BACKGROUND: As single-cell genomics experiments increase in complexity and scale, the need to integrate multiple datasets has grown. Such integration enhances cellular feature identification by leveraging larger data volumes. However, batch effects-technical variations arising from differences in labs, times, or protocols-pose a significant challenge. Despite numerous proposed batch correction methods, many still have limitations, such as outputting only dimension-reduced data, relying on computationally intensive models, or resulting in overcorrection for batches with diverse cell type composition. RESULTS: We introduce a novel method for batch effect correction named SCITUNA, a Single-Cell data Integration Tool Using Network Alignment. We perform evaluations on 39 individual batches from four real datasets and a simulated dataset, which include both scRNA-seq and scATAC-seq datasets, spanning multiple organisms and tissues. A thorough comparison of existing batch correction methods using 13 metrics reveals that SCITUNA outperforms current approaches and is successful at preserving biological signals present in the original data. In particular, SCITUNA shows a better performance than the current methods in all the comparisons except for the multiple batch integration of the lung dataset where the difference is 0.004. CONCLUSION: SCITUNA effectively removes batch effects while retaining the biological signals present in the data. Our extensive experiments reveal that SCITUNA will be a valuable tool for diverse integration tasks.

Since many biological processes are governed by protein-protein interactions, understanding which mutations lead to a disruption in these interactions is profoundly important for cancer research. Most of the existing methods focus on the stability of the protein without considering the specific effects of a mutation on its interactions with other proteins. Here, we focus on somatic mutations that appear on the interface regions of the protein and predict the interactions that would be affected by a mutation of interest. We build an ensemble model, Predator, that classifies the interface mutations as disruptive or nondisruptive based on the predicted effects of mutations on specific protein-protein interactions. We show that Predator outperforms existing approaches in literature in terms of prediction accuracy. We then apply Predator on various TCGA cancer cohorts and perform comprehensive analysis at cohort level, patient level, and gene level in determining the genes whose interface mutations tend to yield a disruption in its interactions. The predictions obtained by Predator shed light on interesting patterns on several genes for each cohort regarding their potential as cancer drivers. Our analyses further reveal that the identified genes and their frequently disrupted partners exhibit patterns of mutually exclusivity across cancer cohorts under study.

MOTIVATION: A major challenge in cancer genomics is to distinguish the driver mutations that are causally linked to cancer from passenger mutations that do not contribute to cancer development. The majority of existing methods provide a single driver gene list for the entire cohort of patients. However, since mutation profiles of patients from the same cancer type show a high degree of heterogeneity, a more ideal approach is to identify patient-specific drivers. RESULTS: We propose a novel method that integrates genomic data, biological pathways and protein connectivity information for personalized identification of driver genes. The method is formulated on a personalized bipartite graph for each patient. Our approach provides a personalized ranking of the mutated genes of a patient based on the sum of weighted 'pairwise pathway coverage' scores across all the samples, where appropriate pairwise patient similarity scores are used as weights to normalize these coverage scores. We compare our method against five state-of-the-art patient-specific cancer gene prioritization methods. The comparisons are with respect to a novel evaluation method that takes into account the personalized nature of the problem. We show that our approach outperforms the existing alternatives for both the TCGA and the cell line data. In addition, we show that the KEGG/Reactome pathways enriched in our ranked genes and those that are enriched in cell lines' reference sets overlap significantly when compared to the overlaps achieved by the rankings of the alternative methods. Our findings can provide valuable information toward the development of personalized treatments and therapies. AVAILABILITY AND IMPLEMENTATION: All the codes and data are available at https://github.com/abu-compbio/PersonaDrive, and the data underlying this article are available in Zenodo, at https://doi.org/10.5281/zenodo.6520187. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: Recent cancer genomic studies have generated detailed molecular data on a large number of cancer patients. A key remaining problem in cancer genomics is the identification of driver genes. RESULTS: We propose BetweenNet, a computational approach that integrates genomic data with a protein-protein interaction network to identify cancer driver genes. BetweenNet utilizes a measure based on betweenness centrality on patient specific networks to identify the so-called outlier genes that correspond to dysregulated genes for each patient. Setting up the relationship between the mutated genes and the outliers through a bipartite graph, it employs a random-walk process on the graph, which provides the final prioritization of the mutated genes. We compare BetweenNet against state-of-the art cancer gene prioritization methods on lung, breast, and pan-cancer datasets. CONCLUSIONS: Our evaluations show that BetweenNet is better at recovering known cancer genes based on multiple reference databases. Additionally, we show that the GO terms and the reference pathways enriched in BetweenNet ranked genes and those that are enriched in known cancer genes overlap significantly when compared to the overlaps achieved by the rankings of the alternative methods.

BACKGROUND: Matrix factorization methods are linear models, with limited capability to model complex relations. In our work, we use tropical semiring to introduce non-linearity into matrix factorization models. We propose a method called Sparse Tropical Matrix Factorization (STMF) for the estimation of missing (unknown) values in sparse data. RESULTS: We evaluate the efficiency of the STMF method on both synthetic data and biological data in the form of gene expression measurements downloaded from The Cancer Genome Atlas (TCGA) database. Tests on unique synthetic data showed that STMF approximation achieves a higher correlation than non-negative matrix factorization (NMF), which is unable to recover patterns effectively. On real data, STMF outperforms NMF on six out of nine gene expression datasets. While NMF assumes normal distribution and tends toward the mean value, STMF can better fit to extreme values and distributions. CONCLUSION: STMF is the first work that uses tropical semiring on sparse data. We show that in certain cases semirings are useful because they consider the structure, which is different and simpler to understand than it is with standard linear algebra.

MOTIVATION: Genomic analyses from large cancer cohorts have revealed the mutational heterogeneity problem which hinders the identification of driver genes based only on mutation profiles. One way to tackle this problem is to incorporate the fact that genes act together in functional modules. The connectivity knowledge present in existing protein-protein interaction (PPI) networks together with mutation frequencies of genes and the mutual exclusivity of cancer mutations can be utilized to increase the accuracy of identifying cancer driver modules. RESULTS: We present a novel edge-weighted random walk-based approach that incorporates connectivity information in the form of protein-protein interactions (PPIs), mutual exclusivity and coverage to identify cancer driver modules. MEXCOwalk outperforms several state-of-the-art computational methods on TCGA pan-cancer data in terms of recovering known cancer genes, providing modules that are capable of classifying normal and tumor samples and that are enriched for mutations in specific cancer types. Furthermore, the risk scores determined with output modules can stratify patients into low-risk and high-risk groups in multiple cancer types. MEXCOwalk identifies modules containing both well-known cancer genes and putative cancer genes that are rarely mutated in the pan-cancer data. The data, the source code and useful scripts are available at: https://github.com/abu-compbio/MEXCOwalk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

SUMMARY: Long non-coding RNAs (lncRNAs) can act as molecular sponge or decoys for an RNA-binding protein (RBP) through their RBP-binding sites, thereby modulating the expression of all target genes of the corresponding RBP of interest. Here, we present a web tool named RBPSponge to explore lncRNAs based on their potential to act as a sponge for an RBP of interest. RBPSponge identifies the occurrences of RBP-binding sites and CLIP peaks on lncRNAs, and enables users to run statistical analyses to investigate the regulatory network between lncRNAs, RBPs and targets of RBPs. AVAILABILITY AND IMPLEMENTATION: The web server is available at https://www.RBPSponge.com. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Rapid advances in genotyping and genome-wide association studies have enabled the discovery of many new genotype-phenotype associations at the resolution of individual markers. However, these associations explain only a small proportion of theoretically estimated heritability of most diseases. In this work, we propose an integrative mixture model called JBASE: joint Bayesian analysis of subphenotypes and epistasis. JBASE explores two major reasons of missing heritability: interactions between genetic variants, a phenomenon known as epistasis and phenotypic heterogeneity, addressed via subphenotyping. RESULTS: Our extensive simulations in a wide range of scenarios repeatedly demonstrate that JBASE can identify true underlying subphenotypes, including their associated variants and their interactions, with high precision. In the presence of phenotypic heterogeneity, JBASE has higher Power and lower Type 1 Error than five state-of-the-art approaches. We applied our method to a sample of individuals from Mexico with Type 2 diabetes and discovered two novel epistatic modules, including two loci each, that define two subphenotypes characterized by differences in body mass index and waist-to-hip ratio. We successfully replicated these subphenotypes and epistatic modules in an independent dataset from Mexico genotyped with a different platform. AVAILABILITY AND IMPLEMENTATION: JBASE is implemented in C++, supported on Linux and is available at http://www.cs.toronto.edu/∼goldenberg/JBASE/jbase.tar.gz. The genotype data underlying this study are available upon approval by the ethics review board of the Medical Centre Siglo XXI. Please contact Dr Miguel Cruz at [email protected] for assistance with the application. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: RNA molecules fold into complex three-dimensional shapes, guided by the pattern of hydrogen bonding between nucleotides. This pattern of base pairing, known as RNA secondary structure, is critical to their cellular function. Recently several diverse methods have been developed to assay RNA secondary structure on a transcriptome-wide scale using high-throughput sequencing. Each approach has its own strengths and caveats, however there is no widely available tool for visualizing and comparing the results from these varied methods. METHODS: To address this, we have developed Structure Surfer, a database and visualization tool for inspecting RNA secondary structure in six transcriptome-wide data sets from human and mouse ( http://tesla.pcbi.upenn.edu/strucuturesurfer/ ). The data sets were generated using four different high-throughput sequencing based methods. Each one was analyzed with a scoring pipeline specific to its experimental design. Users of Structure Surfer have the ability to query individual loci as well as detect trends across multiple sites. RESULTS: Here, we describe the included data sets and their differences. We illustrate the database's function by examining known structural elements and we explore example use cases in which combined data is used to detect structural trends. CONCLUSIONS: In total, Structure Surfer provides an easy-to-use database and visualization interface for allowing users to interrogate the currently available transcriptome-wide RNA secondary structure information for mammals.

Metazoan genomes encode hundreds of RNA-binding proteins (RBPs). These proteins regulate post-transcriptional gene expression and have critical roles in numerous cellular processes including mRNA splicing, export, stability and translation. Despite their ubiquity and importance, the binding preferences for most RBPs are not well characterized. In vitro and in vivo studies, using affinity selection-based approaches, have successfully identified RNA sequence associated with specific RBPs; however, it is difficult to infer RBP sequence and structural preferences without specifically designed motif finding methods. In this study, we introduce a new motif-finding method, RNAcontext, designed to elucidate RBP-specific sequence and structural preferences with greater accuracy than existing approaches. We evaluated RNAcontext on recently published in vitro and in vivo RNA affinity selected data and demonstrate that RNAcontext identifies known binding preferences for several control proteins including HuR, PTB, and Vts1p and predicts new RNA structure preferences for SF2/ASF, RBM4, FUSIP1 and SLM2. The predicted preferences for SF2/ASF are consistent with its recently reported in vivo binding sites. RNAcontext is an accurate and efficient motif finding method ideally suited for using large-scale RNA-binding affinity datasets to determine the relative binding preferences of RBPs for a wide range of RNA sequences and structures.