Library size-stabilized metacells construction enhances co-expression network analysis in single-cell data

Single-cell RNA sequencing (scRNA-seq) deciphers cell type-specific co-expression networks to resolve biological functions but remains constrained by data sparsity and compositional biases. Conventional metacells construction strategies mitigate sparsity by aggregating transcriptionally similar cell...

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Veröffentlicht in:PLoS computational biology Jg. 21; H. 11; S. e1013697
Hauptverfasser: Zhang, Tianjiao, Zhu, Haibin
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Public Library of Science (PLoS) 01.11.2025
Schlagworte:
Algorithms
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Brain - metabolism
Computational Biology - methods
Computer Simulation
Gene Expression Profiling - methods
Gene Library
Gene Regulatory Networks - genetics
Humans
RNA-Seq - methods
Sequence Analysis, RNA - methods
Single-Cell Analysis - methods
Single-Cell Analysis - statistics & numerical data
ISSN:1553-7358, 1553-734X, 1553-7358
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Zusammenfassung:Single-cell RNA sequencing (scRNA-seq) deciphers cell type-specific co-expression networks to resolve biological functions but remains constrained by data sparsity and compositional biases. Conventional metacells construction strategies mitigate sparsity by aggregating transcriptionally similar cells but often neglect systematic biases introduced by compositional data. This problem leads to spurious co-expression correlations and obscuring biologically meaningful interactions. Through mathematical modeling and simulations, we demonstrate that uncontrolled library size variance in traditional metacells inflates false-positive correlations and distorts co-expression networks. Here, we present LSMetacell (Library Size-stabilized Metacells), a computational framework that explicitly stabilizes library sizes across metacells to reduce compositional noise while preserving cellular heterogeneity. LSMetacell addresses this by stabilizing library sizes during metacells aggregation, thereby enhancing the accuracy of downstream analyses such as Weighted Gene Co-expression Network Analysis (WGCNA). Applied to a postmortem Alzheimer’s disease brain scRNA-seq dataset, LSMetacell revealed robust, cell type-specific co-expression modules enriched for disease-relevant pathways, outperforming the conventional metacells approach. Our work establishes a principled strategy for resolving compositional biases in scRNA-seq data, advancing the reliability of co-expression network inference in studying complex biological systems. This framework provides a generalizable solution for improving transcriptional analyses in single-cell studies.
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ISSN:1553-7358
1553-734X
1553-7358
DOI:10.1371/journal.pcbi.1013697