Imputing single-cell RNA-seq data by combining graph convolution and autoencoder neural networks.
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ABSTRACT:
SUBMITTER: Rao J
PROVIDER: S-EPMC8091052 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Single-cell RNA-sequencing (scRNA-seq) has emerged as a powerful technique for studying gene expression patterns at the single-cell level. Inferring gene regulatory networks (GRNs) from scRNA-seq data provides insight into cellular phenotypes from the genomic level. However, the high sparsity, noise and dropout events inherent in scRNA-seq data present challenges for GRN inference. In recent years, the dramatic increase in data on experimentally validated transcription factors binding to DNA has made it possible to infer GRNs by supervised methods. In this study, we address the problem of GRN inference by framing it as a graph link prediction task. In this paper, we propose a novel framework called GNNLink, which leverages known GRNs to deduce the potential regulatory interdependencies between genes. First, we preprocess the raw scRNA-seq data. Then, we introduce a graph convolutional network-based interaction graph encoder to effectively refine gene features by capturing interdependencies between nodes in the network. Finally, the inference of GRN is obtained by performing matrix completion operation on node features. The features obtained from model training can be applied to downstream tasks such as measuring similarity and inferring causality between gene pairs. To evaluate the performance of GNNLink, we compare it with six existing GRN reconstruction methods using seven scRNA-seq datasets. These datasets encompass diverse ground truth networks, including functional interaction networks, Loss of Function/Gain of Function data, non-specific ChIP-seq data and cell-type-specific ChIP-seq data. Our experimental results demonstrate that GNNLink achieves comparable or superior performance across these datasets, showcasing its robustness and accuracy. Furthermore, we observe consistent performance across datasets of varying scales. For reproducibility, we provide the data and source code of GNNLink on our GitHub repository: https://github.com/sdesignates/GNNLink.
| S-EPMC10661972 | biostudies-literature
Project description:Dimensionality reduction is crucial for the visualization and interpretation of the high-dimensional single-cell RNA sequencing (scRNA-seq) data. However, preserving topological structure among cells to low dimensional space remains a challenge. Here, we present the single-cell graph autoencoder (scGAE), a dimensionality reduction method that preserves topological structure in scRNA-seq data. scGAE builds a cell graph and uses a multitask-oriented graph autoencoder to preserve topological structure information and feature information in scRNA-seq data simultaneously. We further extended scGAE for scRNA-seq data visualization, clustering, and trajectory inference. Analyses of simulated data showed that scGAE accurately reconstructs developmental trajectory and separates discrete cell clusters under different scenarios, outperforming recently developed deep learning methods. Furthermore, implementation of scGAE on empirical data showed scGAE provided novel insights into cell developmental lineages and preserved inter-cluster distances.
| S-EPMC8501122 | biostudies-literature
Project description:Autoencoders are the backbones of many imputation methods that aim to relieve the sparsity issue in single-cell RNA sequencing (scRNA-seq) data. The imputation performance of an autoencoder relies on both the neural network architecture and the hyperparameter choice. So far, literature in the single-cell field lacks a formal discussion on how to design the neural network and choose the hyperparameters. Here, we conducted an empirical study to answer this question. Our study used many real and simulated scRNA-seq datasets to examine the impacts of the neural network architecture, the activation function, and the regularization strategy on imputation accuracy and downstream analyses. Our results show that (i) deeper and narrower autoencoders generally lead to better imputation performance; (ii) the sigmoid and tanh activation functions consistently outperform other commonly used functions including ReLU; (iii) regularization improves the accuracy of imputation and downstream cell clustering and DE gene analyses. Notably, our results differ from common practices in the computer vision field regarding the activation function and the regularization strategy. Overall, our study offers practical guidance on how to optimize the autoencoder design for scRNA-seq data imputation.
| S-EPMC10475479 | biostudies-literature
Project description:BackgroundSingle cell RNA sequencing (scRNA-seq) is applied to assay the individual transcriptomes of large numbers of cells. The gene expression at single-cell level provides an opportunity for better understanding of cell function and new discoveries in biomedical areas. To ensure that the single-cell based gene expression data are interpreted appropriately, it is crucial to develop new computational methods.ResultsIn this article, we try to re-construct a neural network based on Gene Ontology (GO) for dimension reduction of scRNA-seq data. By integrating GO with both unsupervised and supervised models, two novel methods are proposed, named GOAE (Gene Ontology AutoEncoder) and GONN (Gene Ontology Neural Network) respectively.ConclusionsThe evaluation results show that the proposed models outperform some state-of-the-art dimensionality reduction approaches. Furthermore, incorporating with GO, we provide an opportunity to interpret the underlying biological mechanism behind the neural network-based model.
| S-EPMC6557741 | biostudies-literature
Project description:Deep neural networks have been widely applied for missing data imputation. However, most existing studies have been focused on imputing continuous data, while discrete data imputation is under-explored. Discrete data is common in real world, especially in research areas of bioinformatics, genetics, and biochemistry. In particular, large amounts of recent genomic data are discrete count data generated from single-cell RNA sequencing (scRNA-seq) technology. Most scRNA-seq studies produce a discrete matrix with prevailing 'false' zero count observations (missing values). To make downstream analyses more effective, imputation, which recovers the missing values, is often conducted as the first step in pre-processing scRNA-seq data. In this paper, we propose a novel Zero-Inflated Negative Binomial (ZINB) model-based autoencoder for imputing discrete scRNA-seq data. The novelties of our method are twofold. First, in addition to optimizing the ZINB likelihood, we propose to explicitly model the dropout events that cause missing values by using the Gumbel-Softmax distribution. Second, the zero-inflated reconstruction is further optimized with respect to the raw count matrix. Extensive experiments on simulation datasets demonstrate that the zero-inflated reconstruction significantly improves imputation accuracy. Real data experiments show that the proposed imputation can enhance separating different cell types and improve the accuracy of differential expression analysis.
| S-EPMC8592282 | biostudies-literature
Project description:In this paper, we introduce Gene Knockout Inference (GenKI), a virtual knockout (KO) tool for gene function prediction using single-cell RNA sequencing (scRNA-seq) data in the absence of KO samples when only wild-type (WT) samples are available. Without using any information from real KO samples, GenKI is designed to capture shifting patterns in gene regulation caused by the KO perturbation in an unsupervised manner and provide a robust and scalable framework for gene function studies. To achieve this goal, GenKI adapts a variational graph autoencoder (VGAE) model to learn latent representations of genes and interactions between genes from the input WT scRNA-seq data and a derived single-cell gene regulatory network (scGRN). The virtual KO data is then generated by computationally removing all edges of the KO gene-the gene to be knocked out for functional study-from the scGRN. The differences between WT and virtual KO data are discerned by using their corresponding latent parameters derived from the trained VGAE model. Our simulations show that GenKI accurately approximates the perturbation profiles upon gene KO and outperforms the state-of-the-art under a series of evaluation conditions. Using publicly available scRNA-seq data sets, we demonstrate that GenKI recapitulates discoveries of real-animal KO experiments and accurately predicts cell type-specific functions of KO genes. Thus, GenKI provides an in-silico alternative to KO experiments that may partially replace the need for genetically modified animals or other genetically perturbed systems.
| S-EPMC10359630 | biostudies-literature
Project description:The emergence of single-cell RNA sequencing (scRNA-seq) technologies has enabled us to measure the expression levels of thousands of genes at single-cell resolution. However, insufficient quantities of starting RNA in the individual cells cause significant dropout events, introducing a large number of zero counts in the expression matrix. To circumvent this, we developed an autoencoder-based sparse gene expression matrix imputation method. AutoImpute, which learns the inherent distribution of the input scRNA-seq data and imputes the missing values accordingly with minimal modification to the biologically silent genes. When tested on real scRNA-seq datasets, AutoImpute performed competitively wrt., the existing single-cell imputation methods, on the grounds of expression recovery from subsampled data, cell-clustering accuracy, variance stabilization and cell-type separability.
| S-EPMC6218547 | biostudies-literature
Project description:Single-cell RNA sequencing (scRNA-seq) has enabled researchers to study gene expression at a cellular resolution. However, noise due to amplification and dropout may obstruct analyses, so scalable denoising methods for increasingly large but sparse scRNA-seq data are needed. We propose a deep count autoencoder network (DCA) to denoise scRNA-seq datasets. DCA takes the count distribution, overdispersion and sparsity of the data into account using a negative binomial noise model with or without zero-inflation, and nonlinear gene-gene dependencies are captured. Our method scales linearly with the number of cells and can, therefore, be applied to datasets of millions of cells. We demonstrate that DCA denoising improves a diverse set of typical scRNA-seq data analyses using simulated and real datasets. DCA outperforms existing methods for data imputation in quality and speed, enhancing biological discovery.
| S-EPMC6344535 | biostudies-literature
Project description:MotivationSingle-cell RNA sequencing has emerged as a powerful technology for studying gene expression at the individual cell level. Clustering individual cells into distinct subpopulations is fundamental in scRNA-seq data analysis, facilitating the identification of cell types and exploration of cellular heterogeneity. Despite the recent development of many deep learning-based single-cell clustering methods, few have effectively exploited the correlations among genes, resulting in suboptimal clustering outcomes.ResultsHere, we propose a novel masked autoencoder-based method, scMAE, for cell clustering. scMAE perturbs gene expression and employs a masked autoencoder to reconstruct the original data, learning robust and informative cell representations. The masked autoencoder introduces a masking predictor, which captures relationships among genes by predicting whether gene expression values are masked. By integrating this masking mechanism, scMAE effectively captures latent structures and dependencies in the data, enhancing clustering performance. We conducted extensive comparative experiments using various clustering evaluation metrics on 15 scRNA-seq datasets from different sequencing platforms. Experimental results indicate that scMAE outperforms other state-of-the-art methods on these datasets. In addition, scMAE accurately identifies rare cell types, which are challenging to detect due to their low abundance. Furthermore, biological analyses confirm the biological significance of the identified cell subpopulations.Availability and implementationThe source code of scMAE is available at: https://zenodo.org/records/10465991.
| S-EPMC10832357 | biostudies-literature
Project description:Single-cell RNA-sequencing (scRNA-Seq) is widely used to reveal the heterogeneity and dynamics of tissues, organisms, and complex diseases, but its analyses still suffer from multiple grand challenges, including the sequencing sparsity and complex differential patterns in gene expression. We introduce the scGNN (single-cell graph neural network) to provide a hypothesis-free deep learning framework for scRNA-Seq analyses. This framework formulates and aggregates cell-cell relationships with graph neural networks and models heterogeneous gene expression patterns using a left-truncated mixture Gaussian model. scGNN integrates three iterative multi-modal autoencoders and outperforms existing tools for gene imputation and cell clustering on four benchmark scRNA-Seq datasets. In an Alzheimer's disease study with 13,214 single nuclei from postmortem brain tissues, scGNN successfully illustrated disease-related neural development and the differential mechanism. scGNN provides an effective representation of gene expression and cell-cell relationships. It is also a powerful framework that can be applied to general scRNA-Seq analyses.
| S-EPMC7994447 | biostudies-literature