TwoDOptimization.h

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//                   OpenMS -- Open-Source Mass Spectrometry
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// Copyright The OpenMS Team -- Eberhard Karls University Tuebingen,
// ETH Zurich, and Freie Universitaet Berlin 2002-2020.
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// $Maintainer: Timo Sachsenberg $
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#pragma once
 
//#define DEBUG_2D
#undef DEBUG_2D
 
#ifdef DEBUG_2D
#include <iostream>
#include <fstream>
#endif
 
#include <vector>
#include <utility>
#include <cmath>
#include <set>
 
#include <OpenMS/KERNEL/StandardTypes.h>
#include <OpenMS/TRANSFORMATIONS/RAW2PEAK/PeakShape.h>
#include <OpenMS/TRANSFORMATIONS/RAW2PEAK/OptimizePeakDeconvolution.h>
#include <OpenMS/KERNEL/MSExperiment.h>
#include <OpenMS/KERNEL/MSSpectrum.h>
#include <OpenMS/KERNEL/PeakIndex.h>
#include <OpenMS/CONCEPT/Exception.h>
#include <OpenMS/DATASTRUCTURES/IsotopeCluster.h>
#include <OpenMS/DATASTRUCTURES/DefaultParamHandler.h>
#include <OpenMS/MATH/MISC/MathFunctions.h>
 
#include <Eigen/Core>
#include <unsupported/Eigen/NonLinearOptimization>
 
#ifndef OPENMS_SYSTEM_STOPWATCH_H
#endif
 
#include <boost/math/special_functions/acosh.hpp>
#include <OpenMS/TRANSFORMATIONS/RAW2PEAK/OptimizePick.h>
#include <OpenMS/TRANSFORMATIONS/RAW2PEAK/PeakShape.h>
 
namespace OpenMS
{
 
  class OPENMS_DLLAPI TwoDOptimization :
    public DefaultParamHandler
  {
public:
 
    TwoDOptimization();
 
    TwoDOptimization(const TwoDOptimization& opt);
 
    ~TwoDOptimization() override{}
 
    TwoDOptimization& operator=(const TwoDOptimization& opt);
 
 
    inline double getMZTolerance() const {return tolerance_mz_; }
    inline void setMZTolerance(double tolerance_mz)
    {
      tolerance_mz_ = tolerance_mz;
      param_.setValue("2d:tolerance_mz", tolerance_mz);
    }
 
    inline double getMaxPeakDistance() const {return max_peak_distance_; }
    inline void setMaxPeakDistance(double max_peak_distance)
    {
      max_peak_distance_ = max_peak_distance;
      param_.setValue("2d:max_peak_distance", max_peak_distance);
    }
 
    inline UInt getMaxIterations() const {return max_iteration_; }
    inline void setMaxIterations(UInt max_iteration)
    {
      max_iteration_ = max_iteration;
      param_.setValue("iterations", max_iteration);
    }
 
    inline const OptimizationFunctions::PenaltyFactorsIntensity& getPenalties() const {return penalties_; }
    inline void setPenalties(OptimizationFunctions::PenaltyFactorsIntensity& penalties)
    {
      penalties_ = penalties;
      param_.setValue("penalties:position", penalties.pos);
      param_.setValue("penalties:height", penalties.height);
      param_.setValue("penalties:left_width", penalties.lWidth);
      param_.setValue("penalties:right_width", penalties.rWidth);
    }
 
    template <typename InputSpectrumIterator>
    void optimize(InputSpectrumIterator first,
                  InputSpectrumIterator last,
                  PeakMap& ms_exp, bool real2D = true);
 
 
protected:
    struct Data
    {
      std::vector<std::pair<SignedSize, SignedSize> > signal2D;
      std::multimap<double, IsotopeCluster>::iterator iso_map_iter;
      Size total_nr_peaks;
      std::map<Int, std::vector<PeakIndex> > matching_peaks;
      PeakMap picked_peaks;
      PeakMap::ConstIterator raw_data_first;
      OptimizationFunctions::PenaltyFactorsIntensity penalties;
      std::vector<double> positions;
      std::vector<double> signal;
    };
 
    class OPENMS_DLLAPI TwoDOptFunctor
    {
    public:
      int inputs() const { return m_inputs; }
      int values() const { return m_values; }
 
      TwoDOptFunctor(unsigned dimensions, unsigned num_data_points, const TwoDOptimization::Data* data)
      : m_inputs(dimensions), m_values(num_data_points), m_data(data) {}
 
      int operator()(const Eigen::VectorXd &x, Eigen::VectorXd &fvec);
      // compute Jacobian matrix for the different parameters
      int df(const Eigen::VectorXd &x, Eigen::MatrixXd &J);
 
    private:
      const int m_inputs, m_values;
      const TwoDOptimization::Data* m_data;
    };
 
 
    std::multimap<double, IsotopeCluster> iso_map_;
 
    std::multimap<double, IsotopeCluster>::const_iterator curr_region_;
 
    double max_peak_distance_;
 
    double tolerance_mz_;
 
    //  std::map<Int, std::vector<PeakMap::SpectrumType::Iterator > > matching_peaks_;
    std::map<Int, std::vector<PeakIndex> > matching_peaks_;
 
 
    UInt max_iteration_;
 
    bool real_2D_;
 
 
    OptimizationFunctions::PenaltyFactorsIntensity penalties_;
 
 
    std::vector<double>::iterator searchInScan_(std::vector<double>::iterator scan_begin,
                                                    std::vector<double>::iterator scan_end,
                                                    double current_mz);
 
    template <typename InputSpectrumIterator>
    void optimizeRegions_(InputSpectrumIterator& first,
                          InputSpectrumIterator& last,
                          PeakMap& ms_exp);
 
    template <typename InputSpectrumIterator>
    void optimizeRegionsScanwise_(InputSpectrumIterator& first,
                                  InputSpectrumIterator& last,
                                  PeakMap& ms_exp);
 
 
    template <typename InputSpectrumIterator>
    void getRegionEndpoints_(PeakMap& exp,
                             InputSpectrumIterator& first,
                             InputSpectrumIterator& last,
                             Size iso_map_idx,
                             double noise_level,
                             TwoDOptimization::Data& d);
 
    void findMatchingPeaks_(std::multimap<double, IsotopeCluster>::iterator& it,
                            PeakMap& ms_exp);
 
 
    void updateMembers_() override;
  };
 
 
  template <typename InputSpectrumIterator>
  void TwoDOptimization::optimize(InputSpectrumIterator first, InputSpectrumIterator last, PeakMap& ms_exp, bool real2D)
  {
    //#define DEBUG_2D
    //check if the input maps have the same number of spectra
    if ((UInt)distance(first, last) != ms_exp.size())
    {
      throw Exception::IllegalArgument(__FILE__, __LINE__, OPENMS_PRETTY_FUNCTION, "Error in Two2Optimization: Raw and peak map do not have the same number of spectra");
    }
    //do nothing if there are no scans
    if (ms_exp.empty())
    {
      return;
    }
    //check if required meta data arrays are present (for each scan)
    for (Size i = 0; i < ms_exp.size(); ++i)
    {
      //check if enough meta data arrays are present
      if (ms_exp[i].getFloatDataArrays().size() < 6)
      {
        throw Exception::IllegalArgument(__FILE__, __LINE__, OPENMS_PRETTY_FUNCTION, "Error in Two2Optimization: Not enough meta data arrays present (1:area, 5:shape, 3:left width, 4:right width)");
      }
      bool area = ms_exp[i].getFloatDataArrays()[1].getName() == "maximumIntensity";
      bool wleft = ms_exp[i].getFloatDataArrays()[3].getName() == "leftWidth";
      bool wright = ms_exp[i].getFloatDataArrays()[4].getName() == "rightWidth";
      bool shape = ms_exp[i].getFloatDataArrays()[5].getName() == "peakShape";
 
      if (!area || !wleft || !wright || !shape)
      {
        throw Exception::IllegalArgument(__FILE__, __LINE__, OPENMS_PRETTY_FUNCTION, "Error in Two2Optimization: One or several meta data arrays missing (1:intensity, 5:shape, 3:left width, 4:right width)");
      }
    }
    real_2D_ = real2D;
    typedef MSSpectrum SpectrumType;
 
    typename PeakMap::Iterator ms_exp_it = ms_exp.begin();
    typename PeakMap::Iterator ms_exp_it_end = ms_exp.end();
    if (ms_exp.empty())
    {
      return;
    }
    // stores the monoisotopic peaks of isotopic clusters
    std::vector<double> iso_last_scan;
    std::vector<double> iso_curr_scan;
    std::vector<std::multimap<double, IsotopeCluster>::iterator> clusters_last_scan;
    std::vector<std::multimap<double, IsotopeCluster>::iterator> clusters_curr_scan;
    std::multimap<double, IsotopeCluster>::iterator cluster_iter;
    double current_rt = ms_exp_it->getRT(), last_rt  = 0;
 
    // retrieve values for accepted peaks distances
    max_peak_distance_ = param_.getValue("2d:max_peak_distance");
    double tolerance_mz = param_.getValue("2d:tolerance_mz");
 
    UInt current_charge     = 0; // charge state of the current isotopic cluster
    double mz_in_hash   = 0; // used as reference to the current isotopic peak
 
    // sweep through scans
    for (UInt curr_scan = 0; ms_exp_it + curr_scan != ms_exp_it_end; ++curr_scan)
    {
      Size nr_peaks_in_scan = (ms_exp_it + curr_scan)->size();
      if (nr_peaks_in_scan == 0)
        continue;
 
      //last_rt = current_rt;
      current_rt = (ms_exp_it + curr_scan)->getRT();
      typename PeakMap::SpectrumType::Iterator peak_it  = (ms_exp_it + curr_scan)->begin();
 
      // copy cluster information of least scan
      iso_last_scan = iso_curr_scan;
      iso_curr_scan.clear();
      clusters_last_scan = clusters_curr_scan;
      clusters_curr_scan.clear();
 
#ifdef DEBUG_2D
      std::cout << "Next scan with rt: " << current_rt << std::endl;
      std::cout << "Next scan, rt = " << current_rt << " last_rt: " << last_rt << std::endl;
      std::cout << "---------------------------------------------------------------------------" << std::endl;
#endif
      MSSpectrum s;
      s.setRT(current_rt);
      // check if there were scans in between
      if (last_rt == 0 || // are we in the first scan
          ((lower_bound(first, last, s, typename SpectrumType::RTLess()) - 1)->getRT() == last_rt))
      {
 
 
        for (UInt curr_peak = 0; curr_peak < (ms_exp_it + curr_scan)->size() - 1; ++curr_peak)
        {
 
          // store the m/z of the current peak
          double curr_mz         = (peak_it + curr_peak)->getMZ();
          double dist2nextpeak = (peak_it + curr_peak + 1)->getMZ() - curr_mz;
 
          if (dist2nextpeak <= max_peak_distance_) // one single peak without neighbors isn't optimized
          {
#ifdef DEBUG_2D
            std::cout << "Isotopic pattern found ! " << std::endl;
            std::cout << "We are at: " << (peak_it + curr_peak)->getMZ()  << " " << curr_mz << std::endl;
#endif
            if (!iso_last_scan.empty()) // Did we find any isotopic cluster in the last scan?
            {
              std::sort(iso_last_scan.begin(), iso_last_scan.end());
              // there were some isotopic clusters in the last scan...
              std::vector<double>::iterator it =
                searchInScan_(iso_last_scan.begin(), iso_last_scan.end(), curr_mz);
 
              double delta_mz = fabs(*it - curr_mz);
              //std::cout << delta_mz << " "<< tolerance_mz << std::endl;
              if (delta_mz > tolerance_mz) // check if first peak of last cluster is close enough
              {
                mz_in_hash = curr_mz; // update current hash key
 
                // create new isotopic cluster
// #ifdef DEBUG_2D
//                                                      std::cout << "Last peak cluster too far, creating new cluster at "<<curr_mz << std::endl;
// #endif
                IsotopeCluster new_cluster;
                new_cluster.peaks.charge  = current_charge;
                new_cluster.scans.push_back(curr_scan);
                cluster_iter = iso_map_.insert(std::pair<double, IsotopeCluster>(mz_in_hash, new_cluster));
 
              }
              else
              {
// //#ifdef DEBUG_2D
//                                                      std::cout << "Found neighbouring peak with distance (m/z) " << delta_mz << std::endl;
// //#endif
                cluster_iter = clusters_last_scan[distance(iso_last_scan.begin(), it)];
 
                // check whether this scan is already contained
                if (find(cluster_iter->second.scans.begin(), cluster_iter->second.scans.end(), curr_scan)
                    == cluster_iter->second.scans.end())
                {
                  cluster_iter->second.scans.push_back(curr_scan);
                }
 
//                                                      //#ifdef DEBUG_2D
//                                                      std::cout << "Cluster with " << cluster_iter->second.peaks.size()
//                                                                          << " peaks retrieved." << std::endl;
//                                                      //#endif
              }
 
            }
            else                             // last scan did not contain any isotopic cluster
            {
//                                              //#ifdef DEBUG_2D
//                                              std::cout << "Last scan was empty => creating new cluster." << std::endl;
//                                              std::cout << "Creating new cluster at m/z: " << curr_mz << std::endl;
//                                              //#endif
 
              mz_in_hash = curr_mz; // update current hash key
 
              // create new isotopic cluster
              IsotopeCluster new_cluster;
              new_cluster.peaks.charge  = current_charge;
              new_cluster.scans.push_back(curr_scan);
              cluster_iter = iso_map_.insert(std::pair<double, IsotopeCluster>(mz_in_hash, new_cluster));
 
            }
 
//                                      //#ifdef DEBUG_2D
//                                      std::cout << "Storing found peak in current isotopic cluster" << std::endl;
//                                      //#endif
 
 
 
            cluster_iter->second.peaks.insert(std::pair<UInt, UInt>(curr_scan, curr_peak));
 
            iso_curr_scan.push_back(mz_in_hash);
            clusters_curr_scan.push_back(cluster_iter);
            ++curr_peak;
 
            cluster_iter->second.peaks.insert(std::pair<UInt, UInt>(curr_scan, curr_peak));
            iso_curr_scan.push_back((peak_it + curr_peak)->getMZ());
            clusters_curr_scan.push_back(cluster_iter);
 
            // check distance to next peak
            if ((curr_peak + 1) >= nr_peaks_in_scan)
              break;
            dist2nextpeak = (peak_it + curr_peak + 1)->getMZ() -  (peak_it + curr_peak)->getMZ();
 
 
            // loop until end of isotopic pattern in this scan
            while (dist2nextpeak <= max_peak_distance_
                  &&  curr_peak < (nr_peaks_in_scan - 1))
            {
              cluster_iter->second.peaks.insert(std::pair<UInt, UInt>(curr_scan, curr_peak + 1)); // save peak in cluster
              iso_curr_scan.push_back((peak_it + curr_peak + 1)->getMZ());
              clusters_curr_scan.push_back(cluster_iter);
              // std::cout << "new entered: "<<(peak_it+curr_peak+1)->getMZ()<<" im while"<<std::endl;
              ++curr_peak;
              if (curr_peak >= nr_peaks_in_scan - 1)
                break;
              dist2nextpeak = (peak_it + curr_peak + 1)->getMZ() -  (peak_it + curr_peak)->getMZ(); // get distance to next peak
 
 
            } // end while(...)
 
 
 
          } // end of if (dist2nextpeak <= max_peak_distance_)
          else
          {
            if (!iso_last_scan.empty()) // Did we find any isotopic cluster in the last scan?
            {
              std::sort(iso_last_scan.begin(), iso_last_scan.end());
              // there were some isotopic clusters in the last scan...
              std::vector<double>::iterator it =
                searchInScan_(iso_last_scan.begin(), iso_last_scan.end(), curr_mz);
 
              double delta_mz = fabs(*it - curr_mz);
              // std::cout << delta_mz << " "<< tolerance_mz << std::endl;
              if (delta_mz > tolerance_mz) // check if first peak of last cluster is close enough
              {
                mz_in_hash = curr_mz; // update current hash key
 
                // create new isotopic cluster
//                                                      //#ifdef DEBUG_2D
//                                                      std::cout << "Last peak cluster too far, creating new cluster at "<<curr_mz << std::endl;
//                                                      //#endif
                IsotopeCluster new_cluster;
                new_cluster.peaks.charge  = current_charge;
                new_cluster.scans.push_back(curr_scan);
                cluster_iter = iso_map_.insert(std::pair<double, IsotopeCluster>(mz_in_hash, new_cluster));
 
              }
              else
              {
//                                                      //#ifdef DEBUG_2D
//                                                      std::cout << "Found neighbouring peak with distance (m/z) " << delta_mz << std::endl;
//                                                      //#endif
                cluster_iter = clusters_last_scan[distance(iso_last_scan.begin(), it)];
 
                // check whether this scan is already contained
                if (find(cluster_iter->second.scans.begin(), cluster_iter->second.scans.end(), curr_scan)
                    == cluster_iter->second.scans.end())
                {
                  cluster_iter->second.scans.push_back(curr_scan);
                }
 
//                                                      //#ifdef DEBUG_2D
//                                                      std::cout << "Cluster with " << cluster_iter->second.peaks.size()
//                                                                          << " peaks retrieved." << std::endl;
//                                                      //#endif
              }
 
            }
            else                             // last scan did not contain any isotopic cluster
            {
//                                              //#ifdef DEBUG_2D
//                                              std::cout << "Last scan was empty => creating new cluster." << std::endl;
//                                              std::cout << "Creating new cluster at m/z: " << curr_mz << std::endl;
//                                              //#endif
 
              mz_in_hash = curr_mz; // update current hash key
 
              // create new isotopic cluster
              IsotopeCluster new_cluster;
              new_cluster.peaks.charge  = current_charge;
              new_cluster.scans.push_back(curr_scan);
              cluster_iter = iso_map_.insert(std::pair<double, IsotopeCluster>(mz_in_hash, new_cluster));
 
            }
 
//                                      //#ifdef DEBUG_2D
//                                      std::cout << "Storing found peak in current isotopic cluster" << std::endl;
//                                      //#endif
 
 
 
            cluster_iter->second.peaks.insert(std::pair<UInt, UInt>(curr_scan, curr_peak));
 
            iso_curr_scan.push_back(mz_in_hash);
            clusters_curr_scan.push_back(cluster_iter);
 
 
          }
 
          current_charge = 0; // reset charge
        } // end for (...)
      }
      last_rt = current_rt;
    }
    curr_region_ = iso_map_.begin();
#ifdef DEBUG_2D
    std::cout << iso_map_.size() << " isotopic clusters were found ! " << std::endl;
#endif
 
    if (real_2D_)
      optimizeRegions_(first, last, ms_exp);
    else
      optimizeRegionsScanwise_(first, last, ms_exp);
    //#undef DEBUG_2D
  }
 
 
 
  template <typename InputSpectrumIterator>
  void TwoDOptimization::optimizeRegions_(InputSpectrumIterator& first,
                                          InputSpectrumIterator& last,
                                          PeakMap& ms_exp)
  {
    Int counter = 0;
    // go through the clusters
    for (std::multimap<double, IsotopeCluster>::iterator it = iso_map_.begin();
         it != iso_map_.end();
         ++it)
    {
#ifdef DEBUG_2D
      std::cout << "element: " << counter << std::endl;
      std::cout << "mz: " << it->first << std::endl << "rts: ";
//              for(Size i=0;i<it->second.scans.size();++i) std::cout << it->second.scans[i] << "\n";
      std::cout << std::endl << "peaks: ";
      IsotopeCluster::IndexSet::const_iterator iter = it->second.peaks.begin();
      for (; iter != it->second.peaks.end(); ++iter)
        std::cout << ms_exp[iter->first].getRT() << " " << (ms_exp[iter->first][iter->second]).getMZ() << std::endl;
 
//for(Size i=0;i<it->second.peaks.size();++i) std::cout << ms_exp[it->first].getRT() << " "<<(ms_exp[it->first][it->second]).getMZ()<<std::endl;
      std::cout << std::endl << std::endl;
 
#endif
 
      // prepare for optimization:
      // determine the matching peaks
      matching_peaks_.clear();
      findMatchingPeaks_(it, ms_exp);
      TwoDOptimization::Data twoD_data;
      twoD_data.penalties = penalties_;
      twoD_data.matching_peaks = matching_peaks_;
      // and the endpoints of each isotope pattern in the cluster
      getRegionEndpoints_(ms_exp, first, last, counter, 400, twoD_data);
 
      // peaks have to be stored globally
      twoD_data.iso_map_iter = it;
 
      twoD_data.picked_peaks = ms_exp;
      twoD_data.raw_data_first =  first;
 
      Size nr_diff_peaks = matching_peaks_.size();
      twoD_data.total_nr_peaks = it->second.peaks.size();
 
      Size nr_parameters = nr_diff_peaks * 3 + twoD_data.total_nr_peaks;
 
      // initialize and set parameters for optimization
      Eigen::VectorXd x_init (nr_parameters);
      x_init.setZero();
 
      std::map<Int, std::vector<PeakIndex> >::iterator m_peaks_it = twoD_data.matching_peaks.begin();
      Int peak_counter = 0;
      Int diff_peak_counter = 0;
      // go through the matching peaks
      for (; m_peaks_it != twoD_data.matching_peaks.end(); ++m_peaks_it)
      {
        double av_mz = 0, av_lw = 0, av_rw = 0, avr_height = 0, height;
        std::vector<PeakIndex>::iterator iter_iter = (m_peaks_it)->second.begin();
        for (; iter_iter != m_peaks_it->second.end(); ++iter_iter)
        {
          height = ms_exp[(iter_iter)->spectrum].getFloatDataArrays()[1][(iter_iter)->peak]; //(iter_iter)->getPeak(ms_exp).getIntensity();
          avr_height += height;
          av_mz += (iter_iter)->getPeak(ms_exp).getMZ() * height;
          av_lw += ms_exp[(iter_iter)->spectrum].getFloatDataArrays()[3][(iter_iter)->peak] * height; //left width
          av_rw +=    ms_exp[(iter_iter)->spectrum].getFloatDataArrays()[4][(iter_iter)->peak] * height; //right width
          x_init(peak_counter) = height;
          ++peak_counter;
        }
        x_init(twoD_data.total_nr_peaks + 3 * diff_peak_counter) = av_mz / avr_height;
        x_init(twoD_data.total_nr_peaks + 3 * diff_peak_counter + 1) = av_lw / avr_height;
        x_init(twoD_data.total_nr_peaks + 3 * diff_peak_counter + 2) = av_rw / avr_height;
        ++diff_peak_counter;
      }
 
#ifdef DEBUG_2D
      std::cout << "----------------------------\n\nstart_value: " << std::endl;
      for (Size k = 0; k < start_value->size; ++k)
      {
          std::cout << x_init(k) << std::endl;
      }
#endif
      Int num_positions = 0;
      for (Size i = 0; i < twoD_data.signal2D.size(); i += 2)
      {
        num_positions += (twoD_data.signal2D[i + 1].second - twoD_data.signal2D[i].second + 1);
#ifdef DEBUG_2D
        std::cout << twoD_data.signal2D[i + 1].second << " - " << twoD_data.signal2D[i].second << " +1 " << std::endl;
#endif
 
      }
#ifdef DEBUG_2D
      std::cout << "num_positions : " << num_positions << std::endl;
#endif
      
      TwoDOptFunctor functor (nr_parameters, std::max(num_positions + 1, (Int)(nr_parameters)), &twoD_data);
      Eigen::LevenbergMarquardt<TwoDOptFunctor> lmSolver (functor);
      Eigen::LevenbergMarquardtSpace::Status status = lmSolver.minimize(x_init);
 
      //the states are poorly documented. after checking the source, we believe that
      //all states except NotStarted, Running and ImproperInputParameters are good
      //termination states.
      if (status <= Eigen::LevenbergMarquardtSpace::ImproperInputParameters)
      {
          throw Exception::UnableToFit(__FILE__, __LINE__, OPENMS_PRETTY_FUNCTION, "UnableToFit-TwoDOptimization:", "Could not fit the data: Error " + String(status));
      }
 
      Int peak_idx = 0;
      std::map<Int, std::vector<PeakIndex> >::iterator itv
        = twoD_data.matching_peaks.begin();
      for (; itv != twoD_data.matching_peaks.end(); ++itv)
      {
        Int i = distance(twoD_data.matching_peaks.begin(), itv);
        for (Size j = 0; j < itv->second.size(); ++j)
        {
 
#ifdef DEBUG_2D
          std::cout << "pos: " << itv->second[j].getPeak(ms_exp).getMZ() << "\nint: " << itv->second[j].getSpectrum(ms_exp).getFloatDataArrays()[1][itv->second[j].peak] //itv->second[j].getPeak(ms_exp).getIntensity()
                    << "\nlw: " << itv->second[j].getSpectrum(ms_exp).getFloatDataArrays()[3][itv->second[j].peak]
                    << "\nrw: " << itv->second[j].getSpectrum(ms_exp).getFloatDataArrays()[4][itv->second[j].peak] << "\n";
 
#endif
          double mz = x_init(twoD_data.total_nr_peaks + 3 * i);
          ms_exp[itv->second[j].spectrum][itv->second[j].peak].setMZ(mz);
          double height = x_init(peak_idx);
          ms_exp[itv->second[j].spectrum].getFloatDataArrays()[1][itv->second[j].peak] = height;
          double left_width = x_init(twoD_data.total_nr_peaks + 3 * i + 1);
          ms_exp[itv->second[j].spectrum].getFloatDataArrays()[3][itv->second[j].peak] = left_width;
          double right_width = x_init(twoD_data.total_nr_peaks + 3 * i + 2);
 
          ms_exp[itv->second[j].spectrum].getFloatDataArrays()[4][itv->second[j].peak] = right_width;
          // calculate area
          if ((PeakShape::Type)(Int)ms_exp[itv->second[j].spectrum].getFloatDataArrays()[5][itv->second[j].peak] == PeakShape::LORENTZ_PEAK)
          {
            double x_left_endpoint = mz - 1 / left_width* sqrt(height / 1 - 1);
            double x_right_endpoint = mz + 1 / right_width* sqrt(height / 1 - 1);
            double area_left = -height / left_width* atan(left_width * (x_left_endpoint - mz));
            double area_right = -height / right_width* atan(right_width * (mz - x_right_endpoint));
            ms_exp[itv->second[j].spectrum][itv->second[j].peak].setIntensity(area_left + area_right);
          }
          else         // it's a sech peak
          {
            double x_left_endpoint = mz - 1 / left_width* boost::math::acosh(sqrt(height / 0.001));
            double x_right_endpoint = mz + 1 / right_width* boost::math::acosh(sqrt(height / 0.001));
            double area_left = -height / left_width * (sinh(left_width * (mz - x_left_endpoint)) / cosh(left_width * (mz - x_left_endpoint)));
            double area_right = -height / right_width * (sinh(right_width * (mz - x_right_endpoint)) / cosh(right_width * (mz - x_right_endpoint)));
            ms_exp[itv->second[j].spectrum][itv->second[j].peak].setIntensity(area_left + area_right);
          }
 
 
#ifdef DEBUG_2D
          std::cout << "pos: " << itv->second[j].getPeak(ms_exp).getMZ() << "\nint: " << itv->second[j].getSpectrum(ms_exp).getFloatDataArrays()[1][itv->second[j].peak] //itv->second[j].getPeak(ms_exp).getIntensity()
                    << "\nlw: " << itv->second[j].getSpectrum(ms_exp).getFloatDataArrays()[3][itv->second[j].peak]
                    << "\nrw: " << itv->second[j].getSpectrum(ms_exp).getFloatDataArrays()[4][itv->second[j].peak] << "\n";
#endif
 
          ++peak_idx;
 
 
        }
      }
 
      ++counter;
    } // end for
    //#undef DEBUG_2D
  }
 
  template <typename InputSpectrumIterator>
  void TwoDOptimization::optimizeRegionsScanwise_(InputSpectrumIterator& first,
                                                  InputSpectrumIterator& last,
                                                  PeakMap& ms_exp)
  {
    Int counter = 0;
    TwoDOptimization::Data d;
    d.picked_peaks = ms_exp;
    d.raw_data_first =  first;
 
    //std::cout << "richtig hier" << std::endl;
    struct OpenMS::OptimizationFunctions::PenaltyFactors penalties;
 
 
    DataValue dv = param_.getValue("penalties:position");
    if (dv.isEmpty() || dv.toString() == "")
      penalties.pos = 0.;
    else
      penalties.pos = (float)dv;
 
    dv = param_.getValue("penalties:left_width");
    if (dv.isEmpty() || dv.toString() == "")
      penalties.lWidth = 1.;
    else
      penalties.lWidth = (float)dv;
 
    dv = param_.getValue("penalties:right_width");
    if (dv.isEmpty() || dv.toString() == "")
      penalties.rWidth = 1.;
    else
      penalties.rWidth = (float)dv;
#ifdef DEBUG_2D
    std::cout << penalties.pos << " "
              << penalties.rWidth << " "
              << penalties.lWidth << std::endl;
#endif
//      PeakMap::const_iterator help = first;
//      // std::cout << "\n\n\n\n---------------------------------------------------------------";
//      while(help!=last)
//          {
//              // std::cout<<help->getRT()<<std::endl;
//              ++help;
//          }
    // std::cout << "---------------------------------------------------------------\n\n\n\n";
 
    UInt max_iteration;
    dv = param_.getValue("iterations");
    if (dv.isEmpty() || dv.toString() == "")
      max_iteration = 15;
    else
      max_iteration = (UInt)dv;
 
    std::vector<PeakShape> peak_shapes;
 
 
    // go through the clusters
    for (std::multimap<double, IsotopeCluster>::iterator it = iso_map_.begin();
         it != iso_map_.end();
         ++it)
    {
      d.iso_map_iter = it;
#ifdef DEBUG_2D
      std::cerr << "element: " << counter << std::endl;
      std::cerr << "mz: " << it->first << std::endl << "rts: ";
      for (Size i = 0; i < it->second.scans.size(); ++i)
        std::cerr << it->second.scans[i] << "\n";
      std::cerr << std::endl << "peaks: ";
      IsotopeCluster::IndexSet::const_iterator iter = it->second.peaks.begin();
      for (; iter != it->second.peaks.end(); ++iter)
        std::cerr << ms_exp[iter->first].getRT() << " " << (ms_exp[iter->first][iter->second]).getMZ() << std::endl;
      //for(Size i=0;i<it->second.peaks_.size();++i) std::cout << ms_exp[it->first].getRT() << " "<<(ms_exp[it->first][it->second]).getMZ()<<std::endl;
      std::cerr << std::endl << std::endl;
 
#endif
      // prepare for optimization:
      // determine the matching peaks
      // and the endpoints of each isotope pattern in the cluster
 
      getRegionEndpoints_(ms_exp, first, last, counter, 400, d);
      OptimizePick::Data data;
 
 
      Size idx = 0;
      for (Size i = 0; i < d.signal2D.size() / 2; ++i)
      {
        data.positions.clear();
        data.signal.clear();
 
        PeakMap::SpectrumType::const_iterator ms_it =
          (d.raw_data_first + d.signal2D[2 * i].first)->begin() + d.signal2D[2 * i].second;
        Int size = distance(ms_it, (d.raw_data_first + d.signal2D[2 * i].first)->begin() + d.signal2D[2 * i + 1].second);
        data.positions.reserve(size);
        data.signal.reserve(size);
 
        while (ms_it != (d.raw_data_first + d.signal2D[2 * i].first)->begin() + d.signal2D[2 * i + 1].second)
        {
          data.positions.push_back(ms_it->getMZ());
          data.signal.push_back(ms_it->getIntensity());
          ++ms_it;
        }
 
 
        IsotopeCluster::IndexPair pair;
        pair.first =  d.iso_map_iter->second.peaks.begin()->first + idx;
 
        IsotopeCluster::IndexSet::const_iterator set_iter = lower_bound(d.iso_map_iter->second.peaks.begin(),
                                                                        d.iso_map_iter->second.peaks.end(),
                                                                        pair, PairComparatorFirstElement<IsotopeCluster::IndexPair>());
 
 
        // find the last entry with this rt-value
        ++pair.first;
        IsotopeCluster::IndexSet::const_iterator set_iter2 = lower_bound(d.iso_map_iter->second.peaks.begin(),
                                                                         d.iso_map_iter->second.peaks.end(),
                                                                         pair, PairComparatorFirstElement<IsotopeCluster::IndexPair>());
 
        while (set_iter != set_iter2)
        {
          const Size peak_index = set_iter->second;
          const MSSpectrum& spec = ms_exp[set_iter->first];
          PeakShape shape(spec.getFloatDataArrays()[1][peak_index], //intensity
                          spec[peak_index].getMZ(),
                          spec.getFloatDataArrays()[3][peak_index], //left width
                          spec.getFloatDataArrays()[4][peak_index], //right width
                          spec[peak_index].getIntensity(), //area is stored in peak intensity
                          PeakShape::Type(Int(spec.getFloatDataArrays()[5][peak_index]))); //shape
          peak_shapes.push_back(shape);
          ++set_iter;
        }
#ifdef DEBUG_2D
        std::cout << "rt "
                  << (d.raw_data_first + d.signal2D[2 * i].first)->getRT()
                  << "\n";
#endif
        OptimizePick opt(penalties, max_iteration);
#ifdef DEBUG_2D
        std::cout << "vorher\n";
 
        for (Size p = 0; p < peak_shapes.size(); ++p)
        {
          std::cout << peak_shapes[p].mz_position << "\t" << peak_shapes[p].height
                    << "\t" << peak_shapes[p].left_width << "\t" << peak_shapes[p].right_width  << std::endl;
        }
#endif
        opt.optimize(peak_shapes, data);
#ifdef DEBUG_2D
        std::cout << "nachher\n";
        for (Size p = 0; p < peak_shapes.size(); ++p)
        {
          std::cout << peak_shapes[p].mz_position << "\t" << peak_shapes[p].height
                    << "\t" << peak_shapes[p].left_width << "\t" << peak_shapes[p].right_width  << std::endl;
        }
#endif
        std::sort(peak_shapes.begin(), peak_shapes.end(), PeakShape::PositionLess());
        pair.first =  d.iso_map_iter->second.peaks.begin()->first + idx;
 
        set_iter = lower_bound(d.iso_map_iter->second.peaks.begin(),
                               d.iso_map_iter->second.peaks.end(),
                               pair, PairComparatorFirstElement<IsotopeCluster::IndexPair>());
        Size p = 0;
        while (p < peak_shapes.size())
        {
          MSSpectrum& spec = ms_exp[set_iter->first];
          spec[set_iter->second].setMZ(peak_shapes[p].mz_position);
          spec.getFloatDataArrays()[3][set_iter->second] = peak_shapes[p].left_width;
          spec.getFloatDataArrays()[4][set_iter->second] = peak_shapes[p].right_width;
          spec.getFloatDataArrays()[1][set_iter->second] = peak_shapes[p].height; // maximum intensity
          // calculate area
          if (peak_shapes[p].type == PeakShape::LORENTZ_PEAK)
          {
            PeakShape& ps = peak_shapes[p];
            double x_left_endpoint = ps.mz_position - 1 / ps.left_width* sqrt(ps.height / 1 - 1);
            double x_right_endpoint = ps.mz_position + 1 / ps.right_width* sqrt(ps.height / 1 - 1);
            double area_left = -ps.height / ps.left_width* atan(ps.left_width * (x_left_endpoint - ps.mz_position));
            double area_right = -ps.height / ps.right_width* atan(ps.right_width * (ps.mz_position - x_right_endpoint));
            spec[set_iter->second].setIntensity(area_left + area_right); // area is stored as peak intensity
          }
          else        //It's a Sech - Peak
          {
            PeakShape& ps = peak_shapes[p];
            double x_left_endpoint = ps.mz_position - 1 / ps.left_width* boost::math::acosh(sqrt(ps.height / 0.001));
            double x_right_endpoint = ps.mz_position + 1 / ps.right_width* boost::math::acosh(sqrt(ps.height / 0.001));
            double area_left = ps.height / ps.left_width * (sinh(ps.left_width * (ps.mz_position - x_left_endpoint)) / cosh(ps.left_width * (ps.mz_position - x_left_endpoint)));
            double area_right = -ps.height / ps.right_width * (sinh(ps.right_width * (ps.mz_position - x_right_endpoint)) / cosh(ps.right_width * (ps.mz_position - x_right_endpoint)));
            spec[set_iter->second].setIntensity(area_left + area_right); // area is stored as peak intensity
          }
          ++set_iter;
          ++p;
        }
        ++idx;
        peak_shapes.clear();
      }
 
      ++counter;
    }
  }
 
  template <typename InputSpectrumIterator>
  void TwoDOptimization::getRegionEndpoints_(PeakMap& exp,
                                             InputSpectrumIterator& first,
                                             InputSpectrumIterator& last,
                                             Size iso_map_idx,
                                             double noise_level,
                                             TwoDOptimization::Data& d)
  {
    d.signal2D.clear();
    typedef typename InputSpectrumIterator::value_type InputExperimentType;
    typedef typename InputExperimentType::value_type InputPeakType;
    typedef std::multimap<double, IsotopeCluster> MapType;
 
    double rt, first_peak_mz, last_peak_mz;
 
    typename PeakMap::SpectrumType spec;
    InputPeakType peak;
 
    MapType::iterator iso_map_iter = iso_map_.begin();
    for (Size i = 0; i < iso_map_idx; ++i)
      ++iso_map_iter;
 
#ifdef DEBUG2D
    std::cout << "rt begin: " << exp[iso_map_iter->second.scans[0]].getRT()
              << "\trt end: " << exp[iso_map_iter->second.scans[iso_map_iter->second.scans.size() - 1]].getRT()
              << " \t" << iso_map_iter->second.scans.size() << " scans"
              << std::endl;
#endif
 
    // get left and right endpoint for all scans in the current cluster
    for (Size i = 0; i < iso_map_iter->second.scans.size(); ++i)
    {
      typename PeakMap::iterator exp_it;
 
      // first the right scan through binary search
      rt = exp[iso_map_iter->second.scans[i]].getRT();
      spec.setRT(rt);
      InputSpectrumIterator iter = lower_bound(first, last, spec, MSSpectrum::RTLess());
      //  if(iter->getRT() != rt) --iter;
      exp_it = exp.RTBegin(rt);
#ifdef DEBUG2D
      std::cout << exp_it->getRT() << " vs " << iter->getRT() << std::endl;
#endif
      // now the right mz
      IsotopeCluster::IndexPair pair;
      pair.first =  iso_map_iter->second.peaks.begin()->first + i;
      // get iterator in peaks-set that points to the first peak in the current scan
      IsotopeCluster::IndexSet::const_iterator set_iter = lower_bound(iso_map_iter->second.peaks.begin(),
                                                                      iso_map_iter->second.peaks.end(),
                                                                      pair, PairComparatorFirstElement<IsotopeCluster::IndexPair>());
 
      // consider a bit more of the signal to the left
      first_peak_mz = (exp_it->begin() + set_iter->second)->getMZ() - 1;
 
      // find the last entry with this rt-value
      ++pair.first;
      IsotopeCluster::IndexSet::const_iterator set_iter2 = lower_bound(iso_map_iter->second.peaks.begin(),
                                                                       iso_map_iter->second.peaks.end(),
                                                                       pair, PairComparatorFirstElement<IsotopeCluster::IndexPair>());
 
      if (i == iso_map_iter->second.scans.size() - 1)
      {
        set_iter2 = iso_map_iter->second.peaks.end();
        --set_iter2;
      }
      else if (set_iter2 != iso_map_iter->second.peaks.begin())
        --set_iter2;
 
      last_peak_mz = (exp_it->begin() + set_iter2->second)->getMZ() + 1;
 
      //std::cout << rt<<": first peak mz "<<first_peak_mz << "\tlast peak mz "<<last_peak_mz <<std::endl;
      peak.setPosition(first_peak_mz);
      typename PeakMap::SpectrumType::const_iterator raw_data_iter
        = lower_bound(iter->begin(), iter->end(), peak, typename InputPeakType::PositionLess());
      if (raw_data_iter != iter->begin())
      {
        --raw_data_iter;
      }
      double intensity = raw_data_iter->getIntensity();
      // while the intensity is falling go to the left
      while (raw_data_iter != iter->begin() && (raw_data_iter - 1)->getIntensity() < intensity &&
             (raw_data_iter - 1)->getIntensity() > noise_level)
      {
        --raw_data_iter;
        intensity = raw_data_iter->getIntensity();
      }
      ++raw_data_iter;
      IsotopeCluster::IndexPair left, right;
      left.first = distance(first, iter);
      left.second = raw_data_iter - iter->begin();
#ifdef DEBUG2D
      std::cout << "left: " << iter->getRT() << "\t" << raw_data_iter->getMZ() << std::endl;
#endif
      // consider a bit more of the signal to the right
      peak.setPosition(last_peak_mz + 1);
      raw_data_iter
        = upper_bound(iter->begin(), iter->end(), peak, typename InputPeakType::PositionLess());
      if (raw_data_iter == iter->end())
        --raw_data_iter;
      intensity = raw_data_iter->getIntensity();
      // while the intensity is falling go to the right
      while (raw_data_iter + 1 != iter->end() && (raw_data_iter + 1)->getIntensity() < intensity)
      {
        ++raw_data_iter;
        intensity = raw_data_iter->getIntensity();
        if ((raw_data_iter + 1 != iter->end()) && (raw_data_iter + 1)->getIntensity() > noise_level)
          break;
      }
      right.first = left.first;
      right.second = raw_data_iter - iter->begin();
#ifdef DEBUG2D
      std::cout << "right: " << iter->getRT() << "\t" << raw_data_iter->getMZ() << std::endl;
#endif
      // region endpoints are stored in global vector
      d.signal2D.push_back(left);
      d.signal2D.push_back(right);
    }
#ifdef DEBUG2D
    //std::cout << "fertig"<< std::endl;
    std::cout << first_peak_mz << "\t" << last_peak_mz << std::endl;
#endif
  }
 
}