def _visualize(self, obj, **kwargs):
fnResults = self.protocol._getPath("results.txt")
if exists(fnResults):
X, Y, _, _ = self.protocol.getXYValues(False)
minX = min(X)
maxX = max(X)
step = (maxX - minX) / 50
xValues = np.arange(minX, maxX+step, step)
yValues = self.protocol.evalFunction(xValues)
plotter = EmPlotter()
varNameX = self.protocol.labelX.get()
varNameY = self.protocol.labelY.get()
ax = plotter.createSubPlot("Regression Plot",
"%s [%s]"%(varNameX,strUnit(self.protocol.experiment.variables[varNameX].units.unit)),
"%s [%s]"%(varNameY,strUnit(self.protocol.experiment.variables[varNameY].units.unit)))
ax.plot(xValues, yValues)
ax.plot(X, Y, 'o')
return [plotter]
else:
return [self.errorMessage("Result file '%s' not produced yet. "
% fnResults)]
def prepareForSampleAnalysis(self, sampleName):
sample = self.experiment.samples[sampleName]
sampleFit = self.eliminationFitting.getSampleFit(sampleName)
sample.interpretDose()
self.model.D = sample.getDoseAt(0.0)
self.model.Dunits = sample.getDoseUnits()
if sampleFit == None:
print(
" Cannot process %s because its elimination rate cannot be found\n\n"
% sampleName)
return False
self.model.C0 = sampleFit.parameters[0]
self.model.C0units = self.eliminationFitting.modelParameterUnits[0]
self.model.Ke = sampleFit.parameters[1]
self.model.KeUnits = self.eliminationFitting.modelParameterUnits[1]
print("Concentration at t=0 = %f [%s]" %
(self.model.C0, strUnit(self.model.C0units)))
print("Elimination rate = %f [%s]" %
(self.model.Ke, strUnit(self.model.KeUnits)))
self.experiment.addParameterToSample(
sampleName, "Ke", self.model.KeUnits,
"Automatically estimated elimination rate", self.model.Ke)
return True
def _visualize(self, obj, **kwargs):
fnResults = self.protocol._getPath("results.txt")
if exists(fnResults):
X, Y, _, _ = self.protocol.getXYValues(False)
minX = min(X)
maxX = max(X)
step = (maxX - minX) / 50
xValues = np.arange(minX, maxX + step, step)
yValues = self.protocol.evalFunction(xValues)
plotter = EmPlotter()
varNameX = self.protocol.labelX.get()
varNameY = self.protocol.labelY.get()
ax = plotter.createSubPlot(
"Regression Plot", "%s [%s]" %
(varNameX,
strUnit(
self.protocol.experiment.variables[varNameX].units.unit)),
"%s [%s]" %
(varNameY,
strUnit(
self.protocol.experiment.variables[varNameY].units.unit)))
ax.plot(xValues, yValues)
ax.plot(X, Y, 'o')
return [plotter]
else:
return [
self.errorMessage("Result file '%s' not produced yet. " %
fnResults)
]
def postSampleAnalysis(self, sampleName):
xunits = self.experiment.getVarUnits(self.varNameX)
Cunits = self.experiment.getVarUnits(self.varNameY)
Ka = self.model.parameters[0]
Ke = self.model.Ke
tmax = math.log(Ka/Ke)/(Ka-Ke)
self.experiment.addParameterToSample(sampleName, "tmax", xunits, "Estimated time of the Maximum of the non-iv peak", tmax)
Cmax = self.model.forwardModel(self.model.parameters,x=[np.atleast_1d(np.array(tmax))])[0][0]
self.experiment.addParameterToSample(sampleName, "Cmax", Cunits, "Estimated concentration of the Maximum of the non-iv peak", Cmax)
print("tmax = %f [%s]"%(tmax,strUnit(xunits)))
print("Cmax = %f [%s]"%(Cmax,strUnit(Cunits)))
def postSampleAnalysis(self, sampleName):
xunits = self.experiment.getVarUnits(self.varNameX)
Cunits = self.experiment.getVarUnits(self.varNameY)
Ka = self.model.parameters[0]
Ke = self.model.Ke
tmax = math.log(Ka / Ke) / (Ka - Ke)
self.experiment.addParameterToSample(
sampleName, "tmax", xunits,
"Estimated time of the Maximum of the non-iv peak", tmax)
Cmax = self.model.forwardModel(self.model.parameters,
x=[np.atleast_1d(np.array(tmax))])[0][0]
self.experiment.addParameterToSample(
sampleName, "Cmax", Cunits,
"Estimated concentration of the Maximum of the non-iv peak", Cmax)
print("tmax = %f [%s]" % (tmax, strUnit(xunits)))
print("Cmax = %f [%s]" % (Cmax, strUnit(Cunits)))
def runStatistcs(self, objId):
experiment = self.readExperiment(self.inputExperiment.get().fnPKPD)
self.printSection("Calculating statistical descriptors")
fnStatistics = self._getPath("statistics.txt")
fhOut = open(fnStatistics, 'w')
for varName, variable in experiment.variables.iteritems():
if variable.role == PKPDVariable.ROLE_LABEL:
varValues = experiment.getSubGroupLabels("True", varName)
if variable.varType == PKPDVariable.TYPE_TEXT:
self.doublePrint(fhOut, "%s ------------" % varName)
counter = {}
for value in varValues:
if value in counter:
counter[value] += 1
else:
counter[value] = 1
for value in counter:
self.doublePrint(
fhOut, "Value=%s Total count=%d (%f%%)" %
(value, counter[value],
100 * float(counter[value]) / len(varValues)))
elif variable.varType == PKPDVariable.TYPE_NUMERIC:
self.doublePrint(
fhOut, "%s [%s] ------------" %
(varName, strUnit(variable.units.unit)))
varValues = np.asarray(varValues, np.double)
self.doublePrint(
fhOut, "Number of observations= %d" % len(varValues))
self.doublePrint(
fhOut, "Range= [%f,%f]" %
(np.min(varValues), np.max(varValues)))
self.doublePrint(fhOut,
"Mean= %f" % np.mean(varValues))
self.doublePrint(fhOut, "StdDev= %f" % np.std(varValues))
self.doublePrint(
fhOut, "Skewness= %f" % scipy.stats.skew(varValues))
self.doublePrint(
fhOut,
"Kurtosis= %f" % scipy.stats.kurtosis(varValues))
self.doublePrint(
fhOut,
"Quantile 5%%= %f" % np.percentile(varValues, 5))
self.doublePrint(
fhOut,
"Quantile 25%%= %f" % np.percentile(varValues, 25))
self.doublePrint(
fhOut,
"Quantile 50%%= %f" % np.percentile(varValues, 50))
self.doublePrint(
fhOut,
"Quantile 75%%= %f" % np.percentile(varValues, 75))
self.doublePrint(
fhOut,
"Quantile 95%%= %f" % np.percentile(varValues, 95))
self.doublePrint(fhOut, " ")
fhOut.close()
def prepareForSampleAnalysis(self, sampleName):
sample = self.experiment.samples[sampleName]
sampleFit = self.eliminationFitting.getSampleFit(sampleName)
sample.interpretDose()
self.model.D = sample.getDoseAt(0.0)
self.model.Dunits = sample.getDoseUnits()
if sampleFit == None:
print(" Cannot process %s because its elimination rate cannot be found\n\n"%sampleName)
return False
self.model.C0 = sampleFit.parameters[0]
self.model.C0units = self.eliminationFitting.modelParameterUnits[0]
self.model.Ke = sampleFit.parameters[1]
self.model.KeUnits = self.eliminationFitting.modelParameterUnits[1]
print("Concentration at t=0 = %f [%s]"%(self.model.C0,strUnit(self.model.C0units)))
print("Elimination rate = %f [%s]"%(self.model.Ke,strUnit(self.model.KeUnits)))
self.experiment.addParameterToSample(sampleName, "Ke", self.model.KeUnits, "Automatically estimated elimination rate", self.model.Ke)
return True
def _validate(self):
errors=[]
experiment = self.readExperiment(self.inputExperiment.get().fnPKPD, False)
if not self.labelToChange.get() in experiment.variables:
errors.append("Cannot find %s as variable"%self.labelToChange)
else:
variable = experiment.variables[self.labelToChange.get()]
if variable.varType!=PKPDVariable.TYPE_NUMERIC:
errors.append("%s is not a numeric variable"%variable.varName)
else:
currentUnit = experiment.getVarUnits(self.labelToChange.get())
newUnit = unitFromString(self._getNewUnit())
try:
K=convertUnits(1,currentUnit,newUnit)
if K==None:
errors.append("Unknown conversion from %s to %s. If it makes sense and it is not implemented you may contact [email protected]"%\
(strUnit(currentUnit),strUnit(newUnit)))
except:
errors.append("Unknown conversion from %s to %s. If it makes sense and it is not implemented you may contact [email protected]"%(currentUnit,newUnit))
return errors
def _validate(self):
errors = []
experiment = self.readExperiment(self.inputExperiment.get().fnPKPD,
False)
if not self.labelToChange.get() in experiment.variables:
errors.append("Cannot find %s as variable" % self.labelToChange)
else:
variable = experiment.variables[self.labelToChange.get()]
if variable.varType != PKPDVariable.TYPE_NUMERIC:
errors.append("%s is not a numeric variable" %
variable.varName)
else:
currentUnit = experiment.getVarUnits(self.labelToChange.get())
newUnit = unitFromString(self._getNewUnit())
try:
K = convertUnits(1, currentUnit, newUnit)
if K == None:
errors.append("Unknown conversion from %s to %s. If it makes sense and it is not implemented you may contact [email protected]"%\
(strUnit(currentUnit),strUnit(newUnit)))
except:
errors.append(
"Unknown conversion from %s to %s. If it makes sense and it is not implemented you may contact [email protected]"
% (currentUnit, newUnit))
return errors
def postAnalysis(self, sampleName):
if self.experimentIV!=None:
if sampleName in self.experimentIV.samples:
sampleNIV = self.experiment.samples[sampleName]
DNIV= self.analysis.D
sampleIV = self.experimentIV.samples[sampleName]
sampleIV.interpretDose()
DIV = sampleIV.getDoseAt(0.0)
F = float(sampleNIV.descriptors['AUC_0inf'])/float(sampleNIV.descriptors['AUC_0inf'])*DIV/DNIV
MAT = float(sampleNIV.descriptors['MRT']) - float(sampleIV.descriptors['MRT'])
self.experiment.addParameterToSample(sampleName, "F", PKPDUnit.UNIT_NONE, "Estimated bioavailability", F)
self.experiment.addParameterToSample(sampleName, "MAT", self.analysis.parameterUnits[-1], "Estimated Mean Absorption Time", MAT)
print("F = %f"%F)
print("MAT = %f [%s]"%(MAT,strUnit(self.analysis.parameterUnits[-1])))
def _createSlidersFrame(self, content):
frame = tk.Frame(content, bg='white')
lfBounds = tk.LabelFrame(frame, text="Parameter Bounds", bg='white')
gui.configureWeigths(frame)
i = 0
self.sliders = {}
paramUnits = self.targetProtocol.parameterUnits
for paramName, bounds in self.targetProtocol.getParameterBounds().iteritems():
bounds = bounds or (0, 1)
slider = MinMaxSlider(lfBounds, "%s [%s]"%(paramName,strUnit(paramUnits[i])),
bounds[0], bounds[1],
callback=self._onVarChanged)
slider.grid(row=i, column=0, padx=5, pady=5)
self.sliders[paramName] = slider
i += 1
lfBounds.grid(row=0, column=0, sticky='news', padx=5, pady=5)
frame.grid(row=0, column=1, sticky='news', padx=5, pady=5)
def _createSlidersFrame(self, content):
frame = tk.Frame(content, bg='white')
lfBounds = tk.LabelFrame(frame, text="Parameter Bounds", bg='white')
gui.configureWeigths(frame)
i = 0
self.sliders = {}
paramUnits = self.targetProtocol.parameterUnits
for paramName, bounds in self.targetProtocol.getParameterBounds(
).iteritems():
bounds = bounds or (0, 1)
slider = MinMaxSlider(lfBounds,
"%s [%s]" %
(paramName, strUnit(paramUnits[i])),
bounds[0],
bounds[1],
callback=self._onVarChanged)
slider.grid(row=i, column=0, padx=5, pady=5)
self.sliders[paramName] = slider
i += 1
lfBounds.grid(row=0, column=0, sticky='news', padx=5, pady=5)
frame.grid(row=0, column=1, sticky='news', padx=5, pady=5)
def runStatistcs(self, objId):
experiment = self.readExperiment(self.inputExperiment.get().fnPKPD)
self.printSection("Calculating statistical descriptors")
fnStatistics = self._getPath("statistics.txt")
fhOut = open(fnStatistics,'w')
for varName, variable in experiment.variables.iteritems():
if variable.role == PKPDVariable.ROLE_LABEL:
varValues = experiment.getSubGroupLabels("True",varName)
if variable.varType == PKPDVariable.TYPE_TEXT:
self.doublePrint(fhOut,"%s ------------"%varName)
counter = {}
for value in varValues:
if value in counter:
counter[value]+=1
else:
counter[value]=1
for value in counter:
self.doublePrint(fhOut,"Value=%s Total count=%d (%f%%)"%(value,counter[value],100*float(counter[value])/len(varValues)))
elif variable.varType == PKPDVariable.TYPE_NUMERIC:
self.doublePrint(fhOut,"%s [%s] ------------"%(varName,strUnit(variable.units.unit)))
varValues = np.asarray(varValues,np.double)
self.doublePrint(fhOut,"Number of observations= %d"%len(varValues))
self.doublePrint(fhOut,"Range= [%f,%f]"%(np.min(varValues),np.max(varValues)))
self.doublePrint(fhOut,"Mean= %f"%np.mean(varValues))
self.doublePrint(fhOut,"StdDev= %f"%np.std(varValues))
self.doublePrint(fhOut,"Skewness= %f"%scipy.stats.skew(varValues))
self.doublePrint(fhOut,"Kurtosis= %f"%scipy.stats.kurtosis(varValues))
self.doublePrint(fhOut,"Quantile 5%%= %f"%np.percentile(varValues,5))
self.doublePrint(fhOut,"Quantile 25%%= %f"%np.percentile(varValues,25))
self.doublePrint(fhOut,"Quantile 50%%= %f"%np.percentile(varValues,50))
self.doublePrint(fhOut,"Quantile 75%%= %f"%np.percentile(varValues,75))
self.doublePrint(fhOut,"Quantile 95%%= %f"%np.percentile(varValues,95))
self.doublePrint(fhOut," ")
fhOut.close()
def runSimulate(self, objId, Nsimulations, confidenceInterval, doses):
self.protODE = self.inputODE.get()
if hasattr(self.protODE, "outputExperiment"):
self.experiment = self.readExperiment(
self.protODE.outputExperiment.fnPKPD)
elif hasattr(self.protODE, "outputExperiment1"):
self.experiment = self.readExperiment(
self.protODE.outputExperiment1.fnPKPD)
else:
raise Exception("Cannot find an outputExperiment in the input ODE")
if self.paramsSource == ProtPKPDODESimulate.PRM_POPULATION:
self.fitting = self.readFitting(
self.inputPopulation.get().fnFitting,
cls="PKPDSampleFitBootstrap")
else:
if hasattr(self.protODE, "outputFitting"):
self.fitting = self.readFitting(
self.protODE.outputFitting.fnFitting)
elif hasattr(self.protODE, "outputFitting1"):
self.fitting = self.readFitting(
self.protODE.outputFitting1.fnFitting)
self.varNameX = self.fitting.predictor.varName
if type(self.fitting.predicted) != list:
self.varNameY = self.fitting.predicted.varName
else:
self.varNameY = [var.varName for var in self.fitting.predicted]
# Create drug source
self.clearGroupParameters()
self.createDrugSource()
# Create output object
self.outputExperiment = PKPDExperiment()
tvar = PKPDVariable()
tvar.varName = "t"
tvar.varType = PKPDVariable.TYPE_NUMERIC
tvar.role = PKPDVariable.ROLE_TIME
tvar.units = createUnit("min")
self.outputExperiment.variables[self.varNameX] = tvar
if type(self.fitting.predicted) != list:
self.outputExperiment.variables[
self.varNameY] = self.experiment.variables[self.varNameY]
else:
for varName in self.varNameY:
self.outputExperiment.variables[
varName] = self.experiment.variables[varName]
self.outputExperiment.general["title"] = "Simulated ODE response"
self.outputExperiment.general["comment"] = "Simulated ODE response"
self.outputExperiment.vias = self.experiment.vias
# Setup model
self.model = self.protODE.createModel()
self.model.setExperiment(self.outputExperiment)
if hasattr(self.protODE, "deltaT"):
self.model.deltaT = self.protODE.deltaT.get()
self.model.setXVar(self.varNameX)
self.model.setYVar(self.varNameY)
Nsamples = int(60 * math.ceil(
(self.tF.get() - self.t0.get()) / self.model.deltaT)) + 1
self.model.x = [
self.t0.get() + i * self.model.deltaT for i in range(0, Nsamples)
]
self.modelList.append(self.model)
# Read the doses
for line in self.doses.get().replace('\n', ';;').split(';;'):
tokens = line.split(';')
if len(tokens) < 5:
print("Skipping dose: ", line)
continue
dosename = tokens[0].strip()
self.outputExperiment.doses[dosename] = PKPDDose()
self.outputExperiment.doses[dosename].parseTokens(
tokens, self.experiment.vias)
auxSample = PKPDSample()
auxSample.descriptors = {}
auxSample.doseDictPtr = self.outputExperiment.doses
auxSample.variableDictPtr = self.outputExperiment.variables
auxSample.doseList = [dosename]
auxSample.interpretDose()
self.drugSource.setDoses(auxSample.parsedDoseList,
self.t0.get() - 10,
self.tF.get() + 10)
self.model.drugSource = self.drugSource
# Check units
# Dunits = self.outputExperiment.doses[dosename].dunits
# Cunits = self.experiment.variables[self.varNameY].units
# Process user parameters
if self.paramsSource == ProtPKPDODESimulate.PRM_POPULATION:
Nsimulations = self.Nsimulations.get()
else:
lines = self.prmUser.get().strip().replace('\n', ';;').split(';;')
Nsimulations = len(lines)
prmUser = []
for line in lines:
tokens = line.strip().split(',')
prmUser.append([float(token) for token in tokens])
# Simulate the different responses
simulationsX = self.model.x
simulationsY = np.zeros(
(Nsimulations, len(simulationsX), self.getResponseDimension()))
AUCarray = np.zeros(Nsimulations)
AUMCarray = np.zeros(Nsimulations)
MRTarray = np.zeros(Nsimulations)
CminArray = np.zeros(Nsimulations)
CmaxArray = np.zeros(Nsimulations)
CavgArray = np.zeros(Nsimulations)
fluctuationArray = np.zeros(Nsimulations)
percentageAccumulationArray = np.zeros(Nsimulations)
for i in range(0, Nsimulations):
self.setTimeRange(None)
if self.paramsSource == ProtPKPDODESimulate.PRM_POPULATION:
# Take parameters randomly from the population
nfit = int(random.uniform(0, len(self.fitting.sampleFits)))
sampleFit = self.fitting.sampleFits[nfit]
nprm = int(random.uniform(0, sampleFit.parameters.shape[0]))
parameters = sampleFit.parameters[nprm, :]
else:
parameters = np.asarray(prmUser[i], np.double)
print("Simulated sample %d: %s" % (i, str(parameters)))
# Prepare source and this object
self.drugSource.setDoses(auxSample.parsedDoseList, self.model.t0,
self.model.tF)
self.protODE.configureSource(self.drugSource)
self.model.drugSource = self.drugSource
parameterNames = self.getParameterNames(
) # Necessary to count the number of source and PK parameters
# Prepare the model
self.setParameters(parameters)
y = self.forwardModel(parameters,
[simulationsX] * self.getResponseDimension())
# Create AUC, AUMC, MRT variables and units
if i == 0:
if type(self.varNameY) != list:
self.Cunits = self.experiment.variables[
self.varNameY].units
else:
self.Cunits = self.experiment.variables[
self.varNameY[0]].units
self.AUCunits = multiplyUnits(tvar.units.unit,
self.Cunits.unit)
self.AUMCunits = multiplyUnits(tvar.units.unit, self.AUCunits)
if self.addStats or self.addIndividuals:
AUCvar = PKPDVariable()
AUCvar.varName = "AUC0t"
AUCvar.varType = PKPDVariable.TYPE_NUMERIC
AUCvar.role = PKPDVariable.ROLE_LABEL
AUCvar.units = createUnit(strUnit(self.AUCunits))
AUMCvar = PKPDVariable()
AUMCvar.varName = "AUMC0t"
AUMCvar.varType = PKPDVariable.TYPE_NUMERIC
AUMCvar.role = PKPDVariable.ROLE_LABEL
AUMCvar.units = createUnit(strUnit(self.AUMCunits))
MRTvar = PKPDVariable()
MRTvar.varName = "MRT"
MRTvar.varType = PKPDVariable.TYPE_NUMERIC
MRTvar.role = PKPDVariable.ROLE_LABEL
MRTvar.units = createUnit("min")
self.outputExperiment.variables["AUC0t"] = AUCvar
self.outputExperiment.variables["AUMC0t"] = AUMCvar
self.outputExperiment.variables["MRT"] = MRTvar
# Evaluate AUC, AUMC and MRT in the last full period
self.NCA(self.model.x, y[0])
# Keep results
for j in range(self.getResponseDimension()):
simulationsY[i, :, j] = y[j]
AUCarray[i] = self.AUC0t
AUMCarray[i] = self.AUMC0t
MRTarray[i] = self.MRT
CminArray[i] = self.Cmin
CmaxArray[i] = self.Cmax
CavgArray[i] = self.Cavg
fluctuationArray[i] = self.fluctuation
percentageAccumulationArray[i] = self.percentageAccumulation
if self.addIndividuals or self.paramsSource == ProtPKPDODESimulate.PRM_USER_DEFINED:
self.addSample("Simulation_%d" % i, dosename, simulationsX, y)
# Report NCA statistics
alpha_2 = (100 - self.confidenceLevel.get()) / 2
limits = np.percentile(AUCarray, [alpha_2, 100 - alpha_2])
print("AUC %f%% confidence interval=[%f,%f] [%s] mean=%f" %
(self.confidenceLevel.get(), limits[0], limits[1],
strUnit(self.AUCunits), np.mean(AUCarray)))
limits = np.percentile(AUMCarray, [alpha_2, 100 - alpha_2])
print("AUMC %f%% confidence interval=[%f,%f] [%s] mean=%f" %
(self.confidenceLevel.get(), limits[0], limits[1],
strUnit(self.AUMCunits), np.mean(AUMCarray)))
limits = np.percentile(MRTarray, [alpha_2, 100 - alpha_2])
print("MRT %f%% confidence interval=[%f,%f] [min] mean=%f" %
(self.confidenceLevel.get(), limits[0], limits[1],
np.mean(MRTarray)))
limits = np.percentile(CminArray, [alpha_2, 100 - alpha_2])
print("Cmin %f%% confidence interval=[%f,%f] [%s] mean=%f" %
(self.confidenceLevel.get(), limits[0], limits[1],
strUnit(self.Cunits.unit), np.mean(CminArray)))
limits = np.percentile(CmaxArray, [alpha_2, 100 - alpha_2])
print("Cmax %f%% confidence interval=[%f,%f] [%s] mean=%f" %
(self.confidenceLevel.get(), limits[0], limits[1],
strUnit(self.Cunits.unit), np.mean(CmaxArray)))
limits = np.percentile(CavgArray, [alpha_2, 100 - alpha_2])
print("Cavg %f%% confidence interval=[%f,%f] [%s] mean=%f" %
(self.confidenceLevel.get(), limits[0], limits[1],
strUnit(self.Cunits.unit), np.mean(CavgArray)))
limits = np.percentile(fluctuationArray, [alpha_2, 100 - alpha_2])
print("Fluctuation %f%% confidence interval=[%f,%f] [%%] mean=%f" %
(self.confidenceLevel.get(), limits[0] * 100, limits[1] * 100,
np.mean(fluctuationArray) * 100))
limits = np.percentile(percentageAccumulationArray,
[alpha_2, 100 - alpha_2])
print("Accum(1) %f%% confidence interval=[%f,%f] [%%] mean=%f" %
(self.confidenceLevel.get(), limits[0] * 100, limits[1] * 100,
np.mean(percentageAccumulationArray) * 100))
# Calculate statistics
if self.addStats:
if self.paramsSource != ProtPKPDODESimulate.PRM_USER_DEFINED:
limits = np.percentile(simulationsY, [alpha_2, 100 - alpha_2],
axis=0)
print("Lower limit NCA")
self.NCA(simulationsX, limits[0])
self.addSample("LowerLimit", dosename, simulationsX, limits[0])
print("Mean profile NCA")
if self.getResponseDimension() == 1:
mu = np.mean(simulationsY, axis=0)
self.NCA(simulationsX, mu)
else:
mu = []
for j in range(self.getResponseDimension()):
mu.append(np.mean(simulationsY[:, :, j], axis=0))
self.NCA(simulationsX, mu[0])
self.addSample("Mean", dosename, simulationsX, mu)
if self.paramsSource != ProtPKPDODESimulate.PRM_USER_DEFINED:
print("Upper limit NCA")
self.NCA(simulationsX, limits[1])
self.addSample("UpperLimit", dosename, simulationsX, limits[1])
self.outputExperiment.write(self._getPath("experiment.pkpd"))
def NCA(self, t, C):
AUClist = []
AUMClist = []
Cminlist = []
Cavglist = []
Cmaxlist = []
Tmaxlist = []
Tminlist = []
Ndoses = len(self.drugSource.parsedDoseList)
for ndose in range(0, max(Ndoses - 1, 1)):
tperiod0 = self.drugSource.parsedDoseList[ndose].t0
if ndose + 1 < Ndoses:
tperiodF = self.drugSource.parsedDoseList[
ndose + 1].t0 - self.model.deltaT
else:
tperiodF = np.max(t) - 1
idx0 = find_nearest(t, tperiod0)
idxF = find_nearest(t, tperiodF)
AUC0t = 0
AUMC0t = 0
t0 = t[idx0 + 1]
for idx in range(idx0, idxF + 1):
dt = (t[idx + 1] - t[idx])
if C[idx + 1] >= C[idx]: # Trapezoidal in the raise
AUC0t += 0.5 * dt * (C[idx] + C[idx + 1])
AUMC0t += 0.5 * dt * (C[idx] * t[idx] +
C[idx + 1] * t[idx + 1])
else: # Log-trapezoidal in the decay
decrement = C[idx] / C[idx + 1]
K = math.log(decrement)
B = K / dt
AUC0t += dt * (C[idx] - C[idx + 1]) / K
AUMC0t += (C[idx] * (t[idx] - tperiod0) - C[idx + 1] *
(t[idx + 1] - tperiod0)) / B - (
C[idx + 1] - C[idx]) / (B * B)
if idx == idx0:
Cmax = C[idx]
Tmax = t[idx] - t0
Cmin = C[idx]
Tmin = t[idx] - t0
else:
if C[idx] < Cmin:
Cmin = C[idx]
Tmin = t[idx] - t0
elif C[idx] > Cmax:
Cmax = C[idx]
Tmax = t[idx] - t0
if ndose == 0:
Cmin = C[idx]
Tmin = t[idx] - t0
AUClist.append(AUC0t)
AUMClist.append(AUMC0t)
Cminlist.append(Cmin)
Cmaxlist.append(Cmax)
Tmaxlist.append(Tmax)
Tminlist.append(Tmin)
Cavglist.append(AUC0t / (t[idxF] - t[idx0]))
print("Fluctuation = Cmax/Cmin")
print("Accumulation(1) = Cavg(n)/Cavg(1) %")
print("Accumulation(n) = Cavg(n)/Cavg(n-1) %")
print("Steady state fraction(n) = Cavg(n)/Cavg(last) %")
for ndose in range(0, len(AUClist)):
fluctuation = Cmaxlist[ndose] / Cminlist[ndose]
if ndose > 0:
accumn = Cavglist[ndose] / Cavglist[ndose - 1]
else:
accumn = 0
print("Dose #%d: Cavg= %f [%s] Cmin= %f [%s] Tmin= %d [min] Cmax= %f [%s] Tmax= %d [min] Fluct= %f %% Accum(1)= %f %% Accum(n)= %f %% SSFrac(n)= %f %% AUC= %f [%s] AUMC= %f [%s]"%\
(ndose+1,Cavglist[ndose], strUnit(self.Cunits.unit), Cminlist[ndose],strUnit(self.Cunits.unit), int(Tminlist[ndose]), Cmaxlist[ndose], strUnit(self.Cunits.unit),
int(Tmaxlist[ndose]), fluctuation*100, Cavglist[ndose]/Cavglist[0]*100, accumn*100, Cavglist[ndose]/Cavglist[-1]*100, AUClist[ndose],strUnit(self.AUCunits),
AUMClist[ndose],strUnit(self.AUMCunits)))
self.AUC0t = AUClist[-1]
self.AUMC0t = AUMClist[-1]
self.MRT = self.AUMC0t / self.AUC0t
self.Cmin = Cminlist[-1]
self.Cmax = Cmaxlist[-1]
self.Cavg = Cavglist[-1]
self.fluctuation = self.Cmax / self.Cmin
self.percentageAccumulation = Cavglist[-1] / Cavglist[0]
print(" AUC0t=%f [%s]" % (self.AUC0t, strUnit(self.AUCunits)))
print(" AUMC0t=%f [%s]" % (self.AUMC0t, strUnit(self.AUMCunits)))
print(" MRT=%f [min]" % self.MRT)
def runSimulate(self, objId, Nsimulations, confidenceInterval, doses):
self.protODE = self.inputODE.get()
if hasattr(self.protODE,"outputExperiment"):
self.experiment = self.readExperiment(self.protODE.outputExperiment.fnPKPD)
elif hasattr(self.protODE,"outputExperiment1"):
self.experiment = self.readExperiment(self.protODE.outputExperiment1.fnPKPD)
else:
raise Exception("Cannot find an outputExperiment in the input ODE")
if self.paramsSource==ProtPKPDODESimulate.PRM_POPULATION:
self.fitting = self.readFitting(self.inputPopulation.get().fnFitting, cls="PKPDSampleFitBootstrap")
else:
if hasattr(self.protODE, "outputFitting"):
self.fitting = self.readFitting(self.protODE.outputFitting.fnFitting)
elif hasattr(self.protODE, "outputFitting1"):
self.fitting = self.readFitting(self.protODE.outputFitting1.fnFitting)
self.varNameX = self.fitting.predictor.varName
if type(self.fitting.predicted)!=list:
self.varNameY = self.fitting.predicted.varName
else:
self.varNameY = [var.varName for var in self.fitting.predicted]
# Create drug source
self.clearGroupParameters()
self.createDrugSource()
# Create output object
self.outputExperiment = PKPDExperiment()
tvar = PKPDVariable()
tvar.varName = "t"
tvar.varType = PKPDVariable.TYPE_NUMERIC
tvar.role = PKPDVariable.ROLE_TIME
tvar.units = createUnit("min")
self.outputExperiment.variables[self.varNameX] = tvar
if type(self.fitting.predicted)!=list:
self.outputExperiment.variables[self.varNameY] = self.experiment.variables[self.varNameY]
else:
for varName in self.varNameY:
self.outputExperiment.variables[varName] = self.experiment.variables[varName]
self.outputExperiment.general["title"]="Simulated ODE response"
self.outputExperiment.general["comment"]="Simulated ODE response"
self.outputExperiment.vias = self.experiment.vias
# Setup model
self.model = self.protODE.createModel()
self.model.setExperiment(self.outputExperiment)
if hasattr(self.protODE,"deltaT"):
self.model.deltaT = self.protODE.deltaT.get()
self.model.setXVar(self.varNameX)
self.model.setYVar(self.varNameY)
Nsamples = int(60*math.ceil((self.tF.get()-self.t0.get())/self.model.deltaT))+1
self.model.x = [self.t0.get()+i*self.model.deltaT for i in range(0,Nsamples)]
self.modelList.append(self.model)
# Read the doses
for line in self.doses.get().replace('\n',';;').split(';;'):
tokens = line.split(';')
if len(tokens)<5:
print("Skipping dose: ",line)
continue
dosename = tokens[0].strip()
self.outputExperiment.doses[dosename] = PKPDDose()
self.outputExperiment.doses[dosename].parseTokens(tokens,self.experiment.vias)
auxSample = PKPDSample()
auxSample.descriptors = {}
auxSample.doseDictPtr = self.outputExperiment.doses
auxSample.variableDictPtr = self.outputExperiment.variables
auxSample.doseList = [dosename]
auxSample.interpretDose()
self.drugSource.setDoses(auxSample.parsedDoseList, self.t0.get()-10, self.tF.get()+10)
self.model.drugSource = self.drugSource
# Check units
# Dunits = self.outputExperiment.doses[dosename].dunits
# Cunits = self.experiment.variables[self.varNameY].units
# Process user parameters
if self.paramsSource==ProtPKPDODESimulate.PRM_POPULATION:
Nsimulations = self.Nsimulations.get()
else:
lines = self.prmUser.get().strip().replace('\n',';;').split(';;')
Nsimulations = len(lines)
prmUser = []
for line in lines:
tokens = line.strip().split(',')
prmUser.append([float(token) for token in tokens])
# Simulate the different responses
simulationsX = self.model.x
simulationsY = np.zeros((Nsimulations,len(simulationsX),self.getResponseDimension()))
AUCarray = np.zeros(Nsimulations)
AUMCarray = np.zeros(Nsimulations)
MRTarray = np.zeros(Nsimulations)
CminArray = np.zeros(Nsimulations)
CmaxArray = np.zeros(Nsimulations)
CavgArray = np.zeros(Nsimulations)
fluctuationArray = np.zeros(Nsimulations)
percentageAccumulationArray = np.zeros(Nsimulations)
for i in range(0,Nsimulations):
self.setTimeRange(None)
if self.paramsSource==ProtPKPDODESimulate.PRM_POPULATION:
# Take parameters randomly from the population
nfit = int(random.uniform(0,len(self.fitting.sampleFits)))
sampleFit = self.fitting.sampleFits[nfit]
nprm = int(random.uniform(0,sampleFit.parameters.shape[0]))
parameters = sampleFit.parameters[nprm,:]
else:
parameters = np.asarray(prmUser[i],np.double)
print("Simulated sample %d: %s"%(i,str(parameters)))
# Prepare source and this object
self.drugSource.setDoses(auxSample.parsedDoseList, self.model.t0, self.model.tF)
self.protODE.configureSource(self.drugSource)
self.model.drugSource = self.drugSource
parameterNames = self.getParameterNames() # Necessary to count the number of source and PK parameters
# Prepare the model
self.setParameters(parameters)
y = self.forwardModel(parameters, [simulationsX]*self.getResponseDimension())
# Create AUC, AUMC, MRT variables and units
if i == 0:
if type(self.varNameY)!=list:
self.Cunits = self.experiment.variables[self.varNameY].units
else:
self.Cunits = self.experiment.variables[self.varNameY[0]].units
self.AUCunits = multiplyUnits(tvar.units.unit, self.Cunits.unit)
self.AUMCunits = multiplyUnits(tvar.units.unit, self.AUCunits)
if self.addStats or self.addIndividuals:
AUCvar = PKPDVariable()
AUCvar.varName = "AUC0t"
AUCvar.varType = PKPDVariable.TYPE_NUMERIC
AUCvar.role = PKPDVariable.ROLE_LABEL
AUCvar.units = createUnit(strUnit(self.AUCunits))
AUMCvar = PKPDVariable()
AUMCvar.varName = "AUMC0t"
AUMCvar.varType = PKPDVariable.TYPE_NUMERIC
AUMCvar.role = PKPDVariable.ROLE_LABEL
AUMCvar.units = createUnit(strUnit(self.AUMCunits))
MRTvar = PKPDVariable()
MRTvar.varName = "MRT"
MRTvar.varType = PKPDVariable.TYPE_NUMERIC
MRTvar.role = PKPDVariable.ROLE_LABEL
MRTvar.units = createUnit("min")
self.outputExperiment.variables["AUC0t"] = AUCvar
self.outputExperiment.variables["AUMC0t"] = AUMCvar
self.outputExperiment.variables["MRT"] = MRTvar
# Evaluate AUC, AUMC and MRT in the last full period
self.NCA(self.model.x,y[0])
# Keep results
for j in range(self.getResponseDimension()):
simulationsY[i,:,j] = y[j]
AUCarray[i] = self.AUC0t
AUMCarray[i] = self.AUMC0t
MRTarray[i] = self.MRT
CminArray[i] = self.Cmin
CmaxArray[i] = self.Cmax
CavgArray[i] = self.Cavg
fluctuationArray[i] = self.fluctuation
percentageAccumulationArray[i] = self.percentageAccumulation
if self.addIndividuals or self.paramsSource==ProtPKPDODESimulate.PRM_USER_DEFINED:
self.addSample("Simulation_%d"%i, dosename, simulationsX, y)
# Report NCA statistics
alpha_2 = (100-self.confidenceLevel.get())/2
limits = np.percentile(AUCarray,[alpha_2,100-alpha_2])
print("AUC %f%% confidence interval=[%f,%f] [%s] mean=%f"%(self.confidenceLevel.get(),limits[0],limits[1],strUnit(self.AUCunits),np.mean(AUCarray)))
limits = np.percentile(AUMCarray,[alpha_2,100-alpha_2])
print("AUMC %f%% confidence interval=[%f,%f] [%s] mean=%f"%(self.confidenceLevel.get(),limits[0],limits[1],strUnit(self.AUMCunits),np.mean(AUMCarray)))
limits = np.percentile(MRTarray,[alpha_2,100-alpha_2])
print("MRT %f%% confidence interval=[%f,%f] [min] mean=%f"%(self.confidenceLevel.get(),limits[0],limits[1],np.mean(MRTarray)))
limits = np.percentile(CminArray,[alpha_2,100-alpha_2])
print("Cmin %f%% confidence interval=[%f,%f] [%s] mean=%f"%(self.confidenceLevel.get(),limits[0],limits[1],strUnit(self.Cunits.unit),np.mean(CminArray)))
limits = np.percentile(CmaxArray,[alpha_2,100-alpha_2])
print("Cmax %f%% confidence interval=[%f,%f] [%s] mean=%f"%(self.confidenceLevel.get(),limits[0],limits[1],strUnit(self.Cunits.unit),np.mean(CmaxArray)))
limits = np.percentile(CavgArray,[alpha_2,100-alpha_2])
print("Cavg %f%% confidence interval=[%f,%f] [%s] mean=%f"%(self.confidenceLevel.get(),limits[0],limits[1],strUnit(self.Cunits.unit),np.mean(CavgArray)))
limits = np.percentile(fluctuationArray,[alpha_2,100-alpha_2])
print("Fluctuation %f%% confidence interval=[%f,%f] [%%] mean=%f"%(self.confidenceLevel.get(),limits[0]*100,limits[1]*100,np.mean(fluctuationArray)*100))
limits = np.percentile(percentageAccumulationArray,[alpha_2,100-alpha_2])
print("Accum(1) %f%% confidence interval=[%f,%f] [%%] mean=%f"%(self.confidenceLevel.get(),limits[0]*100,limits[1]*100,np.mean(percentageAccumulationArray)*100))
# Calculate statistics
if self.addStats:
if self.paramsSource!=ProtPKPDODESimulate.PRM_USER_DEFINED:
limits = np.percentile(simulationsY,[alpha_2,100-alpha_2],axis=0)
print("Lower limit NCA")
self.NCA(simulationsX,limits[0])
self.addSample("LowerLimit", dosename, simulationsX, limits[0])
print("Mean profile NCA")
if self.getResponseDimension()==1:
mu = np.mean(simulationsY,axis=0)
self.NCA(simulationsX, mu)
else:
mu = []
for j in range(self.getResponseDimension()):
mu.append(np.mean(simulationsY[:,:,j],axis=0))
self.NCA(simulationsX,mu[0])
self.addSample("Mean", dosename, simulationsX, mu)
if self.paramsSource!=ProtPKPDODESimulate.PRM_USER_DEFINED:
print("Upper limit NCA")
self.NCA(simulationsX,limits[1])
self.addSample("UpperLimit", dosename, simulationsX, limits[1])
self.outputExperiment.write(self._getPath("experiment.pkpd"))
def NCA(self,t,C):
AUClist = []
AUMClist = []
Cminlist = []
Cavglist = []
Cmaxlist = []
Tmaxlist = []
Tminlist = []
Ndoses=len(self.drugSource.parsedDoseList)
for ndose in range(0,max(Ndoses-1,1)):
tperiod0 = self.drugSource.parsedDoseList[ndose].t0
if ndose+1<Ndoses:
tperiodF = self.drugSource.parsedDoseList[ndose+1].t0-self.model.deltaT
else:
tperiodF = np.max(t)-1
idx0 = find_nearest(t,tperiod0)
idxF = find_nearest(t,tperiodF)
AUC0t = 0
AUMC0t = 0
t0 = t[idx0+1]
for idx in range(idx0,idxF+1):
dt = (t[idx+1]-t[idx])
if C[idx+1]>=C[idx]: # Trapezoidal in the raise
AUC0t += 0.5*dt*(C[idx]+C[idx+1])
AUMC0t += 0.5*dt*(C[idx]*t[idx]+C[idx+1]*t[idx+1])
else: # Log-trapezoidal in the decay
decrement = C[idx]/C[idx+1]
K = math.log(decrement)
B = K/dt
AUC0t += dt*(C[idx]-C[idx+1])/K
AUMC0t += (C[idx]*(t[idx]-tperiod0)-C[idx+1]*(t[idx+1]-tperiod0))/B-(C[idx+1]-C[idx])/(B*B)
if idx==idx0:
Cmax=C[idx]
Tmax=t[idx]-t0
Cmin=C[idx]
Tmin=t[idx]-t0
else:
if C[idx]<Cmin:
Cmin=C[idx]
Tmin=t[idx]-t0
elif C[idx]>Cmax:
Cmax=C[idx]
Tmax=t[idx]-t0
if ndose==0:
Cmin=C[idx]
Tmin=t[idx]-t0
AUClist.append(AUC0t)
AUMClist.append(AUMC0t)
Cminlist.append(Cmin)
Cmaxlist.append(Cmax)
Tmaxlist.append(Tmax)
Tminlist.append(Tmin)
Cavglist.append(AUC0t/(t[idxF]-t[idx0]))
print("Fluctuation = Cmax/Cmin")
print("Accumulation(1) = Cavg(n)/Cavg(1) %")
print("Accumulation(n) = Cavg(n)/Cavg(n-1) %")
print("Steady state fraction(n) = Cavg(n)/Cavg(last) %")
for ndose in range(0,len(AUClist)):
fluctuation = Cmaxlist[ndose]/Cminlist[ndose]
if ndose>0:
accumn = Cavglist[ndose]/Cavglist[ndose-1]
else:
accumn = 0
print("Dose #%d: Cavg= %f [%s] Cmin= %f [%s] Tmin= %d [min] Cmax= %f [%s] Tmax= %d [min] Fluct= %f %% Accum(1)= %f %% Accum(n)= %f %% SSFrac(n)= %f %% AUC= %f [%s] AUMC= %f [%s]"%\
(ndose+1,Cavglist[ndose], strUnit(self.Cunits.unit), Cminlist[ndose],strUnit(self.Cunits.unit), int(Tminlist[ndose]), Cmaxlist[ndose], strUnit(self.Cunits.unit),
int(Tmaxlist[ndose]), fluctuation*100, Cavglist[ndose]/Cavglist[0]*100, accumn*100, Cavglist[ndose]/Cavglist[-1]*100, AUClist[ndose],strUnit(self.AUCunits),
AUMClist[ndose],strUnit(self.AUMCunits)))
self.AUC0t = AUClist[-1]
self.AUMC0t = AUMClist[-1]
self.MRT = self.AUMC0t/self.AUC0t
self.Cmin = Cminlist[-1]
self.Cmax = Cmaxlist[-1]
self.Cavg = Cavglist[-1]
self.fluctuation = self.Cmax/self.Cmin
self.percentageAccumulation = Cavglist[-1]/Cavglist[0]
print(" AUC0t=%f [%s]"%(self.AUC0t,strUnit(self.AUCunits)))
print(" AUMC0t=%f [%s]"%(self.AUMC0t,strUnit(self.AUMCunits)))
print(" MRT=%f [min]"%self.MRT)
def runFit(self, predictor, avgParameters, confidenceInterval):
self.scaleModel = PKPDAllometricScale()
self.scaleModel.confidence = float(self.confidenceInterval.get())
self.scaleModel.predictor = self.predictor.get()
if self.allometricParameters.get().strip()!="":
for token in self.allometricParameters.get().split(','):
self.scaleModel.scaled_vars.append(token.strip())
if self.avgParameters.get().strip()!="":
for token in self.avgParameters.get().split(','):
self.scaleModel.averaged_vars.append(token.strip())
X=[]
Y={}
for varName in self.scaleModel.scaled_vars+self.scaleModel.averaged_vars:
Y[varName]=[]
for experimentPtr in self.inputExps:
# Load experiment
experiment = PKPDExperiment()
experiment.load(experimentPtr.get().fnPKPD)
# Get the first sample
sample = experiment.samples.values()[0]
# Extract X
retval = sample.getDescriptorValue(self.predictor.get())
if retval:
X.append(float(retval))
else:
raise Exception("Cannot find %s in %s"%(self.predictor.get(),experiment.fnPKPD))
# Extract Y
for varName in self.scaleModel.scaled_vars+self.scaleModel.averaged_vars:
retval = sample.getDescriptorValue(varName)
if retval:
Y[varName].append(float(retval))
else:
raise Exception("Cannot find %s in %s"%(varName,experiment.fnPKPD))
self.scaleModel.predictorUnits = strUnit(experiment.variables[self.predictor.get()].units.unit)
varList = []
for varName in self.scaleModel.scaled_vars:
varList.append((varName,strUnit(experiment.variables[varName].units.unit)))
self.scaleModel.scaled_vars = copy.copy(varList)
varList = []
for varName in self.scaleModel.averaged_vars:
varList.append((varName,strUnit(experiment.variables[varName].units.unit)))
self.scaleModel.averaged_vars = copy.copy(varList)
print("X: %s"%str(X))
logx=np.log10(np.asarray(X))
self.scaleModel.X = X
self.scaleModel.Y = Y
fhSummary=open(self._getPath("summary.txt"),"w")
fhSummary.write("Predictor variable: %s\n"%self.predictor.get())
fhSummary.write("Parameters to average: %s\n"%self.avgParameters.get())
fhSummary.write("Confidence interval: %f\n"%self.confidenceInterval.get())
for varName, varUnits in self.scaleModel.scaled_vars:
print("%s: %s"%(varName,str(Y[varName])))
y = np.asarray(Y[varName])
logy = np.log10(y)
A=np.ones((logx.size,2))
A[:,0]=logx.T
F=np.linalg.inv(np.dot(A.T,A))
p = np.dot(F,np.dot(A.T,logy.T))
logyPredicted=np.dot(A,p)
e=logy-logyPredicted
sigma2=np.var(e)
V=sigma2*F
# We manually implement the regression because np.polyfit has an unbiased estimator of V that
# does not work well with 4 samples
# p, V = np.polyfit(logx, logy, 1, cov=True)
# e = logy - logyPredicted
R2 = (1 - np.var(e) / np.var(logy))
from scipy.stats import norm
nstd = norm.ppf(1-(1-self.scaleModel.confidence/100)/2)
perr = np.sqrt(np.diag(V))
lowerBound = p - nstd * perr
upperBound = p + nstd * perr
# Back to natural units
p[1]=math.pow(10.0,p[1])
lowerBound[1]=math.pow(10.0,lowerBound[1])
upperBound[1]=math.pow(10.0,upperBound[1])
self.scaleModel.models[varName] = [p[1],p[0]]
self.scaleModel.qualifiers[varName] = [R2,lowerBound[1],upperBound[1],lowerBound[0],upperBound[0]]
self.doublePrint(fhSummary,
"%s=(%f)*%s^(%f) R2=%f %f%% Confidence intervals (y=k*x^a): k=[%f,%f] a=[%f,%f]; %s" % \
(varName, p[1], self.predictor, p[0], R2, self.confidenceInterval, lowerBound[1],upperBound[1],lowerBound[0],upperBound[0],
varUnits))
for varName, varUnits in self.scaleModel.averaged_vars:
print("%s: %s"%(varName,str(Y[varName])))
y = np.asarray(Y[varName])
self.scaleModel.models[varName] = [np.mean(y)]
self.scaleModel.qualifiers[varName] = [np.std(y)]
self.doublePrint(fhSummary,
"%s avg=%f std=%f; %s"%(varName,self.scaleModel.models[varName][0],self.scaleModel.qualifiers[varName][0],varUnits))
fhSummary.close()
self.scaleModel.write(self._getPath("allometricScale.pkpd"))
