Visual Acuity as an Outcome Measure in Clinical Trials of Retinal Diseases Roy W. Beck, MD, PhD, 1 Maureen G. Maguire, PhD, 2 Neil M. Bressler, MD, 3 Adam R. Glassman, MS, 1 Anne S. Lindblad, PhD, 4 Frederick L. Ferris, MD 5 Purpose: Visual acuity (VA) is the primary outcome measure in many studies involving eye diseases. A standard statistical approach for comparing a continuous measurement such as a VA letter score between 2 treatment groups is to perform a t test comparing the means. However, frequently a binary variable is created from the continuous VA letter score based on whether or not there has been a worsening (or gain) of 15 letters (equivalent to 3 lines), and a chi square or similar statistical test is performed to compare the proportions of success (or failure) between groups. The purpose of this article is to contrast these 2 approaches. Methods: Clinical trial reports of retinal disorders were used to compare results using mean change in the VA letter score versus binary proportions created from the VA letter score. Additionally, analyses were performed using generated data to gain a perspective on the magnitude of differences that might be expected between the 2 methods. Results: Studies from the literature showed that differences of 6% to 15% in 15-letter worsening corre- sponded to mean differences in letter scores between groups of 3.0 to 7.0 (approximately 0.6 to 1.4 lines). Analyses using generated data demonstrated that a mean improvement in the VA letter score of 5 corresponded to a doubling of the proportion of eyes with 15-letter improvement and a 28% relative reduction in the proportion of eyes with 15-letter worsening. Conclusions: How VA data should be analyzed in a clinical trial depends to large extent on the research question. The frequently used outcome of 15-letter change has several drawbacks, including loss of efficiency (need for a larger sample), misclassification of the outcome, and potential for a ceiling or floor effect. Therefore, for most clinical trials we believe that the primary outcome analysis should be a comparison of changes in the VA letter score, and created binary variables should be reported as secondary outcomes. This approach maximizes the information gained from the data and accommodates both improvement and worsening of acuity. Ophthalmology 2007;114:1804 –1809 © 2007 by the American Academy of Ophthalmology. Visual acuity (VA) has been the primary outcome measure for evaluation of the efficacy of most treatments for retinal diseases. The testing procedure that was developed for the Early Treatment Diabetic Retinopathy Study (ETDRS) 1 has been the standard for more than 20 years. The chart consists of 5-letter lines that are constructed such that there is a geometric progression from line to line, with every third line representing a doubling of the visual angle (a doubling of the size of the letters). As originally described, testing is performed at 4 m, with measurements at 1 m when fewer than 15 letters are read at 4 m. A computerized adaptation of the ETDRS method has been developed that provides a letter score at a single 3-m testing distance comparable to the score from ETDRS chart testing. 2 Testing with either the ETDRS charts or the computer- ized adaptation results in a letter score ranging from a maximum score of 100, corresponding to a Snellen fraction approximation of 20/10, to a minimum score of 0, corre- sponding to a Snellen fraction approximation worse than 20/800. A score of 85 approximates 20/20. A change of 5 in the score between examinations approximates a 1-line change. For eyes with acuity better than 20/100, a change in VA between 2 time points of 5 letters has a high proba- bility (90% or higher) of being a real change in VA and not a difference due to chance. For eyes with VA worse than 20/100, a change of 10 letters would be necessary for the same degree of assurance. 2,3 In a clinical trial comparing 2 treatment groups, a deter- mination of the better treatment is often a question of whether VA has improved more (or worsened less) in one group than in the other group. The 2 groups may be a no-treatment group and an active treatment group or involve the comparison of 2 different active treatment groups. A common analytic approach is to create a success–failure outcome variable based on the change in the VA letter score Originally received: April 5, 2007. Final revision: June 12, 2007. Accepted: June 29, 2007. Manuscript no. 2007-473. 1 Jaeb Center for Health Research, Tampa, Florida. 2 Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania. 3 Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. 4 EMMES Corporation, Rockville, Maryland. 5 National Eye Institute, Bethesda, Maryland. Correspondence to Roy W. Beck, MD, PhD, Jaeb Center for Health Research, 15310 Amberly Drive, Suite 350, Tampa, FL 33647. 1804 © 2007 by the American Academy of Ophthalmology ISSN 0161-6420/07/$–see front matter Published by Elsevier Inc. doi:10.1016/j.ophtha.2007.06.047