Cataract Classification Using Serial Examinations in the Age-Related Eye Disease Study: Age-Related Eye Disease Study Report No. 24 ROBERT D. SPERDUTO, TRACI E. CLEMONS, ANNE S. LINDBLAD, AND FREDERICK L. FERRIS III, ON BEHALF OF THE AGE-RELATED EYE DISEASE STUDY RESEARCH GROUP ● PURPOSE: To describe use of serial lens examinations to assign cataract phenotype in the Age-Related Eye Disease Study (AREDS). ● DESIGN: Cohort study. ● METHODS: Lens photographs were graded annually using the AREDS system for classifying cataracts. Nu- clear grades (0.9 to 6.1) were assigned using standard photographs. Percentage of pupillary involvement was used to assign cortical and posterior subcapsular grades. Cutpoints were established for the presence or absence of each type of opacity (absent <4.0 for nuclear, <10% for cortical, and <5% of central 5 mm for posterior subcap- sular). An algorithm weighted for grades at the last three examinations was used to assign cataract phenotype. Separately, cataract phenotype was assigned as grade predicted at final visit by linear regression of serial grades. Results from the two approaches were compared and final person phenotypes were established. These person cataract phenotype assignments were compared with phenotype assignments based on the last serial grade alone. ● RESULTS: Four thousand six hundred and twenty-eight AREDS participants aged 55 to 80 years at baseline had median follow-up of 10.6 years. Person phenotype assign- ments agreed for the two approaches in 4,557 (98.5%) participants after some algorithmic adjudication. Pheno- types were no cataract (n  1,418), nuclear (n  1,287), cortical (n  1,396), posterior subcapsular (n  541), cataract surgery and no specific opacity type (n  335), and questionable (n  426). Phenotype assignments based on serial grades and on last examination alone were in good agreement. ● CONCLUSIONS: Serial lens photographs obtained over a 10-year period were used to provide a robust assignment of cataract phenotype. Well-characterized cataract phe- notypes are of importance as genetic studies of the AREDS cohort are considered. (Am J Ophthalmol 2008;145:504 –508. © 2008 by Elsevier Inc. All rights reserved.) M ANY CLINICAL STUDIES, INCLUDING GENETIC studies of age-related cataract, 1–4 establish cat- aract phenotype based on the results of a single examination. Even when established clinical or photo- graphic grading systems 5–9 are used, misclassification can be of concern because of the many sources or error that can affect the largely subjective cataract grading process. Dif- ferences in phenotype assignment can occur because of intraobserver or interobserver grading variability, edge effects when cutpoints are used to establish the presence or absence of cataract, inadequate examiner training, and inherent differences between grading systems. Many clin- ical studies can tolerate small amounts of misclassification, but in some studies, such as genetic studies and studies with few participants, even relatively little misclassifica- tion of phenotype can lead to substantial misinterpretation of results. The Age-Related Eye Disease Study (AREDS), 10 an 11-center prospective study of the clinical course of age- related cataract and macular degeneration, is unique in that lens and macular photographic examinations were conducted at baseline and annually starting in year 2. Examinations of the large AREDS cohort continued for more than 10 years. Participant deoxyribonucleic acid (DNA) and data on environmental exposures were col- lected. It is important that cataract phenotypes be well characterized as genetic studies are considered. The serial examinations in AREDS provide an opportunity for robust assignment of cataract phenotype. In this study, we de- scribe how the serial lens examinations were used to make phenotype assignments and how the assignments based on the serial grades compare with assignments based on the grade at the last visit alone. METHODS THE AREDS IS A STUDY OF THE NATURAL HISTORY OF age-related cataract and macular degeneration. 10 It in- cluded a randomized clinical trial that evaluated the effect of high doses of selected nutritional supplements on the Accepted for publication Oct 24, 2007. From the National Eye Institute, National Institutes of Health, Bethesda, Maryland (R.D.S., F.L.F.); and The EMMES Corporation, Rockville, Maryland (T.E.C., A.S.L.). Inquiries to Traci E. Clemons, The EMMES Corporation, 401 North Washington Street, Suite 700, Rockville, MD 20850; e-mail: tclemons@ emmes.com © 2008 BY ELSEVIER INC.ALL RIGHTS RESERVED. 504 0002-9394/08/$34.00 doi:10.1016/j.ajo.2007.10.024