.getClass <- function(obj) {
   cls <- class(obj)
   return(cls[1])
}

NetSAM <- function(inputNetwork, outputFileName, outputFormat="nsm", edgeType="unweighted", map_to_genesymbol=FALSE, organism="hsapiens", idType="auto", minModule=0.003, stepIte=FALSE, maxStep=4, moduleSigMethod="cutoff", modularityThr=0.2, ZRanNum=10, PerRanNum=100, ranSig=0.05, edgeThr=(-1), nodeThr=(-1), nThreads=3){
  organisms <- c("hsapiens","mmusculus","rnorvegicus","drerio","celegans","scerevisiae","cfamiliaris","dmelanogaster","athaliana")
  names(organisms) <- c("Hs","Mm","Rn","Dr","Ce","Sc","Cf","Dm","At")

  if(length(which(organisms==organism))==0){
    stop("Currently, the package supports the following nine organisms: hsapiens, mmusculus, rnorvegicus, drerio, celegans, scerevisiae, cfamiliaris, dmelanogaster and athaliana!")
  }

  if(missing(inputNetwork)){
    stop("Please input the network!\n")
  }

  #load Network
  if(.getClass(inputNetwork)=="character"){
    if(file_ext(inputNetwork)!="net"){
      stop("The extension of the input file should be 'net'!\n")
    }else{
      network <- read_graph_ncol(inputNetwork)
      if(edgeType=="weighted"){
        if(is.null(E(network)$weight)){
          stop("The input network does not contain edge weights. Please add the edge weights or change parameter 'edgeType' to 'unweigthed'!")
        }
      }else{
        if(!is.null(E(network)$weight)){
          stop("The input network contains edge weights. Please remove the edge weights or change parameter 'edgeType' to 'weigthed'!")
        }
      }
    }
  }else{
    if(.getClass(inputNetwork)=="data.frame" || .getClass(inputNetwork)=="matrix"){
      if(edgeType=="weighted"){
        if(ncol(inputNetwork)!=3){
          stop("Data object should contain three columns: interactor1, interactor2 and edge weight!")
        }else{
          weight <- inputNetwork[,3]
          if(!is.numeric(weight)){
            stop("The edge weight should be numeric!")
          }else{
            inputNetwork <- as.matrix(inputNetwork[,c(1,2)])
            inputNetwork_S <- as.character(inputNetwork)
            inputNetwork_S <- array(inputNetwork_S,dim=dim(inputNetwork))
            network <- graph.edgelist(inputNetwork_S,directed=F)
            E(network)$weight <- weight
          }
        }
      }else{
        if(ncol(inputNetwork)!=2){
          stop("data object should contain two columns!\n");
        }else{
          inputNetwork <- as.matrix(inputNetwork)
          inputNetwork_S <- as.character(inputNetwork)
          inputNetwork_S <- array(inputNetwork_S,dim=dim(inputNetwork))
          network <- graph.edgelist(inputNetwork_S,directed=F)
        }
      }
      rm(inputNetwork,inputNetwork_S)
      gc()
    }else{
      if(.getClass(inputNetwork)=="igraph"){
        if(edgeType=="unweighted"){
          if(!is.null(E(inputNetwork)$weight)){
            stop("The input network contains edge weights. Please remove the edge weights or change parameter 'edgeType' to 'weigthed'!")
          }else{
            network <- inputNetwork
          }
        }else{
          if(is.null(E(inputNetwork)$weight)){
            stop("The input network does not contain edge weights. Please add the edge weights or change parameter 'edgeType' to 'unweigthed'!")
          }else{
            network <- inputNetwork
          }
        }
        rm(inputNetwork)
        gc()
      }else{
        if(.getClass(inputNetwork)=="graphNEL"){
          network <- igraph.from.graphNEL(inputNetwork)
          if(edgeType=="unweighted"){
            if(!is.null(E(network)$weight)){
              stop("The input network contains edge weights. Please remove the edge weights or change parameter 'edgeType' to 'weigthed'!")
            }
          }else{
            if(is.null(E(network)$weight)){
              stop("The input network does not contain edge weights. Please add the edge weights or change parameter 'edgeType' to 'unweigthed'!")
            }
          }
          rm(inputNetwork)
          gc()
        }else{
          stop("The input network should be from a file or a data object with data.frame, matrix, graphNEL or igraph class. Other types of input are invalid!\n")
        }

      }
    }
  }

  if(outputFormat != "none" && missing(outputFileName)){
    stop("Please input the output file name!\n")
  }else{
    if(substr(outputFileName,nchar(outputFileName),nchar(outputFileName))=="/"){
      stop("Please input the output file name!\n")
    }
  }

  if(!(outputFormat %in% c("nsm","gmt","multiple","none"))){
    stop("The input 'outputFormat' is invalid! Please select an output format from 'nsm', 'gmt', 'multiple' and 'none'!\n")
  }

  if(!is.logical(map_to_genesymbol)){
    stop("The input 'map_to_genesymbol' is invalid! 'map_to_genesymbol' should only be TRUE or FALSE!\n")
  }

  if(!(organism %in% organisms)){
    stop("Currently, the package supports the following nine organisms: hsapiens, mmusculus, rnorvegicus, drerio, celegans, scerevisiae, cfamiliaris, dmelanogaster and athaliana!")
  }

  if(minModule<0 || minModule>0.2){
    stop("The input 'minModule' is invalid! 'minModule' should be between 0 and  0.2!\n")
  }

  if(maxStep<2 || .getClass(maxStep)!="numeric"){
    stop("The input 'maxStep' is invalid! 'maxStep' should be a number and larger than 2!\n")
  }

  if(!(moduleSigMethod %in% c("cutoff","zscore","permutation"))){
    stop("The input 'moduleSigMethod' is invalid! Please select an option from 'cutoff','zscore' and 'permutation'!\n")
  }

  if(modularityThr>1 || modularityThr<0 || .getClass(modularityThr)!="numeric"){
    stop("The input 'modularityThr' is invalid! 'modularityThr' should be a positive number and less than 1!\n")
  }

  if(ZRanNum<10 || .getClass(ZRanNum)!="numeric"){
    stop("The input 'ZRanNum' is invalid! 'ZRanNum' should be a number and larger than 10!\n")
  }

  if(PerRanNum<10 || .getClass(PerRanNum)!="numeric"){
    stop("The input 'PerRanNum' is invalid! 'PerRanNum' should be a number and larger than 10!\n")
  }

  if(ranSig>1 || ranSig <0 || .getClass(ranSig)!="numeric"){
    stop("The input 'ranSig' is invalid! 'ranSig' should be a positive number and less than 1!\n")
  }

  if(edgeThr<(-1) || .getClass(edgeThr)!="numeric"){
    stop("The input 'edgeThr' is invalid! 'edgeThr' should be -1 or a positive number!\n")
  }

  if(nodeThr<(-1) || .getClass(nodeThr)!="numeric"){
    stop("The input 'nodeThr' is invalid! 'nodeThr' should be -1 or a positive number!\n")
  }

  if(nThreads<1 || .getClass(nThreads)!="numeric"){
    stop("The input 'nThreads' is invalid! 'nThreads' should be a number and greater than 1!\n")
  }

  if(!is.simple(network)){
    warning("The input network contain loop or multiple edges. For unweighted network, NetSAM will remove loop or multiple edges. For weighted network, NetSAM will sum the weights from loop or multiple edges!!!")
    network <- simplify(network)
  }

  if(nodeThr!=(-1)){
    if(vcount(network)>nodeThr){
      stop("The number of nodes in the network is over the threshold ",nodeThr,". Please adjust the parameters to decrease the network size!\n")
    }
  }

  if(edgeThr!=(-1)){
    if(ecount(network)>edgeThr){
      stop("The number of edges in the network is over the threshold ",edgeThr,". Please adjust the parameters to decrease the network size!\n")
    }
  }


  ###################Get the whole gene symbols for the given organism###################
  if(organism=="scerevisiae"){
    #require("org.Sc.sgd.db") || stop("package org.Sc.sgd.db is required!!\n")
    genesymbol <- keys(eval(parse(text="org.Sc.sgd.db::org.Sc.sgdCOMMON2ORF")))
  }else{
    if(organism=="athaliana"){
      #require("org.At.tair.db") || stop("package org.At.tair.db is required!!\n")
      genesymbol <- unlist(as.list(eval(parse(text="org.At.tair.db::org.At.tairSYMBOL"))))
      names(genesymbol) <- NULL
      genesymbol <- unique(genesymbol)
      genesymbol <- genesymbol[!is.na(genesymbol)]
    }else{
      or <- names(organisms)[which(organisms==organism)]
      #require(paste("org.",or,".eg.db",sep=""),character.only = TRUE) || stop(paste("package org.", or, ".eg.db is required!!\n", sep=""))
      genesymbol <- keys(eval(parse(text=paste("org.",or,".eg.db::","org.",or,".egSYMBOL2EG",sep=""))))
    }
  }
  ########################################################################################

  geneid <- V(network)$name

  is.genesymbol <- FALSE
  if(length(intersect(geneid,genesymbol))>0.6*length(geneid)){
    is.genesymbol <- TRUE
  }else{
    is.genesymbol <- FALSE
  }

  mapping.status <- 0

  if(map_to_genesymbol==TRUE){
    ne <- mapToSymbol(inputData=network,organism=organism,inputType="network",idType=idType, edgeType=edgeType, verbose=TRUE)
    if(!is.null(ne)){
      network_edgelist <- ne$network
      netMat <- as.matrix(network_edgelist[,c(1,2)])
      network <- graph.edgelist(netMat,directed=FALSE)
      if(edgeType=="weighted"){
        E(network)$weight <- network_edgelist[,3]
      }
      mapping.status <- 0
    }else{
      stop("Please check the parameter 'idType' or set the parameter 'map_to_genesymbol' as FALSE!\n")
    }
  }else{
    if(is.genesymbol==TRUE){
      mapping.status <- 0
    }else{
      if(idType==""){     #NONE OF THE ABOVE
        mapping.status <- 1
      }else{
        ne <- mapToSymbol(inputData=network,organism=organism,inputType="network",idType=idType,edgeType=edgeType,verbose=FALSE)
        if(!is.null(ne)){
          idmap <- ne$idmap
          mapping.status <- 2
        }else{
          mapping.status <- 1
        }
      }
    }
  }

  minModule <- round(vcount(network)*minModule)
  if(minModule<5){
    minModule <- 5
  }

  allowWGCNAThreads(nThreads=nThreads)
  threNum <- WGCNAnThreads()
  if(threNum>nThreads){
    threNum <- nThreads
  }

  network_module <- .identifyModule(network,minModule,stepIte,maxStep,moduleSigMethod,modularityThr,ZRanNum,PerRanNum,ranSig,threNum,edgeType)
  geneorder <- network_module$geneorder
  disableWGCNAThreads()

  if(outputFormat=="nsm" || outputFormat=="none" || outputFormat=="multiple"){

    network_edges <- get.edgelist(network)
    if(edgeType=="weighted"){
      if(ecount(network)>500000){
        warning("The input weighted network contain over 500,000 edges. Because nsm file contains edge information, remaining all edges of the network will cause a very large size of nsm file, which will be difficult to upload to NetGestalt. NetSAM only remains top 500,000 edges based on the edge weights from largest to smallest!!\n")
        w <- E(network)$weight
        w <- order(w,decreasing=T)
        network_edges <- network_edges[w,]
        network_edges <- network_edges[1:500000,]
      }
    }

    hmiFile <- .createHMIFile(network_module$allHir,geneorder)

    rownames(geneorder) <- geneorder[,4]
    netgestalt <- list(rulfile=geneorder,hmifile=hmiFile,network=network_edges)

    if(outputFormat=="multiple"){
      outputFile <- paste(outputFileName,"_rulerfile.rul",sep="")
      write.table(geneorder,file=outputFile,row.names=F,col.names=T,sep="\t",quote=F)

      outputFile <- paste(outputFileName,"_hmifile.hmi",sep="")
      write.table(hmiFile,file=outputFile,row.names=F,col.names=T,sep="\t",quote=F)

      outputFile <- paste(outputFileName,"_network.net",sep="")
      write.table(network_edges,file=outputFile,row.names=F,col.names=F,sep="\t",quote=F)

    }

    if(outputFormat=="nsm"){
      outputFile <- paste(outputFileName,".nsm",sep="")
      note <- "##  Ruler file  ##"
      write.table(note,file=outputFile,row.names=F,col.names=F,quote=F)
      suppressWarnings(write.table(geneorder,file=outputFile,row.names=F,col.names=T,append=T,quote=F,sep="\t"))
      note <- "##  HMI file ##"
      write.table(note,file=outputFile,row.names=F,col.names=F,quote=F,append=T)
      suppressWarnings(write.table(hmiFile,file=outputFile,row.names=F,col.names=T,quote=F,append=T,sep="\t"))
      note <- "##  Network file  ##"
      write.table(note,file=outputFile,row.names=F,col.names=F,quote=F,append=T)
      write.table(network_edges,file=outputFile,row.names=F,col.names=F,quote=F,append=T,sep="\t")

      netgestalt$mapping.status <- mapping.status

      note <- "##  Mapping Status  ##"
      write.table(note,file=outputFile,row.names=F,col.names=F,quote=F,append=T)
      suppressWarnings(write.table(paste("mapping.status=",mapping.status,sep=""),file=outputFile,row.names=F,col.names=F,quote=F,append=T,sep="\t"))


      if(mapping.status==2){
        note <- "##  Gene Annotation  ##"
        write.table(note,file=outputFile,row.names=F,col.names=F,quote=F,append=T)
        suppressWarnings(write.table(idmap,file=outputFile,row.names=F,col.names=T,quote=F,append=T,sep="\t"))
        netgestalt$geneAnn <- idmap
      }

    }

    cat("NetSAM identified ",(nrow(hmiFile)-1)," modules in ",(length(unique(hmiFile[,2]))-1)," levels!\n",sep="")
    cat("Processing completed!\n\n")
    return(netgestalt)


  }else{
    hmiFile <- .createHMIFile(network_module$allHir,geneorder)
    gmtFile <- .createGMTFile(hmiFile,geneorder)
    outputFile1 <- paste(outputFileName,".gmt",sep="")
    write.table(gmtFile,file=outputFile1,row.names=F,col.names=F,sep="\t",quote=F)
    result <- gmtFile
    cat("NetSAM identified ",(nrow(hmiFile)-1)," modules in ",(length(unique(hmiFile[,2]))-1)," levels!\n",sep="")
    cat("Processing completed!\n\n")
    return(result)
  }

}


.identifyModule <- function(network, minModule, stepIte, maxStep, moduleSigMethod, modularityThr, ZRanNum, PerRanNum, ranSig, threNum, edgeType){

  cat("\nIdentifying the hierarchical modules of the network...\n")
  overlap_genesymbol_networkP <- V(network)$name
  subnetworkInfo <- list()
  subnetworkInfo_index <- 1
  network_cluster <- clusters(network)
  network_cluster_size <- network_cluster$csize

  if(length(network_cluster_size[network_cluster_size>=minModule])==0){
    stop("The size of all subnetworks are less than ",minModule,". Please adjust the parameter 'minModule'!\n\n")
  }

  network_cluster_size <- data.frame(id=c(1:length(network_cluster_size)),cluster_size=network_cluster_size,stringsAsFactors=F)
  network_cluster_size <- network_cluster_size[order(-network_cluster_size[,2]),]
  network_cluster_membership <- network_cluster$membership

  network_ordered_node <- vector()
  subnetwork_id <- 1
  for(i in c(1:nrow(network_cluster_size))){
    sub_network_size <- network_cluster_size[i,2]
    if(sub_network_size>=minModule){
      cat("Starting to analysis connected component ",subnetwork_id,"!\n",sep="")
      subnetwork_id <- subnetwork_id+1
      subnetwork_node <- overlap_genesymbol_networkP[which(network_cluster_membership==network_cluster_size[i,1])]
      subnetwork <- .extractSubNetwork(network,subnetwork_node,edgeType)
      allHir <- .identifyHierOr(subnetwork, minModule, stepIte, maxStep, moduleSigMethod, modularityThr, ZRanNum, PerRanNum, ranSig, threNum, edgeType)
      subnetworkInfo[[subnetworkInfo_index]] <- allHir
      subnetworkInfo_index <- subnetworkInfo_index+1
      network_ordered_node <- c(network_ordered_node,subnetwork_node)
      cat("\n")
    }
  }
  cat("\nReordering the genes in the one dimentional layout...\n")
  geneorder <- data.frame(ruler_id=c(1:length(overlap_genesymbol_networkP)),node_type="Gene",node_db="Entrez Gene",node_db_id=overlap_genesymbol_networkP,node_name=overlap_genesymbol_networkP,stringsAsFactors=F)
  rownames(geneorder) <- overlap_genesymbol_networkP
  unann_node <- setdiff(overlap_genesymbol_networkP,network_ordered_node)
  if(length(unann_node) !=0){
    network_ordered_node <- c(network_ordered_node,unann_node)
  }
  geneorder <- geneorder[network_ordered_node,]


  geneorder <- .orderDiffLevel(subnetworkInfo,geneorder)

  result <- list(network=network,allHir=subnetworkInfo,geneorder=geneorder)
  return(result)
}


.calculateRandomWalkerAdjectMatrix <- function(network_igraph,step,edgeType){

  #calculate the random walk distance for the network
  protein_in_ppi <- V(network_igraph)$name
  if(edgeType=="unweighted"){
    E(network_igraph)$weight <- rep(1,ecount(network_igraph))
  }

  nweight <- graph.strength(network_igraph,mode="all")
  V(network_igraph)$weight <- as.numeric(nweight)


  eweight <- E(network_igraph)$weight

  degree_node <- igraph::degree(network_igraph)
  network_igraph <- add.edges(network_igraph,rbind(protein_in_ppi,protein_in_ppi)) #walktrap algorithm adds all self interactions for each node
  E(network_igraph)$weight <- c(eweight,V(network_igraph)$weight/degree_node)
  V(network_igraph)$weight <- V(network_igraph)$weight+ V(network_igraph)$weight/degree_node

  nweight <- V(network_igraph)$weight

  adjMatrix <- get.adjacency(network_igraph,attr="weight")
  adjMatrix <- as.matrix(adjMatrix)

  W_weighted <- adjMatrix/nweight

  rm(adjMatrix,network_igraph,eweight,degree_node)
  gc()

  #cat("Create transition Matrix...\n")

  tranM <- W_weighted

  if(step>1){
    for(i in c(1:(step-1))){
      tranM <- tranM%*%W_weighted
    }
  }

  rm(W_weighted)
  gc()

  #tranM <- as.matrix(tranM)

  tranM <- t(tranM)/sqrt(nweight)
  tranM <- t(tranM)

  #cat("Calculate EU distance...\n")

  smat <- apply(tranM,1,crossprod)
  mat1 <- matrix(smat,nrow=length(protein_in_ppi),ncol=length(protein_in_ppi))
  mat3 <- tcrossprod(tranM)
  mat4 <- mat1+t(mat1)-2*mat3
  rm(smat,mat1,mat3,tranM)
  gc()
  mat4[mat4<0] <- 0
  diag(mat4) <- 0
  mat4 <- sqrt(mat4)

  return(mat4)
}


.transformFromWalktrapToHclust <- function(walktrap){

  #transform walktrap to hclust

  merge <- walktrap$merges
  name <- walktrap$names
  N <- length(name)

  merge[which(merge[,1]<=N),1] <- (-merge[which(merge[,1]<=N),1])
  merge[which(merge[,2]<=N),2] <- (-merge[which(merge[,2]<=N),2])

  merge[which(merge[,1]>N),1] <- (merge[which(merge[,1]>N),1]-N)
  merge[which(merge[,2]>N),2] <- (merge[which(merge[,2]>N),2]-N)

  height <- c(1:(N-1))

  dend <- as.dendrogram(walktrap)
  order <- order.dendrogram(dend)

  labels <- name

  ht <- list(merge=merge,height=height,order=order,labels=labels,method="walktrap",call=match.call(),dist.method="randomwalk")

  class(ht) <- "hclust"

  return(ht)
}

.walktrapcommunity <- function(network_igraph,steps,edgeType){
  if(edgeType=="weighted"){
    network_walktrap <- walktrap.community(network_igraph,weights=E(network_igraph)$weight,steps=steps)
  }else{
    network_walktrap <- walktrap.community(network_igraph,steps=steps)
  }
  return(network_walktrap)
}

.evaluateWalktrapStep <- function(network_igraph,stepIte,maxStep,level,threNum,edgeType,subM){

  #evaluate the optimal Step for the network

  if(stepIte==FALSE || maxStep==2 || level==1){
    network_walktrap <- .walktrapcommunity(network_igraph,steps=maxStep,edgeType)
    network_adjMatrix <- .calculateRandomWalkerAdjectMatrix(network_igraph,maxStep,edgeType)
    rm(network_igraph)
    gc()
    network_adjMatrix <- as.dist(network_adjMatrix)
    network_hclust <- .transformFromWalktrapToHclust(network_walktrap)
    network_order <- seriate(network_adjMatrix,method="OLO",control=list(hclust=network_hclust))
    network_order <- get_order(network_order)
    network_info <- list(gene=network_walktrap$names,membership=network_walktrap$membership,modularity=max(network_walktrap$modularity),step=maxStep,order=network_order,level=level)
    return(network_info)
  }else{

    if(maxStep < threNum){
      threNum <- maxStep
      perN <- 1
    }else{
      perN <- floor((maxStep-1)/threNum)
    }


    cl <- makeCluster(threNum)
    registerDoParallel(cl)


    i <- 1
    optimalM <- foreach(i=1:threNum, .packages="igraph") %dopar% {
      finalStep <- data.frame(step=0,modularity=1,stringsAsFactors=F)
      fi <- 1
      if(i==1){
        step_start <- 2
        step_end <- i*perN+1
      }else{
        step_start <- i*perN-(perN-2)
        if(i==threNum){
          step_end <- maxStep
        }else{
          step_end <- i*perN+1
        }
      }
      for(j in c(step_start:step_end)){
        if(edgeType=="weighted"){
          w <- walktrap.community(network_igraph,weights=E(network_igraph)$weight,steps=j)
        }else{
          w <- walktrap.community(network_igraph,steps=j)
        }
        m <- max(w$modularity)
        finalStep[fi,1] <- j
        finalStep[fi,2] <- m
        fi <- fi + 1
      }

      return(finalStep)
    }
    stopCluster(cl)

    finalStep <- data.frame(step=0,modularity=1,stringsAsFactors=F)
    for(i in c(1:length(optimalM))){
      finalStep <- rbind(finalStep,optimalM[[i]])
    }
    finalStep <- finalStep[finalStep[,1]!=0,]
    finalStep <- finalStep[order(-finalStep[,2],finalStep[,1]),]

    optimalStep <- finalStep[1,1]
    cat("The optimal Step of network ",subM," is ",optimalStep," !\n",sep="")

    optimalwalktrap <- .walktrapcommunity(network_igraph,steps=optimalStep,edgeType)
    network_adjMatrix <- .calculateRandomWalkerAdjectMatrix(network_igraph,optimalStep,edgeType)
    rm(network_igraph)
    gc()
    network_adjMatrix <- as.dist(network_adjMatrix)
    network_hclust <- .transformFromWalktrapToHclust(optimalwalktrap)
    network_order <- seriate(network_adjMatrix,method="OLO",control=list(hclust=network_hclust))
    network_order <- get_order(network_order)
    maxWalktrap <- list(gene=optimalwalktrap$names,membership=optimalwalktrap$membership,modularity=max(optimalwalktrap$modularity),step=optimalStep,order=network_order,level=level)
    return(maxWalktrap)
  }
}


.identifySig_Unweighted <- function(network_igraph,network_modularity,step,moduleSigMethod,modularityThr, ZRanNum, PerRanNum, ranSig, threNum){

  #identify whether the network can be separated again

  degree <- igraph::degree(network_igraph)
  sig <- 0
  i <- 1

  if(moduleSigMethod=="cutoff"){
    if(network_modularity>modularityThr){
      sig <- 1
    }
  }

  if(moduleSigMethod=="zscore"){

    if(ZRanNum<threNum){
      threNum <- ZRanNum
      perN <- 1
    }else{
      perN <- floor(ZRanNum/threNum)
    }


    cl <- makeCluster(threNum)
    registerDoParallel(cl)

    ranmodu <- foreach(i=1:threNum, .combine="c", .packages="igraph") %dopar%{

      randomM <- c()

      rN <- perN
      if(i==threNum){
        rN <- ZRanNum-(i-1)*perN
      }

      for(j in c(1:rN)){
        suppressWarnings(rannet <- degree.sequence.game(degree,method="vl"))
        ran_walktrap <- walktrap.community(rannet,steps=step)
        ranModularity <- max(ran_walktrap$modularity)
        randomM <- c(randomM,ranModularity)
      }
      return(randomM)
    }
    stopCluster(cl)

    ranmodu_mean <- mean(ranmodu)
    ranmodu_sd <- sd(ranmodu)
    if(ranmodu_sd == 0){
      if(network_modularity>ranmodu_mean){
        sig <- 1
      }
    }else{
      Z_network_modularity <- (network_modularity-ranmodu_mean)/ranmodu_sd
      p <- pnorm(Z_network_modularity,mean=0,sd=1,lower.tail=F)
      if(p<ranSig){
        sig <- 1
      }
    }
  }

  if(moduleSigMethod=="permutation"){

    if(PerRanNum<threNum){
      threNum <- PerRanNum
      perN <- 1
    }else{
      perN <- floor(PerRanNum/threNum)
    }


    cl <- makeCluster(threNum)
    registerDoParallel(cl)

    ranmodu <- foreach(i=1:threNum, .combine="c", .packages="igraph") %dopar%{

      randomM <- c()

      rN <- perN
      if(i==threNum){
        rN <- PerRanNum-(i-1)*perN
      }

      for(j in c(1:rN)){

        suppressWarnings(rannet <- degree.sequence.game(degree,method="vl"))
        ran_walktrap <- walktrap.community(rannet,steps=step)
        ranModularity <- max(ran_walktrap$modularity)
        randomM <- c(randomM,ranModularity)
      }
      return(randomM)
    }
    stopCluster(cl)

    p <- length(ranmodu[ranmodu>=network_modularity])/PerRanNum
    if(p<ranSig){
      sig <- 1
    }
  }

  return(sig)
}


.identifySig_Weighted <- function(network_igraph, network_modularity, step, moduleSigMethod, modularityThr, ZRanNum, PerRanNum, ranSig, threNum){

  #identify whether the network can be separated again


  sig <- 0
  i <- 1
  if(moduleSigMethod=="cutoff"){
    if(network_modularity>modularityThr){
      sig <- 1
    }
  }

  if(moduleSigMethod=="zscore"){

    #network_igraph <- network_info$network
    weight <- E(network_igraph)$weight
    #ranmodu <- vector()
    #step <- network_info$step

    if(ZRanNum<threNum){
      threNum <- ZRanNum
      perN <- 1
    }else{
      perN <- floor(ZRanNum/threNum)
    }

    cl <- makeCluster(threNum)
    registerDoParallel(cl)

    ranmodu <- foreach(i=1:threNum, .combine="c", .packages="igraph") %dopar%{

      randomM <- c()

      rN <- perN
      if(i==threNum){
        rN <- ZRanNum-(i-1)*perN
      }

      for(j in c(1:rN)){

        ranWeight <- sample(weight,length(weight))
        ranModularity <- max(walktrap.community(network_igraph,weights=ranWeight,steps=step)$modularity)
        randomM <- c(randomM,ranModularity)
      }
      return(randomM)
    }
    stopCluster(cl)
    rm(network_igraph,weight)
    gc()
    #cat("randomMo:",ranmodu,"\n")
    ranmodu_mean <- mean(ranmodu)
    ranmodu_sd <- sd(ranmodu)
    if(ranmodu_sd == 0){
      if(network_modularity>ranmodu_mean){
        sig <- 1
      }
    }else{
      Z_network_modularity <- (network_modularity-ranmodu_mean)/ranmodu_sd
      p <- pnorm(Z_network_modularity,mean=0,sd=1,lower.tail=F)
      if(p<ranSig){
        sig <- 1
      }
    }
  }

  if(moduleSigMethod=="permutation"){

    #network_igraph <- network_info$network
    weight <- E(network_igraph)$weight
    #step <- network_info$step

    if(PerRanNum<threNum){
      threNum <- PerRanNum
      perN <- 1
    }else{
      perN <- floor(PerRanNum/threNum)
    }

    cl <- makeCluster(threNum)
    registerDoParallel(cl)

    ranmodu <- foreach(i=1:threNum, .combine="c", .packages="igraph") %dopar%{

      randomM <- c()

      rN <- perN
      if(i==threNum){
        rN <- PerRanNum-(i-1)*perN
      }

      for(j in c(1:rN)){

        ranWeight <- sample(weight,length(weight))
        ranModularity <- max(walktrap.community(network_igraph,weights=ranWeight,steps=step)$modularity)
        randomM <- c(randomM,ranModularity)
      }
      return(randomM)
    }
    stopCluster(cl)
    rm(network_igraph,weight)
    gc()

    p <- length(ranmodu[ranmodu>=network_modularity])/PerRanNum
    if(p<ranSig){
      sig <- 1
    }
  }

  return(sig)
}


.identifySig <- function(network_igraph, network_modularity, step, moduleSigMethod, modularityThr, ZRanNum, PerRanNum, ranSig, threNum, edgeType){
  if(edgeType=="weighted"){
    sig <- .identifySig_Weighted(network_igraph, network_modularity, step, moduleSigMethod, modularityThr, ZRanNum, PerRanNum, ranSig, threNum)
  }else{
    sig <- .identifySig_Unweighted(network_igraph, network_modularity, step, moduleSigMethod, modularityThr, ZRanNum, PerRanNum, ranSig, threNum)
  }

  return(sig)
}


.identifyHierOr <- function(network_maxComponent, minModule, stepIte, maxStep, moduleSigMethod, modularityThr, ZRanNum, PerRanNum, ranSig, threNum, edgeType){

  #identify hierarchical organization of network

  allHir <- list()
  ai <- 1
  sigHir <- vector()
  si <- 1

  start <- 1

  cat("Evaluating networks in Level 1 ...\n")

  levelid <- 2

  network_info <- .evaluateWalktrapStep(network_maxComponent, stepIte, maxStep, level=1, threNum, edgeType, subM=1)
  cat("Network modularity: ",network_info$modularity,"\n\n",sep="")

  network_sig <- .identifySig(network_maxComponent, network_info$modularity, network_info$step, moduleSigMethod, modularityThr, ZRanNum, PerRanNum, ranSig, threNum, edgeType)

  allHir[[ai]] <- network_info
  rm(network_info)
  gc()


  if(network_sig==1){
    sigHir <- c(sigHir,ai)
    si <- si+1
  }

  ai <- ai+1

  while(length(sigHir)>0 && start!=si){
    currentPos <- sigHir[start]
    currentNetwork <- allHir[[currentPos]]
    start <- start+1

    currentNetwork_level <- currentNetwork$level
    currentNetwork_node <- currentNetwork$gene

    currentNetwork_membership <- currentNetwork$membership
    currentNetwork_membership <- data.frame(node=currentNetwork_node,membership=currentNetwork_membership,stringsAsFactors=F)
    currentNetwork_membership_count <- tapply(currentNetwork_membership[,1],currentNetwork_membership[,2],length)
    currentNetwork_membership_count <- currentNetwork_membership_count[currentNetwork_membership_count>=minModule]

    if(length(currentNetwork_membership_count)==0){
      next
    }

    currentNetwork_membership_group <- as.integer(names(currentNetwork_membership_count))
    rm(currentNetwork_membership_count,currentNetwork_node)
    gc()

    subLevel <- currentNetwork_level+1
    if(subLevel==levelid){
      cat("Evaluating networks in Level ",levelid," ...\n",sep="")
      levelid <- levelid+1
      subM <- 1
    }
    for(i in c(1:length(currentNetwork_membership_group))){
      subnetwork_node <- currentNetwork_membership[currentNetwork_membership[,2]==currentNetwork_membership_group[i],1]
      subnetwork_igraph <- .extractSubNetwork(network_maxComponent,subnetwork_node,edgeType)
      subnetwork_info <- .evaluateWalktrapStep(subnetwork_igraph, stepIte, maxStep, subLevel, threNum, edgeType, subM)
      cat("Modularity of network ",subM,": ",subnetwork_info$modularity,"\n\n",sep="")
      subnetwork_sig <- .identifySig(subnetwork_igraph, subnetwork_info$modularity, subnetwork_info$step, moduleSigMethod, modularityThr, ZRanNum, PerRanNum, ranSig, threNum, edgeType)

      allHir[[ai]] <- subnetwork_info
      rm(subnetwork_node,subnetwork_igraph,subnetwork_info)
      gc()

      if(subnetwork_sig==1){
        sigHir <- c(sigHir,ai)
        si <- si+1
      }

      ai <- ai+1
      subM <- subM + 1
    }
  }

  return(allHir)
}


.orderDiffLevel <- function(subnetworkInfo,geneorder){

  #reorder all genes in the network according to the optimal position in each level

  for(l in c(1:length(subnetworkInfo))){
    allHir <- subnetworkInfo[[l]]

    for(i in c(1:length(allHir))){
      ori <- allHir[[i]]$order
      node <- allHir[[i]]$gene
      node <- node[ori]
      node <- data.frame(id=c(1:length(node)),name=node,stringsAsFactors=F)
      node <- node[order(node[,2]),]

      geneorder_subpos <- which(geneorder[,5] %in% node[,2])
      geneorder_sub <- geneorder[geneorder_subpos,]
      geneorder_sub <- geneorder_sub[order(geneorder_sub[,5]),]
      geneorder_sub <- cbind(geneorder_sub,node[,1])
      geneorder_sub <- geneorder_sub[order(geneorder_sub[,6]),]
      geneorder_sub <- geneorder_sub[,c(1:5)]
      geneorder[geneorder_subpos,] <- geneorder_sub

    }

  }
  geneorder[,1] <- c(1:nrow(geneorder))
  return(geneorder)
}

.createHMIFile <- function(subnetworkInfo,geneorder){
  #create HMI file
  hmiFile <- data.frame(best="N",level=0,order=1,name="ALL",start=1,end=nrow(geneorder),stringsAsFactors=F)
  hi <- 2
  for(l in c(1:length(subnetworkInfo))){
    allHir <- subnetworkInfo[[l]]
    for(i in c(1:length(allHir))){
      node <- allHir[[i]]$gene
      position <- which(geneorder[,5] %in% node)
      start <- min(position)
      end <- max(position)
      level <- allHir[[i]]$level
      if(level==2){
        best <- "Y"
      }else{
        best <- "N"
      }
      hmiFile[hi,1] <- best
      hmiFile[hi,2] <- level
      hmiFile[hi,3] <- 0
      hmiFile[hi,4] <- ""
      hmiFile[hi,5] <- start
      hmiFile[hi,6] <- end
      hi <- hi+1
    }
  }

  hmiFile <- hmiFile[order(hmiFile[,2],hmiFile[,5]),]
  allLevel <- sort(unique(hmiFile[,2]))
  for(i in c(1:length(allLevel))){
    position <- which(hmiFile[,2]==allLevel[i])
    start <- min(position)
    end <- max(position)
    hmiFile[start:end,3] <- c(1:(end-start+1))
  }
  hmiFile[,4] <- paste("Level",hmiFile[,2],"Module",hmiFile[,3],sep="_")
  return(hmiFile)
}


.createGMTFile <- function(hmiFile,geneorder){
  allgene <- geneorder[,4]
  allgene <- paste(allgene,collapse="\t")
  humancatfile <- data.frame(name="01",childnum=1,gene=allgene,start=1,end=nrow(geneorder),level=0,stringsAsFactors=F)

  for(i in c(2:nrow(hmiFile))){
    st <- hmiFile[i,5]
    en <- hmiFile[i,6]
    l <- hmiFile[i,2]
    for(j in c(1:nrow(humancatfile))){
      pl <- humancatfile[j,6]
      if(pl==(l-1)){
        ps <- humancatfile[j,4]
        pe <- humancatfile[j,5]
        if(st>=ps && en<=pe){
          pcu <- humancatfile[j,1]
          pcu_c <- humancatfile[j,2]
          if(pcu_c < 10){
            pcu_c <- paste("0",pcu_c,sep="")
          }else{
            pcu_c <- as.character(pcu_c)
          }

          c_cu <- paste(pcu,pcu_c,sep="-")
          humancatfile[j,2] <- humancatfile[j,2] + 1
          humancatfile[i,1] <- c_cu
          humancatfile[i,2] <- 1
          cg <- geneorder[c(st:en),4]
          cg <- paste(cg,collapse="\t")
          humancatfile[i,3] <- cg
          humancatfile[i,4] <- st
          humancatfile[i,5] <- en
          humancatfile[i,6] <- l
          break
        }
      }
    }
  }
  humancatfile[,7] <- humancatfile[,5]-humancatfile[,4]+1
  gmtFile <- humancatfile[,c(1,7,3)]
  return(gmtFile)
}


.extractSubNetwork <- function(network,subList,edgeType){
  if(edgeType=="unweighted"){
    x <- get.edgelist(network)
    x <- x[x[,1] %in% subList & x[,2] %in% subList,]
    network <- graph.edgelist(x,directed=F)
  }else{
    x <- get.edgelist(network)
    weight <- get.edge.attribute(network,"weight")
    ind <- which(x[,1] %in% subList & x[,2] %in% subList)
    x <- x[ind,]
    weight <- weight[ind]
    network <- graph.edgelist(x,directed=F)
    E(network)$weight <- weight
  }
  return(network)
}
