A primer on correlation-based dimension reduction methods for multi-omics analysis

The continuing advances of omic technologies mean that it is now more tangible to measure the numerous features collectively reflecting the molecular properties of a sample. When multiple omic methods are used, statistical and computational approaches can exploit these large, connected profiles. Multi-omics is the integration of different omic data sources from the same biological sample. In this review, we focus on correlation-based dimension reduction approaches for single omic datasets, followed by methods for pairs of omics datasets, before detailing further techniques for three or more omic datasets. We also briefly detail network methods when three or more omic datasets are available and which complement correlation-oriented tools. To aid readers new to this area, these are all linked to relevant R packages that can implement these procedures. Finally, we discuss scenarios of experimental design and present road maps that simplify the selection of appropriate analysis methods. This review will guide researchers navigate the emerging methods for multi-omics and help them integrate diverse omic datasets appropriately and embrace the opportunity of population multi-omics.Comment: 30 pages, 2 figures, 6 table

Probabilistic methods in the analysis of protein interaction networks

Imperial Users onl

Immersive analytics for oncology patient cohorts

This thesis proposes a novel interactive immersive analytics tool and methods to interrogate the cancer patient cohort in an immersive virtual environment, namely Virtual Reality to Observe Oncology data Models (VROOM). The overall objective is to develop an immersive analytics platform, which includes a data analytics pipeline from raw gene expression data to immersive visualisation on virtual and augmented reality platforms utilising a game engine. Unity3D has been used to implement the visualisation. Work in this thesis could provide oncologists and clinicians with an interactive visualisation and visual analytics platform that helps them to drive their analysis in treatment efficacy and achieve the goal of evidence-based personalised medicine. The thesis integrates the latest discovery and development in cancer patients’ prognoses, immersive technologies, machine learning, decision support system and interactive visualisation to form an immersive analytics platform of complex genomic data. For this thesis, the experimental paradigm that will be followed is in understanding transcriptomics in cancer samples. This thesis specifically investigates gene expression data to determine the biological similarity revealed by the patient's tumour samples' transcriptomic profiles revealing the active genes in different patients. In summary, the thesis contributes to i) a novel immersive analytics platform for patient cohort data interrogation in similarity space where the similarity space is based on the patient's biological and genomic similarity; ii) an effective immersive environment optimisation design based on the usability study of exocentric and egocentric visualisation, audio and sound design optimisation; iii) an integration of trusted and familiar 2D biomedical visual analytics methods into the immersive environment; iv) novel use of the game theory as the decision-making system engine to help the analytics process, and application of the optimal transport theory in missing data imputation to ensure the preservation of data distribution; and v) case studies to showcase the real-world application of the visualisation and its effectiveness

Analysing functional genomics data using novel ensemble, consensus and data fusion techniques

Motivation: A rapid technological development in the biosciences and in computer science in the last decade has enabled the analysis of high-dimensional biological datasets on standard desktop computers. However, in spite of these technical advances, common properties of the new high-throughput experimental data, like small sample sizes in relation to the number of features, high noise levels and outliers, also pose novel challenges. Ensemble and consensus machine learning techniques and data integration methods can alleviate these issues, but often provide overly complex models which lack generalization capability and interpretability. The goal of this thesis was therefore to develop new approaches to combine algorithms and large-scale biological datasets, including novel approaches to integrate analysis types from different domains (e.g. statistics, topological network analysis, machine learning and text mining), to exploit their synergies in a manner that provides compact and interpretable models for inferring new biological knowledge. Main results: The main contributions of the doctoral project are new ensemble, consensus and cross-domain bioinformatics algorithms, and new analysis pipelines combining these techniques within a general framework. This framework is designed to enable the integrative analysis of both large- scale gene and protein expression data (including the tools ArrayMining, Top-scoring pathway pairs and RNAnalyze) and general gene and protein sets (including the tools TopoGSA , EnrichNet and PathExpand), by combining algorithms for different statistical learning tasks (feature selection, classification and clustering) in a modular fashion. Ensemble and consensus analysis techniques employed within the modules are redesigned such that the compactness and interpretability of the resulting models is optimized in addition to the predictive accuracy and robustness. The framework was applied to real-word biomedical problems, with a focus on cancer biology, providing the following main results: (1) The identification of a novel tumour marker gene in collaboration with the Nottingham Queens Medical Centre, facilitating the distinction between two clinically important breast cancer subtypes (framework tool: ArrayMining) (2) The prediction of novel candidate disease genes for Alzheimer’s disease and pancreatic cancer using an integrative analysis of cellular pathway definitions and protein interaction data (framework tool: PathExpand, collaboration with the Spanish National Cancer Centre) (3) The prioritization of associations between disease-related processes and other cellular pathways using a new rule-based classification method integrating gene expression data and pathway definitions (framework tool: Top-scoring pathway pairs) (4) The discovery of topological similarities between differentially expressed genes in cancers and cellular pathway definitions mapped to a molecular interaction network (framework tool: TopoGSA, collaboration with the Spanish National Cancer Centre) In summary, the framework combines the synergies of multiple cross-domain analysis techniques within a single easy-to-use software and has provided new biological insights in a wide variety of practical settings

Visualisation of bioinformatics datasets

Analysing the molecular polymorphism and interactions of DNA, RNA and proteins is of fundamental importance in biology. Predicting functions of polymorphic molecules is important in order to design more effective medicines. Analysing major histocompatibility complex (MHC) polymorphism is important for mate choice, epitope-based vaccine design and transplantation rejection etc. Most of the existing exploratory approaches cannot analyse these datasets because of the large number of molecules with a high number of descriptors per molecule. This thesis develops novel methods for data projection in order to explore high dimensional biological dataset by visualising them in a low-dimensional space. With increasing dimensionality, some existing data visualisation methods such as generative topographic mapping (GTM) become computationally intractable. We propose variants of these methods, where we use log-transformations at certain steps of expectation maximisation (EM) based parameter learning process, to make them tractable for high-dimensional datasets. We demonstrate these proposed variants both for synthetic and electrostatic potential dataset of MHC class-I. We also propose to extend a latent trait model (LTM), suitable for visualising high dimensional discrete data, to simultaneously estimate feature saliency as an integrated part of the parameter learning process of a visualisation model. This LTM variant not only gives better visualisation by modifying the project map based on feature relevance, but also helps users to assess the significance of each feature. Another problem which is not addressed much in the literature is the visualisation of mixed-type data. We propose to combine GTM and LTM in a principled way where appropriate noise models are used for each type of data in order to visualise mixed-type data in a single plot. We call this model a generalised GTM (GGTM). We also propose to extend GGTM model to estimate feature saliencies while training a visualisation model and this is called GGTM with feature saliency (GGTM-FS). We demonstrate effectiveness of these proposed models both for synthetic and real datasets. We evaluate visualisation quality using quality metrics such as distance distortion measure and rank based measures: trustworthiness, continuity, mean relative rank errors with respect to data space and latent space. In cases where the labels are known we also use quality metrics of KL divergence and nearest neighbour classifications error in order to determine the separation between classes. We demonstrate the efficacy of these proposed models both for synthetic and real biological datasets with a main focus on the MHC class-I dataset

A new computational framework for the classification and function prediction of long non-coding RNAs

Long non-coding RNAs (lncRNAs) are known to play a significant role in several biological processes. These RNAs possess sequence length greater than 200 base pairs (bp), and so are often misclassified as protein-coding genes. Most Coding Potential Computation (CPC) tools fail to accurately identify, classify and predict the biological functions of lncRNAs in plant genomes, due to previous research being limited to mammalian genomes. In this thesis, an investigation and extraction of various sequence and codon-bias features for identification of lncRNA sequences has been carried out, to develop a new CPC Framework. For identification of essential features, the framework implements regularisation-based selection. A novel classification algorithm is implemented, which removes the dependency on experimental datasets and provides a coordinate-based solution for sub-classification of lncRNAs. For imputing the lncRNA functions, lncRNA-protein interactions have been first determined through co-expression of genes which were re-analysed by a sequence similaritybased approach for identification of novel interactions and prediction of lncRNA functions in the genome. This integrates a D3-based application for visualisation of lncRNA sequences and their associated functions in the genome. Standard evaluation metrics such as accuracy, sensitivity, and specificity have been used for benchmarking the performance of the framework against leading CPC tools. Case study analyses were conducted with plant RNA-seq datasets for evaluating the effectiveness of the framework using a cross-validation approach. The tests show the framework can provide significant improvements on existing CPC models for plant genomes: 20-40% greater accuracy. Function prediction analysis demonstrates results are consistent with the experimentally-published findings

Analysing functional genomics data using novel ensemble, consensus and data fusion techniques

Motivation: A rapid technological development in the biosciences and in computer science in the last decade has enabled the analysis of high-dimensional biological datasets on standard desktop computers. However, in spite of these technical advances, common properties of the new high-throughput experimental data, like small sample sizes in relation to the number of features, high noise levels and outliers, also pose novel challenges. Ensemble and consensus machine learning techniques and data integration methods can alleviate these issues, but often provide overly complex models which lack generalization capability and interpretability. The goal of this thesis was therefore to develop new approaches to combine algorithms and large-scale biological datasets, including novel approaches to integrate analysis types from different domains (e.g. statistics, topological network analysis, machine learning and text mining), to exploit their synergies in a manner that provides compact and interpretable models for inferring new biological knowledge. Main results: The main contributions of the doctoral project are new ensemble, consensus and cross-domain bioinformatics algorithms, and new analysis pipelines combining these techniques within a general framework. This framework is designed to enable the integrative analysis of both large- scale gene and protein expression data (including the tools ArrayMining, Top-scoring pathway pairs and RNAnalyze) and general gene and protein sets (including the tools TopoGSA , EnrichNet and PathExpand), by combining algorithms for different statistical learning tasks (feature selection, classification and clustering) in a modular fashion. Ensemble and consensus analysis techniques employed within the modules are redesigned such that the compactness and interpretability of the resulting models is optimized in addition to the predictive accuracy and robustness. The framework was applied to real-word biomedical problems, with a focus on cancer biology, providing the following main results: (1) The identification of a novel tumour marker gene in collaboration with the Nottingham Queens Medical Centre, facilitating the distinction between two clinically important breast cancer subtypes (framework tool: ArrayMining) (2) The prediction of novel candidate disease genes for Alzheimer’s disease and pancreatic cancer using an integrative analysis of cellular pathway definitions and protein interaction data (framework tool: PathExpand, collaboration with the Spanish National Cancer Centre) (3) The prioritization of associations between disease-related processes and other cellular pathways using a new rule-based classification method integrating gene expression data and pathway definitions (framework tool: Top-scoring pathway pairs) (4) The discovery of topological similarities between differentially expressed genes in cancers and cellular pathway definitions mapped to a molecular interaction network (framework tool: TopoGSA, collaboration with the Spanish National Cancer Centre) In summary, the framework combines the synergies of multiple cross-domain analysis techniques within a single easy-to-use software and has provided new biological insights in a wide variety of practical settings

Parenclitic and Synolytic Networks Revisited

Parenclitic networks provide a powerful and relatively new way to coerce multidimensional data into a graph form, enabling the application of graph theory to evaluate features. Different algorithms have been published for constructing parenclitic networks, leading to the question-which algorithm should be chosen? Initially, it was suggested to calculate the weight of an edge between two nodes of the network as a deviation from a linear regression, calculated for a dependence of one of these features on the other. This method works well, but not when features do not have a linear relationship. To overcome this, it was suggested to calculate edge weights as the distance from the area of most probable values by using a kernel density estimation. In these two approaches only one class (typically controls or healthy population) is used to construct a model. To take account of a second class, we have introduced synolytic networks, using a boundary between two classes on the feature-feature plane to estimate the weight of the edge between these features. Common to all these approaches is that topological indices can be used to evaluate the structure represented by the graphs. To compare these network approaches alongside more traditional machine-learning algorithms, we performed a substantial analysis using both synthetic data with a priori known structure and publicly available datasets used for the benchmarking of ML-algorithms. Such a comparison has shown that the main advantage of parenclitic and synolytic networks is their resistance to over-fitting (occurring when the number of features is greater than the number of subjects) compared to other ML approaches. Secondly, the capability to visualise data in a structured form, even when this structure is not a priori available allows for visual inspection and the application of well-established graph theory to their interpretation/application, eliminating the "black-box" nature of other ML approaches