View PowerPoint Presentation - Vision Research Coordinating Center

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

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
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

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

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

CSLO Ancillary Study:
7of the 22 OHTS Study Centers Participating
• 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

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 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

CSLO OHTS Ancillary Study Participants
Demographic 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

CSLO Ancillary
Study to the OHTS
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;137:219-227

CSLO Ancillary
Study to the OHTS
Conclusions
Arch Ophthalmol
2004;122:22-28
• 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

Racial Differences in Optic Disc Area
(both eyes)
3
2
1
Other
(N=725)
p=

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

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
Caucasian Eye
Disc area: 1.9 mm 2
Cup area: 0.4 mm 2
Rim area: 1.5 mm 2
Rim/Disc area: 0.8

AreaBRefG
2
1
0
p

0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
p

mm2
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
p Median
(n=434)
African American
Other

Multivariate Results:
Racial Differences are no Longer Statistically Significant
(P-Values Adjusted for optic disc area, IOP, first study visit and age)
mm2
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
p=.39
p=.5
p=.49
Cup Area Mean Cup Depth Cup Volume
African American
Other

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
within normal limits (WNL)
Classified as:
outside normal limits (ONL)

Moorfields Regression Analyses
Outside Normal Limits

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)
OR
• 3 consecutive visual field endpoints (Visual Field Reading Center)
Endpoint committee for final determination

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

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

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

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%

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
(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 Inferior 5.8 (1.6, 21.0)
Nasal Inferior 4.2 (1.6, 10.9)
Temporal Superior 3.3 (0.98, 11.0)

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)

Mean Height Contour
(above and below median values)
Kaplan-Meier Survival Curves
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.
• Majority 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)
HRT
Classification
Outside
Normal
Limits
MRA Overall Outside
Normal
Limits
MRA Global Outside
Normal
Limits
MRA Temporal
Inferior
MRA nasal
Inferior
MRA
temporal
superior
Outside
Normal
Limits
Outside
Normal
Limits
Outside
Normal
Limits
Not at
POAG
(n=402)
POAG
(n=36)
Sensitivity Specificity Negative
Predictive
Value
Positive
Predictive
Value
128 20 55% 68% 95% 14%
61 10 28% 85% 93% 14%
14 5 14% 96% 93% 27%
13 3 8% 97% 92% 19%
24 7 19% 94% 93% 23%
6 4 11% 99% 93% 40%

“Predictive accuracy” during follow-up period
(% of POAG and non-POAG correctly classified at baseline)
HRT
Classification
Outside
Normal
Limits
MRA Overall Outside
Normal
Limits
MRA Global Outside
Normal
Limits
MRA Temporal
Inferior
MRA nasal
Inferior
MRA
temporal
superior
Outside
Normal
Limits
Outside
Normal
Limits
Outside
Normal
Limits
Not at
POAG
(n=402)
POAG
(n=36)
Sensitivity Specificity Negative
Predictive
Value
Positive
Predictive
Value
128 20 55% 68% 95% 14%
61 10 28% 85% 93% 14%
14 5 14% 96% 93% 27%
13 3 8% 97% 92% 19%
24 7 19% 94% 93% 23%
6 4 11% 99% 93% 40%

“Predictive accuracy” during follow-up period
(% of POAG and non-POAG correctly classified at baseline)
HRT
Classification
Outside
Normal
Limits
MRA Overall Outside
Normal
Limits
MRA Global Outside
Normal
Limits
MRA Temporal
Inferior
MRA nasal
Inferior
MRA
temporal
superior
Outside
Normal
Limits
Outside
Normal
Limits
Outside
Normal
Limits
Not at
POAG
(n=402)
POAG
(n=36)
Sensitivity Specificity Negative
Predictive
Value
Positive
Predictive
Value
128 20 55% 68% 95% 14%
61 10 28% 85% 93% 14%
14 5 14% 96% 93% 27%
13 3 8% 97% 92% 19%
24 7 19% 94% 93% 23%
6 4 11% 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.

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

Thank You
UCSD Hamilton Glaucoma Center

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

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)
0 (zero)
+ (positive values)
Back of retina
Average height in
parapapillary region

Sample HRT Data from OHTS CSLO
Ancillary Study Patient
HRT Classification