Statistical methods for co-expression network analysis of population-scale scRNA-seq data

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Project Summary Gene co-expression network analysis is a key inference tool for detecting latent relationships invisible to standard workflows of clustering and differential expression analysis. Such a network approach was instrumental in bulk RNA-seq analysis to link genes with biological processes. Despite the remarkable progress in method development for scRNA-seq analysis, there are no established best practices for constructing robust gene co-expression networks from scRNA-seq data. With the wide availability of scRNA-seq technology, population-scale scRNA-seq datasets across multiple subjects and time points/perturbations are emerging. Although the immediate analyses of these datasets focus on the standard analysis of clustering and differential expression, leveraging the power of scRNA-seq at the co-expression network level has the potential to unlock genes converging into key disrupted regulatory pathways. Network-level variation, when associated with phenotypic variation (e.g., severity of response to virus), can reveal critical biological insights. Such an advancement presents constructing personalized dynamic co-expression networks and identifying dynamic gene modules by taking into account the individualized nature of the networks as the next critical challenge in population-scale scRNA-seq analysis. This proposal will address these challenges in two aims. Aim 1 will develop a de-biasing approach to estimate gene-gene correlations from scRNA-seq data with safeguards against low sequencing depth, data sparsity, and varying numbers of cells and detect correlations that are otherwise obscured by technical limitations. Aim 2 will innovate a regularized spectral clustering method that takes in as input co-expression networks of genes at the subject and time/perturbation levels and infers dynamic gene modules. Both aims will be accomplished through a combination of methodological development, theoretical analysis, data-driven simulation, computational analysis, and experimental validation. Successful completion of the project will deliver foundational methods and software that are applicable to a wide range of scRNA-seq datasets and are uniquely positioned for analyzing population-scale scRNA-seq data.