9 KSTREAM_INIT(gzFile, gzread, 16384)
11 #define MC_MAX_EM_ITER 16
12 #define MC_EM_EPS 1e-4
13 #define MC_DEF_INDEL 0.15
15 unsigned char seq_nt4_table[256] = {
16 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
17 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
18 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 /*'-'*/, 4, 4,
19 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
20 4, 0, 4, 1, 4, 4, 4, 2, 4, 4, 4, 4, 4, 4, 4, 4,
21 4, 4, 4, 4, 3, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
22 4, 0, 4, 1, 4, 4, 4, 2, 4, 4, 4, 4, 4, 4, 4, 4,
23 4, 4, 4, 4, 3, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
24 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
25 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
26 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
27 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
28 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
29 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
30 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
31 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4
34 struct __bcf_p1aux_t {
35 int n, M, n1, is_indel, is_folded;
36 double *q2p, *pdg; // pdg -> P(D|g)
37 double *phi, *phi_indel;
38 double *z, *zswap; // aux for afs
39 double *z1, *z2, *phi1, *phi2; // only calculated when n1 is set
41 double *afs, *afs1; // afs: accumulative AFS; afs1: site posterior distribution
42 const uint8_t *PL; // point to PL
46 static void fold_array(int M, double *x)
49 for (k = 0; k < M/2; ++k)
50 x[k] = x[M-k] = (x[k] + x[M-k]) / 2.;
53 void bcf_p1_indel_prior(bcf_p1aux_t *ma, double x)
56 for (i = 0; i < ma->M; ++i)
57 ma->phi_indel[i] = ma->phi[i] * x;
58 ma->phi_indel[ma->M] = 1. - ma->phi[ma->M] * x;
61 static void init_prior(int type, double theta, int M, double *phi)
64 if (type == MC_PTYPE_COND2) {
65 for (i = 0; i <= M; ++i)
66 phi[i] = 2. * (i + 1) / (M + 1) / (M + 2);
67 } else if (type == MC_PTYPE_FLAT) {
68 for (i = 0; i <= M; ++i)
69 phi[i] = 1. / (M + 1);
72 for (i = 0, sum = 0.; i < M; ++i)
73 sum += (phi[i] = theta / (M - i));
78 void bcf_p1_init_prior(bcf_p1aux_t *ma, int type, double theta)
80 init_prior(type, theta, ma->M, ma->phi);
81 bcf_p1_indel_prior(ma, MC_DEF_INDEL);
84 void bcf_p1_init_subprior(bcf_p1aux_t *ma, int type, double theta)
86 if (ma->n1 <= 0 || ma->n1 >= ma->M) return;
87 init_prior(type, theta, 2*ma->n1, ma->phi1);
88 init_prior(type, theta, 2*(ma->n - ma->n1), ma->phi2);
91 int bcf_p1_read_prior(bcf_p1aux_t *ma, const char *fn)
98 memset(&s, 0, sizeof(kstring_t));
99 fp = strcmp(fn, "-")? gzopen(fn, "r") : gzdopen(fileno(stdin), "r");
101 memset(ma->phi, 0, sizeof(double) * (ma->M + 1));
102 while (ks_getuntil(ks, '\n', &s, &dret) >= 0) {
103 if (strstr(s.s, "[afs] ") == s.s) {
105 for (k = 0; k <= ma->M; ++k) {
108 x = strtol(p, &p, 10);
109 if (x != k && (errno == EINVAL || errno == ERANGE)) return -1;
112 if (y == 0. && (errno == EINVAL || errno == ERANGE)) return -1;
113 ma->phi[ma->M - k] += y;
120 for (sum = 0., k = 0; k <= ma->M; ++k) sum += ma->phi[k];
121 fprintf(stderr, "[prior]");
122 for (k = 0; k <= ma->M; ++k) ma->phi[k] /= sum;
123 for (k = 0; k <= ma->M; ++k) fprintf(stderr, " %d:%.3lg", k, ma->phi[ma->M - k]);
125 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));
126 fprintf(stderr, "[%s] heterozygosity=%lf, ", __func__, (double)sum);
127 for (sum = 0., k = 1; k <= ma->M; ++k) sum += k * ma->phi[ma->M - k] / ma->M;
128 fprintf(stderr, "theta=%lf\n", (double)sum);
129 bcf_p1_indel_prior(ma, MC_DEF_INDEL);
133 bcf_p1aux_t *bcf_p1_init(int n)
137 ma = calloc(1, sizeof(bcf_p1aux_t));
139 ma->n = n; ma->M = 2 * n;
140 ma->q2p = calloc(256, sizeof(double));
141 ma->pdg = calloc(3 * ma->n, sizeof(double));
142 ma->phi = calloc(ma->M + 1, sizeof(double));
143 ma->phi_indel = calloc(ma->M + 1, sizeof(double));
144 ma->phi1 = calloc(ma->M + 1, sizeof(double));
145 ma->phi2 = calloc(ma->M + 1, sizeof(double));
146 ma->z = calloc(2 * ma->n + 1, sizeof(double));
147 ma->zswap = calloc(2 * ma->n + 1, sizeof(double));
148 ma->z1 = calloc(ma->M + 1, sizeof(double)); // actually we do not need this large
149 ma->z2 = calloc(ma->M + 1, sizeof(double));
150 ma->afs = calloc(2 * ma->n + 1, sizeof(double));
151 ma->afs1 = calloc(2 * ma->n + 1, sizeof(double));
152 for (i = 0; i < 256; ++i)
153 ma->q2p[i] = pow(10., -i / 10.);
154 bcf_p1_init_prior(ma, MC_PTYPE_FULL, 1e-3); // the simplest prior
158 int bcf_p1_set_n1(bcf_p1aux_t *b, int n1)
160 if (n1 == 0 || n1 >= b->n) return -1;
165 void bcf_p1_set_folded(bcf_p1aux_t *p1a)
169 fold_array(p1a->M, p1a->phi);
170 fold_array(p1a->M, p1a->phi_indel);
174 void bcf_p1_destroy(bcf_p1aux_t *ma)
177 free(ma->q2p); free(ma->pdg);
178 free(ma->phi); free(ma->phi_indel); free(ma->phi1); free(ma->phi2);
179 free(ma->z); free(ma->zswap); free(ma->z1); free(ma->z2);
180 free(ma->afs); free(ma->afs1);
185 static int cal_pdg(const bcf1_t *b, bcf_p1aux_t *ma)
189 p = alloca(b->n_alleles * sizeof(long));
190 memset(p, 0, sizeof(long) * b->n_alleles);
191 for (j = 0; j < ma->n; ++j) {
192 const uint8_t *pi = ma->PL + j * ma->PL_len;
193 double *pdg = ma->pdg + j * 3;
194 pdg[0] = ma->q2p[pi[b->n_alleles]]; pdg[1] = ma->q2p[pi[1]]; pdg[2] = ma->q2p[pi[0]];
195 for (i = k = 0; i < b->n_alleles; ++i) {
197 k += b->n_alleles - i;
200 for (i = 0; i < b->n_alleles; ++i) p[i] = p[i]<<4 | i;
201 for (i = 1; i < b->n_alleles; ++i) // insertion sort
202 for (j = i; j > 0 && p[j] < p[j-1]; --j)
203 tmp = p[j], p[j] = p[j-1], p[j-1] = tmp;
204 for (i = b->n_alleles - 1; i >= 0; --i)
205 if ((p[i]&0xf) == 0) break;
208 // f0 is the reference allele frequency
209 static double mc_freq_iter(double f0, const bcf_p1aux_t *ma)
213 f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
214 for (i = 0, f = 0.; i < ma->n; ++i) {
216 pdg = ma->pdg + i * 3;
217 f += (pdg[1] * f3[1] + 2. * pdg[2] * f3[2])
218 / (pdg[0] * f3[0] + pdg[1] * f3[1] + pdg[2] * f3[2]);
224 int bcf_p1_call_gt(const bcf_p1aux_t *ma, double f0, int k)
227 double max, f3[3], *pdg = ma->pdg + k * 3;
229 f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
230 for (i = 0, sum = 0.; i < 3; ++i)
231 sum += (g[i] = pdg[i] * f3[i]);
232 for (i = 0, max = -1., max_i = 0; i < 3; ++i) {
234 if (g[i] > max) max = g[i], max_i = i;
237 if (max < 1e-308) max = 1e-308;
238 q = (int)(-4.343 * log(max) + .499);
245 static void mc_cal_y_core(bcf_p1aux_t *ma, int beg)
247 double *z[2], *tmp, *pdg;
248 int _j, last_min, last_max;
252 memset(z[0], 0, sizeof(double) * (ma->M + 1));
253 memset(z[1], 0, sizeof(double) * (ma->M + 1));
255 last_min = last_max = 0;
257 for (_j = beg; _j < ma->n; ++_j) {
258 int k, j = _j - beg, _min = last_min, _max = last_max;
260 pdg = ma->pdg + _j * 3;
261 p[0] = pdg[0]; p[1] = 2. * pdg[1]; p[2] = pdg[2];
262 for (; _min < _max && z[0][_min] < TINY; ++_min) z[0][_min] = z[1][_min] = 0.;
263 for (; _max > _min && z[0][_max] < TINY; --_max) z[0][_max] = z[1][_max] = 0.;
266 k = 0, z[1][k] = (2*j+2-k)*(2*j-k+1) * p[0] * z[0][k];
268 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];
269 for (k = _min < 2? 2 : _min; k <= _max; ++k)
270 z[1][k] = (2*j+2-k)*(2*j-k+1) * p[0] * z[0][k]
271 + k*(2*j+2-k) * p[1] * z[0][k-1]
272 + k*(k-1)* p[2] * z[0][k-2];
273 for (k = _min, sum = 0.; k <= _max; ++k) sum += z[1][k];
274 ma->t += log(sum / ((2. * j + 2) * (2. * j + 1)));
275 for (k = _min; k <= _max; ++k) z[1][k] /= sum;
276 if (_min >= 1) z[1][_min-1] = 0.;
277 if (_min >= 2) z[1][_min-2] = 0.;
278 if (j < ma->n - 1) z[1][_max+1] = z[1][_max+2] = 0.;
279 if (_j == ma->n1 - 1) { // set pop1
281 memcpy(ma->z1, z[1], sizeof(double) * (ma->n1 * 2 + 1));
283 tmp = z[0]; z[0] = z[1]; z[1] = tmp;
284 last_min = _min; last_max = _max;
286 if (z[0] != ma->z) memcpy(ma->z, z[0], sizeof(double) * (ma->M + 1));
289 static void mc_cal_y(bcf_p1aux_t *ma)
291 if (ma->n1 > 0 && ma->n1 < ma->n) {
294 memset(ma->z1, 0, sizeof(double) * (2 * ma->n1 + 1));
295 memset(ma->z2, 0, sizeof(double) * (2 * (ma->n - ma->n1) + 1));
296 ma->t1 = ma->t2 = 0.;
297 mc_cal_y_core(ma, ma->n1);
299 memcpy(ma->z2, ma->z, sizeof(double) * (2 * (ma->n - ma->n1) + 1));
300 mc_cal_y_core(ma, 0);
302 x = expl(ma->t - (ma->t1 + ma->t2));
303 for (k = 0; k <= ma->M; ++k) ma->z[k] *= x;
304 } else mc_cal_y_core(ma, 0);
307 static void contrast(bcf_p1aux_t *ma, double pc[4]) // mc_cal_y() must be called before hand
309 int k, n1 = ma->n1, n2 = ma->n - ma->n1;
310 long double sum1, sum2;
311 pc[0] = pc[1] = pc[2] = pc[3] = -1.;
312 if (n1 <= 0 || n2 <= 0) return;
313 for (k = 0, sum1 = 0.; k <= 2*n1; ++k) sum1 += ma->phi1[k] * ma->z1[k];
314 for (k = 0, sum2 = 0.; k <= 2*n2; ++k) sum2 += ma->phi2[k] * ma->z2[k];
315 pc[2] = ma->phi1[2*n1] * ma->z1[2*n1] / sum1;
316 pc[3] = ma->phi2[2*n2] * ma->z2[2*n2] / sum2;
317 for (k = 2; k < 4; ++k) {
318 pc[k] = pc[k] > .5? -(-4.343 * log(1. - pc[k] + TINY) + .499) : -4.343 * log(pc[k] + TINY) + .499;
320 if (pc[k] > 99) pc[k] = 99;
321 if (pc[k] < -99) pc[k] = -99;
323 pc[0] = ma->phi2[2*n2] * ma->z2[2*n2] / sum2 * (1. - ma->phi1[2*n1] * ma->z1[2*n1] / sum1);
324 pc[1] = ma->phi1[2*n1] * ma->z1[2*n1] / sum1 * (1. - ma->phi2[2*n2] * ma->z2[2*n2] / sum2);
325 pc[0] = pc[0] == 1.? 99 : (int)(-4.343 * log(1. - pc[0]) + .499);
326 pc[1] = pc[1] == 1.? 99 : (int)(-4.343 * log(1. - pc[1]) + .499);
329 static double mc_cal_afs(bcf_p1aux_t *ma)
332 long double sum = 0.;
333 double *phi = ma->is_indel? ma->phi_indel : ma->phi;
334 memset(ma->afs1, 0, sizeof(double) * (ma->M + 1));
336 for (k = 0, sum = 0.; k <= ma->M; ++k)
337 sum += (long double)phi[k] * ma->z[k];
338 for (k = 0; k <= ma->M; ++k) {
339 ma->afs1[k] = phi[k] * ma->z[k] / sum;
340 if (isnan(ma->afs1[k]) || isinf(ma->afs1[k])) return -1.;
342 for (k = 0, sum = 0.; k <= ma->M; ++k) {
343 ma->afs[k] += ma->afs1[k];
344 sum += k * ma->afs1[k];
349 long double bcf_p1_cal_g3(bcf_p1aux_t *p1a, double g[3])
351 long double pd = 0., g2[3];
353 memset(g2, 0, sizeof(long double) * 3);
354 for (k = 0; k < p1a->M; ++k) {
355 double f = (double)k / p1a->M, f3[3], g1[3];
357 g1[0] = g1[1] = g1[2] = 0.;
358 f3[0] = (1. - f) * (1. - f); f3[1] = 2. * f * (1. - f); f3[2] = f * f;
359 for (i = 0; i < p1a->n; ++i) {
360 double *pdg = p1a->pdg + i * 3;
361 double x = pdg[0] * f3[0] + pdg[1] * f3[1] + pdg[2] * f3[2];
363 g1[0] += pdg[0] * f3[0] / x;
364 g1[1] += pdg[1] * f3[1] / x;
365 g1[2] += pdg[2] * f3[2] / x;
367 pd += p1a->phi[k] * z;
368 for (i = 0; i < 3; ++i)
369 g2[i] += p1a->phi[k] * z * g1[i];
371 for (i = 0; i < 3; ++i) g[i] = g2[i] / pd;
375 int bcf_p1_cal(bcf1_t *b, bcf_p1aux_t *ma, bcf_p1rst_t *rst)
378 long double sum = 0.;
379 ma->is_indel = bcf_is_indel(b);
381 for (i = 0; i < b->n_gi; ++i) {
382 if (b->gi[i].fmt == bcf_str2int("PL", 2)) {
383 ma->PL = (uint8_t*)b->gi[i].data;
384 ma->PL_len = b->gi[i].len;
388 if (b->n_alleles < 2) return -1; // FIXME: find a better solution
390 rst->rank0 = cal_pdg(b, ma);
391 rst->f_exp = mc_cal_afs(ma);
392 rst->p_ref = ma->is_folded? ma->afs1[ma->M] + ma->afs1[0] : ma->afs1[ma->M];
393 // calculate f_flat and f_em
394 for (k = 0, sum = 0.; k <= ma->M; ++k)
395 sum += (long double)ma->z[k];
397 for (k = 0; k <= ma->M; ++k) {
398 double p = ma->z[k] / sum;
399 rst->f_flat += k * p;
401 rst->f_flat /= ma->M;
403 double flast = rst->f_flat;
404 for (i = 0; i < MC_MAX_EM_ITER; ++i) {
405 rst->f_em = mc_freq_iter(flast, ma);
406 if (fabs(rst->f_em - flast) < MC_EM_EPS) break;
410 { // estimate equal-tail credible interval (95% level)
413 for (i = 0, p = 0.; i < ma->M; ++i)
414 if (p + ma->afs1[i] > 0.025) break;
415 else p += ma->afs1[i];
417 for (i = ma->M-1, p = 0.; i >= 0; --i)
418 if (p + ma->afs1[i] > 0.025) break;
419 else p += ma->afs1[i];
421 rst->cil = (double)(ma->M - h) / ma->M; rst->cih = (double)(ma->M - l) / ma->M;
423 rst->g[0] = rst->g[1] = rst->g[2] = -1.;
424 contrast(ma, rst->pc);
428 void bcf_p1_dump_afs(bcf_p1aux_t *ma)
431 if (ma->is_folded) fold_array(ma->M, ma->afs);
432 fprintf(stderr, "[afs]");
433 for (k = 0; k <= ma->M; ++k)
434 fprintf(stderr, " %d:%.3lf", k, ma->afs[ma->M - k]);
435 fprintf(stderr, "\n");
436 memset(ma->afs, 0, sizeof(double) * (ma->M + 1));