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Estimation of Physiological Parameters Using a Physiologically Based Model

Overview

To evalute glucose trasnport and phosphorylation in skeletal muscle,a physiologically based model has been proposed by our group. The below figure shows the kinetics of a phosphorylatable glucsoe analog (e.g. ¹⁸F-labeled 2-fluoro-2-deoxy-D-glucose) in skeletal muscle. The model has three tissue compartments with five rate constants.

Example of Implementation of the Physiologically Based Model

Here, we show an example of implementation of the proposed model using COMKAT.

cm=compartmentModel;

% Define parameters
cm=addParameter(cm,'k1',0.1);
cm=addParameter(cm,'k2','k1/Fis');
cm=addParameter(cm,'k3','VG/(Fis*KGa+Fis*ISg*KGa/KGg)');
cm=addParameter(cm,'k4','VG/(Fic*KGa+Fic*ICg*KGa/KGg)');
cm=addParameter(cm,'k5','VH/(Fic*KHa+Fic*ICg*KHa/KHg)');

cm=addParameter(cm,'Fb',0.02);         % fraction of total space occupied by blood
cm=addParameter(cm,'Fis',0.3);          % fraction of total space occupied by interstitial space
cm=addParameter(cm,'Fic','1-Fis-Fb');  % fraction of total space occupied by intracellular space
cm=addParameter(cm,'F',1);

cm=addParameter(cm,'Pg',6);   % Plasma glucose concentration (mM)
cm=addParameter(cm,'ISg',5.4); % Interstitial glucose concentration (mM)
cm=addParameter(cm,'ICg',0.2); % Intracellular glucose concentration (mM)

cm=addParameter(cm,'KGg',3.5); % Michaelis constant of glucose transporter (GLUT) for glucose (mM)
cm=addParameter(cm,'KHg',0.13); % Michaelis constant of hexokinase for glucose (mM)

cm=addParameter(cm,'KGa',14); % Michaelis constant of glucose transporter (GLUT) for glucose analog (mM)
cm=addParameter(cm,'KHa',0.17); % Michaelis constant of hexokinase for glucose analog (mM)

cm=addParameter(cm,'VG','(k1*Pg-k1*ISg)/(ISg/(KGg+ISg)-ICg/(KGg+ICg))'); % Maximal velocity of glucose transport for glucose=6FDG=2FDG
cm=addParameter(cm,'VH','(k1*Pg-k1*ISg)/(ICg/(KHg+ICg))'); % Maximal velocity of glucose phosphorylation for glucose=6FDG=2FDG

% Specific activity (sa): if the unit of image data is the same with that of input function, the specific activity is 1.
cm=addParameter(cm,'sa',1); 
% Usually, the decay time correction of image data is performed. So, dk is zero. 
cm=addParameter(cm,'dk',0);

% Define scan time (minutes)
delay = 0.0;
scanduration = 120; 

t=[ones(5,1)/30;ones(10,1)/12;ones(12,1)*0.5;ones(8,1);ones(21,1)*5];
scant = [[0;cumsum(t(1:(length(t)-1)))] cumsum(t)];
scanTime  = [scant(:,1),scant(:,2)];

cm = set(cm, 'ScanTime', scanTime);

lambda = [-12.02 -2.57 -0.02];

a = [1771.5 94.55 14.27];

cm = addParameter(cm, 'pfeng', [delay a lambda]');

% Define input function
cm = addInput(cm, 'Cp', 'sa', 'dk', 'fengInputByPar','pfeng'); % Cp is the plasma input function
cm = addInput(cm, 'Ca',1,0, 'fengInputByPar', 'pfeng'); % Ca is the decay-corrected whole-blood input function. Herein, we assume that Cp=Ca.

% Define compartment
cm=addCompartment(cm,'IS'); % interstitial 
cm=addCompartment(cm,'IC'); % intracellular
cm=addCompartment(cm,'IP'); % intracellular phosphorylated 
cm=addCompartment(cm,'Junk');

% Define link
cm=addLink(cm,'L','Cp','IS','k1');
cm=addLink(cm,'K','IS','Junk','k2');
cm=addLink(cm,'K','IS','IC','k3');
cm=addLink(cm,'K','IC','IS','k4');
cm=addLink(cm,'K','IC','IP','k5');

% Define output obtained from each normalized compartment
wlistTotal={'IS','F';'IC','F';'IP','F'};
xlistTotal={'Ca','Fb'};
cm=addOutput(cm,'TissueTotal',wlistTotal,xlistTotal);

% Define model parameters to be esimated
cm=addSensitivity(cm,'k1','ISg','ICg','Fis','Fb'); 

[PET,PETIndex,Output,OutputIndex]=solve(cm);

noise_level=0.05;

sd=noise_level*sqrt(PET(:,3)./(PET(:,2)-PET(:,1)));

data=sd.*randn(size(PET(:,3)))+PET(:,3);

cm=set(cm,'ExperimentalData',data);

cm = set(cm,'ExperimentalDataSD',sd);

optsIRLS = setopt('SDModelFunction', @IRLSnoiseModel);
cm = set(cm, 'IRLSOptions', optsIRLS);

oo = optimset('TolFun', 1e-8, 'TolX', 1e-4,'Algorithm','interior-point');
cm = set(cm, 'OptimizerOptions', oo);

% Set initial conditions and bounds
%        k1,    ISg,   ICg,     Fs,     Fb
pinit = [0.01  ; 4.4 ; 0.1    ;0.15 ; 0.01];
plb   = [0.001; 1    ; 0.001;0.10 ; 0     ];
pub  = [0.5   ; 6    ; 1       ;0.60 ; 0.04];

[pfit, qfit, modelfit, exitflag, output, lambda, grad, hessian, objfunval] = fitGen(cm, pinit, plb, pub, 'IRLS'); 

figure;
t = 0.5*(PET(:,1)+PET(:,2));
plot(t,PET(:,3),'g-',t,data,'ro','LineWidth',2);
xlabel('Time (minutes)');
ylabel('Concentrations (uCi/mL)');
legend('Noisy data','Noise-free data');

figure;
t = 0.5*(PET(:,1)+PET(:,2));
plot(t,data,'ro',t,modelfit,'b-','LineWidth',2);
xlabel('Time (minutes)');
ylabel('Concentrations (uCi/mL)');
legend('Noisy data', 'Model fit');

Pg=6;KGa=14;KHa=0.17;KGg=3.5;KHg=0.13; % Units are mM

k1=pfit(1);k2=pfit(1)/pfit(4);ISg=pfit(2);ICg=pfit(3);Fis=pfit(4);Fb=pfit(5);

% Physiological parameters 

VG=(k1*ISg-k1*Pg)/(ICg/(KGg+ICg)-ISg/(KGg+ISg))      
 
VH=(k1*Pg-k1*ISg)/(ICg/(KHg+ICg))            
           
CI=VG*ISg/(KGg+ISg)           
                           
CE=VG*ICg/(KGg+ICg)    
                               
PR=VH*ICg/(KHg+ICg) 
                            

Results