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)
17 double *phi, *CMk; // CMk=\binom{M}{k}
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->phi[i] = 2. * (i + 1) / (2 * ma->n + 1) / (2 * ma->n + 2);
29 } else if (type == MC_PTYPE_FLAT) {
30 for (i = 0; i <= ma->M; ++i)
31 ma->phi[i] = 1. / (ma->M + 1);
34 for (i = 0, sum = 0.; i < 2 * ma->n; ++i)
35 sum += (ma->phi[i] = theta / (2 * ma->n - i));
36 ma->phi[2 * ma->n] = 1. - sum;
40 mc_aux_t *mc_init(int n) // FIXME: assuming diploid
44 ma = calloc(1, sizeof(mc_aux_t));
45 ma->n = n; ma->M = 2 * n;
46 ma->q2p = calloc(MC_MAX_SUMQ + 1, sizeof(double));
47 ma->qsum = calloc(4 * ma->n, sizeof(int));
48 ma->bcnt = calloc(4 * ma->n, sizeof(int));
49 ma->pdg = calloc(3 * ma->n, sizeof(double));
50 ma->phi = calloc(ma->M + 1, sizeof(double));
51 ma->CMk = calloc(ma->M + 1, sizeof(double));
52 ma->z = calloc(2 * ma->n + 1, sizeof(double));
53 ma->zswap = calloc(2 * ma->n + 1, sizeof(double));
54 ma->afs = calloc(2 * ma->n + 1, sizeof(double));
55 ma->afs1 = calloc(2 * ma->n + 1, sizeof(double));
56 for (i = 0; i <= MC_MAX_SUMQ; ++i)
57 ma->q2p[i] = pow(10., -i / 10.);
58 for (i = 0; i <= ma->M; ++i)
59 ma->CMk[i] = exp(lgamma(ma->M + 1) - lgamma(i + 1) - lgamma(ma->M - i + 1));
60 mc_init_prior(ma, MC_PTYPE_FULL, 1e-3); // the simplest prior
64 void mc_destroy(mc_aux_t *ma)
67 free(ma->qsum); free(ma->bcnt);
68 free(ma->q2p); free(ma->pdg);
69 free(ma->phi); free(ma->CMk);
70 free(ma->z); free(ma->zswap);
71 free(ma->afs); free(ma->afs1);
76 static int sum_err(int *n, const bam_pileup1_t **plp, mc_aux_t *ma)
79 memset(ma->qsum, 0, sizeof(int) * 4 * ma->n);
80 memset(ma->bcnt, 0, sizeof(int) * 4 * ma->n);
81 for (j = 0; j < ma->n; ++j) {
82 int *qsum = ma->qsum + j * 4;
83 int *bcnt = ma->bcnt + j * 4;
84 for (i = 0; i < n[j]; ++i) {
85 const bam_pileup1_t *p = plp[j] + i;
87 if (p->is_del || (p->b->core.flag&BAM_FUNMAP)) continue;
88 q = bam1_qual(p->b)[p->qpos];
89 if (p->b->core.qual < q) q = p->b->core.qual;
90 if (q < MC_MIN_QUAL) continue; // small qual
91 b = bam_nt16_nt4_table[(int)bam1_seqi(bam1_seq(p->b), p->qpos)];
92 if (b > 3) continue; // N
101 static void set_allele(int ref, mc_aux_t *ma)
103 int i, j, sum[4], tmp;
104 sum[0] = sum[1] = sum[2] = sum[3] = 0;
105 for (i = 0; i < ma->n; ++i)
106 for (j = 0; j < 4; ++j)
107 sum[j] += ma->qsum[i * 4 + j];
108 for (j = 0; j < 4; ++j) sum[j] = sum[j]<<2 | j;
109 for (i = 1; i < 4; ++i) // insertion sort
110 for (j = i; j > 0 && sum[j] < sum[j-1]; --j)
111 tmp = sum[j], sum[j] = sum[j-1], sum[j-1] = tmp;
112 ma->ref = sum[3]&3; ma->alt = sum[2]&3; ma->alt2 = -1;
113 if (ma->ref != ref) { // the best base is not ref
114 if (ref >= 0 && ref <= 3) { // ref is not N
115 if (ma->alt == ref) tmp = ma->ref, ma->ref = ma->alt, ma->alt = tmp; // then switch alt and ref
116 else ma->alt2 = ma->alt, ma->alt = ma->ref, ma->ref = ref; // then set ref as ref
117 } else ma->alt2 = ma->alt, ma->alt = ma->ref, ma->ref = sum[0]&3; // then set the weakest as ref
121 static void cal_pdg(mc_aux_t *ma)
124 for (j = 0; j < ma->n; ++j) {
125 int pi[3], *qsum, *bcnt;
126 double *pdg = ma->pdg + j * 3;
127 qsum = ma->qsum + j * 4;
128 bcnt = ma->bcnt + j * 4;
129 pi[1] = 3 * (bcnt[ma->ref] + bcnt[ma->alt]);
130 pi[0] = qsum[ma->ref];
131 pi[2] = qsum[ma->alt];
132 for (i = 0; i < 3; ++i)
133 pdg[i] = pi[i] > MC_MAX_SUMQ? MC_MAX_SUMQP : ma->q2p[pi[i]];
136 // this calculates the naive allele frequency and Nielsen's frequency
137 static double mc_freq0(const mc_aux_t *ma, double *_f)
140 double f, f_nielsen, w_sum;
142 for (i = cnt = 0, f = f_nielsen = w_sum = 0.; i < ma->n; ++i) {
143 int *bcnt = ma->bcnt + i * 4;
144 int x = bcnt[ma->ref] + bcnt[ma->alt];
148 f += (double)bcnt[ma->ref] / x;
149 p = (bcnt[ma->ref] - MC_AVG_ERR * x) / (1. - 2. * MC_AVG_ERR) / x;
150 w = 2. * x / (1. + x);
157 if (f_nielsen < 0.) f_nielsen = 0.;
158 if (f_nielsen > 1.) f_nielsen = 1.;
163 // f0 is the reference allele frequency
164 static double mc_freq_iter(double f0, const mc_aux_t *ma)
168 f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
169 for (i = 0, f = 0.; i < ma->n; ++i) {
171 pdg = ma->pdg + i * 3;
172 f += (pdg[1] * f3[1] + 2. * pdg[2] * f3[2])
173 / (pdg[0] * f3[0] + pdg[1] * f3[1] + pdg[2] * f3[2]);
179 int mc_call_gt(const mc_aux_t *ma, double f0, int k)
182 double max, f3[3], *pdg = ma->pdg + k * 3;
184 f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
185 for (i = 0, sum = 0.; i < 3; ++i)
186 sum += (g[i] = pdg[i] * f3[i]);
187 for (i = 0, max = -1., max_i = 0; i < 3; ++i) {
189 if (g[i] > max) max = g[i], max_i = i;
192 if (max < 1e-308) max = 1e-308;
193 q = (int)(-3.434 * log(max) + .499);
198 static void mc_cal_z(mc_aux_t *ma)
200 double *z[2], *tmp, *pdg;
205 z[0][0] = 1.; z[0][1] = z[0][2] = 0.;
206 for (j = 0; j < ma->n; ++j) {
207 int max = (j + 1) * 2;
209 pdg = ma->pdg + j * 3;
210 p[0] = pdg[0]; p[1] = 2. * pdg[1]; p[2] = pdg[2];
211 z[1][0] = p[0] * z[0][0];
212 z[1][1] = p[0] * z[0][1] + p[1] * z[0][0];
213 for (i = 2; i <= max; ++i)
214 z[1][i] = p[0] * z[0][i] + p[1] * z[0][i-1] + p[2] * z[0][i-2];
215 if (j < ma->n - 1) z[1][max+1] = z[1][max+2] = 0.;
216 // int k; for (k = 0; k <= max; ++k) printf("%d:%.3lg ", k, z[1][k]); putchar('\n');
217 tmp = z[0]; z[0] = z[1]; z[1] = tmp;
219 if (z[0] != ma->z) memcpy(ma->z, z[0], sizeof(double) * (2 * ma->n + 1));
222 static double mc_add_afs(mc_aux_t *ma)
225 long double sum = 0.;
226 memset(ma->afs1, 0, sizeof(double) * (ma->M + 1));
228 for (k = 0, sum = 0.; k <= ma->M; ++k)
229 sum += (long double)ma->phi[k] * ma->z[k] / ma->CMk[k];
230 for (k = 0; k <= ma->M; ++k) {
231 ma->afs1[k] = ma->phi[k] * ma->z[k] / ma->CMk[k] / sum;
232 if (isnan(ma->afs1[k]) || isinf(ma->afs1[k])) return -1.;
234 for (k = 0, sum = 0.; k <= ma->M; ++k) {
235 ma->afs[k] += ma->afs1[k];
236 sum += k * ma->afs1[k];
241 int mc_cal(int ref, int *n, const bam_pileup1_t **plp, mc_aux_t *ma, mc_rst_t *rst, int level)
244 memset(rst, 0, sizeof(mc_rst_t));
245 rst->f_em = rst->f_exp = -1.; rst->ref = rst->alt = -1;
247 tot = sum_err(n, plp, ma);
248 if (tot == 0) return 0; // no good bases
251 // set ref/major allele
252 rst->ref = ma->ref; rst->alt = ma->alt; rst->alt2 = ma->alt2;
253 // calculate naive and Nielsen's freq
254 rst->f_naive = mc_freq0(ma, &rst->f_nielsen);
256 double flast = rst->f_naive;
257 for (i = 0; i < MC_MAX_EM_ITER; ++i) {
258 rst->f_em = mc_freq_iter(flast, ma);
259 if (fabs(rst->f_em - flast) < MC_EM_EPS) break;
264 rst->f_exp = mc_add_afs(ma);
265 rst->p_ref = ma->afs1[ma->M];
270 void mc_dump_afs(mc_aux_t *ma)
273 fprintf(stderr, "[afs]");
274 for (k = 0; k <= ma->M; ++k)
275 fprintf(stderr, " %d:%.3lf", k, ma->afs[ma->M - k]);
276 fprintf(stderr, "\n");
277 memset(ma->afs, 0, sizeof(double) * (ma->M + 1));