NetAnalyzer 0.1.5 → 0.6.2

data/lib/NetAnalyzer/network.rb

@@ -1,22 +1,54 @@
-require 'nodes'
-require 'nmatrix'
-require 'pp'
+require 'rubystats'
+require 'gv'
+#require 'nmatrix'
+#require 'nmatrix/lapacke'
+require 'numo/narray'
+require 'numo/linalg'
+require 'parallel'
+
+#require 'pp'
 require 'bigdecimal'
 require 'benchmark'
+#require 'nmatrix_expansion'
+
+
+#For javascrip plotting
+require 'erb'
+require 'base64'
+require 'json'
+require 'zlib'
+
+require 'semtools'
+require 'expcalc'
+TEMPLATES = File.join(File.dirname(__FILE__), 'templates')
 
 class Network
 
-	attr_accessor :association_values, :control_connections
+	attr_accessor :association_values, :control_connections, :kernels, :reference_nodes, :group_nodes, :threads
 
 	## BASIC METHODS
 	############################################################
 	def initialize(layers)
-		@nodes = {} 
+		@threads = 0
+		@nodes = {}
 		@edges = {}
+		@reference_nodes = []
+		@group_nodes = {}
 		@adjacency_matrices = {}
+		@kernels = {}
 		@layers = layers
 		@association_values = {}
 		@control_connections = {}
+		@compute_pairs = :conn
+		@compute_autorelations = true
+		@loaded_obos = []
+		@ontologies = []
+		@layer_ontologies = {}
+	end
+
+	def set_compute_pairs(use_pairs, get_autorelations)
+		@compute_pairs = use_pairs
+		@compute_autorelations = get_autorelations
 	end
 
 	def add_node(nodeID, nodeType = 0)
@@ -37,8 +69,49 @@ class Network
 		end
 	end
 
+	def delete_nodes(node_list, mode='d')
+		if mode == 'd'
+			@nodes.reject!{|n| node_list.include?(n)}
+			@edges.reject!{|n, connections| node_list.include?(n)}
+			@edges.each do |n, connections|
+				connections.reject!{|c| node_list.include?(c)}
+			end
+		elsif mode == 'r'
+			@nodes.select!{|n| node_list.include?(n)}
+			@edges.select!{|n, connections| node_list.include?(n)}
+			@edges.each do |n, connections|
+				connections.select!{|c| node_list.include?(c)}
+			end
+		end
+		@edges.reject!{|n, connections| connections.empty?}
+	end
+
+	def get_connected_nodes(node_id, from_layer)
+		return @edges[node_id].map{|id| @nodes[id]}.select{|node| node.type == from_layer}.map{|node| node.id}
+	end
+
+	def get_nodes_from_layer(from_layer)
+		return @nodes.values.select{|node| node.type == from_layer}.map{|node| node.id}
+	end
+
+	def get_bipartite_subgraph(from_layer_node_ids, from_layer, to_layer)
+		bipartite_subgraph = {}
+		from_layer_node_ids.each do |from_layer_node_id| 
+			connected_nodes = @edges[from_layer_node_id]
+			connected_nodes.each do |connected_node| 
+				if @nodes[connected_node].type == to_layer
+					query = bipartite_subgraph[connected_node]
+					if query.nil?
+						bipartite_subgraph[connected_node] = get_connected_nodes(connected_node, from_layer)
+					end
+				end
+			end
+		end
+		return bipartite_subgraph
+	end
+
 	def load_network_by_pairs(file, layers, split_character="\t")
-		File.open(file).each("\n") do |line|
+		File.open(file).each do |line|
 			line.chomp!
 			pair = line.split(split_character)
 			node1 = pair[0]
@@ -49,57 +122,371 @@ class Network
 		end
 	end
 
+	def load_network_by_bin_matrix(input_file, node_file, layers)
+		node_names = load_input_list(node_file)
+		@adjacency_matrices[layers.map{|l| l.first}] = [Numo::NArray.load(input_file, type='npy'), node_names, node_names]
+	end
+
+	def load_network_by_plain_matrix(input_file, node_file, layers, splitChar)
+		node_names = load_input_list(node_file)
+		@adjacency_matrices[layers.map{|l| l.first}] = [Numo::NArray.load(input_file, type='txt', splitChar=splitChar), node_names, node_names]
+	end
+
 	def get_edge_number
-		node_connections = @edges.values.map{|connections| connections.length}.inject(0){|sum, n| sum + n}
+		node_connections = get_degree.values.inject(0){|sum, n| sum + n}
 		return node_connections/2
 	end
 
-	def plot(output_filename, layout="dot")		
-		roboWrite = File.open(output_filename, 'w')
-		roboWrite.puts "digraph g {"
+	def get_degree(zscore=false)
+		degree = {}
+		@edges.each do |id, nodes|
+			degree[id] = nodes.length
+		end
+		if !zscore
+			degree_values = degree.values
+			mean_degree = degree_values.mean
+			std_degree = degree_values.standard_deviation
+			degree.transform_values!{|v| (v - mean_degree).fdiv(std_degree)}
+		end
+		return degree
+	end
+
+	def get_node_attributes(attr_names)
+		attrs = []
+		attr_names.each do |attr_name|
+			if attr_name == 'get_degree'
+				attrs << get_degree
+			elsif attr_name == 'get_degreeZ'
+				attrs << get_degree(zscore=true)
+			end
+		end
+		node_ids = attrs.first.keys
+		node_attrs = []
+		node_ids.each do |n|
+			node_attrs << [n].concat(attrs.map{|at| at[n]})
+		end
+		return node_attrs
+	end
+
+	def plot_network(options = {})
+		if options[:method] == 'graphviz'
+			plot_dot(options)
+		else
+			if options[:method] == 'elgrapho'
+				template = 'el_grapho'
+			elsif options[:method] == 'cytoscape'
+				template = 'cytoscape'
+			elsif options[:method] == 'sigma'
+				template = 'sigma'
+			end
+			renderered_template = ERB.new(File.open(File.join(TEMPLATES, template + '.erb')).read).result(binding)
+			File.open(options[:output_file] + '.html', 'w'){|f| f.puts renderered_template}
+		end	
+	end
+
+	def plot_dot(user_options = {}) # input keys: layout
+		options = {layout: "sfdp"}
+		options = options.merge(user_options)
+		graphviz_colors = %w[lightsteelblue1 lightyellow1 lightgray orchid2]
+		palette = {}
+		@layers.each do |layer|
+			palette[layer] = graphviz_colors.shift
+		end
+		graph = GV::Graph.open('g', type = :undirected)
+		plotted_edges = {}
 		@edges.each do |nodeID, associatedIDs|
 			associatedIDs.each do |associatedID|
-				roboWrite.puts "\"#{nodeID}\"->\"#{associatedID}\";"
+				pair = [nodeID, associatedID].sort.join('_').to_sym
+				if !plotted_edges[pair]
+					graph.edge 'e', 
+						graph.node(nodeID, label: '', style: 'filled', fillcolor: palette[@nodes[nodeID].type]), 
+						graph.node(associatedID, label: '', style: 'filled' , fillcolor: palette[@nodes[associatedID].type])
+					plotted_edges[pair] = true
+				end
+			end
+		end
+		@reference_nodes.each do |nodeID|
+			graph.node(nodeID, style: 'filled', fillcolor: 'firebrick1', label: '')
+		end
+		graphviz_border_colors = %w[blue darkorange red olivedrab4]
+		@group_nodes.each do |groupID, gNodes|
+			border_color = graphviz_border_colors.shift
+			gNodes.each do |nodeID|
+					graph.node(nodeID, color: border_color, penwidth: '10', label: '')
+			end
+		end
+		graph[:overlap] = false
+		STDERR.puts 'Save graph'
+		graph.save(options[:output_file] + '.png', format='png', layout=options[:layout])
+	end
+
+	def compute_group_metrics(output_filename)
+		metrics = []
+		header = ['group']
+		@group_nodes.keys.each do |k|
+			metrics << [k]
+		end
+		header << 'comparative_degree'
+		comparative_degree = communities_comparative_degree(@group_nodes)
+		comparative_degree.each_with_index{|val,i| metrics[i] << replace_nil_vals(val)}
+		header << 'avg_sht_path'
+		avg_sht_path = communities_avg_sht_path(@group_nodes)
+		avg_sht_path.each_with_index{|val,i| metrics[i] << replace_nil_vals(val)}
+		if !@reference_nodes.empty?
+			header.concat(%w[node_com_assoc_by_edge node_com_assoc_by_node])
+			node_com_assoc = compute_node_com_assoc_in_precomputed_communities(@group_nodes, @reference_nodes.first)
+			node_com_assoc.each_with_index{|val,i| metrics[i].concat(val)}
+		end
+		File.open(output_filename, 'w') do |f|
+			f.puts header.join("\t")
+			metrics.each do |gr|
+				f. puts gr.join("\t")
+			end
+		end
+	end
+
+	def replace_nil_vals(val)
+		return val.nil? ? 'NULL' : val
+	end
+
+	def communities_comparative_degree(coms) 
+		comparative_degrees = []
+		coms.each do |com_id, com|
+			comparative_degrees << compute_comparative_degree(com)
+		end
+		return comparative_degrees
+	end
+
+	def communities_avg_sht_path(coms) 
+		avg_sht_path = []
+		coms.each do |com_id, com|
+			dist, paths = compute_avg_sht_path(com)
+			avg_sht_path << dist
+		end
+		return avg_sht_path
+	end
+
+	def compute_node_com_assoc_in_precomputed_communities(coms, ref_node)
+		node_com_assoc = []
+		coms.each do |com_id, com|
+			node_com_assoc << [compute_node_com_assoc(com, ref_node)]
+		end
+		return node_com_assoc
+	end
+
+	def compute_comparative_degree(com) # see Girvan-Newman Benchmark control parameter in http://networksciencebook.com/chapter/9#testing (communities chapter)
+		internal_degree = 0
+		external_degree = 0
+		com.each do |nodeID|
+			nodeIDneigh = @edges[nodeID]
+			next if nodeIDneigh.nil?
+			internal_degree += (nodeIDneigh & com).length
+			external_degree += (nodeIDneigh - com).length
+		end
+		comparative_degree = external_degree.fdiv(external_degree + internal_degree)
+		return comparative_degree
+	end
+
+	def compute_avg_sht_path(com, paths=false)
+		path_lengths = []
+		all_paths = []
+		group = com.dup
+		while !group.empty?
+			node_start = group.shift
+			sht_paths = Parallel.map(group, in_processes: @threads) do |node_stop|
+			#group.each do |node_stop|
+				dist, path = shortest_path(node_start, node_stop, paths)
+				[dist, path]
+				#path_lengths << dist if !dist.nil?
+				#all_paths << path if !path.empty?
+			end
+			sht_paths.each do |dist, path|
+				path_lengths << dist
+				all_paths << path				
+			end
+		end
+		if path_lengths.include?(nil)
+			avg_sht_path = nil
+		else
+			avg_sht_path = path_lengths.inject(0){|sum,l| sum + l}.fdiv(path_lengths.length)
+		end
+		return avg_sht_path, all_paths
+	end
+
+	# https://pythoninwonderland.wordpress.com/2017/03/18/how-to-implement-breadth-first-search-in-python/
+	# finds shortest path between 2 nodes of a graph using BFS
+	def bfs_shortest_path(start, goal, paths=false)
+		dist = nil
+	    explored = {} # keep track of explored nodes
+	    previous = {}
+	    queue = [[start, 0]] # keep track of all the paths to be checked
+	    is_goal = false
+	    while !queue.empty? && !is_goal # keeps looping until all possible paths have been checked
+	        node, dist = queue.pop # pop the first path from the queue
+	        if !explored.include?(node) # get the last node from the path
+	            neighbours = @edges[node] 
+	            explored[node] = true # mark node as explored
+	            next if neighbours.nil?
+	            dist += 1 
+	            neighbours.each do |neighbour| # go through all neighbour nodes, construct a new path
+	            	next if explored.include?(neighbour)
+	                queue.unshift([neighbour, dist]) # push it into the queue
+	                previous[neighbour] = node if paths
+	                if neighbour == goal # return path if neighbour is goal
+	                	is_goal = true
+	                	break
+	                end
+	            end
+	        end
+	    end
+		if is_goal
+			path = build_path(previous, start, goal) if paths
+		else
+			dist = nil 
+			path = []
+		end
+	    return dist, path
+	end
+
+	def build_path(previous, startNode, stopNode)
+		path = []
+		currentNode = stopNode
+		path << currentNode
+		while currentNode != startNode
+		    currentNode = previous[currentNode]
+			path << currentNode
+		end
+		return path
+	end
+
+	def shortest_path(node_start, node_stop, paths=false)
+		#https://betterprogramming.pub/5-ways-to-find-the-shortest-path-in-a-graph-88cfefd0030f
+		#return bidirectionalSearch(node_start, node_stop)
+		#https://efficientcodeblog.wordpress.com/2017/12/13/bidirectional-search-two-end-bfs/
+		dist, all_paths = bfs_shortest_path(node_start, node_stop, paths)
+		return  dist, all_paths
+	end
+
+	def expand_clusters(expand_method)
+		clusters = {}
+		@group_nodes.each do |id, nodes|
+			if expand_method == 'sht_path'
+				dist, paths = compute_avg_sht_path(nodes, paths=true) # this uses bfs, maybe Dijkstra is the best one
+				new_nodes = paths.flatten.uniq
+				clusters[id] = nodes | new_nodes # If some node pair are not connected, recover them
 			end
 		end
-		roboWrite.puts "}"
-		roboWrite.close
-		cmd = "#{layout} -Tpng #{output_filename} -o #{output_filename}.png"
-		system(cmd)
+		return clusters
+	end
+
+	def compute_node_com_assoc(com, ref_node)
+		ref_cons = 0
+		ref_secondary_cons = 0
+		secondary_nodes = {}
+		other_cons = 0
+		other_nodes = {}
+
+		refNneigh = @edges[ref_node]
+		com.each do |nodeID|
+			nodeIDneigh = @edges[nodeID]
+			next if nodeIDneigh.nil?
+			ref_cons += 1 if nodeIDneigh.include?(ref_node)
+			if !refNneigh.nil?
+				common_nodes = nodeIDneigh & refNneigh
+				common_nodes.each {|id| secondary_nodes[id] = true}
+				ref_secondary_cons += common_nodes.length 
+			end
+			specific_nodes = nodeIDneigh - refNneigh - [ref_node]
+			specific_nodes.each {|id| other_nodes[id] = true}
+			other_cons += specific_nodes.length
+		end
+		by_edge = (ref_cons + ref_secondary_cons).fdiv(other_cons)
+		by_node = (ref_cons + secondary_nodes.length).fdiv(other_nodes.length)
+		return by_edge, by_node
 	end
 
 	def get_all_intersections
-		intersection_lengths = []
-		get_all_pairs do |node1, node2|
-			intersection_lengths << intersection(node1, node2).length
+		intersection_lengths = get_all_pairs do |node1, node2|
+			intersection(node1, node2).length
 		end
 		return intersection_lengths
 	end
 
 	def get_all_pairs(args = {})
-		default = {:meth => :all, :layers => :all}
+		all_pairs = []
+		default = {:layers => :all}
 		args = default.merge(args)
-		if args[:layers] == :all
-			nodeIDs = @nodes.keys
+		nodeIDsA, nodeIDsB = collect_nodes(args)
+		if @compute_autorelations
+			if @compute_pairs == :all
+				while !nodeIDsA.empty?
+					node1 = nodeIDsA.shift
+					pairs = Parallel.map(nodeIDsA, in_processes: @threads) do |node2|
+						yield(node1, node2)
+					end
+					all_pairs.concat(pairs)
+				end
+			elsif @compute_pairs == :conn # TODO: Review this case to avoid return nil values
+				while !nodeIDsA.empty?
+					node1 = nodeIDsA.shift
+					ids_connected_to_n1 = @edges[node1]
+					pairs = Parallel.map(nodeIDsA, in_processes: @threads) do |node2|
+						result = nil
+						ids_connected_to_n2 = @edges[node2]
+						if exist_connections?(ids_connected_to_n1, ids_connected_to_n2)
+							result = yield(node1, node2)
+						end
+						result
+					end
+					pairs.compact!
+					all_pairs.concat(pairs)
+				end
+			end
 		else
-			nodeIDs = []
-			args[:layers].each do |layer|
-				nodeIDs.concat(@nodes.select{|id, node| node.type == layer}.keys)
+			#MAIN METHOD
+			if @compute_pairs == :conn
+				all_pairs = Parallel.map(nodeIDsA, in_processes: @threads) do |node1|
+					ids_connected_to_n1 = @edges[node1]
+					node1_pairs = []
+					nodeIDsB.each do |node2|
+						ids_connected_to_n2 = @edges[node2]
+						if exist_connections?(ids_connected_to_n1, ids_connected_to_n2)
+							node1_pairs << yield(node1, node2)
+						end
+					end
+					node1_pairs
+				end
+				all_pairs.flatten!(1)
+			elsif @compute_pairs == :all
+				raise 'Not implemented'
 			end
 		end
 
-		if args[:meth] == :all
-			while !nodeIDs.empty?
-				node1 = nodeIDs.shift
-				nodeIDs.each do |node2|
-					yield(node1, node2)
+		return all_pairs
+	end
+
+	def collect_nodes(args)
+		nodeIDsA = nil
+		nodeIDsB = nil
+		if @compute_autorelations
+			if args[:layers] == :all
+				nodeIDsA = @nodes.keys
+			else
+				nodeIDsA = []
+				args[:layers].each do |layer|
+					nodeIDsA.concat(@nodes.select{|id, node| node.type == layer}.keys)
 				end
 			end
-		#elsif args[:meth] == :conn
-			
+		else
+			if args[:layers] != :all
+				nodeIDsA = @nodes.select{|id, node| node.type == args[:layers][0]}.keys
+				nodeIDsB = @nodes.select{|id, node| node.type == args[:layers][1]}.keys
+			end
 		end
+		return nodeIDsA, nodeIDsB
 	end
 
+
 	def get_nodes_layer(layers)
 		#for creating ny value in hypergeometric and pcc index
 		nodes = []
@@ -123,17 +510,16 @@ class Network
 	def generate_adjacency_matrix(layerA, layerB)
 		layerAidNodes = @nodes.select{|id, node| node.type == layerA}.keys
 		layerBidNodes = @nodes.select{|id, node| node.type == layerB}.keys
-		adjacency_matrix = []
-		layerAidNodes.each do |nodeA|
-			layerBidNodes.each do |nodeB|
+		matrix = Numo::DFloat.zeros(layerAidNodes.length, layerBidNodes.length)
+		layerAidNodes.each_with_index do |nodeA, i|
+			layerBidNodes.each_with_index do |nodeB, j|
 				if @edges[nodeB].include?(nodeA)
-					adjacency_matrix << 1
+					matrix[i, j] = 1
 				else
-					adjacency_matrix << 0
+					matrix[i, j] = 0
 				end
 			end
 		end
-		matrix = NMatrix.new([layerAidNodes.length, layerBidNodes.length], adjacency_matrix)
 		all_info_matrix = [matrix, layerAidNodes, layerBidNodes]
 		@adjacency_matrices[[layerA, layerB]] = all_info_matrix
 		return all_info_matrix
@@ -161,6 +547,14 @@ class Network
 			relations = get_pcc_associations(layers, base_layer)
 		elsif meth == :hypergeometric #all networks
 			relations = get_hypergeometric_associations(layers, base_layer)
+		elsif meth == :hypergeometric_bf #all networks
+			relations = get_hypergeometric_associations(layers, base_layer, :bonferroni)
+		elsif meth == :hypergeometric_bh #all networks
+			relations = get_hypergeometric_associations(layers, base_layer, :benjamini_hochberg)
+		elsif meth == :hypergeometric_elim #tripartite networks?
+			relations = get_hypergeometric_associations_with_topology(layers, base_layer, :elim)
+		elsif meth == :hypergeometric_weight #tripartite networks?
+			relations = get_hypergeometric_associations_with_topology(layers, base_layer, :weight)			
 		elsif meth == :csi #all networks
 			relations = get_csi_associations(layers, base_layer)
 		elsif meth == :transference #tripartite networks
@@ -173,20 +567,19 @@ class Network
 	#---------------------------------------------------------
 	# Alaimo 2014, doi: 10.3389/fbioe.2014.00071
 	def get_association_by_transference_resources(firstPairLayers, secondPairLayers, lambda_value1 = 0.5, lambda_value2 = 0.5)
+		relations = []
 		matrix1 = @adjacency_matrices[firstPairLayers].first
 		rowIds = @adjacency_matrices[firstPairLayers][1]
 		matrix2 = @adjacency_matrices[secondPairLayers].first
 		colIds =  @adjacency_matrices[secondPairLayers][2]
-		m1rowNumber = matrix1.rows
-		m1colNumber = matrix1.cols
-		m2rowNumber = matrix2.rows
-		m2colNumber = matrix2.cols
+		m1rowNumber, m1colNumber = matrix1.shape
+		m2rowNumber, m2colNumber = matrix2.shape
 		#puts m1rowNumber, m1colNumber, m2rowNumber, m2colNumber
 		matrix1Weight = graphWeights(m1colNumber, m1rowNumber, matrix1.transpose, lambda_value1)
 		matrix2Weight = graphWeights(m2colNumber, m2rowNumber, matrix2.transpose, lambda_value2)
-		matrixWeightProduct = matrix1Weight.dot(matrix2.dot(matrix2Weight))
-		finalMatrix = matrix1.dot(matrixWeightProduct)
-		relations = nmatrix2relations(finalMatrix, rowIds, colIds)
+		matrixWeightProduct = Numo::Linalg.dot(matrix1Weight, Numo::Linalg.dot(matrix2, matrix2Weight))
+		finalMatrix = Numo::Linalg.dot(matrix1, matrixWeightProduct)
+		relations = matrix2relations(finalMatrix, rowIds, colIds)
 		@association_values[:transference] = relations
 		return relations
 	end
@@ -195,15 +588,14 @@ class Network
 	#---------------------------------------------------------
 	# Bass 2013, doi:10.1038/nmeth.2728
 	def get_associations(layers, base_layer) # BASE METHOD
-		relations = []
-		get_all_pairs(layers: layers) do |node1, node2|
+		associations = get_all_pairs(layers: layers) do |node1, node2|
 			associatedIDs_node1 = @edges[node1].map{|id| @nodes[id]}.select{|node| node.type == base_layer}.map{|node| node.id}
 			associatedIDs_node2 = @edges[node2].map{|id| @nodes[id]}.select{|node| node.type == base_layer}.map{|node| node.id}
 			intersectedIDs = associatedIDs_node1 & associatedIDs_node2
 			associationValue = yield(associatedIDs_node1, associatedIDs_node2, intersectedIDs, node1, node2)
-			relations << [node1, node2, associationValue]  
+			[node1, node2, associationValue]  
 		end
-		return relations
+		return associations
 	end
 
 	def get_jaccard_association(layers, base_layer)
@@ -246,7 +638,8 @@ class Network
 
 	def get_pcc_associations(layers, base_layer)
 		#for Ny calcule use get_nodes_layer
-		ny = get_nodes_layer([base_layer]).length
+		base_layer_nodes = get_nodes_layer([base_layer])
+		ny = base_layer_nodes.length
 		relations = get_associations(layers, base_layer) do |associatedIDs_node1, associatedIDs_node2, intersectedIDs, node1, node2|
 			intersProd = intersectedIDs.length * ny
 			nodesProd = associatedIDs_node1.length * associatedIDs_node2.length
@@ -259,33 +652,95 @@ class Network
 		return relations
 	end
 
-	def get_hypergeometric_associations(layers, base_layer)
+	def get_hypergeometric_associations(layers, base_layer, pvalue_adj_method= nil)
 		ny = get_nodes_layer([base_layer]).length
+		fet = Rubystats::FishersExactTest.new
 		relations = get_associations(layers, base_layer) do |associatedIDs_node1, associatedIDs_node2, intersectedIDs, node1, node2|
-			minLength = [associatedIDs_node1.length, associatedIDs_node2.length].min
+			fisher = 0
 			intersection_lengths = intersectedIDs.length
-			sum = 0
 			if intersection_lengths > 0
-				nA = associatedIDs_node1.length
-				nB = associatedIDs_node2.length
-				#Using index from A layer proyected to B
-				hyper_denom = binom(ny, nB)
-				(intersection_lengths..minLength).each do |i|
-					binom_product = binom(nA, i) * binom(ny - nA, nB - i)
-					sum += binom_product.fdiv(hyper_denom)
-				end
+				n1_items = associatedIDs_node1.length
+				n2_items = associatedIDs_node2.length
+				fisher = fet.calculate(
+						intersection_lengths,
+						n1_items - intersection_lengths,
+						n2_items - intersection_lengths, 
+						ny - (n1_items + n2_items - intersection_lengths)
+				)
+				fisher = fisher[:right]
 			end
-			if sum == 0
-				hypergeometricValue = 0
-			else
-				hypergeometricValue = -Math.log10(sum)
-			end
-			hypergeometricValue
+			fisher
 		end
-		@association_values[:hypergeometric] = relations
+		if pvalue_adj_method == :bonferroni
+			meth = :hypergeometric_bf
+			compute_adjusted_pvalue_bonferroni(relations)
+		elsif pvalue_adj_method == :benjamini_hochberg
+			meth = :hypergeometric_bh
+			compute_adjusted_pvalue_benjaminiHochberg(relations)
+		else
+			meth = :hypergeometric
+			compute_log_transformation(relations)
+		end
+		@association_values[meth] = relations
 		return relations
 	end
 
+	def get_hypergeometric_associations_with_topology(layers, base_layer, mode, thresold = 0.01)
+		relations = []
+		reference_layer = (layers - @layer_ontologies.keys).first
+		ontology_layer = (layers - [reference_layer]).first
+		ref_nodes = get_nodes_from_layer(reference_layer) # get nodes from NOT ontology layer
+		ontology = @layer_ontologies[ontology_layer]
+		base_layer_length = @nodes.values.count{|n| n.type == base_layer}
+		ref_nodes.each do |ref_node|
+			base_nodes = get_connected_nodes(ref_node, base_layer)
+			ontology_base_subgraph = get_bipartite_subgraph(base_nodes, base_layer, ontology_layer) # get shared nodes between nodes from NOT ontology layer and ONTOLOGY layer. Also get the conections between shared nodes and ontology nodes.
+			next if ontology_base_subgraph.empty?
+			ontology_base_subgraph.transform_keys!{|k| k.to_sym}
+			ontology.load_item_relations_to_terms(ontology_base_subgraph, remove_old_relations = true)
+			term_pvals = ontology.compute_relations_to_items(base_nodes, base_layer_length, mode, thresold)
+			relations.concat(term_pvals.map{|term| [ref_node, term[0], term[1]]})
+		end
+		compute_log_transformation(relations)
+		if mode == :elim
+			meth = :hypergeometric_elim
+		elsif mode == :weight
+			meth = :hypergeometric_weight
+		end
+		@association_values[meth] = relations
+		return relations
+	end
+
+	def compute_adjusted_pvalue(relations, log_val=true)
+		relations.each_with_index do |data, i| #p1, p2, pval
+			pval_adj = yield(data.last, i)		
+			pval_adj = -Math.log10(pval_adj) if log_val && pval_adj > 0
+			data[2] = pval_adj 
+		end
+	end
+
+	def compute_log_transformation(relations) #Only perform log transform whitout adjust pvalue. Called when adjusted method is not defined 
+		compute_adjusted_pvalue(relations) do |pval, index| 
+			pval
+		end
+	end
+
+	def compute_adjusted_pvalue_bonferroni(relations)
+		n_comparations = relations.length
+		compute_adjusted_pvalue(relations) do |pval, index|
+			adj = pval * n_comparations
+			adj = 1 if adj > 1
+			adj
+		end
+	end
+
+	def compute_adjusted_pvalue_benjaminiHochberg(relations)
+		adj_pvalues = get_benjaminiHochberg_pvalues(relations.map{|rel| rel.last})
+		compute_adjusted_pvalue(relations) do |pval, index|
+			adj_pvalues[index]
+		end
+	end
+
 	def add_record(hash, node1, node2)
 		query = hash[node1]
 		if query.nil?
@@ -411,12 +866,108 @@ class Network
 		return prec, rec
 	end
 
+	## KERNEL METHODS
+	#######################################################################################
+	def get_kernel(layer2kernel, kernel, normalization=false)
+		matrix, node_names = @adjacency_matrices[layer2kernel]
+		#I = identity matrix
+		#D = Diagonal matrix
+		#A = adjacency matrix
+		#L = laplacian matrix = D − A
+		matrix_result = nil
+		dimension_elements = matrix.shape.last
+		# In scuba code, the diagonal values of A is set to 0. In weighted matrix the kernel result is the same with or without this operation. Maybe increases the computing performance?
+		# In the md kernel this operation affects the values of the final kernel
+		#dimension_elements.times do |n|
+		#	matrix[n,n] = 0.0
+		#end
+		if kernel == 'el' || kernel == 'ct' || kernel == 'rf' || 
+			kernel.include?('vn') || kernel.include?('rl') || kernel == 'me'
+			diagonal_matrix = matrix.sum(1).diag 	# get the total sum for each row, for this reason the sum method takes the 1 value. If sum colums is desired, use 0
+													# Make a matrix whose diagonal is row_sum
+			matrix_L = diagonal_matrix - matrix
+			if kernel == 'el' #Exponential Laplacian diffusion kernel(active). F Fouss 2012 | doi: 10.1016/j.neunet.2012.03.001
+			    beta = 0.02
+			    beta_product = matrix_L * -beta
+			    #matrix_result = beta_product.expm
+			    matrix_result = Numo::Linalg.expm(beta_product, 14)
+			elsif kernel == 'ct' # Commute time kernel (active). J.-K. Heriche 2014 | doi: 10.1091/mbc.E13-04-0221
+			    matrix_result = Numo::Linalg.pinv(matrix_L) # Anibal saids that this kernel was normalized. Why?. Paper do not seem to describe this operation for ct, it describes for Kvn or for all kernels, it is not clear.
+			elsif kernel == 'rf' # Random forest kernel. J.-K. Heriche 2014 | doi: 10.1091/mbc.E13-04-0221
+			    matrix_result = Numo::Linalg.inv(Numo::DFloat.eye(dimension_elements) + matrix_L) #Krf = (I +L ) ^ −1
+			elsif kernel.include?('vn') # von Neumann diffusion kernel. J.-K. Heriche 2014 | doi: 10.1091/mbc.E13-04-0221
+			    alpha = kernel.gsub('vn', '').to_f * matrix.max_eigenvalue ** -1  # alpha = impact_of_penalization (1, 0.5 or 0.1) * spectral radius of A. spectral radius of A = absolute value of max eigenvalue of A 
+			    matrix_result = Numo::Linalg.inv(Numo::DFloat.eye(dimension_elements) - matrix * alpha ) #  (I -alphaA ) ^ −1
+			elsif kernel.include?('rl') # Regularized Laplacian kernel matrix (active)
+			    alpha = kernel.gsub('rl', '').to_f * matrix.max_eigenvalue ** -1  # alpha = impact_of_penalization (1, 0.5 or 0.1) * spectral radius of A. spectral radius of A = absolute value of max eigenvalue of A
+			    matrix_result = Numo::Linalg.inv(Numo::DFloat.eye(dimension_elements) + matrix_L * alpha ) #  (I + alphaL ) ^ −1
+			elsif kernel == 'me' # Markov exponential diffusion kernel (active). G Zampieri 2018 | doi.org/10.1186/s12859-018-2025-5 . Taken from compute_kernel script
+				beta=0.04
+				#(beta/N)*(N*I - D + A)
+				id_mat = Numo::DFloat.eye(dimension_elements)
+				m_matrix = (id_mat * dimension_elements - diagonal_matrix + matrix ) * (beta/dimension_elements)
+				#matrix_result = m_matrix.expm
+			    matrix_result = Numo::Linalg.expm(m_matrix, 16)
+			end
+		elsif kernel == 'ka' # Kernelized adjacency matrix (active). J.-K. Heriche 2014 | doi: 10.1091/mbc.E13-04-0221
+			lambda_value = matrix.min_eigenvalue
+			matrix_result = matrix + Numo::DFloat.eye(dimension_elements) * lambda_value.abs # Ka = A + lambda*I # lambda = the absolute value of the smallest eigenvalue of A
+		elsif kernel.include?('md') # Markov diffusion kernel matrix. G Zampieri 2018 | doi.org/10.1186/s12859-018-2025-5 . Taken from compute_kernel script
+			t = kernel.gsub('md', '').to_i
+			#TODO: check implementation with Numo::array
+			col_sum = matrix.sum(1)
+			p_mat = matrix.div_by_vector(col_sum)
+			p_temp_mat = p_mat.clone
+			zt_mat = p_mat.clone
+			(t-1).times do
+				p_temp_mat = p_temp_mat.dot(p_mat)
+				zt_mat = zt_mat + p_temp_mat
+			end
+			zt_mat = zt_mat * (1.0/t)
+			matrix_result = zt_mat.dot(zt_mat.transpose)
+		else
+			matrix_result = matrix
+			warn('Warning: The kernel method was not specified or not exists. The adjacency matrix will be given as result')
+			# This allows process a previous kernel and perform the normalization in a separated step.
+		end
+		matrix_result = matrix_result.cosine_normalization if normalization #TODO: check implementation with Numo::array
+		@kernels[layer2kernel] = matrix_result
+	end
+
+	def write_kernel(layer2kernel, output_file)
+		@kernels[layer2kernel].save(output_file)
+	end
+
+	def link_ontology(ontology_file_path, layer_name)
+		if !@loaded_obos.include?(ontology_file_path) #Load new ontology
+			ontology = Ontology.new(file: ontology_file_path, load_file: true)
+			@loaded_obos << ontology_file_path
+			@ontologies << ontology
+		else #Link loaded ontology to current layer
+			ontology = @ontologies[@loaded_obos.index(ontology_file_path)]
+		end
+		@layer_ontologies[layer_name] = ontology
+	end
 
 
 	## AUXILIAR METHODS
 	#######################################################################################
 	private
 
+	def load_input_list(file)
+		return File.open(file).readlines.map!{|line| line.chomp}
+	end
+
+ 	def exist_connections?(ids_connected_to_n1, ids_connected_to_n2)
+		res = false
+		if !ids_connected_to_n1.nil? && 
+			!ids_connected_to_n2.nil? && 
+			!(ids_connected_to_n1 & ids_connected_to_n2).empty? # check that at least exists one node that connect to n1 and n2
+			res = true
+		end
+		return res
+	end
+
 	def set_layer(layer_definitions, node_name)
 		layer = nil
 		if layer_definitions.length > 1
@@ -426,9 +977,11 @@ class Network
 					break
 				end
 			end
+			raise("The node '#{node_name}' not match with any layer regex") if layer.nil?			
 		else
 			layer = layer_definitions.first.first
 		end
+		@layers << layer if !@layers.include?(layer)
 		return layer
 	end
 
@@ -453,35 +1006,46 @@ class Network
 	end
 	
 	def graphWeights (rowsNumber, colsNumber, inputMatrix, lambdaValue = 0.5)
-		invMatrix = inputMatrix.sum(0).map{|e| 1.0/ e}
-	 	diagonalColSums = NMatrix.diag(invMatrix)
-	 	rowsSums = inputMatrix.sum(1).to_flat_a
-	 	ky = NMatrix.new([rowsNumber, rowsNumber], rowsSums).map{|e| e ** lambdaValue } 	
-	 	invertLambdaVal = (1 - lambdaValue)
-	 	kx = NMatrix.new([rowsNumber, rowsNumber], rowsSums).transpose.map{|e| e ** invertLambdaVal } 
-	 	nx = (ky * kx).map{|e| 1.0/ e}
-	 	weigth = (inputMatrix.dot(diagonalColSums)).transpose
-	 	weigth = inputMatrix.dot(weigth)
-	 	weigth = nx * weigth
+	 	ky = (1.0 / inputMatrix.sum(0)).diag #sum cols
+	 	weigth = Numo::Linalg.dot(inputMatrix, ky).transpose
+	 	ky = nil #free memory
+	 	weigth = Numo::Linalg.dot(inputMatrix, weigth)
+
+	 	kx = inputMatrix.sum(1) #sum rows
+	 	
+	 	kx_lamb = kx ** lambdaValue
+	 	kx_lamb_mat = Numo::DFloat.zeros(rowsNumber, rowsNumber)
+	 	rowsNumber.times do |j|
+	 		rowsNumber.times do |i|	 			
+	 			kx_lamb_mat[j,i] = kx_lamb[i]
+	 		end
+	 	end
+	 	kx_lamb = nil #free memory
+
+	 	kx_inv_lamb = kx ** (1 - lambdaValue)
+	 	kx_inv_lamb_mat = Numo::DFloat.zeros(rowsNumber, rowsNumber)
+	 	rowsNumber.times do |j|
+	 		rowsNumber.times do |i|
+	 			kx_inv_lamb_mat[i, j] = kx_inv_lamb[i]
+	 		end
+	 	end
+	 	kx_inv_lamb = nil #free memory
+
+	 	nx = 1.0/(kx_lamb_mat.inplace * kx_inv_lamb_mat).inplace # inplace marks a matrix to be used by reference, not for value
+	 	kx_lamb_mat = nil #free memory
+	 	kx_inv_lamb_mat = nil #free memory
+	 	weigth.inplace * nx
 	 	return weigth
 	end
 
-	def nmatrix2relations(finalMatrix, rowIds, colIds)
+	def matrix2relations(finalMatrix, rowIds, colIds)
 		relations = []
 		rowIds.each_with_index do |rowId, rowPos|
 			colIds.each_with_index do |colId, colPos|
 				associationValue = finalMatrix[rowPos, colPos]
-				relations << [rowId, colId, associationValue]
+				relations << [rowId, colId, associationValue] if associationValue > 0
 			end
 		end
 		return relations
 	end
-
-	def binom(n,k)
-		if k > 0 && k < n
-  			res = (1+n-k..n).inject(:*)/(1..k).inject(:*)
-  		else
-  			res = 1
-  		end
-	end
 end