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1. Multi-omics data integration by generative adversarial network

   https://doi.org/10.1093/bioinformatics/btab608  

   Ahmed, Khandakar Tanvir ; Sun, Jiao ; Cheng, Sze ; Yong, Jeongsik ; Zhang, Wei ( August 2021 , Bioinformatics)

   Robinson, Peter (Ed.)

   Abstract Motivation Accurate disease phenotype prediction plays an important role in the treatment of heterogeneous diseases like cancer in the era of precision medicine. With the advent of high throughput technologies, more comprehensive multi-omics data is now available that can effectively link the genotype to phenotype. However, the interactive relation of multi-omics datasets makes it particularly challenging to incorporate different biological layers to discover the coherent biological signatures and predict phenotypic outcomes. In this study, we introduce omicsGAN, a generative adversarial network model to integrate two omics data and their interaction network. The model captures information from the interaction network as well as the two omics datasets and fuse them to generate synthetic data with better predictive signals. Results Large-scale experiments on The Cancer Genome Atlas breast cancer, lung cancer and ovarian cancer datasets validate that (i) the model can effectively integrate two omics data (e.g. mRNA and microRNA expression data) and their interaction network (e.g. microRNA-mRNA interaction network). The synthetic omics data generated by the proposed model has a better performance on cancer outcome classification and patients survival prediction compared to original omics datasets. (ii) The integrity of the interaction network plays a vital role in the generation ofmore »synthetic data with higher predictive quality. Using a random interaction network does not allow the framework to learn meaningful information from the omics datasets; therefore, results in synthetic data with weaker predictive signals. Availability and implementation Source code is available at: https://github.com/CompbioLabUCF/omicsGAN. Supplementary information Supplementary data are available at Bioinformatics online.« less
2. RVAgene: generative modeling of gene expression time series data

   https://doi.org/10.1093/bioinformatics/btab260  

   Mitra, Raktim ; MacLean, Adam L ( May 2021 , Bioinformatics)

   Mathelier, Anthony (Ed.)

   Abstract Motivation Methods to model dynamic changes in gene expression at a genome-wide level are not currently sufficient for large (temporally rich or single-cell) datasets. Variational autoencoders offer means to characterize large datasets and have been used effectively to characterize features of single-cell datasets. Here, we extend these methods for use with gene expression time series data. Results We present RVAgene: a recurrent variational autoencoder to model gene expression dynamics. RVAgene learns to accurately and efficiently reconstruct temporal gene profiles. It also learns a low dimensional representation of the data via a recurrent encoder network that can be used for biological feature discovery, and from which we can generate new gene expression data by sampling the latent space. We test RVAgene on simulated and real biological datasets, including embryonic stem cell differentiation and kidney injury response dynamics. In all cases, RVAgene accurately reconstructed complex gene expression temporal profiles. Via cross validation, we show that a low-error latent space representation can be learnt using only a fraction of the data. Through clustering and gene ontology term enrichment analysis on the latent space, we demonstrate the potential of RVAgene for unsupervised discovery. In particular, RVAgene identifies new programs of shared gene regulationmore »of Lox family genes in response to kidney injury. Availability and implementation All datasets analyzed in this manuscript are publicly available and have been published previously. RVAgene is available in Python, at GitHub: https://github.com/maclean-lab/RVAgene; Zenodo archive: http://doi.org/10.5281/zenodo.4271097. Supplementary information Supplementary data are available at Bioinformatics online.« less
3. iDINGO—integrative differential network analysis in genomics with Shiny application

   https://doi.org/10.1093/bioinformatics/btx750  

   Class, Caleb A. ; Ha, Min Jin ; Baladandayuthapani, Veerabhadran ; Do, Kim-Anh ; Berger, ed., Bonnie ( November 2017 , Bioinformatics)

   Differential network analysis is an important way to understand network rewiring involved in disease progression and development. Building differential networks from multiple ‘omics data provides insight into the holistic differences of the interactive system under different patient-specific groups. DINGO was developed to infer group-specific dependencies and build differential networks. However, DINGO and other existing tools are limited to analyze data arising from a single platform, and modeling each of the multiple ‘omics data independently does not account for the hierarchical structure of the data.

   We developed the iDINGO R package to estimate group-specific dependencies and make inferences on the integrative differential networks, considering the biological hierarchy among the platforms. A Shiny application has also been developed to facilitate easier analysis and visualization of results, including integrative differential networks and hub gene identification across platforms.

   R package is available on CRAN (https://cran.r-project.org/web/packages/iDINGO) and Shiny application at https://github.com/MinJinHa/iDINGO.

   Supplementary data are available at Bioinformatics online.
4. High-sensitivity pattern discovery in large, paired multiomic datasets

   https://doi.org/10.1093/bioinformatics/btac232  

   Ghazi, Andrew R. ; Sucipto, Kathleen ; Rahnavard, Ali ; Franzosa, Eric A. ; McIver, Lauren J. ; Lloyd-Price, Jason ; Schwager, Emma ; Weingart, George ; Moon, Yo Sup ; Morgan, Xochitl C. ; et al ( June 2022 , Bioinformatics)

   Modern biological screens yield enormous numbers of measurements, and identifying and interpreting statistically significant associations among features are essential. In experiments featuring multiple high-dimensional datasets collected from the same set of samples, it is useful to identify groups of associated features between the datasets in a way that provides high statistical power and false discovery rate (FDR) control.

   Here, we present a novel hierarchical framework, HAllA (Hierarchical All-against-All association testing), for structured association discovery between paired high-dimensional datasets. HAllA efficiently integrates hierarchical hypothesis testing with FDR correction to reveal significant linear and non-linear block-wise relationships among continuous and/or categorical data. We optimized and evaluated HAllA using heterogeneous synthetic datasets of known association structure, where HAllA outperformed all-against-all and other block-testing approaches across a range of common similarity measures. We then applied HAllA to a series of real-world multiomics datasets, revealing new associations between gene expression and host immune activity, the microbiome and host transcriptome, metabolomic profiling and human health phenotypes.

   An open-source implementation of HAllA is freely available at http://huttenhower.sph.harvard.edu/halla along with documentation, demo datasets and a user group.

   Supplementary data are available at Bioinformatics online.
5. SSIPe: accurately estimating protein–protein binding affinity change upon mutations using evolutionary profiles in combination with an optimized physical energy function

   https://doi.org/10.1093/bioinformatics/btz926  

   Huang, Xiaoqiang ; Zheng, Wei ; Pearce, Robin ; Zhang, Yang ; Valencia, ed., Alfonso ( December 2019 , Bioinformatics)

   Most proteins perform their biological functions through interactions with other proteins in cells. Amino acid mutations, especially those occurring at protein interfaces, can change the stability of protein–protein interactions (PPIs) and impact their functions, which may cause various human diseases. Quantitative estimation of the binding affinity changes (ΔΔGbind) caused by mutations can provide critical information for protein function annotation and genetic disease diagnoses.

   We present SSIPe, which combines protein interface profiles, collected from structural and sequence homology searches, with a physics-based energy function for accurate ΔΔGbind estimation. To offset the statistical limits of the PPI structure and sequence databases, amino acid-specific pseudocounts were introduced to enhance the profile accuracy. SSIPe was evaluated on large-scale experimental data containing 2204 mutations from 177 proteins, where training and test datasets were stringently separated with the sequence identity between proteins from the two datasets below 30%. The Pearson correlation coefficient between estimated and experimental ΔΔGbind was 0.61 with a root-mean-square-error of 1.93 kcal/mol, which was significantly better than the other methods. Detailed data analyses revealed that the major advantage of SSIPe over other traditional approaches lies in the novel combination of the physical energy function with the new knowledge-based interface profile. SSIPe also considerablymore »outperformed a former profile-based method (BindProfX) due to the newly introduced sequence profiles and optimized pseudocount technique that allows for consideration of amino acid-specific prior mutation probabilities.

   Web-server/standalone program, source code and datasets are freely available at https://zhanglab.ccmb.med.umich.edu/SSIPe and https://github.com/tommyhuangthu/SSIPe.

   Supplementary data are available at Bioinformatics online.

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