Continuous glucose monitoring sensors: Past, present and future algorithmic challenges

Continuous glucose monitoring (CGM) sensors are portable devices that allow measuring and visualizing the glucose concentration in real time almost continuously for several days and are provided with hypo/hyperglycemic alerts and glucose trend information. CGM sensors have revolutionized Type 1 diabetes (T1D) management, improving glucose control when used adjunctively to self-monitoring blood glucose systems. Furthermore, CGM devices have stimulated the development of applications that were impossible to create without a continuous-time glucose signal, e.g., real-time predictive alerts of hypo/hyperglycemic episodes based on the prediction of future glucose concentration, automatic basal insulin attenuation methods for hypoglycemia prevention, and the artificial pancreas. However, CGM sensors’ lack of accuracy and reliability limited their usability in the clinical practice, calling upon the academic community for the development of suitable signal processing methods to improve CGM performance. The aim of this paper is to review the past and present algorithmic challenges of CGM sensors, to show how they have been tackled by our research group, and to identify the possible future ones

Clinical decision support systems in the care of hospitalised patients with diabetes

This thesis explored the role of health informatics (decision support systems) in caring for hospitalised patients with diabetes through a systematic review and by analysing data from University Hospital Birmingham, UK. Findings from the thesis: 1) highlight the potential role of computerised physician order entry system in improving guideline based anti-diabetic medication prescription in particular insulin prescription, and their effectiveness in contributing to better glycaemic control; 2) quantify the occurrence of missed discharge diagnostic codes for diabetes using electronic prescription data and suggests 60% of this could be potentially reduced using an algorithm that could be introduced as part of the information system; 3) found that hypoglycaemia and foot disease in hospitalised diabetes patients were independently associated with higher in-hospital mortality rates and longer length of stay; 4) quantify the hypoglycaemia rates in non-diabetic patients and proposes one method of establishing a surveillance system to identify non diabetic hypoglycaemic patients; and 5) introduces a prediction model that may be useful to identify patients with diabetes at risk of poor clinical outcomes during their hospital stay

Implementation of Food Insecurity Screening in Clinical Setting

This project used the Stetler model of research utilization framework to apply evidence-based findings to clinical settings screening adults with type II diabetes mellitus (T2DM) and low incomes for food insecurity. The project involved the review and critical appraisal of research studies and translation of research-based knowledge into a protocol for the Peach Tree Clinic with respect to the impact of food insecurity on diabetes outcomes in adults with T2DM and low incomes who were at risk of food insecurity. In addition, the proportion of screened at-risk patients who received nutritional counseling was calculated. The proportion of patients with T2DM screened for food insecurity increased from the baseline value of 0% to 82%, over the 3-month implementation period. Therefore, the project aim was surpassed. The quality improvement committee was presented with the project results for incorporation into the clinic’s policies and procedures for sustainability

Hypoglycemia event prediction from CGM using ensemble learning

This work sought to explore the potential of using standalone continuous glucose monitor (CGM) data for the prediction of hypoglycemia utilizing a large cohort of type 1 diabetes patients during free-living. We trained and tested an algorithm for the prediction of hypoglycemia within 40 minutes on 3.7 million CGM measurements from 225 patients using ensemble learning. The algorithm was also validated using 11.5 million synthetic CGM data. The results yielded a receiver operating characteristic area under the curve (ROC AUC) of 0.988 and a precision-recall area under the curve (PR AUC) of 0.767. In an event-based analysis for predicting hypoglycemic events, the algorithm had a sensitivity of 90%, a lead-time of 17.5 minutes and a false-positive rate of 38%. In conclusion, this work demonstrates the potential of using ensemble learning to predict hypoglycemia, using only CGM data. This could help alarm patients of a future hypoglycemic event so countermeasures can be initiated

Effectiveness of Order Sets in the Management of Diabetic Ketoacidosis and Hyperosmolar Hyperglycemia

Diabetes mellitus (DM) is an endocrine disorder that affects the metabolism of glucose, for which there were an estimated 415 million cases world-wide. There are two common types of DM, Type 1 and Type 2. A significant difference between the two types of DM is the underlying cause of the disease but the two disease processes have similar characteristics. Both Type 1 and Type 2 DM can be associated with severe complications. Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are two of the most common medical emergencies. DKA is commonly found in those with Type 1 DM and can be characterized by elevated serum glucose levels, decreased serum pH, and the presence of ketones the serum and urine. HHS is more commonly found in those with Type 2 DM and can be characterized by serum glucose levels \u3e 600 mg/dl and serum osmolality \u3e 320 mOsm/kg. Ketones and severe metabolic acidosis are not typically present with HHS. While there are some differences among the two types of complications, the management of DKA and HHS are similar. Major components of management of both conditions includes intravenous fluid resuscitation, electrolyte replacement, and insulin therapy to manage serum glucose levels. Order sets are often used in medicine and in other industries to guide treatment or processes. A comprehensive literature review was conducted to examine the effectiveness of order sets in the treatment of DKA and HHS. Despite a lack of high-level evidence, outcomes showed consistent improvements in patient outcomes status post the implementation of a treatment guided order set. Common outcomes measured included hospital length of stay, intensive care unit length of stay, time to anion gap closure, hypoglycemic events, time to ketone clearance, and compliance with treatment guidelines. The outcomes of focus of this literature review were the hospital and intensive care unit length of stay and time to closure of the anion gap. Since the use of order sets for the treatment of DKA and HHS has been shown to improve patient outcomes, hospitals and hospital groups should work to implement order sets for the treatment of hyperglycemic emergencies

Contributions to interoperability, scalability and formalization of personal health systems

The ageing of the world's population combined with unhealthy lifestyles are contributing to a major prevalence of chronic diseases. This scenario poses the challenge of providing good healthcare services to that people affected by chronic illnesses, but without increasing its costs. A prominent way to face this challenge is through pervasive healthcare. Research in pervasive healthcare tries to shift the current centralized healthcare delivery model focused on the doctors, to a more distributed model focused on the patients. In this context Personal Health Systems (PHSs) consists on approaching sampling technologies into the hands of the patients, without disturbing its activities of the daily life, to monitor patient's physiological parameters and providing feedback on their state. The use of PHSs involves the patients in the management of their illness and in their own well being too. The development of PHSs has to face technological issues in order to be accepted by our society. Within them it is important to ensure interoperability between different systems in order to make them work together. Scalability it is also a concern, as their performance must not decrease when increasing the number of users. Another issue is how to formalize the medical knowledge for each patient, as different patients may have different target goals. Security and privacy are a must feature because of the sensitive nature of medical data. Other issues involve the the integration with legacy systems, and the usability of graphical user interfaces in order to encourage old people with the use these technologies. The aim of this PhD thesis is to contribute into the state-of-the-art of PHSs by tackling together different of the above-mentioned challenges. First, to achieve interoperability we use the CDA standard as a format to encode and exchange health data and alerts related with the status of the patient. We show how these documents can be generated automatically through the use of XML templates. Second, we address the scalability by distributing the computations needed to monitor the patients over their devices, rather than performing them in a centralized server. In this context we develop the MAGPIE agent platform, which runs on Android devices, as a framework able to provide intelligence to PHSs, and generate alerts that can be of interest for the patients and the medical doctors. Third, we focus on the formalization of PHSs by providing a tool for the practitioners where they can define, in a graphical way, monitoring rules related with chronic diseases that are integrated with the MAGPIE agent platform. The thesis also explores different ways to share the data collected with PHSs in order to improve the outcomes obtained with the use of this technology. Data is shared between individuals following a Distributed Event-Based System (DEBS) approach, where different people can subscribe to the alerts produced by the patient. Data is also shared between institutions with a network protocol called MOSAIC, and we focus on the security aspects of this protocol. The research in this PhD focuses in the use case of Diabetes Mellitus; and it has been developed in the context of the projects MONDAINE, MAGPIE, COMMODITY12 and TAMESIS.L'envelliment de la població mundial combinat amb uns estils de vida no saludables contribueixen a una major prevalença d'enfermetats cròniques. Aquest escenari presenta el repte de proporcionar uns bons serveis sanitaris a les persones afectades per aquestes enfermetats, sense incrementar-ne els costos. Una solució prometedora a aquest repte és mitjançant l'aplicació del que en anglès s'anomena "pervasive healthcare". L'investigació en aquesta camp tracta de canviar l'actual model centralitzat de serveis sanitaris enfocat en el personal sanitari, per un model de serveis distribuït enfocat en els pacients. En aquest context, els Personal Health Systems (PHSs) consisteixen en posar a l'abast dels pacients les tecnologies de monitorització, i proporcionar-los informació sobre el seu estat. L'ús de PHSs involucra els pacients en la gestió de la seva enfermetat i del seu propi benestar. L'acceptació dels PHSs per part de la societat implica certs reptes tecnològics en el seu desenvolupament. És important garantir la seva interoperabilitat per tal de que puguin treballar conjuntament. La seva escalabilitat també s'ha de tenir en compte, ja que el seu rendiment no s'ha de veure afectat al incrementar-ne el número d'usuaris. Un altre aspecte a considerar és com formalitzar el coneixement mèdic per cada pacient, ja que cada un d'ells pot tenir objectius diferents. La seguretat i privacitat són característiques desitjades degut a la naturalesa sensible de les dades mèdiques. Altres problemàtiques impliquen la integració amb sistemes heretats, i la usabilitat de les interfícies gràfiques per fomentar-ne el seu ús entre les persones grans. L'objectiu d'aquesta tesi és contribuir a l'estat de l'art dels PHSs tractant de manera conjunta varis dels reptes mencionats. Per abordar l'interoperabilitat s'utilitza l'estàndard CDA com a format per codificar les dades mèdiques i alertes relacionades amb el pacient. A més es mostra com aquests documents poden generar-se de forma automàtica mitjançant l' ús de plantilles XML. Per tractar l'escalabilitat es distribueixen les computacions per monitoritzar els pacients entre els seus terminals mòbils, en comptes de realitzar-les en un servidor central. En aquest context es desenvolupa la plataforma d'agents MAGPIE com a framework per proporcionar intelligència als PHSs i generar alertes d'interès per al metge i el pacient. La formalització s'aborda mitjançant una eina que permet als metges definir de manera gràfica regles de monitorització relacionades amb enfermetats cròniques, que a més estan integrades amb la plataforma d'agents MAGPIE. La tesi també explora diferents maneres de compartir les dades recol·lectades amb un PHS, amb l'objectiu de millorar els resultats obtinguts amb aquesta tecnologia. Les dades es comparteixen entre individus seguint un enfoc de sistemes distribuïts basats en events (DEBS), on diferents usuaris poden subscriure's a les alertes produïdes per el pacient. Les dades també es comparteixen entre institucions mitjançant un protocol de xarxa anomenat MOSAIC. A la tesi es desenvolupen els aspectes de seguretat d'aquest protocol. La test es centra en la Diabetis Mellitus com a cas d'ús, i s'ha realitzat en el context dels projectes MONDAINE, MAGPIE, COMMODITY12 i TAMESIS.El envejecimiento de la población mundial combinado con unos estilos de vida no saludables contribuyen a una mayor prevalencia de enfermedades crónicas. Este escenario presenta el reto de proporcionar unos buenos servicios sanitarios a las personas afectadas por estas enfermedades, sin incrementar sus costes. Una solución prometedora a este reto es mediante la aplicación de lo que en inglés se denomina "pervasive healthcare". La investigación en este campo trata de cambiar el actual modelo centralizado de servicios sanitarios enfocado hacia el personal sanitario, por un modelo distribuido enfocado hacia los pacientes. En este contexto, los Personal Health Systems (PHSs) consisten en poner al alcance de los pacientes las tecnologías de monitorización, y proporcionarles información sobre su estado. El uso de PHSs involucra a los pacientes en la gestión de su enfermedad y en su propio bienestar. La aceptación de los PHSs por parte de la sociedad implica ciertos retos tecnológicos en su desarrollo. Es importante garantizar su interoperabilidad para que puedan trabajar conjuntamente. Su escalabilidad también se debe tener en cuenta, ya que su rendimiento no tiene que verse afectado al incrementar su número de usuarios. Otro aspecto a considerar es cómo formalizar el conocimiento médico para cada paciente, ya que cada uno puede tener objetivos distintos. La seguridad y privacidad son características deseadas debido a la naturaleza sensible de los datos médicos. Otras problemáticas implican la integración con sistemas heredados, y la usabilidad de las interfaces gráficas para fomentar su uso entre las personas mayores. El objetivo de esta tesis es contribuir al estado del arte de los PHSs tratando de manera conjunta varios de los retos mencionados. Para abordar la interoperabilidad se usa el estándar CDA como formato para codificar los datos médicos y alertas relacionados con el paciente. Además se muestra como estros documentos pueden generarse de forma automática mediante el uso de plantillas XML. Para tratar la escalabilidad se distribuye la computación para monitorizar a los pacientes en sus terminales móbiles, en lugar de realizarla en un servidor central. En este contexto se desarrolla la plataforma de agentes MAGPIE como framework para proporcionar inteligencia a los PHSs y generar alertas de interés para el médico y el paciente. La formalización se aborda mediante una herramienta que permite a los médicos definir de manera gráfica reglas de monitorización relacionadas con enfermedades crónicas, que ademas están integradas con la plataforma de agentes MAGPIE. La tesis también explora distintas formas de compartir los datos recolectados con un PHS, con el fin de mejorar los resultados obtenidos mediante esta tecnología. Los datos se comparten entre individuos siguiendo un enfoque de sistemas distribuidos basados en eventos (DEBS), donde distintos usuarios pueden suscribirse a las alertas producidas por el paciente. Los datos también se comparten entre instituciones mediante un protocolo dered llamado MOSAIC. En la tesis se desarrollan los aspectos de seguridad de este protocolo. La tesis se centra en la Diabetes Mellitus como caso de uso, y se ha realizado en el contexto de los proyectos MONDAINE, MAGPIE, COMMODITY12 y TAMESIS.Postprint (published version

Online Glucose Prediction in Type-1 Diabetes by Neural Network Models

Diabetes mellitus is a chronic disease characterized by dysfunctions of the normal regulation of glucose concentration in the blood. In Type 1 diabetes the pancreas is unable to produce insulin, while in Type 2 diabetes derangements in insulin secretion and action occur. As a consequence, glucose concentration often exceeds the normal range (70-180 mg/dL), with short- and long-term complications. Hypoglycemia (glycemia below 70 mg/dL) can progress from measurable cognition impairment to aberrant behaviour, seizure and coma. Hyperglycemia (glycemia above 180 mg/dL) predisposes to invalidating pathologies, such as neuropathy, nephropathy, retinopathy and diabetic foot ulcers. Conventional diabetes therapy aims at maintaining glycemia in the normal range by tuning diet, insulin infusion and physical activity on the basis of 4-5 daily self-monitoring of blood glucose (SMBG) measurements, obtained by the patient using portable minimally-invasive lancing sensor devices. New scenarios in diabetes treatment have been opened in the last 15 years, when minimally invasive continuous glucose monitoring (CGM) sensors, able to monitor glucose concentration in the subcutis continuously (i.e. with a reading every 1 to 5 min) over several days (7-10 consecutive days), entered clinical research. CGM allows tracking glucose dynamics much more effectively than SMBG and glycemic time-series can be used both retrospectively, e.g. to optimize metabolic control therapy, and in real-time applications, e.g. to generate alerts when glucose concentration exceeds the normal range thresholds or in the so-called “artificial pancreas”, as inputs of the closed loop control algorithm. For what concerns real time applications, the possibility of preventing critical events is, clearly, even more appealing than just detecting them as they occur. This would be doable if glucose concentration were known in advance, approximately 30-45 min ahead in time. The quasi continuous nature of the CGM signal renders feasible the use of prediction algorithms which could allow the patient to take therapeutic decisions on the basis of future instead of current glycemia, possibly mitigating/ avoiding imminent critical events. Since the introduction of CGM devices, various methods for short-time prediction of glucose concentration have been proposed in the literature. They are mainly based on black box time series models and the majority of them uses only the history of the CGM signal as input. However, glucose dynamics are influenced by many factors, e.g. quantity of ingested carbohydrates, administration of drugs including insulin, physical activity, stress, emotions and inter- and intra-individual variability is high. For these reasons, prediction of glucose time course is a challenging topic and results obtained so far may be improved. The aim of this thesis is to investigate the possibility of predicting future glucose concentration, in the short term, using new models based on neural networks (NN) exploiting, apart from CGM history, other available information. In particular, we first develop an original model which uses, as inputs, the CGM signal and information on timing and carbohydrate content of ingested meals. The prediction algorithm is based on a feedforward NN in parallel with a linear predictor. Results are promising: the predictor outperforms widely used state of art techniques and forecasts are accurate and allow obtaining a satisfactory time anticipation. Then we propose a second model, which exploits a different NN architecture, a jump NN, which combines benefits of both feedforward NN and linear algorithm obtaining performance similar to the previously developed predictor, although the simpler structure. To conclude the analysis, information on doses of injected bolus of insulin are added as input of the jump NN and the relative importance of every input signal in determining the NN output is investigated by developing an original sensitivity analysis. All the proposed predictors are assessed on real data of Type 1 diabetics, collected during the European FP7 project DIAdvisor. To evaluate the clinical usefulness of prediction in improving diabetes management we also propose a new strategy to quantify, using an in silico environment, the reduction of hypoglycemia when alerts and relative therapy are triggered on the basis of prediction, obtained with our NN algorithm, instead of CGM. Finally, possible inclusion of additional pieces of information such as physical activity is investigated, though at a preliminary level. The thesis is organized as follows. Chapter 1 gives an introduction to the diabetes disease and the current technologies for CGM, presents state of art techniques for short-time prediction of glucose concentration of diabetics and states the aim and the novelty of the thesis. Chapter 2 discusses NN paradigms from a theoretical point of view and specifies technical details common to the design and implementation of all the NN algorithms proposed in the following. Chapter 3 describes the first prediction model we propose, based on a NN in parallel with a linear algorithm. Chapter 4 presents an alternative simpler architecture, based on a jump NN, and demonstrates its equivalence, in terms of performance, with the previously proposed algorithm. Chapter 5 further improves the jump NN, by adding new inputs and investigating their effective utility by a sensitivity analysis. Chapter 6 points out possible future developments, as the possibility of exploiting information on physical activity, reporting also a preliminary analysis. Finally, Chapter 7 describes the application of NN for generation of preventive hypoglycemic alerts and evaluates improvement of diabetes management in a simulated environment. Some concluding remarks end the thesis

EDMON - Electronic Disease Surveillance and Monitoring Network: A Personalized Health Model-based Digital Infectious Disease Detection Mechanism using Self-Recorded Data from People with Type 1 Diabetes

Through time, we as a society have been tested with infectious disease outbreaks of different magnitude, which often pose major public health challenges. To mitigate the challenges, research endeavors have been focused on early detection mechanisms through identifying potential data sources, mode of data collection and transmission, case and outbreak detection methods. Driven by the ubiquitous nature of smartphones and wearables, the current endeavor is targeted towards individualizing the surveillance effort through a personalized health model, where the case detection is realized by exploiting self-collected physiological data from wearables and smartphones. This dissertation aims to demonstrate the concept of a personalized health model as a case detector for outbreak detection by utilizing self-recorded data from people with type 1 diabetes. The results have shown that infection onset triggers substantial deviations, i.e. prolonged hyperglycemia regardless of higher insulin injections and fewer carbohydrate consumptions. Per the findings, key parameters such as blood glucose level, insulin, carbohydrate, and insulin-to-carbohydrate ratio are found to carry high discriminative power. A personalized health model devised based on a one-class classifier and unsupervised method using selected parameters achieved promising detection performance. Experimental results show the superior performance of the one-class classifier and, models such as one-class support vector machine, k-nearest neighbor and, k-means achieved better performance. Further, the result also revealed the effect of input parameters, data granularity, and sample sizes on model performances. The presented results have practical significance for understanding the effect of infection episodes amongst people with type 1 diabetes, and the potential of a personalized health model in outbreak detection settings. The added benefit of the personalized health model concept introduced in this dissertation lies in its usefulness beyond the surveillance purpose, i.e. to devise decision support tools and learning platforms for the patient to manage infection-induced crises