Design and Validation of an Open-Source Closed-Loop Testbed for Artificial Pancreas Systems

The development of a fully autonomous artificial pancreas system (APS) to independently regulate the glucose levels of a patient with Type 1 diabetes has been a long-standing goal of diabetes research. A significant barrier to progress is the difficulty of testing new control algorithms and safety features, since clinical trials are time- and resource-intensive. To facilitate ease of validation, we propose an open-source APS testbed by integrating APS controllers with two state-of-the-art glucose simulators and a novel fault injection engine. The testbed is able to reproduce the blood glucose trajectories of real patients from a clinical trial conducted over six months. We evaluate the performance of two closed-loop control algorithms (OpenAPS and Basal Bolus) using the testbed and find that more advanced control algorithms are able to keep blood glucose in a safe region 93.49% and 79.46% of the time on average, compared with 66.18% of the time for the clinical trial. The fault injection engine simulates the real recalls and adverse events reported to the U.S. Food and Drug Administration (FDA) and demonstrates the resilience of the controller in hazardous conditions. We used the testbed to generate 2.5 years of synthetic data representing 20 different patient profiles with realistic adverse event scenarios, which would have been expensive and risky to collect in a clinical trial. The proposed testbed is a valid tool that can be used by the research community to demonstrate the effectiveness of different control algorithms and safety features for APS.Comment: 12 pages, 12 figures, to appear in the IEEE/ACM International Conference on Connected Health: Applications, Systems and Engineering Technologies (CHASE), 202

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

Consensus Recommendations for the Use of Automated Insulin Delivery (AID) Technologies in Clinical Practice

International audienceThe significant and growing global prevalence of diabetes continues to challenge people with diabetes (PwD), healthcare providers and payers. While maintaining near-normal glucose levels has been shown to prevent or delay the progression of the long-term complications of diabetes, a significant proportion of PwD are not attaining their glycemic goals. During the past six years, we have seen tremendous advances in automated insulin delivery (AID) technologies. Numerous randomized controlled trials and real-world studies have shown that the use of AID systems is safe and effective in helping PwD achieve their long-term glycemic goals while reducing hypoglycemia risk. Thus, AID systems have recently become an integral part of diabetes management. However, recommendations for using AID systems in clinical settings have been lacking. Such guided recommendations are critical for AID success and acceptance. All clinicians working with PwD need to become familiar with the available systems in order to eliminate disparities in diabetes quality of care. This report provides much-needed guidance for clinicians who are interested in utilizing AIDs and presents a comprehensive listing of the evidence payers should consider when determining eligibility criteria for AID insurance coverage

Consensus recommendations for the use of automated insulin delivery technologies in clinical practice

The significant and growing global prevalence of diabetes continues to challenge people with diabetes (PwD), healthcare providers, and payers. While maintaining near-normal glucose levels has been shown to prevent or delay the progression of the long-term complications of diabetes, a significant proportion of PwD are not attaining their glycemic goals. During the past 6 years, we have seen tremendous advances in automated insulin delivery (AID) technologies. Numerous randomized controlled trials and real-world studies have shown that the use of AID systems is safe and effective in helping PwD achieve their long-term glycemic goals while reducing hypoglycemia risk. Thus, AID systems have recently become an integral part of diabetes management. However, recommendations for using AID systems in clinical settings have been lacking. Such guided recommendations are critical for AID success and acceptance. All clinicians working with PwD need to become familiar with the available systems in order to eliminate disparities in diabetes quality of care. This report provides much-needed guidance for clinicians who are interested in utilizing AIDs and presents a comprehensive listing of the evidence payers should consider when determining eligibility criteria for AID insurance coverage

Real-world evidence for the management of blood glucose in the intensive care unit

Glycaemic control is a core aspect of patient management in the intensive care unit (ICU). Blood glucose has a well-known U-shaped relationship with mortality and morbidity in ICU patients, with both hypo- and hyper-glycaemia associated with poor patient outcomes. As a result, up to 40-90% of ICU patients receive insulin, depending on illness severity and variation in clinical practice. Generally, clinical guidelines for glycaemic control are based on a series of trials that culminated in the NICE-SUGAR study in 2009, a multicentre study demonstrating that tight glycaemic control (a target of 80-110 mg/dL) did not improve patient outcomes compared to moderate control (<180 mg/dL). However, there remain open questions around the potential for more personalised blood glucose management, which real-world evidence sources such as electronic medical records (EMRs) can play a role in answering. This thesis investigates the role that EMRs can play in glycaemic control in the ICU using open access EMR databases, covering a heterogenous 208 hospital USA based patient cohort (the eICU collaborative research database, eICU-CRD) and a large tertiary medical centre in Boston, USA (MIMIC-III and MIMIC-IV). This thesis covers: i) curation and characterisation of the eICU-CRD cohort as a data resource for real-world evidence in glycaemic control; ii) investigation of whether blood lactate modifies the relationship between blood glucose and patient outcome across different subgroups; and iii) the development and comparison of machine learning and deep learning probabilistic forecasting algorithms for blood glucose. The analysis of the eICU-CRD demonstrated that there is wide variety in clinical practice around glycaemic control in the ICU. The results enable comparison with other data resources and assessment of the suitability of the eICU-CRD for addressing specific research questions related to glycaemic control and nutrition support. Informed by this descriptive analysis, the eICU-CRD was used to examine whether blood lactate modifies the relationship between blood glucose and patient outcome across different subgroups. While adjustment for blood lactate attenuated the relationship between blood glucose and patient outcome, blood glucose remained a marker of poor prognosis. Diabetic status was found to influence this relationship, in line with increasing evidence that diabetics and non-diabetics should be considered distinct populations for the purpose of glycaemic control in the ICU. The forecasting algorithms developed using MIMIC-III and MIMIC-IV were designed to account for the intrinsic statistical difficulties present in EMRs. These include large numbers of potentially sparsely and irregularly measured input variables. The focus was on development of probabilistic approaches given the measurement error in blood glucose measures, and their potential conversion into categorical forecasts if required. Two alternative approaches were proposed. The first was to use gradient boosted tree (GBT) algorithms, along with extensive feature engineering. The second was to use continuous time recurrent neural networks (CTRNNs), which learn their own hidden features and account for irregular measurements through evolving the model hidden state using continuous time dynamics. However, several CTRNN architectures are outperformed by an autoregressive GBT model (Catboost), with only a long short-term memory (LSTM) and neural ODE based architecture (ODE-LSTM) achieving comparable performance on probabilistic forecasting metrics such as the continuous ranked probability score (ODE-LSTM: 0.118±0.001; Catboost: 0.118±0.001), ignorance score (0.152±0.008; 0.149±0.002) and interval score (175±1; 176±1). Further, the GBT method was far easier and faster to train, highlighting the importance of using appropriate non-deep learning benchmarks in the academic literature on novel statistical methodologies for analysis of EMRs. The findings highlight that EMRs are a valuable resource in medical evidence generation and characterisation of current clinical practice. Future research should aim to continue investigation of subgroup differences and utilise the forecasting algorithms as part of broader goals such as development of personalised insulin recommendation algorithms

Optimal Control Strategies for Complex Biological Systems

To better understand and to improve therapies for complex diseases such as cancer or diabetes, it is not sufficient to identify and characterize the interactions between molecules and pathways in complex biological systems, such as cells, tissues, and the human body. It also is necessary to characterize the response of a biological system to externally supplied agents (e.g., drugs, insulin), including a proper scheduling of these drugs, and drug combinations in multi drugs therapies. This obviously becomes important in applications which involve control of physiological processes, such as controlling the number of autophagosome vesicles in a cell, or regulating the blood glucose level in patients affected by diabetes. A critical consideration when controlling physiological processes in biological systems is to reduce the amount of drugs used, as in some therapies drugs may become toxic when they are overused. All of the above aspects can be addressed by using tools provided by the theory of optimal control, where the externally supplied drugs or hormones are the inputs to the system. Another important aspect of using optimal control theory in biological systems is to identify the drug or the combination of drugs that are effective in regulating a given therapeutic target, i.e., a biological target of the externally supplied stimuli. The dynamics of the key features of a biological system can be modeled and described as a set of nonlinear differential equations. For the implementation of optimal control theory in complex biological systems, in what follows we extract \textit{a network} from the dynamics. Namely, to each state variable $x_i$ we will assign a network node $v_i$ ($i=1,...,N$) and a network directed edge from node $v_i$ to another node $v_j$ will be assigned every time $x_j$ is present in the time derivative of $x_i$. The node which directly receives an external stimulus is called a \emph{driver nodes} in a network. The node which directly connected to an output sensor is called a \emph{target node}. %, and it has a prescribed final state that we wish to achieve in finite time. From the control point of view, the idea of controllability of a system describes the ability to steer the system in a certain time interval towards thea desired state with a suitable choice of control inputs. However, defining controllability of large complex networks is quite challenging, primarily because of the large size of the network, its complex structure, and poor knowledge of the precise network dynamics. A network can be controllable in theory but not in practice when a very large control effort is required to steer the system in the desired direction. This thesis considers several approaches to address some of these challenges. Our first approach is to reduce the control effort is to reduce the number of target nodes. We see that by controlling the states of a subset of the network nodes, rather than the state of every node, while holding the number of control signals constant, the required energy to control a portion of the network can be reduced substantially. The energy requirements exponentially decay with the number of target nodes, suggesting that large networks can be controlled by a relatively small number of inputs as long as the target set is appropriately sized. We call this strategy \emph{target control}. As our second approach is based on reducing the control efforts by allowing the prescribed final states are satisfied approximately rather than strictly. We introduce a new control strategy called \textit{balanced control} for which we set our objective function as a convex combination of two competitive terms: (i) the distance between the output final states at a given final time and given prescribed states and (ii) the total control efforts expenditure over the given time period. Based on the above two approaches, we propose an algorithm which provides a locally optimal control technique for a network with nonlinear dynamics. We also apply pseudo-spectral optimal control, together with the target and balance control strategies previously described, to complex networks with nonlinear dynamics. These optimal control techniques empower us to implement the theoretical control techniques to biological systems evolving with very large, complex and nonlinear dynamics. We use these techniques to derive the optimal amounts of several drugs in a combination and their optimal dosages. First, we provide a prediction of optimal drug schedules and combined drug therapies for controlling the cell signaling network that regulates autophagy in a cell. Second, we compute an optimal dual drug therapy based on administration of both insulin and glucagon to control the blood glucose level in type I diabetes. Finally, we also implement the combined control strategies to investigate the emergence of cascading failures in the power grid networks