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Stratification of Normative Data

Stratification of Normative Data. Linda M. Zangwill, Ph.D. Professor Hamilton Glaucoma Center Diagnostic Imaging Laboratories Department of Ophthalmology University of California, San Diego. Financial Disclosures. National Eye Institute Research Support:

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Stratification of Normative Data

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  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: • EYR0111008, EYU1014267, EYR01019869 Research Instrument Support: • Heidelberg Engineering • Carl Zeiss Meditec • Optovue • Nidek • Topcon Reading Center Services: • Optovue • Nidek • Topcon

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

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

  7. Age: What is the Evidence?

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

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

  10. Rate varies by sector and baseline thickness0.21 um/yr (temporal) to -1.35 um/yr (Superior) Mean follow-up 30 months Range 24-41 months Leung et al 2012 Ophthalmol 119:731-737

  11. Adjust for Age? 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 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

  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 Knight et al. Arch Ophthalmol 2012 Girkin et al. Ophthalmol 2011

  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 mm2vs Indian:1.27 mm2) Largest difference in mean Rim area between races =0.09 mm2(Hispanic: 1.38 mm2vs European:1.29 mm2) Knight et al. Arch Ophthalmol 2012 Girkin et al. Ophthalmol 2011

  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: 6148-53

  18. Stratify by Race? For • 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 5.2% (RNFL) to 42.6% (Cup Area) (RTVue) Sinai white Paper PN 300-46043 Rev A

  21. Strength of Disc Area Association with Vertical Cup Disc Ratio Varies by Instrument Cirrus R2=52.7% RTVue R2=19.3% Knight et al Arch Ophthalmol 2012 Sinai white Paper PN 300-46043 Rev A

  22. Adjust for Optic Disc Size? 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 Against • Automated software delineation of disc margin is not always accurate

  23. Signal Strength and Axial Length Statistically Significant but small R2 Signal Strength • R2 =3.7% (RTVue) Axial Length • R2 < 7% RNFL and ONH (Cirrus*) *Cirrus User Manual 2660021142073 D Sinai White Paper PN 300-46043 Rev A

  24. Adjust for Signal Strength and Axial Length? For • 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. 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?

  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

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