7 #define MC_AVG_ERR 0.007
8 #define MC_MAX_SUMQ 3000
9 #define MC_MAX_SUMQP 1e-300
10 #define MC_MAX_EM_ITER 16
11 #define MC_EM_EPS 1e-4
16 double *q2p, *pdg; // pdg -> P(D|g)
18 double *z, *zswap; // aux for afs
19 double *afs, *afs1; // afs: accumulative AFS; afs1: site posterior distribution
23 void mc_init_prior(mc_aux_t *ma, int type, double theta)
26 if (type == MC_PTYPE_COND2) {
27 for (i = 0; i <= 2 * ma->n; ++i)
28 ma->alpha[i] = 2. * (i + 1) / (2 * ma->n + 1) / (2 * ma->n + 2);
31 for (i = 0, sum = 0.; i < 2 * ma->n; ++i)
32 sum += (ma->alpha[i] = theta / (2 * ma->n - i));
33 ma->alpha[2 * ma->n] = 1. - sum;
37 mc_aux_t *mc_init(int n) // FIXME: assuming diploid
41 ma = calloc(1, sizeof(mc_aux_t));
42 ma->n = n; ma->M = 2 * n;
43 ma->q2p = calloc(MC_MAX_SUMQ + 1, sizeof(double));
44 ma->qsum = calloc(4 * ma->n, sizeof(int));
45 ma->bcnt = calloc(4 * ma->n, sizeof(int));
46 ma->pdg = calloc(3 * ma->n, sizeof(double));
47 ma->alpha = calloc(2 * ma->n + 1, sizeof(double));
48 ma->beta = calloc((2 * ma->n + 1) * 3, sizeof(double));
49 ma->z = calloc(2 * ma->n + 1, sizeof(double));
50 ma->zswap = calloc(2 * ma->n + 1, sizeof(double));
51 ma->afs = calloc(2 * ma->n + 1, sizeof(double));
52 ma->afs1 = calloc(2 * ma->n + 1, sizeof(double));
53 for (i = 0; i <= MC_MAX_SUMQ; ++i)
54 ma->q2p[i] = pow(10., -i / 10.);
55 for (i = 0; i <= ma->M; ++i) { // beta[k][g]=P(g|k/M)
56 double *bi = ma->beta + 3 * i;
57 double f = (double)i / ma->M;
58 bi[0] = (1. - f) * (1. - f);
59 bi[1] = 2 * f * (1. - f);
62 mc_init_prior(ma, MC_PTYPE_FULL, 1e-3); // the simplest prior
66 void mc_destroy(mc_aux_t *ma)
69 free(ma->qsum); free(ma->bcnt);
70 free(ma->q2p); free(ma->pdg);
71 free(ma->alpha); free(ma->beta);
72 free(ma->z); free(ma->zswap);
73 free(ma->afs); free(ma->afs1);
78 static int sum_err(int *n, const bam_pileup1_t **plp, mc_aux_t *ma)
81 memset(ma->qsum, 0, sizeof(int) * 4 * ma->n);
82 memset(ma->bcnt, 0, sizeof(int) * 4 * ma->n);
83 for (j = 0; j < ma->n; ++j) {
84 int *qsum = ma->qsum + j * 4;
85 int *bcnt = ma->bcnt + j * 4;
86 for (i = 0; i < n[j]; ++i) {
87 const bam_pileup1_t *p = plp[j] + i;
89 if (p->is_del || (p->b->core.flag&BAM_FUNMAP)) continue;
90 q = bam1_qual(p->b)[p->qpos];
91 if (p->b->core.qual < q) q = p->b->core.qual;
92 if (q < MC_MIN_QUAL) continue; // small qual
93 b = bam_nt16_nt4_table[(int)bam1_seqi(bam1_seq(p->b), p->qpos)];
94 if (b > 3) continue; // N
103 static void set_allele(int ref, mc_aux_t *ma)
105 int i, j, sum[4], tmp;
106 sum[0] = sum[1] = sum[2] = sum[3] = 0;
107 for (i = 0; i < ma->n; ++i)
108 for (j = 0; j < 4; ++j)
109 sum[j] += ma->qsum[i * 4 + j];
110 for (j = 0; j < 4; ++j) sum[j] = sum[j]<<2 | j;
111 for (i = 1; i < 4; ++i) // insertion sort
112 for (j = i; j > 0 && sum[j] < sum[j-1]; --j)
113 tmp = sum[j], sum[j] = sum[j-1], sum[j-1] = tmp;
114 ma->ref = sum[3]&3; ma->alt = sum[2]&3;
115 if (ref == ma->alt) tmp = ma->ref, ma->ref = ma->alt, ma->alt = tmp;
116 // note that ma->ref might not be ref in case of triallele
119 static void cal_pdg(mc_aux_t *ma)
122 for (j = 0; j < ma->n; ++j) {
123 int pi[3], *qsum, *bcnt;
124 double *pdg = ma->pdg + j * 3;
125 qsum = ma->qsum + j * 4;
126 bcnt = ma->bcnt + j * 4;
127 pi[1] = 3 * (bcnt[ma->ref] + bcnt[ma->alt]);
128 pi[0] = qsum[ma->ref];
129 pi[2] = qsum[ma->alt];
130 for (i = 0; i < 3; ++i)
131 pdg[i] = pi[i] > MC_MAX_SUMQ? MC_MAX_SUMQP : ma->q2p[pi[i]];
134 // this calculates the naive allele frequency and Nielsen's frequency
135 static double mc_freq0(const mc_aux_t *ma, double *_f)
138 double f, f_nielsen, w_sum;
140 for (i = cnt = 0, f = f_nielsen = w_sum = 0.; i < ma->n; ++i) {
141 int *bcnt = ma->bcnt + i * 4;
142 int x = bcnt[ma->ref] + bcnt[ma->alt];
146 f += (double)bcnt[ma->ref] / x;
147 p = (bcnt[ma->ref] - MC_AVG_ERR * x) / (1. - 2. * MC_AVG_ERR) / x;
148 w = 2. * x / (1. + x);
155 if (f_nielsen < 0.) f_nielsen = 0.;
156 if (f_nielsen > 1.) f_nielsen = 1.;
161 // f0 is the reference allele frequency
162 static double mc_freq_iter(double f0, const mc_aux_t *ma)
166 f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
167 for (i = 0, f = 0.; i < ma->n; ++i) {
169 pdg = ma->pdg + i * 3;
170 f += (pdg[1] * f3[1] + 2. * pdg[2] * f3[2])
171 / (pdg[0] * f3[0] + pdg[1] * f3[1] + pdg[2] * f3[2]);
177 static double mc_ref_prob(const mc_aux_t *ma, double *_PD, double *f_exp)
180 long double PD = 0., Pref = 0., Ef = 0.;
181 for (k = 0; k <= ma->M; ++k) {
182 long double x = 1., y = 0.;
183 double *bk = ma->beta + k * 3;
184 for (i = 0; i < ma->n; ++i) {
185 double *pdg = ma->pdg + i * 3;
186 double z = pdg[0] * bk[0] + pdg[1] * bk[1] + pdg[2] * bk[2];
188 y += (pdg[1] * bk[1] + 2. * pdg[2] * bk[2]) / z;
190 PD += x * ma->alpha[k];
191 Ef += x * y * ma->alpha[k];
193 for (k = 0; k <= ma->n * 2; ++k) {
195 for (i = 0; i < ma->n; ++i)
196 x *= ma->pdg[i * 3 + 2] * ma->beta[k * 3 + 2];
197 Pref += x * ma->alpha[k];
199 *f_exp = (double)(Ef / PD / ma->M);
204 int mc_call_gt(const mc_aux_t *ma, double f0, int k)
207 double max, f3[3], *pdg = ma->pdg + k * 3;
209 f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
210 for (i = 0, sum = 0.; i < 3; ++i)
211 sum += (g[i] = pdg[i] * f3[i]);
212 for (i = 0, max = -1., max_i = 0; i < 3; ++i) {
214 if (g[i] > max) max = g[i], max_i = i;
217 if (max < 1e-308) max = 1e-308;
218 q = (int)(-3.434 * log(max) + .499);
222 // calculate z_{nr}^{(k)}
223 static void mc_cal_z(mc_aux_t *ma, int k)
225 double *z[2], *tmp, *bk, *pdg;
229 bk = ma->beta + k * 3; pdg = ma->pdg;
230 z[0][0] = 1.; z[0][1] = z[0][2] = 0.;
231 for (j = 0; j < ma->n; ++j) {
232 int max = (j + 1) * 2;
234 pdg = ma->pdg + j * 3;
235 p[0] = bk[0] * pdg[0]; p[1] = bk[1] * pdg[1]; p[2] = bk[2] * pdg[2];
236 z[1][0] = p[0] * z[0][0];
237 z[1][1] = p[0] * z[0][1] + p[1] * z[0][0];
238 for (i = 2; i <= max; ++i)
239 z[1][i] = p[0] * z[0][i] + p[1] * z[0][i-1] + p[2] * z[0][i-2];
240 if (j < ma->n - 1) z[1][max+1] = z[1][max+2] = 0.;
241 tmp = z[0]; z[0] = z[1]; z[1] = tmp;
243 if (z[0] != ma->z) memcpy(ma->z, z[0], sizeof(double) * (2 * ma->n + 1));
245 // Warning: this is cubic in ma->n, very sloooooow
246 static void mc_add_afs(mc_aux_t *ma, double PD, double *f_map, double *p_map)
250 memset(ma->afs1, 0, sizeof(double) * (2 * ma->n + 1));
251 for (k = 0; k <= 2 * ma->n; ++k) {
253 for (l = 0; l <= 2 * ma->n; ++l)
254 ma->afs1[l] += ma->alpha[k] * ma->z[l] / PD;
256 for (k = 0; k <= 2 * ma->n; ++k) {
257 ma->afs[k] += ma->afs1[k];
262 double max = -1., e = 0.;
263 for (k = 0; k <= 2 * ma->n; ++k) {
264 if (ma->afs1[k] > max) max = ma->afs1[k], max_k = k;
265 e += k * ma->afs1[k];
267 *f_map = .5 * max_k / ma->n; *p_map = max; // e should equal mc_rst_t::f_exp
268 // printf(" * %.3lg:%.3lg:%.3lg:%.3lg * ", sum, 1.-.5*max_k/ma->n, max, 1.-.5*e/ma->n);
272 int mc_cal(int ref, int *n, const bam_pileup1_t **plp, mc_aux_t *ma, mc_rst_t *rst, int level)
275 memset(rst, 0, sizeof(mc_rst_t));
276 rst->f_em = rst->f_exp = -1.; rst->ref = rst->alt = -1;
278 tot = sum_err(n, plp, ma);
279 if (tot == 0) return 0; // no good bases
282 // set ref/major allele
283 rst->ref = ma->ref; rst->alt = ma->alt;
284 // calculate naive and Nielsen's freq
285 rst->f_naive = mc_freq0(ma, &rst->f_nielsen);
287 double flast = rst->f_naive;
288 for (i = 0; i < MC_MAX_EM_ITER; ++i) {
289 rst->f_em = mc_freq_iter(flast, ma);
290 if (fabs(rst->f_em - flast) < MC_EM_EPS) break;
294 if (level >= 2) // quadratic-time calculations; necessary for genotyping
295 rst->p_ref = mc_ref_prob(ma, &rst->PD, &rst->f_exp);
297 mc_add_afs(ma, rst->PD, &rst->f_map, &rst->p_map);
301 void mc_dump_afs(mc_aux_t *ma)
304 fprintf(stderr, "[afs]");
305 for (k = 0; k <= ma->M; ++k)
306 fprintf(stderr, " %d:%.3lf", k, ma->afs[ma->M - k]);
307 fprintf(stderr, "\n");
308 memset(ma->afs, 0, sizeof(double) * (ma->M + 1));