Knowledge-based Biomedical Data Science 2019

Knowledge-based biomedical data science (KBDS) involves the design and implementation of computer systems that act as if they knew about biomedicine. Such systems depend on formally represented knowledge in computer systems, often in the form of knowledge graphs. Here we survey the progress in the last year in systems that use formally represented knowledge to address data science problems in both clinical and biological domains, as well as on approaches for creating knowledge graphs. Major themes include the relationships between knowledge graphs and machine learning, the use of natural language processing, and the expansion of knowledge-based approaches to novel domains, such as Chinese Traditional Medicine and biodiversity.Comment: Manuscript 43 pages with 3 tables; Supplemental material 43 pages with 3 table

Natural Language Processing for Drug Discovery Knowledge Graphs: promises and pitfalls

Building and analysing knowledge graphs (KGs) to aid drug discovery is a topical area of research. A salient feature of KGs is their ability to combine many heterogeneous data sources in a format that facilitates discovering connections. The utility of KGs has been exemplified in areas such as drug repurposing, with insights made through manual exploration and modelling of the data. In this article, we discuss promises and pitfalls of using natural language processing (NLP) to mine unstructured text typically from scientific literature as a data source for KGs. This draws on our experience of initially parsing structured data sources such as ChEMBL as the basis for data within a KG, and then enriching or expanding upon them using NLP. The fundamental promise of NLP for KGs is the automated extraction of data from millions of documents a task practically impossible to do via human curation alone. However, there are many potential pitfalls in NLP-KG pipelines such as incorrect named entity recognition and ontology linking all of which could ultimately lead to erroneous inferences and conclusions.Comment: 17 pages, 7 figure

Accelerating COVID-19 research with graph mining and transformer-based learning

In 2020, the White House released the, "Call to Action to the Tech Community on New Machine Readable COVID-19 Dataset," wherein artificial intelligence experts are asked to collect data and develop text mining techniques that can help the science community answer high-priority scientific questions related to COVID-19. The Allen Institute for AI and collaborators announced the availability of a rapidly growing open dataset of publications, the COVID-19 Open Research Dataset (CORD-19). As the pace of research accelerates, biomedical scientists struggle to stay current. To expedite their investigations, scientists leverage hypothesis generation systems, which can automatically inspect published papers to discover novel implicit connections. We present an automated general purpose hypothesis generation systems AGATHA-C and AGATHA-GP for COVID-19 research. The systems are based on graph-mining and the transformer model. The systems are massively validated using retrospective information rediscovery and proactive analysis involving human-in-the-loop expert analysis. Both systems achieve high-quality predictions across domains (in some domains up to 0.97% ROC AUC) in fast computational time and are released to the broad scientific community to accelerate biomedical research. In addition, by performing the domain expert curated study, we show that the systems are able to discover on-going research findings such as the relationship between COVID-19 and oxytocin hormone

Computationally Linking Chemical Exposure to Molecular Effects with Complex Data: Comparing Methods to Disentangle Chemical Drivers in Environmental Mixtures and Knowledge-based Deep Learning for Predictions in Environmental Toxicology

Chemical exposures affect the environment and may lead to adverse outcomes in its organisms. Omics-based approaches, like standardised microarray experiments, have expanded the toolbox to monitor the distribution of chemicals and assess the risk to organisms in the environment. The resulting complex data have extended the scope of toxicological knowledge bases and published literature. A plethora of computational approaches have been applied in environmental toxicology considering systems biology and data integration. Still, the complexity of environmental and biological systems given in data challenges investigations of exposure-related effects. This thesis aimed at computationally linking chemical exposure to biological effects on the molecular level considering sources of complex environmental data. The first study employed data of an omics-based exposure study considering mixture effects in a freshwater environment. We compared three data-driven analyses in their suitability to disentangle mixture effects of chemical exposures to biological effects and their reliability in attributing potentially adverse outcomes to chemical drivers with toxicological databases on gene and pathway levels. Differential gene expression analysis and a network inference approach resulted in toxicologically meaningful outcomes and uncovered individual chemical effects — stand-alone and in combination. We developed an integrative computational strategy to harvest exposure-related gene associations from environmental samples considering mixtures of lowly concentrated compounds. The applied approaches allowed assessing the hazard of chemicals more systematically with correlation-based compound groups. This dissertation presents another achievement toward a data-driven hypothesis generation for molecular exposure effects. The approach combined text-mining and deep learning. The study was entirely data-driven and involved state-of-the-art computational methods of artificial intelligence. We employed literature-based relational data and curated toxicological knowledge to predict chemical-biomolecule interactions. A word embedding neural network with a subsequent feed-forward network was implemented. Data augmentation and recurrent neural networks were beneficial for training with curated toxicological knowledge. The trained models reached accuracies of up to 94% for unseen test data of the employed knowledge base. However, we could not reliably confirm known chemical-gene interactions across selected data sources. Still, the predictive models might derive unknown information from toxicological knowledge sources, like literature, databases or omics-based exposure studies. Thus, the deep learning models might allow predicting hypotheses of exposure-related molecular effects. Both achievements of this dissertation might support the prioritisation of chemicals for testing and an intelligent selection of chemicals for monitoring in future exposure studies.:Table of Contents ... I Abstract ... V Acknowledgements ... VII Prelude ... IX 1 Introduction 1.1 An overview of environmental toxicology ... 2 1.1.1 Environmental toxicology ... 2 1.1.2 Chemicals in the environment ... 4 1.1.3 Systems biological perspectives in environmental toxicology ... 7 Computational toxicology ... 11 1.2.1 Omics-based approaches ... 12 1.2.2 Linking chemical exposure to transcriptional effects ... 14 1.2.3 Up-scaling from the gene level to higher biological organisation levels ... 19 1.2.4 Biomedical literature-based discovery ... 24 1.2.5 Deep learning with knowledge representation ... 27 1.3 Research question and approaches ... 29 2 Methods and Data ... 33 2.1 Linking environmental relevant mixture exposures to transcriptional effects ... 34 2.1.1 Exposure and microarray data ... 34 2.1.2 Preprocessing ... 35 2.1.3 Differential gene expression ... 37 2.1.4 Association rule mining ... 38 2.1.5 Weighted gene correlation network analysis ... 39 2.1.6 Method comparison ... 41 Predicting exposure-related effects on a molecular level ... 44 2.2.1 Input ... 44 2.2.2 Input preparation ... 47 2.2.3 Deep learning models ... 49 2.2.4 Toxicogenomic application ... 54 3 Method comparison to link complex stream water exposures to effects on the transcriptional level ... 57 3.1 Background and motivation ... 58 3.1.1 Workflow ... 61 3.2 Results ... 62 3.2.1 Data preprocessing ... 62 3.2.2 Differential gene expression analysis ... 67 3.2.3 Association rule mining ... 71 3.2.4 Network inference ... 78 3.2.5 Method comparison ... 84 3.2.6 Application case of method integration ... 87 3.3 Discussion ... 91 3.4 Conclusion ... 99 4 Deep learning prediction of chemical-biomolecule interactions ... 101 4.1 Motivation ... 102 4.1.1Workflow ...105 4.2 Results ... 107 4.2.1 Input preparation ... 107 4.2.2 Model selection ... 110 4.2.3 Model comparison ... 118 4.2.4 Toxicogenomic application ... 121 4.2.5 Horizontal augmentation without tail-padding ...123 4.2.6 Four-class problem formulation ... 124 4.2.7 Training with CTD data ... 125 4.3 Discussion ... 129 4.3.1 Transferring biomedical knowledge towards toxicology ... 129 4.3.2 Deep learning with biomedical knowledge representation ...133 4.3.3 Data integration ...136 4.4 Conclusion ... 141 5 Conclusion and Future perspectives ... 143 5.1 Conclusion ... 143 5.1.1 Investigating complex mixtures in the environment ... 144 5.1.2 Complex knowledge from literature and curated databases predict chemical- biomolecule interactions ... 145 5.1.3 Linking chemical exposure to biological effects by integrating CTD ... 146 5.2 Future perspectives ... 147 S1 Supplement Chapter 1 ... 153 S1.1 Example of an estrogen bioassay ... 154 S1.2 Types of mode of action ... 154 S1.3 The dogma of molecular biology ... 157 S1.4 Transcriptomics ... 159 S2 Supplement Chapter 3 ... 161 S3 Supplement Chapter 4 ... 175 S3.1 Hyperparameter tuning results ... 176 S3.2 Functional enrichment with predicted chemical-gene interactions and CTD reference pathway genesets ... 179 S3.3 Reduction of learning rate in a model with large word embedding vectors ... 183 S3.4 Horizontal augmentation without tail-padding ... 183 S3.5 Four-relationship classification ... 185 S3.6 Interpreting loss observations for SemMedDB trained models ... 187 List of Abbreviations ... i List of Figures ... vi List of Tables ... x Bibliography ... xii Curriculum scientiae ... xxxix Selbständigkeitserklärung ... xlii

Doctor of Philosophy

dissertationThe use of the various complementary and alternative medicine (CAM) modalities for the management of chronic illnesses is widespread, and still on the rise. Unfortunately, tools to support consumers in seeking information on the efficacy of these treatments are sparse and incomplete. The goals of this work were to understand CAM information needs in acquiring CAM information, assess currently available information resources, and investigate informatics methods to provide a foundation for the development of CAM information resources. This dissertation consists of four studies. The first was a quantitative study that aimed to assess the feasibility of delivering CAM-drug interaction information through a web-based application. This study resulted in an 85% participation rate and 33% of those patients reported the use of CAMs that had potential interactions with their conventional treatments. The next study aimed to assess online CAM information resources that provide information on drug-herb interactions to consumers. None of the sites scored high on the combination of completeness and accuracy and all sites were beyond the recommended reading level per the US Department of Health and Human Services. The third study investigated information-seeking behaviors for CAM information using an existing cohort of cancer survivors. The study showed that patients in the cohort continued to use CAM well into survivorship. Patients felt very much on their own in dealing with issues outside of direct treatment, which often resulted in a search for options and CAM use. Finally, a study was conducted to investigate two methods to semi-automatically extract CAM treatment relations from the biomedical literature. The methods rely on a database (SemMedDB) of semantic relations extracted from PubMed abstracts. This study demonstrated that SemMedDB can be used to reduce manual efforts, but review of the extracted sentences is still necessary due to a low mean precision of 23.7% and 26.4%. In summary, this dissertation provided greater insight into consumer information needs for CAM. Our findings provide an opportunity to leverage existing resources to improve the information-seeking experience for consumers through high-quality online tools, potentially moving them beyond the reliance on anecdotal evidence in the decision-making process for CAM

Fast Machine Learning Algorithms for Massive Datasets with Applications in the Biomedical Domain

The continuous increase in the size of datasets introduces computational challenges for machine learning algorithms. In this dissertation, we cover the machine learning algorithms and applications in large-scale data analysis in manufacturing and healthcare. We begin with introducing a multilevel framework to scale the support vector machine (SVM), a popular supervised learning algorithm with a few tunable hyperparameters and highly accurate prediction. The computational complexity of nonlinear SVM is prohibitive on large-scale datasets compared to the linear SVM, which is more scalable for massive datasets. The nonlinear SVM has shown to produce significantly higher classification quality on complex and highly imbalanced datasets. However, a higher classification quality requires a computationally expensive quadratic programming solver and extra kernel parameters for model selection. We introduce a generalized fast multilevel framework for regular, weighted, and instance weighted SVM that achieves similar or better classification quality compared to the state-of-the-art SVM libraries such as LIBSVM. Our framework improves the runtime more than two orders of magnitude for some of the well-known benchmark datasets. We cover multiple versions of our proposed framework and its implementation in detail. The framework is implemented using PETSc library which allows easy integration with scientific computing tasks. Next, we propose an adaptive multilevel learning framework for SVM to reduce the variance between prediction qualities across the levels, improve the overall prediction accuracy, and boost the runtime. We implement multi-threaded support to speed up the parameter fitting runtime that results in more than an order of magnitude speed-up. We design an early stopping criteria to reduce the extra computational cost when we achieve expected prediction quality. This approach provides significant speed-up, especially for massive datasets. Finally, we propose an efficient low dimensional feature extraction over massive knowledge networks. Knowledge networks are becoming more popular in the biomedical domain for knowledge representation. Each layer in knowledge networks can store the information from one or multiple sources of data. The relationships between concepts or between layers represent valuable information. The proposed feature engineering approach provides an efficient and highly accurate prediction of the relationship between biomedical concepts on massive datasets. Our proposed approach utilizes semantics and probabilities to reduce the potential search space for the exploration and learning of machine learning algorithms. The calculation of probabilities is highly scalable with the size of the knowledge network. The number of features is fixed and equivalent to the number of relationships or classes in the data. A comprehensive comparison of well-known classifiers such as random forest, SVM, and deep learning over various features extracted from the same dataset, provides an overview for performance and computational trade-offs. Our source code, documentation and parameters will be available at https://github.com/esadr/

Exploiting Latent Features of Text and Graphs

As the size and scope of online data continues to grow, new machine learning techniques become necessary to best capitalize on the wealth of available information. However, the models that help convert data into knowledge require nontrivial processes to make sense of large collections of text and massive online graphs. In both scenarios, modern machine learning pipelines produce embeddings --- semantically rich vectors of latent features --- to convert human constructs for machine understanding. In this dissertation we focus on information available within biomedical science, including human-written abstracts of scientific papers, as well as machine-generated graphs of biomedical entity relationships. We present the Moliere system, and our method for identifying new discoveries through the use of natural language processing and graph mining algorithms. We propose heuristically-based ranking criteria to augment Moliere, and leverage this ranking to identify a new gene-treatment target for HIV-associated Neurodegenerative Disorders. We additionally focus on the latent features of graphs, and propose a new bipartite graph embedding technique. Using our graph embedding, we advance the state-of-the-art in hypergraph partitioning quality. Having newfound intuition of graph embeddings, we present Agatha, a deep-learning approach to hypothesis generation. This system learns a data-driven ranking criteria derived from the embeddings of our large proposed biomedical semantic graph. To produce human-readable results, we additionally propose CBAG, a technique for conditional biomedical abstract generation

The Knowledge Graph Construction in the Educational Domain: Take an Australian School Science Course as an Example

The evolution of the Internet technology and artificial intelligence has changed the ways we gain knowledge, which has expanded to every aspect of our lives. In recent years, Knowledge Graphs technology as one of the artificial intelligence techniques has been widely used in the educational domain. However, there are few studies dedicating the construction of knowledge graphs for K-10 education in Australia, and most of the existing studies only focus on at the theory level, and little research shows practical pipeline steps to complete the complex flow of constructing the educational knowledge graph. Apart from that, most studies focused on concept entities and their relations but ignored the features of concept entities and the relations between learning knowledge points and required learning outcomes. To overcome these shortages and provide the data foundation for the development of downstream research and applications in this educational domain, the construction processes of building a knowledge graph for Australian K-10 education were analyzed at the theory level and implemented in a practical way in this research. We took the Year 9 science course as a typical data source example fed to the proposed method called K10EDU-RCF-KG to construct this educational knowledge graph and to enrich the features of entities in the knowledge graph. In the construction pipeline, a variety of techniques were employed to complete the building process. Firstly, the POI and OCR techniques were applied to convert Word and PDF format files into text, followed by developing an educational resources management platform where the machine-readable text could be stored in a relational database management system. Secondly, we designed an architecture framework as the guidance of the construction pipeline. According to this architecture, the educational ontology was initially designed, and a backend microservice was developed to process the entity extraction and relation extraction by NLP-NER and probabilistic association rule mining algorithms, respectively. We also adopted the NLP-POS technique to find out the neighbor adjectives related to entitles to enrich features of these concept entitles. In addition, a subject dictionary was introduced during the refinement process of the knowledge graph, which reduced the data noise rate of the knowledge graph entities. Furthermore, the connections between learning outcome entities and topic knowledge point entities were directly connected, which provides a clear and efficient way to identify what corresponding learning objectives are related to the learning unit. Finally, a set of REST APIs for querying this educational knowledge graph were developed