Computational Analysis of Structure-Activity Relationships : From Prediction to Visualization Methods

Understanding how structural modifications affect the biological activity of small molecules is one of the central themes in medicinal chemistry. By no means is structure-activity relationship (SAR) analysis a priori dependent on computational methods. However, as molecular data sets grow in size, we quickly approach our limits to access and compare structures and associated biological properties so that computational data processing and analysis often become essential. Here, different types of approaches of varying complexity for the analysis of SAR information are presented, which can be applied in the context of screening and chemical optimization projects. The first part of this thesis is dedicated to machine-learning strategies that aim at de novo ligand prediction and the preferential detection of potent hits in virtual screening. High emphasis is put on benchmarking of different strategies and a thorough evaluation of their utility in practical applications. However, an often claimed disadvantage of these prediction methods is their "black box" character because they do not necessarily reveal which structural features are associated with biological activity. Therefore, these methods are complemented by more descriptive SAR analysis approaches showing a higher degree of interpretability. Concepts from information theory are adapted to identify activity-relevant structure-derived descriptors. Furthermore, compound data mining methods exploring prespecified properties of available bioactive compounds on a large scale are designed to systematically relate molecular transformations to activity changes. Finally, these approaches are complemented by graphical methods that primarily help to access and visualize SAR data in congeneric series of compounds and allow the formulation of intuitive SAR rules applicable to the design of new compounds. The compendium of SAR analysis tools introduced in this thesis investigates SARs from different perspectives

Knowledge representation and text mining in biomedical, healthcare, and political domains

Knowledge representation and text mining can be employed to discover new knowledge and develop services by using the massive amounts of text gathered by modern information systems. The applied methods should take into account the domain-specific nature of knowledge. This thesis explores knowledge representation and text mining in three application domains. Biomolecular events can be described very precisely and concisely with appropriate representation schemes. Protein–protein interactions are commonly modelled in biological databases as binary relationships, whereas the complex relationships used in text mining are rich in information. The experimental results of this thesis show that complex relationships can be reduced to binary relationships and that it is possible to reconstruct complex relationships from mixtures of linguistically similar relationships. This encourages the extraction of complex relationships from the scientific literature even if binary relationships are required by the application at hand. The experimental results on cross-validation schemes for pair-input data help to understand how existing knowledge regarding dependent instances (such those concerning protein–protein pairs) can be leveraged to improve the generalisation performance estimates of learned models. Healthcare documents and news articles contain knowledge that is more difficult to model than biomolecular events and tend to have larger vocabularies than biomedical scientific articles. This thesis describes an ontology that models patient education documents and their content in order to improve the availability and quality of such documents. The experimental results of this thesis also show that the Recall-Oriented Understudy for Gisting Evaluation measures are a viable option for the automatic evaluation of textual patient record summarisation methods and that the area under the receiver operating characteristic curve can be used in a large-scale sentiment analysis. The sentiment analysis of Reuters news corpora suggests that the Western mainstream media portrays China negatively in politics-related articles but not in general, which provides new evidence to consider in the debate over the image of China in the Western media

Graph Deep Learning: Methods and Applications

The past few years have seen the growing prevalence of deep neural networks on various application domains including image processing, computer vision, speech recognition, machine translation, self-driving cars, game playing, social networks, bioinformatics, and healthcare etc. Due to the broad applications and strong performance, deep learning, a subfield of machine learning and artificial intelligence, is changing everyone\u27s life.Graph learning has been another hot field among the machine learning and data mining communities, which learns knowledge from graph-structured data. Examples of graph learning range from social network analysis such as community detection and link prediction, to relational machine learning such as knowledge graph completion and recommender systems, to mutli-graph tasks such as graph classification and graph generation etc.An emerging new field, graph deep learning, aims at applying deep learning to graphs. To deal with graph-structured data, graph neural networks (GNNs) are invented in recent years which directly take graphs as input and output graph/node representations. Although GNNs have shown superior performance than traditional methods in tasks such as semi-supervised node classification, there still exist a wide range of other important graph learning problems where either GNNs\u27 applicabilities have not been explored or GNNs only have less satisfying performance.In this dissertation, we dive deeper into the field of graph deep learning. By developing new algorithms, architectures and theories, we push graph neural networks\u27 boundaries to a much wider range of graph learning problems. The problems we have explored include: 1) graph classification; 2) medical ontology embedding; 3) link prediction; 4) recommender systems; 5) graph generation; and 6) graph structure optimization.We first focus on two graph representation learning problems: graph classification and medical ontology embedding.For graph classification, we develop a novel deep GNN architecture which aggregates node features through a novel SortPooling layer that replaces the simple summing used in previous works. We demonstrate its state-of-the-art graph classification performance on benchmark datasets. For medical ontology embedding, we propose a novel hierarchical attention propagation model, which uses attention mechanism to learn embeddings of medical concepts from hierarchically-structured medical ontologies such as ICD-9 and CCS. We validate the learned embeddings on sequential procedure/diagnosis prediction tasks with real patient data.Then we investigate GNNs\u27 potential for predicting relations, specifically link prediction and recommender systems. For link prediction, we first develop a theory unifying various traditional link prediction heuristics, and then design a framework to automatically learn suitable heuristics from a given network based on GNNs. Our model shows unprecedented strong link prediction performance, significantly outperforming all traditional methods. For recommender systems, we propose a novel graph-based matrix completion model, which uses a GNN to learn graph structure features from the bipartite graph formed by user and item interactions. Our model not only outperforms various matrix completion baselines, but also demonstrates excellent transfer learning ability -- a model trained on MovieLens can be directly used to predict Douban movie ratings with high performance.Finally, we explore GNNs\u27 applicability to graph generation and graph structure optimization. We focus on a specific type of graphs which usually carry computations on them, namely directed acyclic graphs (DAGs). We develop a variational autoencoder (VAE) for DAGs and prove that it can injectively map computations into a latent space. This injectivity allows us to perform optimization in the continuous latent space instead of the original discrete structure space. We then apply our VAE to two types of DAGs, neural network architectures and Bayesian networks. Experiments show that our model not only generates novel and valid DAGs, but also finds high-quality neural architectures and Bayesian networks through performing Bayesian optimization in its latent space

Pattern Mining and Sense-Making Support for Enhancing the User Experience

While data mining techniques such as frequent itemset and sequence mining are well established as powerful pattern discovery tools in domains from science, medicine to business, a detriment is the lack of support for interactive exploration of high numbers of patterns generated with diverse parameter settings and the relationships among the mined patterns. To enhance the user experience, real-time query turnaround times and improved support for interactive mining are desired. There is also an increasing interest in applying data mining solutions for mobile data. Patterns mined over mobile data may enable context-aware applications ranging from automating frequently repeated tasks to providing personalized recommendations. Overall, this dissertation addresses three problems that limit the utility of data mining, namely, (a.) lack of interactive exploration tools for mined patterns, (b.) insufficient support for mining localized patterns, and (c.) high computational mining requirements prohibiting mining of patterns on smaller compute units such as a smartphone. This dissertation develops interactive frameworks for the guided exploration of mined patterns and their relationships. Contributions include the PARAS pre- processing and indexing framework; enabling analysts to gain key insights into rule relationships in a parameter space view due to the compact storage of rules that enables query-time reconstruction of complete rulesets. Contributions also include the visual rule exploration framework FIRE that presents an interactive dual view of the parameter space and the rule space, that together enable enhanced sense-making of rule relationships. This dissertation also supports the online mining of localized association rules computed on data subsets by selectively deploying alternative execution strategies that leverage multidimensional itemset-based data partitioning index. Finally, we designed OLAPH, an on-device context-aware service that learns phone usage patterns over mobile context data such as app usage, location, call and SMS logs to provide device intelligence. Concepts introduced for modeling mobile data as sequences include compressing context logs to intervaled context events, adding generalized time features, and identifying meaningful sequences via filter expressions

Concept graphs: Applications to biomedical text categorization and concept extraction

As science advances, the underlying literature grows rapidly providing valuable knowledge mines for researchers and practitioners. The text content that makes up these knowledge collections is often unstructured and, thus, extracting relevant or novel information could be nontrivial and costly. In addition, human knowledge and expertise are being transformed into structured digital information in the form of vocabulary databases and ontologies. These knowledge bases hold substantial hierarchical and semantic relationships of common domain concepts. Consequently, automating learning tasks could be reinforced with those knowledge bases through constructing human-like representations of knowledge. This allows developing algorithms that simulate the human reasoning tasks of content perception, concept identification, and classification. This study explores the representation of text documents using concept graphs that are constructed with the help of a domain ontology. In particular, the target data sets are collections of biomedical text documents, and the domain ontology is a collection of predefined biomedical concepts and relationships among them. The proposed representation preserves those relationships and allows using the structural features of graphs in text mining and learning algorithms. Those features emphasize the significance of the underlying relationship information that exists in the text content behind the interrelated topics and concepts of a text document. The experiments presented in this study include text categorization and concept extraction applied on biomedical data sets. The experimental results demonstrate how the relationships extracted from text and captured in graph structures can be used to improve the performance of the aforementioned applications. The discussed techniques can be used in creating and maintaining digital libraries through enhancing indexing, retrieval, and management of documents as well as in a broad range of domain-specific applications such as drug discovery, hypothesis generation, and the analysis of molecular structures in chemoinformatics

Supervision distante pour l'apprentissage de structures discursives dans les conversations multi-locuteurs

L'objectif principal de cette thèse est d'améliorer l'inférence automatique pour la modélisation et la compréhension des communications humaines. En particulier, le but est de faciliter considérablement l'analyse du discours afin d'implémenter, au niveau industriel, des outils d'aide à l'exploration des conversations. Il s'agit notamment de la production de résumés automatiques, de recommandations, de la détection des actes de dialogue, de l'identification des décisions, de la planification et des relations sémantiques entre les actes de dialogue afin de comprendre les dialogues. Dans les conversations à plusieurs locuteurs, il est important de comprendre non seulement le sens de l'énoncé d'un locuteur et à qui il s'adresse, mais aussi les relations sémantiques qui le lient aux autres énoncés de la conversation et qui donnent lieu à différents fils de discussion. Une réponse doit être reconnue comme une réponse à une question particulière ; un argument, comme un argument pour ou contre une proposition en cours de discussion ; un désaccord, comme l'expression d'un point de vue contrasté par rapport à une autre idée déjà exprimée. Malheureusement, les données de discours annotées à la main et de qualités sont coûteuses et prennent du temps, et nous sommes loin d'en avoir assez pour entraîner des modèles d'apprentissage automatique traditionnels, et encore moins des modèles d'apprentissage profond. Il est donc nécessaire de trouver un moyen plus efficace d'annoter en structures discursives de grands corpus de conversations multi-locuteurs, tels que les transcriptions de réunions ou les chats. Un autre problème est qu'aucune quantité de données ne sera suffisante pour permettre aux modèles d'apprentissage automatique d'apprendre les caractéristiques sémantiques des relations discursives sans l'aide d'un expert ; les données sont tout simplement trop rares. Les relations de longue distance, dans lesquelles un énoncé est sémantiquement connecté non pas à l'énoncé qui le précède immédiatement, mais à un autre énoncé plus antérieur/tôt dans la conversation, sont particulièrement difficiles et rares, bien que souvent centrales pour la compréhension. Notre objectif dans cette thèse a donc été non seulement de concevoir un modèle qui prédit la structure du discours pour une conversation multipartite sans nécessiter de grandes quantités de données annotées manuellement, mais aussi de développer une approche qui soit transparente et explicable afin qu'elle puisse être modifiée et améliorée par des experts.The main objective of this thesis is to improve the automatic capture of semantic information with the goal of modeling and understanding human communication. We have advanced the state of the art in discourse parsing, in particular in the retrieval of discourse structure from chat, in order to implement, at the industrial level, tools to help explore conversations. These include the production of automatic summaries, recommendations, dialogue acts detection, identification of decisions, planning and semantic relations between dialogue acts in order to understand dialogues. In multi-party conversations it is important to not only understand the meaning of a participant's utterance and to whom it is addressed, but also the semantic relations that tie it to other utterances in the conversation and give rise to different conversation threads. An answer must be recognized as an answer to a particular question; an argument, as an argument for or against a proposal under discussion; a disagreement, as the expression of a point of view contrasted with another idea already expressed. Unfortunately, capturing such information using traditional supervised machine learning methods from quality hand-annotated discourse data is costly and time-consuming, and we do not have nearly enough data to train these machine learning models, much less deep learning models. Another problem is that arguably, no amount of data will be sufficient for machine learning models to learn the semantic characteristics of discourse relations without some expert guidance; the data are simply too sparse. Long distance relations, in which an utterance is semantically connected not to the immediately preceding utterance, but to another utterance from further back in the conversation, are particularly difficult and rare, though often central to comprehension. It is therefore necessary to find a more efficient way to retrieve discourse structures from large corpora of multi-party conversations, such as meeting transcripts or chats. This is one goal this thesis achieves. In addition, we not only wanted to design a model that predicts discourse structure for multi-party conversation without requiring large amounts of hand-annotated data, but also to develop an approach that is transparent and explainable so that it can be modified and improved by experts. The method detailed in this thesis achieves this goal as well

Close and Distant Reading Visualizations for the Comparative Analysis of Digital Humanities Data

Traditionally, humanities scholars carrying out research on a specific or on multiple literary work(s) are interested in the analysis of related texts or text passages. But the digital age has opened possibilities for scholars to enhance their traditional workflows. Enabled by digitization projects, humanities scholars can nowadays reach a large number of digitized texts through web portals such as Google Books or Internet Archive. Digital editions exist also for ancient texts; notable examples are PHI Latin Texts and the Perseus Digital Library. This shift from reading a single book “on paper” to the possibility of browsing many digital texts is one of the origins and principal pillars of the digital humanities domain, which helps developing solutions to handle vast amounts of cultural heritage data – text being the main data type. In contrast to the traditional methods, the digital humanities allow to pose new research questions on cultural heritage datasets. Some of these questions can be answered with existent algorithms and tools provided by the computer science domain, but for other humanities questions scholars need to formulate new methods in collaboration with computer scientists. Developed in the late 1980s, the digital humanities primarily focused on designing standards to represent cultural heritage data such as the Text Encoding Initiative (TEI) for texts, and to aggregate, digitize and deliver data. In the last years, visualization techniques have gained more and more importance when it comes to analyzing data. For example, Saito introduced her 2010 digital humanities conference paper with: “In recent years, people have tended to be overwhelmed by a vast amount of information in various contexts. Therefore, arguments about ’Information Visualization’ as a method to make information easy to comprehend are more than understandable.” A major impulse for this trend was given by Franco Moretti. In 2005, he published the book “Graphs, Maps, Trees”, in which he proposes so-called distant reading approaches for textual data that steer the traditional way of approaching literature towards a completely new direction. Instead of reading texts in the traditional way – so-called close reading –, he invites to count, to graph and to map them. In other words, to visualize them. This dissertation presents novel close and distant reading visualization techniques for hitherto unsolved problems. Appropriate visualization techniques have been applied to support basic tasks, e.g., visualizing geospatial metadata to analyze the geographical distribution of cultural heritage data items or using tag clouds to illustrate textual statistics of a historical corpus. In contrast, this dissertation focuses on developing information visualization and visual analytics methods that support investigating research questions that require the comparative analysis of various digital humanities datasets. We first take a look at the state-of-the-art of existing close and distant reading visualizations that have been developed to support humanities scholars working with literary texts. We thereby provide a taxonomy of visualization methods applied to show various aspects of the underlying digital humanities data. We point out open challenges and we present our visualizations designed to support humanities scholars in comparatively analyzing historical datasets. In short, we present (1) GeoTemCo for the comparative visualization of geospatial-temporal data, (2) the two tag cloud designs TagPies and TagSpheres that comparatively visualize faceted textual summaries, (3) TextReuseGrid and TextReuseBrowser to explore re-used text passages among the texts of a corpus, (4) TRAViz for the visualization of textual variation between multiple text editions, and (5) the visual analytics system MusikerProfiling to detect similar musicians to a given musician of interest. Finally, we summarize our and the collaboration experiences of other visualization researchers to emphasize the ingredients required for a successful project in the digital humanities, and we take a look at future challenges in that research field

Exploring the visualisation of hierarchical cybersecurity data within the Metaverse

A prototype Metaverse experience was created in which users could explore hierarchical cybersecurity data. A small group of participants were surveyed on their attitudes to the Metaverse. They then completed a short series of tasks in the environment. Questions were asked to assess if they were suffering from Cybersickness. After completing further tasks, their attitudes were surveyed regarding future uses of the metaverse in the organisation. A second cohort of participants attended an online seminar. They completed a survey about their attitudes to the Metaverse. They then watched a short video of the Metaverse experience. Afterwards, they answered questions related to their attitudes towards future uses of the metaverse in the organisation. The results of these questionnaires were assessed to see whether participants were receptive to the idea of working with data inside the Metaverse in the future.Comment: MSc Dissertatio