Agreement between automated and manual quantification of corneal nerve fiber length: Implications for diabetic neuropathy research.

Aims: Quantification of corneal nerve fiber length (CNFL) by in vivo corneal confocal microscopy represents a promising diabetic neuropathy biomarker, but applicability is limited by resource-intensive image analysis. We aimed to evaluate, in cross-sectional analysis of non-diabetic controls and patients with type 1 and type 2 diabetes with and without neuropathy, the agreement between manual and automated analysis protocols.

Methods: Sixty-eight controls, 139 type 1 diabetes, and 249 type 2 diabetes participants underwent CNFL measurement (N=456). Neuropathy status was determined by clinical and electrophysiological criteria. CNFL was determined by manual (CNFL, reference standard) and automated (CNFL) protocols, and results were compared for correlation and agreement using Spearman coefficients and the method of Bland and Altman (CNFL subtracted from CNFL).

Results: Participants demonstrated broad variability in clinical characteristics associated with neuropathy. The mean age, diabetes duration, and HbA1c were 53±18years, 15.9±12.6years, and 7.4±1.7%, respectively, and 218 (56%) individuals with diabetes had neuropathy. Mean CNFL was 15.1±4.9mm/mm, and mean CNFL was 10.5±3.7mm/mm (CNFL underestimation bias, -4.6±2.6mm/mm corresponding to -29±17%). Percent bias was similar across non-diabetic controls (-33±12%), type 1 (-30±20%), and type 2 diabetes (-28±16%) subgroups (ANOVA, p=0.068), and similarly in diabetes participants with and without neuropathy. Levels of CNFL and CNFL were both inversely associated with neuropathy status.

Conclusions: Although CNFL substantially underestimated CNFL, its bias was non-differential between diverse patient groups and its relationship with neuropathy status was preserved. Determination of diagnostic thresholds specific to CNFL should be pursued in diagnostic studies of diabetic neuropathy.