In this work, we develop an ordinary differential equations (ODE) model of physiological regulation of glycemia in type 1 diabetes mellitus (T1DM) patients in response to meals and intravenous insulin infusion. Unlike for majority of existing mathematical models of glucose-insulin dynamics, parameters in our model are estimable from a relatively small number of noisy observations of plasma glucose and insulin concentrations. For estimation, we adopt the generalized smoothing estimation of nonlinear dynamic systems of Ramsay et al. (2007). In this framework, the ODE solution is approximated with a penalized spline, where the ODE model is incorporated in the penalty. We propose to optimize the generalized smoothing by using penalty weights that minimize the covariance penalties criterion (Efron, 2004). The covariance penalties criterion provides an estimate of the prediction error for nonlinear estimation rules resulting from nonlinear and/or non-homogeneous ODE models, such as our model of glucose-insulin dynamics. We also propose to select the optimal number and location of knots for B-spline bases used to represent the ODE solution. The results of the small simulation study demonstrate advantages of optimized generalized smoothing in terms of smaller estimation errors for ODE parameters and smaller prediction errors for solutions of differential equations. Using the proposed approach to analyze the glucose and insulin concentration data in T1DM patients we obtained good approximation of global glucose-insulin dynamics and physiologically meaningful parameter estimates.
Keywords: Covariance penalties; Generalized profiling; Parameter cascading; Penalized smoothing; Prediction error; Profiled penalty estimation.