Complex systems and the technology of variability analysis

Characteristic patterns of variation over time, namely rhythms, represent a defining feature of complex systems, one that is synonymous with life. Despite the intrinsic dynamic, interdependent and nonlinear relationships of their parts, complex biological systems exhibit robust systemic stability. Applied to critical care, it is the systemic properties of the host response to a physiological insult that manifest as health or illness and determine outcome in our patients. Variability analysis provides a novel technology with which to evaluate the overall properties of a complex system. This review highlights the means by which we scientifically measure variation, including analyses of overall variation (time domain analysis, frequency distribution, spectral power), frequency contribution (spectral analysis), scale invariant (fractal) behaviour (detrended fluctuation and power law analysis) and regularity (approximate and multiscale entropy). Each technique is presented with a definition, interpretation, clinical application, advantages, limitations and summary of its calculation. The ubiquitous association between altered variability and illness is highlighted, followed by an analysis of how variability analysis may significantly improve prognostication of severity of illness and guide therapeutic intervention in critically ill patients

Wearable and Nearable Biosensors and Systems for Healthcare

Biosensors and systems in the form of wearables and “nearables” (i.e., everyday sensorized objects with transmitting capabilities such as smartphones) are rapidly evolving for use in healthcare. Unlike conventional approaches, these technologies can enable seamless or on-demand physiological monitoring, anytime and anywhere. Such monitoring can help transform healthcare from the current reactive, one-size-fits-all, hospital-centered approach into a future proactive, personalized, decentralized structure. Wearable and nearable biosensors and systems have been made possible through integrated innovations in sensor design, electronics, data transmission, power management, and signal processing. Although much progress has been made in this field, many open challenges for the scientific community remain, especially for those applications requiring high accuracy. This book contains the 12 papers that constituted a recent Special Issue of Sensors sharing the same title. The aim of the initiative was to provide a collection of state-of-the-art investigations on wearables and nearables, in order to stimulate technological advances and the use of the technology to benefit healthcare. The topics covered by the book offer both depth and breadth pertaining to wearable and nearable technology. They include new biosensors and data transmission techniques, studies on accelerometers, signal processing, and cardiovascular monitoring, clinical applications, and validation of commercial devices

QUANTITATIVE IMAGING FOR PRECISION MEDICINE IN HEAD AND NECK CANCER PATIENTS

The purpose of this work was to determine if prediction models using quantitative imaging measures in head and neck squamous cell carcinoma (HNSCC) patients could be improved when noise due to imaging was reduced. This was investigated separately for salivary gland function using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), overall survival using computed tomography (CT)-based radiomics, and overall survival using positron emission tomography (PET)-based radiomics. From DCE-MRI, where T1-weighted images are serially acquired after injection of contrast, quantitative measures of diffusion can be obtained from the series of images. Radiomics is the study of the relationship of voxels to one another providing measures of texture from the area of interest. Quantitative information obtained from imaging could help in radiation treatment planning by providing quantifiable spatial information with computational models for assigning dose to regions to improve patient outcome, both survival and quality of life. By reducing the noise within the quantitative data, the prediction accuracy could improve to move this type of work closer to clinical practice. For each imaging modality sources of noise that could impact the patient analysis were identified, quantified, and if possible minimized during the patient analysis. In MRI, a large potential source of uncertainty was the image registration. To evaluate this, both physical and synthetic phantoms were used, which showed that registration of MR images was high, with all root mean square errors below 3 mm. Then, 15 HNSCC patients with pre-, mid-, and post-treatment DCE-MRI scans were evaluated. However, differences in algorithm output were found to be a large source of noise as different algorithms could not consistently rank patients as above or below the median for quantitative metrics from DCE-MRI. Therefore, further analysis using this modality was not pursued. In CT, a large potential source of noise that could impact patient analysis was the inter-scanner variability. To investigate this a controlled protocol was designed and used to image, along with the local head and chest protocols, a radiomics phantom on 100 CT scanners. This demonstrated that the inter-scanner variability could be reduced by over 50% using a controlled protocol compared to local protocols. Additionally, it was shown that the reconstruction parameters impact feature values while most acquisition parameters do not, therefore, most of this benefit can be achieved using a radiomics reconstruction with no additional dose to the patient. Then to evaluate this impact in patient studies, 726 HNSCC patients with CT images were used to create and test a Cox proportional hazards model for overall survival. Those patients with the same imaging protocol were subset and a new Cox proportional hazards model was created and tested in order to determine if the reduction in noise due to controlling the imaging protocol translated into improved prediction. However, noise between patient populations from different institutions was shown to be larger than the reduction in noise due to a controlled imaging protocol. In PET, a large potential source of noise that could impact patient analysis was the imaging protocol. A phantom scanned on three different scanners and vendors demonstrated that on a single vendor, imaging parameter choices did not affect radiomics feature values, but inter-scanner variances could be large. Then, 686 HNSCC patients with PET images were used to create and test a Cox proportional hazards model for overall survival. Those patients with the same imaging protocol were subset and a new Cox proportional hazards model was created and tested in order to determine if the reduction in noise due to controlling the imaging protocol on a vendor translated into improved prediction. However, no predictive radiomics signature could be determined for any subset of the patient cohort that resulted in significant stratification of patients into high and low risk. This study demonstrated that the imaging variability could be quantified and controlled for in each modality. However, for each modality there were larger sources of noise identified that did not allow for improvement in prediction modeling of salivary gland function or overall survival using quantitative imaging metrics for MRI, CT, or PET

Models and Analysis of Vocal Emissions for Biomedical Applications

The International Workshop on Models and Analysis of Vocal Emissions for Biomedical Applications (MAVEBA) came into being in 1999 from the particularly felt need of sharing know-how, objectives and results between areas that until then seemed quite distinct such as bioengineering, medicine and singing. MAVEBA deals with all aspects concerning the study of the human voice with applications ranging from the neonate to the adult and elderly. Over the years the initial issues have grown and spread also in other aspects of research such as occupational voice disorders, neurology, rehabilitation, image and video analysis. MAVEBA takes place every two years always in Firenze, Italy. This edition celebrates twenty years of uninterrupted and succesfully research in the field of voice analysis

Automatic Pain Assessment by Learning from Multiple Biopotentials

Kivun täsmällinen arviointi on tärkeää kivunhallinnassa, erityisesti sairaan- hoitoa vaativille ipupotilaille. Kipu on subjektiivista, sillä se ei ole pelkästään aistituntemus, vaan siihen saattaa liittyä myös tunnekokemuksia. Tällöin itsearviointiin perustuvat kipuasteikot ovat tärkein työkalu, niin auan kun potilas pystyy kokemuksensa arvioimaan. Arviointi on kuitenkin haasteellista potilailla, jotka eivät itse pysty kertomaan kivustaan. Kliinisessä hoito- työssä kipua pyritään objektiivisesti arvioimaan esimerkiksi havainnoimalla fysiologisia muuttujia kuten sykettä ja käyttäytymistä esimerkiksi potilaan kasvonilmeiden perusteella. Tutkimuksen päätavoitteena on automatisoida arviointiprosessi hyödyntämällä koneoppimismenetelmiä yhdessä biosignaalien prosessointnin kanssa. Tavoitteen saavuttamiseksi mitattiin autonomista keskushermoston toimintaa kuvastavia biopotentiaaleja: sydänsähkökäyrää, galvaanista ihoreaktiota ja kasvolihasliikkeitä mittaavaa lihassähkökäyrää. Mittaukset tehtiin terveillä vapaaehtoisilla, joille aiheutettiin kokeellista kipuärsykettä. Järestelmän kehittämiseen tarvittavaa tietokantaa varten rakennettiin biopotentiaaleja keräävä Internet of Things -pohjainen tallennusjärjestelmä. Koostetun tietokannan avulla kehitettiin biosignaaleille prosessointimenetelmä jatku- vaan kivun arviointiin. Signaaleista eroteltiin piirteitä sekuntitasoon mukautetuilla aikaikkunoilla. Piirteet visualisoitiin ja tarkasteltiin eri luokittelijoilla kivun ja kiputason tunnistamiseksi. Parhailla luokittelumenetelmillä saavutettiin kivuntunnistukseen 90% herkkyyskyky (sensitivity) ja 84% erottelukyky (specificity) ja kivun voimakkuuden arviointiin 62,5% tarkkuus (accuracy). Tulokset vahvistavat kyseisen käsittelytavan käyttökelpoisuuden erityis- esti tunnistettaessa kipua yksittäisessä arviointi-ikkunassa. Tutkimus vahvistaa biopotentiaalien avulla kehitettävän automatisoidun kivun arvioinnin toteutettavuuden kokeellisella kivulla, rohkaisten etenemään todellisen kivun tutkimiseen samoilla menetelmillä. Menetelmää kehitettäessä suoritettiin lisäksi vertailua ja yhteenvetoa automaattiseen kivuntunnistukseen kehitettyjen eri tutkimusten välisistä samankaltaisuuksista ja eroista. Tarkastelussa löytyi signaalien eroavaisuuksien lisäksi tutkimusmuotojen aiheuttamaa eroa arviointitavoitteisiin, mikä hankaloitti tutkimusten vertailua. Lisäksi pohdit- tiin mitkä perinteisten prosessointitapojen osiot rajoittavat tai edistävät ennustekykyä ja miten, sekä tuoko optimointi läpimurtoa järjestelmän näkökulmasta.Accurate pain assessment plays an important role in proper pain management, especially among hospitalized people experience acute pain. Pain is subjective in nature which is not only a sensory feeling but could also combine affective factors. Therefore self-report pain scales are the main assessment tools as long as patients are able to self-report. However, it remains a challenge to assess the pain from the patients who cannot self-report. In clinical practice, physiological parameters like heart rate and pain behaviors including facial expressions are observed as empirical references to infer pain objectively. The main aim of this study is to automate such process by leveraging machine learning methods and biosignal processing. To achieve this goal, biopotentials reflecting autonomic nervous system activities including electrocardiogram and galvanic skin response, and facial expressions measured with facial electromyograms were recorded from healthy volunteers undergoing experimental pain stimulus. IoT-enabled biopotential acquisition systems were developed to build the database aiming at providing compact and wearable solutions. Using the database, a biosignal processing flow was developed for continuous pain estimation. Signal features were extracted with customized time window lengths and updated every second. The extracted features were visualized and fed into multiple classifiers trained to estimate the presence of pain and pain intensity separately. Among the tested classifiers, the best pain presence estimating sensitivity achieved was 90% (specificity 84%) and the best pain intensity estimation accuracy achieved was 62.5%. The results show the validity of the proposed processing flow, especially in pain presence estimation at window level. This study adds one more piece of evidence on the feasibility of developing an automatic pain assessment tool from biopotentials, thus providing the confidence to move forward to real pain cases. In addition to the method development, the similarities and differences between automatic pain assessment studies were compared and summarized. It was found that in addition to the diversity of signals, the estimation goals also differed as a result of different study designs which made cross dataset comparison challenging. We also tried to discuss which parts in the classical processing flow would limit or boost the prediction performance and whether optimization can bring a breakthrough from the system’s perspective

Noninvasive autonomic nervous system assessment in respiratory disorders and sport sciences applications

La presente tesis está centrada en el análisis no invasivo de señales cardíacas y respiratorias, con el objetivo de evaluar la actividad del sistema nervioso autónomo (ANS) en diferentes escenarios, tanto clínicos como no clínicos. El documento está estructurado en tres partes principales. La primera parte consiste en una introducción a los aspectos fisiológicos y metodológicos que serán cubiertos en el resto de la tesis. En la segunda parte, se analiza la variabilidad del ritmo cardiaco (HRV) en el contexto de enfermedades respiratorias, concretamente asma (tanto en niños como en adultos) y apnea del sueño. En la tercera parte, se estudian algunas aplicaciones novedosas del análisis de señales cardiorespiratorias en el campo de las ciencias del deporte. La primera parte está compuesta por los capítulos 1 y 2. El capítulo 1 consiste en una extensa introducción al funcionamiento del sistema nervioso autónomo y las características de las bioseñales analizadas a lo largo de la tesis. Por otro lado, se aborda la patofisiología del asma y la apnea del sueño, su relación con el funcionamiento del ANS y las estrategias de diagnóstico y tratamiento de lasmismas. El capítulo concluye con una introducción a la fisiología del ejercicio, así como al interés en la estimación del volumen tidal y del umbral anaeróbico en el campo de las ciencias del deporte.En cuanto al capítulo 2, se presenta un marco de trabajo para el análisis contextualizado de la HRV. Después de una descripción de las técnicas de evaluación y acondicionamiento de la señal de HRV, el capítulo se centra en el efecto de los latidos ectópicos, la arritmia sinusal respiratoria y la frecuencia respiratoria en el análisis de la HRV.Además, se discute el uso de un índice para la evaluación de la distribución de la potencia en los espectros de HRV, así como diferentes medidas de acoplo cardiorespiratorio.La segunda parte está compuesta por los capítulos 3, 4 y 5, todos ellos relacionados con el análisis de la HRV en enfermedades respiratorias. Mientras que los capítulos 3 y 4 están centrados en asma infantil y en adultos respectivamente, el capítulo 5 aborda la apnea del sueño. El asma es una enfermedad respiratoria crónica que aparece habitualmente acompañada por una inflamación de las vías respiratorias. Aunque afecta a personas detodas las edades, normalmente se inicia en edades tempranas, y ha llegado a constituir una de las enfermedades crónicasmás comunes durante la infancia. Sin embargo, todavía no existe un método adecuado para el diagnóstico de asma en niños pequeños. Por otro lado, el rol fundamental que desempeña el sistema nervioso parasimpático en el control del tono bronco-motor y la bronco-dilatación sugiere que la rama parasimpática del ANS podría estar implicada en la patogénesis del asma. De estemodo, en el capítulo 3 se evalúa el ANS mediante el análisis de la HRV en dos bases de datos diferentes, compuestas por niños en edad pre-escolar clasificados en función de su riesgo de desarrollar asma, o de su condición asmática actual. Los resultados del análisis revelaron un balance simpáticovagal reducido y una componente espectral de alta frecuencia más picuda en aquellos niños con un mayor riesgo de desarrollar asma. Además, la actividad parasimpática y el acoplo cardiorespiratorio se redujeron en un grupo de niños con bajo riesgo de asma al finalizar un tratamiento para bronquitis obstructiva, mientras que estos permanecieron inalterados en aquellos niños con una peor prógnosis.A diferencia de los niños pequeños, en el caso de adultos el diagnóstico de asma se realiza a través de una rutina clínica bien definida. Sin embargo, la estratificación de los pacientes en función de su grado de control de los síntomas se basa generalmente en el uso de cuestionarios auto-aplicados, que pueden tener un carácter subjetivo. Por otro lado, la evaluación de la severidad del asma requiere de una visita hospitalaria y de incómodas pruebas, que no pueden aplicarse de una forma continua en el tiempo. De este modo, en el capítulo 4 se estudia el valor de la evaluación del ANS para la estratificación de adultos asmáticos. Para ello, se emplearon diferentes características extraídas de la HRV y la respiración, junto con varios parámetros clínicos, para entrenar un conjunto de algoritmos de clasificación. La inclusión de características relacionadas con el ANS para clasificar los sujetos atendiendo a la severidad del asma derivó en resultados similares al caso de utilizar únicamente parámetros clínicos, superando el desempeño de estos últimos en algunos casos. Por lo tanto, la evaluación del ANS podría representar un potencial complemento para la mejora de la monitorización de sujetos asmáticos.En el capítulo 5, se analiza la HRV en sujetos que padecen el síndrome de apnea del sueño (SAS) y comorbididades cardíacas asociadas. El SAS se ha relacionado con un incremento de 5 veces en el riesgo de desarrollar enfermedades cardiovasculares (CVD), que podría aumentar hasta 11 veces si no se trata convenientemente. Por otro lado, una HRV alterada se ha relacionado independientemente con el SAS y con numerosos factores de riesgo para el desarrollo de CVD. De este modo, este capítulo se centra en evaluar si una actividad autónoma desbalanceada podría estar relacionada con el desarrollo de CVD en pacientes de SAS. Los resultados del análisis revelaron una dominancia simpática reducida en aquellos sujetos que padecían SAS y CVD, en comparación con aquellos sin CVD. Además, un análisis retrospectivo en una base de datos de sujetos con SAS que desarollarán CVD en el futuro también reveló una actividad simpática reducida, sugiriendo que un ANS desbalanceado podría constituir un factor de riesgo adicional para el desarrollo de CVD en pacientes de SAS.La tercera parte está formada por los capítulos 6 y 7, y está centrada en diferentes aplicaciones del análisis de señales cardiorespiratorias en el campo de las ciencias del deporte. El capítulo 6 aborda la estimación del volumen tidal (TV) a partir del electrocardiograma (ECG). A pesar de que una correcta monitorización de la actividad respiratoria es de gran interés en ciertas enfermedades respiratorias y en ciencias del deporte, la mayor parte de la actividad investigadora se ha centrado en la estimación de la frecuencia respiratoria, con sólo unos pocos estudios centrados en el TV, la mayoría de los cuales se basan en técnicas no relacionadas con el ECG. En este capítulo se propone un marco de trabajo para la estimación del TV en reposo y durante una prueba de esfuerzo en tapiz rodante utilizando únicamente parámetros derivados del ECG. Errores de estimación del 14% en la mayoría de los casos y del 6% en algunos sugieren que el TV puede estimarse a partir del ECG, incluso en condiciones no estacionarias.Por último, en el capítulo 7 se propone una metodología novedosa para la estimación del umbral anaeróbico (AT) a partir del análisis de las dinámicas de repolarización ventricular. El AT representa la frontera a partir de la cual el sistema cardiovascular limita la actividad física de resistencia, y aunque fue inicialmente concebido para la evaluación de la capacidad física de pacientes con CVD, también resulta de gran interés en el campo de las ciencias del deporte, permitiendo diseñar mejores rutinas de entrenamiento o para prevenir el sobre-entrenamiento. Sin embargo, la evaluación del AT requiere de técnicas invasivas o de dispositivos incómodos. En este capítulo, el AT fue estimado a partir del análisis de las variaciones de las dinámicas de repolarización ventricular durante una prueba de esfuerzo en cicloergómetro. Errores de estimación de 25 W, correspondientesa 1 minuto en este estudio, en un 63% de los sujetos (y menores que 50 W en un 74% de ellos) sugieren que el AT puede estimarse de manera no invasiva, utilizando únicamente registros de ECG.<br /

Symbolic Dynamics Analysis: a new methodology for foetal heart rate variability analysis

Cardiotocography (CTG) is a widespread foetal diagnostic methods. However, it lacks of objectivity and reproducibility since its dependence on observer's expertise. To overcome these limitations, more objective methods for CTG interpretation have been proposed. In particular, many developed techniques aim to assess the foetal heart rate variability (FHRV). Among them, some methodologies from nonlinear systems theory have been applied to the study of FHRV. All the techniques have proved to be helpful in specific cases. Nevertheless, none of them is more reliable than the others. Therefore, an in-depth study is necessary. The aim of this work is to deepen the FHRV analysis through the Symbolic Dynamics Analysis (SDA), a nonlinear technique already successfully employed for HRV analysis. Thanks to its simplicity of interpretation, it could be a useful tool for clinicians. We performed a literature study involving about 200 references on HRV and FHRV analysis; approximately 100 works were focused on non-linear techniques. Then, in order to compare linear and non-linear methods, we carried out a multiparametric study. 580 antepartum recordings of healthy fetuses were examined. Signals were processed using an updated software for CTG analysis and a new developed software for generating simulated CTG traces. Finally, statistical tests and regression analyses were carried out for estimating relationships among extracted indexes and other clinical information. Results confirm that none of the employed techniques is more reliable than the others. Moreover, in agreement with the literature, each analysis should take into account two relevant parameters, the foetal status and the week of gestation. Regarding the SDA, results show its promising capabilities in FHRV analysis. It allows recognizing foetal status, gestation week and global variability of FHR signals, even better than other methods. Nevertheless, further studies, which should involve even pathological cases, are necessary to establish its reliability.La Cardiotocografia (CTG) è una diffusa tecnica di diagnostica fetale. Nonostante ciò, la sua interpretazione soffre di forte variabilità intra- e inter- osservatore. Per superare tali limiti, sono stati proposti più oggettivi metodi di analisi. Particolare attenzione è stata rivolta alla variabilità della frequenza cardiaca fetale (FHRV). Nel presente lavoro abbiamo suddiviso le tecniche di analisi della FHRV in tradizionali, o lineari, e meno convenzionali, o non-lineari. Tutte si sono rivelate efficaci in casi specifici ma nessuna si è dimostrata più utile delle altre. Pertanto, abbiamo ritenuto necessario effettuare un’indagine più dettagliata. In particolare, scopo della tesi è stato approfondire una specifica metodologia non-lineare, la Symbolic Dynamics Analysis (SDA), data la sua notevole semplicità di interpretazione che la renderebbe un potenziale strumento di ausilio all’attività clinica. Sono stati esaminati all’incirca 200 riferimenti bibliografici sull’analisi di HRV e FHRV; di questi, circa 100 articoli specificamente incentrati sulle tecniche non-lineari. E’ stata condotta un’analisi multiparametrica su 580 tracciati CTG di feti sani per confrontare le metodologie adottate. Sono stati realizzati due software, uno per l’analisi dei segnali CTG reali e l’altro per la generazione di tracciati CTG simulati. Infine, sono state effettuate analisi statistiche e di regressione per esaminare le correlazioni tra indici calcolati e parametri di interesse clinico. I risultati dimostrano che nessuno degli indici calcolati risulta più vantaggioso rispetto agli altri. Inoltre, in accordo con la letteratura, lo stato del feto e le settimane di gestazione sono parametri di riferimento da tenere sempre in considerazione per ogni analisi effettuata. Riguardo la SDA, essa risulta utile all’analisi della FHRV, permettendo di distinguere – meglio o al pari di altre tecniche – lo stato del feto, la settimana di gestazione e la variabilità complessiva del segnale. Tuttavia, sono necessari ulteriori studi, che includano anche casi di feti patologici, per confermare queste evidenze

The 2023 wearable photoplethysmography roadmap

Photoplethysmography is a key sensing technology which is used in wearable devices such as smartwatches and fitness trackers. Currently, photoplethysmography sensors are used to monitor physiological parameters including heart rate and heart rhythm, and to track activities like sleep and exercise. Yet, wearable photoplethysmography has potential to provide much more information on health and wellbeing, which could inform clinical decision making. This Roadmap outlines directions for research and development to realise the full potential of wearable photoplethysmography. Experts discuss key topics within the areas of sensor design, signal processing, clinical applications, and research directions. Their perspectives provide valuable guidance to researchers developing wearable photoplethysmography technology