Kurkiewicz, A. et al. (2020) Towards development of a statistical framework to evaluate myotonic dystrophy type 1 mRNA biomarkers in the context of a clinical trial. PLoS ONE, 15(4), e0231000. (doi: 10.1371/journal.pone.0231000) (PMID:32287265) (PMCID:PMC7156058)
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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 trans-dysregulation 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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Rogers, Dr Simon and Kurkiewicz, Mr Adam and Monckton, Professor Darren and Cumming, Dr Sarah and Cooper, Dr Anneli and Adam, Mrs Berit and McClure, Dr John |
| Creator Roles: | Kurkiewicz, A.Conceptualization, Data curation, Formal analysis, Methodology, Software, Visualization, Writing – original draft Cooper, A.Investigation Cumming, S.Investigation Adam, B.Investigation Rogers, S.Conceptualization, Project administration, Supervision, Writing – review and editing McClure, J. D.Project administration, Supervision, Validation Monckton, D.Conceptualization, Data curation, Project administration, Supervision, Writing – review and editing |
| Authors: | Kurkiewicz, A., Cooper, A., McIlwaine, E., Cumming, S. A., Adam, B., Krahe, R., Puymirat, J., Schoser, B., Timchenko, L., Ashizawa, T., Thornton, C. A., Rogers, S., McClure, J. D., and Monckton, D. G. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Molecular Biosciences College of Science and Engineering > School of Computing Science College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine |
| Journal Name: | PLoS ONE |
| Publisher: | Public Library of Science |
| ISSN: | 1932-6203 |
| ISSN (Online): | 1932-6203 |
| Copyright Holders: | Copyright © 2020 The Authors |
| First Published: | First published in PLoS ONE 15(4):e0231000 |
| Publisher Policy: | Reproduced under a Creative Commons License |
| Related URLs: |
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