A Probabilistic Approach to Blood Glucose Prediction in Type 1 Diabetes Under Meal Uncertainties.

Currently, most reliable and commercialized artificial pancreas systems for type 1 diabetes are hybrid closed-loop systems, which require the user to announce every meal and its size. However, estimating the amount of carbohydrates in a meal and announcing each and every meal is an error-prone process that introduces important uncertainties to the problem, which when not considered, lead to sub-optimal outcomes of the controller. To address this problem, we propose a novel deep-learning-based model for probabilistic glucose prediction, called the Input and State Recurrent Kalman Network (ISRKN), which consists in the incorporation of an input and state Kalman filter in the latent space of a deep neural network so that the posterior distributions can be computed in closed form and the uncertainty can be propagated using the Kalman equations. In addition, the proposed architecture allows explicit estimation of the meal uncertainty distribution, whose parameters are encoded in the filter parameters. Results using the UVA/Padova simulator and data from a clinical trial show that the proposed model outperforms other probabilistic models using several probabilistic metrics across different degrees of distributional shifts.

Examining the Acute Glycemic Effects of Different Types of Structured Exercise Sessions in Type 1 Diabetes in a Real-World Setting: The Type 1 Diabetes and Exercise Initiative (T1DEXI).

OBJECTIVE: Maintenance of glycemic control during and after exercise remains a major challenge for individuals with type 1 diabetes. Glycemic responses to exercise may differ by exercise type (aerobic, interval, or resistance), and the effect of activity type on glycemic control after exercise remains unclear. RESEARCH DESIGN AND METHODS: The Type 1 Diabetes Exercise Initiative (T1DEXI) was a real-world study of at-home exercise. Adult participants were randomly assigned to complete six structured aerobic, interval, or resistance exercise sessions over 4 weeks. Participants self-reported study and nonstudy exercise, food intake, and insulin dosing (multiple daily injection [MDI] users) using a custom smart phone application and provided pump (pump users), heart rate, and continuous glucose monitoring data. RESULTS: A total of 497 adults with type 1 diabetes (mean age ± SD 37 ± 14 years; mean HbA1c ± SD 6.6 ± 0.8% [49 ± 8.7 mmol/mol]) assigned to structured aerobic (n = 162), interval (n = 165), or resistance (n = 170) exercise were analyzed. The mean (± SD) change in glucose during assigned exercise was -18 ± 39, -14 ± 32, and -9 ± 36 mg/dL for aerobic, interval, and resistance, respectively (P < 0.001), with similar results for closed-loop, standard pump, and MDI users. Time in range 70-180 mg/dL (3.9-10.0 mmol/L) was higher during the 24 h after study exercise when compared with days without exercise (mean ± SD 76 ± 20% vs. 70 ± 23%; P < 0.001). CONCLUSIONS: Adults with type 1 diabetes experienced the largest drop in glucose level with aerobic exercise, followed by interval and resistance exercise, regardless of insulin delivery modality. Even in adults with well-controlled type 1 diabetes, days with structured exercise sessions contributed to clinically meaningful improvement in glucose time in range but may have slightly increased time below range.

Safe and Personalized Meal Bolus Calculator for Type-1 Diabetes Using Bayesian Optimization.

Despite several developments in artificial pancreas technology, postprandial glycemic regulation remains to be a major challenge for type 1 diabetes management. Typically, the large spike in blood glucose concentration induced by meals require an appropriate dose of bolus insulin. Although matching bolus insulin to carbohydrate intake has been shown to improve glycemic regulation, current state-of-the-art meal bolus calculators depend on patient-specific parameters and/or historical clinical data, which may not be easily available. In this paper, we propose a model-free safe and personalized bolus calculator algorithm that is based on safe contextual Bayesian optimization. The proposed algorithm neither requires any patient-specific parameters, nor historical clinical data. Furthermore, the proposed algorithm focuses on patient safety, and ensures satisfaction of the safety-critical hypoglycemia constraint with high probability. In silico experiments conducted on the 10-adult cohort of the FDA-accepted UVA/Padova T1DM simulator, as well as on a cohort of 50 virtual patients based on the Hovorka T1D model in open-loop mode, demonstrate that our algorithm is able to quickly learn the optimum bolus insulin dose for the announced meals using only the patient's CGM data while ensuring patient safety.

Outpatient Randomized Crossover Automated Insulin Delivery Versus Conventional Therapy with Induced Stress Challenges.

Background: Automated insulin delivery (AID) systems have not been evaluated in the context of psychological and pharmacological stress in type 1 diabetes. Our objective was to determine glycemic control and insulin use with Zone Model Predictive Control (zone-MPC) AID system enhanced for states of persistent hyperglycemia versus sensor-augmented pump (SAP) during outpatient use, including in-clinic induced stress. Materials and Methods: Randomized, crossover, 2-week trial of zone-MPC AID versus SAP in 14 adults with type 1 diabetes. In each arm, each participant was studied in-clinic with psychological stress induction (Trier Social Stress Test [TSST] and Socially Evaluated Cold Pressor Test [SECPT]), followed by pharmacological stress induction with oral hydrocortisone (total four sessions per participant). The main outcomes were 2-week continuous glucose monitor percent time in range (TIR) 70-180 mg/dL, and glucose and insulin outcomes during and overnight following stress induction. Results: During psychological stress, AID decreased glycemic variability percentage by 13.4% (P = 0.009). During pharmacological stress, including the following overnight, there were no differences in glucose outcomes and total insulin between AID and physician-assisted SAP. However, with AID total user-requested insulin was lower by 6.9 U (P = 0.01) for pharmacological stress. Stress induction was validated by changes in heart rate and salivary cortisol levels. During the 2-week AID use, TIR was 74.4% (vs. SAP 63.1%, P = 0.001) and overnight TIR was 78.3% (vs. SAP 63.1%, P = 0.004). There were no adverse events. Conclusions: Zone-MPC AID can reduce glycemic variability and the need for user-requested insulin during pharmacological stress and can improve overall glycemic outcomes. Clinical Trial Identifier NCT04142229.

Activity detection and classification from wristband accelerometer data collected on people with type 1 diabetes in free-living conditions.

This paper introduces methods to estimate aspects of physical activity and sedentary behavior from three-axis accelerometer data collected with a wrist-worn device at a sampling rate of 32 [Hz] on adults with type 1 diabetes (T1D) in free-living conditions. In particular, we present two methods able to detect and grade activity based on its intensity and individual fitness as sedentary, mild, moderate or vigorous, and a method that performs activity classification in a supervised learning framework to predict specific user behaviors. Population results for activity level grading show multi-class average accuracy of 99.99%, precision of 98.0 ± 2.2%, recall of 97.9 ± 3.5% and F1 score of 0.9 ± 0.0. As for the specific behavior prediction, our best performing classifier, gave population multi-class average accuracy of 92.43 ± 10.32%, precision of 92.94 ± 9.80%, recall of 92.20 ± 10.16% and F1 score of 92.56 ± 9.94%. Our investigation showed that physical activity and sedentary behavior can be detected, graded and classified with good accuracy and precision from three-axial accelerometer data collected in free-living conditions on people with T1D. This is particularly significant in the context of automated glucose control systems for diabetes, in that the methods we propose have the potential to inform changes in treatment parameters in response to the intensity of physical activity, allowing patients to meet their glycemic targets.

More Time in Glucose Range During Exercise Days than Sedentary Days in Adults Living with Type 1 Diabetes.

Objective: This study analysis was designed to examine the 24-h effects of exercise on glycemic control as measured by continuous glucose monitoring (CGM). Methods: Individuals with type 1 diabetes (ages: 15-68 years; hemoglobin A1c: 7.5% ± 1.5% [mean ± standard deviation (SD)]) were randomly assigned to complete twice-weekly aerobic, high-intensity interval, or resistance-based exercise sessions in addition to their personal exercise sessions for a period of 4 weeks. Exercise was tracked with wearables and glucose concentrations assessed using CGM. An exercise day was defined as a 24-h period after the end of exercise, while a sedentary day was defined as any 24-h period with no recorded exercise ≥10 min long. Sedentary days start at least 24 h after the end of exercise. Results: Mean glucose was lower (150 ± 45 vs. 166 ± 49 mg/dL, P = 0.01), % time in range [70-180 mg/dL] higher (62% ± 23% vs. 56% ± 25%, P = 0.03), % time >180 mg/dL lower (28% ± 23% vs. 37% ± 26%, P = 0.01), and % time <70 mg/dL higher (9.3% ± 11.0% vs. 7.1% ± 9.1%, P = 0.04) on exercise days compared with sedentary days. Glucose variability and % time <54 mg/dL did not differ significantly between exercise and sedentary days. No significant differences in glucose control by exercise type were observed. Conclusion: Participants had lower 24-h mean glucose levels and a greater time in range on exercise days compared with sedentary days, with mode of exercise affecting glycemia similarly. In summary, this study offers data supporting frequency of exercise as a method of facilitating glucose control but does not suggest an effect for mode of exercise.

Using Iterative Learning for Insulin Dosage Optimization in Multiple-Daily-Injections Therapy for People With Type 1 Diabetes.

OBJECTIVE: In this work, we design iterative algorithms for the delivery of long-acting (basal) and rapid-acting (bolus) insulin, respectively, for people with type 1 diabetes (T1D) on multiple-daily-injections (MDIs) therapy using feedback from self-monitoring of blood glucose (SMBG) measurements. METHODS: Iterative learning control (ILC) updates basal therapy consisting of one long-acting insulin injection per day, while run-to-run (R2R) adapts meal bolus therapy via the update of the mealtime-specific insulin-to-carbohydrate ratio (CR). Updates are due weekly and are based upon sparse SMBG measurements. RESULTS: Upon termination of the 20 weeks long in-silico trial, in a scenario characterized by meal carbohydrate (CHO) normally distributed with mean µ = [50, 75, 75] grams and standard deviation σ = [5, 7, 7] grams, our strategy produced statistically significant improvements in time in range (70--180) [mg/dl], from 66.9(33.1) % to 93.6(6.7) %, p = 0.02. CONCLUSIONS: Iterative learning shows potential to improve glycemic regulation over time by driving blood glucose closer to the recommended glycemic targets. SIGNIFICANCE: Decision support systems (DSSs) and automated therapy advisors such as the one proposed here are expected to improve glycemic outcomes reducing the burden on patients on MDI therapy.

Randomized Crossover Comparison of Automated Insulin Delivery Versus Conventional Therapy Using an Unlocked Smartphone with Scheduled Pasta and Rice Meal Challenges in the Outpatient Setting.

Background: Automated Insulin Delivery (AID) hybrid closed-loop systems have not been well studied in the context of prescribed meals. We evaluated performance of our interoperable artificial pancreas system (iAPS) in the at-home setting, running on an unlocked smartphone, with scheduled meal challenges in a randomized crossover trial. Methods: Ten adults with type 1 diabetes completed 2 weeks of AID-based control and 2 weeks of conventional therapy in random order where they consumed regular pasta or extra-long grain white rice as part of a complete dinner meal on six different occasions in both arms (each meal thrice in random order). Surveys assessed satisfaction with AID use. Results: Postprandial differences in conventional therapy were 10,919.0 mg/dL × min (95% confidence interval [CI] 3190.5-18,648.0, P = 0.009) for glucose area under the curve (AUC) and 40.9 mg/dL (95% CI 4.6-77.3, P = 0.03) for peak continuous glucose monitor glucose, with rice showing greater increases than pasta. White rice resulted in a lower estimate over pasta by a factor of 0.22 (95% CI 0.08-0.63, P = 0.004) for AUC under 70 mg/dL. These glycemic differences in both meal types were reduced under AID-based control and were not statistically significant, where 0-2 h insulin delivery decreased by 0.45 U for pasta (P = 0.001) and by 0.27 U for white rice (P = 0.01). Subjects reported high overall satisfaction with the iAPS. Conclusions: The AID system running on an unlocked smartphone improved postprandial glucose control over conventional therapy in the setting of challenging meals in the outpatient setting. Clinical Trial Registry: clinicaltrials.gov NCT03767790.

The Effect of Two Types of Pasta Versus White Rice on Postprandial Blood Glucose Levels in Adults with Type 1 Diabetes: A Randomized Crossover Trial.

Background: Food choices are essential to successful glycemic control for people with diabetes. We compared the impact of three carbohydrate-rich meals on the postprandial glycemic response in adults with type 1 diabetes (T1D). Methods: We performed a randomized crossover study in 12 adults with T1D (age 58.7 ± 14.2 years, baseline hemoglobin A1c 7.5% ± 1.3%) comparing the postprandial glycemic response to three meals using continuous glucose monitoring: (1) "higher protein" pasta containing 10 g protein/serving, (2) regular pasta with 7 g protein/serving, and (3) extra-long grain white rice. All meals contained 42 g carbohydrate; were served with homemade tomato sauce, green salad, and balsamic dressing; and were repeated twice in random order. After their insulin bolus, subjects were observed in clinic for 5 h. Linear mixed effects models were used to assess the glycemic response. Results: Compared with white rice, peak glucose levels were significantly lower for higher protein pasta (-32.6 mg/dL; 95% CI -48.4 to -17.2; P < 0.001) and regular pasta (-43.2 mg/dL, 95% CI -58.7 to -27.7; P < 0.001). The difference between the two types of pastas did not reach statistical significance (-11 mg/dL; 95% CI -24.1 to 3.4; P = 0.17). Total glucose area under the curve was also significantly higher for white rice compared with both pastas (P < 0.001 for both comparisons). Conclusions: This exploratory study concluded that different food types of similar macronutrient content (e.g., rice and pasta) generate significantly different postprandial glycemic responses in persons with T1D. These results provide useful insights into the impact of food choices on and optimization of glucose control. Clinical Trial Registry: clinicaltrials.gov NCT03362151.

Accuracy of Wrist-Worn Activity Monitors During Common Daily Physical Activities and Types of Structured Exercise: Evaluation Study.

BACKGROUND: Wrist-worn activity monitors are often used to monitor heart rate (HR) and energy expenditure (EE) in a variety of settings including more recently in medical applications. The use of real-time physiological signals to inform medical systems including drug delivery systems and decision support systems will depend on the accuracy of the signals being measured, including accuracy of HR and EE. Prior studies assessed accuracy of wearables only during steady-state aerobic exercise. OBJECTIVE: The objective of this study was to validate the accuracy of both HR and EE for 2 common wrist-worn devices during a variety of dynamic activities that represent various physical activities associated with daily living including structured exercise. METHODS: We assessed the accuracy of both HR and EE for two common wrist-worn devices (Fitbit Charge 2 and Garmin vívosmart HR+) during dynamic activities. Over a 2-day period, 20 healthy adults (age: mean 27.5 [SD 6.0] years; body mass index: mean 22.5 [SD 2.3] kg/m2; 11 females) performed a maximal oxygen uptake test, free-weight resistance circuit, interval training session, and activities of daily living. Validity was assessed using an HR chest strap (Polar) and portable indirect calorimetry (Cosmed). Accuracy of the commercial wearables versus research-grade standards was determined using Bland-Altman analysis, correlational analysis, and error bias. RESULTS: Fitbit and Garmin were reasonably accurate at measuring HR but with an overall negative bias. There was more error observed during high-intensity activities when there was a lack of repetitive wrist motion and when the exercise mode indicator was not used. The Garmin estimated HR with a mean relative error (RE, %) of -3.3% (SD 16.7), whereas Fitbit estimated HR with an RE of -4.7% (SD 19.6) across all activities. The highest error was observed during high-intensity intervals on bike (Fitbit: -11.4% [SD 35.7]; Garmin: -14.3% [SD 20.5]) and lowest error during high-intensity intervals on treadmill (Fitbit: -1.7% [SD 11.5]; Garmin: -0.5% [SD 9.4]). Fitbit and Garmin EE estimates differed significantly, with Garmin having less negative bias (Fitbit: -19.3% [SD 28.9], Garmin: -1.6% [SD 30.6], P<.001) across all activities, and with both correlating poorly with indirect calorimetry measures. CONCLUSIONS: Two common wrist-worn devices (Fitbit Charge 2 and Garmin vívosmart HR+) show good HR accuracy, with a small negative bias, and reasonable EE estimates during low to moderate-intensity exercise and during a variety of common daily activities and exercise. Accuracy was compromised markedly when the activity indicator was not used on the watch or when activities involving less wrist motion such as cycle ergometry were done.

Reducing risks in type 1 diabetes using H∞ control.

A control scheme was designed in order to reduce the risks of hyperglycemia and hypoglycemia in type 1 diabetes mellitus (T1DM). This structure is composed of three main components: an H∞ robust controller, an insulin feedback loop (IFL), and a safety mechanism (SM). A control-relevant model that is employed to design the robust controller is identified. The identification procedure is based on the distribution version of the UVA/Padova metabolic simulator using the simulation adult cohort. The SM prevents dangerous scenarios by acting upon a prediction of future glucose levels, and the IFL modifies the loop gain in order to reduce postprandial hypoglycemia risks. The procedure is tested on the complete alic>in silico adult cohort of the UVA/Padova metabolic simulator, which has been accepted by the Food and Drug Administration (FDA) in lieu of animal trials.

Estimating optimal profiles of genetic alterations using constraint-based models.

Metabolic engineering involves application of recombinant DNA methods to manipulate metabolic networks to improve cellular properties. It is critical that the genetic alterations be performed in an optimal manner to maximize profit. In addition to the product yield, productivity consideration is also critical, especially for the production of bulk chemicals such as 1,3-propanediol. In this work, we demonstrate that it is suboptimal from the standpoint of productivity to induce genetic alteration at the start of the production process. A bi-level optimization scheme is formulated to determine the optimal temporal flux profile for the manipulated reaction. In the first case study, an optimal flux in the reaction catalyzed by glycerol kinase is determined to maximize the glycerol production at the end of a 6-h batch cultivation of Escherichia coli under aerobic conditions. The final glycerol concentration is 30% higher for the optimal flux profile compared with having an active flux during the entire batch. The effect of the mass transfer coefficient on the optimal profile and the glycerol concentration is also determined. In the second case study, the anaerobic batch fermentation of the ldh(-) strain of Escherichia coli is considered. The optimal flux in the acetate pathway is determined to maximize the final ethanol concentration. The optimal flux results in higher ethanol concentration (11.92 mmol L(-1)) compared to strains with no acetate flux (8.36 mmol L(-1)) and fully active acetate flux (6.22 mmol L(-1)). We also examine the effects of growth inhibition due to high ethanol concentrations and variations in final batch time on ethanol production.

On-line optimization of recombinant product in a fed-batch bioreactor.

In this paper, an efficient scheme for on-line optimization of a recombinant product in a fed-batch bioreactor is presented. This scheme is based on the parametrization of the system states and the elimination of a subset of the dynamic equations in the mathematical model of the fed-batch bioreactor. The fed-batch bioreactor considered here involves the production of chloramphenicol acetyltransferase (CAT) in a genetically modified E. coli. The optimal inducer and the glucose feed rates are obtained using the proposed optimization approach. This approach is compared with the traditional optimization approach, where all the states and the manipulated variables are parametrized. The approach presented in this paper results in a 5-fold improvement in the computational time for the recombinant product optimization. The optimization technique is employed in an on-line optimization scheme, when parametric drift and a disturbance in the manipulated variable is present. Feedback from the process is introduced through resetting the initial conditions of the model and through an observer for estimating the time varying parameter. The simulation results indicated improvement in the amount of product formed, when the optimal profile is regenerated during the course of the batch.