Baseline topographic optic disc measurements are associated with the development of POAG: The CSLO Ancillary Study to the OHTS Linda M Zangwill Robert N Weinreb Julie Beiser Chuck C Berry George A Cioffi Anne L Coleman Gary Trick Jeffrey M Liebmann James D. Brandt Jody R Pitz-Seymour Keri A Dirkes Suzanne Vega Michael A Kass Mae O Gordon and the OHTS CSLO Ancillary Study Group

Financial Disclosures Linda M Zangwill: (F) Heidelberg Engineering, Carl Zeiss Meditec Robert N Weinreb: (F) Heidelberg Engineering, Carl Zeiss Meditec Julie Beiser: None Chuck C Berry: None George A Cioffi: None Anne L Coleman: None Gary Trick: (C,R) Heidelberg Engineering Jeffrey M Liebmann: (F,C) Heidelberg Engineering James D. Brandt: None Jody R Pitz-Seymour: None Keri A Dirkes: None Suzanne Vega: None Michael A Kass: None Mae O Gordon: None Grant Support NEI EY11158 NEI EY09341 and EY09307 and the National Center on Minority Health and Health Disparities, Merck Research Laboratories Unrestricted grants from Research to Prevent Blindness

CSLO Ancillary Study to the OHTS Objectives: To determine the effectiveness of HRT to objectively and quantitatively detect glaucomatous changes of the optic disc in ocular hypertensive patientsTo determine the effectiveness of HRT to objectively and quantitatively detect glaucomatous changes of the optic disc in ocular hypertensive patients To describe racial differences in optic disc topography in ocular hypertensive patientsTo describe racial differences in optic disc topography in ocular hypertensive patients To assess the effect of ocular hypotensive treatment on optic disc topographyTo assess the effect of ocular hypotensive treatment on optic disc topography To determine whether optic disk topographic measurements are an accurate predictor of glaucomaTo determine whether optic disk topographic measurements are an accurate predictor of glaucoma

CSLO Ancillary Study to the OHTS Objectives: To determine the effectiveness of HRT to objectively and quantitatively detect glaucomatous changes of the optic disc in ocular hypertensive patientsTo determine the effectiveness of HRT to objectively and quantitatively detect glaucomatous changes of the optic disc in ocular hypertensive patients To describe racial differences in optic disc topography in ocular hypertensive patientsTo describe racial differences in optic disc topography in ocular hypertensive patients To assess the effect of ocular hypotensive treatment on optic disc topographyTo assess the effect of ocular hypotensive treatment on optic disc topography To determine whether optic disk topographic measurements are an accurate predictor of glaucomaTo determine whether optic disk topographic measurements are an accurate predictor of glaucoma

Devers Eye InstituteDevers Eye Institute –PI: Jack A. Cioffi, MD –Coordinator: Kathryn Sherman Henry Ford Medical CenterHenry Ford Medical Center –PI: Gary Trick, PhD –Coordinator: Melanie Gutowski Jules Stein Eye Institute, UCLAJules Stein Eye Institute, UCLA –PI: Anne L. Coleman, MD, PhD –Coordinators: Tina Gonzales, Jackie Sanguinet New York Eye and Ear InfirmaryNew York Eye and Ear Infirmary –PI: Jeffrey M. Liebmann, MD –Coordinator: Jean Walker CSLO Ancillary Study: 7of the 22 OHTS Study Centers Participating Scheie Eye Institute, U. of PennsylvaniaScheie Eye Institute, U. of Pennsylvania –PI: Jody R. Piltz-Seymour, MD –Coordinator: Jane Anderson University of California-Davis,University of California-Davis, –PI: James D. Brandt, MD –Coordinators: Ingrid Clark, Vickie Jaicheum University of California-San DiegoUniversity of California-San Diego –PI: Robert N. Weinreb MD – Rigby Slight, MD –Coordinators: Valerie Lepper, R.N. Eva Kroneker, Rivak Hoffman

UCSD CSLO Reading Center Robert N. Weinreb, MD, Primary Investigator Linda M. Zangwill, PhD, Co-investigator Chuck C Berry, PhD, Biostatistician Keri L. Dirkes, MPH, Supervisor Suzanne Vega, MPH, Coordinator Amanda Policastro, Coordinator Amanda R. Smith, MPH, Coordinator Michelle Cambou, MPH, Coordinator Chris Asvar, Coordinator Isabela Niculae, MPH, Coordinator

Image Acquisition Methods Heidelberg Retina Tomograph (HRT1) images acquired annually at dilated exam Both eyes: 10-degree field of view images OD: An additional 15 degree field of view 3 scans taken for each field of view K-values used to correct for magnification error Image series exported to CSLO Reading Center No processing at study centers

Standardized, centralized image processing at CSLO Reading Center (UC San Diego) Quality Assurance Data CompletenessData Completeness Image QualityImage Quality Only Certified Operators Acquire ImagesOnly Certified Operators Acquire Images Image Processing Creation of Mean TopographiesCreation of Mean Topographies Outlining of Disc MarginOutlining of Disc Margin Exporting Data to OHTS Data Coordinating CenterExporting Data to OHTS Data Coordinating Center

CSLO OHTS Ancillary Study Participants Demographic Characteristics African-AmericanOther Total Number of subjects* 75 (17%)376 (83%)451 Gender (% male) 29%45%42% Mean Age (years) 54.4 ± ± ± 9.3 * With informed consent

Conclusions HRT topographic measurements are strongly correlated with stereophotographic assessment of horizontal and vertical cup disc ratios - even in OHTS participants with normal appearing optic discs These results suggest that the HRT optic disc measurements describe features that are reflected in standardized assessment of cup-to-disk diameter ratios from stereophotographs AJO 2004 ;137: CSLO Ancillary Study to the OHTS

Conclusions African-Americans have significantly larger optic discs, cups, neuroretinal rims and cup-to-disc ratios, and smaller rim-to-disc ratios than other OHTS CSLO Ancillary Study participants After adjusting for the difference in disc area, none of the differences in optic disc topography between African-Americans and other participants remained statistically significant These results highlight the need to consider race and optic disc size when evaluating the appearance of the optic disc in glaucoma Arch Ophthalmol 2004;122:22-28 CSLO Ancillary Study to the OHTS

Racial Differences in Optic Disc Area (both eyes) p=<.0001 Other (N=725) African-American (N=148) Optic Disc Area (mm 2 )

African Americans had larger: Disc areaDisc area Cup area, volume and depthCup area, volume and depth Rim area and volumeRim area and volume RNFL cross-sectional areaRNFL cross-sectional area African Americans had smaller: Rim to disc ratiosRim to disc ratios Univariate Results: Racial Differences in Optic Disc Topopgraphy

African American Eye Disc area: 2.2 mm 2 Cup area:0.9 mm 2 Rim area:1.4 mm 2 Rim/Disc area:0.6 Disc area: 1.9 mm 2 Cup area:0.4 mm 2 Rim area:1.5 mm 2 Rim/Disc area:0.8 Caucasian Eye

Differences by Race p<.001 Cup Area (mm 2 ) Rim Area (mm 2 ) p<.001

Disc Size is Important (e.g. Cup Area) Cup Area (mm 2 ) p<.001

Disc Size is Important (e.g. Cup Area) Cup Area (mm 2 ) p=.7 p<.001

Multivariate Results: Racial Differences are no Longer Statistically Significant (P-Values Adjusted for optic disc area, IOP, first study visit and age) p=.39 p=.5 p=.49

Objective: To determine whether baseline confocal scanning laser ophthalmoscopy (CSLO) optic disc topographic measurements are associated with the development of primary open angle glaucoma (POAG) in ocular hypertension.

Risk Factor versus Predictive Factor Epidemiologists differentiate between risk factors and early damage Structural and functional indices of glaucoma may be predictive factors but are not risk factors

Optic Disc Parameters Evaluated Included Disc Area Cup Area Cup/Disc Area Ratio Cup Volume Cup Shape Rim Area Rim/Disc Area Ratio Rim Volume Cup Depth RNFL Thickness RNFL Cross-sectional Area Mean Height Contour

Optic Disc Parameters Indices Included (Outside normal limits or within normal limits compared to normative data) HRT Classification (linear discriminant function) Moorfields Regression Analysis Global Six regions Overall (If any of the six regions or global is outside normal limits)

Moorfields Regression Analysis Measured rim area compared to predicted age-corrected rim area, adjusted for disc area Classified as: outside normal limits (ONL) within normal limits (WNL)

Moorfields Regression Analyses Outside Normal Limits

Borderline: Considered WNL for this analysis

Sample HRT Data from OHTS CSLO Ancillary Study Patient

OHTS POAG Endpoints 2 consecutive optic disc endpoints (Optic Disc Reading Center)2 consecutive optic disc endpoints (Optic Disc Reading Center)OR 3 consecutive visual field endpoints (Visual Field Reading Center)3 consecutive visual field endpoints (Visual Field Reading Center) Endpoint committee for final determination

Subjects Included in Analysis Good quality baseline imagesGood quality baseline images –most baseline CSLO images obtained after randomization –CSLO Ancillary Study was funded in July 1995 after OHTS began recruitment –Added site later to increase African American enrollment If first CSLO image was acquired on or after the OHTS examination with a suspicious photographic or visual field finding later confirmed as POAG by the OHTS endpoint committee, that eye was excluded from the analysisIf first CSLO image was acquired on or after the OHTS examination with a suspicious photographic or visual field finding later confirmed as POAG by the OHTS endpoint committee, that eye was excluded from the analysis

Baseline Predictors of POAG Endpoints CSLO Ancillary Study to the OHTS Subjects 439 with CSLO imaging (n=874 eyes) 36 Reached POAG Endpoint (n=41 eyes) Subjects for this study 432 Did not reach a POAG Endpoint (n=824 eyes) { 438 with CSLO before POAG (n=865 eyes) Images not acquired before POAG (1 participant (OU) & 7 unilateral eyes)

POAG Endpoints in 41 eyes of 36 participants POAGPOAG initial suspicious dates before October confirmed and entered into the database by February 9, bilateral POAG, 31 unilateral POAG – –9 (22%) eyes reached a visual field endpoint first – –31 (76%) eyes reached an optic disc endpoint first – –1 (2%) eye reached visual field and optic disc endpoint concurrently

CSLO OHTS Ancillary Study Participants POAG (n=36) Not POAG (n=402) Mean Age (years) 57.5 ± ± 9.1 Mean IOP (mm Hg) Mean Visual Field PSD (dB) Mean Photo based VCDR Mean Corneal Thickness (µm) Mean Follow-up (months) % African Americans 14% 21%

Significant Baseline CSLO Measurements Associated with the Development of POAG from Multivariate Proportional Hazards Models Significant Baseline CSLO Measurements Associated with the Development of POAG from Multivariate Proportional Hazards Models (Adjusting for age, IOP, PSD, CCT and history of heart disease, with medication status as a time dependent covariate) Hazards Ratio (95% CI) Mean Height Contour (per.1 mm greater) 2.7 (1.6, 4.5) Mean Cup Depth (per.1 mm greater) 1.6 (1.1, 2.2) Reference Plane Height (per.1 mm greater) 1.5 (1.0, 2.2) Cup Area-to-Disc area (per.1 greater) 1.2 (1.0, 1.5) Cup Volume below reference (per.1 mm 3 greater) 1.2 (1.0, 1.4) Rim Area (per.1 mm 2 greater) 0.6 (0.4, 0.8) Rim Volume (per.1 mm 3 greater) 0.6 (0.5, 0.9) Rim Area-to-Disc area (per.1 greater) 0.8 (0.6, 0.9)

Significant Baseline CSLO Indices Associated with the Development of POAG from Multivariate Proportional Hazards Models Significant Baseline CSLO Indices Associated with the Development of POAG from Multivariate Proportional Hazards Models (Adjusting for age, IOP, PSD, CCT and history of heart disease, with medication status as a time dependent covariate) Hazards Ratio (95% CI) (outside normal limits versus not) HRT Classification (LDF) 2.5 (1.3, 4.9) Moorfields Regression Analysis Overall (Any region ONL)2.4 (1.0, 5.6) Global (Global values ONL)3.4 (1.1, 10.0) Temporal Inferior5.8 (1.6, 21.0) Nasal Inferior4.2 (1.6, 10.9) Temporal Superior3.3 (0.98, 11.0)

Baseline CSLO measurements Not Associated with the Development of POAG from Multivariate Proportional Hazards Models Baseline CSLO measurements Not Associated with the Development of POAG from Multivariate Proportional Hazards Models (Adjusting for age, IOP, PSD, CCT, history of heart disease, with medication status as a time dependent covariate) Hazards Ratio (95% CI) Disc area (per.4 mm 2 greater) 0.9 (0.6, 1.3) RNFL thickness (per.1mm greater) 0.6 (0.4, 1.2) Cup Shape (per.1 greater) 1.0 (0.6, 1.7) RNFL Cross Sectional area (per.3mm 2 greater) 0.7 (0.5, 1.1)

Kaplan-Meier Survival Curves Mean Height Contour (above and below median values) Rim Area (above and below median values) Moorfields Regression Analysis Global

Summary of Results Baseline CSLO topographic optic disc measurements when used alone or combined with central corneal thickness, IOP, history of vascular disease are significantly associated with the development of POAG among individuals with ocular hypertension.Baseline CSLO topographic optic disc measurements when used alone or combined with central corneal thickness, IOP, history of vascular disease are significantly associated with the development of POAG among individuals with ocular hypertension. Majority of eyes with CSLO classifications “outside normal limits” at baseline did not develop POAG within the follow-up period of this analysisMajority of eyes with CSLO classifications “outside normal limits” at baseline did not develop POAG within the follow-up period of this analysis

“Predictive accuracy” during follow-up period (% of POAG and non-POAG correctly classified at baseline) Not at POAG (n=402)POAG(n=36)SensitivitySpecificity Negative Predictive Value Positive Predictive Value HRT Classification Outside Normal Limits %68%95%14% MRA Overall Outside Normal Limits %85%93%14% MRA Global Outside Normal Limits 14514%96%93%27% MRA Temporal Inferior Outside Normal Limits 1338%97%92%19% MRA nasal Inferior Outside Normal Limits 24719%94%93%23% MRA temporal superior Outside Normal Limits 6411%99%93%40%

“Predictive accuracy” during follow-up period (% of POAG and non-POAG correctly classified at baseline) Not at POAG (n=402)POAG(n=36)SensitivitySpecificity Negative Predictive Value Positive Predictive Value HRT Classification Outside Normal Limits %68%95%14% MRA Overall Outside Normal Limits %85%93%14% MRA Global Outside Normal Limits 14514%96%93%27% MRA Temporal Inferior Outside Normal Limits 1338%97%92%19% MRA nasal Inferior Outside Normal Limits 24719%94%93%23% MRA temporal superior Outside Normal Limits 6411%99%93%40%

“Predictive accuracy” during follow-up period (% of POAG and non-POAG correctly classified at baseline) Not at POAG (n=402)POAG(n=36)SensitivitySpecificity Negative Predictive Value Positive Predictive Value HRT Classification Outside Normal Limits %68%95%14% MRA Overall Outside Normal Limits %85%93%14% MRA Global Outside Normal Limits 14514%96%93%27% MRA Temporal Inferior Outside Normal Limits 1338%97%92%19% MRA nasal Inferior Outside Normal Limits 24719%94%93%23% MRA temporal superior Outside Normal Limits 6411%99%93%40%

Need for Longer Follow-up to better evaluate predictive accuracy Majority of eyes with outside normal limit values did not develop POAG during current follow-up period. Important to determine whether participants with POAG endpoints and CSLO indices within normal limits at baseline, had CSLO measurements outside normal limits during their later follow-up examinations.

Determine whether the OHTS prediction model that includes baseline CSLO measurements is improved over one that includes baseline stereophotograph cup-disc ratio measurements – –additional POAG endpoints are needed Determine whether CSLO is a better predictive tool than other instruments, such as the GDX or the OCT Recommend specific CSLO parameters This Study Did Not:

UCSD Hamilton Glaucoma Center Thank You

Mean Height Contour Displays height values moving around optic disc, in order: Temporal -> Superior -> Nasal -> Inferior -> Temporal Normal Eye Double hump pattern Glaucoma Eye Inferior RNFL Loss TempSuperiorInferiorNasalTemp SuperiorInferiorNasalTemp

Y axis goes from negative to positive values, moving from inside the eye outward toward the back of the retina - (negative values) 0 (zero) + (positive values) Inside Eye Back of retina Average height in parapapillary region Mean Height Contour

Sample HRT Data from OHTS CSLO Ancillary Study Patient HRT Classification