import os
import sys

import numpy as np

from GenNet_utils.hase.config import MAPPER_CHUNK_SIZE, basedir, CONVERTER_SPLIT_SIZE, PYTHON_PATH

os.environ['HASEDIR'] = basedir
if PYTHON_PATH is not None:
    for i in PYTHON_PATH: sys.path.insert(0, i)
from GenNet_utils.hase.hdgwas.tools import Timer, Checker, study_indexes, Mapper, HaseAnalyser, merge_genotype, \
    check_np, check_converter
from GenNet_utils.hase.hdgwas.converter import GenotypePLINK, GenotypeMINIMAC, GenotypeVCF
from GenNet_utils.hase.hdgwas.data import Reader, MetaParData, MetaPhenotype
from GenNet_utils.hase.hdgwas.fake import Encoder
from GenNet_utils.hase.hdgwas.hdregression import HASE, A_inverse, B4
import argparse
import gc
from GenNet_utils.hase.hdgwas.pard import partial_derivatives
from GenNet_utils.hase.hdgwas.regression import haseregression
import pandas as pd
import time
from GenNet_utils.hase.hdgwas.protocol import Protocol

__version__ = '1.1.0'

HEAD = "*********************************************************************\n"
HEAD += "* HASE: Framework for efficient high-dimensional association analyses \n"
HEAD += "* Version {V}\n".format(V=__version__)
HEAD += "* (C) 2015-2017 Gennady Roshchupkin and Hieab Adams\n"
HEAD += "* Erasmus MC, Rotterdam /  Department of Medical Informatics, Radiology and Epidemiology \n"
HEAD += "* GNU General Public License v3\n"
HEAD += "*********************************************************************\n"

if __name__ == '__main__':

    start = time.time()

    parser = argparse.ArgumentParser(description='Script to use HASE in command line')

    # MAIN SETTINGS
    parser.add_argument("-thr", type=float,
                        help="predefined threshold for t-value, if not defined save everything")

    parser.add_argument("-o", "--out", type=str, required=True, help="path to save result folder")

    parser.add_argument("-mode", required=True, type=str,
                        choices=['regression', 'converting', 'single-meta', 'meta-stage', 'encoding'],
                        help='Main argument, specify type of analysis'
                             '*****************'
                             'converting - before start to use any kind of analysis you need to convert data, it could take some time, '
                             'you need to do it ones and then everything will be super fast'
                             '*****************'
                             'single-meta - if you are the part of meta-analysis and will send data to main center, use this mode'
                             '*****************'
                             'encoding - if you are doing HD association, before send data to main center create fake data'
                             '*****************'
                             'meta-stage - if you are the main center of meta-analysis and already got precomputed data from all sites, use it'
                             '*****************'
                             'regression - if you want run everything yourself and do not use precomputed data use it'

                             'If you want to run single site full association analysis run (1) single-meta mode and then (2) meta-stage'

                             '*****************'
                        )

    parser.add_argument("-g", "--genotype", nargs='+', type=str, help="path/paths to genotype data folder")
    parser.add_argument("-ph", "--phenotype", nargs='+', type=str, help="path to phenotype data folder")
    parser.add_argument("-cov", "--covariates", type=str, help="path to covariates data folder")

    parser.add_argument("-derivatives", nargs='+', type=str, help="path to derivatives data folder")

    parser.add_argument("-protocol", type=str, help="path to study protocol file")

    parser.add_argument('-study_name', type=str, required=True, nargs='+',
                        help=' Name for saved genotype data, without ext')

    parser.add_argument('-mapper', type=str, help='Mapper data folder')

    parser.add_argument('-ref_name', type=str, default='1000Gp1v3_ref', help='Reference panel name')

    # ADDITIONAL SETTINGS
    parser.add_argument("-snp_id_inc", type=str, help="path to file with SNPs id to include to analysis")
    parser.add_argument("-snp_id_exc", type=str, help="path to file with SNPs id to exclude from analysis")
    parser.add_argument("-ph_id_inc", type=str, help="path to file with phenotype id to exclude from analysis")
    parser.add_argument("-ph_id_exc", type=str, help="path to file with phenotype id to exclude from analysis")

    # parser.add_argument("-ind_id_inc", type=str, help="path to file with individuals id to include to analysis") #TODO (low)
    # parser.add_argument("-ind_id_exc", type=str, help="path to file with individuals id to exclude from analysis")#TODO (low)
    # parser.add_argument("-cov_name_inc", type=str, help="path to file with covariates names to include to analysis")#TODO (low)
    # parser.add_argument("-cov_name_exc", type=str, help="path to file with covariates names to exclude from analysis")#TODO (low)

    parser.add_argument('-intercept', type=str, default='y', choices=['y', 'n'],
                        help='include intercept to regression, default yes')

    parser.add_argument('-maf', type=float, default=0.0, help='MAF for genetics data')

    parser.add_argument('-encoded', nargs='+', type=int, help='Value per every study, 1 - if encoded, 0 - if not')
    ###

    # FLAGS
    parser.add_argument('-hdf5', action='store_true', default=True, help='flag for genotype data format')
    parser.add_argument('-id', action='store_true', default=False,
                        help='Flag to convert minimac data to genotype per subject files first (default False)')
    parser.add_argument('-pd_full', action='store_true', default=False, help='For not HD association study')
    parser.add_argument('-effect_intercept', action='store_true', default=False,
                        help='Flag for add study effect to PD regression model')
    parser.add_argument('-permute_ph', action='store_true', default=False, help='Flag for phenotype permutation')
    parser.add_argument('-vcf', action='store_true', default=False, help='Flag for VCF data to convert')
    parser.add_argument('-np', action='store_true', default=True, help='Check BLAS/LAPACK/MKL')

    # TODO (low) save genotype after MAF
    ###

    ###CLUSTER SETTING
    parser.add_argument('-cluster', type=str, default='n', choices=['y', 'n'],
                        help=' Is it parallel cluster job, default no')
    parser.add_argument('-node', nargs='+', type=int, help='number of nodes / this node number, example: 10 2 ')
    ###

    # ADVANCED SETTINGS
    parser.add_argument('-interaction', type=str,
                        help='path to file with data for genotype interaction test')  # TODO (low)
    parser.add_argument('-mapper_chunk', type=int, help='Change mapper chunk size from config file')
    ###
    args = parser.parse_args()
    if not args.thr:
        print('WARNING!!! You did not set threshold for t-value, all results will be saved')
    if args.mapper_chunk:
        MAPPER_CHUNK_SIZE = args.mapper_chunk
    ARG_CHECKER = Checker()
    print(args)
    os.environ['HASEOUT'] = args.out

    if args.cluster == 'y':
        if args.node is not None:
            if args.node[1] > args.node[0]:
                raise ValueError('Node # {} > {} total number of nodes'.format(args.node[1], args.node[0]))

    if not os.path.isdir(args.out):
        print("Creating output folder {}".format(args.out))
        os.mkdir(args.out)

    if args.np:
        check_np()

    ################################### CONVERTING ##############################
    if args.mode == 'converting':

        # ARG_CHECKER.check(args,mode='converting')

        R = Reader('genotype')
        R.start(args.genotype[0], vcf=args.vcf)

        with Timer() as t:
            if R.format == 'PLINK':
                G = GenotypePLINK(args.study_name[0], reader=R)
                G.split_size = CONVERTER_SPLIT_SIZE
                G.plink2hdf5(out=args.out)

            elif R.format == 'MINIMAC':
                G = GenotypeMINIMAC(args.study_name[0], reader=R)
                if args.cluster == 'y':
                    G.cluster = True
                G.split_size = CONVERTER_SPLIT_SIZE
                G.MACH2hdf5(args.out, id=args.id)

            elif R.format == 'VCF':
                G = GenotypeVCF(args.study_name[0], reader=R)
                if args.cluster == 'y':
                    G.cluster = True
                G.split_size = CONVERTER_SPLIT_SIZE
                G.VCF2hdf5(args.out)
            else:
                raise ValueError('Genotype data should be in PLINK/MINIMAC/VCF format and alone in folder')

        check_converter(args.out, args.study_name[0])
        print(('Time to convert all data: {} sec'.format(t.secs)))

    ################################### ENCODING ##############################

    elif args.mode == 'encoding':

        # ARG_CHECKER.check(args,mode='encoding')
        mapper = Mapper()
        mapper.genotype_names = args.study_name
        mapper.chunk_size = MAPPER_CHUNK_SIZE
        mapper.reference_name = args.ref_name
        mapper.load_flip(args.mapper)
        mapper.load(args.mapper)

        phen = Reader('phenotype')
        phen.start(args.phenotype[0])

        gen = Reader('genotype')
        gen.start(args.genotype[0], hdf5=args.hdf5, study_name=args.study_name[0], ID=False)

        e = Encoder(args.out)
        e.study_name = args.study_name[0]

        row_index, ids = study_indexes(phenotype=phen.folder._data, genotype=gen.folder._data)
        with Timer() as t:

            e.matrix(len(ids), save=True)
            N_snps_read = 0
            while True:
                with Timer() as t_gen:
                    genotype = gen.get_next()
                    if isinstance(genotype, type(None)):
                        break

                    flip = mapper.flip[args.study_name[0]][N_snps_read:N_snps_read + genotype.shape[0]]
                    N_snps_read += genotype.shape[0]
                    flip_index = (flip == -1)
                    genotype = np.apply_along_axis(lambda x: flip * (x - 2 * flip_index), 0, genotype)
                    genotype = genotype[:, row_index[0]]
                    encode_genotype = e.encode(genotype, data_type='genotype')
                    e.save_hdf5(encode_genotype, os.path.join(args.out, 'encode_genotype'), info=gen.folder,
                                index=row_index[0])
                    encode_genotype = None
                    gc.collect()

                print(('Time to create fake genotype is {}sec'.format(t_gen.secs)))

            while True:
                with Timer() as t_phen:
                    phenotype = phen.get_next(index=row_index[1])
                    if isinstance(phenotype, type(None)):
                        break
                    encode_phenotype = e.encode(phenotype, data_type='phenotype')
                    if phen.folder.format == '.npy':
                        e.save_npy(encode_phenotype, save_path=os.path.join(args.out, 'encode_phenotype'),
                                   info=phen.folder, index=row_index[1])
                    if phen.folder.format in ['.csv', '.txt']:
                        e.save_csv(encode_phenotype, save_path=os.path.join(args.out, 'encode_phenotype'),
                                   info=phen.folder, index=row_index[1])
                    encode_phenotype = None
                    gc.collect()
            if phen.folder.format == '.npy':
                np.save(os.path.join(os.path.join(args.out, 'encode_phenotype', 'info_dic.npy')), e.phen_info_dic)
            print(('Time to create fake phenotype is {}sec'.format(t_phen.secs)))

        print(('Time to encode all data: {} sec'.format(t.secs)))

    ################################### SINGLE META STAGE ##############################

    elif args.mode == 'single-meta':

        # ARG_CHECKER.check(args,mode='single-meta')
        mapper = Mapper()
        mapper.genotype_names = args.study_name
        mapper.chunk_size = MAPPER_CHUNK_SIZE
        mapper.reference_name = args.ref_name
        mapper.load_flip(args.mapper)
        mapper.load(args.mapper)
        mapper.cluster = args.cluster
        mapper.node = args.node

        phen = Reader('phenotype')
        phen.start(args.phenotype[0])

        cov = Reader('covariates')
        cov.start(args.covariates)

        if cov.folder.n_files > 1:
            raise ValueError('In covariates folder should be only one file!')

        gen = Reader('genotype')
        gen.start(args.genotype[0], hdf5=args.hdf5, study_name=args.study_name[0], ID=False)

        with Timer() as t:
            partial_derivatives(save_path=args.out, COV=cov, PHEN=phen, GEN=gen,
                                MAP=mapper, MAF=args.maf, R2=None, B4_flag=args.pd_full,
                                study_name=args.study_name[0], intercept=args.intercept)
        print(('Time to compute partial derivatives : {} sec'.format(t.secs)))

    ################################### MULTI META STAGE ##############################

    elif args.mode == 'meta-stage':

        # ARG_CHECKER.check(args,mode='meta-stage')

        ##### Init data readers #####
        if args.derivatives is None:
            raise ValueError('For meta-stage analysis partial derivatives data are required!')
        mapper = Mapper()
        mapper.chunk_size = MAPPER_CHUNK_SIZE
        mapper.genotype_names = args.study_name
        mapper.reference_name = args.ref_name
        if args.snp_id_inc is not None:
            mapper.include = pd.DataFrame.from_csv(args.snp_id_inc, index_col=None)
            print('Include:')
            print(mapper.include.head())
            if 'ID' not in mapper.include.columns and (
                    'CHR' not in mapper.include.columns or 'bp' not in mapper.include.columns):
                raise ValueError('{} table does not have ID or CHR,bp columns'.format(args.snp_id_inc))
        if args.snp_id_exc is not None:
            mapper.exclude = pd.DataFrame.from_csv(args.snp_id_exc, index_col=None)
            print('Exclude:')
            print(mapper.exclude.head())
            if 'ID' not in mapper.exclude.columns and (
                    'CHR' not in mapper.exclude.columns or 'bp' not in mapper.exclude.columns):
                raise ValueError('{} table does not have ID or CHR,bp columns'.format(args.snp_id_exc))
        mapper.load(args.mapper)
        mapper.load_flip(args.mapper, encode=args.encoded)
        mapper.cluster = args.cluster
        mapper.node = args.node

        Analyser = HaseAnalyser()

        pard = []

        with Timer() as t:
            for i, j in enumerate(args.derivatives):
                pard.append(Reader('partial'))
                pard[i].start(j, study_name=args.study_name[i])
                pard[i].folder.load()

        print("time to set PD is {}s".format(t.secs))

        PD = [False if isinstance(i.folder._data.b4, type(None)) else True for i in pard]

        if np.sum(PD) != len(pard) and np.sum(PD) != 0:
            raise ValueError('All study should have b4 data for partial derivatives!')

        if args.protocol is not None:
            protocol = Protocol(args.protocol)
        else:
            protocol = None

        meta_pard = MetaParData(pard, args.study_name, protocol=protocol)

        if np.sum(PD) == 0:
            phen = []

            with Timer() as t:
                for i, j in enumerate(args.phenotype):
                    phen.append(Reader('phenotype'))
                    phen[i].start(j)
            print("Time to set pheno {} s".format(t.secs))
            meta_phen = MetaPhenotype(phen, include=args.ph_id_inc, exclude=args.ph_id_exc)

            N_studies = len(args.genotype)

            gen = []
            with Timer() as t:
                for i, j in enumerate(args.genotype):
                    gen.append(Reader('genotype'))
                    gen[i].start(j, hdf5=args.hdf5, study_name=args.study_name[i], ID=False)
            print("Time to set gen {}s".format(t.secs))

            row_index, ids = study_indexes(phenotype=tuple(i.folder._data for i in phen),
                                           genotype=tuple(i.folder._data for i in gen),
                                           covariates=tuple(i.folder._data.metadata for i in pard))
            if row_index[2].shape[0] != np.sum([i.folder._data.metadata['id'].shape[0] for i in pard]):
                raise ValueError(
                    'Partial Derivatives covariates have different number of subjects {} than genotype and phenotype {}'.format(
                        row_index[2].shape[0],
                        np.sum([i.folder._data.metadata['id'].shape[0] for i in pard])))
        while True:
            if mapper.cluster == 'n':
                SNPs_index, keys = mapper.get()
            else:
                ch = mapper.chunk_pop()
                if ch is None:
                    SNPs_index = None
                    break
                SNPs_index, keys = mapper.get(chunk_number=ch)

            if isinstance(SNPs_index, type(None)):
                break

            Analyser.rsid = keys
            if np.sum(PD) == 0:
                genotype = np.array([])
                with Timer() as t_g:
                    genotype = merge_genotype(gen, SNPs_index, mapper)
                    genotype = genotype[:, row_index[0]]
                print("Time to get G {}s".format(t_g.secs))
            # TODO (low) add interaction

            a_test = np.array([])
            b_cov = np.array([])
            C = np.array([])
            a_cov = np.array([])
            b4 = np.array([])

            if args.protocol is not None:
                if protocol.enable:
                    regression_model = protocol.regression_model()
            else:
                regression_model = None

            with Timer() as t_pd:
                if np.sum(PD) == 0:
                    a_test, b_cov, C, a_cov = meta_pard.get(SNPs_index=SNPs_index, regression_model=regression_model,
                                                            random_effect_intercept=args.effect_intercept)
                else:
                    a_test, b_cov, C, a_cov, b4 = meta_pard.get(SNPs_index=SNPs_index, B4=True,
                                                                regression_model=regression_model,
                                                                random_effect_intercept=args.effect_intercept)

            print("Time to get PD {}s".format(t_pd.secs))

            MAF = meta_pard.maf_pard(SNPs_index=SNPs_index)

            if args.maf != 0:
                filter = (MAF > args.maf) & (MAF < 1 - args.maf) & (MAF != 0.5)
                a_test = a_test[filter, :]
                Analyser.MAF = MAF[filter]
                if np.sum(PD) == 0:
                    genotype = genotype[filter, :]
                else:
                    b4 = b4[filter, :]
                Analyser.rsid = Analyser.rsid[filter]
                if a_test.shape[0] == 0:
                    print('NO SNPs > MAF')
                    continue
            else:
                Analyser.MAF = MAF

            a_inv = A_inverse(a_cov, a_test)
            N_con = a_inv.shape[1] - 1
            print('There are {} subjects in study.'.format(meta_pard.get_n_id()))
            DF = (meta_pard.get_n_id() - a_inv.shape[1])

            if np.sum(PD) == 0:

                while True:
                    phenotype = np.array([])
                    with Timer() as t_ph:
                        phenotype, phen_names = meta_phen.get()
                    print("Time to get PH {}s".format(t_ph.secs))

                    if isinstance(phenotype, type(None)):
                        meta_phen.processed = 0
                        print('All phenotypes processed!')
                        break
                    print(("Merged phenotype shape {}".format(phenotype.shape)))
                    # TODO (middle) select phen from protocol
                    phenotype = phenotype[row_index[1], :]
                    print(("Selected phenotype shape {}".format(phenotype.shape)))
                    keys = list(meta_pard.phen_mapper.dic.keys())
                    phen_ind_dic = {k: i for i, k in enumerate(keys)}
                    phen_ind = np.array([phen_ind_dic.get(i, -1) for i in phen_names])
                    if np.sum(phen_ind == -1) == len(phen_ind):
                        print('There is no common ids in phenotype files and PD data!')
                        break
                    else:
                        print('There are {} common ids in phenotype files and PD data!'.format(np.sum(phen_ind != -1)))
                    C_test = C[phen_ind]
                    b_cov_test = b_cov[:, phen_ind]

                    b4 = B4(phenotype, genotype)
                    print(("B4 shape is {}".format(b4.shape)))
                    t_stat, SE = HASE(b4, a_inv, b_cov_test, C_test, N_con, DF)

                    if mapper.cluster == 'y':
                        Analyser.cluster = True
                        Analyser.chunk = ch
                        Analyser.node = mapper.node[1]
                    Analyser.t_stat = t_stat
                    Analyser.SE = SE
                    Analyser.threshold = args.thr
                    Analyser.out = args.out
                    Analyser.save_result(phen_names[(phen_ind != -1)])

                    t_stat = None
                    Analyser.t_stat = None
                    gc.collect()

            else:
                t_stat, SE = HASE(b4, a_inv, b_cov, C, N_con, DF)

                Analyser.t_stat = t_stat
                Analyser.SE = SE
                Analyser.threshold = args.thr
                Analyser.out = args.out
                Analyser.save_result(np.array(list(meta_pard.phen_mapper.dic.keys())))

                t_stat = None
                Analyser.t_stat = None
                gc.collect()



    ################################### TO DO EVERYTHING IN ONE GO ##############################

    elif args.mode == 'regression':

        # ARG_CHECKER.check(args,mode='regression')

        print('START regression mode...')
        if args.mapper is None:
            os.environ['MAPPER'] = "False"  # need to set it here, before genotype Reader start

        phen = Reader('phenotype')
        phen.start(args.phenotype[0])
        phen.permutation = args.permute_ph

        cov = Reader('covariates')
        cov.start(args.covariates)

        interaction = None
        if args.interaction is not None:
            interaction = Reader('interaction')
            interaction.start(args.interaction)

        if (cov.folder.n_files > 1 and cov.folder.format != '.npy') or (
                cov.folder.n_files > 2 and cov.folder.format == '.npy'):  # TODO (middle) test
            raise ValueError('In covariates folder should be only one file!')

        gen = []
        for i, j in enumerate(args.genotype):
            gen.append(Reader('genotype'))
            gen[i].start(j, hdf5=args.hdf5, study_name=args.study_name[i], ID=False)

        if args.mapper is not None:
            mapper = Mapper()
            mapper.chunk_size = MAPPER_CHUNK_SIZE
            mapper.genotype_names = args.study_name
            mapper.reference_name = args.ref_name
            if args.snp_id_inc is not None:
                mapper.include = pd.DataFrame.from_csv(args.snp_id_inc, index_col=None)
                print('Include:')
                print(mapper.include.head())
                if 'ID' not in mapper.include.columns and (
                        'CHR' not in mapper.include.columns or 'bp' not in mapper.include.columns):
                    raise ValueError('{} table does not have ID or CHR,bp columns'.format(args.snp_id_inc))
            if args.snp_id_exc is not None:
                mapper.exclude = pd.DataFrame.from_csv(args.snp_id_exc, index_col=None)
                print('Exclude:')
                print(mapper.exclude.head())
                if 'ID' not in mapper.exclude.columns and (
                        'CHR' not in mapper.exclude.columns or 'bp' not in mapper.exclude.columns):
                    raise ValueError('{} table does not have ID or CHR,bp columns'.format(args.snp_id_exc))
            mapper.load(args.mapper)
            mapper.load_flip(args.mapper)
            mapper.cluster = args.cluster
            mapper.node = args.node
        else:
            if len(args.genotype) == 1:
                mapper = Mapper()
                mapper.chunk_size = MAPPER_CHUNK_SIZE
                mapper.genotype_names = args.study_name
                mapper.reference_name = args.ref_name
                mapper.cluster = args.cluster
                mapper.node = args.node
                mapper.n_study = 1
                mapper.n_keys = gen[0].folder._data.names.shape[0]
                mapper.keys = np.array(gen[0].folder._data.names.tolist())
                mapper.values = np.array(list(range(mapper.n_keys))).reshape(-1, 1)
                mapper.flip[args.study_name[0]] = np.array([1] * mapper.n_keys)
                if args.snp_id_exc is not None or args.snp_id_inc is not None:
                    raise ValueError('You can not exclude or include variants to analysis without mapper!')
            else:
                raise ValueError('You can not run regression analysis with several genotype data without mapper!')
        # mapper=None

        Analyser = HaseAnalyser()
        Analyser.threshold = args.thr
        Analyser.out = args.out
        haseregression(phen, gen, cov, mapper, Analyser, args.maf, intercept=args.intercept, interaction=interaction)

end = time.time()

print(('experiment finished in {} s'.format((end - start))))
