Cristina Tarín

Comprehensive pharmacokinetic model of insulin Glargine and other insulin formulations

In this paper, a comprehensive pharmacokinetic model for different insulin formulations including insulin Glargine is developed based on the model proposed by Trajanoski et al. (1993). Current models show limitations for insulin Glargine due to the appearance of an uncharacteristic peak in the concentration-time evolution of plasma insulin that does not coincide with real experimental data. This important limitation has been solved in this paper by introducing a new virtual insulin state called the bound state, in addition to the dimeric and hexameric ones. Trying to describe the retarded action of insulin Glargine, the modeling idea behind this approach is that immediately after the subcutaneous injection all the insulin resides in the bound state, and only then small amounts of insulin in the hexameric form disengage from the bound state. For the model evaluation different simulation results are compared. Using experimental data published by Lepore et al. (2000), the developed model turned out to be capable of at least qualitatively predicting the concentration-time profile of plasma insulin. Both exogenous insulin flow simulations and spatial diffusion simulations show the plausibility and correct implementation of the derived model. Considering all these simulation results, the here presented new pharmacokinetic model demonstrates to be able to reproduce real patient behavior simulating even complete insulin regimes including long-acting, intermediate and short-acting insulin formulations.

Robust Sliding Mode Closed-loop Glucose Control with Meal Compensation in Type 1 Diabetes Mellitus

Abstract This work addresses the design of a robust closed-loop plasma glucose controller for Type 1 Diabetes Mellitus patients. The feedback controller is based on Sliding Mode Control (SMC) while robust feedforward boluses to compensate food intake are calculated in a robust way by means of an interval glucose predictor that minimizes the risk of hypoglycaemia. The designed controller has been validated in a virtual environment following standard protocols. The resulting control algorithm shows a considerable robustness regarding intra-patient variability in insulin sensitivity as well as an enhanced ability to handle disturbance rejection. The International Diabetes Federation guidelines for glycaemia targets in Diabetes Mellitus are fulfilled by the designed control strategy.

Using Support Vector Machines to Detect Therapeutically Incorrect Measurements by the MiniMed CGMS

Background: Current continuous glucose monitors have limited accuracy mainly in the low range of glucose measurements. This lack of accuracy is a limiting factor in their clinical use and in the development of the so-called artificial pancreas. The ability to detect incorrect readings provided by continuous glucose monitors from raw data and other information supplied by the monitor itself is of utmost clinical importance. In this study, support vector machines (SVMs), a powerful statistical learning technique, were used to detect therapeutically incorrect measurements made by the Medtronic MiniMed CGMS®. Methods: Twenty patients were monitored for three days (first day at the hospital and two days at home) using the MiniMed CGMS. After the third day, the monitor data were downloaded to the physicians computer. During the first 12 hours, the patients stayed in the hospital, and blood samples were taken every 15 minutes for two hours after meals and every 30 minutes otherwise. Plasma glucose measurements were interpolated using a cubic method for time synchronization with simultaneous MiniMed CGMS measurements every five minutes, obtaining a total of 2281 samples. A Gaussian SVM classifier trained on the monitors electrical signal and glucose estimation was tuned and validated using multiple runs of k-fold cross-validation. The classes considered were Clarke error grid zones A+B and C+D+E. Results: After ten runs of ten-fold cross-validation, an average specificity and sensitivity of 92.74% and 75.49%, respectively, were obtained (see Figure 4). The average correct rate was 91.67%. Conclusions: Overall, the SVM performed well, in spite of the somewhat low sensitivity. The classifier was able to detect the time intervals when the monitors glucose profile could not be trusted due to incorrect measurements. As a result, hypoglycemic episodes missed by the monitor were detected.

Insulin dosage optimization based on prediction of postprandial glucose excursions under uncertain parameters and food intake

Considering the difficulty in selecting correct insulin doses and the problem of hyper- and hypoglycemia episodes in type 1 diabetes, dosage-aid systems are very useful for these patients. A model-based approach to this problem must unavoidably consider uncertainty sources such as large intra-patient variability and food intake. In the present study, postprandial glucose is predicted considering this uncertain information using modal interval analysis. This approach calculates a safer prediction of possible hyper- and hypoglycemia episodes induced by insulin therapy for an individual patients parameters and integrates this information into a dosage-aid system. Predictions of a patients postprandial glucose at 5-h intervals are used to predict the risk for a given therapy. Then the insulin dose and injection-to-meal time with the lowest risk are calculated. The method has been validated for three different scenarios corresponding to preprandial glucose values of 100, 180 and 250mg/dl.

Incorporating a Generic Model of Subcutaneous Insulin Absorption into the AIDA v4 Diabetes Simulator 1. A Prospective Collaborative Development Plan

Introduction: AIDA v4 is an interactive educational diabetes simulator that has been made available, for over a decade, without charge via the Internet. The software is currently freely accessible at http://www.2aida.org. This report sets out a collaborative development plan to enhance the program with a new model of subcutaneous insulin absorption, which permits the simulation of rapidly acting and very long-acting insulin analogues, as well as insulin injection doses larger than 40 units. Methods: A novel, generic, physiological subcutaneous insulin absorption model is overviewed and a methodology is proposed by which this can be substituted in place of the previously adopted insulin absorption model utilized within AIDA v4.3a. Apart from this substitution it is proposed to retain the existing model of the glucoregulatory system currently used in AIDA v4.3a. Results: Initial simulation results based on bench testing of this approach using MATLAB are presented for the exogenous insulin flow profile (Iex ) following subcutaneous injections of a rapidly acting insulin analogue, a short-acting (regular) insulin preparation, intermediate-acting insulins (both Semilente and neutral protamine Hagedorn types), and a very long-acting insulin analogue. Discussion It is proposed to implement this collaborative development plan—first by bench testing the approach in MATLAB and then by integrating the generic subcutaneous insulin absorption Iex model into the AIDA simulator in Pascal. The aim is to provide enhanced functionality and educational simulations of regimens utilizing novel insulin analogues, as well as injections larger than 40 units of insulin.

Nonlinear adaptive and tracking control of a pneumatic actuator via immersion and invariance

The present publication is focussed on the application of the immersion and invariance (I&I) control methodology on a pneumatic actuator. The utilization of I&I for tracking control is investigated and a tracking theorem is explicitly provided and proved. Based on this theorem, a tracking controller for the nonlinear system is designed. Furthermore, in order to deal with unknown parameters, we state and prove an adaptive tracking theorem. Using this theorem, the designed controller is extended in order to be able to estimate the current friction force. This renders the controller adaptive and enhances its tracking capability. Simulations as well as measurement results show the excellent performance of the adaptive I&I tracking controller.

Development of AIDA v4.3b Diabetes Simulator: Technical Upgrade to Support Incorporation of Lispro, Aspart, and Glargine Insulin Analogues

Introduction. AIDA is an interactive educational diabetes simulator available on the Internet without charge since 1996 (accessible at: http://www.2aida.org/). Since the program’s original release, users have developed new requirements, with new operating systems coming into use and more complex insulin management regimens being adopted. The current work has aimed to design a comprehensive diabetes simulation system from both a clinical and information technology perspective. Methods. A collaborative development is taking place with a new generic model of subcutaneous insulin absorption, permitting the simulation of rapidly-acting and very long-acting insulin analogues, as well as insulin injections larger than 40 units. This novel, physiological insulin absorption model has been incorporated into AIDA v4. Technical work has also been undertaken to install and operate the AIDA software within a DOSBox emulator, to ensure compatibility with Windows XP, Vista and 7 operating systems as well as Apple Macintosh computers running Parallels PC emulation software. Results. Plasma insulin simulations are demonstrated following subcutaneous injections of a rapidly-acting insulin analogue, a short-acting insulin preparation, intermediate-acting insulin, and a very long-acting insulin analogue for injected insulin doses up to 60 units of insulin. Discussion. The current work extends the useful life of the existing AIDA v4 program.

UWB Channel Measurements for Hand-Portable Devices: A Comparative Study

On-body UWB signal propagation is analyzed using two different types of UWB antennas. For the study, measurements of the frequency response by means of a VNA (vector network analyzer) are performed at 2001 discrete frequency points in the 3 to 6 GHz range. Separated measures are taken for four different transmitter positions on the head and six receiver positions on the body. Channel estimation parameters, such as mean excess delay, delay spread and path loss are obtained. Results are similar for both types of antennas regarding path loss exponent and average power delay profiles.

Prediction of glucose excursions under uncertain parameters and food intake in intensive insulin therapy for type 1 diabetes mellitus

Considering the difficulty in the insulin dosage selection and the problem of hyper- and hypoglycaemia episodes in type 1 diabetes, dosage-aid systems appear as tremendously helpful for these patients. A model-based approach to this problem must unavoidably consider uncertainty sources such as the large intra-patient variability and food intake. This work addresses the prediction of glycaemia for a given insulin therapy face to parametric and input uncertainty, by means of modal interval analysis. As result, a band containing all possible glucose excursions suffered by the patient for the given uncertainty is obtained. From it, a safer prediction of possible hyper- and hypoglycaemia episodes can be calculated.

An immersion and invariance based speed and rotation angle observer for the ball and beam system

The present contribution introduces a nonlinear observer for the rotation angle and the velocities of the ball and beam system. It is based upon the Immersion and Invariance (I&I) methodology and it uses measurements of the relative rotation angle and the absolute ball position. Significant practical relevance of this contribution is due to the relative rotation angle measurement, provided by most commercially available encoders. Observability of the system is studied and the nonlinear observer is designed using the (reduced-order) observer theorem of the I&I technique. The asymptotical convergence of the observation error is proved by means of Lyapunov arguments. Simulation experiments illustrate the theory and show the effectiveness of the proposed design.