Robust Markers and Sample Sizes for Multicenter Trials of Huntington Disease

Peter A Wijeratne; Eileanoir B Johnson; Arman Eshaghi; Leon Aksman; Sarah Gregory; Hans J Johnson; Govinda R Poudel; Amrita Mohan; Cristina Sampaio; Nellie Georgiou-Karistianis; Jane S Paulsen; Sarah J Tabrizi; Rachael I Scahill; Daniel C Alexander; IMAGE-HD, PREDICT-HD, and TRACK-HD investigators

doi:10.1002/ana.25709

Back

Robust Markers and Sample Sizes for Multicenter Trials of Huntington Disease

Journal article

Open access

Peer reviewed

Robust Markers and Sample Sizes for Multicenter Trials of Huntington Disease

Peter A Wijeratne, Eileanoir B Johnson, Arman Eshaghi, Leon Aksman, Sarah Gregory, Hans J Johnson, Govinda R Poudel, Amrita Mohan, Cristina Sampaio, Nellie Georgiou-Karistianis, …

Annals of neurology, Vol.87(5), pp.751-762

05/2020

DOI: 10.1002/ana.25709

PMCID: PMC7187160

PMID: 32105364

Files and links (1)

url

https://doi.org/10.1002/ana.25709View

Published (Version of record) Open Access

Abstract

The identification of sensitive biomarkers is essential to validate therapeutics for Huntington disease (HD). We directly compare structural imaging markers across the largest collective imaging HD dataset to identify a set of imaging markers robust to multicenter variation and to derive upper estimates on sample sizes for clinical trials in HD. We used 1 postprocessing pipeline to retrospectively analyze T1-weighted magnetic resonance imaging (MRI) scans from 624 participants at 3 time points, from the PREDICT-HD, TRACK-HD, and IMAGE-HD studies. We used mixed effects models to adjust regional brain volumes for covariates, calculate effect sizes, and simulate possible treatment effects in disease-affected anatomical regions. We used our model to estimate the statistical power of possible treatment effects for anatomical regions and clinical markers. We identified a set of common anatomical regions that have similarly large standardized effect sizes (>0.5) between healthy control and premanifest HD (PreHD) groups. These included subcortical, white matter, and cortical regions and nonventricular cerebrospinal fluid (CSF). We also observed a consistent spatial distribution of effect size by region across the whole brain. We found that multicenter studies were necessary to capture treatment effect variance; for a 20% treatment effect, power of >80% was achieved for the caudate (n = 661), pallidum (n = 687), and nonventricular CSF (n = 939), and, crucially, these imaging markers provided greater power than standard clinical markers. Our findings provide the first cross-study validation of structural imaging markers in HD, supporting the use of these measurements as endpoints for both observational studies and clinical trials. ANN NEUROL 2020;87:751-762.

Magnetic Resonance Imaging

Adult

Clinical Trials as Topic

Female

Humans

Huntington Disease - diagnostic imaging

Huntington Disease - pathology

Huntington Disease - therapy

Image Interpretation, Computer-Assisted - methods

Male

Middle Aged

Multicenter Studies as Topic

Neuroimaging - methods

Observational Studies as Topic

Retrospective Studies

Details

Title: Subtitle: Robust Markers and Sample Sizes for Multicenter Trials of Huntington Disease
Creators: Peter A Wijeratne - University College London
Eileanoir B Johnson - University College London
Arman Eshaghi - University College London
Leon Aksman - University College London
Sarah Gregory - University College London
Hans J Johnson - University of Iowa
Govinda R Poudel - Australian Catholic University
Amrita Mohan - CHDI Foundation
Cristina Sampaio - CHDI Foundation
Nellie Georgiou-Karistianis - Monash University
Jane S Paulsen - University of Iowa
Sarah J Tabrizi - University College London
Rachael I Scahill - University College London
Daniel C Alexander - University College London
IMAGE-HD, PREDICT-HD, and TRACK-HD investigators
Resource Type: Journal article
Publication Details: Annals of neurology, Vol.87(5), pp.751-762
DOI: 10.1002/ana.25709
PMID: 32105364
PMCID: PMC7187160
NLM abbreviation: Ann Neurol
ISSN: 0364-5134
eISSN: 1531-8249
Grant note: MR/T027770/1 / Medical Research Council 200181/Z/15/Z / Wellcome Trust M01 RR000059 / NCRR NIH HHS
Language: English
Date published: 05/2020
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Psychiatry; Psychological and Brain Sciences
Record Identifier: 9984185468502771

Metrics

84 Record Views

24 Times Cited - Web of Science