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

Insulin Estimation and Prediction A REVIEW OF THE ESTIMATION AND PREDICTION OF SUBCUTANEOUS INSULIN PHARMACOKINETICS IN CLOSED-LOOP GLUCOSE CONTROL

This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO) through grant DPI2013-46982-C2-1-R and the EU through FEDER funds.Bondía Company, J.; Romero Vivó, S.; Ricarte Benedito, B.; Diez, J. (2018). Insulin Estimation and Prediction A REVIEW OF THE ESTIMATION AND PREDICTION OF SUBCUTANEOUS INSULIN PHARMACOKINETICS IN CLOSED-LOOP GLUCOSE CONTROL. IEEE Control Systems. 38(1):47-66. https://doi.org/10.1109/MCS.2017.2766312S476638

Diabetes Mellitus Glucose Prediction by Linear and Bayesian Ensemble Modeling

Diabetes Mellitus is a chronic disease of impaired blood glucose control due to degraded or absent bodily-specific insulin production, or utilization. To the affected, this in many cases implies relying on insulin injections and blood glucose measurements, in order to keep the blood glucose level within acceptable limits. Risks of developing short- and long-term complications, due to both too high and too low blood glucose concentrations are severalfold, and, generally, the glucose dynamics are not easy too fully comprehend for the affected individual—resulting in poor glucose control. To reduce the burden this implies to the patient and society, in terms of physiological and monetary costs, different technical solutions, based on closed or semi-closed loop blood glucose control, have been suggested. To this end, this thesis investigates simplified linear and merged models of glucose dynamics for the purpose of short-term prediction, developed within the EU FP7 DIAdvisor project. These models could, e.g., be used, in a decision support system, to alert the user of future low and high glucose levels, and, when implemented in a control framework, to suggest proactive actions. The simplified models were evaluated on 47 patient data records from the first DIAdvisor trial. Qualitatively physiological correct responses were imposed, and model-based prediction, up to two hours ahead, and specifically for low blood glucose detection, was evaluated. The glucose raising, and lowering effect of meals and insulin were estimated, together with the clinically relevant carbohydrate-to-insulin ratio. The model was further expanded to include the blood-to-interstitial lag, and tested for one patient data set. Finally, a novel algorithm for merging of multiple prediction models was developed and validated on both artificial data and 12 datasets from the second DIAdvisor trial

Modeling and Prediction in Diabetes Physiology

Diabetes is a group of metabolic diseases characterized by the inability of the organism to autonomously regulate the blood glucose levels. It requires continuing medical care to prevent acute complications and to reduce the risk of long-term complications. Inadequate glucose control is associated with damage, dysfunction and failure of various organs. The management of the disease is non trivial and demanding. With today’s standards of current diabetes care, good glucose regulation needs constant attention and decision-making by the individuals with diabetes. Empowering the patients with a decision support system would, therefore, improve their quality of life without additional burdens nor replacing human expertise. This thesis investigates the use of data-driven techniques to the purpose of glucose metabolism modeling and short-term blood-glucose predictions in Type I Diabetes Mellitus (T1DM). The goal was to use models and predictors in an advisory tool able to produce personalized short-term blood glucose predictions and on-the-spot decision making concerning the most adequate choice of insulin delivery, meal intake and exercise, to help diabetic subjects maintaining glycemia as close to normal as possible. The approaches taken to describe the glucose metabolism were discrete-time and continuous-time models on input-output form and statespace form, while the blood glucose short-term predictors, i.e., up to 120 minutes ahead, used ARX-, ARMAX- and subspace-based prediction

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

Linear Modeling and Prediction in Diabetes Physiology

Diabetes Mellitus is a chronic disease characterized by the inability of the organism to autonomously regulate the blood glucose level due to insulin deficiency or resistance, leading to serious health damages. The therapy is essentially based on insulin injections and depends strongly on patient daily decisions, being mainly based upon empirical experience and rules of thumb. The development of a prediction engine capable of personalized on-the-spot decision making concerning the most adequate choice of insulin delivery, meal intake and exercise would therefore be a valuable initiative towards an improved management of the desease. This thesis presents work on data-driven glucose metabolism modeling and short-term, that is, up to 120 minutes, blood-glucose prediction in Type 1 Diabetes Mellitus (T1DM) subjects. In order to address model-based control for blood glucose regulation, low-order, individualized, data-driven, stable, physiological relevant models were identified from a population of 9 T1DM patients data. Model structures include: autoregressive moving average with exogenous inputs (ARMAX) models and state-space models.ARMAX multi-step-ahead predictors were estimated by means of least-squares estimation; next regularization of the autoregressive coefficients was introduced. ARMAX-based predictors and zero-order hold were computed to allow comparison.Finally, preliminary results on subspace-based multi-step-ahead multivariate predictors is presented

Robust strategies for glucose control in type 1 diabetes

[EN] Type 1 diabetes mellitus is a chronic and incurable disease that affects millions of people all around the world. Its main characteristic is the destruction (totally or partially) of the beta cells of the pancreas. These cells are in charge of producing insulin, main hormone implied in the control of blood glucose. Keeping high levels of blood glucose for a long time has negative health effects, causing different kinds of complications. For that reason patients with type 1 diabetes mellitus need to receive insulin in an exogenous way. Since 1921 when insulin was first isolated to be used in humans and first glucose monitoring techniques were developed, many advances have been done in clinical treatment with insulin. Currently 2 main research lines focused on improving the quality of life of diabetic patients are opened. The first one is concentrated on the research of stem cells to replace damaged beta cells and the second one has a more technological orientation. This second line focuses on the development of new insulin analogs to allow emulating with higher fidelity the endogenous pancreas secretion, the development of new noninvasive continuous glucose monitoring systems and insulin pumps capable of administering different insulin profiles and the use of decision-support tools and telemedicine. The most important challenge the scientific community has to overcome is the development of an artificial pancreas, that is, to develop algorithms that allow an automatic control of blood glucose. The main difficulty avoiding a tight glucose control is the high variability found in glucose metabolism. This fact is especially important during meal compensation. This variability, together with the delay in subcutaneous insulin absorption and action causes controller overcorrection that leads to late hypoglycemia (the most important acute complication of insulin treatment). The proposals of this work pay special attention to overcome these difficulties. In that way interval models are used to represent the patient physiology and to be able to take into account parametric uncertainty. This type of strategy has been used in both the open loop proposal for insulin dosage and the closed loop algorithm. Moreover the idea behind the design of this last proposal is to avoid controller overcorrection to minimize hypoglycemia while adding robustness against glucose sensor failures and over/under- estimation of meal carbohydrates. The algorithms proposed have been validated both in simulation and in clinical trials.[ES] La diabetes mellitus tipo 1 es una enfermedad crónica e incurable que afecta a millones de personas en todo el mundo. Se caracteriza por una destrucción total o parcial de las células beta del páncreas. Estas células son las encargadas de producir la insulina, hormona principal en el control de glucosa en sangre. Valores altos de glucosa en la sangre mantenidos en el tiempo afectan negativamente a la salud, provocando complicaciones de diversa índole. Es por eso que los pacientes con diabetes mellitus tipo 1 necesitan recibir insulina de forma exógena. Desde que se consiguiera en 1921 aislar la insulina para poder utilizarla en clínica humana, y se empezaran a desarrollar las primeras técnicas de monitorización de glucemia, se han producido grandes avances en el tratamiento con insulina. Actualmente, las líneas de investigación que se están siguiendo en relación a la mejora de la calidad de vida de los pacientes diabéticos, tienen fundamentalmente 2 vertientes: una primera que se centra en la investigación en células madre para la reposición de las células beta y una segunda vertiente de carácter más tecnológico. Dentro de esta segunda vertiente, están abiertas varias líneas de investigación, entre las que se encuentran el desarrollo de nuevos análogos de insulina que permitan emular más fielmente la secreción endógena del páncreas, el desarrollo de monitores continuos de glucosa no invasivos, bombas de insulina capaces de administrar distintos perfiles de insulina y la inclusión de sistemas de ayuda a la decisión y telemedicina. El mayor reto al que se enfrentan los investigadores es el de conseguir desarrollar un páncreas artificial, es decir, desarrollar algoritmos que permitan disponer de un control automático de la glucosa. La principal barrera que se encuentra para conseguir un control riguroso de la glucosa es la alta variabilidad que presenta su metabolismo. Esto es especialmente significativo durante la compensación de las comidas. Esta variabilidad junto con el retraso en la absorción y actuación de la insulina administrada de forma subcutánea favorece la aparición de hipoglucemias tardías (complicación aguda más importante del tratamiento con insulina) a consecuencia de la sobreactuación del controlador. Las propuestas presentadas en este trabajo hacen especial hincapié en sobrellevar estas dificultades. Así, se utilizan modelos intervalares para representar la fisiología del paciente, y poder tener en cuenta la incertidumbre en sus parámetros. Este tipo de estrategia se ha utilizado tanto en la propuesta de dosificación automática en lazo abierto como en el algoritmo en lazo cerrado. Además la principal idea de diseño de esta última propuesta es evitar la sobreactuación del controlador evitando hipoglucemias y añadiendo robustez ante fallos en el sensor de glucosa y en la estimación de las comidas. Los algoritmos propuestos han sido validados en simulación y en clínica.[CA] La diabetis mellitus tipus 1 és una malaltia crònica i incurable que afecta milions de persones en tot el món. Es caracteritza per una destrucció total o parcial de les cèl.lules beta del pàncrees. Aquestes cèl.lules són les encarregades de produir la insulina, hormona principal en el control de glucosa en sang. Valors alts de glucosa en la sang mantinguts en el temps afecten negativament la salut, provocant complicacions de diversa índole. És per això que els pacients amb diabetis mellitus tipus 1 necessiten rebre insulina de forma exògena. Des que s'aconseguís en 1921 aïllar la insulina per a poder utilitzar-la en clínica humana, i es començaren a desenrotllar les primeres tècniques de monitorització de glucèmia, s'han produït grans avanços en el tractament amb insulina. Actualment, les línies d'investigació que s'estan seguint en relació a la millora de la qualitat de vida dels pacients diabètics, tenen fonamentalment 2 vessants: un primer que es centra en la investigació de cèl.lules mare per a la reposició de les cèl.lules beta i un segon vessant de caràcter més tecnològic. Dins d' aquest segon vessant, estan obertes diverses línies d'investigació, entre les que es troben el desenrotllament de nous anàlegs d'insulina que permeten emular més fidelment la secreció del pàncrees, el desenrotllament de monitors continus de glucosa no invasius, bombes d'insulina capaces d'administrar distints perfils d'insulina i la inclusió de sistemes d'ajuda a la decisió i telemedicina. El major repte al què s'enfronten els investigadors és el d'aconseguir desenrotllar un pàncrees artificial, és a dir, desenrotllar algoritmes que permeten disposar d'un control automàtic de la glucosa. La principal barrera que es troba per a aconseguir un control rigorós de la glucosa és l'alta variabilitat que presenta el seu metabolisme. Açò és especialment significatiu durant la compensació dels menjars. Aquesta variabilitat junt amb el retard en l'absorció i actuació de la insulina administrada de forma subcutània afavorix l'aparició d'hipoglucèmies tardanes (complicació aguda més important del tractament amb insulina) a conseqüència de la sobreactuació del controlador. Les propostes presentades en aquest treball fan especial insistència en suportar aquestes dificultats. Així, s'utilitzen models intervalares per a representar la fisiologia del pacient, i poder tindre en compte la incertesa en els seus paràmetres. Aquest tipus d'estratègia s'ha utilitzat tant en la proposta de dosificació automàtica en llaç obert com en l' algoritme en llaç tancat. A més, la principal idea de disseny d'aquesta última proposta és evitar la sobreactuació del controlador evitant hipoglucèmies i afegint robustesa.Revert Tomás, A. (2015). Robust strategies for glucose control in type 1 diabetes [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/56001TESI

Development of a Clinical Type 1 Diabetes Metabolic System Model and in Silico Simulation Tool

Invited journal symposium paperObjectives: To develop a safe and effective protocol for the clinical control of Type 1 diabetes using conventional self-monitoring blood glucose (SMBG) measurements, and multiple daily injection (MDI) with insulin analogues. To develop an in silico simulation tool of Type 1 diabetes to predict long-term glycaemic control outcomes of clinical interventions. Methods: The virtual patient method is used to develop a simulation tool for Type 1 diabetes using data from a Type 1 diabetes patient cohort (n=40). The tool is used to test the adaptive protocol (AC) and a conventional intensive insulin therapy (CC) against results from a representative control cohort. Optimal and suboptimal basal insulin replacement are evaluated as a function of self-monitoring blood glucose (SMBG) frequency in conjunction with the (AC and CC) prandial control protocols. Results: In long-term glycaemic control, the AC protocol significantly decreases HbA1c in conditions of suboptimal basal insulin replacement for SMBG frequencies =6/day, and reduced the occurrence of mild and severe hypoglycaemia by 86-100% over controls over all SMBG frequencies in conditions of optimal basal insulin. Conclusions: A simulation tool to predict long-term glycaemic control outcomes from clinical interventions is developed to test a novel, adaptive control protocol for Type 1 diabetes. The protocol is effective and safe compared to conventional intensive insulin therapy and controls. As fear of hypoglycaemia is a large psychological barrier to glycaemic control, the AC protocol may represent the next evolution of intensive insulin therapy to deliver increased glycaemic control with increased safety. Further clinical or experimental validation is needed to fully prove the concept

STOCHASTIC SEASONAL MODELS FOR GLUCOSE PREDICTION IN TYPE 1 DIABETES

[ES] La diabetes es un importante problema de salud mundial, siendo una de las enfermedades no transmisibles más graves después de las enfermedades cardiovasculares, el cáncer y las enfermedades respiratorias crónicas. La prevalencia de la diabetes ha aumentado constantemente en las últimas décadas, especialmente en países de ingresos bajos y medios. Se estima que 425 millones de personas en todo el mundo tenían diabetes en 2017, y para 2045 este número puede aumentar a 629 millones. Alrededor del 10% de las personas con diabetes padecen diabetes tipo 1, caracterizada por una destrucción autoinmune de las células beta en el páncreas, responsables de la secreción de la hormona insulina. Sin insulina, la glucosa plasmática aumenta a niveles nocivos, provocando complicaciones vasculares a largo plazo. Hasta que se encuentre una cura, el manejo de la diabetes depende de los avances tecnológicos para terapias de reemplazo de insulina. Con la llegada de los monitores continuos de glucosa, la tecnología ha evolucionado hacia sistemas automatizados. Acuñados como "páncreas artificial", los dispositivos de control de glucosa en lazo cerrado suponen hoy en día un cambio de juego en el manejo de la diabetes. La investigación en las últimas décadas ha sido intensa, dando lugar al primer sistema comercial a fines de 2017, y muchos más están siendo desarrollados por las principales industrias de dispositivos médicos. Sin embargo, como dispositivo de primera generación, muchos problemas aún permanecen abiertos y nuevos avances tecnológicos conducirán a mejoras del sistema para obtener mejores resultados de control glucémico y reducir la carga del paciente, mejorando significativamente la calidad de vida de las personas con diabetes tipo 1. En el centro de cualquier sistema de páncreas artificial se encuentra la predicción de glucosa, tema abordado en esta tesis. La capacidad de predecir la glucosa a lo largo de un horizonte de predicción dado, y la estimación de las tendencias futuras de glucosa, es la característica más importante de cualquier sistema de páncreas artificial, para poder tomar medidas preventivas que eviten por completo el riesgo para el paciente. La predicción de glucosa puede aparecer como parte del algoritmo de control en sí, como en sistemas basados en técnicas de control predictivo basado en modelo (MPC), o como parte de un sistema de supervisión para evitar episodios de hipoglucemia. Sin embargo, predecir la glucosa es un problema muy desafiante debido a la gran variabilidad inter e intra-sujeto que sufren los pacientes, cuyas fuentes solo se entienden parcialmente. Esto limita las prestaciones predictivas de los modelos, imponiendo horizontes de predicción relativamente cortos, independientemente de la técnica de modelado utilizada (modelos fisiológicos, basados en datos o híbridos). La hipótesis de partida de esta tesis es que la complejidad de la dinámica de la glucosa requiere la capacidad de caracterizar grupos de comportamientos en los datos históricos del paciente que llevan naturalmente al concepto de modelado local. Además, la similitud de las respuestas en un grupo puede aprovecharse aún más para introducir el concepto clásico de estacionalidad en la predicción de glucosa. Como resultado, los modelos locales estacionales están en el centro de esta tesis. Se utilizan varias bases de datos clínicas que incluyen comidas mixtas y ejercicio para demostrar la viabilidad y superioridad de las prestaciones de este enfoque.[CA] La diabetisés un important problema de salut mundial, sent una de les malalties no transmissibles més greus després de les malalties cardiovasculars, el càncer i les malalties respiratòries cròniques. La prevalença de la diabetis ha augmentat constantment en les últimes dècades, especialment en països d'ingressos baixos i mitjans. S'estima que 425 milions de persones a tot el món tenien diabetis en 2017, i per 2045 aquest nombre pot augmentar a 629 milions. Al voltant del 10% de les persones amb diabetis pateixen diabetis tipus 1, caracteritzada per una destrucció autoimmune de les cèl·lules beta en el pàncrees, responsables de la secreció de l'hormona insulina. Sense insulina, la glucosa plasmàtica augmenta a nivells nocius, provocant complicacions vasculars a llarg termini. Fins que es trobi una cura, el maneig de la diabetis depén dels avenços tecnològics per a teràpies de reemplaçament d'insulina. Amb l'arribada dels monitors continus de glucosa, la tecnologia ha evolucionat cap a sistemes automatitzats. Encunyats com "pàncrees artificial", els dispositius de control de glucosa en llaç tancat suposen avui dia un canvi de joc en el maneig de la diabetis. La investigació en les últimes dècades ha estat intensa, donant lloc al primer sistema comercial a finals de 2017, i molts més estan sent desenvolupats per les principals indústries de dispositius mèdics. No obstant això, com a dispositiu de primera generació, molts problemes encara romanen oberts i nous avenços tecnològics conduiran a millores del sistema per obtenir millors resultats de control glucèmic i reduir la càrrega del pacient, millorant significativament la qualitat de vida de les persones amb diabetis tipus 1. Al centre de qualsevol sistema de pàncrees artificial es troba la predicció de glucosa, tema abordat en aquesta tesi. La capacitat de predir la glucosa al llarg d'un horitzó de predicció donat, i l'estimació de les tendències futures de glucosa, és la característica més important de qualsevol sistema de pàncrees artificial, per poder prendre mesures preventives que evitin completament el risc per el pacient. La predicció de glucosa pot aparèixer com a part de l'algoritme de control en si, com en sistemes basats en técniques de control predictiu basat en model (MPC), o com a part d'un sistema de supervisió per evitar episodis d'hipoglucèmia. No obstant això, predir la glucosa és un problema molt desafiant degut a la gran variabilitat inter i intra-subjecte que pateixen els pacients, les fonts només s'entenen parcialment. Això limita les prestacions predictives dels models, imposant horitzons de predicció relativament curts, independentment de la tècnica de modelatge utilitzada (models fisiològics, basats en dades o híbrids). La hipòtesi de partida d'aquesta tesi és que la complexitat de la dinàmica de la glucosa requereix la capacitat de caracteritzar grups de comportaments en les dades històriques del pacient que porten naturalment al concepte de modelatge local. A més, la similitud de les respostes en un grup pot aprofitar-se encara més per introduir el concepte clàssic d'estacionalitat en la predicció de glucosa. Com a resultat, els models locals estacionals estan al centre d'aquesta tesi. S'utilitzen diverses bases de dades clíniques que inclouen menjars mixtes i exercici per demostrar la viabilitat i superioritat de les prestacions d'aquest enfocament.[EN] Diabetes is a significant global health problem, one of the most serious noncommunicable diseases after cardiovascular diseases, cancer and chronic respiratory diseases. Diabetes prevalence has been steadily increasing over the past decades, especially in low- and middle-income countries. It is estimated that 425 million people worldwide had diabetes in 2017, and by 2045 this number may rise to 629 million. About 10% of people with diabetes suffer from type 1 diabetes, characterized by autoimmune destruction of the beta-cells in the pancreas, responsible for the secretion of the hormone insulin. Without insulin, plasma glucose rises to deleterious levels, provoking long-term vascular complications. Until a cure is found, the management of diabetes relies on technological developments for insulin replacement therapies. With the advent of continuous glucose monitors, technology has been evolving towards automated systems. Coined as "artificial pancreas", closed-loop glucose control devices are nowadays a game-changer in diabetes management. Research in the last decades has been intense, yielding a first commercial system in late 2017 and many more are in the pipeline of the main medical devices industry. However, as a first-generation device, many issues still remain open and new technological advancements will lead to system improvements for better glycemic control outputs and reduced patient's burden, improving significantly the quality of life of people with type 1 diabetes. At the core of any artificial pancreas system is glucose prediction, the topic addressed in this thesis. The ability to predict glucose along a given prediction horizon, and estimation of future glucose trends, is the most important feature of any artificial pancreas system, in order to be able to take preventive actions to entirely avoid risk to the patient. Glucose prediction can appear as part of the control algorithm itself, such as in systems based on model predictive control (MPC) techniques, or as part of a monitoring system to avoid hypoglycemic episodes. However, predicting glucose is a very challenging problem due to the large inter- and intra-subject variability that patients suffer, whose sources are only partially understood. These limits models forecasting performance, imposing relatively short prediction horizons, despite the modeling technique used (physiological, data-driven or hybrid approaches). The starting hypothesis of this thesis is that the complexity of glucose dynamics requires the ability to characterize clusters of behaviors in the patient's historical data naturally yielding to the concept of local modeling. Besides, the similarity of responses in a cluster can be further exploited to introduce the classical concept of seasonality into glucose prediction. As a result, seasonal local models are at the core of this thesis. Several clinical databases including mixed meals and exercise are used to demonstrate the feasibility and superiority of the performance of this approach.This work has been supported by the Spanish Ministry of Economy and Competitiveness (MINECO) under the FPI grant BES-2014-069253 and projects DPI2013-46982-C2-1-R and DPI2016-78831-C2-1-R. Moreover, with relation to this grant, a short stay was done at the end of 2017 at the Illinois Institute of Technology, Chicago, United States of America, under the supervision of Prof. Ali Cinar, for four months from 01/09/2017 to 29/12/2017.Montaser Roushdi Ali, E. (2020). STOCHASTIC SEASONAL MODELS FOR GLUCOSE PREDICTION IN TYPE 1 DIABETES [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/136574TESI