scAI: an unsupervised approach for the integrative analysis of parallel single-cell transcriptomic and epigenomic profiles.

Simultaneous measurements of transcriptomic and epigenomic profiles in the same individual cells provide an unprecedented opportunity to understand cell fates. However, effective approaches for the integrative analysis of such data are lacking. Here, we present a single-cell aggregation and integration (scAI) method to deconvolute cellular heterogeneity from parallel transcriptomic and epigenomic profiles. Through iterative learning, scAI aggregates sparse epigenomic signals in similar cells learned in an unsupervised manner, allowing coherent fusion with transcriptomic measurements. Simulation studies and applications to three real datasets demonstrate its capability of dissecting cellular heterogeneity within both transcriptomic and epigenomic layers and understanding transcriptional regulatory mechanisms

Integrative clustering by non-negative matrix factorization can reveal coherent functional groups from gene profile data

Recent developments in molecular biology and tech- niques for genome-wide data acquisition have resulted in abun- dance of data to profile genes and predict their function. These data sets may come from diverse sources and it is an open question how to commonly address them and fuse them into a joint prediction model. A prevailing technique to identify groups of related genes that exhibit similar profiles is profile-based clustering. Cluster inference may benefit from consensus across different clustering models. In this paper we propose a technique that develops separate gene clusters from each of available data sources and then fuses them by means of non-negative matrix factorization. We use gene profile data on the budding yeast S. cerevisiae to demonstrate that this approach can successfully integrate heterogeneous data sets and yields high-quality clusters that could otherwise not be inferred by simply merging the gene profiles prior to clustering

Integrative clustering by non-negative matrix factorization can reveal coherent functional groups from gene profile data

Recent developments in molecular biology and tech- niques for genome-wide data acquisition have resulted in abun- dance of data to profile genes and predict their function. These data sets may come from diverse sources and it is an open question how to commonly address them and fuse them into a joint prediction model. A prevailing technique to identify groups of related genes that exhibit similar profiles is profile-based clustering. Cluster inference may benefit from consensus across different clustering models. In this paper we propose a technique that develops separate gene clusters from each of available data sources and then fuses them by means of non-negative matrix factorization. We use gene profile data on the budding yeast S. cerevisiae to demonstrate that this approach can successfully integrate heterogeneous data sets and yields high-quality clusters that could otherwise not be inferred by simply merging the gene profiles prior to clustering

The Reasonable Effectiveness of Randomness in Scalable and Integrative Gene Regulatory Network Inference and Beyond

Gene regulation is orchestrated by a vast number of molecules, including transcription factors and co-factors, chromatin regulators, as well as epigenetic mechanisms, and it has been shown that transcriptional misregulation, e.g., caused by mutations in regulatory sequences, is responsible for a plethora of diseases, including cancer, developmental or neurological disorders. As a consequence, decoding the architecture of gene regulatory networks has become one of the most important tasks in modern (computational) biology. However, to advance our understanding of the mechanisms involved in the transcriptional apparatus, we need scalable approaches that can deal with the increasing number of large-scale, high-resolution, biological datasets. In particular, such approaches need to be capable of efficiently integrating and exploiting the biological and technological heterogeneity of such datasets in order to best infer the underlying, highly dynamic regulatory networks, often in the absence of sufficient ground truth data for model training or testing. With respect to scalability, randomized approaches have proven to be a promising alternative to deterministic methods in computational biology. As an example, one of the top performing algorithms in a community challenge on gene regulatory network inference from transcriptomic data is based on a random forest regression model. In this concise survey, we aim to highlight how randomized methods may serve as a highly valuable tool, in particular, with increasing amounts of large-scale, biological experiments and datasets being collected. Given the complexity and interdisciplinary nature of the gene regulatory network inference problem, we hope our survey maybe helpful to both computational and biological scientists. It is our aim to provide a starting point for a dialogue about the concepts, benefits, and caveats of the toolbox of randomized methods, since unravelling the intricate web of highly dynamic, regulatory events will be one fundamental step in understanding the mechanisms of life and eventually developing efficient therapies to treat and cure diseases

Integrative computational methodologies on single cell datasets

High throughput single cell sequencing has seen exciting developments in recent years. With its high resolution characterization of genetics, genomics, proteomics, and epigenomics features, single cell data offer more insights on the underlying biological processes than those from bulk sequencing data. The most well developed single cell technologies are single cell RNA-seq (scRNA-seq) on transcriptomics and flow cytometry on proteomics. Many multi-omics single cell sequencing platforms have also emerged recently, such as CITE-seq, which profiles both epitope and transcriptome simultaneously. But some well known limitations of single cell data, such as batch variations, shallow sequencing depth, and sparsity also present many challenges. Many computational approaches built on machine learning and deep learning methods have been proposed to address these challenges. In this dissertation, I present three computational methods for joint analysis of single cell sequencing data either by multi-omics integration or joint analysis of multiple datasets. In the first chapter, we focus on single cell proteomics data, specifically, the antibody profiling of CITE-seq and cytometry by time of flight (CyTOF) applied to single cells to measure surface marker abundance. Although CyTOF has high accuracy and was introduced earlier than scRNA-seq, there is a lack of computational methods on cell type classification and annotations for these data. We propose a novel automated cell type annotation tool by incorporating CITE-seq data from the same tissue, publicly available annotated scRNA-seq data, and prior knowledge of surface markers in the literature. Our new method, called automated single cell proteomics data annotation approach (ProtAnno), is based on non-negative matrix factorization. We demonstrate the annotation accuracy and robustness of ProtAnno through extensive applications, especially for peripheral blood mononuclear cells (PBMC). The second chapter introduces an integrative method improving bulk sequencing data decomposition into cell type proportions by harmonizing scRNA-seq data across multiple tissues or multiple studies. As a Bayesian model, our method, called tranSig, is able to construct a more reliable signature matrix for decomposition by borrowing information from other tissues and/or studies. Our method can be considered an add-on step in cell type decomposition. Our method can better derive signature gene matrix and better characterize the biological heterogeneity from bulk sequencing datasets. Finally, in the last chapter, we propose a method to jointly analyze scRNA-seq data with summary statistics from genome wide association studies (GWAS). Our method generates a set of SNP (single nucelotide polymorphism)-level weight scores for each cell type or tissue type using scRNA-seq atlas. These scores are combined with risk allele effect sizes to decompose polygenic risk score (PRS) into cell types or tissue types. We show through enrichment analysis and phenome-wide association study (PheWAS) that the decomposed PRSs can better explain the biological mechanisms of genetic effects on complex traits mediated through transcription regulation and the differences across cell types and tissues

Expression cartography of human tissues using self organizing maps

Background: The availability of parallel, high-throughput microarray and sequencing experiments poses a challenge how to best arrange and to analyze the obtained heap of multidimensional data in a concerted way. Self organizing maps (SOM), a machine learning method, enables the parallel sample- and gene-centered view on the data combined with strong visualization and second-level analysis capabilities. The paper addresses aspects of the method with practical impact in the context of expression analysis of complex data sets.
Results: The method was applied to generate a SOM characterizing the whole genome expression profiles of 67 healthy human tissues selected from ten tissue categories (adipose, endocrine, homeostasis, digestion, exocrine, epithelium, sexual reproduction, muscle, immune system and nervous tissues). SOM mapping reduces the dimension of expression data from ten thousands of genes to a few thousands of metagenes where each metagene acts as representative of a minicluster of co-regulated single genes. Tissue-specific and common properties shared between groups of tissues emerge as a handful of localized spots in the tissue maps collecting groups of co-regulated and co-expressed metagenes. The functional context of the spots was discovered using overrepresentation analysis with respect to pre-defined gene sets of known functional impact. We found that tissue related spots typically contain enriched populations of gene sets well corresponding to molecular processes in the respective tissues. Analysis techniques normally used at the gene-level such as two-way hierarchical clustering provide a better signal-to-noise ratio and a better representativeness of the method if applied to the metagenes. Metagene-based clustering analyses aggregate the tissues into essentially three clusters containing nervous, immune system and the remaining tissues. 
Conclusions: The global view on the behavior of a few well-defined modules of correlated and differentially expressed genes is more intuitive and more informative than the separate discovery of the expression levels of hundreds or thousands of individual genes. The metagene approach is less sensitive to a priori selection of genes. It can detect a coordinated expression pattern whose components would not pass single-gene significance thresholds and it is able to extract context-dependent patterns of gene expression in complex data sets.
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Expression cartography of human tissues using self organizing maps

Background: The availability of parallel, high-throughput microarray and sequencing experiments poses a challenge how to best arrange and to analyze the obtained heap of multidimensional data in a concerted way. Self organizing maps (SOM), a machine learning method, enables the parallel sample- and gene-centered view on the data combined with strong visualization and second-level analysis capabilities. The paper addresses aspects of the method with practical impact in the context of expression analysis of complex data sets.
Results: The method was applied to generate a SOM characterizing the whole genome expression profiles of 67 healthy human tissues selected from ten tissue categories (adipose, endocrine, homeostasis, digestion, exocrine, epithelium, sexual reproduction, muscle, immune system and nervous tissues). SOM mapping reduces the dimension of expression data from ten thousands of genes to a few thousands of metagenes where each metagene acts as representative of a minicluster of co-regulated single genes. Tissue-specific and common properties shared between groups of tissues emerge as a handful of localized spots in the tissue maps collecting groups of co-regulated and co-expressed metagenes. The functional context of the spots was discovered using overrepresentation analysis with respect to pre-defined gene sets of known functional impact. We found that tissue related spots typically contain enriched populations of gene sets well corresponding to molecular processes in the respective tissues. Analysis techniques normally used at the gene-level such as two-way hierarchical clustering provide a better signal-to-noise ratio and a better representativeness of the method if applied to the metagenes. Metagene-based clustering analyses aggregate the tissues into essentially three clusters containing nervous, immune system and the remaining tissues. 
Conclusions: The global view on the behavior of a few well-defined modules of correlated and differentially expressed genes is more intuitive and more informative than the separate discovery of the expression levels of hundreds or thousands of individual genes. The metagene approach is less sensitive to a priori selection of genes. It can detect a coordinated expression pattern whose components would not pass single-gene significance thresholds and it is able to extract context-dependent patterns of gene expression in complex data sets.
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Recent advances in clustering methods for protein interaction networks

The increasing availability of large-scale protein-protein interaction data has made it possible to understand the basic components and organization of cell machinery from the network level. The arising challenge is how to analyze such complex interacting data to reveal the principles of cellular organization, processes and functions. Many studies have shown that clustering protein interaction network is an effective approach for identifying protein complexes or functional modules, which has become a major research topic in systems biology. In this review, recent advances in clustering methods for protein interaction networks will be presented in detail. The predictions of protein functions and interactions based on modules will be covered. Finally, the performance of different clustering methods will be compared and the directions for future research will be discussed