323-OR: Prediction of Future Neuropathy Onset Using Corneal Confocal Microscopy: A Longitudinal Multinational Consortium Study
Authors: PERKINS BRUCE A. , LOVBLOM LEIF ERIK , BRIL VERA , FERDOUSI MARYAM , ORSZAG ANDREJ , EDWARDS KATIE , PRITCHARD NICOLA , RUSSELL ANTHONY W. , DEHGHANI CIROUS , PACAUD DANIÈLE , ROMANCHUK KENNETH , MAH JEAN , JEZIORSKA MARIA , MARSHALL ANDREW , SHTEIN RONI M. , POP-BUSUI RODICA , LENTZ STEPHEN I. , BOULTON ANDREW J. , TAVAKOLI MITRA , EFRON NATHAN , MALIK RAYAZ A. 
Published: June 2019

Corneal Nerve Fibre Length (CNFL) reasonably identifies the presence of neuropathy in patients with T1D and T2D. In this longitudinal diagnostic study, we aimed to determine its ability to predict future neuropathy. Among 998 participants with diabetes, we examined the 387 who did not have neuropathy at baseline and who had follow-up in a 5-centre multinational consortium study. Participants underwent corneal nerve quantification and clinical and electrophysiological examination for neuropathy at baseline and in scheduled follow-up. Predictive validity and diagnostic thresholds were determined using time-dependent receiver operating characteristic (ROC) curves that accounted for censoring, and used baseline and time-updated CNFL. Estimates were derived in the T1D subcohort and validated in the T2D subcohort. The 387 participants had mean follow-up of 4.8 years (interquartile range 3-7y). 288 had T1D (baseline mean age 35±17 years and A1c 8.2±1.5%) and 99 had T2D (baseline age 59±8 years and A1c 7.3±1.1%). New onset neuropathy occurred in 85 participants (22%; incidence rate 5.05 events per 100 person years). The crude area under the ROC curve (AUC) for CNFL was 0.64 (95% CI 0.56-0.73, p=0.001) in the T1D derivation set, which was confirmed in the T2D validation set (AUC 0.69, 95% CI 0.57-0.81, p=0.002). In the combined cohort, time-dependent ROC curves were generated for 2, 4, 6, and 8 years; AUC ranged from 0.67 to 0.71 for baseline CNFL, and 0.66 to 0.68 for time-updated CNFL. The optimal diagnostic threshold for baseline CNFL was 14.1mm/mm2 (sensitivity 67%, specificity 63%, 1ikelihood ratio (LR) positive 1.8, LR negative 0.5, Cox proportional hazard rate ratio 2.79, p&lt;0.001). CNFL showed modest but statistically significant predictive validity. Though its utility may be limited as a diagnostic tool in estimating risk for individual patients, it could play a role in identifying higher-risk groups of individuals for inclusion in clinical research and trials.

Disclosure
B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. L. Lovblom: None. V. Bril: Advisory Panel; Self; Akcea Therapeutics, Alexion Pharmaceuticals, Inc., Alnylam, CSL Behring. Consultant; Self; Pfizer Inc. Research Support; Self; Baxter, Biogen, Grifols, UCB, Inc. M. Ferdousi: None. A. Orszag: None. K. Edwards: None. N. Pritchard: None. A.W. Russell: None. C. Dehghani: None. D. Pacaud: Other Relationship; Self; Novo Nordisk A/S, Sandoz, TOLMAR. K. Romanchuk: None. J. Mah: None. M. Jeziorska: None. A. Marshall: None. R.M. Shtein: None. R. Pop-Busui: Consultant; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca. Other Relationship; Self; American Diabetes Association. S.I. Lentz: None. A.J. Boulton: None. M. Tavakoli: None. N. Efron: None. R.A. Malik: None.

Funding
National Institutes of Health