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
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 {
36 double *q2p, *pdg; // pdg -> P(D|g)
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 init_prior(int type, double theta, int M, double *phi)
49 if (type == MC_PTYPE_COND2) {
50 for (i = 0; i <= M; ++i)
51 phi[i] = 2. * (i + 1) / (M + 1) / (M + 2);
52 } else if (type == MC_PTYPE_FLAT) {
53 for (i = 0; i <= M; ++i)
54 phi[i] = 1. / (M + 1);
57 for (i = 0, sum = 0.; i < M; ++i)
58 sum += (phi[i] = theta / (M - i));
63 void bcf_p1_init_prior(bcf_p1aux_t *ma, int type, double theta)
65 init_prior(type, theta, ma->M, ma->phi);
68 void bcf_p1_init_subprior(bcf_p1aux_t *ma, int type, double theta)
70 if (ma->n1 <= 0 || ma->n1 >= ma->M) return;
71 init_prior(type, theta, 2*ma->n1, ma->phi1);
72 init_prior(type, theta, 2*(ma->n - ma->n1), ma->phi2);
75 int bcf_p1_read_prior(bcf_p1aux_t *ma, const char *fn)
82 memset(&s, 0, sizeof(kstring_t));
83 fp = strcmp(fn, "-")? gzopen(fn, "r") : gzdopen(fileno(stdin), "r");
85 memset(ma->phi, 0, sizeof(double) * (ma->M + 1));
86 while (ks_getuntil(ks, '\n', &s, &dret) >= 0) {
87 if (strstr(s.s, "[afs] ") == s.s) {
89 for (k = 0; k <= ma->M; ++k) {
92 x = strtol(p, &p, 10);
93 if (x != k && (errno == EINVAL || errno == ERANGE)) return -1;
96 if (y == 0. && (errno == EINVAL || errno == ERANGE)) return -1;
97 ma->phi[ma->M - k] += y;
104 for (sum = 0., k = 0; k <= ma->M; ++k) sum += ma->phi[k];
105 fprintf(stderr, "[prior]");
106 for (k = 0; k <= ma->M; ++k) ma->phi[k] /= sum;
107 for (k = 0; k <= ma->M; ++k) fprintf(stderr, " %d:%.3lg", k, ma->phi[ma->M - k]);
109 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));
110 fprintf(stderr, "[%s] heterozygosity=%lf, ", __func__, (double)sum);
111 for (sum = 0., k = 1; k <= ma->M; ++k) sum += k * ma->phi[ma->M - k] / ma->M;
112 fprintf(stderr, "theta=%lf\n", (double)sum);
116 bcf_p1aux_t *bcf_p1_init(int n)
120 ma = calloc(1, sizeof(bcf_p1aux_t));
122 ma->n = n; ma->M = 2 * n;
123 ma->q2p = calloc(256, sizeof(double));
124 ma->pdg = calloc(3 * ma->n, sizeof(double));
125 ma->phi = calloc(ma->M + 1, sizeof(double));
126 ma->phi1 = calloc(ma->M + 1, sizeof(double));
127 ma->phi2 = calloc(ma->M + 1, sizeof(double));
128 ma->z = calloc(2 * ma->n + 1, sizeof(double));
129 ma->zswap = calloc(2 * ma->n + 1, sizeof(double));
130 ma->z1 = calloc(ma->M + 1, sizeof(double)); // actually we do not need this large
131 ma->z2 = calloc(ma->M + 1, sizeof(double));
132 ma->afs = calloc(2 * ma->n + 1, sizeof(double));
133 ma->afs1 = calloc(2 * ma->n + 1, sizeof(double));
134 for (i = 0; i < 256; ++i)
135 ma->q2p[i] = pow(10., -i / 10.);
136 bcf_p1_init_prior(ma, MC_PTYPE_FULL, 1e-3); // the simplest prior
140 int bcf_p1_set_n1(bcf_p1aux_t *b, int n1)
142 if (n1 == 0 || n1 >= b->n) return -1;
147 void bcf_p1_destroy(bcf_p1aux_t *ma)
150 free(ma->q2p); free(ma->pdg);
151 free(ma->phi); free(ma->phi1); free(ma->phi2);
152 free(ma->z); free(ma->zswap); free(ma->z1); free(ma->z2);
153 free(ma->afs); free(ma->afs1);
158 #define char2int(s) (((int)s[0])<<8|s[1])
160 static int cal_pdg(const bcf1_t *b, bcf_p1aux_t *ma)
164 p = alloca(b->n_alleles * sizeof(long));
165 memset(p, 0, sizeof(long) * b->n_alleles);
166 for (j = 0; j < ma->n; ++j) {
167 const uint8_t *pi = ma->PL + j * ma->PL_len;
168 double *pdg = ma->pdg + j * 3;
169 pdg[0] = ma->q2p[pi[b->n_alleles]]; pdg[1] = ma->q2p[pi[1]]; pdg[2] = ma->q2p[pi[0]];
170 for (i = k = 0; i < b->n_alleles; ++i) {
172 k += b->n_alleles - i;
175 for (i = 0; i < b->n_alleles; ++i) p[i] = p[i]<<4 | i;
176 for (i = 1; i < b->n_alleles; ++i) // insertion sort
177 for (j = i; j > 0 && p[j] < p[j-1]; --j)
178 tmp = p[j], p[j] = p[j-1], p[j-1] = tmp;
179 for (i = b->n_alleles - 1; i >= 0; --i)
180 if ((p[i]&0xf) == 0) break;
183 // f0 is the reference allele frequency
184 static double mc_freq_iter(double f0, const bcf_p1aux_t *ma)
188 f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
189 for (i = 0, f = 0.; i < ma->n; ++i) {
191 pdg = ma->pdg + i * 3;
192 f += (pdg[1] * f3[1] + 2. * pdg[2] * f3[2])
193 / (pdg[0] * f3[0] + pdg[1] * f3[1] + pdg[2] * f3[2]);
199 int bcf_p1_call_gt(const bcf_p1aux_t *ma, double f0, int k)
202 double max, f3[3], *pdg = ma->pdg + k * 3;
204 f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
205 for (i = 0, sum = 0.; i < 3; ++i)
206 sum += (g[i] = pdg[i] * f3[i]);
207 for (i = 0, max = -1., max_i = 0; i < 3; ++i) {
209 if (g[i] > max) max = g[i], max_i = i;
212 if (max < 1e-308) max = 1e-308;
213 q = (int)(-4.343 * log(max) + .499);
220 static void mc_cal_y_core(bcf_p1aux_t *ma, int beg)
222 double *z[2], *tmp, *pdg;
223 int _j, last_min, last_max;
227 memset(z[0], 0, sizeof(double) * (ma->M + 1));
228 memset(z[1], 0, sizeof(double) * (ma->M + 1));
230 last_min = last_max = 0;
232 for (_j = beg; _j < ma->n; ++_j) {
233 int k, j = _j - beg, _min = last_min, _max = last_max;
235 pdg = ma->pdg + _j * 3;
236 p[0] = pdg[0]; p[1] = 2. * pdg[1]; p[2] = pdg[2];
237 for (; _min < _max && z[0][_min] < TINY; ++_min) z[0][_min] = z[1][_min] = 0.;
238 for (; _max > _min && z[0][_max] < TINY; --_max) z[0][_max] = z[1][_max] = 0.;
241 k = 0, z[1][k] = (2*j+2-k)*(2*j-k+1) * p[0] * z[0][k];
243 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];
244 for (k = _min < 2? 2 : _min; k <= _max; ++k)
245 z[1][k] = (2*j+2-k)*(2*j-k+1) * p[0] * z[0][k]
246 + k*(2*j+2-k) * p[1] * z[0][k-1]
247 + k*(k-1)* p[2] * z[0][k-2];
248 for (k = _min, sum = 0.; k <= _max; ++k) sum += z[1][k];
249 ma->t += log(sum / ((2. * j + 2) * (2. * j + 1)));
250 for (k = _min; k <= _max; ++k) z[1][k] /= sum;
251 if (_min >= 1) z[1][_min-1] = 0.;
252 if (_min >= 2) z[1][_min-2] = 0.;
253 if (j < ma->n - 1) z[1][_max+1] = z[1][_max+2] = 0.;
254 if (_j == ma->n1 - 1) { // set pop1
256 memcpy(ma->z1, z[1], sizeof(double) * (ma->n1 * 2 + 1));
258 tmp = z[0]; z[0] = z[1]; z[1] = tmp;
259 last_min = _min; last_max = _max;
261 if (z[0] != ma->z) memcpy(ma->z, z[0], sizeof(double) * (ma->M + 1));
264 static void mc_cal_y(bcf_p1aux_t *ma)
266 if (ma->n1 > 0 && ma->n1 < ma->n) {
269 memset(ma->z1, 0, sizeof(double) * (2 * ma->n1 + 1));
270 memset(ma->z2, 0, sizeof(double) * (2 * (ma->n - ma->n1) + 1));
271 ma->t1 = ma->t2 = 0.;
272 mc_cal_y_core(ma, ma->n1);
274 memcpy(ma->z2, ma->z, sizeof(double) * (2 * (ma->n - ma->n1) + 1));
275 mc_cal_y_core(ma, 0);
277 x = expl(ma->t - (ma->t1 + ma->t2));
278 for (k = 0; k <= ma->M; ++k) ma->z[k] *= x;
279 } else mc_cal_y_core(ma, 0);
282 static void contrast(bcf_p1aux_t *ma, double pc[4]) // mc_cal_y() must be called before hand
284 int k, n1 = ma->n1, n2 = ma->n - ma->n1;
285 long double sum1, sum2;
286 pc[0] = pc[1] = pc[2] = pc[3] = -1.;
287 if (n1 <= 0 || n2 <= 0) return;
288 for (k = 0, sum1 = 0.; k <= 2*n1; ++k) sum1 += ma->phi1[k] * ma->z1[k];
289 for (k = 0, sum2 = 0.; k <= 2*n2; ++k) sum2 += ma->phi2[k] * ma->z2[k];
290 pc[2] = ma->phi1[2*n1] * ma->z1[2*n1] / sum1;
291 pc[3] = ma->phi2[2*n2] * ma->z2[2*n2] / sum2;
292 for (k = 2; k < 4; ++k) {
293 pc[k] = pc[k] > .5? -(-4.343 * log(1. - pc[k] + TINY) + .499) : -4.343 * log(pc[k] + TINY) + .499;
295 if (pc[k] > 99) pc[k] = 99;
296 if (pc[k] < -99) pc[k] = -99;
298 pc[0] = ma->phi2[2*n2] * ma->z2[2*n2] / sum2 * (1. - ma->phi1[2*n1] * ma->z1[2*n1] / sum1);
299 pc[1] = ma->phi1[2*n1] * ma->z1[2*n1] / sum1 * (1. - ma->phi2[2*n2] * ma->z2[2*n2] / sum2);
300 pc[0] = pc[0] == 1.? 99 : (int)(-4.343 * log(1. - pc[0]) + .499);
301 pc[1] = pc[1] == 1.? 99 : (int)(-4.343 * log(1. - pc[1]) + .499);
304 static double mc_cal_afs(bcf_p1aux_t *ma)
307 long double sum = 0.;
308 memset(ma->afs1, 0, sizeof(double) * (ma->M + 1));
310 for (k = 0, sum = 0.; k <= ma->M; ++k)
311 sum += (long double)ma->phi[k] * ma->z[k];
312 for (k = 0; k <= ma->M; ++k) {
313 ma->afs1[k] = ma->phi[k] * ma->z[k] / sum;
314 if (isnan(ma->afs1[k]) || isinf(ma->afs1[k])) return -1.;
316 for (k = 0, sum = 0.; k <= ma->M; ++k) {
317 ma->afs[k] += ma->afs1[k];
318 sum += k * ma->afs1[k];
323 long double bcf_p1_cal_g3(bcf_p1aux_t *p1a, double g[3])
325 long double pd = 0., g2[3];
327 memset(g2, 0, sizeof(long double) * 3);
328 for (k = 0; k < p1a->M; ++k) {
329 double f = (double)k / p1a->M, f3[3], g1[3];
331 g1[0] = g1[1] = g1[2] = 0.;
332 f3[0] = (1. - f) * (1. - f); f3[1] = 2. * f * (1. - f); f3[2] = f * f;
333 for (i = 0; i < p1a->n; ++i) {
334 double *pdg = p1a->pdg + i * 3;
335 double x = pdg[0] * f3[0] + pdg[1] * f3[1] + pdg[2] * f3[2];
337 g1[0] += pdg[0] * f3[0] / x;
338 g1[1] += pdg[1] * f3[1] / x;
339 g1[2] += pdg[2] * f3[2] / x;
341 pd += p1a->phi[k] * z;
342 for (i = 0; i < 3; ++i)
343 g2[i] += p1a->phi[k] * z * g1[i];
345 for (i = 0; i < 3; ++i) g[i] = g2[i] / pd;
349 int bcf_p1_cal(bcf1_t *b, bcf_p1aux_t *ma, bcf_p1rst_t *rst)
352 long double sum = 0.;
354 for (i = 0; i < b->n_gi; ++i) {
355 if (b->gi[i].fmt == char2int("PL")) {
356 ma->PL = (uint8_t*)b->gi[i].data;
357 ma->PL_len = b->gi[i].len;
361 if (b->n_alleles < 2) return -1; // FIXME: find a better solution
363 rst->rank0 = cal_pdg(b, ma);
364 rst->f_exp = mc_cal_afs(ma);
365 rst->p_ref = ma->afs1[ma->M];
366 // calculate f_flat and f_em
367 for (k = 0, sum = 0.; k <= ma->M; ++k)
368 sum += (long double)ma->z[k];
370 for (k = 0; k <= ma->M; ++k) {
371 double p = ma->z[k] / sum;
372 rst->f_flat += k * p;
374 rst->f_flat /= ma->M;
376 double flast = rst->f_flat;
377 for (i = 0; i < MC_MAX_EM_ITER; ++i) {
378 rst->f_em = mc_freq_iter(flast, ma);
379 if (fabs(rst->f_em - flast) < MC_EM_EPS) break;
383 rst->g[0] = rst->g[1] = rst->g[2] = -1.;
384 contrast(ma, rst->pc);
388 void bcf_p1_dump_afs(bcf_p1aux_t *ma)
391 fprintf(stderr, "[afs]");
392 for (k = 0; k <= ma->M; ++k)
393 fprintf(stderr, " %d:%.3lf", k, ma->afs[ma->M - k]);
394 fprintf(stderr, "\n");
395 memset(ma->afs, 0, sizeof(double) * (ma->M + 1));