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|
//////////////////////////////////////////////////////////////////
// //
// PLINK (c) 2005-2006 Shaun Purcell //
// //
// This file is distributed under the GNU General Public //
// License, Version 2. Please see the file COPYING for more //
// details //
// //
//////////////////////////////////////////////////////////////////
#include <iostream>
#include <iomanip>
#include <string>
#include "options.h"
#include "helper.h"
#include "plink.h"
#include "phase.h"
#include "stats.h"
extern Plink * PP;
void Plink::performMisHapTests()
{
printLOG("\nPerforming haplotype-based tests for non-random missingness\n");
if (!par::SNP_major)
Ind2SNP();
// Consider 1 SNP at a time
// Form haplotypes based on the surrounding SNPs
// Form phenotype based on the patterns of missingness for test SNP
// Is there any association?
bool old_silent = par::silent;
string f = par::output_file_name + ".missing.hap";
haplo->HTEST.open(f.c_str(),ios::out);
haplo->HTEST.precision(3);
printLOG("Writing haplotype-based missingness results to [ " + f + " ] \n");
haplo->HTEST << setw(par::pp_maxsnp) << "SNP" << " "
<< setw(10) << "HAPLOTYPE" << " "
<< setw(8) << "F_0" << " "
<< setw(8) << "F_1" << " "
<< setw(20) << "M_H1" << " "
<< setw(20) << "M_H2" << " "
<< setw(8) << "CHISQ" << " "
<< setw(8) << "P" << " "
<< "FLANKING" << "\n";
//////////////////////////////////
// Set up a single haplotype entry
haplo->new_pred_locus.resize(1);
// Make new entry in MAP file
Locus * loc = new Locus;
loc->name = "";
loc->chr = 0;
loc->pos = 1;
loc->bp = 1;
loc->allele1 = "1";
loc->allele2 = "2";
// Add this single dummy locus to the list
haplo->new_map.clear();
haplo->new_map.push_back(loc);
vector<CSNP*>::iterator s = SNP.begin();
int l=0;
while ( s != SNP.end() )
{
if (!par::silent)
cout << l+1 << " of " << nl_all << " SNPs tested \r";
/////////////////////////////////
// Currently, skipped haplod SNPs
if (par::chr_sex[locus[l]->chr] ||
par::chr_haploid[locus[l]->chr] )
{
s++;
l++;
continue;
}
////////////////////////////////////////////
// Form phenotype (missingness for this SNP)
vector<Individual*>::iterator person = sample.begin();
vector<bool>::iterator i1 = (*s)->one.begin();
vector<bool>::iterator i2 = (*s)->two.begin();
int nmiss=0;
while ( person != sample.end() )
{
// Missing at test SNP?
if ( *i1 && ! *i2 )
{
nmiss++;
(*person)->aff = true;
}
else
(*person)->aff = false;
// Include all individuals in this analysis
(*person)->missing = false;
i1++;
i2++;
person++;
}
////////////////////////////////////////
// Enough missingness to warrant a test?
if (nmiss<5)
{
s++;
l++;
continue;
}
///////////////////////
// Form test haplotypes
haplo->reset();
// Add which allele to look for (corresponding to allele1)
vector<int> tmp;
for ( int i = l - par::mishap_window ;
i <= l + par::mishap_window ; i++ )
{
if ( i >= 0 && i < nl_all && i != l )
if ( locus[i]->chr == locus[l]->chr )
tmp.push_back(i);
}
haplo->new_pred_locus[0] = tmp;
haplo->new_map[0] = locus[l];
///////////////////
// Phase haplotypes
par::silent = true;
haplo->new_pred_allele = listPossibleHaplotypes(*this,
haplo->new_pred_locus[0]);
haplo->phaseAllHaplotypes(false,*PP->pperm);
haplo->hname = locus[l]->name;
par::silent = old_silent;
///////////////////////////////////////
// Test association with each haplotype
map<int,int> tests;
for (int h=0; h < haplo->nh; h++)
{
if (haplo->f[h] >= par::min_af)
{
tests.clear();
for (int h2=0; h2 < haplo->nh; h2++)
{
if (haplo->f[h2] >= par::min_af)
{
if (h==h2)
{
tests.insert(make_pair(h2,0));
}
else tests.insert(make_pair(h2,1));
}
}
//////////////////////
// Test each haplotype
int nt = 2;
vector<double> caseN(nt,0);
vector<double> controlN(nt,0);
// Consider each individual
for (int i=0; i<n; i++)
{
Individual * person = sample[i];
if ( person->aff )
{
for (int z = 0 ; z < haplo->hap1[i].size(); z++)
{
map<int,int>::iterator i1 = tests.find(haplo->hap1[i][z]);
map<int,int>::iterator i2 = tests.find(haplo->hap2[i][z]);
if ( i1 != tests.end() )
{
if (!haplo->ambig[i])
caseN[i1->second]++;
else
caseN[i1->second] += haplo->pp[i][z];
}
if ( i2 != tests.end() )
{
if (!haplo->ambig[i])
caseN[i2->second]++;
else
caseN[i2->second] += haplo->pp[i][z];
}
}
}
// Or control?
else
{
for (int z = 0 ; z < haplo->hap1[i].size(); z++)
{
map<int,int>::iterator i1 = tests.find(haplo->hap1[i][z]);
map<int,int>::iterator i2 = tests.find(haplo->hap2[i][z]);
if ( i1 != tests.end() )
{
if (!haplo->ambig[i])
controlN[i1->second]++;
else
controlN[i1->second] += haplo->pp[i][z];
}
if ( i2 != tests.end() )
{
if (!haplo->ambig[i])
controlN[i2->second]++;
else
controlN[i2->second] += haplo->pp[i][z];
}
}
}
} // next individual
haplo->HTEST << setw(par::pp_maxsnp) << haplo->hname << " ";
// Find test haplotype
int hh=0;
map<int,int>::iterator i1 = tests.begin();
while ( i1 != tests.end() )
{
if ( i1->second == 0 )
hh = i1->first;
i1++;
}
haplo->HTEST << setw(10) << haplo->haplotypeName(hh) << " ";
if ( caseN[0] + caseN[1] == 0 )
haplo->HTEST << setw(8) << "NA" << " ";
else
haplo->HTEST << setw(8) << caseN[0] / ( caseN[0] + caseN[1] ) << " ";
if ( controlN[0] + controlN[1] == 0 )
haplo->HTEST << setw(8) << "NA" << " ";
else
haplo->HTEST << setw(8) << controlN[0] / ( controlN[0] + controlN[1] ) << " ";
haplo->HTEST << setw(20) << (dbl2str(caseN[0])+"/"+dbl2str(controlN[0])) << " "
<< setw(20) << (dbl2str(caseN[1])+"/"+dbl2str(controlN[1])) << " ";
vector<double> rowT(nt);
double caseT = 0;
double controlT = 0;
for (int h=0; h<nt; h++)
{
rowT[h] = caseN[h] + controlN[h];
caseT += caseN[h];
controlT += controlN[h];
}
double chi2 = 0;
for (int h=0; h<nt; h++)
{
double exp = ( rowT[h] * caseT ) / (caseT + controlT);
chi2 += ( ( caseN[h] - exp ) * ( caseN[h] - exp ) ) / exp ;
exp = ( rowT[h] * controlT ) / (caseT + controlT);
chi2 += ( ( controlN[h] - exp ) * ( controlN[h] - exp ) ) / exp ;
}
if ( realnum(chi2) )
haplo->HTEST << setw(8) << chi2 << " "
<< setw(8) << chiprobP(chi2,nt-1) << " ";
else
haplo->HTEST << setw(8) << "NA" << " "
<< setw(8) << "NA" << " ";
for (int snps=0; snps<haplo->ns-1; snps++)
haplo->HTEST << locus[haplo->S[snps]]->name << "|";
haplo->HTEST << locus[haplo->S[haplo->ns-1]]->name << "\n";
} // next haplotype
}
//////////////////////
// Heterozygsote test
double caseHET=0;
double controlHET=0;
double caseHOM=0;
double controlHOM=0;
// Consider each individual
for (int i=0; i<n; i++)
{
Individual * person = sample[i];
if (person->aff )
{
for (int z = 0 ; z < haplo->hap1[i].size(); z++)
{
if ( haplo->hap1[i][z] != haplo->hap2[i][z] )
{
if (!haplo->ambig[i])
caseHET++;
else
caseHET += haplo->pp[i][z];
}
else
{
if (!haplo->ambig[i])
caseHOM++;
else
caseHOM += haplo->pp[i][z];
}
}
}
// Or control?
else
{
for (int z = 0 ; z < haplo->hap1[i].size(); z++)
{
if ( haplo->hap1[i][z] != haplo->hap2[i][z] )
{
if (!haplo->ambig[i])
controlHET++;
else
controlHET += haplo->pp[i][z];
}
else
{
if (!haplo->ambig[i])
controlHOM++;
else
controlHOM += haplo->pp[i][z];
}
}
}
} // next individual
double chi2 = 0;
double total = caseHET + caseHOM + controlHET + controlHOM;
double total_case = caseHET + caseHOM;
double total_control = controlHET + controlHOM;
double total_het = caseHET + controlHET;
double total_hom = caseHOM + controlHOM;
double exp_caseHET = ( total_case * total_het ) / total;
double exp_controlHET = ( total_control * total_het ) / total;
double exp_caseHOM = ( total_case * total_hom ) / total;
double exp_controlHOM = ( total_control * total_hom ) / total;
chi2 += ( ( caseHET - exp_caseHET ) * ( caseHET - exp_caseHET ) ) / exp_caseHET
+ ( ( caseHOM - exp_caseHOM ) * ( caseHOM - exp_caseHOM ) ) / exp_caseHOM
+ ( ( controlHET - exp_controlHET ) * ( controlHET - exp_controlHET ) ) / exp_controlHET
+ ( ( controlHOM - exp_controlHOM ) * ( controlHOM - exp_controlHOM ) ) / exp_controlHOM;
haplo->HTEST << setw(par::pp_maxsnp) << haplo->hname << " ";
haplo->HTEST << setw(10) << "HETERO" << " ";
if ( caseHET + caseHOM == 0 )
haplo->HTEST << setw(8) << "NA" << " ";
else
haplo->HTEST << setw(8) << caseHET / ( caseHET + caseHOM ) << " ";
if ( controlHET + controlHOM == 0 )
haplo->HTEST << setw(8) << "NA" << " ";
else
haplo->HTEST << setw(8) << controlHET / ( controlHET + controlHOM ) << " ";
haplo->HTEST << setw(20) << (dbl2str(caseHET)+"/"+dbl2str(controlHET)) << " "
<< setw(20) << (dbl2str(caseHOM)+"/"+dbl2str(controlHOM)) << " ";
if ( realnum(chi2) )
haplo->HTEST << setw(8) << chi2 << " "
<< setw(8) << chiprobP(chi2,1) << " ";
else
haplo->HTEST << setw(8) << "NA" << " "
<< setw(8) << "NA" << " ";
for (int snps=0; snps<haplo->ns-1; snps++)
haplo->HTEST << locus[haplo->S[snps]]->name << "|";
haplo->HTEST << locus[haplo->S[haplo->ns-1]]->name << "\n";
// Next test SNP
s++;
l++;
}
if (!par::silent)
cout << "\n";
// Shut down results file
haplo->HTEST.close();
}
|
