Normative Data and Conversion Equation for Spectral-Domain Optical Coherence Tomography in an International Healthy Control Cohort
Authors: Kenney Rachel , Liu Mengling , Hasanaj Lisena , Joseph Binu , Al-Hassan Abdullah A. , Balk Lisanne , Behbehani Raed , Brandt Alexander U. , Calabresi Peter A. , Frohman Elliot M. , Frohman Teresa , Havla Joachim , Hemmer Bernhard , Jiang Hong , Knier Benjamin , Korn Thomas , Leocani Letizia , Martínez-Lapiscina Elena H. , Papadopoulou Athina , Paul Friedemann , Petzold Axel , Pisa Marco , Villoslada Pablo , Zimmermann Hanna , Ishikawa Hiroshi , Schuman Joel S. , Wollstein Gadi , Chen Yu , Saidha Shiv , Thorpe Lorna E. , Galetta Steven L. , Balcer Laura J. ,   on behalf of the IMSVISUAL Consortium
Published: September 2022

Background:
Spectral-domain (SD-) optical coherence tomography (OCT) can reliably measure axonal (peripapillary retinal nerve fiber layer [pRNFL]) and neuronal (macular ganglion cell + inner plexiform layer [GCIPL]) thinning in the retina. Measurements from 2 commonly used SD-OCT devices are often pooled together in multiple sclerosis (MS) studies and clinical trials despite software and segmentation algorithm differences; however, individual pRNFL and GCIPL thickness measurements are not interchangeable between devices. In some circumstances, such as in the absence of a consistent OCT segmentation algorithm across platforms, a conversion equation to transform measurements between devices may be useful to facilitate pooling of data. The availability of normative data for SD-OCT measurements is limited by the lack of a large representative world-wide sample across various ages and ethnicities. Larger international studies that evaluate the effects of age, sex, and race/ethnicity on SD-OCT measurements in healthy control participants are needed to provide normative values that reflect these demographic subgroups to provide comparisons to MS retinal degeneration.

Methods:
Participants were part of an 11-site collaboration within the International Multiple Sclerosis Visual System (IMSVISUAL) consortium. SD-OCT was performed by a trained technician for healthy control subjects using Spectralis or Cirrus SD-OCT devices. Peripapillary pRNFL and GCIPL thicknesses were measured on one or both devices. Automated segmentation protocols, in conjunction with manual inspection and correction of lines delineating retinal layers, were used. A conversion equation was developed using structural equation modeling, accounting for clustering, with healthy control data from one site where participants were scanned on both devices on the same day. Normative values were evaluated, with the entire cohort, for pRNFL and GCIPL thicknesses for each decade of age, by sex, and across racial groups using generalized estimating equation (GEE) models, accounting for clustering and adjusting for within-patient, intereye correlations. Change-point analyses were performed to determine at what age pRNFL and GCIPL thicknesses exhibit accelerated rates of decline.

Results:
The healthy control cohort (n = 546) was 54% male and had a wide distribution of ages, ranging from 18 to 87 years, with a mean (SD) age of 39.3 (14.6) years. Based on 346 control participants at a single site, the conversion equation for pRNFL was Cirrus = −5.0 + (1.0 × Spectralis global value). Based on 228 controls, the equation for GCIPL was Cirrus = −4.5 + (0.9 × Spectralis global value). Standard error was 0.02 for both equations. After the age of 40 years, there was a decline of −2.4 μm per decade in pRNFL thickness (P < 0.001, GEE models adjusting for sex, race, and country) and −1.4 μm per decade in GCIPL thickness (P < 0.001). There was a small difference in pRNFL thickness based on sex, with female participants having slightly higher thickness (2.6 μm, P = 0.003). There was no association between GCIPL thickness and sex. Likewise, there was no association between race/ethnicity and pRNFL or GCIPL thicknesses.

Conclusions:
A conversion factor may be required when using data that are derived between different SD-OCT platforms in clinical trials and observational studies; this is particularly true for smaller cross-sectional studies or when a consistent segmentation algorithm is not available. The above conversion equations can be used when pooling data from Spectralis and Cirrus SD-OCT devices for pRNFL and GCIPL thicknesses. A faster decline in retinal thickness may occur after the age of 40 years, even in the absence of significant differences across racial groups.