@@ -2,15 +2,23 @@ Package: bnem

 Type: Package

 Title: Training of logical models from indirect measurements of perturbation

     experiments

-Version: 0.99.1

-Authors@R: person("Martin", "Pirkl", email = "martinpirkl@yahoo.de",role = c("aut", "cre"))

+Version: 0.99.3

+Authors@R: person("Martin", "Pirkl",

+    email = "martinpirkl@yahoo.de",

+    role = c("aut", "cre"))

 Description: bnem combines the use of indirect measurements of Nested Effects

-    Models (package mnem) with the Boolean networks of CellNOptR. Perturbation experiments of signalling nodes in cells are analysed for their effect on the global gene expression profile. Those profiles give evidence for the Boolean regulation of down-stream nodes in the network, e.g., whether two parents activate their child independently (OR-gate) or jointly (AND-gate).

+    Models (package mnem) with the Boolean networks of CellNOptR. Perturbation

+    experiments of signalling nodes in cells are analysed for their effect 

+    on the global gene expression profile. Those profiles give evidence 

+    for the Boolean regulation of down-stream nodes in the network, 

+    e.g., whether two parents activate their child independently 

+    (OR-gate) or jointly (AND-gate).

 Depends:

     R (>= 4.0)

 License: GPL-3

 Encoding: UTF-8

-biocViews: Pathways, SystemsBiology, NetworkInference, Network, GeneExpression, GeneRegulation, Preprocessing

+biocViews: Pathways, SystemsBiology, NetworkInference, Network, 

+    GeneExpression, GeneRegulation, Preprocessing

 Imports:

     CellNOptR,

     matrixStats,

@@ -36,4 +44,6 @@ VignetteBuilder: knitr

 Suggests:

     knitr, 

     BiocGenerics

+BugReports: https://github.com/MartinFXP/bnem/issues

+URL: https://github.com/MartinFXP/bnem/

 RoxygenNote: 7.1.1

@@ -1,10 +1,11 @@

 # Generated by roxygen2: do not edit by hand

 S3method(plot,bnem)

-S3method(plot,bnembs)

+S3method(plot,bnemBs)

 S3method(plot,bnemsim)

 export(absorption)

 export(absorptionII)

+export(addNoise)

 export(bnem)

 export(bnemBs)

 export(computeFc)

@@ -51,10 +52,11 @@ importFrom(limma,contrasts.fit)

 importFrom(limma,eBayes)

 importFrom(limma,lmFit)

 importFrom(limma,makeContrasts)

+importFrom(matrixStats,rowMaxs)

 importFrom(matrixStats,rowMins)

 importFrom(mnem,plotDnf)

 importFrom(sva,ComBat)

 importFrom(utils,combn)

-importFrom(utils,flush.console)

+importFrom(utils,glob2rx)

 importFrom(utils,write.table)

 importFrom(vsn,justvsn)

@@ -1,77 +1,76 @@

 #' @noRd

 preprocessInput <- function(stimuli=NULL, inhibitors=NULL, signals=NULL,

-                            design = NULL, exprs=NULL, fc=NULL, pkn,

+                            design = NULL, expression=NULL, fc=NULL, pkn,

                             maxInputsPerGate=100) {

-

+    

     if (is.null(design)) {

-

+        

         stimcols <- stimcols2 <- matrix(0, length(stimuli), ncol(fc))

-

+        

         for (i in seq_len(length(stimuli))) {

-

+            

             tmp <- numeric(ncol(fc))

-

+            

             tmp[grep(stimuli[i], gsub("_vs_.*", "", colnames(fc)))] <- 1

-

+            

             stimcols[i, ] <- tmp

-

+            

             tmp <- numeric(ncol(fc))

-

+            

             tmp[grep(stimuli[i], gsub(".*_vs_", "", colnames(fc)))] <- 1

-

+            

             stimcols2[i, ] <- tmp

-

+            

         }

-

-        maxStim <- max(c(apply(stimcols, 2, sum), apply(stimcols2, 2, sum)))

-

+        

+        maxStim <- max(c(colSums(stimcols), colSums(stimcols2)))

+        

         inhibitcols <- inhibitcols2 <- matrix(0, length(inhibitors), ncol(fc))

-

+        

         for (i in seq_len(length(inhibitors))) {

-

+            

             tmp <- numeric(ncol(fc))

-

+            

             tmp[grep(inhibitors[i], gsub("_vs_.*", "", colnames(fc)))] <- 1

-

+            

             inhibitcols[i, ] <- tmp

-

+            

             tmp <- numeric(ncol(fc))

-

+            

             tmp[grep(inhibitors[i], gsub(".*_vs_", "", colnames(fc)))] <- 1

-

+            

             inhibitcols2[i, ] <- tmp

-

+            

         }

-

-        maxInhibit <- max(c(apply(inhibitcols, 2, sum), apply(inhibitcols2, 2,

-                                                              sum)))

-

+        

+        maxInhibit <- max(c(colSums(inhibitcols), colSums(inhibitcols2)))

+        

         if (is.null(signals)) { signals <- unique(c(stimuli, inhibitors)) }

-

+        

         CNOlist <- dummyCNOlist(stimuli=stimuli, inhibitors=inhibitors,

                                 maxStim=maxStim, maxInhibit=maxInhibit,

                                 signals=signals)

-

+        

         model <- preprocessing(CNOlist, pkn, maxInputsPerGate=maxInputsPerGate)

-

+        

     }

-

+    

     NEMlist <- list()

-

+    

     NEMlist$fc <- fc

-

-    if (is.null(exprs)) {

-        NEMlist$exprs <- matrix(rnorm(nrow(CNOlist@cues)*10), 10,

-                                nrow(CNOlist@cues))

+    

+    if (is.null(expression)) {

+        NEMlist$expression <- matrix(rnorm(nrow(getCues(CNOlist))*10), 10,

+                                nrow(getCues(CNOlist)))

     } else {

-        NEMlist$exprs <- exprs

+        NEMlist$expression <- expression

     }

-

+    

     return(list(CNOlist=CNOlist, model=model, NEMlist=NEMlist))

-

+    

 }

 #' @importFrom graphics abline axis legend mtext par screen split.screen

-#' @importFrom utils combn flush.console write.table

+#' @importFrom utils combn write.table

 #' @noRd

 addEdge <-

     function(edges, CNOlist, model, n = 100, full = FALSE) {

@@ -86,14 +85,14 @@ addEdge <-

                                                 tmp2[2]))

             }

         }

-        write.table(sifMatrix, file = "temp.sif", sep = "\t", row.names = FALSE,

+        temp.file <- tempfile(pattern="interaction",fileext=".sif")

+        write.table(sifMatrix, file = temp.file, sep = "\t", row.names = FALSE,

                     col.names = FALSE, quote = FALSE)

-        PKN2 <- readSIF("temp.sif")

-        unlink("temp.sif")

+        PKN2 <- readSIF(temp.file)

         model2 <- preprocessing(CNOlist, PKN2, maxInputsPerGate=n)

         if (!full) {

-            index <- which(!(model2$reacID %in% model$reacID) &

-                           !(model2$reacID %in% edges))

+            index <- !(model2$reacID %in% model$reacID) &

+                !(model2$reacID %in% edges)

             model2$reacID <- model2$reacID[-index]

             model2$interMat[, -index]

             model2$notMat[, -index]

@@ -104,37 +103,39 @@ addEdge <-

 addSignal <-

     function(s, CNOlist, stim = NULL, inhibit = NULL) {

         CNOlist2 <- CNOlist

-        CNOlist2@signals[[1]] <- cbind(CNOlist2@signals[[1]], s = 0)

-        CNOlist2@signals[[2]] <- cbind(CNOlist2@signals[[2]], s = 0)

-        colnames(CNOlist2@signals[[1]]) <- c(colnames(CNOlist@signals[[1]]), s)

-        colnames(CNOlist2@signals[[2]]) <- c(colnames(CNOlist@signals[[2]]), s)

+        CNOlist2@signals[[1]] <- cbind(getSignals(CNOlist2)[[1]], s = 0)

+        CNOlist2@signals[[2]] <- cbind(getSignals(CNOlist2)[[2]], s = 0)

+        colnames(CNOlist2$signals[[1]]) <-

+            c(colnames(getSignals(CNOlist)[[1]]), s)

+        colnames(CNOlist2$signals[[2]]) <-

+            c(colnames(getSignals(CNOlist)[[2]]), s)

         if (!is.null(inhibit)) {

-            CNOlist2@cues <- cbind(CNOlist2@cues, 0)

-            CNOlist2@cues <- rbind(CNOlist2@cues,

+            CNOlist2@cues <- cbind(getCues(CNOlist2), 0)

+            CNOlist2@cues <- rbind(getCues(CNOlist2),

                                    matrix(0, nrow =nrow(inhibit),

-                                          ncol = ncol(CNOlist2@cues)))

-            CNOlist2@cues[(nrow(CNOlist2@cues) -

-                           nrow(inhibit) + 1):nrow(CNOlist2@cues),

-                          which(colnames(CNOlist2@cues) %in%

-                                colnames(inhibit))] <- inhibit

-            CNOlist2@cues[(nrow(CNOlist2@cues) -

-                           nrow(inhibit) + 1):nrow(CNOlist2@cues),

-                          ncol(CNOlist2@cues)] <- 1

-            colnames(CNOlist2@cues)[ncol(CNOlist2@cues)] <- s

+                                          ncol = ncol(getCues(CNOlist2))))

+            CNOlist2@cues[(nrow(getCues(CNOlist2)) -

+                               nrow(inhibit) + 1):nrow(getCues(CNOlist2)),

+                          colnames(getCues(CNOlist2)) %in%

+                              colnames(inhibit)] <- inhibit

+            CNOlist2@cues[(nrow(getCues(CNOlist2)) -

+                               nrow(inhibit) + 1):nrow(getCues(CNOlist2)),

+                          ncol(getCues(CNOlist2))] <- 1

+            colnames(CNOlist2@cues)[ncol(getCues(CNOlist2))] <- s

             CNOlist2@stimuli <-

-                CNOlist2@cues[, which(colnames(CNOlist2@cues) %in%

-                                      colnames(CNOlist2@stimuli))]

+                getCues(CNOlist2)[, colnames(getCues(CNOlist2)) %in%

+                                      colnames(getStimuli(CNOlist2))]

             CNOlist2@inhibitors <-

-                CNOlist2@cues[, which(colnames(CNOlist2@cues) %in%

-                                      c(colnames(CNOlist2@inhibitors), s))]

+                getCues(CNOlist2)[, colnames(getCues(CNOlist2)) %in%

+                                      c(colnames(getInhibitors(CNOlist2)), s)]

             CNOlist2@signals[[1]] <-

-                rbind(CNOlist2@signals[[1]],

+                rbind(getSignals(CNOlist2)[[1]],

                       matrix(0, nrow = nrow(inhibit),

-                             ncol = ncol(CNOlist2@signals[[1]])))

+                             ncol = ncol(getSignals(CNOlist2)[[1]])))

             CNOlist2@signals[[2]] <-

-                rbind(CNOlist2@signals[[2]],

+                rbind(getSignals(CNOlist2)[[2]],

                       matrix(0, nrow = nrow(inhibit),

-                             ncol = ncol(CNOlist2@signals[[2]])))

+                             ncol = ncol(getSignals(CNOlist2)[[2]])))

         }

         CNOlist2 <- checkCNOlist(CNOlist2)

         return(CNOlist2)

@@ -142,27 +143,19 @@ addSignal <-

 #' @noRd

 adj2dnf <-

     function(A) {

-

         dnf <- NULL

-

-        for (i in seq_len(ncol(A))) {

-            for (j in seq_len(nrow(A))) {

-                if (i %in% j) { next() }

-                if (A[i, j] == 1) {

-                    dnf <- c(dnf, paste(colnames(A)[i], rownames(A)[j],

-                                        sep = "="))

-                }

-                if (A[i, j] == -1) {

-                    dnf <- c(dnf, paste("!", colnames(A)[i], "=",

-                                        rownames(A)[j], sep = ""))

-                }

+        edges <- which(A!=0,arr.ind=TRUE)

+        for (i in seq_len(nrow(edges))) {

+            if (A[edges[i,1],edges[i,2]]>0) {

+                dnf <- c(dnf, paste(colnames(A)[edges[i,1]],

+                                    rownames(A)[edges[i,2]], sep = "="))

+            } else {

+                dnf <- c(dnf, paste0("!",colnames(A)[edges[i,1]],"=",

+                                     rownames(A)[edges[i,2]]))

             }

         }

-

         dnf <- unique(dnf)

-

         return(dnf)

-

     }

 #' @noRd

 adj2graph <-

@@ -178,31 +171,35 @@ adj2graph <-

         return(gR)

     }

 #' @noRd

+#' @import CellNOptR

 checkCNOlist <-

     function(CNOlist) {

-        if (dim(CNOlist@stimuli)[2] > 1) {

-            CNOlist@stimuli <- CNOlist@stimuli[,

-                                               order(colnames(CNOlist@stimuli))]

+        if (ncol(getStimuli(CNOlist)) > 1) {

+            CNOlist@stimuli <- getStimuli(CNOlist)[,

+                                                   order(colnames(

+                                                       getStimuli(CNOlist)))]

         }

-        if (dim(CNOlist@inhibitors)[2] > 1) {

+        if (ncol(getInhibitors(CNOlist)) > 1) {

             CNOlist@inhibitors <-

-                CNOlist@inhibitors[, order(colnames(CNOlist@inhibitors))]

+                getInhibitors(CNOlist)[, order(colnames(

+                    getInhibitors(CNOlist)))]

         }

-        CNOlist@cues <- cbind(CNOlist@stimuli, CNOlist@inhibitors)

-        if (ncol(CNOlist@signals[[1]]) > 1) {

-            for (i in seq_len(length(CNOlist@signals))) {

+        CNOlist@cues <- cbind(getStimuli(CNOlist), getInhibitors(CNOlist))

+        if (ncol(getSignals(CNOlist)[[1]]) > 1) {

+            for (i in seq_len(length(getSignals(CNOlist)))) {

                 CNOlist@signals[[i]] <-

-                    CNOlist@signals[[i]][,

-                                         order(colnames(CNOlist@signals[[i]]))]

+                    getSignals(CNOlist)[[i]][,

+                                             order(colnames(

+                                                 getSignals(CNOlist)[[i]]))]

             }

         }

         rownames(CNOlist@cues) <- rownames(CNOlist@stimuli) <-

             rownames(CNOlist@inhibitors) <-

-            unlist(lapply(rownames(CNOlist@cues), function(x) {

+            unlist(lapply(rownames(getCues(CNOlist)), function(x) {

                 y <- unlist(strsplit(x, "_"))

-                y <- paste(c(sort(y[which(y %in% colnames(CNOlist@stimuli))]),

-                             sort(y[which(!(y %in%

-                                            colnames(CNOlist@stimuli)))])),

+                y <- paste(c(sort(y[y %in% colnames(getStimuli(CNOlist))]),

+                             sort(y[!(y %in%

+                                          colnames(getStimuli(CNOlist)))])),

                            collapse = "_")

                 return(y)

             }))

@@ -222,11 +219,10 @@ checkMethod <-

         if (!(any(c("llr", "cosine", "euclidean", "maximum", "manhattan",

                     "canberra", "binary", "minkowski", "spearman", "pearson",

                     "kendall", "mLL", "cp", "none") %in% method))) {

-            stop(paste0("I'm sorry, Dave. I'm afraid I can't do that. ",

-                        "You have to pick a valid method: ",

-                        "llr, cosine, euclidean, maximum, manhattan, ",

-                        "canberra, binary, ",

-                        "minkowski, spearman, pearson, kendall"))

+            stop("You have to pick a valid method: ",

+                 "llr, cosine, euclidean, maximum, manhattan, ",

+                 "canberra, binary, ",

+                 "minkowski, spearman, pearson, kendall")

             ## , mLL, cp, none"))

         }

         return(method)

@@ -234,66 +230,58 @@ checkMethod <-

 #' @noRd

 #' @importFrom matrixStats rowMins

 checkNEMlist <-

-    function(NEMlist, CNOlist, parameters, approach, method) {

+    function(NEMlist, CNOlist, parameters, approach, method,verbose=FALSE) {

         NEMlistTmp <- NEMlist

         if("abs" %in% approach) {

-            if (length(table(NEMlist$exprs)) == 2) {

-                NEMlist$norm <- NEMlist$exprs

-                NEMlist$norm[

-                            which(NEMlist$norm

-                                  ==

-                                  as.numeric(names(

-                                      table(NEMlist$exprs))[1]))] <-

-                    0

-                NEMlist$norm[

-                            which(NEMlist$norm

-                                  ==

-                                  as.numeric(

-                                      names(table(NEMlist$exprs))[2]))] <-

-                    1

+            if (length(table(NEMlist$expression)) == 2) {

+                NEMlist$norm <- NEMlist$expression

+                NEMlist$norm[NEMlist$norm==as.numeric(names(

+                    table(NEMlist$expression))[1])] <- 0

+                NEMlist$norm[NEMlist$norm==as.numeric(

+                    names(table(NEMlist$expression))[2])] <- 1

             }

             if (length(NEMlist$norm) == 0 &

                 !any(c("pearson", "spearman", "kendall") %in% method)) {

                 if ("pam" %in% approach) {

-                    print("data is not discretized/normed to (0,1);

+                    warning("data is not discretized/normalized to (0,1);

 performing two cluster pam normalization")

-                    NEMlist$norm <- pamNorm(NEMlist$exprs)

+                    NEMlist$norm <- pamNorm(NEMlist$expression)

                 } else {

-                    print("data is not discretized/normed to (0,1);

+                    warning("data is not discretized/normalized to (0,1);

 performing simple normalization")

-                    NEMlist$norm <- simpleNorm(NEMlist$exprs)

+                    NEMlist$norm <- simpleNorm(NEMlist$expression)

                 }

                 if ("kmeans" %in% approach) {

-                    print("data is not discretized/normed to (0,1);

+                    warning("data is not discretized/normalized to (0,1);

 performing two means normalization")

-                    NEMlist$norm <- pamNorm(NEMlist$exprs)

+                    NEMlist$norm <- pamNorm(NEMlist$expression)

                 } else {

-                    print("data is not discretized/normed to (0,1);

+                    warning("data is not discretized/normed to (0,1);

 performing simple normalization")

-                    NEMlist$norm <- simpleNorm(NEMlist$exprs)

+                    NEMlist$norm <- simpleNorm(NEMlist$expression)

                 }

             }

             if ("spearman" %in% method) {

-                colnames.exprs <- colnames(NEMlist$exprs)

-                rownames.exprs <- rownames(NEMlist$exprs)

-                NEMlist$exprs <- t(apply(NEMlist$exprs, 1, rank))

-                colnames(NEMlist$exprs) <- colnames.exprs

-                rownames(NEMlist$exprs) <- rownames.exprs

+                colnames.expression <- colnames(NEMlist$expression)

+                rownames.expression <- rownames(NEMlist$expression)

+                NEMlist$expression <- t(apply(NEMlist$expression, 1, rank))

+                colnames(NEMlist$expression) <- colnames.expression

+                rownames(NEMlist$expression) <- rownames.expression

             }

             if ("cosine" %in% method) {

-                colnames.exprs <- colnames(NEMlist$exprs)

-                rownames.exprs <- rownames(NEMlist$exprs)

+                colnames.expression <- colnames(NEMlist$expression)

+                rownames.expression <- rownames(NEMlist$expression)

                 vprod <- function(x) { return(x%*%x) }

-                NEMlist$exprs <-

-                    NEMlist$exprs/(apply(NEMlist$exprs, 1, vprod)^0.5)

-                colnames(NEMlist$exprs) <- colnames.exprs

-                rownames(NEMlist$exprs) <- rownames.exprs

+                NEMlist$expression <-

+                    NEMlist$expression/(apply(NEMlist$expression, 1, vprod)^0.5)

+                colnames(NEMlist$expression) <- colnames.expression

+                rownames(NEMlist$expression) <- rownames.expression

             }

         }

         if ("fc" %in% approach) {

             if (length(NEMlist$fc) == 0)  {

-                print("foldchanges missing; automatic calculation")

-                NEMlist$fc <- computeFc(CNOlist, NEMlist$exprs)

+                warning("foldchanges missing; automatic calculation")

+                NEMlist$fc <- computeFc(CNOlist, NEMlist$expression)

                 egenes <- NEMlist$egenes

                 if (parameters$cutOffs[2] != 0) {

                     NEMlist <- computeSm(CNOlist, NEMlist, parameters,

@@ -329,22 +317,22 @@ performing simple normalization")

         }

         if (!is.null(NEMlist$egenes) & is.null(NEMlist$geneGrid)) {

             sgeneAdd <- matrix(Inf, nrow = nrow(NEMlist$fc),

-                               ncol = (ncol(CNOlist@signals[[1]])*2))

+                               ncol = (ncol(getSignals(CNOlist)[[1]])*2))

             for (i in seq_len(nrow(NEMlist$fc))) {

                 egeneName <- rownames(NEMlist$fc)[i]

                 sgeneCols <- numeric()

                 for (j in seq_len(length(NEMlist$egenes))) {

                     if (egeneName %in% NEMlist$egenes[[j]]) {

-                        colTmp <- which(colnames(CNOlist@signals[[1]]) ==

-                                        names(NEMlist$egenes)[j])

+                        colTmp <- which(colnames(getSignals(CNOlist)[[1]]) ==

+                                            names(NEMlist$egenes)[j])

                         sgeneCols <- c(sgeneCols, colTmp,

-                        (colTmp+ncol(CNOlist@signals[[1]])))

+                                       (colTmp+ncol(getSignals(CNOlist)[[1]])))

                     }

                 }

                 sgeneAdd[i, sgeneCols] <- 0

             }

             sgeneAddCheck <- rowMins(sgeneAdd)

-            sgeneAdd[which(sgeneAddCheck == Inf), ] <- 0

+            sgeneAdd[sgeneAddCheck == Inf, ] <- 0

             NEMlist$geneGrid <- sgeneAdd

         }

         if (!is.null(NEMlistTmp$weights)) {

@@ -359,10 +347,6 @@ computeFcII <-

         design <- makeDesign(y, stimuli, inhibitors, c(batches, runs))

         CompMat <- numeric()

         CompMatNames <- character()

-        ctrlsSum <- apply(design[, -grep(paste(c(runs, batches),

-                                               collapse = "|"),

-                                         colnames(design))], 1, sum)

-        ctrlsSum <- which(ctrlsSum == 0)

         stimuliDesign <- design[, grep(paste(stimuli, collapse = "|"),

                                        colnames(design))]

         inhibitorsDesign <- design[, grep(paste(inhibitors, collapse = "|"),

@@ -386,9 +370,9 @@ computeFcII <-

                 stimuliSum <- design[, grep(paste(stimuli, collapse = "|"),

                                             colnames(design))]

             } else {

-                stimuliSum <- apply(design[, grep(paste(stimuli,

-                                                        collapse = "|"),

-                                                  colnames(design))], 1, sum)

+                stimuliSum <- rowSums(design[, grep(paste(stimuli,

+                                                          collapse = "|"),

+                                                    colnames(design))])

             }

         }

         if (is.null(inhibitors) == TRUE) {

@@ -400,13 +384,13 @@ computeFcII <-

                                                colnames(design))]

             } else {

                 inhibitorsSum <-

-                    apply(design[, grep(paste(inhibitors, collapse = "|"),

-                                        colnames(design))], 1, sum)

+                    rowSums(design[, grep(paste(inhibitors, collapse = "|"),

+                                          colnames(design))])

             }

         }

         cuesSum <-

-            apply(design[, grep(paste(c(stimuli, inhibitors), collapse = "|"),

-                                colnames(design))], 1, sum)

+            rowSums(design[, grep(paste(c(stimuli, inhibitors), collapse = "|"),

+                                  colnames(design))])

         maxStim <- max(stimuliSum)

         maxKd <- max(inhibitorsSum)

         for (run in runs) {

@@ -426,9 +410,9 @@ computeFcII <-

                                           targetRows)

                 grepStimsStims <- intersect(intersect(which(stimuliSum >= 2),

                                                       which(inhibitorsSum ==

-                                                            0)),

+                                                                0)),

                                             targetRows)

-                                        # get ctrl_vs_stim:

+                # get ctrl_vs_stim:

                 for (i in grepStims) {

                     if (is.na(grepCtrl)) { next() }

                     stimNames <-

@@ -442,7 +426,7 @@ computeFcII <-

                         CompMat <- cbind(CompMat, (y[, i] - y[, grepCtrl]))

                     }

                 }

-                                        # get ctrl_vs_kd:

+                # get ctrl_vs_kd:

                 for (i in grepKds) {

                     if (is.na(grepCtrl)) { next() }

                     kdNames <-

@@ -456,7 +440,7 @@ computeFcII <-

                         CompMat <- cbind(CompMat, (y[, i] - y[, grepCtrl]))

                     }

                 }

-                                        # get kd_vs_kd_stim:

+                # get kd_vs_kd_stim:

                 for (i in grepKds) {

                     kdNames <-

                         paste(sort(names(which(inhibitorsDesign[i, ] >= 1))),

@@ -481,7 +465,7 @@ computeFcII <-

                         }

                     }

                 }

-                                        # get stim_vs_stim_kd:

+                # get stim_vs_stim_kd:

                 for (i in grepStims) {

                     if (is.na(grepCtrl)) { next() }

                     stimNames <-

@@ -517,8 +501,8 @@ computeFcII <-

                             if (length(unlist(strsplit(stimNames, "_")) %in%

                                        names(which(stimuliDesign[j, ] >= 1)))

                                 == length(unlist(strsplit(stimNames, "_"))) &

-                                   length(unlist(strsplit(stimNames, "_")) %in%

-                                          names(which(stimuliDesign[j, ] >= 1)))

+                                length(unlist(strsplit(stimNames, "_")) %in%

+                                       names(which(stimuliDesign[j, ] >= 1)))

                                 < length(names(which(stimuliDesign[j, ] >= 1))))

                             {

                                 stim2Names <-

@@ -556,7 +540,7 @@ computeFcII <-

                         }

                     }

                 }

-                                        # get s - sk - (k - ctrl): not trivial

+                # get s - sk - (k - ctrl): not trivial

                 ## for (i in stimuli) {

                 ##   for (j in inhibitors) {

                 ##     name <-

@@ -587,7 +571,7 @@ computeScoreNemT1 <-

              method = "s",

              verbose = TRUE,

              opt = "min"

-             ) {

+    ) {

         cutModel2 <- function (model, bString) {

             if (sum(bString == 1) > 0) {

                 bs = as.logical(bString)

@@ -608,7 +592,7 @@ computeScoreNemT1 <-

             }

             return(newmodel)

         }

-

+        

         method <- checkMethod(method)

         ## if (is.null(simList) == TRUE) {

         ##   simList = prep4sim(model)

@@ -629,17 +613,17 @@ computeScoreNemT1 <-

                     simulateStatesRecursive(CNOlist = CNOlist, model = modelCut,

                                             bString =

                                                 (numeric(

-                                                length(modelCut$reacID)) + 1),

-                                            NEMlist)

+                                                    length(modelCut$reacID))

+                                                 + 1), NEMlist)

             }

         }

         nInTot <- length(unlist(strsplit(model$reacID, "\\+")))

-        nTmp <- unlist(strsplit(model$reacID[which(bString == 1)], "\\+"))

+        nTmp <- unlist(strsplit(model$reacID[bString == 1], "\\+"))

         nInputsNeg <- length(grep("!", nTmp))

         nInputs <- length(nTmp) - nInputsNeg

         ## nInTot <- 1 # use this for no normalization

         sizePen <- sum((c(nInputs, nInputsNeg)/nInTot)*sizeFac)

-                                        #/nrow(NEMlist$fc)

+        #/nrow(NEMlist$fc)

         suppressWarnings(Score <- getNemFit(simResults = simResults,

                                             CNOlist = CNOlist, model = modelCut,

                                             timePoint = timeIndex,

@@ -651,7 +635,7 @@ computeScoreNemT1 <-

                                             relFit = relFit, method = method,

                                             verbose = verbose, opt = opt))

         if (!is(CNOlist, "CNOlist")) {

-            CNOlist = CNOlist(CNOlist)

+            CNOlist <- CNOlist(CNOlist)

         }

         return(Score)

     }

@@ -661,90 +645,90 @@ computeSm <-

               NEMlist,

               parameters,

               method="standard"

-              ) {

+    ) {

         CompMatCont <- NEMlist$fc

         fitScore <- -1 # match of high degree

         errorScore <- parameters$scoring[3] # mismatch of high degree

         fitMult <- parameters$scoring[2] # multiplicator for match of low degree

         errorMult <- parameters$scoring[2] # multi. mismatch of low degree

         zeroMult <- parameters$scoring[1]

-

+        

         CompMat <- CompMatCont

         Epos <- CompMat

         Eneg <- CompMat

         E0 <- CompMat

         EposI <- CompMat*(-1)

         EnegI <- CompMat*(-1)

-

+        

         beta <- parameters$cutOffs[2]

         alpha <- parameters$cutOffs[1]

-

-        wrongPos <- which(Epos < -beta)

-        rightPosII <- which(Epos > alpha & Epos < beta)

-        rightPosI <- which(Epos >= beta)

-        zerosPosI <- which(Epos <= alpha & Epos >= -alpha)

-        zerosPosII <- which(Epos < -alpha & Epos > -beta)

-

-        wrongNeg <- which(Eneg > beta)

-        rightNegII <- zerosPosII # which(Eneg < -alpha & Eneg > -beta)

-        rightNegI <- which(Eneg <= -beta)

-        zerosNegI <- zerosPosI # which(Eneg >= -alpha & Eneg <= alpha)

-        zerosNegII <- rightPosII # which(Eneg > alpha & Eneg < beta)

-

-        right0I <- which(abs(E0) <= alpha)

-        right0II <- which(abs(E0) > alpha & abs(E0) < beta)

-        wrong0 <- which(abs(E0) >= beta)

-

+        

+        wrongPos <- Epos < -beta

+        rightPosII <- Epos > alpha & Epos < beta

+        rightPosI <- Epos >= beta

+        zerosPosI <- Epos <= alpha & Epos >= -alpha

+        zerosPosII <- Epos < -alpha & Epos > -beta

+        

+        wrongNeg <- Eneg > beta

+        rightNegII <- zerosPosII # Eneg < -alpha & Eneg > -beta

+        rightNegI <- Eneg <= -beta

+        zerosNegI <- zerosPosI # Eneg >= -alpha & Eneg <= alpha

+        zerosNegII <- rightPosII # Eneg > alpha & Eneg < beta

+        

+        right0I <- abs(E0) <= alpha

+        right0II <- abs(E0) > alpha & abs(E0) < beta

+        wrong0 <- abs(E0) >= beta

+        

         if ("mLL" %in% method | "cp" %in% method) {

-

+            

             E0 <- E0*0

             E0[right0I] <- 1

-

+            

             Epos <- Epos*0

             Epos[rightPosI] <- 1

-

+            

             Eneg <- Eneg*0

             Eneg[rightNegI] <- 1

-

+            

             EposI <- EposI*0

             EposI[rightPosII] <- 1

-

+            

             EnegI <- EnegI*0

             EnegI[rightNegII] <- 1

-

+            

         } else {

-

+            

             E0[wrong0] <- errorScore*zeroMult

             E0[right0II] <- fitScore*zeroMult*fitMult

             E0[right0I] <- fitScore*zeroMult

-

+            

             Epos[zerosPosI] <- errorScore*errorMult*zeroMult

             Epos[zerosPosII] <- errorScore*errorMult

             Epos[wrongPos] <- errorScore

             Epos[rightPosI] <- fitScore

             Epos[rightPosII] <- fitScore*fitMult

-

+            

             Eneg[zerosNegI] <- -errorScore*errorMult*zeroMult

             Eneg[zerosNegII] <- -errorScore*errorMult

             Eneg[wrongNeg] <- -errorScore

             Eneg[rightNegI] <- -fitScore

             Eneg[rightNegII] <- -fitScore*fitMult

-

+            

             EposI[zerosNegI] <- errorScore*errorMult*zeroMult

             EposI[zerosNegII] <- errorScore*errorMult

             EposI[wrongNeg] <- errorScore

             EposI[rightNegI] <- fitScore

             EposI[rightNegII] <- fitScore*fitMult

-

+            

             EnegI[zerosPosI] <- -errorScore*errorMult*zeroMult

             EnegI[zerosPosII] <- -errorScore*errorMult

             EnegI[wrongPos] <- -errorScore

             EnegI[rightPosI] <- -fitScore

             EnegI[rightPosII] <- -fitScore*fitMult

-

+            

         }

-

-        return(list(exprs = NEMlist$exprs, fc = CompMatCont, E0 = E0,

+        

+        return(list(expression = NEMlist$expression, fc = CompMatCont, E0 = E0,

                     Epos = Epos, Eneg = Eneg, EposI = EposI, EnegI = EnegI))

     }

 #' @noRd

@@ -754,7 +738,7 @@ deleteEdge <-

         graph <- model$reacID[-grep("\\+", model$reacID)]

         for (i in edges) {

             if (i %in% graph) {

-                graph <- graph[-which(graph %in% i)]

+                graph <- graph[!graph %in% i]

             }

         }

         for (i in graph) {

@@ -766,10 +750,10 @@ deleteEdge <-

                                                 tmp2[2]))

             }

         }

-        write.table(sifMatrix, file = "temp.sif", sep = "\t", row.names = FALSE,

+        temp.file <- tempfile(pattern="interaction",fileext=".sif")

+        write.table(sifMatrix, file = temp.file, sep = "\t", row.names = FALSE,

                     col.names = FALSE, quote = FALSE)

-        PKN2 <- readSIF("temp.sif")

-        unlink("temp.sif")

+        PKN2 <- readSIF(temp.file)

         checkSignals(CNOlist,PKN2)

         indices<-indexFinder(CNOlist,PKN2,verbose=FALSE)

         NCNOindices<-findNONC(PKN2,indices,verbose=FALSE)

@@ -788,48 +772,48 @@ deleteSignal <-

     function(s, CNOlist) {

         CNOlist2 <- CNOlist

         for (i in s) {

-            if (i %in% colnames(CNOlist2@signals[[1]])) {

+            if (i %in% colnames(getSignals(CNOlist2)[[1]])) {

                 CNOlist2@signals[[1]] <-

-                    CNOlist2@signals[[1]][

-                               , -which(colnames(CNOlist2@signals[[1]]) %in% i)]

+                    getSignals(CNOlist2)[[1]][

+                        , !colnames(getSignals(CNOlist2)[[1]]) %in% i]

                 CNOlist2@signals[[2]] <-

-                    CNOlist2@signals[[2]][

-                               , -which(colnames(CNOlist2@signals[[2]]) %in% i)]

+                    getSignals(CNOlist2)[[2]][

+                        , !colnames(getSignals(CNOlist2)[[2]]) %in% i]

             }

-            if (i %in% colnames(CNOlist2@stimuli)) {

+            if (i %in% colnames(getStimuli(CNOlist2))) {

                 CNOlist2@cues <-

-                    CNOlist2@cues[, -which(colnames(CNOlist2@cues) %in% i)]

+                    getCues(CNOlist2)[, !colnames(getCues(CNOlist2)) %in% i]

                 if (!is.null(

-                         dim(CNOlist2@stimuli[

-                                        , -which(colnames(CNOlist2@stimuli)

-                                                 %in% i)]))) {

+                    dim(getStimuli(CNOlist2)[

+                        , colnames(getStimuli(CNOlist2))

+                        %in% i]))) {

                     CNOlist2@stimuli <-

-                        CNOlist2@stimuli[

-                                   , -which(colnames(CNOlist2@stimuli) %in% i)]

+                        getStimuli(CNOlist2)[

+                            , !colnames(getStimuli(CNOlist2)) %in% i]

                 } else {

                     CNOlist2@stimuli <-

-                        as.matrix(CNOlist2@stimuli[

-                                             , -which(colnames(CNOlist2@stimuli)

-                                                      %in% i)])

+                        as.matrix(getStimuli(CNOlist2)[

+                            , !colnames(getStimuli(CNOlist2))

+                            %in% i])

                 }

             }

-            if (i %in% colnames(CNOlist2@inhibitors)) {

+            if (i %in% colnames(getInhibitors(CNOlist2))) {

                 CNOlist2@cues <-

-                    CNOlist2@cues[, -which(colnames(CNOlist2@cues) %in% i)]

+                    getCues(CNOlist2)[, !colnames(getCues(CNOlist2)) %in% i]

                 if (!is.null(

-                         dim(CNOlist2@inhibitors[

-                                        , -which(colnames(CNOlist2@inhibitors)

-                                                 %in% i)]))) {

+                    dim(getInhibitors(CNOlist2)[

+                        , !colnames(getInhibitors(CNOlist2))

+                        %in% i]))) {

                     CNOlist2@inhibitors <-

-                        CNOlist2@inhibitors[

-                                   , -which(colnames(CNOlist2@inhibitors)

-                                            %in% i)]

+                        getInhibitors(CNOlist2)[

+                            , !colnames(getInhibitors(CNOlist2))

+                            %in% i]

                 } else {

                     CNOlist2@inhibitors <-

                         as.matrix(

-                            CNOlist2@inhibitors[

-                                       , -which(colnames(CNOlist2@inhibitors)

-                                                %in% i)])

+                            getInhibitors(CNOlist2)[

+                                , !colnames(getInhibitors(CNOlist2))

+                                %in% i])

                 }

             }

         }

@@ -839,9 +823,9 @@ deleteSignal <-

 disc <-

     function(x, beta = 0.5) { # simple discretization

         x.disc <- x

-        x.disc[which(abs(x.disc) <= beta)] <- 0

-        x.disc[which(x.disc > beta)] <- 1

-        x.disc[which(x.disc < -beta)] <- -1

+        x.disc[abs(x.disc) <= beta] <- 0

+        x.disc[x.disc > beta] <- 1

+        x.disc[x.disc < -beta] <- -1

         return(x.disc)

     }

 #' @noRd

@@ -865,11 +849,11 @@ dnf2adj <-

                 parents <- unlist(strsplit(tmp[1], "\\+"))

                 for (j in parents) {

                     if (gsub("!", "", j) %in% j) {

-                        adjmat[which(rownames(adjmat) %in% j),

-                               which(colnames(adjmat) %in% child)] <- 1

+                        adjmat[rownames(adjmat) %in% j,

+                               colnames(adjmat) %in% child] <- 1

                     } else {

-                        adjmat[which(rownames(adjmat) %in% gsub("!", "", j)),

-                               which(colnames(adjmat) %in% child)] <- -1

+                        adjmat[rownames(adjmat) %in% gsub("!", "", j),

+                               colnames(adjmat) %in% child] <- -1