unsigned int OptimizationTools::optimizeNumericalParametersWithGlobalClock2(
  DiscreteRatesAcrossSitesClockTreeLikelihood* cl,
  const ParameterList& parameters,
  OptimizationListener* listener,
  double tolerance,
  unsigned int tlEvalMax,
  OutputStream* messageHandler,
  OutputStream* profiler,
  unsigned int verbose,
  const std::string& optMethodDeriv)
throw (Exception)
{
  AbstractNumericalDerivative* fun = 0;

  // Build optimizer:
  Optimizer* optimizer = 0;
  if (optMethodDeriv == OPTIMIZATION_GRADIENT)
  {
    fun = new TwoPointsNumericalDerivative(cl);
    fun->setInterval(0.0000001);
    optimizer = new ConjugateGradientMultiDimensions(fun);
  }
  else if (optMethodDeriv == OPTIMIZATION_NEWTON)
  {
    fun = new ThreePointsNumericalDerivative(cl);
    fun->setInterval(0.0001);
    optimizer = new PseudoNewtonOptimizer(fun);
  }
  else
    throw Exception("OptimizationTools::optimizeBranchLengthsParameters. Unknown optimization method: " + optMethodDeriv);

  // Numerical derivatives:
  ParameterList tmp = parameters.getCommonParametersWith(cl->getParameters());
  fun->setParametersToDerivate(tmp.getParameterNames());

  optimizer->setVerbose(verbose);
  optimizer->setProfiler(profiler);
  optimizer->setMessageHandler(messageHandler);
  optimizer->setMaximumNumberOfEvaluations(tlEvalMax);
  optimizer->getStopCondition()->setTolerance(tolerance);

  // Optimize TreeLikelihood function:
  optimizer->setConstraintPolicy(AutoParameter::CONSTRAINTS_AUTO);
  if (listener)
    optimizer->addOptimizationListener(listener);
  optimizer->init(parameters);
  optimizer->optimize();
  if (verbose > 0)
    ApplicationTools::displayMessage("\n");

  // We're done.
  unsigned int n = optimizer->getNumberOfEvaluations();
  delete optimizer;

  // We're done.
  return n;
}
unsigned int OptimizationTools::optimizeNumericalParameters2(
  DiscreteRatesAcrossSitesTreeLikelihood* tl,
  const ParameterList& parameters,
  OptimizationListener* listener,
  double tolerance,
  unsigned int tlEvalMax,
  OutputStream* messageHandler,
  OutputStream* profiler,
  bool reparametrization,
  bool useClock,
  unsigned int verbose,
  const std::string& optMethodDeriv)
throw (Exception)
{
  DerivableSecondOrder* f = tl;
  ParameterList pl = parameters;
  // Shall we use a molecular clock constraint on branch lengths?
  auto_ptr<GlobalClockTreeLikelihoodFunctionWrapper> fclock;
  if (useClock)
  {
    fclock.reset(new GlobalClockTreeLikelihoodFunctionWrapper(tl));
    f = fclock.get();
    if (verbose > 0)
      ApplicationTools::displayResult("Log-likelihood after adding clock", -tl->getLogLikelihood()); 
    
    // Reset parameters to use new branch lengths. WARNING! 'old' branch parameters do not exist anymore and have been replaced by heights
    pl = fclock->getParameters().getCommonParametersWith(parameters);
    pl.addParameters(fclock->getHeightParameters());
  }
  // Shall we reparametrize the function to remove constraints?
  auto_ptr<DerivableSecondOrder> frep;
  if (reparametrization)
  {
    frep.reset(new ReparametrizationDerivableSecondOrderWrapper(f, pl));
    f = frep.get();

    // Reset parameters to remove constraints:
    pl = f->getParameters().subList(pl.getParameterNames());
  }

  auto_ptr<AbstractNumericalDerivative> fnum;
  // Build optimizer:
  auto_ptr<Optimizer> optimizer;
  if (optMethodDeriv == OPTIMIZATION_GRADIENT)
  {
    fnum.reset(new TwoPointsNumericalDerivative(f));
    fnum->setInterval(0.0000001);
    optimizer.reset(new ConjugateGradientMultiDimensions(fnum.get()));
  }
  else if (optMethodDeriv == OPTIMIZATION_NEWTON)
  {
    fnum.reset(new ThreePointsNumericalDerivative(f));
    fnum->setInterval(0.0001);
    optimizer.reset(new PseudoNewtonOptimizer(fnum.get()));
  }
  else if (optMethodDeriv == OPTIMIZATION_BFGS)
  {
    fnum.reset(new TwoPointsNumericalDerivative(f));
    fnum->setInterval(0.0001);
    optimizer.reset(new BfgsMultiDimensions(fnum.get()));
  }
  else
    throw Exception("OptimizationTools::optimizeNumericalParameters2. Unknown optimization method: " + optMethodDeriv);

  // Numerical derivatives:
  ParameterList tmp = tl->getNonDerivableParameters(); 
  if (useClock)
    tmp.addParameters(fclock->getHeightParameters());
  fnum->setParametersToDerivate(tmp.getParameterNames());
  optimizer->setVerbose(verbose);
  optimizer->setProfiler(profiler);
  optimizer->setMessageHandler(messageHandler);
  optimizer->setMaximumNumberOfEvaluations(tlEvalMax);
  optimizer->getStopCondition()->setTolerance(tolerance);

  // Optimize TreeLikelihood function:
  optimizer->setConstraintPolicy(AutoParameter::CONSTRAINTS_AUTO);
  NaNListener* nanListener = new NaNListener(optimizer.get(), tl);
  optimizer->addOptimizationListener(nanListener);
  if (listener)
    optimizer->addOptimizationListener(listener);
  optimizer->init(pl);
  optimizer->optimize();

  if (verbose > 0)
    ApplicationTools::displayMessage("\n");

  // We're done.
  return optimizer->getNumberOfEvaluations();
}
unsigned int OptimizationTools::optimizeNumericalParametersWithGlobalClock(
  DiscreteRatesAcrossSitesClockTreeLikelihood* cl,
  const ParameterList& parameters,
  OptimizationListener* listener,
  unsigned int nstep,
  double tolerance,
  unsigned int tlEvalMax,
  OutputStream* messageHandler,
  OutputStream* profiler,
  unsigned int verbose,
  const std::string& optMethodDeriv)
throw (Exception)
{
  AbstractNumericalDerivative* fun = 0;

  // Build optimizer:
  MetaOptimizerInfos* desc = new MetaOptimizerInfos();
  if (optMethodDeriv == OPTIMIZATION_GRADIENT)
  {
    fun = new TwoPointsNumericalDerivative(cl);
    fun->setInterval(0.0000001);
    desc->addOptimizer("Branch length parameters", new ConjugateGradientMultiDimensions(fun), cl->getBranchLengthsParameters().getParameterNames(), 2, MetaOptimizerInfos::IT_TYPE_FULL);
  }
  else if (optMethodDeriv == OPTIMIZATION_NEWTON)
  {
    fun = new ThreePointsNumericalDerivative(cl);
    fun->setInterval(0.0001);
    desc->addOptimizer("Branch length parameters", new PseudoNewtonOptimizer(fun), cl->getBranchLengthsParameters().getParameterNames(), 2, MetaOptimizerInfos::IT_TYPE_FULL);
  }
  else
    throw Exception("OptimizationTools::optimizeNumericalParametersWithGlobalClock. Unknown optimization method: " + optMethodDeriv);

  // Numerical derivatives:
  ParameterList tmp = parameters.getCommonParametersWith(cl->getBranchLengthsParameters());
  fun->setParametersToDerivate(tmp.getParameterNames());

  ParameterList plsm = parameters.getCommonParametersWith(cl->getSubstitutionModelParameters());
  if (plsm.size() < 10)
    desc->addOptimizer("Substitution model parameter", new SimpleMultiDimensions(cl), plsm.getParameterNames(), 0, MetaOptimizerInfos::IT_TYPE_STEP);
  else
    desc->addOptimizer("Substitution model parameters", new DownhillSimplexMethod(cl), plsm.getParameterNames(), 0, MetaOptimizerInfos::IT_TYPE_FULL);

  ParameterList plrd = parameters.getCommonParametersWith(cl->getRateDistributionParameters());
  if (plrd.size() < 10)
    desc->addOptimizer("Rate distribution parameter", new SimpleMultiDimensions(cl), plrd.getParameterNames(), 0, MetaOptimizerInfos::IT_TYPE_STEP);
  else
    desc->addOptimizer("Rate dsitribution parameters", new DownhillSimplexMethod(cl), plrd.getParameterNames(), 0, MetaOptimizerInfos::IT_TYPE_FULL);

  MetaOptimizer optimizer(fun, desc, nstep);
  optimizer.setVerbose(verbose);
  optimizer.setProfiler(profiler);
  optimizer.setMessageHandler(messageHandler);
  optimizer.setMaximumNumberOfEvaluations(tlEvalMax);
  optimizer.getStopCondition()->setTolerance(tolerance);

  // Optimize TreeLikelihood function:
  optimizer.setConstraintPolicy(AutoParameter::CONSTRAINTS_AUTO);
  if (listener)
    optimizer.addOptimizationListener(listener);
  optimizer.init(parameters);
  optimizer.optimize();
  if (verbose > 0)
    ApplicationTools::displayMessage("\n");

  // We're done.
  return optimizer.getNumberOfEvaluations();
}
unsigned int OptimizationTools::optimizeNumericalParameters(
  DiscreteRatesAcrossSitesTreeLikelihood* tl,
  const ParameterList& parameters,
  OptimizationListener* listener,
  unsigned int nstep,
  double tolerance,
  unsigned int tlEvalMax,
  OutputStream* messageHandler,
  OutputStream* profiler,
  bool reparametrization,
  unsigned int verbose,
  const std::string& optMethodDeriv,
  const std::string& optMethodModel)
throw (Exception)
{
  DerivableSecondOrder* f = tl;
  ParameterList pl = parameters;

  // Shall we reparametrize the function to remove constraints?
  auto_ptr<DerivableSecondOrder> frep;
  if (reparametrization)
  {
    frep.reset(new ReparametrizationDerivableSecondOrderWrapper(f, parameters));
    f = frep.get();

    // Reset parameters to remove constraints:
    pl = f->getParameters().subList(parameters.getParameterNames());
  }

  // ///////////////
  // Build optimizer:

  // Branch lengths

  MetaOptimizerInfos* desc = new MetaOptimizerInfos();
  MetaOptimizer* poptimizer = 0;
  AbstractNumericalDerivative* fnum = new ThreePointsNumericalDerivative(f);

  if (optMethodDeriv == OPTIMIZATION_GRADIENT)
    desc->addOptimizer("Branch length parameters", new ConjugateGradientMultiDimensions(f), tl->getBranchLengthsParameters().getParameterNames(), 2, MetaOptimizerInfos::IT_TYPE_FULL);
  else if (optMethodDeriv == OPTIMIZATION_NEWTON)
    desc->addOptimizer("Branch length parameters", new PseudoNewtonOptimizer(f), tl->getBranchLengthsParameters().getParameterNames(), 2, MetaOptimizerInfos::IT_TYPE_FULL);
  else if (optMethodDeriv == OPTIMIZATION_BFGS)
    desc->addOptimizer("Branch length parameters", new BfgsMultiDimensions(f), tl->getBranchLengthsParameters().getParameterNames(), 2, MetaOptimizerInfos::IT_TYPE_FULL);
  else
    throw Exception("OptimizationTools::optimizeNumericalParameters. Unknown optimization method: " + optMethodDeriv);

  // Other parameters

  if (optMethodModel == OPTIMIZATION_BRENT)
  {
    ParameterList plsm = parameters.getCommonParametersWith(tl->getSubstitutionModelParameters());
    desc->addOptimizer("Substitution model parameter", new SimpleMultiDimensions(f), plsm.getParameterNames(), 0, MetaOptimizerInfos::IT_TYPE_STEP);


    ParameterList plrd = parameters.getCommonParametersWith(tl->getRateDistributionParameters());
    desc->addOptimizer("Rate distribution parameter", new SimpleMultiDimensions(f), plrd.getParameterNames(), 0, MetaOptimizerInfos::IT_TYPE_STEP);
    poptimizer = new MetaOptimizer(f, desc, nstep);
  }
  else if (optMethodModel == OPTIMIZATION_BFGS)
  {
    vector<string> vNameDer;

    ParameterList plsm = parameters.getCommonParametersWith(tl->getSubstitutionModelParameters());
    vNameDer = plsm.getParameterNames();

    ParameterList plrd = parameters.getCommonParametersWith(tl->getRateDistributionParameters());

    vector<string> vNameDer2 = plrd.getParameterNames();

    vNameDer.insert(vNameDer.begin(), vNameDer2.begin(), vNameDer2.end());
    fnum->setParametersToDerivate(vNameDer);

    desc->addOptimizer("Rate & model distribution parameters", new BfgsMultiDimensions(fnum), vNameDer, 1, MetaOptimizerInfos::IT_TYPE_FULL);
    poptimizer = new MetaOptimizer(fnum, desc, nstep);
  }
  else
    throw Exception("OptimizationTools::optimizeNumericalParameters. Unknown optimization method: " + optMethodModel);

  poptimizer->setVerbose(verbose);
  poptimizer->setProfiler(profiler);
  poptimizer->setMessageHandler(messageHandler);
  poptimizer->setMaximumNumberOfEvaluations(tlEvalMax);
  poptimizer->getStopCondition()->setTolerance(tolerance);

  // Optimize TreeLikelihood function:
  poptimizer->setConstraintPolicy(AutoParameter::CONSTRAINTS_AUTO);
  NaNListener* nanListener = new NaNListener(poptimizer, tl);
  poptimizer->addOptimizationListener(nanListener);
  if (listener)
    poptimizer->addOptimizationListener(listener);
  poptimizer->init(pl);
  poptimizer->optimize();

  if (verbose > 0)
    ApplicationTools::displayMessage("\n");

  // We're done.
  unsigned int nb = poptimizer->getNumberOfEvaluations();
  delete poptimizer;
  return nb;
}