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abcAsso.cpp
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/*
emil [email protected] jan9 2019
has implemented new methods -doAsso 4, 5 and 6
thorfinn [email protected] dec17 2012
has modified so no sites[].chromo etc are used
anders [email protected] made this.
logistic regression changed 612new/613
part of angsd
*/
#include <cmath>
#include <htslib/kstring.h>
#include "shared.h"
#include "analysisFunction.h"
#include "abcFreq.h"
#include "abcAsso.h"
#include "aio.h"
void abcAsso::printArg(FILE *argFile){
fprintf(argFile,"-------------\n%s:\n",__FILE__);
fprintf(argFile,"\t-doAsso\t%d\n",doAsso);
fprintf(argFile,"\t1: Frequency Test (Known Major and Minor)\n");
fprintf(argFile,"\t2: Score Test\n");
fprintf(argFile,"\t4: Latent genotype model\n");
fprintf(argFile,"\t5: Score Test with latent genotype model - hybrid test\n");
fprintf(argFile,"\t6: Dosage regression\n");
fprintf(argFile,"\t7: Latent genotype model (wald test) - NOT PROPERLY TESTED YET!\n");
fprintf(argFile," Frequency Test Options:\n");
fprintf(argFile,"\t-yBin\t\t%s\t(File containing disease status)\t\n\n",yfile1);
fprintf(argFile," Score, Latent, Hybrid and Dosage Test Options:\n");
fprintf(argFile,"\t-yBin\t\t%s\t(File containing disease status)\n",yfile1);
fprintf(argFile,"\t-yCount\t\t%s\t(File containing count phenotypes)\n",yfile2);
fprintf(argFile,"\t-yQuant\t\t%s\t(File containing phenotypes)\n",yfile3);
fprintf(argFile,"\t-cov\t\t%s\t(File containing additional covariates)\n",covfile);
fprintf(argFile,"\t-sampleFile\t\t%s\t(.sample File containing phenotypes and covariates)\n",sampleFile);
fprintf(argFile,"\t-model\t%d\n",model);
fprintf(argFile,"\t1: Additive/Log-Additive (Default)\n");
fprintf(argFile,"\t2: Dominant\n");
fprintf(argFile,"\t3: Recessive\n\n");
fprintf(argFile,"\t-minHigh\t%d\t(Require atleast minHigh number of high credible genotypes)\n",minHigh);
fprintf(argFile,"\t-minCount\t%d\t(Require this number of minor alleles, estimated from MAF)\n",minCount);
fprintf(argFile,"\t-assoThres\t%f\tThreshold for logistic regression\n",assoThres);
fprintf(argFile,"\t-assoIter\t%d\tNumber of iterations for logistic regression\n",assoIter);
fprintf(argFile,"\t-emThres\t%f\tThreshold for convergence of EM algorithm in doAsso 4 and 5\n",emThres);
fprintf(argFile,"\t-emIter\t%d\tNumber of max iterations for EM algorithm in doAsso 4 and 5\n\n",emIter);
fprintf(argFile,"\t-doPriming\t%d\tPrime EM algorithm with dosage derived coefficients (0: no, 1: yes - default) \n\n",doPriming);
fprintf(argFile,"\t-Pvalue\t%d\tPrints a P-value instead of a likelihood ratio (0: no - default, 1: yes) \n\n",Pvalue);
fprintf(argFile," Hybrid Test Options:\n");
fprintf(argFile,"\t-hybridThres\t\t%f\t(p-value value threshold for when to perform latent genotype model)\n",hybridThres);
fprintf(argFile,"Examples:\n\tPerform Frequency Test\n\t \'./angsd -yBin pheno.ybin -doAsso 1 -GL 1 -out out -doMajorMinor 1 -minLRT 24 -doMaf 2 -doSNP 1 -bam bam.filelist'\n");
fprintf(argFile,"\tPerform Score Test\n\t \'./angsd -yBin pheno.ybin -doAsso 2 -GL 1 -doPost 1 -out out -doMajorMinor 1 -minLRT 24 -doMaf 2 -doSNP 1 -bam bam.filelist'\n");
fprintf(argFile,"\n");
}
void abcAsso::getOptions(argStruct *arguments){
doAsso=angsd::getArg("-doAsso",doAsso,arguments);
if(doAsso==3){
fprintf(stderr,"\t-> -doAsso 3 is deprecated from version 0.615 \n");
exit(0);
}
if(doAsso==0)
return;
doMaf=angsd::getArg("-doMaf",doMaf,arguments);
adjust=angsd::getArg("-adjust",adjust,arguments);
model=angsd::getArg("-model",model,arguments);
minCov=angsd::getArg("-minCov",minCov,arguments);
dynCov=angsd::getArg("-dynCov",dynCov,arguments);
minHigh=angsd::getArg("-minHigh",minHigh,arguments);
doPrint=angsd::getArg("-doPrint",doPrint,arguments);
minCount=angsd::getArg("-minCount",minCount,arguments);
sitePerm=angsd::getArg("-sitePerm",sitePerm,arguments);
GL=angsd::getArg("-GL",GL,arguments);
covfile=angsd::getArg("-cov",covfile,arguments);
doPost=angsd::getArg("-doPost",doPost,arguments);
hybridThres=angsd::getArg("-hybridThres",hybridThres,arguments);
assoThres=angsd::getArg("-assoThres",assoThres,arguments);
assoIter=angsd::getArg("-assoIter",assoIter,arguments);
emThres=angsd::getArg("-emThres",emThres,arguments);
emIter=angsd::getArg("-emIter",emIter,arguments);
doPriming=angsd::getArg("-doPriming",doPriming,arguments);
Pvalue=angsd::getArg("-Pvalue",Pvalue,arguments);
yfile1=angsd::getArg("-yBin",yfile1,arguments);
if(yfile1!=NULL)
isBinary=1;
yfile2=angsd::getArg("-yCount",yfile2,arguments);
if(yfile2!=NULL)
isCount=1;
yfile3=angsd::getArg("-yQuant",yfile3,arguments);
if(yfile3!=NULL)
isQuant=1;
sampleFile=angsd::getArg("-sampleFile",sampleFile,arguments);
if(doAsso==7){
fprintf(stderr,"Warning: Wald test is not properly tested and might give inflated test statistics!\n");
}
if(doPrint)
fprintf(stderr,"finished [%s]\t[%s]\n",__FILE__,__FUNCTION__);
if(doPrint)
fprintf(stderr,"staring [%s]\t[%s]\n",__FILE__,__FUNCTION__);
if(doAsso && doMaf==0){
fprintf(stderr,"Error: you must estimate the maf (-doMaf) in order to perform association \n");
exit(0);
}
if(doAsso && (yfile1!=NULL || yfile2!=NULL || yfile3!=NULL) && sampleFile!=NULL){
fprintf(stderr,"Error: you must provide either a phenotype file (-yBin or -yQuant) or sample file (-sampleFile) not both \n");
exit(0);
}
if(doAsso && yfile1==NULL && yfile2==NULL && yfile3==NULL && sampleFile==NULL){
fprintf(stderr,"Error: you must provide a phenotype file (-yBin or -yQuant) to perform association \n");
exit(0);
}
if(doAsso && ((arguments->inputtype==INPUT_BEAGLE && doAsso==1) || (arguments->inputtype==INPUT_BGEN && doAsso==1) || (arguments->inputtype==INPUT_VCF_GP && doAsso==1))){
fprintf(stderr,"Error: Only doAsso=2 can be performed on posterior input\n");
exit(0);
}
if(doAsso && arguments->inputtype!=INPUT_VCF_GP && arguments->inputtype!=INPUT_BEAGLE && arguments->inputtype!=INPUT_BGEN && (doAsso==2||doAsso==4||doAsso==5||doAsso==6) && doPost==0){
fprintf(stderr,"Error: For doAsso=2 you must estimate the posterior probabilites for the genotypes (-doPost 1) \n");
exit(0);
}
if((isBinary+isCount+isQuant)>1){
fprintf(stderr,"Error: Only one of -yBin, yQuant and -yCount \n");
exit(0);
}
}
abcAsso::abcAsso(const char *outfiles,argStruct *arguments,int inputtype){
multiOutfile=NULL;
bufstr.s=NULL;bufstr.l=bufstr.m=0;
model=1;
doPrint=0;
doAsso=0;
GL=0;
doPost=0;
isBinary=0;
isCount=0;
isQuant=0;
sitePerm=0;//not for users
covfile=NULL;
yfile1=NULL;
yfile2=NULL;
yfile3=NULL;
sampleFile=NULL;
minHigh=10;
minCount=10;
dynCov=0;//not for users
minCov=5;//not for users
adjust=1;//not for users
doMaf=0;
assoIter=100;
assoThres=1e-06;
emIter=40;
emThres=1e-04;
hybridThres=0.05;
doPriming=1;
Pvalue=0;
//from command line
if(arguments->argc==2){
if(!strcasecmp(arguments->argv[1],"-doAsso")){
printArg(stdout);
exit(0);
} else{
return;
}
}
getOptions(arguments);
if(doAsso==0){
shouldRun[index] =0;
return;
}
printArg(arguments->argumentFile);
//read phenotype - binary or count (poisson)
if(sampleFile==NULL){
if(isBinary)
ymat = angsd::getMatrix(yfile1,1,100000);
else if(isCount)
ymat = angsd::getMatrix(yfile2,1,100000);
else
ymat = angsd::getMatrix(yfile3,0,100000);
//read covariates
if(covfile!=NULL)
covmat = angsd::getMatrix(covfile,0,100000);
else{
covmat.x=0;
covmat.y=0;
covmat.matrix=NULL;
}
} else{
dT = angsd::getSample(sampleFile,100000);
ymat.matrix=dT.matrix0;
ymat.x = dT.x0;
ymat.y = dT.y0;
isBinary = dT.isBinary;
if(dT.x1>0){
//just to make it read the covariate file
char test[30];
strcpy(test, "dada");
covfile=test;
covmat.matrix=dT.matrix1;
covmat.x = dT.x1;
covmat.y = dT.y1;
} else{
covmat.x=0;
covmat.y=0;
covmat.matrix=NULL;
}
}
if(covfile!=NULL&&(covmat.x!=ymat.x)){
fprintf(stderr,"The number of covariates (%d) does not match the number of phenotypes (%d)\n",covmat.x,ymat.x);
exit(0);
}
if(!isBinary && doAsso==1){
fprintf(stderr,"Error: Only doAsso=2 can be performed on quantitative traits\n");
exit(0);
}
// check cov and ymat
check_pars(covmat,ymat,isBinary);
//make output files
multiOutfile = new BGZF*[ymat.y];
const char* postfix;
postfix=".lrt";
if(covfile!=NULL&&minCov>0){
int keepList[ymat.x];
for(int i=0 ; i < ymat.x;i++) {
keepList[i]=1;
for(int yi=0;yi<ymat.y;yi++) {
if(isMinus999(ymat.matrix[i][yi]))
keepList[i]=0;
}
for(int ci=0;ci<covmat.y;ci++) {
if(isMinus999(covmat.matrix[i][ci]))
keepList[i]=0;
}
}
int nCov=0;
int count[covmat.y];
for(int ci=0;ci<covmat.y;ci++) {
count[ci]=0;
for(int i=0 ; i < ymat.x;i++) {
if(keepList[i]==0)
continue;
if(covmat.matrix[i][ci]!=0){
count[ci]++;
}
}
if(count[ci]<minCov){
fprintf(stderr,"Error: Cov #%d only has %d non zero entries\n",ci,count[ci]);
}
else{
nCov++;
}
}
if(!dynCov&&covmat.y!=nCov){
fprintf(stderr,"Error: Creating new covariant matrix with %d columns\n",nCov);
exit(0);
}
else if(covmat.y!=nCov){
// angsd::printMatrix(covmat,stderr);
fprintf(stderr,"Error: Creating new covariant matrix with %d columns\n",nCov);
angsd::Matrix<double> newmat;
newmat.x=covmat.x;
newmat.y=nCov;
newmat.matrix=new double*[covmat.x];
for(int xi=0;xi<covmat.x;xi++){
newmat.matrix[xi] = new double[nCov];
int tempCount=0;
for(int ci=0;ci<covmat.y;ci++){
if(count[ci]>minCov){
newmat.matrix[xi][tempCount]=covmat.matrix[xi][ci];
tempCount++;
}
}
}
angsd::deleteMatrix(covmat);
covmat=newmat;
}
}
//open outfiles
for(int i=0;i<ymat.y;i++){
char ary[5000];
snprintf(ary,5000,"%s%d.gz",postfix,i);
multiOutfile[i] = NULL;
multiOutfile[i] = aio::openFileBG(outfiles,ary);
}
//print header
bufstr.l=0;
// hybrid model score model first, then if significant use EM asso
if(doAsso==5){
if(Pvalue==1){
ksprintf(&bufstr,"Chromosome\tPosition\tMajor\tMinor\tFrequency\tN\tPscore\thigh_WT/HE/HO\tPem\tbeta\tSE\temIter\n");
} else{
ksprintf(&bufstr,"Chromosome\tPosition\tMajor\tMinor\tFrequency\tN\tLRTscore\thigh_WT/HE/HO\tLRTem\tbeta\tSE\temIter\n");
}
//EM asso or dosage model
} else if(doAsso==4 or doAsso==7){
if(Pvalue==1){
ksprintf(&bufstr,"Chromosome\tPosition\tMajor\tMinor\tFrequency\tN\tP\tbeta\tSE\thigh_WT/HE/HO\temIter\n");
} else{
ksprintf(&bufstr,"Chromosome\tPosition\tMajor\tMinor\tFrequency\tN\tLRT\tbeta\tSE\thigh_WT/HE/HO\temIter\n");
}
} else if(doAsso==6){
if(Pvalue==1){
ksprintf(&bufstr,"Chromosome\tPosition\tMajor\tMinor\tFrequency\tN\tP\tbeta\tSE\thigh_WT/HE/HO\n");
} else{
ksprintf(&bufstr,"Chromosome\tPosition\tMajor\tMinor\tFrequency\tN\tLRT\tbeta\tSE\thigh_WT/HE/HO\n");
}
} else if(doAsso==2)
if(Pvalue==1){
ksprintf(&bufstr,"Chromosome\tPosition\tMajor\tMinor\tFrequency\tN\tP\thigh_WT/HE/HO\n");
} else{
ksprintf(&bufstr,"Chromosome\tPosition\tMajor\tMinor\tFrequency\tN\tLRT\thigh_WT/HE/HO\n");
}
else
if(Pvalue==1){
ksprintf(&bufstr,"Chromosome\tPosition\tMajor\tMinor\tFrequency\tP\n");
} else{
ksprintf(&bufstr,"Chromosome\tPosition\tMajor\tMinor\tFrequency\tLRT\n");
}
for(int yi=0;yi<ymat.y;yi++)
aio::bgzf_write(multiOutfile[yi],bufstr.s,bufstr.l);
bufstr.l=0;
}
// desctructor
abcAsso::~abcAsso(){
if(doPrint)
fprintf(stderr,"staring [%s]\t[%s]\n",__FILE__,__FUNCTION__);
if(doAsso==0)
return;
for(int i=0;i<ymat.y;i++)
if(multiOutfile[i]!=NULL)
bgzf_close(multiOutfile[i]);
delete [] multiOutfile;
if(covfile!=NULL)
angsd::deleteMatrix(covmat);
angsd::deleteMatrix(ymat);
}
void abcAsso::clean(funkyPars *pars){
if(doAsso==0)
return;
assoStruct *assoc =(assoStruct*) pars->extras[index];
if(assoc->stat!=NULL)
for(int yi=0;yi<ymat.y;yi++)
delete[] assoc->stat[yi];
delete[] assoc->stat;
if(doAsso==5){
delete[] assoc->highWt;
delete[] assoc->highHe;
delete[] assoc->highHo;
delete[] assoc->betas;
delete[] assoc->SEs;
for(int yi=0;yi<ymat.y;yi++)
delete[] assoc->statOther[yi];
delete[] assoc->statOther;
} else if(doAsso==2){
delete[] assoc->highWt;
delete[] assoc->highHe;
delete[] assoc->highHo;
} else if(doAsso==4 or doAsso==6 or doAsso==7){
delete[] assoc->highWt;
delete[] assoc->highHe;
delete[] assoc->highHo;
delete[] assoc->betas;
delete[] assoc->SEs;
}
if(doAsso==4 or doAsso==5 or doAsso==7){
delete[] assoc->emIter;
}
if(assoc->keepInd!=NULL)
for( int yi =0;yi<ymat.y;yi++)
delete[] assoc->keepInd[yi];
delete[] assoc->keepInd;
delete assoc;
//to delete if has not been deleted in other abc Classes
if(pars->post!=NULL){
for(int i=0;i<pars->numSites;i++)
delete [] pars->post[i];
delete [] pars->post;
pars->post =NULL;
}
}
void abcAsso::print(funkyPars *pars){
if(doAsso==0)
return;
if(doPrint)
fprintf(stderr,"staring [%s]\t[%s]\n",__FILE__,__FUNCTION__);
printDoAsso(pars);
}
assoStruct *allocAssoStruct(){
assoStruct *assoc = new assoStruct;
assoc->SEs=NULL;
assoc->betas=NULL;
assoc->stat=NULL;
assoc->statOther=NULL;
assoc->keepInd=NULL;
assoc->highWt = NULL;
assoc->highHe = NULL;
assoc->highHo = NULL;
assoc->emIter = NULL;
return assoc;
}
void abcAsso::run(funkyPars *pars){
if(doAsso==0)
return;
assoStruct *assoc = allocAssoStruct();
pars->extras[index] = assoc;
if(doAsso==2 or doAsso==4 or doAsso==5 or doAsso==6 or doAsso==7){
assoc->highWt=new int[pars->numSites];
assoc->highHe=new int[pars->numSites];
assoc->highHo=new int[pars->numSites];
}
if(doAsso==1){
frequencyAsso(pars,assoc);
} else if(doAsso==2){
scoreAsso(pars,assoc);
} else if(doAsso==4){
assoc->betas=new double[pars->numSites];
assoc->SEs=new double[pars->numSites];
assoc->emIter=new int[pars->numSites];
emAsso(pars,assoc);
} else if(doAsso==6){
assoc->betas=new double[pars->numSites];
assoc->SEs=new double[pars->numSites];
dosageAsso(pars,assoc);
} else if(doAsso==5){
assoc->betas=new double[pars->numSites];
assoc->SEs=new double[pars->numSites];
assoc->emIter=new int[pars->numSites];
hybridAsso(pars,assoc);
} else if(doAsso==7){
assoc->betas=new double[pars->numSites];
assoc->SEs=new double[pars->numSites];
assoc->emIter=new int[pars->numSites];
emAssoWald(pars,assoc);
}
}
void abcAsso::check_pars(angsd::Matrix<double> &cov, angsd::Matrix<double> &phe, int isBinary){
// check if all values of first column in cov file is 1
int interceptChecker = 0;
// check if phenotype 0 or 1 - for quantitative
int isBinaryQuan = 1;
for(int j=0;j<phe.y;j++){
for(int i=0;i<phe.x;i++){
//if logistic regression check if phenotypes are 0 or 1
if(isBinary){
isBinaryQuan = 0;
if(phe.matrix[i][j]!=0 and phe.matrix[i][j]!=1 and !isMinus999(phe.matrix[i][j])){
fprintf(stderr,"Phenotypes are not binary (0 or 1) for logistic model!\n");
exit(1);
}
} else if(isCount){
isBinaryQuan = 0;
if(ceil(phe.matrix[i][j])!=floor(phe.matrix[i][j])){
fprintf(stderr,"Phenotypes are not count data (must be integer) for poisson model!\n");
exit(1);
}
} else{
if(phe.matrix[i][j]!=0 and phe.matrix[i][j]!=1){
isBinaryQuan = 0;
}
}
}
if(isBinaryQuan){
fprintf(stderr,"\n");
fprintf(stderr,"#######################################################################################\n");
fprintf(stderr,"#######################################################################################\n");
fprintf(stderr,"WARNING: Phenotype nr. %i for linear model appears to be binary, run a logistic model instead!\n",j);
fprintf(stderr,"#######################################################################################\n");
fprintf(stderr,"#######################################################################################\n");
fprintf(stderr,"\n");
}
isBinaryQuan=1;
}
for(int j=0;j<cov.y;j++){
for(int i=0;i<cov.x;i++){
if(cov.matrix[i][j]==1){
interceptChecker++;
}
}
// p->len is equal to number of indis in plink file
// if these are same length, means user has column of 1s in .cov file
if(interceptChecker==cov.x){
fprintf(stderr,"Column of 1s for intercept should not be included in covariate,\n");
fprintf(stderr,"as this will be added automatically.\n");
exit(1);
}
interceptChecker=0;
}
}
// stupid little functions to see if int/double value "is" -999 (for missing data)
int abcAsso::isMinus999(double x){
int per = (x/1.0 > -999.1 & x/1.0 < -998.9);
return(per);
}
int abcAsso::isMinus999(int x){
int per = (x/1.0 > -999.1 & x/1.0 < -998.9);
return(per);
}
void abcAsso::frequencyAsso(funkyPars *pars,assoStruct *assoc){
if(doPrint)
fprintf(stderr,"staring [%s]\t[%s]\n",__FILE__,__FUNCTION__);
if(pars->nInd!=ymat.x){
fprintf(stderr,"The number of sequenced individuals (%d) does not match the number of phenotypes (%d)\n",pars->nInd,ymat.x);
fflush(stderr);
exit(0);
}
if(ymat.y!=1){
fprintf(stderr,"Only one phenotype allowed for -doAsso 1\n");
fflush(stderr);
exit(0);
}
double **stat = new double*[ymat.y];
for(int yi=0;yi<ymat.y;yi++)
stat[yi] = new double[pars->numSites];
int y[pars->nInd];
for(int i=0;i<pars->nInd;i++)
y[i]=ymat.matrix[i][0];
double **like0;//genotype likelihood for controls
double **like1;//genotype likelihood for cases
double **likeAll;//genotype likelihood for cases and controls
int Ncases=0; //number of cases
int Ncontrols=0; //number of cases
int Nall=0; //number of cases and controls
int cases[pars->nInd];
int controls[pars->nInd];
int all[pars->nInd];
for(int i=0;i<pars->nInd;i++){
cases[i]=0;
controls[i]=0;
all[i]=0;
if((int)y[i]==1){
Ncases++;
cases[i]=1;
Nall++;
all[i]=1;
}
if((int)y[i]==0){
Ncontrols++;
controls[i]=1;
Nall++;
all[i]=1;
}
if(doPrint)
fprintf(stderr,"all, case, control: %d %d %d\n",all[i],cases[i],controls[i]);
}
if(doPrint)
fprintf(stderr,"count complete [%s]\t[%s]\n",__FILE__,__FUNCTION__);
if(doAsso==1){
like0=angsd::get3likesRMlow(pars,controls);
like1=angsd::get3likesRMlow(pars,cases);
likeAll=angsd::get3likesRMlow(pars,all);
}
if(doPrint)
fprintf(stderr,"like complete [%s]\t[%s]\n",__FILE__,__FUNCTION__);
for(int s=0;s<pars->numSites;s++){//loop overs sites
stat[0][s]=-999;
if(pars->keepSites[s]==0)
continue;
if(doAsso==1){
if(doPrint)
fprintf(stderr,"do freq [%s]\t[%s]\n",__FILE__,__FUNCTION__);
double score0=abcFreq::likeFixedMinor(abcFreq::emFrequency_ext(like0[s],Ncontrols,NULL,Ncontrols),like0[s],Ncontrols);
//likelihood for the cases
double score1=abcFreq::likeFixedMinor(abcFreq::emFrequency_ext(like1[s],Ncases,NULL,Ncases),like1[s],Ncases);
//likelihood for all individuals
double scoreNull=abcFreq::likeFixedMinor(abcFreq::emFrequency_ext(likeAll[s],Nall,NULL,Nall),likeAll[s],Nall);
//likelhood ratio statistics \sim chi^2
double LRT=-2*(score0+score1-scoreNull);
stat[0][s]=LRT;
}
}
assoc->stat=stat;
for(int s=0;s<pars->numSites;s++){
delete[] like0[s];
delete[] like1[s];
delete[] likeAll[s];
}
delete[] like0;
delete[] like1;
delete[] likeAll;
if(doPrint)
fprintf(stderr,"finish [%s]\t[%s]\n",__FILE__,__FUNCTION__);
}
void abcAsso::scoreAsso(funkyPars *pars,assoStruct *assoc){
if(doPrint)
fprintf(stderr,"staring [%s]\t[%s]\n",__FILE__,__FUNCTION__);
if(pars->nInd!=ymat.x){
fprintf(stderr,"The number of sequenced individuals (%d) does not match the number of phenotypes (%d)\n",pars->nInd,ymat.x);
exit(0);
}
int **keepInd = new int*[ymat.y];
double **stat = new double*[ymat.y];
for(int yi=0;yi<ymat.y;yi++){
stat[yi] = new double[pars->numSites];
keepInd[yi]= new int[pars->numSites];
}
for(int s=0;s<pars->numSites;s++){//loop overs sites
if(pars->keepSites[s]==0)
continue;
int *keepListAll = new int[pars->nInd];
for(int i=0 ; i<pars->nInd ;i++){
keepListAll[i]=1;
}
for(int yi=0;yi<ymat.y;yi++) { //loop over phenotypes
int *keepList = new int[pars->nInd];
keepInd[yi][s]=0;
for(int i=0 ; i<pars->nInd ;i++) {
keepList[i]=1;
if(keepListAll[i]==0||isMinus999(ymat.matrix[i][yi]))
keepList[i]=0;
if(covfile!=NULL)
for(int ci=0;ci<covmat.y;ci++) {
if(isMinus999(covmat.matrix[i][ci]))
keepList[i]=0;
}
if(keepList[i]==1)
keepInd[yi][s]++;
}
double *y = new double[pars->nInd];
for(int i=0 ; i<pars->nInd ;i++)
y[i]=ymat.matrix[i][yi];
freqStruct *freq = (freqStruct *) pars->extras[7];
stat[yi][s]=doAssociation(pars,pars->post[s],y,keepInd[yi][s],keepList,freq->freq[s],s,assoc);
//cleanup
delete [] y;
delete [] keepList;
} //phenotypes end
delete [] keepListAll;
} // sites end
assoc->stat=stat;
assoc->keepInd=keepInd;
}
///////////////////////////////////////////////////////////////////////////////
// INSERTED BY EMIL
///////////////////////////////////////////////////////////////////////////////
double abcAsso::standardError(double* start, angsd::Matrix<double> *design, angsd::Matrix<double> *postAll, double *y, double *post, int isBinary, int isCount,int *keepList, int nInd){
//problem is that not all y values might be included since some might have missing information
std::vector<double> ynew(design->x);
//only need individuals with valid phenotypic information
int count=0;
for(int i=0;i<nInd;i++){
if(keepList[i]){
ynew[count]=y[i];
count++;
}
}
if(postAll!=NULL){
double ret;
for(int i=0;i<design->x;i++){
double m = 0;
for(int j=0;j<design->y;j++){
m += design->matrix[i][j]*start[j];
}
// because y is indis long, each entry has to be used 3 times - design has 3*indis rows
size_t indexy = (size_t)floor(i/3);
if(isBinary){
double prob = exp(m)/(exp(m)+1.0);
// now handling if p is 0 or 1 (makes it very small or large)
m = angsd::bernoulli(ynew[indexy],prob,1);
} else if(isCount){
double lambda = exp(m);
m = angsd::poisson(ynew[indexy],lambda,1);
} else{
// density function of normal distribution
m = angsd::dnorm(ynew[indexy],m,start[design->y],1);
}
double tmp = m + log(post[i]);
postAll->matrix[(size_t)floor(i/3)][i % 3] = tmp;
}
// x is number of indis, y is 3
postAll->x = (size_t) design->x/3;
postAll->y = 3;
// to get rowSums
std::vector<double> postTmp(postAll->x);
for(int i=0;i<postAll->x;i++){
double tmp = 0;
double maxval = postAll->matrix[i][0];
for(int j=0;j<postAll->y;j++){
// find max - part of trick for doing log(p1+p2+p3)
maxval = std::max(maxval,postAll->matrix[i][j]);
}
// trick to avoid over/underflow - log(exp(log(val1)-log(max)) + ...) + log(max) = (exp(log(val1))/exp(log(max)))*(max) + ...
// same (exp(log(val1))/exp(log(max)))*(max)
postTmp[i] = log(exp(postAll->matrix[i][0]-maxval)+exp(postAll->matrix[i][1]-maxval)+exp(postAll->matrix[i][2]-maxval)) + maxval;
}
// divide each entry of a row with sum of that row
int df = postAll->x - design->y;
for(int i=0;i<postAll->x;i++){
double tmp = 0;
for(int j=0;j<postAll->y;j++){
postAll->matrix[i][j] -= postTmp[i];
}
}
//need to flatten the weights, which is p(s|y,G,phi,Q,f)
// so first four values is for first indi, and so on...
double* weights = new double[postAll->x*postAll->y];
int a = 0;
for(int i=0;i<postAll->x;i++)
for(int j=0;j<postAll->y;j++){
weights[a++] = exp(postAll->matrix[i][j]);
//check if issue with weights
if(exp(postAll->matrix[i][j])!=exp(postAll->matrix[i][j]) or std::isinf(exp(postAll->matrix[i][j]))){
fprintf(stderr,"Issue with weights being nan or inf\n");
delete [] weights;
return(-9);
}
}
std::vector<double> yTilde(design->x);
for(int i=0;i<design->x;i++)
for(int x=0;x<design->y;x++){
yTilde[i] += design->matrix[i][x]*start[x];
}
// has to be expected value - mu, therefore using link function exp/(1+exp)
if(isBinary){
for(int i=0;i<design->x;i++)
yTilde[i] = exp(yTilde[i]) / (1+exp(yTilde[i]));
}
// link function exp
if(isCount){
for(int i=0;i<design->x;i++)
yTilde[i] = exp(yTilde[i]);
}
int count=0;
// this has colSums for each col for each indi (3 rows)
std::vector<double> summedDesign((design->x/3)*design->y);
std::vector<double> tmp(design->x);
for(int i=0;i<design->x;i++){
// because y is indis long, each entry has to be used 3 times - design has 3*indis rows
size_t indexy = (size_t)floor(i/3);
// getting the residuals
if(isBinary || isCount){
tmp[i] = (ynew[indexy]-yTilde[i]) * weights[i];
} else{
tmp[i] = ((ynew[indexy]-yTilde[i]) / (start[design->y]*start[design->y]))*weights[i];
}
for(int x=0;x<design->y;x++){
if(i % 3 == 2){
// for each col take 3 rows for indis and take sum
summedDesign[count*design->y+x]=design->matrix[i-2][x]*tmp[i-2]+design->matrix[i-1][x]*tmp[i-1]+design->matrix[i][x]*tmp[i];
}
}
if(i % 3 == 2){
count++;
}
}
double invSummedDesign[design->y*design->y];
for(int i=0;i<design->y*design->y;i++)
invSummedDesign[i]=0;
// this is doing the matrix product of (X)^T*W*X
for(int x=0;x<design->y;x++)
for(int y=0;y<design->y;y++)
for(int i=0;i<(int)floor(design->x/3);i++){
invSummedDesign[x*design->y+y]+=summedDesign[i*design->y+x]*summedDesign[i*design->y+y];
}
// doing inv((X)^T*W*X)
int singular=angsd::svd_inverse(invSummedDesign, design->y, design->y);
delete [] weights;
return(sqrt(invSummedDesign[0]));
} else{
std::vector<double> yTilde(design->x);
for(int i=0;i<design->x;i++)
for(int x=0;x<design->y;x++){
yTilde[i] += design->matrix[i][x]*start[x];
}
// has to be expected value - mu, therefore using link function exp/(1+exp)
if(isBinary){
for(int i=0;i<design->x;i++)
yTilde[i] = exp(yTilde[i]) / (1+exp(yTilde[i]));
}
// link function exp
if(isCount){
for(int i=0;i<design->x;i++)
yTilde[i] = exp(yTilde[i]);
}
std::vector<double> summedDesign(design->x*design->y);
std::vector<double> tmp(design->x);
//design has 3*indis rows
for(int i=0;i<design->x;i++){
//ynew is indis long, so this is to be able to use that each value 3 times
size_t indexy = (size_t)floor(i/3);
if(isBinary || isCount){
tmp[i] = (ynew[indexy]-yTilde[i]);
} else{
tmp[i] = ((ynew[indexy]-yTilde[i]) / (start[design->y]*start[design->y]));
}
for(int x=0;x<design->y;x++){
summedDesign[i*design->y+x]=design->matrix[i][x]*tmp[i];
}
}
double invSummedDesign[design->y*design->y];
for(int i=0;i<design->y*design->y;i++)
invSummedDesign[i]=0;
// this is doing the matrix product of (X)^T*W*X
for(int x=0;x<design->y;x++)
for(int y=0;y<design->y;y++)
for(int i=0;i<design->x;i++){
invSummedDesign[x*design->y+y]+=summedDesign[i*design->y+x]*summedDesign[i*design->y+y];
}
// doing inv((X)^T*W*X)
int singular=angsd::svd_inverse(invSummedDesign, design->y, design->y);
return(sqrt(invSummedDesign[0]));
}
}
double abcAsso::dosageAssoc(funkyPars *p,angsd::Matrix<double> *design,angsd::Matrix<double> *designNull,double *postOrg,double *yOrg,int keepInd,int *keepList,double freq,int s,assoStruct *assoc,int model, int isBinary, int isCount, double* start, int fullModel){
int maf0=1;
// if too rare do not run analysis
if(freq>0.995||freq<0.005){
maf0=0;
}
int highWT=0;
int highHE=0;
int highHO=0;
double* post = new double[keepInd*3];
double* y = new double[3*keepInd];
//////////////////////////// check if site can be run first - checking data for full model
int count=0;
design->x=keepInd;
design->y=covmat.y+2;
double* covMatrix = new double[(covmat.y+2)*keepInd];