Stratification of Normative Data

Linda M. Zangwill, Ph.D.

Professor Hamilton Glaucoma Center

Diagnostic Imaging LaboratoriesDepartment of Ophthalmology

University of California, San Diego

Financial Disclosures

National Eye Institute Research Support: – EYR0111008, EYU1014267, EYR01019869

Research Instrument Support:– Heidelberg Engineering– Carl Zeiss Meditec– Optovue– Nidek– Topcon

Reading Center Services:– Optovue– Nidek– Topcon

Questions To Be Covered: Stratification in Normative Databases

1. What magnitude of difference between subgroups is clinically important to warrant stratified databases or adjustment of the normal limits?

2. For which covariates are covariate specific normal limits needed?

3. How should individuals be selected with respect to the covariates to construct the database?  

Candidate Covariates for Stratification/ Adjustment(Consistent Evidence: histology, clinical imaging studies)

• Age• Race• Optic disc size• Image quality (signal strength)• Axial length/Refractive error

SDOCT Normative Database Covariate Adjustments(Retinal Nerve Fiber Layer (RNFL) and Optic Nerve Head (ONH))

Device Number Subjects

AgeMean

(range)

Race

RNFL Adjustment

ONH Adjustment

Ganglion Cell

Adjustment

RTVue 480 49.4 (18-84)

33% Caucasian22% Asian20% African12% Hispanic12% Indian

Age, Signal

strength, Disc area

Age, Signal

strength, Disc area

Age, Signal

strength

Cirrus 284 (19-84) 43% Caucasian24% Asian18% African12% Hispanic1% Indian

Age

Age, Disc area

Age

Spectralis 201 48 ± 14 (18-78)

Caucasian Only

Age (Not all

Sectors)

SDOCT Normative Database Covariate Adjustments(Retinal Nerve Fiber Layer (RNFL) and Optic Nerve Head (ONH))

Device Number Subjects

AgeMean

(range)

Race

RNFL Adjustment

ONH Adjustment

Ganglion Cell

Adjustment

RTVue 480 49.4 (18-84)

33% Caucasian22% Asian20% African12% Hispanic12% Indian

Age, Signal

strength, Disc area

Age, Signal

strength, Disc area

Age, Signal

strength

Cirrus 284 (19-84) 43% Caucasian24% Asian18% African12% Hispanic1% Indian

Age

Age, Disc area

Age

Spectralis 201 48 ± 14 (18-78)

Caucasian Only

Age (Not all

Sectors)

Age: What is the Evidence?

RNFL Age Related Decrease

Mwanza et al AJO 2011Girkin et al. Ophthalmol 2011

RTVueRate of decrease: -.17 um / yrR2=7.0%

CirrusRate of decrease: -.19 um / yrR2=11.8%

RNFL Age Related Decrease: Magnitude < 10 um between 40-80 years

RTVueRate of decrease: -.17 um / yrR2=7.0%

CirrusRate of decrease: -.19 um / yrR2=11.8%

Mwanza et al AJO 2011Girkin et al. Ophthalmol 2011

Leung et al 2012 Ophthalmol 119:731-737

Mean follow-up 30 monthsRange 24-41 months

Cirrus RNFL Sector

Longitudinal*(n=35)

um/yr (95% CI)

Average -0.52 (-0.86 to -0.17)

Superior -1.35 (-2.05 to -0.65)

Inferior -1.25 (-1.78 to -0.71)

Temporal 0.21 (-0.10 tp0.53)

Nasal 0.31 (-0.25 to 0.86)

* Adjusted for disc area, signal strength, refraction

Rate varies by sector and baseline thickness0.21 um/yr (temporal) to -1.35 um/yr (Superior)

Adjust for Age?

For• 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

Race: What is the Evidence?

Racial Differences in Disc Area(African, Hispanic > European)

AD: African

ED: European

HE: Hispanic

IN: Indian

JA: Japanese

Girkin et al. Ophthalmol 2011

Small significant differences by race for some parameters even after adjusting for disc area and age

Girkin et al. Ophthalmol 2011

RTVue

Cirrus

Knight et al. Arch Ophthalmol 2012

Small significant differences by race for some parameters even after adjusting for disc area and age

Girkin et al. Ophthalmol 2011

RTVue

Cirrus

Knight et al. Arch Ophthalmol 2012

Largest difference in meanRim area between races =0.09 mm2 (Hispanic: 1.38 mm2 vs European:1.29 mm2)

Largest difference in meanRim area between races =0.21 mm2

(Hispanic: 1.48 mm2 vs Indian:1.27 mm2)

Rim Area Average RNFL

Normal Comparison Group: AD and ED from the RTVue Normative Database (n=167)

RNFL Diagnostic Accuracy is Similar Regardless of Whether Normal Comparison Group is of European

or African Descent

Girkin et al IOVS 2011: 52: 6148-53

POAG European Descent (ED)

POAG African Descent (AD) 0.5

0.55

0.6

0.65

0.7

0.75

0.8

0.85

0.9

0.95

1

0.880.890.89 0.89

0.880.87

Normals AD & ED (n=167) Normals AD only (n=62) Normals ED only (n=105)

Are

a U

nd

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RO

C C

urv

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Stratify by Race?

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

For• Clear evidence of optic nerve head

racial differences (not “small”)• Misclassification of Individuals will

be reduced

Optic Disc Size: What is the Evidence?

Strong Associations of ONH Parameters w/Disc Area

R2 ranged from 5.2% (RNFL) to 42.6% (Cup Area)

Sinai white Paper PN 300-46043 Rev A

(RTVue)

Strength of Disc Area Association with Vertical Cup Disc Ratio Varies by Instrument

RTVue

R2=19.3%

Cirrus

R2=52.7%

Knight et al Arch Ophthalmol 2012Sinai white Paper PN 300-46043 Rev A

Adjust for Optic Disc Size?

Against• Automated software delineation

of disc margin is not always accurate

For• 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

Signal Strength and Axial Length Statistically Significant but small R2

Signal Strength• R2 =3.7% (RTVue)

Sinai White Paper PN 300-46043 Rev A

Axial Length• R2 < 7% RNFL and ONH

(Cirrus*)

*Cirrus User Manual 2660021142073 D

Adjust for Signal Strength and Axial Length?

Against

• Explains a small proportion of the variability in RNFL and ONH parameters (small R2)

For

• Consistent evidence of weak associations with RNFL and ONH parameters

SummaryImportance 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?

Stratification in Normative Databases

1. 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

2. For which covariates are covariate specific limits needed? Strongest evidence for age for RNFL and disc size for ONH

3. 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

Thank You