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Progression, reliability, predicting parameters and sample size calculations for quantitative fundus autofluorescence measures in ABCA4-related retinopathy
  1. Philipp L Müller1,2,3,
  2. Tim Treis4,
  3. Adnan Tufail1,5,
  4. Frank G Holz3
  1. 1 Moorfields Eye Hospital NHS Foundation Trust, London, UK
  2. 2 Makula Center, Südblick Eye Centers, Augsburg, Germany
  3. 3 Department of Ophthalmology, Rheinische Friedrich-Wilhelms-Universitat Bonn, Bonn, Germany
  4. 4 German Cancer Research Center, Heidelberg, Germany
  5. 5 Institute of Ophthalmology, University College London, London, UK
  1. Correspondence to Dr Philipp L Müller, Moorfields Eye Hospital NHS Foundation Trust, London, EC1V 2PD, UK; study-enquiry{at}


Background/aims To investigate the progression of quantitative autofluorescence (qAF) measures and the potential as clinical trial endpoint in ABCA4-related retinopathy.

Methods In this longitudinal monocentre study, 64 patients with ABCA4-related retinopathy (age (mean±SD), 34.84±16.36 years) underwent serial retinal imaging, including optical coherence tomography (OCT) and qAF (488 nm excitation) imaging using a modified confocal scanning laser ophthalmoscope with a mean (±SD) review period of 20.32±10.90 months. A group of 110 healthy subjects served as controls. Retest variability, changes of qAF measures over time and its association with genotype and phenotype were analysed. Furthermore, individual prognostic feature importance was assessed, and sample size calculations for future interventional trials were performed.

Results Compared with controls, qAF levels of patients were significantly elevated. The test–retest reliability revealed a 95% coefficient of repeatability of 20.37. During the observation time, young patients, patients with a mild phenotype (morphological and functional) and patients with mild mutations showed an absolute and relative increase in qAF values, while patients with advanced disease manifestation (morphological and functional), and homozygous mutations at adulthood revealed a decrease in qAF. Considering these parameters, required sample size and study duration could significantly be reduced.

Conclusion Under standardised settings with elaborated conditions towards operators and analysis to counterbalance variability, qAF imaging might be reliable, suitable for quantifying disease progression and constitutes a potential clinical surrogate marker in ABCA4-related retinopathy. Trial design based on patients’ baseline characteristics and genotype has the potential to provide benefits regarding required cohort size and absolute number of visits.

  • Retina
  • Clinical Trial
  • Imaging
  • Macula

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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  • X @PhilippLMuller

  • Contributors Study concept and design and drafting of the manuscript: PLM; acquisition, analysis or interpretation of data: all authors; critical revision of the manuscript for important intellectual content: TT, AT and FGH,

    guarantor: PLM.

  • Funding This work was supported by the German Research Foundation (DFG, Grant MU4279/1-1 and MU4279/2-1 to PLM) and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology (support to AT). Heidelberg Engineering, Heidelberg, Germany has provided research material for the conduct of this study.

  • Disclaimer The views expressed are those of the authors, not necessarily those of the NHS, the NIHR, or the Department of Health. The sponsor and funding organisation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

  • Competing interests PLM received grants and personal fees from Novartis, grants from Bayer and grants Santen outside the submitted work. AT received personal fees from Allergan, grants and personal fees from Bayer, personal fees from Kanghong, personal fees from Heidelberg Engineering, grants and personal fees from Novartis, personal fees from Roche/Genentech, personal fees from Iveric Bio, personal fees from Apellis and personal fees from Thea outside the submitted work. FGH received grants, personal fees and non-financial support from Heidelberg Engineering, grants and personal fees from Novartis, grants and personal fees from Bayer, grants and personal fees from Acucela, grants and personal fees from Alcon, grants and personal fees from Allergan, grants, personal fees and non-financial support from Optos, personal fees from Boehringer Ingelheim and non-financial support from Carl Zeiss MediTec AG outside the submitted work. No other conflicting relationship exists for any author.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.