Purpose: To quantify relevant fundus autofluorescence (FAF) image features cross-sectionally and longitudinally in a large cohort of inherited retinal diseases (IRDs) patients. Design: Retrospective study of imaging data (55-degree blue-FAF on Heidelberg Spectralis) from patients. Participants: Patients with a clinical and molecularly confirmed diagnosis of IRD who have undergone FAF 55-degree imaging at Moorfields Eye Hospital (MEH) and the Royal Liverpool Hospital (RLH) between 2004 and 2019. Methods: Five FAF features of interest were defined: vessels, optic disc, perimacular ring of increased signal (ring), relative hypo-autofluorescence (hypo-AF) and hyper-autofluorescence (hyper-AF). Features were manually annotated by six graders in a subset of patients based on a defined grading protocol to produce segmentation masks to train an AI model, AIRDetect, which was then applied to the entire imaging dataset. Main Outcome Measures: Quantitative FAF imaging features including area in mm2 and vessel metrics, were analysed cross-sectionally by gene and age, and longitudinally to determine rate of progression. AIRDetect feature segmentation and detection were validated with Dice score and precision/recall, respectively. Results: A total of 45,749 FAF images from 3,606 IRD patients from MEH covering 170 genes were automatically segmented using AIRDetect. Model-grader Dice scores for disc, hypo-AF, hyper-AF, ring and vessels were respectively 0.86, 0.72, 0.69, 0.68 and 0.65. The five genes with the largest hypo-AF areas were CHM, ABCC6, ABCA4, RDH12, and RPE65, with mean per-patient areas of 41.5, 30.0, 21.9, 21.4, and 15.1 mm2. The five genes with the largest hyper-AF areas were BEST1, CDH23, RDH12, MYO7A, and NR2E3, with mean areas of 0.49, 0.45, 0.44, 0.39, and 0.34 mm2 respectively. The five genes with largest ring areas were CDH23, NR2E3, CRX, EYS and MYO7A, with mean areas of 3.63, 3.32, 2.84, 2.39, and 2.16 mm2. Vessel density was found to be highest in EFEMP1, BEST1, TIMP3, RS1, and PRPH2 (10.6%, 10.3%, 9.8%, 9.7%, 8.9%) and was lower in Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis genes. Longitudinal analysis of decreasing ring area in four RP genes (RPGR, USH2A, RHO, EYS) found EYS to be the fastest progressor at -0.18 mm2/year. Conclusions: We have conducted the first large-scale cross-sectional and longitudinal quantitative analysis of FAF features across a diverse range of IRDs using a novel AI approach.

The authors have declared no competing interest.

This work is primarily funded by a NIHR AI Award (AI_AWARD02488) which supported NP, WAW, MM, KB, SD and SM. The research was also supported by a grant from the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. NP was also previously funded by Moorfields Eye Charity Career Development Award (R190031A). BJ was partially funded by IIR-DE-002818 from Shire/Takeda and by the European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders (ERN-ITHACA). OAM is supported by the Wellcome Trust (206619/Z/17/Z). AYL is supported by an unrestricted and career development award from RPB, Latham Vision Science Awards, NIH OT2OD032644, NEI/NIH K23EY029246, and NIA/NIH U19AG066567. SA is supported by a scholarship from Qatar National Research Fund (GSRA6-1-0329-19010).This project was also supported by a generous donation by Stephen and Elizabeth Archer in memory of Marion Woods. The hardware used for analysis was supported by the BRC Challenge Fund (BRC3_027). We also gratefully acknowledge the support of NVIDIA Corporation with the donation of the Titan Xp GPU used for this research. The views expressed are those of the authors and not the funding organisations.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This research was approved by the IRB and the UK Health Research Authority Research Ethics Committee (REC) reference (22/WA/0049) "Eye2Gene: accelerating the diagnosis of inherited retinal diseases" Integrated Research Application System (IRAS) (project ID: 242050). All research adhered to the tenets of the Declaration of Helsinki.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The data that support the findings of this study are divided into two groups, published data and restricted data. Published data are available from the Github repository. Restricted data are curated for AIRDetect users under a license and cannot be published, to protect patient privacy and intellectual property. Synthetic data derived from the test data has been made available at https://github.com/Eye2Gene/.

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