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################################################################################
#
#   MRC FGU Computational Genomics Group
#
#   $Id: script_template.py 2871 2010-03-03 10:20:44Z andreas $
#
#   Copyright (C) 2009 Andreas Heger
#
#   This program is free software; you can redistribute it and/or
#   modify it under the terms of the GNU General Public License
#   as published by the Free Software Foundation; either version 2
#   of the License, or (at your option) any later version.
#
#   This program is distributed in the hope that it will be useful,
#   but WITHOUT ANY WARRANTY; without even the implied warranty of
#   MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE.  See the
#   GNU General Public License for more details.
#
#   You should have received a copy of the GNU General Public License
#   along with this program; if not, write to the Free Software
#   Foundation, Inc., 59 Temple Place - Suite 330, Boston, MA  02111-1307, USA.
#################################################################################
'''
great - run great analysis
==========================

:Author: Andreas Heger
:Release: $Id$
:Date: |today|
:Tags: Python

Purpose
-------

This script compares one or more genomic segments of interest 
against one more other genomic annotations.

GREAT says that a segment overlaps an annotation if the midpoint
of the segment overlaps the annotation.

The GREAT analysis is done on a per-isochore basis and overall.
For the overall analysis, there is no isochore correction
as the union of all isochores is treated as a single workspace.

This script implies several counters (``--counter`` option):

binom
    binomial model (as implemented by GREAT). Returns the probability
    of a certain number of segments overlapping (mid-point overlap) 
    an annotation

hyperg
    hypergeometric model. Returns the probabibility of a certain
    number of nucleotides within segments overlapping an annotation.
    Conceptually, all genomic positions are treated independently and 
    segments are fragmented into a collection of single bases that are
    placed indepently. This is valid for point intervals such as SNPs,
    but of course ignores segment size, though it might be used as a
    guide towards the expected fold enrichment, that can be computed
    more accurately using :mod:`gat-run.py`

Usage
-----

Example::

   python gat-run.py 
      --segment-file=segments.bed.gz 
      --workspace-file=workspace.bed.gz 
      --annotation-file=annotations_architecture.bed.gz  
 
Type::

   python gat-run.py --help

for command line help.

Documentation
-------------

Code
----

'''

import os, sys, re, optparse, collections, types, glob, time
import numpy
import numpy.random

import gat
import gat.Experiment as E
import gat.IOTools as IOTools
import gat.IO as IO
import csegmentlist

import scipy.stats

GREAT_RESULT = collections.namedtuple( "GREAT",
                                       ("track",
                                        "annotation",
                                        "isochore",
                                        "counter",
                                        "observed", # nsegments_overlapping_annotations
                                        "expected",
                                        "nsegments_in_workspace",
                                        "nannotations_in_workspace",
                                        "nsegments_overlapping_annotation",
                                        "nannotations_overlapping_segments",
                                        "basecoverage_intersection",
                                        "basecoverage_segments",
                                        "basecoverage_annotation",
                                        "basecoverage_workspace",
                                        "fraction_coverage_annotation",
                                        "fold",
                                        "pvalue",
                                        "qvalue" ) )

def main( argv ):

    if not argv: argv = sys.argv

    # setup command line parser
    parser = optparse.OptionParser( version = "%prog version: $Id: script_template.py 2871 2010-03-03 10:20:44Z andreas $", 
                                    usage = globals()["__doc__"] )

    parser.add_option("-a", "--annotation-file", "--annotations", dest="annotation_files", type="string", action="append",
                      help="filename with annotations [default=%default]."  )

    parser.add_option("-s", "--segment-file", "--segments", dest="segment_files", type="string", action="append",
                      help="filename with segments. Also accepts a glob in parentheses [default=%default]."  )

    parser.add_option("-w", "--workspace-file", "--workspace", dest="workspace_files", type="string", action="append",
                      help="filename with workspace segments. Also accepts a glob in parentheses [default=%default]."  )

    parser.add_option("-i", "--isochore-file", "--isochores", dest="isochore_files", type="string", action="append",
                      help="filename with isochore segments. Also accepts a glob in parentheses [default=%default]."  )

    parser.add_option("-o", "--order", dest="output_order", type="choice",
                      choices = ( "track", "annotation", "fold", "pvalue", "qvalue" ),
                      help="order results in output by fold, track, etc. [default=%default]."  )

    parser.add_option("-q", "--qvalue-method", dest="qvalue_method", type="choice",
                      choices = ( "storey", "BH", "bonferroni", "holm", "hommel", "hochberg", "BY", "none" ),
                      help="method to perform multiple testing correction by controlling the fdr [default=%default]."  )

    parser.add_option( "--qvalue-lambda", dest="qvalue_lambda", type="float",
                      help="fdr computation: lambda [default=%default]."  )

    parser.add_option( "--qvalue-pi0-method", dest="qvalue_pi0_method", type="choice",
                       choices = ("smoother", "bootstrap" ),
                       help="fdr computation: method for estimating pi0 [default=%default]."  )
    parser.add_option( "--descriptions", dest="input_filename_descriptions", type="string", 
                       help="filename mapping annotation terms to descriptions. "
                            " if given, the output table will contain additional columns "
                            " [default=%default]" )

    parser.add_option( "--ignore-segment-tracks", dest="ignore_segment_tracks", action="store_true", 
                       help="ignore segment tracks - all segments belong to one track [default=%default]" )

    parser.add_option( "--enable-split-tracks", dest="enable_split_tracks", action="store_true", 
                       help="permit the same track to be in multiple files [default=%default]" )

    parser.add_option( "--output-bed", dest="output_bed", type="choice", action="append",
                       choices = ( "all", 
                                   "annotations", "segments", 
                                   "workspaces", "isochores",
                                   "overlap" ),
                       help="output bed files [default=%default]."  )

    parser.add_option( "--output-stats", dest="output_stats", type="choice", action="append",
                       choices = ( "all", 
                                   "annotations", "segments", 
                                   "workspaces", "isochores",
                                   "overlap" ),
                       help="output overlap summary stats [default=%default]."  )

    parser.add_option( "--restrict-workspace", dest="restrict_workspace", action="store_true", 
                       help="restrict workspace to those segments that contain both track"
                       " and annotations [default=%default]" )

    parser.add_option( "--counter", dest="counters", type="choice", action="append",
                       choices = ( "binom", "hyperg" ),
                       help="counter to use [default=%default]."  )

    parser.add_option( "--output-tables-pattern", dest="output_tables_pattern", type="string", 
                      help="output pattern for result tables. Used if there are multiple counters used [default=%default]."  )

    parser.set_defaults(
        annotation_files = [],
        segment_files = [],
        workspace_files = [],  
        sample_files = [],
        counters = [],
        output_stats = [],
        output_bed = [],
        output_tables_pattern = "%s.tsv.gz",
        output_order = "fold",
        input_filename_counts = None,
        input_filename_results = None,
        pvalue_method = "empirical",
        output_plots_pattern = None,
        output_samples_pattern = None,
        qvalue_method = "storey",
        qvalue_lambda = None,
        qvalue_pi0_method = "smoother",
        ignore_segment_tracks = False,
        input_filename_descriptions = None,
        conditional = "unconditional",
        conditional_extension = None,
        conditional_expansion = None,
        restrict_workspace = False,
        enable_split_tracks = False,
        shift_expansion = 2.0,
        shift_extension = 0,
        overlap_mode = "midpoint",
        truncate_workspace_to_annotations = False,
        )

    ## add common options (-h/--help, ...) and parse command line 
    (options, args) = E.Start( parser, argv = argv, add_output_options = True )

    tstart = time.time()

    if len(options.counters) == 0:
        options.counters.append("binom")

    ############################################
    segments, annotations, workspaces, isochores = IO.buildSegments( options )
    E.info( "intervals loaded in %i seconds" % (time.time() - tstart) )

    # filter segments by workspace
    workspace = IO.applyIsochores( segments, annotations, workspaces, options, isochores )

    ############################################
    description_header, descriptions, description_width = IO.readDescriptions( options )

    ############################################
    ############################################
    ## compute per contig

    # compute bases covered by workspace
    workspace2basecoverage, isochores = {}, []
    for contig, ww in workspace.iteritems():
        workspace2basecoverage[contig] = ww.sum()
        isochores.append( contig )
    
    # compute percentage of bases covered by annotations in workspace
    # per isochore
    annotation2basecoverage = collections.defaultdict( dict )
    for annotation, aa in annotations.iteritems():
        for isochore, a in aa.iteritems():
            # need to truncate to workspace?
            annotation2basecoverage[annotation][isochore] = a.sum()
            
    results_per_contig = collections.defaultdict( list )

    E.info( "computing counts per isochore" )
    # results per isochore 
    def emptyResult( segment, annotation, isochore, 
                     counter,
                     nsegments_in_workspace,
                     basecoverage_annotation,
                     basecoverage_workspace):
        return GREAT_RESULT._make( (
                segment, annotation, isochore, 
                counter,
                0, # observed
                0, # expected
                nsegments_in_workspace,
                0, # nannotations_in_workspace
                0, # nsegments_overlapping_annotation
                0, # nannotations_overlapping_segments
                0, # basecoverage_intersection
                0, # basecoverage_segments
                basecoverage_annotation,
                basecoverage_workspace,
                0.0,
                1.0,
                1.0,
                1.0 ))

    for isochore in isochores:    
        basecoverage_workspace = workspace2basecoverage[isochore]

        # iterate over all isochores        
        for segment, segmentdict in segments.iteritems():
            try:
                ss = segmentdict[isochore]
                # select segments overlapping workspace
                segments_in_workspace = csegmentlist.SegmentList( clone = ss )
                segments_in_workspace.intersect( workspace[isochore] )
                # number of segments in workspace
                nsegments_in_workspace = len(segments_in_workspace)
            except KeyError:
                ss = None

            basecoverage_segments = segments_in_workspace.sum()

            for annotation, annotationdict in annotations.iteritems():
                
                # if annotation != "GO:0030957": continue

                try:
                    aa = annotationdict[isochore]
                except KeyError:
                    aa = None

                # p_A: proportion of bases covered by annotation
                try:
                    basecoverage_annotation = annotation2basecoverage[annotation][isochore]
                except KeyError:
                    basecoverage_annotation = 0

                if ss == None or aa == None:
                    for counter in options.counters:
                        results_per_contig[(counter,segment,annotation)].append( emptyResult(segment, annotation,
                                                                                             isochore, 
                                                                                             counter,
                                                                                             nsegments_in_workspace,
                                                                                             basecoverage_annotation,
                                                                                             basecoverage_workspace ) )
                    continue
                
                # select segments overlapping annotation
                segments_overlapping_annotation = csegmentlist.SegmentList( clone = ss )
                segments_overlapping_annotation.intersect( annotations[annotation][isochore] )
                # number of segments in annotation
                nsegments_overlapping_annotation = ss.intersectionWithSegments( annotations[annotation][isochore],
                                                                                mode = options.overlap_mode )
                                         
                # number of nucleotides at the intersection of segments, annotation and workspace
                basecoverage_intersection = segments_overlapping_annotation.sum()

                annotations_overlapping_segments = csegmentlist.SegmentList( clone = aa )
                annotations_overlapping_segments.intersect( ss )
                nannotations_overlapping_segments = len( annotations_overlapping_segments )

                nannotations_in_workspace = len( aa )
                if nannotations_in_workspace == 0: 
                    for counter in options.counters:
                        results_per_contig[(counter,segment,annotation)].append( emptyResult(segment, 
                                                                                             annotation, 
                                                                                             isochore, 
                                                                                             counter,
                                                                                             nsegments_in_workspace,
                                                                                             basecoverage_annotation,
                                                                                             basecoverage_workspace ) )
                    continue

                fraction_coverage_annotation = basecoverage_annotation / float( basecoverage_workspace )
                fraction_hit_annotation = float(nannotations_overlapping_segments) / nannotations_in_workspace
                
                for counter in options.counters:
                    if counter.startswith( "binom" ):
                        # GREAT binomial probability over "regions"
                        # n = number of genomic regions = nannotations_in_workspace
                        # ppi = fraction of genome annotated by annotation = fraction_coverage_annotation
                        # kpi = genomic regions with annotation hit by segments = nannotations_in_segments
                        # sf = survival functions = 1 -cdf
                        # probability of observing >kpi in a sample of n where the probabily of succes is
                        # ppi.
                        pvalue = scipy.stats.binom.sf( nsegments_overlapping_annotation - 1, 
                                                       nsegments_in_workspace, 
                                                       fraction_coverage_annotation )
                        
                        expected = fraction_coverage_annotation * nsegments_in_workspace
                        observed = nsegments_overlapping_annotation 

                    elif counter.startswith( "hyperg" ):
                        
                        # hypergeometric probability over nucleotides
                        # Sampling without replacement
                        # x,M,n,M
                        # x = observed number of nucleotides in overlap of segments,annotations and workspace
                        # M = number of nucleotides in workspace
                        # n = number of nucleotides in annotations (and workspace)
                        # N = number of nucleotides in segments (and workspace)
                        # P-value of obtaining >x number of nucleotides overlapping.
                        rv = scipy.stats.hypergeom( basecoverage_workspace,
                                                    basecoverage_annotation,
                                                basecoverage_segments )
                    
                        pvalue = rv.sf( basecoverage_intersection )
                        expected = rv.mean()
                        observed = basecoverage_intersection

                    if expected != 0:
                        fold = float(observed) / expected
                    else:
                        fold = 1.0

                    r = GREAT_RESULT._make( (
                            segment, annotation, isochore,
                            counter,
                            observed,
                            expected,
                            nsegments_in_workspace,
                            nannotations_in_workspace,
                            nsegments_overlapping_annotation,
                            nannotations_overlapping_segments,
                            basecoverage_intersection,
                            basecoverage_segments,
                            basecoverage_annotation,
                            basecoverage_workspace,
                            fraction_coverage_annotation,
                            fold,
                            pvalue,
                            1.0 ))
                    # print "\t".join( map(str, r))
                    results_per_contig[ (counter,segment,annotation) ].append( r )

    E.info( "merging counts per isochore" )

    # compute sums
    results = []
    
    for niteration, pair in enumerate(results_per_contig.iteritems()):

        counter, segment, annotation = pair[0]
        data = pair[1]
            
        nsegments_in_workspace = sum( [x.nsegments_in_workspace for x in data ] )
        nsegments_overlapping_annotation = sum( [x.observed for x in data ] )
        nannotations_in_workspace = sum( [x.nannotations_in_workspace for x in data ] )
        nannotations_overlapping_segments = sum( [x.nannotations_overlapping_segments for x in data ] )

        basecoverage_intersection = sum( [x.basecoverage_intersection for x in data ] )
        basecoverage_segments = sum( [x.basecoverage_segments for x in data ] )
        basecoverage_annotation = sum( [x.basecoverage_annotation for x in data ] )
        basecoverage_workspace = sum( [x.basecoverage_workspace for x in data ] )

        fraction_coverage_annotation = basecoverage_annotation / float( basecoverage_workspace )

        if counter.startswith( "binom" ):
            pvalue = scipy.stats.binom.sf( nsegments_overlapping_annotation-1, 
                                            nsegments_in_workspace, 
                                            fraction_coverage_annotation )
            expected = fraction_coverage_annotation * nsegments_in_workspace
            observed = nsegments_overlapping_annotation 
        elif counter.startswith( "hyperg" ):
            rv = scipy.stats.hypergeom( basecoverage_workspace,
                                        basecoverage_annotation,
                                        basecoverage_segments )
            
            pvalue = rv.sf( basecoverage_intersection )
            expected = rv.mean()
            observed = basecoverage_intersection


        if expected != 0:
            fold = float(observed) / expected
        else:
            fold = 1.0

        r = GREAT_RESULT._make( (
                segment, annotation, "all",
                counter,
                observed,
                expected,
                nsegments_in_workspace,
                nannotations_in_workspace,
                nsegments_overlapping_annotation,
                nannotations_overlapping_segments,
                basecoverage_intersection,
                basecoverage_segments,
                basecoverage_annotation,
                basecoverage_workspace,
                fraction_coverage_annotation,
                fold,
                pvalue,
                1.0 ))

        results.append( r )

    IO.outputResults( results, 
                      options, 
                      GREAT_RESULT._fields, 
                      description_header, 
                      description_width,
                      descriptions )

    E.Stop()

if __name__ == "__main__":
    sys.exit( main( sys.argv) )