A Markov Model of Gap Occurrence in Continuous Glucose Monitoring Data for Realistic in Silico Clinical Trials.

BACKGROUND AND OBJECTIVE: Continuous glucose monitoring (CGM) sensors measure interstitial glucose concentration every 1-5 min for days or weeks. New CGM-based diabetes therapies are often tested in in silico clinical trials (ISCTs) using diabetes simulators. Accurate models of CGM sensor inaccuracies and failures could help improve the realism of ISCTs. However, the modeling of CGM failures has not yet been fully addressed in the literature. This work aims to develop a mathematical model of CGM gaps, i.e., occasional portions of missing data generated by temporary sensor errors (e.g., excessive noise or artifacts). METHODS: Two datasets containing CGM traces collected in 167 adults and 205 children, respectively, using the Dexcom G6 sensor (Dexcom Inc., San Diego, CA) were used. Four Markov models, of increasing complexity, were designed to describe three main characteristics: number of gaps for each sensor, gap distribution in the monitoring days, and gap duration. Each model was identified on a portion of each dataset (training set). The remaining portion of each dataset (real test set) was used to evaluate model performance through a Monte Carlo simulation approach. Each model was used to generate 100 simulated test sets with the same size as the real test set. The distributions of gap characteristics on the simulated test sets were compared with those observed on the real test set, using the two-sample Kolmogorov-Smirnov test and the Jensen-Shannon divergence. RESULTS: A six-state Markov model, having two states to describe normal sensor operation and four states to describe gap occurrence, achieved the best results. For this model, the Kolmogorov-Smirnov test found no significant differences between the distribution of simulated and real gap characteristics. Moreover, this model obtained significantly lower Jensen-Shannon divergence values than the other models. CONCLUSIONS: A Markov model describing CGM gaps was developed and validated on two real datasets. The model describes well the number of gaps for each sensor, the gap distribution over monitoring days, and the gap durations. Such a model can be integrated into existing diabetes simulators to realistically simulate CGM gaps in ISCTs and thus enable the development of more effective and robust diabetes management strategies.

In silico design and validation of a time-varying PID controller for an artificial pancreas with intraperitoneal insulin delivery and glucose sensing.

Type 1 diabetes (T1D) is a chronic autoimmune disease featured by the loss of beta cell function and the need for lifetime insulin replacement. Over the recent decade, the use of automated insulin delivery systems (AID) has shifted the paradigm of treatment: the availability of continuous subcutaneous (SC) glucose sensors to guide SC insulin delivery through a control algorithm has allowed, for the first time, to reduce the daily burden of the disease as well as to abate the risk for hypoglycemia. AID use is still limited by individual acceptance, local availability, coverage, and expertise. A major drawback of SC insulin delivery is the need for meal announcement and the peripheral hyperinsulinemia that, over time, contributes to macrovascular complications. Inpatient trials using intraperitoneal (IP) insulin pumps have demonstrated that glycemic control can be improved without meal announcement due to the faster insulin delivery through the peritoneal space. This calls for novel control algorithms able to account for the specificities of IP insulin kinetics. Recently, our group described a two-compartment model of IP insulin kinetics demonstrating that the peritoneal space acts as a virtual compartment and IP insulin delivery is virtually intraportal (intrahepatic), thus closely mimicking the physiology of insulin secretion. The FDA-accepted T1D simulator for SC insulin delivery and sensing has been updated for IP insulin delivery and sensing. Herein, we design and validate-in silico-a time-varying proportional integrative derivative controller to guide IP insulin delivery in a fully closed-loop mode without meal announcement.

Data Gap Modeling in Continuous Glucose Monitoring Sensor Data.

Continuous glucose monitoring (CGM) sensors are minimally-invasive sensors used in diabetes therapy to monitor interstitial glucose concentration. The measurements are collected almost continuously (e.g. every 5 min) and permit the detection of dangerous hypo/hyperglycemic episodes. Modeling the various error components affecting CGM sensors is very important (e.g., to generate realistic scenarios for developing and testing CGM-based applications in type 1 diabetes simulators). In this work we focus on data gaps, which are portions of missing data due to a disconnection or a temporary sensor error. A dataset of 167 adults monitored with the Dexcom (San Diego, CA) G6 sensor is considered. After the evaluation of some statistics (the number of gaps for each sensor, the gap distribution over the monitoring days and the data gap durations), we develop a two-state Markov model to describe such statistics about data gap occurrence. Statistics about data gaps are compared between real data and simulated data generated by the model with a Monte Carlo simulation. Results show that the model describes quite accurately the occurrence and the duration of data gaps observed in real data.