Retinal Fractal Dimension Is a Potential Biomarker for Systemic Health-Evidence From a Mixed-Age, Primary-Care Population

Abstract

Purpose: To investigate whether fractal dimension (FD), a retinal trait relating to vascular complexity and a potential "oculomics" biomarker for systemic disease, is applicable to a mixed-age, primary-care population.

Methods: We used cross-sectional data (96 individuals; 183 eyes; ages 18-81 years) from a university-based optometry clinic in Glasgow, Scotland, to study the association between FD and systemic health. We computed FD from color fundus images using Deep Approximation of Retinal Traits (DART), an artificial intelligence-based method designed to be more robust to poor image quality.

Results: Despite DART being designed to be more robust, a significant association (P < 0.001) between image quality and FD remained. Consistent with previous literature, age was associated with lower FD (P < 0.001 univariate and when adjusting for image quality). However, FD variance was higher in older patients, and some patients over 60 had FD comparable to those of patients in their 20s. Prevalent systemic conditions were significantly (P = 0.037) associated with lower FD when adjusting for image quality and age.

Conclusions: Our work suggests that FD as a biomarker for systemic health extends to mixed-age, primary-care populations. FD decreases with age but might not substantially decrease in everyone. This should be further investigated using longitudinal data. Finally, image quality was associated with FD, but it is unclear whether this finding is measurement error caused by image quality or confounded by age and health. Future work should investigate this to clarify whether adjusting for image quality is appropriate.

Translational relevance: FD could potentially be used in regular screening settings, but questions around image quality remain.

Figure 1.

Association of retinal FD and age. (a) Raw data. (b) FD adjusted for image quality using a mixed-effects model with random intercepts for each patient at the eye-level (i.e., each point corresponds to one eye). (c) The same model as in part (b) but with values at the patient level (i.e., each point is one patient). For parts (b) and (c), the coefficient for age is −0.007 per decade of age (95% CI, −0.009 to −0.004; P < 0.001).

Figure 2.

Simplified causal diagram for FD measurements. The dashed orange arrow indicates the undesirable potential effect of image quality on FD. The dashed pink arrow indicates a potential direct effect of age on retinal vascular complexity that could occur in healthy aging.