".getmeasuredgenesinpathway"<-
function(syms,allgenes) 
{
	l<-length(syms)
	pathways<-vector('list',l)
	for (i in 1:l) {
		n<-length(syms[[i]])
		isin<-matrix(FALSE,n)
		for(j in 1:n) {		
			isin[j]<-(length(grep(paste('\\b',trim(syms[[i]][j]),'\\b',sep=""),allgenes))>0)		
		}
		pathways[[i]]<-unique(syms[[i]][isin])
	}
	pathways
}

".getpathway"<-
function(sym,allgenes,data) 
{
	l<-length(sym)
	x<-NULL
	isin<-rep(FALSE,l);
	for(i in 1:l) {		
		ind<-unique(grep(paste('\\b',trim(sym[i]),'\\b',sep=""),allgenes))
		n<-length(ind)
		if (n>0) {			
			if (n==1)
				t<-data[ind,]
			else
				t<-colMeans(data[ind,])
			if (var(t)>0) {
				isin[i]=TRUE;	
				x<-c(x,t)
			}
		}		
	}
	if (is.null(x)) {
		list(x=NULL,isin=isin)
	} else {
		list(x=matrix(x,nrow=ncol(data)),isin=isin)
	}
}

".score_pathway"<-
function(x,m,ranks,calcerr=FALSE,thresh = 0.0005,maxit=200,start,logfile = "",i) 
{	
	x<-x[,apply(x,2,sd)>0.001]
	k<-dim(x)[2]
	if (k<3) {
		c<-NULL
		cat(file=logfile,append=TRUE,'scoring failed (k=',k,').\n')	
	} else {
	d<-matrix(0,1,m)
	if (start == "by pca") {
		start <- NULL
	} else if (start == "by ranks") {
		start <- aggregate(x, by=list(ranks), FUN=mean)
		start <- as.matrix(start[,-1])
    }
    c <- tryCatch(principal.curve(x, ranks, start=start, thresh=thresh, maxit=maxit, plot.true=FALSE) , error=function(e){})
	}	
	if (!is.null(c)) {
		d[c$tag[1]]=0
		for (j in 2:m) {			
			d[c$tag[j]]<-d[c$tag[j-1]]+dist(c$s[c$tag[(j-1):j],])
		}		
		d=d/d[c$tag[m]]		
		if (calcerr) {
			e<-matrix(0,1,k)
			for (i in 1:k) {	
				e[i]<-mean((c$s[,i]-x[,i])^2)
			}
		} else {
			e <- FALSE;
		}
		list(score=d,error=e,thecurve=c)
	} else {
		cat(file=logfile,append=TRUE,'pathway ', i, '> scoring failed.\n')
		NULL
	}
}

".samplings_stdev"<-
function(m,n,attempts,z,ranks,samplings,start,logfile = "",i)
{
	dall<-array(dim=c(attempts,n))
	skip<-0	
	for(a in 1:attempts) {			
		res<-.score_pathway(z[samplings[a,],],m,ranks[samplings[a,]],start=start,logfile=logfile,i=i)
		if (!is.null(res)) {			
			dall[a,samplings[a,]] <- res$score
		} else {
			skip <- skip+1
		}
	}	
	if (skip < attempts/2) {
		mean(apply(dall,2,sd,'na.rm'=TRUE), 'na.rm'=TRUE)
	} else {
		Inf
	}
	
}

".score_all_pathways_helper"<-
function(z, ranks, samplings, i, attempts, maximize_stability, logfile = "",start)
{	
	n<-dim(z)[1]	
	k<-dim(z)[2]		
	m<-dim(samplings)[2]
	mincheck<-5
	kmin=max(floor(0.8*k),mincheck+1)
	mindelta=min(0.009,max(0.002,1.5/k))
	sig<-matrix(0,1,k)		
	res<-.score_pathway(z,n,ranks,calcerr=TRUE,start=start,logfile=logfile,i=i)	
	if (is.null(res)) {
		cat(file=logfile,append=TRUE,'pathway ', i, '> scoring failed 1.\n')		
	} else { 
		sig<-.samplings_stdev(m,n,attempts,z,ranks,samplings,start=start,i=i)
		if (sig>10000) {
			cat(file=logfile,append=TRUE,'pathway ', i, '> scoring failed 2 (sig:', sig, ').\n')		
			res<-NULL
		} else {
			origsig<-sig
			cat(file=logfile,append=TRUE,'pathway ', i, '> sig:', sig, '\n')
			isin<-1:k
			if (maximize_stability) {
				testsig<-max(mincheck,floor(0.1*k))
				newsig<-rep(0,testsig)
				while ((k>=kmin)&(sig>0.05)) {
					se<-sort(res$error,index.return=TRUE,decreasing=TRUE)			
					for (j in 1:testsig) {				
						newsig[j]<-.samplings_stdev(m,n,attempts,z[,-se$ix[j]],ranks,samplings,start=start,i=i)
					}
					wj<-which.min(newsig)			
					cat(file=logfile,append=TRUE,'pathway ', i, ' k=', k, '(', ncol(res$thecurve$s), ') wj=', wj, '>new sig:', newsig[wj])
					if (sig-newsig[wj]<mindelta) {
						cat(file=logfile,append=TRUE,' x rejected\n')
						break
					}					
					cat(file=logfile,append=TRUE,' | accepted!\n')
					sig<-newsig[wj]						
					isin<-isin[-se$ix[wj]];
					z<-z[,-se$ix[wj]]			
					k<-k-1			
					res<-.score_pathway(z,n,ranks,calcerr=TRUE,start=start,logfile=logfile,i=i)
					if (is.null(res)) {
						cat(file=logfile,append=TRUE,'pathway ', i, '> scoring failed 3.\n')						
						break;						
					}
				}					
			}
		}
	}
	if (is.null(res)) {
		NULL
	} else {
		list(score=res$score,thecurve=res$thecurve,z=z,isin=isin,sig=sig,origsig=origsig,k=k)
	}
}

".quantify_one_pathway_deregulation"<-
function(i,ind,data,allgenes,pathway,normals,ranks,attempts,maximize_stability,logfile,samplings,min_exp,min_std,start)
{
  n<-ncol(data)	
  pathwayindata<-.getpathway(pathway,allgenes,data)
  k1=sum(pathwayindata$isin)	
  if (k1<3) {		  
    si<-NULL
    cat(file=logfile,append=TRUE,'skipping pathway ',i,' k1=', k1,'\n')
  } else {		
    x<-pathwayindata$x
    pathway<-pathway[pathwayindata$isin]			
    xm<-colMeans(x[normals,])
    xs<-apply(x[normals,],2,sd)			
    xs[xs<min_std]=min_std;						
    if (0 %in% xs) {
      si<-NULL
      cat(file=logfile,append=TRUE,'skipping pathway ',i,' (0 in xs)\n')
    } else {
      z<-(x-matrix(rep(xm,each=n),nrow=n))/(matrix(rep(xs,each=n),nrow=n))		
      t<-prcomp(z)							
      k2=max(sum(t$sdev>1.1),4)				
      k2=min(k2,k1,0.75*dim(x)[1],sum(t$sdev>0.25))
      if (k2<3) {						
        si<-NULL
        cat(file=logfile,append=TRUE,'skipping pathway ',i,' k2=', k2,'\n')
      } else {
        pca<-t$x[,1:k2]											
        res<-.score_all_pathways_helper(pca, ranks, samplings, i, attempts, maximize_stability, logfile, start=start)					
        if (is.null(res)) {
          si<-NULL
          cat(file=logfile,append=TRUE,'skipping pathway ',i,'\n')
        } else {
          ind<-c(ind,i)
          si<-list(res$score,pathway,res$sig,res$origsig,res$k,res$thecurve$s,res$thecurve$tag,res$z,res$isin,xm,xs,t$center,t$rotation,k2)					
        }
      }
    }
  }
  list(si=si,ind=ind)
}
  
"quantify_pathways_deregulation"<-
function(data, allgenes, syms, pathwaynames, normals = NULL, ranks = NULL, attempts = 100, maximize_stability = TRUE, logfile = "", samplings=NULL, min_exp=4, min_std=0.4, parallel = FALSE)
{
	cat(file=logfile,append=FALSE,'robust_score_bydist. min_exp=',min_exp,', min_std=',min_std,'\n')
	data[data<min_exp]=min_exp;
	n<-ncol(data)	
	if (is.null(normals)) {
		normals <- rep(TRUE,n);
		start <- "by pca";
	} else {
		start <- "by ranks"
	}
	if (is.null(ranks)) ranks <- !normals;	
	ranks <- rank(ranks)
	if ((length(normals)!=n)||(length(ranks)!=n)) {
		stop("invalid dimentions");
	}
	l<-length(syms)	
	nn<-sum(normals)
	m<-floor(0.8*(n-nn))+nn	
	if (is.null(samplings)) {
		samplings<-matrix(0,attempts,m)
		w<-which(!normals)
		for(a in 1:attempts) {		
			samplings[a,]<-sort(c(w[sample(n-nn,m-nn)],which(normals)))
		}	
	}
  s<-NULL
	ind<-NULL
	if (parallel) {
	  s <- foreach (i=1:l, .options.multicore=list(preschedule=FALSE), .combine=rbind, .inorder=FALSE, .verbose=FALSE, .errorhandling='stop', .multicombine=TRUE) %dopar% {  							
	    q<-.quantify_one_pathway_deregulation(i,ind,data,allgenes,syms[[i]],normals,ranks,attempts,maximize_stability,logfile,samplings,min_exp,min_std,start);      
	    #      cat(file=logfile,append=TRUE,'ind=',ind,' qind=',q$ind)
	    #      ind<-q$ind;
	    q$si
	  }	
	  ind<-as.numeric(substr(rownames(s),8,99));
	} else {
	  for (i in 1:l) {
	    q<-.quantify_one_pathway_deregulation(i,ind,data,allgenes,syms[[i]],normals,ranks,attempts,maximize_stability,logfile,samplings,min_exp,min_std,start);
	    s<-rbind(s,q$si);
	    ind<-q$ind;
	  }	
	}
	cat(file=logfile,append=TRUE,length(ind),'pathways processed with start=',start,'\n')	
	rownames(s)<-pathwaynames[ind]
	list(scores = s[,1], genesinpathway=s[,2], newmeanstd=s[,3], origmeanstd=s[,4], pathwaysize=s[,5], curves=s[,6], curves_order=s[,7], z=s[,8],compin=s[,9],xm=s[,10],xs=s[,11],center=s[,12],rot=s[,13],pctaken=s[,14],samplings=samplings,sucess=ind,logfile=logfile)	
}