Risk of hypoglycemia in type 1 diabetes management: An in-silico sensitivity analysis to assess and rank the quantitative impact of different behavioral factors.

BACKGROUND AND OBJECTIVE: In type 1 diabetes (T1D), a quantitative evaluation of the impact on hypoglycemia of suboptimal therapeutic decision (e.g. incorrect estimation of the ingested carbohydrates, inaccurate insulin timing, etc) is unavailable. Clinical trials to measure sensitivity to patient actions would be expensive, exposed to confounding factors and risky for the participants. In this work, a T1D patient decision simulator (T1D-PDS), realistically reproducing blood glucose dynamics in a large virtual population, is used to perform extensive in-silico trials and the so-derived data employed to implement a sensitivity analysis that ranks different behavioral factors based on their impact on a clinically meaningful parameter, the time below range (TBR). METHODS: Eleven behavioral factors impacting on hypoglycemia are considered. The T1D-PDS was used to perform multiple 2-week simulations involving 100 adults, by testing about 3500 different perturbations for nominal behavior. A local linear approximation of the function linking the TBR and the factors were computed to derive sensitivity indices (SIs), quantifying the impact of each factor on TBR variations. RESULTS: The obtained ranking quantifies importance of factors w.r.t. the others. Factors apparently related to hypoglycemia were correctly placed on the top of the ranking, including systematic (SI=2.05%) and random (SI=1.35%) carb-counting error, hypotreatment dose (SI=-1.21%), insulin bolus time w.r.t. mealtime (SI=1.09%). CONCLUSIONS: The obtained SIs allowed to rank behavioral factors based on their impact on TBR. The behavioral factors identified as most influential can be prioritized in patient training.

Monitoring Gait and Physical Activity of Elderly Frail Individuals in Free-Living Environment: A Feasibility Study.

INTRODUCTION: Frailty is conventionally diagnosed using clinical tests and self-reported assessments. However, digital health technologies (DHTs), such as wearable accelerometers, can capture physical activity and gait during daily life, enabling more objective assessments. In this study, we assess the feasibility of deploying DHTs in community-dwelling older individuals, and investigate the relationship between digital measurements of physical activity and gait in naturalistic environments and participants' frailty status, as measured by conventional assessments. METHODS: Fried Frailty Score (FFS) was used to classify fifty healthy individuals as non-frail (FFS = 0, n/female = 21/11, mean ± SD age: 71.10 ± 3.59 years), pre-frail (FFS = 1-2, n/female = 23/9, age: 73.74 ± 5.52 years), or frail (FFS = 3+, n/female = 6/6, age: 70.70 ± 6.53 years). Participants wore wrist-worn and lumbar-worn GENEActiv accelerometers (Activinsights Ltd., Kimbolton, UK) during three in-laboratory visits, and at-home for 2 weeks, to measure physical activity and gait. After this period, they completed a comfort and usability questionnaire. Compliant days at-home were defined as follows: those with ≥18 h of wear time, for the wrist-worn accelerometer, and those with ≥1 detected walking bout, for the lumbar-worn accelerometer. For each at-home measurement, a group analysis was performed using a linear regression model followed by ANOVA, to investigate the effect of frailty on physical activity and gait. Correlation between at-home digital measurements and conventional in-laboratory assessments was also investigated. RESULTS: Participants were highly compliant in wearing the accelerometers, as 94% indicated willingness to wear the wrist device, and 66% the lumbar device, for at least 1 week. Time spent in sedentary activity and time spent in moderate activity as measured from the wrist device, as well as average gait speed and its 95th percentile from the lumbar device were significantly different between frailty groups. Moderate correlations between digital measurements and self-reported physical activity were found. CONCLUSIONS: This work highlights the feasibility of deploying DHTs in studies involving older individuals. The potential of digital measurements in distinguishing frailty phenotypes, while unobtrusively collecting unbiased data, thus minimizing participants' travels to sites, will be further assessed in a follow-up study.

Bayesian denoising algorithm dealing with colored, non-stationary noise in continuous glucose monitoring timeseries.

Introduction: The retrospective analysis of continuous glucose monitoring (CGM) timeseries can be hampered by colored and non-stationary measurement noise. Here, we introduce a Bayesian denoising (BD) algorithm to address both autocorrelation of measurement noise and temporal variability of its variance. Methods: BD utilizes adaptive, a-priori models of signal and noise, whose unknown variances are derived on partially-overlapped CGM windows, via smoothing approach based on linear mean square estimation. The CGM signal and noise variability profiles are then reconstructed using a kernel smoother. BD is first assessed on two simulated datasets, DS1 and DS2. On DS1, the effectiveness of accounting for colored noise is evaluated by comparison against a literature algorithm; on DS2, the effectiveness of accounting for the noise variance temporal variability is evaluated by comparison against a Butterworth filter. BD is then evaluated on 15 CGM timeseries measured by the Dexcom G6 (DR). Results: On DS1, BD allows reducing the root-mean-square-error (RMSE) from 8.10 [6.79-9.24] mg/dL to 6.28 [5.47-7.27] mg/dL (median [IQR]); on DS2, RMSE decreases from 6.85 [5.50-8.72] mg/dL to 5.35 [4.48-6.49] mg/dL. On DR, BD performs a reasonable tracking of noise variance variability and a satisfactory denoising. Discussion: The new algorithm effectively addresses the nature of CGM measurement error, outperforming existing denoising algorithms.

Choosing the duration of continuous glucose monitoring for reliable assessment of time in range: A new analytical approach to overcome the limitations of correlation-based methods.

AIMS: Reliable estimation of the time spent in different glycaemic ranges (time-in-ranges) requires sufficiently long continuous glucose monitoring. In a 2019 paper (Battelino et al., Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range. Diabetes Care. 2019;42:1593-1603), an international panel of experts suggested using a correlation-based approach to obtain the minimum number of days for reliable time-in-ranges estimates. More recently (in Camerlingo et al., Design of clinical trials to assess diabetes treatment: minimum duration of continuous glucose monitoring data to estimate time-in-ranges with the desired precision. Diabetes Obes Metab. 2021;23:2446-2454) we presented a mathematical equation linking the number of monitoring days to the uncertainty around time-in-ranges estimates. In this work, we compare these two approaches, mainly focusing on time spent in (70-180) mg/dL range (TIR). METHODS: The first 100 and 150 days of data were extracted from study A (148 subjects, ~180 days), and the first 100, 150, 200, 250 and 300 days of data from study B (45 subjects, ~365 days). For each of these data windows, the minimum monitoring duration was computed using correlation-based and equation-based approaches. The suggestions were compared for the windows of different durations extracted from the same study, and for the windows of equal duration extracted from different studies. RESULTS: When changing the dataset duration, the correlation-based approach produces inconsistent results, ranging from 23 to 64 days, for TIR. The equation-based approach was found to be robust versus this issue, as it is affected only by the characteristics of the population being monitored. Indeed, to grant a confidence interval of 5% around TIR, it suggests 18 days for windows from study A, and 17 days for windows from study B. Similar considerations hold for other time-in-ranges. CONCLUSIONS: The equation-based approach offers advantages for the design of clinical trials having time-in-ranges as final end points, with focus on trial duration.

A New Decision Support System for Type 1 Diabetes Management.

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.

Design of clinical trials to assess diabetes treatment: Minimum duration of continuous glucose monitoring data to estimate time-in-ranges with the desired precision.

AIM: To compute the uncertainty of time-in-ranges, such as time in range (TIR), time in tight range (TITR), time below range (TBR) and time above range (TAR), to evaluate glucose control and to determine the minimum duration of a trial to achieve the desired precision. MATERIALS AND METHODS: Four formulas for the aforementioned time-in-ranges were obtained by estimating the equation's parameters on a training set extracted from study A (226 subjects, ~180 days, 5-minute Dexcom G4 Platinum sensor). The formulas were then validated on the remaining data. We also illustrate how to adjust the parameters for sensors with different sampling rates. Finally, we used study B (45 subjects, ~365 days, 15-minute Abbott Freestyle Libre sensor) to further validate our results. RESULTS: Our approach was effective in predicting the uncertainty when time-in-ranges are estimated using n days of continuous glucose monitoring (CGM), matching the variability observed in the data. As an example, monitoring a population with TIR = 70%, TITR = 50%, TBR = 5% and TAR = 25% for 30 days warrants a precision of ±3.50%, ±3.68%, ±1.33% and ±3.66%, respectively. CONCLUSIONS: The presented approach can be used to both compute the uncertainty of time-in-ranges and determine the minimum duration of a trial to achieve the desired precision. An online tool to facilitate its implementation is made freely available to the clinical investigator.

Mathematical Models of Meal Amount and Timing Variability With Implementation in the Type-1 Diabetes Patient Decision Simulator.

BACKGROUND: In type 1 diabetes (T1D) research, in-silico clinical trials (ISCTs) have proven effective in accelerating the development of new therapies. However, published simulators lack a realistic description of some aspects of patient lifestyle which can remarkably affect glucose control. In this paper, we develop a mathematical description of meal carbohydrates (CHO) amount and timing, with the aim to improve the meal generation module in the T1D Patient Decision Simulator (T1D-PDS) published in Vettoretti et al. METHODS: Data of 32 T1D subjects under free-living conditions for 4874 days were used. Univariate probability density function (PDF) parametric models with different candidate shapes were fitted, individually, against sample distributions of: CHO amounts of breakfast (CHOB), lunch (CHOL), dinner (CHOD), and snack (CHOS); breakfast timing (TB); and time between breakfast-lunch (TBL) and between lunch-dinner (TLD). Furthermore, a support vector machine (SVM) classifier was developed to predict the occurrence of a snack in future fixed-length time windows. Once embedded inside the T1D-PDS, an ISCT was performed. RESULTS: Resulting PDF models were: gamma (CHOB, CHOS), lognormal (CHOL, TB), loglogistic (CHOD), and generalized-extreme-values (TBL, TLD). The SVM showed a classification accuracy of 0.8 over the test set. The distributions of simulated meal data were not statistically different from the distributions of the real data used to develop the models (α = 0.05). CONCLUSIONS: The models of meal amount and timing variability developed are suitable for describing real data. Their inclusion in modules that describe patient behavior in the T1D-PDS can permit investigators to perform more realistic, reliable, and insightful ISCTs.

An analytical approach to determine the optimal duration of continuous glucose monitoring data required to reliably estimate time in hypoglycemia.

Diabetes is a chronic metabolic disease that causes blood glucose (BG) concentration to make dangerous excursions outside its physiological range. Measuring the fraction of time spent by BG outside this range, and, specifically, the time-below-range (TBR), is a clinically common way to quantify the effectiveness of therapies. TBR is estimated from data recorded by continuous glucose monitoring (CGM) sensors, but the duration of CGM recording guaranteeing a reliable indicator is under debate in the literature. Here we framed the problem as random variable estimation problem and studied the convergence of the estimator, deriving a formula that links the TBR estimation error variance with the CGM recording length. Validation is performed on CGM data of 148 subjects with type-1-diabetes. First, we show the ability of the formula to predict the uncertainty of the TBR estimate in a single patient, using patient-specific parameters; then, we prove its applicability on population data, without the need of parameters individualization. The approach can be straightforwardly extended to other similar metrics, such as time-in-range and time-above-range, widely adopted by clinicians. This strengthens its potential utility in diabetes research, e.g., in the design of those clinical trials where minimal CGM monitoring duration is crucial in cost-effectiveness terms.

A Real-Time Continuous Glucose Monitoring-Based Algorithm to Trigger Hypotreatments to Prevent/Mitigate Hypoglycemic Events.

Background: The standard treatment for hypoglycemia recommended by the American Diabetes Association (ADA) suggests patients with diabetes to take small amounts of carbohydrates, the so-called hypotreatments (HTs), as soon as blood glucose concentration goes below 70 mg/dL. However, prevention, or at least mitigation, of hypoglycemic events could be achieved by triggering HTs ahead of time thanks to the use of the predictive capabilities of suitable real-time algorithms fed by continuous glucose monitoring (CGM) sensor data. Materials and Methods: The algorithm proposed in this article to trigger HTs for preventing forthcoming hypoglycemic events is based on the computation of the "dynamic risk", there is a nonlinear function combining current glycemia with its rate-of-change, both provided by CGM. A comparison of performance of the proposed algorithm against the ADA guidelines is made, in silico, on datasets of 100 virtual patients undergoing a single-meal experiment, with induced postmeal hypoglycemia, generated by the UVA/Padova type 1 diabetes simulator. Results: On noise-free CGM data, the proposed algorithm reduces the time spent in hypoglycemia, on median [25th-75th percentiles] from 36 [29-43] to 0 [0-11] min (P < 0.0001), with a concomitant decrease of the post-treatment rebound (PTR) in glucose concentration, on median [25th-75th percentiles] from 136 [121-148] to 121 [116-127] mg/dL (P < 0.0001). On noisy CGM data, there is still a reduction of both time spent in hypoglycemia from 41 [28-49] min to 25 [0-41] min (P < 0.0001) and PTR from 174 [146-189] mg/dL to 137 [123-151] mg/dL (P < 0.0001). Conclusions: The potentiality of the new algorithm in generating preventive HTs, which can allow significant reduction of hypoglycemia without concomitant increase of hyperglycemia, suggests its further development and test in silico, for example, simulating both insulin pump and multiple-daily-injection therapies.

In-silico Assessment of Preventive Hypotreatment Efficacy and Development of a Continuous Glucose Monitoring Based Algorithm to Prevent/Mitigate Hypoglycemia in Type 1 Diabetes.

In Type 1 diabetes (T1D) standard treatment, the mitigation of hypoglycemia is achieved by the assumption of small amounts of carbohydrates (CHO), called hypotreatments (HTs), as soon as hypoglycemia is revealed. However, since CHO takes time to reach the blood stream, hypoglycemia cannot be totally avoided. Our purpose is to evaluate in-silico the effectiveness of preventive HTs and to propose a new real-time algorithm for the mitigation/avoidance of hypoglycemia, based on continuous glucose monitoring (CGM) sensor data. To such a purpose, the algorithm exploits the "dynamic risk" non linear-function that, by combining CGM value and trend, allows predicting the forthcoming hypoglycemic event. The algorithm is tested in an ideal noise-free environment on 100 virtual subjects (VSs) generated by the UVA/Padova T1D simulator and undergoing a single-meal experiment, with induced post-meal hypoglycemia. Compared to a reference HT rule, which suggest to assume HTs when hypoglycemia is detected, the algorithm reduces, on median [25th - 75th percentiles], both the time spent in hypoglycemia (from 36 [29 - 43] min to 10 [0 - 20] min) and the post-treatment rebound (from 136 [121 - 148] mg/dl to 114 [98 - 130] mg/dl). In conclusion, the proposed real-time algorithm efficiently generates preventive HTs that allow to almost totally avoid hypoglycemia. Future work will concern to modify the algorithm for detecting in advance the severity of the hypoglycemic episode -since performance are influenced on the hypoglycemic episode aggressiveness level- and to assess algorithm in a more challenging environment, including CGM measurement error.