The bio-inspired artificial pancreas for type 1 diabetes control in the home: System architecture and preliminary results

BACKGROUND: Artificial pancreas (AP) technology has been proven to improve glucose and patient-centered outcomes for people with type 1 diabetes (T1D). Several approaches to implement the AP have been described, clinically evaluated, and in one case, commercialized. However, none of these approaches has shown a clear superiority with respect to others. In addition, several challenges still need to be solved before achieving a fully automated AP that fulfills the users' expectations. We have introduced the Bio-inspired Artificial Pancreas (BiAP), a hybrid adaptive closed-loop control system based on beta-cell physiology and implemented directly in hardware to provide an embedded low-power solution in a dedicated handheld device. In coordination with the closed-loop controller, the BiAP system incorporates a novel adaptive bolus calculator which aims at improving postprandial glycemic control. This paper focuses on the latest developments of the BiAP system for its utilization in the home environment. METHODS: The hardware and software architectures of the BiAP system designed to be used in the home environment are described. Then, the clinical trial design proposed to evaluate the BiAP system in an ambulatory setting is introduced. Finally, preliminary results corresponding to two participants enrolled in the trial are presented. RESULTS: Apart from minor technical issues, mainly due to wireless communications between devices, the BiAP system performed well (~88% of the time in closed-loop) during the clinical trials conducted so far. Preliminary results show that the BiAP system might achieve comparable glycemic outcomes to the existing AP systems (~73% time in target range 70-180 mg/dL). CONCLUSION: The BiAP system is a viable platform to conduct ambulatory clinical trials and a potential solution for people with T1D to control their glucose control in a home environment

A hybrid automata approach for monitoring the patient in the loop in artificial pancreas systems

The use of automated insulin delivery systems has become a reality for people with type 1 diabetes (T1D), with several hybrid systems already on the market. One of the particularities of this technology is that the patient is in the loop. People with T1D are the plant to control and also a plant operator, because they may have to provide information to the control loop. The most immediate information provided by patients that affects performance and safety are the announcement of meals and exercise. Therefore, to ensure safety and performance, the human factor impact needs to be addressed by designing fault monitoring strategies. In this paper, a monitoring system is developed to diagnose potential patient modes and faults. The monitoring system is based on the residual generation of a bank of observers. To that aim, a linear parameter varying (LPV) polytopic representation of the system is adopted and a bank of Kalman filters is designed using linear matrix inequalities (LMI). The system uncertainty is propagated using a zonotopic-set representation, which allows determining confidence bounds for each of the observer outputs and residuals. For the detection of modes, a hybrid automaton model is generated and diagnosis is performed by interpreting the events and transitions within the automaton. The developed system is tested in simulation, showing the potential benefits of using the proposed approach for artificial pancreas systems.Peer ReviewedPostprint (published version

Combining continuous glucose monitoring and insulin pumps to automatically tune the basal insulin infusion in diabetes therapy: a review

For individuals affected by Type 1 diabetes (T1D), a chronic disease in which the pancreas does not produce any insulin, maintaining the blood glucose (BG) concentration as much as possible within the safety range (70-180\ua0mg/dl) allows avoiding short- and long-term complications. The tuning of exogenous insulin infusion can be difficult, especially because of the inter- and intra-day variability of physiological and behavioral factors. Continuous glucose monitoring (CGM) sensors, which monitor glucose concentration in the subcutaneous tissue almost continuously, allowed improving the detection of critical hypo- and hyper-glycemic episodes. Moreover, their integration with insulin pumps for continuous subcutaneous insulin infusion allowed developing algorithms that automatically tune insulin dosing based on CGM measurements in order to mitigate the incidence of critical episodes. In this work, we aim at reviewing the literature on methods for CGM-based automatic attenuation or suspension of basal insulin with a focus on algorithms, their implementation in commercial devices and clinical evidence of their effectiveness and safety

Clinical evaluation of a novel adaptive bolus calculator and safety system in Type 1 diabetes

Bolus calculators are considered state-of-the-art for insulin dosing decision support for people with Type 1 diabetes (T1D). However, they all lack the ability to automatically adapt in real-time to respond to an individual’s needs or changes in insulin sensitivity. A novel insulin recommender system based on artificial intelligence has been developed to provide personalised bolus advice, namely the Patient Empowerment through Predictive Personalised Decision Support (PEPPER) system. Besides adaptive bolus advice, the decision support system is coupled with a safety system which includes alarms, predictive glucose alerts, predictive low glucose suspend for insulin pump users, personalised carbohydrate recommendations and dynamic bolus insulin constraint. This thesis outlines the clinical evaluation of the PEPPER system in adults with T1D on multiple daily injections (MDI) and insulin pump therapy. The hypothesis was that the PEPPER system is safe, feasible and effective for use in people with TID using MDI or pump therapy. Safety and feasibility of the safety system was initially evaluated in the first phase, with the second phase evaluating feasibility of the complete system (safety system and adaptive bolus advisor). Finally, the whole system was clinically evaluated in a randomised crossover trial with 58 participants. No significant differences were observed for percentage times in range between the PEPPER and Control groups. For quality of life, participants reported higher perceived hypoglycaemia with the PEPPER system despite no objective difference in time spent in hypoglycaemia. Overall, the studies demonstrated that the PEPPER system is safe and feasible for use when compared to conventional therapy (continuous glucose monitoring and standard bolus calculator). Further studies are required to confirm overall effectiveness.Open Acces

From Chemical Plants to Clinical Patients: Process Control Applications in Biomedicine

In recent times, there has been a convergence and interaction between the age-long principles of chemical process control (hitherto exclusive to the world of man-made industrial chemical process plants) and the life sciences (particularly biomedicine). This review article presents some examples of application areas in biomedicine where process dynamics and control, as a sub-discipline of process engineering, is being utilized to save human lives. It especially focuses on the extension of the chemical engineer’s “process” and “system” to embrace parts of the human body or microbial cells. The aim of the article is to make the reader appreciate how the traditional chemical engineering tools of process dynamics and control can be applied newly to biomedical problems. This is to stir the readers’ mind to explore other exciting ways of applying control engineering knowledge to solve modern healthcare challenges. The review was conducted under three broad application headings: medical device engineering applications, industrial-scale production of therapeutic substances and elucidatory investigations into complex physiologies

Processing Diabetes mellitus composite events in MAGPIE

The focus of this research is in the definition of programmable expert Personal Health Systems (PHS) to monitor patients affected by chronic diseases using agent oriented programming and mobile computing to represent the interactions happening amongst the components of the system. The paper also discusses issues of knowledge representation within the medical domain when dealing with temporal patterns concerning the physiological values of the patient. In the presented agent based PHS the doctors can personalize for each patient monitoring rules that can be defined in a graphical way. Furthermore, to achieve better scalability, the computations for monitoring the patients are distributed among their devices rather than being performed in a centralized server. The system is evaluated using data of 21 diabetic patients to detect temporal patterns according to a set of monitoring rules defined. The system’s scalability is evaluated by comparing it with a centralized approach. The evaluation concerning the detection of temporal patterns highlights the system’s ability to monitor chronic patients affected by diabetes. Regarding the scalability, the results show the fact that an approach exploiting the use of mobile computing is more scalable than a centralized approach. Therefore, more likely to satisfy the needs of next generation PHSs. PHSs are becoming an adopted technology to deal with the surge of patients affected by chronic illnesses. This paper discusses architectural choices to make an agent based PHS more scalable by using a distributed mobile computing approach. It also discusses how to model the medical knowledge in the PHS in such a way that it is modifiable at run time. The evaluation highlights the necessity of distributing the reasoning to the mobile part of the system and that modifiable rules are able to deal with the change in lifestyle of the patients affected by chronic illnesses.Peer ReviewedPostprint (author's final draft

Evidence-based Development of Trustworthy Mobile Medical Apps

abstract: Widespread adoption of smartphone based Mobile Medical Apps (MMAs) is opening new avenues for innovation, bringing MMAs to the forefront of low cost healthcare delivery. These apps often control human physiology and work on sensitive data. Thus it is necessary to have evidences of their trustworthiness i.e. maintaining privacy of health data, long term operation of wearable sensors and ensuring no harm to the user before actual marketing. Traditionally, clinical studies are used to validate the trustworthiness of medical systems. However, they can take long time and could potentially harm the user. Such evidences can be generated using simulations and mathematical analysis. These methods involve estimating the MMA interactions with human physiology. However, the nonlinear nature of human physiology makes the estimation challenging. This research analyzes and develops MMA software while considering its interactions with human physiology to assure trustworthiness. A novel app development methodology is used to objectively evaluate trustworthiness of a MMA by generating evidences using automatic techniques. It involves developing the Health-Dev β tool to generate a) evidences of trustworthiness of MMAs and b) requirements assured code generation for vulnerable components of the MMA without hindering the app development process. In this method, all requests from MMAs pass through a trustworthy entity, Trustworthy Data Manager which checks if the app request satisfies the MMA requirements. This method is intended to expedite the design to marketing process of MMAs. The objectives of this research is to develop models, tools and theory for evidence generation and can be divided into the following themes: • Sustainable design configuration estimation of MMAs: Developing an optimization framework which can generate sustainable and safe sensor configuration while considering interactions of the MMA with the environment. • Evidence generation using simulation and formal methods: Developing models and tools to verify safety properties of the MMA design to ensure no harm to the human physiology. • Automatic code generation for MMAs: Investigating methods for automatically • Performance analysis of trustworthy data manager: Evaluating response time generating trustworthy software for vulnerable components of a MMA and evidences.performance of trustworthy data manager under interactions from non-MMA smartphone apps.Dissertation/ThesisDoctoral Dissertation Computer Science 201

Optimization and Control of Cyber-Physical Vehicle Systems

A cyber-physical system (CPS) is composed of tightly-integrated computation, communication and physical elements. Medical devices, buildings, mobile devices, robots, transportation and energy systems can benefit from CPS co-design and optimization techniques. Cyber-physical vehicle systems (CPVSs) are rapidly advancing due to progress in real-time computing, control and artificial intelligence. Multidisciplinary or multi-objective design optimization maximizes CPS efficiency, capability and safety, while online regulation enables the vehicle to be responsive to disturbances, modeling errors and uncertainties. CPVS optimization occurs at design-time and at run-time. This paper surveys the run-time cooperative optimization or co-optimization of cyber and physical systems, which have historically been considered separately. A run-time CPVS is also cooperatively regulated or co-regulated when cyber and physical resources are utilized in a manner that is responsive to both cyber and physical system requirements. This paper surveys research that considers both cyber and physical resources in co-optimization and co-regulation schemes with applications to mobile robotic and vehicle systems. Time-varying sampling patterns, sensor scheduling, anytime control, feedback scheduling, task and motion planning and resource sharing are examined

Model-Based Analysis of User Behaviors in Medical Cyber-Physical Systems

Human operators play a critical role in various Cyber-Physical System (CPS) domains, for example, transportation, smart living, robotics, and medicine. The rapid advancement of automation technology is driving a trend towards deep human-automation cooperation in many safety-critical applications, making it important to explicitly consider user behaviors throughout the system development cycle. While past research has generated extensive knowledge and techniques for analyzing human-automation interaction, in many emerging applications, it remains an open challenge to develop quantitative models of user behaviors that can be directly incorporated into the system-level analysis. This dissertation describes methods for modeling different types of user behaviors in medical CPS and integrating the behavioral models into system analysis. We make three main contributions. First, we design a model-based analysis framework to evaluate, improve, and formally verify the robustness of generic (i.e., non-personalized) user behaviors that are typically driven by rule-based clinical protocols. We conceptualize a data-driven technique to predict safety-critical events at run-time in the presence of possible time-varying process disturbances. Second, we develop a methodology to systematically identify behavior variables and functional relationships in healthcare applications. We build personalized behavior models and analyze population-level behavioral patterns. Third, we propose a sequential decision filtering technique by leveraging a generic parameter-invariant test to validate behavior information that may be measured through unreliable channels, which is a practical challenge in many human-in-the-loop applications. A unique strength of this validation technique is that it achieves high inter-subject consistency despite uncertain parametric variances in the physiological processes, without needing any individual-level tuning. We validate the proposed approaches by applying them to several case studies