Sparse graphical models for cancer signalling

Protein signalling networks play a key role in cellular function, and their dysregulation is central to many diseases, including cancer. Recent advances in biochemical technology have begun to allow high-throughput, data-driven studies of signalling. In this thesis, we investigate multivariate statistical methods, rooted in sparse graphical models, aimed at probing questions in cancer signalling. First, we propose a Bayesian variable selection method for identifying subsets of proteins that jointly in uence an output of interest, such as drug response. Ancillary biological information is incorporated into inference using informative prior distributions. Prior information is selected and weighted in an automated manner using an empirical Bayes formulation. We present examples of informative pathway and network-based priors, and illustrate the proposed method on both synthetic and drug response data. Second, we use dynamic Bayesian networks to perform structure learning of context-specific signalling network topology from proteomic time-course data. We exploit a connection between variable selection and network structure learning to efficiently carry out exact inference. Existing biology is incorporated using informative network priors, weighted automatically by an empirical Bayes approach. The overall approach is computationally efficient and essentially free of user-set parameters. We show results from an empirical investigation, comparing the approach to several existing methods, and from an application to breast cancer cell line data. Hypotheses are generated regarding novel signalling links, some of which are validated by independent experiments. Third, we describe a network-based clustering approach for the discovery of cancer subtypes that differ in terms of subtype-specific signalling network structure. Model-based clustering is combined with penalised likelihood estimation of undirected graphical models to allow simultaneous learning of cluster assignments and cluster-specific network structure. Results are shown from an empirical investigation comparing several penalisation regimes, and an application to breast cancer proteomic data

Market state discovery

We explore the concept of financial market state discovery by assessing the robustness of two unsupervised machine learning algorithms: Inverse Covariance Clustering (ICC) and Agglomerative Super Paramagnetic Clustering (ASPC). The assessment is carried out by: simulating market datasets varying in complexity; implementing ICC and ASPC to estimate the underlying states (using only simulated log-returns as inputs); and measuring the algorithms' ability to recover the underlying states, using the Adjusted Rand Index (ARI) as a performance metric. Experiments revealed that ASPC is a more robust and better performing algorithm than ICC. ICC is able to produce competitive results in 2-state markets; however, ICC's primary disadvantage is its inability to maintain strong performance in 3, 4 and 5-state markets. For example, ASPC produced ARI numbers that were up to 800% superior to ICC in 5-state markets. Furthermore, ASPC does not rely on the art of selecting good hyper-parameters such as, the number of states a priori. ICC's utility as a market state discovery algorithm is limited

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

Multivariate Analysis of Tumour Gene Expression Profiles Applying Regularisation and Bayesian Variable Selection Techniques

High-throughput microarray technology is here to stay, e.g. in oncology for tumour classification and gene expression profiling to predict cancer pathology and clinical outcome. The global objective of this thesis is to investigate multivariate methods that are suitable for this task. After introducing the problem and the biological background, an overview of multivariate regularisation methods is given in Chapter 3 and the binary classification problem is outlined (Chapter 4). The focus of applications presented in Chapters 5 to 7 is on sparse binary classifiers that are both parsimonious and interpretable. Particular emphasis is on sparse penalised likelihood and Bayesian variable selection models, all in the context of logistic regression. The thesis concludes with a final discussion chapter. The variable selection problem is particularly challenging here, since the number of variables is much larger than the sample size, which results in an ill-conditioned problem with many equally good solutions. Thus, one open problem is the stability of gene expression profiles. In a resampling study, various characteristics including stability are compared between a variety of classifiers applied to five gene expression data sets and validated on two independent data sets. Bayesian variable selection provides an alternative to resampling for estimating the uncertainty in the selection of genes. MCMC methods are used for model space exploration, but because of the high dimensionality standard algorithms are computationally expensive and/or result in poor Markov chain mixing. A novel MCMC algorithm is presented that uses the dependence structure between input variables for finding blocks of variables to be updated together. This drastically improves mixing while keeping the computational burden acceptable. Several algorithms are compared in a simulation study. In an ovarian cancer application in Chapter 7, the best-performing MCMC algorithms are combined with parallel tempering and compared with an alternative method

Improving the Practicality of Model-Based Reinforcement Learning: An Investigation into Scaling up Model-Based Methods in Online Settings

This thesis is a response to the current scarcity of practical model-based control algorithms in the reinforcement learning (RL) framework. As of yet there is no consensus on how best to integrate imperfect transition models into RL whilst mitigating policy improvement instabilities in online settings. Current state-of-the-art policy learning algorithms that surpass human performance often rely on model-free approaches that enjoy unmitigated sampling of transition data. Model-based RL (MBRL) instead attempts to distil experience into transition models that allow agents to plan new policies without needing to return to the environment and sample more data. The initial focus of this investigation is on kernel conditional mean embeddings (CMEs) (Song et al., 2009) deployed in an approximate policy iteration (API) algorithm (Grünewälder et al., 2012a). This existing MBRL algorithm boasts theoretically stable policy updates in continuous state and discrete action spaces. The Bellman operator’s value function and (transition) conditional expectation are modelled and embedded respectively as functions in a reproducing kernel Hilbert space (RKHS). The resulting finite-induced approximate pseudo-MDP (Yao et al., 2014a) can be solved exactly in a dynamic programming algorithm with policy improvement suboptimality guarantees. However model construction and policy planning scale cubically and quadratically respectively with the training set size, rendering the CME impractical for sampleabundant tasks in online settings. Three variants of CME API are investigated to strike a balance between stable policy updates and reduced computational complexity. The first variant models the value function and state-action representation explicitly in a parametric CME (PCME) algorithm with favourable computational complexity. However a soft conservative policy update technique is developed to mitigate policy learning oscillations in the planning process. The second variant returns to the non-parametric embedding and contributes (along with external work) to the compressed CME (CCME); a sparse and computationally more favourable CME. The final variant is a fully end-to-end differentiable embedding trained with stochastic gradient updates. The value function remains modelled in an RKHS such that backprop is driven by a non-parametric RKHS loss function. Actively compressed CME (ACCME) satisfies the pseudo-MDP contraction constraint using a sparse softmax activation function. The size of the pseudo-MDP (i.e. the size of the embedding’s last layer) is controlled by sparsifying the last layer weight matrix by extending the truncated gradient method (Langford et al., 2009) with group lasso updates in a novel ‘use it or lose it’ neuron pruning mechanism. Surprisingly this technique does not require extensive fine-tuning between control tasks

Sparse graphical models for cancer signalling

Protein signalling networks play a key role in cellular function, and their dysregulation is central to many diseases, including cancer. Recent advances in biochemical technology have begun to allow high-throughput, data-driven studies of signalling. In this thesis, we investigate multivariate statistical methods, rooted in sparse graphical models, aimed at probing questions in cancer signalling. First, we propose a Bayesian variable selection method for identifying subsets of proteins that jointly in uence an output of interest, such as drug response. Ancillary biological information is incorporated into inference using informative prior distributions. Prior information is selected and weighted in an automated manner using an empirical Bayes formulation. We present examples of informative pathwayand network-based priors, and illustrate the proposed method on both synthetic and drug response data. Second, we use dynamic Bayesian networks to perform structure learning of context-specific signalling network topology from proteomic time-course data. We exploit a connection between variable selection and network structure learning to efficiently carry out exact inference. Existing biology is incorporated using informative network priors, weighted automatically by an empirical Bayes approach. The overall approach is computationally efficient and essentially free of user-set parameters. We show results from an empirical investigation, comparing the approach to several existing methods, and from an application to breast cancer cell line data. Hypotheses are generated regarding novel signalling links, some of which are validated by independent experiments. Third, we describe a network-based clustering approach for the discovery of cancer subtypes that differ in terms of subtype-specific signalling network structure. Model-based clustering is combined with penalised likelihood estimation of undirected graphical models to allow simultaneous learning of cluster assignments and cluster-specific network structure. Results are shown from an empirical investigation comparing several penalisation regimes, and an application to breast cancer proteomic data.EThOS - Electronic Theses Online ServiceEngineering and Physical Sciences Research Council (EPSRC)GBUnited Kingdo