TestTroublesomeApEvaluations.hpp

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#ifndef TESTTROUBLESOMEAPEVALUATIONS_HPP_
#define TESTTROUBLESOMEAPEVALUATIONS_HPP_

#include <cxxtest/TestSuite.h>
#include "SetupModel.hpp"
#include "SingleActionPotentialPrediction.hpp"
#include "ZeroStimulus.hpp"

class TestTroublesomeApEvaluations : public CxxTest::TestSuite
{
private:
    std::string Run(boost::shared_ptr<AbstractCvodeCell> pModel,
                    unsigned maxNumPaces = 1800u,
                    bool printTrace = false,
                    double voltageThreshold = DOUBLE_UNSET,
                    double defaultApd90 = DOUBLE_UNSET,
                    std::string fileSuffix = "",
                    double defaultTimePeakVm = DOUBLE_UNSET)
    {
        SingleActionPotentialPrediction runner(pModel);
        runner.SetMaxNumPaces(maxNumPaces);
        runner.SetAlternansIsError();
        runner.SetLackOfOneToOneCorrespondenceIsError();
        if (voltageThreshold != DOUBLE_UNSET)
        {
            runner.SetVoltageThresholdForRecordingAsActionPotential(voltageThreshold);
        }
        if (defaultApd90 != DOUBLE_UNSET)
        {
            runner.SetControlActionPotentialDuration90(defaultApd90);
        }
        if (defaultTimePeakVm != DOUBLE_UNSET)
        {
            runner.SetControlTimeOfPeakVoltage(defaultTimePeakVm);
        }
        OdeSolution soln = runner.RunSteadyPacingExperiment();

        if (printTrace)
        {
            OutputFileHandler handler("Troublesome_AP_debug", false);
            out_stream p_file = handler.OpenOutputFile("voltage_trace" + fileSuffix + ".txt");
            std::vector<double> voltage = soln.GetAnyVariable("membrane_voltage");
            for (unsigned t = 0; t < soln.rGetTimes().size(); t++)
            {
                *p_file << soln.rGetTimes()[t] << "\t" << voltage[t] << std::endl;
            }
            *p_file << std::flush;
            p_file->close();
        }

        if (runner.DidErrorOccur())
        {
            return runner.GetErrorMessage();
        }
        else
        {
            return "No error";
        }
    }

public:
    void TestTroublesomeTenTusscherCases()
    {
        SetupModel setup(1.0, 2u); // TT06, 1.0Hz
        boost::shared_ptr<AbstractCvodeCell> p_model = setup.GetModel();

        const std::string gkr_name = "membrane_rapid_delayed_rectifier_potassium_current_conductance_scaling_factor";
        const std::string gks_name = "membrane_slow_delayed_rectifier_potassium_current_conductance";

        const double gKr_max = p_model->GetParameter(gkr_name);
        const double gKs_max = p_model->GetParameter(gks_name);

        std::cout << "Normal model:\n";
        std::string message = Run(p_model);

        TS_ASSERT_EQUALS(message, "No error");

        // We are now in a steady state.
        N_Vector steady_state = p_model->GetStateVariables(); // Take a copy of the state variables.

        std::cout << "Case 1:\n";
        // Alternans, one AP followed by fail to repolarize.
        p_model->SetParameter(gkr_name, gKr_max * 0.0234375);
        p_model->SetParameter(gks_name, gKs_max * 0.046875);
        message = Run(p_model);

        TS_ASSERT_EQUALS(message, "NoActionPotential_2");

        // Alternans, failure to repolarize followed by one AP.
        std::cout << "Case 2:\n";
        p_model->SetStateVariables(steady_state);
        p_model->SetParameter(gkr_name, gKr_max * 0.0390625);
        p_model->SetParameter(gks_name, gKs_max * 0.046875);
        message = Run(p_model);

        TS_ASSERT_EQUALS(message, "NoActionPotential_2");

        // Alternans, two different failures to repolarize.
        std::cout << "Case 3:\n";
        p_model->SetStateVariables(steady_state);
        p_model->SetParameter(gkr_name, gKr_max * 0.265625);
        p_model->SetParameter(gks_name, gKs_max * 0.0234375);
        message = Run(p_model);

        TS_ASSERT_EQUALS(message, "NoActionPotential_2");

        // Lack of 1:1 stimulus APD.
        std::cout << "Case 4:\n";
        p_model->SetStateVariables(steady_state);
        p_model->SetParameter(gkr_name, gKr_max * 0.0);
        p_model->SetParameter(gks_name, gKs_max * 0.075);
        message = Run(p_model);

        TS_ASSERT_EQUALS(message, "NoActionPotential_3");

        // Failure to depolarize (use an effectively ZeroStimulus,
        // very difficult to get TT06 not to fire by blocking currents when threshold is -50 (default)
        std::cout << "Case 5:\n";
        p_model->SetStimulusFunction(boost::shared_ptr<ZeroStimulus>(new ZeroStimulus));
        p_model->SetStateVariables(steady_state);
        p_model->SetParameter(gkr_name, gKr_max);
        p_model->SetParameter(gks_name, gKs_max);

        TS_ASSERT_THROWS_THIS(Run(p_model),
                              "AbstractActionPotentialMethod only works with cells that have a RegularStimulus set.");

        // Make a really weak stimulus.
        p_model->SetStimulusFunction(boost::shared_ptr<RegularStimulus>(new RegularStimulus(-0.01, 3, 1000, 1)));
        message = Run(p_model);

        // So that cell does not depolarize.
        TS_ASSERT_EQUALS(message, "NoActionPotential_1");

        DeleteVector(steady_state);
    }

    void TestTroublesomeOHaraActionPotentials()
    {
        SetupModel setup(1.0, 6u); // O'Hara, 1.0Hz
        boost::shared_ptr<AbstractCvodeCell> p_model = setup.GetModel();

        const std::string gkr_name = "membrane_rapid_delayed_rectifier_potassium_current_conductance_scaling_factor";
        const std::string gna_name = "membrane_fast_sodium_current_conductance";

        const double gKr_max = p_model->GetParameter(gkr_name);
        const double gNa_max = p_model->GetParameter(gna_name);
        const double voltage_threshold = -40.42461370307312; // From 10% over max V with gNa=0.

        std::cout << "Normal model:\n";
        std::string message = Run(p_model);
        TS_ASSERT_EQUALS(message, "No error");
        // We are now in a steady state.
        N_Vector steady_state = p_model->GetStateVariables(); // Take a copy of the state variables.

        p_model->SetParameter(gkr_name, gKr_max * 0.5); // For all of these set gKr = 0.5 and vary gNa.

        {
            std::cout << "\nCase 1a: no depolarisation:\n"
                      << std::endl;
            p_model->SetStateVariables(steady_state);
            p_model->SetParameter(gna_name, gNa_max * 0);
            message = Run(p_model, 100, false, voltage_threshold);
            TS_ASSERT_EQUALS(message, "NoActionPotential_1");
        }

        {
            std::cout << "\nCase 1b: no depolarisation again:\n"
                      << std::endl;
            p_model->SetStateVariables(steady_state);
            p_model->SetParameter(gna_name, gNa_max * 0.05);
            message = Run(p_model, 100, false, voltage_threshold);
            TS_ASSERT_EQUALS(message, "NoActionPotential_1");
        }

        {
            std::cout << "\nCase 2: no depolarisation on second AP:\n"
                      << std::endl;
            p_model->SetStateVariables(steady_state);
            p_model->SetParameter(gna_name, gNa_max * 0.065);
            message = Run(p_model, 100, false, voltage_threshold);
            TS_ASSERT_EQUALS(message, "NoActionPotential_5");
        }

        {
            std::cout << "\nCase 3: alternans:\n"
                      << std::endl;
            p_model->SetStateVariables(steady_state);
            p_model->SetParameter(gna_name, gNa_max * 0.081);
            message = Run(p_model, 100, false, voltage_threshold);
            TS_ASSERT_EQUALS(message, "NoActionPotential_4");
        }

        {
            std::cout << "\nCase 4: alternans again 1:\n"
                      << std::endl;
            p_model->SetStateVariables(steady_state);
            p_model->SetParameter(gna_name, gNa_max * 0.092);
            message = Run(p_model, 100, false, voltage_threshold);
            TS_ASSERT_EQUALS(message, "NoActionPotential_4");
        }

        {
            std::cout << "\nCase 5: alternans again 2:\n"
                      << std::endl;
            p_model->SetStateVariables(steady_state);
            p_model->SetParameter(gna_name, gNa_max * 0.093);
            message = Run(p_model, 100, false, voltage_threshold);
            TS_ASSERT_EQUALS(message, "NoActionPotential_4");
        }

        {
            std::cout << "\nCase 6: alternans again 3:\n"
                      << std::endl;
            p_model->SetStateVariables(steady_state);
            p_model->SetParameter(gna_name, gNa_max * 0.094);
            message = Run(p_model, 100, false, voltage_threshold);
            TS_ASSERT_EQUALS(message, "NoActionPotential_4");
        }

        {
            std::cout << "\nCase 7: behaves:\n"
                      << std::endl;
            p_model->SetStateVariables(steady_state);
            p_model->SetParameter(gna_name, gNa_max * 0.1);
            message = Run(p_model, 100, false, voltage_threshold);
            TS_ASSERT_EQUALS(message, "No error");
        }

        const double default_apd = 500.0;

        // Now set sodium and vary gKr in the test cases:
        p_model->SetParameter(gna_name, gNa_max * 0.5);

        std::cout << "Appears that some of the tests below may be sensitive to CVODE version and a bit fragile."
                     " Don't panic if they fail!"
                  << std::endl;

        {
            std::cout << "\nCase 8a: NoAP6 (but a bit like 5):\n"
                      << std::endl;
            p_model->SetStateVariables(steady_state);
            p_model->SetParameter(gkr_name, gKr_max * 0.0407);
            message = Run(p_model, 100, true, voltage_threshold, default_apd, "_gKr_0.0407");
            TS_ASSERT_EQUALS(message, "NoActionPotential_6");
        }

        {
            std::cout << "\nCase 8b: NoAP6 (but a bit like 5):\n"
                      << std::endl;
            p_model->SetStateVariables(steady_state);
            p_model->SetParameter(gkr_name, gKr_max * 0.0408);
            message = Run(p_model, 100, true, voltage_threshold, default_apd, "_gKr_0.0408");
            TS_ASSERT_EQUALS(message, "NoActionPotential_6");
        }

        {
            std::cout << "\nCase 8c: NoAP6 (but a bit like 4 but longer APDs):\n"
                      << std::endl;
            p_model->SetStateVariables(steady_state);
            p_model->SetParameter(gkr_name, gKr_max * 0.0409);
            message = Run(p_model, 100, true, voltage_threshold, default_apd, "_gKr_0.0409");
            TS_ASSERT_EQUALS(message, "NoActionPotential_6");
        }

        {
            std::cout << "\nCase 9: Depolarisation failure long APDs and alternans:\n"
                      << std::endl;
            p_model->SetStateVariables(steady_state);
            p_model->SetParameter(gkr_name, gKr_max * 0.697631);
            p_model->SetParameter(gna_name, gNa_max * 0.0992804);
            message = Run(p_model, 100, true, voltage_threshold, default_apd, "_gNa_0.0992804_gKr_0.697631");
            // These are long alternans, but caused by depolarisation failure, so should get error code 4.
            TS_ASSERT_EQUALS(message, "NoActionPotential_4");
        }

        const double default_time_of_peak_Vm = 6.0;

        {
            std::cout << "\nCase 10: Only-just-firing sodium channels:\n"
                      << std::endl;
            p_model->SetStateVariables(steady_state);
            p_model->SetParameter(gkr_name, gKr_max * 0.6266);
            p_model->SetParameter(gna_name, gNa_max * 0.1);
            message = Run(p_model, 100, true, voltage_threshold, default_apd, "_gNa_0.1_gKr_0.6266", default_time_of_peak_Vm);
            // These are long alternans, but caused by depolarisation failure, so should get error code 7.
            TS_ASSERT_EQUALS(message, "NoActionPotential_7");
        }

        DeleteVector(steady_state);
    }
};

#endif // TESTTROUBLESOMEAPEVALUATIONS_HPP_