On the prediction of glucose concentration under intra-patient variability in type 1 diabetes: A monotone systems approach

Insulin therapy in type 1 diabetes aims to mimic the pattern of endogenous insulin secretion found in healthy subjects. Glucose-insulin models are widely used in the development of new predictive control strategies in order to maintain the plasma glucose concentration within a narrow range, avoiding the risks of high or low levels of glucose in the blood. However, due to the high variability of this biological process, the exact values of the model parameters are unknown, but they can be bounded by intervals. In this work, the computation of tight glucose concentration bounds under parametric uncertainty for the development of robust prediction tools is addressed. A monotonicity analysis of the model states and parameters is performed. An analysis of critical points, state transformations and application of differential inequalities are proposed to deal with non-monotone parameters. In contrast to current methods, the guaranteed simulations for the glucose-insulin model are carried out by considering uncertainty in all the parameters and initial conditions. Furthermore, no time-discretisation is required, which helps to reduce the computational time significantly. As a result, we are able to compute a tight glucose envelope that bounds all the possible patient's glycemic responses with low computational effort. (C) 2012 Elsevier Ireland Ltd. All rights reserved.This work was partially supported by the Spanish Ministerio de Ciencia e Innovacion through Grant DPI-2010-20764-C02, by the Universitat Politecnica de Valencia through Grant PAID-05-09-4334, and by the Generalitat Valenciana through Grant GV/2012/085.De Pereda Sebastián, D.; Romero Vivó, S.; Ricarte Benedito, B.; Bondía Company, J. (2012). On the prediction of glucose concentration under intra-patient variability in type 1 diabetes: A monotone systems approach. Computer Methods and Programs in Biomedicine. 108(3):993-1001. https://doi.org/10.1016/j.cmpb.2012.05.012S9931001108

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

Methods for the treatment of uncertainty in dynamical systems: Application to diabetes

[EN] Patients suffering from Type 1 Diabetes are not able to secrete insulin, thus, they have to get it administered externally. Current research is focused on developing an artificial pancreas, a control system that automatically administers insulin according to patient's needs. The work presented here aims to improve the efficiency and safety of control algorithms for artificial pancreas. Glucose-insulin models try to mimic the administration of external insulin, the absorption of carbohydrates, and the influence of both of them in blood glucose concentration. However, these processes are infinitely complex and they are characterized by their high variability. The mathematical models used are often a simplified version which does not include all the process variability and, therefore, they do not always match reality. This deficiency on the models can be addressed by considering uncertainty on their parameters and initial conditions. In this way, the exact values are unknown but they can be bounded by intervals that comprehend all the variability of the considered process. When the value of the parameters and initial conditions is known, there is usually just one possible behaviour. However, if they are bounded by intervals, a set of possible solutions exists. In this case, it is interesting to compute a solution envelope that guarantees the inclusion of all the possible behaviours. A common technique to compute this envelope is the monotonicity analysis of the system. Nevertheless, some overestimation is produced if the system is not fully monotone. In this thesis, several methods and approaches have been developed to reduce, or even eliminate, the overestimation in the computation of solution envelopes, while satisfying the inclusion guarantee. Another problem found during the use of an artificial pancreas is that only the subcutaneous glucose concentration can be measured in real time, with some noise in the measurements. The rest of the system states are unknown, but they could be estimated from this set of noisy measurements by state observers, like Kalman filters. A detailed example is shown at the end of this thesis, where an Extended Kalman Filter is used to estimate in real time insulin concentration based on the food ingested and in periodical measurements of subcutaneous glucose.[ES] Los pacientes que sufren de diabetes tipo 1 no son capaces de secretar insulina, por lo que tienen que administrársela externamente. La investigación actual se centra en el desarrollo de un páncreas artificial, un sistema de control que administre automáticamente la insulina en función de las necesidades del paciente. El trabajo que aquí se presenta tiene como objetivo mejorar la eficiencia y la seguridad de los algoritmos de control para el páncreas artificial. Los modelos de glucosa-insulina tratan de emular la administración externa de la insulina, la absorción de carbohidratos y la influencia de ambos en la concentración de glucosa en sangre. El problema es que estos procesos son infinitamente complejos y se caracterizan por su alta variabilidad. Los modelos matemáticos utilizados suelen ser una versión simplificada que no incluye toda la variabilidad del proceso y, por lo tanto, no coinciden con la realidad. Esta deficiencia de los modelos puede subsanarse considerando inciertos sus parámetros y las condiciones iniciales, de manera que se desconoce su valor exacto pero sí podemos englobarlos en ciertos intervalos que comprendan toda la variabilidad del proceso considerado. Cuando los valores de los parámetros y de las condiciones iniciales son conocidos, existe, por lo general, un único comportamiento posible. Sin embargo, si están delimitados por intervalos se obtiene un conjunto de posibles soluciones. En este caso, interesa obtener una envoltura de las soluciones que garantice la inclusión de todos los comportamientos posibles. Una técnica habitual que facilita el cómputo de esta envoltura es el análisis de la monotonicidad del sistema. Sin embargo, si el sistema no es totalmente monótono la envoltura obtenida estará sobrestimada. En esta tesis se han desarrollado varios métodos para reducir, o incluso eliminar, la sobrestimación en el cálculo de envolturas, al tiempo que se satisface la garantía de inclusión. Otro inconveniente con el que nos encontramos durante el uso de un páncreas artificial es que solo es posible medir en tiempo real, con cierto ruido en la medida, la glucosa subcutánea. El resto de los estados del sistema son desconocidos, pero podrían ser estimados a partir de este conjunto limitado de mediciones con ruido utilizando observadores de estado, como el Filtro de Kalman. Un ejemplo detallado se muestra al final de la tesis, donde se estima en tiempo real la concentración de insulina en plasma en función de la comida ingerida y de mediciones periódicas de la glucosa subcutánea con ayuda de un Filtro de Kalman Extendido.[CA] Els pacients que pateixen de diabetis tipus 1 no són capaços de secretar insulina, motiu pel qual han d'administrar-se-la externament. La investigació actual es centra en el desenvolupament d'un pàncrees artificial, un sistema de control que administre automàticament la insulina en funció de les necessitats del pacient. El treball que ací es presenta té com a objectiu millorar l'eficiència i la seguretat dels algorismes de control per al pàncrees artificial. Els models de glucosa-insulina tracten d'emular l'administració externa de la insulina, l'absorció de carbohidrats i la influència d'ambdós factors en la concentració de glucosa en sang. El problema és que estos processos són infinitament complexos i es caracteritzen per la seua alta variabilitat. Els models matemàtics emprats solen ser una versió simplificada que no inclou tota la variabilitat del procés i, per tant, no coincideixen amb la realitat. Esta deficiència dels models pot esmenar-se considerant incerts els seus paràmetres i les condicions inicials, de manera que es desconeix el seu valor exacte però sí podem englobar-los en certs intervals que comprenguen tota la variabilitat del procés considerat. Quan els valors dels paràmetres i de les condicions inicials són coneguts, existeix, en general, un únic comportament possible. No obstant, si estan delimitats per intervals s'obté un conjunt de possibles solucions. En este cas, interessa obtindre un embolcall de les solucions que assegure la inclusió de tots els comportaments possibles. Una tècnica habitual que facilita el còmput d'este embolcall és l'anàlisi de la monotonicitat del sistema. No obstant, si el sistema no és totalment monòton l'embolcall obtingut estarà sobreestimat. En esta tesi s'han desenvolupat diversos mètodes per a reduir, o fins i tot eliminar, la sobreestimació en el càlcul dels embolcalls, al temps que se satisfà la garantia d'inclusió. Altre inconvenient amb què ens trobem durant l'ús d'un pàncrees artificial és que només és possible mesurar en temps real, amb cert soroll en la mesura, la glucosa subcutània. La resta dels estats del sistema són desconeguts, però podrien ser estimats a partir d'este conjunt limitat de mesures amb soroll utilitzant observadors d'estat, com el Filtre de Kalman. Un exemple detallat es mostra al final de la tesi, on s'estima en temps real la concentració d'insulina en plasma en funció del menjar ingerit i de les mesures periòdiques de la glucosa subcutània amb ajuda d'un Filtre de Kalman Estés.Pereda Sebastián, DD. (2015). Methods for the treatment of uncertainty in dynamical systems: Application to diabetes [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/54121TESI

Temporal case-based reasoning for insulin decision support

Type 1 diabetes mellitus is an autoimmune disease resulting in insucient insulin to regulate blood glucose levels. The condition can be successfully managed through eective blood glucose control, one aspect of which is the administration of bolus insulin. Formulas exist to estimate the required bolus, and have been adopted by existing mobile expert systems. These formulas are shown to be eective but are unable to automatically adapt to an individual. This research resolves the limitations of existing formula based calculators by using case-based reasoning to automatically improve bolus advice. Case-based reasoning is a method of articial intelligence that has successfully been adopted in the diabetes domain previously, but has primarily been limited to assisting doctors with therapy adjustments. Here case-based reasoning is instead used to directly assist the patient. The case-based reasoning process is enhanced for bolus advice through a temporal retrieval algorithm coupled with domain specic automated adjustment and revision. This temporal retrieval algorithm includes factors from previous events to improve the prediction of a bolus dose. The automated adjustment then renes the predicted bolus dose, and automated revision improves the prediction for future advice through the evaluation of the resulting blood glucose level. Analysis of the temporal retrieval algorithm found that it is capable of predicting bolus advice comparable to closed-loop simulation and existing formulas, with adapted advice resulting in improvements to simulated blood glucose control. The learning potential of the model is made evident through further improvements in blood glucose control when using revised advice. The system is implemented on a mobile device with a focus on safety using formal methods to help ensure actions performed do not violate the system constraints. Performance analysis demonstrated acceptable response times, providing evidence that this approach is viable. The research demonstrates how formula based mobile bolus calculators can be replaced by an articially intelligent alternative which continuously learns to improve advice

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

Model-Based Therapeutics for Type 1 Diabetes Mellitus

The incidence of Type 1 diabetes is growing yearly. Worryingly, the aetiology of the disease is inconclusive. What is known is that the total number of affected individuals, as well as the severity and number of associated complications are growing for this chronic disease. With increasing complications due to severity, length of exposure, and poor control, the disease is beginning to consume an increasingly major portion of healthcare costs to the extent that it poses major economic risks in several nations. Research has shown that intensive insulin therapy aimed at certain minimum glycosylated haemoglobin threshold levels reduces the incidence of complications by up to 76% compared to conventional insulin therapy. Moreover, the effects of such intensive therapy regimes over a 6.5y duration persists for at least 10y after, a so called metabolic memory. Thus, early intervention can slow the momentum of complications far more easily than later intervention. Early, safe, intensive therapy protocols offer potential solutions to the growing social and economic effects of diabetes. Since the 1970s, the artificial endocrine pancreas has been heralded as just this type of solution. However, no commercial product currently exists, and ongoing limitations in sensors and pumps have resulted in, at best, modest clinical advantages over conventional methods of insulin administration or multiple daily injection. With high upfront costs, high costs of consumables, significant complexity, and the extensive infrastructure and support required, these systems and devices are only used by 2-15% of individuals with Type 1 diabetes. Clearly, there is an urgent need to address the large majority of the Type 1 diabetes population using conventional glucose measurement and insulin administration. For these individuals, current conventional or intensive therapies are failing to deliver recommended levels of glycaemic control. This research develops an understanding of clinical glycaemic control using conventional insulin administration and glucose measurement techniques in Type 1 diabetes based on a clinically validated in silico virtual patient simulation. Based on this understanding, a control protocol for Type 1 diabetes that is relatively simple and clinically practical is developed. The protocol design incorporates physiological modelling and engineering techniques to adapt to individual patient clinical requirements. By doing so, it produces accurate, patient-specific recommendations for insulin interventions. Initially, a simple, physiological compartmental model for the pharmacokinetics of subcutaneously injected insulin is developed. While the absorption process itself is subject to significant potential variability, such models enable a real-time estimation of plasma insulin concentration. This information would otherwise be lacking in the clinical environment of outpatient Type 1 diabetes treatment due to the inconvenience, cost, and laboratory turnaround for plasma insulin measurements. Hence, this validated model offers significant opportunity to optimise therapy selection. An in silico virtual patient simulation tool is also developed. A virtual patient cohort is developed on patient data from a representative cohort of the broad diabetes population. The simulation tool is used to develop a robust, adaptive protocol for prandial insulin dosing against a conventional intensive insulin therapy, as well as a controls group representative of the general diabetes population. The effect on glycaemic control of suboptimal and optimal, prandial and basal insulin therapies is also investigated, with results matching clinical expectations. To gauge the robustness of the developed adaptive protocol, a Monte Carlo analysis is performed, incorporating realistic and physiological errors and variability. Due to the relatively infrequent glucose measurement in outpatient Type 1 diabetes, a method for identifying the diurnal cycle in effective insulin sensitivity and modelling it in retrospective patient data is also presented. The method consists of identifying deterministic and stochastic components in the patient effective insulin sensitivity profile. Circadian rhythmicity and sleep-wake phases have profound effects on effective insulin sensitivity. Identification and prediction of this rhythm is of utmost clinical relevance, with the potential for safer and more effective glycaemic control, with less frequent measurement. It is thus a means of further enhancing any robust protocol and making it more clinically practical to implement. Finally, this research presents an entire framework for the realistic, and rapid development and testing of clinical glycaemic control protocols for outpatient Type 1 diabetes. The models and methods developed within this framework allow rapid and physiological identification of time-variant, patient-specific, effective insulin sensitivity profiles. These profiles form the responses of the virtual patient and can be used to develop and robustly test clinical glycaemic control protocols in a broad range of patients. These effective insulin sensitivity profiles are also rich in dynamics, specifically those circadian in nature which can be identified, and used to provide more accurate glycaemic prediction with the potential for safer and more effective control

A Simple Modeling Framework For Prediction In The Human Glucose-Insulin System

In this paper, we build a new, simple, and interpretable mathematical model to describe the human glucose-insulin system. Our ultimate goal is the robust control of the blood glucose (BG) level of individuals to a desired healthy range, by means of adjusting the amount of nutrition and/or external insulin appropriately. By constructing a simple yet flexible model class, with interpretable parameters, this general model can be specialized to work in different settings, such as type 2 diabetes mellitus (T2DM) and intensive care unit (ICU); different choices of appropriate model functions describing uptake of nutrition and removal of glucose differentiate between the models. In both cases, the available data is sparse and collected in clinical settings, major factors that have constrained our model choice to the simple form adopted. The model has the form of a linear stochastic differential equation (SDE) to describe the evolution of the BG level. The model includes a term quantifying glucose removal from the bloodstream through the regulation system of the human body, and another two terms representing the effect of nutrition and externally delivered insulin. The parameters entering the equation must be learned in a patient-specific fashion, leading to personalized models. We present numerical results on patient-specific parameter estimation and future BG level forecasting in T2DM and ICU settings. The resulting model leads to the prediction of the BG level as an expected value accompanied by a band around this value which accounts for uncertainties in the prediction. Such predictions, then, have the potential for use as part of control systems which are robust to model imperfections and noisy data. Finally, a comparison of the predictive capability of the model with two different models specifically built for T2DM and ICU contexts is also performed.Comment: 47 pages, 9 figures, 7 table

Model Identification from Ambulatory Data for Post-Prandial Glucose Control in type 1 Diabetes

Several glucoregulatory models are studies and a new model is proposed. Experiments are developed following an optimal design methodology. The designed experiments are applied in home monitoring of diabetic patients.Laguna Sanz, AJ. (2010). Model Identification from Ambulatory Data for Post-Prandial Glucose Control in type 1 Diabetes. http://hdl.handle.net/10251/14052Archivo delegad

Personalized glucose forecasting for type 2 diabetes using data assimilation

Type 2 diabetes leads to premature death and reduced quality of life for 8% of Americans. Nutrition management is critical to maintaining glycemic control, yet it is difficult to achieve due to the high individual differences in glycemic response to nutrition. Anticipating glycemic impact of different meals can be challenging not only for individuals with diabetes, but also for expert diabetes educators. Personalized computational models that can accurately forecast an impact of a given meal on an individual’s blood glucose levels can serve as the engine for a new generation of decision support tools for individuals with diabetes. However, to be useful in practice, these computational engines need to generate accurate forecasts based on limited datasets consistent with typical self-monitoring practices of individuals with type 2 diabetes. This paper uses three forecasting machines: (i) data assimilation, a technique borrowed from atmospheric physics and engineering that uses Bayesian modeling to infuse data with human knowledge represented in a mechanistic model, to generate real-time, personalized, adaptable glucose forecasts; (ii) model averaging of data assimilation output; and (iii) dynamical Gaussian process model regression. The proposed data assimilation machine, the primary focus of the paper, uses a modified dual unscented Kalman filter to estimate states and parameters, personalizing the mechanistic models. Model selection is used to make a personalized model selection for the individual and their measurement characteristics. The data assimilation forecasts are empirically evaluated against actual postprandial glucose measurements captured by individuals with type 2 diabetes, and against predictions generated by experienced diabetes educators after reviewing a set of historical nutritional records and glucose measurements for the same individual. The evaluation suggests that the data assimilation forecasts compare well with specific glucose measurements and match or exceed in accuracy expert forecasts. We conclude by examining ways to present predictions as forecast-derived range quantities and evaluate the comparative advantages of these ranges

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