Purpose: To describe and demonstrate appropriate statistical approaches for estimating sensitivity, specificity, predictive values and their 95% confidence intervals (95% CI) for correlated eye data.
Methods: We described generalized estimating equations (GEE) and cluster bootstrap to account for inter-eye correlation and applied them for analyzing the data from a clinical study of telemedicine for the detection of retinopathy of prematurity (ROP).
Results: Among 100 infants (200 eyes) selected for analysis, 20 infants had referral-warranted ROP (RW-ROP) in both eyes and 9 infants with RW-ROP only in one eye based on clinical eye examination. In the per-eye analysis that included both eyes of an infant, the image evaluation for RW-ROP had sensitivity of 83.7% and specificity of 86.8%. The 95% CI's from the naïve approach that ignored the inter-eye correlation were narrower than those of the GEE approach and cluster bootstrap for both sensitivity (width of 95% CI: 22.4% vs. 23.2% vs. 23.9%) and specificity (11.4% vs. 12.5% vs. 11.6%). The 95% CIs for sensitivity and specificity calculated from left eyes and right eyes separately were wider (35.2% and 30.8% respectively for sensitivity, 25.4% and 17.3% respectively for specificity).
Conclusions: When an ocular test is performed in both eyes of some or all of the study subjects, the statistical analyses are best performed at the eye-level and account for the inter-eye correlation by using either the GEE or cluster bootstrap. Ignoring the inter-eye correlation results in 95% CIs that are inappropriately narrow and analyzing data from two eyes separately are not efficient.