Nonlinear Stochastic Modeling and Analysis of Cardiovascular System Dynamics - Diagnostic and Prognostic Applications

The purpose of this investigation is to develop monitoring, diagnostic and prognostic schemes for cardiovascular diseases by studying the nonlinear stochastic dynamics underlying complex heart system. The employment of a nonlinear stochastic analysis combined with wavelet representations can extract effective cardiovascular features, which will be more sensitive to the pathological dynamics instead of the extraneous noises. While conventional statistical and linear systemic approaches have limitations for capturing signal variations resulting from changes in the cardiovascular system states. The research methodology includes signal representation using optimal wavelet function design, feature extraction using nonlinear recurrence analysis, and local recurrence modeling for state prediction.Industrial Engineering & Managemen

Computational Analysis of Complex Beat-to-Beat Dynamics in Heart Cells

Contrary to the popular belief that the heart maintains a regular rhythm, healthy heartbeats fluctuate in a chaotic way. We now know that the fluctuations do not display uncorrelated randomness, but they contain long-range correlations and can be characterized by a fractal. This behavior supports the adaptability of the heart and may thus protect it from external stress. The fractal complexity is also found in the smallest parts of the heart: the cells. In the dawn of advanced pluripotent stem cell technology, producing independently beating cardiomyocytes in a laboratory, the beat-rate fluctuations of heart cells can be directly studied. In this thesis, we investigate the complex fluctuations in the field potentials generated by clusters of human cardiomyocytes. We show that the heart cells exhibit similar correlation properties in the beat-to-beat intervals and field potential durations comparable to RR and QT intervals, i.e., time between consecutive R waves and time from Q wave to the end of T wave, respectively, in an electrocardiogram of a heart. The cells are studied under conditions resembling real-life situations such as cardiac disorders, application of cardioactive drugs, and injuries. The results show significant alteration of the scaling properties in the beat rates, reflecting the changes in the intrinsic mechanism at the cellular level. By employing a set of nonlinear time series analysis tools, we explore their powerful applicability as well as their limitations. Our main method of choice throughout the work is detrended fluctuation analysis, which is designed to detect the degree of correlation in nonstationary time series. We demonstrate that detrended fluctuation analysis and its extensions are extremely useful in dealing with the field potential data of the heart cells despite the presence of abnormalities and irregular trends. The study of heartbeat dynamics at the cellular level using computational methods has important advantages. In particular, the methods provide non-invasive and versatile ways to improve our understanding of the intrinsic firing patterns of the heart cells, which play a crucial role in the future applications of in vitro human cardiomyocytes

Multidimensional embedded MEMS motion detectors for wearable mechanocardiography and 4D medical imaging

Background: Cardiovascular diseases are the number one cause of death. Of these deaths, almost 80% are due to coronary artery disease (CAD) and cerebrovascular disease. Multidimensional microelectromechanical systems (MEMS) sensors allow measuring the mechanical movement of the heart muscle offering an entirely new and innovative solution to evaluate cardiac rhythm and function. Recent advances in miniaturized motion sensors present an exciting opportunity to study novel device-driven and functional motion detection systems in the areas of both cardiac monitoring and biomedical imaging, for example, in computed tomography (CT) and positron emission tomography (PET). Methods: This Ph.D. work describes a new cardiac motion detection paradigm and measurement technology based on multimodal measuring tools — by tracking the heart’s kinetic activity using micro-sized MEMS sensors — and novel computational approaches — by deploying signal processing and machine learning techniques—for detecting cardiac pathological disorders. In particular, this study focuses on the capability of joint gyrocardiography (GCG) and seismocardiography (SCG) techniques that constitute the mechanocardiography (MCG) concept representing the mechanical characteristics of the cardiac precordial surface vibrations. Results: Experimental analyses showed that integrating multisource sensory data resulted in precise estimation of heart rate with an accuracy of 99% (healthy, n=29), detection of heart arrhythmia (n=435) with an accuracy of 95-97%, ischemic disease indication with approximately 75% accuracy (n=22), as well as significantly improved quality of four-dimensional (4D) cardiac PET images by eliminating motion related inaccuracies using MEMS dual gating approach. Tissue Doppler imaging (TDI) analysis of GCG (healthy, n=9) showed promising results for measuring the cardiac timing intervals and myocardial deformation changes. Conclusion: The findings of this study demonstrate clinical potential of MEMS motion sensors in cardiology that may facilitate in time diagnosis of cardiac abnormalities. Multidimensional MCG can effectively contribute to detecting atrial fibrillation (AFib), myocardial infarction (MI), and CAD. Additionally, MEMS motion sensing improves the reliability and quality of cardiac PET imaging.Moniulotteisten sulautettujen MEMS-liiketunnistimien käyttö sydänkardiografiassa sekä lääketieteellisessä 4D-kuvantamisessa Tausta: Sydän- ja verisuonitaudit ovat yleisin kuolinsyy. Näistä kuolemantapauksista lähes 80% johtuu sepelvaltimotaudista (CAD) ja aivoverenkierron häiriöistä. Moniulotteiset mikroelektromekaaniset järjestelmät (MEMS) mahdollistavat sydänlihaksen mekaanisen liikkeen mittaamisen, mikä puolestaan tarjoaa täysin uudenlaisen ja innovatiivisen ratkaisun sydämen rytmin ja toiminnan arvioimiseksi. Viimeaikaiset teknologiset edistysaskeleet mahdollistavat uusien pienikokoisten liiketunnistusjärjestelmien käyttämisen sydämen toiminnan tutkimuksessa sekä lääketieteellisen kuvantamisen, kuten esimerkiksi tietokonetomografian (CT) ja positroniemissiotomografian (PET), tarkkuuden parantamisessa. Menetelmät: Tämä väitöskirjatyö esittelee uuden sydämen kineettisen toiminnan mittaustekniikan, joka pohjautuu MEMS-anturien käyttöön. Uudet laskennalliset lähestymistavat, jotka perustuvat signaalinkäsittelyyn ja koneoppimiseen, mahdollistavat sydämen patologisten häiriöiden havaitsemisen MEMS-antureista saatavista signaaleista. Tässä tutkimuksessa keskitytään erityisesti mekanokardiografiaan (MCG), joihin kuuluvat gyrokardiografia (GCG) ja seismokardiografia (SCG). Näiden tekniikoiden avulla voidaan mitata kardiorespiratorisen järjestelmän mekaanisia ominaisuuksia. Tulokset: Kokeelliset analyysit osoittivat, että integroimalla usean sensorin dataa voidaan mitata syketiheyttä 99% (terveillä n=29) tarkkuudella, havaita sydämen rytmihäiriöt (n=435) 95-97%, tarkkuudella, sekä havaita iskeeminen sairaus noin 75% tarkkuudella (n=22). Lisäksi MEMS-kaksoistahdistuksen avulla voidaan parantaa sydämen 4D PET-kuvan laatua, kun liikeepätarkkuudet voidaan eliminoida paremmin. Doppler-kuvantamisessa (TDI, Tissue Doppler Imaging) GCG-analyysi (terveillä, n=9) osoitti lupaavia tuloksia sydänsykkeen ajoituksen ja intervallien sekä sydänlihasmuutosten mittaamisessa. Päätelmä: Tämän tutkimuksen tulokset osoittavat, että kardiologisilla MEMS-liikeantureilla on kliinistä potentiaalia sydämen toiminnallisten poikkeavuuksien diagnostisoinnissa. Moniuloitteinen MCG voi edistää eteisvärinän (AFib), sydäninfarktin (MI) ja CAD:n havaitsemista. Lisäksi MEMS-liiketunnistus parantaa sydämen PET-kuvantamisen luotettavuutta ja laatua

Pulse Rate Variability for the Assessment of Cardiovascular Changes

Pulse rate variability (PRV) describes the way pulse rate changes through time and is measured from pulsatile signals such as the photoplethysmogram (PPG). It has been proposed as a surrogate for heart rate variability (HRV). Nonetheless, the relationship between these variables is not entirely clear, probably due to both physiological and technical aspects involved in the extraction of PRV. Moreover, the effects of cardiovascular changes on PRV have not been elucidated. In this thesis, four studies were performed to (1) determine the best combination of some technical aspects for the extraction of PRV from PPG signals; (2) evaluate the relationship between PRV and HRV under different cardiovascular conditions; and (3) explore the effects of cardiovascular changes on PRV. First, PRV extraction gave lower errors when (1) signals were acquired for at least 120 s with a 256 Hz sampling rate and filtered with lower low cut-off frequencies and elliptic, equiripple or Parks-McClellan filter; (2) cardiac cycles were determined using the D2max algorithm and the a fiducial points; and (3) the Fast Fourier Transform was applied to obtain frequency spectra. Secondly, the relationship between HRV and PRV was found to be affected by cold exposure and changes in blood pressure, while PRV was found to be different at different body sites. Finally, PRV was affected by haemodynamic changes, such as target flow, stroke rate and blood pressure, both in an in-vitro model and in-vivo data. Additionally, PRV was found to be a potential tool for the estimation of blood pressure, with errors as low as 1:54 ± 0:17 mmHg, 1:07 ± 0:06 mmHg and 1:22 ± 0:09 mmHg for the estimation of systolic, diastolic and mean arterial pressure. Although more studies are needed to fully understand PRV and its clinical potential, PRV should not be regarded as the same as HRV, and it could be consider as a potential valuable biomarker for cardiovascular health

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

From Ecological Epitome to Medical Model: An investigation into Applications for the use of Daphnia in Heart Science.

The primary aim of this research was to determine whether Daphnia might become a model for cardiovascular concentration-response trials. This would provide a high throughput means of testing cardiac therapeutics without resort to small mammal trials. We found Daphnia are inappropriate in this context due to high population variance and sensitivity to small, subtle, environmental changes. A new aim was developed to determine whether beat-to-beat variation could be correlated with an individual’s response to toxic insult. Further, to develop more accurate and efficient means of gathering heart rhythm data by recording heart movement from whole live Daphnia. This opens the way to individualising cardio therapeutics; by correlating the stability of individual hearts with response to cardiac insult, regression analysis provides a means of finding a prediction tool. Daphnia are a convenient example here, but successful scoring systems might also be applied to the human heart via analysis of ECG readouts. Collecting signals from whole live Daphnia did not fulfil the goal of gathering heart data as this instead recorded limb movement. However, this provides a means of improving toxicology testing in aquatic ecology. This thesis offers three contributions to knowledge: 1. Daphnia are an inappropriate model for cardiovascular therapeutic dose-response trials due to extreme environmental sensitivities. 2. Baseline heart rhythm can be correlated with paired response to cardiac insult, with significance at the 0.01 alpha level, using an adjusted version of the Lyapnov equation; Finite Time Growth (Wessel, 2010). However, this is only if population variation is adequate. It is better applied to a natural in situ population than a homegenic lab population. 3. A novel technique for measuring Daphnia electromechanical movement records feeding limbs rather than the heart. This offers a novel and more efficient technique for aquatic ecotoxicology, where visual observation or films of the same are currently used

Advanced analyses of physiological signals and their role in Neonatal Intensive Care

Preterm infants admitted to the neonatal intensive care unit (NICU) face an array of life-threatening diseases requiring procedures such as resuscitation and invasive monitoring, and other risks related to exposure to the hospital environment, all of which may have lifelong implications. This thesis examined a range of applications for advanced signal analyses in the NICU, from identifying of physiological patterns associated with neonatal outcomes, to evaluating the impact of certain treatments on physiological variability. Firstly, the thesis examined the potential to identify infants at risk of developing intraventricular haemorrhage, often interrelated with factors leading to preterm birth, mechanical ventilation, hypoxia and prolonged apnoeas. This thesis then characterised the cardiovascular impact of caffeine therapy which is often administered to prevent and treat apnoea of prematurity, finding greater pulse pressure variability and enhanced responsiveness of the autonomic nervous system. Cerebral autoregulation maintains cerebral blood flow despite fluctuations in arterial blood pressure and is an important consideration for preterm infants who are especially vulnerable to brain injury. Using various time and frequency domain correlation techniques, the thesis found acute changes in cerebral autoregulation of preterm infants following caffeine therapy. Nutrition in early life may also affect neurodevelopment and morbidity in later life. This thesis developed models for identifying malnutrition risk using anthropometry and near-infrared interactance features. This thesis has presented a range of ways in which advanced analyses including time series analysis, feature selection and model development can be applied to neonatal intensive care. There is a clear role for such analyses in early detection of clinical outcomes, characterising the effects of relevant treatments or pathologies and identifying infants at risk of later morbidity

Methods and techniques for analyzing human factors facets on drivers

Mención Internacional en el título de doctorWith millions of cars moving daily, driving is the most performed activity worldwide. Unfortunately, according to the World Health Organization (WHO), every year, around 1.35 million people worldwide die from road traffic accidents and, in addition, between 20 and 50 million people are injured, placing road traffic accidents as the second leading cause of death among people between the ages of 5 and 29. According to WHO, human errors, such as speeding, driving under the influence of drugs, fatigue, or distractions at the wheel, are the underlying cause of most road accidents. Global reports on road safety such as "Road safety in the European Union. Trends, statistics, and main challenges" prepared by the European Commission in 2018 presented a statistical analysis that related road accident mortality rates and periods segmented by hours and days of the week. This report revealed that the highest incidence of mortality occurs regularly in the afternoons during working days, coinciding with the period when the volume of traffic increases and when any human error is much more likely to cause a traffic accident. Accordingly, mitigating human errors in driving is a challenge, and there is currently a growing trend in the proposal for technological solutions intended to integrate driver information into advanced driving systems to improve driver performance and ergonomics. The study of human factors in the field of driving is a multidisciplinary field in which several areas of knowledge converge, among which stand out psychology, physiology, instrumentation, signal treatment, machine learning, the integration of information and communication technologies (ICTs), and the design of human-machine communication interfaces. The main objective of this thesis is to exploit knowledge related to the different facets of human factors in the field of driving. Specific objectives include identifying tasks related to driving, the detection of unfavorable cognitive states in the driver, such as stress, and, transversely, the proposal for an architecture for the integration and coordination of driver monitoring systems with other active safety systems. It should be noted that the specific objectives address the critical aspects in each of the issues to be addressed. Identifying driving-related tasks is one of the primary aspects of the conceptual framework of driver modeling. Identifying maneuvers that a driver performs requires training beforehand a model with examples of each maneuver to be identified. To this end, a methodology was established to form a data set in which a relationship is established between the handling of the driving controls (steering wheel, pedals, gear lever, and turn indicators) and a series of adequately identified maneuvers. This methodology consisted of designing different driving scenarios in a realistic driving simulator for each type of maneuver, including stop, overtaking, turns, and specific maneuvers such as U-turn and three-point turn. From the perspective of detecting unfavorable cognitive states in the driver, stress can damage cognitive faculties, causing failures in the decision-making process. Physiological signals such as measurements derived from the heart rhythm or the change of electrical properties of the skin are reliable indicators when assessing whether a person is going through an episode of acute stress. However, the detection of stress patterns is still an open problem. Despite advances in sensor design for the non-invasive collection of physiological signals, certain factors prevent reaching models capable of detecting stress patterns in any subject. This thesis addresses two aspects of stress detection: the collection of physiological values during stress elicitation through laboratory techniques such as the Stroop effect and driving tests; and the detection of stress by designing a process flow based on unsupervised learning techniques, delving into the problems associated with the variability of intra- and inter-individual physiological measures that prevent the achievement of generalist models. Finally, in addition to developing models that address the different aspects of monitoring, the orchestration of monitoring systems and active safety systems is a transversal and essential aspect in improving safety, ergonomics, and driving experience. Both from the perspective of integration into test platforms and integration into final systems, the problem of deploying multiple active safety systems lies in the adoption of monolithic models where the system-specific functionality is run in isolation, without considering aspects such as cooperation and interoperability with other safety systems. This thesis addresses the problem of the development of more complex systems where monitoring systems condition the operability of multiple active safety systems. To this end, a mediation architecture is proposed to coordinate the reception and delivery of data flows generated by the various systems involved, including external sensors (lasers, external cameras), cabin sensors (cameras, smartwatches), detection models, deliberative models, delivery systems and machine-human communication interfaces. Ontology-based data modeling plays a crucial role in structuring all this information and consolidating the semantic representation of the driving scene, thus allowing the development of models based on data fusion.I would like to thank the Ministry of Economy and Competitiveness for granting me the predoctoral fellowship BES-2016-078143 corresponding to the project TRA2015-63708-R, which provided me the opportunity of conducting all my Ph. D activities, including completing an international internship.Programa de Doctorado en Ciencia y Tecnología Informática por la Universidad Carlos III de MadridPresidente: José María Armingol Moreno.- Secretario: Felipe Jiménez Alonso.- Vocal: Luis Mart