B. Wayne Bequette

Prevention of Nocturnal Hypoglycemia Using Predictive Alarm Algorithms and Insulin Pump Suspension

OBJECTIVE The aim of this study was to develop a partial closed-loop system to safely prevent nocturnal hypoglycemia by suspending insulin delivery when hypoglycemia is predicted in type 1 diabetes. RESEARCH DESIGN AND METHODS Forty subjects with type 1 diabetes (age range 12–39 years) were studied overnight in the hospital. For the first 14 subjects, hypoglycemia (<60 mg/dl) was induced by gradually increasing the basal insulin infusion rate (without the use of pump shutoff algorithms). During the subsequent 26 patient studies, pump shutoff occurred when either three of five (n = 10) or two of five (n = 16) algorithms predicted hypoglycemia based on the glucose levels measured with the FreeStyle Navigator (Abbott Diabetes Care). RESULTS The standardized protocol induced hypoglycemia on 13 (93%) of the 14 nights. With use of a voting scheme that required three algorithms to trigger insulin pump suspension, nocturnal hypoglycemia was prevented during 6 (60%) of 10 nights. When the voting scheme was changed to require only two algorithms to predict hypoglycemia to trigger pump suspension, hypoglycemia was prevented during 12 (75%) of 16 nights. In the latter study, there were 25 predictions of hypoglycemia because some subjects had multiple hypoglycemic events during a night, and hypoglycemia was prevented for 84% of these events. CONCLUSIONS Using algorithms to shut off the insulin pump when hypoglycemia is predicted, it is possible to prevent hypoglycemia on 75% of nights (84% of events) when it would otherwise be predicted to occur.

Continuous Glucose Monitoring: Real-Time Algorithms for Calibration, Filtering, and Alarms

Algorithms for real-time use in continuous glucose monitors are reviewed, including calibration, filtering of noisy signals, glucose predictions for hypoglycemic and hyperglycemic alarms, compensation for capillary blood glucose to sensor time lags, and fault detection for sensor degradation and dropouts. A tutorial on Kalman filtering for real-time estimation, prediction, and lag compensation is presented and demonstrated via simulation examples. A limited number of fault detection methods for signal degradation and dropout have been published, making that an important area for future work.

Real-Time hypoglycemia prediction suite using continuous glucose monitoring: a safety net for the artificial pancreas.

OBJECTIVE The purpose of this study was to develop an advanced algorithm that detects pending hypoglycemia and then suspends basal insulin delivery. This approach can provide a solution to the problem of nocturnal hypoglycemia, a major concern of patients with diabetes. RESEARCH DESIGN AND METHODS This real-time hypoglycemia prediction algorithm (HPA) combines five individual algorithms, all based on continuous glucose monitoring 1-min data. A predictive alarm is issued by a voting algorithm when a hypoglycemic event is predicted to occur in the next 35 min. The HPA system was developed using data derived from 21 Navigator studies that assessed Navigator function over 24 h in children with type 1 diabetes. We confirmed the function of the HPA using a separate dataset from 22 admissions of type 1 diabetic subjects. During these admissions, hypoglycemia was induced by gradual increases in the basal insulin infusion rate up to 180% from the subjects own baseline infusion rate. RESULTS Using a prediction horizon of 35 min, a glucose threshold of 80 mg/dl, and a voting threshold of three of five algorithms to predict hypoglycemia (defined as a FreeStyle plasma glucose readings <60 mg/dl), the HPA predicted 91% of the hypoglycemic events. When four of five algorithms were required to be positive, then 82% of the events were predicted. CONCLUSIONS The HPA will enable automated insulin-pump suspension in response to a pending event that has been detected prior to severe immediate complications.

A Closed-Loop Artificial Pancreas Using Model Predictive Control and a Sliding Meal Size Estimator

The objective of this article is to present a comprehensive strategy for a closed-loop artificial pancreas. A meal detection and meal size estimation algorithm is developed for situations in which the subject forgets to provide a meal insulin bolus. A pharmacodynamic model of insulin action is used to provide insulin-on-board constraints to explicitly include the future effect of past and currently delivered insulin boluses. In addition, a supervisory pump shut-off feature is presented to avoid hypoglycemia. All of these components are used in conjunction with a feedback control algorithm using model predictive control (MPC). A model for MPC is developed based on a study of 20 subjects and is tested in a hypothetical clinical trial of 100 adolescent and 100 adult subjects using a Food and Drug Administration-approved diabetic subject simulator. In addition, a performance comparison of previously and newly proposed meal size estimation algorithms using 200 in silico subjects is presented. Using the new meal size estimation algorithm, the integrated artificial pancreas system yielded a daily mean glucose of 138 and 132 mg/dl for adolescents and adults, respectively, which is a substantial improvement over the MPC-only case, which yielded 159 and 145 mg/dl.

Product property and production rate control of styrene polymerization

Abstract A multivariable multi-rate nonlinear model predictive control (NMPC) strategy is applied to styrene polymerization. The NMPC algorithm incorporates a multi-rate Extended Kalman Filter (EKF) to handle state variable and parameter estimation. A fundamental model is developed for the styrene polymerization CSTR, and control of polymer properties such as number average molecular weight (NAMW) and polydispersity is considered. These properties characterize the final polymer distribution and are strong indicators of the polymer qualities of interest. Production rate control is also demonstrated. Temperature measurements are available frequently while laboratory measurements of concentration and molecular weight distribution are available infrequently with substantial time delays between sampling and analysis. Observability analysis of the augmented system provides guidelines for the design of the augmented disturbance model for use in estimation using the multi-rate EKF. The observability analysis links measurement sets and corresponding observable disturbance models, and shows that measurements of moments of the polymer distribution are essential for good estimation and control. The CSTR is operated at an open-loop unstable steady state. Control simulations are performed under conditions of plant-model structural mismatch and in the presence of parameter uncertainty and disturbances, and the proposed multi-rate NMPC algorithm is shown to provide superior performance compared to linear multi-rate and nonlinear single-rate MPC algorithms. The major contributions of this work are the development of the multi-rate estimator and the measurement design study based on the observability analysis.

Detection of a Meal Using Continuous Glucose Monitoring: Implications for an artificial β-cell

OBJECTIVE—The purpose of this study was to introduce a novel meal detection algorithm (MDA) to be used as part of an artificial β-cell that uses a continuous glucose monitor (CGM). RESEARCH DESIGN AND METHODS—We developed our MDA on a dataset of 26 meal events using records from 19 children aged 1–6 years who used the MiniMed CGMS Gold. We then applied this algorithm to CGM records from a DirecNet pilot study of the FreeStyle Navigator continuous glucose sensor. During a research center admission, breakfast insulin was withheld for 1 h, and discrete glucose levels were obtained every 10 min after the meal. RESULTS—Based on the Navigator readings, the MDA detected a meal at a mean time of 30 min from the onset of eating, at which time the mean serum glucose was 21 mg/dl above baseline (range 2–36 mg/dl), and >90% of meals were detected before the glucose had risen 40 mg/dl from baseline. CONCLUSIONS—The MDA will enable automated insulin dosing in response to meals, facilitating the development of an artificial pancreas.

A Randomized Trial of a Home System to Reduce Nocturnal Hypoglycemia in Type 1 Diabetes

OBJECTIVE Overnight hypoglycemia occurs frequently in individuals with type 1 diabetes and can result in loss of consciousness, seizure, or even death. We conducted an in-home randomized trial to determine whether nocturnal hypoglycemia could be safely reduced by temporarily suspending pump insulin delivery when hypoglycemia was predicted by an algorithm based on continuous glucose monitoring (CGM) glucose levels. RESEARCH DESIGN AND METHODS Following an initial run-in phase, a 42-night trial was conducted in 45 individuals aged 15–45 years with type 1 diabetes in which each night was assigned randomly to either having the predictive low-glucose suspend system active (intervention night) or inactive (control night). The primary outcome was the proportion of nights in which ≥1 CGM glucose values ≤60 mg/dL occurred. RESULTS Overnight hypoglycemia with at least one CGM value ≤60 mg/dL occurred on 196 of 942 (21%) intervention nights versus 322 of 970 (33%) control nights (odds ratio 0.52 [95% CI 0.43–0.64]; P < 0.001). Median hypoglycemia area under the curve was reduced by 81%, and hypoglycemia lasting >2 h was reduced by 74%. Overnight sensor glucose was >180 mg/dL during 57% of control nights and 59% of intervention nights (P = 0.17), while morning blood glucose was >180 mg/dL following 21% and 27% of nights, respectively (P < 0.001), and >250 mg/dL following 6% and 6%, respectively. Morning ketosis was present <1% of the time in each arm. CONCLUSIONS Use of a nocturnal low-glucose suspend system can substantially reduce overnight hypoglycemia without an increase in morning ketosis.

Model predictive control of processes with input multiplicities

Abstract Chemical processes with input multiplicity behavior place a limitation on the structure of the feedback controller. Systems with right-half-plane zeroes (characteristic inverse response) also pose inherent feedback performance limitations. In this paper we prove that systems with input multiplicity must, under some assumptions, have right-half-plane zeroes on one “side” of the steady-state operating curve. A discrete dynamic model of a system with input multiplicity is shown to exhibit nonminimum-phase behavior. Stabilizing tuning parameters (prediction horizon and weighting on the inputs) for unconstrained nonlinear predictive control of nonlinear processes are found using the convergence theory of iterative processes. Closed-loop regions of attraction are constructed using a numerical Lyapunov function. Stabilization using nonlinear predictive control and significance of the closed-loop region of attraction are demonstrated on the isothermal Van de Vusse reaction and on the classic irreversible adiabatic CSTR.

Extension of dynamic matrix control to multiple models

The purpose of the paper is to extend dynamic matrix control (DMC) to handle different operating regimes and to reject parameter disturbances. This is done by two new multiple model predictive control (MMPC) schemes: one based on actual step response tests and the other on a minimal knowledge based first order plus dead time models (FOPDT). Both approaches do not require fundamental modeling. As a benchmark comparison, the two controllers are compared with a nonlinear model predictive controller (NL-MPC) using an extended Kalman filter (EKF) with no initial model/plant mismatch. The application example is the isothermal Van de Vusse reaction, which exhibits challenging input multiplicity. Simulations include disturbances in the feed concentration, kinetic parameters, and additive input and output noise. The two controllers have comparable performance to NL-MPC and in the case of multiple disturbances can outperform NL-MPC.

In silico preclinical trials: methodology and engineering guide to closed-loop control in type 1 diabetes mellitus.

This article sets forth guidelines for in silico (simulation-based) proof-of-concept testing of artificial pancreas control algorithms. The goal was to design a test procedure that can facilitate regulatory approval [e.g., Food and Drug Administration Investigational Device Exemption] for General Clinical Research Center experiments without preliminary testing on animals. The methodology is designed around a software package, based on a recent meal simulation model of the glucose-insulin system. Putting a premium on generality, this document starts by specifying a generic, rather abstract, meta-algorithm for control. The meta-algorithm has two main components: (1) patient assessment and tuning of control parameters, i.e., algorithmic processes for collection and processing patient data prior to closed-loop operation, and (2) controller warm-up and run-time operation, i.e., algorithmic processes for initializing controller states and managing blood glucose. The simulation-based testing methodology is designed to reveal the conceptual/mathematical operation of both main components, as applied to a large population of in silico patients with type 1 diabetes mellitus.