void
indel_digt_caller::
starling_indel_call_pprob_digt(const starling_options& opt,
const starling_deriv_options& dopt,
const starling_sample_options& sample_opt,
const double indel_error_prob,
const double ref_error_prob,
const indel_key& ik,
const indel_data& id,
const bool is_use_alt_indel,
starling_diploid_indel& dindel) const {
// no immediate plans to include this for regular indel-calling:
static const bool is_tier2_pass(false);
if (opt.is_noise_indel_filter && is_diploid_indel_noise(dopt,id,is_tier2_pass)) {
dindel.is_indel=false;
return;
}
// get likelihood of each genotype:
double lhood[STAR_DIINDEL::SIZE];
get_indel_digt_lhood(opt,dopt,sample_opt,indel_error_prob,ref_error_prob,ik,id,
opt.is_bindel_diploid_het_bias,opt.bindel_diploid_het_bias,
is_tier2_pass,is_use_alt_indel,lhood);
// mult by prior distro to get unnormalized pprob:
const double* indel_lnprior(lnprior_genomic());
for (unsigned gt(0); gt<STAR_DIINDEL::SIZE; ++gt) {
dindel.pprob[gt] = lhood[gt] + indel_lnprior[gt];
}
normalize_ln_distro(dindel.pprob,dindel.pprob+STAR_DIINDEL::SIZE,dindel.max_gt);
#ifdef DEBUG_INDEL_CALL
log_os << "INDEL_CALL pprob(noindel),pprob(hom),pprob(het): " << dindel.pprob[STAR_DIINDEL::NOINDEL] << " " << dindel.pprob[STAR_DIINDEL::HOM] << " " << dindel.pprob[STAR_DIINDEL::HET] << "\n";
#endif
dindel.indel_qphred=error_prob_to_qphred(dindel.pprob[STAR_DIINDEL::NOINDEL]);
dindel.max_gt_qphred=error_prob_to_qphred(prob_comp(dindel.pprob,dindel.pprob+STAR_DIINDEL::SIZE,dindel.max_gt));
// add new poly calls:
normalize_ln_distro(lhood,lhood+STAR_DIINDEL::SIZE,dindel.max_gt_poly);
dindel.max_gt_poly_qphred=error_prob_to_qphred(prob_comp(lhood,lhood+STAR_DIINDEL::SIZE,dindel.max_gt_poly));
// old report criteria:
//dindel.is_indel=(dindel.max_gt != STAR_DIINDEL::NOINDEL);
dindel.is_indel=(dindel.indel_qphred != 0);
}
void
write_nonref_2allele_test(const blt_options& opt,
const snp_pos_info& pi,
const nonref_test_call& nrc,
std::ostream& os) {
os << nrc.snp_qphred
<< '\t' << NR2TEST::label(static_cast<NR2TEST::index_t>(nrc.max_gt)) << "_" << id_to_base(nrc.nonref_id)
<< '\t' << nrc.max_gt_qphred;
//if(opt.is_print_used_allele_counts) {
pi.print_known_counts(os,opt.used_allele_count_min_qscore);
pi.print_known_qscore(os,opt.used_allele_count_min_qscore);
//}
#if 0
if (opt.is_print_all_poly_gt) {
for (unsigned gt(0); gt<DIGT::SIZE; ++gt) {
#if 1
// print GT as prob:
os << '\t' << po.pprob[gt];
#else
// print GT as qval:
os << '\t' << error_prob_to_qphred(prob_comp(po.pprob,po.pprob+DIGT::SIZE,gt));
#endif
}
}
const result_set& ge(dgt.genome);
const result_set& po(dgt.poly);
#endif
#if 0
if (nrc.is_freq) {
os << std::setprecision(8) << std::fixed;
for (unsigned i(0); i<N_BASE; ++i) {
os << '\t' << nrc.allele_freq[i];
}
os.unsetf(std::ios::fixed);
}
#endif
}
void
position_nonref_2allele_test(const snp_pos_info& pi,
const blt_options& opt,
const bool /*is_always_test*/,
nonref_test_call& nrc) {
static const bool is_mle_freq(false);
if (pi.ref_base=='N') return;
// add early escape test here?
// 1. Determine the two 'primary' alleles -- Simple test just adds
// up qscores to determine which alleles are primary.
//
nrc.nonref_id=(BASE_ID::ANY);
//unsigned nonref2_id(BASE_ID::ANY); // just ignore this value for now....
{
double qtot[N_BASE];
for (unsigned i(0); i<N_BASE; ++i) qtot[i] = 0;
const unsigned n_calls(pi.calls.size());
for (unsigned i(0); i<n_calls; ++i) {
if (pi.calls[i].base_id==BASE_ID::ANY) continue;
qtot[pi.calls[i].base_id] += pi.calls[i].get_qscore();
}
// get max and max2:
unsigned max_id=0;
unsigned max2_id=1;
for (unsigned b(1); b<N_BASE; ++b) {
if (qtot[b] > qtot[max_id]) {
max2_id = max_id;
max_id = b;
} else if (qtot[b] > qtot[max2_id]) {
max2_id = b;
}
}
const unsigned ref_id=base_to_id(pi.ref_base);
if (ref_id==max_id) {
nrc.nonref_id=max2_id;
#if 0
} else if (ref_id==max2_id) {
nrc.nonref_id=max_id;
#endif
} else {
nrc.nonref_id=max_id;
//nonref2_id=max2_id;
}
}
blt_float_t lhood[NR2TEST::SIZE];
lhood[NR2TEST::REF] = calc_pos_nonref_freq_loghood(pi,0.);
sparse_function sf;
nonref_allele_freq_loghood_sparse_func nlf(pi,nrc.nonref_id,sf);
sample_uniform_range(0.,1.,nlf);
//sample_uniform_range(min_nonref_freq,1.,nlf);
lhood[NR2TEST::NONREF_MF] = integrate_ln_sparsefunc(sf, opt.min_nonref_freq, 1,1,1);
lhood[NR2TEST::NONREF_MF_NOISE] = integrate_ln_sparsefunc(sf, 0, opt.nonref_site_error_decay_freq,1,0);
static const blt_float_t neginf(-std::numeric_limits<blt_float_t>::infinity());
lhood[NR2TEST::NONREF_OTHER] = neginf;
//std::cerr << "WAGART: logh ref/nonef: " << lhood[0] << " " << lhood[1] << "\n";
// TODO: ctor compute this:
// this goes in here just in case someone cranks both parameters up near 1:
//
const double nonref_variant_rate_used = opt.nonref_variant_rate*(1-opt.nonref_site_error_rate);
blt_float_t prior[NR2TEST::SIZE];
prior[NR2TEST::REF] = log1p_switch(-(nonref_variant_rate_used+opt.nonref_site_error_rate));
prior[NR2TEST::NONREF_MF] = std::log(nonref_variant_rate_used/3);
prior[NR2TEST::NONREF_MF_NOISE] = std::log(opt.nonref_site_error_rate);
prior[NR2TEST::NONREF_OTHER] = std::log(2*nonref_variant_rate_used/3);
double pprob[NR2TEST::SIZE];
for (unsigned i(0); i<NR2TEST::SIZE; ++i) {
pprob[i] = lhood[i] + prior[i];
}
normalize_ln_distro(pprob,pprob+NR2TEST::SIZE,nrc.max_gt);
nrc.snp_qphred=error_prob_to_qphred(pprob[NR2TEST::REF]+pprob[NR2TEST::NONREF_MF_NOISE]);
nrc.max_gt_qphred=error_prob_to_qphred(prob_comp(pprob,pprob+NR2TEST::SIZE,nrc.max_gt));
nrc.is_snp=(nrc.snp_qphred != 0);
if (! (is_mle_freq && nrc.is_snp)) return;
#if 0
const double null_loghood(calc_pos_nonref_freq_loghood(pi,0.));
// heuristic to escape early:
static const double p_delta(0.001);
const double delta_loghood(calc_pos_nonref_freq_loghood(pi,p_delta));
if (null_loghood > delta_loghood) return;
double x_nonref_freq;
double x_loghood;
position_nonref_freq_loghood_minfunc mf(epi);
static const double x1(0.5);
static const double x2(0.4);
codemin::minimize_1d(x1,x2,mf.val(x1),mf,x_nonref_freq,x_loghood);
x_nonref_freq = mf.arg_to_prob(x_nonref_freq);
const double log_lrt(-2.*(x_loghood+null_loghood));
// becuase null has the parameter fixed to a boundary value, the
// asymmtotic distribution is a 50:50 mixture of csq(0) and chq(1)
// -- the same effect as multiplying alpha of csq(1) by 2, dividing
// the null prob by 2. (as we do below):
boost::math::chi_squared dist(1);
const double null_prob((1.-boost::math::cdf(dist,log_lrt))/2.);
sc.is_snp=(null_prob<alpha);
sc.null_loghood=null_loghood;
sc.min_test_loghood=-x_loghood;
sc.snp_prob=1.-null_prob;
// if it's a snp then get additional information on non-reference
// allele frequencies.
//
if (not sc.is_snp) return;
static const double line_tol(1e-7);
static const double start_ratio(0.05);
static const double min_start_dist(1e-6);
static const double end_tol(1e-7);
static const unsigned max_iter(200);
const unsigned ref_base_id(base_to_id(pi.ref_base));
const double ref_freq(1.-x_nonref_freq);
const double nonref_freq((x_nonref_freq)/3.);
for (unsigned i(0); i<N_BASE; ++i) {
if (i==ref_base_id) sc.allele_freq[i] = ref_freq;
else sc.allele_freq[i] = nonref_freq;
}
static const unsigned N_BASE2(N_BASE*N_BASE);
double conj_dir[N_BASE2];
std::fill(conj_dir,conj_dir+N_BASE2,0.);
for (unsigned i(0); i<N_BASE; ++i) {
const double start_dist( std::max(std::fabs(sc.allele_freq[i]*start_ratio),min_start_dist) );
conj_dir[i*(N_BASE+1)] = start_dist;
}
double start_tol(end_tol);
unsigned iter;
double x_all_loghood;
double final_dlh;
position_allele_distro_loghood_minfunc alm(epi);
codemin::minimize_conj_direction(sc.allele_freq,conj_dir,alm,start_tol,end_tol,line_tol,
x_all_loghood,iter,final_dlh,max_iter);
alm.arg_to_prob(sc.allele_freq,sc.allele_freq);
sc.min_loghood=-x_all_loghood;
#endif
}
static
void
calculate_result_set(const strelka_options& opt,
const double* normal_lnprior,
const double lnmatch,
const double lnmismatch,
const double* normal_lhood,
const double* tumor_lhood,
result_set& rs) {
#ifdef SOMATIC_DEBUG
std::vector<double> check_prior(DDIINDEL::SIZE);
for (unsigned ngt(0); ngt<STAR_DIINDEL::SIZE; ++ngt) {
const double base_prior(normal_lnprior[ngt]);
for (unsigned tgt(0); tgt<STAR_DIINDEL::SIZE; ++tgt) {
const unsigned dgt(DDIINDEL::get_state(ngt,tgt));
check_prior[dgt] =
base_prior+
((tgt==ngt) ? lnmatch : lnmismatch);
}
}
check_ln_distro(check_prior.begin(),
check_prior.end(),
"somatic indel full prior");
#endif
// get unnormalized posterior:
std::vector<double> pprob(DDIINDEL::SIZE);
for (unsigned ngt(0); ngt<STAR_DIINDEL::SIZE; ++ngt) {
const double base_prior(normal_lnprior[ngt]);
for (unsigned tgt(0); tgt<STAR_DIINDEL::SIZE; ++tgt) {
const unsigned dgt(DDIINDEL::get_state(ngt,tgt));
pprob[dgt] =
normal_lhood[ngt]+
tumor_lhood[tgt]+
base_prior+
((tgt==ngt) ? lnmatch : lnmismatch);
}
}
normalize_ln_distro(pprob.begin(),pprob.end(),rs.max_gt);
#ifdef DEBUG_INDEL_CALL
log_os << "INDEL_CALL pprob(noindel),pprob(hom),pprob(het): " << pprob[STAR_DIINDEL::NOINDEL] << " " << pprob[STAR_DIINDEL::HOM] << " " << pprob[STAR_DIINDEL::HET] << "\n";
#endif
double nonsomatic_sum(0);
for (unsigned gt(0); gt<STAR_DIINDEL::SIZE; ++gt) {
nonsomatic_sum += pprob[DDIINDEL::get_state(gt,gt)];
}
rs.sindel_qphred=error_prob_to_qphred(nonsomatic_sum);
double not_somfrom_sum[STAR_DIINDEL::SIZE];
for (unsigned sgt(0); sgt<STAR_DIINDEL::SIZE; ++sgt) {
not_somfrom_sum[sgt]=nonsomatic_sum;
for (unsigned ngt(0); ngt<STAR_DIINDEL::SIZE; ++ngt) {
if (sgt==ngt) continue;
for (unsigned tgt(0); tgt<STAR_DIINDEL::SIZE; ++tgt) {
if (tgt==ngt) continue;
not_somfrom_sum[sgt] += pprob[DDIINDEL::get_state(ngt,tgt)];
}
}
}
rs.sindel_from_ref_qphred=error_prob_to_qphred(not_somfrom_sum[STAR_DIINDEL::NOINDEL]);
rs.sindel_from_het_qphred=error_prob_to_qphred(not_somfrom_sum[STAR_DIINDEL::HET]);
rs.sindel_from_hom_qphred=error_prob_to_qphred(not_somfrom_sum[STAR_DIINDEL::HOM]);
double not_somfromanyhom_sum(nonsomatic_sum);
for (unsigned ngt(0); ngt<STAR_DIINDEL::SIZE; ++ngt) {
if (STAR_DIINDEL::HET != ngt) continue;
for (unsigned tgt(0); tgt<STAR_DIINDEL::SIZE; ++tgt) {
if (tgt==ngt) continue;
not_somfromanyhom_sum += pprob[DDIINDEL::get_state(ngt,tgt)];
}
}
rs.sindel_from_anyhom_qphred=error_prob_to_qphred(not_somfromanyhom_sum);
rs.max_gt_qphred=error_prob_to_qphred(prob_comp(pprob.begin(),pprob.end(),rs.max_gt));
}
// Given the likelihood, go through the final computations to get the
// posterior and derived values.
//
static
void
calculate_result_set_grid(const blt_float_t* normal_lhood,
const blt_float_t* tumor_lhood,
const somatic_snv_caller_strand_grid::prior_set& pset,
const blt_float_t lnmatch,
const blt_float_t lnmismatch,
const unsigned /*ref_gt*/,
result_set& rs) {
// a piece transplanted from 1150 to make a formal correction to
// the priors which should have a low-impact on the results.
// the prior below is incomplete
#ifdef DEBUG_ALTERNATE_PRIOR
static const double neginf(-std::numeric_limits<double>::infinity());
std::vector<double> prior(DDIGT_SGRID::SIZE);
std::fill(prior.begin(),prior.end(),neginf);
// this zero'd code is incomplete and abandoned for now...:
#if 0
for(unsigned ngt(0); ngt<DIGT_SGRID::PRESTRAND_SIZE; ++ngt) {
double base_prior(neginf);
const bool is_noise(ngt>=STAR_DIINDEL::SIZE);
if(is_noise) {
base_prior=pset.normal[ngt];
} else {
base_prior=pset.nonoise[ngt];
}
for(unsigned tgt(0); tgt<DIGT_SGRID::PRESTRAND_SIZE; ++tgt) {
const blt_float_t tgt_prior_mod( (tgt==ngt) ? lnmatch : lnmismatch );
const unsigned dgt(DDIGT_SGRID::get_state(ngt,tgt));
prior[dgt] = normal_genomic_lnprior[ngt]+tgt_prior_mod;
}
}
for(unsigned gt(DIGT_SGRID::PRESTRAND_SIZE); gt<DIGT_SGRID::SIZE; ++gt) {
const unsigned dgt(DDIGT_SGRID::get_state(gt,gt));
prior[dgt] = normal_genomic_lnprior[gt]+lnmatch;
}
#endif
check_ln_distro(prior.begin(),
prior.end(),
"somatic snv full prior");
#endif
// intentionally use higher float res for this structure:
std::vector<double> pprob(DDIGT_SGRID::SIZE);
// mult by prior distro to get unnormalized pprob for states in
// the regular grid model:
//
for(unsigned ngt(0); ngt<DIGT_SGRID::PRESTRAND_SIZE; ++ngt) {
for(unsigned tgt(0); tgt<DIGT_SGRID::PRESTRAND_SIZE; ++tgt) {
const unsigned dgt(DDIGT_SGRID::get_state(ngt,tgt));
#if 0
// the trusty old way...:
const blt_float_t tgt_prior_mod( (tgt==ngt) ? lnmatch : lnmismatch );
pprob[dgt] = normal_lhood[ngt]+tumor_lhood[tgt]+pset.normal[ngt]+tgt_prior_mod;
#else
// unorm takes the role of the normal prior for the somatic case:
// static const blt_float_t unorm(std::log(static_cast<blt_float_t>(DIGT_SGRID::PRESTRAND_SIZE)));
blt_float_t prior;
if(tgt==ngt) {
prior=pset.normal[ngt]+lnmatch;
} else {
prior=pset.somatic_marginal[ngt]+lnmismatch;
}
pprob[dgt] = normal_lhood[ngt]+tumor_lhood[tgt]+prior;
#endif
}
}
// Now add the single-strand noise states. note that these states
// are unique in that we don't look for mixtures of somatic
// variation with these noise states, b/c single-strand
// observations can almost exclusively be ruled out as noise:
//
for(unsigned gt(DIGT_SGRID::PRESTRAND_SIZE); gt<DIGT_SGRID::SIZE; ++gt) {
const unsigned dgt(DDIGT_SGRID::get_state(gt,gt));
pprob[dgt] = normal_lhood[gt]+tumor_lhood[gt]+pset.normal[gt]+lnmatch;
}
opt_normalize_ln_distro(pprob.begin(),pprob.end(),DDIGT_SGRID::is_nonsom.val.begin(),rs.max_gt);
//normalize_ln_distro(pprob.begin(),pprob.end(),rs.max_gt);
double nonsomatic_sum(0);
for(unsigned gt(0); gt<DIGT_SGRID::SIZE; ++gt) {
nonsomatic_sum += pprob[DDIGT_SGRID::get_state(gt,gt)];
}
rs.snv_qphred=error_prob_to_qphred(nonsomatic_sum);
if(0==rs.snv_qphred) return;
#if 0
// alternate way to calculate the joint:
//
double min_not_somfrom_sum(0);
for(unsigned dgt(0); dgt<DIGT::SIZE; ++dgt) {
double not_somfrom_sum(nonsomatic_sum);
for(unsigned ngt(0); ngt<DIGT_SGRID::PRESTRAND_SIZE; ++ngt) {
// we're looking for the joint prob when state dgt is true
// in the normal, so skip this as a normal state here:
//
if(dgt==ngt) continue;
for(unsigned tgt(0); tgt<DIGT_SGRID::PRESTRAND_SIZE; ++tgt) {
// we've already started from the nonsomatic som, so we can skip the equal states:
//
if(ngt==tgt) continue;
not_somfrom_sum += pprob[DDIGT_SGRID::get_state(ngt,tgt)];
}
}
if((dgt==0) || (!_somfrom_sum<min_not_somfrom_sum)) {
min_not_somfrom_sum=not_somfrom_sum;
rs.snv_from_ntype_qphred=error_prob_to_qphred(not_somfrom_sum);
rs.ntype=dgt;
}
}
#endif
#if 0
// reset max_gt to the most likely state excluding normal noise states:
//
rs.max_gt=0;
for(unsigned dgt(0); dgt<DIGT::SIZE; ++dgt) {
for(unsigned tgt(0); tgt<DIGT_SGRID::PRESTRAND_SIZE; ++tgt) {
const unsigned xgt(DDIGT_SGRID::get_state(dgt,tgt));
if(pprob[xgt] > pprob[rs.max_gt]) rs.max_gt=xgt;
}
}
#endif
// Calculate normal distribution alone so that we can classify this call:
//
// Polymorphic prior is used because in this situation we want to
// be conservative about the reference classification --
// ie. conditioned on only looking at putative somatic sites, we
// require evidence to show that the normal is in fact reference
// and not simply an unsampled copy of the somatic variation.
//
std::vector<double> normal_pprob(DIGT_SGRID::PRESTRAND_SIZE);
for(unsigned ngt(0); ngt<DIGT_SGRID::PRESTRAND_SIZE; ++ngt) {
normal_pprob[ngt] = normal_lhood[ngt]+pset.normal_poly[ngt];
}
unsigned max_norm_gt(0);
normalize_ln_distro(normal_pprob.begin(),normal_pprob.end(),max_norm_gt);
// find the probability of max_norm_gt:
const double ngt_prob(prob_comp(normal_pprob.begin(),normal_pprob.end(),max_norm_gt));
// (1-(1-a)(1-b)) -> a+b-(ab)
double not_somfrom_sum(nonsomatic_sum+ngt_prob-(nonsomatic_sum*ngt_prob));
rs.snv_from_ntype_qphred=error_prob_to_qphred(not_somfrom_sum);
rs.ntype=max_norm_gt;
}