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Discovering key transcriptomic regulators in pancreatic ductal adenocarcinoma using Dirichlet process Gaussian mixture model.

ABSTRACT: Pancreatic Ductal Adenocarcinoma (PDAC) is the most lethal type of pancreatic cancer, late detection leading to its therapeutic failure. This study aims to determine the key regulatory genes and their impacts on the disease's progression, helping the disease's etiology, which is still mostly unknown. We leverage the landmark advantages of time-series gene expression data of this disease and thereby identified the key regulators that capture the characteristics of gene activity patterns in the cancer progression. We have identified the key gene modules and predicted the functions of top genes from a reconstructed gene association network (GAN). A variation of the partial correlation method is utilized to analyze the GAN, followed by a gene function prediction task. Moreover, we have identified regulators for each target gene by gene regulatory network inference using the dynamical GENIE3 (dynGENIE3) algorithm. The Dirichlet process Gaussian process mixture model and cubic spline regression model (splineTimeR) are employed to identify the key gene modules and differentially expressed genes, respectively. Our analysis demonstrates a panel of key regulators and gene modules that are crucial for PDAC disease progression.

SUBMITTER: Hossain SMM

PROVIDER: S-EPMC8041769 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:MotivationSingle cell transcriptome sequencing (scRNA-Seq) has become a revolutionary tool to study cellular and molecular processes at single cell resolution. Among existing technologies, the recently developed droplet-based platform enables efficient parallel processing of thousands of single cells with direct counting of transcript copies using Unique Molecular Identifier (UMI). Despite the technology advances, statistical methods and computational tools are still lacking for analyzing droplet-based scRNA-Seq data. Particularly, model-based approaches for clustering large-scale single cell transcriptomic data are still under-explored.ResultsWe developed DIMM-SC, a Dirichlet Mixture Model for clustering droplet-based Single Cell transcriptomic data. This approach explicitly models UMI count data from scRNA-Seq experiments and characterizes variations across different cell clusters via a Dirichlet mixture prior. We performed comprehensive simulations to evaluate DIMM-SC and compared it with existing clustering methods such as K-means, CellTree and Seurat. In addition, we analyzed public scRNA-Seq datasets with known cluster labels and in-house scRNA-Seq datasets from a study of systemic sclerosis with prior biological knowledge to benchmark and validate DIMM-SC. Both simulation studies and real data applications demonstrated that overall, DIMM-SC achieves substantially improved clustering accuracy and much lower clustering variability compared to other existing clustering methods. More importantly, as a model-based approach, DIMM-SC is able to quantify the clustering uncertainty for each single cell, facilitating rigorous statistical inference and biological interpretations, which are typically unavailable from existing clustering methods.Availability and implementationDIMM-SC has been implemented in a user-friendly R package with a detailed tutorial available on www.pitt.edu/∼wec47/singlecell.html.Contactwei.chen@chp.edu or hum@ccf.org.Supplementary informationSupplementary data are available at Bioinformatics online.

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Discovering key transcriptomic regulators in pancreatic ductal adenocarcinoma using Dirichlet process Gaussian mixture model.

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