/
plink.h
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plink.h
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//////////////////////////////////////////////////////////////////
// //
// LAMPLINK (c) 2015 LAMP development team //
// //
// This code is modified from PLINK v1.07 //
// (http://pngu.mgh.harvard.edu/~purcell/plink/) to implement //
// additional options (--lamp and --lamp-ld-removed) //
// for the combinatorial detection with LAMP //
// (http://a-terada.github.io/lamp/). //
// //
// This file is distributed under the GNU General Public //
// License, Version 2. Please see the file COPYING for more //
// details //
// //
//////////////////////////////////////////////////////////////////
#ifndef __PLINK_H__
#define __PLINK_H__
#include <string>
#include <iostream>
#include <fstream>
#include <vector>
#include <set>
#include <map>
#include <functional>
#include <new>
#include "zed.h"
class CArgs;
class Perm;
class Set;
class Family;
class Cluster;
class HaploPhase;
class Locus;
class WMLocus;
class Individual;
class CSNP;
class Model;
class Chap;
class Variant;
class GVariant;
class Lamp;
class LampAssoc;
class readLamp;
class readLamplink;
using namespace std;
typedef vector<vector<int> > table_t;
typedef vector<vector<double> > matrix_t;
typedef vector<double> vector_t;
typedef vector<bool> boolvec_t;
typedef vector<vector<bool> > boolmatrix_t;
typedef vector<int> intvec_t;
typedef vector<vector<double> > fmatrix_t;
typedef vector<float> floatvec_t;
typedef vector<Individual*>::iterator iIndividual;
typedef vector<Locus*>::iterator iLocus;
typedef vector<CSNP*>::iterator iSNP;
typedef vector<bool>::iterator iAllele;
typedef vector<Lamp*>::iterator ilamp;
typedef vector<LampAssoc*>::iterator ilampassoc;
typedef vector<readLamp*>::iterator ireadLamp;
typedef vector<readLamplink*>::iterator ireadLamplink;
class int2 {
public:
int p1;
int p2;
int2() { p1=p2=0; }
int2(int a, int b) { p1=a; p2=b; }
bool operator< (const int2 & b) const
{
return (p1 < b.p1 || (p1 == b.p1 && p2 < b.p2) );
}
bool operator== (const int2 & b) const
{
return (p1 == b.p1 && p2 == b.p2 );
}
};
class double2 {
public:
double p1;
double p2;
double2() { p1=p2=0; }
double2(double a, double b) { p1=a; p2=b; }
bool operator< (const double2 & b) const
{
return (p1 < b.p1 || (p1 == b.p1 && p2 < b.p2) );
}
bool operator== (const double2 & b) const
{
return (p1 == b.p1 && p2 == b.p2 );
}
};
class Pair2
{
public:
double p;
int l;
bool operator< (const Pair2 & p2) const
{
return ( p < p2.p );
}
};
class indivPair
{
public:
Individual * p1;
Individual * p2;
bool operator< (const indivPair & b) const
{
return (p1 < b.p1 || (p1 == b.p1 && p2 < b.p2) );
}
};
class Range {
public:
int chr;
int start;
int stop;
string name;
int group;
static map<string,int> groupNames;
Range() { }
Range(int p1, int p2, int p3, string p4)
{
chr = p1;
start = p2;
stop = p3;
name = p4;
}
bool operator< (const Range & b) const
{
if ( chr < b.chr )
return true;
else if ( chr > b.chr )
return false;
if ( start < b.start )
return true;
else if ( start > b.start )
return false;
return stop < b.stop;
}
bool operator== (const Range & b) const
{
return chr == b.chr && start == b.start && stop == b.stop;
}
};
class WMLocus {
public:
WMLocus() { chr=0; name=""; }
void reset()
{
allele.clear();
weight.clear();
}
int chr;
string name;
vector<string> allele;
vector<double> weight;
};
class Individual {
public:
Individual() {
fid=iid=pat=mat="";
ip=im=-1;
sex=false; phenotype=-9;
sexcode="";
aff=false;
covar=-9;
bcovar=false;
clist.resize(0);
clistMissing.resize(0);
plist.resize(0);
plistMissing.resize(0);
missing=false;
missing2=false;
flag=true;
one.resize(0);
two.resize(0);
sol=0;
founder=true;
pp=pm=NULL;
family=NULL;
kids.resize(0);
pperson=this;
T=W=B=0;
gvar.resize(0);
}
string fid;
string iid;
// Parental codes
string pat;
string mat;
// Pointers to parents
Individual * pp;
Individual * pm;
// Parent slot number
int ip;
int im;
// Relatedness functions
int countMeioses(Individual*);
// Permuted self
Individual * pperson;
// Children (pointers, slot numbers)
vector<Individual*> kids;
vector<int> ikids;
bool sex;
string sexcode;
double phenotype;
bool aff;
double covar;
bool bcovar;
vector_t clist; // multiple covariates
vector<bool> clistMissing;
vector_t plist; // multiple phenotypes
vector<bool> plistMissing;
bool missing;
bool missing2;
bool flag;
int sol;
bool founder;
Family * family;
// SNP data
vector<bool> one; // Person-major mode genotypes
vector<bool> two;
vector<bool>::iterator i1;
vector<bool>::iterator i2;
// Generic variant data
vector<GVariant*> gvar;
// Weighted, multi-allelic single marker
WMLocus wmlocus;
// For QFAM, within and total scores (temporary variables)
double T;
double B;
double W;
};
// Main genotype storage, ordered by SNP
class CSNP
{
public:
vector<bool> one; // SNP-major mode genotypes
vector<bool> two;
};
class Cluster
{
public:
vector<Individual*> person;
};
class Family
{
public:
Family()
{
include = false;
parents = false;
discordant_parents = false;
singleton = false;
sibship = false;
TDT = false;
pat = mat = NULL;
kid.clear();
}
void copy(const Family & rhs)
{
include = rhs.include;
pat = rhs.pat;
mat = rhs.mat;
kid.clear();
for (unsigned int c=0; c<rhs.kid.size(); c++)
kid.push_back(rhs.kid[c]);
}
Family & operator = (const Family & rhs)
{
copy(rhs);
return *this;
}
bool include;
bool parents;
bool sibship;
bool discordant_parents;
bool singleton;
bool TDT;
Individual * pat;
Individual * mat;
vector<Individual *> kid;
// Between-family genotypic score
double B;
};
class Locus {
public:
Locus() { chr=0; name=""; allele1=""; allele2=""; freq=0; pos=0; bp=0; nm=0; }
int chr;
string name;
string allele1;
string allele2;
double freq; // of allele1
double pos; // cM map positions
int bp; // base-pair position
int nm; // number of non-missing alleles
// Copy constructor
Locus(const Locus& h1) { copy(h1); }
Locus & operator= (const Locus & h1) { copy(h1); return *this; }
void copy(const Locus &h1)
{
chr = h1.chr;
name = h1.name;
allele1 = h1.allele1;
allele2 = h1.allele2;
freq = h1.freq;
pos = h1.pos;
bp = h1.bp;
nm = h1.nm;
}
bool operator< (const Locus & p2) const
{
return (chr < p2.chr || (chr == p2.chr && bp < p2.bp) );
}
bool operator== (const Locus & p2) const
{
return ( name == p2.name );
}
};
namespace std
{
template<>
class less<Locus*> {
public:
bool operator()(Locus const* p1, Locus const* p2)
{
// Locus comparison based first on distance,
// but then pointers in case we have a degenerate map
// file (i.e. so we can sort on position, but so that
// set<Locus*> still works
if(!p1)
return true;
if(!p2)
return false;
if (p1->chr < p2->chr)
return true;
if (p1->chr > p2->chr)
return false;
if (p1->bp < p2->bp)
return true;
return false;
}
};
};
class MainExitException {
public:
void exitMessage()
{
cout << "Exception: ending...\n";
}
};
class Z {
public:
Z() { z0=z1=z2=0;}
double z0;
double z1;
double z2;
};
class CInfo {
public:
int lstart;
int lstop;
int bpstart;
int bpstop;
};
class Segment {
public:
Segment()
{
start = finish = 0;
p1 = p2 = NULL;
count = baseline = freq = type = sites = 0;
score = 0.0;
}
int start; // based on map position [0..nl_all]
int finish;
Individual * p1;
Individual * p2;
// Generics
int count;
int baseline;
double weightedCount;
double weightedBaseline;
int freq;
int type;
int sites;
double score;
// Just base for CNVs for now (i.e. only consider p1)
bool operator< (const Segment & b) const
{
if ( start < b.start ) return true;
if ( start > b.start ) return false;
if ( finish < b.finish ) return true;
if ( finish > b.finish ) return false;
if ( p1 < b.p1 ) return true;
return false;
}
bool operator== (const Segment & b) const
{
return ( start == b.start &&
finish == b.finish &&
p1 == b.p1 );
}
};
class ZZ {
public:
ZZ() { z00=z01=z02=0;
z10=z11=z12=0;
z20=z21=z22=0; }
double z00;
double z10;
double z20;
double z01;
double z11;
double z21;
double z02;
double z12;
double z22;
};
class Plink
{
public:
Plink() {
sample.resize(0);
locus.resize(0);
phenotype.resize(0);
clistname.resize(0);
plistname.resize(0);
m1.resize(0);
m2.resize(0);
pos.resize(0);
pihat_G.resize(0);
warnings=false;
n=0;
nl_all=0;
ngvar=0;
cnt_f=npheno=nl=0;
nk=1;
kname.resize(1,"0");
phenotype_name = "";
scaffold.clear();
}
// Genotype/phenotype per individual file
vector<Individual*> sample;
// SNP information (ordered by SNP/individual)
vector<CSNP*> SNP;
// Locus information
vector<Locus*> locus;
// Marker scaffold
map<int,CInfo> scaffold;
// Genetic variant information
vector<Variant*> gvar;
// Family data
vector<Family*> family;
// Phenotype names
string phenoLabel;
vector<string> clistname;
vector<string> plistname;
// number of individuals, pairs
int n; // total number of individuals
int cnt_f; // number of founders
int npheno; // number of individuals with informative phenotypes
int np;
int nl_all; // all loci
int ngvar; // generic variants (non-SNP)
int nl; // test loci
int nk; // number of clusters
string phenotype_name;
// Generic output file
ofstream OUTFILE;
ZOutput ZOUTFILE;
// Were any warnings set?
bool warnings;
// Cluster names
map<string,int> kmap;
vector<string> kname;
vector<Cluster*> klist;
// List of oblig-missing SNP/clusters
set<int2> oblig_missing;
// Conditioning SNPs, and mask
vector<int> conditioner;
vector<bool> conditioner_mask;
// Skip the pair if not informative
vector<bool> skip_pair;
// String for current multipoint pair IDs
string pairid;
// Singlepoint locus-specific IBD, singlepoint
// for each pair (one at a time)
vector<Z> Zlocus;
// Store genome-wide IBD only for informative pairs
vector<Z> saved_IBDg;
// Multipoint map variables
vector<int> m1; // left flanking marker
vector<int> m2; // right flanking marker
vector<double> pos; // relative position between
// Final matrices: pihats and squared differences, cross-products
vector< vector<double> > pihat; // row=marker, col=pair
// Segments; CNVs, ROHs, IBD segments
vector<Segment> segment; // condensed IBD segment record
set<Range> geneList; // Genic/regional intersection range list
map<Range,set<Segment> > gene2segment; // Map of segments per gene
vector<int> indivSegmentGroup; // allelic group for each segment(per-ind)
vector<double> pihat_G; // global pi-hat
set<int2> related; // set of T pairs above threshold
vector<double> phenotype; // SD or CP
vector<int> pair1; // First member of pair
vector<int> pair2; // Second member of pair
vector<int> in_anal; // Unique'd list of inds in regression
// Variances, means
double m_phenotype;
double v_phenotype;
double prev_bt;
vector<double> m_pihat;
vector<double> v_pihat;
// Expected frequencies for IBS|IBD
double E00, E10, E20;
double E01, E11, E21;
double E02, E12, E22;
// T matrix elements
double T00, T01, T02;
double T10, T11, T12;
double T20, T21, T22;
// Storage for genome-wide max(r^2) values
vector<double> maxr2;
// Association SETs
vector<string> setname;
vector<vector<int> > snpset;
// Storage for original results
vector<vector<double> > original;
// IBS matrix and cluster variables
vector<vector<double> > mdist; // IBS metric
double pv; // temporary holder of p-value
double dst; // temporary holder of IBS
double pvIBS0; // holder for IBS0 pvalue count
double pvIBS2het; // holder for IBS2 het/het count
// Epistasis tests
vector<bool> epi1;
vector<bool> epi2;
// Lists of individuals
set<Individual*> gset1;
set<Individual*> gset2;
// Working variables for merge_mode >=6
long int diff_overlap;
long int diff_nonmissing_overlap;
long int diff_concordant_overlap;
// Association test p-value storage: # inds
vector_t tcnt;
// Cache for LD values in proxy-windows
map<int2,double> proxyLD;
// Segmental test help variables
map<indivPair,int> segmentCount;
map<indivPair,double> segmentLength;
map<indivPair,double> segmentCount2;
map<indivPair,double> segmentCount2Baseline;
// Expected overlap
vector_t expectedOverlap;
vector_t expectedOverlapBaseline;
// Pointer to permutation class
Perm * pperm;
//lamp class
vector<Lamp*> lamp;
vector<LampAssoc*> lampassoc;
vector<readLamp*> readlamp;
vector<readLamplink*> readlamplink;
map<string,int> lamp_format;
map<string,int> lamplink_format;
int combcount;
///////////////////////
// Functions
// Input/output functions
void readData();
void readDataLongFormat();
void readFamFile(string);
void readMapFile(string,vector<bool>&,vector<int>&,int&);
void readTransposedData();
void readGenericVariantData();
void outputGenericVariantFile();
void convertGenericVariantData();
void updateMapFile();
void updateFamFile();
void updateAlleles();
void readStdIn();
void mergeData();
bool reconcileMerge(int,int,string,string,bool,bool,ofstream&,map<string,int>&);
void mergeBinaryData();
void mergeList();
void dummyLoader();
void simulateSNPs();
void simulateSNPs_QT();
bool readPhenoFile();
bool readMultiplePhenoFile();
bool readCovariateFile();
bool readCovListFile();
bool readClusterFile(bool verbose=true);
void readConditioningList();
void readBinData();
void readSet();
void prettyPrintLengths();
void printLOG(string);
void outputSetFile();
void setAssocSummary();
void Ind2SNP();
void SNP2Ind();
// Summary statistic / data cleaning functions
void filterSNPs();
void processGVAR();
void calcStratifiedAlleleFreqs();
void hardyWeinbergCheck();
double calcInbreeding(Individual *,int,int,ofstream&);
void sexCheck();
void calcFst();
void findAllHomozygousRuns(Perm &);
void findHomoRuns(Individual *,ofstream&);
void findHomoWindow(Individual *,ofstream&);
void summariseHomoRuns();
void findIBSRuns(Individual *,Individual *,ofstream&);
void findMissRuns(Individual *,ofstream&);
void groupSegmentsSpanning(int);
void displaySegmentsLong();
void displaySegmentsBED();
// CNV segment functions
void setUpForCNVList();
void readCNVList();
void processCNVList();
vector_t glmCNVBurdenModel(Perm &, bool);
// Helper functions
bool missingGenotype(int,int);
bool obligMissing(int,int);
void outputPermedPhenotypes(Perm &);
void countCNVPerRegion(vector<int>&,vector<int>&);
void initialiseGeneCountAssociation(Perm &);
// Family-based functions
void parseTrios();
void makeFounders();
void makeMissingParents();
void linkRelateds(map<Individual*,int> &,
map<string,Individual*> &);
void checkMendel();
void pseudoCaseControl();
vector<double> testTDT(bool,bool,
Perm &,
vector<bool> &,
vector<bool> & );
void perm_testTDT(Perm &);
vector<double> testSibTDT(bool,bool,
Perm &,
vector<bool> &,
vector<bool> & );
void perm_testQTDT(Perm &);
vector<double> calcQTDT(vector<int> &,
ofstream&,
bool,
Perm &,
vector<int> &,
vector<bool> &);
vector<double> testTDT_POO(bool,bool,
Perm &,
vector<bool> &,
vector<bool> & );
void perm_testTDT_POO(Perm &);
// IBS sharing test statistics
vector<double> sharingIBSTest(Perm &);
void perm_sharingIBSTest(Perm &);
////////////////////////////////////
// Main pointers to other classes
// Haplotype phasing/testing
HaploPhase * haplo;
// GLM models
Model * model;
// Conditional haplotype tests (WHAP)
Chap * whap;
// Set-based functions
Set * pS;
// PLINK Functions
int readInformative();
int calcInformative();
void writeInformative();
void displayGenomeWideInfo();
void testGenomeIBDByCovariate(Perm &);
void permutationIBSTest(Perm &);
void displayGMULTI(Individual *, Individual *, int, ofstream &);
void preCalcGenomeIBD();
void preCalcMultiPoint();
void preCalcSinglePoint();
void preCalcPhenotypes();
Z calcGenomeIBS(Individual *, Individual *);
void calcGenomeIBM(Individual *, Individual *);
Z calcGenomeIBD(Individual *, Individual *, Z);
vector<Z> calcLocusIBD(Individual *, Individual *, Z);
vector<double> calcMultiPoint(vector<Z> &, Z, ofstream &);
vector<double> calcSinglePoint(vector<Z> &, Z);
short calcPhenotypes(vector<double> &, Individual *p1, Individual *p2);
void calcRegression(int);
vector<double> doRegression(int,vector<double>&);
void preCalcRegression_PHENO(vector<double>&);
void preCalcRegression_PIHAT();
// Association tests
void calcAssociationWithPermutation(Perm&);
void calcAssociationWithBootstrap();
void perm_testGXE2(Perm &);
vector<double> testQAssocGXE2(bool,Perm &);
void calcGXE(Perm&);
void perm_testHotel(Perm &);
vector<double> calcHotel(bool, Perm &, Set &,int,int);
void calcMH();
void calcHomog();
vector<double> calcMantelHaenszel_2x2xK(Perm &, bool);
vector<double> calcMantelHaenszel_ORD(vector<int>&,vector<int>&,vector<int>&);
vector<double> calcMantelHaenszel_IxJxK(vector<int>&,vector<int>&,vector<int>&);
void calcLDStatistics();
void calcPairwiseLD();
double correlation2SNP(int,int,bool,bool,bool useFlag=false);
void pruneLD();
void calcFlipScan();
void setReferenceAllele();
map<Range,vector<int> > mkBlks(int, int );
void setFlagToCase();
void setFlagToControl();
void calcEpistasis();
void driverSCREEPI();
vector<double> testMiss(Perm &,bool);
void performMisHapTests();
void proxyWrapper();
void performProxyTests(int);
void scoreIndividuals();
void calculateProfile(map<int,double> &, map<int,bool> &, vector_t &, matrix_t &, vector<int> &,vector<int> &);
vector<double> testAssoc(int &, int &,
vector<int> &, vector<int> &, vector<int> &,
vector<double> &,
vector<double> &,vector<double> &,
vector<double> &,vector<double> &,
Perm &,
bool);
vector<double> testQAssoc(bool, Perm &);
vector<double> fullModelAssoc(bool, Perm &);
void displayQTMeans(ofstream &, int l);
vector_t glmAssoc(bool, Perm &);
vector_t conditionalHaplotypeTest(bool, Perm &);
vector_t glmHaplotypeTest(bool, Perm &);
void multcomp(vector<double>&,string);
void buildT(double,bool,double,double);
void setMarkerRange();
void buildCluster();
void generateMDS();
void groupGenome();
void summaryIBD();
void findSegments(int,int,vector_t &,ofstream &);
void summaryIBDsegments(Perm & perm);
void summaryIBSsegments(Perm & perm);
void indivSegmentSummary();
void indivSegmentSummaryCalc(map<indivPair,int>&, map<indivPair,double>&,bool,bool);
void readSegmentFile(ifstream &);
void readSegmentFileMinimal(ifstream &);
void readHomozygSegmentFile(ifstream &);
void segmentPermutationTest(Perm &,bool,string,vector<int>&,vector<int>&,vector<int>&);
void segmentIndividualTest(Perm &);
vector_t perm_segmentIndividualTest(Perm&,bool,int,int,map<Individual*,int>&);
void homozygousSegmentPermutationTest(Perm &,string,vector<int>&,vector<int>&);
void validateSegments();
void positionPermuteSegments();
void runTestCNVwithQT(Perm &);
vector_t testCNVwithQT(double,int,int,vector_t&,vector_t&,vector_t&);
void runTestCNVwithGLM(Perm &);
vector_t testCNVwithGLM(bool, Perm &, vector<int> & );
void displayGenomePV();
void extractExcludeSet(bool);
void removeIndividuals(bool);
void keep2SetsForGenome();
void filterQualSNPs();
void filterQualGenotypes();
void makePhenotype();
void filterOnCovariate();
void filterOnCase();
void filterOnControl();
void filterOnMale();
void filterOnFemale();
void filterOnFounder();
void filterOnNonFounder();
void attribFilterSNP();
void attribFilterInd();