A graphical method for practical and informative identifiability analyses of physiological models: A case study of insulin kinetics and sensitivity

peer reviewedBackground: Derivative based a-priori structural identifiability analyses of mathematical models can offer valuable insight into the identifiability of model parameters. However, these analyses are only capable of a binary confirmation of the mathematical distinction of parameters and a positive outcome can begin to lose relevance when measurement error is introduced. This article presents an integral based method that allows the observation of the identifiability of models with two-parameters in the presence of assay error. Methods: The method measures the distinction of the integral formulations of the parameter coefficients at the proposed sampling times. It can thus predict the susceptibility of the parameters to the effects of measurement error. The method is tested in-silico with Monte Carlo analyses of a number of insulin sensitivity test applications. Results: The method successfully captured the analogous nature of identifiability observed in Monte Carlo analyses of a number of cases including protocol alterations, parameter changes and differences in participant behaviour. However, due to the numerical nature of the analyses, prediction was not perfect in all cases. Conclusions: Thus although the current method has valuable and significant capabilities in terms of study or test protocol design, additional developments would further strengthen the predictive capability of the method. Finally, the method captures the experimental reality that sampling error and timing can negate assumed parameter identifiability and that identifiability is a continuous rather than discrete phenomenon

In-Silico Evaluation of Glucose Regulation Using Policy Gradient Reinforcement Learning for Patients with Type 1 Diabetes Mellitus

In this paper, we test and evaluate policy gradient reinforcement learning for automated blood glucose control in patients with Type 1 Diabetes Mellitus. Recent research has shown that reinforcement learning is a promising approach to accommodate the need for individualized blood glucose level control algorithms. The motivation for using policy gradient algorithms comes from the fact that adaptively administering insulin is an inherently continuous task. Policy gradient algorithms are known to be superior in continuous high-dimensional control tasks. Previously, most of the approaches for automated blood glucose control using reinforcement learning has used a finite set of actions. We use the Trust-Region Policy Optimization algorithm in this work. It represents the state of the art for deep policy gradient algorithms. The experiments are carried out in-silico using the Hovorka model, and stochastic behavior is modeled through simulated carbohydrate counting errors to illustrate the full potential of the framework. Furthermore, we use a model-free approach where no prior information about the patient is given to the algorithm. Our experiments show that the reinforcement learning agent is able to compete with and sometimes outperform state-of-the-art model predictive control in blood glucose regulation

Design and Validation of an Open-Source Closed-Loop Testbed for Artificial Pancreas Systems

The development of a fully autonomous artificial pancreas system (APS) to independently regulate the glucose levels of a patient with Type 1 diabetes has been a long-standing goal of diabetes research. A significant barrier to progress is the difficulty of testing new control algorithms and safety features, since clinical trials are time- and resource-intensive. To facilitate ease of validation, we propose an open-source APS testbed by integrating APS controllers with two state-of-the-art glucose simulators and a novel fault injection engine. The testbed is able to reproduce the blood glucose trajectories of real patients from a clinical trial conducted over six months. We evaluate the performance of two closed-loop control algorithms (OpenAPS and Basal Bolus) using the testbed and find that more advanced control algorithms are able to keep blood glucose in a safe region 93.49% and 79.46% of the time on average, compared with 66.18% of the time for the clinical trial. The fault injection engine simulates the real recalls and adverse events reported to the U.S. Food and Drug Administration (FDA) and demonstrates the resilience of the controller in hazardous conditions. We used the testbed to generate 2.5 years of synthetic data representing 20 different patient profiles with realistic adverse event scenarios, which would have been expensive and risky to collect in a clinical trial. The proposed testbed is a valid tool that can be used by the research community to demonstrate the effectiveness of different control algorithms and safety features for APS.Comment: 12 pages, 12 figures, to appear in the IEEE/ACM International Conference on Connected Health: Applications, Systems and Engineering Technologies (CHASE), 202

A personalised and adaptive insulin dosing decision support system for type 1 diabetes

People with type 1 diabetes (T1D) rely on exogenous insulin to maintain stable glucose levels. Despite the advent of diabetes technologies such as continuous glucose monitors and insulin infusion pumps, the majority of people with T1D do not manage to bring back glucose levels into a healthy target after meals. In addition to patient compliance, this is due to the complexity of the decision-making on how much insulin is required. Commercial insulin bolus calculators exist that help with the calculation of insulin for meals but these lack fine-tuning and adaptability. This thesis presents a novel insulin dosing decision support system for people with T1D that is able to provide individualised insulin dosing advice. The proposed research utilises Case-Based Reasoning (CBR), an artificial intelligence methodology, that is able to learn over time based on the behaviour of the patient and optimises the insulin therapy for various diabetes scenarios. The decision support system has been implemented into a user-friendly smartphone-based patient platform and communicates with a clinical platform for remote supervision. In-silico studies are presented demonstrating the overall performance of CBR as well as metrics used to adapt the insulin therapy. Safety and feasibility of the developed system have been assessed incrementally in clinical trials; initially during an eight-hour study in hospital settings followed by a six-week study in the home environment of the user. Human factors play an important role in the clinical adoption of technologies such as the one proposed. System usability and acceptability were evaluated during the second study phase based on feedback obtained from study participants. Results from in-silico tests show the potential of the proposed research to safely automate the process of optimising the insulin therapy for people with T1D. In the six-week study, the system demonstrated safety in maintaining glycemic control with a trend suggesting improvement in postprandial glucose outcomes. Feedback from participants showed favourable outcomes when assessing device satisfaction and usability. A six-month large-scale randomised controlled study to evaluate the efficacy of the system is currently ongoing.Open Acces

Clinical evaluation of a novel adaptive bolus calculator and safety system in Type 1 diabetes

Bolus calculators are considered state-of-the-art for insulin dosing decision support for people with Type 1 diabetes (T1D). However, they all lack the ability to automatically adapt in real-time to respond to an individual’s needs or changes in insulin sensitivity. A novel insulin recommender system based on artificial intelligence has been developed to provide personalised bolus advice, namely the Patient Empowerment through Predictive Personalised Decision Support (PEPPER) system. Besides adaptive bolus advice, the decision support system is coupled with a safety system which includes alarms, predictive glucose alerts, predictive low glucose suspend for insulin pump users, personalised carbohydrate recommendations and dynamic bolus insulin constraint. This thesis outlines the clinical evaluation of the PEPPER system in adults with T1D on multiple daily injections (MDI) and insulin pump therapy. The hypothesis was that the PEPPER system is safe, feasible and effective for use in people with TID using MDI or pump therapy. Safety and feasibility of the safety system was initially evaluated in the first phase, with the second phase evaluating feasibility of the complete system (safety system and adaptive bolus advisor). Finally, the whole system was clinically evaluated in a randomised crossover trial with 58 participants. No significant differences were observed for percentage times in range between the PEPPER and Control groups. For quality of life, participants reported higher perceived hypoglycaemia with the PEPPER system despite no objective difference in time spent in hypoglycaemia. Overall, the studies demonstrated that the PEPPER system is safe and feasible for use when compared to conventional therapy (continuous glucose monitoring and standard bolus calculator). Further studies are required to confirm overall effectiveness.Open Acces

Model Identification from Ambulatory Data for Post-Prandial Glucose Control in type 1 Diabetes

Several glucoregulatory models are studies and a new model is proposed. Experiments are developed following an optimal design methodology. The designed experiments are applied in home monitoring of diabetic patients.Laguna Sanz, AJ. (2010). Model Identification from Ambulatory Data for Post-Prandial Glucose Control in type 1 Diabetes. http://hdl.handle.net/10251/14052Archivo delegad

Model-Based Analysis of User Behaviors in Medical Cyber-Physical Systems

Human operators play a critical role in various Cyber-Physical System (CPS) domains, for example, transportation, smart living, robotics, and medicine. The rapid advancement of automation technology is driving a trend towards deep human-automation cooperation in many safety-critical applications, making it important to explicitly consider user behaviors throughout the system development cycle. While past research has generated extensive knowledge and techniques for analyzing human-automation interaction, in many emerging applications, it remains an open challenge to develop quantitative models of user behaviors that can be directly incorporated into the system-level analysis. This dissertation describes methods for modeling different types of user behaviors in medical CPS and integrating the behavioral models into system analysis. We make three main contributions. First, we design a model-based analysis framework to evaluate, improve, and formally verify the robustness of generic (i.e., non-personalized) user behaviors that are typically driven by rule-based clinical protocols. We conceptualize a data-driven technique to predict safety-critical events at run-time in the presence of possible time-varying process disturbances. Second, we develop a methodology to systematically identify behavior variables and functional relationships in healthcare applications. We build personalized behavior models and analyze population-level behavioral patterns. Third, we propose a sequential decision filtering technique by leveraging a generic parameter-invariant test to validate behavior information that may be measured through unreliable channels, which is a practical challenge in many human-in-the-loop applications. A unique strength of this validation technique is that it achieves high inter-subject consistency despite uncertain parametric variances in the physiological processes, without needing any individual-level tuning. We validate the proposed approaches by applying them to several case studies

Modeling and control to improve blood glucose concentration for people with diabetes

Diabetes mellitus is a chronical condition that features either the lack of insulin or increased insulin resistance. It is a disorder in the human metabolic system. To combat insufficiency of insulin released by pancreas, a closed-loop control system, also known as artificial pancreas (AP) in this application, have been created to mimic the functionality of a human pancreas. An AP is used to regulate blood glucose concentration (BGC) by managing the release of insulin. Therefore, an algorithm, which can administer insulin to reduce the variation of BGC and minimize the occurrences of hyper-/ hypoglycemia episodes, is the key component of an AP. The objective of the dissertation is to develop an optimal algorithm to better control BGC for people with diabetes. For people with Type 2 diabetes, prevention or treatment of diabetes mellitus can typically be done via a change of lifestyle and weight management. A virtual sensing system that does not require many manual inputs from patients can ease the burden for people with Type 2 diabetes. This dissertation covers the development of a monitoring system for Type 2 diabetes. To achieve the goal of tighter control of BGC for people with Type 1 diabetes, dynamic modeling methodology for capturing the cause-and-effect relationship between manipulated variable (i.e. insulin) and controlled variable (i.e. BGC) has been developed. Theoretically, this dissertation has established that physiologically based nonlinear parameterized wiener models being superior to nonlinear autoregressive moving average with exogenous inputs (NARMAX) models in capturing dynamic relationships in processes with correlated inputs. Based on these results, wiener models have been applied in the modeling of BGC for real subjects with Type 1 diabetes under free-living conditions. With promising results shown in wiener models, an extended physiologically based model (i.e. semi-coupled model) has been developed from wiener structure, which enables the development of a phenomenologically sound feedforward control law. The feedforward control law based on wiener models has been tested in simulated continuous-stirred-tank reactor (CSTR) that demonstrates tight control of controlled variables. Further simulation runs with a CSTR also shows feedforward predictive control (FFPC) can provide tighter control over model predictive control (MPC). Lastly, for the special application of BGC control for people with Type 1 diabetes, FFPC demonstrates tighter control than MPC under simulation environment. To account for unmeasured disturbances and inaccurate models for manipulated variable in real life scenarios, feedback predictive control (FBPC) is developed and proven to be a more effective control algorithm under both CSTR and diabetes simulation environment, which can establish the foundation for tightening BGC in real subject clinical studies