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

Integration of multi-scale protein interactions for biomedical data analysis

With the advancement of modern technologies, we observe an increasing accumulation of biomedical data about diseases. There is a need for computational methods to sift through and extract knowledge from the diverse data available in order to improve our mechanistic understanding of diseases and improve patient care. Biomedical data come in various forms as exemplified by the various omics data. Existing studies have shown that each form of omics data gives only partial information on cells state and motivated jointly mining multi-omics, multi-modal data to extract integrated system knowledge. The interactome is of particular importance as it enables the modelling of dependencies arising from molecular interactions. This Thesis takes a special interest in the multi-scale protein interactome and its integration with computational models to extract relevant information from biomedical data. We define multi-scale interactions at different omics scale that involve proteins: pairwise protein-protein interactions, multi-protein complexes, and biological pathways. Using hypergraph representations, we motivate considering higher-order protein interactions, highlighting the complementary biological information contained in the multi-scale interactome. Based on those results, we further investigate how those multi-scale protein interactions can be used as either prior knowledge, or auxiliary data to develop machine learning algorithms. First, we design a neural network using the multi-scale organization of proteins in a cell into biological pathways as prior knowledge and train it to predict a patient's diagnosis based on transcriptomics data. From the trained models, we develop a strategy to extract biomedical knowledge pertaining to the diseases investigated. Second, we propose a general framework based on Non-negative Matrix Factorization to integrate the multi-scale protein interactome with multi-omics data. We show that our approach outperforms the existing methods, provide biomedical insights and relevant hypotheses for specific cancer types

Generative Models of Biological Variations in Bulk and Single-cell RNA-seq

The explosive growth of next-generation sequencing data enhances our ability to understand biological process at an unprecedented resolution. Meanwhile organizing and utilizing this tremendous amount of data becomes a big challenge. High-throughput technology provides us a snapshot of all underlying biological activities, but this kind of extremely high-dimensional data is hard to interpret. Due to the curse of dimensionality, the measurement is sparse and far from enough to shape the actual manifold in the high-dimensional space. On the other hand, the measurements may contain structured noise such as technical or nuisance biological variation which can interfere downstream interpretation. Generative modeling is a powerful tool to make sense of the data and generate compact representations summarizing the embedded biological information. This thesis introduces three generative models that help amplifying biological signals buried in the noisy bulk and single-cell RNA-seq data. In Chapter 2, we propose a semi-supervised deconvolution framework called PLIER which can identify regulations in cell-type proportions and specific pathways that control gene expression. PLIER has inspired the development of MultiPLIER and has been used to infer context-specific genotype effects in the brain. In Chapter 3, we construct a supervised transformation named DataRemix to normalize bulk gene expression profiles in order to maximize the biological findings with respect to a variety of downstream tasks. By reweighing the contribution of hidden factors, we are able to reveal the hidden biological signals without any external dataset-specific knowledge. We apply DataRemix to the ROSMAP dataset and report the first replicable trans-eQTL effect in human brain. In Chapter 4, we focus on scRNA-seq and introduce NIFA which is an unsupervised decomposition framework that combines the desired properties of PCA, ICA and NMF. It simultaneously models uni- and multi-modal factors isolating discrete cell-type identity and continuous pathway-level variations into separate components. The work presented in Chapter 2 has been published as a journal article. The work in Chapter 3 and Chapter 4 are under submission and they are available as preprints on bioRxiv

Bayesian multi-view models for data-driven drug response analysis

A central challenge faced by biological and medical research is to understand the impact of chemical entities on living cells. Identifying the relationships between the chemical structures and their cellular responses is valuable for improving drug design and targeted therapies. The chemical structures and their detailed molecular responses need to be combined through a systematic analysis to learn the complex dependencies, which can then assist in improving understanding of the molecular mechanisms of drugs as well as predictions on the effects of unknown molecules. Moreover, with emerging drug-response data sets being profiled over several disease types and phenotypic details, it is pertinent to develop advanced computational methods that can be used to study multiple sets of data together. In this thesis, a novel multi-disciplinary challenge is undertaken for computationally analyzing interactions between multiple biological responses and chemical properties of drugs, while simultaneously advancing the computational methods to better learn these interactions. Specifically, multi-view dependency modeling of paired data sets is formulated as a means of systematically studying the drug-response relationships. First, the systematic analysis of drug structures and their genome-wide responses is presented as a multi-set dependency modeling problem and established methods are adopted to test the novel hypothesis. Several novel extensions of the drug-response analysis are then presented that explore responses measured over multiple disease types and multiple levels of phenotypic detail, uncovering novel biological insights of potential impact. These analyses are made possible by novel advancements in multi-view methods. Specifically, the first Bayesian tensor canonical correlation analysis and its extensions are introduced to capture the underlying multi-way structure and applied in analyzing novel toxicogenomic interactions. The results illustrate that modeling the precise multi-view and multi-way formulation of the data is valuable for discovering interpretable latent components as well as for the prediction of unseen responses of drugs. Therefore, the original contribution to knowledge in this dissertation is two-fold: first, the data-driven identification of relationships between structural properties of drugs and their genome-wide responses in cells and, second, novel advancements of multi-view methods that find dependencies between paired data sets. Open source implementations of the new methods have been released to facilitate further research

Cancer Subtyping Detection using Biomarker Discovery in Multi-Omics Tensor Datasets

This thesis begins with a thorough review of research trends from 2015 to 2022, examining the challenges and issues related to biomarker discovery in multi-omics datasets. The review covers areas of application, proposed methodologies, evaluation criteria used to assess performance, as well as limitations and drawbacks that require further investigation and improvement. This comprehensive overview serves to provide a deeper understanding of the current state of research in this field and the opportunities for future research. It will be particularly useful for those who are interested in this area of study and seeking to expand their knowledge. In the second part of this thesis, a novel methodology is proposed for the identification of significant biomarkers in a multi-omics colon cancer dataset. The integration of clinical features with biomarker discovery has the potential to facilitate the early identification of mortality risk and the development of personalized therapies for a range of diseases, including cancer and stroke. Recent advancements in “omics� technologies have opened up new avenues for researchers to identify disease biomarkers through system-level analysis. Machine learning methods, particularly those based on tensor decomposition techniques, have gained popularity due to the challenges associated with integrative analysis of multi-omics data owing to the complexity of biological systems. Despite extensive efforts towards discovering disease-associated biomolecules by analyzing data from various “omics� experiments, such as genomics, transcriptomics, and metabolomics, the poor integration of diverse forms of 'omics' data has made the integrative analysis of multi-omics data a daunting task. Our research includes ANOVA simultaneous component analysis (ASCA) and Tucker3 modeling to analyze a multivariate dataset with an underlying experimental design. By comparing the spaces spanned by different model components we showed how the two methods can be used for confirmatory analysis and provide complementary information. we demonstrated the novel use of ASCA to analyze the residuals of Tucker3 models to find the optimum one. Increasing the model complexity to more factors removed the last remaining ASCA detectable structure in the residuals. Bootstrap analysis of the core matrix values of the Tucker3 models used to check that additional triads of eigenvectors were needed to describe the remaining structure in the residuals. Also, we developed a new simple, novel strategy for aligning Tucker3 bootstrap models with the Tucker3 model of the original data so that eigenvectors of the three modes, the order of the values in the core matrix, and their algebraic signs match the original Tucker3 model without the need for complicated bookkeeping strategies or performing rotational transformations. Additionally, to avoid getting an overparameterized Tucker3 model, we used the bootstrap method to determine 95% confidence intervals of the loadings and core values. Also, important variables for classification were identified by inspection of loading confidence intervals. The experimental results obtained using the colon cancer dataset demonstrate that our proposed methodology is effective in improving the performance of biomarker discovery in a multi-omics cancer dataset. Overall, our study highlights the potential of integrating multi-omics data with machine learning methods to gain deeper insights into the complex biological mechanisms underlying cancer and other diseases. The experimental results using NIH colon cancer dataset demonstrate that the successful application of our proposed methodology in cancer subtype classification provides a foundation for further investigation into its utility in other disease areas

Learning by Fusing Heterogeneous Data

It has become increasingly common in science and technology to gather data about systems at different levels of granularity or from different perspectives. This often gives rise to data that are represented in totally different input spaces. A basic premise behind the study of learning from heterogeneous data is that in many such cases, there exists some correspondence among certain input dimensions of different input spaces. In our work we found that a key bottleneck that prevents us from better understanding and truly fusing heterogeneous data at large scales is identifying the kind of knowledge that can be transferred between related data views, entities and tasks. We develop interesting and accurate data fusion methods for predictive modeling, which reduce or entirely eliminate some of the basic feature engineering steps that were needed in the past when inferring prediction models from disparate data. In addition, our work has a wide range of applications of which we focus on those from molecular and systems biology: it can help us predict gene functions, forecast pharmacological actions of small chemicals, prioritize genes for further studies, mine disease associations, detect drug toxicity and regress cancer patient survival data. Another important aspect of our research is the study of latent factor models. We aim to design latent models with factorized parameters that simultaneously tackle multiple types of data heterogeneity, where data diversity spans across heterogeneous input spaces, multiple types of features, and a variety of related prediction tasks. Our algorithms are capable of retaining the relational structure of a data system during model inference, which turns out to be vital for good performance of data fusion in certain applications. Our recent work included the study of network inference from many potentially nonidentical data distributions and its application to cancer genomic data. We also model the epistasis, an important concept from genetics, and propose algorithms to efficiently find the ordering of genes in cellular pathways. A central topic of our Thesis is also the analysis of large data compendia as predictions about certain phenomena, such as associations between diseases and involvement of genes in a certain phenotype, are only possible when dealing with lots of data. Among others, we analyze 30 heterogeneous data sets to assess drug toxicity and over 40 human gene association data collections, the largest number of data sets considered by a collective latent factor model up to date. We also make interesting observations about deciding which data should be considered for fusion and develop a generic approach that can estimate the sensitivities between different data sets

Vertical integration of multiple high-dimensional datasets

Research in genomics and related fields now often requires the analysis of emph{multi-block} data, in which multiple high-dimensional types of data are available for a common set of objects. We introduce Joint and Individual Variation Explained (JIVE), a general decomposition of variation for the integrated analysis of multi-block datasets. The decomposition consists of three terms: a low-rank approximation capturing joint variation across datatypes, low-rank approximations for structured variation individual to each datatype, and residual noise. JIVE quantifies the amount of joint variation between datatypes, reduces the dimensionality of the data, and allows for the visual exploration of joint and individual structure. JIVE is an extension of Principal Components Analysis and has clear advantages over popular two-block methods such as Canonical Correlation and Partial Least Squares. Research in a number of fields also requires the analysis of emph{multi-way data}. Multi-way data take the form of a three (or higher) dimensional array. We compare several existing factorization methods for multi-way data, and we show that these methods belong to the same unified framework. The final portion of this dissertation concerns biclustering. We introduce an approach to biclustering a binary data matrix, and discuss the application of biclustering to classification problems

Structured data abstractions and interpretable latent representations for single-cell multimodal genomics

Single-cell multimodal genomics involves simultaneous measurement of multiple types of molecular data, such as gene expression, epigenetic marks and protein abundance, in individual cells. This allows for a comprehensive and nuanced understanding of the molecular basis of cellular identity and function. The large volume of data generated by single-cell multimodal genomics experiments requires specialised methods and tools for handling, storing, and analysing it. This work provides contributions on multiple levels. First, it introduces a single-cell multimodal data standard — MuData — designed to facilitate the handling, storage and exchange of multimodal data. MuData provides interfaces that enable transparent access to multimodal annotations as well as data from individual modalities. This data structure has formed the foundation for the multimodal integration framework, which enables complex and composable workflows that can be naturally integrated with existing omics-specific analysis approaches. Joint analysis of multimodal data can be performed using integration methods. In order to enable integration of single-cell data, an improved multi-omics factor analysis model (MOFA+) has been designed and implemented building on the canonical dimensionality reduction approach for multi-omics integration. Inferring later factors that explain variation across multiple modalities of the data, MOFA+ enables the modelling of latent factors with cell group-specific patterns of activity. MOFA+ model has been implemented as part of the respective multi-omics integration framework, and its utility has been extended by software solutions that facilitate interactive model exploration and interpretation. The newly improved model for multi-omics integration of single cells has been applied to the study of gene expression signatures upon targeted gene activation. In a dataset featuring targeted activation of candidate regulators of zygotic genome activation (ZGA) — a crucial transcriptional event in early embryonic development, — modelling expression of both coding and non-coding loci with MOFA+ allowed to rank genes by their potency to activate a ZGA-like transcriptional response. With identification of Patz1, Dppa2 and Smarca5 as potent inducers of ZGA-like transcription in mouse embryonic stem cells, these findings have contributed to the understanding of molecular mechanisms behind ZGA and laid the foundation for future research of ZGA in vivo. In summary, this work’s contributions include the development of data handling and integration methods as well as new biological insights that arose from applying these methods to studying gene expression regulation in early development. This highlights how single-cell multimodal genomics can aid to generate valuable insights into complex biological systems

Data integration for the analysis of uncharacterized proteins in Mycobacterium tuberculosis

Includes abstract.Includes bibliographical references (leaves 126-150).Mycobacterium tuberculosis is a bacterial pathogen that causes tuberculosis, a leading cause of human death worldwide from infectious diseases, especially in Africa. Despite enormous advances achieved in recent years in controlling the disease, tuberculosis remains a public health challenge. The contribution of existing drugs is of immense value, but the deadly synergy of the disease with Human Immunodeficiency Virus (HIV) or Acquired Immunodeficiency Syndrome (AIDS) and the emergence of drug resistant strains are threatening to compromise gains in tuberculosis control. In fact, the development of active tuberculosis is the outcome of the delicate balance between bacterial virulence and host resistance, which constitute two distinct and independent components. Significant progress has been made in understanding the evolution of the bacterial pathogen and its interaction with the host. The end point of these efforts is the identification of virulence factors and drug targets within the bacterium in order to develop new drugs and vaccines for the eradication of the disease