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clumpld.cpp
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clumpld.cpp
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//////////////////////////////////////////////////////////////////
// //
// PLINK (c) 2005-2008 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 <fstream>
#include <sstream>
#include <algorithm>
#include "clumpld.h"
#include "phase.h"
#include "options.h"
#include "plink.h"
//////////////////////////////////////////////////
// Set user-defined parameters within constructor
clump_LD::clump_LD(Plink * pp,
HaploPhase * hp_,
double sig,
double dist,
double secondp,
float r2c)
{
P = pp;
hp = hp_;
pval_cutoff = sig;
ld_distance = dist;
second_pval_cutoff = secondp;
r2_cutoff = r2c;
}
/////////////
// helper functions
string returnFullRangeList(Range & r1, map<string, set<Range> > & ranges, bool verbose);
/////////////
// accessors
void clump_LD::set_pval( double sig ){
pval_cutoff = sig;
}
void clump_LD::set_second_pval( double secondp ){
second_pval_cutoff = secondp;
}
void clump_LD::set_ld( double dist ){
ld_distance = dist;
}
void clump_LD::set_r2( double r2c ){
r2_cutoff = r2c;
}
//////////////////////////////////////////////////
// read association file and pull out significant
// results sort by pvalue
vector<ResultTrio> clump_LD::read_assoc_file(string fileList)
{
vector<ResultTrio> sp;
// We may be reading a single file, or more than one file
fileList = searchAndReplace(fileList,","," ");
// Tokenize
filename.clear();
string buf;
stringstream ss(fileList);
while (ss >> buf)
filename.push_back(buf);
// Read each file
for (int f=0; f<filename.size(); f++)
{
checkFileExists(filename[f]);
ifstream RESIN( filename[f].c_str(), ios::in );
int snp_column = -1;
int pval_column = -1;
vector<int> annot_field;
// Get header row
char cline[par::MAX_LINE_LENGTH];
RESIN.getline(cline,par::MAX_LINE_LENGTH,'\n');
string sline = cline;
if (sline=="")
error("Problem reading [ " + par::clumpld_results + " ]\n");
vector<string> tok_annot;
if ( par::clumpld_annot )
{
string afields = searchAndReplace(par::clumpld_annot_fields,","," ");
string buf;
stringstream ss(afields);
while (ss >> buf)
tok_annot.push_back(buf);
}
string buf;
stringstream ss(sline);
vector<string> tokens;
while (ss >> buf)
tokens.push_back(buf);
for (int i=0; i<tokens.size(); i++)
{
if ( tokens[i] == "SNP" )
snp_column = i;
if ( tokens[i] == par::clumpld_column )
pval_column = i;
if ( par::clumpld_annot )
for ( int f=0; f<tok_annot.size(); f++)
if ( tokens[i] == tok_annot[f] )
annot_field.push_back(i);
}
//////////////////////////////////////
// Did we find the necessary columns?
if ( snp_column < 0 || pval_column < 0 )
{
error("Could not find [" + par::clumpld_column
+ "] as given in --clump-field\n");
}
P->printLOG("Reading results for clumping from [ "
+ filename[f] + " ]\n");
P->printLOG("Extracting fields SNP and "
+ par::clumpld_column + "\n");
while (!RESIN.eof())
{
char cline[par::MAX_LINE_LENGTH];
RESIN.getline(cline,par::MAX_LINE_LENGTH,'\n');
string sline = cline;
if (sline=="")
continue;
string buf;
stringstream ss(sline);
vector<string> tokens;
while (ss >> buf)
tokens.push_back(buf);
if ( tokens.size() <= snp_column ||
tokens.size() <= pval_column )
continue;
ResultTrio pt;
// Keep track of which file this is from
pt.f = f+1;
if ( ! from_string<double>( pt.p, tokens[pval_column] , std::dec))
continue;
pt.s = tokens[snp_column];
// Create clumped vector, based just on SNP name
if( pt.p <= pval_cutoff )
clumped.insert(make_pair(pt.s,false));
ClumpPair cp;
cp.snp = pt.s;
cp.f = f+1;
ClumpResults cr;
cr.p = pt.p;
cr.annot = "";
if ( par::clumpld_annot )
{
for (int f=0; f<annot_field.size(); f++)
{
cr.annot += tokens[annot_field[f]];
if ( f < annot_field.size() - 1 )
cr.annot += ", ";
}
}
assoc_results.insert( make_pair( cp, cr ));
sp.push_back(pt);
}
RESIN.close();
// Read in next results file
}
sort(sp.begin(), sp.end());
return sp;
}
///////////////////////////////
// Perform clumping operation
void clump_LD::clump()
{
P->printLOG("\nParameters for --clump:\n");
P->printLOG(" p-value threshold for index SNPs = "
+ dbl2str(pval_cutoff) + "\n");
P->printLOG(" Physical (kb) threshold for clumping = "
+ dbl2str(ld_distance/1000.0) + "\n");
P->printLOG(" LD (r-squared) threshold for clumping = "
+ dbl2str(r2_cutoff) + "\n");
P->printLOG(" p-value threshold for clumped SNPs = "
+ dbl2str(second_pval_cutoff) + "\n\n");
if ( par::clumpld_annot )
P->printLOG("Including annotation fields: " + par::clumpld_annot_fields +"\n");
vector<ResultTrio> sp = read_assoc_file( par::clumpld_results );
if ( par::clumpld_index1 )
P->printLOG("Indexing only on [ " + filename[0] + " ]\n");
else
P->printLOG("Indexing on all files\n");
if ( par::clumpld_only_show_replications )
P->printLOG("Only showing cross-file clumps\n");
if ( par::clumpld_only_show_replications_list )
P->printLOG("Only showing non-index clumped SNPs\n");
int zero, one, two, three, four;
map<string,int> mlocus;
map<int2,double> grouped_snps;
ofstream CLMP;
CLMP.open( (par::output_file_name + ".clumped").c_str() , ios::out);
CLMP.precision(3);
P->printLOG("Writing clumped results file to [ " +
par::output_file_name + ".clumped ]\n");
ofstream CLMP2;
if ( par::clumpld_range_annotate && ! par::clumpld_verbose )
{
P->printLOG("Writing clumped ranges file to [ " +
par::output_file_name + ".clumped.ranges ]\n");
CLMP2.open( (par::output_file_name + ".clumped.ranges").c_str() , ios::out);
CLMP2 << setw(4) << "CHR" << " "
<< setw(par::pp_maxsnp) << "SNP" << " "
<< setw(10) << "P" << " "
<< setw(6) << "N" << " "
<< setw(28) << "POS" << " "
<< setw(10) << "KB" << " "
<< "RANGES" << "\n";
}
ofstream BEST;
if ( par::clumpld_best )
{
BEST.open( (par::output_file_name + ".clumped.best").c_str() , ios::out);
BEST.precision(3);
P->printLOG("Writing best per clump to [ "
+ par::output_file_name
+ ".clumped.best" + " ]\n");
BEST << setw(par::pp_maxsnp) << "INDEX" << " "
<< setw(par::pp_maxsnp) << "PSNP" << " "
<< setw(6) << "RSQ" << " "
<< setw(8) << "KB" << " "
<< setw(8) << "P" << " "
<< setw(8) << "ALLELES" << " "
<< setw(8) << "F" << "\n";
}
//////////////////////////
// Read a list of ranges?
map<string, set<Range> > ranges;
map<int,set<Range*> > snp2range;
if ( par::clumpld_range_annotate )
{
// Helper function to map ranges to SNPs
mapRangesToSNPs( par::clumpld_range_file,
ranges,
snp2range );
}
string vmessage;
/////////////////
// Output header
if ( ! par::clumpld_verbose )
CLMP << setw(4) << "CHR" << " "
<< setw(4) << "F" << " "
<< setw(par::pp_maxsnp) << "SNP" << " "
<< setw(10) << "BP" << " "
<< setw(8) << "P" << " "
<< setw(8) << "TOTAL" << " "
<< setw(6) << "NSIG" << " "
<< setw(6) << "S05" << " "
<< setw(6) << "S01" << " "
<< setw(6) << "S001" << " "
<< setw(6) << "S0001" << " "
<< setw(6) << "SP2" << "\n";
//////////////////
// Build SNP map
for (int l=0; l<P->nl_all; l++)
mlocus.insert(make_pair(P->locus[l]->name, l));
if (sp.size()==0)
{
P->printLOG("No significant results given --clump parameters\n");
return;
}
////////////////////////////////////////////////
// Iterate through all association results by
// decreasing p-value until cutoff is reached
int clumpCount = 0;
for (int i = 0; i < sp.size(); i++)
{
// if ( ! par::silent)
// cout << "Tested " << i << " of " << sp.size() << " SNPs \r";
zero=one=two=three=four=0;
////////////////////////////////////
// End if p-value cutoff is reached
if( sp[i].p > pval_cutoff )
break;
//////////////////////////////////
// Skip already clumped this SNP
// (unless running in "best" mode
// where we always want to pull the
// best SNP
if( clumped[sp[i].s] && ! par::clumpld_best )
{
continue;
}
/////////////////////////////////////////////
// Are we only indexing based on first file?
if ( par::clumpld_index1 && sp[i].f > 1 )
{
continue;
}
///////////////////////////////////////////
// Record dataset of index SNP
int indexF = sp[i].f;
///////////////////////////////////////////
// Make sure associated SNP is in SNP map
map<string,int>::iterator ilocus;
ilocus = mlocus.find(sp[i].s);
int l = -1;
if (ilocus != mlocus.end())
{
l = ilocus->second;
}
else
{
if ( !par::clumpld_verbose )
CLMP << setw(4) << "NA" << " "
<< setw(4) << "NA" << " "
<< setw(par::pp_maxsnp) << sp[i].s << " "
<< setw(10) << "NA" << " "
<< setw(10) << sp[i].p << " "
<< setw(8) << "NA" << " "
<< setw(6) << "NA" << " "
<< setw(6) << "NA" << " "
<< setw(6) << "NA" << " "
<< setw(6) << "NA" << " "
<< setw(6) << "NA" << " "
<< setw(6) << "NA" << "\n";
else
vmessage += sp[i].s + " not found in dataset\n";
if ( par::clumpld_best )
{
BEST << setw(par::pp_maxsnp) << sp[i].s << " "
<< setw(par::pp_maxsnp) << "NF" << " "
<< setw(6) << "NF" << " "
<< setw(8) << "NF" << " "
<< setw(8) << "NF" << " "
<< setw(8) << "NF" << " "
<< setw(8) << "NF" << " ";
BEST << "\n";
}
continue;
}
///////////////////////////////
// Check all SNPs in LD range
// Set at reference SNP, l, and move out
// left and right (l1,l2)
int l1 = l;
int l2 = l;
// If multiple files, allow for self comparison also
if ( filename.size()>1 ) --l1;
set<string> willClump;
map<int,string> inPhaseAllele;
while(1)
{
bool failed1 = false, failed2 = false;
// Expand outwards to physical limits/SNP sets
// Moving right
if( l1 < P->locus.size()-1 )
{
// Advance a position
l1++;
double r2a = -1;
// Compute r-squared if this SNP is close
// enough to the index SNP, physically
if( P->locus[l1]->chr == P->locus[l]->chr &&
P->locus[l1]->bp - P->locus[l]->bp < ld_distance )
r2a = hp->rsq( l, l1 );
else
failed1 = true;
//////////////////////////////////
// Skip already clumped this SNP
if( par::clumpld_indep && clumped[ P->locus[l1]->name ] )
continue;
// If in LD with association result
if( r2a > r2_cutoff )
{
// Record which alleles are correlated
inPhaseAllele.insert(make_pair(l1, allelePairs(l,l1)));
// Record that this SNP has been clumped
willClump.insert(P->locus[l1]->name);
// Now look at the assocations (in the multiple files)
// with this SNP
for (int f=1; f<=filename.size(); f++)
{
// Do not clump with self
if ( l == l1 && f == sp[i].f )
continue;
// Are we requiring that only cross-file
// (i.e. no index) SNPs are listed?
if ( par::clumpld_only_show_replications_list && f == indexF )
continue;
ClumpPair result;
result.snp = P->locus[l1]->name;
result.f = f;
// Result not found
if ( assoc_results.find(result) == assoc_results.end() )
continue;
double pval = assoc_results[result].p;
if( pval < second_pval_cutoff )
{
int2 t(l1,f);
grouped_snps.insert(make_pair(t,r2a));
}
if( pval < .0001 )
four++;
else
if( pval < .001 )
three++;
else
if( pval < .01 )
two++;
else
if( pval < .05 )
one++;
else
zero++;
}
}
}
else
failed1 = true;
//////////////
// Move left
if( l2 > 0 )
{
l2--;
double r2b = -1;
if( P->locus[l2]->chr == P->locus[l]->chr &&
P->locus[l]->bp - P->locus[l2]->bp < ld_distance )
r2b = hp->rsq( l, l2 );
else
failed2 = true;
//////////////////////////////////
// Skip already clumped this SNP
if( par::clumpld_indep && clumped[ P->locus[l2]->name ] )
continue;
/////////////////////////////////////
// Does this SNP meet r-sq threshold?
if( r2b > r2_cutoff )
{
// Find the allele in phase with rare allele for l
inPhaseAllele.insert(make_pair(l2, allelePairs(l,l2)));
// Record that this SNP is clumped
willClump.insert(P->locus[l2]->name);
// Now look at associations
for (int f=1; f<=filename.size(); f++)
{
// Are we requiring that only cross-file
// (i.e. no index) SNPs are listed?
if ( par::clumpld_only_show_replications_list && f == indexF )
continue;
ClumpPair result;
result.snp = P->locus[l2]->name;
result.f = f;
// Result not found
if ( assoc_results.find(result) == assoc_results.end() )
continue;
double pval = assoc_results[result].p;
if( pval < second_pval_cutoff )
{
int2 t(l2,f);
grouped_snps.insert(make_pair(t,r2b));
}
if( pval < .0001 )
four++;
else
if( pval < .001 )
three++;
else
if( pval < .01 )
two++;
else
if( pval < .05 )
one++;
else
zero++;
}
}
}
else
failed2 = true;
// No point in looking further?
if( failed1 && failed2 )
break;
}
//////////////////////////////////////////////////////////
// Report results
// Are we only interested in cross-file clumpings?
if ( par::clumpld_only_show_replications )
{
bool seen_replication = false;
map<int2,double>::iterator gi = grouped_snps.begin();
int cnt=0;
int lastf;
while( gi != grouped_snps.end() )
{
if ( cnt > 0 )
{
if ( gi->first.p2 != lastf )
seen_replication = true;
else if ( gi->first.p2 != indexF )
seen_replication = true;
}
lastf = gi->first.p2;
++cnt;
++gi;
}
// If no cross-file results, then do not report this
// clump -- clear all flags for it
if ( ! par::clumpld_best )
if ( ! seen_replication )
{
grouped_snps.clear();
continue;
}
}
// Indicate that this SNP has now been clumped
set<string>::iterator si = willClump.begin();
while ( si != willClump.end() )
{
clumped[ *si ] = true;
++si;
}
int total = zero+one+two+three+four;
if ( par::clumpld_verbose )
{
// Repeat header
CLMP << "\n"
<< setw(4) << "CHR" << " "
<< setw(4) << "F" << " "
<< setw(par::pp_maxsnp) << "SNP" << " "
<< setw(10) << "BP" << " "
<< setw(10) << "P" << " "
<< setw(8) << "TOTAL" << " "
<< setw(6) << "NSIG" << " "
<< setw(6) << "S05" << " "
<< setw(6) << "S01" << " "
<< setw(6) << "S001" << " "
<< setw(6) << "S0001" << "\n";
}
ClumpPair cp;
cp.snp = P->locus[l]->name;
cp.f = sp[i].f;
CLMP << setw(4) << P->locus[l]->chr << " "
<< setw(4) << cp.f << " "
<< setw(par::pp_maxsnp) << P->locus[l]->name << " "
<< setw(10) << P->locus[l]->bp << " "
<< setw(10) << assoc_results[cp].p << " "
<< setw(8) << total << " "
<< setw(6) << zero << " "
<< setw(6) << one << " "
<< setw(6) << two << " "
<< setw(6) << three << " "
<< setw(6) << four << " ";
/////////////////////////////////////
// Convenient format that just gives
// the single best SNP
if ( par::clumpld_best )
{
// BEST, index SNP, best SNP (or NA), r^2, KB
int bestSNP = -1;
double bestRsq = -1;
double bestP = -1;
string bestAllele = "NA";
int bestF = -1;
string bestAnnot = "";
double bestKB = 0;
bool foundSelf = false;
map<int2,double>::iterator gi = grouped_snps.begin();
while( gi != grouped_snps.end() )
{
int l0 = gi->first.p1;
int f = gi->first.p2;
// The same SNP?
bool isSelf = false;
if ( l == l0 )
{
foundSelf = true;
isSelf = true;
}
ClumpPair cp;
cp.snp = P->locus[l0]->name;
cp.f = f;
if ( par::clumpld_only_show_replications && f == indexF )
{
++gi;
continue;
}
if ( assoc_results.find(cp) != assoc_results.end() )
{
if ( isSelf || ( ( ! foundSelf ) && gi->second > bestRsq ) )
{
bestRsq = gi->second;
bestSNP = l0;
bestF = f;
bestAllele = inPhaseAllele.find(l0)->second;
bestP = assoc_results[cp].p;
if ( par::clumpld_annot )
bestAnnot = assoc_results[cp].annot;
bestKB = (double)(P->locus[l0]->bp - P->locus[l]->bp)/1000.0;
}
}
// Consider next proxy SNP
++gi;
}
// Report Best SNP
if ( bestSNP > -1 )
{
BEST << setw(par::pp_maxsnp) << P->locus[l]->name << " "
<< setw(par::pp_maxsnp) << P->locus[bestSNP]->name << " ";
if ( foundSelf )
BEST << setw(6) << "*" << " ";
else
BEST << setw(6) << bestRsq << " ";
BEST << setw(8) << bestKB << " "
<< setw(8) << bestP << " "
<< setw(8) << bestAllele << " "
<< setw(8) << bestF << " ";
if ( par::clumpld_annot )
BEST << bestAnnot;
}
else
{
BEST << setw(par::pp_maxsnp) << P->locus[l]->name << " "
<< setw(par::pp_maxsnp) << "NA" << " "
<< setw(6) << "NA" << " "
<< setw(8) << "NA" << " "
<< setw(8) << "NA" << " "
<< setw(8) << "NA" << " "
<< setw(8) << "NA" << " ";
}
BEST << "\n";
}
//////////////////////////////////
// verbose output
if ( par::clumpld_verbose )
{
int minBP = P->locus[l]->bp;
int maxBP = P->locus[l]->bp;
set<string> range_notes;
// Now list one per line, sorted by distance
CLMP << "\n";
if ( grouped_snps.size() > 0 )
{
CLMP << "\n"
<< setw(4) << " " << " "
<< setw(4) << " " << " "
<< setw(par::pp_maxsnp) << " " << " "
<< setw(10) << "KB" << " "
<< setw(8) << "RSQ" << " "
<< setw(8) << "ALLELES" << " "
<< setw(4) << "F" << " "
<< setw(12) << "P" << " ";
if ( par::clumpld_annot )
CLMP << setw(12) << "ANNOT" << "\n";
else
CLMP << "\n";
CLMP << setw(4) << " (INDEX) "
<< setw(par::pp_maxsnp) << P->locus[l]->name << " ";
CLMP << setw(10) << (double)(P->locus[l]->bp - P->locus[l]->bp)/1000.0 << " ";
CLMP << setw(8) << "1.000" << " "
<< setw(8) << P->locus[l]->allele1 << " "
<< setw(4) << sp[i].f << " "
<< setw(12) << assoc_results[cp].p << " ";
if ( par::clumpld_annot )
CLMP << setw(12) << assoc_results[cp].annot << "\n";
else
CLMP << "\n";
CLMP << "\n";
//////////////////////////////////////////////////
// Track if SNP info already listed in this group
set<int> infoDisplayed;
// Are we tracking ranges?
if ( par::clumpld_range_annotate )
{
map<int,set<Range*> >::iterator mi = snp2range.find(l);
if ( mi != snp2range.end() )
{
set<Range*>::iterator si = mi->second.begin();
while ( si != mi->second.end() )
{
range_notes.insert( (*si)->name );
++si;
}
}
}
map<int2,double>::iterator gi = grouped_snps.begin();
while( gi != grouped_snps.end() )
{
int l0 = gi->first.p1;
int f = gi->first.p2;
ClumpPair cp;
cp.snp = P->locus[l0]->name;
cp.f = f;
if ( assoc_results.find(cp) != assoc_results.end() )
{
if ( infoDisplayed.find(l0) == infoDisplayed.end() )
{
CLMP << setw(4) << " " << " "
<< setw(4) << " " << " "
<< setw(par::pp_maxsnp) << P->locus[l0]->name << " "
<< setw(10)
<< (double)(P->locus[l0]->bp - P->locus[l]->bp)/1000.0
<< " ";
CLMP << setw(8) << gi->second << " ";
CLMP << setw(8) << inPhaseAllele.find(l0)->second << " "
<< setw(4) << f << " "
<< setw(12) << assoc_results[cp].p << " ";
if ( par::clumpld_annot )
CLMP << setw(12) << assoc_results[cp].annot << "\n";
else
CLMP << "\n";
// Note that we have now seen it
infoDisplayed.insert(l0);
// Track overall range of this clump
if ( P->locus[l0]->bp < minBP )
minBP = P->locus[l0]->bp;
if ( P->locus[l0]->bp > maxBP )
maxBP = P->locus[l0]->bp;
////////////////////////////////
// Are we also tracking ranges?
if ( par::clumpld_range_annotate )
{
map<int,set<Range*> >::iterator mi = snp2range.find(l0);
if ( mi != snp2range.end() )
{
set<Range*>::iterator si = mi->second.begin();
while ( si != mi->second.end() )
{
range_notes.insert( (*si)->name );
++si;
}
}
}
}
else
{
CLMP << setw(4) << " " << " "
<< setw(4) << " " << " "
<< setw(par::pp_maxsnp) << " " << " "
<< setw(10) << " " << " "
<< setw(8) << " " << " "
<< setw(8) << " " << " "
<< setw(4) << f << " "
<< setw(12) << assoc_results[cp].p << " ";
if ( par::clumpld_annot )
CLMP << setw(12) << assoc_results[cp].annot << "\n";
else
CLMP << "\n";
}
}
gi++;
}