Abstract
purpose. To evaluate whether baseline visual field data and asymmetries between eyes predict the onset of primary open-angle glaucoma (POAG) in Ocular Hypertension Treatment Study (OHTS) participants.
methods. A new index, mean prognosis (MP), was designed for optimal combination of visual field thresholds, to discriminate between eyes that developed POAG from eyes that did not. Baseline intraocular pressure (IOP) in fellow eyes was used to construct measures of IOP asymmetry. Age-adjusted baseline thresholds were used to develop indicators of visual field asymmetry and summary measures of visual field defects. Marginal multivariate failure time models were constructed that relate the new index MP, IOP asymmetry, and visual field asymmetry to POAG onset for OHTS participants.
results. The marginal multivariate failure time analysis showed that the MP index is significantly related to POAG onset (P < 0.0001) and appears to be a more highly significant predictor of POAG onset than either mean deviation (MD; P = 0.17) or pattern standard deviation (PSD; P = 0.046). A 1-mm Hg increase in IOP asymmetry between fellow eyes is associated with a 17% increase in risk for development of POAG. When threshold asymmetry between eyes existed, the eye with lower thresholds was at a 37% greater risk of development of POAG, and this feature was more predictive of POAG onset than the visual field index MD, though not as strong a predictor as PSD.
conclusions. The MP index, IOP asymmetry, and binocular test point asymmetry can assist in clinical evaluation of eyes at risk of development of POAG.
Mean deviation (MD), pattern standard deviation (PSD), short-term fluctuation (SF), and corrected pattern standard deviation (CPSD) are now, or have been available on standard Humphrey STATPAC outputs (Carl Zeiss Meditec, Dublin CA) as summary statistics that describe certain features of the visual field. However, these indices do not take advantage of the fact that visual field defects indicative of glaucoma tend to occur in specific locations.
10 Consequently, a study of individual perimetry thresholds may be informative. Recognizing that test points within a visual field correlate highly, we sought to find a summary of test point thresholds that avoids multicollinearity across visual field locations and can serve as a predictor of POAG.
Although IOP is a major risk factor for POAG, its diagnostic usefulness is limited by the large overlap in IOPs obtained from people with and without POAG. For cross-sectional data without a longitudinal component, one way to define “normal” for a subject is to compare fellow eyes. Eyes with high IOP are at an increased risk of development of POAG. However, eyes of two subjects with equal IOP may not be at the same risk of development of POAG. If asymmetry exists in which one eye displays a significantly higher IOP than its fellow, it may be at a greater risk of development of POAG than eyes with similarly elevated IOPs but no interocular asymmetry.
A note on terminology: By “within normal limits,” we mean eyes that may or may not have disease, but for which the index under discussion is within age-specific normal limits (95% confidence limits) for that index. However, it should be noted that being “within normal limits” is not the same as saying that sensitivity has not decreased. Sensitivity may have been decreasing for some time but has remained within normal limits. This phrasing should be distinguished from the term “normal eye,” which denotes an eye without disease that can affect the visual field. In addition, throughout the paper, we will use the phrase “developing POAG” to mean “reaching an OHTS POAG endpoint.”
Participating Clinics, Committees, and Resource Centers in the Ocular Hypertension Treatment Study, Current to April 1, 2005 (*Principal Investigator)
CLINICAL CENTERS: Bascom Palmer Eye Institute, University of Miami, Miami, Florida: Investigators: *Donald L. Budenz, Francisco E. Fantes, Steven J. Gedde, Richard K. Parrish II; Coordinator: Madeline L. Del Calvo.
Eye Consultants of Atlanta, Formerly M. Angela Vela, MD, PC, Atlanta, Georgia: Investigators: *Thomas S. Harbin, Jr, Paul McManus, Charles J. Patorgis; Coordinator and Staff: Montana L. Hooper, Stacey S. Goldstein, Debbie L. Lee, Lea Morton, Marianne L. Perry, Teresa A. Long, Shelly R. Smith, Julie M. Wright.
Cullen Eye Institute, Baylor College of Medicine, Houston, Texas: Investigators: *Ronald L. Gross, Silvia Orengo-Nania; Coordinator and Staff: Pamela M. Frady, Benita D. Slight.
Devers Eye Institute, Portland, Oregon: Investigators: *George A. (Jack) Cioffi, Annisa L. Jamil, Steven Mansberger, Emily L. Patterson; Coordinator and Staff: Kathryn Sherman, JoAnne M. Fraser.
Emory University Eye Center, Atlanta, Georgia: Investigators: *Allen D. Beck, Anastasias Costarides, Camilele M. Hylton; Coordinator: Donna Leef.
Henry Ford Medical Center, Troy Michigan: Investigators: *Nauman R. Imami, Deborah Darnley-Fisch, Aldo Fantin; Coordinator and Staff: Melanie Gutkowski, Elizabeth Carnegie, Sheila Rock.
Johns Hopkins University School of Medicine, Baltimore, Maryland: Investigators: *Donald J. Zack, Donald A. Abrams, Nathan G. Congdon, Robert A. Copeland, David S. Friedman, Ramzi Hemady, Eve J. Higginbotham, Henry D. Jampel, Irvin P. Pollack, Harry A. Quigley, Alan L. Robin; Coordinator and Staff: Rachel Scott, Felicia Keel, Lisa Levin, Kevin L. Powdrill, Robyn Priest-Reed.
Charles R. Drew University, Jules Stein Eye Institute, UCLA, Los Angeles, California: Investigators: *Anne L. Coleman, Richard S. Baker, Y. P. Dang, JoAnn A. Giaconi, Simon K. Law; Coordinator and Staff: Bobbie Ballenberg, Salvador Murillo, Manju Sharma.
W. K. Kellogg Eye Center, Ann Arbor, Michigan: Investigators: *Terry J. Bergstrom, Christina A. Bruno, Sayoko E. Moroi; Coordinator and Staff: Carol J. Pollack-Rundle, Michelle A. Tehranisa.
Kresge Eye Institute, Wayne State University, Detroit, Michigan: Investigators: *Bret A. Hughes, Monica Y. Allen, Mark S. Juzych, Mark L. McDermott, John M. Ramocki; Coordinator and Staff: Juan Allen, Laura L. Schulz.
Great Lakes Eye Institute Sagninaw, Michigan: Investigator: *John M. O’Grady; Coordinator and Staff: Linda A. Van Conett, Mary B. Hall.
University of Louisville, Louisville, Kentucky: Investigators: *Joern B. Soltau, Judit Mohay, Robb R. Shrader; Coordinator: Sandy Lear.
Mayo Clinic/Foundation, Rochester, Minnesota: Investigators: *David C. Herman, Douglas H. Johnson; Coordinator and Staff: Becky A. Nielsen, Nancy J. Tvedt.
New York Eye & Ear Infirmary, New York, New York: Investigators: *Jeffrey M. Liebmann, Robert Ritch, Celso A. Tello; Coordinator and Staff: Jean L. Walker, Nina C. Mondoc, Deborah L. Simon.
Ohio State University, Columbus, Ohio: Investigators: *Paul Weber, N. Douglas Baker, Robert J. Derick, David Lehmann; Coordinator and Staff: Kathyrne McKinney, Diane Moore.
Pennsylvania College of Optometry/MCP Hahnemann University School of Medicine, Philadelphia, Pennsylvania: Investigators: *G. Richard Bennett, Myron Yanoff; Coordinator and Staff: Lindsay C. Bennett, Mary Jameson.
Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania: Investigators: *Jody R. Piltz-Seymour, Hina N. Ahmed, Eydie G. Miller, Prithvi S. Sankar; Coordinator and Staff: Cheryl McGill, Janice T. Petner.
University of California-Davis, Sacramento, California: Investigators: *James D. Brandt, Jeffrey J. Casper, Michele C. Lim, Ivan R. Schwab; Coordinator and Staff: Ingrid J. Clark, Denise M. Owensby, Marilyn A. Sponzo.
University of California-San Diego, La Jolla, California: Investigators: *Robert N. Weinreb, J. Rigby Slight; Coordinator: Osaro A. Okuonghae.
University of California-San Francisco, San Francisco, California: Investigators: *Michael V. Drake, Allan J. Flach, Shan C. Lin, Robert Stamper; Coordinator and Staff: Fermin P. Ballesteros, Jr,Valerie Margol.
University Suburban Health Center, South Euclid, Ohio: Investigator: *Kathleen A. Lamping; Coordinator and Staff: Cheryl L. Vitelli, Bettina J. Modica.
Washington OHTS Center, Washington, District of Columbia: University of Ophthalmic Consultants of Washington, DC: Investigator: *Douglas E. Gaasterland; Coordinator: Robin L. Montgomery; Eye Associates of Washington, DC: Investigator: Frank S. Ashburn; Coordinator: Karen D. Schacht; Washington Eye Physicians and Surgeons, Chevy Chase, Maryland: Investigators: Arthur L. Schwartz, Howard S. Weiss; Coordinator and Staff:: Clete Clark, Anne M. Boeckl.
Washington University School of Medicine, St. Louis, Missouri: Investigators: *Edward M. Barnett, Bernard Becker, Anjali M. Bhorade, Michael A. Kass, Allan E. Kolker, Carla J. Siegfried; Coordinator and Staff: Sandra Quirin, Fortunata Darmody.
COMMITTEES: Executive/Steering Committee: Douglas R. Anderson, George A. Cioffi, Donald F. Everett, Mae E. Gordon, Dale K. Heuer, Eve J. Higginbotham, Bret A. Hughes, Chris A. Johnson, Michael A. Kass (Chair), John L. Keltner, Richard K. Parrish II, M. Roy Wilson; Coordinator and Staff: Pamela Frady, Patricia A. Morris (nonvoting), Teresa A. Roediger (nonvoting).
Data and Safety Monitoring Committee: John Connett, Claude Cowan, Barry Davis (Chair), Donald F. Everett, (nonvoting), Mae O. Gordon, (nonvoting), Michael A. Kass, (nonvoting), JoAnne Katz, Ronald Munson, Mark Sherwood, Gregory L. Skuta.
Endpoint Committee: Dale K. Heuer, Eve J. Higginbotham, Richard K. Parrish II, Mae O. Gordon.
RESOURCE CENTERS: Coordinating Center, Washington University School of Medicine, St. Louis, Missouri: Investigators: *Mae O. Gordon, Steven Kymes, J. Philip Miller; Coordinator and Staff: Mary Bednarski, Julia Beiser, Karen Clark, Betsy Hornbeck, Ellen Long, Patricia Morris, Teresa A. Roediger.
Chairman’s Office, Washington University School of Medicine, St. Louis, Missouri: Investigator: *Michael A. Kass; Coordinator and Staff: Deborah Dunn, Ellen Long.
Project Office, National Eye Institute, Rockville, Maryland: Investigator: Donald F. Everett.
Optic Disc Reading Center, Bascom Palmer Eye Institute, University of Miami, Miami, Florida: Investigators: *Richard K. Parrish II, Douglas R. Anderson, Donald L. Budenz; Coordinator and Staff: Maria-Cristina Wells-Albornoz, Ruth Vandenbroucke, Heather Johnson, William Feuer, Joyce Schiffman, Ditte Hess.
Visual Field Reading Center, 1 University of California, Davis, Sacramento, California, 2 Discoveries in Sight, Devers Eye Institute, Portland, Oregon: Investigators: *John L. Keltner,1 Chris A. Johnson2; Coordinators and Staff: Kimberly E. Cello,1 Shannan E. Bandermann,1 Bhupinder S. Dhillon.1
ANCILLARY STUDY READING CENTERS: Confocal Scanning Laser Ophthalmoscopy Reading Center, University of California, San Diego, La Jolla, California: Investigators: *Robert N. Weinreb, Linda Zangwill; Coordinator: Keri Dirkes.
Short Wave Length Automated Perimetry Reading Center, Devers Eye Institute, Legacy Portland Hospitals, Portland, Oregon: *Chris A. Johnson, Pamela A. Sample.
Corneal Endothelial Cell Density Reading Center, Mayo Clinic/Foundation, Rochester, Minnesota: Investigator: *William M. Bourne.
See the
Appendix for a listing of the members.
Supported by the National Center on Minority Health and Health Disparities, National Eye Institute Grants EY09341 and EY09307; Merck Research Laboratories; an unrestricted grant from Research to Prevent Blindness; and the Oregon Lions Sight and Hearing Foundation.
Submitted for publication April 15, 2005; revised September 8, 2005, and February 2, April 19, and April 27, 2006; accepted June 27, 2006.
Disclosure:
R.A. Levine, None;
S. Demirel, None;
J. Fan, None;
J.L. Keltner, None;
C.A. Johnson, None;
M.A. Kass, None
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “
advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Corresponding author: Richard A. Levine, Department of Mathematics and Statistics, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182;
[email protected].
Table 1. Frequency Distribution of Differences in IOP (ΔIOP) between Fellow Eyes in OHTS
Table 1. Frequency Distribution of Differences in IOP (ΔIOP) between Fellow Eyes in OHTS
ΔIOP (mm Hg) | 0 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | Total |
Subjects (n) | 313 | 540 | 375 | 216 | 94 | 46 | 15 | 10 | 7 | 0 | 2 | 1618 |
Cumulative distribution | 0.19 | 0.53 | 0.76 | 0.89 | 0.95 | 0.98 | 0.99 | 0.99 | 1.00 | 1.00 | 1.00 | |
Table 2. OHTS Baseline Predictor Variables Included in the Multivariate Analysis
Table 2. OHTS Baseline Predictor Variables Included in the Multivariate Analysis
Variable | Unit | Abbreviation |
Visual field variables | | |
Mean deviation | dB | MD |
Short-term fluctuation | dB | SF |
Pattern standard deviation | dB | PSD |
Corrected PSD | dB | CPSD |
Clinical variables | | |
Intraocular pressure | mm Hg | IOP |
Treatment | Factor | TRT |
Family Hx glaucoma | Factor | Hx |
Central corneal thickness | μm | CCT |
Horizontal cup-to-disc ratio | No unit | CD |
Vertical CD | No unit | VCD |
Systemic/demographic variables | | |
Race | Factor (African-Am. versus all others) | RACE |
Gender | Factor | GENDER |
Age at baseline | Years | AGE |
High blood pressure | Factor | HBP |
Diabetes | Factor | DIAB |
Heart attack | Factor | HEART |
Migraine | Factor | MIGR |
Table 3. Relating POAG Onset to MP
Table 3. Relating POAG Onset to MP
Variable | P | Risk Ratio | 95% CI |
MP | 0.0075 | 1.34 | 1.08–1.66 |
MD | 0.80 | 0.97 | 0.75–1.25 |
PSD | 0.0017 | 3.80 | 1.65–8.77 |
TRT | 0.0001 | 0.30 | 0.17–0.56 |
Table 4. Relating POAG Onset to IOP_ASYM in the Total OHTS Data Set
Table 4. Relating POAG Onset to IOP_ASYM in the Total OHTS Data Set
Variable | P | Risk Ratio | 95% CI |
IOP_ASYM | 0.0004 | 1.21 | 1.09–1.34 |
IOP | <0.0001 | 1.24 | 1.13–1.36 |
TRT | <0.0001 | 0.48 | 0.34–0.67 |
Table 5. Relating POAG Onset to VF_ASYM in the Total OHTS Data Set
Table 5. Relating POAG Onset to VF_ASYM in the Total OHTS Data Set
Variable | P | Risk Ratio | 95% CI |
VF_ASYM | 0.0077 | 1.59 | 1.13–2.23 |
MD | 0.064 | 0.86 | 0.74–1.01 |
PSD | <0.0001 | 3.45 | 1.89–6.33 |
TRT | <0.0001 | 0.47 | 0.34–0.66 |
Table 6. Relating POAG Onset to MP, IOP_ASYM, and VF_ASYM
Table 6. Relating POAG Onset to MP, IOP_ASYM, and VF_ASYM
Variable | P | Risk Ratio | 95% CI |
IOP_ASYM | 0.0038 | 1.17 | 1.05–1.30 |
VF_ASYM | 0.075 | 1.37 | 0.97–1.93 |
MP | <0.0001 | 1.96 | 1.62–2.36 |
IOP | <0.0001 | 1.21 | 1.11–1.32 |
MD | 0.17 | 0.89 | 0.76–1.05 |
PSD | 0.046 | 1.99 | 1.01–3.90 |
TRT | <0.0001 | 0.39 | 0.27–0.57 |
The authors thank Elliot Werner, MD, for editorial contributions to the manuscript.
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