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The age-related eye disease study (AREDS) system for classifying cataracts from photographs: AREDS report no. 4∗
The Age-Related Eye Disease Study (AREDS) System for Classifying Cataracts From Photographs: AREDS Report No. 4 THE AGE-RELATED EYE DISEASE STUDY RESEARCH GROUP*
● PURPOSE:
To describe the system for grading cataracts from photographs in the Age-Related Eye Disease Study (AREDS). ● METHODS: The system for grading cataracts in AREDS uses photographs taken in a standardized fashion with specially modified cameras at 11 clinical centers. The photographs are evaluated by graders for quality and cataract severity at a central reading center. The area of lens involvement is used to assess the severity of cortical and posterior subcapsular opacities. Optical density of nuclear opacity is graded against a series of seven standard photographs. Contemporaneous variability in grading is evaluated periodically by having a second examiner regrade a subset of the photographs. Temporal variability is assessed by annually regrading a subset of photographs. ● RESULTS: Photographs of 925 eyes, most with no or early lens opacities, were regraded to assess intergrader reliability. For cortical opacities, there was an absolute difference of 10% or greater of area involved in 1.9% of the replicate gradings. For posterior subcapsular opacities an absolute difference of 5% of area involved was noted in 2.8% of the regraded photographs. For nuclear opacities, absolute differences of 1.5 or more steps were observed in 0.6% of eyes. There was little evidence of temporal drift in grading any of the three types of opacity during four annual regrades. ● CONCLUSIONS: We have demonstrated a high degree of reliability in grading the severity of lens opacities in a large study cohort with mostly early lens changes, the type of cohort most likely to be entered in clinical trials involving cataract prevention. The Age-Related Eye Disease Study System for Classifying Cataracts From PhoAccepted for publication Aug 4, 2000. *Members of the Age-Related Eye Disease Study Research Group are listed at the end of the article. Supported by contracts from the National Eye Institute, National Institutes of Health, Bethesda, Maryland. Reprint requests and correspondence to AREDS Coordinating Center, The EMMES Corporation, 11325 Seven Locks Rd, Ste 214, Potomac, MD 20854-3205; (301) 299 – 8655; fax: (301) 299-3991; e-mail: [email protected] 0002-9394/01/$20.00 PII S0002-9394(00)00732-7
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tographs could be useful in studies where there is a need to standardize data collection over time and across different data collection sites. Limitations of the system include the cost of implementation and, currently, the limited amount of data on grading reproducibility for more advanced lens opacities. (Am J Ophthalmol 2001;131:167–175. © 2001 by Elsevier Science Inc. All rights reserved.)
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HE AGE-RELATED EYE DISEASE STUDY (AREDS) SYS-
tem for classifying cataracts is an extension of the Wisconsin System for Classifying Cataracts From Photographs.1,2 The system is being used in a multiyear, multicenter follow-up study of 4,757 participants, which is designed to assess the clinical course, prognosis, and risk factors for age-related macular degeneration and cataract.3 The study is also testing the effects of antioxidant vitamins on the incidence and progression of age-related macular degeneration and cataract in a randomized clinical trial. Lens status is evaluated in AREDS at the baseline visit, at the 2-year visit, and annually thereafter. Several considerations influenced the selection of the lens classification procedures that are being used in AREDS. These included a need to (1) collect comparable lens data from participants at 11 geographically scattered clinical centers, (2) standardize data collection and grading procedures in a long-term prospective study, and (3) reliably detect clinically important changes in lens status. We chose to adopt and modify the Wisconsin System for Classifying Cataracts.1 The AREDS system uses photographs, which are taken by certified photographers in a standardized fashion using specially modified cameras. Photographs are graded at the study’s reading center by specially trained and certified observers. In this report we briefly describe the AREDS system for grading cataracts and provide data on the reliability of the system as used in AREDS. A more detailed description of the lens grading system is available in the AREDS Manual of Operations (The EMMES Corporation, Potomac, Maryland).
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FIGURE 1. Standard photographs 1 (no opacity) through 7 (extremely severe opacity) for grading nuclear opacities. A–G represent standard photographs 1–7.
slit-lamp beam was similar in each eye. The locked-in place beam comes from the temporal side of the right eye and the nasal side of the left eye. A single slit-lamp photograph is taken of each eye, with the slit-beam bisecting the central lens from the 12:00 to 6:00 o’clock position and focused near the center of the lens sulcus. Modifications to the Neitz cameras included installation of a linear potentiometer capable of measuring anterior– posterior movement to an accuracy of 0.01 mm and the addition of fixation targets for each eye. Two retroillumination photographs are taken with the Neitz camera, one focused on the iris at the pupillary margin and a second
METHODS ● EQUIPMENT/PHOTOGRAPHIC PROCEDURES:
Topcon slit-lamp and Neitz retroillumination cameras (Topcon Corporation, Tokyo, Japan; Neitz Instruments Company, LTD, Tokyo, Japan) were specially modified to collect photographic data in a standardized fashion. Modifications to the Topcon SL-6E Photo Slit-Lamp Cameras included fixing the slit-beam width and height at 0.3 and 9.0 mm, respectively; locking the slit-lamp beam at an angle of 45 degrees; and installing custom fixation lights for each eye. The fixation lights were mounted so that the path of the
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focused on posterior subcapsular opacities, if present; if such opacities are absent, the camera is focused 3 to 5 mm posterior to the plane of the anterior photograph. The lens photographs are sent to the study’s reading center, the University of Wisconsin, where trained and certified graders evaluate the photographs. A quality grade of good, fair, borderline, or ungradable is assigned to each photograph. The quality grades are based on focus, beam placement of slit-lamp photographs, anterioposterior placement of retroillumination photographs, and the presence or absence of problems that prevent adequate evaluation (for example, inadequate illumination, a small pupil, or lid/lash artifacts). The quality grading data are used to identify photographs that need to be retaken. Attempts are made to avoid and correct problems with photographic data by having a photography monitor conduct site visits, which were originally done annually and now are done as needed. Of the approximately 77,600 lens photographs reviewed at the reading center for AREDS randomized participants through mid-1999, only 2.2% of slit-lamp photographs and 0.8% of Neitz photographs were “ungradable.” ● GRADING PROCEDURES:
The slit-lamp photographs are used to grade nuclear opacities by comparing the photograph with seven standard photographs of lenses with increasingly severe nuclear opacities (Figure 1). A set of standard photographs is available from the Fundus Photograph Reading Center, University of Wisconsin— Madison, 610 N. Walnut St, Room 438, Madison, Wisconsin 53705. The seven standard photographs consist of the four used in the Wisconsin System for Grading Cataracts From Photographs and three additional ones inserted into intervals between the original four.1 Standard photographs 1 and 3 through 7 are approximately linearly spaced with respect to optical density, as measured by a digital image processor. A decimal grade ranging from 0.9 (less severe than Standard 1) to 7.1 (more severe than Standard 7) is assigned. Standard 2, which represents approximately a half step between Standards 1 and 3 on the optical density scale, is retained from the Wisconsin System for comparability and is rescaled as such (that is, 1.5) when assessing change in lens status. The revised scale, with Standard 2 representing a half step between Standards 1 and 3, results in a scale ranging from 0.9 to 6.1. Two main factors are considered in grading nuclear sclerosis: (1) the opalescence of the nuclear landmarks, especially the sulcus, and (2) the definition of the nuclear surface bands. Opalescence, particularly that of the sulcus, is given greater weight, largely because it is less influenced by suboptimal focus than the definition of nuclear landmarks. The retroillumination photographs are used to grade cortical and posterior subcapsular opacities following the Wisconsin System for Classifying Cataracts From Photographs.1,2 Cortical and posterior subcapsular opacities ap-
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FIGURE 2. Grid used with retroillumination photographs to grade cortical and posterior subcapsular opacities.
pear as darkly shaded interruptions of the reddish-orange fundus reflex. Any lens area that is definitely darkened is considered involved, regardless of the density of the opacity. The extent and location of opacity is recorded using a grid to divide the Neitz photograph into 17 subfields (Figure 2). The grid has three concentric circles with diameters of 4, 10 and 16 mm on the film. (The original Wisconsin System used a grid without the 10-mm circle.) Because the Neitz camera has a twofold magnification, these circles correspond to circles with diameters of about 2, 5 and 8 mm on the lens. The outer circle is used to facilitate concentric placement of the grid. The pupillary margin defines the outer limits of the outer subfields. Equally spaced radial lines at the 10:30, 12:00, 1:30, 3:00, 4:30, 6:00, 7:30, and 9:00 o’clock positions divide the zones between the central and inner circles and between the inner circle and the pupillary margin into eight subfields each. For grading cortical opacities, the grid is placed on the anterior retroillumination photograph and both the anterior and posterior Neitz photographs are mounted side by side, so they can be viewed simultaneously or in rapid succession by closing one eye and then the other. This allows the grader to combine lesions seen in the anterior cortex with those seen in the posterior cortex, resulting in a single cortical grade for each subfield. The percentage of each of the subfields involved with a definite cortical opacity is estimated. For grading posterior subcapsular opacities, the posterior retroillumination photograph is centered over the grid and used to estimate the percentage of each of the central nine subfields of the grid involved. For cortical and posterior subcapsular opacities, individual subfield percentages are combined (weighted according to the size of each subfield) into an overall percentage involvement of a 5-mm diameter circle of the central lens (Figures 3 and 4). For cortical opacities only, the percentage of the entire visible lens involved is also calculated. The retroillumination lens photographs are also graded for lens vacuoles, white anterior cortical
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FIGURE 3. (Left) Retroillumination photograph of a cortical opacity. (Right) Retroillumination photograph of cortical opacity with overlying grid. The cortical opacity occupies 12% of the area within the central two circles of the grid (central 5 mm of the lens) and 25% of the full visible lens.
FIGURE 4. (Left) Retroillumination photograph of a posterior subcapsular opacity. (Right) Retroillumination photograph of a posterior subcapsular opacity with overlying grid. The posterior subcapsular opacity occupies 15% of the area within the central two circles of the grid (central 5 mm of the lens).
opacities, Mittendorf dots, pseudoexfoliation of the lens capsule, and opacities other than those described above.
Gradings are compared and discussed at the monthly meetings. The reliability of the gradings is evaluated in two ways. In an ongoing process designed to evaluate contemporaneous variability, different sets of lens photographs have been selected two to four times a year starting in 1992 and regraded by an examiner other than the one who did the initial grading. The process used to select the eyes for regrading is not random; photographs are selected to represent particular opacities and to cover a range of grades. In this report we have pooled the results from all regradings, because the various grading exercises produced similar results. To date, a total of 925 eyes have been evaluated for contemporaneous variability. The possibility of temporal drift in the gradings has been evaluated by annually regrading a sample of 99 lens photographs taken at the end of the first year of the study. The sample was selected to provide a range of severity, although only limited numbers of eyes with more severe
● QUALITY CONTROL:
The quality control and monitoring program has three components: initial grader training and certification, ongoing grading exercises that provide feedback to the graders to help them maintain and/or improve their performance, and masked replicate gradings of samples of the photographs to assess contemporaneous and temporal grading variability. Training of graders is based on a tutorial approach, using written protocols and teaching sets of photographs for which accepted grades have been established. When training is completed, graders become certified by satisfactorily completing grading tests. Thereafter, monthly quality control meetings are held to provide continual feedback to the graders regarding difficult lesions and problematic cases. Before the meeting, appropriate photographs are selected from current work and circulated to the graders for independent grading. 170
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FIGURE 5. Comparison of two contemporaneous grades of cortical opacity from retroillumination photographs (n ⴝ 925 eyes). Scatter plot of minimum grade compared with the absolute difference in grades. Cortical opacity grade is the percent of involvement by the opacity of the central 5-mm diameter circle of the lens. The points above the horizontal reference line have an absolute difference in grades of more than 10%. Points above the diagonal line have a relative difference of more than 50%. Intraclass correlation coefficient ⴝ 0.94.
cortical and posterior subcapsular grades were available because of study eligibility criteria that required relatively clear ocular media at baseline to facilitate the taking of fundus photographs. Additional photographs that were taken early in the study were selected to enlarge the sample to 200 eyes for the fourth regrading exercise. ● DATA ANALYSES:
Comparison of paired contemporaneous photograph regradings is displayed in scatter plots and quantified by the intraclass correlation coefficient. Temporal drift in photograph grading is graphically assessed through box plots.
RESULTS PHOTOGRAPHS OF 925 EYES WERE REGRADED TO ASSESS
intergrader variability. Most eyes had no or only early cortical and posterior subcapsular opacities, reflecting AREDS eligibility criteria, which required relatively clear ocular media to allow retinal photographs. Forty percent of the eyes had no cortical opacities for either of the paired gradings; 15% had more than 10% cortical opacities for at least one of the paired grades. Twenty-eight percent of eyes had some degree of posterior subcapsular opacity for at VOL. 131, NO. 2
FIGURE 6. Comparison of two contemporaneous grades of posterior subcapsular opacity from retroillumination photographs (n ⴝ 925 eyes). Scatter plot of minimum grade compared with the absolute difference in grades. The posterior subcapsular opacity grade is the percent of involvement by the opacity of the central 5-mm diameter circle of the lens. Points above the horizontal reference line have an absolute difference in grades of more than 5%. Intraclass correlation coefficient ⴝ 0.82.
least one of the gradings. For nuclear opacities, 13% of eyes had a grade of four or more for at least one of the two grades. Intergrader variability was relatively constant across the grading exercises. For cortical opacities there was an absolute difference of 10% or greater in the estimated extent of the opacities for only 1.9% of the regraded photographs (Figure 5). As expected, a 50% relative difference in paired gradings was more likely for eyes that had lesser amounts of cortical opacity. There was an absolute difference of 5% or greater in 2.8% of the regraded photographs for posterior subcapsular opacities (Figure 6). For nuclear opacities, absolute differences of 1.5 or more steps were observed in 0.6% of eyes (Figure 7). A set of photographs of 99 eyes (later increased to 200 eyes) was identified and graded annually to assess temporal drift in the grading process. Although attempts were made to identify a set of eyes with a range of lens pathology, most eyes in the set had only early cortical and posterior subcapsular changes because of a limited range of pathology in the cohort. Table 1 and Figure 8 show the comparison between baseline grades and each of four annual regrades for the opacity types. There was little evidence of any temporal drift in the gradings for eyes with no or early cortical, posterior subcapsular, or nuclear opacities. Few regradings demonstrated a drift of more than
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TABLE 1. Percent Agreement Between Baseline Photograph Grades and Annual Regrades Percent Agreement
Regrade
FIGURE 7. Comparison of two contemporaneous grades of nuclear opacity from slit-lamp photographs (n ⴝ 925 eyes). Scatter plot of minimum grade compared with the absolute difference in grades. Nuclear opacity grade ranges from 1.0 to 5.0, with respect to standard photographs of nuclear opacity. Points above the horizontal reference line have an absolute difference in grades of more than 1.5 units. Intraclass correlation coefficient ⴝ 0.90.
First Second Third Fourth
99 99 99 200
41 37 43 34.5
First Second Third Fourth
99 99 99 200
First Second Third Fourth
98 98 97 194
74 76 74 52 Within 67 67 77 67
Within 1%
Cortical 70 77 71 64 PSC Opacities 82 90 86 70 0.5 Within 1.0 Nuclear 94 87 95 92
Within 5%
Within 10%
89 90 85 86
94 97 97 95.5
99 99 97 90.5 Within 1.5 97 95 99 100
though other retroillumination cameras are still available. Also, the characteristics of film available for purchase may change over time, which may lead to a shift in assessment. Furthermore, variation in film development can perceptibly alter the appearance of the lens photographs. This can be a particular problem in grading nuclear changes on slit-lamp photographs, where subtle changes in nuclear density are being evaluated. The use of photographs also requires careful standardization and monitoring of the quality of the photographs. Finally, in a large study, the photographs must be read by a corps of graders who have to be specially trained and monitored. In AREDS we have adopted a system that depends on photographs because the disadvantages of the system can be addressed, and the advantages of such a system outweigh the disadvantages, especially in a large multicenter study. A major advantage of systems that use photographs is the availability of a permanent record that documents lens status. Photographs can be used to monitor grading reliability and substantiate study conclusions more easily than systems that rely on slit-lamp assessments of lens status, where no permanent record is available. Potential problems with photographic quality that might influence grading are addressed in AREDS by having a detailed written protocol for photographic procedures, special training and certification sessions for photographers, ongoing monitoring of the quality of the photographs, and close supervision of all photographic procedures by a photography monitor who conducts regular site visits. Photographs were read at a reading center in AREDS by a
DISCUSSION THE AGE-RELATED EYE DISEASE STUDY IS A MULTIYEAR
multicenter study designed in part to trace the clinical course of age-related cataracts and to evaluate the effect of antioxidant vitamins on the incidence and progression of cataract. We have chosen a modification of the Wisconsin System for Classifying Cataracts for use in AREDS, because it meets our need to standardize data collection over a long follow-up interval across 11 different clinical centers and to reliably detect changes in lens status. Although the AREDS system for Classifying Cataracts From Photographs meets the needs of our study, it does have drawbacks that must be considered when planning cataract studies. The use of photographs for classifying lens status requires the purchase of expensive cameras that may not be easy to obtain or maintain. For example, the Neitz CTR retroillumination camera used in AREDS is no longer being manufactured and may be difficult to obtain, AMERICAN JOURNAL
On Zero
PSC ⫽ posterior subcapsular.
10% for cortical opacities, more than 5% for posterior subcapsular opacities, and more than 1.5 units for nuclear opacities. When drift was present for cortical and nuclear opacities, baseline gradings tended to be somewhat higher than subsequent gradings for eyes with higher severity grades at baseline (data not shown).
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FIGURE 8. Comparison of baseline grades with each of four annual regrades. Box plots of baseline grade minus regrade. Positive differences indicate regrades lower than baseline. In a box plot, the horizontal line in the box is the median; the lower (upper) edge of the box is the 25th (75th) percentile; the lower and upper vertical lines extend to the fifth and 95th percentiles; the distinct points indicate extreme differences that are in the lower or upper 5% of values. The off-center location of the median in the box or vertical lines of unequal length indicate an asymmetrical distribution. A cortical opacity, B posterior subcapsular opacity, C nuclear opacity.
specially trained, certified, and monitored corps of graders in an effort to increase the reliability of gradings. When using a detailed lens classification system, it is less difficult to train and monitor the performance of a limited number of graders at a central location than a large number of examiners at many sites. Age-Related Eye Disease Study quality control procedures call for a periodic assessment of intergrader variability. Intergrader agreement was high. For cortical opacities, for which percent area of involvement of the central 5 mm of the lens is graded, 2% of the regrades had an absolute difference of VOL. 131, NO. 2
10% or more. For posterior subcapsular opacities, which are graded similarly, about 3% of the regrades had an absolute difference of 5% or more. Only 0.6% of the regrades for nuclear opacities, which are graded using standard photographs for comparison, had an absolute difference of 1.5 units or more. There also was no evidence of systematic temporal drift in the gradings for any of the three opacity types. The thresholds selected for monitoring the reliability of grading were chosen because they represent changes that were thought to be clinically relevant and were large enough to be graded with reasonable reliability.
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The data presented here show a high degree of reproducibility when the AREDS System for Classifying Cataracts was used to grade lens opacities in AREDS participants. Nevertheless, at the present time we cannot comment on the reproducibility of the system when it is used for grading more severe lens opacities, because most grades in AREDS participants were clustered at the lower end of the severity scale. Additional data will be available for evaluating the reproducibility of grading more severe opacities after a longer follow-up of AREDS participants.
National Eye Institute Clinical Center: Emily Y. Chew, MD, Frederick L. Ferris III, MD, Karl Csaky, MD, PhD, Katherine Hall Dabas, RN, COT, Linda Goodman, Young Ja Kim, CRNO, Richard Mercer, COT, Marilois (Chicca) Palmer,Patrick F. Ciatto, Ernest Kuehl, Iris Kivitz, Dessie Koutsandreas, COA, Roula Nashwinter, COA, Mary Haughey, Gloria Babilonia-Ayukawa, RN, MHCA, Antoinette LaReau, COT. Past Participating Personnel: Sally A. McCarthy, RN, MSN, Leanne M. Ayres, Patrick Lopez, Anne Randall. University of Pittsburgh: Thomas R. Friberg, MD, Andrew Eller, MD, Michael B. Gorin, MD, PhD, Jane Alexander, Barbara Mack, Melissa K. Paine, Patricia S. Corbin, Diane Y. Curtin, Phyllis P. Ostroska, Joseph Warnicki, Edward Fijewski.
*AGE-RELATED EYE DISEASE STUDY RESEARCH GROUP The Eye Center at Memorial: Aaron Kassoff, MD, Jordan Kassoff, MD, Michel Mehu, JoAnne Buehler, Mary Eglow, RN, Francine Kaufman. Past Participating Personnel: Shalom Kieval, MD.
The Johns Hopkins Medical Institutions: Susan B. Bressler, MD, Neil M. Bressler, MD, Gary Cassel, MD, Daniel Finkelstein, MD, Morton Goldberg, MD, Julia A. Haller, MD, Lois Ratner, MD, Andrew P. Schachat, MD, Steven H. Sherman, MD, Janet S. Sunness, MD, Sherrie Schenning, Catherine Sackett, CANP, Judith Belt, Dennis Cain, David Emmert, Mark Herring, Terry George, Stacy Wheeler.
Associated Retinal Consultants, PC: Raymond R. Margherio, MD, Morton S. Cox, MD, Bruce Garretson, MD, Tarek Hassan, MD, Alan Ruby, MD, Michael T. Trese, MD, Jane Camille Werner, MD, George A. Williams, MD, Virginia Regan, RN, Patricia Manatrey, RN, Kristi Cumming, RN, Bobbie Lewis, RN, Mary Zajechowski, Rachel Falk, Patricia Streasick, Lynette Szydlowski, Fran McIver, Craig Bridges, Cheryl Stanley.
Elman Retina Group, PA: Michael J. Elman, MD, Rex Ballinger, OD, Arturo Betancourt, MD, David Glasser, MD, Joyce Lammlein, MD, Ronald Seff, MD, Martin Shuman, MD, JoAnn Starr, Anita Carrigan, Terri Mathews, Peter Sotirakos, Theresa Cain. Past Participating Personnel: Christine Ringrose.
Devers Eye Institute: Michael L. Klein, MD, Joseph E. Robertson, MD, David J. Wilson, MD, Carolyn Beardsley, Garland Smith, Shannon Howard. Past Participating Personnel: Richard F. Dreyer, MD, Colin Ma, MD, Richard G. Chenoweth, MD, John D. Zilis, MD, Harold Crider, COT, Sheryl Parker, Kathryn Sherman.
University of Wisconsin—Madison: Suresh R. Chandra, MD, Matthew D. Davis, MD, Michael Ip, MD, Ronald Klein, MD, T. Michael Nork, MD, Thomas Stevens, MD, Barbara Blodi, MD, Justin Gottlieb, MD, Wendy Walker, Barbara Soderling, Michelle Schmitz, Tracy Perkins, MPH, Margo Blatz, Bob Harrison, Gene Knutson, Michael Neider, John Peterson, Denise Krolnik, Guy Somers. Past Participating Personnel: Frank L. Myers, MD.
Emory University: Daniel Martin, MD, Thomas M. Aaberg, MD, Thomas M. Aaberg, Jr, MD, Paul Sternberg, Jr, MD, Linda Curtis, James Gilman, Bob Myles, Denise Armiger. Past Participating Personnel: Antonio Capone, Jr, MD, David Saperstein, MD, Barbara Stribling, Ray Swords.
University of Wisconsin—Reading Center: Matthew D. Davis, MD, Barbara E. K. Klein, MD, Ronald Klein, MD, Larry Hubbard, MA, Jane Armstrong, Michael Neider, Hugh Wabers, Linda Kastorff, Kristine Lang, Darlene Badal, Patricia L. Geithman, Kathleen D. Miner, Kristi L. Dohm, James A. Onofrey, Barbara Esser, Cynthia Hurtenbach, Marian R. Fisher, Nancy L. Robinson, James Baliker, Chunyang Gai, Shirley Craanen, Mary Webster, Julee Elledge, Susan Reed, Wendy Benz, Kathleen E. Glander, Kurt R. Osterby, James Reimers. Past Participating Personnel: Yvonne L. Magli, Judith Brickbauer, Sarah Ansay, William N. King.
Ingalls Memorial Hospital: David H. Orth, MD, Timothy P. Flood, MD, Joseph Civantos, MD, Serge deBustros, MD, Kirk H. Packo, MD, Pauline T. Merrill, MD, Celeste MacLeod, Chris Morrison, Douglas A. Bryant, Don Doherty, Sharon Sandoval. Massachusetts Eye and Ear Infirmary: Johanna M. Seddon, MD, Michael K. Pinnolis, MD, Desiree A. Jones-Devonish, Claudia Evans, OD, Nancy Davis, Charlene Callahan, David Walsh, Jennifer Dubois, Ilene Burton, RN, N. Jennifer Rosenberg, RN, MPH, Payal Patel. Past Participating Personnel: Valerie D. Crouse, MS, Kristin K. Snow, MS. 174
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Coordinating Center—The EMMES Corporation: Anne S. Lindblad, PhD, Fred Ederer, MA, FACE, Roy C. Milton, PhD, Traci Clemons, PhD, Gary Gensler, MS, Alice Keller, MS, Gary Entler, COT, Elaine Stine, Kiana Brunson, Stuart H. Berlin, Sophia Pallas, MM, Susan A. Mengers. Past Participating Personnel: Phyllis R. Scholl, Ravinder Anand, PhD.
Strahlman, MD, Matthew D. Davis, MD, Fred Ederer, MA, FACE, Frederick L. Ferris III, MD, Karen Gamble, Carl Kupfer, MD, Natalie Kurinij, PhD, Anne S. Lindblad, PhD, Robert Sperduto, MD.
National Eye Institute Project Office: Frederick L. Ferris III, MD, Emily Y. Chew, MD, Robert Sperduto, MD, Natalie Kurinij, PhD.
Bausch and Lomb Pharmaceuticals: Ellen Strahlman, MD.
National Institutes of Health Division of Contracts and Grants: Karen Gamble.
REFERENCES ACKNOWLEDGMENTS Data and Safety Monitoring Committee (DSMC) Officios: Janet Wittes, PhD-Chairperson, Gladys Block, PhD, David DeMets, PhD, Stuart Fine, MD, Curt Furberg, MD, PhD, M. Cristina Leske, MD, MPH, Professor Giovanni Maraini, Donald Patrick, PhD, MSPH, Robert Veatch, PhD. Data and Safety Monitoring Committee (DSMC) ExOfficios: Anne Sowell, PhD, Wiley Chambers, MD, Ellen
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1. Klein BEK, Klein R, Linton KLP, Magli YL, Neider M. Assessment of cataracts from photographs in the Beaver Dam Eye Study. Ophthalmology 1990;97:1428 –1433. 2. Magli YL, Klein BEK, Sperduto RD, Hubbard LD, Neider MW, King WN, Davis MD for the Age-Related Eye Disease Study (AREDS) Research Group. AREDS extension of the Wisconsin Lens Opacity Grading System. Invest Ophthalmol Vis Sci 1997;38:S177. 3. Age-Related Eye Disease Study Research Group. The AgeRelated Eye Disease Study (AREDS): Design implications. AREDS Report No. 1. Controlled Clin Trials 1999;20:573– 600.
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● PURPOSE:
To describe the system for grading cataracts from photographs in the Age-Related Eye Disease Study (AREDS). ● METHODS: The system for grading cataracts in AREDS uses photographs taken in a standardized fashion with specially modified cameras at 11 clinical centers. The photographs are evaluated by graders for quality and cataract severity at a central reading center. The area of lens involvement is used to assess the severity of cortical and posterior subcapsular opacities. Optical density of nuclear opacity is graded against a series of seven standard photographs. Contemporaneous variability in grading is evaluated periodically by having a second examiner regrade a subset of the photographs. Temporal variability is assessed by annually regrading a subset of photographs. ● RESULTS: Photographs of 925 eyes, most with no or early lens opacities, were regraded to assess intergrader reliability. For cortical opacities, there was an absolute difference of 10% or greater of area involved in 1.9% of the replicate gradings. For posterior subcapsular opacities an absolute difference of 5% of area involved was noted in 2.8% of the regraded photographs. For nuclear opacities, absolute differences of 1.5 or more steps were observed in 0.6% of eyes. There was little evidence of temporal drift in grading any of the three types of opacity during four annual regrades. ● CONCLUSIONS: We have demonstrated a high degree of reliability in grading the severity of lens opacities in a large study cohort with mostly early lens changes, the type of cohort most likely to be entered in clinical trials involving cataract prevention. The Age-Related Eye Disease Study System for Classifying Cataracts From PhoAccepted for publication Aug 4, 2000. *Members of the Age-Related Eye Disease Study Research Group are listed at the end of the article. Supported by contracts from the National Eye Institute, National Institutes of Health, Bethesda, Maryland. Reprint requests and correspondence to AREDS Coordinating Center, The EMMES Corporation, 11325 Seven Locks Rd, Ste 214, Potomac, MD 20854-3205; (301) 299 – 8655; fax: (301) 299-3991; e-mail: [email protected] 0002-9394/01/$20.00 PII S0002-9394(00)00732-7
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tographs could be useful in studies where there is a need to standardize data collection over time and across different data collection sites. Limitations of the system include the cost of implementation and, currently, the limited amount of data on grading reproducibility for more advanced lens opacities. (Am J Ophthalmol 2001;131:167–175. © 2001 by Elsevier Science Inc. All rights reserved.)
T
HE AGE-RELATED EYE DISEASE STUDY (AREDS) SYS-
tem for classifying cataracts is an extension of the Wisconsin System for Classifying Cataracts From Photographs.1,2 The system is being used in a multiyear, multicenter follow-up study of 4,757 participants, which is designed to assess the clinical course, prognosis, and risk factors for age-related macular degeneration and cataract.3 The study is also testing the effects of antioxidant vitamins on the incidence and progression of age-related macular degeneration and cataract in a randomized clinical trial. Lens status is evaluated in AREDS at the baseline visit, at the 2-year visit, and annually thereafter. Several considerations influenced the selection of the lens classification procedures that are being used in AREDS. These included a need to (1) collect comparable lens data from participants at 11 geographically scattered clinical centers, (2) standardize data collection and grading procedures in a long-term prospective study, and (3) reliably detect clinically important changes in lens status. We chose to adopt and modify the Wisconsin System for Classifying Cataracts.1 The AREDS system uses photographs, which are taken by certified photographers in a standardized fashion using specially modified cameras. Photographs are graded at the study’s reading center by specially trained and certified observers. In this report we briefly describe the AREDS system for grading cataracts and provide data on the reliability of the system as used in AREDS. A more detailed description of the lens grading system is available in the AREDS Manual of Operations (The EMMES Corporation, Potomac, Maryland).
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FIGURE 1. Standard photographs 1 (no opacity) through 7 (extremely severe opacity) for grading nuclear opacities. A–G represent standard photographs 1–7.
slit-lamp beam was similar in each eye. The locked-in place beam comes from the temporal side of the right eye and the nasal side of the left eye. A single slit-lamp photograph is taken of each eye, with the slit-beam bisecting the central lens from the 12:00 to 6:00 o’clock position and focused near the center of the lens sulcus. Modifications to the Neitz cameras included installation of a linear potentiometer capable of measuring anterior– posterior movement to an accuracy of 0.01 mm and the addition of fixation targets for each eye. Two retroillumination photographs are taken with the Neitz camera, one focused on the iris at the pupillary margin and a second
METHODS ● EQUIPMENT/PHOTOGRAPHIC PROCEDURES:
Topcon slit-lamp and Neitz retroillumination cameras (Topcon Corporation, Tokyo, Japan; Neitz Instruments Company, LTD, Tokyo, Japan) were specially modified to collect photographic data in a standardized fashion. Modifications to the Topcon SL-6E Photo Slit-Lamp Cameras included fixing the slit-beam width and height at 0.3 and 9.0 mm, respectively; locking the slit-lamp beam at an angle of 45 degrees; and installing custom fixation lights for each eye. The fixation lights were mounted so that the path of the
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focused on posterior subcapsular opacities, if present; if such opacities are absent, the camera is focused 3 to 5 mm posterior to the plane of the anterior photograph. The lens photographs are sent to the study’s reading center, the University of Wisconsin, where trained and certified graders evaluate the photographs. A quality grade of good, fair, borderline, or ungradable is assigned to each photograph. The quality grades are based on focus, beam placement of slit-lamp photographs, anterioposterior placement of retroillumination photographs, and the presence or absence of problems that prevent adequate evaluation (for example, inadequate illumination, a small pupil, or lid/lash artifacts). The quality grading data are used to identify photographs that need to be retaken. Attempts are made to avoid and correct problems with photographic data by having a photography monitor conduct site visits, which were originally done annually and now are done as needed. Of the approximately 77,600 lens photographs reviewed at the reading center for AREDS randomized participants through mid-1999, only 2.2% of slit-lamp photographs and 0.8% of Neitz photographs were “ungradable.” ● GRADING PROCEDURES:
The slit-lamp photographs are used to grade nuclear opacities by comparing the photograph with seven standard photographs of lenses with increasingly severe nuclear opacities (Figure 1). A set of standard photographs is available from the Fundus Photograph Reading Center, University of Wisconsin— Madison, 610 N. Walnut St, Room 438, Madison, Wisconsin 53705. The seven standard photographs consist of the four used in the Wisconsin System for Grading Cataracts From Photographs and three additional ones inserted into intervals between the original four.1 Standard photographs 1 and 3 through 7 are approximately linearly spaced with respect to optical density, as measured by a digital image processor. A decimal grade ranging from 0.9 (less severe than Standard 1) to 7.1 (more severe than Standard 7) is assigned. Standard 2, which represents approximately a half step between Standards 1 and 3 on the optical density scale, is retained from the Wisconsin System for comparability and is rescaled as such (that is, 1.5) when assessing change in lens status. The revised scale, with Standard 2 representing a half step between Standards 1 and 3, results in a scale ranging from 0.9 to 6.1. Two main factors are considered in grading nuclear sclerosis: (1) the opalescence of the nuclear landmarks, especially the sulcus, and (2) the definition of the nuclear surface bands. Opalescence, particularly that of the sulcus, is given greater weight, largely because it is less influenced by suboptimal focus than the definition of nuclear landmarks. The retroillumination photographs are used to grade cortical and posterior subcapsular opacities following the Wisconsin System for Classifying Cataracts From Photographs.1,2 Cortical and posterior subcapsular opacities ap-
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FIGURE 2. Grid used with retroillumination photographs to grade cortical and posterior subcapsular opacities.
pear as darkly shaded interruptions of the reddish-orange fundus reflex. Any lens area that is definitely darkened is considered involved, regardless of the density of the opacity. The extent and location of opacity is recorded using a grid to divide the Neitz photograph into 17 subfields (Figure 2). The grid has three concentric circles with diameters of 4, 10 and 16 mm on the film. (The original Wisconsin System used a grid without the 10-mm circle.) Because the Neitz camera has a twofold magnification, these circles correspond to circles with diameters of about 2, 5 and 8 mm on the lens. The outer circle is used to facilitate concentric placement of the grid. The pupillary margin defines the outer limits of the outer subfields. Equally spaced radial lines at the 10:30, 12:00, 1:30, 3:00, 4:30, 6:00, 7:30, and 9:00 o’clock positions divide the zones between the central and inner circles and between the inner circle and the pupillary margin into eight subfields each. For grading cortical opacities, the grid is placed on the anterior retroillumination photograph and both the anterior and posterior Neitz photographs are mounted side by side, so they can be viewed simultaneously or in rapid succession by closing one eye and then the other. This allows the grader to combine lesions seen in the anterior cortex with those seen in the posterior cortex, resulting in a single cortical grade for each subfield. The percentage of each of the subfields involved with a definite cortical opacity is estimated. For grading posterior subcapsular opacities, the posterior retroillumination photograph is centered over the grid and used to estimate the percentage of each of the central nine subfields of the grid involved. For cortical and posterior subcapsular opacities, individual subfield percentages are combined (weighted according to the size of each subfield) into an overall percentage involvement of a 5-mm diameter circle of the central lens (Figures 3 and 4). For cortical opacities only, the percentage of the entire visible lens involved is also calculated. The retroillumination lens photographs are also graded for lens vacuoles, white anterior cortical
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FIGURE 3. (Left) Retroillumination photograph of a cortical opacity. (Right) Retroillumination photograph of cortical opacity with overlying grid. The cortical opacity occupies 12% of the area within the central two circles of the grid (central 5 mm of the lens) and 25% of the full visible lens.
FIGURE 4. (Left) Retroillumination photograph of a posterior subcapsular opacity. (Right) Retroillumination photograph of a posterior subcapsular opacity with overlying grid. The posterior subcapsular opacity occupies 15% of the area within the central two circles of the grid (central 5 mm of the lens).
opacities, Mittendorf dots, pseudoexfoliation of the lens capsule, and opacities other than those described above.
Gradings are compared and discussed at the monthly meetings. The reliability of the gradings is evaluated in two ways. In an ongoing process designed to evaluate contemporaneous variability, different sets of lens photographs have been selected two to four times a year starting in 1992 and regraded by an examiner other than the one who did the initial grading. The process used to select the eyes for regrading is not random; photographs are selected to represent particular opacities and to cover a range of grades. In this report we have pooled the results from all regradings, because the various grading exercises produced similar results. To date, a total of 925 eyes have been evaluated for contemporaneous variability. The possibility of temporal drift in the gradings has been evaluated by annually regrading a sample of 99 lens photographs taken at the end of the first year of the study. The sample was selected to provide a range of severity, although only limited numbers of eyes with more severe
● QUALITY CONTROL:
The quality control and monitoring program has three components: initial grader training and certification, ongoing grading exercises that provide feedback to the graders to help them maintain and/or improve their performance, and masked replicate gradings of samples of the photographs to assess contemporaneous and temporal grading variability. Training of graders is based on a tutorial approach, using written protocols and teaching sets of photographs for which accepted grades have been established. When training is completed, graders become certified by satisfactorily completing grading tests. Thereafter, monthly quality control meetings are held to provide continual feedback to the graders regarding difficult lesions and problematic cases. Before the meeting, appropriate photographs are selected from current work and circulated to the graders for independent grading. 170
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FIGURE 5. Comparison of two contemporaneous grades of cortical opacity from retroillumination photographs (n ⴝ 925 eyes). Scatter plot of minimum grade compared with the absolute difference in grades. Cortical opacity grade is the percent of involvement by the opacity of the central 5-mm diameter circle of the lens. The points above the horizontal reference line have an absolute difference in grades of more than 10%. Points above the diagonal line have a relative difference of more than 50%. Intraclass correlation coefficient ⴝ 0.94.
cortical and posterior subcapsular grades were available because of study eligibility criteria that required relatively clear ocular media at baseline to facilitate the taking of fundus photographs. Additional photographs that were taken early in the study were selected to enlarge the sample to 200 eyes for the fourth regrading exercise. ● DATA ANALYSES:
Comparison of paired contemporaneous photograph regradings is displayed in scatter plots and quantified by the intraclass correlation coefficient. Temporal drift in photograph grading is graphically assessed through box plots.
RESULTS PHOTOGRAPHS OF 925 EYES WERE REGRADED TO ASSESS
intergrader variability. Most eyes had no or only early cortical and posterior subcapsular opacities, reflecting AREDS eligibility criteria, which required relatively clear ocular media to allow retinal photographs. Forty percent of the eyes had no cortical opacities for either of the paired gradings; 15% had more than 10% cortical opacities for at least one of the paired grades. Twenty-eight percent of eyes had some degree of posterior subcapsular opacity for at VOL. 131, NO. 2
FIGURE 6. Comparison of two contemporaneous grades of posterior subcapsular opacity from retroillumination photographs (n ⴝ 925 eyes). Scatter plot of minimum grade compared with the absolute difference in grades. The posterior subcapsular opacity grade is the percent of involvement by the opacity of the central 5-mm diameter circle of the lens. Points above the horizontal reference line have an absolute difference in grades of more than 5%. Intraclass correlation coefficient ⴝ 0.82.
least one of the gradings. For nuclear opacities, 13% of eyes had a grade of four or more for at least one of the two grades. Intergrader variability was relatively constant across the grading exercises. For cortical opacities there was an absolute difference of 10% or greater in the estimated extent of the opacities for only 1.9% of the regraded photographs (Figure 5). As expected, a 50% relative difference in paired gradings was more likely for eyes that had lesser amounts of cortical opacity. There was an absolute difference of 5% or greater in 2.8% of the regraded photographs for posterior subcapsular opacities (Figure 6). For nuclear opacities, absolute differences of 1.5 or more steps were observed in 0.6% of eyes (Figure 7). A set of photographs of 99 eyes (later increased to 200 eyes) was identified and graded annually to assess temporal drift in the grading process. Although attempts were made to identify a set of eyes with a range of lens pathology, most eyes in the set had only early cortical and posterior subcapsular changes because of a limited range of pathology in the cohort. Table 1 and Figure 8 show the comparison between baseline grades and each of four annual regrades for the opacity types. There was little evidence of any temporal drift in the gradings for eyes with no or early cortical, posterior subcapsular, or nuclear opacities. Few regradings demonstrated a drift of more than
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TABLE 1. Percent Agreement Between Baseline Photograph Grades and Annual Regrades Percent Agreement
Regrade
FIGURE 7. Comparison of two contemporaneous grades of nuclear opacity from slit-lamp photographs (n ⴝ 925 eyes). Scatter plot of minimum grade compared with the absolute difference in grades. Nuclear opacity grade ranges from 1.0 to 5.0, with respect to standard photographs of nuclear opacity. Points above the horizontal reference line have an absolute difference in grades of more than 1.5 units. Intraclass correlation coefficient ⴝ 0.90.
First Second Third Fourth
99 99 99 200
41 37 43 34.5
First Second Third Fourth
99 99 99 200
First Second Third Fourth
98 98 97 194
74 76 74 52 Within 67 67 77 67
Within 1%
Cortical 70 77 71 64 PSC Opacities 82 90 86 70 0.5 Within 1.0 Nuclear 94 87 95 92
Within 5%
Within 10%
89 90 85 86
94 97 97 95.5
99 99 97 90.5 Within 1.5 97 95 99 100
though other retroillumination cameras are still available. Also, the characteristics of film available for purchase may change over time, which may lead to a shift in assessment. Furthermore, variation in film development can perceptibly alter the appearance of the lens photographs. This can be a particular problem in grading nuclear changes on slit-lamp photographs, where subtle changes in nuclear density are being evaluated. The use of photographs also requires careful standardization and monitoring of the quality of the photographs. Finally, in a large study, the photographs must be read by a corps of graders who have to be specially trained and monitored. In AREDS we have adopted a system that depends on photographs because the disadvantages of the system can be addressed, and the advantages of such a system outweigh the disadvantages, especially in a large multicenter study. A major advantage of systems that use photographs is the availability of a permanent record that documents lens status. Photographs can be used to monitor grading reliability and substantiate study conclusions more easily than systems that rely on slit-lamp assessments of lens status, where no permanent record is available. Potential problems with photographic quality that might influence grading are addressed in AREDS by having a detailed written protocol for photographic procedures, special training and certification sessions for photographers, ongoing monitoring of the quality of the photographs, and close supervision of all photographic procedures by a photography monitor who conducts regular site visits. Photographs were read at a reading center in AREDS by a
DISCUSSION THE AGE-RELATED EYE DISEASE STUDY IS A MULTIYEAR
multicenter study designed in part to trace the clinical course of age-related cataracts and to evaluate the effect of antioxidant vitamins on the incidence and progression of cataract. We have chosen a modification of the Wisconsin System for Classifying Cataracts for use in AREDS, because it meets our need to standardize data collection over a long follow-up interval across 11 different clinical centers and to reliably detect changes in lens status. Although the AREDS system for Classifying Cataracts From Photographs meets the needs of our study, it does have drawbacks that must be considered when planning cataract studies. The use of photographs for classifying lens status requires the purchase of expensive cameras that may not be easy to obtain or maintain. For example, the Neitz CTR retroillumination camera used in AREDS is no longer being manufactured and may be difficult to obtain, AMERICAN JOURNAL
On Zero
PSC ⫽ posterior subcapsular.
10% for cortical opacities, more than 5% for posterior subcapsular opacities, and more than 1.5 units for nuclear opacities. When drift was present for cortical and nuclear opacities, baseline gradings tended to be somewhat higher than subsequent gradings for eyes with higher severity grades at baseline (data not shown).
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FIGURE 8. Comparison of baseline grades with each of four annual regrades. Box plots of baseline grade minus regrade. Positive differences indicate regrades lower than baseline. In a box plot, the horizontal line in the box is the median; the lower (upper) edge of the box is the 25th (75th) percentile; the lower and upper vertical lines extend to the fifth and 95th percentiles; the distinct points indicate extreme differences that are in the lower or upper 5% of values. The off-center location of the median in the box or vertical lines of unequal length indicate an asymmetrical distribution. A cortical opacity, B posterior subcapsular opacity, C nuclear opacity.
specially trained, certified, and monitored corps of graders in an effort to increase the reliability of gradings. When using a detailed lens classification system, it is less difficult to train and monitor the performance of a limited number of graders at a central location than a large number of examiners at many sites. Age-Related Eye Disease Study quality control procedures call for a periodic assessment of intergrader variability. Intergrader agreement was high. For cortical opacities, for which percent area of involvement of the central 5 mm of the lens is graded, 2% of the regrades had an absolute difference of VOL. 131, NO. 2
10% or more. For posterior subcapsular opacities, which are graded similarly, about 3% of the regrades had an absolute difference of 5% or more. Only 0.6% of the regrades for nuclear opacities, which are graded using standard photographs for comparison, had an absolute difference of 1.5 units or more. There also was no evidence of systematic temporal drift in the gradings for any of the three opacity types. The thresholds selected for monitoring the reliability of grading were chosen because they represent changes that were thought to be clinically relevant and were large enough to be graded with reasonable reliability.
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The data presented here show a high degree of reproducibility when the AREDS System for Classifying Cataracts was used to grade lens opacities in AREDS participants. Nevertheless, at the present time we cannot comment on the reproducibility of the system when it is used for grading more severe lens opacities, because most grades in AREDS participants were clustered at the lower end of the severity scale. Additional data will be available for evaluating the reproducibility of grading more severe opacities after a longer follow-up of AREDS participants.
National Eye Institute Clinical Center: Emily Y. Chew, MD, Frederick L. Ferris III, MD, Karl Csaky, MD, PhD, Katherine Hall Dabas, RN, COT, Linda Goodman, Young Ja Kim, CRNO, Richard Mercer, COT, Marilois (Chicca) Palmer,Patrick F. Ciatto, Ernest Kuehl, Iris Kivitz, Dessie Koutsandreas, COA, Roula Nashwinter, COA, Mary Haughey, Gloria Babilonia-Ayukawa, RN, MHCA, Antoinette LaReau, COT. Past Participating Personnel: Sally A. McCarthy, RN, MSN, Leanne M. Ayres, Patrick Lopez, Anne Randall. University of Pittsburgh: Thomas R. Friberg, MD, Andrew Eller, MD, Michael B. Gorin, MD, PhD, Jane Alexander, Barbara Mack, Melissa K. Paine, Patricia S. Corbin, Diane Y. Curtin, Phyllis P. Ostroska, Joseph Warnicki, Edward Fijewski.
*AGE-RELATED EYE DISEASE STUDY RESEARCH GROUP The Eye Center at Memorial: Aaron Kassoff, MD, Jordan Kassoff, MD, Michel Mehu, JoAnne Buehler, Mary Eglow, RN, Francine Kaufman. Past Participating Personnel: Shalom Kieval, MD.
The Johns Hopkins Medical Institutions: Susan B. Bressler, MD, Neil M. Bressler, MD, Gary Cassel, MD, Daniel Finkelstein, MD, Morton Goldberg, MD, Julia A. Haller, MD, Lois Ratner, MD, Andrew P. Schachat, MD, Steven H. Sherman, MD, Janet S. Sunness, MD, Sherrie Schenning, Catherine Sackett, CANP, Judith Belt, Dennis Cain, David Emmert, Mark Herring, Terry George, Stacy Wheeler.
Associated Retinal Consultants, PC: Raymond R. Margherio, MD, Morton S. Cox, MD, Bruce Garretson, MD, Tarek Hassan, MD, Alan Ruby, MD, Michael T. Trese, MD, Jane Camille Werner, MD, George A. Williams, MD, Virginia Regan, RN, Patricia Manatrey, RN, Kristi Cumming, RN, Bobbie Lewis, RN, Mary Zajechowski, Rachel Falk, Patricia Streasick, Lynette Szydlowski, Fran McIver, Craig Bridges, Cheryl Stanley.
Elman Retina Group, PA: Michael J. Elman, MD, Rex Ballinger, OD, Arturo Betancourt, MD, David Glasser, MD, Joyce Lammlein, MD, Ronald Seff, MD, Martin Shuman, MD, JoAnn Starr, Anita Carrigan, Terri Mathews, Peter Sotirakos, Theresa Cain. Past Participating Personnel: Christine Ringrose.
Devers Eye Institute: Michael L. Klein, MD, Joseph E. Robertson, MD, David J. Wilson, MD, Carolyn Beardsley, Garland Smith, Shannon Howard. Past Participating Personnel: Richard F. Dreyer, MD, Colin Ma, MD, Richard G. Chenoweth, MD, John D. Zilis, MD, Harold Crider, COT, Sheryl Parker, Kathryn Sherman.
University of Wisconsin—Madison: Suresh R. Chandra, MD, Matthew D. Davis, MD, Michael Ip, MD, Ronald Klein, MD, T. Michael Nork, MD, Thomas Stevens, MD, Barbara Blodi, MD, Justin Gottlieb, MD, Wendy Walker, Barbara Soderling, Michelle Schmitz, Tracy Perkins, MPH, Margo Blatz, Bob Harrison, Gene Knutson, Michael Neider, John Peterson, Denise Krolnik, Guy Somers. Past Participating Personnel: Frank L. Myers, MD.
Emory University: Daniel Martin, MD, Thomas M. Aaberg, MD, Thomas M. Aaberg, Jr, MD, Paul Sternberg, Jr, MD, Linda Curtis, James Gilman, Bob Myles, Denise Armiger. Past Participating Personnel: Antonio Capone, Jr, MD, David Saperstein, MD, Barbara Stribling, Ray Swords.
University of Wisconsin—Reading Center: Matthew D. Davis, MD, Barbara E. K. Klein, MD, Ronald Klein, MD, Larry Hubbard, MA, Jane Armstrong, Michael Neider, Hugh Wabers, Linda Kastorff, Kristine Lang, Darlene Badal, Patricia L. Geithman, Kathleen D. Miner, Kristi L. Dohm, James A. Onofrey, Barbara Esser, Cynthia Hurtenbach, Marian R. Fisher, Nancy L. Robinson, James Baliker, Chunyang Gai, Shirley Craanen, Mary Webster, Julee Elledge, Susan Reed, Wendy Benz, Kathleen E. Glander, Kurt R. Osterby, James Reimers. Past Participating Personnel: Yvonne L. Magli, Judith Brickbauer, Sarah Ansay, William N. King.
Ingalls Memorial Hospital: David H. Orth, MD, Timothy P. Flood, MD, Joseph Civantos, MD, Serge deBustros, MD, Kirk H. Packo, MD, Pauline T. Merrill, MD, Celeste MacLeod, Chris Morrison, Douglas A. Bryant, Don Doherty, Sharon Sandoval. Massachusetts Eye and Ear Infirmary: Johanna M. Seddon, MD, Michael K. Pinnolis, MD, Desiree A. Jones-Devonish, Claudia Evans, OD, Nancy Davis, Charlene Callahan, David Walsh, Jennifer Dubois, Ilene Burton, RN, N. Jennifer Rosenberg, RN, MPH, Payal Patel. Past Participating Personnel: Valerie D. Crouse, MS, Kristin K. Snow, MS. 174
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Centers for Disease Control and Prevention—Central Laboratory: Dayton Miller, PhD, Anne Sowell, PhD, Elaine Gunter, MT. Past Participating Personnel: Barbara Bowman, PhD. OF
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Coordinating Center—The EMMES Corporation: Anne S. Lindblad, PhD, Fred Ederer, MA, FACE, Roy C. Milton, PhD, Traci Clemons, PhD, Gary Gensler, MS, Alice Keller, MS, Gary Entler, COT, Elaine Stine, Kiana Brunson, Stuart H. Berlin, Sophia Pallas, MM, Susan A. Mengers. Past Participating Personnel: Phyllis R. Scholl, Ravinder Anand, PhD.
Strahlman, MD, Matthew D. Davis, MD, Fred Ederer, MA, FACE, Frederick L. Ferris III, MD, Karen Gamble, Carl Kupfer, MD, Natalie Kurinij, PhD, Anne S. Lindblad, PhD, Robert Sperduto, MD.
National Eye Institute Project Office: Frederick L. Ferris III, MD, Emily Y. Chew, MD, Robert Sperduto, MD, Natalie Kurinij, PhD.
Bausch and Lomb Pharmaceuticals: Ellen Strahlman, MD.
National Institutes of Health Division of Contracts and Grants: Karen Gamble.
REFERENCES ACKNOWLEDGMENTS Data and Safety Monitoring Committee (DSMC) Officios: Janet Wittes, PhD-Chairperson, Gladys Block, PhD, David DeMets, PhD, Stuart Fine, MD, Curt Furberg, MD, PhD, M. Cristina Leske, MD, MPH, Professor Giovanni Maraini, Donald Patrick, PhD, MSPH, Robert Veatch, PhD. Data and Safety Monitoring Committee (DSMC) ExOfficios: Anne Sowell, PhD, Wiley Chambers, MD, Ellen
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1. Klein BEK, Klein R, Linton KLP, Magli YL, Neider M. Assessment of cataracts from photographs in the Beaver Dam Eye Study. Ophthalmology 1990;97:1428 –1433. 2. Magli YL, Klein BEK, Sperduto RD, Hubbard LD, Neider MW, King WN, Davis MD for the Age-Related Eye Disease Study (AREDS) Research Group. AREDS extension of the Wisconsin Lens Opacity Grading System. Invest Ophthalmol Vis Sci 1997;38:S177. 3. Age-Related Eye Disease Study Research Group. The AgeRelated Eye Disease Study (AREDS): Design implications. AREDS Report No. 1. Controlled Clin Trials 1999;20:573– 600.
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