IsotopeWaveletTransform.h

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// --------------------------------------------------------------------------
//                   OpenMS -- Open-Source Mass Spectrometry
// --------------------------------------------------------------------------
// Copyright The OpenMS Team -- Eberhard Karls University Tuebingen,
// ETH Zurich, and Freie Universitaet Berlin 2002-2023.
//
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//    may be used to endorse or promote products derived from this software
//    without specific prior written permission.
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// $Maintainer: Timo Sachsenberg$
// $Authors: $
// --------------------------------------------------------------------------
 
#pragma once
 
#include <OpenMS/TRANSFORMATIONS/FEATUREFINDER/IsotopeWaveletConstants.h>
#include <OpenMS/TRANSFORMATIONS/FEATUREFINDER/IsotopeWavelet.h>
#include <OpenMS/KERNEL/StandardTypes.h>
#include <OpenMS/KERNEL/FeatureMap.h>
#include <OpenMS/KERNEL/MSExperiment.h>
#include <OpenMS/KERNEL/MSSpectrum.h>
#include <OpenMS/CONCEPT/Exception.h>
#include <OpenMS/MATH/STATISTICS/LinearRegression.h>
#include <OpenMS/DATASTRUCTURES/ConstRefVector.h>
 
#include <cmath>
#include <vector>
#include <map>
#include <sstream>
#include <fstream>
#include <iomanip>
 
// TODO: move this to cpp and use STL once it is available in clang on Mac
#include <boost/math/special_functions/bessel.hpp>
 
// This code has quite a few strange things in it triggering warnings which
// clutters the rest of the diagnostics
#pragma clang diagnostic push
#pragma clang diagnostic ignored "-Wfloat-equal"
#pragma clang diagnostic ignored "-Wconversion"
#pragma clang diagnostic ignored "-Wshorten-64-to-32"
 
namespace OpenMS
{
 
  template <typename PeakType>
  class IsotopeWaveletTransform
  {
public:
 
 
    struct BoxElement
    {
      double mz; 
      UInt c; 
      double score; 
      double intens; 
      double ref_intens;
      double RT; 
      UInt RT_index; 
      UInt MZ_begin; 
      UInt MZ_end; 
    };
 
    typedef std::multimap<UInt, BoxElement> Box; 
 
 
    class TransSpectrum
    {
      friend class IsotopeWaveletTransform;
 
public:
 
      TransSpectrum() :
        reference_(nullptr), trans_intens_(nullptr)
      {
      }
 
      TransSpectrum(const MSSpectrum* reference) :
        reference_(reference)
      {
        trans_intens_ = new std::vector<float>(reference_->size(), 0.0);
      }
 
      virtual ~TransSpectrum()
      {
        delete (trans_intens_);
      }
 
      virtual void destroy()
      {
        delete (trans_intens_);
        trans_intens_ = NULL;
        delete (reference_);
        reference_ = NULL;
      }
 
      inline double getRT() const
      {
        return reference_->getRT();
      }
 
      inline double getMZ(const UInt i) const
      {
        return (*reference_)[i].getMZ();
      }
 
      inline double getRefIntensity(const UInt i) const
      {
        return (*reference_)[i].getIntensity();
      }
 
      inline double getTransIntensity(const UInt i) const
      {
        return (*trans_intens_)[i];
      }
 
      inline void setTransIntensity(const UInt i, const double intens)
      {
        (*trans_intens_)[i] = intens;
      }
 
      inline Size size() const
      {
        return trans_intens_->size();
      }
 
      inline const MSSpectrum* getRefSpectrum()
      {
        return reference_;
      }
 
      inline const MSSpectrum* getRefSpectrum() const
      {
        return reference_;
      }
 
      inline typename MSSpectrum::const_iterator MZBegin(const double mz) const
      {
        return reference_->MZBegin(mz);
      }
 
      inline typename MSSpectrum::const_iterator MZEnd(const double mz) const
      {
        return reference_->MZEnd(mz);
      }
 
      inline typename MSSpectrum::const_iterator end() const
      {
        return reference_->end();
      }
 
      inline typename MSSpectrum::const_iterator begin() const
      {
        return reference_->begin();
      }
 
protected:
 
      const MSSpectrum* reference_; 
      std::vector<float>* trans_intens_; 
 
    };
 
 
 
    IsotopeWaveletTransform(const double min_mz, const double max_mz, const UInt max_charge, const Size max_scan_size = 0, const bool hr_data = false, const String intenstype = "ref");
 
    virtual ~IsotopeWaveletTransform();
 
 
    virtual void getTransform(MSSpectrum& c_trans, const MSSpectrum& c_ref, const UInt c);
 
    virtual void getTransformHighRes(MSSpectrum& c_trans, const MSSpectrum& c_ref, const UInt c);
 
    virtual void identifyCharge(const MSSpectrum& candidates, const MSSpectrum& ref, const UInt scan_index, const UInt c,
                                const double ampl_cutoff, const bool check_PPMs);
 
    virtual void initializeScan(const MSSpectrum& c_ref, const UInt c = 0);
 
    void updateBoxStates(const PeakMap& map, const Size scan_index, const UInt RT_interleave,
                         const UInt RT_votes_cutoff, const Int front_bound = -1, const Int end_bound = -1);
 
 
    FeatureMap mapSeeds2Features(const PeakMap& map, const UInt RT_votes_cutoff);
 
    virtual std::multimap<double, Box> getClosedBoxes()
    { return closed_boxes_;  }
 
 
    inline double getLinearInterpolation(const typename MSSpectrum::const_iterator& left_iter, const double mz_pos, const typename MSSpectrum::const_iterator& right_iter)
    {
      return left_iter->getIntensity() + (right_iter->getIntensity() - left_iter->getIntensity()) / (right_iter->getMZ() - left_iter->getMZ()) * (mz_pos - left_iter->getMZ());
    }
 
    inline double getLinearInterpolation(const double mz_a, const double intens_a, const double mz_pos, const double mz_b, const double intens_b)
    {
      return intens_a + (intens_b - intens_a) / (mz_b - mz_a) * (mz_pos - mz_a);
    }
 
    inline double getSigma() const
    {
      return sigma_;
    }
 
    inline void setSigma(const double sigma)
    {
      sigma_ = sigma;
    }
 
    virtual void computeMinSpacing(const MSSpectrum& c_ref);
 
    inline double getMinSpacing() const
    {
      return min_spacing_;
    }
 
    inline Size getMaxScanSize() const
    {
      return max_scan_size_;
    }
 
protected:
 
 
    IsotopeWaveletTransform();
 
 
    inline void sampleTheCMarrWavelet_(const MSSpectrum& scan, const Int wavelet_length, const Int mz_index, const UInt charge);
 
 
    virtual double scoreThis_(const TransSpectrum& candidate, const UInt peak_cutoff,
                                  const double seed_mz, const UInt c, const double ampl_cutoff);
 
    virtual double scoreThis_(const MSSpectrum& candidate, const UInt peak_cutoff,
                                  const double seed_mz, const UInt c, const double ampl_cutoff);
 
 
    virtual bool checkPositionForPlausibility_(const TransSpectrum& candidate, const MSSpectrum& ref, const double seed_mz,
                                               const UInt c, const UInt scan_index, const bool check_PPMs, const double transintens, const double prev_score);
 
    virtual bool checkPositionForPlausibility_(const MSSpectrum& candidate, const MSSpectrum& ref, const double seed_mz,
                                               const UInt c, const UInt scan_index, const bool check_PPMs, const double transintens, const double prev_score);
 
    virtual std::pair<double, double> checkPPMTheoModel_(const MSSpectrum& ref, const double c_mz, const UInt c);
 
 
    inline double getAvIntens_(const TransSpectrum& scan);
    inline double getAvIntens_(const MSSpectrum& scan);
 
    inline double getSdIntens_(const TransSpectrum& scan, const double mean);
    inline double getSdIntens_(const MSSpectrum& scan, const double mean);
 
    virtual void push2Box_(const double mz, const UInt scan, UInt c, const double score,
                           const double intens, const double rt, const UInt MZ_begin, const UInt MZ_end, const double ref_intens);
 
    virtual void push2TmpBox_(const double mz, const UInt scan, UInt charge, const double score,
                              const double intens, const double rt, const UInt MZ_begin, const UInt MZ_end);
 
    inline double getAvMZSpacing_(const MSSpectrum& scan);
 
 
    void clusterSeeds_(const TransSpectrum& candidates, const MSSpectrum& ref,
                       const UInt scan_index, const UInt c, const bool check_PPMs);
 
    virtual void clusterSeeds_(const MSSpectrum& candidates, const MSSpectrum& ref,
                               const UInt scan_index, const UInt c, const bool check_PPMs);
 
 
    void extendBox_(const PeakMap& map, const Box& box);
 
    inline double peptideMassRule_(const double c_mass) const
    {
      double correction_fac = c_mass / Constants::PEPTIDE_MASS_RULE_BOUND;
      double old_frac_mass = c_mass - (Int)(c_mass);
      double new_mass = ((Int)(c_mass)) * (1. + Constants::PEPTIDE_MASS_RULE_FACTOR) - (Int)(correction_fac);
      double new_frac_mass = new_mass - (Int)(new_mass);
 
      if (new_frac_mass - old_frac_mass > 0.5)
      {
        new_mass -= 1.;
      }
 
      if (new_frac_mass - old_frac_mass < -0.5)
      {
        new_mass += 1.;
      }
 
      return new_mass;
    }
 
    inline double getPPMs_(const double mass_a, const double mass_b) const
    {
      return fabs(mass_a - mass_b) / (0.5 * (mass_a + mass_b)) * 1e6;
    }
 
    //internally used data structures for the sweep line algorithm
    std::multimap<double, Box> open_boxes_, closed_boxes_, end_boxes_, front_boxes_; //double = average m/z position
    std::vector<std::multimap<double, Box> >* tmp_boxes_; //for each charge we need a separate container
 
    double av_MZ_spacing_, sigma_;
    std::vector<double> c_mzs_, c_spacings_, psi_, prod_, xs_;
    std::vector<double> interpol_xs_, interpol_ys_;
 
    Size max_scan_size_;
    UInt max_num_peaks_per_pattern_, max_charge_, data_length_;
    bool hr_data_;
    String intenstype_;
    Int from_max_to_left_, from_max_to_right_;
    std::vector<int> indices_;
 
    double min_spacing_, max_mz_cutoff_;
    std::vector<float> scores_, zeros_;
  };
 
  template <typename PeakType>
  bool intensityComparator(const PeakType& a, const PeakType& b)
  {
    return a.getIntensity() > b.getIntensity();
  }
 
  template <typename PeakType>
  bool intensityAscendingComparator(const PeakType& a, const PeakType& b)
  {
    return a.getIntensity() < b.getIntensity();
  }
 
  template <typename PeakType>
  bool intensityPointerComparator(PeakType* a, PeakType* b)
  {
    return a->getIntensity() > b->getIntensity();
  }
 
  template <typename PeakType>
  bool positionComparator(const PeakType& a, const PeakType& b)
  {
    return a.getMZ() < b.getMZ();
  }
 
  template <typename PeakType>
  IsotopeWaveletTransform<PeakType>::IsotopeWaveletTransform()
  {
    tmp_boxes_ = new std::vector<std::multimap<double, Box> >(1);
    av_MZ_spacing_ = 1;
    max_scan_size_ = 0;
    max_mz_cutoff_ = 3;
    max_num_peaks_per_pattern_ = 3;
    hr_data_ = false;
    intenstype_ = "ref";
  }
 
  template <typename PeakType>
  IsotopeWaveletTransform<PeakType>::IsotopeWaveletTransform(const double min_mz, const double max_mz, const UInt max_charge, const Size max_scan_size, const bool hr_data, String intenstype)
  {
    max_charge_ = max_charge;
    max_scan_size_ = max_scan_size;
    hr_data_ = hr_data;
    intenstype_ = intenstype;
    tmp_boxes_ = new std::vector<std::multimap<double, Box> >(max_charge);
    if (max_scan_size <= 0) //only important for the CPU
    {
      IsotopeWavelet::init(max_mz, max_charge);
    }
 
    av_MZ_spacing_ = 1;
    max_mz_cutoff_ =  IsotopeWavelet::getMzPeakCutOffAtMonoPos(max_mz, max_charge);
    max_num_peaks_per_pattern_ =  IsotopeWavelet::getNumPeakCutOff(max_mz, max_charge);
 
    Int size_estimate((Int)ceil(max_scan_size_ / (max_mz - min_mz)));
    Int to_reserve((Int)ceil(size_estimate * max_num_peaks_per_pattern_ * Constants::IW_NEUTRON_MASS));
    psi_.reserve(to_reserve); //The wavelet
    prod_.reserve(to_reserve);
    xs_.reserve(to_reserve);
    interpol_xs_.resize(Constants::DEFAULT_NUM_OF_INTERPOLATION_POINTS);
    interpol_ys_.resize(Constants::DEFAULT_NUM_OF_INTERPOLATION_POINTS);
  }
 
  template <typename PeakType>
  IsotopeWaveletTransform<PeakType>::~IsotopeWaveletTransform()
  {
    delete (tmp_boxes_);
  }
 
  template <typename PeakType>
  void IsotopeWaveletTransform<PeakType>::getTransform(MSSpectrum& c_trans, const MSSpectrum& c_ref, const UInt c)
  {
    Int spec_size((Int)c_ref.size());
    //in the very unlikely case that size_t will not fit to int anymore this will be a problem of course
    //for the sake of simplicity (we need here a signed int) we do not cast at every following comparison individually
    UInt charge = c + 1;
    double value, T_boundary_left, T_boundary_right, old, c_diff, current, old_pos, my_local_MZ, my_local_lambda, origin, c_mz;
 
    for (Int my_local_pos = 0; my_local_pos < spec_size; ++my_local_pos)
    {
      value = 0; T_boundary_left = 0; T_boundary_right = IsotopeWavelet::getMzPeakCutOffAtMonoPos(c_ref[my_local_pos].getMZ(), charge) / (double)charge;
      old = 0; old_pos = (my_local_pos - from_max_to_left_ - 1 >= 0) ? c_ref[my_local_pos - from_max_to_left_ - 1].getMZ() : c_ref[0].getMZ() - min_spacing_;
      my_local_MZ = c_ref[my_local_pos].getMZ(); my_local_lambda = IsotopeWavelet::getLambdaL(my_local_MZ * charge);
      c_diff = 0;
      origin = -my_local_MZ + Constants::IW_QUARTER_NEUTRON_MASS / (double)charge;
 
      for (Int current_conv_pos =  std::max(0, my_local_pos - from_max_to_left_); c_diff < T_boundary_right; ++current_conv_pos)
      {
        if (current_conv_pos >= spec_size)
        {
          value += 0.5 * old * min_spacing_;
          break;
        }
 
        c_mz = c_ref[current_conv_pos].getMZ();
        c_diff = c_mz + origin;
 
        //Attention! The +1. has nothing to do with the charge, it is caused by the wavelet's formula (tz1).
        current = c_diff > T_boundary_left && c_diff <= T_boundary_right ? IsotopeWavelet::getValueByLambda(my_local_lambda, c_diff * charge + 1.) * c_ref[current_conv_pos].getIntensity() : 0;
 
        value += 0.5 * (current + old) * (c_mz - old_pos);
 
        old = current;
        old_pos = c_mz;
      }
 
 
 
      c_trans[my_local_pos].setIntensity(value);
    }
  }
 
  template <typename PeakType>
  void IsotopeWaveletTransform<PeakType>::getTransformHighRes(MSSpectrum& c_trans, const MSSpectrum& c_ref, const UInt c)
  {
    Int spec_size((Int)c_ref.size());
    //in the very unlikely case that size_t will not fit to int anymore this will be a problem of course
    //for the sake of simplicity (we need here a signed int) we do not cast at every following comparison individually
    UInt charge = c + 1;
    double value, T_boundary_left, T_boundary_right, c_diff, current, my_local_MZ, my_local_lambda, origin, c_mz;
 
    for (Int my_local_pos = 0; my_local_pos < spec_size; ++my_local_pos)
    {
      value = 0; T_boundary_left = 0; T_boundary_right = IsotopeWavelet::getMzPeakCutOffAtMonoPos(c_ref[my_local_pos].getMZ(), charge) / (double)charge;
 
 
      my_local_MZ = c_ref[my_local_pos].getMZ(); my_local_lambda = IsotopeWavelet::getLambdaL(my_local_MZ * charge);
      c_diff = 0;
      origin = -my_local_MZ + Constants::IW_QUARTER_NEUTRON_MASS / (double)charge;
 
      for (Int current_conv_pos =  std::max(0, my_local_pos - from_max_to_left_); c_diff < T_boundary_right; ++current_conv_pos)
      {
        if (current_conv_pos >= spec_size)
        {
          break;
        }
 
        c_mz = c_ref[current_conv_pos].getMZ();
        c_diff = c_mz + origin;
 
        //Attention! The +1. has nothing to do with the charge, it is caused by the wavelet's formula (tz1).
        current = c_diff > T_boundary_left && c_diff <= T_boundary_right ? IsotopeWavelet::getValueByLambda(my_local_lambda, c_diff * charge + 1.) * c_ref[current_conv_pos].getIntensity() : 0;
 
        value += current;
      }
 
      c_trans[my_local_pos].setIntensity(value);
    }
  }
 
  template <typename PeakType>
  void IsotopeWaveletTransform<PeakType>::initializeScan(const MSSpectrum& c_ref, const UInt c)
  {
    data_length_ = (UInt) c_ref.size();
    computeMinSpacing(c_ref);
    Int wavelet_length = 0, quarter_length = 0;
 
    if (hr_data_) //We have to check this separately, because the simply estimation for LowRes data is destroyed by large gaps
    {
      UInt c_mz_cutoff;
      typename MSSpectrum::const_iterator start_iter, end_iter;
      for (UInt i = 0; i < data_length_; ++i)
      {
        c_mz_cutoff =  IsotopeWavelet::getMzPeakCutOffAtMonoPos(c_ref[i].getMZ(), c + 1);
        start_iter = c_ref.MZEnd(c_ref[i].getMZ());
        end_iter = c_ref.MZBegin(c_ref[i].getMZ() + c_mz_cutoff);
        wavelet_length = std::max((SignedSize) wavelet_length, distance(start_iter, end_iter) + 1);
        end_iter = c_ref.MZEnd(c_ref[i].getMZ() - Constants::IW_QUARTER_NEUTRON_MASS / double(c + 1.));
        quarter_length = std::max((SignedSize) quarter_length, distance(end_iter, start_iter) + 1);
      }
    }
    else
    {
      //CHANGED
      max_mz_cutoff_ =  IsotopeWavelet::getMzPeakCutOffAtMonoPos(c_ref[data_length_ - 1].getMZ(), max_charge_);
      wavelet_length = (UInt) ceil(max_mz_cutoff_ / min_spacing_);
    }
    //... done
 
 
    if (wavelet_length > (Int) c_ref.size())
    {
      std::cout << "Warning: the extremal length of the wavelet is larger (" << wavelet_length << ") than the number of data points (" << c_ref.size() << "). This might (!) severely affect the transform." << std::endl;
      std::cout << "Minimal spacing: " << min_spacing_ << std::endl;
      std::cout << "Warning/Error generated at scan with RT " << c_ref.getRT() << "." << std::endl;
    }
 
    Int max_index = (UInt) (Constants::IW_QUARTER_NEUTRON_MASS / min_spacing_);
    from_max_to_left_ = max_index;
    from_max_to_right_ = wavelet_length - 1 - from_max_to_left_;
  }
 
  template <typename PeakType>
  void IsotopeWaveletTransform<PeakType>::computeMinSpacing(const MSSpectrum& c_ref)
  {
    min_spacing_ = INT_MAX;
    for (UInt c_conv_pos = 1; c_conv_pos < c_ref.size(); ++c_conv_pos)
    {
      min_spacing_ = std::min(min_spacing_, c_ref[c_conv_pos].getMZ() - c_ref[c_conv_pos - 1].getMZ());
    }
  }
 
  template <typename PeakType>
  void IsotopeWaveletTransform<PeakType>::identifyCharge(const MSSpectrum& candidates,
                                                         const MSSpectrum& ref, const UInt scan_index, const UInt c, const double ampl_cutoff, const bool check_PPMs)
  {
    Size scan_size(candidates.size());
    typename ConstRefVector<MSSpectrum >::iterator iter;
    typename MSSpectrum::const_iterator iter_start, iter_end, seed_iter, iter2;
    double mz_cutoff, seed_mz, c_av_intens = 0, c_score = 0, c_sd_intens = 0, threshold = 0, help_mz, share, share_pos, bwd, fwd;
    UInt MZ_start, MZ_end;
 
    MSSpectrum diffed(candidates);
    diffed[0].setIntensity(0); diffed[scan_size - 1].setIntensity(0);
 
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
    std::stringstream stream;
    stream << "diffed_" << ref.getRT() << "_" << c + 1 << ".trans\0";
    std::ofstream ofile(stream.str().c_str());
#endif
 
    if (!hr_data_) //LowRes data
    {
      for (UInt i = 0; i < scan_size - 2; ++i)
      {
        share = candidates[i + 1].getIntensity(); share_pos = candidates[i + 1].getMZ();
        bwd = (share - candidates[i].getIntensity()) / (share_pos - candidates[i].getMZ());
        fwd = (candidates[i + 2].getIntensity() - share) / (candidates[i + 2].getMZ() - share_pos);
 
        if (!(bwd >= 0 && fwd <= 0) || share > ref[i + 1].getIntensity())
        {
          diffed[i + 1].setIntensity(0);
        }
 
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
        ofile << diffed[i + 1].getMZ() << "\t" <<  diffed[i + 1].getIntensity() << std::endl;
#endif
      }
    }
    else //HighRes data
    {
      for (UInt i = 0; i < scan_size - 2; ++i)
      {
        share = candidates[i + 1].getIntensity(); share_pos = candidates[i + 1].getMZ();
        bwd = (share - candidates[i].getIntensity()) / (share_pos - candidates[i].getMZ());
        fwd = (candidates[i + 2].getIntensity() - share) / (candidates[i + 2].getMZ() - share_pos);
 
        if (!(bwd >= 0 && fwd <= 0))
        {
          diffed[i + 1].setIntensity(0);
        }
 
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
        ofile << diffed[i + 1].getMZ() << "\t" <<  diffed[i + 1].getIntensity() << std::endl;
#endif
      }
    }
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
    ofile.close();
#endif
 
    ConstRefVector<MSSpectrum > c_sorted_candidate(diffed.begin(), diffed.end());
 
    //Sort the transform in descending order according to the intensities present in the transform
    c_sorted_candidate.sortByIntensity();
 
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
    std::stringstream stream2;
    stream2 << "sorted_cpu_" << candidates.getRT() << "_" << c + 1 << ".trans\0";
    std::ofstream ofile2(stream2.str().c_str());
    for (iter = c_sorted_candidate.end() - 1; iter != c_sorted_candidate.begin(); --iter)
    {
      ofile2 << iter->getMZ() << "\t" << iter->getIntensity() << std::endl;
    }
    ofile2.close();
#endif
 
    std::vector<UInt> processed(scan_size, 0);
 
    if (ampl_cutoff < 0)
    {
      threshold = 0;
    }
    else
    {
      c_av_intens = getAvIntens_(candidates);
      c_sd_intens = getSdIntens_(candidates, c_av_intens);
      threshold = ampl_cutoff * c_sd_intens + c_av_intens;
    }
 
    for (iter = c_sorted_candidate.end() - 1; iter != c_sorted_candidate.begin(); --iter)
    {
      if (iter->getIntensity() <= 0)
      {
        break;
      }
 
      seed_mz = iter->getMZ();
      seed_iter = ref.MZBegin(seed_mz);
 
      if (seed_iter == ref.end() || processed[distance(ref.begin(), seed_iter)])
      {
        continue;
      }
 
      mz_cutoff = IsotopeWavelet::getMzPeakCutOffAtMonoPos(seed_mz, c + 1);
      //Mark the region as processed
      //Do not move this further down, since we have to mark this as processed in any case,
      //even when score <=0; otherwise we would look around the maximum's position unless
      //any significant point is found
      iter_start = ref.MZBegin(ref.begin(), seed_mz - Constants::IW_QUARTER_NEUTRON_MASS / (c + 1.), seed_iter);
      iter_end = ref.MZEnd(seed_iter, seed_mz + mz_cutoff / (c + 1.), ref.end());
      if (iter_end == ref.end())
      {
        --iter_end;
      }
 
      MZ_start = distance(ref.begin(), iter_start);
      MZ_end = distance(ref.begin(), iter_end);
 
      memset(&(processed[MZ_start]), 1, sizeof(UInt) * (MZ_end - MZ_start + 1));
 
      c_score = scoreThis_(candidates, IsotopeWavelet::getNumPeakCutOff(seed_mz * (c + 1.)), seed_mz, c, threshold);
 
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
      if (trunc(seed_mz) == 874)
        std::cout << seed_mz << "\t" << c_score << std::endl;
#endif
 
      if (c_score <= 0 && c_score != -1000)
      {
        continue;
      }
 
      //Push the seed into its corresponding box (or create a new one, if necessary)
      //Do ***NOT*** move this further down!
      push2TmpBox_(seed_mz, scan_index, c, c_score, iter->getIntensity(), ref.getRT(), MZ_start, MZ_end);
 
      help_mz = seed_mz - Constants::IW_NEUTRON_MASS / (c + 1.);
      iter2 = candidates.MZBegin(help_mz);
      if (iter2 == candidates.end() || iter2 == candidates.begin())
      {
        continue;
      }
 
      if (fabs(iter2->getMZ() - seed_mz) > 0.5 * Constants::IW_NEUTRON_MASS / (c + 1.))
      {
        //In the other case, we are too close to the peak, leading to incorrect derivatives.
        if (iter2 != candidates.end())
        {
          push2TmpBox_(iter2->getMZ(), scan_index, c, 0, getLinearInterpolation(iter2 - 1, help_mz, iter2), ref.getRT(), MZ_start, MZ_end);
        }
      }
 
      help_mz = seed_mz + Constants::IW_NEUTRON_MASS / (c + 1.);
      iter2 = candidates.MZBegin(help_mz);
      if (iter2 == candidates.end() || iter2 == candidates.begin())
      {
        continue;
      }
 
      if (fabs(iter2->getMZ() - seed_mz) > 0.5 * Constants::IW_NEUTRON_MASS / (c + 1.))
      {
        //In the other case, we are too close to the peak, leading to incorrect derivatives.
        if (iter2 != candidates.end())
        {
          push2TmpBox_(iter2->getMZ(), scan_index, c, 0, getLinearInterpolation(iter2 - 1, help_mz, iter2), ref.getRT(), MZ_start, MZ_end);
        }
      }
    }
 
    clusterSeeds_(candidates, ref, scan_index, c, check_PPMs);
  }
 
  template <typename PeakType>
  double IsotopeWaveletTransform<PeakType>::scoreThis_(const MSSpectrum& candidate,
                                                           const UInt peak_cutoff, const double seed_mz, const UInt c, const double ampl_cutoff)
  {
    double c_score = 0, c_val;
    typename MSSpectrum::const_iterator c_left_iter2, c_right_iter2;
    Int signal_size((Int)candidate.size());
    //in the very unlikely case that size_t will not fit to int anymore this will be a problem of course
    //for the sake of simplicity (we need here a signed int) we do not cast at every following comparison individually
 
    //p_h_ind indicates if we are looking for a whole or a peak
    Int p_h_ind = 1, end = 4 * (peak_cutoff - 1) - 1; //4 times and not 2 times, since we move by 0.5 m/z entities
 
    std::vector<double> positions(end);
    for (Int i = 0; i < end; ++i)
    {
      positions[i] =  seed_mz - ((peak_cutoff - 1) * Constants::IW_NEUTRON_MASS - (i + 1) * Constants::IW_HALF_NEUTRON_MASS) / ((double)c + 1);
    }
 
    double l_score = 0, mid_val = 0;
    Int start_index = distance(candidate.begin(), candidate.MZBegin(positions[0])) - 1;
    for (Int v = 1; v <= end; ++v, ++p_h_ind)
    {
      do
      {
        if (start_index < signal_size - 1)
          ++start_index;
        else
          break;
      }
      while (candidate[start_index].getMZ() < positions[v - 1]);
 
      if (start_index <= 0 || start_index >= signal_size - 1) //unable to interpolate
      {
        continue;
      }
 
      c_left_iter2 = candidate.begin() + start_index - 1;
      c_right_iter2 = c_left_iter2 + 1;
 
      c_val = c_left_iter2->getIntensity() + (c_right_iter2->getIntensity() - c_left_iter2->getIntensity()) / (c_right_iter2->getMZ() - c_left_iter2->getMZ()) * (positions[v - 1] - c_left_iter2->getMZ());
 
      if (v == (int)(ceil(end / 2.)))
      {
        l_score = c_score;
        mid_val = c_val;
      }
 
      if (p_h_ind % 2 == 1) //I.e. a whole
      {
        c_score -= c_val;
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
        if (trunc(seed_mz) == 874)
          std::cout << -c_val << std::endl;
#endif
      }
      else
      {
        c_score += c_val;
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
        if (trunc(seed_mz) == 874)
          std::cout << c_val << std::endl;
#endif
      }
 
 
      start_index = distance(candidate.begin(), c_left_iter2);
    }
 
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
    std::ofstream ofile_score("scores.dat", ios::app);
    std::ofstream ofile_check_score("check_scores.dat", ios::app);
    ofile_score.close();
    ofile_check_score.close();
#endif
 
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
    if (trunc(seed_mz) == 874)
      std::cout << "final_score: " <<  seed_mz << "\t" << c_score << "\t l_score: " << l_score << "\t" << c_score - l_score - mid_val << "\t" <<  c_score - mid_val << "\t" << ampl_cutoff << std::endl;
#endif
 
    if (c_score - mid_val <= 0)
    {
      return 0;
    }
 
    if (c_score - mid_val <= ampl_cutoff)
    {
      return -1000;
    }
 
    if (l_score <= 0 || c_score - l_score - mid_val <= 0)
    {
      return 0;
    }
 
    return c_score;
  }
 
  template <typename PeakType>
  double IsotopeWaveletTransform<PeakType>::scoreThis_(const TransSpectrum& candidate,
                                                           const UInt peak_cutoff, const double seed_mz, const UInt c, const double ampl_cutoff)
  {
    double c_score = 0, c_val;
    typename MSSpectrum::const_iterator c_left_iter2, c_right_iter2;
    Int signal_size((Int)candidate.size());
 
    //p_h_ind indicates if we are looking for a whole or a peak
    Int p_h_ind = 1, end = 4 * (peak_cutoff - 1) - 1; //4 times and not 2 times, since we move by 0.5 m/z entities
 
    std::vector<double> positions(end);
    for (Int i = 0; i < end; ++i)
    {
      positions[i] =  seed_mz - ((peak_cutoff - 1) * Constants::IW_NEUTRON_MASS - (i + 1) * Constants::IW_HALF_NEUTRON_MASS) / ((double)c + 1);
    }
 
    double l_score = 0, mid_val = 0;
    Int start_index = distance(candidate.begin(), candidate.MZBegin(positions[0])) - 1;
    for (Int v = 1; v <= end; ++v, ++p_h_ind)
    {
      do
      {
        if (start_index < signal_size - 1)
          ++start_index;
        else
          break;
      }
      while (candidate.getMZ(start_index) < positions[v - 1]);
 
      if (start_index <= 0 || start_index >= signal_size - 1) //unable to interpolate
      {
        continue;
      }
 
      c_left_iter2 = candidate.begin() + start_index - 1;
      c_right_iter2 = c_left_iter2 + 1;
 
      c_val = candidate.getTransIntensity(start_index - 1) + (candidate.getTransIntensity(start_index) - candidate.getTransIntensity(start_index - 1)) / (c_right_iter2->getMZ() - c_left_iter2->getMZ()) * (positions[v - 1] - c_left_iter2->getMZ());
      if (v == (int)(ceil(end / 2.)))
      {
        l_score = c_score;
        mid_val = c_val;
      }
 
      if (p_h_ind % 2 == 1) //I.e. a whole
      {
        c_score -= c_val;
      }
      else
      {
        c_score += c_val;
      }
 
      start_index = distance(candidate.begin(), c_left_iter2);
    }
 
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
    std::ofstream ofile_score("scores.dat", ios::app);
    std::ofstream ofile_check_score("check_scores.dat", ios::app);
    ofile_score << c_check_point << "\t" << c_score << std::endl;
    ofile_score.close();
    ofile_check_score.close();
#endif
 
    if (l_score <= 0 || c_score - l_score - mid_val <= 0 || c_score - mid_val <= ampl_cutoff)
    {
      return 0;
    }
 
    return c_score;
  }
 
  template <typename PeakType>
  void IsotopeWaveletTransform<PeakType>::clusterSeeds_(const MSSpectrum& candidate,
                                                        const MSSpectrum& ref, const UInt scan_index, const UInt c, const bool check_PPMs)
  {
    typename std::multimap<double, Box>::iterator iter;
    typename Box::iterator box_iter;
    std::vector<BoxElement> final_box;
    double c_mz, av_score = 0, av_mz = 0, av_intens = 0, av_abs_intens = 0, count = 0;
    double virtual_av_mz = 0, virtual_av_intens = 0, virtual_av_abs_intens = 0, virtual_count = 0;
 
    for (iter = tmp_boxes_->at(c).begin(); iter != tmp_boxes_->at(c).end(); ++iter)
    {
 
      Box& c_box = iter->second;
      av_score = 0; av_mz = 0; av_intens = 0; av_abs_intens = 0; count = 0;
      virtual_av_mz = 0; virtual_av_intens = 0; virtual_av_abs_intens = 0; virtual_count = 0;
 
      //Now, let's get the RT boundaries for the box
      for (box_iter = c_box.begin(); box_iter != c_box.end(); ++box_iter)
      {
        if (box_iter->second.score == 0) //virtual helping point
        {
          if (count != 0)
            continue; //it is in any way not pure virtual
 
          c_mz = box_iter->second.mz;
          virtual_av_intens += box_iter->second.intens;
          virtual_av_abs_intens += fabs(box_iter->second.intens);
          virtual_av_mz += c_mz * fabs(box_iter->second.intens);
          ++virtual_count;
        }
        else
        {
          c_mz = box_iter->second.mz;
          av_score += box_iter->second.score;
          av_intens += box_iter->second.intens;
          av_abs_intens += fabs(box_iter->second.intens);
          av_mz += c_mz * fabs(box_iter->second.intens);
          ++count;
        }
      }
 
      if (count == 0) //pure virtual helping box
      {
        av_intens = virtual_av_intens / virtual_count;
        av_score = 0;
        av_mz = virtual_av_mz / virtual_av_abs_intens;
      }
      else
      {
        av_intens /= count;
        av_score /= count;
        av_mz /= av_abs_intens;
      }
 
      BoxElement c_box_element;
      c_box_element.mz = av_mz;
      c_box_element.c = c;
      c_box_element.score = av_score;
      c_box_element.intens = av_intens;
 
      c_box_element.RT = c_box.begin()->second.RT;
      final_box.push_back(c_box_element);
    }
 
    Size num_o_feature = final_box.size();
    if (num_o_feature == 0)
    {
      tmp_boxes_->at(c).clear();
      return;
    }
 
    //Computing the derivatives
    std::vector<double> bwd_diffs(num_o_feature, 0);
 
    bwd_diffs[0] = 0;
    for (Size i = 1; i < num_o_feature; ++i)
    {
      bwd_diffs[i] = (final_box[i].intens - final_box[i - 1].intens) / (final_box[i].mz - final_box[i - 1].mz);
    }
 
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
    std::ofstream ofile_bwd("bwd_cpu.dat");
    for (Size i = 0; i < num_o_feature; ++i)
    {
      ofile_bwd << final_box[i].mz << "\t" << bwd_diffs[i] << std::endl;
    }
    ofile_bwd.close();
#endif
 
 
    for (Size i = 0; i < num_o_feature - 1; ++i)
    {
      while (i < num_o_feature - 2)
      {
        if (final_box[i].score > 0 || final_box[i].score == -1000) //this has been an helping point
          break;
        ++i;
      }
 
      if (bwd_diffs[i] > 0 && bwd_diffs[i + 1] < 0)
      {
        checkPositionForPlausibility_(candidate, ref, final_box[i].mz, final_box[i].c, scan_index, check_PPMs, final_box[i].intens, final_box[i].score);
        continue;
      }
    }
 
    tmp_boxes_->at(c).clear();
  }
 
  template <typename PeakType>
  double IsotopeWaveletTransform<PeakType>::getAvIntens_(const MSSpectrum& scan)
  {
    double av_intens = 0;
    for (UInt i = 0; i < scan.size(); ++i)
    {
      if (scan[i].getIntensity() >= 0)
      {
        av_intens += scan[i].getIntensity();
      }
    }
    return av_intens / (double)scan.size();
  }
 
  template <typename PeakType>
  double IsotopeWaveletTransform<PeakType>::getSdIntens_(const MSSpectrum& scan, const double mean)
  {
    double res = 0, intens;
    for (UInt i = 0; i < scan.size(); ++i)
    {
      if (scan[i].getIntensity() >= 0)
      {
        intens = scan[i].getIntensity();
        res += (intens - mean) * (intens - mean);
      }
    }
    return sqrt(res / (double)(scan.size() - 1));
  }
 
  template <typename PeakType>
  double IsotopeWaveletTransform<PeakType>::getAvMZSpacing_(const MSSpectrum& scan) //, Int start_index, Int end_index)
  {
    std::vector<double> diffs(scan.size() - 1, 0);
    for (UInt i = 0; i < scan.size() - 1; ++i)
    {
      diffs[i] = scan[i + 1].getMZ() - scan[i].getMZ();
    }
 
    sort(diffs.begin(), diffs.end());
    double av_MZ_spacing = 0;
    for (UInt i = 0; i < diffs.size() / 2; ++i)
    {
      av_MZ_spacing += diffs[i];
    }
 
    return av_MZ_spacing / (diffs.size() / 2);
  }
 
  template <typename PeakType>
  double IsotopeWaveletTransform<PeakType>::getAvIntens_(const TransSpectrum& scan)
  {
    double av_intens = 0;
    for (UInt i = 0; i < scan.size(); ++i)
    {
      if (scan.getTransIntensity(i) >= 0)
      {
        av_intens += scan.getTransIntensity(i);
      }
    }
    return av_intens / (double)scan.size();
  }
 
  template <typename PeakType>
  double IsotopeWaveletTransform<PeakType>::getSdIntens_(const TransSpectrum& scan, const double mean)
  {
    double res = 0, intens;
    for (UInt i = 0; i < scan.size(); ++i)
    {
      if (scan.getTransIntensity(i) >= 0)
      {
        intens = scan.getTransIntensity(i);
        res += (intens - mean) * (intens - mean);
      }
    }
    return sqrt(res / (double)(scan.size() - 1));
  }
 
  template <typename PeakType>
  void IsotopeWaveletTransform<PeakType>::push2Box_(const double mz, const UInt scan, UInt c,
                                                    const double score, const double intens, const double rt, const UInt MZ_begin, const UInt MZ_end, double ref_intens)
  {
    const double dist_constraint(Constants::IW_HALF_NEUTRON_MASS / (double)max_charge_);
 
    typename std::multimap<double, Box>::iterator upper_iter(open_boxes_.upper_bound(mz));
    typename std::multimap<double, Box>::iterator lower_iter(open_boxes_.lower_bound(mz));
 
    if (lower_iter != open_boxes_.end())
    {
      //Ugly, but necessary due to the implementation of STL lower_bound
      if (mz != lower_iter->first && lower_iter != open_boxes_.begin())
      {
        --lower_iter;
      }
    }
 
    typename std::multimap<double, Box>::iterator insert_iter;
    bool create_new_box = true;
    if (lower_iter == open_boxes_.end()) //I.e. there is no open Box for that mz position
    {
      //There is another special case to be considered here:
      //Assume that the current box contains only a single element that is (slightly) smaller than the new mz value,
      //then the lower bound for the new mz value is box.end and this would usually force a new entry
      if (!open_boxes_.empty())
      {
        if (fabs((--lower_iter)->first - mz) < dist_constraint) //matching box
        {
          create_new_box = false;
          insert_iter = lower_iter;
        }
      }
      else
      {
        create_new_box = true;
      }
    }
    else
    {
      if (upper_iter == open_boxes_.end() && fabs(lower_iter->first - mz) < dist_constraint) //Found matching Box
      {
        insert_iter = lower_iter;
        create_new_box = false;
      }
      else
      {
        create_new_box = true;
      }
    }
 
 
    if (upper_iter != open_boxes_.end() && lower_iter != open_boxes_.end())
    {
      //Here is the question if you should figure out the smallest charge .... and then
 
      //Figure out which entry is closer to m/z
      double dist_lower = fabs(lower_iter->first - mz);
      double dist_upper = fabs(upper_iter->first - mz);
      dist_lower = (dist_lower < dist_constraint) ? dist_lower : INT_MAX;
      dist_upper = (dist_upper < dist_constraint) ? dist_upper : INT_MAX;
 
      if (dist_lower >= dist_constraint && dist_upper >= dist_constraint) // they are both too far away
      {
        create_new_box = true;
      }
      else
      {
        insert_iter = (dist_lower < dist_upper) ? lower_iter : upper_iter;
        create_new_box = false;
      }
    }
 
    BoxElement element;
    element.c = c; element.mz = mz; element.score = score; element.RT = rt; element.intens = intens; element.ref_intens = ref_intens;
    element.RT_index = scan; element.MZ_begin = MZ_begin; element.MZ_end = MZ_end;
 
 
    if (create_new_box == false)
    {
      std::pair<UInt, BoxElement> help2(scan, element);
      insert_iter->second.insert(help2);
 
      //Unfortunately, we need to change the m/z key to the average of all keys inserted in that box.
      Box replacement(insert_iter->second);
 
      //We cannot divide both m/z by 2, since we already inserted some m/zs whose weight would be lowered.
      //Also note that we already inserted the new entry, leading to size-1.
      double c_mz = insert_iter->first * (insert_iter->second.size() - 1) + mz;
      c_mz /= ((double) insert_iter->second.size());
 
      //Now let's remove the old and insert the new one
      open_boxes_.erase(insert_iter);
      std::pair<double, std::multimap<UInt, BoxElement> > help3(c_mz, replacement);
      open_boxes_.insert(help3);
    }
    else
    {
      std::pair<UInt, BoxElement> help2(scan, element);
      std::multimap<UInt, BoxElement> help3;
      help3.insert(help2);
      std::pair<double, std::multimap<UInt, BoxElement> > help4(mz, help3);
      open_boxes_.insert(help4);
    }
  }
 
  template <typename PeakType>
  void IsotopeWaveletTransform<PeakType>::push2TmpBox_(const double mz, const UInt scan, UInt c,
                                                       const double score, const double intens, const double rt, const UInt MZ_begin, const UInt MZ_end)
  {
    const double dist_constraint(Constants::IW_HALF_NEUTRON_MASS / (double)max_charge_);
 
    std::multimap<double, Box>& tmp_box(tmp_boxes_->at(c));
    typename std::multimap<double, Box>::iterator upper_iter(tmp_box.upper_bound(mz));
    typename std::multimap<double, Box>::iterator lower_iter(tmp_box.lower_bound(mz));
 
    if (lower_iter != tmp_box.end())
    {
      //Ugly, but necessary due to the implementation of STL lower_bound
      if (mz != lower_iter->first && lower_iter != tmp_box.begin())
      {
        --lower_iter;
      }
    }
 
    typename std::multimap<double, Box>::iterator insert_iter;
    bool create_new_box = true;
    if (lower_iter == tmp_box.end()) //I.e. there is no tmp Box for that mz position
    {
      //There is another special case to be considered here:
      //Assume that the current box contains only a single element that is (slightly) smaller than the new mz value,
      //then the lower bound for the new mz value is box.end and this would usually force a new entry
      if (!tmp_box.empty())
      {
        if (fabs((--lower_iter)->first - mz) < dist_constraint) //matching box
        {
          create_new_box = false;
          insert_iter = lower_iter;
        }
      }
      else
      {
        create_new_box = true;
      }
    }
    else
    {
      if (upper_iter == tmp_box.end() && fabs(lower_iter->first - mz) < dist_constraint) //Found matching Box
      {
        insert_iter = lower_iter;
        create_new_box = false;
      }
      else
      {
        create_new_box = true;
      }
    }
 
 
    if (upper_iter != tmp_box.end() && lower_iter != tmp_box.end())
    {
      //Figure out which entry is closer to m/z
      double dist_lower = fabs(lower_iter->first - mz);
      double dist_upper = fabs(upper_iter->first - mz);
      dist_lower = (dist_lower < dist_constraint) ? dist_lower : INT_MAX;
      dist_upper = (dist_upper < dist_constraint) ? dist_upper : INT_MAX;
 
      if (dist_lower >= dist_constraint && dist_upper >= dist_constraint) // they are both too far away
      {
        create_new_box = true;
      }
      else
      {
        insert_iter = (dist_lower < dist_upper) ? lower_iter : upper_iter;
        create_new_box = false;
      }
    }
 
    BoxElement element;
    element.c = c; element.mz = mz; element.score = score; element.RT = rt; element.intens = intens; element.ref_intens = -1000;
    element.RT_index = scan; element.MZ_begin = MZ_begin; element.MZ_end = MZ_end;
 
    if (create_new_box == false)
    {
      std::pair<UInt, BoxElement> help2(scan, element);
      insert_iter->second.insert(help2);
 
      //Unfortunately, we need to change the m/z key to the average of all keys inserted in that box.
      Box replacement(insert_iter->second);
 
      //We cannot divide both m/z by 2, since we already inserted some m/zs whose weight would be lowered.
      //Also note that we already inserted the new entry, leading to size-1.
      double c_mz = insert_iter->first * (insert_iter->second.size() - 1) + mz;
      c_mz /= ((double) insert_iter->second.size());
 
      //Now let's remove the old and insert the new one
      tmp_box.erase(insert_iter);
      std::pair<double, std::multimap<UInt, BoxElement> > help3(c_mz, replacement);
      tmp_box.insert(help3);
    }
    else
    {
      std::pair<UInt, BoxElement> help2(scan, element);
      std::multimap<UInt, BoxElement> help3;
      help3.insert(help2);
 
      std::pair<double, std::multimap<UInt, BoxElement> > help4(mz, help3);
      tmp_box.insert(help4);
    }
  }
 
  template <typename PeakType>
  void IsotopeWaveletTransform<PeakType>::updateBoxStates(const PeakMap& map, const Size scan_index, const UInt RT_interleave,
                                                          const UInt RT_votes_cutoff, const Int front_bound, const Int end_bound)
  {
    typename std::multimap<double, Box>::iterator iter, iter2;
 
    if ((Int)scan_index == end_bound && end_bound != (Int)map.size() - 1)
    {
      for (iter = open_boxes_.begin(); iter != open_boxes_.end(); ++iter)
      {
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
        std::cout << "LOW THREAD insert in end_box " << iter->first << std::endl;
        typename Box::iterator dings;
        for (dings = iter->second.begin(); dings != iter->second.end(); ++dings)
          std::cout << map[dings->first].getRT() << "\t" << dings->second.c + 1 <<  std::endl;
#endif
        end_boxes_.insert(*iter);
      }
      open_boxes_.clear();
      return;
    }
 
    for (iter = open_boxes_.begin(); iter != open_boxes_.end(); )
    {
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
      if (front_bound > 0)
      {
        std::cout << "HIGH THREAD open box. " << iter->first << "\t current scan index " << scan_index << "\t" << ((iter->second.begin()))->first << "\t of last scan " << map.size() - 1 << "\t" << front_bound << std::endl;
      }
#endif
 
      //For each Box we need to figure out, if and when the last RT value has been inserted
      UInt lastScan = (--(iter->second.end()))->first;
      if (scan_index - lastScan > RT_interleave + 1 || scan_index == map.size() - 1) //I.e. close the box!
      {
        if (iter->second.begin()->first - front_bound <= RT_interleave + 1 && front_bound > 0)
        {
          iter2 = iter;
          ++iter2;
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
          std::cout << "HIGH THREAD insert in front_box " << iter->first << std::endl;
#endif
          front_boxes_.insert(*iter);
          open_boxes_.erase(iter);
          iter = iter2;
          continue;
        }
 
        iter2 = iter;
        ++iter2;
        //Please do **NOT** simplify the upcoming lines.
        //The 'obvious' overhead is necessary since the object represented by iter might be erased
        //by push2Box which might be called by extendBox_.
        if (iter->second.size() >= RT_votes_cutoff)
        {
          //extendBox_ (map, iter->second);
          iter = iter2;
          closed_boxes_.insert(*(--iter));
        }
        open_boxes_.erase(iter);
        iter = iter2;
      }
      else
      {
        ++iter;
      }
    }
  }
 
  template <typename PeakType>
  void IsotopeWaveletTransform<PeakType>::extendBox_(const PeakMap& map, const Box& box)
  {
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
    std::cout << "**** CHECKING FOR BOX EXTENSIONS ****" << std::endl;
#endif
 
    //Determining the elution profile
    typename Box::const_iterator iter;
    std::vector<double> elution_profile(box.size());
    UInt index = 0;
    for (iter = box.begin(); iter != box.end(); ++iter, ++index)
    {
      for (Size i = iter->second.MZ_begin; i != iter->second.MZ_end; ++i)
      {
        elution_profile[index] += map[iter->second.RT_index][i].getIntensity();
      }
      elution_profile[index] /= iter->second.MZ_end - iter->second.MZ_begin + 1.;
    }
 
    double max = 0;
    Int max_index = INT_MIN;
    for (Size i = 0; i < elution_profile.size(); ++i)
    {
      if (elution_profile[i] > max)
      {
        max_index = i;
        max = elution_profile[i];
      }
    }
 
    Int max_extension = (Int)(elution_profile.size()) - 2 * max_index;
 
    double av_elution = 0;
    for (Size i = 0; i < elution_profile.size(); ++i)
    {
      av_elution += elution_profile[i];
    }
    av_elution /= (double)elution_profile.size();
 
    double sd_elution = 0;
    for (Size i = 0; i < elution_profile.size(); ++i)
    {
      sd_elution += (av_elution - elution_profile[i]) * (av_elution - elution_profile[i]);
    }
    sd_elution /= (double)(elution_profile.size() - 1);
    sd_elution = sqrt(sd_elution);
 
    //Determine average m/z monoisotopic pos
    double av_mz = 0;
    for (iter = box.begin(); iter != box.end(); ++iter, ++index)
    {
      av_mz += iter->second.mz;
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
      std::cout << iter->second.RT << "\t" << iter->second.mz << "\t" << iter->second.c + 1 << std::endl;
#endif
    }
    av_mz /= (double)box.size();
 
 
    //Boundary check
    if ((Int)(box.begin()->second.RT_index) - 1 < 0)
    {
      return;
    }
 
    UInt pre_index =  box.begin()->second.RT_index - 1;
    typename MSSpectrum::const_iterator c_iter =  map[pre_index].MZBegin(av_mz);
    double pre_elution = 0;
 
    double mz_start = map[pre_index + 1][box.begin()->second.MZ_begin].getMZ();
    double mz_end = map[pre_index + 1][box.begin()->second.MZ_end].getMZ();
 
    typename MSSpectrum::const_iterator mz_start_iter = map[pre_index].MZBegin(mz_start), mz_end_iter = map[pre_index].MZBegin(mz_end);
    for (typename MSSpectrum::const_iterator mz_iter = mz_start_iter; mz_iter != mz_end_iter; ++mz_iter)
    {
      pre_elution += mz_iter->getIntensity();
    }
 
 
    //Do we need to extend at all?
    if (pre_elution <= av_elution - 2 * sd_elution)
    {
      return;
    }
 
    Int first_index = box.begin()->second.RT_index;
    for (Int i = 1; i < max_extension; ++i)
    {
      Int c_index = first_index - i;
      if (c_index < 0)
      {
        break;
      }
 
      //CHECK Majority vote for charge???????????????
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
      std::cout << box.begin()->second.RT << "\t" << av_mz << "\t" << box.begin()->second.c + 1 << "\t" << " extending the box " << std::endl;
#endif
 
      push2Box_(av_mz, c_index, box.begin()->second.c, box.begin()->second.score, c_iter->getIntensity(),
                map[c_index].getRT(), box.begin()->second.MZ_begin, box.begin()->second.MZ_end);
    }
  }
 
  template <typename PeakType>
  void IsotopeWaveletTransform<PeakType>::clusterSeeds_(const TransSpectrum& candidates,
                                                        const MSSpectrum& ref, const UInt scan_index, const UInt c, const bool check_PPMs)
  {
    typename std::multimap<double, Box>::iterator iter;
    typename Box::iterator box_iter;
    std::vector<BoxElement> final_box;
    double c_mz, av_score = 0, av_mz = 0, av_intens = 0, av_abs_intens = 0, count = 0;
    double virtual_av_mz = 0, virtual_av_intens = 0, virtual_av_abs_intens = 0, virtual_count = 0;
 
    for (iter = tmp_boxes_->at(c).begin(); iter != tmp_boxes_->at(c).end(); ++iter)
    {
      Box& c_box = iter->second;
      av_score = 0; av_mz = 0; av_intens = 0; av_abs_intens = 0; count = 0;
      virtual_av_mz = 0; virtual_av_intens = 0; virtual_av_abs_intens = 0; virtual_count = 0;
 
      for (box_iter = c_box.begin(); box_iter != c_box.end(); ++box_iter)
      {
        if (box_iter->second.score == 0) //virtual helping point
        {
          if (count != 0)
            continue; //it is in any way not pure virtual
 
          c_mz = box_iter->second.mz;
          virtual_av_intens += box_iter->second.intens;
          virtual_av_abs_intens += fabs(box_iter->second.intens);
          virtual_av_mz += c_mz * fabs(box_iter->second.intens);
          ++virtual_count;
        }
        else
        {
          c_mz = box_iter->second.mz;
          av_score += box_iter->second.score;
          av_intens += box_iter->second.intens;
          av_abs_intens += fabs(box_iter->second.intens);
          av_mz += c_mz * fabs(box_iter->second.intens);
          ++count;
        }
      }
 
      if (count == 0) //pure virtual helping box
      {
        av_intens = virtual_av_intens / virtual_count;
        av_score = 0;
        av_mz = virtual_av_mz / virtual_av_abs_intens;
      }
      else
      {
        av_intens /= count;
        av_score /= count;
        av_mz /= av_abs_intens;
      }
 
      BoxElement c_box_element;
      c_box_element.mz = av_mz;
      c_box_element.c = c;
      c_box_element.score = av_score;
      c_box_element.intens = av_intens;
 
      c_box_element.RT = c_box.begin()->second.RT;
 
      final_box.push_back(c_box_element);
    }
 
    UInt num_o_feature = final_box.size();
    if (num_o_feature == 0)
    {
      tmp_boxes_->at(c).clear();
      return;
    }
 
    //Computing the derivatives
    std::vector<double> bwd_diffs(num_o_feature, 0);
 
    bwd_diffs[0] = 0;
    for (UInt i = 1; i < num_o_feature; ++i)
    {
      bwd_diffs[i] = (final_box[i].intens - final_box[i - 1].intens) / (final_box[i].mz - final_box[i - 1].mz);
    }
 
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
    std::ofstream ofile_bwd("bwd_gpu.dat");
    for (UInt i = 0; i < num_o_feature; ++i)
    {
      ofile_bwd << final_box[i].mz << "\t" << bwd_diffs[i] << std::endl;
    }
    ofile_bwd.close();
#endif
 
    for (UInt i = 0; i < num_o_feature - 1; ++i)
    {
      while (i < num_o_feature - 2)
      {
        if (final_box[i].score > 0 || final_box[i].score == -1000) //this has been an helping point
          break;
        ++i;
      }
 
      if (bwd_diffs[i] > 0 && bwd_diffs[i + 1] < 0)
      {
        checkPositionForPlausibility_(candidates, ref, final_box[i].mz, final_box[i].c, scan_index, check_PPMs, final_box[i].intens, final_box[i].score);
        continue;
      }
    }
 
    tmp_boxes_->at(c).clear();
  }
 
  template <typename PeakType>
  FeatureMap IsotopeWaveletTransform<PeakType>::mapSeeds2Features(const PeakMap& map, const UInt RT_votes_cutoff)
  {
    FeatureMap feature_map;
    typename std::multimap<double, Box>::iterator iter;
    typename Box::iterator box_iter;
    UInt best_charge_index; double best_charge_score, c_mz, c_RT; UInt c_charge;
    double av_intens = 0, av_ref_intens = 0, av_score = 0, av_mz = 0, av_RT = 0, mz_cutoff, sum_of_ref_intenses_g;
 
    for (iter = closed_boxes_.begin(); iter != closed_boxes_.end(); ++iter)
    {
      sum_of_ref_intenses_g = 0;
      Box& c_box = iter->second;
      std::vector<double> charge_votes(max_charge_, 0), charge_binary_votes(max_charge_, 0);
      bool restart = false;
 
      //Let's first determine the charge
      //Therefore, we can use two types of votes: qualitative ones (charge_binary_votes) or quantitative ones (charge_votes)
      for (box_iter = c_box.begin(); box_iter != c_box.end(); ++box_iter)
      {
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
        if (trunc(box_iter->second.mz) == 874)
          std::cout << box_iter->second.c << "\t" <<  box_iter->second.intens  << "\t" << box_iter->second.score << std::endl;
#endif
 
        if (box_iter->second.score == -1000)
        {
          restart = true;
          break;
        }
 
        charge_votes[box_iter->second.c] += box_iter->second.intens; //score; Do not use score, can get problematic for charge state 2 vs 4
        ++charge_binary_votes[box_iter->second.c];
      }
 
      if (restart)
      {
        continue;
      }
 
      //... determining the best fitting charge
      best_charge_index = 0; best_charge_score = 0;
      for (UInt i = 0; i < max_charge_; ++i)
      {
        if (charge_votes[i] > best_charge_score)
        {
          best_charge_index = i;
          best_charge_score = charge_votes[i];
        }
      }
 
      //Pattern found in too few RT scan
      if (charge_binary_votes[best_charge_index] < RT_votes_cutoff && RT_votes_cutoff <= map.size())
      {
        continue;
      }
 
      c_charge = best_charge_index + 1; //that's the finally predicted charge state for the pattern
 
      av_intens = 0; av_ref_intens = 0; av_score = 0; av_mz = 0; av_RT = 0;
      //Now, let's get the RT boundaries for the box
      std::vector<DPosition<2> > point_set;
      double sum_of_ref_intenses_l;
      for (box_iter = c_box.begin(); box_iter != c_box.end(); ++box_iter)
      {
        sum_of_ref_intenses_l = 0;
        c_mz = box_iter->second.mz;
        c_RT = box_iter->second.RT;
 
        mz_cutoff = IsotopeWavelet::getMzPeakCutOffAtMonoPos(c_mz, c_charge);
 
        point_set.push_back(DPosition<2>(c_RT, c_mz - Constants::IW_QUARTER_NEUTRON_MASS / (double)c_charge));
        //-1 since we are already at the first peak and +0.75, since this includes the last peak of the wavelet as a whole
        point_set.push_back(DPosition<2>(c_RT, c_mz + mz_cutoff / (double)c_charge));
 
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
        std::cout << "Intenstype: " << intenstype_ << std::endl;
#endif
        if (intenstype_ == "ref")
        {
          //Find monoisotopic max
          const MSSpectrum& c_spec(map[box_iter->second.RT_index]);
          //'Correct' possible shift
          for (unsigned int i = 0; i < mz_cutoff; ++i)
          {
            typename MSSpectrum::const_iterator h_iter = c_spec.MZBegin(c_mz + i * Constants::IW_NEUTRON_MASS / c_charge + Constants::IW_QUARTER_NEUTRON_MASS / (double)c_charge), hc_iter = c_spec.MZBegin(c_mz + i * Constants::IW_NEUTRON_MASS / c_charge);
 
            hc_iter = c_spec.MZBegin(c_mz + i * Constants::IW_NEUTRON_MASS / c_charge);
 
            while (h_iter != c_spec.begin())
            {
 
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
              if (trunc(c_mz) == 874)
              {
                std::cout << "cmz: " << c_mz + i * Constants::IW_NEUTRON_MASS / c_charge << "\t" << hc_iter->getMZ() << "\t" << hc_iter->getIntensity() << "\t" << h_iter->getMZ() << "\t" << h_iter->getIntensity() << std::endl;
              }
#endif
 
              --h_iter;
              if (h_iter->getIntensity() > hc_iter->getIntensity() || (h_iter->getIntensity() == hc_iter->getIntensity() && hc_iter->getIntensity() == 0))
              {
                hc_iter = h_iter;
              }
 
              if (c_mz + i * Constants::IW_NEUTRON_MASS / c_charge - h_iter->getMZ() > Constants::IW_QUARTER_NEUTRON_MASS / (double)c_charge)
              {
                break;
              }
            }
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
            if (trunc(c_mz) == 874)
            {
              std::cout << "c_mz: " << c_mz + i * Constants::IW_NEUTRON_MASS / c_charge << "\t" << hc_iter->getMZ() << "\t" << hc_iter->getIntensity() << "\t" << i * Constants::IW_NEUTRON_MASS / c_charge << "\t";
            }
#endif
            sum_of_ref_intenses_l += hc_iter->getIntensity();
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
            if (trunc(c_mz) == 874)
            {
              std::cout << sum_of_ref_intenses_l <<  "********" << std::endl;
            }
#endif
          }
        }
 
        if (best_charge_index == box_iter->second.c)
        {
          av_score += box_iter->second.score;
          av_intens += box_iter->second.intens;
          av_ref_intens += box_iter->second.ref_intens;
          sum_of_ref_intenses_g += sum_of_ref_intenses_l;
          av_mz += c_mz * box_iter->second.intens;
        }
        av_RT += c_RT;
      }
 
      av_mz /= av_intens;
      av_ref_intens /= (double)charge_binary_votes[best_charge_index];
      av_score /= (double)charge_binary_votes[best_charge_index];
      av_RT /= (double)c_box.size();
 
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
      if (trunc(av_mz) == 874)
        std::cout << av_mz << "\t" << best_charge_index << "\t" << best_charge_score << std::endl;
#endif
 
      Feature c_feature;
      ConvexHull2D c_conv_hull;
      c_conv_hull.addPoints(point_set);
      c_feature.setCharge(c_charge);
      c_feature.setConvexHulls(std::vector<ConvexHull2D>(1, c_conv_hull));
 
      //This makes the intensity value independent of the m/z (the lambda) value (Skellam distribution)
      if (intenstype_ == "corrected")
      {
        double lambda = IsotopeWavelet::getLambdaL(av_mz * c_charge);
        av_intens /= exp(-2 * lambda) * boost::math::cyl_bessel_i(0.0, 2.0 * lambda);
      }
      if (intenstype_ == "ref")
      {
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
        if (trunc(c_mz) == 874)
        {
          std::cout << sum_of_ref_intenses_g <<  "####" << std::endl;
        }
#endif
 
        av_intens = sum_of_ref_intenses_g;
      }
 
      c_feature.setMZ(av_mz);
      c_feature.setIntensity(av_intens);
      c_feature.setRT(av_RT);
      c_feature.setOverallQuality(av_score);
      feature_map.push_back(c_feature);
    }
 
    return feature_map;
  }
 
  template <typename PeakType>
  bool IsotopeWaveletTransform<PeakType>::checkPositionForPlausibility_(const MSSpectrum& candidate,
                                                                        const MSSpectrum& ref, const double seed_mz, const UInt c, const UInt scan_index, const bool check_PPMs, const double transintens, const double prev_score)
  {
    typename MSSpectrum::const_iterator iter, ref_iter;
    UInt peak_cutoff;
    peak_cutoff = IsotopeWavelet::getNumPeakCutOff(seed_mz, c + 1);
 
    iter = candidate.MZBegin(seed_mz);
    //we can ignore those cases
    if (iter == candidate.begin() || iter == candidate.end())
    {
      return false;
    }
 
    std::pair<double, double> reals;
    ref_iter =  ref.MZBegin(seed_mz);
    //Correct the position
    double real_mz, real_intens;
    if (check_PPMs)
    {
      //reals = checkPPMTheoModel_(ref, iter->getMZ(), c);
      //real_mz = reals.first; real_intens = reals.second;
      //if (real_mz <= 0 || real_intens <= 0)
      //{
      typename MSSpectrum::const_iterator h_iter = ref_iter, hc_iter = ref_iter;
      while (h_iter != ref.begin())
      {
        --h_iter;
        if (h_iter->getIntensity() > hc_iter->getIntensity() || (h_iter->getIntensity() == hc_iter->getIntensity() && hc_iter->getIntensity() == 0))
        {
          hc_iter = h_iter;
        }
        else
        {
          break;
        }
 
        if (seed_mz - h_iter->getMZ() > Constants::IW_QUARTER_NEUTRON_MASS / (c + 1.))
        {
          return false;
        }
      }
      reals = checkPPMTheoModel_(ref, h_iter->getMZ(), c);
      real_mz = reals.first; real_intens = reals.second;
      if (real_mz <= 0 || real_intens <= 0)
      {
        return false;
      }
      real_mz = h_iter->getMZ();
      real_intens = h_iter->getIntensity();
      //}
    }
    else
    {
      reals = std::pair<double, double>(seed_mz, ref_iter->getIntensity());
      real_mz = reals.first; real_intens = reals.second;
 
      if (real_mz <= 0 || real_intens <= 0)
      {
        typename MSSpectrum::const_iterator h_iter = ref_iter, hc_iter = ref_iter;
        while (h_iter != ref.begin())
        {
          --h_iter;
          if (h_iter->getIntensity() > hc_iter->getIntensity() || (h_iter->getIntensity() == hc_iter->getIntensity() && hc_iter->getIntensity() == 0))
          {
            hc_iter = h_iter;
          }
          else
          {
            break;
          }
 
          if (seed_mz - h_iter->getMZ() > Constants::IW_QUARTER_NEUTRON_MASS / (c + 1.))
          {
            return false;
          }
        }
        real_mz = h_iter->getMZ(); real_intens = h_iter->getIntensity();
        if (real_mz <= 0 || real_intens <= 0)
        {
          return false;
        }
        real_mz = h_iter->getMZ();
        real_intens = h_iter->getIntensity();
      }
    }
 
    double c_score = scoreThis_(candidate, peak_cutoff, real_mz, c, 0);
 
    if (c_score <= 0)
    {
      return false;
    }
 
    double mz_cutoff = IsotopeWavelet::getMzPeakCutOffAtMonoPos(real_mz, c + 1);
    typename MSSpectrum::const_iterator real_l_MZ_iter = ref.MZBegin(real_mz - Constants::IW_QUARTER_NEUTRON_MASS / (c + 1.));
    typename MSSpectrum::const_iterator real_r_MZ_iter = ref.MZBegin(real_l_MZ_iter, real_mz + mz_cutoff / (c + 1.), ref.end());
    if (real_r_MZ_iter == ref.end())
    {
      --real_r_MZ_iter;
    }
 
 
    UInt real_mz_begin = distance(ref.begin(), real_l_MZ_iter);
    UInt real_mz_end = distance(ref.begin(), real_r_MZ_iter);
 
    if (prev_score == -1000)
    {
      push2Box_(real_mz, scan_index, c, prev_score, transintens, ref.getRT(), real_mz_begin, real_mz_end, real_intens);
    }
    else
    {
      push2Box_(real_mz, scan_index, c, c_score, transintens, ref.getRT(), real_mz_begin, real_mz_end, real_intens);
    }
    return true;
  }
 
  template <typename PeakType>
  bool IsotopeWaveletTransform<PeakType>::checkPositionForPlausibility_(const TransSpectrum& candidate,
                                                                        const MSSpectrum& ref, const double seed_mz, const UInt c, const UInt scan_index, const bool check_PPMs, const double transintens, const double prev_score)
  {
    typename MSSpectrum::const_iterator iter, ref_iter;
    UInt peak_cutoff;
    peak_cutoff = IsotopeWavelet::getNumPeakCutOff(seed_mz, c + 1);
 
    iter = candidate.MZBegin(seed_mz);
    //we can ignore those cases
    if (iter == candidate.begin() || iter == candidate.end())
    {
      return false;
    }
 
    std::pair<double, double> reals;
    ref_iter =  ref.MZBegin(seed_mz);
    //Correct the position
    double real_mz, real_intens;
    if (check_PPMs)
    {
      reals = checkPPMTheoModel_(ref, iter->getMZ(), c);
      real_mz = reals.first; real_intens = reals.second;
      //if (real_mz <= 0 || real_intens <= 0)
      //{
      auto h_iter = ref_iter, hc_iter = ref_iter;
      while (h_iter != ref.begin())
      {
        --h_iter;
        if (h_iter->getIntensity() > hc_iter->getIntensity() || (h_iter->getIntensity() == hc_iter->getIntensity() && hc_iter->getIntensity() == 0))
        {
          hc_iter = h_iter;
        }
        else
        {
          break;
        }
 
        if (seed_mz - h_iter->getMZ() > Constants::IW_QUARTER_NEUTRON_MASS / (c + 1.))
        {
          return false;
        }
      }
      ++h_iter;
      reals = checkPPMTheoModel_(ref, h_iter->getMZ(), c);
      real_mz = reals.first; real_intens = reals.second;
 
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
      std::cout << "Plausibility check old_mz: " << iter->getMZ() << "\t" << real_mz << std::endl;
#endif
 
      if (real_mz <= 0 || real_intens <= 0)
      {
        return false;
      }
      real_mz = h_iter->getMZ();
      real_intens = h_iter->getIntensity();
      //}
    }
    else
    {
      reals = std::pair<double, double>(seed_mz, ref_iter->getIntensity());
      real_mz = reals.first; real_intens = reals.second;
 
      if (real_mz <= 0 || real_intens <= 0)
      {
        auto h_iter = ref_iter, hc_iter = ref_iter;
        while (h_iter != ref.begin())
        {
          --h_iter;
          if (h_iter->getIntensity() > hc_iter->getIntensity() || (h_iter->getIntensity() == hc_iter->getIntensity() && hc_iter->getIntensity() == 0))
          {
            hc_iter = h_iter;
          }
          else
          {
            break;
          }
 
          if (seed_mz - h_iter->getMZ() > Constants::IW_QUARTER_NEUTRON_MASS / (c + 1.))
          {
            return false;
          }
        }
        real_mz = h_iter->getMZ(); real_intens = h_iter->getIntensity();
        if (real_mz <= 0 || real_intens <= 0)
        {
          return false;
        }
        real_mz = h_iter->getMZ();
        real_intens = h_iter->getIntensity();
      }
    }
 
    double c_score = scoreThis_(candidate, peak_cutoff, real_mz, c, 0);
 
    if (c_score <= 0)
    {
      return false;
    }
 
    double mz_cutoff = IsotopeWavelet::getMzPeakCutOffAtMonoPos(real_mz, c + 1);
    typename MSSpectrum::const_iterator real_l_MZ_iter = ref.MZBegin(real_mz - Constants::IW_QUARTER_NEUTRON_MASS / (c + 1.));
    typename MSSpectrum::const_iterator real_r_MZ_iter = ref.MZBegin(real_l_MZ_iter, real_mz + mz_cutoff / (c + 1.), ref.end());
    if (real_r_MZ_iter == ref.end())
    {
      --real_r_MZ_iter;
    }
 
 
    UInt real_mz_begin = distance(ref.begin(), real_l_MZ_iter);
    UInt real_mz_end = distance(ref.begin(), real_r_MZ_iter);
 
    if (prev_score == -1000)
    {
      push2Box_(real_mz, scan_index, c, prev_score, transintens, ref.getRT(), real_mz_begin, real_mz_end, real_intens);
    }
    else
    {
      push2Box_(real_mz, scan_index, c, c_score, transintens, ref.getRT(), real_mz_begin, real_mz_end, real_intens);
    }
 
    return true;
  }
 
  template <typename PeakType>
  std::pair<double, double> IsotopeWaveletTransform<PeakType>::checkPPMTheoModel_(const MSSpectrum& ref, const double c_mz, const UInt c)
  {
    double mass = c_mz * (c + 1) - Constants::IW_PROTON_MASS * (c);
    double ppms = getPPMs_(peptideMassRule_(mass), mass);
    if (ppms >= Constants::PEPTIDE_MASS_RULE_THEO_PPM_BOUND)
    {
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
      std::cout << ::std::setprecision(8) << std::fixed << c_mz << "\t =(" << "ISO_WAVE" << ")> " << "REJECT \t" << ppms << " (rule: " << peptideMassRule_(mass) << " got: " << mass << ")" << std::endl;
#endif
      return std::pair<double, double>(-1, -1);
    }
 
#ifdef OPENMS_DEBUG_ISOTOPE_WAVELET
    std::cout << ::std::setprecision(8) << std::fixed << c_mz << "\t =(" << "ISO_WAVE" << ")> " << "ACCEPT \t" << ppms << " (rule: " << peptideMassRule_(mass) << " got: " << mass << ")" << std::endl;
#endif
    return std::pair<double, double>(c_mz, ref.MZBegin(c_mz)->getIntensity());
  }
 
} //namespace
 
#pragma clang diagnostic pop