fprintf(argFile,"-------------\n%s:\n",__FILE__);

fprintf(argFile,"\t-HWE_pval\t%f\n",HWE_pval);

fprintf(argFile,"\n");

int GL =0;

HWE_pval = angsd::getArg("-HWE_pval",HWE_pval,arguments);

if(HWE_pval==0)

return;

doHWE=1;

chisq = new Chisqdist(1);//<- 1degree of freedom;

LRT_thres = chisq->invcdf(1-HWE_pval);

fprintf(stderr,"\t-> HWE-filter using a pvalue: %.4e correspond to %.4f likelihood units\n",HWE_pval,LRT_thres);

if(doHWE==0)

return;

GL=angsd::getArg("-GL",GL,arguments);

if(arguments->inputtype==INPUT_BEAGLE||arguments->inputtype==INPUT_VCF_GP){

fprintf(stderr,"Error: you cannot estimate HWE based on posterior probabilities \n");

exit(0);

}

chisq = NULL;

outfileZ = NULL;

doHWE=0;

HWE_pval = 0;

testMe=0;

tolStop = 0.00001;

bufstr.s=NULL;bufstr.l=bufstr.m=0;

if(arguments->argc==2){

if(!strcasecmp(arguments->argv[1],"-HWE_pval")){

printArg(stdout);

exit(0);

}else

return;

}

getOptions(arguments);

if(doHWE==0){

shouldRun[index] = 0;

return;

}

printArg(arguments->argumentFile);

//make output files

const char* postfix;

postfix=".hwe.gz";

if(doHWE>0){

outfileZ = aio::openFileBG(outfiles,postfix);

//print header

const char *str = "Chromo\tPosition\tMajor\tMinor\thweFreq\tFreq\tF\tLRT\tp-value\n";

aio::bgzf_write(outfileZ,str,strlen(str));

}

if(doHWE==0)

return;

funkyHWE *hweStruct =(funkyHWE *) pars->extras[index];

delete[] hweStruct->freq;

delete[] hweStruct->freqHWE;

delete[] hweStruct->F;

delete[] hweStruct->like0;

delete[] hweStruct->likeF;

delete hweStruct;

if(doHWE<=0)

return;

funkyHWE *hweStruct = (funkyHWE *) pars->extras[index];//new

bufstr.l=0;

for(int s=0;s<pars->numSites;s++){

if(pars->keepSites[s]==0)

continue;

float lrt= 2*hweStruct->like0[s]-2*hweStruct->likeF[s];

//DRAGON lrt is sometimes nan

float pval;

if(std::isnan(lrt))

pval=lrt;

else if(lrt<0)

pval=1;

else

pval=1-chisq->cdf(lrt);

// fprintf(stderr,"lrt:%f\n",lrt);

ksprintf(&bufstr,"%s\t%d\t%c\t%c\t%f\t%f\t%f\t%e\t%e\n",header->target_name[pars->refId],pars->posi[s]+1,intToRef[pars->major[s]],intToRef[pars->minor[s]],hweStruct->freqHWE[s],hweStruct->freq[s],hweStruct->F[s],lrt,pval);

}

aio::bgzf_write(outfileZ,bufstr.s,bufstr.l);bufstr.l=0;

if(doHWE==0)

return;

funkyHWE *hweStruct = new funkyHWE;

double *freq = new double[pars->numSites];

double *freqHWE = new double[pars->numSites];

double *F = new double[pars->numSites];

double *like0 = new double[pars->numSites];

double *likeF = new double[pars->numSites];

double **loglike3;

loglike3=angsd::get3likesRescale(pars);

for(int s=0;s<pars->numSites;s++){

if(pars->keepSites[s]==0)

continue;

//est under HWE

freqHWE[s] = angsd::estFreq(loglike3[s],pars->nInd);

//start parameter

double x[2];

x[1]=0.0; //F

x[0]=freqHWE[s]; // freq

//log like for HWE freq

like0[s] = HWE_like(x,loglike3[s],pars->nInd);

//start parameter for EM_F

x[0]=freqHWE[s];

x[1]=0.05;

estHWE(x,loglike3[s],pars->nInd);

freq[s]=x[0];

F[s]=x[1];

likeF[s] = HWE_like(x,loglike3[s],pars->nInd);

// fprintf(stderr,"%f\t%f\n",x[0],x[1]);

//fprintf(stderr,"%f\t%f\t%f\n",loglike3[s][0],loglike3[s][1],loglike3[s][2]);

float lrt= 2*like0[s]-2*likeF[s];

if(lrt<0)

lrt=0;

if(lrt<LRT_thres)

pars->keepSites[s] =0;

}

hweStruct->freq=freq;

hweStruct->freqHWE=freqHWE;

hweStruct->F=F;

hweStruct->like0=like0;

hweStruct->likeF=likeF;

pars->extras[index] = hweStruct;

for(int s=0;s<pars->numSites;s++)

delete[] loglike3[s];

delete[] loglike3;

// freq2HWE <- function(x) { freq <- x[2]*0.5 + x[1]; F <- 1 - x[2]/(2*freq*(1-freq)); c(freq,F);}

double freq0,freq1,freq2;

if(1){ // use F formulation instead of p0,p1,p2: compatable with the likelihood function

double freq = x[0];

double Fadj = freq*(1-freq)*x[1];

freq0= pow(1-freq,2) + Fadj;

freq1= 2*freq*(1-freq) - 2*Fadj;

freq2= pow(freq,2) + Fadj;

}

else{

freq2 = x[0];

freq1 = x[1];

freq0 = 1- x[0] - x[1];

}

double newFreq0=0;

double newFreq1=0;

double newFreq2=0;

double norm;

for(int i=0;i<nInd;i++){

norm=angsd::addProtect3(log(freq0)+loglike[i*3+0],log(freq1)+loglike[i*3+1],log(freq2)+loglike[i*3+2]);

newFreq0 += exp(log(freq0)+loglike[i*3+0] - norm);

newFreq1 += exp(log(freq1)+loglike[i*3+1] - norm);

newFreq2 += exp(log(freq2)+loglike[i*3+2] - norm);

}

newFreq0 = newFreq0/nInd;

newFreq1 = newFreq1/nInd;

newFreq2 = newFreq2/nInd;

if(newFreq0 < 0.0001)

newFreq0 = 0.0001;

if(newFreq1 < 0.0001)

newFreq1 = 0.0001;

if(newFreq2 < 0.0001)

newFreq2 = 0.0001;

norm = newFreq0 + newFreq1 + newFreq2;

newFreq0 = newFreq0/norm;

newFreq1 = newFreq1/norm;

newFreq2 = newFreq2/norm;

if(newFreq0 + newFreq1 >1.00001){

fprintf(stderr,"something is wrong i HWE\t freq %f\t F %f\n",x[0],x[1]);

fflush(stderr);

exit(0);

}

if(1){

if(isnan(newFreq1*0.5 + newFreq2)){

fprintf(stderr,"problems in abcHWE: \tx[0] %f\tx[1] %f\told 1 %f 2 %f 3 %f\tnew 1 %f 2 %f 3 %f \n",x[0],x[1],freq0,freq1,freq2,newFreq0,newFreq1,newFreq2);

// exit(0);

}

x[0] = newFreq1*0.5 + newFreq2;

x[1] = 1 - newFreq1/(2*x[0]*(1-x[0])) ;

}

else{

x[0] = newFreq2;

x[1] = newFreq1;

}

double freq=x[0];

double F=x[1];

double p0=(pow(1-freq,2)+freq*(1-freq)*F);

double p1=(2*freq*(1-freq)-2*freq*(1-freq)*F);

double p2=(pow(freq,2)+freq*(1-freq)*F);

double totalLogLike=0;

for(int i=0;i<nInd;i++)

totalLogLike+=angsd::addProtect3(log(p0)+loglike[i*3+0],log(p1) + loglike[i*3+1],log(p2) + loglike[i*3+2]);

return -totalLogLike;

double y[2];// = new double[2];

y[0] = x[0]+2;

y[1] = x[1]+2;

int iter=50;

double dif;

//fprintf(stderr,"%f\n",differ(x,y));

int printer=0;

for(int i=0;i<iter;i++){

HWE_EM(x,loglike,nInd);

dif = differ(x,y);

// fprintf(stderr,"%f\n",dif);

if(dif<tolStop)

break;

y[0] = x[0];

y[1] = x[1];

}