# Usage: python create_edges4.py parameter_for_net.txt
# Purpose:
# This script will generate a few WORK20170328_1026_AGI_one_K2/3.R scripts, each for a target gene. Treat each target separately and at the same, to speed things up.
# The results will be saved as edges.txt.AT2G40300.Apr.04.2017.11:45:30.k3, where AT3G12580 is gene id, and k3 means K=3 in Mixture of Regressions.
# The edges.txt files will be merged together later by update_network.py.
# Make it faster by handling each target separately.
# Make memory footprint smaller by spliting TPM.txt into small json files (in JSON_DIR), and converting binding.txt to target_tf.txt (in target_tf_fname) first.
# So we only load necessary gene expression vectors each time.  So we don't need to load the big matrices, TPM.txt and binding.txt.
#
#  7 Mar 2017, slcu, hui
#  Last modified 23 Mar 2017, slcu, hui
#  Last modified 23 Mar 2017, slcu, hui. Check edges.txt to determine update.

import sys, os, operator, itertools
from datetime import datetime
import time
import json
import subprocess
from geneid2name import make_gene_name_AGI_map_dict
from param4net import make_global_param_dict

EDGE_FILE = '../Data/history/edges/edges.txt'  # recent, merged edges from various sources
EDGE_DIR = '../Data/history/edges/one_target'  # a directory for storing all edge files generated by this script, one for each target gene
TIME_INTERVAL = 2 # wait 5 seconds before launching a R Rscript
MAX_PROCESS   = 10 # CHANGE this to a larger number if you have many CPUs
AVERAGE_LIKELIHOOD_TAU = -0.5 # a value betweeo -0.1 to -998.  must be negative, lower this value make less effort in creating brand-new edges.
EDGE_AGE = 30 # if an edge's age is less than 30 days, don't need to update it.

####################################
DATA_SYMBOL         = '@'
####################################

def get_gene_list(fname):
    result = []
    f = open(fname)
    for line in f:
        line = line.strip()
        lst = line.split()
        result.append(lst[0])
    f.close()
    return result

def get_ordered_gene_list(fname):
    gene_list = get_gene_list(fname)
    d = {}
    if not os.path.exists(EDGE_FILE):
        return gene_list    
    f = open(EDGE_FILE)
    lines = f.readlines()
    f.close()
    for line in lines:
        line = line.strip()
        lst = line.split('\t')
        target = lst[0].split()[0]
        tf     = lst[1].split()[0]
        if not target in d:
            d[target] = 1
        else:
            d[target] += 1
            
    result_gene_lst = []
    for t in sorted(d.items(), key=operator.itemgetter(1)): # targets with fewer edges will be on the top
        g = t[0]
        if g in gene_list:
            result_gene_lst.append(g)
    return result_gene_lst


def make_tf_dict(fname):
    d = {}
    f = open(fname)
    for line in f:
        line = line.strip()
        lst = line.split('\t')
        target = lst[0]
        tf     = lst[1]
        cond   = lst[2]
        if not target in d:
            d[target] = {tf:cond}
        else:
            d[target][tf] = cond
    f.close()
    return d

def make_target_dict(fname):
    d = {}
    f = open(fname)
    for line in f:
        line = line.strip()
        lst = line.split('\t')
        target = lst[0]
        tf     = lst[1]
        cond   = lst[2]
        if not tf in d:
            d[tf] = {target:cond}
        else:
            d[tf][target] = cond
    f.close()
    return d

def not_bad_line(s):
    if s.strip() == '':
        return False
    if 'WARNING' in s:
        return False
    if 'number' in s:
        return False
    if 'Need' in s:
        return False
    if 'Error' in s:
        return False
    if 'Too' in s:
        return False
    if not s.startswith('AT'):
        return False
    return True

def make_edge_dict(fname):
    d = {}
    if not os.path.exists(fname):
        return d
    f = open(fname)
    for line in f:
        line = line.strip()
        if not_bad_line(line):
            lst = line.split('\t')
            target_id = lst[0].split()[0]
            tf_id = lst[1].split()[0]
            date = '20161201'
            num_rcond = len(lst[4].split())
            avg_loglik = -999 # very low likelihood
            loglik = lst[6]
            if loglik != '.':
                if '=' in loglik:
                    avg_loglik = float(loglik.split('=')[1])/num_rcond
                else:
                    avg_loglik = float(loglik)/num_rcond
            if len(lst) == 8:
                date = lst[7]
            if not tf_id in d:
                d[tf_id] = {target_id:{'date':date, 'loglikelihood':avg_loglik}}
            else:
                d[tf_id][target_id] = {'date':date, 'loglikelihood':avg_loglik}
    f.close()
    return d

def make_r_script(fname, target, tf_dict, abs_jsonTPM_dir, num_component, edge_dict):
    head =  'k.lst <- c(%d)\n' % (num_component) 
    head += 'target <- \'%s\'\n' % (target)
    head += 'id2 <- target\n'
    tfs = ''
    conds = ''
    recent_edge = ''
    curr_time = datetime.now().strftime('%Y%m%d')
    for k in tf_dict.keys(): # k is tf
        tfs += '\'%s\',' % (k)
        conds += '\'%s\',' % (tf_dict[k])
        if k in edge_dict and target in edge_dict[k] and (int(curr_time) - int(edge_dict[k][target]['date']) <= EDGE_AGE or edge_dict[k][target]['loglikelihood'] >= AVERAGE_LIKELIHOOD_TAU): # recent and good
            recent_edge += '%d,' % (1)
        else:
            recent_edge += '%d,' % (0)

    head += 'tfs <- c(' + tfs.rstrip(',') + ')\n'
    head += 'conditions <- c(' + conds.rstrip(',') + ')\n'
    head += 'recent.edge <- c(' + recent_edge.rstrip(',') + ')\n'    
    head += 'jsonTPM.dir <- \'%s\'\n' % (abs_jsonTPM_dir)
    head += 'AGINAME_FILE   <- \'%s\'\n' % (os.path.abspath(GENE_ID_TO_GENE_NAME))
    body = '''
	post.translation <- function(x, y) {
	  mean.x <- mean(x)
	  sd.x  <- sd(x)
	  index <- x > mean.x - sd.x & x < mean.x + sd.x
	  sd.y <- sd(y[index])
	  result <- list(value=ifelse(mean.x < 2.0, 0.0, (mean.x/max(x)) * sd.y * sum(index)/length(index)), index=which(index==T), percent=sum(index)/length(index))
	}

	post.translation.2 <- function(x, y) {
	  # x is consititutively high while y varies a lot
	  mean.x <- mean(x)
	  sd.x  <- max(sd(x), 1) # a number above 1
	  index <- x > mean.x - sd.x & x < mean.x + sd.x # points within the window +/- sd.x
	  sd.y <- quantile(y[index],0.85)-quantile(y[index],0.15) # dispersion of y within the window
	  sd.y.2 <- quantile(y,0.85)-quantile(y,0.15) # dispersion of all y
	  v.disp <- sd.y/max(1, sd.y.2) # how disperse y is within the windown, a number between 0 and 1
	  # value measure dispersion of y and percent of points within a window
	  result <- list(value=ifelse(mean.x < 2.0, 0.0, v.disp * sum(index)/length(index)), index=which(index==T), percent=sum(index)/length(index))
	}

	post.translation.3 <- function(x, y) {
	  # x is consititutively high while y varies a lot
	  mean.x <- mean(x)
	  upper.percentile <- 0.85 # used for computing vertical dispersion
	  lowest.n <- 3 # number of points with lowest x values
	  min.mean.x <- max(2.0, quantile(x, 0.25)) # mean of x must be greater than this value
	  sd.x  <- min(sd(x), 1) # a number between 0 and 1
	  index <- x > mean.x - sd.x & x < mean.x + sd.x # points within the window +/- sd.x
	  sd.y <- quantile(y[index],upper.percentile)-quantile(y[index],1-upper.percentile) # dispersion of y within the window
	  sd.y.2 <- quantile(y,upper.percentile)-quantile(y,1-upper.percentile) # dispersion of all y
	  v.disp <- sd.y/max(1, sd.y.2) # how disperse y is within the window, a number between 0 and 1
	  
	  rst <- sort(x, index.return=T)
	  top.n <- sum(rst$x < 1)
	  top.n <- max(1, min(top.n, lowest.n))
	  small.y <- min(mean(y[rst$ix[1:top.n]]), mean(y[x<1])) # use the smaller value
	  small.y <- ifelse(is.nan(small.y)==T, 999, small.y)
	  # value measure dispersion of y and percent of points within a window
	  result <- list(valid=small.y, value=ifelse(mean.x < min.mean.x, 0.0, v.disp * sum(index)/length(index)), index=which(index==T), percent=sum(index)/length(index))
	}
	
	in.component <- function(posterior, k) {
	  # posterior is an Nxk matrix, each row is a data points, and each col is prob belonging to a component
	  p = posterior[,k]
	  n = length(p)
	  index <- rep(F,n)
	  for (i in 1:n) {
	    if (p[i] > runif(1)) {
	      index[i] = T
	    }
	  }
	  result <- index
	}
			
	####### Read data #########################################
	CORR_THRESHOLD <- 0.7
	agi        <- read.table(AGINAME_FILE, sep='\\t', header=FALSE, row.names=1, stringsAsFactors=F) # AGINAME_FILE cannot contain quotes
	#######################################################
	library(mixtools)
	library(rjson)
	name2 <- agi[id2,1]
	result <- ''
	for (i in 1:length(tfs)) {
	    if (recent.edge[i] == 1) {
	        next
	    }
	    curr.date <- gsub('-','',Sys.Date())
	    id1 <- tfs[i]
	    name1 <- agi[id1,1]
	    cond <- conditions[i]

	    file.x <- paste(jsonTPM.dir, paste(id1, '.json', sep=''), sep='/')
	    if (!file.exists(file.x)) { next }
	    x <- as.data.frame(fromJSON(file = file.x))
	    x <- log(x+1)
	    rcond.x <- names(x)
	    x <- as.vector(t(x)) # convert it to a vector

	    file.y <- paste(jsonTPM.dir, paste(id2, '.json', sep=''), sep='/')
	    if (!file.exists(file.y)) { break }
	    y <- as.data.frame(fromJSON(file = file.y))
	    y <- log(y+1)
	    rcond.y <- names(y)
	    y <- as.vector(t(y)) # convert it to a vector

	    rna.sample.id <- rcond.x
	    if (all(rcond.x == rcond.y) == FALSE | id1 == id2) { # if the IDs in two json files do not match, or target is the same as tf, then ignore 
	       next
	    }

	    MIN_SIZE <- min(100, max(10, ceiling(0.5 * length(x))))

	    index <- x < 0.01 | y < 0.01 # don't include data that is too small
	    x <- x[!index]
	    y <- y[!index]

	    if (length(x) < MIN_SIZE) {
	       next
	    }
	    r <- cor(x, y)
	    if (abs(r) >= CORR_THRESHOLD) {
	        #s = sprintf('%s %s\\t%s %s\\t%4.2f\\t%s\\t%s\\t%s\\t%s\\t%s\\n', id2, name2, id1, name1, r, 'all', '.', cond, '.', curr.date)
	        #result <- paste(result, s, sep='')
	        next  # a good correlation is found using all experiments, so not necessary to look further
	    }
	
	    rna.sample.id <- rna.sample.id[!index] # this step is important to make the following index work

	    pos_r_max   <- -2
	    pos_r_N     <- 0
	    pos_r_index <- c()
	    pos_r_loglik <- -100000000
	
	    neg_r_max   <- 2
	    neg_r_N     <- 0
	    neg_r_index <- c()
	    neg_r_loglik <- -100000000

	    for (k in k.lst) {
	        em.out <- regmixEM(y, x, maxit=150, epsilon=1e-04, k=k)
	        for (j in seq(1,k,1)) {
	            index <- in.component(em.out$posterior, j)
	            size <- sum(index)
	            r <- cor(em.out$x[index,2], em.out$y[index])
	            if (!is.na(r) && r >= CORR_THRESHOLD && size >= MIN_SIZE && r > pos_r_max && size > pos_r_N) {
	                pos_r_max <- r
	                pos_r_N   <- size
	                pos_r_index <- index
	                pos_r_loglik <- em.out$loglik
	            }
	            if (!is.na(r) && r <= -CORR_THRESHOLD && size >= MIN_SIZE && r < neg_r_max && size > neg_r_N) {
	                neg_r_max <- r
	                neg_r_N   <- size
	                neg_r_index <- index
	                neg_r_loglik <- em.out$loglik
	            }
	        }
	    }
	    hit <- 0
	    if (pos_r_max > 0) { # has a good positive correlation
	        sub.cond <- paste(rna.sample.id[pos_r_index], collapse=' ')
	        s = sprintf('%s %s\\t%s %s\\t%4.2f\\t%s\\t%s\\t%s\\t%4.2f\\t%s\\n', id2, name2, id1, name1, pos_r_max, 'mix', sub.cond, cond, pos_r_loglik, curr.date)
	        result <- paste(result, s, sep='')
	        hit <- hit + 1
	    } 
	    if (neg_r_max < 0) { # has a good negative correlation
	        sub.cond <- paste(rna.sample.id[neg_r_index], collapse=' ')
	        s = sprintf('%s %s\\t%s %s\\t%4.2f\\t%s\\t%s\\t%s\\t%4.2f\\t%s\\n', id2, name2, id1, name1, neg_r_max, 'mix', sub.cond, cond, neg_r_loglik, curr.date)
	        result <- paste(result, s, sep='')
	        hit <- hit + 1
	    }
	    if (hit == 0) {
	        t <- post.translation.3(x, y)
	        post.r <- t$percent
	        if (t$valid < quantile(y,0.25) & t$value > 0.69 & post.r >= 0.70 & length(t$index) > MIN_SIZE) {
	          sub.cond <- paste(rna.sample.id[t$index], collapse=' ')
	          s = sprintf('%s %s\\t%s %s\\t%4.2f\\t%s\\t%s\\t%s\\t%s\\t%s\\n', id2, name2, id1, name1, post.r, 'mix', sub.cond, cond, '.', curr.date)
	          result <- paste(result, s, sep='')
	        }
	    }
	}
    '''
    tail = '\n'
    tail += 'output.file <- paste(\'%s/edges.txt\', id2, format(Sys.time(), \'%%b.%%d.%%Y.%%X\'), \'k%d\', sep=\'.\')\n' % (EDGE_DIR, num_component)
    tail += 'if (result != \'\') cat(result, file=output.file, sep=\'\')\n'
    f = open(fname, 'w')
    content = head + body + tail
    f.write('\n'.join([line.lstrip('\t').rstrip() for line in content.split('\n')]))
    f.close()
    return fname

def number_of_running_process(lst):
    ''' get number of running processes (with CPU usage greater than 0) '''
    count = 0
    for x in lst:
        x = x.strip()
        if x != '':
            count += 1 if x.split()[2] > '0.0' else 0 # CPU usage great than 0.0
    return count

def wait_a_moment(n, prefix):
    ''' if there are more than n work_on...R scripts running, wait... '''
    time.sleep(TIME_INTERVAL)
    ps = subprocess.Popen('ps aux | grep %s' % (prefix), shell=True, stdout=subprocess.PIPE)  # CHANGE
    num_proc = number_of_running_process(ps.communicate()[0].split('\n'))
    while (num_proc > n):
        #print('number of running processes %d' % (len(process_lst)))
        time.sleep(TIME_INTERVAL)        
        ps = subprocess.Popen('ps aux | grep %s' % (prefix), shell=True, stdout=subprocess.PIPE)
        process_lst = ps.communicate()[0].split('\n')
        num_proc = number_of_running_process(process_lst)
    
def establish_edges(jsonTPM_dir, d, d2, glb_param_dict, rprefix, edge_dict):
    ''' 
    jsonTPM_dir -- contain gene expression json files, one for each gene
    d - binding dictionary {target:{tf1:c1, tf2:c2}, ...  }, c1 c2 are strings of conditions  
    d2 - binding dictionary {tf:{target1:c1, target2:c2}, ...}, c1 c2 are strings of conditions
    '''

    gene_lst = get_ordered_gene_list(glb_param_dict['GENE_LIST']) # targets with fewer edges will get higher priority.  For example, those targets never having an edge will be treated first
    high_gene_lst = glb_param_dict['HIGH_PRIORITY_GENE'].split() # high priority genes CHANGE
    
    if not os.path.isdir(EDGE_DIR):
        os.makedirs(EDGE_DIR)

    # make a list of targets, putting high-priority target in the beginning
    final_gene_lst = high_gene_lst
    for x in gene_lst:
        if not x in high_gene_lst:
            final_gene_lst.append(x)
            
    # process each target.  First consider all TFs of the target (if any).  then consider the target's targets (if any).
    for target in final_gene_lst: # high priority genes are processed first
        if target in d: # target g is in binding dictionary d
            tf_dict = d[target] # a dictionary of upstream genes, in the form of {tf1:c1, tf2:c2}
            if target in d2:
                target_dict = d2[target] # a dictionary downstream genes, in the form of {target1:c1, target2:c2}
            else:
                target_dict = {}
                
            if len(tf_dict) > 0: # the target has TFs (upstream genes)
                r_file = '../Data/temp/%s_%s_K%d.R' % (rprefix, target, 2) # k is 2
                fname = make_r_script(r_file, target, tf_dict, jsonTPM_dir, 2, edge_dict)
                cmd = 'Rscript %s &' % (r_file) # run the Rscript in background
                os.system(cmd) # UNCOMMENT ME
                r_file = '../Data/temp/%s_%s_K%d.R' % (rprefix, target, 3) # k is 3
                fname = make_r_script(r_file, target, tf_dict, jsonTPM_dir, 3, edge_dict)
                cmd = 'Rscript %s &' % (r_file) # run the Rscript in background
                os.system(cmd) # UNCOMMENT ME
                wait_a_moment(MAX_PROCESS, rprefix) # make sure there are not too many R process running in the same time.  If too many, wait.  MAX_PROCESS sets the limit.

            if len(target_dict) > 0: # the target has targets
                count = 0
                for k in target_dict:
                    successor = k # successos is target's target
                    tf_dict2 = {target:target_dict[k]} # now target becomes TF, and its successor becomes targets
                    r_file = '../Data/temp/%s_%s_one_K%d.R' % (rprefix, successor, 2) # k is 2, one means consider one edge each time.
                    fname = make_r_script(r_file, successor, tf_dict2, jsonTPM_dir, 2, edge_dict)
                    cmd = 'Rscript %s &' % (r_file) # run the Rscript in background
                    os.system(cmd)
                    r_file = '../Data/temp/%s_%s_one_K%d.R' % (rprefix, successor, 3) # k is 3
                    fname = make_r_script(r_file, successor, tf_dict2, jsonTPM_dir, 3, edge_dict)
                    cmd = 'Rscript %s &' % (r_file) # run the Rscript in background
                    os.system(cmd)
                    count = count + 1
                    if count % MAX_PROCESS == 0:
                        wait_a_moment(MAX_PROCESS, rprefix) # make sure there are not too many R process running in the same time.  If too many, wait.  MAX_PROCESS sets the limit.
                
                
## main
param_file = sys.argv[1] # a single prameter file for building network, parameter_for_net.txt, in Data/parameter/
glb_param_dict = make_global_param_dict(param_file)
GENE_ID_TO_GENE_NAME = glb_param_dict['GENE_ID_AND_GENE_NAME']
agi2name_dict = make_gene_name_AGI_map_dict(GENE_ID_TO_GENE_NAME)# for gene names
curr_time = datetime.now().strftime('%Y%m%d_%H%M%S')

#print('Make target tf using binding.txt')
#if os.path.exists('../Data/information/target_tf.txt'):
#    cmd = 'cp ../Data/information/target_tf.txt ../Data/information/target_tf.txt.%s' % (curr_time)
#    os.system(cmd)

target_tf_fname = '../Data/information/target_tf.txt.%s' % (curr_time) 
cmd = 'python make_target_tf.py %s > %s' % (param_file, target_tf_fname)  # make target_tf.txt CHANGE better to make a temperory copy for this program
os.system(cmd)


#print('Make jsonTPM ...')  # CHANGE
cmd = 'python TPM2JSON.py %s' % (param_file) # make jsonTPM directory. The TPM values are not log-transformed.
os.system(cmd)
JSON_DIR = '../Data/history/expr/jsonTPM_%s' % (curr_time) # for each TPM.txt, there should be a unique jsonTPM directory.
cmd = 'mv ../Data/history/expr/jsonTPM %s' % (JSON_DIR)
os.system(cmd)


#JSON_DIR = '../Data/history/expr/jsonTPM_20170424_154323'
#target_tf_fname = '../Data/information/target_tf.txt.20170424_154323'
#print('Establish edges')
big_tf_dict = make_tf_dict(target_tf_fname) # key is target
big_target_dict = make_target_dict(target_tf_fname) # key is tf
rscript_prefix = 'Work' + datetime.now().strftime('%Y%m%d%H%M') # each R script's name starts with WORK followed by time
edge_dict = make_edge_dict(EDGE_FILE)
establish_edges(os.path.abspath(JSON_DIR), big_tf_dict, big_target_dict, glb_param_dict, rscript_prefix, edge_dict)