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Background and Objectives: One of the major problems related to type 1 diabetes (T1D) management is hypoglycemia, a condition characterized by low blood glucose levels and responsible for reduced quality of life and increased mortality. Fast-acting carbohydrates, also known as hypoglycemic treatments (HT), can counteract this event. In the literature, dosage and timing of HT are usually based on heuristic rules. In the present work, we propose an algorithm for mitigating hypoglycemia by suggesting preventive HT consumption, with dosages and timing determined by solving an optimization problem., Methods: By leveraging integer programming and linear inequality constraints, the algorithm can bind the amount of suggested carbohydrates to standardized quantities (i.e., those available in "off-the-shelf" HT) and the minimal distance between consecutive suggestions (to reduce the nuisance for patients)., Results: The proposed method was tested in silico and compared with competitor algorithms using the UVa/Padova T1D simulator. At the cost of a slight increase of HT consumed per day, the proposed algorithm produces the lowest median and interquartile range of the time spent in hypoglycemia, with a statistically significant improvement over most competitor algorithms. Also, the average number of hypoglycemic events per day is reduced to 0 in median., Conclusions: Thanks to its positive performances and reduced computational burden, the proposed algorithm could be a candidate tool for integration in a DSS aimed at improving T1D management., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The research presented in this work was supported by Dexcom Inc., San Diego, CA. The authors hold a patent application on the technology presented in this work., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Mealtime insulin dosing is a major challenge for people living with type 1 diabetes (T1D). This task is typically performed using a standard formula that, despite containing some patient-specific parameters, often leads to sub-optimal glucose control due to lack of personalization and adaptation. To overcome the previous limitations here we propose an individualized and adaptive mealtime insulin bolus calculator based on double deep Q-learning (DDQ), which is tailored to the patient thanks to a personalization procedure relying on a two-step learning framework. The DDQ-learning bolus calculator was developed and tested using the UVA/Padova T1D simulator modified to reliably mimic real-world scenarios by introducing multiple variability sources impacting glucose metabolism and technology. The learning phase included a long-term training of eight sub-population models, one for each representative subject, selected thanks to a clustering procedure applied to the training set. Then, for each subject of the testing set, a personalization procedure was performed, by initializing the models based on the cluster to which the patient belongs. We evaluated the effectiveness of the proposed bolus calculator on a 60-day simulation, using several metrics representing the goodness of glycemic control, and comparing the results with the standard guidelines for mealtime insulin dosing. The proposed method improved the time in target range from 68.35% to 70.08% and significantly reduced the time in hypoglycemia (from 8.78% to 4.17%). The overall glycemic risk index decreased from 8.2 to 7.3, indicating the benefit of our method when applied for insulin dosing compared to standard guidelines.

Background: Providing real-time magnitude and direction of glucose rate-of-change (ROC) via trend arrows represents one of the major strengths of continuous glucose monitoring (CGM) sensors in managing type 1 diabetes (T1D). Several literature methods were proposed to adjust the standard formula (SF) used for insulin bolus calculation by accounting for glucose ROC, but each of them provides different suggestions, making it difficult to understand which should be applied in practice. This work aims at performing an extensive in-silico assessment of their performance and safety., Methods: The methods of Buckingham (BU), Scheiner (SC), Pettus/Edelman (PE), Klonoff/Kerr (KL), Aleppo/Laffel (AL), Ziegler (ZI), and Bruttomesso (BR) were evaluated using the UVa/Padova T1D simulator, in single-meal scenarios, where ROC and glucose at mealtime varied between [-2,+2] mg/dL/min and [80,200] mg/dL, respectively. Efficacy of postprandial glucose control was quantitatively assessed by time in, above and below range (TIR, TAR, and TBR, respectively)., Results: For negative ROCs, all methods proved to increase TIR and decrease TAR and TBR vs SF, with KL, PE, and BR being the most effective. For positive ROCs, a general worsening of the performances is present, only BR improved the glycemic control when mealtime glucose was close to hypoglycemia, while SC resulted the safest in the other conditions., Conclusions: Insulin bolus adjustment methods are effective for negative ROCs, but they generally appear to overdose for positive ROCs, calling for safer strategies in such a scenario. These results can be useful in outlining guidelines to identify which adjustment to apply based on the mealtime condition.

People with type 1 diabetes (T1D) need exogenous insulin administrations several times a day. The amount of injected insulin is key for maintaining the concentration of blood glucose (BG) within a physiological safe range. According to well-established clinical guidelines, insulin dosing at mealtime is calculated through an empirical formula which, however, does not take advantage of the knowledge of BG trend provided in real-time by continuous glucose monitoring (CGM) sensors. To overcome suboptimal insulin dosage, we recently used machine learning techniques to build two new models, one linear and one nonlinear, which incorporate BG trend information.In this work, we propose an ensemble learning method for mealtime insulin bolus estimation based on dynamic voting, which combines the two models by taking advantage of where each alternative performs better. Being the resulting model black-box, a tool that enables its interpretability was applied to evaluate the contribution of each feature. The proposed model was trained using a synthetic dataset having information on 100 virtual subjects with different mealtime conditions, and its performance was evaluated within a simulated environment.The benefit given by the ensemble method compared to the single models was confirmed by the high time within the target glycemic range, and the trade-off reached in terms of time spent below and above this range. Moreover, the model interpretation pointed out the key role played by the information on BG dynamics in the estimation of insulin dosage.

Type 1 diabetes (T1D) is a chronic life-threatening metabolic condition which needs to be accurately and continuously managed with care by multiple daily exogenous insulin injections, frequent blood glucose concentration monitoring, ad-hoc diet, and physical activity. In the last decades, new technologies, such as continuous glucose monitoring sensors, eased the burden for T1D patients and opened new therapy perspectives by fostering the development of decision support systems (DSS). A DSS for T1D should be able to provide patients with advice aimed at improving metabolic control and reducing the number of actions related to therapy handling. Major challenges are the vast intra-/inter-subject physiological variability and the many factors that impact glucose metabolism. The present work illustrates a new DSS for T1D management. The algorithmic core includes a module for optimal, personalized, insulin dose calculation and a module that triggers the assumption of rescue carbohydrates to avoid/mitigate impending hypoglycemic events. The algorithms are integrated within a prototype communication platform that comprises a mobile app, a real-time telemonitoring interface, and a cloud server to safely store patients' data. Tests made in silico show that the use of the new algorithms lead to metabolic control indices significantly better than those obtained by the standard care for T1D. The preliminary test of the prototype platform suggests that it is robust, performant, and well-accepted by both patients and clinicians. Future work will focus on the refinement of the communication platform and the design of a clinical trial to assess the system effectiveness in real-life conditions.Clinical Relevance- The presented DSS is a promising tool to facilitate T1D daily management and improve therapy efficacy.

Objective: This paper aims at proposing a new machine-learning based model to improve the calculation of mealtime insulin boluses (MIB) in type 1 diabetes (T1D) therapy using continuous glucose monitoring (CGM) data. Indeed, MIB is still often computed through the standard formula (SF), which does not account for glucose rate-of-change ( ∆G), causing critical hypo/hyperglycemic episodes., Methods: Four candidate models for MIB calculation, based on multiple linear regression (MLR) and least absolute shrinkage and selection operator (LASSO) are developed. The proposed models are assessed in silico, using the UVa/Padova T1D simulator, in different mealtime scenarios and compared to the SF and three ∆G-accounting variants proposed in the literature. An assessment on real data, by retrospectively analyzing 218 glycemic traces, is also performed., Results: All four tested models performed better than the existing techniques. LASSO regression with extended feature-set including quadratic terms (LASSO Q ) produced the best results. In silico, LASSO Q reduced the error in estimating the optimal bolus to only 0.86 U (1.45 U of SF and 1.36-1.44 U of literature methods), as well as hypoglycemia incidence (from 44.41% of SF and 44.60-45.01% of literature methods, to 35.93%). Results are confirmed by the retrospective application to real data., Conclusion: New models to improve MIB calculation accounting for CGM- ∆G and easy-to-measure features can be developed within a machine learning framework. Particularly, in this paper, a new LASSO Q model was developed, which ensures better glycemic control than SF and other literature methods., Significance: MIB dosage with the proposed LASSO Q model can potentially reduce the risk of adverse events in T1D therapy.

Type 1 diabetes (T1D) therapy requires multiple daily insulin injections to compensate the lack of endogenous insulin production due to β-cells destruction. An empirical standard formula (SF) is commonly used for such a task. Unfortunately, SF does not include information on glucose dynamics, e.g. the glucose rate-of-change (ROC) provided by continuous glucose monitoring (CGM) sensor. Hence, SF can sometimes lead to under/overestimations that can cause critical hypo/hyperglycemic episodes during/after the meal. Recently, to overcome this limitation, we proposed new linear regression models, integrating ROC information and personalized features. Despite the first encouraging results, the nonlinear nature of the problem calls for the application of nonlinear models. In this work, random forest (RF) and gradient boosting tree (GBT), nonlinear machine learning methodologies, were investigated. A dataset of 100 virtual subjects, opportunely divided into training and testing sets, was used. For each individual, a single-meal scenario with different meal conditions (preprandial ROC, BG and meal amounts) was simulated. The assessment was performed both in terms of accuracy in estimating the optimal bolus and glycemic control. Results were compared to the best performing linear model previously developed. The two tree-based models proposed lead to a statistically significant improvement of glycemic control compared to the linear approach, reducing the time spent in hypoglycemia (from 32.49% to 27.57-25.20% for RF and GBT, respectively). These results represent a preliminary step to prove that nonlinear machine learning techniques can improve the estimation of insulin bolus in T1D therapy. Particularly, RF and GBT were shown to outperform the previously linear models proposed.Clinical Relevance- Insulin bolus estimation with nonlinear machine learning techniques reduces the risk of adverse events in T1D therapy.