ldsc.py

#!/usr/bin/env python
'''
(c) 2014 Brendan Bulik-Sullivan and Hilary Finucane

LDSC is a command line tool for estimating
    1. LD Score
    2. heritability / partitioned heritability
    3. genetic covariance / correlation

'''

import ldsc_polyfun.ldscore as ld
import ldsc_polyfun.parse as ps
import ldsc_polyfun.sumstats as sumstats
import ldsc_polyfun.regressions as reg
import numpy as np
import pandas as pd
from subprocess import call
from itertools import product
import time, sys, traceback, argparse
from functools import reduce

try:
    x = pd.DataFrame({'A': [1, 2, 3]})
    x.sort_values(by='A')
except AttributeError:
    raise ImportError('LDSC requires pandas version >= 0.17.0')

__version__ = '1.0.0'
MASTHEAD = "*********************************************************************\n"
MASTHEAD += "* LD Score Regression (LDSC)\n"
MASTHEAD += "* Version {V}\n".format(V=__version__)
MASTHEAD += "* (C) 2014-2015 Brendan Bulik-Sullivan and Hilary Finucane\n"
MASTHEAD += "* Broad Institute of MIT and Harvard / MIT Department of Mathematics\n"
MASTHEAD += "* GNU General Public License v3\n"
MASTHEAD += "*********************************************************************\n"
pd.set_option('display.max_rows', 500)
pd.set_option('display.max_columns', 500)
pd.set_option('display.width', 1000)
pd.set_option('display.precision', 4)
pd.set_option('display.max_colwidth',1000)
np.set_printoptions(linewidth=1000)
np.set_printoptions(precision=4)


def sec_to_str(t):
    '''Convert seconds to days:hours:minutes:seconds'''
    [d, h, m, s, n] = reduce(lambda ll, b : divmod(ll[0], b) + ll[1:], [(t, 1), 60, 60, 24])
    f = ''
    if d > 0:
        f += '{D}d:'.format(D=d)
    if h > 0:
        f += '{H}h:'.format(H=h)
    if m > 0:
        f += '{M}m:'.format(M=m)

    f += '{S}s'.format(S=s)
    return f


def _remove_dtype(x):
    '''Removes dtype: float64 and dtype: int64 from pandas printouts'''
    x = str(x)
    x = x.replace('\ndtype: int64', '')
    x = x.replace('\ndtype: float64', '')
    return x


class Logger(object):
    '''
    Lightweight logging.
    TODO: replace with logging module

    '''
    def __init__(self, fh):
        self.log_fh = open(fh, 'w')

    def log(self, msg):
        '''
        Print to log file and stdout with a single command.

        '''
        print(msg, file=self.log_fh)
        print(msg)


def __filter__(fname, noun, verb, merge_obj):
    merged_list = None
    if fname:
        f = lambda x,n: x.format(noun=noun, verb=verb, fname=fname, num=n)
        x = ps.FilterFile(fname)
        c = 'Read list of {num} {noun} to {verb} from {fname}'
        print(f(c, len(x.IDList)))
        merged_list = merge_obj.loj(x.IDList)
        len_merged_list = len(merged_list)
        if len_merged_list > 0:
            c = 'After merging, {num} {noun} remain'
            print(f(c, len_merged_list))
        else:
            error_msg = 'No {noun} retained for analysis'
            raise ValueError(f(error_msg, 0))

        return merged_list

def annot_sort_key(s):
    '''For use with --cts-bin. Fixes weird pandas crosstab column order.'''
    if type(s) == tuple:
        s = [x.split('_')[0] for x in s]
        s = [float(x) if x != 'min' else -float('inf') for x in s]
    else:  # type(s) = str:
        s = s.split('_')[0]
        if s == 'min':
            s = float('-inf')
        else:
            s = float(s)

    return s

def ldscore(args, log):
    '''
    Wrapper function for estimating l1, l1^2, l2 and l4 (+ optionally standard errors) from
    reference panel genotypes.

    Annot format is
    chr snp bp cm <annotations>

    '''

    if args.bfile:
        snp_file, snp_obj = args.bfile+'.bim', ps.PlinkBIMFile
        ind_file, ind_obj = args.bfile+'.fam', ps.PlinkFAMFile
        array_file, array_obj = args.bfile+'.bed', ld.PlinkBEDFile

    # read bim/snp
    array_snps = snp_obj(snp_file)
    m = len(array_snps.IDList)
    log.log('Read list of {m} SNPs from {f}'.format(m=m, f=snp_file))
    if args.annot is not None:  # read --annot
        try:
            if args.thin_annot: # annot file has only annotations
                annot = ps.ThinAnnotFile(args.annot)
                n_annot, ma = len(annot.df.columns), len(annot.df)
                log.log("Read {A} annotations for {M} SNPs from {f}".format(f=args.annot,
                    A=n_annot, M=ma))
                annot_matrix = annot.df.values
                annot_colnames = annot.df.columns
                keep_snps = None
            else:
                annot = ps.AnnotFile(args.annot)
                n_annot, ma = len(annot.df.columns) - 4, len(annot.df)
                log.log("Read {A} annotations for {M} SNPs from {f}".format(f=args.annot,
                    A=n_annot, M=ma))
                annot_matrix = np.array(annot.df.iloc[:,4:])
                annot_colnames = annot.df.columns[4:]
                keep_snps = None
                if np.any(annot.df.SNP.values != array_snps.df.SNP.values):
                    raise ValueError('The .annot file must contain the same SNPs in the same'+\
                        ' order as the .bim file.')
        except Exception:
            log.log('Error parsing .annot file')
            raise

    elif args.extract is not None:  # --extract
        keep_snps = __filter__(args.extract, 'SNPs', 'include', array_snps)
        annot_matrix, annot_colnames, n_annot = None, None, 1


    elif args.cts_bin is not None and args.cts_breaks is not None:  # --cts-bin
        cts_fnames = sumstats._splitp(args.cts_bin)  # read filenames
        args.cts_breaks = args.cts_breaks.replace('N','-')  # replace N with negative sign
        try:  # split on x
            breaks = [[float(x) for x in y.split(',')] for y in args.cts_breaks.split('x')]
        except ValueError as e:
            raise ValueError('--cts-breaks must be a comma-separated list of numbers: '
                +str(e.args))

        if len(breaks) != len(cts_fnames):
            raise ValueError('Need to specify one set of breaks for each file in --cts-bin.')

        if args.cts_names:
            cts_colnames = [str(x) for x in args.cts_names.split(',')]
            if len(cts_colnames) != len(cts_fnames):
                msg = 'Must specify either no --cts-names or one value for each file in --cts-bin.'
                raise ValueError(msg)

        else:
            cts_colnames = ['ANNOT'+str(i) for i in range(len(cts_fnames))]

        log.log('Reading numbers with which to bin SNPs from {F}'.format(F=args.cts_bin))

        cts_levs = []
        full_labs = []
        for i,fh in enumerate(cts_fnames):
            vec = ps.read_cts(cts_fnames[i], array_snps.df.SNP.values)

            max_cts = np.max(vec)
            min_cts = np.min(vec)
            cut_breaks = list(breaks[i])
            name_breaks = list(cut_breaks)
            if np.all(cut_breaks >= max_cts) or np.all(cut_breaks <= min_cts):
                raise ValueError('All breaks lie outside the range of the cts variable.')

            if np.all(cut_breaks <= max_cts):
                name_breaks.append(max_cts)
                cut_breaks.append(max_cts+1)

            if np.all(cut_breaks >= min_cts):
                name_breaks.append(min_cts)
                cut_breaks.append(min_cts-1)

            name_breaks.sort()
            cut_breaks.sort()
            n_breaks = len(cut_breaks)
            # so that col names are consistent across chromosomes with different max vals
            name_breaks[0] = 'min'
            name_breaks[-1] = 'max'
            name_breaks = [str(x) for x in name_breaks]
            labs = [name_breaks[i]+'_'+name_breaks[i+1] for i in range(n_breaks-1)]
            cut_vec = pd.Series(pd.cut(vec, bins=cut_breaks, labels=labs))
            cts_levs.append(cut_vec)
            full_labs.append(labs)

        annot_matrix = pd.concat(cts_levs, axis=1)
        annot_matrix.columns = cts_colnames
        # crosstab -- for now we keep empty columns
        annot_matrix = pd.crosstab(annot_matrix.index,
            [annot_matrix[i] for i in annot_matrix.columns], dropna=False,
            colnames=annot_matrix.columns)

        # add missing columns
        if len(cts_colnames) > 1:
            for x in product(*full_labs):
                if x not in annot_matrix.columns:
                    annot_matrix[x] = 0
        else:
            for x in full_labs[0]:
                if x not in annot_matrix.columns:
                    annot_matrix[x] = 0

        annot_matrix = annot_matrix[sorted(annot_matrix.columns, key=annot_sort_key)]
        if len(cts_colnames) > 1:
            # flatten multi-index
            annot_colnames = ['_'.join([cts_colnames[i]+'_'+b for i,b in enumerate(c)])
                for c in annot_matrix.columns]
        else:
            annot_colnames = [cts_colnames[0]+'_'+b for b in annot_matrix.columns]

        annot_matrix = np.matrix(annot_matrix)
        keep_snps = None
        n_annot = len(annot_colnames)
        if np.any(np.sum(annot_matrix, axis=1) == 0):
            # This exception should never be raised. For debugging only.
            raise ValueError('Some SNPs have no annotation in --cts-bin. This is a bug!')

    else:
        annot_matrix, annot_colnames, keep_snps = None, None, None,
        n_annot = 1

    # read fam
    array_indivs = ind_obj(ind_file)
    n = len(array_indivs.IDList)
    log.log('Read list of {n} individuals from {f}'.format(n=n, f=ind_file))
    # read keep_indivs
    if args.keep:
        keep_indivs = __filter__(args.keep, 'individuals', 'include', array_indivs)
    else:
        keep_indivs = None

    # read genotype array
    log.log('Reading genotypes from {fname}'.format(fname=array_file))
    geno_array = array_obj(array_file, n, array_snps, keep_snps=keep_snps,
        keep_indivs=keep_indivs, mafMin=args.maf)

    # filter annot_matrix down to only SNPs passing MAF cutoffs
    if annot_matrix is not None:
        annot_keep = geno_array.kept_snps
        annot_matrix = annot_matrix[annot_keep,:]

    # determine block widths
    x = np.array((args.ld_wind_snps, args.ld_wind_kb, args.ld_wind_cm), dtype=bool)
    if np.sum(x) != 1:
        raise ValueError('Must specify exactly one --ld-wind option')

    if args.ld_wind_snps:
        max_dist = args.ld_wind_snps
        coords = np.array(range(geno_array.m))
    elif args.ld_wind_kb:
        max_dist = args.ld_wind_kb*1000
        coords = np.array(array_snps.df['BP'])[geno_array.kept_snps]
    elif args.ld_wind_cm:
        max_dist = args.ld_wind_cm
        coords = np.array(array_snps.df['CM'])[geno_array.kept_snps]

    block_left = ld.getBlockLefts(coords, max_dist)
    if block_left[len(block_left)-1] == 0 and not args.yes_really:
        error_msg = 'Do you really want to compute whole-chomosome LD Score? If so, set the '
        error_msg += '--yes-really flag (warning: it will use a lot of time / memory)'
        raise ValueError(error_msg)

    scale_suffix = ''
    if args.pq_exp is not None:
        log.log('Computing LD with pq ^ {S}.'.format(S=args.pq_exp))
        msg = 'Note that LD Scores with pq raised to a nonzero power are'
        msg += 'not directly comparable to normal LD Scores.'
        log.log(msg)
        scale_suffix = '_S{S}'.format(S=args.pq_exp)
        pq = np.matrix(geno_array.maf*(1-geno_array.maf)).reshape((geno_array.m, 1))
        pq = np.power(pq, args.pq_exp)

        if annot_matrix is not None:
            annot_matrix = np.multiply(annot_matrix, pq)
        else:
            annot_matrix = pq

    log.log("Estimating LD Score.")
    lN = geno_array.ldScoreVarBlocks(block_left, args.chunk_size, annot=annot_matrix)
    col_prefix = "L2"; file_suffix = "l2"

    if n_annot == 1:
        ldscore_colnames = [col_prefix+scale_suffix]
    else:
        ldscore_colnames =  [y+col_prefix+scale_suffix for y in annot_colnames]

    # print .ldscore. Output columns: CHR, BP, RS, [LD Scores]
    out_fname = args.out + '.' + file_suffix + '.ldscore'
    new_colnames = geno_array.colnames + ldscore_colnames
    df = pd.DataFrame.from_records(np.c_[geno_array.df, lN])
    df.columns = new_colnames
    if args.print_snps:
        if args.print_snps.endswith('gz'):
            print_snps = pd.read_csv(args.print_snps, header=None, compression='gzip')
        elif args.print_snps.endswith('bz2'):
            print_snps = pd.read_csv(args.print_snps, header=None, compression='bz2')
        else:
            print_snps = pd.read_csv(args.print_snps, header=None)
        if len(print_snps.columns) > 1:
            raise ValueError('--print-snps must refer to a file with a one column of SNP IDs.')
        log.log('Reading list of {N} SNPs for which to print LD Scores from {F}'.format(\
                        F=args.print_snps, N=len(print_snps)))

        print_snps.columns=['SNP']
        df = df.loc[df.SNP.isin(print_snps.SNP),:]
        if len(df) == 0:
            raise ValueError('After merging with --print-snps, no SNPs remain.')
        else:
            msg = 'After merging with --print-snps, LD Scores for {N} SNPs will be printed.'
            log.log(msg.format(N=len(df)))

    l2_suffix = '.gz'
    log.log("Writing LD Scores for {N} SNPs to {f}.gz".format(f=out_fname, N=len(df)))
    df.drop(['CM','MAF'], axis=1).to_csv(out_fname, sep="\t", header=True, index=False,
        float_format='%.3f')
    call(['gzip', '-f', out_fname])
    if annot_matrix is not None:
        M = np.atleast_1d(np.squeeze(np.asarray(np.sum(annot_matrix, axis=0))))
        ii = geno_array.maf > 0.05
        M_5_50 = np.atleast_1d(np.squeeze(np.asarray(np.sum(annot_matrix[ii,:], axis=0))))
    else:
        M = [geno_array.m]
        M_5_50 = [np.sum(geno_array.maf > 0.05)]

    # print .M
    fout_M = open(args.out + '.'+ file_suffix +'.M','w')
    print('\t'.join(map(str,M)), file=fout_M)
    fout_M.close()

    # print .M_5_50
    fout_M_5_50 = open(args.out + '.'+ file_suffix +'.M_5_50','w')
    print('\t'.join(map(str,M_5_50)), file=fout_M_5_50)
    fout_M_5_50.close()

    # print annot matrix
    if (args.cts_bin is not None) and not args.no_print_annot:
        out_fname_annot = args.out + '.annot'
        new_colnames = geno_array.colnames + ldscore_colnames
        annot_df = pd.DataFrame(np.c_[geno_array.df, annot_matrix])
        annot_df.columns = new_colnames
        del annot_df['MAF']
        log.log("Writing annot matrix produced by --cts-bin to {F}".format(F=out_fname+'.gz'))
        annot_df.to_csv(out_fname_annot, sep="\t", header=True, index=False)
        call(['gzip', '-f', out_fname_annot])

    # print LD Score summary
    pd.set_option('display.max_rows', 200)
    log.log('\nSummary of LD Scores in {F}'.format(F=out_fname+l2_suffix))
    t = df.iloc[:,4:].describe()
    log.log( t.iloc[1:,:] )

    np.seterr(divide='ignore', invalid='ignore')  # print NaN instead of weird errors
    # print correlation matrix including all LD Scores and sample MAF
    log.log('')
    log.log('MAF/LD Score Correlation Matrix')
    log.log( df.iloc[:,4:].corr() )

    # print condition number
    if n_annot > 1: # condition number of a column vector w/ nonzero var is trivially one
        log.log('\nLD Score Matrix Condition Number')
        cond_num = np.linalg.cond(df.iloc[:,5:])
        log.log( reg.remove_brackets(str(np.matrix(cond_num))) )
        if cond_num > 10000:
            log.log('WARNING: ill-conditioned LD Score Matrix!')

    # summarize annot matrix if there is one
    if annot_matrix is not None:
        # covariance matrix
        x = pd.DataFrame(annot_matrix, columns=annot_colnames)
        log.log('\nAnnotation Correlation Matrix')
        log.log( x.corr() )

        # column sums
        log.log('\nAnnotation Matrix Column Sums')
        log.log(_remove_dtype(x.sum(axis=0)))

        # row sums
        log.log('\nSummary of Annotation Matrix Row Sums')
        row_sums = x.sum(axis=1).describe()
        log.log(_remove_dtype(row_sums))

    np.seterr(divide='raise', invalid='raise')


parser = argparse.ArgumentParser()
parser.add_argument('--out', default='ldsc', type=str,
    help='Output filename prefix. If --out is not set, LDSC will use ldsc as the '
    'defualt output filename prefix.')
# Basic LD Score Estimation Flags'
parser.add_argument('--bfile', default=None, type=str,
    help='Prefix for Plink .bed/.bim/.fam file')
parser.add_argument('--l2', default=False, action='store_true',
    help='Estimate l2. Compatible with both jackknife and non-jackknife.')
# Filtering / Data Management for LD Score
parser.add_argument('--extract', default=None, type=str,
    help='File with SNPs to include in LD Score estimation. '
    'The file should contain one SNP ID per row.')
parser.add_argument('--keep', default=None, type=str,
    help='File with individuals to include in LD Score estimation. '
    'The file should contain one individual ID per row.')
parser.add_argument('--ld-wind-snps', default=None, type=int,
    help='Specify the window size to be used for estimating LD Scores in units of '
    '# of SNPs. You can only specify one --ld-wind-* option.')
parser.add_argument('--ld-wind-kb', default=None, type=float,
    help='Specify the window size to be used for estimating LD Scores in units of '
    'kilobase-pairs (kb). You can only specify one --ld-wind-* option.')
parser.add_argument('--ld-wind-cm', default=None, type=float,
    help='Specify the window size to be used for estimating LD Scores in units of '
    'centiMorgans (cM). You can only specify one --ld-wind-* option.')
parser.add_argument('--print-snps', default=None, type=str,
    help='This flag tells LDSC to only print LD Scores for the SNPs listed '
    '(one ID per row) in PRINT_SNPS. The sum r^2 will still include SNPs not in '
    'PRINT_SNPs. This is useful for reducing the number of LD Scores that have to be '
    'read into memory when estimating h2 or rg.' )
# Fancy LD Score Estimation Flags
parser.add_argument('--annot', default=None, type=str,
    help='Filename prefix for annotation file for partitioned LD Score estimation. '
    'LDSC will automatically append .annot or .annot.gz to the filename prefix. '
    'See docs/file_formats_ld for a definition of the .annot format.')
parser.add_argument('--thin-annot', action='store_true', default=False,
    help='This flag says your annot files have only annotations, with no SNP, CM, CHR, BP columns.')
parser.add_argument('--cts-bin', default=None, type=str,
    help='This flag tells LDSC to compute partitioned LD Scores, where the partition '
    'is defined by cutting one or several continuous variable[s] into bins. '
    'The argument to this flag should be the name of a single file or a comma-separated '
    'list of files. The file format is two columns, with SNP IDs in the first column '
    'and the continuous variable in the second column. ')
parser.add_argument('--cts-breaks', default=None, type=str,
    help='Use this flag to specify names for the continuous variables cut into bins '
    'with --cts-bin. For each continuous variable, specify breaks as a comma-separated '
    'list of breakpoints, and separate the breakpoints for each variable with an x. '
    'For example, if binning on MAF and distance to gene (in kb), '
    'you might set --cts-breaks 0.1,0.25,0.4x10,100,1000 ')
parser.add_argument('--cts-names', default=None, type=str,
    help='Use this flag to specify names for the continuous variables cut into bins '
    'with --cts-bin. The argument to this flag should be a comma-separated list of '
    'names. For example, if binning on DAF and distance to gene, you might set '
    '--cts-bin DAF,DIST_TO_GENE ')
parser.add_argument('--per-allele', default=False, action='store_true',
    help='Setting this flag causes LDSC to compute per-allele LD Scores, '
    'i.e., \ell_j := \sum_k p_k(1-p_k)r^2_{jk}, where p_k denotes the MAF '
    'of SNP j. ')
parser.add_argument('--pq-exp', default=None, type=float,
    help='Setting this flag causes LDSC to compute LD Scores with the given scale factor, '
    'i.e., \ell_j := \sum_k (p_k(1-p_k))^a r^2_{jk}, where p_k denotes the MAF '
    'of SNP j and a is the argument to --pq-exp. ')
parser.add_argument('--no-print-annot', default=False, action='store_true',
    help='By defualt, seting --cts-bin or --cts-bin-add causes LDSC to print '
    'the resulting annot matrix. Setting --no-print-annot tells LDSC not '
    'to print the annot matrix. ')
parser.add_argument('--maf', default=None, type=float,
    help='Minor allele frequency lower bound. Default is MAF > 0.')
# Basic Flags for Working with Variance Components
parser.add_argument('--h2', default=None, type=str,
    help='Filename for a .sumstats[.gz] file for one-phenotype LD Score regression. '
    '--h2 requires at minimum also setting the --ref-ld and --w-ld flags.')
parser.add_argument('--h2-cts', default=None, type=str,
    help='Filename for a .sumstats[.gz] file for cell-type-specific analysis. '
    '--h2-cts requires the --ref-ld-chr, --w-ld, and --ref-ld-chr-cts flags.')
parser.add_argument('--rg', default=None, type=str,
    help='Comma-separated list of prefixes of .chisq filed for genetic correlation estimation.')
parser.add_argument('--ref-ld', default=None, type=str,
    help='Use --ref-ld to tell LDSC which LD Scores to use as the predictors in the LD '
    'Score regression. '
    'LDSC will automatically append .l2.ldscore/.l2.ldscore.gz to the filename prefix.')
parser.add_argument('--ref-ld-chr', default=None, type=str,
    help='Same as --ref-ld, but will automatically concatenate .l2.ldscore files split '
    'across 22 chromosomes. LDSC will automatically append .l2.ldscore/.l2.ldscore.gz '
    'to the filename prefix. If the filename prefix contains the symbol @, LDSC will '
    'replace the @ symbol with chromosome numbers. Otherwise, LDSC will append chromosome '
    'numbers to the end of the filename prefix.'
    'Example 1: --ref-ld-chr ld/ will read ld/1.l2.ldscore.gz ... ld/22.l2.ldscore.gz'
    'Example 2: --ref-ld-chr ld/@_kg will read ld/1_kg.l2.ldscore.gz ... ld/22_kg.l2.ldscore.gz')
parser.add_argument('--w-ld', default=None, type=str,
    help='Filename prefix for file with LD Scores with sum r^2 taken over SNPs included '
    'in the regression. LDSC will automatically append .l2.ldscore/.l2.ldscore.gz.')
parser.add_argument('--w-ld-chr', default=None, type=str,
    help='Same as --w-ld, but will read files split into 22 chromosomes in the same '
    'manner as --ref-ld-chr.')
parser.add_argument('--overlap-annot', default=False, action='store_true',
    help='This flag informs LDSC that the partitioned LD Scores were generates using an '
    'annot matrix with overlapping categories (i.e., not all row sums equal 1), '
    'and prevents LDSC from displaying output that is meaningless with overlapping categories.')
parser.add_argument('--print-coefficients',default=False,action='store_true',
    help='when categories are overlapping, print coefficients as well as heritabilities.')
parser.add_argument('--frqfile', type=str,
    help='For use with --overlap-annot. Provides allele frequencies to prune to common '
    'snps if --not-M-5-50 is not set.')
parser.add_argument('--frqfile-chr', type=str,
    help='Prefix for --frqfile files split over chromosome.')
parser.add_argument('--no-intercept', action='store_true',
    help = 'If used with --h2, this constrains the LD Score regression intercept to equal '
    '1. If used with --rg, this constrains the LD Score regression intercepts for the h2 '
    'estimates to be one and the intercept for the genetic covariance estimate to be zero.')
parser.add_argument('--intercept-h2', action='store', default=None,
    help = 'Intercepts for constrained-intercept single-trait LD Score regression.')
parser.add_argument('--intercept-gencov', action='store', default=None,
    help = 'Intercepts for constrained-intercept cross-trait LD Score regression.'
    ' Must have same length as --rg. The first entry is ignored.')
parser.add_argument('--M', default=None, type=str,
    help='# of SNPs (if you don\'t want to use the .l2.M files that came with your .l2.ldscore.gz files)')
parser.add_argument('--two-step', default=None, type=float,
    help='Test statistic bound for use with the two-step estimator. Not compatible with --no-intercept and --constrain-intercept.')
parser.add_argument('--chisq-max', default=None, type=float,
    help='Max chi^2.')
parser.add_argument('--ref-ld-chr-cts', default=None, type=str,
    help='Name of a file that has a list of file name prefixes for cell-type-specific analysis.')
parser.add_argument('--print-all-cts', action='store_true', default=False)

parser.add_argument('--max-chi2', type=float, default=80, help='Remove SNPs with chi2 > this value (if it''s larger than 0.001*N)')

# Flags for both LD Score estimation and h2/gencor estimation
parser.add_argument('--print-cov', default=False, action='store_true',
    help='For use with --h2/--rg. This flag tells LDSC to print the '
    'covaraince matrix of the estimates.')
parser.add_argument('--print-delete-vals', default=False, action='store_true',
    help='If this flag is set, LDSC will print the block jackknife delete-values ('
    'i.e., the regression coefficeints estimated from the data with a block removed). '
    'The delete-values are formatted as a matrix with (# of jackknife blocks) rows and '
    '(# of LD Scores) columns.')
# Flags you should almost never use
parser.add_argument('--chunk-size', default=50, type=int,
    help='Chunk size for LD Score calculation. Use the default.')
parser.add_argument('--pickle', default=False, action='store_true',
    help='Store .l2.ldscore files as pickles instead of gzipped tab-delimited text.')
parser.add_argument('--yes-really', default=False, action='store_true',
    help='Yes, I really want to compute whole-chromosome LD Score.')
parser.add_argument('--invert-anyway', default=False, action='store_true',
    help="Force LDSC to attempt to invert ill-conditioned matrices.")
parser.add_argument('--n-blocks', default=200, type=int,
    help='Number of block jackknife blocks.')
parser.add_argument('--not-M-5-50', default=False, action='store_true',
    help='This flag tells LDSC to use the .l2.M file instead of the .l2.M_5_50 file.')
parser.add_argument('--return-silly-things', default=False, action='store_true',
    help='Force ldsc to return silly genetic correlation estimates.')
parser.add_argument('--no-check-alleles', default=False, action='store_true',
    help='For rg estimation, skip checking whether the alleles match. This check is '
    'redundant for pairs of chisq files generated using munge_sumstats.py and the '
    'same argument to the --merge-alleles flag.')
# transform to liability scale
parser.add_argument('--samp-prev',default=None,
    help='Sample prevalence of binary phenotype (for conversion to liability scale).')
parser.add_argument('--pop-prev',default=None,
    help='Population prevalence of binary phenotype (for conversion to liability scale).')
    
parser.add_argument('--keep-large', default=False, action='store_true',
    help='If this is invoked, large chi2 SNPs will not be removed from any jackknife block')
    
parser.add_argument('--skip-cond-check', default=False, action='store_true', 
    help='Skip checking the condition number of the LD scores')    
    
parser.add_argument('--evenodd-split', default=False, action='store_true', 
    help='Compute LOCO even/odd split tau estimates')


parser.add_argument('--nn', default=False, action='store_true',
    help='If this is invoked, S-LDSC will only estimate non-negative taus (this only makes sense for non-overlapping annotations)')

parser.add_argument('--nnls-exact', default=False, action='store_true',
    help='If this is invoked, S-LDSC will estimate non-negative taus using an exact instead of an approximate solver (this will be slower but slightly more accurate)')

#LOCO estimates
parser.add_argument('--loco', default=False, action='store_true', 
    help='Compute Ridge-regression-based leave-one-chromosome-out (LOCO) estimates')
    
parser.add_argument('--num-chr-sets', type=int, default=22,
    help='Number of chromosome sets for loco computations')
    
parser.add_argument('--num-chr', type=int, default=22,
    help='Number of chromosomes for the target organism (default is 22)')


parser.add_argument('--no-standardize-ridge', default=False, action='store_true', 
    help='disable Ridge standardization')    
        
#List of annotations to use
parser.add_argument('--anno', default=None, help='comma-separated list of annotations to use')

#List of annotations to use
parser.add_argument('--ridge_lambda', default=None, help='Lambda value for ridge (selected automatically if not set)')

parser.add_argument('--reestimate-lambdas', default=False, action='store_true', 
    help='If turned on, will reevaluate Ridge regression regularization parameter for each jackknife sample')
parser.add_argument('--ridge-jackknife', default=False, action='store_true', 
    help='If turned on, will perform jackknife when ridge is turned on (i.e., when using --loco)')




if __name__ == '__main__':

    args = parser.parse_args()
    if args.out is None:
        raise ValueError('--out is required.')

    log = Logger(args.out+'.log')
    try:
        defaults = vars(parser.parse_args(''))
        opts = vars(args)
        non_defaults = [x for x in opts.keys() if opts[x] != defaults[x]]
        header = MASTHEAD
        header += "Call: \n"
        header += './ldsc.py \\\n'
        options = ['--'+x.replace('_','-')+' '+str(opts[x])+' \\' for x in non_defaults]
        header += '\n'.join(options).replace('True','').replace('False','')
        header = header[0:-1]+'\n'
        log.log(header)
        log.log('Beginning analysis at {T}'.format(T=time.ctime()))
        start_time = time.time()
        if args.ridge_lambda:
            assert args.loco, '--ridge_lambda can only be used with --loco'

        if args.n_blocks <= 1:
            raise ValueError('--n-blocks must be an integer > 1.')
        if args.bfile is not None:
            if args.l2 is None:
                raise ValueError('Must specify --l2 with --bfile.')
            if args.annot is not None and args.extract is not None:
                raise ValueError('--annot and --extract are currently incompatible.')
            if args.cts_bin is not None and args.extract is not None:
                raise ValueError('--cts-bin and --extract are currently incompatible.')
            if args.annot is not None and args.cts_bin is not None:
                raise ValueError('--annot and --cts-bin are currently incompatible.')
            if (args.cts_bin is not None) != (args.cts_breaks is not None):
                raise ValueError('Must set both or neither of --cts-bin and --cts-breaks.')
            if args.per_allele and args.pq_exp is not None:
                raise ValueError('Cannot set both --per-allele and --pq-exp (--per-allele is equivalent to --pq-exp 1).')
            if args.per_allele:
                args.pq_exp = 1


            ldscore(args, log)
        # summary statistics
        elif (args.h2 or args.rg or args.h2_cts) and (args.ref_ld or args.ref_ld_chr) and (args.w_ld or args.w_ld_chr):
            if args.h2 is not None and args.rg is not None:
                raise ValueError('Cannot set both --h2 and --rg.')
            if args.ref_ld and args.ref_ld_chr:
                raise ValueError('Cannot set both --ref-ld and --ref-ld-chr.')
            if args.w_ld and args.w_ld_chr:
                raise ValueError('Cannot set both --w-ld and --w-ld-chr.')
            if (args.samp_prev is not None) != (args.pop_prev is not None):
                raise ValueError('Must set both or neither of --samp-prev and --pop-prev.')

            if not args.overlap_annot or args.not_M_5_50:
                if args.frqfile is not None or args.frqfile_chr is not None:
                    log.log('The frequency file is unnecessary and is being ignored.')
                    args.frqfile = None
                    args.frqfile_chr = None
            if args.overlap_annot and not args.not_M_5_50:
                if not ((args.frqfile and args.ref_ld) or (args.frqfile_chr and args.ref_ld_chr)):
                    raise ValueError('Must set either --frqfile and --ref-ld or --frqfile-chr and --ref-ld-chr')

            if args.rg:
                sumstats.estimate_rg(args, log)
            elif args.h2:
                sumstats.estimate_h2(args, log)
            elif args.h2_cts:
                sumstats.cell_type_specific(args, log)

            # bad flags
        else:
            print(header)
            print('Error: no analysis selected.')
            print('ldsc.py -h describes options.')
    except Exception:
        #ex_type, ex, tb = sys.exc_info()
        log.log( traceback.format_exc() )
        raise
    finally:
        log.log('Analysis finished at {T}'.format(T=time.ctime()) )
        time_elapsed = round(time.time()-start_time,2)
        log.log('Total time elapsed: {T}'.format(T=sec_to_str(time_elapsed)))