i < b->n_alleles; ++i) // insertion sort
+ for (j = i; j > 0 && p[j] < p[j-1]; --j)
+ tmp = p[j], p[j] = p[j-1], p[j-1] = tmp;
+ for (i = b->n_alleles - 1; i >= 0; --i)
+ if ((p[i]&0xf) == 0) break;
+ return i;
}
+
int bcf_p1_call_gt(const bcf_p1aux_t *ma, double f0, int k)
{
double sum, g[3];
double max, f3[3], *pdg = ma->pdg + k * 3;
- int q, i, max_i;
- f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
+ int q, i, max_i, ploidy;
+ ploidy = ma->ploidy? ma->ploidy[k] : 2;
+ if (ploidy == 2) {
+ f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
+ } else {
+ f3[0] = 1. - f0; f3[1] = 0; f3[2] = f0;
+ }
for (i = 0, sum = 0.; i < 3; ++i)
sum += (g[i] = pdg[i] * f3[i]);
for (i = 0, max = -1., max_i = 0; i < 3; ++i) {
{
double *z[2], *tmp, *pdg;
int _j, last_min, last_max;
+ assert(beg == 0 || ma->M == ma->n*2);
z[0] = ma->z;
z[1] = ma->zswap;
pdg = ma->pdg;
z[0][0] = 1.;
last_min = last_max = 0;
ma->t = 0.;
- for (_j = beg; _j < ma->n; ++_j) {
- int k, j = _j - beg, _min = last_min, _max = last_max;
- double p[3], sum;
- pdg = ma->pdg + _j * 3;
- p[0] = pdg[0]; p[1] = 2. * pdg[1]; p[2] = pdg[2];
- for (; _min < _max && z[0][_min] < TINY; ++_min) z[0][_min] = z[1][_min] = 0.;
- for (; _max > _min && z[0][_max] < TINY; --_max) z[0][_max] = z[1][_max] = 0.;
- _max += 2;
- if (_min == 0)
- k = 0, z[1][k] = (2*j+2-k)*(2*j-k+1) * p[0] * z[0][k];
- if (_min <= 1)
- k = 1, z[1][k] = (2*j+2-k)*(2*j-k+1) * p[0] * z[0][k] + k*(2*j+2-k) * p[1] * z[0][k-1];
- for (k = _min < 2? 2 : _min; k <= _max; ++k)
- z[1][k] = (2*j+2-k)*(2*j-k+1) * p[0] * z[0][k]
- + k*(2*j+2-k) * p[1] * z[0][k-1]
- + k*(k-1)* p[2] * z[0][k-2];
- for (k = _min, sum = 0.; k <= _max; ++k) sum += z[1][k];
- ma->t += log(sum / ((2. * j + 2) * (2. * j + 1)));
- for (k = _min; k <= _max; ++k) z[1][k] /= sum;
- if (_min >= 1) z[1][_min-1] = 0.;
- if (_min >= 2) z[1][_min-2] = 0.;
- if (j < ma->n - 1) z[1][_max+1] = z[1][_max+2] = 0.;
- if (_j == ma->n1 - 1) { // set pop1
- ma->t1 = ma->t;
- memcpy(ma->z1, z[1], sizeof(double) * (ma->n1 * 2 + 1));
+ if (ma->M == ma->n * 2) {
+ int M = 0;
+ for (_j = beg; _j < ma->n; ++_j) {
+ int k, j = _j - beg, _min = last_min, _max = last_max, M0;
+ double p[3], sum;
+ M0 = M; M += 2;
+ pdg = ma->pdg + _j * 3;
+ p[0] = pdg[0]; p[1] = 2. * pdg[1]; p[2] = pdg[2];
+ for (; _min < _max && z[0][_min] < TINY; ++_min) z[0][_min] = z[1][_min] = 0.;
+ for (; _max > _min && z[0][_max] < TINY; --_max) z[0][_max] = z[1][_max] = 0.;
+ _max += 2;
+ if (_min == 0) k = 0, z[1][k] = (M0-k+1) * (M0-k+2) * p[0] * z[0][k];
+ if (_min <= 1) k = 1, z[1][k] = (M0-k+1) * (M0-k+2) * p[0] * z[0][k] + k*(M0-k+2) * p[1] * z[0][k-1];
+ for (k = _min < 2? 2 : _min; k <= _max; ++k)
+ z[1][k] = (M0-k+1)*(M0-k+2) * p[0] * z[0][k] + k*(M0-k+2) * p[1] * z[0][k-1] + k*(k-1)* p[2] * z[0][k-2];
+ for (k = _min, sum = 0.; k <= _max; ++k) sum += z[1][k];
+ ma->t += log(sum / (M * (M - 1.)));
+ for (k = _min; k <= _max; ++k) z[1][k] /= sum;
+ if (_min >= 1) z[1][_min-1] = 0.;
+ if (_min >= 2) z[1][_min-2] = 0.;
+ if (j < ma->n - 1) z[1][_max+1] = z[1][_max+2] = 0.;
+ if (_j == ma->n1 - 1) { // set pop1; ma->n1==-1 when unset
+ ma->t1 = ma->t;
+ memcpy(ma->z1, z[1], sizeof(double) * (ma->n1 * 2 + 1));
+ }
+ tmp = z[0]; z[0] = z[1]; z[1] = tmp;
+ last_min = _min; last_max = _max;
+ }
+ //for (_j = 0; _j < last_min; ++_j) z[0][_j] = 0.; // TODO: are these necessary?
+ //for (_j = last_max + 1; _j < ma->M; ++_j) z[0][_j] = 0.;
+ } else { // this block is very similar to the block above; these two might be merged in future
+ int j, M = 0;
+ for (j = 0; j < ma->n; ++j) {
+ int k, M0, _min = last_min, _max = last_max;
+ double p[3], sum;
+ pdg = ma->pdg + j * 3;
+ for (; _min < _max && z[0][_min] < TINY; ++_min) z[0][_min] = z[1][_min] = 0.;
+ for (; _max > _min && z[0][_max] < TINY; --_max) z[0][_max] = z[1][_max] = 0.;
+ M0 = M;
+ M += ma->ploidy[j];
+ if (ma->ploidy[j] == 1) {
+ p[0] = pdg[0]; p[1] = pdg[2];
+ _max++;
+ if (_min == 0) k = 0, z[1][k] = (M0+1-k) * p[0] * z[0][k];
+ for (k = _min < 1? 1 : _min; k <= _max; ++k)
+ z[1][k] = (M0+1-k) * p[0] * z[0][k] + k * p[1] * z[0][k-1];
+ for (k = _min, sum = 0.; k <= _max; ++k) sum += z[1][k];
+ ma->t += log(sum / M);
+ for (k = _min; k <= _max; ++k) z[1][k] /= sum;
+ if (_min >= 1) z[1][_min-1] = 0.;
+ if (j < ma->n - 1) z[1][_max+1] = 0.;
+ } else if (ma->ploidy[j] == 2) {
+ p[0] = pdg[0]; p[1] = 2 * pdg[1]; p[2] = pdg[2];
+ _max += 2;
+ if (_min == 0) k = 0, z[1][k] = (M0-k+1) * (M0-k+2) * p[0] * z[0][k];
+ if (_min <= 1) k = 1, z[1][k] = (M0-k+1) * (M0-k+2) * p[0] * z[0][k] + k*(M0-k+2) * p[1] * z[0][k-1];
+ for (k = _min < 2? 2 : _min; k <= _max; ++k)
+ z[1][k] = (M0-k+1)*(M0-k+2) * p[0] * z[0][k] + k*(M0-k+2) * p[1] * z[0][k-1] + k*(k-1)* p[2] * z[0][k-2];
+ for (k = _min, sum = 0.; k <= _max; ++k) sum += z[1][k];
+ ma->t += log(sum / (M * (M - 1.)));
+ for (k = _min; k <= _max; ++k) z[1][k] /= sum;
+ if (_min >= 1) z[1][_min-1] = 0.;
+ if (_min >= 2) z[1][_min-2] = 0.;
+ if (j < ma->n - 1) z[1][_max+1] = z[1][_max+2] = 0.;
+ }
+ tmp = z[0]; z[0] = z[1]; z[1] = tmp;
+ last_min = _min; last_max = _max;
}
- tmp = z[0]; z[0] = z[1]; z[1] = tmp;
- last_min = _min; last_max = _max;
}
if (z[0] != ma->z) memcpy(ma->z, z[0], sizeof(double) * (ma->M + 1));
}
static void mc_cal_y(bcf_p1aux_t *ma)
{
- if (ma->n1 > 0 && ma->n1 < ma->n) {
+ if (ma->n1 > 0 && ma->n1 < ma->n && ma->M == ma->n * 2) { // NB: ma->n1 is ineffective when there are haploid samples
int k;
long double x;
memset(ma->z1, 0, sizeof(double) * (2 * ma->n1 + 1));
} else mc_cal_y_core(ma, 0);
}
-static void contrast(bcf_p1aux_t *ma, double pc[4]) // mc_cal_y() must be called before hand
+#define CONTRAST_TINY 1e-30
+
+extern double kf_gammaq(double s, double z); // incomplete gamma function for chi^2 test
+
+static inline double chi2_test(int a, int b, int c, int d)
+{
+ double x, z;
+ x = (double)(a+b) * (c+d) * (b+d) * (a+c);
+ if (x == 0.) return 1;
+ z = a * d - b * c;
+ return kf_gammaq(.5, .5 * z * z * (a+b+c+d) / x);
+}
+
+// chi2=(a+b+c+d)(ad-bc)^2/[(a+b)(c+d)(a+c)(b+d)]
+static inline double contrast2_aux(const bcf_p1aux_t *p1, double sum, int k1, int k2, double x[3])
{
- int k, n1 = ma->n1, n2 = ma->n - ma->n1;
- long double sum1, sum2;
- pc[0] = pc[1] = pc[2] = pc[3] = 0.;
- if (n1 <= 0 || n2 <= 0) return;
- for (k = 0, sum1 = 0.; k <= 2*n1; ++k) sum1 += ma->phi1[k] * ma->z1[k];
- for (k = 0, sum2 = 0.; k <= 2*n2; ++k) sum2 += ma->phi2[k] * ma->z2[k];
- pc[2] = ma->phi1[2*n1] * ma->z1[2*n1] / sum1;
- pc[3] = ma->phi2[2*n2] * ma->z2[2*n2] / sum2;
- for (k = 2; k < 4; ++k) {
- pc[k] = pc[k] > .5? -(-4.343 * log(1. - pc[k] + TINY) + .499) : -4.343 * log(pc[k] + TINY) + .499;
- pc[k] = (int)pc[k];
- if (pc[k] > 99) pc[k] = 99;
- if (pc[k] < -99) pc[k] = -99;
+ double p = p1->phi[k1+k2] * p1->z1[k1] * p1->z2[k2] / sum * p1->hg[k1][k2];
+ int n1 = p1->n1, n2 = p1->n - p1->n1;
+ if (p < CONTRAST_TINY) return -1;
+ if (.5*k1/n1 < .5*k2/n2) x[1] += p;
+ else if (.5*k1/n1 > .5*k2/n2) x[2] += p;
+ else x[0] += p;
+ return p * chi2_test(k1, k2, (n1<<1) - k1, (n2<<1) - k2);
+}
+
+static double contrast2(bcf_p1aux_t *p1, double ret[3])
+{
+ int k, k1, k2, k10, k20, n1, n2;
+ double sum;
+ // get n1 and n2
+ n1 = p1->n1; n2 = p1->n - p1->n1;
+ if (n1 <= 0 || n2 <= 0) return 0.;
+ if (p1->hg == 0) { // initialize the hypergeometric distribution
+ /* NB: the hg matrix may take a lot of memory when there are many samples. There is a way
+ to avoid precomputing this matrix, but it is slower and quite intricate. The following
+ computation in this block can be accelerated with a similar strategy, but perhaps this
+ is not a serious concern for now. */
+ double tmp = lgamma(2*(n1+n2)+1) - (lgamma(2*n1+1) + lgamma(2*n2+1));
+ p1->hg = calloc(2*n1+1, sizeof(void*));
+ for (k1 = 0; k1 <= 2*n1; ++k1) {
+ p1->hg[k1] = calloc(2*n2+1, sizeof(double));
+ for (k2 = 0; k2 <= 2*n2; ++k2)
+ p1->hg[k1][k2] = exp(lgamma(k1+k2+1) + lgamma(p1->M-k1-k2+1) - (lgamma(k1+1) + lgamma(k2+1) + lgamma(2*n1-k1+1) + lgamma(2*n2-k2+1) + tmp));
+ }
+ }
+ { // compute
+ long double suml = 0;
+ for (k = 0; k <= p1->M; ++k) suml += p1->phi[k] * p1->z[k];
+ sum = suml;
+ }
+ { // get the max k1 and k2
+ double max;
+ int max_k;
+ for (k = 0, max = 0, max_k = -1; k <= 2*n1; ++k) {
+ double x = p1->phi1[k] * p1->z1[k];
+ if (x > max) max = x, max_k = k;
+ }
+ k10 = max_k;
+ for (k = 0, max = 0, max_k = -1; k <= 2*n2; ++k) {
+ double x = p1->phi2[k] * p1->z2[k];
+ if (x > max) max = x, max_k = k;
+ }
+ k20 = max_k;
+ }
+ { // We can do the following with one nested loop, but that is an O(N^2) thing. The following code block is much faster for large N.
+ double x[3], y;
+ long double z = 0., L[2];
+ x[0] = x[1] = x[2] = 0; L[0] = L[1] = 0;
+ for (k1 = k10; k1 >= 0; --k1) {
+ for (k2 = k20; k2 >= 0; --k2) {
+ if ((y = contrast2_aux(p1, sum, k1, k2, x)) < 0) break;
+ else z += y;
+ }
+ for (k2 = k20 + 1; k2 <= 2*n2; ++k2) {
+ if ((y = contrast2_aux(p1, sum, k1, k2, x)) < 0) break;
+ else z += y;
+ }
+ }
+ ret[0] = x[0]; ret[1] = x[1]; ret[2] = x[2];
+ x[0] = x[1] = x[2] = 0;
+ for (k1 = k10 + 1; k1 <= 2*n1; ++k1) {
+ for (k2 = k20; k2 >= 0; --k2) {
+ if ((y = contrast2_aux(p1, sum, k1, k2, x)) < 0) break;
+ else z += y;
+ }
+ for (k2 = k20 + 1; k2 <= 2*n2; ++k2) {
+ if ((y = contrast2_aux(p1, sum, k1, k2, x)) < 0) break;
+ else z += y;
+ }
+ }
+ ret[0] += x[0]; ret[1] += x[1]; ret[2] += x[2];
+ if (ret[0] + ret[1] + ret[2] < 0.95) { // in case of bad things happened
+ ret[0] = ret[1] = ret[2] = 0; L[0] = L[1] = 0;
+ for (k1 = 0, z = 0.; k1 <= 2*n1; ++k1)
+ for (k2 = 0; k2 <= 2*n2; ++k2)
+ if ((y = contrast2_aux(p1, sum, k1, k2, ret)) >= 0) z += y;
+ if (ret[0] + ret[1] + ret[2] < 0.95) // It seems that this may be caused by floating point errors. I do not really understand why...
+ z = 1.0, ret[0] = ret[1] = ret[2] = 1./3;
+ }
+ return (double)z;
}
- pc[0] = ma->phi2[2*n2] * ma->z2[2*n2] / sum2 * (1. - ma->phi1[2*n1] * ma->z1[2*n1] / sum1);
- pc[1] = ma->phi1[2*n1] * ma->z1[2*n1] / sum1 * (1. - ma->phi2[2*n2] * ma->z2[2*n2] / sum2);
- pc[0] = pc[0] == 1.? 99 : (int)(-4.343 * log(1. - pc[0]) + .499);
- pc[1] = pc[1] == 1.? 99 : (int)(-4.343 * log(1. - pc[1]) + .499);
}
-static double mc_cal_afs(bcf_p1aux_t *ma)
+static double mc_cal_afs(bcf_p1aux_t *ma, double *p_ref_folded, double *p_var_folded)
{
int k;
- long double sum = 0.;
+ long double sum = 0., sum2;
+ double *phi = ma->is_indel? ma->phi_indel : ma->phi;
memset(ma->afs1, 0, sizeof(double) * (ma->M + 1));
mc_cal_y(ma);
+ // compute AFS
for (k = 0, sum = 0.; k <= ma->M; ++k)
- sum += (long double)ma->phi[k] * ma->z[k];
+ sum += (long double)phi[k] * ma->z[k];
for (k = 0; k <= ma->M; ++k) {
- ma->afs1[k] = ma->phi[k] * ma->z[k] / sum;
+ ma->afs1[k] = phi[k] * ma->z[k] / sum;
if (isnan(ma->afs1[k]) || isinf(ma->afs1[k])) return -1.;
}
+ // compute folded variant probability
+ for (k = 0, sum = 0.; k <= ma->M; ++k)
+ sum += (long double)(phi[k] + phi[ma->M - k]) / 2. * ma->z[k];
+ for (k = 1, sum2 = 0.; k < ma->M; ++k)
+ sum2 += (long double)(phi[k] + phi[ma->M - k]) / 2. * ma->z[k];
+ *p_var_folded = sum2 / sum;
+ *p_ref_folded = (phi[k] + phi[ma->M - k]) / 2. * (ma->z[ma->M] + ma->z[0]) / sum;
+ // the expected frequency
for (k = 0, sum = 0.; k <= ma->M; ++k) {
ma->afs[k] += ma->afs1[k];
sum += k * ma->afs1[k];
return sum / ma->M;
}
-long double bcf_p1_cal_g3(bcf_p1aux_t *p1a, double g[3])
-{
- long double pd = 0., g2[3];
- int i, k;
- memset(g2, 0, sizeof(long double) * 3);
- for (k = 0; k < p1a->M; ++k) {
- double f = (double)k / p1a->M, f3[3], g1[3];
- long double z = 1.;
- g1[0] = g1[1] = g1[2] = 0.;
- f3[0] = (1. - f) * (1. - f); f3[1] = 2. * f * (1. - f); f3[2] = f * f;
- for (i = 0; i < p1a->n; ++i) {
- double *pdg = p1a->pdg + i * 3;
- double x = pdg[0] * f3[0] + pdg[1] * f3[1] + pdg[2] * f3[2];
- z *= x;
- g1[0] += pdg[0] * f3[0] / x;
- g1[1] += pdg[1] * f3[1] / x;
- g1[2] += pdg[2] * f3[2] / x;
- }
- pd += p1a->phi[k] * z;
- for (i = 0; i < 3; ++i)
- g2[i] += p1a->phi[k] * z * g1[i];
- }
- for (i = 0; i < 3; ++i) g[i] = g2[i] / pd;
- return pd;
-}
-
-int bcf_p1_cal(bcf1_t *b, bcf_p1aux_t *ma, bcf_p1rst_t *rst)
+int bcf_p1_cal(const bcf1_t *b, int do_contrast, bcf_p1aux_t *ma, bcf_p1rst_t *rst)
{
int i, k;
long double sum = 0.;
+ ma->is_indel = bcf_is_indel(b);
+ rst->perm_rank = -1;
// set PL and PL_len
for (i = 0; i < b->n_gi; ++i) {
- if (b->gi[i].fmt == char2int("PL")) {
+ if (b->gi[i].fmt == bcf_str2int("PL", 2)) {
ma->PL = (uint8_t*)b->gi[i].data;
ma->PL_len = b->gi[i].len;
break;
}
}
+ if (i == b->n_gi) return -1; // no PL
if (b->n_alleles < 2) return -1; // FIXME: find a better solution
//
rst->rank0 = cal_pdg(b, ma);
- rst->f_exp = mc_cal_afs(ma);
+ rst->f_exp = mc_cal_afs(ma, &rst->p_ref_folded, &rst->p_var_folded);
rst->p_ref = ma->afs1[ma->M];
+ for (k = 0, sum = 0.; k < ma->M; ++k)
+ sum += ma->afs1[k];
+ rst->p_var = (double)sum;
+ { // compute the allele count
+ double max = -1;
+ rst->ac = -1;
+ for (k = 0; k <= ma->M; ++k)
+ if (max < ma->z[k]) max = ma->z[k], rst->ac = k;
+ rst->ac = ma->M - rst->ac;
+ }
// calculate f_flat and f_em
for (k = 0, sum = 0.; k <= ma->M; ++k)
sum += (long double)ma->z[k];
rst->f_flat += k * p;
}
rst->f_flat /= ma->M;
- { // calculate f_em
- double flast = rst->f_flat;
- for (i = 0; i < MC_MAX_EM_ITER; ++i) {
- rst->f_em = mc_freq_iter(flast, ma);
- if (fabs(rst->f_em - flast) < MC_EM_EPS) break;
- flast = rst->f_em;
- }
+ { // estimate equal-tail credible interval (95% level)
+ int l, h;
+ double p;
+ for (i = 0, p = 0.; i <= ma->M; ++i)
+ if (p + ma->afs1[i] > 0.025) break;
+ else p += ma->afs1[i];
+ l = i;
+ for (i = ma->M, p = 0.; i >= 0; --i)
+ if (p + ma->afs1[i] > 0.025) break;
+ else p += ma->afs1[i];
+ h = i;
+ rst->cil = (double)(ma->M - h) / ma->M; rst->cih = (double)(ma->M - l) / ma->M;
}
- rst->g[0] = rst->g[1] = rst->g[2] = -1.;
- contrast(ma, rst->pc);
+ if (ma->n1 > 0) { // compute LRT
+ double max0, max1, max2;
+ for (k = 0, max0 = -1; k <= ma->M; ++k)
+ if (max0 < ma->z[k]) max0 = ma->z[k];
+ for (k = 0, max1 = -1; k <= ma->n1 * 2; ++k)
+ if (max1 < ma->z1[k]) max1 = ma->z1[k];
+ for (k = 0, max2 = -1; k <= ma->M - ma->n1 * 2; ++k)
+ if (max2 < ma->z2[k]) max2 = ma->z2[k];
+ rst->lrt = log(max1 * max2 / max0);
+ rst->lrt = rst->lrt < 0? 1 : kf_gammaq(.5, rst->lrt);
+ } else rst->lrt = -1.0;
+ rst->cmp[0] = rst->cmp[1] = rst->cmp[2] = rst->p_chi2 = -1.0;
+ if (do_contrast && rst->p_var > 0.5) // skip contrast2() if the locus is a strong non-variant
+ rst->p_chi2 = contrast2(ma, rst->cmp);
return 0;
}
projects / samtools.git / blobdiff