This thesis focuses on data found in the field of computational drug discovery. New insight can be obtained by applying machine learning in various ways and in a variety of domains. Two studies... Show moreThis thesis focuses on data found in the field of computational drug discovery. New insight can be obtained by applying machine learning in various ways and in a variety of domains. Two studies delved into the application of proteochemometrics (PCM), a machine learning technique that can be used to find relations in protein-ligand bioactivity data and then predict using a virtual screen whether compounds that had never been tested on a particular protein, or set of proteins. With this, sets of compounds were suggested for experimental validation that were significant in a myriad of ways. Another study investigated the mutational patterns in cancer, applying a large dataset of mutation data and identifying several motifs in G protein-coupled receptors. The thesis also contains the work done on the Papyrus dataset, a large scale bioactivity dataset that focuses on standardising data for computational drug discovery and providing an out-of-the-box set that can be used in a variety of settings. Show less
AI-powered emotion recognition, typing with thoughts or eavesdropping virtual assistants: three non-fictional examples illustrate how AI may impact society. AI-related products and services... Show moreAI-powered emotion recognition, typing with thoughts or eavesdropping virtual assistants: three non-fictional examples illustrate how AI may impact society. AI-related products and services increasingly find their way into daily life. Are the EU's fundamental rights to privacy and data protection equipped to protect individuals effectively? In addressing this question, the dissertation concludes that no new legal framework is needed. Instead, adjustments are required. First, the extent of adjustments depends on the AI discipline. There is nothing like 'the AI'. AI covers various concepts, including the disciplines machine learning, natural language processing, computer vision, affective computing and automated reasoning. Second, the extent of adjustments depends on the type of legal problem: legal provisions are violated (type 1), cannot be enforced (type 2) or are not fit for purpose (type 3). Type 2 and 3 problems require either adjustments of current provisions or new judicial interpretations. Two instruments might be helpful for more effective legislation: rebuttable presumptions and reversal of proof. In some cases, the solution is technical, not legal. Research in AI should solve reasoning deficiencies in AI systems and their lack of common sense. Show less
Contrary to common belief, sign languages are distinct across different communities and cultures, evolving organically through interactions among deaf people, rather than being based on spoken... Show moreContrary to common belief, sign languages are distinct across different communities and cultures, evolving organically through interactions among deaf people, rather than being based on spoken languages. Each sign language has its own grammar, vocabulary, and cultural nuances, with variations even within a single country, showcasing the diverse communication methods within the deaf community. Deaf individuals often face encouragement to use spoken language techniques like lipreading or text communication, highlighting a bias towards spoken languages. This is compounded by the lack of sign languages in linguistic technologies, emphasizing the need for more inclusive research and development. This dissertation aims to address this gap using machine and deep learning to improve sign language processing and recognition. It covers six chapters, introducing methods for video-based sign annotation, webcam-based sign language dictionary search, and ranking systems for sign suggestions. It also explores tools for visualizing and comparing sign language variation, contributing valuable resources to linguistic research. Show less
This thesis investigates the contribution of quantum computers to machine learning, a field called Quantum Machine Learning. Quantum Machine Learning promises innovative perspectives and methods... Show moreThis thesis investigates the contribution of quantum computers to machine learning, a field called Quantum Machine Learning. Quantum Machine Learning promises innovative perspectives and methods for solving complex problems in machine learning, leveraging the unique capabilities of quantum computers. These computers differ fundamentally from classical computers by exploiting certain quantum mechanical phenomena. The thesis explores various proposals within quantum machine learning, such as the application of quantum algorithms in topological data analysis. With respect to topological data analysis, results demonstrate that quantum algorithms solve problems considered inefficient in classical settings. The thesis also explores structural risk minimization in quantum machine learning models, identifying crucial design choices for new quantum machine learning models. Additionally, it introduces quantum models in reinforcement learning, which deliver comparable performance to traditional models and are superior in certain scenarios. The final part identifies learning tasks in computational learning theory where quantum learning algorithms have exponential advantages. In summary, this thesis contributes to understanding how quantum computers can address complex machine learning problems, from topological data analysis to reinforcement learning and computational learning tasks. Show less
Bacteriophages, or phages for short, are the most abundant biological entity in nature. They shape bacterial communities and are a major driving force in bacterial evolution. Their ubiquitous... Show moreBacteriophages, or phages for short, are the most abundant biological entity in nature. They shape bacterial communities and are a major driving force in bacterial evolution. Their ubiquitous nature and their potential use in medical and industrial applications make them attractive targets for fundamental and applied scientific studies. Understanding their structure and function at the molecular level is essential for understanding phage life cycles. In this thesis, I applied different cryo-EM techniques combined with advanced image processing and artificial intelligence methods to gain insight into structure and function of two bacteriophages. In both cases, these phages contain flexible elements which are essential for the infection process. While biologically highly interesting, these flexible components are especially challenging for structural studies. With the advances in computer technology and electron microscopy, researchers can now use various research methods to study different proteins and the structure and function of biological macromolecular machines. The studies presented in this thesis provide valuable insights into phages with flexible components, and provide a useful workflow for researchers with similar research topics. Show less
Transport inspectorates are looking for novel methods to identify dangerous behavior, ultimately to reduce risks associated to the movements of people and goods. We explore a data-driven approach... Show moreTransport inspectorates are looking for novel methods to identify dangerous behavior, ultimately to reduce risks associated to the movements of people and goods. We explore a data-driven approach to arrive at smart inspections of vehicles. Inspections are smart when they are performed (1) accurate, (2) automated, (3) fair, and (4) in an interpretable manner. We leverage tools from the network science and machine learning domain to encode the behavioral aspect of vehicle’s behavior. Tools used in this thesis include community detection, link prediction, and assortativity. We explore their applicability and provide technical methods. In the final chapter, we also discuss the matter of fairness in machine learning. Show less
Sewer pipes are an essential infrastructure in modern society and their proper operation is important for public health. To keep sewer pipes operational as much as possible, periodical inspections... Show moreSewer pipes are an essential infrastructure in modern society and their proper operation is important for public health. To keep sewer pipes operational as much as possible, periodical inspections for defects are performed. Instead of repairing sewer pipes when a problem becomes critical, such inspections allow municipalities to plan maintenance.Sewer pipe inspections are an attractive target for automation. While a potential improvement in terms of assessment quality and processing efficiency is generally promised by automation, in this case we would also decrease the variability which is a current problem. Besides the reasons for automating, the methods for automating are also attractive: a lot of (visual) data has been gathered over the past decades which may be used to train algorithms.This thesis compiles the results of five years of research into the possible automation of sewer pipe inspections with the tools of machine learning and computer vision. In this thesis, three distinct, yet complementary approaches to automating sewer pipe inspections are described:- Image-Based Unsupervised Anomaly Detection- Convolutional Neural Network Classification- Stereovision and Geometry Reconstruction Show less
This thesis looks at Artificial Intelligence (AI) and its potential to revolutionise the healthcare sector. The first part of this thesis focuses on the responsible development and validation of AI... Show moreThis thesis looks at Artificial Intelligence (AI) and its potential to revolutionise the healthcare sector. The first part of this thesis focuses on the responsible development and validation of AI-based clinical prediction algorithms, exploring the prime considerations in this process. The second part of this thesis addresses the opportunities for classical statistics and machine learning techniques for developing prediction algorithms. It also examines the performance, potential, and challenges of AI prediction algorithms for clinical practice. The conclusion states that cross-discipline collaboration, exchangeability of knowledge and results, and validation of AI for healthcare practice are essential for realising the potential of AI in healthcare. Show less
In this thesis, we examine various systems through the lens of several numerical methods. We delve into questions concerning thermalization in closed unitary systems, lattice gauge theories, and... Show moreIn this thesis, we examine various systems through the lens of several numerical methods. We delve into questions concerning thermalization in closed unitary systems, lattice gauge theories, and the intriguing properties of deep neural network phase spaces. Leveraging modern advancements in both software and hardware, we scrutinize these systems in greater detail, accessing previously unreachable regimes. Show less
This dissertation investigates the early recognition of persistent somatic symptoms (PSS) in primary care. A stepwise approach was used mapping the optimal methods for re-using primary care records... Show moreThis dissertation investigates the early recognition of persistent somatic symptoms (PSS) in primary care. A stepwise approach was used mapping the optimal methods for re-using primary care records for predictive modeling of PSS. This is important since up to 10% of the general population experiences PSS. Moreover, general practitioners (GPs) often encounter difficulties in recognizing PSS, which may delay adequate intervention, subsequently resulting in unnecessary high burden on the patient and health care system. The findings from this dissertation show that a complex interplay between factors from all biopsychosocial domains contribute to PSS-onset. Survey results show that GPs differ in their methods of PSS-registration. Many GPs indicate missing an unambiguous classification scheme and report needing more support, tools, and/or education for PSS-related consultations. Predictive modeling of different PSS-syndromes shows both overlapping and syndrome-specific predictors. Early predictive modeling of the broad spectrum of PSS shows moderate predictive accuracy based on seven approaches for candidate-predictor selection, including theory-driven and temporal and non-temporal data-driven approaches. In conclusion, this dissertation provides comprehensive evidence of the complexity of identification of PSS. Furthermore, it indicates that simple data-driven approaches could support PSS classification in primary care, although this should be combined with a multidisciplinary care approach. Show less
Stroke is one of the leading causes of disability and death worldwide. Prevention of stroke is therefore essential. Effective prevention should be tailored to the clinical characteristics,... Show moreStroke is one of the leading causes of disability and death worldwide. Prevention of stroke is therefore essential. Effective prevention should be tailored to the clinical characteristics, lifestyle, and environment of the individual, among others. This is also known as precision prevention. An important example illustrating the need for precision prevention is the existence of sex differences in stroke occurrence. In practice, for predicting stroke risk, only traditional risk factors (such as smoking and hypertension) are included, and women-specific risk factors are not yet routinely included. As a result, women with an increased risk of stroke may be missed, which also prevents timely initiation of preventive treatments. In this thesis, I tried to lay the foundation for precision prevention of stroke in women.Part I discussed the pathophysiology underlying women-specific risk factors for stroke, and gender differences in the clinical presentation of stroke. I found that the mechanisms underlying the relationship between women-specific risk factors and stroke, in particular the relationship between migraine and cerebral infarctions, seem to be particularly significant in the childbearing phase of life.In Part II, I described how health data from the EHR can be used to develop prediction models for the risk of myocardial infarction or stroke specifically for women under 50 years of age, and found that women-specific risk factors can add value in the predictions. However, there is still a long way to go to actually implement these models in practice, such as testing them on new datasets, and complying with current laws and regulations for safe application. Show less
The societal burden of spinal conditions is vast and continues to grow with the in- creasing prevalence of patients with spinal degenerative disease, spinal metasta- ses, and spinal infections.... Show moreThe societal burden of spinal conditions is vast and continues to grow with the in- creasing prevalence of patients with spinal degenerative disease, spinal metasta- ses, and spinal infections. Recent application of artificial intelligence in healthcare have shown great promise and similar extensions in spine surgery may improve decision-making. The purpose of this thesis was to examine the utility of predictive analytics and natural language processing in spine surgery. Show less
The aim of this thesis is to determine diagnostic performance of machine learning in differentiating between atypical cartilaginous tumor (ACT) and high-grade chondrosarcoma (CS) based on radiomic... Show moreThe aim of this thesis is to determine diagnostic performance of machine learning in differentiating between atypical cartilaginous tumor (ACT) and high-grade chondrosarcoma (CS) based on radiomic features derived from magnetic resonance imaging (MRI) and computed tomography (CT). In chapter 2, the concept of radiomics of musculoskeletal sarcomas is introduced and a systematic review on radiomic feature reproducibility and validation strategies is conducted. In chapter 3, a preliminary study is performed to investigate the performance of MRI radiomics-based machine learning in discriminating ACT from high-grade CS, using a single-center cohort, in comparison with an expert radiologist. In chapter 4, the influence of interobserver segmentation variability on the reproducibility of CT and MRI radiomic features of cartilaginous bone tumors is assessed. In chapter 5, the performance of CT radiomics-based machine learning in discriminating ACT from high-grade CS of long bones is determined and validated using independent data from a multicenter cohort, compared to an expert radiologist. In chapter 6, the performance of MRI radiomics-based machine learning in differentiating between ACT and grade II CS of long bones is determined and validated using independent data from a multicenter cohort, in comparison with an expert radiologist. Finally, in chapter 7, the main results and implications of this thesis are summarized and discussed. Show less
Despite improved surgical and adjuvant treatment options, malignant brain tumors remain non-curable to date. The thin line between treatment effectiveness and patient harms underpins the importance... Show moreDespite improved surgical and adjuvant treatment options, malignant brain tumors remain non-curable to date. The thin line between treatment effectiveness and patient harms underpins the importance of tailoring clinical management to the individual brain tumor patient. Over the past decades, the volume and complexity of clinically-derived patient data (i.e., imaging, genomics, free-text etc.) is increasing exponentially. Machine learning provides a vast range of algorithms that can learn from this data and guide clinical decision-making by providing accurate patient-level predictions. The current thesis describes several studies along the continuum of the machine learning spectrum as it applies to neurosurgical oncology. Part I investigates postoperative complications and risk factors in patients operated for a primary malignant brain tumor. Part II describes de development of a model for the prediction of individual-patient survival in glioblastoma patients. Part III encompasses the development of a natural language processing framework for automated medical text analysis. Machine learning algorithms should be considered as an extension to statistical approaches and exist along a continuum determined by how much is specified by humans and how much is learnt by the machine. Although machine learning algorithms can produce highly accurate predictions based on high-dimensional data, clinicians and researchers should interpret the clinical implications of these predictions on case-by-case basis. Show less
Image registration is the process of aligning images by finding the spatial relation between the images. Assuming two images called fixed and moving images are taken at different time, different... Show moreImage registration is the process of aligning images by finding the spatial relation between the images. Assuming two images called fixed and moving images are taken at different time, different spatial location, or via a different imaging technique, the aim of image registration is to find an optimal transformation that aligns the fixed and the moving images. Performing an automatic fast image registration with less manual finetuning can speed up numerous medical image processing procedures. In addition, an automatic quality assessment of registration can speed up this time-consuming task. In this thesis, we developed a fast learning-based image registration technique called RegNet.Predicting registration error can be useful for evaluation of registration procedures, which is important for the adoption of registration techniques in the clinic. In addition, quantitative error prediction can be helpful in improving the registration quality. In this thesis, we proposed two quality assessment mechanisms using random forests (RF) and convolutional long short term memory (ConvLSTM), in which the latter performs faster and more accurate. Show less
Inflammatory Bowel Diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC) are chronic immunological digestive diseases with a progressive character and associated with significant... Show moreInflammatory Bowel Diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC) are chronic immunological digestive diseases with a progressive character and associated with significant healthcare costs. Different solutions have been proposed such as innovation in care monitoring or implementation of electronic health (eHealth). IBD is one of many chronic diseases that could benefit from eHealth, adding smartphone applications to the toolbox for care management has the potential improve disease understanding, enhance medication adherence, improve patient-physician communications, and for earlier interventions by medical professionals when problems arise. Furthermore, the accessibility to Big Data and increased computational resources have paved the way for Artificial Intelligence (AI) to provide potential solutions for the management of prototypical complex diseases with advanced heterogeneity and alternating disease states, like IBD. In this thesis we assessed the current economic and psychosocial impact of IBD by assessing its effect on indirect costs, productivity and caregiving. Furthermore, we observed if we can proactively identify IBD patients’ needs using eHealth and Artificial Intelligence. Lastly, we analyze the impact of monitoring IBD patients using eHealth interventions in order to facilitate the delivery of high-value care. Show less
People diagnosed with Borderline Personality Disorder (BPD) continuously struggle with knowing who they are and maintaining relationships. Fortunately, psychotherapies for BPD have proven effective... Show morePeople diagnosed with Borderline Personality Disorder (BPD) continuously struggle with knowing who they are and maintaining relationships. Fortunately, psychotherapies for BPD have proven effective. However, not everyone benefits from treatment with particular challenges remaining in social relations and finding meaning in life. Therefore, it is important to understand how we can better support people with BPD.We know that identity disturbances relate to interpersonal difficulties but we do not really understand how. Therefore, we investigated how interactions with others are influenced by how people see themselves, in the general population and in people diagnosed with BPD. To this end, we studied brain activation and the role of childhood trauma and low self-esteem. In addition, we investigated whether self-views can be strengthened using positive memories.We found that the way people respond to critiques and compliments relates to how positive or negative they see themselves. Moreover, vivid positive memories can benefit mood and self-esteem. However, people with BPD seem to not sufficiently distance themselves from critiques nor engage in positive memories and compliments. Finding the right balance between distance from critiques and engagement with a positive self-image may break the cycle of negative self-knowledge and contribute to better social interactions. Show less
Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder with a broad spectrum of clinical features. The disease is caused by a mutation in the Huntingtin gene (HTT... Show moreHuntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder with a broad spectrum of clinical features. The disease is caused by a mutation in the Huntingtin gene (HTT) on the short arm of chromosome 4. In September 2015, the first-in-human study looking into the safety of an intrathecally administered antisense oligonucleotide therapy to reduce mutant HTT (mHTT) protein was launched in HD patients, where the drug proved to be safe and the intended mHTT lowering was demonstrated. The aim of this thesis is to find biomarkers corresponding with disease state and measuring progression in different stages of HD, which in turn can be used as suitable objective surrogate clinical trial endpoints. We put special emphasis on longitudinal study designs, as these provide the most useful clinical progression and parameter change associations. Although previous neuroimaging studies have shown potential markers, findings remain inconsistent or lacking association with disease state. As such, further exploration of neuroimaging techniques is of great relevance. Using different approaches to evaluate the potential usefulness of specific markers, we demonstrate biomarkers that may assist in the objective assessment of a potential disease-modifying intervention. Show less
Prostate cancer (PCa) is frequently treated with radiotherapy. However, depending on the aggressiveness of the disease, the risk of recurrence can be up to 35% within five years of the initial... Show moreProstate cancer (PCa) is frequently treated with radiotherapy. However, depending on the aggressiveness of the disease, the risk of recurrence can be up to 35% within five years of the initial treatment. Patients with localised recurrent PCa are candidates for curative (i.e. salvage) treatment. To overcome the toxicity associated with whole-gland approaches, focal salvage treatments target the index lesion while sparing the surrounding tissue. The studies described in this thesis elaborate on the use of quantitative multi-parametric MRI (mp-MRI) for the detection and localisation of locally recurrent PCa after radiotherapy. Pre-treatment radiomic imaging features were found to have potential to improve recurrence-risk prediction models for high-risk PCa patients treated with radiotherapy. In this thesis, the mp-MRI properties of irradiated benign tissue and recurrent tumour were characterised, with access to pathological samples. These findings can be used as a foundation to establish guidelines (which are currently absent) on how to assess and score MRI scans after radiotherapy. Improving radiological knowledge in the recurrent setting can lead to improved staging and result in better patient selection for salvage treatments. Lastly, this thesis provides evidence on how best to define the region to target, leading to a refinement of focal salvage strategies. Show less
The major challenge in analysing omic datasets is the strong dependencies which are present between samples and features. Taking into account and modelling the different dependency structures can... Show moreThe major challenge in analysing omic datasets is the strong dependencies which are present between samples and features. Taking into account and modelling the different dependency structures can lead to further improvements of our knowledge of the biological mechanisms. Therefore, improving our ability to predict diseases. This dissertation focuses on the development of new statistical methods designed to take into account the existing structures inside omic datasets by using mixed models, Gaussian graphical models, and machine learning approaches. Show less
