Towards development of a statistical framework to evaluate myotonic dystrophy type 1 mRNA biomarkers in the context of a clinical trial
Open Access
- 14 April 2020
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 15 (4), e0231000
- https://doi.org/10.1371/journal.pone.0231000
Abstract
Myotonic dystrophy type 1 (DM1) is a rare genetic disorder, characterised by muscular dystrophy, myotonia, and other symptoms. DM1 is caused by the expansion of a CTG repeat in the 3'-untranslated region of DMPK. Longer CTG expansions are associated with greater symptom severity and earlier age at onset. The primary mechanism of pathogenesis is thought to be mediated by a gain of function of the CUG-containing RNA, that leads to transdysregulation of RNA metabolism of many other genes. Specifically, the alternative splicing (AS) and alternative polyadenylation (APA) of many genes is known to be disrupted. In the context of clinical trials of emerging DM1 treatments, it is important to be able to objectively quantify treatment efficacy at the level of molecular biomarkers. We show how previously described candidate mRNA biomarkers can be used to model an effective reduction in CTG length, using modern high-dimensional statistics (machine learning), and a blood and muscle mRNA microarray dataset. We show how this model could be used to detect treatment effects in the context of a clinical trial.This publication has 27 references indexed in Scilit:
- Efficient network-guided multi-locus association mapping with graph cutsBioinformatics, 2013
- Chapter 11: Genome-Wide Association StudiesPLoS Computational Biology, 2012
- Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severityHuman Molecular Genetics, 2012
- Biopython: freely available Python tools for computational molecular biology and bioinformaticsBioinformatics, 2009
- Muscleblind-Like Proteins: Similarities and Differences in Normal and Myotonic Dystrophy MuscleThe American Journal of Pathology, 2009
- Invited Review: Reliability of genomic predictions for North American Holstein bullsJournal of Dairy Science, 2009
- Effects of Atmospheric Ozone on Microarray Data QualityAnalytical Chemistry, 2003
- Non‐inferiority trials: design concepts and issues – the encounters of academic consultants in statisticsStatistics in Medicine, 2002
- Somatic mosaicism, germline expansions, germline reversions and intergenerational reductions in myotonic dystrophy males: small pool PCR analysesHuman Molecular Genetics, 1995
- Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family memberCell, 1992