Digital Oculomotor Biomarkers in Dementia

Dementia is an umbrella term that covers a number of neurodegenerative syndromes featuring gradual disturbance of various cognitive functions that are severe enough to interfere with tasks of daily life. The diagnosis of dementia occurs frequently when pathological changes have been developing for years, symptoms of cognitive impairment are evident and the quality of life of the patients has already been deteriorated significantly. Although brain imaging and fluid biomarkers allow the monitoring of disease progression in vivo, they are expensive, invasive and not necessarily diagnostic in isolation. Recent studies suggest that eye-tracking technology is an innovative tool that holds promise for accelerating early detection of the disease, as well as, supporting the development of strategies that minimise impairment during every day activities. However, the optimal methods for quantitative evaluation of oculomotor behaviour during complex and naturalistic tasks in dementia have yet to be determined. This thesis investigates the development of computational tools and techniques to analyse eye movements of dementia patients and healthy controls under naturalistic and less constrained scenarios to identify novel digital oculomotor biomarkers. Three key contributions are made. First, the evaluation of the role of environment during navigation in patients with typical Alzheimer disease and Posterior Cortical Atrophy compared to a control group using a combination of eye movement and egocentric video analysis. Secondly, the development of a novel method of extracting salient features directly from the raw eye-tracking data of a mixed sample of dementia patients during a novel instruction-less cognitive test to detect oculomotor biomarkers of dementia-related cognitive dysfunction. Third, the application of unsupervised anomaly detection techniques for visualisation of oculomotor anomalies during various cognitive tasks. The work presented in this thesis furthers our understanding of dementia-related oculomotor dysfunction and gives future research direction for the development of computerised cognitive tests and ecological interventions

Automatic Detection of Dementia and related Affective Disorders through Processing of Speech and Language

In 2019, dementia is has become a trillion dollar disorder. Alzheimer’s disease (AD) is a type of dementia in which the main observable symptom is a decline in cognitive functions, notably memory, as well as language and problem-solving. Experts agree that early detection is crucial to effectively develop and apply interventions and treatments, underlining the need for effective and pervasive assessment and screening tools. The goal of this thesis is to explores how computational techniques can be used to process speech and language samples produced by patients suffering from dementia or related affective disorders, to the end of automatically detecting them in large populations us- ing machine learning models. A strong focus is laid on the detection of early stage dementia (MCI), as most clinical trials today focus on intervention at this level. To this end, novel automatic and semi-automatic analysis schemes for a speech-based cogni- tive task, i.e., verbal fluency, are explored and evaluated to be an appropriate screening task. Due to a lack of available patient data in most languages, world-first multilingual approaches to detecting dementia are introduced in this thesis. Results are encouraging and clear benefits on a small French dataset become visible. Lastly, the task of detecting these people with dementia who also suffer from an affective disorder called apathy is explored. Since they are more likely to convert into later stage of dementia faster, it is crucial to identify them. These are the fist experiments that consider this task us- ing solely speech and language as inputs. Results are again encouraging, both using only speech or language data elicited using emotional questions. Overall, strong results encourage further research in establishing speech-based biomarkers for early detection and monitoring of these disorders to better patients’ lives.Im Jahr 2019 ist Demenz zu einer Billionen-Dollar-Krankheit geworden. Die Alzheimer- Krankheit (AD) ist eine Form der Demenz, bei der das Hauptsymptom eine Abnahme der kognitiven Funktionen ist, insbesondere des Gedächtnisses sowie der Sprache und des Problemlösungsvermögens. Experten sind sich einig, dass eine frühzeitige Erkennung entscheidend für die effektive Entwicklung und Anwendung von Interventionen und Behandlungen ist, was den Bedarf an effektiven und durchgängigen Bewertungsund Screening-Tools unterstreicht. Das Ziel dieser Arbeit ist es zu erforschen, wie computergest ützte Techniken eingesetzt werden können, um Sprach- und Sprechproben von Patienten, die an Demenz oder verwandten affektiven Störungen leiden, zu verarbeiten, mit dem Ziel, diese in großen Populationen mit Hilfe von maschinellen Lernmodellen automatisch zu erkennen. Ein starker Fokus liegt auf der Erkennung von Demenz im Frühstadium (MCI), da sich die meisten klinischen Studien heute auf eine Intervention auf dieser Ebene konzentrieren. Zu diesem Zweck werden neuartige automatische und halbautomatische Analyseschemata für eine sprachbasierte kognitive Aufgabe, d.h. die verbale Geläufigkeit, erforscht und als geeignete Screening-Aufgabe bewertet. Aufgrund des Mangels an verfügbaren Patientendaten in den meisten Sprachen werden in dieser Arbeit weltweit erstmalig mehrsprachige Ansätze zur Erkennung von Demenz vorgestellt. Die Ergebnisse sind ermutigend und es werden deutliche Vorteile an einem kleinen französischen Datensatz sichtbar. Schließlich wird die Aufgabe untersucht, jene Menschen mit Demenz zu erkennen, die auch an einer affektiven Störung namens Apathie leiden. Da sie mit größerer Wahrscheinlichkeit schneller in ein späteres Stadium der Demenz übergehen, ist es entscheidend, sie zu identifizieren. Dies sind die ersten Experimente, die diese Aufgabe unter ausschließlicher Verwendung von Sprache und Sprache als Input betrachten. Die Ergebnisse sind wieder ermutigend, sowohl bei der Verwendung von reiner Sprache als auch bei der Verwendung von Sprachdaten, die durch emotionale Fragen ausgelöst werden. Insgesamt sind die Ergebnisse sehr ermutigend und ermutigen zu weiterer Forschung, um sprachbasierte Biomarker für die Früherkennung und Überwachung dieser Erkrankungen zu etablieren und so das Leben der Patienten zu verbessern

Translating Predictive Models for Alzheimer’s Disease to Clinical Practice: User Research, Adoption Opportunities, and Conceptual Design of a Decision Support Tool

Alzheimer’s Disease (AD) is a common form of Dementia with terrible impact on patients, families, and the healthcare sector. Recent computational advances, such as predictive models, have improved AD data collection and analysis, disclosing the progression pattern of the disease. Whilst clinicians currently rely on a qualitative, experience-led approach to make decisions on patients’ care, the Event-Based Model (EBM) has shown promising results for familial and sporadic AD, making it well positioned to inform clinical decision-making. What proves to be challenging is the translation of computational implementations to clinical applications, due to lack of human factors considerations. The aim of this Ph.D. thesis is to (1) explore barriers and opportunities to the adoption of predictive models for AD in clinical practice; and (2) develop and test the design concept of a tool to enable EBM exploitation by AD clinicians. Following a user-centred design approach, I explored current clinical needs and practices, by means of field observations, interviews, and surveys. I framed the technical-clinical gap, identifying the technical features that were better suited for clinical use, and research-oriented clinicians as the best placed to initially adopt the technology. I designed and tested with clinicians a prototype, icompass, and reviewed it with the technical teams through a series of workshops. This approach fostered a thorough understanding of clinical users’ context and perceptions of the tool’s potential. Furthermore, it provided recommendations to computer scientists pushing forward the models and tool’s development, to enhance user relevance in the future. This thesis is one of the few works addressing a lack of consensus on successful adoption and integration of such innovations to the healthcare environment, from a human factors’ perspective. Future developments should improve prototype fidelity, with interleaved clinical testing, refining design, algorithm, and strategies to facilitate the tool’s integration within clinical practice

Time-Series Embedded Feature Selection Using Deep Learning: Data Mining Electronic Health Records for Novel Biomarkers

As health information technologies continue to advance, routine collection and digitisation of patient health records in the form of electronic health records present as an ideal opportunity for data-mining and exploratory analysis of biomarkers and risk factors indicative of a potentially diverse domain of patient outcomes. Patient records have continually become more widely available through various initiatives enabling open access whilst maintaining critical patient privacy. In spite of such progress, health records remain not widely adopted within the current clinical statistical analysis domain due to challenging issues derived from such “big data”.Deep learning based temporal modelling approaches present an ideal solution to health record challenges through automated self-optimisation of representation learning, able to man-ageably compose the high-dimensional domain of patient records into data representations able to model complex data associations. Such representations can serve to condense and reduce dimensionality to emphasise feature sparsity and importance through novel embedded feature selection approaches. Accordingly, application towards patient records enable complex mod-elling and analysis of the full domain of clinical features to select biomarkers of predictive relevance.Firstly, we propose a novel entropy regularised neural network ensemble able to highlight risk factors associated with hospitalisation risk of individuals with dementia. The application of which, was able to reduce a large domain of unique medical events to a small set of relevant risk factors able to maintain hospitalisation discrimination.Following on, we continue our work on ensemble architecture approaches with a novel cas-cading LSTM ensembles to predict severe sepsis onset within critical patients in an ICU critical care centre. We demonstrate state-of-the-art performance capabilities able to outperform that of current related literature.Finally, we propose a novel embedded feature selection application dubbed 1D convolu-tion feature selection using sparsity regularisation. Said methodology was evaluated on both domains of dementia and sepsis prediction objectives to highlight model capability and generalisability. We further report a selection of potential biomarkers for the aforementioned case study objectives highlighting clinical relevance and potential novelty value for future clinical analysis.Accordingly, we demonstrate the effective capability of embedded feature selection ap-proaches through the application of temporal based deep learning architectures in the discovery of effective biomarkers across a variety of challenging clinical applications

Improved Segmentation of the Intracranial and Ventricular Volumes in Populations with Cerebrovascular Lesions and Atrophy Using 3D CNNs

Successful segmentation of the total intracranial vault (ICV) and ventricles is of critical importance when studying neurodegeneration through neuroimaging. We present iCVMapper and VentMapper, robust algorithms that use a convolutional neural network (CNN) to segment the ICV and ventricles from both single and multi-contrast MRI data. Our models were trained on a large dataset from two multi-site studies (N = 528 subjects for ICV, N = 501 for ventricular segmentation) consisting of older adults with varying degrees of cerebrovascular lesions and atrophy, which pose significant challenges for most segmentation approaches. The models were tested on 238 participants, including subjects with vascular cognitive impairment and high white matter hyperintensity burden. Two of the three test sets came from studies not used in the training dataset. We assessed our algorithms relative to four state-of-the-art ICV extraction methods (MONSTR, BET, Deep Extraction, FreeSurfer, DeepMedic), as well as two ventricular segmentation tools (FreeSurfer, DeepMedic). Our multi-contrast models outperformed other methods across many of the evaluation metrics, with average Dice coefficients of 0.98 and 0.96 for ICV and ventricular segmentation respectively. Both models were also the most time efficient, segmenting the structures in orders of magnitude faster than some of the other available methods. Our networks showed an increased accuracy with the use of a conditional random field (CRF) as a post-processing step. We further validated both segmentation models, highlighting their robustness to images with lower resolution and signal-to-noise ratio, compared to tested techniques. The pipeline and models are available at: https://icvmapp3r.readthedocs.io and https://ventmapp3r.readthedocs.io to enable further investigation of the roles of ICV and ventricles in relation to normal aging and neurodegeneration in large multi-site studies

A deformation-based morphometry framework for disentangling Alzheimer's disease from normal aging using learned normal aging templates

Alzheimer's Disease and normal aging are both characterized by brain atrophy. The question of whether AD-related brain atrophy represents accelerated aging or a neurodegeneration process distinct from that in normal aging remains unresolved. Moreover, precisely disentangling AD-related brain atrophy from normal aging in a clinical context is complex. In this study, we propose a deformation-based morphometry framework to estimate normal aging and AD-specific atrophy patterns of subjects from morphological MRI scans. We first leverage deep-learning-based methods to create age-dependent templates of cognitively normal (CN) subjects. These templates model the normal aging atrophy patterns in a CN population. Then, we use the learned diffeomorphic registration to estimate the one-year normal aging pattern at the voxel level. We register the testing image to the 60-year-old CN template in the second step. Finally, normal aging and AD-specific scores are estimated by measuring the alignment of this registration with the one-year normal aging pattern. The methodology was developed and evaluated on the OASIS3 dataset with 1,014 T1-weighted MRI scans. Of these, 326 scans were from CN subjects, and 688 scans were from individuals clinically diagnosed with AD at different stages of clinical severity defined by clinical dementia rating (CDR) scores. The results show that ventricles predominantly follow an accelerated normal aging pattern in subjects with AD. In turn, hippocampi and amygdala regions were affected by both normal aging and AD-specific factors. Interestingly, hippocampi and amygdala regions showed more of an accelerated normal aging pattern for subjects during the early clinical stages of the disease, while the AD-specific score increases in later clinical stages. Our code is freely available at https://github.com/Fjr9516/DBM_with_DL.Comment: 21 pages, 8 figure

Quantifying cognitive and mortality outcomes in older patients following acute illness using epidemiological and machine learning approaches

Introduction: Cognitive and functional decompensation during acute illness in older people are poorly understood. It remains unclear how delirium, an acute confusional state reflective of cognitive decompensation, is contextualised by baseline premorbid cognition and relates to long-term adverse outcomes. High-dimensional machine learning offers a novel, feasible and enticing approach for stratifying acute illness in older people, improving treatment consistency while optimising future research design. Methods: Longitudinal associations were analysed from the Delirium and Population Health Informatics Cohort (DELPHIC) study, a prospective cohort ≥70 years resident in Camden, with cognitive and functional ascertainment at baseline and 2-year follow-up, and daily assessments during incident hospitalisation. Second, using routine clinical data from UCLH, I constructed an extreme gradient-boosted trees predicting 600-day mortality for unselected acute admissions of oldest-old patients with mechanistic inferences. Third, hierarchical agglomerative clustering was performed to demonstrate structure within DELPHIC participants, with predictive implications for survival and length of stay. Results: i. Delirium is associated with increased rates of cognitive decline and mortality risk, in a dose-dependent manner, with an interaction between baseline cognition and delirium exposure. Those with highest delirium exposure but also best premorbid cognition have the “most to lose”. ii. High-dimensional multimodal machine learning models can predict mortality in oldest-old populations with 0.874 accuracy. The anterior cingulate and angular gyri, and extracranial soft tissue, are the highest contributory intracranial and extracranial features respectively. iii. Clinically useful acute illness subtypes in older people can be described using longitudinal clinical, functional, and biochemical features. Conclusions: Interactions between baseline cognition and delirium exposure during acute illness in older patients result in divergent long-term adverse outcomes. Supervised machine learning can robustly predict mortality in in oldest-old patients, producing a valuable prognostication tool using routinely collected data, ready for clinical deployment. Preliminary findings suggest possible discernible subtypes within acute illness in older people

Equitable modelling of brain imaging by counterfactual augmentation with morphologically constrained 3D deep generative models

We describe CounterSynth, a conditional generative model of diffeomorphic deformations that induce label-driven, biologically plausible changes in volumetric brain images. The model is intended to synthesise counterfactual training data augmentations for downstream discriminative modelling tasks where fidelity is limited by data imbalance, distributional instability, confounding, or underspecification, and exhibits inequitable performance across distinct subpopulations. Focusing on demographic attributes, we evaluate the quality of synthesised counterfactuals with voxel-based morphometry, classification and regression of the conditioning attributes, and the Fréchet inception distance. Examining downstream discriminative performance in the context of engineered demographic imbalance and confounding, we use UK Biobank and OASIS magnetic resonance imaging data to benchmark CounterSynth augmentation against current solutions to these problems. We achieve state-of-the-art improvements, both in overall fidelity and equity. The source code for CounterSynth is available at https://github.com/guilherme-pombo/CounterSynth

Predictive analytics applied to Alzheimer’s disease : a data visualisation framework for understanding current research and future challenges

Dissertation as a partial requirement for obtaining a master’s degree in information management, with a specialisation in Business Intelligence and Knowledge Management.Big Data is, nowadays, regarded as a tool for improving the healthcare sector in many areas, such as in its economic side, by trying to search for operational efficiency gaps, and in personalised treatment, by selecting the best drug for the patient, for instance. Data science can play a key role in identifying diseases in an early stage, or even when there are no signs of it, track its progress, quickly identify the efficacy of treatments and suggest alternative ones. Therefore, the prevention side of healthcare can be enhanced with the usage of state-of-the-art predictive big data analytics and machine learning methods, integrating the available, complex, heterogeneous, yet sparse, data from multiple sources, towards a better disease and pathology patterns identification. It can be applied for the diagnostic challenging neurodegenerative disorders; the identification of the patterns that trigger those disorders can make possible to identify more risk factors, biomarkers, in every human being. With that, we can improve the effectiveness of the medical interventions, helping people to stay healthy and active for a longer period. In this work, a review of the state of science about predictive big data analytics is done, concerning its application to Alzheimer’s Disease early diagnosis. It is done by searching and summarising the scientific articles published in respectable online sources, putting together all the information that is spread out in the world wide web, with the goal of enhancing knowledge management and collaboration practices about the topic. Furthermore, an interactive data visualisation tool to better manage and identify the scientific articles is develop, delivering, in this way, a holistic visual overview of the developments done in the important field of Alzheimer’s Disease diagnosis.Big Data é hoje considerada uma ferramenta para melhorar o sector da saúde em muitas áreas, tais como na sua vertente mais económica, tentando encontrar lacunas de eficiência operacional, e no tratamento personalizado, selecionando o melhor medicamento para o paciente, por exemplo. A ciência de dados pode desempenhar um papel fundamental na identificação de doenças em um estágio inicial, ou mesmo quando não há sinais dela, acompanhar o seu progresso, identificar rapidamente a eficácia dos tratamentos indicados ao paciente e sugerir alternativas. Portanto, o lado preventivo dos cuidados de saúde pode ser bastante melhorado com o uso de métodos avançados de análise preditiva com big data e de machine learning, integrando os dados disponíveis, geralmente complexos, heterogéneos e esparsos provenientes de múltiplas fontes, para uma melhor identificação de padrões patológicos e da doença. Estes métodos podem ser aplicados nas doenças neurodegenerativas que ainda são um grande desafio no seu diagnóstico; a identificação dos padrões que desencadeiam esses distúrbios pode possibilitar a identificação de mais fatores de risco, biomarcadores, em todo e qualquer ser humano. Com isso, podemos melhorar a eficácia das intervenções médicas, ajudando as pessoas a permanecerem saudáveis e ativas por um período mais longo. Neste trabalho, é feita uma revisão do estado da arte sobre a análise preditiva com big data, no que diz respeito à sua aplicação ao diagnóstico precoce da Doença de Alzheimer. Isto foi realizado através da pesquisa exaustiva e resumo de um grande número de artigos científicos publicados em fontes online de referência na área, reunindo a informação que está amplamente espalhada na world wide web, com o objetivo de aprimorar a gestão do conhecimento e as práticas de colaboração sobre o tema. Além disso, uma ferramenta interativa de visualização de dados para melhor gerir e identificar os artigos científicos foi desenvolvida, fornecendo, desta forma, uma visão holística dos avanços científico feitos no importante campo do diagnóstico da Doença de Alzheimer