#!/usr/bin/env python

# Hamming distance analysis of SSCSs
#
# Author: Monika Heinzl, Johannes-Kepler University Linz (Austria)
# Contact: monika.heinzl@edumail.at
#
# Takes at least one TABULAR file with tags before the alignment to the SSCS and
# optionally a second TABULAR file as input. The program produces a plot which shows a histogram of Hamming distances
# separated after family sizes, a family size distribution separated after Hamming distances for all (sample_size=0)
# or a given sample of SSCSs or SSCSs, which form a DCS. In additon, the tool produces HD and FSD plots for the
# difference between the HDs of both parts of the tags and for the chimeric reads and finally a CSV file with the
# data of the plots. It is also possible to perform the HD analysis with shortened tags with given sizes as input.
# The tool can run on a certain number of processors, which can be defined by the user.

# USAGE: python hd.py --inputFile filename --inputName1 filename --sample_size int /
#        --only_DCS True --FamilySize3 True --subset_tag True --nproc int --minFS int --maxFS int
#        --nr_above_bars True/False --output_tabular outptufile_name_tabular

import argparse
import itertools
import operator
import sys
from collections import Counter, defaultdict
from functools import partial
from multiprocessing.pool import Pool
import random
import os

import matplotlib.pyplot as plt
import numpy
from matplotlib.backends.backend_pdf import PdfPages

plt.switch_backend('agg')


def plotFSDwithHD2(familySizeList1, maximumXFS, minimumXFS, originalCounts,
                   subtitle, pdf, relative=False, diff=True, rel_freq=False):
    if diff is False:
        colors = ["#e6194b", "#3cb44b", "#ffe119", "#0082c8", "#f58231", "#911eb4"]
        labels = ["HD=1", "HD=2", "HD=3", "HD=4", "HD=5-8", "HD>8"]
    else:
        colors = ["#93A6AB", "#403C14", "#731E41", "#BAB591", "#085B6F", "#E8AA35", "#726C66"]
        if relative is True:
            labels = ["d=0", "d=0.1", "d=0.2", "d=0.3", "d=0.4", "d=0.5-0.8", "d>0.8"]
        else:
            labels = ["d=0", "d=1", "d=2", "d=3", "d=4", "d=5-8", "d>8"]

    fig = plt.figure(figsize=(6, 7))
    ax = fig.add_subplot(111)
    plt.subplots_adjust(bottom=0.1)
    p1 = numpy.bincount(numpy.concatenate(familySizeList1))
    maximumY = numpy.amax(p1)

    if len(range(minimumXFS, maximumXFS)) == 0:
        range1 = range(minimumXFS - 1, minimumXFS + 2)
    else:
        range1 = range(0, maximumXFS + 2)

    if rel_freq:
        w = [numpy.zeros_like(data) + 1. / len(numpy.concatenate(familySizeList1)) for data in familySizeList1]
        counts = plt.hist(familySizeList1, label=labels, weights=w, color=colors, stacked=True,
                          rwidth=0.8, alpha=1, align="left", edgecolor="None", bins=range1)
        plt.ylabel("Relative Frequency", fontsize=14)
        plt.ylim((0, (float(maximumY) / sum(p1)) * 1.1))
    else:
        counts = plt.hist(familySizeList1, label=labels, color=colors, stacked=True,
                          rwidth=0.8, alpha=1, align="left", edgecolor="None", bins=range1)
        if len(numpy.concatenate(familySizeList1)) != 0:
            plt.ylim((0, max(numpy.bincount(numpy.concatenate(familySizeList1))) * 1.1))
        plt.ylabel("Absolute Frequency", fontsize=14)
        plt.ylim((0, maximumY * 1.2))
    plt.legend(loc='upper right', fontsize=14, frameon=True, bbox_to_anchor=(1.45, 1))
    plt.suptitle(subtitle, y=1, x=0.5, fontsize=14)
    plt.xlabel("Family size", fontsize=14)
    ticks = numpy.arange(0, maximumXFS + 1, 1)
    ticks1 = map(str, ticks)
    if maximumXFS >= 20:
        ticks1[len(ticks1) - 1] = ">=20"
    plt.xticks(numpy.array(ticks), ticks1)
    [l.set_visible(False) for (i, l) in enumerate(ax.get_xticklabels()) if i % 5 != 0]
    plt.xlim((0, maximumXFS + 1))
    legend = "\nfamily size: \nabsolute frequency: \nrelative frequency: "
    plt.text(0.15, -0.08, legend, size=12, transform=plt.gcf().transFigure)

    count = numpy.bincount(originalCounts)  # original counts
    if max(originalCounts) >= 20:
        max_count = ">= 20"
    else:
        max_count = max(originalCounts)
    legend1 = "{}\n{}\n{:.5f}".format(max_count, p1[len(p1) - 1], float(p1[len(p1) - 1]) / sum(p1))
    plt.text(0.5, -0.08, legend1, size=12, transform=plt.gcf().transFigure)
    legend3 = "singletons\n{:,}\n{:.5f}".format(int(p1[1]), float(p1[1]) / sum(p1))
    plt.text(0.7, -0.08, legend3, transform=plt.gcf().transFigure, size=12)
    plt.grid(b=True, which='major', color='#424242', linestyle=':')
    pdf.savefig(fig, bbox_inches="tight")
    plt.close("all")


def plotHDwithFSD(list1, maximumX, minimumX, subtitle, lenTags, pdf, xlabel, relative=False,
                  nr_above_bars=True, nr_unique_chimeras=0, len_sample=0, rel_freq=False):
    if relative is True:
        step = 0.1
    else:
        step = 1

    fig = plt.figure(figsize=(6, 8))
    plt.subplots_adjust(bottom=0.1)
    p1 = numpy.array([v for k, v in sorted(Counter(numpy.concatenate(list1)).iteritems())])
    maximumY = numpy.amax(p1)
    if relative is True:  # relative difference
        bin1 = numpy.arange(-1, maximumX + 0.2, 0.1)
    else:
        bin1 = maximumX + 1

    if rel_freq:
        w = [numpy.zeros_like(data) + 1. / len(numpy.concatenate(list1)) for data in list1]
        counts = plt.hist(list1, bins=bin1, edgecolor='black', linewidth=1, weights=w,
                          label=["FS=1", "FS=2", "FS=3", "FS=4", "FS=5-10", "FS>10"], rwidth=0.8,
                          color=["#808080", "#FFFFCC", "#FFBF00", "#DF0101", "#0431B4", "#86B404"],
                          stacked=True, alpha=1, align="left", range=(0, maximumX + 1))
        plt.ylim((0, (float(maximumY) / sum(p1)) * 1.2))
        plt.ylabel("Relative Frequency", fontsize=14)
        bins = counts[1]  # width of bins
        counts = numpy.array(map(float, counts[0][5]))

    else:
        counts = plt.hist(list1, bins=bin1, edgecolor='black', linewidth=1,
                          label=["FS=1", "FS=2", "FS=3", "FS=4", "FS=5-10", "FS>10"], rwidth=0.8,
                          color=["#808080", "#FFFFCC", "#FFBF00", "#DF0101", "#0431B4", "#86B404"],
                          stacked=True, alpha=1, align="left", range=(0, maximumX + 1))
        maximumY = numpy.amax(p1)
        plt.ylim((0, maximumY * 1.2))
        plt.ylabel("Absolute Frequency", fontsize=14)
        bins = counts[1]  # width of bins
        counts = numpy.array(map(int, counts[0][5]))

    plt.legend(loc='upper right', fontsize=14, frameon=True, bbox_to_anchor=(1.45, 1))
    plt.suptitle(subtitle, y=1, x=0.5, fontsize=14)
    plt.xlabel(xlabel, fontsize=14)
    plt.grid(b=True, which='major', color='#424242', linestyle=':')
    plt.xlim((minimumX - step, maximumX + step))
    # plt.axis((minimumX - step, maximumX + step, 0, numpy.amax(counts) + sum(counts) * 0.1))
    plt.xticks(numpy.arange(0, maximumX + step, step))

    if nr_above_bars:
        bin_centers = -0.4 * numpy.diff(bins) + bins[:-1]
        for x_label, label in zip(counts, bin_centers):  # labels for values
            if x_label == 0:
                continue
            else:
                if rel_freq:
                    plt.annotate("{:,}\n{:.3f}".format(int(round(x_label * len(numpy.concatenate(list1)))),
                                                       float(x_label)),
                                 xy=(label, x_label + len(numpy.concatenate(list1)) * 0.0001),
                                 xycoords="data", color="#000066", fontsize=10)
                else:
                    plt.annotate("{:,}\n{:.3f}".format(x_label, float(x_label) / sum(counts)),
                                 xy=(label, x_label + len(numpy.concatenate(list1)) * 0.01),
                                 xycoords="data", color="#000066", fontsize=10)

    if nr_unique_chimeras != 0:
        if (relative and ((counts[len(counts)-1] / nr_unique_chimeras) == 2)) or \
                (sum(counts) / nr_unique_chimeras) == 2:
            legend = "nr. of tags = {:,}\nsample size = {:,}\nnr. of data points = {:,}\nnr. of CF = {:,} ({:,})"\
                .format(lenTags, len_sample, len(numpy.concatenate(list1)), nr_unique_chimeras, nr_unique_chimeras * 2)
        else:
            legend = "nr. of tags = {:,}\nsample size = {:,}\nnr. of data points = {:,}\nnr. of CF = {:,}".format(
                lenTags, len_sample, len(numpy.concatenate(list1)), nr_unique_chimeras)
    else:
        legend = "nr. of tags = {:,}\nsample size = {:,}\nnr. of data points = {:,}".format(
            lenTags, len_sample, len(numpy.concatenate(list1)))

    plt.text(0.14, -0.07, legend, size=12, transform=plt.gcf().transFigure)
    pdf.savefig(fig, bbox_inches="tight")
    plt.close("all")
    plt.clf()


def plotHDwithDCS(list1, maximumX, minimumX, subtitle, lenTags, pdf, xlabel, relative=False,
                  nr_above_bars=True, nr_unique_chimeras=0, len_sample=0, rel_freq=False):
    step = 1
    fig = plt.figure(figsize=(6, 8))
    plt.subplots_adjust(bottom=0.1)
    p1 = numpy.array([v for k, v in sorted(Counter(numpy.concatenate(list1)).iteritems())])
    maximumY = numpy.amax(p1)
    bin1 = maximumX + 1
    if rel_freq:
        w = [numpy.zeros_like(data) + 1. / len(numpy.concatenate(list1)) for data in list1]
        counts = plt.hist(list1, bins=bin1, edgecolor='black', linewidth=1, weights=w,
                          label=["DCS", "ab", "ba"], rwidth=0.8, color=["#FF0000", "#5FB404", "#FFBF00"],
                          stacked=True, alpha=1, align="left", range=(0, maximumX + 1))
        plt.ylim((0, (float(maximumY) / sum(p1)) * 1.2))
        plt.ylabel("Relative Frequency", fontsize=14)
        bins = counts[1]  # width of bins
        counts = numpy.array(map(float, counts[0][2]))

    else:
        counts = plt.hist(list1, bins=bin1, edgecolor='black', linewidth=1,
                          label=["DCS", "ab", "ba"], rwidth=0.8, color=["#FF0000", "#5FB404", "#FFBF00"],
                          stacked=True, alpha=1, align="left", range=(0, maximumX + 1))
        plt.ylim((0, maximumY * 1.2))
        plt.ylabel("Absolute Frequency", fontsize=14)
        bins = counts[1]  # width of bins
        counts = numpy.array(map(int, counts[0][2]))

    plt.legend(loc='upper right', fontsize=14, frameon=True, bbox_to_anchor=(1.45, 1))
    plt.suptitle(subtitle, y=1, x=0.5, fontsize=14)
    plt.xlabel(xlabel, fontsize=14)
    plt.grid(b=True, which='major', color='#424242', linestyle=':')
    plt.xlim((minimumX - step, maximumX + step))
    # plt.axis((minimumX - step, maximumX + step, 0, numpy.amax(counts) + sum(counts) * 0.1))
    plt.xticks(numpy.arange(0, maximumX + step, step))

    if nr_above_bars:
        bin_centers = -0.4 * numpy.diff(bins) + bins[:-1]
        for x_label, label in zip(counts, bin_centers):  # labels for values
            if x_label == 0:
                continue
            else:
                if rel_freq:
                    plt.annotate("{:,}\n{:.3f}".format(int(round(x_label * len(numpy.concatenate(list1)))),
                                                       float(x_label)),
                                 xy=(label, x_label + len(numpy.concatenate(list1)) * 0.0001),
                                 xycoords="data", color="#000066", fontsize=10)
                else:
                    plt.annotate("{:,}\n{:.3f}".format(x_label, float(x_label) / sum(counts)),
                                 xy=(label, x_label + len(numpy.concatenate(list1)) * 0.01),
                                 xycoords="data", color="#000066", fontsize=10)

    if nr_unique_chimeras != 0:
        if (sum(counts) / nr_unique_chimeras) == 2:
            legend = "nr. of tags = {:,}\nsample size = {:,}\nnr. of data points = {:,}\nnr. of CF = {:,} ({:,})".\
                format(lenTags, len_sample, len(numpy.concatenate(list1)), nr_unique_chimeras, nr_unique_chimeras * 2)
        else:
            legend = "nr. of tags = {:,}\nsample size = {:,}\nnr. of data points = {:,}\nnr. of CF = {:,}".format(
                lenTags, len_sample, len(numpy.concatenate(list1)), nr_unique_chimeras)
    else:
        legend = "nr. of tags = {:,}\nsample size = {:,}\nnr. of data points = {:,}".format(
            lenTags, len_sample, len(numpy.concatenate(list1)))
    plt.text(0.14, -0.07, legend, size=12, transform=plt.gcf().transFigure)

    legend2 = "SSCS ab = {:,}\nSSCS ba = {:,}\nDCS = {:,}".format(len(list1[1]), len(list1[2]), len(list1[0]))
    plt.text(0.6, -0.047, legend2, size=12, transform=plt.gcf().transFigure)

    pdf.savefig(fig, bbox_inches="tight")
    plt.close("all")
    plt.clf()


def plotHDwithinSeq(sum1, sum1min, sum2, sum2min, min_value, lenTags, pdf, len_sample, rel_freq=False):
    fig = plt.figure(figsize=(6, 8))
    plt.subplots_adjust(bottom=0.1)

    ham_partial = [sum1, sum1min, sum2, sum2min, numpy.array(min_value)]  # new hd within tags
    maximumX = numpy.amax(numpy.concatenate(ham_partial))
    minimumX = numpy.amin(numpy.concatenate(ham_partial))
    maximumY = numpy.amax(numpy.array(numpy.concatenate(map(lambda x: numpy.bincount(x), ham_partial))))

    if len(range(minimumX, maximumX)) == 0:
        range1 = minimumX
    else:
        range1 = range(minimumX, maximumX + 2)

    if rel_freq:
        w = [numpy.zeros_like(data) + 1. / len(data) for data in ham_partial]
        plt.hist(ham_partial, align="left", rwidth=0.8, stacked=False, weights=w,
                 label=["HD a", "HD b'", "HD b", "HD a'", "HD a+b', a'+b"],
                 bins=range1, color=["#58ACFA", "#0404B4", "#FE642E", "#B40431", "#585858"],
                 edgecolor='black', linewidth=1)
        plt.ylabel("Relative Frequency", fontsize=14)
        # plt.ylim(-0.1, (float(maximumY) / len(numpy.concatenate(ham_partial))) * 1.2)
    else:
        plt.hist(ham_partial, align="left", rwidth=0.8, stacked=False,
                 label=["HD a", "HD b'", "HD b", "HD a'", "HD a+b', a'+b"],
                 bins=range1, color=["#58ACFA", "#0404B4", "#FE642E", "#B40431", "#585858"],
                 edgecolor='black', linewidth=1)
        plt.ylabel("Absolute Frequency", fontsize=14)

    plt.legend(loc='upper right', fontsize=14, frameon=True, bbox_to_anchor=(1.55, 1))
    plt.suptitle('Hamming distances within tags', fontsize=14)
    plt.xlabel("HD", fontsize=14)
    plt.grid(b=True, which='major', color='#424242', linestyle=':')
    plt.xlim((minimumX - 1, maximumX + 1))
    # plt.axis((minimumX - 1, maximumX + 1, 0, maximumY * 1.2))
    plt.xticks(numpy.arange(0, maximumX + 1, 1.0))
    legend = "nr. of tags = {:,}\nsample size = {:,}\nnr. of data points = {:,}".format(
        lenTags, len_sample, len(numpy.concatenate(ham_partial)))
    plt.text(0.14, -0.05, legend, size=12, transform=plt.gcf().transFigure)
    pdf.savefig(fig, bbox_inches="tight")
    plt.close("all")
    plt.clf()


def createTableFSD2(list1, diff=True):
    selfAB = numpy.concatenate(list1)
    uniqueFS = numpy.unique(selfAB)
    nr = numpy.arange(0, len(uniqueFS), 1)
    if diff is False:
        count = numpy.zeros((len(uniqueFS), 6))
    else:
        count = numpy.zeros((len(uniqueFS), 7))
    state = 1
    for i in list1:
        counts = list(Counter(i).items())
        hd = [item[0] for item in counts]
        c = [item[1] for item in counts]
        table = numpy.column_stack((hd, c))
        if len(table) == 0:
            state = state + 1
            continue
        else:
            if state == 1:
                for k, l in zip(uniqueFS, nr):
                    for j in table:
                        if j[0] == uniqueFS[l]:
                            count[l, 0] = j[1]
            if state == 2:
                for k, l in zip(uniqueFS, nr):
                    for j in table:
                        if j[0] == uniqueFS[l]:
                            count[l, 1] = j[1]
            if state == 3:
                for k, l in zip(uniqueFS, nr):
                    for j in table:
                        if j[0] == uniqueFS[l]:
                            count[l, 2] = j[1]
            if state == 4:
                for k, l in zip(uniqueFS, nr):
                    for j in table:
                        if j[0] == uniqueFS[l]:
                            count[l, 3] = j[1]
            if state == 5:
                for k, l in zip(uniqueFS, nr):
                    for j in table:
                        if j[0] == uniqueFS[l]:
                            count[l, 4] = j[1]
            if state == 6:
                for k, l in zip(uniqueFS, nr):
                    for j in table:
                        if j[0] == uniqueFS[l]:
                            count[l, 5] = j[1]
            if state == 7:
                for k, l in zip(uniqueFS, nr):
                    for j in table:
                        if j[0] == uniqueFS[l]:
                            count[l, 6] = j[1]
            state = state + 1
        sumRow = count.sum(axis=1)
        sumCol = count.sum(axis=0)
    uniqueFS = uniqueFS.astype(str)
    if uniqueFS[len(uniqueFS) - 1] == "20":
        uniqueFS[len(uniqueFS) - 1] = ">20"
    first = ["FS={}".format(i) for i in uniqueFS]
    final = numpy.column_stack((first, count, sumRow))
    return (final, sumCol)


def createFileFSD2(summary, sumCol, overallSum, output_file, name, sep, rel=False, diff=True):
    output_file.write(name)
    output_file.write("\n")
    if diff is False:
        output_file.write("{}HD=1{}HD=2{}HD=3{}HD=4{}HD=5-8{}HD>8{}sum{}\n".format(
            sep, sep, sep, sep, sep, sep, sep, sep))
    else:
        if rel is False:
            output_file.write("{}diff=0{}diff=1{}diff=2{}diff=3{}diff=4{}diff=5-8{}diff>8{}sum{}\n".format(
                sep, sep, sep, sep, sep, sep, sep, sep, sep))
        else:
            output_file.write("{}diff=0{}diff=0.1{}diff=0.2{}diff=0.3{}diff=0.4{}diff=0.5-0.8{}diff>0.8{}sum{}\n".
                              format(sep, sep, sep, sep, sep, sep, sep, sep, sep))
    for item in summary:
        for nr in item:
            if "FS" not in nr and "diff" not in nr:
                nr = nr.astype(float)
                nr = nr.astype(int)
            output_file.write("{}{}".format(nr, sep))
        output_file.write("\n")
    output_file.write("sum{}".format(sep))
    sumCol = map(int, sumCol)
    for el in sumCol:
        output_file.write("{}{}".format(el, sep))
    output_file.write("{}{}".format(overallSum.astype(int), sep))
    output_file.write("\n\n")


def createTableHD(list1, row_label):
    selfAB = numpy.concatenate(list1)
    uniqueHD = numpy.unique(selfAB)
    nr = numpy.arange(0, len(uniqueHD), 1)
    count = numpy.zeros((len(uniqueHD), 6))
    state = 1
    for i in list1:
        counts = list(Counter(i).items())
        hd = [item[0] for item in counts]
        c = [item[1] for item in counts]
        table = numpy.column_stack((hd, c))
        if len(table) == 0:
            state = state + 1
            continue
        else:
            if state == 1:
                for k, l in zip(uniqueHD, nr):
                    for j in table:
                        if j[0] == uniqueHD[l]:
                            count[l, 0] = j[1]
            if state == 2:
                for k, l in zip(uniqueHD, nr):
                    for j in table:
                        if j[0] == uniqueHD[l]:
                            count[l, 1] = j[1]
            if state == 3:
                for k, l in zip(uniqueHD, nr):
                    for j in table:
                        if j[0] == uniqueHD[l]:
                            count[l, 2] = j[1]
            if state == 4:
                for k, l in zip(uniqueHD, nr):
                    for j in table:
                        if j[0] == uniqueHD[l]:
                            count[l, 3] = j[1]
            if state == 5:
                for k, l in zip(uniqueHD, nr):
                    for j in table:
                        if j[0] == uniqueHD[l]:
                            count[l, 4] = j[1]
            if state == 6:
                for k, l in zip(uniqueHD, nr):
                    for j in table:
                        if j[0] == uniqueHD[l]:
                            count[l, 5] = j[1]
            state = state + 1
        sumRow = count.sum(axis=1)
        sumCol = count.sum(axis=0)
        first = ["{}{}".format(row_label, i) for i in uniqueHD]
        final = numpy.column_stack((first, count, sumRow))
    return (final, sumCol)


def createTableHDwithTags(list1):
    selfAB = numpy.concatenate(list1)
    uniqueHD = numpy.unique(selfAB)
    nr = numpy.arange(0, len(uniqueHD), 1)
    count = numpy.zeros((len(uniqueHD), 5))
    state = 1
    for i in list1:
        counts = list(Counter(i).items())
        hd = [item[0] for item in counts]
        c = [item[1] for item in counts]
        table = numpy.column_stack((hd, c))
        if len(table) == 0:
            state = state + 1
            continue
        else:
            if state == 1:
                for k, l in zip(uniqueHD, nr):
                    for j in table:
                        if j[0] == uniqueHD[l]:
                            count[l, 0] = j[1]
            if state == 2:
                for k, l in zip(uniqueHD, nr):
                    for j in table:
                        if j[0] == uniqueHD[l]:
                            count[l, 1] = j[1]
            if state == 3:
                for k, l in zip(uniqueHD, nr):
                    for j in table:
                        if j[0] == uniqueHD[l]:
                            count[l, 2] = j[1]
            if state == 4:
                for k, l in zip(uniqueHD, nr):
                    for j in table:
                        if j[0] == uniqueHD[l]:
                            count[l, 3] = j[1]
            if state == 5:
                for k, l in zip(uniqueHD, nr):
                    for j in table:
                        if j[0] == uniqueHD[l]:
                            count[l, 4] = j[1]
            state = state + 1
        sumRow = count.sum(axis=1)
        sumCol = count.sum(axis=0)
        first = ["HD={}".format(i) for i in uniqueHD]
        final = numpy.column_stack((first, count, sumRow))
    return (final, sumCol)


def createTableHDwithDCS(list1):
    selfAB = numpy.concatenate(list1)
    uniqueHD = numpy.unique(selfAB)
    nr = numpy.arange(0, len(uniqueHD), 1)
    count = numpy.zeros((len(uniqueHD), len(list1)))
    state = 1
    for i in list1:
        counts = list(Counter(i).items())
        hd = [item[0] for item in counts]
        c = [item[1] for item in counts]
        table = numpy.column_stack((hd, c))
        if len(table) == 0:
            state = state + 1
            continue
        else:
            if state == 1:
                for k, l in zip(uniqueHD, nr):
                    for j in table:
                        if j[0] == uniqueHD[l]:
                            count[l, 0] = j[1]
            if state == 2:
                for k, l in zip(uniqueHD, nr):
                    for j in table:
                        if j[0] == uniqueHD[l]:
                            count[l, 1] = j[1]
            if state == 3:
                for k, l in zip(uniqueHD, nr):
                    for j in table:
                        if j[0] == uniqueHD[l]:
                            count[l, 2] = j[1]
            state = state + 1
        sumRow = count.sum(axis=1)
        sumCol = count.sum(axis=0)
        first = ["HD={}".format(i) for i in uniqueHD]
        final = numpy.column_stack((first, count, sumRow))
    return (final, sumCol)


def createFileHD(summary, sumCol, overallSum, output_file, name, sep):
    output_file.write(name)
    output_file.write("\n")
    output_file.write("{}FS=1{}FS=2{}FS=3{}FS=4{}FS=5-10{}FS>10{}sum{}\n".format(
        sep, sep, sep, sep, sep, sep, sep, sep))
    for item in summary:
        for nr in item:
            if "HD" not in nr and "diff" not in nr:
                nr = nr.astype(float)
                nr = nr.astype(int)
            output_file.write("{}{}".format(nr, sep))
        output_file.write("\n")
    output_file.write("sum{}".format(sep))
    sumCol = map(int, sumCol)
    for el in sumCol:
        output_file.write("{}{}".format(el, sep))
    output_file.write("{}{}".format(overallSum.astype(int), sep))
    output_file.write("\n\n")


def createFileHDwithDCS(summary, sumCol, overallSum, output_file, name, sep):
    output_file.write(name)
    output_file.write("\n")
    output_file.write("{}DCS{}SSCS ab{}SSCS ba{}sum{}\n".format(sep, sep, sep, sep, sep))
    for item in summary:
        for nr in item:
            if "HD" not in nr:
                nr = nr.astype(float)
                nr = nr.astype(int)
            output_file.write("{}{}".format(nr, sep))
        output_file.write("\n")
    output_file.write("sum{}".format(sep))
    sumCol = map(int, sumCol)
    for el in sumCol:
        output_file.write("{}{}".format(el, sep))
    output_file.write("{}{}".format(overallSum.astype(int), sep))
    output_file.write("\n\n")


def createFileHDwithinTag(summary, sumCol, overallSum, output_file, name, sep):
    output_file.write(name)
    output_file.write("\n")
    output_file.write("{}HD DCS{}HD b'{}HD b{}HD a'{}HD a+b', a'+b{}sum{}\n".format(sep, sep, sep, sep, sep, sep, sep))
    for item in summary:
        for nr in item:
            if "HD" not in nr:
                nr = nr.astype(float)
                nr = nr.astype(int)
            output_file.write("{}{}".format(nr, sep))
        output_file.write("\n")
    output_file.write("sum{}".format(sep))
    sumCol = map(int, sumCol)
    for el in sumCol:
        output_file.write("{}{}".format(el, sep))
    output_file.write("{}{}".format(overallSum.astype(int), sep))
    output_file.write("\n\n")


def hamming(array1, array2):
    res = 99 * numpy.ones(len(array1))
    i = 0
    array2 = numpy.unique(array2)  # remove duplicate sequences to decrease running time
    for a in array1:
        dist = numpy.array([sum(itertools.imap(operator.ne, a, b)) for b in array2])  # fastest
        res[i] = numpy.amin(dist[dist > 0])  # pick min distance greater than zero
        i += 1
    return res


def hamming_difference(array1, array2, mate_b):
    array2 = numpy.unique(array2)  # remove duplicate sequences to decrease running time
    array1_half = numpy.array([i[0:(len(i)) / 2] for i in array1])  # mate1 part1
    array1_half2 = numpy.array([i[len(i) / 2:len(i)] for i in array1])  # mate1 part 2
    array2_half = numpy.array([i[0:(len(i)) / 2] for i in array2])  # mate2 part1
    array2_half2 = numpy.array([i[len(i) / 2:len(i)] for i in array2])  # mate2 part2

    # diff11 = 999 * numpy.ones(len(array2))
    # relativeDiffList = 999 * numpy.ones(len(array2))
    # ham1 = 999 * numpy.ones(len(array2))
    # ham2 = 999 * numpy.ones(len(array2))
    # min_valueList = 999 * numpy.ones(len(array2))
    # min_tagsList = 999 * numpy.ones(len(array2))
    # diff11_zeros = 999 * numpy.ones(len(array2))
    # min_tagsList_zeros = 999 * numpy.ones(len(array2))

    diff11 = []
    relativeDiffList = []
    ham1 = []
    ham2 = []
    ham1min = []
    ham2min = []
    min_valueList = []
    min_tagsList = []
    diff11_zeros = []
    min_tagsList_zeros = []
    max_tag_list = []
    i = 0  # counter, only used to see how many HDs of tags were already calculated
    if mate_b is False:  # HD calculation for all a's
        half1_mate1 = array1_half
        half2_mate1 = array1_half2
        half1_mate2 = array2_half
        half2_mate2 = array2_half2
    elif mate_b is True:  # HD calculation for all b's
        half1_mate1 = array1_half2
        half2_mate1 = array1_half
        half1_mate2 = array2_half2
        half2_mate2 = array2_half

    # half1_mate1, index_halves = numpy.unique(half1_mate1, return_index=True)
    # print(len(half1_mate1))
    # half2_mate1 = half2_mate1[index_halves]
    # array1 = array1[index_halves]

    for a, b, tag in zip(half1_mate1, half2_mate1, array1):
        # exclude identical tag from array2, to prevent comparison to itself
        sameTag = numpy.where(array2 == tag)[0]
        indexArray2 = numpy.arange(0, len(array2), 1)
        index_withoutSame = numpy.delete(indexArray2, sameTag)  # delete identical tag from the data

        # all tags without identical tag
        array2_half_withoutSame = half1_mate2[index_withoutSame]
        array2_half2_withoutSame = half2_mate2[index_withoutSame]
        array2_withoutSame = array2[index_withoutSame]  # whole tag (=not splitted into 2 halfs)
        # calculate HD of "a" in the tag to all "a's" or "b" in the tag to all "b's"
        dist = numpy.array([sum(itertools.imap(operator.ne, a, c)) for c in
                            array2_half_withoutSame])
        min_index = numpy.where(dist == dist.min())[0]  # get index of min HD
        min_value = dist.min()
        # min_value = dist[min_index]  # get minimum HDs
        # get all "b's" of the tag or all "a's" of the tag with minimum HD
        min_tag_half2 = array2_half2_withoutSame[min_index]
        min_tag_array2 = array2_withoutSame[min_index]  # get whole tag with min HD

        dist_second_half = numpy.array([sum(itertools.imap(operator.ne, b, e)) for e in
                                        min_tag_half2])  # calculate HD of "b" to all "b's" or "a" to all "a's"
        max_value = dist_second_half.max()
        max_index = numpy.where(dist_second_half == dist_second_half.max())[0]  # get index of max HD
        max_tag = min_tag_array2[max_index]

        # for d, d2 in zip(min_value, max_value):
        if mate_b is True:  # half2, corrects the variable of the HD from both halfs if it is a or b
            ham2.append(min_value)
            ham2min.append(max_value)
        else:  # half1, corrects the variable of the HD from both halfs if it is a or b
            ham1.append(min_value)
            ham1min.append(max_value)

        min_valueList.append(min_value + max_value)
        min_tagsList.append(tag)
        difference1 = abs(min_value - max_value)
        diff11.append(difference1)
        rel_difference = round(float(difference1) / (min_value + max_value), 1)
        relativeDiffList.append(rel_difference)

        # tags which have identical parts:
        if min_value == 0 or max_value == 0:
            min_tagsList_zeros.append(numpy.array(tag))
            difference1_zeros = abs(min_value - max_value)  # hd of non-identical part
            diff11_zeros.append(difference1_zeros)
            max_tag_list.append(numpy.array(max_tag))
        else:
            min_tagsList_zeros.append(None)
            diff11_zeros.append(None)
            max_tag_list.append(None)
        i += 1

    # print(i)
    # diff11 = [st for st in diff11 if st != 999]
    # ham1 = [st for st in ham1 if st != 999]
    # ham2 = [st for st in ham2 if st != 999]
    # min_valueList = [st for st in min_valueList if st != 999]
    # min_tagsList = [st for st in min_tagsList if st != 999]
    # relativeDiffList = [st for st in relativeDiffList if st != 999]
    # diff11_zeros = [st for st in diff11_zeros if st != 999]
    # min_tagsList_zeros = [st for st in min_tagsList_zeros if st != 999]
    return ([diff11, ham1, ham2, min_valueList, min_tagsList, relativeDiffList, diff11_zeros,
             min_tagsList_zeros, ham1min, ham2min, max_tag_list])


def readFileReferenceFree(file):
    with open(file, 'r') as dest_f:
        data_array = numpy.genfromtxt(dest_f, skip_header=0, delimiter='\t', comments='#', dtype='string')
        integers = numpy.array(data_array[:, 0]).astype(int)
        return(integers, data_array)


def hammingDistanceWithFS(fs, ham):
    fs = numpy.asarray(fs)
    maximum = max(ham)
    minimum = min(ham)
    ham = numpy.asarray(ham)

    singletons = numpy.where(fs == 1)[0]
    data = ham[singletons]

    hd2 = numpy.where(fs == 2)[0]
    data2 = ham[hd2]

    hd3 = numpy.where(fs == 3)[0]
    data3 = ham[hd3]

    hd4 = numpy.where(fs == 4)[0]
    data4 = ham[hd4]

    hd5 = numpy.where((fs >= 5) & (fs <= 10))[0]
    data5 = ham[hd5]

    hd6 = numpy.where(fs > 10)[0]
    data6 = ham[hd6]

    list1 = [data, data2, data3, data4, data5, data6]
    return(list1, maximum, minimum)


def familySizeDistributionWithHD(fs, ham, diff=False, rel=True):
    hammingDistances = numpy.unique(ham)
    fs = numpy.asarray(fs)
    ham = numpy.asarray(ham)
    bigFamilies2 = numpy.where(fs > 19)[0]
    if len(bigFamilies2) != 0:
        fs[bigFamilies2] = 20
    maximum = max(fs)
    minimum = min(fs)
    if diff is True:
        hd0 = numpy.where(ham == 0)[0]
        data0 = fs[hd0]

    if rel is True:
        hd1 = numpy.where(ham == 0.1)[0]
    else:
        hd1 = numpy.where(ham == 1)[0]
    data = fs[hd1]

    if rel is True:
        hd2 = numpy.where(ham == 0.2)[0]
    else:
        hd2 = numpy.where(ham == 2)[0]
    data2 = fs[hd2]

    if rel is True:
        hd3 = numpy.where(ham == 0.3)[0]
    else:
        hd3 = numpy.where(ham == 3)[0]
    data3 = fs[hd3]

    if rel is True:
        hd4 = numpy.where(ham == 0.4)[0]
    else:
        hd4 = numpy.where(ham == 4)[0]
    data4 = fs[hd4]

    if rel is True:
        hd5 = numpy.where((ham >= 0.5) & (ham <= 0.8))[0]
    else:
        hd5 = numpy.where((ham >= 5) & (ham <= 8))[0]
    data5 = fs[hd5]

    if rel is True:
        hd6 = numpy.where(ham > 0.8)[0]
    else:
        hd6 = numpy.where(ham > 8)[0]
    data6 = fs[hd6]

    if diff is True:
        list1 = [data0, data, data2, data3, data4, data5, data6]
    else:
        list1 = [data, data2, data3, data4, data5, data6]

    return(list1, hammingDistances, maximum, minimum)


def hammingDistanceWithDCS(minHD_tags_zeros, diff_zeros, data_array):
    diff_zeros = numpy.array(diff_zeros)
    maximum = numpy.amax(diff_zeros)
    minimum = numpy.amin(diff_zeros)
    minHD_tags_zeros = numpy.array(minHD_tags_zeros)

    idx = numpy.concatenate([numpy.where(data_array[:, 1] == i)[0] for i in minHD_tags_zeros])
    subset_data = data_array[idx, :]

    seq = numpy.array(subset_data[:, 1])

    # find all unique tags and get the indices for ALL tags, but only once
    u, index_unique, c = numpy.unique(numpy.array(seq), return_counts=True, return_index=True)
    DCS_tags = u[c == 2]
    rest_tags = u[c == 1]

    dcs = numpy.repeat("DCS", len(DCS_tags))
    idx_sscs = numpy.concatenate([numpy.where(subset_data[:, 1] == i)[0] for i in rest_tags])
    sscs = subset_data[idx_sscs, 2]

    all_tags = numpy.column_stack((numpy.concatenate((DCS_tags, subset_data[idx_sscs, 1])),
                                   numpy.concatenate((dcs, sscs))))
    hd_DCS = []
    ab_SSCS = []
    ba_SSCS = []

    for i in range(len(all_tags)):
        tag = all_tags[i, :]
        hd = diff_zeros[numpy.where(minHD_tags_zeros == tag[0])[0]]

        if tag[1] == "DCS":
            hd_DCS.append(hd)
        elif tag[1] == "ab":
            ab_SSCS.append(hd)
        elif tag[1] == "ba":
            ba_SSCS.append(hd)

    if len(hd_DCS) != 0:
        hd_DCS = numpy.concatenate(hd_DCS)
    if len(ab_SSCS) != 0:
        ab_SSCS = numpy.concatenate(ab_SSCS)
    if len(ba_SSCS) != 0:
        ba_SSCS = numpy.concatenate(ba_SSCS)
    list1 = [hd_DCS, ab_SSCS, ba_SSCS]  # list for plotting
    return(list1, maximum, minimum)


def make_argparser():
    parser = argparse.ArgumentParser(description='Hamming distance analysis of duplex sequencing data')
    parser.add_argument('--inputFile',
                        help='Tabular File with three columns: ab or ba, tag and family size.')
    parser.add_argument('--inputName1')
    parser.add_argument('--sample_size', default=1000, type=int,
                        help='Sample size of Hamming distance analysis.')
    parser.add_argument('--subset_tag', default=0, type=int,
                        help='The tag is shortened to the given number.')
    parser.add_argument('--nproc', default=4, type=int,
                        help='The tool runs with the given number of processors.')
    parser.add_argument('--only_DCS', action="store_false",
                        help='Only tags of the DCSs are included in the HD analysis')

    parser.add_argument('--minFS', default=1, type=int,
                        help='Only tags, which have a family size greater or equal than specified, '
                             'are included in the HD analysis')
    parser.add_argument('--maxFS', default=0, type=int,
                        help='Only tags, which have a family size smaller or equal than specified, '
                             'are included in the HD analysis')
    parser.add_argument('--nr_above_bars', action="store_true",
                        help='If False, values above bars in the histograms are removed')
    parser.add_argument('--rel_freq', action="store_false",
                        help='If True, the relative frequencies are displayed.')

    parser.add_argument('--output_tabular', default="data.tabular", type=str,
                        help='Name of the tabular file.')
    parser.add_argument('--output_pdf', default="data.pdf", type=str,
                        help='Name of the pdf file.')
    parser.add_argument('--output_chimeras_tabular', default="data.tabular", type=str,
                        help='Name of the tabular file with all chimeric tags.')

    return parser


def Hamming_Distance_Analysis(argv):
# def Hamming_Distance_Analysis(file1, name1, index_size, title_savedFile_pdf, title_savedFile_csv,
#                               output_chimeras_tabular, onlyDuplicates, minFS=1, maxFS=0, nr_above_bars=True,
#                               subset=False, nproc=12, rel_freq=False):
    parser = make_argparser()
    args = parser.parse_args(argv[1:])
    file1 = args.inputFile
    name1 = args.inputName1
    index_size = args.sample_size
    title_savedFile_pdf = args.output_pdf
    title_savedFile_csv = args.output_tabular
    output_chimeras_tabular = args.output_chimeras_tabular
    onlyDuplicates = args.only_DCS
    rel_freq = args.rel_freq
    minFS = args.minFS
    maxFS = args.maxFS
    nr_above_bars = args.nr_above_bars
    subset = args.subset_tag
    nproc = args.nproc
    sep = "\t"

    # input checks
    if index_size < 0:
        print("index_size is a negative integer.")
        exit(2)
    if nproc <= 0:
        print("nproc is smaller or equal zero")
        exit(3)
    if subset < 0:
        print("subset_tag is smaller or equal zero.")
        exit(5)

    # PLOT
    plt.rcParams['axes.facecolor'] = "E0E0E0"  # grey background color
    plt.rcParams['xtick.labelsize'] = 14
    plt.rcParams['ytick.labelsize'] = 14
    plt.rcParams['patch.edgecolor'] = "#000000"
    plt.rc('figure', figsize=(11.69, 8.27))  # A4 format
    name1 = name1.split(".tabular")[0]

    with open(title_savedFile_csv, "w") as output_file, PdfPages(title_savedFile_pdf) as pdf:
        print("dataset: ", name1)
        integers, data_array = readFileReferenceFree(file1)
        data_array = numpy.array(data_array)
        print("total nr of tags:", len(data_array))

        # filter tags out which contain any other character than ATCG
        valid_bases = ["A", "T", "G", "C"]
        tagsToDelete = []
        for idx, t in enumerate(data_array[:, 1]):
            for char in t:
                if char not in valid_bases:
                    tagsToDelete.append(idx)
                    break

        if len(tagsToDelete) != 0:  # delete tags with N in the tag from data
            print("nr of tags with any other character than A, T, C, G:", len(tagsToDelete),
                  float(len(tagsToDelete)) / len(data_array))
            index_whole_array = numpy.arange(0, len(data_array), 1)
            index_withoutN_inTag = numpy.delete(index_whole_array, tagsToDelete)
            data_array = data_array[index_withoutN_inTag, :]
            integers = integers[index_withoutN_inTag]
            print("total nr of filtered tags:", len(data_array))

        int_f = numpy.array(data_array[:, 0]).astype(int)
        data_array = data_array[numpy.where(int_f >= minFS)]
        integers = integers[integers >= minFS]

        # select family size for tags
        if maxFS > 0:
            int_f2 = numpy.array(data_array[:, 0]).astype(int)
            data_array = data_array[numpy.where(int_f2 <= maxFS)]
            integers = integers[integers <= maxFS]

        if onlyDuplicates is True:
            tags = data_array[:, 2]
            seq = data_array[:, 1]

            # find all unique tags and get the indices for ALL tags, but only once
            u, index_unique, c = numpy.unique(numpy.array(seq), return_counts=True, return_index=True)
            d = u[c == 2]

            # get family sizes, tag for duplicates
            duplTags_double = integers[numpy.in1d(seq, d)]
            duplTags = duplTags_double[0::2]  # ab of DCS
            duplTagsBA = duplTags_double[1::2]  # ba of DCS

            duplTags_tag = tags[numpy.in1d(seq, d)][0::2]  # ab
            duplTags_seq = seq[numpy.in1d(seq, d)][0::2]  # ab - tags

            if minFS > 1:
                duplTags_tag = duplTags_tag[(duplTags >= minFS) & (duplTagsBA >= minFS)]
                duplTags_seq = duplTags_seq[(duplTags >= minFS) & (duplTagsBA >= minFS)]
                duplTags = duplTags[(duplTags >= minFS) & (duplTagsBA >= minFS)]  # ab+ba with FS>=3

            data_array = numpy.column_stack((duplTags, duplTags_seq))
            data_array = numpy.column_stack((data_array, duplTags_tag))
            integers = numpy.array(data_array[:, 0]).astype(int)
            print("DCS in whole dataset", len(data_array))

        print("min FS", min(integers))
        print("max FS", max(integers))

        # HD analysis for a subset of the tag
        if subset > 0:
            tag1 = numpy.array([i[0:(len(i)) / 2] for i in data_array[:, 1]])
            tag2 = numpy.array([i[len(i) / 2:len(i)] for i in data_array[:, 1]])

            flanking_region_float = float((len(tag1[0]) - subset)) / 2
            flanking_region = int(flanking_region_float)
            if flanking_region_float % 2 == 0:
                tag1_shorten = numpy.array([i[flanking_region:len(i) - flanking_region] for i in tag1])
                tag2_shorten = numpy.array([i[flanking_region:len(i) - flanking_region] for i in tag2])
            else:
                flanking_region_rounded = int(round(flanking_region, 1))
                flanking_region_rounded_end = len(tag1[0]) - subset - flanking_region_rounded
                tag1_shorten = numpy.array(
                    [i[flanking_region:len(i) - flanking_region_rounded_end] for i in tag1])
                tag2_shorten = numpy.array(
                    [i[flanking_region:len(i) - flanking_region_rounded_end] for i in tag2])

            data_array_tag = numpy.array([i + j for i, j in zip(tag1_shorten, tag2_shorten)])
            data_array = numpy.column_stack((data_array[:, 0], data_array_tag, data_array[:, 2]))

        print("length of tag= ", len(data_array[0, 1]))
        # select sample: if no size given --> all vs. all comparison
        if index_size == 0:
            result = numpy.arange(0, len(data_array), 1)
        else:
            numpy.random.shuffle(data_array)
            unique_tags, unique_indices = numpy.unique(data_array[:, 1], return_index=True)  # get only unique tags
            result = numpy.random.choice(unique_indices, size=index_size,
                                         replace=False)  # array of random sequences of size=index.size

            # result = numpy.random.choice(len(integers), size=index_size,
            #                             replace=False)  # array of random sequences of size=index.size
            # result = numpy.where(numpy.array(random_tags) == numpy.array(data_array[:,1]))[0]

        # with open("index_result.pkl", "wb") as o:
        #     pickle.dump(result, o, pickle.HIGHEST_PROTOCOL)

        # save counts
        # with open(data_folder + "index_sampleTags1000_Barcode3_DCS.pkl", "wb") as f:
        #     pickle.dump(result, f, pickle.HIGHEST_PROTOCOL)
        # with open(data_folder + "dataArray_sampleTags1000_Barcode3_DCS.pkl", "wb") as f1:
        #     pickle.dump(data_array, f1, pickle.HIGHEST_PROTOCOL)
        #
        # with open(data_folder + "index_sampleTags100.pkl", "rb") as f:
        #     result = pickle.load(f)
        #
        # with open(data_folder + "dataArray_sampleTags100.pkl", "rb") as f1:
        #     data_array = pickle.load(f1)

        # with open(data_folder + "index_result.txt", "w") as t:
        #     for text in result:
        #         t.write("{}\n".format(text))

        # comparison random tags to whole dataset
        result1 = data_array[result, 1]  # random tags
        result2 = data_array[:, 1]  # all tags
        print("sample size= ", len(result1))

        # HD analysis of whole tag
        proc_pool = Pool(nproc)
        chunks_sample = numpy.array_split(result1, nproc)
        ham = proc_pool.map(partial(hamming, array2=result2), chunks_sample)
        proc_pool.close()
        proc_pool.join()
        ham = numpy.concatenate(ham).astype(int)
        # with open("HD_whole dataset_{}.txt".format(app_f), "w") as output_file1:
        # for h, tag in zip(ham, result1):
        #     output_file1.write("{}\t{}\n".format(tag, h))

        # # HD analysis for chimeric reads
        # result2 = data_array_whole_dataset[:,1]

        proc_pool_b = Pool(nproc)
        diff_list_a = proc_pool_b.map(partial(hamming_difference, array2=result2, mate_b=False), chunks_sample)
        diff_list_b = proc_pool_b.map(partial(hamming_difference, array2=result2, mate_b=True), chunks_sample)
        proc_pool_b.close()
        proc_pool_b.join()
        HDhalf1 = numpy.concatenate((numpy.concatenate([item[1] for item in diff_list_a]),
                                     numpy.concatenate([item_b[1] for item_b in diff_list_b]))).astype(int)
        HDhalf2 = numpy.concatenate((numpy.concatenate([item[2] for item in diff_list_a]),
                                     numpy.concatenate([item_b[2] for item_b in diff_list_b]))).astype(int)
        minHDs = numpy.concatenate((numpy.concatenate([item[3] for item in diff_list_a]),
                                    numpy.concatenate([item_b[3] for item_b in diff_list_b]))).astype(int)
        HDhalf1min = numpy.concatenate((numpy.concatenate([item[8] for item in diff_list_a]),
                                        numpy.concatenate([item_b[8] for item_b in diff_list_b]))).astype(int)
        HDhalf2min = numpy.concatenate((numpy.concatenate([item[9] for item in diff_list_a]),
                                        numpy.concatenate([item_b[9] for item_b in diff_list_b]))).astype(int)

        rel_Diff1 = numpy.concatenate([item[5] for item in diff_list_a])
        rel_Diff2 = numpy.concatenate([item[5] for item in diff_list_b])
        diff1 = numpy.concatenate([item[0] for item in diff_list_a])
        diff2 = numpy.concatenate([item[0] for item in diff_list_b])

        diff_zeros1 = numpy.concatenate([item[6] for item in diff_list_a])
        diff_zeros2 = numpy.concatenate([item[6] for item in diff_list_b])
        minHD_tags = numpy.concatenate([item[4] for item in diff_list_a])
        minHD_tags_zeros1 = numpy.concatenate([item[7] for item in diff_list_a])
        minHD_tags_zeros2 = numpy.concatenate([item[7] for item in diff_list_b])

        chimera_tags1 = sum([item[10] for item in diff_list_a], [])
        chimera_tags2 = numpy.concatenate([item[10] for item in diff_list_b])

        rel_Diff = []
        diff_zeros = []
        minHD_tags_zeros = []
        diff = []
        chimera_tags = []
        for d1, d2, rel1, rel2, zeros1, zeros2, tag1, tag2, ctag1, ctag2 in \
                zip(diff1, diff2, rel_Diff1, rel_Diff2, diff_zeros1, diff_zeros2, minHD_tags_zeros1, minHD_tags_zeros2,
                    chimera_tags1, chimera_tags2):
            rel_Diff.append(max(rel1, rel2))
            diff.append(max(d1, d2))

            if all(i is not None for i in [zeros1, zeros2]):
                diff_zeros.append(max(zeros1, zeros2))
                minHD_tags_zeros.append(str(tag1))
                tags = [ctag1, ctag2]
                chimera_tags.append(tags)
            elif zeros1 is not None and zeros2 is None:
                diff_zeros.append(zeros1)
                minHD_tags_zeros.append(str(tag1))
                chimera_tags.append(ctag1)
            elif zeros1 is None and zeros2 is not None:
                diff_zeros.append(zeros2)
                minHD_tags_zeros.append(str(tag2))
                chimera_tags.append(ctag2)

        chimera_tags_new = chimera_tags
        data_chimeraAnalysis = numpy.column_stack((minHD_tags_zeros, chimera_tags_new))
        # chimeras_dic = defaultdict(list)
        #
        # for t1, t2 in zip(minHD_tags_zeros, chimera_tags_new):
        #     if len(t2) >1 and type(t2) is not numpy.ndarray:
        #         t2 = numpy.concatenate(t2)
        #     chimeras_dic[t1].append(t2)

        checked_tags = []
        stat_maxTags = []

        with open(output_chimeras_tabular, "w") as output_file1:
            output_file1.write("chimera tag\tfamily size, read direction\tsimilar tag with HD=0\n")
            for i in range(len(data_chimeraAnalysis)):
                tag1 = data_chimeraAnalysis[i, 0]

                info_tag1 = data_array[data_array[:, 1] == tag1, :]
                fs_tag1 = ["{} {}".format(t[0], t[2]) for t in info_tag1]

                if tag1 in checked_tags:  # skip tag if already written to file
                    continue

                sample_half_a = tag1[0:(len(tag1)) / 2]
                sample_half_b = tag1[len(tag1) / 2:len(tag1)]

                max_tags = data_chimeraAnalysis[i, 1]
                if len(max_tags) > 1 and type(max_tags) is not numpy.ndarray:
                    max_tags = numpy.concatenate(max_tags)
                max_tags = numpy.unique(max_tags)
                stat_maxTags.append(len(max_tags))

                info_maxTags = [data_array[data_array[:, 1] == t, :] for t in max_tags]

                chimera_half_a = numpy.array([t[0:(len(t)) / 2] for t in max_tags])  # mate1 part1
                chimera_half_b = numpy.array([t[len(t) / 2:len(t)] for t in max_tags])  # mate1 part 2

                new_format = []
                for j in range(len(max_tags)):
                    fs_maxTags = ["{} {}".format(t[0], t[2]) for t in info_maxTags[j]]

                    if sample_half_a == chimera_half_a[j]:
                        max_tag = "*{}* {} {}".format(chimera_half_a[j], chimera_half_b[j], ", ".join(fs_maxTags))
                        new_format.append(max_tag)

                    elif sample_half_b == chimera_half_b[j]:
                        max_tag = "{} *{}* {}".format(chimera_half_a[j], chimera_half_b[j], ", ".join(fs_maxTags))
                        new_format.append(max_tag)
                    checked_tags.append(max_tags[j])

                sample_tag = "{} {}\t{}".format(sample_half_a, sample_half_b, ", ".join(fs_tag1))
                output_file1.write("{}\t{}\n".format(sample_tag, ", ".join(new_format)))

                checked_tags.append(tag1)

            output_file1.write(
                "This file contains all tags that were identified as chimeras as the first column and the "
                "corresponding tags which returned a Hamming distance of zero in either the first or the second "
                "half of the sample tag as the second column.\n"
                "The tags were separated by an empty space into their halves and the * marks the identical half.")
            output_file1.write("\n\nStatistics of nr. of tags that returned max. HD (2nd column)\n")
            output_file1.write("minimum\t{}\ttag(s)\n".format(numpy.amin(numpy.array(stat_maxTags))))
            output_file1.write("mean\t{}\ttag(s)\n".format(numpy.mean(numpy.array(stat_maxTags))))
            output_file1.write("median\t{}\ttag(s)\n".format(numpy.median(numpy.array(stat_maxTags))))
            output_file1.write("maximum\t{}\ttag(s)\n".format(numpy.amax(numpy.array(stat_maxTags))))
            output_file1.write("sum\t{}\ttag(s)\n".format(numpy.sum(numpy.array(stat_maxTags))))

        lenTags = len(data_array)
        len_sample = len(result1)

        quant = numpy.array(data_array[result, 0]).astype(int)  # family size for sample of tags
        seq = numpy.array(data_array[result, 1])  # tags of sample
        ham = numpy.asarray(ham)  # HD for sample of tags

        if onlyDuplicates is True:  # ab and ba strands of DCSs
            quant = numpy.concatenate((quant, duplTagsBA[result]))
            seq = numpy.tile(seq, 2)
            ham = numpy.tile(ham, 2)
            diff = numpy.tile(diff, 2)
            rel_Diff = numpy.tile(rel_Diff, 2)
            diff_zeros = numpy.tile(diff_zeros, 2)

        nr_chimeric_tags = len(data_chimeraAnalysis)
        print("nr of chimeras", nr_chimeric_tags)

        # prepare data for different kinds of plots
        # distribution of FSs separated after HD
        familySizeList1, hammingDistances, maximumXFS, minimumXFS = familySizeDistributionWithHD(quant, ham, rel=False)
        list1, maximumX, minimumX = hammingDistanceWithFS(quant, ham)  # histogram of HDs separated after FS

        # get FS for all tags with min HD of analysis of chimeric reads
        # there are more tags than sample size in the plot, because one tag can have multiple minimas
        if onlyDuplicates:
            seqDic = defaultdict(list)
            for s, q in zip(seq, quant):
                seqDic[s].append(q)
        else:
            seqDic = dict(zip(seq, quant))

        lst_minHD_tags = []
        for i in minHD_tags:
            lst_minHD_tags.append(seqDic.get(i))

        if onlyDuplicates:
            lst_minHD_tags = numpy.concatenate(([item[0] for item in lst_minHD_tags],
                                                [item_b[1] for item_b in lst_minHD_tags])).astype(int)
        # histogram with absolute and relative difference between HDs of both parts of the tag
        listDifference1, maximumXDifference, minimumXDifference = hammingDistanceWithFS(lst_minHD_tags, diff)
        listRelDifference1, maximumXRelDifference, minimumXRelDifference = hammingDistanceWithFS(lst_minHD_tags,
                                                                                                 rel_Diff)
        # chimeric read analysis: tags which have HD=0 in one of the halfs
        if len(minHD_tags_zeros) != 0:
            lst_minHD_tags_zeros = []
            for i in minHD_tags_zeros:
                lst_minHD_tags_zeros.append(seqDic.get(i))  # get family size for tags of chimeric reads
            if onlyDuplicates:
                lst_minHD_tags_zeros = numpy.concatenate(([item[0] for item in lst_minHD_tags_zeros],
                                                          [item_b[1] for item_b in lst_minHD_tags_zeros])).astype(int)

            # histogram with HD of non-identical half
            listDifference1_zeros, maximumXDifference_zeros, minimumXDifference_zeros = hammingDistanceWithFS(
            lst_minHD_tags_zeros, diff_zeros)

            if onlyDuplicates is False:
                listDCS_zeros, maximumXDCS_zeros, minimumXDCS_zeros = hammingDistanceWithDCS(minHD_tags_zeros,
                                                                                             diff_zeros, data_array)

        # plot Hamming Distance with Family size distribution
        plotHDwithFSD(list1=list1, maximumX=maximumX, minimumX=minimumX, pdf=pdf, rel_freq=rel_freq,
                      subtitle="Hamming distance separated by family size", lenTags=lenTags,
                      xlabel="HD", nr_above_bars=nr_above_bars, len_sample=len_sample)

        # Plot FSD with separation after
        plotFSDwithHD2(familySizeList1, maximumXFS, minimumXFS, rel_freq=rel_freq,
                       originalCounts=quant, subtitle="Family size distribution separated by Hamming distance",
                       pdf=pdf, relative=False, diff=False)

        # Plot HD within tags
        plotHDwithinSeq(HDhalf1, HDhalf1min, HDhalf2, HDhalf2min, minHDs, pdf=pdf, lenTags=lenTags,
                        rel_freq=rel_freq, len_sample=len_sample)

        # Plot difference between HD's separated after FSD
        plotHDwithFSD(listDifference1, maximumXDifference, minimumXDifference, pdf=pdf,
                      subtitle="Delta Hamming distance within tags", lenTags=lenTags, rel_freq=rel_freq,
                      xlabel="absolute delta HD", relative=False, nr_above_bars=nr_above_bars, len_sample=len_sample)

        plotHDwithFSD(listRelDifference1, maximumXRelDifference, minimumXRelDifference, pdf=pdf,
                      subtitle="Chimera Analysis: relative delta Hamming distance", lenTags=lenTags, rel_freq=rel_freq,
                      xlabel="relative delta HD", relative=True, nr_above_bars=nr_above_bars,
                      nr_unique_chimeras=nr_chimeric_tags, len_sample=len_sample)

        # plots for chimeric reads
        if len(minHD_tags_zeros) != 0:
            # HD
            plotHDwithFSD(listDifference1_zeros, maximumXDifference_zeros, minimumXDifference_zeros, pdf=pdf,
                          subtitle="Hamming distance of chimeric families (CF)", rel_freq=rel_freq,
                          lenTags=lenTags, xlabel="HD", relative=False,
                          nr_above_bars=nr_above_bars, nr_unique_chimeras=nr_chimeric_tags, len_sample=len_sample)

            if onlyDuplicates is False:
                plotHDwithDCS(listDCS_zeros, maximumXDCS_zeros, minimumXDCS_zeros, pdf=pdf,
                              subtitle="Hamming distance of chimeric families (CF)", rel_freq=rel_freq,
                              lenTags=lenTags, xlabel="HD", relative=False,
                              nr_above_bars=nr_above_bars, nr_unique_chimeras=nr_chimeric_tags, len_sample=len_sample)

        # print all data to a CSV file
        # HD
        summary, sumCol = createTableHD(list1, "HD=")
        overallSum = sum(sumCol)  # sum of columns in table

        # FSD
        summary5, sumCol5 = createTableFSD2(familySizeList1, diff=False)
        overallSum5 = sum(sumCol5)

        # HD of both parts of the tag
        summary9, sumCol9 = createTableHDwithTags([HDhalf1, HDhalf1min, HDhalf2, HDhalf2min, numpy.array(minHDs)])
        overallSum9 = sum(sumCol9)

        # HD
        # absolute difference
        summary11, sumCol11 = createTableHD(listDifference1, "diff=")
        overallSum11 = sum(sumCol11)
        # relative difference and all tags
        summary13, sumCol13 = createTableHD(listRelDifference1, "diff=")
        overallSum13 = sum(sumCol13)

        # chimeric reads
        if len(minHD_tags_zeros) != 0:
            # absolute difference and tags where at least one half has HD=0
            summary15, sumCol15 = createTableHD(listDifference1_zeros, "HD=")
            overallSum15 = sum(sumCol15)

            if onlyDuplicates is False:
                summary16, sumCol16 = createTableHDwithDCS(listDCS_zeros)
                overallSum16 = sum(sumCol16)

        output_file.write("{}\n".format(name1))
        output_file.write("nr of tags{}{:,}\nsample size{}{:,}\n\n".format(sep, lenTags, sep, len_sample))

        # HD
        createFileHD(summary, sumCol, overallSum, output_file,
                     "Hamming distance separated by family size", sep)
        # FSD
        createFileFSD2(summary5, sumCol5, overallSum5, output_file,
                       "Family size distribution separated by Hamming distance", sep,
                       diff=False)

        # output_file.write("{}{}\n".format(sep, name1))
        output_file.write("\n")
        max_fs = numpy.bincount(integers[result])
        output_file.write("max. family size in sample:{}{}\n".format(sep, max(integers[result])))
        output_file.write("absolute frequency:{}{}\n".format(sep, max_fs[len(max_fs) - 1]))
        output_file.write(
            "relative frequency:{}{}\n\n".format(sep, float(max_fs[len(max_fs) - 1]) / sum(max_fs)))

        # HD within tags
        output_file.write(
            "The Hamming distances were calculated by comparing the first halve against all halves and selected the "
            "minimum value (HD a).\nFor the second half of the tag, we compared them against all tags which resulted "
            "in the minimum HD of the previous step and selected the maximum value (HD b').\nFinally, it was possible "
            "to calculate the absolute and relative differences between the HDs (absolute and relative delta HD).\n"
            "These calculations were repeated, but starting with the second half in the first step to find all "
            "possible chimeras in the data (HD b and HD  For simplicity we used the maximum value between the delta "
            "values in the end.\nWhen only tags that can form DCS were allowed in the analysis, family sizes for the "
            "forward and reverse (ab and ba) will be included in the plots.\n")

        output_file.write("\nlength of one half of the tag{}{}\n\n".format(sep, len(data_array[0, 1]) / 2))

        createFileHDwithinTag(summary9, sumCol9, overallSum9, output_file,
                              "Hamming distance of each half in the tag", sep)
        createFileHD(summary11, sumCol11, overallSum11, output_file,
                     "Absolute delta Hamming distance within the tag", sep)

        createFileHD(summary13, sumCol13, overallSum13, output_file,
                     "Chimera analysis: relative delta Hamming distance", sep)

        if len(minHD_tags_zeros) != 0:
            output_file.write(
                "All tags were filtered: only those tags where at least one half was identical (HD=0) and therefore, "
                "had a relative delta of 1 were kept. These tags are considered as chimeric.\nSo the Hamming distances "
                "of the chimeric tags are shown.\n")
            createFileHD(summary15, sumCol15, overallSum15, output_file,
                         "Hamming distance of chimeric families separated after FS", sep)

            if onlyDuplicates is False:
                createFileHDwithDCS(summary16, sumCol16, overallSum16, output_file,
                                    "Hamming distance of chimeric families separated after DCS and single SSCS", sep)

        output_file.write("\n")


if __name__ == '__main__':
    sys.exit(Hamming_Distance_Analysis(sys.argv))