1. Stratification of Normative Data
Linda M. Zangwill, Ph.D.
Professor
Hamilton Glaucoma Center
Diagnostic Imaging Laboratories
Department of Ophthalmology
University of California, San Diego

2. Financial Disclosures
National Eye Institute Research Support:
EYR , EYU , EYR
Research Instrument Support:
Heidelberg Engineering
Carl Zeiss Meditec
Optovue
Nidek
Topcon
Reading Center Services:

3. Questions To Be Covered: Stratification in Normative Databases
What magnitude of difference between subgroups is clinically important to warrant stratified databases or adjustment of the normal limits?
For which covariates are covariate specific normal limits needed?
How should individuals be selected with respect to the covariates to construct the database?  

4. Candidate Covariates for Stratification/ Adjustment (Consistent Evidence: histology, clinical imaging studies)
Age
Race
Optic disc size
Image quality (signal strength)
Axial length/Refractive error

5. Ganglion Cell Adjustment Signal strength, Disc area
SDOCT Normative Database Covariate Adjustments (Retinal Nerve Fiber Layer (RNFL) and Optic Nerve Head (ONH))
Device
Number Subjects
Age
Mean
(range)
Race
RNFL Adjustment
ONH Adjustment
Ganglion Cell Adjustment
RTVue
480
49.4
(18-84)
33% Caucasian
22% Asian
20% African
12% Hispanic
12% Indian
Age,
Signal strength, Disc area
Signal strength
Cirrus
284
(19-84)
43% Caucasian
24% Asian
18% African
1% Indian
Disc area
Spectralis
201
48 ± 14 (18-78)
Caucasian Only
(Not all Sectors)

6. Ganglion Cell Adjustment Signal strength, Disc area
SDOCT Normative Database Covariate Adjustments (Retinal Nerve Fiber Layer (RNFL) and Optic Nerve Head (ONH))
Device
Number Subjects
Age
Mean
(range)
Race
RNFL Adjustment
ONH Adjustment
Ganglion Cell Adjustment
RTVue
480
49.4
(18-84)
33% Caucasian
22% Asian
20% African
12% Hispanic
12% Indian
Age,
Signal strength, Disc area
Signal strength
Cirrus
284
(19-84)
43% Caucasian
24% Asian
18% African
1% Indian
Disc area
Spectralis
201
48 ± 14 (18-78)
Caucasian Only
(Not all Sectors)

7. Age: What is the Evidence?

8. RNFL Age Related Decrease
RTVue
Rate of decrease: -.17 um / yr
R2=7.0%
Cirrus
Rate of decrease: -.19 um / yr
R2=11.8%
RTVue Sinai copyright PN Rev A
Girkin et al. Ophthalmol 2011
Mwanza et al AJO 2011

9. RNFL Age Related Decrease: Magnitude < 10 um between 40-80 years
RTVue
Rate of decrease: -.17 um / yr
R2=7.0%
Cirrus
Rate of decrease: -.19 um / yr
R2=11.8%
RTVue Sinai copyright PN Rev A
Girkin et al. Ophthalmol 2011
Mwanza et al AJO 2011

10. Rate varies by sector and baseline thickness 0
Rate varies by sector and baseline thickness 0.21 um/yr (temporal) to um/yr (Superior)
Cirrus RNFL Sector
Longitudinal*
(n=35)
um/yr (95% CI)
Average
( to -0.17)
Superior
( to -0.65)
Inferior
( to -0.71)
Temporal
( tp0.53)
Nasal
( to 0.86)
* Adjusted for disc area, signal strength, refraction
Mean follow-up months
Range months
Leung et al 2012 Ophthalmol 119:

11. Adjust for Age? For Against Small, significant differences
SDOCT
Histology and other imaging
Age explains variability
RNFL: R2 = 7% -12%
Rim Area: R2 = 3-5%
Rate of RNFL decrease
Global: 0.17 to 0.52 um/yr
Sectors: Faster rate of change
May help differentiate between age-related and OAG damage
Against
Small, significant differences
Between 40 and 80 yrs difference in RNFL is small : < 10 um
Large variation
Varies by sector
Varies by baseline thickness

12. Race: What is the Evidence?

13. Racial Differences in Disc Area (African, Hispanic > European)
AD: African
ED: European
HE: Hispanic
IN: Indian
JA: Japanese
Girkin et al. Ophthalmol 2011

14. Small significant differences by race for some parameters even after adjusting for disc area and age
Cirrus
RTVue
Girkin et al. Ophthalmol 2011
Knight et al. Arch Ophthalmol 2012

15. Small significant differences by race for some parameters even after adjusting for disc area and age
Cirrus
RTVue
Largest difference in mean
Rim area between races =0.21 mm2
(Hispanic: 1.48 mm2 vs Indian:1.27 mm2)
Largest difference in mean
Rim area between races =0.09 mm2 (Hispanic: 1.38 mm2 vs European:1.29 mm2)
Girkin et al. Ophthalmol 2011
Knight et al. Arch Ophthalmol 2012

16. Rim Area
Average RNFL
Normal Comparison Group: AD and ED from the RTVue Normative Database (n=167)

17. RNFL Diagnostic Accuracy is Similar Regardless of Whether Normal Comparison Group is of European or African Descent
Girkin et al IOVS 2011: 52:

18. Stratify by Race? For Against
Clear evidence of optic nerve head racial differences (not “small”)
Misclassification of Individuals will be reduced
Against
How to define group?
self report
Large variation within groups
Hispanic (Mexican? South American?)
African (West Africa? Caribbean?)
Asian (Japanese? Chinese? Indian?)
Evidence that overall diagnostic accuracy is similar
Other parameters (i.e. disc area) explain most of the racial variation
Added expense/sample size/sites for stratified race-specific databases

19. Optic Disc Size: What is the Evidence?

20. Strong Associations of ONH Parameters w/Disc Area R2 ranged from 5
Strong Associations of ONH Parameters w/Disc Area R2 ranged from 5.2% (RNFL) to 42.6% (Cup Area)
(RTVue)
Sinai white Paper PN Rev A

21. Strength of Disc Area Association with Vertical Cup Disc Ratio Varies by Instrument
RTVue
R2=19.3%
Cirrus
R2=52.7%
Sinai white Paper PN Rev A
Knight et al Arch Ophthalmol 2012

22. Adjust for Optic Disc Size?
Explains a large proportion of the variability in optic nerve head parameters (large R2)
Explains much of the variation by race without the need for separate databases
Is readily available -measured by SDOCT instruments
Against
Automated software delineation of disc margin is not always accurate

23. Signal Strength and Axial Length Statistically Significant but small R2
R2 =3.7% (RTVue)
Axial Length
R2 < 7% RNFL and ONH (Cirrus*)
Sinai White Paper PN Rev A
*Cirrus User Manual D

24. Adjust for Signal Strength and Axial Length?
Consistent evidence of weak associations with RNFL and ONH parameters
Against
Explains a small proportion of the variability in RNFL and ONH parameters (small R2)

25. Summary Importance of Covariate Depends On:
What is measured: RNFL vs. Optic nerve head (ONH)
Magnitude of difference and/or strength of the association
-Can be statistically significant, but weakly associated (small difference or R2)
Whether another covariate explains the heterogeneity (disc area and race)
Instrument – segmentation and other differences
Sector
Is consistency of adjustment important?

26. Stratification in Normative Databases
What magnitude of difference between subgroups is clinically important to warrant stratified databases or adjustment of the normal limits?
Difficult to set a specific magnitude – perhaps a minimum R2 and/or clinically important difference should be required
Clinically important is different from statistically significant
For which covariates are covariate specific limits needed?
Strongest evidence for age for RNFL and disc size for ONH
How should individuals be selected with respect to the covariates to construct the database?
Large range, yet relevant to the disease
i.e. Older ages well represented

27. Thank You