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NBBt-test: a versatile method for differential analysis of multiple types of RNA-seq data.

ABSTRACT: Rapid development of transcriptome sequencing technologies has resulted in a data revolution and emergence of new approaches to study transcriptomic regulation such as alternative splicing, alternative polyadenylation, CRISPR knockout screening in addition to the regular gene expression. A full characterization of the transcriptional landscape of different groups of cells or tissues holds enormous potential for both basic science as well as clinical applications. Although many methods have been developed in the realm of differential gene expression analysis, they all geared towards a particular type of sequencing data and failed to perform well when applied in different types of transcriptomic data. To fill this gap, we offer a negative beta binomial t-test (NBBt-test). NBBt-test provides multiple functions to perform differential analyses of alternative splicing, polyadenylation, CRISPR knockout screening, and gene expression datasets. Both real and large-scale simulation data show superior performance of NBBt-test with higher efficiency, and lower type I error rate and FDR to identify differential isoforms and differentially expressed genes and differential CRISPR knockout screening genes with different sample sizes when compared against the current very popular statistical methods. An R-package implementing NBBt-test is available for downloading from CRAN ( https://CRAN.R-project.org/package=NBBttest ).

SUBMITTER: Tan YD

PROVIDER: S-EPMC9329447 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundUse of next-generation sequencing technologies to transcriptomics (RNA-seq) for gene expression profiling has found widespread application in studying different biological conditions including cancers. However, RNA-seq experiments are still small sample size experiments due to the cost. Recently, an increased focus has been on meta-analysis methods for integrated differential expression analysis for exploration of potential biomarkers. In this study, we propose a p-value combination method for meta-analysis of multiple independent but related RNA-seq studies that accounts for sample size of a study and direction of expression of genes in individual studies.ResultsThe proposed method generalizes the inverse-normal method without an increase in statistical or computational complexity and does not pre- or post-hoc filter genes that have conflicting direction of expression in different studies. Thus, the proposed method, as compared to the inverse-normal, has better potential for the discovery of differentially expressed genes (DEGs) with potentially conflicting differential signals from multiple studies related to disease. We demonstrated the use of the proposed method in detection of biologically relevant DEGs in glioblastoma (GBM), the most aggressive brain cancer. Our approach notably enabled the identification of over-expressed tumour suppressor gene RAD51 in GBM compared to healthy controls, which has recently been shown to be a target for inhibition to enhance radiosensitivity of GBM cells during treatment. Pathway analysis identified multiple aberrant GBM related pathways as well as novel regulators such as TCF7L2 and MAPT as important upstream regulators in GBM.ConclusionsThe proposed meta-analysis method generalizes the existing inverse-normal method by providing a way to establish differential expression status for genes with conflicting direction of expression in individual RNA-seq studies. Hence, leading to further exploration of them as potential biomarkers for the disease.

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NBBt-test: a versatile method for differential analysis of multiple types of RNA-seq data.

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