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Bioinformatics. 2020 Jan 13. pii: btaa015. doi: 10.1093/bioinformatics/btaa015. [Epub ahead of print]

MDEHT: a Multivariate Approach for Detecting Differential Expression of MicroRNA Isoform Data in RNA Sequencing Studies.

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Center for Uterine Cancer Diagnosis & Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Division of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Department of Pathology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Center of Systems Molecular Medicine, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA.



MiRNA isoforms (isomiRs) are produced from the same arm as the archetype miRNA with a few nucleotides different at 5 and/or 3 termini. These well-conserved isomiRs are functionally important and have contributed to the evolution of miRNA genes. Accurate detection of differential expression of miRNAs can bring new insights into the cellular function of miRNA and a further improvement in miRNA-based diagnostic and prognostic applications. However, very few methods take isomiR variations into account in the analysis of miRNA differential expression.


To overcome this challenge, we developed a novel approach to take advantage of the multidimensional structure of isomiR data from the same miRNAs, termed as a multivariate differential expression by Hotelling's T2test (MDEHT). The utilization of the information hidden in isomiRs enables MDEHT to increase the power of identifying differentially expressed miRNAs that are not marginally detectable in univariate testing methods. We conducted rigorous and unbiased comparisons of MDEHT with seven commonly used tools in simulated and real datasets from The Cancer Genome Atlas. Our comprehensive evaluations demonstrated that the MDEHT method was robust among various datasets and outperformed other commonly used tools in terms of type I error rate, true positive rate, and reproducibility.


The source code for identifying and quantifying isomiRs and performing miRNA differential expression analysis is available at


Supplementary data are available at Bioinformatics online.

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