Abstract Numerous single‐cell transcriptomic datasets from identical tissues or cell lines are generated from different laboratories or single‐cell RNA sequencing (scRNA‐seq) protocols. The denoising of these datasets to eliminate batch effects is crucial for data integration, ensuring accurate interpretation and comprehensive analysis of biological questions. Although many scRNA‐seq data integration methods exist, most are inefficient and/or not conducive to downstream analysis. Here, DeepBID, a novel deep learning‐based method for batch effect correction, non‐linear dimensionality reduction, embedding, and cell clustering concurrently, is introduced. DeepBID utilizes a negative binomial‐based autoencoder with dual Kullback–Leibler divergence loss functions, aligning cell points from different batches within a consistent low‐dimensional latent space and progressively mitigating batch effects through iterative clustering. Extensive validation on multiple‐batch scRNA‐seq datasets demonstrates that DeepBID surpasses existing tools in removing batch effects and achieving superior clustering accuracy. When integrating multiple scRNA‐seq datasets from patients with Alzheimer's disease, DeepBID significantly improves cell clustering, effectively annotating unidentified cells, and detecting cell‐specific differentially expressed genes.
more »
« less
Domain adaptation for supervised integration of scRNA-seq data
Abstract Large-scale scRNA-seq studies typically generate data in batches, which often induce nontrivial batch effects that need to be corrected. Given the global efforts for building cell atlases and the increasing number of annotated scRNA-seq datasets accumulated, we propose a supervised strategy for scRNA-seq data integration called SIDA (SupervisedIntegration usingDomainAdaptation), which uses the cell type annotations to guide the integration of diverse batches. The supervised strategy is based on domain adaptation that was initially proposed in the computer vision field. We demonstrate that SIDA is able to generate comprehensive reference datasets that lead to improved accuracy in automated cell type mapping analyses.
more »
« less
- Award ID(s):
- 2007029
- PAR ID:
- 10403294
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- Communications Biology
- Volume:
- 6
- Issue:
- 1
- ISSN:
- 2399-3642
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract In recent years, the integration of single‐cell multi‐omics data has provided a more comprehensive understanding of cell functions and internal regulatory mechanisms from a non‐single omics perspective, but it still suffers many challenges, such as omics‐variance, sparsity, cell heterogeneity, and confounding factors. As it is known, the cell cycle is regarded as a confounder when analyzing other factors in single‐cell RNA‐seq data, but it is not clear how it will work on the integrated single‐cell multi‐omics data. Here, a cell cycle‐aware network (CCAN) is developed to remove cell cycle effects from the integrated single‐cell multi‐omics data while keeping the cell type‐specific variations. This is the first computational model to study the cell‐cycle effects in the integration of single‐cell multi‐omics data. Validations on several benchmark datasets show the outstanding performance of CCAN in a variety of downstream analyses and applications, including removing cell cycle effects and batch effects of scRNA‐seq datasets from different protocols, integrating paired and unpaired scRNA‐seq and scATAC‐seq data, accurately transferring cell type labels from scRNA‐seq to scATAC‐seq data, and characterizing the differentiation process from hematopoietic stem cells to different lineages in the integration of differentiation data.more » « less
-
Understanding the dynamics of gene regulatory networks (GRNs) across diverse cell types poses a challenge yet holds immense value in unraveling the molecular mechanisms governing cellular processes. Current computational methods, which rely solely on expression changes from bulk RNA-seq and/or scRNA-seq data, often result in high rates of false positives and low precision. Here, we introduce an advanced computational tool, DeepIMAGER, for inferring cell-specific GRNs through deep learning and data integration. DeepIMAGER employs a supervised approach that transforms the co-expression patterns of gene pairs into image-like representations and leverages transcription factor (TF) binding information for model training. It is trained using comprehensive datasets that encompass scRNA-seq profiles and ChIP-seq data, capturing TF-gene pair information across various cell types. Comprehensive validations on six cell lines show DeepIMAGER exhibits superior performance in ten popular GRN inference tools and has remarkable robustness against dropout-zero events. DeepIMAGER was applied to scRNA-seq datasets of multiple myeloma (MM) and detected potential GRNs for TFs of RORC, MITF, and FOXD2 in MM dendritic cells. This technical innovation, combined with its capability to accurately decode GRNs from scRNA-seq, establishes DeepIMAGER as a valuable tool for unraveling complex regulatory networks in various cell types.more » « less
-
Abstract Single cell profiling techniques including multi-omics and spatial-omics technologies allow researchers to study cell-cell variation within a cell population. These variations extend to biological networks within cells, in particular, the gene regulatory networks (GRNs). GRNs rewire as the cells evolve, and different cells can have different governing GRNs. However, existing GRN inference methods usually infer a single GRN for a population of cells, without exploring the cell-cell variation in terms of their regulatory mechanisms. Recently, jointly profiled single cell transcriptomics and chromatin accessibility data have been used to infer GRNs. Although methods based on such multi-omics data were shown to improve over the accuracy of methods using only single cell RNA-seq (scRNA-seq) data, they do not take full advantage of the single cell resolution chromatin accessibility data. We propose CeSpGRN (CellSpecificGeneRegulatoryNetwork inference), which infers cell-specific GRNs from scRNA-seq, single cell multi-omics, or single cell spatial-omics data. CeSpGRN uses a Gaussian weighted kernel that allows the GRN of a given cell to be learned from the sequencing profile of itself and its neighboring cells in the developmental process. The kernel is constructed from the similarity of gene expressions or spatial locations between cells. When the chromatin accessibility data is available, CeSpGRN constructs cell-specific prior networks which are used to further improve the inference accuracy. We applied CeSpGRN to various types of real-world datasets and inferred various regulation changes that were shown to be important in cell development. We also quantitatively measured the performance of CeSpGRN on simulated datasets and compared with baseline methods. The results show that CeSpGRN has a superior performance in reconstructing the GRN for each cell, as well as in detecting the regulatory interactions that differ between cells. CeSpGRN is available athttps://github.com/PeterZZQ/CeSpGRN.more » « less
-
Abstract It is a challenging task to integrate scRNA-seq and scATAC-seq data obtained from different batches. Existing methods tend to use a pre-defined gene activity matrix to convert the scATAC-seq data into scRNA-seq data. The pre-defined gene activity matrix is often of low quality and does not reflect the dataset-specific relationship between the two data modalities. We propose scDART, a deep learning framework that integrates scRNA-seq and scATAC-seq data and learns cross-modalities relationships simultaneously. Specifically, the design of scDART allows it to preserve cell trajectories in continuous cell populations and can be applied to trajectory inference on integrated data.more » « less
An official website of the United States government
