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/*
vcflib C++ library for parsing and manipulating VCF files
Copyright © 2010-2020 Erik Garrison
Copyright © 2020 Pjotr Prins
This software is published under the MIT License. See the LICENSE file.
Note this file is obsolete, see 1b5f1b4be67226501357ec788e8cd37c0f0a9faa
*/
#include "Variant.h"
#include "split.h"
#include "convert.h"
#include <string>
#include <iostream>
#include <set>
#include <sys/time.h>
#include <fsom/fsom.h>
#include <getopt.h>
#include <cmath>
using namespace std;
using namespace vcflib;
double mean(const vector<double>& data) {
double total = 0;
for (vector<double>::const_iterator i = data.begin(); i != data.end(); ++i) {
total += *i;
}
return total/data.size();
}
double median(vector <double>& data) {
double median;
size_t size = data.size();
// ascending order
sort(data.begin(), data.end());
// get middle value
if (size % 2 == 0) {
median = (data[size/2-1] + data[size/2]) / 2;
} else {
median = data[size/2];
}
return median;
}
double variance(const vector <double>& data, const double mean) {
double total = 0;
for (vector <double>::const_iterator i = data.begin(); i != data.end(); ++i) {
total += (*i - mean)*(*i - mean);
}
return total / (data.size());
}
double standard_deviation(const vector <double>& data, const double mean) {
return sqrt(variance(data, mean));
}
struct Stats {
double mean;
double stdev;
Stats(void) : mean(0), stdev(1) { }
};
bool load_som_metadata(string& som_metadata_file, int& x, int& y, vector<string>& fields, map<string, Stats>& stats) {
ifstream in(som_metadata_file.c_str());
if (!in.is_open()) {
return false;
}
string linebuf;
getline(in, linebuf);
vector<string> xy = split(linebuf, "\t ");
convert(xy.front(), x);
convert(xy.back(), y);
while (getline(in, linebuf)) {
// format is: field_name, mean, stdev
vector<string> m = split(linebuf, "\t ");
fields.push_back(m[0]);
Stats& s = stats[m[0]];
convert(m[1], s.mean);
convert(m[2], s.stdev);
}
in.close();
return true;
}
bool save_som_metadata(string& som_metadata_file, int x, int y, vector<string>& fields, map<string, Stats>& stats) {
ofstream out(som_metadata_file.c_str());
if (!out.is_open()) {
return false;
}
out << x << "\t" << y << endl;
for (vector<string>::iterator f = fields.begin(); f != fields.end(); ++f) {
Stats& s = stats[*f];
out << *f << "\t" << s.mean << "\t" << s.stdev << endl;
}
out.close();
return true;
}
void normalize_inputs(vector<double>& record, vector<string>& fields, map<string, Stats>& stats) {
vector<double>::iterator r = record.begin();
for (vector<string>::iterator f = fields.begin(); f != fields.end(); ++f, ++r) {
Stats& s = stats[*f];
*r = (*r - s.mean) / s.stdev;
}
}
void read_fields(Variant& var, int ai, vector<string>& fields, vector<double>& record) {
double td;
vector<string>::iterator j = fields.begin();
for (; j != fields.end(); ++j) {
if (*j == "QUAL") { // special handling...
td = var.quality;
} else {
if (var.info.find(*j) == var.info.end()) {
td = 0;
} else {
if (var.vcf->infoCounts[*j] == 1) { // for non Allele-variant fields
convert(var.info[*j][0], td);
} else {
convert(var.info[*j][ai], td);
}
}
}
record.push_back(td);
}
}
struct SomPaint {
int true_count;
int false_count;
double prob_true;
SomPaint(void) : true_count(0), false_count(0), prob_true(0) { }
};
static unsigned long prev_uticks = 0;
static unsigned long get_uticks(){
struct timeval ts;
gettimeofday(&ts,0);
return ((ts.tv_sec * 1000000) + ts.tv_usec);
}
static void start_timer(){
prev_uticks = get_uticks();
}
static void print_timing( const char *msg ){
#define MS_DELTA (1000.0)
#define SS_DELTA (MS_DELTA * 1000.0)
#define MM_DELTA (SS_DELTA * 60.0)
#define HH_DELTA (MM_DELTA * 60.0)
double ticks = get_uticks() - prev_uticks;
if( ticks < MS_DELTA ){
fprintf(stderr, "%s\t : %lf us\n", msg, ticks );
}
else if( ticks < SS_DELTA ){
fprintf(stderr, "%s\t : %lf ms\n", msg, ticks / MS_DELTA );
}
else if( ticks < MM_DELTA ){
fprintf(stderr, "%s\t : %lf s\n", msg, ticks / SS_DELTA );
}
else if( ticks < HH_DELTA ){
fprintf(stderr, "%s\t : %lf m\n", msg, ticks / MM_DELTA );
}
else{
fprintf(stderr, "%s\t : %lf h\n", msg, ticks / HH_DELTA );
}
start_timer();
}
void printSummary(char** argv) {
cerr << "usage: " << argv[0] << " [options] [vcf file]" << endl
<< endl
<< "training: " << endl
<< " " << argv[0] << " -s output.som -x 20 -y 20 -f \"AF DP ABP\" training.vcf" << endl
<< endl
<< "application: " << endl
<< " " << argv[0] << " -a output.som test.vcf >results.vcf" << endl
<< endl
<< argv[0] << "trains and/or applies a self-organizing map to the input VCF data" << endl
<< "on stdin, adding two columns for the x and y coordinates of the winning" << endl
<< "neuron in the network and an optional euclidean distance from a given" << endl
<< "node (--center)." << endl
<< endl
<< "If a map is provided via --apply, it will be applied to input without" << endl
<< "training. A .meta file describing network parameters and input parameter" << endl
<< "distributions is used to automatically setup the network." << endl
<< endl
<< "options:" << endl
<< endl
<< " -h, --help this dialog" << endl
<< endl
<< "training:" << endl
<< endl
<< " -f, --fields \"FIELD ...\" INFO fields to provide to the SOM" << endl
<< " -a, --apply FILE apply the saved map to input data to FILE" << endl
<< " -s, --save FILE train on input data and save the map to FILE" << endl
<< " -p, --print-training-results" << endl
<< " print results of SOM on training input" << endl
<< " (you can also just use --apply on the same input)" << endl
<< " -x, --width X width in columns of the output array" << endl
<< " -y, --height Y height in columns of the output array" << endl
<< " -i, --iterations N number of training iterations or epochs" << endl
<< " -d, --debug print timing information" << endl
<< endl
<< "recalibration:" << endl
<< endl
<< " -c, --center X,Y annotate with euclidean distance from center" << endl
<< " -T, --paint-true VCF use VCF file to annotate true variants (multiple)" << endl
<< " -F, --paint-false VCF use VCF file to annotate false variants (multiple)" << endl
<< " -R, --paint-tag TAG provide estimated FDR% in TAG in variant INFO" << endl
<< " -N, --false-negative replace FDR% (false detection) with FNR% (false negative)" << endl << endl;
cerr << "This code is deprecated!" << endl << endl;
}
int main(int argc, char** argv) {
int width = 100;
int height = 100;
int num_dimensions = 2;
int iterations = 1000;
string som_file;
string som_metadata_file;
bool apply = false;
bool train = false;
bool apply_to_training_data = false; // print results against training data
bool debug = false;
vector<string> fields;
vector<string> centerv;
int centerx;
int centery;
string trueVCF;
string falseVCF;
bool normalize = true;
int c;
if (argc == 1) {
printSummary(argv);
exit(1);
}
while (true) {
static struct option long_options[] =
{
/* These options set a flag. */
//{"verbose", no_argument, &verbose_flag, 1},
{"help", no_argument, 0, 'h'},
{"iterations", required_argument, 0, 'i'},
{"width", required_argument, 0, 'x'},
{"height", required_argument, 0, 'y'},
{"apply", required_argument, 0, 'a'},
{"save", required_argument, 0, 's'},
{"fields", required_argument, 0, 'f'},
{"print-training-results", no_argument, 0, 'p'},
{"center", required_argument, 0, 'c'},
{"paint-true", required_argument, 0, 'T'},
{"paint-false", required_argument, 0, 'F'},
{"debug", no_argument, 0, 'd'},
{0, 0, 0, 0}
};
/* getopt_long stores the option index here. */
int option_index = 0;
c = getopt_long (argc, argv, "hpdi:x:y:a:s:f:c:T:F:",
long_options, &option_index);
if (c == -1)
break;
string field;
switch (c)
{
case 'x':
if (!convert(optarg, width)) {
cerr << "could not parse --width, -x" << endl;
exit(1);
}
break;
case 'y':
if (!convert(optarg, height)) {
cerr << "could not parse --height, -y" << endl;
exit(1);
}
break;
case 'i':
if (!convert(optarg, iterations)) {
cerr << "could not parse --iterations, -i" << endl;
exit(1);
}
break;
case 'p':
apply_to_training_data = true;
break;
case 'T':
trueVCF = optarg;
break;
case 'F':
falseVCF = optarg;
break;
case 'd':
debug = true;
break;
case 'a':
som_file = optarg;
apply = true;
break;
case 's':
som_file = optarg;
train = true;
break;
case 'f':
fields = split(string(optarg), ' ');
break;
case 'c':
centerv = split(string(optarg), ',');
convert(centerv.at(0), centerx);
convert(centerv.at(1), centery);
break;
case 'h':
printSummary(argv);
exit(0);
break;
default:
break;
}
}
size_t i, j;
som_network_t *net = NULL;
vector<string> inputs;
vector<vector<double> > data;
map<string, Stats> stats;
string line;
stringstream ss;
VariantCallFile variantFile;
bool usingstdin = false;
string inputFilename;
if (optind == argc - 1) {
inputFilename = argv[optind];
variantFile.open(inputFilename);
} else {
variantFile.open(std::cin);
usingstdin = true;
}
if (!variantFile.is_open()) {
cerr << "could not open VCF file" << endl;
return 1;
}
som_metadata_file = som_file + ".meta";
Variant var(variantFile);
variantFile.addHeaderLine("##INFO=<ID=SOMX,Number=A,Type=Integer,Description=\"X position of best neuron for variant in self-ordering map defined in " + som_file + "\">");
variantFile.addHeaderLine("##INFO=<ID=SOMY,Number=A,Type=Integer,Description=\"Y position of best neuron for variant in self-ordering map defined in " + som_file + "\">");
if (!centerv.empty()) {
variantFile.addHeaderLine("##INFO=<ID=SOMD,Number=A,Type=Float,Description=\"Euclidean distance from "
+ convert(centerx) + "," + convert(centery) + " as defined by " + som_file + "\">");
}
if (!trueVCF.empty() && !falseVCF.empty()) {
variantFile.addHeaderLine("##INFO=<ID=SOMP,Number=A,Type=Float,Description=\"Estimated probability the variant is true using som "
+ som_file + ", true variants from " + trueVCF + ", and false variants from " + falseVCF + "\">");
}
if (debug) start_timer();
vector<Variant> variants;
if (train) {
map<string, pair<double, double> > normalizationLimits;
while (variantFile.getNextVariant(var)) {
variants.push_back(var);
int ai = 0;
vector<string>::iterator a = var.alt.begin();
for ( ; a != var.alt.end(); ++a, ++ai) {
vector<double> record;
double td;
vector<string>::iterator j = fields.begin();
for (; j != fields.end(); ++j) {
if (*j == "QUAL") { // special handling...
td = var.quality;
} else {
if (var.info.find(*j) == var.info.end()) {
td = 0;
} else {
if (variantFile.infoCounts[*j] == 1) { // for non Allele-variant fields
convert(var.info[*j][0], td);
} else {
convert(var.info[*j][ai], td);
}
}
}
if (normalize) {
pair<double, double>& limits = normalizationLimits[*j];
if (td < limits.first) limits.first = td;
if (td > limits.second) limits.second = td;
}
record.push_back(td);
}
data.push_back(record);
}
}
// normalize inputs
if (normalize) {
// get normalization vector
// goal is normalization at 0, sd=1
int i = 0;
for (vector<string>::iterator f = fields.begin(); f != fields.end(); ++f, ++i) {
vector<double> fv;
for (vector<vector<double> >::iterator d = data.begin(); d != data.end(); ++d) {
fv.push_back(d->at(i));
}
Stats& s = stats[*f];
// get normalization constants
s.mean = mean(fv);
s.stdev = standard_deviation(fv, s.mean);
// normalize
for (vector<vector<double> >::iterator d = data.begin(); d != data.end(); ++d) {
double v = d->at(i);
d->at(i) = (v - s.mean) / s.stdev;
}
}
}
}
vector<double*> dataptrs (data.size());
for (unsigned i=0, e=dataptrs.size(); i<e; ++i) {
dataptrs[i] = &(data[i][0]); // assuming !thing[i].empty()
}
if (debug) print_timing( "Input Processing" );
if (apply) {
if (! (net = som_deserialize(som_file.c_str()))) {
cerr << "could not load SOM from " << som_file << endl;
return 1;
}
if (!fields.empty()) {
cerr << "fields specified, but a SOM is to be applied, and metadata should be stored at " << som_metadata_file << endl;
return 1;
}
if (!load_som_metadata(som_metadata_file, width, height, fields, stats)) {
cerr << "could not load SOM metadata from " << som_metadata_file << endl;
return 1;
}
} else {
net = som_network_new(data[0].size(), height, width);
if ( !net ) {
printf( "ERROR: som_network_new failed.\n" );
return 1;
}
}
if (debug) print_timing( "Network Creation" );
if (train) {
if (debug) cerr << "Training using " << data.size() << " input vectors" << endl;
som_init_weights ( net, &dataptrs[0], data.size() );
som_train ( net, &dataptrs[0], data.size(), iterations );
}
if (debug) print_timing( "Network Training" );
// open and calibrate using the true and false datasets
if (train && apply_to_training_data) {
// currently disabled
/*
cout << variantFile.header << endl;
vector<Variant>::iterator v = variants.begin(); int di = 0;
for ( ; v != variants.end() && di < data.size(); ++v) {
var.info["SOMX"].clear();
var.info["SOMY"].clear();
var.info["SOMP"].clear();
var.info["SOMD"].clear();
for (vector<string>::iterator a = var.alt.begin(); a != var.alt.end(); ++a, ++di) {
som_set_inputs ( net, dataptrs[di] );
size_t x=0, y=0;
som_get_best_neuron_coordinates ( net, &x, &y );
v->info["SOMX"].push_back(convert(x));
v->info["SOMY"].push_back(convert(y));
if (!centerv.empty()) {
float distance = sqrt(pow(abs((float)centerx - (float)x), 2)
+ pow(abs((float)centery - (float)y), 2));
var.info["SOMD"].clear();
var.info["SOMD"].push_back(convert(distance));
}
}
cout << *v << endl;
}
*/
} else if (apply) {
// if we have true and false sets, use them to "paint" the map
vector<vector<SomPaint> > paintedSOM;
paintedSOM.resize(width);
for (vector<vector<SomPaint> >::iterator t = paintedSOM.begin();
t != paintedSOM.end(); ++t) {
t->resize(height);
}
// handle trues
if (!trueVCF.empty()) {
VariantCallFile trueVariantFile;
trueVariantFile.open(trueVCF);
Variant v(trueVariantFile);
while (trueVariantFile.getNextVariant(v)) {
int ai = 0;
vector<string>::iterator a = v.alt.begin();
for ( ; a != v.alt.end(); ++a, ++ai) {
vector<double> record;
read_fields(v, ai, fields, record);
if (normalize) {
normalize_inputs(record, fields, stats);
}
som_set_inputs ( net, &record[0] );
size_t x=0, y=0;
som_get_best_neuron_coordinates ( net, &x, &y );
paintedSOM[x][y].true_count += 1;
}
}
}
// get falses
if (!falseVCF.empty()) {
VariantCallFile falseVariantFile;
falseVariantFile.open(falseVCF);
Variant v(falseVariantFile);
while (falseVariantFile.getNextVariant(v)) {
int ai = 0;
vector<string>::iterator a = v.alt.begin();
for ( ; a != v.alt.end(); ++a, ++ai) {
vector<double> record;
read_fields(v, ai, fields, record);
if (normalize) {
normalize_inputs(record, fields, stats);
}
som_set_inputs ( net, &record[0] );
size_t x=0, y=0;
som_get_best_neuron_coordinates ( net, &x, &y );
paintedSOM[x][y].false_count += 1;
}
}
}
// estimate probability of each node using true and false set
for (vector<vector<SomPaint> >::iterator t = paintedSOM.begin();
t != paintedSOM.end(); ++t) {
for (vector<SomPaint>::iterator p = t->begin(); p != t->end(); ++p) {
//cout << "count at node " << t - paintedSOM.begin() << "," << p - t->begin()
// << " is " << p->true_count << " true, " << p->false_count << " false" << endl;
if (p->true_count + p->false_count > 0) {
p->prob_true = (double) p->true_count / (double) (p->true_count + p->false_count);
} else {
// for nodes without training data, could we estimate from surrounding nodes?
// yes, TODO, but for now we can be conservative and say "0"
p->prob_true = 0;
}
}
}
cout << variantFile.header << endl;
while (variantFile.getNextVariant(var)) {
var.info["SOMX"].clear();
var.info["SOMY"].clear();
var.info["SOMP"].clear();
var.info["SOMD"].clear();
int ai = 0;
vector<string>::iterator a = var.alt.begin();
for ( ; a != var.alt.end(); ++a, ++ai) {
vector<double> record;
read_fields(var, ai, fields, record);
if (normalize) {
normalize_inputs(record, fields, stats);
}
som_set_inputs ( net, &record[0] );
size_t x=0, y=0;
som_get_best_neuron_coordinates ( net, &x, &y );
if (!trueVCF.empty() && !falseVCF.empty()) {
SomPaint& paint = paintedSOM[x][y];
var.info["SOMP"].push_back(convert(paint.prob_true));
}
var.info["SOMX"].push_back(convert(x));
var.info["SOMY"].push_back(convert(y));
if (!centerv.empty()) {
float distance = sqrt(pow(abs((float)centerx - (float)x), 2)
+ pow(abs((float)centery - (float)y), 2));
var.info["SOMD"].push_back(convert(distance));
}
}
cout << var << endl;
}
}
if (debug) print_timing( "Input Recognition" );
if (train) {
if (!save_som_metadata(som_metadata_file, width, height, fields, stats)) {
cerr << "could not save metadata to " << som_metadata_file << endl;
}
som_serialize(net, som_file.c_str());
}
som_network_destroy ( net );
if (debug) print_timing( "Network Destruction" );
return 0;
}
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