Single-cell RNA sequencing (scRNA-seq) technology has made significant breakthroughs in genomics research in recent years, enabling in-depth analysis of gene expression profiles at the single-cell level. A key step in analyzing scRNA-seq data is clustering cells into subpopulations, which facilitates subsequent downstream analysis. Unfortunately, the rapid growth of scRNAseq data and the prevalence of dropout events pose challenges in cell type annotation. In this paper, we develop a hybrid model, Single-cell Multi-hop Autoencoder (scMAE), based on deep graph embedding clustering. This model combines multi-hop graph convolutional networks (GCNs) to capture cell neighbor information and uses deep graph convolutional networks to identify cell clusters. Additionally, the model integrates a zero-inflated negative binomial (ZINB) model into a topologically adaptive graph convolutional autoencoder to learn low-dimensional latent representations and applies Kullback-Leibler (KL) divergence for the clustering task. By jointly training on the adjacency matrix and gene expression data, the model simultaneously optimizes the clustering results and the generative model. Specifically, the loss function combines four components: adjacency matrix reconstruction loss, ZINB loss, generator loss, and clustering loss, and an alternating training strategy is employed to enhance clustering performance. Extensive experiments on 15 scRNA-seq datasets from different yet representative single-cell sequencing platforms demonstrate that scMAE outperforms various state-of-the-art clustering methods.

MOTIVATION: Spatial transcriptomics can quantify gene expression and its spatial distribution in tissues, thus revealing molecular mechanisms of cellular interactions underlying tissue heterogeneity, tissue regeneration, and spatially localized disease mechanisms. However, existing spatial clustering methods often fail to exploit the full potential of spatial information, resulting in inaccurate identification of spatial domains. RESULTS: In this article, we develop a deep graph contrastive clustering framework, stDGCC, that accurately uncovers underlying spatial domains via explicitly modeling spatial information and gene expression profiles from spatial transcriptomics data. The stDGCC framework proposes a spatially informed graph node embedding model to preserve the topological information of spots and to learn the informative and discriminative characterization of spatial transcriptomics data through self-supervised contrastive learning. By simultaneously optimizing the contrastive learning loss, reconstruction loss, and Kullback-Leibler divergence loss, stDGCC achieves joint optimization of feature learning and topology structure preservation in an end-to-end manner. We validate the effectiveness of stDGCC on various spatial transcriptomics datasets acquired from different platforms, each with varying spatial resolutions. Our extensive experiments demonstrate the superiority of stDGCC over various state-of-the-art clustering methods in accurately identifying cellular-level biological structures. AVAILABILITY AND IMPLEMENTATION: Code and data are available from https://github.com/TimE9527/stDGCC and https://figshare.com/projects/stDGCC/186525.

Cell clustering is a critical step in analyzing single-cell RNA sequencing (scRNA-seq) data, which allows us to characterize the cellular heterogeneity of transcriptional profiling at the single-cell level. Single-cell deep embedded representation models have recently become popular since they can learn feature representation and clustering simultaneously. However, the model still suffers from a variety of significant challenges, including the massive amount of data, pervasive dropout events, and complicated noise patterns in transcriptional profiling. Here, we propose a Single-Cell Deep Embedding Fusion Representation (scDEFR) model, which develop a deep embedded fusion representation to learn fused heterogeneous latent embedding that contains both the transcriptome gene-level information and the cell topology information. We first fuse them layer by layer to obtain compressed representations of intercellular relationships and transcriptome information. After that, the zero-inflated negative binomial model (ZINB)-based decoder is proposed to capture the global probabilistic structure of the data and reconstruct the final gene expression information and cell graph. Finally, by simultaneously integrating the clustering loss, crossentropy loss, ZINB loss, and the cell graph reconstruction loss, scDEFR can optimize clustering performance and learn the latent representation in fused information under a joint mutual supervised strategy. We conducted extensive and comprehensive experiments on 15 single-cell RNA-seq datasets from different sequencing platforms to demonstrate the superiority of scDEFR over a variety of state-of-the-art methods.

This paper proposes a novel learned index called DTtree that can optimize both read and write performance. DTtree adopts two novel designs. (1) To improve write performance, DTtree uses a dynamic filling rate and overflow buffers for each leaf node. The filling rate of a leaf node is dynamically determined according to the read/write tendency of the leaf node so as to improve space efficiency and reduce structure modification operations. In addition, DTtree uses an overflow buffer for a line in each leaf node. The overflow buffer is also dynamically allocated, and only write-intensive leaf nodes may have overflow buffers, reducing unnecessary space costs. (2) To improve read performance, we propose an in-node hot cache to cache hot records within a line of a leaf node, reducing additional memory access to the overflow buffer. As skewed access is common in real-world applications, using in-node hot caches can efficiently improve the read performance of DTtree. We experimentally evaluate DTtree on three datasets. The results on various workloads show that DTtree can reduce SMO operations effectively and achieve higher read/write performance than B+-tree and two representative learned indexes, PGM-Index and ALEX.

MOTIVATION: Single-cell RNA sequencing (scRNA-seq) is an increasingly popular technique for transcriptomic analysis of gene expression at the single-cell level. Cell-type clustering is the first crucial task in the analysis of scRNA-seq data that facilitates accurate identification of cell types and the study of the characteristics of their transcripts. Recently, several computational models based on a deep autoencoder and the ensemble clustering have been developed to analyze scRNA-seq data. However, current deep autoencoders are not sufficient to learn the latent representations of scRNA-seq data, and obtaining consensus partitions from these feature representations remains under-explored. RESULTS: To address this challenge, we propose a single-cell deep clustering model via a dual denoising autoencoder with bipartite graph ensemble clustering called scBGEDA, to identify specific cell populations in single-cell transcriptome profiles. First, a single-cell dual denoising autoencoder network is proposed to project the data into a compressed low-dimensional space and that can learn feature representation via explicit modeling of synergistic optimization of the zero-inflated negative binomial reconstruction loss and denoising reconstruction loss. Then, a bipartite graph ensemble clustering algorithm is designed to exploit the relationships between cells and the learned latent embedded space by means of a graph-based consensus function. Multiple comparison experiments were conducted on 20 scRNA-seq datasets from different sequencing platforms using a variety of clustering metrics. The experimental results indicated that scBGEDA outperforms other state-of-the-art methods on these datasets, and also demonstrated its scalability to large-scale scRNA-seq datasets. Moreover, scBGEDA was able to identify cell-type specific marker genes and provide functional genomic analysis by quantifying the influence of genes on cell clusters, bringing new insights into identifying cell types and characterizing the scRNA-seq data from different perspectives. AVAILABILITY AND IMPLEMENTATION: The source code of scBGEDA is available at https://github.com/wangyh082/scBGEDA. The software and the supporting data can be downloaded from https://figshare.com/articles/software/scBGEDA/19657911. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Single-cell RNA sequencing (scRNA-seq) provides high-throughput information about the genome-wide gene expression levels at the single-cell resolution, bringing a precise understanding on the transcriptome of individual cells. Unfortunately, the rapidly growing scRNA-seq data and the prevalence of dropout events pose substantial challenges for cell type annotation. Here, we propose a single-cell model-based deep graph embedding clustering (scTAG) method, which simultaneously learns cell–cell topology representations and identifies cell clusters based on deep graph convolutional network. scTAG integrates the zero-inflated negative binomial (ZINB) model into a topology adaptive graph convolutional autoencoder to learn the low-dimensional latent representation and adopts Kullback–Leibler (KL) divergence for the clustering tasks. By simultaneously optimizing the clustering loss, ZINB loss, and the cell graph reconstruction loss, scTAG jointly optimizes cluster label assignment and feature learning with the topological structures preserved in an end-to-end manner. Extensive experiments on 16 single-cell RNA-seq datasets from diverse yet representative single-cell sequencing platforms demonstrate the superiority of scTAG over various state-of-the-art clustering methods.

MOTIVATION: Thanks to the development of high-throughput sequencing technologies, massive amounts of various biomolecular data have been accumulated to revolutionize the study of genomics and molecular biology. One of the main challenges in analyzing this biomolecular data is to cluster their subtypes into subpopulations to facilitate subsequent downstream analysis. Recently, many clustering methods have been developed to address the biomolecular data. However, the computational methods often suffer from many limitations such as high dimensionality, data heterogeneity and noise. RESULTS: In our study, we develop a novel Graph-based Multiple Hierarchical Consensus Clustering (GMHCC) method with an unsupervised graph-based feature ranking (FR) and a graph-based linking method to explore the multiple hierarchical information of the underlying partitions of the consensus clustering for multiple types of biomolecular data. Indeed, we first propose to use a graph-based unsupervised FR model to measure each feature by building a graph over pairwise features and then providing each feature with a rank. Subsequently, to maintain the diversity and robustness of basic partitions (BPs), we propose multiple diverse feature subsets to generate several BPs and then explore the hierarchical structures of the multiple BPs by refining the global consensus function. Finally, we develop a new graph-based linking method, which explicitly considers the relationships between clusters to generate the final partition. Experiments on multiple types of biomolecular data including 35 cancer gene expression datasets and eight single-cell RNA-seq datasets validate the effectiveness of our method over several state-of-the-art consensus clustering approaches. Furthermore, differential gene analysis, gene ontology enrichment analysis and KEGG pathway analysis are conducted, providing novel insights into cell developmental lineages and characterization mechanisms. AVAILABILITY AND IMPLEMENTATION: The source code is available at GitHub: https://github.com/yifuLu/GMHCC. The software and the supporting data can be downloaded from: https://figshare.com/articles/software/GMHCC/17111291. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Gene-expression profiling can define the cell state and gene-expression pattern of cells at the genetic level in a high-throughput manner. With the development of transcriptome techniques, processing high-dimensional genetic data has become a major challenge in expression profiling. Thanks to the recent widespread use of matrix decomposition methods in bioinformatics, a computational framework based on compressed sensing was adopted to reduce dimensionality. However, compressed sensing requires an optimization strategy to learn the modular dictionaries and activity levels from the low-dimensional random composite measurements to reconstruct the high-dimensional gene-expression data. Considering this, here we introduce and compare four compressed sensing frameworks coming from nature-inspired optimization algorithms (CSCS, ABCCS, BACS and FACS) to improve the quality of the decompression process. Several experiments establish that the three proposed methods outperform benchmark methods on nine different datasets, especially the FACS method. We illustrate therefore, the robustness and convergence of FACS in various aspects; notably, time complexity and parameter analyses highlight properties of our proposed FACS. Furthermore, differential gene-expression analysis, cell-type clustering, gene ontology enrichment and pathology analysis are conducted, which bring novel insights into cell-type identification and characterization mechanisms from different perspectives. All algorithms are written in Python and available at https://github.com/Philyzh8/Nature-inspired-CS.