Linda M Zangwill Robert N Weinreb Julie Beiser Chuck C Berry George A Cioffi Anne L Coleman

1. 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 Baseline topographic optic disc measurements are associated with the development of POAG: The CSLO Ancillary Study to the OHTS

2. 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 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 Financial Disclosures

3. 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 patients • To describe racial differences in optic disc topography in ocular hypertensive patients • To assess the effect of ocular hypotensive treatment on optic disc topography • To determine whether optic disk topographic measurements are an accurate predictor of glaucoma

4. 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 patients • To describe racial differences in optic disc topography in ocular hypertensive patients • To assess the effect of ocular hypotensive treatment on optic disc topography • To determine whether optic disk topographic measurements are an accurate predictor of glaucoma

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

6. 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

7. 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 Image Acquisition Methods

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

9. CSLO OHTS Ancillary Study ParticipantsDemographic Characteristics African-American Other Total Number of subjects*75 (17%) 376 (83%) 451 Gender (% male)29% 45% 42% Mean Age (years)54.4 ± 8.5 54.4 ± 9.4 54.4 ± 9.3 * With informed consent

10. CSLO Ancillary Study to the OHTS AJO 2004;137:219-227 • 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

11. CSLO Ancillary Study to the OHTS Arch Ophthalmol 2004;122:22-28 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

12. p=<.0001 Other (N=725) African-American (N=148) Racial Differences in Optic Disc Area (both eyes) Optic Disc Area (mm2)

13. Univariate Results:Racial Differences in Optic Disc Topopgraphy African Americans had larger: • Disc area • Cup area, volume and depth • Rim area and volume • RNFL cross-sectional area African Americans had smaller: • Rim to disc ratios

14. Disc area: 2.2 mm2 Cup area: 0.9 mm2 Rim area: 1.4 mm2 Rim/Disc area: 0.6 Disc area: 1.9 mm2 Cup area: 0.4 mm2 Rim area: 1.5 mm2 Rim/Disc area: 0.8 Caucasian Eye African American Eye

15. Differences by Race p<.001 p<.001 Cup Area (mm2) Rim Area (mm2)

16. Disc Size is Important (e.g. Cup Area) p<.001 Cup Area (mm2)

17. Cup Area (mm2) Disc Size is Important (e.g. Cup Area) p=.7 p<.001 p=.7

18. 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

19. 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.

20. 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

21. 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 Evaluated Included

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

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

24. Moorfields Regression AnalysesOutside Normal Limits

25. Moorfields Regression AnalysesOutside Normal Limits Borderline: Considered WNL for this analysis

26. Sample HRT Data from OHTS CSLO Ancillary Study Patient

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

28. Subjects Included in Analysis • Good 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 analysis

29. 439 with CSLO imaging (n=874 eyes) Images not acquired before POAG (1 participant (OU) & 7 unilateral eyes) 438 with CSLO before POAG (n=865 eyes) { 432 Did not reach a POAG Endpoint (n=824 eyes) 36 Reached POAG Endpoint (n=41 eyes) Subjects for this study Baseline Predictors of POAG Endpoints CSLO Ancillary Study to the OHTS Subjects

30. POAG Endpoints in 41 eyes of 36 participants • POAG initial suspicious dates before October 2003- confirmed and entered into the database by February 9, 2004. • 5 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

31. CSLO OHTS Ancillary Study Participants POAG (n=36) Not POAG (n=402) Mean Age (years)57.5 ± 9.4 54.8 ± 9.1 Mean IOP (mm Hg)25.1 + 2.8 25.0 + 2.3 Mean Visual Field PSD (dB) 1.95 + .20 1.90 + .21 Mean Photo based VCDR.47 + .18 .38 + .19 Mean Corneal Thickness (µm)554.3 + 37.4 577.0 + 37.0 Mean Follow-up (months)48.4 + 25.2 79.5 + 20.8 % African Americans 14% 21%

32. Significant Baseline CSLO Measurements Associated with the Development of POAG from Multivariate Proportional Hazards Models(Adjusting forage, 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 mm3 greater)1.2 (1.0, 1.4) Rim Area(per .1 mm2 greater)0.6 (0.4, 0.8) Rim Volume(per .1 mm3 greater)0.6 (0.5, 0.9) Rim Area-to-Disc area (per .1 greater)0.8 (0.6, 0.9)

33. Significant Baseline CSLO Indices Associated with the Development of POAG from Multivariate Proportional Hazards Models(Adjusting forage, 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 Inferior 5.8 (1.6, 21.0) Nasal Inferior 4.2 (1.6, 10.9) Temporal Superior 3.3 (0.98, 11.0)

34. Baseline CSLO measurements Not Associated with the Development of POAG from Multivariate Proportional Hazards Models(Adjusting forage, IOP, PSD, CCT, history of heart disease, with medication status as a time dependent covariate) Hazards Ratio (95% CI) Disc area (per .4 mm2 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 .3mm2 greater)0.7 (0.5, 1.1)

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

36. 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. • Majority of eyes with CSLO classifications “outside normal limits” at baseline did not develop POAG within the follow-up period of this analysis

37. “Predictive accuracy” during follow-up period (% of POAG and non-POAG correctly classified at baseline)

38. “Predictive accuracy” during follow-up period (% of POAG and non-POAG correctly classified at baseline)

39. “Predictive accuracy” during follow-up period (% of POAG and non-POAG correctly classified at baseline)

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.

41. This Study Did Not: • 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

42. Thank You UCSD Hamilton Glaucoma Center

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

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

45. Sample HRT Data from OHTS CSLO Ancillary Study Patient HRT Classification