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;
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 void bcf_p1_indel_prior(bcf_p1aux_t *ma, double x)
49 for (i = 0; i < ma->M; ++i)
50 ma->phi_indel[i] = ma->phi[i] * x;
51 ma->phi_indel[ma->M] = 1. - ma->phi[ma->M] * x;
54 static void init_prior(int type, double theta, int M, double *phi)
57 if (type == MC_PTYPE_COND2) {
58 for (i = 0; i <= M; ++i)
59 phi[i] = 2. * (i + 1) / (M + 1) / (M + 2);
60 } else if (type == MC_PTYPE_FLAT) {
61 for (i = 0; i <= M; ++i)
62 phi[i] = 1. / (M + 1);
65 for (i = 0, sum = 0.; i < M; ++i)
66 sum += (phi[i] = theta / (M - i));
71 void bcf_p1_init_prior(bcf_p1aux_t *ma, int type, double theta)
73 init_prior(type, theta, ma->M, ma->phi);
74 bcf_p1_indel_prior(ma, MC_DEF_INDEL);
77 void bcf_p1_init_subprior(bcf_p1aux_t *ma, int type, double theta)
79 if (ma->n1 <= 0 || ma->n1 >= ma->M) return;
80 init_prior(type, theta, 2*ma->n1, ma->phi1);
81 init_prior(type, theta, 2*(ma->n - ma->n1), ma->phi2);
84 int bcf_p1_read_prior(bcf_p1aux_t *ma, const char *fn)
91 memset(&s, 0, sizeof(kstring_t));
92 fp = strcmp(fn, "-")? gzopen(fn, "r") : gzdopen(fileno(stdin), "r");
94 memset(ma->phi, 0, sizeof(double) * (ma->M + 1));
95 while (ks_getuntil(ks, '\n', &s, &dret) >= 0) {
96 if (strstr(s.s, "[afs] ") == s.s) {
98 for (k = 0; k <= ma->M; ++k) {
101 x = strtol(p, &p, 10);
102 if (x != k && (errno == EINVAL || errno == ERANGE)) return -1;
105 if (y == 0. && (errno == EINVAL || errno == ERANGE)) return -1;
106 ma->phi[ma->M - k] += y;
113 for (sum = 0., k = 0; k <= ma->M; ++k) sum += ma->phi[k];
114 fprintf(stderr, "[prior]");
115 for (k = 0; k <= ma->M; ++k) ma->phi[k] /= sum;
116 for (k = 0; k <= ma->M; ++k) fprintf(stderr, " %d:%.3lg", k, ma->phi[ma->M - k]);
118 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));
119 fprintf(stderr, "[%s] heterozygosity=%lf, ", __func__, (double)sum);
120 for (sum = 0., k = 1; k <= ma->M; ++k) sum += k * ma->phi[ma->M - k] / ma->M;
121 fprintf(stderr, "theta=%lf\n", (double)sum);
122 bcf_p1_indel_prior(ma, MC_DEF_INDEL);
126 bcf_p1aux_t *bcf_p1_init(int n)
130 ma = calloc(1, sizeof(bcf_p1aux_t));
132 ma->n = n; ma->M = 2 * n;
133 ma->q2p = calloc(256, sizeof(double));
134 ma->pdg = calloc(3 * ma->n, sizeof(double));
135 ma->phi = calloc(ma->M + 1, sizeof(double));
136 ma->phi_indel = calloc(ma->M + 1, sizeof(double));
137 ma->phi1 = calloc(ma->M + 1, sizeof(double));
138 ma->phi2 = calloc(ma->M + 1, sizeof(double));
139 ma->z = calloc(2 * ma->n + 1, sizeof(double));
140 ma->zswap = calloc(2 * ma->n + 1, sizeof(double));
141 ma->z1 = calloc(ma->M + 1, sizeof(double)); // actually we do not need this large
142 ma->z2 = calloc(ma->M + 1, sizeof(double));
143 ma->afs = calloc(2 * ma->n + 1, sizeof(double));
144 ma->afs1 = calloc(2 * ma->n + 1, sizeof(double));
145 for (i = 0; i < 256; ++i)
146 ma->q2p[i] = pow(10., -i / 10.);
147 bcf_p1_init_prior(ma, MC_PTYPE_FULL, 1e-3); // the simplest prior
151 int bcf_p1_set_n1(bcf_p1aux_t *b, int n1)
153 if (n1 == 0 || n1 >= b->n) return -1;
158 void bcf_p1_destroy(bcf_p1aux_t *ma)
161 free(ma->q2p); free(ma->pdg);
162 free(ma->phi); free(ma->phi_indel); free(ma->phi1); free(ma->phi2);
163 free(ma->z); free(ma->zswap); free(ma->z1); free(ma->z2);
164 free(ma->afs); free(ma->afs1);
169 static int cal_pdg(const bcf1_t *b, bcf_p1aux_t *ma)
173 p = alloca(b->n_alleles * sizeof(long));
174 memset(p, 0, sizeof(long) * b->n_alleles);
175 for (j = 0; j < ma->n; ++j) {
176 const uint8_t *pi = ma->PL + j * ma->PL_len;
177 double *pdg = ma->pdg + j * 3;
178 pdg[0] = ma->q2p[pi[2]]; pdg[1] = ma->q2p[pi[1]]; pdg[2] = ma->q2p[pi[0]];
179 for (i = 0; i < b->n_alleles; ++i)
180 p[i] += (int)pi[(i+1)*(i+2)/2-1];
182 for (i = 0; i < b->n_alleles; ++i) p[i] = p[i]<<4 | i;
183 for (i = 1; i < b->n_alleles; ++i) // insertion sort
184 for (j = i; j > 0 && p[j] < p[j-1]; --j)
185 tmp = p[j], p[j] = p[j-1], p[j-1] = tmp;
186 for (i = b->n_alleles - 1; i >= 0; --i)
187 if ((p[i]&0xf) == 0) break;
190 // f0 is the reference allele frequency
191 static double mc_freq_iter(double f0, const bcf_p1aux_t *ma)
195 f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
196 for (i = 0, f = 0.; i < ma->n; ++i) {
198 pdg = ma->pdg + i * 3;
199 f += (pdg[1] * f3[1] + 2. * pdg[2] * f3[2])
200 / (pdg[0] * f3[0] + pdg[1] * f3[1] + pdg[2] * f3[2]);
206 int bcf_p1_call_gt(const bcf_p1aux_t *ma, double f0, int k)
209 double max, f3[3], *pdg = ma->pdg + k * 3;
211 f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
212 for (i = 0, sum = 0.; i < 3; ++i)
213 sum += (g[i] = pdg[i] * f3[i]);
214 for (i = 0, max = -1., max_i = 0; i < 3; ++i) {
216 if (g[i] > max) max = g[i], max_i = i;
219 if (max < 1e-308) max = 1e-308;
220 q = (int)(-4.343 * log(max) + .499);
227 static void mc_cal_y_core(bcf_p1aux_t *ma, int beg)
229 double *z[2], *tmp, *pdg;
230 int _j, last_min, last_max;
234 memset(z[0], 0, sizeof(double) * (ma->M + 1));
235 memset(z[1], 0, sizeof(double) * (ma->M + 1));
237 last_min = last_max = 0;
239 for (_j = beg; _j < ma->n; ++_j) {
240 int k, j = _j - beg, _min = last_min, _max = last_max;
242 pdg = ma->pdg + _j * 3;
243 p[0] = pdg[0]; p[1] = 2. * pdg[1]; p[2] = pdg[2];
244 for (; _min < _max && z[0][_min] < TINY; ++_min) z[0][_min] = z[1][_min] = 0.;
245 for (; _max > _min && z[0][_max] < TINY; --_max) z[0][_max] = z[1][_max] = 0.;
248 k = 0, z[1][k] = (2*j+2-k)*(2*j-k+1) * p[0] * z[0][k];
250 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];
251 for (k = _min < 2? 2 : _min; k <= _max; ++k)
252 z[1][k] = (2*j+2-k)*(2*j-k+1) * p[0] * z[0][k]
253 + k*(2*j+2-k) * p[1] * z[0][k-1]
254 + k*(k-1)* p[2] * z[0][k-2];
255 for (k = _min, sum = 0.; k <= _max; ++k) sum += z[1][k];
256 ma->t += log(sum / ((2. * j + 2) * (2. * j + 1)));
257 for (k = _min; k <= _max; ++k) z[1][k] /= sum;
258 if (_min >= 1) z[1][_min-1] = 0.;
259 if (_min >= 2) z[1][_min-2] = 0.;
260 if (j < ma->n - 1) z[1][_max+1] = z[1][_max+2] = 0.;
261 if (_j == ma->n1 - 1) { // set pop1
263 memcpy(ma->z1, z[1], sizeof(double) * (ma->n1 * 2 + 1));
265 tmp = z[0]; z[0] = z[1]; z[1] = tmp;
266 last_min = _min; last_max = _max;
268 if (z[0] != ma->z) memcpy(ma->z, z[0], sizeof(double) * (ma->M + 1));
271 static void mc_cal_y(bcf_p1aux_t *ma)
273 if (ma->n1 > 0 && ma->n1 < ma->n) {
276 memset(ma->z1, 0, sizeof(double) * (2 * ma->n1 + 1));
277 memset(ma->z2, 0, sizeof(double) * (2 * (ma->n - ma->n1) + 1));
278 ma->t1 = ma->t2 = 0.;
279 mc_cal_y_core(ma, ma->n1);
281 memcpy(ma->z2, ma->z, sizeof(double) * (2 * (ma->n - ma->n1) + 1));
282 mc_cal_y_core(ma, 0);
284 x = expl(ma->t - (ma->t1 + ma->t2));
285 for (k = 0; k <= ma->M; ++k) ma->z[k] *= x;
286 } else mc_cal_y_core(ma, 0);
289 static void contrast(bcf_p1aux_t *ma, double pc[4]) // mc_cal_y() must be called before hand
291 int k, n1 = ma->n1, n2 = ma->n - ma->n1;
292 long double sum1, sum2;
293 pc[0] = pc[1] = pc[2] = pc[3] = -1.;
294 if (n1 <= 0 || n2 <= 0) return;
295 for (k = 0, sum1 = 0.; k <= 2*n1; ++k) sum1 += ma->phi1[k] * ma->z1[k];
296 for (k = 0, sum2 = 0.; k <= 2*n2; ++k) sum2 += ma->phi2[k] * ma->z2[k];
297 pc[2] = ma->phi1[2*n1] * ma->z1[2*n1] / sum1;
298 pc[3] = ma->phi2[2*n2] * ma->z2[2*n2] / sum2;
299 for (k = 2; k < 4; ++k) {
300 pc[k] = pc[k] > .5? -(-4.343 * log(1. - pc[k] + TINY) + .499) : -4.343 * log(pc[k] + TINY) + .499;
302 if (pc[k] > 99) pc[k] = 99;
303 if (pc[k] < -99) pc[k] = -99;
305 pc[0] = ma->phi2[2*n2] * ma->z2[2*n2] / sum2 * (1. - ma->phi1[2*n1] * ma->z1[2*n1] / sum1);
306 pc[1] = ma->phi1[2*n1] * ma->z1[2*n1] / sum1 * (1. - ma->phi2[2*n2] * ma->z2[2*n2] / sum2);
307 pc[0] = pc[0] == 1.? 99 : (int)(-4.343 * log(1. - pc[0]) + .499);
308 pc[1] = pc[1] == 1.? 99 : (int)(-4.343 * log(1. - pc[1]) + .499);
311 static double mc_cal_afs(bcf_p1aux_t *ma, double *p_ref_folded, double *p_var_folded)
314 long double sum = 0., sum2;
315 double *phi = ma->is_indel? ma->phi_indel : ma->phi;
316 memset(ma->afs1, 0, sizeof(double) * (ma->M + 1));
319 for (k = 0, sum = 0.; k <= ma->M; ++k)
320 sum += (long double)phi[k] * ma->z[k];
321 for (k = 0; k <= ma->M; ++k) {
322 ma->afs1[k] = phi[k] * ma->z[k] / sum;
323 if (isnan(ma->afs1[k]) || isinf(ma->afs1[k])) return -1.;
325 // compute folded variant probability
326 for (k = 0, sum = 0.; k <= ma->M; ++k)
327 sum += (long double)(phi[k] + phi[ma->M - k]) / 2. * ma->z[k];
328 for (k = 1, sum2 = 0.; k < ma->M; ++k)
329 sum2 += (long double)(phi[k] + phi[ma->M - k]) / 2. * ma->z[k];
330 *p_var_folded = sum2 / sum;
331 *p_ref_folded = (phi[k] + phi[ma->M - k]) / 2. * (ma->z[ma->M] + ma->z[0]) / sum;
332 // the expected frequency
333 for (k = 0, sum = 0.; k <= ma->M; ++k) {
334 ma->afs[k] += ma->afs1[k];
335 sum += k * ma->afs1[k];
340 long double bcf_p1_cal_g3(bcf_p1aux_t *p1a, double g[3])
342 long double pd = 0., g2[3];
344 memset(g2, 0, sizeof(long double) * 3);
345 for (k = 0; k < p1a->M; ++k) {
346 double f = (double)k / p1a->M, f3[3], g1[3];
348 g1[0] = g1[1] = g1[2] = 0.;
349 f3[0] = (1. - f) * (1. - f); f3[1] = 2. * f * (1. - f); f3[2] = f * f;
350 for (i = 0; i < p1a->n; ++i) {
351 double *pdg = p1a->pdg + i * 3;
352 double x = pdg[0] * f3[0] + pdg[1] * f3[1] + pdg[2] * f3[2];
354 g1[0] += pdg[0] * f3[0] / x;
355 g1[1] += pdg[1] * f3[1] / x;
356 g1[2] += pdg[2] * f3[2] / x;
358 pd += p1a->phi[k] * z;
359 for (i = 0; i < 3; ++i)
360 g2[i] += p1a->phi[k] * z * g1[i];
362 for (i = 0; i < 3; ++i) g[i] = g2[i] / pd;
366 int bcf_p1_cal(const bcf1_t *b, bcf_p1aux_t *ma, bcf_p1rst_t *rst)
369 long double sum = 0.;
370 ma->is_indel = bcf_is_indel(b);
372 for (i = 0; i < b->n_gi; ++i) {
373 if (b->gi[i].fmt == bcf_str2int("PL", 2)) {
374 ma->PL = (uint8_t*)b->gi[i].data;
375 ma->PL_len = b->gi[i].len;
379 if (b->n_alleles < 2) return -1; // FIXME: find a better solution
381 rst->rank0 = cal_pdg(b, ma);
382 rst->f_exp = mc_cal_afs(ma, &rst->p_ref_folded, &rst->p_var_folded);
383 rst->p_ref = ma->afs1[ma->M];
384 for (k = 0, sum = 0.; k < ma->M; ++k)
386 rst->p_var = (double)sum;
387 // calculate f_flat and f_em
388 for (k = 0, sum = 0.; k <= ma->M; ++k)
389 sum += (long double)ma->z[k];
391 for (k = 0; k <= ma->M; ++k) {
392 double p = ma->z[k] / sum;
393 rst->f_flat += k * p;
395 rst->f_flat /= ma->M;
397 double flast = rst->f_flat;
398 for (i = 0; i < MC_MAX_EM_ITER; ++i) {
399 rst->f_em = mc_freq_iter(flast, ma);
400 if (fabs(rst->f_em - flast) < MC_EM_EPS) break;
404 { // estimate equal-tail credible interval (95% level)
407 for (i = 0, p = 0.; i < ma->M; ++i)
408 if (p + ma->afs1[i] > 0.025) break;
409 else p += ma->afs1[i];
411 for (i = ma->M-1, p = 0.; i >= 0; --i)
412 if (p + ma->afs1[i] > 0.025) break;
413 else p += ma->afs1[i];
415 rst->cil = (double)(ma->M - h) / ma->M; rst->cih = (double)(ma->M - l) / ma->M;
417 rst->g[0] = rst->g[1] = rst->g[2] = -1.;
418 contrast(ma, rst->pc);
422 void bcf_p1_dump_afs(bcf_p1aux_t *ma)
425 fprintf(stderr, "[afs]");
426 for (k = 0; k <= ma->M; ++k)
427 fprintf(stderr, " %d:%.3lf", k, ma->afs[ma->M - k]);
428 fprintf(stderr, "\n");
429 memset(ma->afs, 0, sizeof(double) * (ma->M + 1));