X-Git-Url: http://woldlab.caltech.edu/gitweb/?p=pysam.git;a=blobdiff_plain;f=samtools%2Fbcftools%2Fprob1.c.pysam.c;fp=samtools%2Fbcftools%2Fprob1.c.pysam.c;h=ac331848f624e466091552f6291ea46e0d239062;hp=0000000000000000000000000000000000000000;hb=bd0c3067c187d1f718004fb38acc093af8810a02;hpb=1b740fc70684c92a5e2293013217d5a2fd661d8a

diff --git a/samtools/bcftools/prob1.c.pysam.c b/samtools/bcftools/prob1.c.pysam.c
new file mode 100644
index 0000000..ac33184
--- /dev/null
+++ b/samtools/bcftools/prob1.c.pysam.c
@@ -0,0 +1,538 @@
+#include "pysam.h"
+
+#include <math.h>
+#include <stdlib.h>
+#include <string.h>
+#include <stdio.h>
+#include <errno.h>
+#include <assert.h>
+#include "prob1.h"
+
+#include "kseq.h"
+KSTREAM_INIT(gzFile, gzread, 16384)
+
+#define MC_MAX_EM_ITER 16
+#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, 
+	4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4, 
+	4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4,  4, 4 /*'-'*/, 4, 4,
+	4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4, 
+	4, 0, 4, 1,  4, 4, 4, 2,  4, 4, 4, 4,  4, 4, 4, 4, 
+	4, 4, 4, 4,  3, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4, 
+	4, 0, 4, 1,  4, 4, 4, 2,  4, 4, 4, 4,  4, 4, 4, 4, 
+	4, 4, 4, 4,  3, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4, 
+	4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4, 
+	4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4, 
+	4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4, 
+	4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4, 
+	4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4, 
+	4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4, 
+	4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4, 
+	4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4,  4, 4, 4, 4
+};
+
+struct __bcf_p1aux_t {
+	int n, M, n1, is_indel;
+	uint8_t *ploidy; // haploid or diploid ONLY
+	double *q2p, *pdg; // pdg -> P(D|g)
+	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;
+	if (type == MC_PTYPE_COND2) {
+		for (i = 0; i <= M; ++i)
+			phi[i] = 2. * (i + 1) / (M + 1) / (M + 2);
+	} else if (type == MC_PTYPE_FLAT) {
+		for (i = 0; i <= M; ++i)
+			phi[i] = 1. / (M + 1);
+	} else {
+		double sum;
+		for (i = 0, sum = 0.; i < M; ++i)
+			sum += (phi[i] = theta / (M - i));
+		phi[M] = 1. - sum;
+	}
+}
+
+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)
+{
+	if (ma->n1 <= 0 || ma->n1 >= ma->M) return;
+	init_prior(type, theta, 2*ma->n1, ma->phi1);
+	init_prior(type, theta, 2*(ma->n - ma->n1), ma->phi2);
+}
+
+int bcf_p1_read_prior(bcf_p1aux_t *ma, const char *fn)
+{
+	gzFile fp;
+	kstring_t s;
+	kstream_t *ks;
+	long double sum;
+	int dret, k;
+	memset(&s, 0, sizeof(kstring_t));
+	fp = strcmp(fn, "-")? gzopen(fn, "r") : gzdopen(fileno(stdin), "r");
+	ks = ks_init(fp);
+	memset(ma->phi, 0, sizeof(double) * (ma->M + 1));
+	while (ks_getuntil(ks, '\n', &s, &dret) >= 0) {
+		if (strstr(s.s, "[afs] ") == s.s) {
+			char *p = s.s + 6;
+			for (k = 0; k <= ma->M; ++k) {
+				int x;
+				double y;
+				x = strtol(p, &p, 10);
+				if (x != k && (errno == EINVAL || errno == ERANGE)) return -1;
+				++p;
+				y = strtod(p, &p);
+				if (y == 0. && (errno == EINVAL || errno == ERANGE)) return -1;
+				ma->phi[ma->M - k] += y;
+			}
+		}
+	}
+	ks_destroy(ks);
+	gzclose(fp);
+	free(s.s);
+	for (sum = 0., k = 0; k <= ma->M; ++k) sum += ma->phi[k];
+	fprintf(pysamerr, "[prior]");
+	for (k = 0; k <= ma->M; ++k) ma->phi[k] /= sum;
+	for (k = 0; k <= ma->M; ++k) fprintf(pysamerr, " %d:%.3lg", k, ma->phi[ma->M - k]);
+	fputc('\n', pysamerr);
+	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(pysamerr, "[%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(pysamerr, "theta=%lf\n", (double)sum);
+	bcf_p1_indel_prior(ma, MC_DEF_INDEL);
+	return 0;
+}
+
+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(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(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(pysamerr, "[%s] unable to set `n1' when there are haploid samples.\n", __func__);
+		return -1;
+	}
+	b->n1 = n1;
+	return 0;
+}
+
+void bcf_p1_destroy(bcf_p1aux_t *ma)
+{
+	if (ma) {
+		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);
+	}
+}
+
+static int cal_pdg(const bcf1_t *b, bcf_p1aux_t *ma)
+{
+	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, 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) {
+		g[i] /= sum;
+		if (g[i] > max) max = g[i], max_i = i;
+	}
+	max = 1. - max;
+	if (max < 1e-308) max = 1e-308;
+	q = (int)(-4.343 * log(max) + .499);
+	if (q > 99) q = 99;
+	return q<<2|max_i;
+}
+
+#define TINY 1e-20
+
+static void mc_cal_y_core(bcf_p1aux_t *ma, int beg)
+{
+	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;
+	memset(z[0], 0, sizeof(double) * (ma->M + 1));
+	memset(z[1], 0, sizeof(double) * (ma->M + 1));
+	z[0][0] = 1.;
+	last_min = last_max = 0;
+	ma->t = 0.;
+	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;
+		}
+	}
+	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 && 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));
+		memset(ma->z2, 0, sizeof(double) * (2 * (ma->n - ma->n1) + 1));
+		ma->t1 = ma->t2 = 0.;
+		mc_cal_y_core(ma, ma->n1);
+		ma->t2 = ma->t;
+		memcpy(ma->z2, ma->z, sizeof(double) * (2 * (ma->n - ma->n1) + 1));
+		mc_cal_y_core(ma, 0);
+		// rescale z
+		x = expl(ma->t - (ma->t1 + ma->t2));
+		for (k = 0; k <= ma->M; ++k) ma->z[k] *= x;
+	} else mc_cal_y_core(ma, 0);
+}
+
+#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])
+{
+	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;
+	}
+}
+
+static double mc_cal_afs(bcf_p1aux_t *ma, double *p_ref_folded, double *p_var_folded)
+{
+	int k;
+	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)phi[k] * ma->z[k];
+	for (k = 0; k <= ma->M; ++k) {
+		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;
+}
+
+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 == 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->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;
+	// calculate f_flat and f_em
+	for (k = 0, sum = 0.; k <= ma->M; ++k)
+		sum += (long double)ma->z[k];
+	rst->f_flat = 0.;
+	for (k = 0; k <= ma->M; ++k) {
+		double p = ma->z[k] / sum;
+		rst->f_flat += k * p;
+	}
+	rst->f_flat /= ma->M;
+	{ // 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-1, 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->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;
+}
+
+void bcf_p1_dump_afs(bcf_p1aux_t *ma)
+{
+	int k;
+	fprintf(pysamerr, "[afs]");
+	for (k = 0; k <= ma->M; ++k)
+		fprintf(pysamerr, " %d:%.3lf", k, ma->afs[ma->M - k]);
+	fprintf(pysamerr, "\n");
+	memset(ma->afs, 0, sizeof(double) * (ma->M + 1));
+}