Martina Vettoretti

From Two to One Per Day Calibration of Dexcom G4 Platinum by a Time-Varying Day-Specific Bayesian Prior.

BACKGROUND In the DexCom G4 Platinum (DG4P) continuous glucose monitoring (CGM) sensor, the raw current signal generated by glucose-oxidase is transformed to glucose concentration by a calibration function whose parameters are periodically updated by matching self-monitoring of blood glucose references, usually twice a day, to compensate for sensor variability in time. The aim of this work is to reduce DG4P calibration frequency to once a day by a recently proposed Bayesian calibration algorithm, which employs a time-varying calibration function and suitable day-specific priors. METHODS The database consists of 57 CGM signals that are collected by the DG4P for 7 days. The Bayesian calibration algorithm is used to calibrate the raw current signal following two different schedules, that is, two and one calibration per day. Calibrated glycemic profiles are compared with those originally acquired by the manufacturer, on days 1, 4, and 7, where frequent blood glucose references were available, by using standard metrics, that is, mean absolute relative difference (MARD), percentage of accurate glucose estimates, and percentage of data in the A-zone of Clarke Error Grid. RESULTS The one per day Bayesian calibration algorithm has accuracy similar to that of two per day (11.8% vs. 11.7% MARD, respectively), and it is statistically better (P-value of 0.0411) than the manufacturer calibration algorithm, which requires two calibrations per day (13.1% MARD). CONCLUSIONS A Bayesian calibration algorithm employing a time-varying calibration function and suitable priors enables a reduction of the calibrations of DG4P sensor from two to one per day.

Online Calibration of Glucose Sensors From the Measured Current by a Time-Varying Calibration Function and Bayesian Priors

Goal: Minimally invasive continuous glucose monitoring (CGM) sensors measure in the subcutis a current signal, which is converted into interstitial glucose (IG) concentration by a calibration process periodically updated using fingerstick blood glucose (BG) references. Though important in diabetes management, CGM sensors still suffer from accuracy problems. Here, we propose a new online calibration method improving accuracy of CGM glucose profiles with respect to manufacturer calibration. Method: The proposed method fits CGM current signal against the BG references collected twice a day for calibration purposes, by a time-varying calibration function whose parameters are identified in a Bayesian framework using a priori second-order statistical knowledge. The distortion introduced by BG-to-IG kinetics is compensated before parameter identification via nonparametric deconvolution. Results: The method was tested on a database where 108 CGM signals were collected for 7 days by the Dexcom G4 Platinum sensor. Results show the new method drives to a statistically significant accuracy improvement as measured by three commonly used metrics: mean absolute relative difference reduced from 12.73% to 11.47%; percentage of accurate glucose estimates increased from 82.00% to 89.19%; and percentage of values falling in the “A” zone of the Clark error grid increased from 82.22% to 88.86%. Conclusion: The new calibration method significantly improves CGM glucose profiles accuracy with respect to manufacturer calibration. Significance: The proposed algorithm provides a real-time improvement of CGM accuracy, which can be crucial in several CGM-based applications, including the artificial pancreas, thus providing a potential great impact in the diabetes technology research community.

A Model of Self-Monitoring Blood Glucose Measurement Error:

Background: A reliable model of the probability density function (PDF) of self-monitoring of blood glucose (SMBG) measurement error would be important for several applications in diabetes, like testing in silico insulin therapies. In the literature, the PDF of SMBG error is usually described by a Gaussian function, whose symmetry and simplicity are unable to properly describe the variability of experimental data. Here, we propose a new methodology to derive more realistic models of SMBG error PDF. Methods: The blood glucose range is divided into zones where error (absolute or relative) presents a constant standard deviation (SD). In each zone, a suitable PDF model is fitted by maximum-likelihood to experimental data. Model validation is performed by goodness-of-fit tests. The method is tested on two databases collected by the One Touch Ultra 2 (OTU2; Lifescan Inc, Milpitas, CA) and the Bayer Contour Next USB (BCN; Bayer HealthCare LLC, Diabetes Care, Whippany, NJ). In both cases, skew-normal and exponential models are used to describe the distribution of errors and outliers, respectively. Results: Two zones were identified: zone 1 with constant SD absolute error; zone 2 with constant SD relative error. Goodness-of-fit tests confirmed that identified PDF models are valid and superior to Gaussian models used so far in the literature. Conclusions: The proposed methodology allows to derive realistic models of SMBG error PDF. These models can be used in several investigations of present interest in the scientific community, for example, to perform in silico clinical trials to compare SMBG-based with nonadjunctive CGM-based insulin treatments.

Calibration of Minimally Invasive Continuous Glucose Monitoring Sensors: State-of-The-Art and Current Perspectives

Minimally invasive continuous glucose monitoring (CGM) sensors are wearable medical devices that provide real-time measurement of subcutaneous glucose concentration. This can be of great help in the daily management of diabetes. Most of the commercially available CGM devices have a wire-based sensor, usually placed in the subcutaneous tissue, which measures a “raw” current signal via a glucose-oxidase electrochemical reaction. This electrical signal needs to be translated in real-time to glucose concentration through a calibration process. For such a scope, the first commercialized CGM sensors implemented simple linear regression techniques to fit reference glucose concentration measurements periodically collected by fingerprick. On the one hand, these simple linear techniques required several calibrations per day, with the consequent patient’s discomfort. On the other, only a limited accuracy was achieved. This stimulated researchers to propose, over the last decade, more sophisticated algorithms to calibrate CGM sensors, resorting to suitable signal processing, modelling, and machine-learning techniques. This review paper will first contextualize and describe the calibration problem and its implementation in the first generation of CGM sensors, and then present the most recently-proposed calibration algorithms, with a perspective on how these new techniques can influence future CGM products in terms of accuracy improvement and calibration reduction.

A Neural-Network-Based Approach to Personalize Insulin Bolus Calculation Using Continuous Glucose Monitoring:

Background: In type 1 diabetes (T1D) therapy, the calculation of the meal insulin bolus is performed according to a standard formula (SF) exploiting carbohydrate intake, carbohydrate-to-insulin ratio, correction factor, insulin on board, and target glucose. Recently, some approaches were proposed to account for preprandial glucose rate of change (ROC) in the SF, including those by Scheiner and by Pettus and Edelman. Here, the aim is to develop a new approach, based on neural networks (NN), to optimize and personalize the bolus calculation using continuous glucose monitoring information and some easily accessible patient parameters. Method: The UVa/Padova T1D Simulator was used to simulate data of 100 virtual adults in a single-meal noise-free scenario with different conditions in terms of meal amount and preprandial blood glucose and ROC values. An NN was trained to learn the optimal insulin dose using the SF parameters, ROC, body weight, insulin pump basal infusion rate and insulin sensitivity as features. The performance of the NN for meal bolus calculation was assessed by blood glucose risk index (BGRI) and compared to the methods by Scheiner and by Pettus and Edelman. Results: The NN approach brings to a small but statistically significant (P < .001) reduction of BGRI value, equal to 0.37, 0.23, and 0.20 versus SF, Scheiner, and Pettus and Edelman, respectively. Conclusion: This preliminary study showed the potentiality of using NNs for the personalization and optimization of the meal insulin bolus calculation. Future work will deal with more realistic scenarios including technological and physiological/behavioral sources of variability.

Reduction of Blood Glucose Measurements to Calibrate Subcutaneous Glucose Sensors: A Bayesian Multiday Framework

Objective: In most continuous glucose monitoring (CGM) devices used for diabetes management, the electrical signal measured by the sensor is transformed to glucose concentration by a calibration function whose parameters are estimated using self-monitoring of blood glucose (SMBG) samples. The calibration function is usually a linear model approximating the nonlinear relationship between electrical signal and glucose concentration in certain time intervals. Thus, CGM devices require frequent calibrations, usually twice a day. The aim here is to develop a new method able to reduce the frequency of calibrations. Methods: The algorithm is based on a multiple-day model of sensor time-variability with second-order statistical priors on its unknown parameters. In an online setting, these parameters are numerically determined by the Bayesian estimation exploiting SMBG sparsely collected by the patient. The method is assessed retrospectively on 108 CGM signals acquired for 7 days by the Dexcom G4 Platinum sensor, testing progressively less-calibration scenarios. Results: Despite the reduction of calibration frequency (on average from 2/day to 0.25/day), the method shows a statistically significant accuracy improvement compared to manufacturer calibration, e.g., mean absolute relative difference when compared to a laboratory reference decreases from 12.83% to 11.62% (p-value of 0.006). Conclusion: The methodology maintains (sometimes improves) CGM sensor accuracy compared to that of the original manufacturer, while reducing the frequency of calibrations. Significance: Reducing the need of calibrations facilitates the adoption of CGM technology both in terms of ease of use and cost, an obvious prerequisite for its use as replacement of traditional SMBG devices.

Type-1 Diabetes Patient Decision Simulator for In Silico Testing Safety and Effectiveness of Insulin Treatments

Objective: Type-1 diabetes (T1D) treatment requires exogenous insulin administrations finely tuned based on glucose monitoring to avoid hyper/hypoglycemia. The safety and effectiveness of insulin treatments is commonly assessed in clinical trials, which are time demanding and expensive. These limitations can be overtaken by in silico clinical trials (ISCT) that require realistic patient and treatment models. The aim is to develop a T1D patient decision simulator usable to perform reliable ISCT. Methods: The T1D patient decision simulator was developed by connecting the UVA/Padova T1D model, which describes glucose, insulin, and glucagon kinetics, with modules describing glucose monitoring devices, like self-monitoring of blood glucose (SMBG) and continuous glucose monitoring (CGM), the patients behavior in making treatment decisions, and insulin administration. The reliability of the simulator was assessed by comparing its predictions with data collected in 44 T1D subjects using the Dexcom G5 Mobile CGM sensor as an adjunct to the Bayer Contour Next USB SMBG device. Results: Metrics like time spent in eu/hypo/hyperglycemia of simulated data well match those observed in subjects. In particular, mean time in euglycemia, mean time in hyperglycemia, and median time in hypoglycemia are 61.75% versus 63.60% (p-value = 0.4825), 33.38% versus 33.40% (p -value = 0.9950), and 3.17% versus 2.14% (p-value = 0.1134), respectively, in real versus simulated data. Conclusion: The proposed simulator can be used to perform credible ISCT in realistic insulin treatment scenarios. Significance: The T1D patient decision simulator can be used to reliably assess novel insulin treatments, e.g., based on use of CGM only, in a realistic multiple-day scenario.

Patient decision-making of CGM sensor driven insulin therapies in type 1 diabetes: In silico assessment

In type 1 diabetes (T1D) therapy, continuous glucose monitoring (CGM) sensors, which provide glucose concentration in the subcutis every 1-5 min for 7 consecutive days, should allow in principle a more efficient insulin dosing than that based on the conventional 3-4 self-monitoring of blood glucose (SMBG) measurements per day. However, CGM, at variance with SMBG, is still not approved for insulin dosing in T1D management because regulatory agencies, e.g. FDA, are looking for more factual evidence on its safety. An in silico assessment of SMBG- vs CGM-driven insulin therapy can be a first step. Here we present a simulation model of T1D patient decision-making obtained by interconnecting models of glucose-insulin dynamics, SMBG and CGM measurement errors, carbohydrates-counting errors, insulin boluses time variability and forgetfulness, and subcutaneous insulin pump delivery. Inter- and intra- patient variability of model parameters are considered. The T1D patient decision-making model allows to run realistic multi-day simulations scenarios in a population of virtual subjects. We present the first results of simulations run in 20 virtual subjects over a 7-day period, which demonstrates that additional information brought by CGM (trend and hypo/hyperglycemic warnings) with respect to SMBG produces a statistically significant increment (about of 9%) of time spent by the patient in the euglycemic range (70-180mg/dl).

The UVA/Padova Type 1 Diabetes Simulator Goes From Single Meal to Single Day:

Background: A new version of the UVA/Padova Type 1 Diabetes (T1D) Simulator is presented which provides a more realistic testing scenario. The upgrades to the previous simulator, which was accepted by the Food and Drug Administration in 2013, are described. Method: Intraday variability of insulin sensitivity (SI) has been modeled, based on clinical T1D data, accounting for both intra- and intersubject variability of daily SI. Thus, time-varying distributions of both subject’s basal insulin infusion and insulin-to-carbohydrate ratio were calculated and made available to the user. A model of “dawn” phenomenon based on clinical T1D data has been also included. Moreover, the model of subcutaneous insulin delivery has been updated with a recently developed model of commercially available fast-acting insulin analogs. Models of both intradermal and inhaled insulin pharmacokinetics have been included. Finally, new models of error affecting continuous glucose monitoring and self-monitoring of blood glucose devices have been added. Results: One hundred in silico adults, adolescent, and children have been generated according to the above modifications. The new simulator reproduces the intraday glucose variability observed in clinical data, also describing the nocturnal glucose increase, and the simulated insulin profiles reflect real life data. Conclusions: The new modifications introduced in the T1D simulator allow to extend its domain of validity from “single-meal” to “single-day” scenarios, thus enabling a more realistic framework for in silico testing of advanced diabetes technologies including glucose sensors, new insulin molecules and artificial pancreas.

A hybrid clustering prediction for type 1 diabetes aid: towards decision support systems based upon scenario profile analysis

Type 1 diabetic patients present large variability reducing dramatically the ability to achieve adequate blood glucose control. Lifestyle and physiological factors highly impact their treatments which require some predictive capabilities to prevent as many adverse events as possible. The identification of the characteristic profiles of these patients would lead to an improvement in the accuracy of treatments in the specific scenarios that they face. This study presents the proof of concept of a clinical decision support system combining a classifier of glycemic profiles and a predictor of blood glucose levels. The system is aimed to identify data profiles according to a given scenario and to generate prediction models based of these scenarios to forecast blood glucose levels. The experiments were conducted in silico, by simulating different characteristics profiles of type 1 diabetic patients, in order to prove the feasibility of the approach. Clinical decision support systems based on this methodology could assist type 1 diabetic patients in their treatments according to patients conditions and to the situations faced by patients.