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

“Smart” Continuous Glucose Monitoring Sensors: On-Line Signal Processing Issues

The availability of continuous glucose monitoring (CGM) sensors allows development of new strategies for the treatment of diabetes. In particular, from an on-line perspective, CGM sensors can become “smart” by providing them with algorithms able to generate alerts when glucose concentration is predicted to exceed the normal range thresholds. To do so, at least four important aspects have to be considered and dealt with on-line. First, the CGM data must be accurately calibrated. Then, CGM data need to be filtered in order to enhance their signal-to-noise ratio (SNR). Thirdly, predictions of future glucose concentration should be generated with suitable modeling methodologies. Finally, generation of alerts should be done by minimizing the risk of detecting false and missing true events. For these four challenges, several techniques, with various degrees of sophistication, have been proposed in the literature and are critically reviewed in this paper

Bayesian denoising algorithm dealing with colored, non-stationary noise in continuous glucose monitoring timeseries

Introduction: The retrospective analysis of continuous glucose monitoring (CGM) timeseries can be hampered by colored and non-stationary measurement noise. Here, we introduce a Bayesian denoising (BD) algorithm to address both autocorrelation of measurement noise and temporal variability of its variance.Methods: BD utilizes adaptive, a-priori models of signal and noise, whose unknown variances are derived on partially-overlapped CGM windows, via smoothing approach based on linear mean square estimation. The CGM signal and noise variability profiles are then reconstructed using a kernel smoother. BD is first assessed on two simulated datasets, DS1 and DS2. On DS1, the effectiveness of accounting for colored noise is evaluated by comparison against a literature algorithm; on DS2, the effectiveness of accounting for the noise variance temporal variability is evaluated by comparison against a Butterworth filter. BD is then evaluated on 15 CGM timeseries measured by the Dexcom G6 (DR).Results: On DS1, BD allows reducing the root-mean-square-error (RMSE) from 8.10 [6.79–9.24] mg/dL to 6.28 [5.47–7.27] mg/dL (median [IQR]); on DS2, RMSE decreases from 6.85 [5.50–8.72] mg/dL to 5.35 [4.48–6.49] mg/dL. On DR, BD performs a reasonable tracking of noise variance variability and a satisfactory denoising.Discussion: The new algorithm effectively addresses the nature of CGM measurement error, outperforming existing denoising algorithms

Interstitial Glucose and Physical Exercise in Type 1 Diabetes: Integrative Physiology, Technology, and the Gap In-Between

Continuous and flash glucose monitoring systems measure interstitial fluid glucose concentrations within a body compartment that is dramatically altered by posture and is responsive to the physiological and metabolic changes that enable exercise performance in individuals with type 1 diabetes. Body fluid redistribution within the interstitial compartment, alterations in interstitial fluid volume, changes in rate and direction of fluid flow between the vasculature, interstitium and lymphatics, as well as alterations in the rate of glucose production and uptake by exercising tissues, make for caution when interpreting device read-outs in a rapidly changing internal environment during acute exercise. We present an understanding of the physiological and metabolic changes taking place with acute exercise and detail the blood and interstitial glucose responses with different forms of exercise, namely sustained endurance, high-intensity, and strength exercises in individuals with type 1 diabetes. Further, we detail novel technical information on currently available patient devices. As more health services and insurance companies advocate their use, understanding continuous and flash glucose monitoring for its strengths and limitations may offer more confidence for patients aiming to manage glycemia around exercise

Analysis of transient failures in continuous glucose monitoring sensors: data modeling and simulation

openEmbargo per motivi di segretezza e/o di proprietà dei risultati e informazioni di enti esterni o aziende private che hanno partecipato alla realizzazione del lavoro di ricerca relativo alla tes

Processing Diabetes mellitus composite events in MAGPIE

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

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

Algoritmi Bayesiani per il filtraggio di segnali di heart rate variability acquisiti da sensori indossabili in individui affetti da sclerosi multipla o sclerosi amiotrofica laterale

L’obiettivo del presente lavoro di tesi è lo sviluppo di un algoritmo di filtraggio del rumore di misura in segnali heart rate variability (HRV) misurati in individui affetti da sclerosi amiotrofica laterale (SLA) o sclerosi multipla (SM) all’interno del progetto europeo Brainteaser. I dati vengono raccolti per mezzo di un sensore wearable (Garmin vivoactive4). Una volta acquisiti, i tracciati HRV vengono processati da una pipeline di processing, sviluppata in python, che permette di visualizzare il tracciato giornaliero, segmentarlo in finestre, e filtrarlo dal rumore di misura mediante un algoritmo di smoothing Bayesiano adattativo che riesce a stimare, nella finestra stessa, il rapporto segnale-rumore. Come ultimo step le finestre vengono tra loro riconciliate per ottenere nuovamente il tracciato giornaliero intero. La capacità dell’algoritmo, che è quella di produrre un filtraggio migliore rispetto alle tecniche di letteratura, è stata validata confrontando l’errore di quantificazione nell’estrazione di features di HRV rispetto ad un segnale gold standard di riferimento

Filtraggio bayesiano on-line per il miglioramento dei sistemi di generazione di allarmi IPO/Iperglicenici in dispositivi per il monitoraggio in continua del glucosio

Nei primi anni di questo millennio sono stati introdotti sul mercato i dispositivi CGM (Continuous Glucose Monitoring), che costituiscono una nuova frontiera nel campo del controllo della terapia del diabete. I dispositivi CGM sono apparecchi mini-invasivi e “wearable”, consentono il monitoraggio della glicemia in modo quasi costante e sono potenzialmente in grado di segnalare episodi ipo/iperglicemici in tempo reale, se non addirittura in anticipo, grazie all’uso di tecniche di predizione. Tuttavia, le prestazioni di questi dispositivi nella generazione di allarmi ipo/iperglicemici sono ancora abbastanza limitate e la percentuale di falsi allarmi è piuttosto elevata (stimata fino al 50%). Una delle principali cause della generazione inefficiente degli allarmi consiste nel rumore di misura di cui il segnale acquisito è inevitabilmente affetto. Al fine di garantire misurazioni più precise, si possono introdurre procedure di filtraggio (denoising) in tempo reale. Lo scopo di questa tesi è verificare e quantificare il miglioramento delle prestazioni dei sistemi per la generazione di allarmi ipo/iperglicemici nei dispositivi CGM attraverso l’applicazione in tempo reale di un metodo di filtraggio bayesiano del segnale glicemico di recente sviluppo. In particolare, si sfrutta il fatto che il metodo è in grado di aumentare la qualità del segnale, incrementando il SNR, e di fornire contestualmente una stima della precisione dei campioni glicemici filtrati, parametro utile per valutare se generare o meno un allarm

CGMLab: una GUI MatLab per l'analisi e l'elaborazione di segnali misurati da sensori continui della glicemia

CGMLab è un'interfaccia grafica utente, composta da multipli moduli grafici e di processamento. Essa è stata costruita per rendere utilizzabili e trasferibili gli algoritmi di elaborazione dei segnali CGM sviluppati dal gruppo di ricerca di bioingegneria di Padova. Inoltre, CGMLab consente una gestione versatile e robusta delle serie temporali in esame e comporta una notevole riduzione dei tempi di studio. Fino ad ora sono stati sviluppati i moduli per lo smoothing e per la predizioneope