/*
 Genome-wide Efficient Mixed Model Association (GEMMA)
 Copyright (C) 2011  Xiang Zhou
 
 This program is free software: you can redistribute it and/or modify
 it under the terms of the GNU General Public License as published by
 the Free Software Foundation, either version 3 of the License, or
 (at your option) any later version.
 
 This program is distributed in the hope that it will be useful,
 but WITHOUT ANY WARRANTY; without even the implied warranty of
 MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE.  See the
 GNU General Public License for more details.
 
 You should have received a copy of the GNU General Public License
 along with this program.  If not, see <http://www.gnu.org/licenses/>.
 */



#include <iostream>
#include <sstream>
#include <fstream>
#include <string>
#include <iomanip>
#include <bitset>
#include <vector>
#include <stdio.h>
#include <stdlib.h> 
#include <cmath>
#include "gsl/gsl_vector.h"
#include "gsl/gsl_matrix.h"
#include "gsl/gsl_linalg.h"
#include "gsl/gsl_blas.h"


#include "io.h"
#include "lapack.h"  //for functions EigenDecomp
#include "gzstream.h"

#ifdef FORCE_FLOAT
#include "io_float.h"
#include "prdt_float.h"
#include "mathfunc_float.h"
#else
#include "io.h"
#include "prdt.h"
#include "mathfunc.h"
#endif

using namespace std;




void PRDT::CopyFromParam (PARAM &cPar) 
{
	a_mode=cPar.a_mode;
	d_pace=cPar.d_pace;
	
	file_bfile=cPar.file_bfile;
	file_geno=cPar.file_geno;
	file_out=cPar.file_out;
	path_out=cPar.path_out;
	
	indicator_pheno=cPar.indicator_pheno;	
	indicator_cvt=cPar.indicator_cvt;
	indicator_idv=cPar.indicator_idv;
	
	snpInfo=cPar.snpInfo;
	mapRS2est=cPar.mapRS2est;
	
	time_eigen=0;
	
	n_ph=cPar.n_ph;
	np_obs=cPar.np_obs;
	np_miss=cPar.np_miss;
	ns_total=cPar.ns_total;
	ns_test=0;	
	
	return;
}

void PRDT::CopyToParam (PARAM &cPar) 
{
	cPar.ns_test=ns_test;
	cPar.time_eigen=time_eigen;
	
	return;
}               




void PRDT::WriteFiles (gsl_vector *y_prdt) 
{
	string file_str;
	file_str=path_out+"/"+file_out;
	file_str+=".";
	file_str+="prdt";
	file_str+=".txt";
	
	ofstream outfile (file_str.c_str(), ofstream::out);
	if (!outfile) {cout<<"error writing file: "<<file_str.c_str()<<endl; return;}
	
	size_t ci_test=0;
	for (size_t i=0; i<indicator_idv.size(); i++) {
		if (indicator_idv[i]==1) {
			outfile<<"NA"<<endl;
		} else {
			outfile<<gsl_vector_get (y_prdt, ci_test)<<endl;
			ci_test++;
		}
	}
	
	outfile.close();
	outfile.clear();
	return;
}


void PRDT::WriteFiles (gsl_matrix *Y_full) 
{
	string file_str;
	file_str=path_out+"/"+file_out;
	file_str+=".prdt.txt";
	
	ofstream outfile (file_str.c_str(), ofstream::out);
	if (!outfile) {cout<<"error writing file: "<<file_str.c_str()<<endl; return;}
	
	size_t ci_test=0;
	for (size_t i=0; i<indicator_cvt.size(); i++) {
		if (indicator_cvt[i]==0) {
			outfile<<"NA"<<endl;
		} else {
			for (size_t j=0; j<Y_full->size2; j++) {
				outfile<<gsl_matrix_get (Y_full, ci_test, j)<<"\t";
			}
			outfile<<endl;
			ci_test++;
		}
	}
	
	outfile.close();
	outfile.clear();
	return;
}




void PRDT::AddBV (gsl_matrix *G, const gsl_vector *u_hat, gsl_vector *y_prdt) 
{
	size_t ni_test=u_hat->size, ni_total=G->size1;
	
	gsl_matrix *Goo=gsl_matrix_alloc (ni_test, ni_test);
	gsl_matrix *Gfo=gsl_matrix_alloc (ni_total-ni_test, ni_test);
	gsl_matrix *U=gsl_matrix_alloc (ni_test, ni_test); 
	gsl_vector *eval=gsl_vector_alloc (ni_test);
	gsl_vector *Utu=gsl_vector_alloc (ni_test);
	gsl_vector *w=gsl_vector_alloc (ni_total);
	gsl_permutation *pmt=gsl_permutation_alloc (ni_test);
	
	//center matrix G based on indicator_idv
	for (size_t i=0; i<ni_total; i++) {
		gsl_vector_set(w, i, indicator_idv[i]);
	}
	CenterMatrix(G, w);
		
	//obtain Koo and Kfo
	size_t o_i=0, o_j=0;
	double d;
	for (size_t i=0; i<indicator_idv.size(); i++) {
		o_j=0;
		for (size_t j=0; j<indicator_idv.size(); j++) {
			d=gsl_matrix_get(G, i, j);
			if (indicator_idv[i]==1 && indicator_idv[j]==1) {
				gsl_matrix_set(Goo, o_i, o_j, d);
			}
			if (indicator_idv[i]==0 && indicator_idv[j]==1) {
				gsl_matrix_set(Gfo, i-o_i, o_j, d);
			}
			if (indicator_idv[j]==1) {o_j++;}
		}
		if (indicator_idv[i]==1) {o_i++;}
	}
		
	//matrix operations to get u_prdt
	cout<<"Start Eigen-Decomposition..."<<endl;
	clock_t time_start=clock();
	EigenDecomp (Goo, U, eval, 0);
	for (size_t i=0; i<eval->size; i++) {
		if (gsl_vector_get(eval,i)<1e-10) {gsl_vector_set(eval, i, 0);}
	}

	time_eigen=(clock()-time_start)/(double(CLOCKS_PER_SEC)*60.0);	
	
	gsl_blas_dgemv (CblasTrans, 1.0, U, u_hat, 0.0, Utu);
	for (size_t i=0; i<eval->size; i++) {
		d=gsl_vector_get(eval, i);
		if (d!=0) {d=gsl_vector_get(Utu, i)/d; gsl_vector_set(Utu, i, d);}
	}
	gsl_blas_dgemv (CblasNoTrans, 1.0, U, Utu, 0.0, eval);
	gsl_blas_dgemv (CblasNoTrans, 1.0, Gfo, eval, 1.0, y_prdt);
	
	//free matrices
	gsl_matrix_free(Goo);
	gsl_matrix_free(Gfo);
	gsl_matrix_free(U);
	gsl_vector_free(eval);
	gsl_vector_free(Utu);
	gsl_vector_free(w);
	gsl_permutation_free(pmt);

	return;	
}



void PRDT::AnalyzeBimbam (gsl_vector *y_prdt) 
{
	igzstream infile (file_geno.c_str(), igzstream::in);
//	ifstream infile (file_geno.c_str(), ifstream::in);
	if (!infile) {cout<<"error reading genotype file:"<<file_geno<<endl; return;}
	
	string line;
	char *ch_ptr;
	string rs;
	
	size_t n_miss, n_train_nomiss, c_phen;
	double geno, x_mean, x_train_mean, effect_size;
	
	gsl_vector *x=gsl_vector_alloc (y_prdt->size);
	gsl_vector *x_miss=gsl_vector_alloc (y_prdt->size);
	
	ns_test=0;

	//start reading genotypes and analyze	
	for (size_t t=0; t<ns_total; ++t) {
		!safeGetline(infile, line).eof();
		if (t%d_pace==0 || t==(ns_total-1)) {ProgressBar ("Reading SNPs  ", t, ns_total-1);}
		
		ch_ptr=strtok ((char *)line.c_str(), " , \t");
		rs=ch_ptr;
		ch_ptr=strtok (NULL, " , \t");
		ch_ptr=strtok (NULL, " , \t");		
		
		if (mapRS2est.count(rs)==0) {continue;} else {effect_size=mapRS2est[rs];}
		
		x_mean=0.0; c_phen=0; n_miss=0; x_train_mean=0; n_train_nomiss=0;
		gsl_vector_set_zero(x_miss);

		for (size_t i=0; i<indicator_idv.size(); ++i) {
			ch_ptr=strtok (NULL, " , \t");
			if (indicator_idv[i]==1) {
				if (strcmp(ch_ptr, "NA")!=0) {
					geno=atof(ch_ptr); 			
					x_train_mean+=geno;
					n_train_nomiss++;
				}
			} else {
				if (strcmp(ch_ptr, "NA")==0) {
					gsl_vector_set(x_miss, c_phen, 0.0); n_miss++;
				} else {
					geno=atof(ch_ptr); 	
					
					gsl_vector_set(x, c_phen, geno); 
					gsl_vector_set(x_miss, c_phen, 1.0); 
					x_mean+=geno;
				}
				c_phen++;
			}
		}

		if (x->size==n_miss) {cout<<"snp "<<rs<<" has missing genotype for all individuals and will be ignored."<<endl; continue;}

		x_mean/=(double)(x->size-n_miss);
		x_train_mean/=(double)(n_train_nomiss);
		
		
		for (size_t i=0; i<x->size; ++i) {
			geno=gsl_vector_get(x, i);
			if (gsl_vector_get (x_miss, i)==0) {
				gsl_vector_set(x, i, x_mean-x_train_mean);
			} else {
				gsl_vector_set(x, i, geno-x_train_mean);
			}
		}

		gsl_vector_scale (x, effect_size);
		gsl_vector_add (y_prdt, x);
		
		ns_test++;
	}	
	cout<<endl;
	
	gsl_vector_free (x);
	gsl_vector_free (x_miss);
	
	infile.close();
	infile.clear();
	
	return;
}







void PRDT::AnalyzePlink (gsl_vector *y_prdt) 
{
	string file_bed=file_bfile+".bed";
	ifstream infile (file_bed.c_str(), ios::binary);
	if (!infile) {cout<<"error reading bed file:"<<file_bed<<endl; return;}
	
	char ch[1];
	bitset<8> b;	
	string rs;
	
	size_t n_bit, n_miss, ci_total, ci_test, n_train_nomiss;
	double geno, x_mean, x_train_mean, effect_size;
	
	gsl_vector *x=gsl_vector_alloc (y_prdt->size);
	
	//calculate n_bit and c, the number of bit for each snp
	if (indicator_idv.size()%4==0) {n_bit=indicator_idv.size()/4;}
	else {n_bit=indicator_idv.size()/4+1; }
	
	//print the first three majic numbers
	for (size_t i=0; i<3; ++i) {
		infile.read(ch,1);
		b=ch[0];
	}	
	
	ns_test=0;
	
	for (vector<SNPINFO>::size_type t=0; t<snpInfo.size(); ++t) {
		if (t%d_pace==0 || t==snpInfo.size()-1) {ProgressBar ("Reading SNPs  ", t, snpInfo.size()-1);}
		//if (indicator_snp[t]==0) {continue;}
		
		rs=snpInfo[t].rs_number;
		
		if (mapRS2est.count(rs)==0) {continue;} else {effect_size=mapRS2est[rs];}
		
		infile.seekg(t*n_bit+3);		//n_bit, and 3 is the number of magic numbers
		
		//read genotypes
		x_mean=0.0;	n_miss=0; ci_total=0; ci_test=0; x_train_mean=0; n_train_nomiss=0;
		for (size_t i=0; i<n_bit; ++i) {
			infile.read(ch,1);
			b=ch[0];
			for (size_t j=0; j<4; ++j) {                //minor allele homozygous: 2.0; major: 0.0;
				if ((i==(n_bit-1)) && ci_total==indicator_idv.size() ) {break;}
				if (indicator_idv[ci_total]==1) {
					if (b[2*j]==0) {
						if (b[2*j+1]==0) {x_train_mean+=2.0; n_train_nomiss++;}
						else {x_train_mean+=1.0; n_train_nomiss++;}
					}
					else {
						if (b[2*j+1]==1) {n_train_nomiss++;}                                  
						else {}
					}
				} else {
					if (b[2*j]==0) {
						if (b[2*j+1]==0) {gsl_vector_set(x, ci_test, 2); x_mean+=2.0; }
						else {gsl_vector_set(x, ci_test, 1); x_mean+=1.0; }
					}
					else {
						if (b[2*j+1]==1) {gsl_vector_set(x, ci_test, 0); }                                  
						else {gsl_vector_set(x, ci_test, -9); n_miss++; }
					}
					ci_test++;
				}
				ci_total++;
				
			}
		}
		
		if (x->size==n_miss) {cout<<"snp "<<rs<<" has missing genotype for all individuals and will be ignored."<<endl; continue;}
		
		x_mean/=(double)(x->size-n_miss);
		x_train_mean/=(double)(n_train_nomiss);
		
		for (size_t i=0; i<x->size; ++i) {
			geno=gsl_vector_get(x, i);
			if (geno==-9) {
				gsl_vector_set(x, i, x_mean-x_train_mean);
			} else {
				gsl_vector_set(x, i, geno-x_train_mean);
			}
		}
		
		gsl_vector_scale (x, effect_size);
		gsl_vector_add (y_prdt, x);
		
		ns_test++;
	}	
	cout<<endl;
	
	gsl_vector_free (x);
	
	infile.close();
	infile.clear();	
	
	return;
}




//predict missing phenotypes using ridge regression
//Y_hat contains fixed effects
void PRDT::MvnormPrdt (const gsl_matrix *Y_hat, const gsl_matrix *H, gsl_matrix *Y_full) 
{	
	gsl_vector *y_obs=gsl_vector_alloc (np_obs);
	gsl_vector *y_miss=gsl_vector_alloc (np_miss);
	gsl_matrix *H_oo=gsl_matrix_alloc (np_obs, np_obs);
	gsl_matrix *H_mo=gsl_matrix_alloc (np_miss, np_obs);
	gsl_vector *Hiy=gsl_vector_alloc (np_obs);
	
	size_t c_obs1=0, c_obs2=0, c_miss1=0, c_miss2=0;
	
	//obtain H_oo, H_mo
	c_obs1=0; c_miss1=0; 
	for (vector<int>::size_type i1=0; i1<indicator_pheno.size(); ++i1) {
		if (indicator_cvt[i1]==0) {continue;}
		for (vector<int>::size_type j1=0; j1<n_ph; ++j1) {
			
			c_obs2=0; c_miss2=0;
			for (vector<int>::size_type i2=0; i2<indicator_pheno.size(); ++i2) {
				if (indicator_cvt[i2]==0) {continue;}
				for (vector<int>::size_type j2=0; j2<n_ph; j2++) {
					
					if (indicator_pheno[i2][j2]==1) {
						if (indicator_pheno[i1][j1]==1) {
							gsl_matrix_set (H_oo, c_obs1, c_obs2, gsl_matrix_get (H, c_obs1+c_miss1, c_obs2+c_miss2) );
						} else {
							gsl_matrix_set (H_mo, c_miss1, c_obs2, gsl_matrix_get (H, c_obs1+c_miss1, c_obs2+c_miss2) );
						}
						c_obs2++;
					} else {
						c_miss2++;
					}
				}				
			}
			
			if (indicator_pheno[i1][j1]==1) {
				c_obs1++;
			} else {
				c_miss1++;
			}
		}
		
	}	
	
	//do LU decomposition of H_oo
	int sig;
	gsl_permutation * pmt=gsl_permutation_alloc (np_obs);
	LUDecomp (H_oo, pmt, &sig);
	
//	if (mode_temp==0) {
		//obtain y_obs=y_full-y_hat
		//add the fixed effects part to y_miss: y_miss=y_hat
		c_obs1=0; c_miss1=0;
		for (vector<int>::size_type i=0; i<indicator_pheno.size(); ++i) {
			if (indicator_cvt[i]==0) {continue;}
			
			for (vector<int>::size_type j=0; j<n_ph; ++j) {
				if (indicator_pheno[i][j]==1) {
					gsl_vector_set (y_obs, c_obs1, gsl_matrix_get (Y_full, i, j)-gsl_matrix_get (Y_hat, i, j) );
					c_obs1++;
				} else {
					gsl_vector_set (y_miss, c_miss1, gsl_matrix_get (Y_hat, i, j) );
					c_miss1++;
				}
			}
		}	
		
		LUSolve (H_oo, pmt, y_obs, Hiy);
		
		gsl_blas_dgemv (CblasNoTrans, 1.0, H_mo, Hiy, 1.0, y_miss);
		
		//put back predicted y_miss to Y_full
		c_miss1=0;
		for (vector<int>::size_type i=0; i<indicator_pheno.size(); ++i) {
			if (indicator_cvt[i]==0) {continue;}
			
			for (vector<int>::size_type j=0; j<n_ph; ++j) {
				if (indicator_pheno[i][j]==0) {
					gsl_matrix_set (Y_full, i, j, gsl_vector_get (y_miss, c_miss1) );
					c_miss1++;
				}
			}
		}
/*
	} else {
		for (size_t k=0; k<mode_temp; k++) {
			c_obs1=0; c_miss1=0;
			for (vector<int>::size_type i=0; i<indicator_pheno.size(); ++i) {
				if (indicator_cvt[i]==0) {continue;}
				
				for (vector<int>::size_type j=0; j<2; ++j) {
					if (indicator_pheno[i][j]==1) {
						gsl_vector_set (y_obs, c_obs1, gsl_matrix_get (Y_full, i, j+k*2)-gsl_matrix_get (Y_hat, i, j) );
						c_obs1++;
					} else {
						gsl_vector_set (y_miss, c_miss1, gsl_matrix_get (Y_hat, i, j) );
						c_miss1++;
					}
				}
			}	
			
			LUSolve (H_oo, pmt, y_obs, Hiy);
			
			gsl_blas_dgemv (CblasNoTrans, 1.0, H_mo, Hiy, 1.0, y_miss);
			
			//put back predicted y_miss to Y_full
			c_miss1=0;
			for (vector<int>::size_type i=0; i<indicator_pheno.size(); ++i) {
				if (indicator_cvt[i]==0) {continue;}
				
				for (vector<int>::size_type j=0; j<2; ++j) {
					if (indicator_pheno[i][j]==0) {
						gsl_matrix_set (Y_full, i, j+k*2, gsl_vector_get (y_miss, c_miss1) );
						c_miss1++;
					}
				}
			}
		}
	}
*/
	//free matrices
	gsl_vector_free(y_obs);
	gsl_vector_free(y_miss);
	gsl_matrix_free(H_oo);
	gsl_matrix_free(H_mo);
	gsl_vector_free(Hiy);
	
	return;
}