eprintid: 10133753 rev_number: 16 eprint_status: archive userid: 608 dir: disk0/10/13/37/53 datestamp: 2021-09-02 10:44:21 lastmod: 2021-10-06 22:38:27 status_changed: 2021-09-02 10:44:21 type: article metadata_visibility: show creators_name: Wijeratne, PA creators_name: Johnson, EB creators_name: Gregory, S creators_name: Georgiou-Karistianis, N creators_name: Paulsen, JS creators_name: Scahill, RI creators_name: Tabrizi, SJ creators_name: Alexander, DC title: A Multi-Study Model-Based Evaluation of the Sequence of Imaging and Clinical Biomarker Changes in Huntington's Disease ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F86 divisions: B04 divisions: C05 divisions: F48 keywords: huntington’s disease, biomarkers, disease progression model, multi-study investigation, clinical staging note: Copyright © 2021 Wijeratne, Johnson, Gregory, Georgiou-Karistianis, Paulsen, Scahill, Tabrizi and Alexander. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. abstract: Understanding the order and progression of change in biomarkers of neurodegeneration is essential to detect the effects of pharmacological interventions on these biomarkers. In Huntington’s disease (HD), motor, cognitive and MRI biomarkers are currently used in clinical trials of drug efficacy. Here for the first time we use directly compare data from three large observational studies of HD (total N = 532) using a probabilistic event-based model (EBM) to characterise the order in which motor, cognitive and MRI biomarkers become abnormal. We also investigate the impact of the genetic cause of HD, cytosine-adenine-guanine (CAG) repeat length, on progression through these stages. We find that EBM uncovers a broadly consistent order of events across all three studies; that EBM stage reflects clinical stage; and that EBM stage is related to age and genetic burden. Our findings indicate that measures of subcortical and white matter volume become abnormal prior to clinical and cognitive biomarkers. Importantly, CAG repeat length has a large impact on the timing of onset of each stage and progression through the stages, with a longer repeat length resulting in earlier onset and faster progression. Our results can be used to help design clinical trials of treatments for Huntington’s disease, influencing the choice of biomarkers and the recruitment of participants. date: 2021-08-05 date_type: published official_url: https://doi.org/10.3389/fdata.2021.662200 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1884085 doi: 10.3389/fdata.2021.662200 lyricists_name: Alexander, Daniel lyricists_name: Scahill, Rachael lyricists_name: Tabrizi, Sarah lyricists_name: Wijeratne, Peter lyricists_id: DALEX06 lyricists_id: RSCAH26 lyricists_id: SJTAB21 lyricists_id: PAWIJ75 actors_name: Barczynska, Patrycja actors_id: PBARC91 actors_role: owner full_text_status: public publication: Frontiers in Big Data volume: 4 article_number: 662200 citation: Wijeratne, PA; Johnson, EB; Gregory, S; Georgiou-Karistianis, N; Paulsen, JS; Scahill, RI; Tabrizi, SJ; Wijeratne, PA; Johnson, EB; Gregory, S; Georgiou-Karistianis, N; Paulsen, JS; Scahill, RI; Tabrizi, SJ; Alexander, DC; - view fewer <#> (2021) A Multi-Study Model-Based Evaluation of the Sequence of Imaging and Clinical Biomarker Changes in Huntington's Disease. Frontiers in Big Data , 4 , Article 662200. 10.3389/fdata.2021.662200 <https://doi.org/10.3389/fdata.2021.662200>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10133753/1/fdata-04-662200.pdf