Rebecca Kaye

Robbie Holland, Oliver Leingang, Christopher Holmes et al.

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Current grading systems based on imaging biomarkers only coarsely group disease stages into broad categories and are unable to predict future disease progression. It is widely believed that this is due to their focus on a single point in time, disregarding the dynamic nature of the disease. In this work, we present the first method to automatically discover biomarkers that capture temporal dynamics of disease progression. Our method represents patient time series as trajectories in a latent feature space built with contrastive learning. Then, individual trajectories are partitioned into atomic sub-sequences that encode transitions between disease states. These are clustered using a newly introduced distance metric. In quantitative experiments we found our method yields temporal biomarkers that are predictive of conversion to late AMD. Furthermore, these clusters were highly interpretable to ophthalmologists who confirmed that many of the clusters represent dynamics that have previously been linked to the progression of AMD, even though they are currently not included in any clinical grading system.

Robbie Holland, Rebecca Kaye, Ahmed M. Hagag et al.

Diseases are currently managed by grading systems, where patients are stratified by grading systems into stages that indicate patient risk and guide clinical management. However, these broad categories typically lack prognostic value, and proposals for new biomarkers are currently limited to anecdotal observations. In this work, we introduce a deep-learning-based biomarker proposal system for the purpose of accelerating biomarker discovery in age-related macular degeneration (AMD). It works by first training a neural network using self-supervised contrastive learning to discover, without any clinical annotations, features relating to both known and unknown AMD biomarkers present in 46,496 retinal optical coherence tomography (OCT) images. To interpret the discovered biomarkers, we partition the images into 30 subsets, termed clusters, that contain similar features. We then conduct two parallel 1.5-hour semi-structured interviews with two independent teams of retinal specialists that describe each cluster in clinical language. Overall, both teams independently identified clearly distinct characteristics in 27 of 30 clusters, of which 23 were related to AMD. Seven were recognised as known biomarkers already used in established grading systems and 16 depicted biomarker combinations or subtypes that are either not yet used in grading systems, were only recently proposed, or were unknown. Clusters separated incomplete from complete retinal atrophy, intraretinal from subretinal fluid and thick from thin choroids, and in simulation outperformed clinically-used grading systems in prognostic value. Overall, contrastive learning enabled the automatic proposal of AMD biomarkers that go beyond the set used by clinically established grading systems. Ultimately, we envision that equipping clinicians with discovery-oriented deep-learning tools can accelerate discovery of novel prognostic biomarkers.