Towards development of a statistical framework to evaluate myotonic dystrophy type 1 mRNA biomarkers in the context of a clinical trial

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)

[img]
Preview
Text
213971.pdf - Published Version
Available under License Creative Commons Attribution.

1MB

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:Cooper, Dr Anneli and Adam, Mrs Berit and Cumming, Dr Sarah and Monckton, Professor Darren and Kurkiewicz, Mr Adam and McClure, Dr John and Rogers, Dr Simon
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 > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Science and Engineering > School of Computing Science
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:

University Staff: Request a correction | Enlighten Editors: Update this record