10 KSTREAM_INIT(gzFile, gzread, 16384)
12 #define MC_MAX_EM_ITER 16
13 #define MC_EM_EPS 1e-4
14 #define MC_DEF_INDEL 0.15
16 unsigned char seq_nt4_table[256] = {
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, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
21 4, 0, 4, 1, 4, 4, 4, 2, 4, 4, 4, 4, 4, 4, 4, 4,
22 4, 4, 4, 4, 3, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
23 4, 0, 4, 1, 4, 4, 4, 2, 4, 4, 4, 4, 4, 4, 4, 4,
24 4, 4, 4, 4, 3, 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,
32 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4
35 struct __bcf_p1aux_t {
36 int n, M, n1, is_indel;
37 uint8_t *ploidy; // haploid or diploid ONLY
38 double *q2p, *pdg; // pdg -> P(D|g)
39 double *phi, *phi_indel;
40 double *z, *zswap; // aux for afs
41 double *z1, *z2, *phi1, *phi2; // only calculated when n1 is set
43 double *afs, *afs1; // afs: accumulative AFS; afs1: site posterior distribution
44 const uint8_t *PL; // point to PL
48 void bcf_p1_indel_prior(bcf_p1aux_t *ma, double x)
51 for (i = 0; i < ma->M; ++i)
52 ma->phi_indel[i] = ma->phi[i] * x;
53 ma->phi_indel[ma->M] = 1. - ma->phi[ma->M] * x;
56 static void init_prior(int type, double theta, int M, double *phi)
59 if (type == MC_PTYPE_COND2) {
60 for (i = 0; i <= M; ++i)
61 phi[i] = 2. * (i + 1) / (M + 1) / (M + 2);
62 } else if (type == MC_PTYPE_FLAT) {
63 for (i = 0; i <= M; ++i)
64 phi[i] = 1. / (M + 1);
67 for (i = 0, sum = 0.; i < M; ++i)
68 sum += (phi[i] = theta / (M - i));
73 void bcf_p1_init_prior(bcf_p1aux_t *ma, int type, double theta)
75 init_prior(type, theta, ma->M, ma->phi);
76 bcf_p1_indel_prior(ma, MC_DEF_INDEL);
79 void bcf_p1_init_subprior(bcf_p1aux_t *ma, int type, double theta)
81 if (ma->n1 <= 0 || ma->n1 >= ma->M) return;
82 init_prior(type, theta, 2*ma->n1, ma->phi1);
83 init_prior(type, theta, 2*(ma->n - ma->n1), ma->phi2);
86 int bcf_p1_read_prior(bcf_p1aux_t *ma, const char *fn)
93 memset(&s, 0, sizeof(kstring_t));
94 fp = strcmp(fn, "-")? gzopen(fn, "r") : gzdopen(fileno(stdin), "r");
96 memset(ma->phi, 0, sizeof(double) * (ma->M + 1));
97 while (ks_getuntil(ks, '\n', &s, &dret) >= 0) {
98 if (strstr(s.s, "[afs] ") == s.s) {
100 for (k = 0; k <= ma->M; ++k) {
103 x = strtol(p, &p, 10);
104 if (x != k && (errno == EINVAL || errno == ERANGE)) return -1;
107 if (y == 0. && (errno == EINVAL || errno == ERANGE)) return -1;
108 ma->phi[ma->M - k] += y;
115 for (sum = 0., k = 0; k <= ma->M; ++k) sum += ma->phi[k];
116 fprintf(stderr, "[prior]");
117 for (k = 0; k <= ma->M; ++k) ma->phi[k] /= sum;
118 for (k = 0; k <= ma->M; ++k) fprintf(stderr, " %d:%.3lg", k, ma->phi[ma->M - k]);
120 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));
121 fprintf(stderr, "[%s] heterozygosity=%lf, ", __func__, (double)sum);
122 for (sum = 0., k = 1; k <= ma->M; ++k) sum += k * ma->phi[ma->M - k] / ma->M;
123 fprintf(stderr, "theta=%lf\n", (double)sum);
124 bcf_p1_indel_prior(ma, MC_DEF_INDEL);
128 bcf_p1aux_t *bcf_p1_init(int n, uint8_t *ploidy)
132 ma = calloc(1, sizeof(bcf_p1aux_t));
134 ma->n = n; ma->M = 2 * n;
136 ma->ploidy = malloc(n);
137 memcpy(ma->ploidy, ploidy, n);
138 for (i = 0, ma->M = 0; i < n; ++i) ma->M += ploidy[i];
139 if (ma->M == 2 * n) {
144 ma->q2p = calloc(256, sizeof(double));
145 ma->pdg = calloc(3 * ma->n, sizeof(double));
146 ma->phi = calloc(ma->M + 1, sizeof(double));
147 ma->phi_indel = calloc(ma->M + 1, sizeof(double));
148 ma->phi1 = calloc(ma->M + 1, sizeof(double));
149 ma->phi2 = calloc(ma->M + 1, sizeof(double));
150 ma->z = calloc(ma->M + 1, sizeof(double));
151 ma->zswap = calloc(ma->M + 1, sizeof(double));
152 ma->z1 = calloc(ma->M + 1, sizeof(double)); // actually we do not need this large
153 ma->z2 = calloc(ma->M + 1, sizeof(double));
154 ma->afs = calloc(ma->M + 1, sizeof(double));
155 ma->afs1 = calloc(ma->M + 1, sizeof(double));
156 for (i = 0; i < 256; ++i)
157 ma->q2p[i] = pow(10., -i / 10.);
158 bcf_p1_init_prior(ma, MC_PTYPE_FULL, 1e-3); // the simplest prior
162 int bcf_p1_set_n1(bcf_p1aux_t *b, int n1)
164 if (n1 == 0 || n1 >= b->n) return -1;
165 if (b->M != b->n * 2) {
166 fprintf(stderr, "[%s] unable to set `n1' when there are haploid samples.\n", __func__);
173 void bcf_p1_destroy(bcf_p1aux_t *ma)
176 free(ma->ploidy); free(ma->q2p); free(ma->pdg);
177 free(ma->phi); free(ma->phi_indel); free(ma->phi1); free(ma->phi2);
178 free(ma->z); free(ma->zswap); free(ma->z1); free(ma->z2);
179 free(ma->afs); free(ma->afs1);
184 static int cal_pdg(const bcf1_t *b, bcf_p1aux_t *ma)
188 p = alloca(b->n_alleles * sizeof(long));
189 memset(p, 0, sizeof(long) * b->n_alleles);
190 for (j = 0; j < ma->n; ++j) {
191 const uint8_t *pi = ma->PL + j * ma->PL_len;
192 double *pdg = ma->pdg + j * 3;
193 pdg[0] = ma->q2p[pi[2]]; pdg[1] = ma->q2p[pi[1]]; pdg[2] = ma->q2p[pi[0]];
194 for (i = 0; i < b->n_alleles; ++i)
195 p[i] += (int)pi[(i+1)*(i+2)/2-1];
197 for (i = 0; i < b->n_alleles; ++i) p[i] = p[i]<<4 | i;
198 for (i = 1; i < b->n_alleles; ++i) // insertion sort
199 for (j = i; j > 0 && p[j] < p[j-1]; --j)
200 tmp = p[j], p[j] = p[j-1], p[j-1] = tmp;
201 for (i = b->n_alleles - 1; i >= 0; --i)
202 if ((p[i]&0xf) == 0) break;
205 // f0 is the reference allele frequency
206 static double mc_freq_iter(double f0, const bcf_p1aux_t *ma)
210 f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
211 for (i = 0, f = 0.; i < ma->n; ++i) {
213 pdg = ma->pdg + i * 3;
214 f += (pdg[1] * f3[1] + 2. * pdg[2] * f3[2])
215 / (pdg[0] * f3[0] + pdg[1] * f3[1] + pdg[2] * f3[2]);
221 int bcf_p1_call_gt(const bcf_p1aux_t *ma, double f0, int k)
224 double max, f3[3], *pdg = ma->pdg + k * 3;
225 int q, i, max_i, ploidy;
226 ploidy = ma->ploidy? ma->ploidy[k] : 2;
228 f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
230 f3[0] = 1. - f0; f3[1] = 0; f3[2] = f0;
232 for (i = 0, sum = 0.; i < 3; ++i)
233 sum += (g[i] = pdg[i] * f3[i]);
234 for (i = 0, max = -1., max_i = 0; i <= ploidy; ++i) {
236 if (g[i] > max) max = g[i], max_i = i;
239 if (max < 1e-308) max = 1e-308;
240 q = (int)(-4.343 * log(max) + .499);
247 static void mc_cal_y_core(bcf_p1aux_t *ma, int beg)
249 double *z[2], *tmp, *pdg;
250 int _j, last_min, last_max;
251 assert(beg == 0 || ma->M == ma->n*2);
255 memset(z[0], 0, sizeof(double) * (ma->M + 1));
256 memset(z[1], 0, sizeof(double) * (ma->M + 1));
258 last_min = last_max = 0;
260 if (ma->M == ma->n * 2) {
261 for (_j = beg; _j < ma->n; ++_j) {
262 int k, j = _j - beg, _min = last_min, _max = last_max;
264 pdg = ma->pdg + _j * 3;
265 p[0] = pdg[0]; p[1] = 2. * pdg[1]; p[2] = pdg[2];
266 for (; _min < _max && z[0][_min] < TINY; ++_min) z[0][_min] = z[1][_min] = 0.;
267 for (; _max > _min && z[0][_max] < TINY; --_max) z[0][_max] = z[1][_max] = 0.;
270 k = 0, z[1][k] = (2*j+2-k)*(2*j-k+1) * p[0] * z[0][k];
272 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];
273 for (k = _min < 2? 2 : _min; k <= _max; ++k)
274 z[1][k] = (2*j+2-k)*(2*j-k+1) * p[0] * z[0][k]
275 + k*(2*j+2-k) * p[1] * z[0][k-1]
276 + k*(k-1)* p[2] * z[0][k-2];
277 for (k = _min, sum = 0.; k <= _max; ++k) sum += z[1][k];
278 ma->t += log(sum / ((2. * j + 2) * (2. * j + 1)));
279 for (k = _min; k <= _max; ++k) z[1][k] /= sum;
280 if (_min >= 1) z[1][_min-1] = 0.;
281 if (_min >= 2) z[1][_min-2] = 0.;
282 if (j < ma->n - 1) z[1][_max+1] = z[1][_max+2] = 0.;
283 if (_j == ma->n1 - 1) { // set pop1; ma->n1==-1 when unset
285 memcpy(ma->z1, z[1], sizeof(double) * (ma->n1 * 2 + 1));
287 tmp = z[0]; z[0] = z[1]; z[1] = tmp;
288 last_min = _min; last_max = _max;
290 } else { // this block is very similar to the block above; these two might be merged in future
292 for (j = 0; j < ma->n; ++j) {
293 int k, M0, _min = last_min, _max = last_max;
295 pdg = ma->pdg + j * 3;
296 for (; _min < _max && z[0][_min] < TINY; ++_min) z[0][_min] = z[1][_min] = 0.;
297 for (; _max > _min && z[0][_max] < TINY; --_max) z[0][_max] = z[1][_max] = 0.;
300 if (ma->ploidy[j] == 1) {
301 p[0] = pdg[0]; p[1] = pdg[2];
303 if (_min == 0) k = 0, z[1][k] = (M0+1-k) * p[0] * z[0][k];
304 for (k = _min < 1? 1 : _min; k <= _max; ++k)
305 z[1][k] = (M0+1-k) * p[0] * z[0][k] + k * p[1] * z[0][k-1];
306 for (k = _min, sum = 0.; k <= _max; ++k) sum += z[1][k];
307 ma->t += log(sum / M);
308 for (k = _min; k <= _max; ++k) z[1][k] /= sum;
309 if (_min >= 1) z[1][_min-1] = 0.;
310 if (j < ma->n - 1) z[1][_max+1] = 0.;
311 } else if (ma->ploidy[j] == 2) {
312 p[0] = pdg[0]; p[1] = 2 * pdg[1]; p[2] = pdg[2];
314 if (_min == 0) k = 0, z[1][k] = (M0-k+1) * (M0-k+2) * p[0] * z[0][k];
315 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];
316 for (k = _min < 2? 2 : _min; k <= _max; ++k)
317 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];
318 for (k = _min, sum = 0.; k <= _max; ++k) sum += z[1][k];
319 ma->t += log(sum / (M * (M - 1.)));
320 for (k = _min; k <= _max; ++k) z[1][k] /= sum;
321 if (_min >= 1) z[1][_min-1] = 0.;
322 if (_min >= 2) z[1][_min-2] = 0.;
323 if (j < ma->n - 1) z[1][_max+1] = z[1][_max+2] = 0.;
325 tmp = z[0]; z[0] = z[1]; z[1] = tmp;
326 last_min = _min; last_max = _max;
329 if (z[0] != ma->z) memcpy(ma->z, z[0], sizeof(double) * (ma->M + 1));
332 static void mc_cal_y(bcf_p1aux_t *ma)
334 if (ma->n1 > 0 && ma->n1 < ma->n && ma->M == ma->n * 2) { // NB: ma->n1 is ineffective when there are haploid samples
337 memset(ma->z1, 0, sizeof(double) * (2 * ma->n1 + 1));
338 memset(ma->z2, 0, sizeof(double) * (2 * (ma->n - ma->n1) + 1));
339 ma->t1 = ma->t2 = 0.;
340 mc_cal_y_core(ma, ma->n1);
342 memcpy(ma->z2, ma->z, sizeof(double) * (2 * (ma->n - ma->n1) + 1));
343 mc_cal_y_core(ma, 0);
345 x = expl(ma->t - (ma->t1 + ma->t2));
346 for (k = 0; k <= ma->M; ++k) ma->z[k] *= x;
347 } else mc_cal_y_core(ma, 0);
350 static void contrast(bcf_p1aux_t *ma, double pc[4]) // mc_cal_y() must be called before hand
352 int k, n1 = ma->n1, n2 = ma->n - ma->n1;
353 long double sum1, sum2;
354 pc[0] = pc[1] = pc[2] = pc[3] = -1.;
355 if (n1 <= 0 || n2 <= 0) return;
356 for (k = 0, sum1 = 0.; k <= 2*n1; ++k) sum1 += ma->phi1[k] * ma->z1[k];
357 for (k = 0, sum2 = 0.; k <= 2*n2; ++k) sum2 += ma->phi2[k] * ma->z2[k];
358 pc[2] = ma->phi1[2*n1] * ma->z1[2*n1] / sum1;
359 pc[3] = ma->phi2[2*n2] * ma->z2[2*n2] / sum2;
360 for (k = 2; k < 4; ++k) {
361 pc[k] = pc[k] > .5? -(-4.343 * log(1. - pc[k] + TINY) + .499) : -4.343 * log(pc[k] + TINY) + .499;
363 if (pc[k] > 99) pc[k] = 99;
364 if (pc[k] < -99) pc[k] = -99;
366 pc[0] = ma->phi2[2*n2] * ma->z2[2*n2] / sum2 * (1. - ma->phi1[2*n1] * ma->z1[2*n1] / sum1);
367 pc[1] = ma->phi1[2*n1] * ma->z1[2*n1] / sum1 * (1. - ma->phi2[2*n2] * ma->z2[2*n2] / sum2);
368 pc[0] = pc[0] == 1.? 99 : (int)(-4.343 * log(1. - pc[0]) + .499);
369 pc[1] = pc[1] == 1.? 99 : (int)(-4.343 * log(1. - pc[1]) + .499);
372 static double mc_cal_afs(bcf_p1aux_t *ma, double *p_ref_folded, double *p_var_folded)
375 long double sum = 0., sum2;
376 double *phi = ma->is_indel? ma->phi_indel : ma->phi;
377 memset(ma->afs1, 0, sizeof(double) * (ma->M + 1));
380 for (k = 0, sum = 0.; k <= ma->M; ++k)
381 sum += (long double)phi[k] * ma->z[k];
382 for (k = 0; k <= ma->M; ++k) {
383 ma->afs1[k] = phi[k] * ma->z[k] / sum;
384 if (isnan(ma->afs1[k]) || isinf(ma->afs1[k])) return -1.;
386 // compute folded variant probability
387 for (k = 0, sum = 0.; k <= ma->M; ++k)
388 sum += (long double)(phi[k] + phi[ma->M - k]) / 2. * ma->z[k];
389 for (k = 1, sum2 = 0.; k < ma->M; ++k)
390 sum2 += (long double)(phi[k] + phi[ma->M - k]) / 2. * ma->z[k];
391 *p_var_folded = sum2 / sum;
392 *p_ref_folded = (phi[k] + phi[ma->M - k]) / 2. * (ma->z[ma->M] + ma->z[0]) / sum;
393 // the expected frequency
394 for (k = 0, sum = 0.; k <= ma->M; ++k) {
395 ma->afs[k] += ma->afs1[k];
396 sum += k * ma->afs1[k];
401 int bcf_p1_cal(const bcf1_t *b, bcf_p1aux_t *ma, bcf_p1rst_t *rst)
404 long double sum = 0.;
405 ma->is_indel = bcf_is_indel(b);
407 for (i = 0; i < b->n_gi; ++i) {
408 if (b->gi[i].fmt == bcf_str2int("PL", 2)) {
409 ma->PL = (uint8_t*)b->gi[i].data;
410 ma->PL_len = b->gi[i].len;
414 if (b->n_alleles < 2) return -1; // FIXME: find a better solution
416 rst->rank0 = cal_pdg(b, ma);
417 rst->f_exp = mc_cal_afs(ma, &rst->p_ref_folded, &rst->p_var_folded);
418 rst->p_ref = ma->afs1[ma->M];
419 for (k = 0, sum = 0.; k < ma->M; ++k)
421 rst->p_var = (double)sum;
422 // calculate f_flat and f_em
423 for (k = 0, sum = 0.; k <= ma->M; ++k)
424 sum += (long double)ma->z[k];
426 for (k = 0; k <= ma->M; ++k) {
427 double p = ma->z[k] / sum;
428 rst->f_flat += k * p;
430 rst->f_flat /= ma->M;
432 double flast = rst->f_flat;
433 for (i = 0; i < MC_MAX_EM_ITER; ++i) {
434 rst->f_em = mc_freq_iter(flast, ma);
435 if (fabs(rst->f_em - flast) < MC_EM_EPS) break;
439 { // estimate equal-tail credible interval (95% level)
442 for (i = 0, p = 0.; i < ma->M; ++i)
443 if (p + ma->afs1[i] > 0.025) break;
444 else p += ma->afs1[i];
446 for (i = ma->M-1, p = 0.; i >= 0; --i)
447 if (p + ma->afs1[i] > 0.025) break;
448 else p += ma->afs1[i];
450 rst->cil = (double)(ma->M - h) / ma->M; rst->cih = (double)(ma->M - l) / ma->M;
452 rst->g[0] = rst->g[1] = rst->g[2] = -1.;
453 contrast(ma, rst->pc);
457 void bcf_p1_dump_afs(bcf_p1aux_t *ma)
460 fprintf(stderr, "[afs]");
461 for (k = 0; k <= ma->M; ++k)
462 fprintf(stderr, " %d:%.3lf", k, ma->afs[ma->M - k]);
463 fprintf(stderr, "\n");
464 memset(ma->afs, 0, sizeof(double) * (ma->M + 1));