Approaches For Capturing Time-Varying Functional Network Connectivity With Application to Normative Development and Mental Illness

Since the beginning of medical science, the human brain has remained an unsolved puzzle; an illusive organ that controls everything- from breathing to heartbeats, from emotion to anger, and more. With the power of advanced neuroimaging techniques, scientists have now started to solve this nearly impossible puzzle, piece by piece. Over the past decade, various in vivo techniques, including functional magnetic resonance imaging (fMRI), have been increasingly used to understand brain functions. fMRI is extensively being used to facilitate the identification of various neuropsychological disorders such as schizophrenia (SZ), bipolar disorder (BP) and autism spectrum disorder (ASD). These disorders are currently diagnosed based on patients’ self-reported experiences, and observed symptoms and behaviors over the course of the illnesses. Therefore, efficient identification of biological-based markers (biomarkers) can lead to early diagnosis of these mental disorders, and provide a trajectory for disease progression. By applying advanced machine learning techniques on fMRI data, significant differences in brain function among patients with mental disorders and healthy controls can be identified. Moreover, by jointly estimating information from multiple modalities, such as, functional brain data and genetic factors, we can now investigate the relationship between brain function and genes. Functional connectivity (FC) has become a very common measure to characterize brain functions, where FC is defined as the temporal covariance of neural signals between multiple spatially distinct brain regions. Recently, researchers are studying the FC among functionally specialized brain networks which can be defined as a higher level of FC, and is termed as functional network connectivity (FNC, defined as the correlation value that summarizes the overall connection between brain ‘networks’ over time). Most functional connectivity studies have made the limiting assumption that connectivity is stationary over multiple minutes, and ignore to identify the time-varying and reoccurring patterns of FNC among brain regions (known as time-varying FNC). In this dissertation, we demonstrate the use of time-varying FNC features as potential biomarkers to differentiate between patients with mental disorders and healthy subjects. The developmental characteristics of time-varying FNC in children with typically developing brain and ASD have been extensively studies in a cross-sectional framework, and age-, sex- and disease-related FNC profiles have been proposed. Also, time-varying FNC is characterized in healthy adults and patients with severe mental disorders (SZ and BP). Moreover, an efficient classification algorithm is designed to identify patients and controls at individual level. Finally, a new framework is proposed to jointly utilize information from brain’s functional network connectivity and genetic features to find the associations between them. The frameworks that we presented here can help us understand the important role played by time-varying FNC to identify potential biomarkers for the diagnosis of severe mental disorders

Statistical inference from large-scale genomic data

This thesis explores the potential of statistical inference methodologies in their applications in functional genomics. In essence, it summarises algorithmic findings in this field, providing step-by-step analytical methodologies for deciphering biological knowledge from large-scale genomic data, mainly microarray gene expression time series. This thesis covers a range of topics in the investigation of complex multivariate genomic data. One focus involves using clustering as a method of inference and another is cluster validation to extract meaningful biological information from the data. Information gained from the application of these various techniques can then be used conjointly in the elucidation of gene regulatory networks, the ultimate goal of this type of analysis. First, a new tight clustering method for gene expression data is proposed to obtain tighter and potentially more informative gene clusters. Next, to fully utilise biological knowledge in clustering validation, a validity index is defined based on one of the most important ontologies within the Bioinformatics community, Gene Ontology. The method bridges a gap in current literature, in the sense that it takes into account not only the variations of Gene Ontology categories in biological specificities and their significance to the gene clusters, but also the complex structure of the Gene Ontology. Finally, Bayesian probability is applied to making inference from heterogeneous genomic data, integrated with previous efforts in this thesis, for the aim of large-scale gene network inference. The proposed system comes with a stochastic process to achieve robustness to noise, yet remains efficient enough for large-scale analysis. Ultimately, the solutions presented in this thesis serve as building blocks of an intelligent system for interpreting large-scale genomic data and understanding the functional organisation of the genome

Statistical inference from large-scale genomic data

This thesis explores the potential of statistical inference methodologies in their applications in functional genomics. In essence, it summarises algorithmic findings in this field, providing step-by-step analytical methodologies for deciphering biological knowledge from large-scale genomic data, mainly microarray gene expression time series. This thesis covers a range of topics in the investigation of complex multivariate genomic data. One focus involves using clustering as a method of inference and another is cluster validation to extract meaningful biological information from the data. Information gained from the application of these various techniques can then be used conjointly in the elucidation of gene regulatory networks, the ultimate goal of this type of analysis. First, a new tight clustering method for gene expression data is proposed to obtain tighter and potentially more informative gene clusters. Next, to fully utilise biological knowledge in clustering validation, a validity index is defined based on one of the most important ontologies within the Bioinformatics community, Gene Ontology. The method bridges a gap in current literature, in the sense that it takes into account not only the variations of Gene Ontology categories in biological specificities and their significance to the gene clusters, but also the complex structure of the Gene Ontology. Finally, Bayesian probability is applied to making inference from heterogeneous genomic data, integrated with previous efforts in this thesis, for the aim of large-scale gene network inference. The proposed system comes with a stochastic process to achieve robustness to noise, yet remains efficient enough for large-scale analysis. Ultimately, the solutions presented in this thesis serve as building blocks of an intelligent system for interpreting large-scale genomic data and understanding the functional organisation of the genome.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Development of methods for Omics Network inference and analysis and their application to disease modeling

With the advent of Next Generation Sequencing (NGS) technologies and the emergence of large publicly available genomics data comes an unprecedented opportunity to model biological networks through a holistic lens using a systems-based approach. Networks provide a mathematical framework for representing biological phenomena that go beyond standard one-gene-at-a-time analyses. Networks can model system-level patterns and the molecular rewiring (i.e. changes in connectivity) occurring in response to perturbations or between distinct phenotypic groups or cell types. This in turn supports the identification of putative mechanisms of actions of the biological processes under study, and thus have the potential to advance prevention and therapy. However, there are major challenges faced by researchers. Inference of biological network structures is often performed on high-dimensional data, yet is hindered by the limited sample size of high throughput omics data. Furthermore, modeling biological networks involves complex analyses capable of integrating multiple sources of omics layers and summarizing large amounts of information. My dissertation aims to address these challenges by presenting new approaches for high-dimensional network inference with limit sample sizes as well as methods and tools for integrated network analysis applied to multiple research domains in cancer genomics. First, I introduce a novel method for reconstructing gene regulatory networks called SHINE (Structure Learning for Hierarchical Networks) and present an evaluation on simulated and real datasets including a Pan-Cancer analysis using The Cancer Genome Atlas (TCGA) data. Next, I summarize the challenges with executing and managing data processing workflows for large omics datasets on high performance computing environments and present multiple strategies for using Nextflow for reproducible scientific workflows including shine-nf - a collection of Nextflow modules for structure learning. Lastly, I introduce the methods, objects, and tools developed for the analysis of biological networks used throughout my dissertation work. Together - these contributions were used in focused analyses of understanding the molecular mechanisms of tumor maintenance and progression in subtype networks of Breast Cancer and Head and Neck Squamous Cell Carcinoma

Conditional Behavior Prediction of Interacting Agents on Map Graphs with Neural Networks

Solange Verkehrsteilnehmer ihre Manöverabsicht und ihre geplante Trajektorie automatischen Fahrzeugen nicht mitteilen können, ist eine Verhaltensvorhersage für alle beteiligten Verkehrsteilnehmer erforderlich. Mit einer solchen Vorhersage kann das Verhalten eines automatischen Fahrzeugs vorausschauend generiert und damit komfortabler und energieeffizienter gemacht werden, was den Verkehrsfluss verbessert. Es wird ein künstliches neuronales Netz für Graphen (GNN) vorgestellt, das verschiedene probabilistische Positionsvorhersagen für interagierende Agenten zur Analyse bereitstellt. Das vorliegende Anwendungsbeispiel ist die Verkehrssituationsanalyse für das automatische Fahren, für welches ein diskretisierter Vorhersagezeitraum von einigen Sekunden als relevant angesehen wird. Das GNN propagiert einen vollvernetzten, gerichteten Agentengraphen probabilistisch durch einen dünnvernetzten, gerichteten Kartengraphen. Merkmale des Agentengraphen, der aus Verkehrsteilnehmern und deren Beziehungen besteht, sowie Merkmale des Kartengraphen, der aus Fahrbahnstücken und deren geometrischer, sowie verkehrsregelbezogenen Verbindungen besteht, können für die Vorhersage verwertet werden. Das Modell prädiziert für jeden Agenten zu jedem Prädiktionszeitpunkt eine diskrete Aufenthaltswahrscheinlichkeitsverteilung über alle Fahrbahnstücke des Kartengraphen. Eine solche Prädiktion ist in der wissenschaftlichen Literatur zwar üblich, setzt aber für deren stochastische Interpretierbarkeit und damit Anwendbarkeit statistische Unabhängigkeit des zukünftigen Verhaltens der Verkehrsteilnehmer voraus. Da diese Annahme bei interagierenden Agenten als unzulässig erachtet wird, prädiziert das Modell darüber hinaus für alle Agentenpaare diskrete Verbundwahrscheinlichkeitsverteilungen. Aus diesen können bedingte Prädiktionen gegeben möglicher zukünftiger Positionen einer der beiden Agenten berechnet werden. In der Evaluierung werden gängige Metriken für den vorliegenden Fall angepasst und verschiedene Modellierungstiefen einander gegenübergestellt. Sowohl die individuelle Prädiktion als auch die bedingte Prädiktion werden erfolgreich auf Genauigkeit und statistischer Zuverlässigkeit untersucht

Conditional Behavior Prediction of Interacting Agents on Map Graphs with Neural Networks

Solange Verkehrsteilnehmer ihre Manöverabsicht und ihre geplante Trajektorie automatischen Fahrzeugen nicht mitteilen können, ist eine Verhaltensvorhersage für alle beteiligten Verkehrsteilnehmer erforderlich. Mit einer solchen Vorhersage kann das Verhalten eines automatischen Fahrzeugs vorausschauend generiert und damit komfortabler und energieeffizienter gemacht werden, was den Verkehrsfluss verbessert. Es wird ein künstliches neuronales Netz für Graphen (GNN) vorgestellt, das verschiedene probabilistische Positionsvorhersagen für interagierende Agenten zur Analyse bereitstellt. Das vorliegende Anwendungsbeispiel ist die Verkehrssituationsanalyse für das automatische Fahren, für welches ein diskretisierter Vorhersagezeitraum von einigen Sekunden als relevant angesehen wird. Das GNN propagiert einen vollvernetzten, gerichteten Agentengraphen probabilistisch durch einen dünnvernetzten, gerichteten Kartengraphen. Merkmale des Agentengraphen, der aus Verkehrsteilnehmern und deren Beziehungen besteht, sowie Merkmale des Kartengraphen, der aus Fahrbahnstücken und deren geometrischer, sowie verkehrsregelbezogenen Verbindungen besteht, können für die Vorhersage verwertet werden. Das Modell prädiziert für jeden Agenten zu jedem Prädiktionszeitpunkt eine diskrete Aufenthaltswahrscheinlichkeitsverteilung über alle Fahrbahnstücke des Kartengraphen. Eine solche Prädiktion ist in der wissenschaftlichen Literatur zwar üblich, setzt aber für deren stochastische Interpretierbarkeit und damit Anwendbarkeit statistische Unabhängigkeit des zukünftigen Verhaltens der Verkehrsteilnehmer voraus. Da diese Annahme bei interagierenden Agenten als unzulässig erachtet wird, prädiziert das Modell darüber hinaus für alle Agentenpaare diskrete Verbundwahrscheinlichkeitsverteilungen. Aus diesen können bedingte Prädiktionen gegeben möglicher zukünftiger Positionen einer der beiden Agenten berechnet werden. In der Evaluierung werden gängige Metriken für den vorliegenden Fall angepasst und verschiedene Modellierungstiefen einander gegenübergestellt. Sowohl die individuelle Prädiktion als auch die bedingte Prädiktion werden erfolgreich auf Genauigkeit und statistischer Zuverlässigkeit untersucht

Towards a Common Software/Hardware Methodology for Future Advanced Driver Assistance Systems

The European research project DESERVE (DEvelopment platform for Safe and Efficient dRiVE, 2012-2015) had the aim of designing and developing a platform tool to cope with the continuously increasing complexity and the simultaneous need to reduce cost for future embedded Advanced Driver Assistance Systems (ADAS). For this purpose, the DESERVE platform profits from cross-domain software reuse, standardization of automotive software component interfaces, and easy but safety-compliant integration of heterogeneous modules. This enables the development of a new generation of ADAS applications, which challengingly combine different functions, sensors, actuators, hardware platforms, and Human Machine Interfaces (HMI). This book presents the different results of the DESERVE project concerning the ADAS development platform, test case functions, and validation and evaluation of different approaches. The reader is invited to substantiate the content of this book with the deliverables published during the DESERVE project. Technical topics discussed in this book include:Modern ADAS development platforms;Design space exploration;Driving modelling;Video-based and Radar-based ADAS functions;HMI for ADAS;Vehicle-hardware-in-the-loop validation system