Validation of the UVA Simulation Replay Methodology Using Clinical Data: Reproducing a Randomized Clinical Trial.

Background: Computer simulators of human metabolism are powerful tools to design and validate new diabetes treatments. However, these platforms are often limited in the diversity of behaviors and glycemic conditions they can reproduce. Replay methodologies leverage field-collected data to create ad hoc simulation environments representative of real-life conditions. After formal validations of our method in prior publications, we demonstrate its capacity to reproduce a recent clinical trial. Methods: Using the replay methodology, an ensemble of replay simulators was generated using data from a randomized crossover clinical trial comparing the hybrid closed loop (HCL) and fully closed loop (FCL) control modalities in automated insulin delivery (AID), creating 64 subject/modality pairs. Each virtual subject was exposed to the alternate AID modality to compare the simulated versus observed glycemic outcomes. Equivalence tests were performed for time in, below, and above range (TIR, TBR, and TAR) and high and low blood glucose indices (HBGI and LBGI) considering equivalence margins corresponding to clinical significance. Results: TIR, TAR, LBGI, and HBGI showed statistical and clinical equivalence between the original and the simulated data; TBR failed the equivalence test. For example, in the HCL mode, simulated TIR was 84.89% versus an observed 84.31% (P = 0.0170, confidence interval [CI] [-3.96, 2.79]), and for FCL mode, TIR was 76.58% versus 77.41% (P = 0.0222, CI [-2.54, 4.20]). Conclusion: Clinical trial data confirm the prior in silico validation of the UVA replay method in predicting the glycemic impact of modified insulin treatments. This in vivo demonstration justifies the application of the replay method to the personalization and adaptation of treatment strategies in people with type 1 diabetes.

Integration of a Safety Module to Prevent Rebound Hypoglycemia in Closed-Loop Artificial Pancreas Systems.

BACKGROUND: With automated insulin delivery (AID) systems becoming widely adopted in the management of type 1 diabetes, we have seen an increase in occurrences of rebound hypoglycemia or generated hypoglycemia induced by the controller's response to rapid glucose rises following rescue carbohydrates. Furthermore, as AID systems aim to enable complete automation of prandial control, algorithms are designed to react even more strongly to glycemic rises. This work introduces a rebound hypoglycemia prevention layer (HypoSafe) that can be easily integrated into any AID system. METHODS: HypoSafe constrains the maximum permissible insulin delivery dose based on the minimum glucose reading from the previous hour and the current glucose level. To demonstrate its efficacy, we integrated HypoSafe into the latest University of Virginia (UVA) AID system and simulated two scenarios using the 100-adult cohort of the UVA/Padova T1D simulator: a nominal case including three unannounced meals, and another case where hypoglycemia was purposely induced by an overestimated manual bolus. RESULTS: In both simulation scenarios, rebound hypoglycemia events were reduced with HypoSafe (nominal: from 39 to 0, hypo-induced: from 55 to 7) by attenuating the commanded basal (nominal: 0.27U vs. 0.04U, hypo-induced: 0.27U vs. 0.03U) and bolus (nominal: 1.02U vs. 0.05U, hypo-induced: 0.43U vs. 0.02U) within the 30-minute interval after treating a hypoglycemia event. No clinically significant changes resulted for time in the range of 70 to 180 mg/dL or above 180 mg/dL. CONCLUSION: HypoSafe was shown to be effective in reducing rebound hypoglycemia events without affecting achieved time in range when combined with an advanced AID system.

Simulation-driven optimization of insulin therapy profiles in a commercial hybrid closed-loop system.

BACKGROUND: Automated insulin delivery (AID) has represented a breakthrough in managing type 1 diabetes (T1D), showing safe and effective glucose control extensively across the board. However, metabolic variability still poses a challenge to commercial hybrid closed-loop (HCL) solutions, whose performance depends on customizable insulin therapy profiles. In this work, we propose an Identification-Replay-Optimization (IRO) approach to optimize gradually and safely such profiles for the Control-IQ AID algorithm. METHODS: Closed-loop data are generated using the full adult cohort of the UVA/Padova T1D simulation platform in diverse glycemic scenarios. For each subject, daily records are processed and used to estimate a personalized model of the underlying insulin-glucose dynamics. Every two weeks, all identified models are integrated into an optimization procedure where daily basal and bolus profiles are adjusted so as to minimize the risks for hypo- and hyperglycemia. The proposed strategy is tested under different scenarios of metabolic and behavioral variability in order to evaluate the efficacy and convergence of the proposed strategy. Finally, glycemic metrics between cycles are compared using paired t-tests with p<0.05 as the significance threshold. RESULTS: Simulations reveal that the proposed IRO approach was able to improve glucose control over time by safely mitigating the risks for both hypo- and hyperglycemia. Furthermore, smaller changes were recommended at each cycle, indicating convergence when simulation conditions were maintained. CONCLUSIONS: The use of reliable simulation-driven tools capable of accurately reproducing field-collected data and predicting changes can substantially shorten the process of optimizing insulin therapy, adjusting it to metabolic changes and leading to improved glucose control.

Accuracy of an Off-Label Transmitter and Data Manager Paired With an Intermittent Scanned Continuous Glucose Monitor in Adults With Type 1 Diabetes.

BACKGROUND: This work evaluates the accuracy and agreement between the FreeStyle Libre sensor (FSL) and an off-label converted real-time continuous glucose monitor (c-rtCGM) device consisting of the MiaoMiao transmitter and the xDrip+ application which can be coupled to the FSL. METHODS: Four weeks of glucose data were collected from 21 participants with type 1 diabetes using the c-rtCGM and FSL: two weeks with a single initial calibration (uncalibrated) and two weeks with a daily calibration (calibrated). Accuracy and agreement evaluation included mean absolute relative difference (MARD), the %20/20 rule, Bland-Altman plots, and the Consensus Error Grid analysis. RESULTS: Values reported by the c-rtCGM system compared with the FSL resulted in an overall MARD of 12.06% and 84.71% of the results falling within Consensus Error Grid Zone A when the device is calibrated. For uncalibrated devices, an overall MARD of 17.49% was obtained. Decreased accuracy was shown in the hypoglycemic range and for rates of change greater than 2 mg/dL/min. The between-device bias also incremented with increasing glucose values. CONCLUSION: Measurements recorded by the c-rtCGM were found to be accurate when compared with FSL data only when performing daily c-rtCGM device calibrations. High drops in accuracy and agreement between devices occurred when the c-rtCGM was not calibrated.

Interval Safety Layer Coupled With an Impulsive MPC for Artificial Pancreas to Handle Intrapatient Variability.

The aim of control strategies for artificial pancreas systems is to calculate the insulin doses required by a subject with type 1 diabetes to regulate blood glucose levels by reducing hyperglycemia and avoiding the induction of hypoglycemia. Several control formulations developed for this end involve a safety constraint given by the insulin on board (IOB) estimation. This constraint has the purpose of reducing hypoglycemic episodes caused by insulin stacking. However, intrapatient variability constantly changes the patient's response to insulin, and thus, an adaptive method is required to restrict the control action according to the current situation of the subject. In this work, the control action computed by an impulsive model predictive controller is modulated with a safety layer to satisfy an adaptive IOB constraint. This constraint is established with two main steps. First, upper and lower IOB bounds are generated with an interval model that accounts for parameter uncertainty, and thus, define the possible system responses. Second, the constraint is selected according to the current value of glycemia, an estimation of the plant-model mismatch, and their corresponding first and second time derivatives to anticipate the changes of both glucose levels and physiological variations. With this strategy satisfactory results were obtained in an adult cohort where random circadian variability and sensor noise were considered. A 92% time in normoglycemia was obtained, representing an increase of time in range compared to previous MPC strategies, and a reduction of time in hypoglycemia to 0% was achieved without dangerously increasing the time in hyperglycemia.

Performance Analysis of Different Embedded Systems and Open-Source Optimization Packages Towards an Impulsive MPC Artificial Pancreas.

Current technological advances have brought closer to reality the project of a safe, portable, and efficient artificial pancreas for people with type 1 diabetes (T1D). Among the developed control strategies for T1D, model predictive control (MPC) has been emphasized in literature as a promising control for glucose regulation. However, these control strategies are commonly designed in a computer environment, regardless of the limitations of a portable device. In this paper, the performances of six embedded platforms and three open-source optimization solver algorithms are assessed for T1D treatment. Their advantages and limitations are clarified using four MPC formulations of increasing complexity and a hardware-in-the-loop methodology to evaluate glucose control in virtual adult subjects. The performance comparison includes the execution time, the difference concerning the evolution obtained in MATLAB, the processor temperature, energy consumption, time percentage in normoglycemia, and the number of hypo- and hyperglycemic events. Results show that Quadprog is the package that faithfully follows the results obtained with control strategies designed and tuned on a computer with the MATLAB software. In addition, the Raspberry Pi 3 and the Tinker Board S embedded systems present the appropriate characteristics to be implemented as portable devices in the artificial pancreas application according to the criteria set out in this work.

Oncolytic virus therapy benefits from control theory.

Oncolytic virus therapy aims to eradicate tumours using viruses which only infect and destroy targeted tumour cells. It is urgent to improve understanding and outcomes of this promising cancer treatment because oncolytic virus therapy could provide sensible solutions for many patients with cancer. Recently, mathematical modelling of oncolytic virus therapy was used to study different treatment protocols for treating breast cancer cells with genetically engineered adenoviruses. Indeed, it is currently challenging to elucidate the number, the schedule, and the dosage of viral injections to achieve tumour regression at a desired level and within a desired time frame. Here, we apply control theory to this model to advance the analysis of oncolytic virus therapy. The control analysis of the model suggests that at least three viral injections are required to control and reduce the tumour from any initial size to a therapeutic target. In addition, we present an impulsive control strategy with an integral action and a state feedback control which achieves tumour regression for different schedule of injections. When oncolytic virus therapy is evaluated in silico using this feedback control of the tumour, the controller automatically tunes the dose of viral injections to improve tumour regression and to provide some robustness to uncertainty in biological rates. Feedback control shows the potential to deliver efficient and personalized dose of viral injections to achieve tumour regression better than the ones obtained by former protocols. The control strategy has been evaluated in silico with parameters that represent five nude mice from a previous experimental work. Together, our findings suggest theoretical and practical benefits by applying control theory to oncolytic virus therapy.

Offset-free MPC strategy for nonzero regulation of linear impulsive systems.

In various biomedical applications, drug administration treatment can be modeled as an impulsive control system. Despite the development of different control strategies for impulsive systems, the elimination of the offset generated by a plant-model mismatch has not yet been researched. In biomedical systems, this mismatch is a consequence of physiological changes and can result in inaccurate treatment of patients. Therefore, control techniques that accomplish the objectives by compensating the effect of variations are required. The present paper proposes and substantiates a novel offset-free model predictive control (MPC) strategy for impulsive systems. To that aim, an impulsive disturbance model is introduced, and an observer design is developed that includes new observability criteria for estimating the disturbance and the state. Further, it is demonstrated that the proposed control strategy achieves zero offset tracking from an analysis of the observer and the controller at steady state. Additionally, the controller incorporates a recent MPC formulation to steer the state to an equilibrium set using artificial/intermediary variables to achieve nonzero regulation. Finally, these results are evaluated and illustrated using a dynamical model for type 1 diabetic patients.