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Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1327.65 kB
Published (Version of record)CC BY-NC-ND V4.0, Open Access
Published (Version of record)CC BY-NC-ND V4.0, Open
Journal article
Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1
Annals of clinical and translational neurology, Vol.6(12), pp.2555-2565
12/2019
PMCID: PMC6917317
PMID: 31797581
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Source: InCites
Abstract
Objective
Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism-based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test-retest reliability of the measures and the application of data reduction techniques to improve reproducibility.
Methods
Data were analyzed from the STARS clinical trial (n = 146), a multi-center double-blind placebo-controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra-class correlation coefficients were generated between pre- and post-performances (16-week interval) on neuropsychological endpoints in the placebo group to determine test-retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error.
Results
Test-retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test-retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data.
Interpretation
These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test-retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design.
Details
- Title
- Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1
- Creators
- Jonathan M. Payne - Murdoch Childrens Research InstituteStephen J. C. Hearps - Murdoch Childrens Research InstituteKarin S. Walsh - Children’s National Health SystemIris Paltin - Children's Hospital of PhiladelphiaBelinda Barton - Children's Hospital at WestmeadNicole J. Ullrich - Boston Children's HospitalKristina M. Haebich - Royal Children's HospitalDavid Coghill - Royal Children's HospitalGerard A. Gioia - Children’s National Health SystemAlan Cantor - University of Alabama at BirminghamGary Cutter - University of Alabama at BirminghamJames H. Tonsgard - Comer Children's HospitalDavid Viskochil - University of UtahCeliane Rey-Casserly - Boston Children's HospitalElizabeth K. Schorry - Cincinnati Children's Hospital Medical CenterJoseph D. Ackerson - University of Alabama at BirminghamLaura Klesse - The University of Texas Southwestern Medical CenterMichael J. Fisher - Children's Hospital of PhiladelphiaDavid H. Gutmann - Washington University in St. LouisTena Rosser - Children's Hospital of Los AngelesRoger J. Packer - Children’s National Health SystemBruce Korf - University of Alabama at BirminghamMaria T. Acosta - National Human Genome Research InstituteKathryn N. North - University of Melbourne
- Publication Details
- Annals of clinical and translational neurology, Vol.6(12), pp.2555-2565
- Publisher
- Wiley
- Number of pages
- 11
- Grant note
- W81XWH05-1-0615 / United States Army Medical Research and Materiel Command, Office of the Congressionally Directed Medical Research Programs, Department of Defense Neurofibromatosis Research Program
- Identifiers
- 991013092667402368
- Copyright
- © 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, (https://creativecommons.org/licenses/by-nc-nd/4.0/).
- Academic Unit
- Faculty of Health
- Language
- English
- Resource Type
- Journal article