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Developing and validating a multivariable prediction model which predicts progression of intermediate to late age-related macular degeneration-the PINNACLE trial protocol

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Janice Sutton, Martin J. Menten, Sophie Riedl, Hrvoje Bogunovic, Oliver Leingang, Philipp Anders, Ahmed M Hagag, Sebastian Waldstein, Amber Wilson, Angela J Cree, Ghislaine Traber, Lars G Fritsche, Hendrik Scholl, Daniel Rueckert, Ursula Schmidt-Erfurth, Sobha Sivaprasad, Toby Prevost, Andrew Lotery

Original languageEnglish
Number of pages9
JournalEye (London, England)
DOIs
Accepted/In press27 Apr 2022
Published25 May 2022

Bibliographical note

Funding Information: AL is a consultant for Gyroscope Therapeutics Ltd, Eyebio, Complement Therapeutics, Novartis, Allergan, Apellis and Tarsus Pharmaceuticals. DR is a co-founder and shareholder of IXICO Plc. SS has attended advisory board meetings and received research grants and is a consultant for Genentech Inc./F. Hoffmann-La Roche Ltd, Allergen, Bayer and Novartis, Oxurion, Ophtea, Optos, Oculis, Apellis, Eyebio, Gyroscope. SW is a consultant to Bayer, Roche, Santen, Böhringer Ingelheim and Novartis. USE receives grant support from Genentech, Kodiak, Novartis, RetInSight and Roche and is a consultant for Apellis. HB has received research grants from Heidelberg Engineering and Apellis, and speaker fees from Bayer, Roche, and Apellis. HS is a member of the Scientific Advisory Board of: Astellas Pharma Global Development, Inc./Astellas Institute for Regenerative Medicine; Boehringer Ingelheim Pharma GmbH & Co; Gyroscope Therapeutics Ltd.; Janssen Research & Development, LLC (Johnson & Johnson); Novartis Pharma AG (CORE); Okuvision GmbH; and Third Rock Ventures, LLC. He is a consultant of Gerson Lehrman Group; Guidepoint Global, LLC; and Tenpoint Therapeutics Limited. HS is a member of the Data Monitoring and Safety Board/Committee of Belite Bio (CT2019-CTN-04690-1), ReNeuron Group Plc/Ora Inc. (NCT02464436), F. Hoffmann-La Roche Ltd (VELODROME trial, NCT04657289; DIAGRID trial, NCT05126966) and member of the Steering Committee of Novo Nordisk (FOCUS trial; NCT03811561). He is a co-director of the Institute of Molecular and Clinical Ophthalmology Basel (IOB) which receives funding from the University of Basel, the University Hospital Basel, Novartis, and the government of Basel-Stadt. Funding Information: The Pinnacle consortium is funded by a Wellcome Trust Collaborative Award, “Deciphering AMD by deep phenotyping and machine learning” (PINNACLE) Ref. 210572/Z/18/Z. Publisher Copyright: © 2022, The Author(s).

King's Authors

Abstract

Aims: Age-related macular degeneration (AMD) is characterised by a progressive loss of central vision. Intermediate AMD is a risk factor for progression to advanced stages categorised as geographic atrophy (GA) and neovascular AMD. However, rates of progression to advanced stages vary between individuals. Recent advances in imaging and computing technologies have enabled deep phenotyping of intermediate AMD. The aim of this project is to utilise machine learning (ML) and advanced statistical modelling as an innovative approach to discover novel features and accurately quantify markers of pathological retinal ageing that can individualise progression to advanced AMD.

Methods: The PINNACLE study consists of both retrospective and prospective parts. In the retrospective part, more than 400,000 optical coherent tomography (OCT) images collected from four University Teaching Hospitals and the UK Biobank Population Study are being pooled, centrally stored and pre-processed. With this large dataset featuring eyes with AMD at various stages and healthy controls, we aim to identify imaging biomarkers for disease progression for intermediate AMD via supervised and unsupervised ML. The prospective study part will firstly characterise the progression of intermediate AMD in patients followed between one and three years; secondly, it will validate the utility of biomarkers identified in the retrospective cohort as predictors of progression towards late AMD. Patients aged 55-90 years old with intermediate AMD in at least one eye will be recruited across multiple sites in UK, Austria and Switzerland for visual function tests, multimodal retinal imaging and genotyping. Imaging will be repeated every four months to identify early focal signs of deterioration on spectral-domain optical coherence tomography (OCT) by human graders. A focal event triggers more frequent follow-up with visual function and imaging tests. The primary outcome is the sensitivity and specificity of the OCT imaging biomarkers. Secondary outcomes include sensitivity and specificity of novel multimodal imaging characteristics at predicting disease progression, ROC curves, time from development of imaging change to development of these endpoints, structure-function correlations, structure-genotype correlation and predictive risk models.

Conclusions: This is one of the first studies in intermediate AMD to combine both ML, retrospective and prospective AMD patient data with the goal of identifying biomarkers of progression and to report the natural history of progression of intermediate AMD with multimodal retinal imaging.

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