Multivariable Automated Insulin Delivery System for Handling Planned and Spontaneous Physical Activities.

BACKGROUND: Hybrid closed-loop control of glucose levels in people with type 1 diabetes mellitus (T1D) is limited by the requirements on users to manually announce physical activity (PA) and meals to the artificial pancreas system. Multivariable automated insulin delivery (mvAID) systems that can handle unannounced PAs and meals without any manual announcements by the user can improve glycemic control by modulating insulin dosing in response to the occurrence and intensity of spontaneous physical activities. METHODS: An mvAID system is developed to supplement the glucose measurements with additional physiological signals from a wristband device, with the signals analyzed using artificial intelligence algorithms to automatically detect the occurrence of PA and estimate its intensity. This additional information gained from the physiological signals enables more proactive insulin dosing adjustments in response to both planned exercise and spontaneous unanticipated physical activities. RESULTS: In silico studies of the mvAID illustrate the safety and efficacy of the system. The mvAID is translated to pilot clinical studies to assess its performance, and the clinical experiments demonstrate an increased time in range and reduced risk of hypoglycemia following unannounced PA and meals. CONCLUSIONS: The mvAID systems can increase the safety and efficacy of insulin delivery in the presence of unannounced physical activities and meals, leading to improved lives and less burden on people with T1D.

Detection of Meals and Physical Activity Events From Free-Living Data of People With Diabetes.

BACKGROUND: Predicting carbohydrate intake and physical activity in people with diabetes is crucial for improving blood glucose concentration regulation. Patterns of individual behavior can be detected from historical free-living data to predict meal and exercise times. Data collected in free-living may have missing values and forgotten manual entries. While machine learning (ML) can capture meal and exercise times, missing values, noise, and errors in data can reduce the accuracy of ML algorithms. METHODS: Two recurrent neural networks (RNNs) are developed with original and imputed data sets to assess detection accuracy of meal and exercise events. Continuous glucose monitoring (CGM) data, insulin infused from pump data, and manual meal and exercise entries from free-living data are used to predict meals, exercise, and their concurrent occurrence. They contain missing values of various lengths in time, noise, and outliers. RESULTS: The accuracy of RNN models range from 89.9% to 95.7% for identifying the state of event (meal, exercise, both, or neither) for various users. "No meal or exercise" state is determined with 94.58% accuracy by using the best RNN (long short-term memory [LSTM] with 1D Convolution). Detection accuracy with this RNN is 98.05% for meals, 93.42% for exercise, and 55.56% for concurrent meal-exercise events. CONCLUSIONS: The meal and exercise times detected by the RNN models can be used to warn people for entering meal and exercise information to hybrid closed-loop automated insulin delivery systems. Reliable accuracy for event detection necessitates powerful ML and large data sets. The use of additional sensors and algorithms for detecting these events and their characteristics provides a more accurate alternative.

Adaptive Personalized Prior-Knowledge-Informed Model Predictive Control for Type 1 Diabetes.

This work considers the problem of adaptive prior-informed model predictive control (MPC) formulations that explicitly incorporate prior knowledge in the model development and is robust to missing data in the output measurements. The proposed prediction model is based on a latent variables model to extract glycemic dynamics from highly-correlated data and incorporates prior knowledge of exponential stability to improve the prediction ability. Missing data structures are formulated to enable model predictions when output measurements are missing for short periods of time. Based on the latent variables model, the MPC strategy and adaptive rules are developed to automatically tune the aggressiveness of the MPC. The adaptive prior-knowledge-informed MPC is evaluated with computer simulations for the control of blood glucose concentrations in people with Type 1 diabetes (T1D) using simulated virtual patients. Due to the variability among people with T1D, the hyperparameters of the prior-knowledge-informed model are personalized to individual subjects. The percentage of time spent in the target range is 76.48% when there are no missing data and 76.52% when there are missing data episodes lasting up to 30 mins (6 samples). Incorporating the adaptive rules further improves the percentage of time in target range to 84.58% and 84.88% for cases with no missing data and missing data, respectively. The proposed adaptive prior-informed MPC formulation provides robust, effective, and safe regulation of glucose concentration in T1D despite disturbances and missing measurements.

A physical activity-intensity driven glycemic model for type 1 diabetes.

BACKGROUND AND OBJECTIVE: The glucose response to physical activity for a person with type 1 diabetes (T1D) depends upon the intensity and duration of the physical activity, plasma insulin concentrations, and the individual physical fitness level. To accurately model the glycemic response to physical activity, these factors must be considered. METHODS: Several physiological models describing the glycemic response to physical activity are proposed by incorporating model terms proportional to the physical activity intensity and duration describing endogenous glucose production (EGP), glucose utilization, and glucose transfer from the plasma to tissues. Leveraging clinical data of T1D during physical activity, each model fit is assessed. RESULTS: The proposed model with terms accommodating EGP, glucose transfer, and insulin-independent glucose utilization allow for an improved simulation of physical activity glycemic responses with the greatest reduction in model error (mean absolute percentage error: 16.11 ± 4.82 vs. 19.49 ± 5.87, p = 0.002). CONCLUSIONS: The development of a physiologically plausible model with model terms representing each major contributor to glucose metabolism during physical activity can outperform traditional models with physical activity described through glucose utilization alone. This model accurately describes the relation of plasma insulin and physical activity intensity on glucose production and glucose utilization to generate the appropriately increasing, decreasing or stable glucose response for each physical activity condition. The proposed model will enable the in silico evaluation of automated insulin dosing algorithms designed to mitigate the effects of physical activity with the appropriate relationship between the reduction in basal insulin and the corresponding glycemic excursion.

Meal and Physical Activity Detection from Free-living Data for Discovering Disturbance Patterns to Glucose Levels in People with Diabetes.

Objective: Interpretation of time series data collected in free-living has gained importance in chronic disease management. Some data are collected objectively from sensors and some are estimated and entered by the individual. In type 1 diabetes (T1D), blood glucose concentration (BGC) data measured by continuous glucose monitoring (CGM) systems and insulin doses administered can be used to detect the occurrences of meals and physical activities and generate the personal daily living patterns for use in automated insulin delivery (AID). Methods: Two challenges in time-series data collected in daily living are addressed: data quality improvement and detection of unannounced disturbances to BGC. CGM data have missing values for varying periods of time and outliers. People may neglect reporting their meal and physical activity information. In this work, novel methods for preprocessing real-world data collected from people with T1D and detection of meal and exercise events are presented. Four recurrent neural network (RNN) models are investigated to detect the occurrences of meals and physical activities disjointly or concurrently. Results: RNNs with long short-term memory (LSTM) with 1D convolution layers and bidirectional LSTM with 1D convolution layers have average accuracy scores of 92.32% and 92.29%, and outper-form other RNN models. The F1 scores for each individual range from 96.06% to 91.41% for these two RNNs. Conclusions: RNNs with LSTM and 1D convolution layers and bidirectional LSTM with 1D convolution layers provide accurate personalized information about the daily routines of individuals. Significance: Capturing daily behavior patterns enables more accurate future BGC predictions in AID systems and improves BGC regulation.

Observational Study of Glycemic Impact of Anticipatory and Early-Race Athletic Competition Stress in Type 1 Diabetes.

Athletic competitions and the associated psychological stress are a challenge for people with type 1 diabetes (T1D). This study aims to understand the influence of anticipatory and early race competition stress on blood glucose concentrations and to identify personality, demographic, or behavioral traits indicative in the scope of the impact. Ten recreational athletes with T1D competed in an athletic competition and an exercise-intensity matched non-competition "training" session for comparison. The two hours prior to exercise and the first 30 minutes of exercise were compared between the paired exercise sessions to assess the influence of anticipatory and early race stress. The effectiveness index, average CGM glucose, and the ingested carbohydrate to injected insulin ratio were compared between the paired sessions through regression. In 9 of 12 races studied, an elevated CGM for the race over the individual training session was observed. The rate of change of the CGM during the first 30 minutes of exercise notably differed between the race and training (p = 0.02) with a less rapid decline in CGM occurring during the race for 11 of 12 paired sessions and an increasing CGM trend during the race for 7 of the 12 sessions with the rate of change (mean ± standard deviation) as 1.36 ± 6.07 and -2.59 ± 2.68 mg/dL per 5 minutes for the race and training, respectively. Individuals with longer durations of diabetes often decreased their carbohydrate-to-insulin ratio on race day, taking more insulin, than on the training day while the reverse was noted for those newly diagnosed (r = -0.52, p = 0.05). The presence of athletic competition stress can impact glycemia. With an increasing duration of diabetes, the athletes may be expecting elevated competition glucose concentrations and take preventive measures.

Incorporating Prior Information in Adaptive Model Predictive Control for Multivariable Artificial Pancreas Systems.

BACKGROUND: Adaptive model predictive control (MPC) algorithms that recursively update the glucose prediction model are shown to be promising in the development of fully automated multivariable artificial pancreas systems. However, the recursively updated glycemic prediction models do not explicitly consider prior knowledge in the identification of the model parameters. Prior information of the glycemic effects of meals and physical activity can improve model accuracy and yield better glycemic control algorithms. METHODS: A glucose prediction model based on regularized partial least squares (rPLS) method where the prior information is encoded as the regularization term is developed to provide accurate predictions of the future glucose concentrations. An adaptive MPC is developed that incorporates dynamic trajectories for the glucose setpoint and insulin dosing constraints based on the estimated plasma insulin concentration (PIC). The proposed adaptive MPC algorithm is robust to disturbances caused by unannounced meals and physical activities even in cases with missing glucose measurements. The effectiveness of the proposed adaptive MPC based on rPLS is investigated with in silico subjects of the multivariable glucose-insulin-physiological variables simulator (mGIPsim). RESULTS: The efficacy of the proposed adaptive MPC strategy in regulating the blood glucose concentration (BGC) of people with T1DM is assessed using the average percent time in range (TIR) for glucose, defined as 70 to 180 mg/dL inclusive, and the average percent time in hypoglycemia (<70 and >54 mg/dL) and level 2 hypoglycemia (≤54 mg/dL). The TIR for a cohort of 20 virtual subjects of mGIPsim is 81.9% ± 7.4% (with no hypoglycemia or severe hypoglycemia) for the proposed MPC compared with 73.9% ± 7.6% (0.2% ± 0.1% in hypoglycemia and 0.1% ± 0.1% in level 2 hypoglycemia) for an MPC based on a recursive autoregressive exogenous (ARX) model. CONCLUSIONS: The adaptive MPC algorithm that incorporates prior knowledge in the recursive updating of the glucose prediction model can contribute to the development of fully automated artificial pancreas systems that can mitigate meal and physical activity disturbances.

Prior Informed Regularization of Recursively Updated Latent-Variables-Based Models with Missing Observations.

Many data-driven modeling techniques identify locally valid, linear representations of time-varying or nonlinear systems, and thus the model parameters must be adaptively updated as the operating conditions of the system vary, though the model identification typically does not consider prior knowledge. In this work, we propose a new regularized partial least squares (rPLS) algorithm that incorporates prior knowledge in the model identification and can handle missing data in the independent covariates. This latent variable (LV) based modeling technique consists of three steps. First, a LV-based model is developed on the historical time series data. In the second step, the missing observations in the new incomplete data sample are estimated. Finally, the future values of the outputs are predicted as a linear combination of estimated scores and loadings. The model is recursively updated as new data are obtained from the system. The performance of the proposed rPLS and rPLS with exogenous inputs (rPLSX) algorithms are evaluated by modeling variations in glucose concentration (GC) of people with Type 1 diabetes (T1D) in response to meals and physical activities for prediction windows up to one hour, or 12 sampling instances, into the future. The proposed rPLS family of GC prediction models are evaluated with both in-silico and clinical experiment data and compared with the performance of recursive time series and kernel-based models. The root mean squared error (RMSE) with simulated subjects in the multivariable T1D simulator where physical activity effects are incorporated in GC variations are 2.52 and 5.81 mg/dL for 30 and 60 mins ahead predictions (respectively) when information for all meals and physical activities are used, increasing to 2.70 and 6.54 mg/dL (respectively) when meals and activities occurred, but the information is with-held from the modeling algorithms. The RMSE is 10.45 and 14.48 mg/dL for clinical study with prediction horizons of 30 and 60 mins, respectively. The low RMSE values demonstrate the effectiveness of the proposed rPLS approach compared to the conventional recursive modeling algorithms.

Physical Activity and Psychological Stress Detection and Assessment of Their Effects on Glucose Concentration Predictions in Diabetes Management.

OBJECTIVE: Continuous glucose monitoring (CGM) enables prediction of the future glucose concentration (GC) trajectory for making informed diabetes management decisions. The glucose concentration values are affected by various physiological and metabolic variations, such as physical activity (PA) and acute psychological stress (APS), in addition to meals and insulin. In this work, we extend our adaptive glucose modeling framework to incorporate the effects of PA and APS on the GC predictions. METHODS: A wristband conducive of use by free-living ambulatory people is used. The measured physiological variables are analyzed to generate new quantifiable input features for PA and APS. Machine learning techniques estimate the type and intensity of the PA and APS when they occur individually and concurrently. Variables quantifying the characteristics of both PA and APS are integrated as exogenous inputs in an adaptive system identification technique for enhancing the accuracy of GC predictions. Data from clinical experiments illustrate the improvement in GC prediction accuracy. RESULTS: The average mean absolute error (MAE) of one-hour-ahead GC predictions with testing data decreases from 35.1 to 31.9 mg/dL (p-value = 0.01) with the inclusion of PA information, and it decreases from 16.9 to 14.2 mg/dL (p-value = 0.006) with the inclusion of PA and APS information. CONCLUSION: The first-ever glucose prediction model is developed that incorporates measures of physical activity and acute psychological stress to improve GC prediction accuracy. SIGNIFICANCE: Modeling the effects of physical activity and acute psychological stress on glucose concentration values will improve diabetes management and enable informed meal, activity and insulin dosing decisions.

Discrimination of simultaneous psychological and physical stressors using wristband biosignals.

BACKGROUND AND OBJECTIVE: In this work, we address the problem of detecting and discriminating acute psychological stress (APS) in the presence of concurrent physical activity (PA) using wristband biosignals. We focused on signals available from wearable devices that can be worn in daily life because the ultimate objective of this work is to provide APS and PA information in real-time management of chronic conditions such as diabetes by automated personalized insulin delivery. Monitoring APS noninvasively throughout free-living conditions remains challenging because the responses to APS and PA of many physiological variables measured by wearable devices are similar. METHODS: Various classification algorithms are compared to simultaneously detect and discriminate the PA (sedentary state, treadmill running, and stationary bike) and the type of APS (non-stress state, mental stress, and emotional anxiety). The impact of APS inducements is verified with commonly used self-reported questionnaires (The State-Trait Anxiety Inventory (STAI)). To aid the classification algorithms, novel features are generated from the physiological variables reported by a wristband device during 117 hours of experiments involving simultaneous APS inducement and PA. We also translate the APS assessment into a quantitative metric for use in predicting the adverse outcomes. RESULTS: An accurate classification of the concurrent PA and APS states is achieved with an overall classification accuracy of 99% for PA and 92% for APS. The average accuracy of APS detection during sedentary state, treadmill running, and stationary bike is 97.3, 94.1, and 84.5%, respectively. CONCLUSIONS: The simultaneous assessment of APS and PA throughout free-living conditions from a convenient wristband device is useful for monitoring the factors contributing to an elevated risk of acute events in people with chronic diseases like cardiovascular complications and diabetes.

Determining Physical Activity Characteristics from Wristband Data for Use in Automated Insulin Delivery Systems.

Algorithms that can determine the type of physical activity (PA) and quantify the intensity can allow precision medicine approaches, such as automated insulin delivery systems that modulate insulin administration in response to PA. In this work, data from a multi-sensor wristband is used to design classifiers to distinguish among five different physical states (PS) (resting, activities of daily living, running, biking, and resistance training), and to develop models to estimate the energy expenditure (EE) of the PA for diabetes therapy. The data collected are filtered, features are extracted from the reconciled signals, and the extracted features are used by machine learning algorithms, including deep-learning techniques, to obtain accurate PS classification and EE estimation. The various machine learning techniques have different success rates ranging from 75.7% to 94.8% in classifying the five different PS. The deep neural network model with long short-term memory has 94.8% classification accuracy. We achieved 0.5 MET (Metabolic Equivalent of Task) root-mean-square error for EE estimation accuracy, relative to indirect calorimetry with randomly selected testing data (10% of collected data). We also demonstrate a 5% improvement in PS classification accuracy and a 0.34 MET decrease in the mean absolute error when using multi-sensor approach relative to using only accelerometer data.

Online Glucose Prediction Using Computationally Efficient Sparse Kernel Filtering Algorithms in Type-1 Diabetes.

Streaming data from continuous glucose monitoring (CGM) systems enable the recursive identification of models to improve estimation accuracy for effective predictive glycemic control in patients with type-1 diabetes. A drawback of conventional recursive identification techniques is the increase in computational requirements, which is a concern for online and real-time applications such as the artificial pancreas systems implemented on handheld devices and smartphones where computational resources and memory are limited. To improve predictions in such computationally constrained hardware settings, efficient adaptive kernel filtering algorithms are developed in this paper to characterize the nonlinear glycemic variability by employing a sparsification criterion based on the information theory to reduce the computation time and complexity of the kernel filters without adversely deteriorating the predictive performance. Furthermore, the adaptive kernel filtering algorithms are designed to be insensitive to abnormal CGM measurements, thus compensating for measurement noise and disturbances. As such, the sparsification-based real-time model update framework can adapt the prediction models to accurately characterize the time-varying and nonlinear dynamics of glycemic measurements. The proposed recursive kernel filtering algorithms leveraging sparsity for improved computational efficiency are applied to both in-silico and clinical subjects, and the results demonstrate the effectiveness of the proposed methods.

Immobilized RGD concentration and proteolytic degradation synergistically enhance vascular sprouting within hydrogel scaffolds of varying modulus.

Insufficient vascularization limits the volume and complexity of engineered tissue. The formation of new blood vessels (neovascularization) is regulated by a complex interplay of cellular interactions with biochemical and biophysical signals provided by the extracellular matrix (ECM) necessitating the development of biomaterial approaches that enable systematic modulation in matrix properties. To address this need poly(ethylene) glycol-based hydrogel scaffolds were engineered with a range of decoupled and combined variations in integrin-binding peptide (RGD) ligand concentration, elastic modulus and proteolytic degradation rate using free-radical polymerization chemistry. The modularity of this system enabled a full factorial experimental design to simultaneously investigate the individual and interaction effects of these matrix cues on vascular sprout formation in 3 D culture. Enhancements in scaffold proteolytic degradation rate promoted significant increases in vascular sprout length and junction number while increases in modulus significantly and negatively impacted vascular sprouting. We also observed that individual variations in immobilized RGD concentration did not significantly impact 3 D vascular sprouting. Our findings revealed a previously unidentified and optimized combination whereby increases in both immobilized RGD concentration and proteolytic degradation rate resulted in significant and synergistic enhancements in 3 D vascular spouting. The above-mentioned findings would have been challenging to uncover using one-factor-at-time experimental analyses.

Seasonal Local Models for Glucose Prediction in Type 1 Diabetes.

Linear empirical dynamic models have been widely used for blood glucose prediction and risks prevention in people with type 1 diabetes. More accurate blood glucose prediction models with longer prediction horizon (PH) are desirable to enable warnings to patients about imminent blood glucose changes with enough time to take corrective actions. In this study, a blood glucose prediction method is developed by integrating the predictions of a set of seasonal local models (each of them corresponding to different glucose profiles observed along historical data). In the modeling step, the number of sets and their corresponding glucose profiles characteristics are obtained by clustering techniques (Fuzzy C-Means). Then, Box-Jenkins methodology is used to identify a seasonal model for each set. Finally, blood glucose predictions of local models are integrated using different techniques. The proposed method is tested by using 18 60-h closed-loop experiments (including different exercise types and artificial pancreas strategies) and achieving mean absolute percentage error (MAPE) of 2.94%, 3.89%, 5.41%, 6.29% and 8.66% for 15-, 30-, 45-, 60-, and 90-min PHs, respectively.

Plasma-Insulin-Cognizant Adaptive Model Predictive Control for Artificial Pancreas Systems.

An adaptive model predictive control (MPC) algorithm with dynamic adjustments of constraints and objective function weights based on estimates of the plasma insulin concentration (PIC) is proposed for artificial pancreas (AP) systems. A personalized compartment model that translates the infused insulin into estimates of PIC is integrated with a recursive subspace-based system identification to characterize the transient dynamics of glycemic measurements. The system identification approach is able to identify stable, reliable linear time-varying models from closed-loop data. An MPC algorithm using the adaptive models is designed to compute the optimal exogenous insulin delivery for AP systems without requiring any manually-entered meal information. A dynamic safety constraint derived from the estimation of PIC is incorporated in the adaptive MPC to improve the efficacy of the AP and prevent insulin overdosing. Simulation case studies demonstrate the performance of the proposed adaptive MPC algorithm.

Controlling the AP Controller: Controller Performance Assessment and Modification.

BACKGROUND: Despite recent advances in closed-loop control of blood glucose concentration (BGC) in people with type 1 diabetes (T1D), online performance assessment and modification of artificial pancreas (AP) control systems remain a challenge as the metabolic characteristics of users change over time. METHODS: A controller performance assessment and modification system (CPAMS) analyzes the glucose concentration variations and controller behavior, and modifies the parameters of the control system used in the multivariable AP system. Various indices are defined to quantitatively evaluate the controller performance in real time. Controller performance assessment and modification system also incorporates online learning from historical data to anticipate impending disturbances and proactively counteract their effects. RESULTS: Using a multivariable simulation platform for T1D, the CPAMS is used to enhance the BGC regulation in people with T1D by means of automated insulin delivery with an adaptive learning predictive controller. Controller performance assessment and modification system increases the percentage of time in the target range (70-180) mg/dL by 52.3% without causing any hypoglycemia and hyperglycemia events. CONCLUSIONS: The results demonstrate a significant improvement in the multivariable AP controller performance by using CPAMS.

Multi-Model Sensor Fault Detection and Data Reconciliation: A Case Study with Glucose Concentration Sensors for Diabetes.

Erroneous information from sensors affect process monitoring and control. An algorithm with multiple model identification methods will improve the sensitivity and accuracy of sensor fault detection and data reconciliation (SFD&DR). A novel SFD&DR algorithm with four types of models including outlier robust Kalman filter, locally weighted partial least squares, predictor-based subspace identification, and approximate linear dependency-based kernel recursive least squares is proposed. The residuals are further analyzed by artificial neural networks and a voting algorithm. The performance of the SFD&DR algorithm is illustrated by clinical data from artificial pancreas experiments with people with diabetes. The glucose-insulin metabolism has time-varying parameters and nonlinearities, providing a challenging system for fault detection and data reconciliation. Data from 17 clinical experiments collected over 896 hours were analyzed; the results indicate that the proposed SFD&DR algorithm is capable of detecting and diagnosing sensor faults and reconciling the erroneous sensor signals with better model-estimated values.

Improving Glucose Prediction Accuracy in Physically Active Adolescents With Type 1 Diabetes.

BACKGROUND: Physical activity presents a significant challenge for glycemic control in individuals with type 1 diabetes. As accurate glycemic predictions are key to successful automated decision-making systems (eg, artificial pancreas, AP), the inclusion of additional physiological variables in the estimation of the metabolic state may improve the glucose prediction accuracy during exercise. METHODS: Predictor-based subspace identification is applied to a dynamic glucose prediction model including heart rate measurements along with variables representing the carbohydrate consumption and insulin boluses. To demonstrate the improvement in prediction ability due to the additional heart rate variable, the performance of the proposed modeling technique is evaluated with (SID-HR) and without heart rate (SID-2) as an additional input using experimental data involving adolescents at ski camp. Furthermore, the performance of the proposed approach is compared to that of the metabolic state observer (MSO) model currently used in the University of Virginia AP algorithm. RESULTS: The addition of heart rate in the subspace-based model (SID-HR) yields a statistically significant improvement in the root-mean-square error compared to the SID-2 model (P < .001) and the standard MSO (P < .001). Furthermore, the SID-HR model performed favorably in comparison to the SID-2 and MSO models after accounting for its increased complexity. CONCLUSIONS: Directly considering the effects of physical activity levels on glycemic dynamics through the inclusion of heart rate as an additional input variable in the glucose dynamics model improves the glucose prediction accuracy. The proposed methodology could improve exercise-informed model-based predictive control algorithms in artificial pancreas systems.

Simulation Software for Assessment of Nonlinear and Adaptive Multivariable Control Algorithms: Glucose - Insulin Dynamics in Type 1 Diabetes.

A simulator for testing automatic control algorithms for nonlinear systems with time-varying parameters, variable time delays, and uncertainties is developed. It is based on simulation of virtual patients with Type 1 diabetes (T1D). Nonlinear models are developed to describe glucose concentration (GC) variations based on user-defined scenarios for meal consumption, insulin administration, and physical activity. They compute GC values and physiological variables, such as heart rate, skin temperature, accelerometer, and energy expenditure, that are indicative of physical activities affecting GC dynamics. This is the first simulator designed for assessment of multivariable controllers that consider supplemental physiological variables in addition to GC measurements to improve glycemic control. Virtual patients are generated from distributions of identified model parameters using clinical data. The simulator will enable testing and evaluation of new control algorithms proposed for automated insulin delivery as well as various control algorithms for nonlinear systems with uncertainties, time-varying parameters and delays.