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1 #include <math.h>
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2 #include <stdlib.h>
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3 #include <string.h>
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4 #include <stdio.h>
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5 #include <errno.h>
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6 #include <assert.h>
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7 #include <limits.h>
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8 #include <zlib.h>
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9 #include "prob1.h"
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10 #include "kstring.h"
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11
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12 #include "kseq.h"
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13 KSTREAM_INIT(gzFile, gzread, 16384)
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14
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15 #define MC_MAX_EM_ITER 16
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16 #define MC_EM_EPS 1e-5
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17 #define MC_DEF_INDEL 0.15
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18
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19 gzFile bcf_p1_fp_lk;
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20
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21 unsigned char seq_nt4_table[256] = {
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22 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
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23 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
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24 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4 /*'-'*/, 4, 4,
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25 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
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26 4, 0, 4, 1, 4, 4, 4, 2, 4, 4, 4, 4, 4, 4, 4, 4,
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27 4, 4, 4, 4, 3, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
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28 4, 0, 4, 1, 4, 4, 4, 2, 4, 4, 4, 4, 4, 4, 4, 4,
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29 4, 4, 4, 4, 3, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
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30 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
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31 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
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32 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
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33 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
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34 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
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35 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
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36 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4,
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37 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4
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38 };
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39
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40 struct __bcf_p1aux_t {
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41 int n, M, n1, is_indel;
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42 uint8_t *ploidy; // haploid or diploid ONLY
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43 double *q2p, *pdg; // pdg -> P(D|g)
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44 double *phi, *phi_indel;
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45 double *z, *zswap; // aux for afs
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46 double *z1, *z2, *phi1, *phi2; // only calculated when n1 is set
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47 double **hg; // hypergeometric distribution
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48 double *lf; // log factorial
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49 double t, t1, t2;
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50 double *afs, *afs1; // afs: accumulative AFS; afs1: site posterior distribution
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51 const uint8_t *PL; // point to PL
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52 int PL_len;
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53 };
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54
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55 void bcf_p1_indel_prior(bcf_p1aux_t *ma, double x)
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56 {
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57 int i;
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58 for (i = 0; i < ma->M; ++i)
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59 ma->phi_indel[i] = ma->phi[i] * x;
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60 ma->phi_indel[ma->M] = 1. - ma->phi[ma->M] * x;
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61 }
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62
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63 static void init_prior(int type, double theta, int M, double *phi)
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64 {
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65 int i;
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66 if (type == MC_PTYPE_COND2) {
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67 for (i = 0; i <= M; ++i)
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68 phi[i] = 2. * (i + 1) / (M + 1) / (M + 2);
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69 } else if (type == MC_PTYPE_FLAT) {
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70 for (i = 0; i <= M; ++i)
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71 phi[i] = 1. / (M + 1);
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72 } else {
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73 double sum;
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74 for (i = 0, sum = 0.; i < M; ++i)
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75 sum += (phi[i] = theta / (M - i));
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76 phi[M] = 1. - sum;
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77 }
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78 }
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79
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80 void bcf_p1_init_prior(bcf_p1aux_t *ma, int type, double theta)
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81 {
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82 init_prior(type, theta, ma->M, ma->phi);
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83 bcf_p1_indel_prior(ma, MC_DEF_INDEL);
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84 }
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85
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86 void bcf_p1_init_subprior(bcf_p1aux_t *ma, int type, double theta)
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87 {
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88 if (ma->n1 <= 0 || ma->n1 >= ma->M) return;
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89 init_prior(type, theta, 2*ma->n1, ma->phi1);
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90 init_prior(type, theta, 2*(ma->n - ma->n1), ma->phi2);
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91 }
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92
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93 int bcf_p1_read_prior(bcf_p1aux_t *ma, const char *fn)
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94 {
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95 gzFile fp;
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96 kstring_t s;
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97 kstream_t *ks;
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98 long double sum;
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99 int dret, k;
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100 memset(&s, 0, sizeof(kstring_t));
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101 fp = strcmp(fn, "-")? gzopen(fn, "r") : gzdopen(fileno(stdin), "r");
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102 ks = ks_init(fp);
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103 memset(ma->phi, 0, sizeof(double) * (ma->M + 1));
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104 while (ks_getuntil(ks, '\n', &s, &dret) >= 0) {
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105 if (strstr(s.s, "[afs] ") == s.s) {
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106 char *p = s.s + 6;
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107 for (k = 0; k <= ma->M; ++k) {
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108 int x;
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109 double y;
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110 x = strtol(p, &p, 10);
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111 if (x != k && (errno == EINVAL || errno == ERANGE)) return -1;
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112 ++p;
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113 y = strtod(p, &p);
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114 if (y == 0. && (errno == EINVAL || errno == ERANGE)) return -1;
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115 ma->phi[ma->M - k] += y;
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116 }
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117 }
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118 }
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119 ks_destroy(ks);
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120 gzclose(fp);
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121 free(s.s);
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122 for (sum = 0., k = 0; k <= ma->M; ++k) sum += ma->phi[k];
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123 fprintf(stderr, "[prior]");
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124 for (k = 0; k <= ma->M; ++k) ma->phi[k] /= sum;
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125 for (k = 0; k <= ma->M; ++k) fprintf(stderr, " %d:%.3lg", k, ma->phi[ma->M - k]);
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126 fputc('\n', stderr);
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127 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));
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128 fprintf(stderr, "[%s] heterozygosity=%lf, ", __func__, (double)sum);
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129 for (sum = 0., k = 1; k <= ma->M; ++k) sum += k * ma->phi[ma->M - k] / ma->M;
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130 fprintf(stderr, "theta=%lf\n", (double)sum);
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131 bcf_p1_indel_prior(ma, MC_DEF_INDEL);
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132 return 0;
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133 }
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134
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135 bcf_p1aux_t *bcf_p1_init(int n, uint8_t *ploidy)
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136 {
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137 bcf_p1aux_t *ma;
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138 int i;
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139 ma = calloc(1, sizeof(bcf_p1aux_t));
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140 ma->n1 = -1;
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141 ma->n = n; ma->M = 2 * n;
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142 if (ploidy) {
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143 ma->ploidy = malloc(n);
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144 memcpy(ma->ploidy, ploidy, n);
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145 for (i = 0, ma->M = 0; i < n; ++i) ma->M += ploidy[i];
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146 if (ma->M == 2 * n) {
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147 free(ma->ploidy);
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148 ma->ploidy = 0;
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149 }
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150 }
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151 ma->q2p = calloc(256, sizeof(double));
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152 ma->pdg = calloc(3 * ma->n, sizeof(double));
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153 ma->phi = calloc(ma->M + 1, sizeof(double));
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154 ma->phi_indel = calloc(ma->M + 1, sizeof(double));
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155 ma->phi1 = calloc(ma->M + 1, sizeof(double));
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156 ma->phi2 = calloc(ma->M + 1, sizeof(double));
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157 ma->z = calloc(ma->M + 1, sizeof(double));
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158 ma->zswap = calloc(ma->M + 1, sizeof(double));
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159 ma->z1 = calloc(ma->M + 1, sizeof(double)); // actually we do not need this large
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160 ma->z2 = calloc(ma->M + 1, sizeof(double));
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161 ma->afs = calloc(ma->M + 1, sizeof(double));
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162 ma->afs1 = calloc(ma->M + 1, sizeof(double));
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163 ma->lf = calloc(ma->M + 1, sizeof(double));
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164 for (i = 0; i < 256; ++i)
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165 ma->q2p[i] = pow(10., -i / 10.);
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166 for (i = 0; i <= ma->M; ++i) ma->lf[i] = lgamma(i + 1);
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167 bcf_p1_init_prior(ma, MC_PTYPE_FULL, 1e-3); // the simplest prior
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168 return ma;
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169 }
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170
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171 int bcf_p1_get_M(bcf_p1aux_t *b) { return b->M; }
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172
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173 int bcf_p1_set_n1(bcf_p1aux_t *b, int n1)
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174 {
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175 if (n1 == 0 || n1 >= b->n) return -1;
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176 if (b->M != b->n * 2) {
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177 fprintf(stderr, "[%s] unable to set `n1' when there are haploid samples.\n", __func__);
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178 return -1;
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179 }
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180 b->n1 = n1;
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181 return 0;
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182 }
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183
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184 void bcf_p1_set_ploidy(bcf1_t *b, bcf_p1aux_t *ma)
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185 {
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186 // bcf_p1aux_t fields are not visible outside of prob1.c, hence this wrapper.
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187 // Ideally, this should set ploidy per site to allow pseudo-autosomal regions
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188 b->ploidy = ma->ploidy;
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189 }
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190
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191 void bcf_p1_destroy(bcf_p1aux_t *ma)
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192 {
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193 if (ma) {
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194 int k;
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195 free(ma->lf);
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196 if (ma->hg && ma->n1 > 0) {
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197 for (k = 0; k <= 2*ma->n1; ++k) free(ma->hg[k]);
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198 free(ma->hg);
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199 }
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200 free(ma->ploidy); free(ma->q2p); free(ma->pdg);
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201 free(ma->phi); free(ma->phi_indel); free(ma->phi1); free(ma->phi2);
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202 free(ma->z); free(ma->zswap); free(ma->z1); free(ma->z2);
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203 free(ma->afs); free(ma->afs1);
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204 free(ma);
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205 }
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206 }
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207
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208 extern double kf_gammap(double s, double z);
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209 int test16(bcf1_t *b, anno16_t *a);
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210
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211 // Wigginton 2005, PMID: 15789306
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212 // written by Jan Wigginton
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213 double calc_hwe(int obs_hom1, int obs_hom2, int obs_hets)
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214 {
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215 if (obs_hom1 + obs_hom2 + obs_hets == 0 ) return 1;
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216
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217 assert(obs_hom1 >= 0 && obs_hom2 >= 0 && obs_hets >= 0);
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218
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219 int obs_homc = obs_hom1 < obs_hom2 ? obs_hom2 : obs_hom1;
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220 int obs_homr = obs_hom1 < obs_hom2 ? obs_hom1 : obs_hom2;
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221
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222 int rare_copies = 2 * obs_homr + obs_hets;
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223 int genotypes = obs_hets + obs_homc + obs_homr;
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224
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225 double *het_probs = (double*) calloc(rare_copies+1, sizeof(double));
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226
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227 /* start at midpoint */
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228 int mid = rare_copies * (2 * genotypes - rare_copies) / (2 * genotypes);
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229
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230 /* check to ensure that midpoint and rare alleles have same parity */
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231 if ((rare_copies & 1) ^ (mid & 1)) mid++;
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232
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233 int curr_hets = mid;
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234 int curr_homr = (rare_copies - mid) / 2;
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235 int curr_homc = genotypes - curr_hets - curr_homr;
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236
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237 het_probs[mid] = 1.0;
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238 double sum = het_probs[mid];
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239 for (curr_hets = mid; curr_hets > 1; curr_hets -= 2)
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240 {
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241 het_probs[curr_hets - 2] = het_probs[curr_hets] * curr_hets * (curr_hets - 1.0) / (4.0 * (curr_homr + 1.0) * (curr_homc + 1.0));
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242 sum += het_probs[curr_hets - 2];
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243
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244 /* 2 fewer heterozygotes for next iteration -> add one rare, one common homozygote */
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245 curr_homr++;
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246 curr_homc++;
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247 }
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248
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249 curr_hets = mid;
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250 curr_homr = (rare_copies - mid) / 2;
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251 curr_homc = genotypes - curr_hets - curr_homr;
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252 for (curr_hets = mid; curr_hets <= rare_copies - 2; curr_hets += 2)
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253 {
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254 het_probs[curr_hets + 2] = het_probs[curr_hets] * 4.0 * curr_homr * curr_homc /((curr_hets + 2.0) * (curr_hets + 1.0));
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255 sum += het_probs[curr_hets + 2];
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256
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257 /* add 2 heterozygotes for next iteration -> subtract one rare, one common homozygote */
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258 curr_homr--;
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259 curr_homc--;
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260 }
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261 int i;
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262 for (i = 0; i <= rare_copies; i++) het_probs[i] /= sum;
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263
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264 /* p-value calculation for p_hwe */
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265 double p_hwe = 0.0;
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266 for (i = 0; i <= rare_copies; i++)
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267 {
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268 if (het_probs[i] > het_probs[obs_hets])
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269 continue;
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270 p_hwe += het_probs[i];
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271 }
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272
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273 p_hwe = p_hwe > 1.0 ? 1.0 : p_hwe;
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274 free(het_probs);
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275 return p_hwe;
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276
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277 }
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278
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279
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280 static void _bcf1_set_ref(bcf1_t *b, int idp)
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281 {
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282 kstring_t s;
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283 int old_n_gi = b->n_gi;
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284 s.m = b->m_str; s.l = b->l_str - 1; s.s = b->str;
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285 kputs(":GT", &s); kputc('\0', &s);
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286 b->m_str = s.m; b->l_str = s.l; b->str = s.s;
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287 bcf_sync(b);
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288
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289 // Call GTs
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290 int isample, an = 0;
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291 for (isample = 0; isample < b->n_smpl; isample++)
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292 {
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293 if ( idp>=0 && ((uint16_t*)b->gi[idp].data)[isample]==0 )
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294 ((uint8_t*)b->gi[old_n_gi].data)[isample] = 1<<7;
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295 else
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296 {
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297 ((uint8_t*)b->gi[old_n_gi].data)[isample] = 0;
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298 an += b->ploidy ? b->ploidy[isample] : 2;
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299 }
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300 }
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301 bcf_fit_alt(b,1);
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302 b->qual = 999;
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303
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304 // Prepare BCF for output: ref, alt, filter, info, format
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305 memset(&s, 0, sizeof(kstring_t)); kputc('\0', &s);
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306 kputs(b->ref, &s); kputc('\0', &s);
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307 kputs(b->alt, &s); kputc('\0', &s); kputc('\0', &s);
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308 {
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309 ksprintf(&s, "AN=%d;", an);
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310 kputs(b->info, &s);
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311 anno16_t a;
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312 int has_I16 = test16(b, &a) >= 0? 1 : 0;
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313 if (has_I16 )
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314 {
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315 if ( a.is_tested) ksprintf(&s, ";PV4=%.2g,%.2g,%.2g,%.2g", a.p[0], a.p[1], a.p[2], a.p[3]);
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316 ksprintf(&s, ";DP4=%d,%d,%d,%d;MQ=%d", a.d[0], a.d[1], a.d[2], a.d[3], a.mq);
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317 }
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318 kputc('\0', &s);
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319 rm_info(&s, "I16=");
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320 rm_info(&s, "QS=");
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321 }
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322 kputs(b->fmt, &s); kputc('\0', &s);
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323 free(b->str);
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324 b->m_str = s.m; b->l_str = s.l; b->str = s.s;
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325 bcf_sync(b);
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326 }
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327
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328 int call_multiallelic_gt(bcf1_t *b, bcf_p1aux_t *ma, double threshold, int var_only)
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329 {
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330 int nals = 1;
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331 char *p;
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332 for (p=b->alt; *p; p++)
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333 {
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334 if ( *p=='X' || p[0]=='.' ) break;
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335 if ( p[0]==',' ) nals++;
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336 }
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337 if ( b->alt[0] && !*p ) nals++;
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338
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339 if ( nals>4 )
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340 {
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341 if ( *b->ref=='N' ) return 0;
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342 fprintf(stderr,"Not ready for this, more than 4 alleles at %d: %s, %s\n", b->pos+1, b->ref,b->alt);
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343 exit(1);
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344 }
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345
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346 // find PL, DV and DP FORMAT indexes
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347 uint8_t *pl = NULL;
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348 int i, npl = 0, idp = -1, idv = -1;
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349 for (i = 0; i < b->n_gi; ++i)
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350 {
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351 if (b->gi[i].fmt == bcf_str2int("PL", 2))
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352 {
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353 pl = (uint8_t*)b->gi[i].data;
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354 npl = b->gi[i].len;
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355 }
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356 else if (b->gi[i].fmt == bcf_str2int("DP", 2)) idp=i;
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357 else if (b->gi[i].fmt == bcf_str2int("DV", 2)) idv=i;
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358 }
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359 if ( nals==1 )
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360 {
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361 if ( !var_only ) _bcf1_set_ref(b, idp);
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362 return 1;
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363 }
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364 if ( !pl ) return -1;
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365
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366 assert(ma->q2p[0] == 1);
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367
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368 // Init P(D|G)
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369 int npdg = nals*(nals+1)/2;
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370 double *pdg,*_pdg;
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371 _pdg = pdg = malloc(sizeof(double)*ma->n*npdg);
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372 for (i=0; i<ma->n; i++)
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373 {
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374 int j;
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375 double sum = 0;
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376 for (j=0; j<npdg; j++)
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377 {
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378 //_pdg[j] = pow(10,-0.1*pl[j]);
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379 _pdg[j] = ma->q2p[pl[j]];
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380 sum += _pdg[j];
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381 }
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382 if ( sum )
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383 for (j=0; j<npdg; j++) _pdg[j] /= sum;
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384 _pdg += npdg;
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385 pl += npl;
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386 }
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387
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388 if ((p = strstr(b->info, "QS=")) == 0) { fprintf(stderr,"INFO/QS is required with -m, exiting\n"); exit(1); }
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389 double qsum[4];
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390 if ( sscanf(p+3,"%lf,%lf,%lf,%lf",&qsum[0],&qsum[1],&qsum[2],&qsum[3])!=4 ) { fprintf(stderr,"Could not parse %s\n",p); exit(1); }
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391
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392
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393 // Calculate the most likely combination of alleles, remembering the most and second most likely set
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394 int ia,ib,ic, max_als=0, max_als2=0;
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395 double ref_lk = 0, max_lk = INT_MIN, max_lk2 = INT_MIN, lk_sum = INT_MIN, lk_sums[3];
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396 for (ia=0; ia<nals; ia++)
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397 {
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398 double lk_tot = 0;
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399 int iaa = (ia+1)*(ia+2)/2-1;
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400 int isample;
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401 for (isample=0; isample<ma->n; isample++)
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402 {
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403 double *p = pdg + isample*npdg;
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404 // assert( log(p[iaa]) <= 0 );
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405 lk_tot += log(p[iaa]);
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406 }
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407 if ( ia==0 ) ref_lk = lk_tot;
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408 if ( max_lk<lk_tot ) { max_lk2 = max_lk; max_als2 = max_als; max_lk = lk_tot; max_als = 1<<ia; }
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409 else if ( max_lk2<lk_tot ) { max_lk2 = lk_tot; max_als2 = 1<<ia; }
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410 lk_sum = lk_tot>lk_sum ? lk_tot + log(1+exp(lk_sum-lk_tot)) : lk_sum + log(1+exp(lk_tot-lk_sum));
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411 }
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412 lk_sums[0] = lk_sum;
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413 if ( nals>1 )
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414 {
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415 for (ia=0; ia<nals; ia++)
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416 {
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417 if ( qsum[ia]==0 ) continue;
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418 int iaa = (ia+1)*(ia+2)/2-1;
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419 for (ib=0; ib<ia; ib++)
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420 {
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421 if ( qsum[ib]==0 ) continue;
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422 double lk_tot = 0;
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423 double fa = qsum[ia]/(qsum[ia]+qsum[ib]);
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424 double fb = qsum[ib]/(qsum[ia]+qsum[ib]);
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425 double fab = 2*fa*fb; fa *= fa; fb *= fb;
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426 int isample, ibb = (ib+1)*(ib+2)/2-1, iab = iaa - ia + ib;
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427 for (isample=0; isample<ma->n; isample++)
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428 {
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429 double *p = pdg + isample*npdg;
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430 //assert( log(fa*p[iaa] + fb*p[ibb] + fab*p[iab]) <= 0 );
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431 if ( b->ploidy && b->ploidy[isample]==1 )
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432 lk_tot += log(fa*p[iaa] + fb*p[ibb]);
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433 else
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434 lk_tot += log(fa*p[iaa] + fb*p[ibb] + fab*p[iab]);
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435 }
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436 if ( max_lk<lk_tot ) { max_lk2 = max_lk; max_als2 = max_als; max_lk = lk_tot; max_als = 1<<ia|1<<ib; }
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437 else if ( max_lk2<lk_tot ) { max_lk2 = lk_tot; max_als2 = 1<<ia|1<<ib; }
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438 lk_sum = lk_tot>lk_sum ? lk_tot + log(1+exp(lk_sum-lk_tot)) : lk_sum + log(1+exp(lk_tot-lk_sum));
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439 }
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440 }
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441 lk_sums[1] = lk_sum;
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442 }
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443 if ( nals>2 )
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444 {
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445 for (ia=0; ia<nals; ia++)
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446 {
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447 if ( qsum[ia]==0 ) continue;
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448 int iaa = (ia+1)*(ia+2)/2-1;
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449 for (ib=0; ib<ia; ib++)
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450 {
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451 if ( qsum[ib]==0 ) continue;
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452 int ibb = (ib+1)*(ib+2)/2-1;
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453 int iab = iaa - ia + ib;
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454 for (ic=0; ic<ib; ic++)
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455 {
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456 if ( qsum[ic]==0 ) continue;
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457 double lk_tot = 0;
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458 double fa = qsum[ia]/(qsum[ia]+qsum[ib]+qsum[ic]);
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459 double fb = qsum[ib]/(qsum[ia]+qsum[ib]+qsum[ic]);
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460 double fc = qsum[ic]/(qsum[ia]+qsum[ib]+qsum[ic]);
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461 double fab = 2*fa*fb, fac = 2*fa*fc, fbc = 2*fb*fc; fa *= fa; fb *= fb; fc *= fc;
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462 int isample, icc = (ic+1)*(ic+2)/2-1;
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463 int iac = iaa - ia + ic, ibc = ibb - ib + ic;
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464 for (isample=0; isample<ma->n; isample++)
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465 {
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466 double *p = pdg + isample*npdg;
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467 //assert( log(fa*p[iaa] + fb*p[ibb] + fc*p[icc] + fab*p[iab] + fac*p[iac] + fbc*p[ibc]) <= 0 );
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468 if ( b->ploidy && b->ploidy[isample]==1 )
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469 lk_tot += log(fa*p[iaa] + fb*p[ibb] + fc*p[icc]);
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470 else
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471 lk_tot += log(fa*p[iaa] + fb*p[ibb] + fc*p[icc] + fab*p[iab] + fac*p[iac] + fbc*p[ibc]);
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472 }
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473 if ( max_lk<lk_tot ) { max_lk2 = max_lk; max_als2 = max_als; max_lk = lk_tot; max_als = 1<<ia|1<<ib|1<<ic; }
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474 else if ( max_lk2<lk_tot ) { max_lk2 = lk_tot; max_als2 = 1<<ia|1<<ib|1<<ic; }
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475 lk_sum = lk_tot>lk_sum ? lk_tot + log(1+exp(lk_sum-lk_tot)) : lk_sum + log(1+exp(lk_tot-lk_sum));
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476 }
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477 }
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478 }
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479 lk_sums[2] = lk_sum;
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480 }
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481
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482 // Should we add another allele, does it increase the likelihood significantly?
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483 int n1=0, n2=0;
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484 for (i=0; i<nals; i++) if ( max_als&1<<i) n1++;
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485 for (i=0; i<nals; i++) if ( max_als2&1<<i) n2++;
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486 if ( n2<n1 && kf_gammap(1,2.0*(max_lk-max_lk2))<threshold )
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487 {
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488 // the threshold not exceeded, use the second most likely set with fewer alleles
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489 max_lk = max_lk2;
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490 max_als = max_als2;
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491 n1 = n2;
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492 }
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493 lk_sum = lk_sums[n1-1];
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494
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495 // Get the BCF record ready for GT and GQ
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496 kstring_t s;
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497 int old_n_gi = b->n_gi;
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498 s.m = b->m_str; s.l = b->l_str - 1; s.s = b->str;
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499 kputs(":GT:GQ", &s); kputc('\0', &s);
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500 b->m_str = s.m; b->l_str = s.l; b->str = s.s;
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501 bcf_sync(b);
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502
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503 // Call GTs
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504 int isample, gts=0, ac[4] = {0,0,0,0};
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505 int nRR = 0, nAA = 0, nRA = 0, max_dv = 0;
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506 for (isample = 0; isample < b->n_smpl; isample++)
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507 {
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508 int ploidy = b->ploidy ? b->ploidy[isample] : 2;
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509 double *p = pdg + isample*npdg;
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510 int ia, als = 0;
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511 double lk = 0, lk_s = 0;
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512 for (ia=0; ia<nals; ia++)
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513 {
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514 if ( !(max_als&1<<ia) ) continue;
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515 int iaa = (ia+1)*(ia+2)/2-1;
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516 double _lk = p[iaa]*qsum[ia]*qsum[ia];
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517 if ( _lk > lk ) { lk = _lk; als = ia<<3 | ia; }
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518 lk_s += _lk;
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519 }
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520 if ( ploidy==2 )
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521 {
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522 for (ia=0; ia<nals; ia++)
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523 {
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524 if ( !(max_als&1<<ia) ) continue;
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525 int iaa = (ia+1)*(ia+2)/2-1;
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526 for (ib=0; ib<ia; ib++)
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527 {
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528 if ( !(max_als&1<<ib) ) continue;
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529 int iab = iaa - ia + ib;
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530 double _lk = 2*qsum[ia]*qsum[ib]*p[iab];
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531 if ( _lk > lk ) { lk = _lk; als = ib<<3 | ia; }
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532 lk_s += _lk;
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533 }
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534 }
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535 }
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536 lk = -log(1-lk/lk_s)/0.2302585;
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537 int dp = 0;
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538 if ( idp>=0 && (dp=((uint16_t*)b->gi[idp].data)[isample])==0 )
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539 {
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540 // no coverage
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541 ((uint8_t*)b->gi[old_n_gi].data)[isample] = 1<<7;
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542 ((uint8_t*)b->gi[old_n_gi+1].data)[isample] = 0;
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543 continue;
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544 }
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545 if ( lk>99 ) lk = 99;
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546 ((uint8_t*)b->gi[old_n_gi].data)[isample] = als;
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547 ((uint8_t*)b->gi[old_n_gi+1].data)[isample] = (int)lk;
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548
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549 // For MDV annotation
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550 int dv;
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551 if ( als && idv>=0 && (dv=((uint16_t*)b->gi[idv].data)[isample]) )
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552 {
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553 if ( max_dv < dv ) max_dv = dv;
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554 }
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555
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556 // For HWE annotation; multiple ALT alleles treated as one
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557 if ( !als ) nRR++;
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558 else if ( !(als>>3&7) || !(als&7) ) nRA++;
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559 else nAA++;
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560
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561 gts |= 1<<(als>>3&7) | 1<<(als&7);
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562 ac[ als>>3&7 ]++;
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563 ac[ als&7 ]++;
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564 }
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565 free(pdg);
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566 bcf_fit_alt(b,max_als);
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567
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568 // The VCF spec is ambiguous about QUAL: is it the probability of anything else
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569 // (that is QUAL(non-ref) = P(ref)+P(any non-ref other than ALT)) or is it
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570 // QUAL(non-ref)=P(ref) and QUAL(ref)=1-P(ref)? Assuming the latter.
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571 b->qual = gts>1 ? -4.343*(ref_lk - lk_sum) : -4.343*log(1-exp(ref_lk - lk_sum));
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572 if ( b->qual>999 ) b->qual = 999;
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573
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574 // Prepare BCF for output: ref, alt, filter, info, format
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575 memset(&s, 0, sizeof(kstring_t)); kputc('\0', &s);
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576 kputs(b->ref, &s); kputc('\0', &s);
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577 kputs(b->alt, &s); kputc('\0', &s); kputc('\0', &s);
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578 {
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579 int an=0, nalts=0;
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580 for (i=0; i<nals; i++)
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581 {
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582 an += ac[i];
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583 if ( i>0 && ac[i] ) nalts++;
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584 }
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585 ksprintf(&s, "AN=%d;", an);
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586 if ( nalts )
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587 {
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588 kputs("AC=", &s);
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589 for (i=1; i<nals; i++)
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590 {
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591 if ( !(gts&1<<i) ) continue;
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592 nalts--;
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593 ksprintf(&s,"%d", ac[i]);
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594 if ( nalts>0 ) kputc(',', &s);
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595 }
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596 kputc(';', &s);
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597 }
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598 kputs(b->info, &s);
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599 anno16_t a;
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600 int has_I16 = test16(b, &a) >= 0? 1 : 0;
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601 if (has_I16 )
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602 {
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603 if ( a.is_tested) ksprintf(&s, ";PV4=%.2g,%.2g,%.2g,%.2g", a.p[0], a.p[1], a.p[2], a.p[3]);
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604 ksprintf(&s, ";DP4=%d,%d,%d,%d;MQ=%d", a.d[0], a.d[1], a.d[2], a.d[3], a.mq);
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605 ksprintf(&s, ";QBD=%e", b->qual/(a.d[0] + a.d[1] + a.d[2] + a.d[3]));
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606 if ( max_dv ) ksprintf(&s, ";MDV=%d", max_dv);
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607 }
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608 if ( nAA+nRA )
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609 {
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610 double hwe = calc_hwe(nAA, nRR, nRA);
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611 ksprintf(&s, ";HWE=%e", hwe);
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612 }
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613 kputc('\0', &s);
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614 rm_info(&s, "I16=");
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615 rm_info(&s, "QS=");
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616 }
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617 kputs(b->fmt, &s); kputc('\0', &s);
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618 free(b->str);
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619 b->m_str = s.m; b->l_str = s.l; b->str = s.s;
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620 bcf_sync(b);
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621
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622 return gts;
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623 }
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624
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625 static int cal_pdg(const bcf1_t *b, bcf_p1aux_t *ma)
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626 {
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627 int i, j;
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628 long *p, tmp;
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629 p = alloca(b->n_alleles * sizeof(long));
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630 memset(p, 0, sizeof(long) * b->n_alleles);
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631 for (j = 0; j < ma->n; ++j) {
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632 const uint8_t *pi = ma->PL + j * ma->PL_len;
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633 double *pdg = ma->pdg + j * 3;
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634 pdg[0] = ma->q2p[pi[2]]; pdg[1] = ma->q2p[pi[1]]; pdg[2] = ma->q2p[pi[0]];
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635 for (i = 0; i < b->n_alleles; ++i)
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636 p[i] += (int)pi[(i+1)*(i+2)/2-1];
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637 }
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638 for (i = 0; i < b->n_alleles; ++i) p[i] = p[i]<<4 | i;
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639 for (i = 1; i < b->n_alleles; ++i) // insertion sort
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640 for (j = i; j > 0 && p[j] < p[j-1]; --j)
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641 tmp = p[j], p[j] = p[j-1], p[j-1] = tmp;
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642 for (i = b->n_alleles - 1; i >= 0; --i)
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643 if ((p[i]&0xf) == 0) break;
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644 return i;
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645 }
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646
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647
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648 int bcf_p1_call_gt(const bcf_p1aux_t *ma, double f0, int k)
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649 {
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650 double sum, g[3];
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651 double max, f3[3], *pdg = ma->pdg + k * 3;
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|
|
652 int q, i, max_i, ploidy;
|
|
|
653 ploidy = ma->ploidy? ma->ploidy[k] : 2;
|
|
|
654 if (ploidy == 2) {
|
|
|
655 f3[0] = (1.-f0)*(1.-f0); f3[1] = 2.*f0*(1.-f0); f3[2] = f0*f0;
|
|
|
656 } else {
|
|
|
657 f3[0] = 1. - f0; f3[1] = 0; f3[2] = f0;
|
|
|
658 }
|
|
|
659 for (i = 0, sum = 0.; i < 3; ++i)
|
|
|
660 sum += (g[i] = pdg[i] * f3[i]);
|
|
|
661 for (i = 0, max = -1., max_i = 0; i < 3; ++i) {
|
|
|
662 g[i] /= sum;
|
|
|
663 if (g[i] > max) max = g[i], max_i = i;
|
|
|
664 }
|
|
|
665 max = 1. - max;
|
|
|
666 if (max < 1e-308) max = 1e-308;
|
|
|
667 q = (int)(-4.343 * log(max) + .499);
|
|
|
668 if (q > 99) q = 99;
|
|
|
669 return q<<2|max_i;
|
|
|
670 }
|
|
|
671
|
|
|
672 #define TINY 1e-20
|
|
|
673
|
|
|
674 static void mc_cal_y_core(bcf_p1aux_t *ma, int beg)
|
|
|
675 {
|
|
|
676 double *z[2], *tmp, *pdg;
|
|
|
677 int _j, last_min, last_max;
|
|
|
678 assert(beg == 0 || ma->M == ma->n*2);
|
|
|
679 z[0] = ma->z;
|
|
|
680 z[1] = ma->zswap;
|
|
|
681 pdg = ma->pdg;
|
|
|
682 memset(z[0], 0, sizeof(double) * (ma->M + 1));
|
|
|
683 memset(z[1], 0, sizeof(double) * (ma->M + 1));
|
|
|
684 z[0][0] = 1.;
|
|
|
685 last_min = last_max = 0;
|
|
|
686 ma->t = 0.;
|
|
|
687 if (ma->M == ma->n * 2) {
|
|
|
688 int M = 0;
|
|
|
689 for (_j = beg; _j < ma->n; ++_j) {
|
|
|
690 int k, j = _j - beg, _min = last_min, _max = last_max, M0;
|
|
|
691 double p[3], sum;
|
|
|
692 M0 = M; M += 2;
|
|
|
693 pdg = ma->pdg + _j * 3;
|
|
|
694 p[0] = pdg[0]; p[1] = 2. * pdg[1]; p[2] = pdg[2];
|
|
|
695 for (; _min < _max && z[0][_min] < TINY; ++_min) z[0][_min] = z[1][_min] = 0.;
|
|
|
696 for (; _max > _min && z[0][_max] < TINY; --_max) z[0][_max] = z[1][_max] = 0.;
|
|
|
697 _max += 2;
|
|
|
698 if (_min == 0) k = 0, z[1][k] = (M0-k+1) * (M0-k+2) * p[0] * z[0][k];
|
|
|
699 if (_min <= 1) k = 1, z[1][k] = (M0-k+1) * (M0-k+2) * p[0] * z[0][k] + k*(M0-k+2) * p[1] * z[0][k-1];
|
|
|
700 for (k = _min < 2? 2 : _min; k <= _max; ++k)
|
|
|
701 z[1][k] = (M0-k+1)*(M0-k+2) * p[0] * z[0][k] + k*(M0-k+2) * p[1] * z[0][k-1] + k*(k-1)* p[2] * z[0][k-2];
|
|
|
702 for (k = _min, sum = 0.; k <= _max; ++k) sum += z[1][k];
|
|
|
703 ma->t += log(sum / (M * (M - 1.)));
|
|
|
704 for (k = _min; k <= _max; ++k) z[1][k] /= sum;
|
|
|
705 if (_min >= 1) z[1][_min-1] = 0.;
|
|
|
706 if (_min >= 2) z[1][_min-2] = 0.;
|
|
|
707 if (j < ma->n - 1) z[1][_max+1] = z[1][_max+2] = 0.;
|
|
|
708 if (_j == ma->n1 - 1) { // set pop1; ma->n1==-1 when unset
|
|
|
709 ma->t1 = ma->t;
|
|
|
710 memcpy(ma->z1, z[1], sizeof(double) * (ma->n1 * 2 + 1));
|
|
|
711 }
|
|
|
712 tmp = z[0]; z[0] = z[1]; z[1] = tmp;
|
|
|
713 last_min = _min; last_max = _max;
|
|
|
714 }
|
|
|
715 //for (_j = 0; _j < last_min; ++_j) z[0][_j] = 0.; // TODO: are these necessary?
|
|
|
716 //for (_j = last_max + 1; _j < ma->M; ++_j) z[0][_j] = 0.;
|
|
|
717 } else { // this block is very similar to the block above; these two might be merged in future
|
|
|
718 int j, M = 0;
|
|
|
719 for (j = 0; j < ma->n; ++j) {
|
|
|
720 int k, M0, _min = last_min, _max = last_max;
|
|
|
721 double p[3], sum;
|
|
|
722 pdg = ma->pdg + j * 3;
|
|
|
723 for (; _min < _max && z[0][_min] < TINY; ++_min) z[0][_min] = z[1][_min] = 0.;
|
|
|
724 for (; _max > _min && z[0][_max] < TINY; --_max) z[0][_max] = z[1][_max] = 0.;
|
|
|
725 M0 = M;
|
|
|
726 M += ma->ploidy[j];
|
|
|
727 if (ma->ploidy[j] == 1) {
|
|
|
728 p[0] = pdg[0]; p[1] = pdg[2];
|
|
|
729 _max++;
|
|
|
730 if (_min == 0) k = 0, z[1][k] = (M0+1-k) * p[0] * z[0][k];
|
|
|
731 for (k = _min < 1? 1 : _min; k <= _max; ++k)
|
|
|
732 z[1][k] = (M0+1-k) * p[0] * z[0][k] + k * p[1] * z[0][k-1];
|
|
|
733 for (k = _min, sum = 0.; k <= _max; ++k) sum += z[1][k];
|
|
|
734 ma->t += log(sum / M);
|
|
|
735 for (k = _min; k <= _max; ++k) z[1][k] /= sum;
|
|
|
736 if (_min >= 1) z[1][_min-1] = 0.;
|
|
|
737 if (j < ma->n - 1) z[1][_max+1] = 0.;
|
|
|
738 } else if (ma->ploidy[j] == 2) {
|
|
|
739 p[0] = pdg[0]; p[1] = 2 * pdg[1]; p[2] = pdg[2];
|
|
|
740 _max += 2;
|
|
|
741 if (_min == 0) k = 0, z[1][k] = (M0-k+1) * (M0-k+2) * p[0] * z[0][k];
|
|
|
742 if (_min <= 1) k = 1, z[1][k] = (M0-k+1) * (M0-k+2) * p[0] * z[0][k] + k*(M0-k+2) * p[1] * z[0][k-1];
|
|
|
743 for (k = _min < 2? 2 : _min; k <= _max; ++k)
|
|
|
744 z[1][k] = (M0-k+1)*(M0-k+2) * p[0] * z[0][k] + k*(M0-k+2) * p[1] * z[0][k-1] + k*(k-1)* p[2] * z[0][k-2];
|
|
|
745 for (k = _min, sum = 0.; k <= _max; ++k) sum += z[1][k];
|
|
|
746 ma->t += log(sum / (M * (M - 1.)));
|
|
|
747 for (k = _min; k <= _max; ++k) z[1][k] /= sum;
|
|
|
748 if (_min >= 1) z[1][_min-1] = 0.;
|
|
|
749 if (_min >= 2) z[1][_min-2] = 0.;
|
|
|
750 if (j < ma->n - 1) z[1][_max+1] = z[1][_max+2] = 0.;
|
|
|
751 }
|
|
|
752 tmp = z[0]; z[0] = z[1]; z[1] = tmp;
|
|
|
753 last_min = _min; last_max = _max;
|
|
|
754 }
|
|
|
755 }
|
|
|
756 if (z[0] != ma->z) memcpy(ma->z, z[0], sizeof(double) * (ma->M + 1));
|
|
|
757 if (bcf_p1_fp_lk)
|
|
|
758 gzwrite(bcf_p1_fp_lk, ma->z, sizeof(double) * (ma->M + 1));
|
|
|
759 }
|
|
|
760
|
|
|
761 static void mc_cal_y(bcf_p1aux_t *ma)
|
|
|
762 {
|
|
|
763 if (ma->n1 > 0 && ma->n1 < ma->n && ma->M == ma->n * 2) { // NB: ma->n1 is ineffective when there are haploid samples
|
|
|
764 int k;
|
|
|
765 long double x;
|
|
|
766 memset(ma->z1, 0, sizeof(double) * (2 * ma->n1 + 1));
|
|
|
767 memset(ma->z2, 0, sizeof(double) * (2 * (ma->n - ma->n1) + 1));
|
|
|
768 ma->t1 = ma->t2 = 0.;
|
|
|
769 mc_cal_y_core(ma, ma->n1);
|
|
|
770 ma->t2 = ma->t;
|
|
|
771 memcpy(ma->z2, ma->z, sizeof(double) * (2 * (ma->n - ma->n1) + 1));
|
|
|
772 mc_cal_y_core(ma, 0);
|
|
|
773 // rescale z
|
|
|
774 x = expl(ma->t - (ma->t1 + ma->t2));
|
|
|
775 for (k = 0; k <= ma->M; ++k) ma->z[k] *= x;
|
|
|
776 } else mc_cal_y_core(ma, 0);
|
|
|
777 }
|
|
|
778
|
|
|
779 #define CONTRAST_TINY 1e-30
|
|
|
780
|
|
|
781 extern double kf_gammaq(double s, double z); // incomplete gamma function for chi^2 test
|
|
|
782
|
|
|
783 static inline double chi2_test(int a, int b, int c, int d)
|
|
|
784 {
|
|
|
785 double x, z;
|
|
|
786 x = (double)(a+b) * (c+d) * (b+d) * (a+c);
|
|
|
787 if (x == 0.) return 1;
|
|
|
788 z = a * d - b * c;
|
|
|
789 return kf_gammaq(.5, .5 * z * z * (a+b+c+d) / x);
|
|
|
790 }
|
|
|
791
|
|
|
792 // chi2=(a+b+c+d)(ad-bc)^2/[(a+b)(c+d)(a+c)(b+d)]
|
|
|
793 static inline double contrast2_aux(const bcf_p1aux_t *p1, double sum, int k1, int k2, double x[3])
|
|
|
794 {
|
|
|
795 double p = p1->phi[k1+k2] * p1->z1[k1] * p1->z2[k2] / sum * p1->hg[k1][k2];
|
|
|
796 int n1 = p1->n1, n2 = p1->n - p1->n1;
|
|
|
797 if (p < CONTRAST_TINY) return -1;
|
|
|
798 if (.5*k1/n1 < .5*k2/n2) x[1] += p;
|
|
|
799 else if (.5*k1/n1 > .5*k2/n2) x[2] += p;
|
|
|
800 else x[0] += p;
|
|
|
801 return p * chi2_test(k1, k2, (n1<<1) - k1, (n2<<1) - k2);
|
|
|
802 }
|
|
|
803
|
|
|
804 static double contrast2(bcf_p1aux_t *p1, double ret[3])
|
|
|
805 {
|
|
|
806 int k, k1, k2, k10, k20, n1, n2;
|
|
|
807 double sum;
|
|
|
808 // get n1 and n2
|
|
|
809 n1 = p1->n1; n2 = p1->n - p1->n1;
|
|
|
810 if (n1 <= 0 || n2 <= 0) return 0.;
|
|
|
811 if (p1->hg == 0) { // initialize the hypergeometric distribution
|
|
|
812 /* NB: the hg matrix may take a lot of memory when there are many samples. There is a way
|
|
|
813 to avoid precomputing this matrix, but it is slower and quite intricate. The following
|
|
|
814 computation in this block can be accelerated with a similar strategy, but perhaps this
|
|
|
815 is not a serious concern for now. */
|
|
|
816 double tmp = lgamma(2*(n1+n2)+1) - (lgamma(2*n1+1) + lgamma(2*n2+1));
|
|
|
817 p1->hg = calloc(2*n1+1, sizeof(void*));
|
|
|
818 for (k1 = 0; k1 <= 2*n1; ++k1) {
|
|
|
819 p1->hg[k1] = calloc(2*n2+1, sizeof(double));
|
|
|
820 for (k2 = 0; k2 <= 2*n2; ++k2)
|
|
|
821 p1->hg[k1][k2] = exp(lgamma(k1+k2+1) + lgamma(p1->M-k1-k2+1) - (lgamma(k1+1) + lgamma(k2+1) + lgamma(2*n1-k1+1) + lgamma(2*n2-k2+1) + tmp));
|
|
|
822 }
|
|
|
823 }
|
|
|
824 { // compute
|
|
|
825 long double suml = 0;
|
|
|
826 for (k = 0; k <= p1->M; ++k) suml += p1->phi[k] * p1->z[k];
|
|
|
827 sum = suml;
|
|
|
828 }
|
|
|
829 { // get the max k1 and k2
|
|
|
830 double max;
|
|
|
831 int max_k;
|
|
|
832 for (k = 0, max = 0, max_k = -1; k <= 2*n1; ++k) {
|
|
|
833 double x = p1->phi1[k] * p1->z1[k];
|
|
|
834 if (x > max) max = x, max_k = k;
|
|
|
835 }
|
|
|
836 k10 = max_k;
|
|
|
837 for (k = 0, max = 0, max_k = -1; k <= 2*n2; ++k) {
|
|
|
838 double x = p1->phi2[k] * p1->z2[k];
|
|
|
839 if (x > max) max = x, max_k = k;
|
|
|
840 }
|
|
|
841 k20 = max_k;
|
|
|
842 }
|
|
|
843 { // We can do the following with one nested loop, but that is an O(N^2) thing. The following code block is much faster for large N.
|
|
|
844 double x[3], y;
|
|
|
845 long double z = 0., L[2];
|
|
|
846 x[0] = x[1] = x[2] = 0; L[0] = L[1] = 0;
|
|
|
847 for (k1 = k10; k1 >= 0; --k1) {
|
|
|
848 for (k2 = k20; k2 >= 0; --k2) {
|
|
|
849 if ((y = contrast2_aux(p1, sum, k1, k2, x)) < 0) break;
|
|
|
850 else z += y;
|
|
|
851 }
|
|
|
852 for (k2 = k20 + 1; k2 <= 2*n2; ++k2) {
|
|
|
853 if ((y = contrast2_aux(p1, sum, k1, k2, x)) < 0) break;
|
|
|
854 else z += y;
|
|
|
855 }
|
|
|
856 }
|
|
|
857 ret[0] = x[0]; ret[1] = x[1]; ret[2] = x[2];
|
|
|
858 x[0] = x[1] = x[2] = 0;
|
|
|
859 for (k1 = k10 + 1; k1 <= 2*n1; ++k1) {
|
|
|
860 for (k2 = k20; k2 >= 0; --k2) {
|
|
|
861 if ((y = contrast2_aux(p1, sum, k1, k2, x)) < 0) break;
|
|
|
862 else z += y;
|
|
|
863 }
|
|
|
864 for (k2 = k20 + 1; k2 <= 2*n2; ++k2) {
|
|
|
865 if ((y = contrast2_aux(p1, sum, k1, k2, x)) < 0) break;
|
|
|
866 else z += y;
|
|
|
867 }
|
|
|
868 }
|
|
|
869 ret[0] += x[0]; ret[1] += x[1]; ret[2] += x[2];
|
|
|
870 if (ret[0] + ret[1] + ret[2] < 0.95) { // in case of bad things happened
|
|
|
871 ret[0] = ret[1] = ret[2] = 0; L[0] = L[1] = 0;
|
|
|
872 for (k1 = 0, z = 0.; k1 <= 2*n1; ++k1)
|
|
|
873 for (k2 = 0; k2 <= 2*n2; ++k2)
|
|
|
874 if ((y = contrast2_aux(p1, sum, k1, k2, ret)) >= 0) z += y;
|
|
|
875 if (ret[0] + ret[1] + ret[2] < 0.95) // It seems that this may be caused by floating point errors. I do not really understand why...
|
|
|
876 z = 1.0, ret[0] = ret[1] = ret[2] = 1./3;
|
|
|
877 }
|
|
|
878 return (double)z;
|
|
|
879 }
|
|
|
880 }
|
|
|
881
|
|
|
882 static double mc_cal_afs(bcf_p1aux_t *ma, double *p_ref_folded, double *p_var_folded)
|
|
|
883 {
|
|
|
884 int k;
|
|
|
885 long double sum = 0., sum2;
|
|
|
886 double *phi = ma->is_indel? ma->phi_indel : ma->phi;
|
|
|
887 memset(ma->afs1, 0, sizeof(double) * (ma->M + 1));
|
|
|
888 mc_cal_y(ma);
|
|
|
889 // compute AFS
|
|
|
890 for (k = 0, sum = 0.; k <= ma->M; ++k)
|
|
|
891 sum += (long double)phi[k] * ma->z[k];
|
|
|
892 for (k = 0; k <= ma->M; ++k) {
|
|
|
893 ma->afs1[k] = phi[k] * ma->z[k] / sum;
|
|
|
894 if (isnan(ma->afs1[k]) || isinf(ma->afs1[k])) return -1.;
|
|
|
895 }
|
|
|
896 // compute folded variant probability
|
|
|
897 for (k = 0, sum = 0.; k <= ma->M; ++k)
|
|
|
898 sum += (long double)(phi[k] + phi[ma->M - k]) / 2. * ma->z[k];
|
|
|
899 for (k = 1, sum2 = 0.; k < ma->M; ++k)
|
|
|
900 sum2 += (long double)(phi[k] + phi[ma->M - k]) / 2. * ma->z[k];
|
|
|
901 *p_var_folded = sum2 / sum;
|
|
|
902 *p_ref_folded = (phi[k] + phi[ma->M - k]) / 2. * (ma->z[ma->M] + ma->z[0]) / sum;
|
|
|
903 // the expected frequency
|
|
|
904 for (k = 0, sum = 0.; k <= ma->M; ++k) {
|
|
|
905 ma->afs[k] += ma->afs1[k];
|
|
|
906 sum += k * ma->afs1[k];
|
|
|
907 }
|
|
|
908 return sum / ma->M;
|
|
|
909 }
|
|
|
910
|
|
|
911 int bcf_p1_cal(const bcf1_t *b, int do_contrast, bcf_p1aux_t *ma, bcf_p1rst_t *rst)
|
|
|
912 {
|
|
|
913 int i, k;
|
|
|
914 long double sum = 0.;
|
|
|
915 ma->is_indel = bcf_is_indel(b);
|
|
|
916 rst->perm_rank = -1;
|
|
|
917 // set PL and PL_len
|
|
|
918 for (i = 0; i < b->n_gi; ++i) {
|
|
|
919 if (b->gi[i].fmt == bcf_str2int("PL", 2)) {
|
|
|
920 ma->PL = (uint8_t*)b->gi[i].data;
|
|
|
921 ma->PL_len = b->gi[i].len;
|
|
|
922 break;
|
|
|
923 }
|
|
|
924 }
|
|
|
925 if (i == b->n_gi) return -1; // no PL
|
|
|
926 if (b->n_alleles < 2) return -1; // FIXME: find a better solution
|
|
|
927 //
|
|
|
928 rst->rank0 = cal_pdg(b, ma);
|
|
|
929 rst->f_exp = mc_cal_afs(ma, &rst->p_ref_folded, &rst->p_var_folded);
|
|
|
930 rst->p_ref = ma->afs1[ma->M];
|
|
|
931 for (k = 0, sum = 0.; k < ma->M; ++k)
|
|
|
932 sum += ma->afs1[k];
|
|
|
933 rst->p_var = (double)sum;
|
|
|
934 { // compute the allele count
|
|
|
935 double max = -1;
|
|
|
936 rst->ac = -1;
|
|
|
937 for (k = 0; k <= ma->M; ++k)
|
|
|
938 if (max < ma->z[k]) max = ma->z[k], rst->ac = k;
|
|
|
939 rst->ac = ma->M - rst->ac;
|
|
|
940 }
|
|
|
941 // calculate f_flat and f_em
|
|
|
942 for (k = 0, sum = 0.; k <= ma->M; ++k)
|
|
|
943 sum += (long double)ma->z[k];
|
|
|
944 rst->f_flat = 0.;
|
|
|
945 for (k = 0; k <= ma->M; ++k) {
|
|
|
946 double p = ma->z[k] / sum;
|
|
|
947 rst->f_flat += k * p;
|
|
|
948 }
|
|
|
949 rst->f_flat /= ma->M;
|
|
|
950 { // estimate equal-tail credible interval (95% level)
|
|
|
951 int l, h;
|
|
|
952 double p;
|
|
|
953 for (i = 0, p = 0.; i <= ma->M; ++i)
|
|
|
954 if (p + ma->afs1[i] > 0.025) break;
|
|
|
955 else p += ma->afs1[i];
|
|
|
956 l = i;
|
|
|
957 for (i = ma->M, p = 0.; i >= 0; --i)
|
|
|
958 if (p + ma->afs1[i] > 0.025) break;
|
|
|
959 else p += ma->afs1[i];
|
|
|
960 h = i;
|
|
|
961 rst->cil = (double)(ma->M - h) / ma->M; rst->cih = (double)(ma->M - l) / ma->M;
|
|
|
962 }
|
|
|
963 if (ma->n1 > 0) { // compute LRT
|
|
|
964 double max0, max1, max2;
|
|
|
965 for (k = 0, max0 = -1; k <= ma->M; ++k)
|
|
|
966 if (max0 < ma->z[k]) max0 = ma->z[k];
|
|
|
967 for (k = 0, max1 = -1; k <= ma->n1 * 2; ++k)
|
|
|
968 if (max1 < ma->z1[k]) max1 = ma->z1[k];
|
|
|
969 for (k = 0, max2 = -1; k <= ma->M - ma->n1 * 2; ++k)
|
|
|
970 if (max2 < ma->z2[k]) max2 = ma->z2[k];
|
|
|
971 rst->lrt = log(max1 * max2 / max0);
|
|
|
972 rst->lrt = rst->lrt < 0? 1 : kf_gammaq(.5, rst->lrt);
|
|
|
973 } else rst->lrt = -1.0;
|
|
|
974 rst->cmp[0] = rst->cmp[1] = rst->cmp[2] = rst->p_chi2 = -1.0;
|
|
|
975 if (do_contrast && rst->p_var > 0.5) // skip contrast2() if the locus is a strong non-variant
|
|
|
976 rst->p_chi2 = contrast2(ma, rst->cmp);
|
|
|
977 return 0;
|
|
|
978 }
|
|
|
979
|
|
|
980 void bcf_p1_dump_afs(bcf_p1aux_t *ma)
|
|
|
981 {
|
|
|
982 int k;
|
|
|
983 fprintf(stderr, "[afs]");
|
|
|
984 for (k = 0; k <= ma->M; ++k)
|
|
|
985 fprintf(stderr, " %d:%.3lf", k, ma->afs[ma->M - k]);
|
|
|
986 fprintf(stderr, "\n");
|
|
|
987 memset(ma->afs, 0, sizeof(double) * (ma->M + 1));
|
|
|
988 }
|
