Invasive and non-invasive assessment of upper airway obstruction and respiratory effort with nasal airflow and esophageal pressure analysis during sleep

La estimación del esfuerzo respiratorio durante el sueño es de una importancia crítica para la identificación correcta de eventos respiratorios en los trastornos respiratorios del sueño (TRS), el diagnóstico correcto de las patologías relacionadas con los TRS y las decisiones sobre la terapia correspondiente. Hoy en día el esfuerzo respiratorio suele ser estimado mediante la polisomnografía (PSG) nocturna con técnicas imprecisas y mediante la evaluación manual por expertos humanos, lo cual es un proceso laborioso que conlleva limitaciones significativas y errores en la clasificación. El objetivo principal de esta tesis es la presentación de nuevos métodos para la estimación automático, invasiva y no-invasiva del esfuerzo respiratorio y cambios en la obstrucción de las vías aéreas superiores (VAS). En especial, la aplicación de estos métodos debería permitir, entre otras cosas, la diferenciación automática invasiva y no-invasiva de eventos centrales y obstructivos durante el sueño. Con este propósito se diseñó y se obtuvo una base de datos de PSG nocturna completamente nueva de 28 pacientes con medición sistemática de presión esofágica (Pes). La Pes está actualmente considerada como el gold-standard para la estimación del esfuerzo respiratorio y la identificación de eventos respiratorios en los TRS. Es sin embargo una técnica invasiva y altamente compleja, lo cual limita su uso en la rutina clínica. Esto refuerza el valor de nuestra base de datos y la dificultad que ha implicado su adquisición. Todos los métodos de procesado propuestos y desarrollados en esta tesis están consecuentemente validados con la señal gold-standard de Pes para asegurar su validez.En un primer paso, se presenta un sistema automático invasivo para la clasificación de limitaciones de flujo inspiratorio (LFI) en los ciclos inspiratorios. La LFI se ha definido como una falta de aumento en flujo respiratorio a pesar de un incremento en el esfuerzo respiratorio, lo cual suele resultar en un patrón de flujo respiratorio característico (flattening). Un total de 38,782 ciclos respiratorios fueron automáticamente extraídos y analizados. Se propone un modelo exponencial que reproduzca la relación entre Pes y flujo respiratorio de una inspiración y permita la estimación objetiva de cambios en la obstrucción de las VAS. La capacidad de caracterización del modelo se estima mediante tres parámetros de evaluación: el error medio cuadrado en la estimación de la resistencia en la presión pico, el coeficiente de determinación y la estimación de episodios de LFI. Los resultados del modelo son comparados a los de los dos mejores modelos en la literatura. Los resultados finales indican que el modelo exponencial caracteriza la LFI y estima los niveles de obstrucción de las VAS con la mayor exactitud y objetividad. Las anotaciones gold-standard de LFI obtenidas, fueron utilizadas para entrenar, testear y validar un nuevo clasificador automático y no-invasivo de LFI basa en la señal de flujo respiratorio nasal. Se utilizaron las técnicas de Discriminant Analysis, Support Vector Machines y Adaboost para la clasificación no-invasiva de inspiraciones con las características extraídas de los dominios temporales y espectrales de los patrones de flujo inspiratorios. Este nuevo clasificador automático no-invasivo también identificó exitosamente los episodios de LFI, alcanzando una sensibilidad de 0.87 y una especificidad de 0.85. La diferenciación entre eventos respiratorios centrales y obstructivos es una de las acciones más recurrentes en el diagnostico de los TRS. Sin embargo únicamente la medición de Pes permite la diferenciación gold-standard de este tipo de eventos. Recientemente se han propuesto nuevas técnicas para la diferenciación no-invasiva de apneas e hipopneas. Sin embargo su adopción ha sido lenta debido a su limitada validación clínica, ya que la creación manual por expertos humanos de sets gold-standard de validación representa un trabajo laborioso. En esta tesis se propone un nuevo sistema para la diferenciación gold-standard automática y objetiva entre hipopneas obstructivas y centrales. Expertos humanos clasificaron manualmente un total de 769 hypopneas en 28 pacientes para crear un set de validación gold-standard. Como siguiente paso se extrajeron características específicas de cada hipopnea para entrenar y testear clasificadores (Discriminant Analysis, Support Vector Machines y adaboost) para diferenciar entre hipopneas centrales y obstructivas mediante la señal gold-standard Pes. El sistema de diferenciación automática alcanzó resultados prometedores, obteniendo una sensibilidad, una especificad y una exactitud de 0.90. Por lo tanto este sistema parece prometedor para la diferenciación automática, gold-standard de hipopneas centrales y obstructivas. Finalmente se propone un sistema no-invasivo para la diferenciación automática de hipopneas centrales y obstructivas. Se propone utilizar la señal de flujo respiratorio para la diferenciación utilizando características de los ciclos inspiratorios de cada hipopnea, entre ellos los patrones flattening. Este sistema automático no-invasivo es una combinación de los sistemas anteriormente presentados y se valida mediante las anotaciones gold-standard obtenidas mediante la señal de Pes por expertos humanos. Los resultados de este sistema son comparados a los resultados obtenidos por expertos humanos que utilizaron un nuevo algoritmo no-invasivo para la diferenciación manual de hipopneas. Los resultados del sistema automático no-invasivo son prometedores y muestran la viabilidad de la metodología empleada. Una vez haya sido validado extensivamente, se ha propuesto este algoritmo para su utilización en dispositivos de terapia de TRS desarrollados por uno de los socios cooperantes en este proyecto.The assessment of respiratory effort during sleep is of major importance for the correct identification of respiratory events in sleep-disordered breathing (SDB), the correct diagnosis of SDB-related pathologies and the consequent choice of treatment. Currently, respiratory effort is usually assessed in night polysomnography (NPSG) with imprecise techniques and manually evaluated by human experts, resulting in a laborious task with significant limitations and missclassifications.The main objective of this thesis is to present new methods for the automatic, invasive and non-invasive assessment of respiratory effort and changes in upper airway (UA) obstruction. Specifically, the application of these methods should, in between others, allow the automatic invasive and non-invasive differentiation of obstructive and central respiratory events during sleep.For this purpose, a completely new NPSG database consisting of 28 patients with systematic esophageal pressure (Pes) measurement was acquired. Pes is currently considered the gold-standard to assess respiratory effort and identify respiratory events in SDB. However, the invasiveness and complexity of Pes measurement prevents its use in clinical routine, underlining the importance of this new database. . . All the processing methods developed in this thesis will consequently be validated with the gold-standard Pes-signal in order to ensure their clinical validity.In a first step, an (invasive) automatic system for the classification of inspiratory flow limitation (IFL) in the inspiratory cycles is presented.IFL has been defined as a lack of increase in airflow despite increasing respiratory effort, which normally results in a characteristic inspiratory airflow pattern (flattening). A total of 38,782 breaths were extracted and automatically analyzed. An exponential model is proposed to reproduce the relationship between Pes and airflow of an inspiration and achieve an objective assessment of changes in upper airway obstruction. The characterization performance of the model is appraised with three evaluation parameters: mean-squared-error when estimating resistance at peakpressure,coefficient of determination and assessment of IFL episodes. The model's results are compared to the two best-performing models in the literature. The results indicated that the exponential model characterizes IFL and assesses levels of upper airway obstruction with the highest accuracy and objectivity.The obtained gold-standard IFL annotations were then employed to train, test and validate a new automatic, non-invasive IFL classification system by means of the nasal airflow signal. Discriminant Analysis, Support Vector Machines and Adaboost algorithms were employed to objectively classify breaths non-invasively with features extracted from the time and frequency domains of the breaths' flow patterns. The new non-invasive automatic classification system also succeeded identifying IFL episodes, achieving a sensitivity of 0.87 and a specificity of 0.85.The differentiation between obstructive and central respiratory events is one of the most recurrent tasks in the diagnosis of sleep disordered breathing, but only Pes measurement allows the gold-standard differentiation of these events. Recently new techniques have been proposed to allow the non-invasive differentiation of hypopneas. However, their adoption has been slow due to their limited clinical validation, as the creation of manual, gold-standard validation sets by human experts is a cumbersome procedure. In this study, a new system is proposed for an objective automatic, gold-standard differentiation between obstructive and central hypopneas with the esophageal pressure signal. An overall of 769 hypopneas of 28 patients were manually scored by human experts to create a gold-standard validation set. Then, features were extracted from each hypopnea to train and test classifiers (Discriminant Analysis, Support Vector Machines and adaboost classifiers) to differentiate between central and obstructive hypopneas with the gold-standard esophageal pressure signal. The automatic differentiation system achieved promising results, with a sensitivity of 0.82, a specificity of 0.87 and an accuracy of 0.85. Hence, this system seems promising for an automatic, goldstandard differentiation between obstructive and central hypopneas.Finally, a non-invasive system is proposed for the automatic differentiation of central and obstructive hypopneas. Only the airflow signal is used for the differentiation, as features of the inspiratory cycles of the hypopnea, such as the flattening patterns, is used. The automatic, non-invasive system represents a combination of the systems that have been presented before and it was validated with the gold-standard scorings obtained with the Pes-signal by human experts. The outcome is compared to the results obtained by human scorers that applied a new non-invasive algorithm for the manual differentiation of hypopneas. The non-invasive system's results are promising and show the viability of this technique. Once validated, this algorithm has been proposed to be used in therapy devices developed by one of the partner institutions cooperating in this project

Gender Differences in Obstructive Sleep Apnea

The overall aim of this thesis was to understand gender differences in obstructive sleep apnea (OSA) and use this information to develop a tailored therapy for female patients. Specific aims were to determine whether gender differences commonly reported in the literature are present in mild OSA and upper airway resistance syndrome (UARS) patient groups, and whether symptoms could be linked to respiratory parameters in these groups. The final aim was to develop, test and validate a new AutoSet treatment for female OSA patients. CHAPTER 1 of this thesis provides a detailed review of gender differences in the prevalence, symptoms, clinical experience, and health outcomes of OSA and UARS patients, with a focus on the implications of different scoring rules. CHAPTER 2 reviews of quality of life questionnaires from 259 untreated patients with mild OSA. Females reported statistically significantly higher levels of sleepiness, fatigue, insomnia, and anxiety/depression compared to males. CHAPTER 3 of this thesis reviews polygraphy data from patients with mild OSA. Male patients were found to have significantly more breathing disturbances than females, however many of these difference disappeared when updated scoring criteria were used. Some weak correlations were found between respiratory parameters and symptoms; however, no clear conclusions could be drawn. CHAPTER 4 outlines the development of a new AutoSet device designed for female- specific breathing patterns. The remaining chapters (CHAPTER 5, and CHAPTER 6) of this thesis describe the testing and validation activities undertaken on the AutoSet F, including a clinical trial to test efficacy; a bench test to compare performance against other commercially available devices; a controlled product launch to validate the features of the algorithm; and finally a clinical trial which demonstrated improvements in sleep efficacy and quality of life over a three-month usage period. In summary, this thesis has shown that at the mild end of the OSA spectrum females are more symptomatic than males, even though respiratory differences in the genders are less pronounced than those described in moderate-to-severe patients. An AutoSet designed specifically for female OSA patients was successful in demonstrating efficacy and clinical effectiveness

Imaging and Treatment of Bronchiectasis:Chest computed tomography to diagnose bronchiectasis and to optimise inhalation treatment

This thesis covers image analysis of bronchiectasis and treatment with inhalation antibiotics

Wearable in-ear pulse oximetry: theory and applications

Wearable health technology, most commonly in the form of the smart watch, is employed by millions of users worldwide. These devices generally exploit photoplethysmography (PPG), the non-invasive use of light to measure blood volume, in order to track physiological metrics such as pulse and respiration. Moreover, PPG is commonly used in hospitals in the form of pulse oximetry, which measures light absorbance by the blood at different wavelengths of light to estimate blood oxygen levels (SpO2). This thesis aims to demonstrate that despite its widespread usage over many decades, this sensor still possesses a wealth of untapped value. Through a combination of advanced signal processing and harnessing the ear as a location for wearable sensing, this thesis introduces several novel high impact applications of in-ear pulse oximetry and photoplethysmography. The aims of this thesis are accomplished through a three pronged approach: rapid detection of hypoxia, tracking of cognitive workload and fatigue, and detection of respiratory disease. By means of the simultaneous recording of in-ear and finger pulse oximetry at rest and during breath hold tests, it was found that in-ear SpO2 responds on average 12.4 seconds faster than the finger SpO2. This is likely due in part to the ear being in close proximity to the brain, making it a priority for oxygenation and thus making wearable in-ear SpO2 a good proxy for core blood oxygen. Next, the low latency of in-ear SpO2 was further exploited in the novel application of classifying cognitive workload. It was found that in-ear pulse oximetry was able to robustly detect tiny decreases in blood oxygen during increased cognitive workload, likely caused by increased brain metabolism. This thesis demonstrates that in-ear SpO2 can be used to accurately distinguish between different levels of an N-back memory task, representing different levels of mental effort. This concept was further validated through its application to gaming and then extended to the detection of driver related fatigue. It was found that features derived from SpO2 and PPG were predictive of absolute steering wheel angle, which acts as a proxy for fatigue. The strength of in-ear PPG for the monitoring of respiration was investigated with respect to the finger, with the conclusion that in-ear PPG exhibits far stronger respiration induced intensity variations and pulse amplitude variations than the finger. All three respiratory modes were harnessed through multivariate empirical mode decomposition (MEMD) to produce spirometry-like respiratory waveforms from PPG. It was discovered that these PPG derived respiratory waveforms can be used to detect obstruction to breathing, both through a novel apparatus for the simulation of breathing disorders and through the classification of chronic obstructive pulmonary disease (COPD) in the real world. This thesis establishes in-ear pulse oximetry as a wearable technology with the potential for immense societal impact, with applications from the classification of cognitive workload and the prediction of driver fatigue, through to the detection of chronic obstructive pulmonary disease. The experiments and analysis in this thesis conclusively demonstrate that widely used pulse oximetry and photoplethysmography possess a wealth of untapped value, in essence teaching the old PPG sensor new tricks.Open Acces

Intelligent Decision Support Systems in Ventilation Management

Introduction: Intensive Care Unit (ICU) medical personnel, in an ongoing process termed ventilation management, utilize patient physiology and pathology data to define ventilator apparatus settings. Aims: The aim of the research is to develop and evaluate in comparison hybrid ventilation advisor systems, that could support ventilation management process, specific to lung pathology for patients ventilated in control mode. Methodology: A questionnaire was designed and circulated to Intensivists. Patient data, as defined by the questionnaire analysis, were collected and categorized into three lung pathologies. Three ICU doctors evaluated correlation analysis of the recorded data. Evaluation results were used for identifying models basic architecture. Two custom software toolboxes were developed for developing hybrid systems; namely the EVolution Of Fuzzy INference Engines (EVOFINE) and the FUzzy Neural (FUN) toolbox. Eight hybrid systems developed with EVOFINE, FUN, ANFIS and ANN techniques were evaluated against applied clinical decisions and patient scenarios. Results: Seventeen (17) models were designed for each of the eight (8) modeling techniques. The modelled process consisted of twelve physiology variables and six ventilator settings. The number of models’ inputs ranged from single to six based on correlation and evaluation findings. Evaluation against clinical recommendations has shown that ANNs performed better; mean average error as percentage for four of the applied techniques was 0.16%, 1.29% & 0.62 for ANN empirical, 0.05%, 2.23% & 2.30% for ANFIS, 0.93%, 2.33% & 1.89% for EVOFINE and 0.73%, 2.63% & 6.56 for FUN NM, in Normal, COPD and ALI-ARDS categories respectively. Additionally evaluation against clinical disagreement SD has shown that 70.6% of the NN empirical models were performing in 90% of their suggestions within clinical SD, while the percentages were 53%, 53% and 59% for the EVOFINE, ANFIS and NN Normalized models respectively. The EVOFINE and ANFIS produced Fuzzy Systems whose architecture is transparent for the user. Visual observation of ANFIS architectures revealed possibly hazardous advices. Evaluation against clinical disagreement has shown that the NN empirical was not producing hazardous advices, while EVOFINE, ANFIS and NN Normalized were shown to produce potentially hazardous advice in 17.6%, 23% and 5.8% of the developed models

Bronchoscopic lung volume reduction for Emphysema: physiological and radiological correlations

Introduction: Patient selection in lung volume reduction (LVR) plays a pivotal role in achieving meaningful clinical outcomes. Currently, LVR patients are selected based on three established criteria: heterogeneity index, percentage of low attenuation area (%LAA), and fissure integrity score. Quantitative computed tomography (QCT) has been developed to quantify lung physiological indices at the lobar level and could potentially revolutionise patient selection in LVR procedures. We developed an in-house QCT software, LungSeg, and used its radiological indices for the purposes of this thesis. The aim of this thesis is to discover potential physiological and radiological indices that could serve as predictors for superior LVR outcomes for better patient selection. Methods: This thesis took two studies and analysed them using LungSeg. The first study was the long-term coil study, a randomised controlled study that had the control group crossing over to the treatment arm at 12 months. At 12 months post-procedure the baseline measurements were assessed against the 12-months post-procedural measurements. The second study was the short-term valve study which was another randomised controlled study that compared the primary and secondary endpoints between the control and the valve-treated group at three months post-procedure. Results: In the long-term coil study, we found that the best statistically significant combination of predictors for change in target lobar volume at inspiration was found to be the combination of baseline target LV at inspiration, -950HU EI at inspiration, and TLCabs with a model adjusted R2 of 0.407 (p = 0.0001). In a subsequent multivariate analysis using ≥45% LAA on the -950HU at Inspiration, the R2 of the same prediction model did improve to 0.493 (P-value = 0.002). Meanwhile, the best statistically significant combination of predictors for change in target lobar volume at inspiration following valve treatment was found to be the combination of baseline target LV at inspiration, target lobar fissure integrity and baseline FEV1abs with a model adjusted R2 of 0.193 (p = 0.105). Conclusion: Using QCT, we have improved the proposed patient selection algorithm for LVR procedures based on the best QCT and lung function predictors.Open Acces

Chest Computed Tomography in early and advanced cystic fibrosis lung disease: Optimizing protocols, image analysis and further validation

Cystic Fibrosis (CF) is one of the most common life-threatening autosomal recessive diseases in the Western World, with a reported incidence rate of approximately 1 in every 2.000 to 5.000 caucasian newborns in most European countries. The gene mutation that plays an important role in the pathoph

The analysis of breathing and rhythm in speech

Speech rhythm can be described as the temporal patterning by which speech events, such as vocalic onsets, occur. Despite efforts to quantify and model speech rhythm across languages, it remains a scientifically enigmatic aspect of prosody. For instance, one challenge lies in determining how to best quantify and analyse speech rhythm. Techniques range from manual phonetic annotation to the automatic extraction of acoustic features. It is currently unclear how closely these differing approaches correspond to one another. Moreover, the primary means of speech rhythm research has been the analysis of the acoustic signal only. Investigations of speech rhythm may instead benefit from a range of complementary measures, including physiological recordings, such as of respiratory effort. This thesis therefore combines acoustic recording with inductive plethysmography (breath belts) to capture temporal characteristics of speech and speech breathing rhythms. The first part examines the performance of existing phonetic and algorithmic techniques for acoustic prosodic analysis in a new corpus of rhythmically diverse English and Mandarin speech. The second part addresses the need for an automatic speech breathing annotation technique by developing a novel function that is robust to the noisy plethysmography typical of spontaneous, naturalistic speech production. These methods are then applied in the following section to the analysis of English speech and speech breathing in a second, larger corpus. Finally, behavioural experiments were conducted to investigate listeners' perception of speech breathing using a novel gap detection task. The thesis establishes the feasibility, as well as limits, of automatic methods in comparison to manual annotation. In the speech breathing corpus analysis, they help show that speakers maintain a normative, yet contextually adaptive breathing style during speech. The perception experiments in turn demonstrate that listeners are sensitive to the violation of these speech breathing norms, even if unconsciously so. The thesis concludes by underscoring breathing as a necessary, yet often overlooked, component in speech rhythm planning and production