Artificial intelligence‐quantified schisis volume as a structural endpoint for gene therapy clinical trials in X‐linked retinoschisis
Acta Ophthalmologica, vol. 103, pp. 715–724
Abstract
PURPOSE: To use artificial intelligence (AI) for quantifying schisis volume (ASV) in X-linked retinoschisis (XLRS) for use as a structural endpoint in gene therapy clinical trials. METHODS: We used data from Singapore, the United Kingdom, the Netherlands, and the United States. The AI model was developed on 250 optical coherence tomography (OCT) slices, with human annotation of schisis cavities (Dataset 1). ASV was quantified on Dataset 2 - 16 OCT scans from 8 eyes with XLRS at two time points, and Dataset 4 - 62 OCT scans from 31 eyes at two time points before and after carbonic anhydrase inhibitor (CAI) treatment. A clinical trial was simulated comparing CAI treatment against control. Changes in ASV, central subfield thickness (CST) and central foveal thickness (CFT) were compared. Effect size (Cohen's d) of the three structural endpoints was determined and used in sample size calculations for a future XLRS gene therapy clinical trial, at a 0.05 significance level and 80% power. RESULTS: In the simulated clinical trial, all structural metrics showed greater reductions with intervention than with control, but only change in ASV reached statistical significance (p = 0.004). Cohen's d for ASV, CST and CFT were 0.972, 0.685 and 0.521, respectively. For the future gene therapy clinical trial, sample sizes required in each arm for ASV, CST and CFT were 18, 35 and 59 participants, respectively. CONCLUSIONS: ASV measurements can track changes in schisis volume in response to treatment. As an endpoint, ASV has a greater statistical effect size than CST/CFT, which reduces sample size requirements for future XLRS gene therapy clinical trials.
Authors 10
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Singapore National Eye Center · University of Oxford · Singapore Eye Research Institute · Duke-NUS Medical School · Oxford University Hospitals NHS Trust
Affiliation as printed
Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences University of Oxford Oxford UK
Ophthalmology and Visual Sciences Academic Clinical Programme (EYE ACP), Duke‐NUS Medical School Singapore Singapore
Oxford Eye Hospital Oxford University Hospitals NHS Foundation Trust Oxford UK
Singapore Eye Research Institute Singapore National Eye Centre Singapore Singapore
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Agency for Science, Technology and Research · Institute of High Performance Computing
Affiliation as printed
Institute of High Performance Computing Agency for Science, Technology and Research (A*STAR) Singapore Singapore
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Amsterdam University Medical Centers
Affiliation as printed
Department of Ophthalmology Amsterdam University Medical Center Amsterdam The Netherlands
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University of Oxford · Oxford University Hospitals NHS Trust
Affiliation as printed
Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences University of Oxford Oxford UK
Oxford Eye Hospital Oxford University Hospitals NHS Foundation Trust Oxford UK
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University of Iowa · Singapore National Eye Center · Singapore Eye Research Institute · Duke-NUS Medical School
Affiliation as printed
Department of Ophthalmology and Visual Sciences, Carver College of Medicine The University of Iowa Iowa City Iowa USA
Ophthalmology and Visual Sciences Academic Clinical Programme (EYE ACP), Duke‐NUS Medical School Singapore Singapore
Singapore Eye Research Institute Singapore National Eye Centre Singapore Singapore
The University of Iowa Institute for Vision Research The University of Iowa Iowa City Iowa USA
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Agency for Science, Technology and Research · Institute of High Performance Computing
Affiliation as printed
Institute of High Performance Computing Agency for Science, Technology and Research (A*STAR) Singapore Singapore
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Affiliation as printed
Department of Ophthalmology and Visual Sciences, Carver College of Medicine The University of Iowa Iowa City Iowa USA
The University of Iowa Institute for Vision Research The University of Iowa Iowa City Iowa USA
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Singapore National Eye Center · Singapore Eye Research Institute · Duke-NUS Medical School
Affiliation as printed
Ophthalmology and Visual Sciences Academic Clinical Programme (EYE ACP), Duke‐NUS Medical School Singapore Singapore
Singapore Eye Research Institute Singapore National Eye Centre Singapore Singapore
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Camiel J. F. Boon Aachen Department of Ophthalmology Leiden University Medical Center Leiden the Netherlands
Leiden University Medical Center · Amsterdam University Medical Centers
Affiliation as printed
Department of Ophthalmology Amsterdam University Medical Center Amsterdam The Netherlands
Department of Ophthalmology Leiden University Medical Center Leiden The Netherlands
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Manuel Dominik Fischer corresponding
University of Oxford · Universitätsklinikum Tübingen · Oxford University Hospitals NHS Trust
Affiliation as printed
Centre for Ophthalmology University Hospital Tuebingen Tuebingen Germany
Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences University of Oxford Oxford UK
Oxford Eye Hospital Oxford University Hospitals NHS Foundation Trust Oxford UK
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