9 KSTREAM_INIT(gzFile, gzread, 16384)
11 #define MC_AVG_ERR 0.007
12 #define MC_MAX_EM_ITER 16
13 #define MC_EM_EPS 1e-4
17 unsigned char seq_nt4_table[256] = {
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, 4, 4, 4, 4, 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, 0, 4, 1, 4, 4, 4, 2, 4, 4, 4, 4, 4, 4, 4, 4,
25 4, 4, 4, 4, 3, 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,
33 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4
36 struct __bcf_p1aux_t {
38 double *q2p, *pdg; // pdg -> P(D|g)
40 double *z, *zswap; // aux for afs
41 double *z1, *z2; // only calculated when n1 is set
43 double *afs, *afs1; // afs: accumulative AFS; afs1: site posterior distribution
45 const uint8_t *PL; // point to PL
49 void bcf_p1_init_prior(bcf_p1aux_t *ma, int type, double theta)
52 if (type == MC_PTYPE_COND2) {
53 for (i = 0; i <= ma->M; ++i)
54 ma->phi[i] = 2. * (i + 1) / (ma->M + 1) / (ma->M + 2);
55 } else if (type == MC_PTYPE_FLAT) {
56 for (i = 0; i <= ma->M; ++i)
57 ma->phi[i] = 1. / (ma->M + 1);
60 for (i = 0, sum = 0.; i < ma->M; ++i)
61 sum += (ma->phi[i] = theta / (ma->M - i));
62 ma->phi[ma->M] = 1. - sum;
66 int bcf_p1_read_prior(bcf_p1aux_t *ma, const char *fn)
73 memset(&s, 0, sizeof(kstring_t));
74 fp = strcmp(fn, "-")? gzopen(fn, "r") : gzdopen(fileno(stdin), "r");
76 memset(ma->phi, 0, sizeof(double) * (ma->M + 1));
77 while (ks_getuntil(ks, '\n', &s, &dret) >= 0) {
78 if (strstr(s.s, "[afs] ") == s.s) {
80 for (k = 0; k <= ma->M; ++k) {
83 x = strtol(p, &p, 10);
84 if (x != k && (errno == EINVAL || errno == ERANGE)) return -1;
87 if (y == 0. && (errno == EINVAL || errno == ERANGE)) return -1;
88 ma->phi[ma->M - k] += y;
95 for (sum = 0., k = 0; k <= ma->M; ++k) sum += ma->phi[k];
96 fprintf(stderr, "[prior]");
97 for (k = 0; k <= ma->M; ++k) ma->phi[k] /= sum;
98 for (k = 0; k <= ma->M; ++k) fprintf(stderr, " %d:%.3lg", k, ma->phi[ma->M - k]);
100 for (sum = 0., k = 1; k <= ma->M; ++k) sum += k * ma->phi[ma->M - k];
101 fprintf(stderr, "[heterozygosity] %lf\n", (double)sum / ma->M);
105 bcf_p1aux_t *bcf_p1_init(int n)
109 ma = calloc(1, sizeof(bcf_p1aux_t));
111 ma->n = n; ma->M = 2 * n;
112 ma->q2p = calloc(256, sizeof(double));
113 ma->pdg = calloc(3 * ma->n, sizeof(double));
114 ma->phi = calloc(ma->M + 1, sizeof(double));
115 ma->z = calloc(2 * ma->n + 1, sizeof(double));
116 ma->zswap = calloc(2 * ma->n + 1, sizeof(double));
117 ma->z1 = calloc(ma->M + 1, sizeof(double)); // actually we do not need this large
118 ma->z2 = calloc(ma->M + 1, sizeof(double));
119 ma->afs = calloc(2 * ma->n + 1, sizeof(double));
120 ma->afs1 = calloc(2 * ma->n + 1, sizeof(double));
121 for (i = 0; i < 256; ++i)
122 ma->q2p[i] = pow(10., -i / 10.);
123 bcf_p1_init_prior(ma, MC_PTYPE_FULL, 1e-3); // the simplest prior
128 static double lbinom(int n, int k)
130 return lgamma(n+1) - lgamma(k+1) - lgamma(n-k+1);
134 int bcf_p1_set_n1(bcf_p1aux_t *b, int n1)
136 if (n1 == 0 || n1 >= b->n) return -1;
140 int k1, k2, n2 = b->n - b->n1;
141 b->k1k2 = calloc((2*n1+1) * (2*n2+1), sizeof(double));
142 for (k1 = 0; k1 <= 2*n1; ++k1)
143 for (k2 = 0; k2 <= 2*n2; ++k2)
144 b->k1k2[k1*(2*n2+1)+k2] = exp(lbinom(2*n1,k1) + lbinom(2*n2,k2) - lbinom(b->M,k1+k2));
150 void bcf_p1_destroy(bcf_p1aux_t *ma)
153 free(ma->q2p); free(ma->pdg);
155 free(ma->z); free(ma->zswap); free(ma->z1); free(ma->z2);
156 free(ma->afs); free(ma->afs1);
162 #define char2int(s) (((int)s[0])<<8|s[1])
164 static int cal_pdg(const bcf1_t *b, bcf_p1aux_t *ma)
168 p = alloca(b->n_alleles * sizeof(long));
169 memset(p, 0, sizeof(long) * b->n_alleles);
170 for (j = 0; j < ma->n; ++j) {
171 const uint8_t *pi = ma->PL + j * ma->PL_len;
172 double *pdg = ma->pdg + j * 3;
173 pdg[0] = ma->q2p[pi[b->n_alleles]]; pdg[1] = ma->q2p[pi[1]]; pdg[2] = ma->q2p[pi[0]];
174 for (i = k = 0; i < b->n_alleles; ++i) {
176 k += b->n_alleles - i;
179 for (i = 0; i < b->n_alleles; ++i) p[i] = p[i]<<4 | i;
180 for (i = 1; i < b->n_alleles; ++i) // insertion sort
181 for (j = i; j > 0 && p[j] < p[j-1]; --j)
182 tmp = p[j], p[j] = p[j-1], p[j-1] = tmp;
183 for (i = b->n_alleles - 1; i >= 0; --i)
184 if ((p[i]&0xf) == 0) break;
187 // f0 is the reference allele frequency
188 static double mc_freq_iter(double f0, const bcf_p1aux_t *ma)
192 f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
193 for (i = 0, f = 0.; i < ma->n; ++i) {
195 pdg = ma->pdg + i * 3;
196 f += (pdg[1] * f3[1] + 2. * pdg[2] * f3[2])
197 / (pdg[0] * f3[0] + pdg[1] * f3[1] + pdg[2] * f3[2]);
203 int bcf_p1_call_gt(const bcf_p1aux_t *ma, double f0, int k)
206 double max, f3[3], *pdg = ma->pdg + k * 3;
208 f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
209 for (i = 0, sum = 0.; i < 3; ++i)
210 sum += (g[i] = pdg[i] * f3[i]);
211 for (i = 0, max = -1., max_i = 0; i < 3; ++i) {
213 if (g[i] > max) max = g[i], max_i = i;
216 if (max < 1e-308) max = 1e-308;
217 q = (int)(-4.343 * log(max) + .499);
224 static void mc_cal_y_core(bcf_p1aux_t *ma, int beg)
226 double *z[2], *tmp, *pdg;
227 int _j, last_min, last_max;
231 memset(z[0], 0, sizeof(double) * (ma->M + 1));
232 memset(z[1], 0, sizeof(double) * (ma->M + 1));
234 last_min = last_max = 0;
236 for (_j = beg; _j < ma->n; ++_j) {
237 int k, j = _j - beg, _min = last_min, _max = last_max;
239 pdg = ma->pdg + _j * 3;
240 p[0] = pdg[0]; p[1] = 2. * pdg[1]; p[2] = pdg[2];
241 for (; _min < _max && z[0][_min] < TINY; ++_min) z[0][_min] = z[1][_min] = 0.;
242 for (; _max > _min && z[0][_max] < TINY; --_max) z[0][_max] = z[1][_max] = 0.;
245 k = 0, z[1][k] = (2*j+2-k)*(2*j-k+1) * p[0] * z[0][k];
247 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];
248 for (k = _min < 2? 2 : _min; k <= _max; ++k)
249 z[1][k] = (2*j+2-k)*(2*j-k+1) * p[0] * z[0][k]
250 + k*(2*j+2-k) * p[1] * z[0][k-1]
251 + k*(k-1)* p[2] * z[0][k-2];
252 for (k = _min, sum = 0.; k <= _max; ++k) sum += z[1][k];
253 ma->t += log(sum / ((2. * j + 2) * (2. * j + 1)));
254 for (k = _min; k <= _max; ++k) z[1][k] /= sum;
255 if (_min >= 1) z[1][_min-1] = 0.;
256 if (_min >= 2) z[1][_min-2] = 0.;
257 if (j < ma->n - 1) z[1][_max+1] = z[1][_max+2] = 0.;
258 if (_j == ma->n1 - 1) { // set pop1
260 memcpy(ma->z1, z[1], sizeof(double) * (ma->n1 * 2 + 1));
262 tmp = z[0]; z[0] = z[1]; z[1] = tmp;
263 last_min = _min; last_max = _max;
265 if (z[0] != ma->z) memcpy(ma->z, z[0], sizeof(double) * (ma->M + 1));
268 static void mc_cal_y(bcf_p1aux_t *ma)
270 if (ma->n1 > 0 && ma->n1 < ma->n) {
273 memset(ma->z1, 0, sizeof(double) * (2 * ma->n1 + 1));
274 memset(ma->z2, 0, sizeof(double) * (2 * (ma->n - ma->n1) + 1));
275 ma->t1 = ma->t2 = 0.;
276 mc_cal_y_core(ma, ma->n1);
278 memcpy(ma->z2, ma->z, sizeof(double) * (2 * (ma->n - ma->n1) + 1));
279 mc_cal_y_core(ma, 0);
281 x = expl(ma->t - (ma->t1 + ma->t2));
282 for (k = 0; k <= ma->M; ++k) ma->z[k] *= x;
283 } else mc_cal_y_core(ma, 0);
286 if (ma->n1 > 0 && ma->n1 < ma->n) { // DEBUG: consistency check; z[i] should equal y[i]
287 int i, k1, k2, n1 = ma->n1, n2 = ma->n - n1;
290 y = calloc(ma->M + 1, sizeof(double));
291 for (k1 = 0; k1 <= 2*n1; ++k1)
292 for (k2 = 0; k2 <= 2*n2; ++k2)
293 y[k1+k2] += ma->k1k2[k1*(2*n2+1)+k2] * ma->z1[k1] * ma->z2[k2];
294 for (i = 0; i <= ma->M; ++i) printf("(%lf,%lf) ", ma->z[i], y[i]);
302 static void contrast(bcf_p1aux_t *ma, double pc[4]) // mc_cal_y() must be called before hand
304 int k, n1 = ma->n1, n2 = ma->n - ma->n1;
305 long double sum = -1., x, sum_alt;
307 pc[0] = pc[1] = pc[2] = pc[3] = -1.;
308 if (n1 <= 0 || n2 <= 0) return;
310 { // FIXME: can be improved by skipping zero cells
313 z[0] = z[1] = z[2] = 0.;
314 for (k1 = 0; k1 <= 2*n1; ++k1)
315 for (k2 = 0; k2 <= 2*n2; ++k2) {
316 double zz = ma->phi[k1+k2] * ma->z1[k1] * ma->z2[k2] * ma->k1k2[k1*(2*n2+1)+k2];
317 if ((double)k1/n1 < (double)k2/n2) z[0] += zz;
318 else if ((double)k1/n1 > (double)k2/n2) z[1] += zz;
321 sum = z[0] + z[1] + z[2];
322 pc[2] = z[0] / sum; pc[3] = z[1] / sum;
327 for (k = 0, sum_alt = 0.; k <= ma->M; ++k)
328 sum_alt += (long double)ma->phi[k] * ma->z[k];
329 // printf("* %lg, %lg *\n", (double)sum, (double)sum_alt); // DEBUG: sum should equal sum_alt
331 // the variant is specific to group2
332 // printf("%lg %lg %lg %lg\n", ma->z[2*(n1+n2)]/exp(ma->t - (ma->t1 + ma->t2)), ma->z1[2*n1], ma->z2[2*n2], (double)sum);
333 y = lgamma(2*n2 + 1) - lgamma(ma->M + 1);
334 for (k = 0, x = 0.; k < 2 * n2; ++k)
335 x += ma->phi[2*n1+k] * ma->z2[k] * expl(lgamma(2*n1 + k + 1) - lgamma(k + 1) + y);
336 pc[1] = ma->z1[2*n1] * x / sum;
337 for (k = 1, x = 0.; k <= 2 * n2; ++k)
338 x += ma->phi[k] * ma->z2[k] * expl(lgamma(ma->M - k + 1) - lgamma(2*n2 - k + 1) + y);
339 pc[1] += ma->z1[0] * x / sum;
340 // the variant is specific to group1
341 y = lgamma(2*n1 + 1) - lgamma(ma->M + 1);
342 for (k = 0, x = 0.; k < 2 * n1; ++k)
343 x += ma->phi[2*n2+k] * ma->z1[k] * expl(lgamma(2*n2 + k + 1) - lgamma(k + 1) + y);
344 pc[0] = ma->z2[2*n2] * x / sum;
345 for (k = 1, x = 0.; k <= 2 * n1; ++k)
346 x += ma->phi[k] * ma->z1[k] * expl(lgamma(ma->M - k + 1) - lgamma(2*n1 - k + 1) + y);
347 pc[0] += ma->z2[0] * x / sum;
349 for (k = 2; k < 4; ++k) {
351 if (y <= 0.) y = 1e-100;
352 pc[k] = (int)(-4.343 * log(y) + .499);
353 if (pc[k] > 99.) pc[k] = 99.;
357 static double mc_cal_afs(bcf_p1aux_t *ma)
360 long double sum = 0.;
361 memset(ma->afs1, 0, sizeof(double) * (ma->M + 1));
363 for (k = 0, sum = 0.; k <= ma->M; ++k)
364 sum += (long double)ma->phi[k] * ma->z[k];
365 for (k = 0; k <= ma->M; ++k) {
366 ma->afs1[k] = ma->phi[k] * ma->z[k] / sum;
367 if (isnan(ma->afs1[k]) || isinf(ma->afs1[k])) return -1.;
369 for (k = 0, sum = 0.; k <= ma->M; ++k) {
370 ma->afs[k] += ma->afs1[k];
371 sum += k * ma->afs1[k];
376 long double bcf_p1_cal_g3(bcf_p1aux_t *p1a, double g[3])
378 long double pd = 0., g2[3];
380 memset(g2, 0, sizeof(long double) * 3);
381 for (k = 0; k < p1a->M; ++k) {
382 double f = (double)k / p1a->M, f3[3], g1[3];
384 g1[0] = g1[1] = g1[2] = 0.;
385 f3[0] = (1. - f) * (1. - f); f3[1] = 2. * f * (1. - f); f3[2] = f * f;
386 for (i = 0; i < p1a->n; ++i) {
387 double *pdg = p1a->pdg + i * 3;
388 double x = pdg[0] * f3[0] + pdg[1] * f3[1] + pdg[2] * f3[2];
390 g1[0] += pdg[0] * f3[0] / x;
391 g1[1] += pdg[1] * f3[1] / x;
392 g1[2] += pdg[2] * f3[2] / x;
394 pd += p1a->phi[k] * z;
395 for (i = 0; i < 3; ++i)
396 g2[i] += p1a->phi[k] * z * g1[i];
398 for (i = 0; i < 3; ++i) g[i] = g2[i] / pd;
402 int bcf_p1_cal(bcf1_t *b, bcf_p1aux_t *ma, bcf_p1rst_t *rst)
405 long double sum = 0.;
407 for (i = 0; i < b->n_gi; ++i) {
408 if (b->gi[i].fmt == char2int("PL")) {
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);
418 rst->p_ref = ma->afs1[ma->M];
419 // calculate f_flat and f_em
420 for (k = 0, sum = 0.; k <= ma->M; ++k)
421 sum += (long double)ma->z[k];
423 for (k = 0; k <= ma->M; ++k) {
424 double p = ma->z[k] / sum;
425 rst->f_flat += k * p;
427 rst->f_flat /= ma->M;
429 double flast = rst->f_flat;
430 for (i = 0; i < MC_MAX_EM_ITER; ++i) {
431 rst->f_em = mc_freq_iter(flast, ma);
432 if (fabs(rst->f_em - flast) < MC_EM_EPS) break;
436 rst->g[0] = rst->g[1] = rst->g[2] = -1.;
437 contrast(ma, rst->pc);
438 // bcf_p1_cal_g3(ma, rst->g);
442 void bcf_p1_dump_afs(bcf_p1aux_t *ma)
445 fprintf(stderr, "[afs]");
446 for (k = 0; k <= ma->M; ++k)
447 fprintf(stderr, " %d:%.3lf", k, ma->afs[ma->M - k]);
448 fprintf(stderr, "\n");
449 memset(ma->afs, 0, sizeof(double) * (ma->M + 1));