changeset 0:23ac9cf12788 draft

Uploaded
author bimib
date Tue, 06 Nov 2018 03:16:21 -0500
parents
children 9e63d5f02d62
files Marea/local/HMRcoreMap.svg Marea/local/HMRcore_genes.p Marea/local/HMRcore_rules.p Marea/local/Recon_genes.p Marea/local/Recon_rules.p Marea/marea.py Marea/marea.xml Marea/marea_cluster.py Marea/marea_cluster.xml
diffstat 9 files changed, 9407 insertions(+), 0 deletions(-) [+]
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--- /dev/null	Thu Jan 01 00:00:00 1970 +0000
+++ b/Marea/local/HMRcoreMap.svg	Tue Nov 06 03:16:21 2018 -0500
@@ -0,0 +1,7702 @@
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Binary file Marea/local/HMRcore_genes.p has changed
Binary file Marea/local/HMRcore_rules.p has changed
Binary file Marea/local/Recon_genes.p has changed
Binary file Marea/local/Recon_rules.p has changed
--- /dev/null	Thu Jan 01 00:00:00 1970 +0000
+++ b/Marea/marea.py	Tue Nov 06 03:16:21 2018 -0500
@@ -0,0 +1,760 @@
+
+from __future__ import division
+import sys
+import pandas as pd
+import itertools as it
+import scipy.stats as st
+import collections
+import lxml.etree as ET
+import pickle as pk
+import math
+import os
+import argparse
+from svglib.svglib import svg2rlg
+from reportlab.graphics import renderPDF
+
+########################## argparse ###########################################
+
+def process_args(args):
+    parser = argparse.ArgumentParser(usage = '%(prog)s [options]',
+                                     description = 'process some value\'s'+
+                                     ' genes to create a comparison\'s map.')
+    parser.add_argument('-rs', '--rules_selector', 
+                        type = str,
+                        default = 'HMRcore',
+                        choices = ['HMRcore', 'Recon', 'Custom'], 
+                        help = 'chose which type of dataset you want use')
+    parser.add_argument('-cr', '--custom',
+                        type = str,
+                        help='your dataset if you want custom rules')
+    parser.add_argument('-na', '--names', 
+                        type = str,
+                        nargs = '+', 
+                        help = 'input names')
+    parser.add_argument('-n', '--none',
+                        type = str,
+                        default = 'true',
+                        choices = ['true', 'false'], 
+                        help = 'compute Nan values')
+    parser.add_argument('-pv' ,'--pValue', 
+                        type = float, 
+                        default = 0.05, 
+                        help = 'P-Value threshold (default: %(default)s)')
+    parser.add_argument('-fc', '--fChange', 
+                        type = float, 
+                        default = 1.5, 
+                        help = 'Fold-Change threshold (default: %(default)s)')
+    parser.add_argument('-td', '--tool_dir',
+                        type = str,
+                        required = True,
+                        help = 'your tool directory')
+    parser.add_argument('-op', '--option', 
+                        type = str, 
+                        choices = ['datasets', 'dataset_class'],
+                        help='dataset or dataset and class')
+    parser.add_argument('-ol', '--out_log', 
+                        help = "Output log")    
+    parser.add_argument('-ids', '--input_datas', 
+                        type = str,
+                        nargs = '+', 
+                        help = 'input datasets')
+    parser.add_argument('-id', '--input_data',
+                        type = str,
+                        help = 'input dataset')
+    parser.add_argument('-ic', '--input_class', 
+                        type = str, 
+                        help = 'sample group specification')
+    parser.add_argument('-cm', '--custom_map', 
+                        type = str, 
+                        help = 'custom map')
+    parser.add_argument('-yn', '--yes_no', 
+                        type = str,
+                        choices = ['yes', 'no'],
+                        help = 'if make or not custom map')
+    args = parser.parse_args()
+    return args
+
+########################### warning ###########################################
+
+def warning(s):
+    args = process_args(sys.argv)
+    with open(args.out_log, 'a') as log:
+            log.write(s)
+            
+############################ dataset input ####################################
+
+def read_dataset(data, name):
+    try:
+        dataset = pd.read_csv(data, sep = '\t', header = 0)
+    except pd.errors.EmptyDataError:
+        sys.exit('Execution aborted: wrong format of ' + name + '\n')
+    if len(dataset.columns) < 2:
+        sys.exit('Execution aborted: wrong format of ' + name + '\n')
+    return dataset
+
+############################ dataset name #####################################
+
+def name_dataset(name_data, count):
+    if str(name_data) == 'Dataset':
+        return str(name_data) + '_' + str(count)
+    else:
+        return str(name_data)
+    
+############################ load id e rules ##################################
+
+def load_id_rules(reactions):
+    ids, rules = [], []
+    for key, value in reactions.items():
+            ids.append(key)
+            rules.append(value)
+    return (ids, rules)
+
+############################ check_methods ####################################
+
+def gene_type(l, name):
+    if check_hgnc(l):
+        return 'hugo_id'
+    elif check_ensembl(l):
+        return 'ensembl_gene_id'
+    elif check_symbol(l):
+        return 'symbol'
+    elif check_entrez(l):
+        return 'entrez_id'
+    else:
+        sys.exit('Execution aborted:\n' +
+                 'gene ID type in ' + name + ' not supported. Supported ID'+
+                 'types are: HUGO ID, Ensemble ID, HUGO symbol, Entrez ID\n')
+
+def check_hgnc(l):
+    if len(l) > 5:
+        if (l.upper()).startswith('HGNC:'):
+            return l[5:].isdigit()
+        else:
+            return False
+    else:
+        return False
+
+def check_ensembl(l): 
+    if len(l) == 15:
+        if (l.upper()).startswith('ENS'):
+            return l[4:].isdigit()
+        else:  
+            return False 
+    else: 
+        return False 
+
+def check_symbol(l):
+    if len(l) > 0:
+        if l[0].isalpha() and l[1:].isalnum():
+            return True
+        else:
+            return False
+    else:
+        return False
+
+def check_entrez(l): 
+    if len(l) > 0:
+        return l.isdigit()
+    else: 
+        return False
+
+def check_bool(b):
+    if b == 'true':
+        return True
+    elif b == 'false':
+        return False
+    
+############################ resolve_methods ##################################
+
+def replace_gene_value(l, d):
+    tmp = []
+    err = []
+    while l:
+        if isinstance(l[0], list):
+            tmp_rules, tmp_err = replace_gene_value(l[0], d)
+            tmp.append(tmp_rules)
+            err.extend(tmp_err)
+        else:
+            value = replace_gene(l[0], d)
+            tmp.append(value)
+            if value == None:
+                err.append(l[0])
+        l = l[1:]
+    return (tmp, err)
+
+def replace_gene(l, d):
+    if l =='and' or l == 'or':
+        return l
+    else:
+        value = d.get(l, None)
+        if not(value == None or isinstance(value, (int, float))):
+            sys.exit('Execution aborted: ' + value + ' value not valid\n')
+        return value
+
+def computes(val1, op, val2, cn):
+    if val1 != None and val2 != None:
+        if op == 'and':
+            return min(val1, val2)
+        else:
+            return val1 + val2
+    elif op == 'and':
+        if cn is True:
+            if val1 != None:
+                return val1
+            elif val2 != None:
+                return val2
+            else:
+                return None
+        else:
+            return None
+    else:
+        if val1 != None:
+            return val1
+        elif val2 != None:
+            return val2
+        else:
+            return None
+
+def control(ris, l, cn):
+    if len(l) == 1:
+        if isinstance(l[0], (float, int)) or l[0] == None:
+            return l[0]
+        elif isinstance(l[0], list):
+            return control(None, l[0], cn)
+        else:
+            return False
+    elif len(l) > 2:
+        return control_list(ris, l, cn)
+    else:
+        return False
+
+def control_list(ris, l, cn):
+    while l:
+        if len(l) == 1:
+            return False
+        elif (isinstance(l[0], (float, int)) or
+              l[0] == None) and l[1] in ['and', 'or']:
+            if isinstance(l[2], (float, int)) or l[2] == None:
+                ris = computes(l[0], l[1], l[2], cn)            
+            elif isinstance(l[2], list):
+                tmp = control(None, l[2], cn)
+                if tmp is False:
+                    return False
+                else:
+                    ris = computes(l[0], l[1], tmp, cn)
+            else:
+                return False
+            l = l[3:]
+        elif l[0] in ['and', 'or']:
+            if isinstance(l[1], (float, int)) or l[1] == None:
+                ris = computes(ris, l[0], l[1], cn)
+            elif isinstance(l[1], list):
+                tmp = control(None,l[1], cn)
+                if tmp is False:
+                    return False
+                else:
+                    ris = computes(ris, l[0], tmp, cn)
+            else:
+                return False
+            l = l[2:]
+        elif isinstance(l[0], list) and l[1] in ['and', 'or']:
+            if isinstance(l[2], (float, int)) or l[2] == None:
+                tmp = control(None, l[0], cn)
+                if tmp is False:
+                    return False
+                else:
+                    ris = computes(tmp, l[1], l[2], cn)
+            elif isinstance(l[2], list):
+                tmp = control(None, l[0], cn)
+                tmp2 = control(None, l[2], cn)
+                if tmp is False or tmp2 is False:
+                    return False
+                else:
+                    ris = computes(tmp, l[1], tmp2, cn)
+            else:
+                return False
+            l = l[3:]
+        else:
+            return False
+    return ris
+
+############################ map_methods ######################################
+
+def fold_change(avg1, avg2):
+    if avg1 == 0 and avg2 == 0:
+        return 0
+    elif avg1 == 0:
+        return '-INF'
+    elif avg2 == 0:
+        return 'INF'
+    else:
+        return math.log(avg1 / avg2, 2)
+    
+def fix_style(l, col, width, dash):
+    tmp = l.split(';')
+    flag_col = False
+    flag_width = False
+    flag_dash = False
+    for i in range(len(tmp)):
+        if tmp[i].startswith('stroke:'):
+            tmp[i] = 'stroke:' + col
+            flag_col = True
+        if tmp[i].startswith('stroke-width:'):
+            tmp[i] = 'stroke-width:' + width
+            flag_width = True
+        if tmp[i].startswith('stroke-dasharray:'):
+            tmp[i] = 'stroke-dasharray:' + dash
+            flag_dash = True
+    if not flag_col:
+        tmp.append('stroke:' + col)
+    if not flag_width:
+        tmp.append('stroke-width:' + width)
+    if not flag_dash:
+        tmp.append('stroke-dasharray:' + dash)
+    return ';'.join(tmp)
+
+def fix_map(d, core_map, threshold_P_V, threshold_F_C, max_F_C):
+    maxT = 12
+    minT = 2
+    grey = '#BEBEBE'
+    blue = '#0000FF'
+    red = '#E41A1C'
+    for el in core_map.iter():
+        el_id = str(el.get('id'))
+        if el_id.startswith('R_'):
+            tmp = d.get(el_id[2:])
+            if tmp != None:
+                p_val = tmp[0]
+                f_c = tmp[1]
+                if p_val < threshold_P_V:
+                    if not isinstance(f_c, str):
+                        if abs(f_c) < math.log(threshold_F_C, 2):
+                            col = grey
+                            width = str(minT)
+                        else:
+                            if f_c < 0:
+                                col = blue
+                            elif f_c > 0:
+                                col = red
+                            width = str(max((abs(f_c) * maxT) / max_F_C, minT))
+                    else:
+                        if f_c == '-INF':
+                            col = blue
+                        elif f_c == 'INF':
+                            col = red
+                        width = str(maxT)
+                    dash = 'none'
+                else:
+                    dash = '5,5'
+                    col = grey
+                    width = str(minT)
+                el.set('style', fix_style(el.get('style'), col, width, dash))
+    return core_map
+
+############################ make recon #######################################
+
+def check_and_doWord(l):
+    tmp = []
+    tmp_genes = []
+    count = 0
+    while l:
+        if count >= 0:
+            if l[0] == '(':
+                count += 1
+                tmp.append(l[0])
+                l.pop(0)
+            elif l[0] == ')':
+                count -= 1
+                tmp.append(l[0])
+                l.pop(0)
+            elif l[0] == ' ':
+                l.pop(0)
+            else:
+                word = []
+                while l:
+                    if l[0] in [' ', '(', ')']:
+                        break
+                    else:
+                        word.append(l[0])
+                        l.pop(0)
+                word = ''.join(word)
+                tmp.append(word)
+                if not(word in ['or', 'and']):
+                    tmp_genes.append(word)
+        else:
+            return False
+    if count == 0:
+        return (tmp, tmp_genes)
+    else:
+        return False
+
+def brackets_to_list(l):
+    tmp = []
+    while l:
+        if l[0] == '(':
+            l.pop(0)
+            tmp.append(resolve_brackets(l))
+        else:
+            tmp.append(l[0])
+            l.pop(0)
+    return tmp
+
+def resolve_brackets(l):
+    tmp = []
+    while l[0] != ')':
+        if l[0] == '(':
+            l.pop(0)
+            tmp.append(resolve_brackets(l))
+        else:
+            tmp.append(l[0])
+            l.pop(0)
+    l.pop(0)
+    return tmp
+
+def priorityAND(l):
+    tmp = []
+    flag = True
+    while l:
+        if len(l) == 1:
+            if isinstance(l[0], list):
+                tmp.append(priorityAND(l[0]))
+            else:
+                tmp.append(l[0])
+            l = l[1:]
+        elif l[0] == 'or':
+            tmp.append(l[0])
+            flag = False
+            l = l[1:]
+        elif l[1] == 'or':
+            if isinstance(l[0], list): 
+                tmp.append(priorityAND(l[0]))
+            else:
+                tmp.append(l[0])
+            tmp.append(l[1])
+            flag = False
+            l = l[2:]
+        elif l[1] == 'and':
+            tmpAnd = []
+            if isinstance(l[0], list): 
+                tmpAnd.append(priorityAND(l[0]))
+            else:
+                tmpAnd.append(l[0])
+            tmpAnd.append(l[1])
+            if isinstance(l[2], list): 
+                tmpAnd.append(priorityAND(l[2]))
+            else:
+                tmpAnd.append(l[2])
+            l = l[3:]
+            while l:
+                if l[0] == 'and':
+                    tmpAnd.append(l[0])
+                    if isinstance(l[1], list): 
+                        tmpAnd.append(priorityAND(l[1]))
+                    else:
+                        tmpAnd.append(l[1])
+                    l = l[2:]
+                elif l[0] == 'or':
+                    flag = False
+                    break
+            if flag == True: #se ci sono solo AND nella lista
+                tmp.extend(tmpAnd)
+            elif flag == False:
+                tmp.append(tmpAnd)
+    return tmp
+
+def checkRule(l):
+    if len(l) == 1:
+        if isinstance(l[0], list):
+            if checkRule(l[0]) is False:
+                return False
+    elif len(l) > 2:
+        if checkRule2(l) is False:
+            return False
+    else:
+        return False
+    return True
+
+def checkRule2(l):
+    while l:
+        if len(l) == 1:
+            return False
+        elif isinstance(l[0], list) and l[1] in ['and', 'or']:
+            if checkRule(l[0]) is False:
+                return False
+            if isinstance(l[2], list):
+                if checkRule(l[2]) is False:
+                    return False
+            l = l[3:]
+        elif l[1] in ['and', 'or']:
+            if isinstance(l[2], list):
+                if checkRule(l[2]) is False:
+                    return False
+            l = l[3:]
+        elif l[0] in ['and', 'or']:
+            if isinstance(l[1], list):
+                if checkRule(l[1]) is False:
+                    return False
+            l = l[2:]
+        else:
+            return False
+    return True
+
+def do_rules(rules):
+    split_rules = []
+    err_rules = []
+    tmp_gene_in_rule = []
+    for i in range(len(rules)):
+        tmp = list(rules[i])
+        if tmp:
+            tmp, tmp_genes = check_and_doWord(tmp)
+            tmp_gene_in_rule.extend(tmp_genes)
+            if tmp is False:
+                split_rules.append([])
+                err_rules.append(rules[i])
+            else:
+                tmp = brackets_to_list(tmp)
+                if checkRule(tmp):
+                    split_rules.append(priorityAND(tmp))
+                else:
+                    split_rules.append([])
+                    err_rules.append(rules[i])
+        else:
+            split_rules.append([])
+    if err_rules:
+        warning('Warning: wrong format rule in ' + str(err_rules) + '\n')
+    return (split_rules, list(set(tmp_gene_in_rule)))
+
+def make_recon(data):
+    try:
+        import cobra as cb
+        import warnings
+        with warnings.catch_warnings():
+            warnings.simplefilter('ignore')
+            recon = cb.io.read_sbml_model(data)
+        react = recon.reactions
+        rules = [react[i].gene_reaction_rule for i in range(len(react))]
+        ids = [react[i].id for i in range(len(react))]
+    except cb.io.sbml3.CobraSBMLError:
+        try:
+            data = (pd.read_csv(data, sep = '\t', dtype = str)).fillna('')
+            if len(data.columns) < 2:
+                sys.exit('Execution aborted: wrong format of '+
+                         'custom datarules\n')
+            if not len(data.columns) == 2:
+                warning('Warning: more than 2 columns in custom datarules.\n' +
+                        'Extra columns have been disregarded\n')
+            ids = list(data.iloc[:, 0])
+            rules = list(data.iloc[:, 1])
+        except pd.errors.EmptyDataError:
+            sys.exit('Execution aborted: wrong format of custom datarules\n')
+        except pd.errors.ParserError:
+            sys.exit('Execution aborted: wrong format of custom datarules\n')            
+    split_rules, tmp_genes = do_rules(rules)
+    gene_in_rule = {}
+    for i in tmp_genes:
+        gene_in_rule[i] = 'ok'
+    return (ids, split_rules, gene_in_rule)
+
+############################ gene #############################################
+
+def data_gene(gene, type_gene, name, gene_custom):
+    args = process_args(sys.argv)
+    for i in range(len(gene)):
+        tmp = gene.iloc[i, 0]
+        if tmp.startswith(' ') or tmp.endswith(' '):
+            gene.iloc[i, 0] = (tmp.lstrip()).rstrip()
+    gene_dup = [item for item, count in 
+               collections.Counter(gene[gene.columns[0]]).items() if count > 1]
+    pat_dup = [item for item, count in 
+               collections.Counter(list(gene.columns)).items() if count > 1]
+    if gene_dup:
+        if gene_custom == None:
+            if args.rules_selector == 'HMRcore':
+                gene_in_rule = pk.load(open(args.tool_dir +
+                                            '/local/HMRcore_genes.p', 'rb'))
+            elif args.rules_selector == 'Recon':
+                gene_in_rule = pk.load(open(args.tool_dir +
+                                            '/local/Recon_genes.p', 'rb'))
+            gene_in_rule = gene_in_rule.get(type_gene)
+        else:
+            gene_in_rule = gene_custom
+        tmp = []
+        for i in gene_dup:
+            if gene_in_rule.get(i) == 'ok':
+                tmp.append(i)
+        if tmp:
+            sys.exit('Execution aborted because gene ID '
+                     +str(tmp)+' in '+name+' is duplicated\n')
+    if pat_dup:
+        warning('Warning: duplicated label\n' + str(pat_dup) + 'in ' + name + 
+                '\n')
+    return (gene.set_index(gene.columns[0])).to_dict()
+
+############################ resolve ##########################################
+
+def resolve(genes, rules, ids, resolve_none, name):
+    resolve_rules = {}
+    not_found = []
+    flag = False
+    for key, value in genes.items():
+        tmp_resolve = []
+        for i in range(len(rules)):
+            tmp = rules[i]
+            if tmp:
+                tmp, err = replace_gene_value(tmp, value)
+                if err:
+                    not_found.extend(err)
+                ris = control(None, tmp, resolve_none)
+                if ris is False or ris == None:
+                    tmp_resolve.append(None)
+                else:
+                    tmp_resolve.append(ris)
+                    flag = True
+            else:
+                tmp_resolve.append(None)        
+        resolve_rules[key] = tmp_resolve
+    if flag is False:
+        warning('Warning: no computable score (due to missing gene values)' +
+                'for class ' + name + ', the class has been disregarded\n')
+        return (None, None)
+    return (resolve_rules, list(set(not_found)))
+
+############################ split class ######################################
+
+def split_class(classes, resolve_rules):
+    class_pat = {}
+    for i in range(len(classes)):
+        classe = classes.iloc[i, 1]
+        if not pd.isnull(classe):
+            l = []
+            for j in range(i, len(classes)):
+                if classes.iloc[j, 1] == classe:
+                    pat_id = classes.iloc[j, 0]
+                    tmp = resolve_rules.get(pat_id, None)
+                    if tmp != None:
+                        l.append(tmp)
+                    classes.iloc[j, 1] = None
+            if l:
+                class_pat[classe] = list(map(list, zip(*l)))
+            else:
+                warning('Warning: no sample found in class ' + classe +
+                        ', the class has been disregarded\n')
+    return class_pat
+
+############################ map ##############################################
+
+def maps(core_map, class_pat, ids, threshold_P_V, threshold_F_C):
+    args = process_args(sys.argv)
+    if (not class_pat) or (len(class_pat.keys()) < 2):
+        sys.exit('Execution aborted: classes provided for comparisons are ' +
+                 'less than two\n')
+    for i, j in it.combinations(class_pat.keys(), 2):
+        tmp = {}
+        count = 0
+        max_F_C = 0
+        for l1, l2 in zip(class_pat.get(i), class_pat.get(j)):
+            try:
+               stat_D, p_value = st.ks_2samp(l1, l2)
+               avg = fold_change(sum(l1) / len(l1), sum(l2) / len(l2))
+               if not isinstance(avg, str):
+                   if max_F_C < abs(avg):
+                       max_F_C = abs(avg)
+               tmp[ids[count]] = [float(p_value), avg]
+               count += 1
+            except (TypeError, ZeroDivisionError):
+               count += 1
+        tab = 'table_out/' + i + '_vs_' + j + '.tsv'
+        tmp_csv = pd.DataFrame.from_dict(tmp, orient = "index")
+        tmp_csv = tmp_csv.reset_index()
+        header = ['ids', 'P_Value', 'Average']
+        tmp_csv.to_csv(tab, sep = '\t', index = False, header = header)
+        if args.rules_selector == 'HMRcore' or (args.rules_selector == 'Custom'
+                                                and args.yes_no == 'yes'):
+            fix_map(tmp, core_map, threshold_P_V, threshold_F_C, max_F_C)
+            file_svg = 'map_svg/' + i + '_vs_' + j + '.svg'
+            with open(file_svg, 'wb') as new_map:
+                new_map.write(ET.tostring(core_map, encoding='UTF-8',
+                                          method='xml'))
+            file_pdf = 'map_pdf/' + i + '_vs_' + j + '.pdf'
+            renderPDF.drawToFile(svg2rlg(file_svg), file_pdf)
+    return None
+
+############################ MAIN #############################################
+
+def main():
+    args = process_args(sys.argv)
+    os.makedirs('table_out')
+    if args.rules_selector == 'HMRcore':
+        os.makedirs('map_svg')
+        os.makedirs('map_pdf')
+        recon = pk.load(open(args.tool_dir + '/local/HMRcore_rules.p', 'rb'))
+    elif args.rules_selector == 'Recon':
+        recon = pk.load(open(args.tool_dir + '/local/Recon_rules.p', 'rb'))
+    elif args.rules_selector == 'Custom':
+        ids, rules, gene_in_rule = make_recon(args.custom)
+    resolve_none = check_bool(args.none)
+    class_pat = {}
+    if args.option == 'datasets':
+        num = 1
+        #if len(args.names) != len(set(args.names)):
+        #    sys.exit('Execution aborted: datasets name duplicated')
+        for i, j in zip(args.input_datas, args.names):
+            name = name_dataset(j, num)
+            dataset = read_dataset(i, name)
+            dataset.iloc[:, 0] = (dataset.iloc[:, 0]).astype(str)
+            type_gene = gene_type(dataset.iloc[0, 0], name)
+            if args.rules_selector != 'Custom':
+                genes = data_gene(dataset, type_gene, name, None)
+                ids, rules = load_id_rules(recon.get(type_gene))
+            elif args.rules_selector == 'Custom':
+                genes = data_gene(dataset, type_gene, name, gene_in_rule)
+            resolve_rules, err = resolve(genes, rules, ids, resolve_none, name)
+            if err != None and err:
+                warning('Warning: gene\n' + str(err) + '\nnot found in class '
+                    + name + ', the expression level for this gene ' +
+                    'will be considered NaN\n')
+            if resolve_rules != None:
+                class_pat[name] = list(map(list, zip(*resolve_rules.values())))
+            num += 1
+    elif args.option == 'dataset_class':
+        name = 'RNAseq'
+        dataset = read_dataset(args.input_data, name)
+        dataset.iloc[:, 0] = (dataset.iloc[:, 0]).astype(str)
+        type_gene = gene_type(dataset.iloc[0, 0], name)
+        classes = read_dataset(args.input_class, 'class')
+        if not len(classes.columns) == 2:
+            warning('Warning: more than 2 columns in class file. Extra' +
+                    'columns have been disregarded\n')
+        classes = classes.astype(str)
+        if args.rules_selector != 'Custom':
+            genes = data_gene(dataset, type_gene, name, None)
+            ids, rules = load_id_rules(recon.get(type_gene))
+        elif args.rules_selector == 'Custom':
+            genes = data_gene(dataset, type_gene, name, gene_in_rule)
+        resolve_rules, err = resolve(genes, rules, ids, resolve_none, name)
+        if err != None and err:
+            warning('Warning: gene\n'+str(err)+'\nnot found in class '
+                    + name + ', the expression level for this gene ' +
+                    'will be considered NaN\n')
+        if resolve_rules != None:
+            class_pat = split_class(classes, resolve_rules)
+    if args.rules_selector == 'Custom':
+        if args.yes_no == 'yes':
+            os.makedirs('map_svg')
+            os.makedirs('map_pdf')
+            try:
+                core_map = ET.parse(args.custom_map)
+            except (ET.XMLSyntaxError, ET.XMLSchemaParseError):
+                sys.exit('Execution aborted: custom map in wrong format')
+        elif args.yes_no == 'no':
+            core_map = ET.parse(args.tool_dir + '/local/HMRcoreMap.svg')
+    else:       
+        core_map = ET.parse(args.tool_dir+'/local/HMRcoreMap.svg')
+    maps(core_map, class_pat, ids, args.pValue, args.fChange)
+    warning('Execution succeeded')
+    return None
+
+###############################################################################
+
+if __name__ == "__main__":
+    main()
--- /dev/null	Thu Jan 01 00:00:00 1970 +0000
+++ b/Marea/marea.xml	Tue Nov 06 03:16:21 2018 -0500
@@ -0,0 +1,240 @@
+<tool id="MaREA" name="Metabolic Enrichment Analysis">
+    <description>for Galaxy</description>
+    <requirements>
+        <requirement type="package">pandas</requirement>
+        <requirement type="package">scipy</requirement>
+        <requirement type="package">lxml</requirement>
+        <requirement type="package">svglib</requirement>
+        <requirement type="package">reportlab</requirement>
+        <requirement type="package">cobrapy</requirement>
+        <requirement type="package">python-libsbml</requirement>
+    </requirements>
+    <command>
+        <![CDATA[
+      	python $__tool_directory__/marea.py
+        --rules_selector $cond_rule.rules_selector
+        #if $cond_rule.rules_selector == 'Custom':
+            --custom ${cond_rule.Custom_rules}
+            --yes_no ${cond_rule.cond_map.yes_no}
+            #if $cond_rule.cond_map.yes_no == 'yes':
+                --custom_map $cond_rule.cond_map.Custom_map
+            #end if
+        #end if
+      	--none $None
+      	--pValue $pValue
+      	--fChange $fChange
+      	--tool_dir $__tool_directory__
+      	--option $cond.type_selector
+        --out_log $log
+        #if $cond.type_selector == 'datasets':
+            --input_datas
+            #for $data in $cond.input_Datasets:
+                ${data.input}
+            #end for
+            --names
+            #for $data in $cond.input_Datasets:
+                ${data.input_name}
+            #end for
+        #elif $cond.type_selector == 'dataset_class':
+            --input_data ${input_data}
+            --input_class ${input_class}
+        #end if
+        ]]>
+    </command>
+    <inputs>
+        <conditional name="cond_rule">
+            <param name="rules_selector" type="select" label="Gene-Protein-Reaction rules:">
+                <option value="HMRcore" selected="true">HMRcore rules</option>
+                <option value="Recon">Recon 2.2 rules</option>
+                <option value="Custom">Custom rules</option>
+            </param>
+            <when value="Custom">
+                <param name="Custom_rules" type="data" format="tabular, csv, tsv, xml" label="Custom rules"/>
+                <conditional name="cond_map">
+                    <param name="yes_no" type="select" label="Custom map? (optional)">
+                        <option value="no" selected="true">no</option>
+                        <option value="yes">yes</option>
+                    </param>
+                    <when value="yes">
+                        <param name="Custom_map" type="data" format="xml, svg" label="custom-map.svg"/>
+                    </when>
+                </conditional>
+            </when>
+        </conditional>
+        <conditional name="cond">
+            <param name="type_selector" type="select" label="Input format:">
+                <option value="datasets" selected="true">RNAseq of group 1 + RNAseq of group 2 + … + RNAseq of group N</option>
+                <option value="dataset_class">RNAseq of all samples + sample group specification</option>
+            </param>
+            <when value="datasets">
+                <repeat name="input_Datasets" title="RNAseq" type="data" min="2">
+                    <param name="input" type="data" format="tabular, csv, tsv" label="add dataset"/>	
+                    <param name="input_name" type="text" label="Dataset's name:" value="Dataset" help="Defalut: Dataset"/>
+	        </repeat>
+            </when>
+            <when value="dataset_class">
+                <param name="input_data" type="data" format="tabular, csv, tsv" label="RNAseq of all samples"/>
+                <param name="input_class" type="data" format="tabular, csv, tsv" label="Sample group specification"/>
+            </when>
+        </conditional>
+        <param name="None" type="boolean" truevalue="true" falsevalue="false" checked="true" label="(A and NaN) solved as (A)?"/> 
+        <param name="pValue" type="float" size="20" value="0.05" max="1" min="0" label="P-value threshold" help="min value 0"/>
+        <param name="fChange" type="float" size="20" value="1.5" min="1" label="Fold-Cahnge threshold" help="min value 1"/>
+    </inputs>
+    <outputs>
+        <data format="txt" name="log" label="Log"/>
+        <collection name="map_svg" type="list" label="file svg">
+            <filter>(cond_rule['rules_selector'] == 'HMRcore') or ((cond_rule['rules_selector'] == 'Custom') and (cond_rule['cond_map']['yes_no'] == 'yes'))</filter>
+            <discover_datasets pattern="__name_and_ext__" directory="map_svg"/>
+        </collection>
+        <collection name="map_pdf" type="list" label="file pdf">
+            <filter>(cond_rule['rules_selector'] == 'HMRcore') or ((cond_rule['rules_selector'] == 'Custom') and (cond_rule['cond_map']['yes_no'] == 'yes'))</filter>
+            <discover_datasets pattern="__name_and_ext__" directory="map_pdf"/>
+        </collection>
+        <collection name="table_out" type="list" label="file table">
+            <discover_datasets pattern="__name_and_ext__" directory="table_out"/>
+        </collection>
+    </outputs>
+    <help>
+<![CDATA[
+
+What it does
+-------------
+
+This tool analyzes RNA-seq dataset(s) as described in Graudenzi et al."`MaREA`_: Metabolic feature extraction, enrichment and visualization of RNAseq data" bioRxiv (2018): 248724.
+
+The tool can be used to generate:
+    1) a tab-separated file: reporting fold-change and p-values of reaction activity scores (RASs) between a pair of conditions/classes
+    2) a metabolic map file (downlodable as .svg): visualizing up- and down-regulated reactions between a pair of conditions/classes
+    3) a log file (.txt) 
+
+Accepted files are: 
+    1) or two or more RNA-seq datasets, each referring to samples in a given condition/class. The user can specify a label for each class (as e.g. “classA” and “classB”).
+    2) or one RNA dataset and one class-file specifying the class/condition each sample belongs to.
+
+
+RNA-seq datasets format: tab-separated text files, reporting the expression level (e.g., TPM, RPKM, …) of each gene (row) for a given sample (column). Header: sample ID.
+
+Class-file format: each row of the class-file reports the sample ID (column1) and the label of the class/condition the sample belongs to (column 2).
+
+To calculate P-Values and Fold-Changes and to generate maps, comparisons are performed for each possible pair of classes.
+
+Output files will be named as classA_vs_classB. Reactions will conventionally be reported as up-regulated (down-regulated) if they are significantly more (less) active in class having label “classA”.
+
+.. _MaREA: https://www.biorxiv.org/content/early/2018/01/16/248724
+
+
+Example input
+-------------
+
+**"RNAseq of group 1 + RNAseq of group 2 + ... + RNAseq of group N" exemple input"** option:
+
+Dataset 1:						
+
++------------+------------+------------+------------+   
+|  Hugo_ID   | TCGAA62670 | TCGAA62671 | TCGAA62672 |   
++============+============+============+============+   
+| HGNC:24086 |  0.523167  |  0.371355  |  0.925661  |   
++------------+------------+------------+------------+    
+| HGNC:24086 |  0.568765  |  0.765567  |  0.456789  |    
++------------+------------+------------+------------+    
+| HGNC:9876  |  0.876545  |  0.768933  |  0.987654  |   
++------------+------------+------------+------------+    
+| HGNC:9     |  0.456788  |  0.876543  |  0.876542  |   
++------------+------------+------------+------------+    
+| HGNC:23    |  0.876543  |  0.786543  |  0.897654  |   
++------------+------------+------------+------------+ 
+   
+|
+
+Dataset 2:
+
++-------------+------------+------------+------------+
+| Hugo_Symbol | TCGAA62670 | TCGAA62671 | TCGAA62672 |
++=============+============+============+============+
+|    A1BG     |  0.523167  |  0.371355  |  0.925661  |
++-------------+------------+------------+------------+
+|    A1CF     |  0.568765  |  0.765567  |  0.456789  |
++-------------+------------+------------+------------+
+|     A2M     |  0.876545  |  0.768933  |  0.987654  |
++-------------+------------+------------+------------+
+|    A4GALT   |  0.456788  |  0.876543  |  0.876542  |
++-------------+------------+------------+------------+
+|   M664Y65   |  0.876543  |  0.786543  |  0.897654  |
++-------------+------------+------------+------------+
+
+|
+
+**"RNAseq of all samples + sample group specification"** option:
+
+Dataset:
+
++------------+------------+------------+------------+   
+|  Hugo_ID   | TCGAA62670 | TCGAA62671 | TCGAA62672 |   
++============+============+============+============+   
+| HGNC:24086 |  0.523167  |  0.371355  |  0.925661  |   
++------------+------------+------------+------------+    
+| HGNC:24086 |  0.568765  |  0.765567  |  0.456789  |    
++------------+------------+------------+------------+    
+| HGNC:9876  |  0.876545  |  0.768933  |  0.987654  |   
++------------+------------+------------+------------+    
+| HGNC:9     |  0.456788  |  0.876543  |  0.876542  |   
++------------+------------+------------+------------+    
+| HGNC:23    |  0.876543  |  0.786543  |  0.897654  |   
++------------+------------+------------+------------+ 
+
+|
+
+Class-file:
+
++------------+------------+   
+| Patient_ID |    class   |   
++============+============+   
+| TCGAAA3529 |     MSI    |   
++------------+------------+    
+| TCGAA62671 |     MSS    |    
++------------+------------+    
+| TCGAA62672 |     MSI    |   
++------------+------------+
+
+|
+
+
+
+.. class:: warningmark
+
+This tool expects input datasets consisting of tab-delimited columns.
+
+
+.. class:: infomark
+
+TIP: If your data is not TAB delimited, use `Convert delimiters to TAB`_.
+
+.. class:: infomark
+
+TIP: If your dataset is not split into classes, use `Cluster for MaREA`_.
+
+This tool is developed by the `nome del gruppo di bioinformatica`_ at the `dipartimento di informatica disco`_.
+
+
+.. _Convert delimiters to TAB: https://usegalaxy.org/?tool_id=Convert+characters1&version=1.0.0&__identifer=6t22teyofhj
+.. _Cluster for MaREA: http://link del tool di cluster.org/
+.. _nome del gruppo di bioinformatica: http://sito di bio.org
+.. _dipartimento di informatica disco : http://www.disco.unimib.it/go/Home/English
+
+]]>
+    </help>
+</tool>
+	
+	
+	
+	
+	
+	
+	
+	
+	
+	
+	
+	
+	
--- /dev/null	Thu Jan 01 00:00:00 1970 +0000
+++ b/Marea/marea_cluster.py	Tue Nov 06 03:16:21 2018 -0500
@@ -0,0 +1,608 @@
+
+from __future__ import division
+import os
+import sys
+import pandas as pd
+import collections
+import pickle as pk
+import argparse
+from sklearn.cluster import KMeans
+import matplotlib.pyplot as plt
+
+########################## argparse ###########################################
+
+def process_args(args):
+    parser = argparse.ArgumentParser(usage = '%(prog)s [options]',
+                                     description = 'process some value\'s' +
+                                     ' genes to create class.')
+    parser.add_argument('-rs', '--rules_selector', 
+                        type = str,
+                        default = 'HMRcore',
+                        choices = ['HMRcore', 'Recon', 'Custom'], 
+                        help = 'chose which type of dataset you want use')
+    parser.add_argument('-cr', '--custom',
+                        type = str,
+                        help='your dataset if you want custom rules')
+    parser.add_argument('-ch', '--cond_hier', 
+                        type = str,
+                        default = 'no',
+                        choices = ['no', 'yes'], 
+                        help = 'chose if you wanna hierical dendrogram')
+    parser.add_argument('-lk', '--k_min', 
+                        type = int,
+                        help = 'min number of cluster')
+    parser.add_argument('-uk', '--k_max', 
+                        type = int,
+                        help = 'max number of cluster')
+    parser.add_argument('-li', '--linkage', 
+                        type = str, 
+                        choices = ['single', 'complete', 'average'], 
+                        help='linkage hierarchical cluster')
+    parser.add_argument('-d', '--data',
+                        type = str,
+                        required = True,
+                        help = 'input dataset')
+    parser.add_argument('-n', '--none',
+                        type = str,
+                        default = 'true',
+                        choices = ['true', 'false'], 
+                        help = 'compute Nan values')
+    parser.add_argument('-td', '--tool_dir',
+                        type = str,
+                        required = True,
+                        help = 'your tool directory')
+    parser.add_argument('-na', '--name',
+                        type = str,
+                        help = 'name of dataset')
+    parser.add_argument('-de', '--dendro', 
+                        help = "Dendrogram out")
+    parser.add_argument('-ol', '--out_log', 
+                        help = "Output log")
+    parser.add_argument('-el', '--elbow', 
+                        help = "Out elbow")
+    args = parser.parse_args()
+    return args
+
+########################### warning ###########################################
+
+def warning(s):
+    args = process_args(sys.argv)
+    with open(args.out_log, 'a') as log:
+            log.write(s)
+            
+############################ dataset input ####################################
+
+def read_dataset(data, name):
+    try:
+        dataset = pd.read_csv(data, sep = '\t', header = 0)
+    except pd.errors.EmptyDataError:
+        sys.exit('Execution aborted: wrong format of '+name+'\n')
+    if len(dataset.columns) < 2:
+        sys.exit('Execution aborted: wrong format of '+name+'\n')
+    return dataset
+
+############################ dataset name #####################################
+
+def name_dataset(name_data, count):
+    if str(name_data) == 'Dataset':
+        return str(name_data) + '_' + str(count)
+    else:
+        return str(name_data)
+    
+############################ load id e rules ##################################
+
+def load_id_rules(reactions):
+    ids, rules = [], []
+    for key, value in reactions.items():
+            ids.append(key)
+            rules.append(value)
+    return (ids, rules)
+
+############################ check_methods ####################################
+
+def gene_type(l, name):
+    if check_hgnc(l):
+        return 'hugo_id'
+    elif check_ensembl(l):
+        return 'ensembl_gene_id'
+    elif check_symbol(l):
+        return 'symbol'
+    elif check_entrez(l):
+        return 'entrez_id'
+    else:
+        sys.exit('Execution aborted:\n' +
+                 'gene ID type in ' + name + ' not supported. Supported ID' +
+                 'types are: HUGO ID, Ensemble ID, HUGO symbol, Entrez ID\n')
+
+def check_hgnc(l):
+    if len(l) > 5:
+        if (l.upper()).startswith('HGNC:'):
+            return l[5:].isdigit()
+        else:
+            return False
+    else:
+        return False
+
+def check_ensembl(l): 
+    if len(l) == 15:
+        if (l.upper()).startswith('ENS'):
+            return l[4:].isdigit()
+        else:  
+            return False 
+    else: 
+        return False 
+
+def check_symbol(l):
+    if len(l) > 0:
+        if l[0].isalpha() and l[1:].isalnum():
+            return True
+        else:
+            return False
+    else:
+        return False
+
+def check_entrez(l): 
+    if len(l) > 0:
+        return l.isdigit()
+    else: 
+        return False
+
+def check_bool(b):
+    if b == 'true':
+        return True
+    elif b == 'false':
+        return False
+    
+############################ make recon #######################################
+
+def check_and_doWord(l):
+    tmp = []
+    tmp_genes = []
+    count = 0
+    while l:
+        if count >= 0:
+            if l[0] == '(':
+                count += 1
+                tmp.append(l[0])
+                l.pop(0)
+            elif l[0] == ')':
+                count -= 1
+                tmp.append(l[0])
+                l.pop(0)
+            elif l[0] == ' ':
+                l.pop(0)
+            else:
+                word = []
+                while l:
+                    if l[0] in [' ', '(', ')']:
+                        break
+                    else:
+                        word.append(l[0])
+                        l.pop(0)
+                word = ''.join(word)
+                tmp.append(word)
+                if not(word in ['or', 'and']):
+                    tmp_genes.append(word)
+        else:
+            return False
+    if count == 0:
+        return (tmp, tmp_genes)
+    else:
+        return False
+
+def brackets_to_list(l):
+    tmp = []
+    while l:
+        if l[0] == '(':
+            l.pop(0)
+            tmp.append(resolve_brackets(l))
+        else:
+            tmp.append(l[0])
+            l.pop(0)
+    return tmp
+
+def resolve_brackets(l):
+    tmp = []
+    while l[0] != ')':
+        if l[0] == '(':
+            l.pop(0)
+            tmp.append(resolve_brackets(l))
+        else:
+            tmp.append(l[0])
+            l.pop(0)
+    l.pop(0)
+    return tmp
+
+def priorityAND(l):
+    tmp = []
+    flag = True
+    while l:
+        if len(l) == 1:
+            if isinstance(l[0], list):
+                tmp.append(priorityAND(l[0]))
+            else:
+                tmp.append(l[0])
+            l = l[1:]
+        elif l[0] == 'or':
+            tmp.append(l[0])
+            flag = False
+            l = l[1:]
+        elif l[1] == 'or':
+            if isinstance(l[0], list): 
+                tmp.append(priorityAND(l[0]))
+            else:
+                tmp.append(l[0])
+            tmp.append(l[1])
+            flag = False
+            l = l[2:]
+        elif l[1] == 'and':
+            tmpAnd = []
+            if isinstance(l[0], list): 
+                tmpAnd.append(priorityAND(l[0]))
+            else:
+                tmpAnd.append(l[0])
+            tmpAnd.append(l[1])
+            if isinstance(l[2], list): 
+                tmpAnd.append(priorityAND(l[2]))
+            else:
+                tmpAnd.append(l[2])
+            l = l[3:]
+            while l:
+                if l[0] == 'and':
+                    tmpAnd.append(l[0])
+                    if isinstance(l[1], list): 
+                        tmpAnd.append(priorityAND(l[1]))
+                    else:
+                        tmpAnd.append(l[1])
+                    l = l[2:]
+                elif l[0] == 'or':
+                    flag = False
+                    break
+            if flag == True: #se ci sono solo AND nella lista
+                tmp.extend(tmpAnd)
+            elif flag == False:
+                tmp.append(tmpAnd)
+    return tmp
+
+def checkRule(l):
+    if len(l) == 1:
+        if isinstance(l[0], list):
+            if checkRule(l[0]) is False:
+                return False
+    elif len(l) > 2:
+        if checkRule2(l) is False:
+            return False
+    else:
+        return False
+    return True
+
+def checkRule2(l):
+    while l:
+        if len(l) == 1:
+            return False
+        elif isinstance(l[0], list) and l[1] in ['and', 'or']:
+            if checkRule(l[0]) is False:
+                return False
+            if isinstance(l[2], list):
+                if checkRule(l[2]) is False:
+                    return False
+            l = l[3:]
+        elif l[1] in ['and', 'or']:
+            if isinstance(l[2], list):
+                if checkRule(l[2]) is False:
+                    return False
+            l = l[3:]
+        elif l[0] in ['and', 'or']:
+            if isinstance(l[1], list):
+                if checkRule(l[1]) is False:
+                    return False
+            l = l[2:]
+        else:
+            return False
+    return True
+
+def do_rules(rules):
+    split_rules = []
+    err_rules = []
+    tmp_gene_in_rule = []
+    for i in range(len(rules)):
+        tmp = list(rules[i])
+        if tmp:
+            tmp, tmp_genes = check_and_doWord(tmp)
+            tmp_gene_in_rule.extend(tmp_genes)
+            if tmp is False:
+                split_rules.append([])
+                err_rules.append(rules[i])
+            else:
+                tmp = brackets_to_list(tmp)
+                if checkRule(tmp):
+                    split_rules.append(priorityAND(tmp))
+                else:
+                    split_rules.append([])
+                    err_rules.append(rules[i])
+        else:
+            split_rules.append([])
+    if err_rules:
+        warning('Warning: wrong format rule in ' + str(err_rules) + '\n')
+    return (split_rules, list(set(tmp_gene_in_rule)))
+
+def make_recon(data):
+    try:
+        import cobra as cb
+        import warnings
+        with warnings.catch_warnings():
+            warnings.simplefilter('ignore')
+            recon = cb.io.read_sbml_model(data)
+        react = recon.reactions
+        rules = [react[i].gene_reaction_rule for i in range(len(react))]
+        ids = [react[i].id for i in range(len(react))]
+    except cb.io.sbml3.CobraSBMLError:
+        try:
+            data = (pd.read_csv(data, sep = '\t', dtype = str)).fillna('')
+            if len(data.columns) < 2:
+                sys.exit('Execution aborted: wrong format of ' +
+                         'custom GPR rules\n')
+            if not len(data.columns) == 2:
+                warning('WARNING: more than 2 columns in custom GPR rules.\n' +
+                        'Extra columns have been disregarded\n')
+            ids = list(data.iloc[:, 0])
+            rules = list(data.iloc[:, 1])
+        except pd.errors.EmptyDataError:
+            sys.exit('Execution aborted: wrong format of custom GPR rules\n')
+        except pd.errors.ParserError:
+            sys.exit('Execution aborted: wrong format of custom GPR rules\n')  
+    split_rules, tmp_genes = do_rules(rules)
+    gene_in_rule = {}
+    for i in tmp_genes:
+        gene_in_rule[i] = 'ok'
+    return (ids, split_rules, gene_in_rule)
+
+############################ resolve_methods ##################################
+
+def replace_gene_value(l, d):
+    tmp = []
+    err = []
+    while l:
+        if isinstance(l[0], list):
+            tmp_rules, tmp_err = replace_gene_value(l[0], d)
+            tmp.append(tmp_rules)
+            err.extend(tmp_err)
+        else:
+            value = replace_gene(l[0],d)
+            tmp.append(value)
+            if value == None:
+                err.append(l[0])
+        l = l[1:]
+    return (tmp, err)
+
+def replace_gene(l, d):
+    if l =='and' or l == 'or':
+        return l
+    else:
+        value = d.get(l, None)
+        if not(value == None or isinstance(value, (int, float))):
+            sys.exit('Execution aborted: ' + value + ' value not valid\n')
+        return value
+
+def compute(val1, op, val2, cn):
+    if val1 != None and val2 != None:
+        if op == 'and':
+            return min(val1, val2)
+        else:
+            return val1 + val2
+    elif op == 'and':
+        if cn is True:
+            if val1 != None:
+                return val1
+            elif val2 != None:
+                return val2
+            else:
+                return None
+        else:
+            return None
+    else:
+        if val1 != None:
+            return val1
+        elif val2 != None:
+            return val2
+        else:
+            return None
+
+def control(ris, l, cn):
+    if len(l) == 1:
+        if isinstance(l[0], (float, int)) or l[0] == None:
+            return l[0]
+        elif isinstance(l[0], list):
+            return control(None, l[0], cn)
+        else:
+            return False
+    elif len(l) > 2:
+        return control_list(ris, l, cn)
+    else:
+        return False
+
+def control_list(ris, l, cn):
+    while l:
+        if len(l) == 1:
+            return False
+        elif (isinstance(l[0], (float, int)) or
+              l[0] == None) and l[1] in ['and', 'or']:
+            if isinstance(l[2], (float, int)) or l[2] == None:
+                ris = compute(l[0], l[1], l[2], cn)            
+            elif isinstance(l[2], list):
+                tmp = control(None, l[2], cn)
+                if tmp is False:
+                    return False
+                else:
+                    ris = compute(l[0], l[1], tmp, cn)
+            else:
+                return False
+            l = l[3:]
+        elif l[0] in ['and', 'or']:
+            if isinstance(l[1], (float, int)) or l[1] == None:
+                ris = compute(ris, l[0], l[1], cn)
+            elif isinstance(l[1], list):
+                tmp = control(None,l[1], cn)
+                if tmp is False:
+                    return False
+                else:
+                    ris = compute(ris, l[0], tmp, cn)
+            else:
+                return False
+            l = l[2:]
+        elif isinstance(l[0], list) and l[1] in ['and', 'or']:
+            if isinstance(l[2], (float, int)) or l[2] == None:
+                tmp = control(None, l[0], cn)
+                if tmp is False:
+                    return False
+                else:
+                    ris = compute(tmp, l[1], l[2], cn)
+            elif isinstance(l[2], list):
+                tmp = control(None, l[0], cn)
+                tmp2 = control(None, l[2], cn)
+                if tmp is False or tmp2 is False:
+                    return False
+                else:
+                    ris = compute(tmp, l[1], tmp2, cn)
+            else:
+                return False
+            l = l[3:]
+        else:
+            return False
+    return ris
+
+############################ gene #############################################
+
+def data_gene(gene, type_gene, name, gene_custom):
+    args = process_args(sys.argv)
+    for i in range(len(gene)):
+        tmp = gene.iloc[i, 0]
+        if tmp.startswith(' ') or tmp.endswith(' '):
+            gene.iloc[i, 0] = (tmp.lstrip()).rstrip()
+    gene_dup = [item for item, count in 
+               collections.Counter(gene[gene.columns[0]]).items() if count > 1]
+    pat_dup = [item for item, count in 
+               collections.Counter(list(gene.columns)).items() if count > 1]
+    if gene_dup:
+        if gene_custom == None:
+            if args.rules_selector == 'HMRcore':
+                gene_in_rule = pk.load(open(args.tool_dir +
+                                            '/local/HMRcore_genes.p', 'rb'))
+            elif args.rules_selector == 'Recon':
+                gene_in_rule = pk.load(open(args.tool_dir +
+                                            '/local/Recon_genes.p', 'rb'))
+            gene_in_rule = gene_in_rule.get(type_gene)
+        else:
+            gene_in_rule = gene_custom
+        tmp = []
+        for i in gene_dup:
+            if gene_in_rule.get(i) == 'ok':
+                tmp.append(i)
+        if tmp:
+            sys.exit('Execution aborted because gene ID '
+                     + str(tmp) + ' in ' + name + ' is duplicated\n')
+    if pat_dup:
+        sys.exit('Execution aborted: duplicated label\n'
+                 + str(pat_dup) + 'in ' + name + '\n')
+    return (gene.set_index(gene.columns[0])).to_dict()
+
+############################ resolve ##########################################
+
+def resolve(genes, rules, ids, resolve_none, name):
+    resolve_rules = {}
+    not_found = []
+    flag = False
+    for key, value in genes.items():
+        tmp_resolve = []
+        for i in range(len(rules)):
+            tmp = rules[i]
+            if tmp:
+                tmp, err = replace_gene_value(tmp, value)
+                if err:
+                    not_found.extend(err)
+                ris = control(None, tmp, resolve_none)
+                if ris is False or ris == None:
+                    tmp_resolve.append(None)
+                else:
+                    tmp_resolve.append(ris)
+                    flag = True
+            else:
+                tmp_resolve.append(None)        
+        resolve_rules[key] = tmp_resolve
+    if flag is False:
+        sys.exit('Execution aborted: no computable score' +
+                 ' (due to missing gene values) for class '
+                 + name + ', the class has been disregarded\n')
+    return (resolve_rules, list(set(not_found)))
+
+################################# clustering ##################################
+
+def f_cluster(resolve_rules):
+    os.makedirs('cluster_out')
+    args = process_args(sys.argv)
+    cluster_data = pd.DataFrame.from_dict(resolve_rules, orient = 'index')
+    for i in cluster_data.columns:
+        tmp = cluster_data[i][0]
+        if tmp == None:
+            cluster_data = cluster_data.drop(columns=[i])
+    distorsion = []
+    for i in range(args.k_min, args.k_max+1):
+        tmp_kmeans = KMeans(n_clusters = i,
+                            n_init = 100, 
+                            max_iter = 300,
+                            random_state = 0).fit(cluster_data)
+        distorsion.append(tmp_kmeans.inertia_)
+        predict = tmp_kmeans.predict(cluster_data)
+        predict = [x+1 for x in predict]
+        classe = (pd.DataFrame(zip(cluster_data.index, predict))).astype(str)
+        dest = 'cluster_out/K=' + str(i) + '_' + args.name+'.tsv'
+        classe.to_csv(dest, sep = '\t', index = False,
+                      header = ['Patient_ID', 'Class'])
+    plt.figure(0)
+    plt.plot(range(args.k_min, args.k_max+1), distorsion, marker = 'o')
+    plt.xlabel('Number of cluster')
+    plt.ylabel('Distorsion')
+    plt.savefig(args.elbow, dpi = 240, format = 'pdf')
+    if args.cond_hier == 'yes':
+        import scipy.cluster.hierarchy as hier
+        lin = hier.linkage(cluster_data, args.linkage)
+        plt.figure(1)
+        plt.figure(figsize=(10, 5))
+        hier.dendrogram(lin, leaf_font_size = 2, labels = cluster_data.index)
+        plt.savefig(args.dendro, dpi = 480, format = 'pdf')
+    return None
+
+################################# main ########################################
+
+def main():
+    args = process_args(sys.argv)
+    if args.k_min > args.k_max:
+        sys.exit('Execution aborted: max cluster > min cluster')
+    if args.rules_selector == 'HMRcore':
+        recon = pk.load(open(args.tool_dir + '/local/HMRcore_rules.p', 'rb'))
+    elif args.rules_selector == 'Recon':
+        recon = pk.load(open(args.tool_dir + '/local/Recon_rules.p', 'rb'))
+    elif args.rules_selector == 'Custom':
+        ids, rules, gene_in_rule = make_recon(args.custom)
+    resolve_none = check_bool(args.none)
+    dataset = read_dataset(args.data, args.name)
+    dataset.iloc[:, 0] = (dataset.iloc[:, 0]).astype(str)
+    type_gene = gene_type(dataset.iloc[0, 0], args.name)
+    if args.rules_selector != 'Custom':
+        genes = data_gene(dataset, type_gene, args.name, None)
+        ids, rules = load_id_rules(recon.get(type_gene))
+    elif args.rules_selector == 'Custom':
+        genes = data_gene(dataset, type_gene, args.name, gene_in_rule)
+    resolve_rules, err = resolve(genes, rules, ids, resolve_none, args.name)
+    if err:
+        warning('WARNING: gene\n' + str(err) + '\nnot found in class '  
+                + args.name + ', the expression level for this gene ' +
+                'will be considered NaN\n')
+    f_cluster(resolve_rules)
+    warning('Execution succeeded')
+    return None
+
+###############################################################################
+
+if __name__ == "__main__":
+    main()
\ No newline at end of file
--- /dev/null	Thu Jan 01 00:00:00 1970 +0000
+++ b/Marea/marea_cluster.xml	Tue Nov 06 03:16:21 2018 -0500
@@ -0,0 +1,97 @@
+<tool id="MaREA_cluester" name="MaREA cluster analysis">
+    <description>of Reaction Activity Scores</description>
+    <requirements>
+        <requirement type="package">pandas</requirement>
+        <requirement type="package">scikit-learn</requirement>
+        <requirement type="package">scipy</requirement>
+        <requirement type="package">matplotlib</requirement>
+        <requirement type="package">cobrapy</requirement>
+        <requirement type="package">python-libsbml</requirement>
+    </requirements>
+    <command>
+        <![CDATA[
+      	python $__tool_directory__/marea_cluster.py
+        --rules_selector $cond_rule.rules_selector
+        #if $cond_rule.rules_selector == 'Custom':
+            --custom ${cond_rule.Custom_rules}
+        #end if
+        --cond_hier $cond_hier.hier
+        #if $cond_hier.hier == 'yes':
+            --linkage ${cond_hier.linkage}
+            --dendro $dendrogram
+        #end if
+        --k_max $k_max
+        --k_min $k_min
+        --data $input
+        --name $name
+      	--none $None
+      	--tool_dir $__tool_directory__
+        --out_log $log
+        --elbow $elbow
+        ]]>
+    </command>
+    <inputs>
+        <conditional name="cond_rule">
+            <param name="rules_selector" type="select" label="Gene-Protein-Reaction rules:">
+                <option value="HMRcore" selected="true">HMRcore rules</option>
+                <option value="Recon">Recon 2.2 rules</option>
+                <option value="Custom">Custom rules</option>
+            </param>
+            <when value="Custom">
+                <param name="Custom_rules" type="data" format="tabular, csv, tsv, xml" label="Custom rules"/>
+            </when>
+        </conditional>
+        <param name="input" type="data" format="tabular, csv, tsv" label="RNAseq of all samples"/>
+        <param name="name" type="text" label="Output name prefix" value = "dataset"/>
+        <param name="k_min" type="integer" size="20" value="3" min="2" max="30" label="min number of clusters (k) to be tested (k-means)"/>
+        <param name="k_max" type="integer" size="20" value="3" min="2" max="30" label="max number of clusters (k) to be tested (k-means)"/>
+        <param name="None" type="boolean" truevalue="true" falsevalue="false" checked="true" label="(A and NaN) solved as (A)?" help="if NO is selected (A and NaN) is solved as (NaN)"/>
+	<conditional name="cond_hier">
+            <param name="hier" type="select" label="Produce dendrogram (hierarchical clustering):">
+                <option value="no" selected="true">no</option>
+                <option value="yes">yes</option>
+            </param>
+            <when value="yes">
+                <param name="linkage" type="select" label="Linkage type:">
+                    <option value="single" selected="true">Single: minimum distance between all observations of two sets</option>
+                    <option value="complete">Complete: maximum distance between all observations of two sets</option>
+                    <option value="average">Average: average distance between all observations of two sets</option>
+                </param>
+            </when>
+        </conditional>
+    </inputs>
+    <outputs>
+        <data format="txt" name="log" label="Log"/>
+        <data format="pdf" name="dendrogram" label="$name dendrogram">
+            <filter>cond_hier['hier'] == 'yes'</filter>
+        </data>
+        <data format="pdf" name="elbow" label="$name elbow evaluation method"/>
+        <collection name="cluster_out" type="list" label="Clusters $k_min - $k_max">
+            <discover_datasets pattern="__name_and_ext__" directory="cluster_out"/>
+        </collection>
+    </outputs>
+    <help>
+
+.. class:: warningmark
+
+This tool expects input datasets consisting of tab-delimited columns.
+
+.. class:: infomark
+
+**TIP:** If your data is not TAB delimited, use *Text Manipulation > Convert delimiters to TAB*
+
+    </help>
+</tool>
+	
+	
+	
+	
+	
+	
+	
+	
+	
+	
+	
+	
+