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Evaluation of Retinal Nerve Fiber Layer, OpticNerve Head, and Macular Thickness
Measurements for Glaucoma Detection Using
Optical Coherence Tomography
FELIPE A. MEDEIROS, MD, LINDA M. ZANGWILL, PHD, CHRISTOPHER BOWD, PHD,
ROBERTO M. VESSANI, MD, REMO SUSANNA JR, MD, AND ROBERT N. WEINREB, MD
PURPOSE: To compare the ability of optical coherence
tomography retinal nerve fiber layer (RNFL), optic nervehead, and macular thickness parameters to differentiatebetween healthy eyes and eyes with glaucomatous visual
field loss. DESIGN: Observational case-control study. METHODS: Eighty-eight patients with glaucoma and 78healthy subjects were included. All patients underwent
ONH, RNFL thickness, and macular thickness scanswith Stratus OCT during the same visit. ROC curves and
sensitivities at fixed specificities were calculated for eachparameter. A discriminant analysis was performed to
develop a linear discriminant function designed to iden-
tify and combine the best parameters. This LDF wassubsequently tested on an independent sample consistingof 63 eyes of 63 subjects (27 glaucomatous and 36
healthy individuals) from a different geographic area. RESULTS: No statistically significant difference was
found between the areas under the ROC curves (AUC)for the RNFL thickness parameter with the largest AUC
(inferior thickness, AUC 0.91) and the ONH param-eter with largest AUC (cup/disk area ratio, AUC
0.88) (P .28). The RNFL parameter inferior thick-ness had a significantly larger AUC than the macular
thickness parameter with largest AUC (inferior outer
macular thickness, AUC 0.81) (P
.004). A com-bination of selected RNFL and ONH parameters resultedin the best classification function for glaucoma detection
with an AUC of 0.97 when applied to the independent
sample. CONCLUSIONS: RNFL and ONH measurements had
the best discriminating performance among the several
Stratus OCT parameters. A combination of ONH and
RNFL parameters improved the diagnostic accuracy for
glaucoma detection using this instrument. (Am J Oph-
thalmol 2005;139:44-55. 2005 by Elsevier Inc. All
rights reserved.)
CHANGES IN THE STRUCTURAL APPEARANCE OF THE
optic nerve head (ONH) and retinal nerve fiber
layer (RNFL) have been reported to precede thedevelopment of visual field loss in glaucoma.13 Detection
of ONH and RNFL damage is, therefore, crucial for early
diagnosis of glaucoma. Recent attention has also been
directed to the role of macular thickness measurements for
glaucoma diagnosis. Retinal ganglion cells also are lost in
the posterior pole in glaucoma,4,5 where these cells may
constitute 30% to 35% of the retinal thickness in the
macular region.
Optical coherence tomography (OCT) is an optical
imaging technique that provides high resolution and re-
producible images of the RNFL that discriminate glauco-
matous from healthy subjects.611 Although OCT has beenused, for the most part, to evaluate RNFL thickness, recent
improvements in the software also have made possible the
evaluation of ONH topography and macular thickness for
glaucoma diagnosis and follow-up. A previous investiga-
tion demonstrated that OCT ONH measurements corre-
late well with topographic measurements obtained by
confocal scanning laser ophthalmoscopy, another imaging
technique that evaluates the ONH.12 Other studies have
also shown that OCT macular thickness measurements are
significantly thinner in glaucomatous compared with
healthy eyes.5,1315 Although the ability of OCT ONH and
Accepted for publication Aug 26, 2004.From the Hamilton Glaucoma Center and Department of Ophthal-
mology, University of California, San Diego, California ( F.A.M., L.M.Z.,C.B., R.N.W.); and Department of Ophthalmology, University of SoPaulo, So Paulo, Brazil (R.M.V., R.S. Jr.).
Supported in part by the Foundation for Eye Research (F.A.M.) andNIH Grant EY11008 (L.M.Z.).
Inquiries to Felipe A. Medeiros, MD, Hamilton Glaucoma Center,University of California, San Diego, 9500 Gilman Drive, La Jolla, CA92093-0946; e-mail: [email protected]
2005 BY ELSEVIER INC. ALL RIGHTS RESERVED.44 0002-9394/05/$30.00doi:10.1016/j.ajo.2004.08.069
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macular thickness measurements to differentiate glauco-
matous from healthy subjects has been reported to be lowerthan RNFL thickness parameters, no study has yet pro-
vided a comparison of these three methods in the samepopulation. Further, it is possible that ONH and macula
measurements provide complementary structural informa-tion that would increase diagnostic accuracy when com-
bined with RNFL evaluation.The purpose of this study was to compare the ability of
OCT RNFL, ONH, and macular thickness parameters todifferentiate between healthy eyes and eyes with glauco-
matous visual field loss in one study population. We alsoinvestigated whether a combination of these analytical
methods improved the accuracy of glaucoma diagnosis byOCT.
METHODS
THIS OBSERVATIONAL CROSS-SECTIONAL STUDY INCLUDED166 eyes of 166 patients (88 glaucomatous patients and 78
healthy control subjects). Mean age ( SD) of glaucoma
patients and healthy individuals was 68 11 years and 65 9 years, respectively (P .09; Students t test). Subjects
were evaluated at the Hamilton Glaucoma Center, Uni-versity of California, San Diego, from April 2002 to
January 2004. These patients were included in a prospec-tive longitudinal study designed to evaluate optic nerve
structure and visual function in glaucoma (DIGSDiag-nostic Innovations in Glaucoma Study). All patients who
met the inclusion criteria described were enrolled in the
current study. Informed consent was obtained from allparticipants. The University of California San DiegoHuman Subjects Committee approved all protocols, and
the methods described adhered to the tenets of theDeclaration of Helsinki.
Each subject underwent a comprehensive ophthalmologicexamination including review of medical history, best-cor-
rected visual acuity, slit-lamp biomicroscopy, intraocularpressure (IOP) measurement using Goldmann applanation
tonometry, gonioscopy, dilated fundoscopic examination us-ing a 78-diopter lens, stereoscopic optic disk photography,
and automated perimetry using 24-2 Swedish InteractiveThreshold Algorithm (Carl Zeiss Meditec Inc., Dublin, Cal-
ifornia, USA). To be included, subjects had to have best-corrected visual acuity of 20/40 or better, spherical refraction
within 5.0 diopters and cylinder correction within 3.0diopters, and open angles on gonioscopy. Eyes with coexisting
retinal disease, uveitis, or nonglaucomatous optic neuropathywere excluded from this investigation. One eye of each
patient was randomly selected for inclusion in the study.Normal control eyes had intraocular pressures of 21 mm
Hg or less with no history of increased IOP and a normalvisual field result. Normal visual field was defined as a
mean deviation and pattern standard deviation within95% confidence limits, and a Glaucoma Hemifield Test
(GHT) within normal limits. Normal control eyes also had
a healthy appearance of the optic disk and RNFL (nodiffuse or focal rim thinning, cupping, optic disk hemor-
rhage, or RNFL defects), as evaluated by clinical exami-nation.
Eyes were classified as glaucomatous if they had repeat-able (two consecutive) abnormal visual field test results,
defined as a PSD outside of the 95% normal confidencelimits or a Glaucoma Hemifield Test result outside normal
limits, regardless of the appearance of the optic disk.Average MD of the glaucomatous eyes on the visual field
test nearest the imaging date was 4.96 dB. According tothe Hodapp-Parrish-Anderson16 grading scale of severity of
visual field defects, 61 patients (69%) were classified ashaving early visual field defects, 15 patients (17%) had
moderate defects, and 12 patients (14%) had severe visualfield defects.
Although the appearance of the optic disk on stereo-photographs was not used as an inclusion criterion, the
results of stereophotograph assessment were used for com-parison with Stratus OCT ONH measurements. Simulta-
neous stereoscopic optic disk photographs (TRC-SS;
Topcon Instrument Corp of America, Paramus, NewJersey, USA) were evaluated by two experienced graders,
and each was masked to the subjects identity and to theother test results. The graders visually estimated the
horizontal and vertical cup/disk ratios based on the con-tour of the cup. The mean value of the two graders was
used as a final grading.Subjects underwent ocular imaging with dilated pupils
using the commercially available optical coherence tomo-
graph, Stratus OCT (Carl Zeiss Meditec, Dublin, Califor-nia, USA). All patients had optic nerve head, RNFLthickness, and macular thickness scans obtained during the
same visit. OCT employs the principles of low-coherenceinterferometry and is analogous to ultrasound B-mode
imaging but uses light instead of sound to acquire high-resolution images of ocular structures. In brief, a low-
coherence near-infrared (840 nm) light beam is directedonto a partially reflective mirror (beam splitter) that
creates two light beams, a reference and a measurementbeam. The measurement beam is directed onto the sub-
jects eye and is reflected from intraocular microstructuresand tissues according to their distance, thickness, and
different reflectivity. The reference beam is reflected fromthe reference mirror at a known, variable position. Both
beams travel back to the partially reflective mirror, recom-bine, and are transmitted to a photosensitive detector. The
pattern of interference is used to provide informationregarding distance and thickness of retinal structures.
Bidimensional images are created by successive longitudi-nal scanning in transverse direction.
Quality assessment of Stratus OCT scans was evaluatedby an experienced examiner masked to the subjects results
of the other tests. Good-quality scans had to have focusedimages from the ocular fundus, an adequate signal-to-noise
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ratio (33 dB for RNFL and macula scans), and the
presence of a centered circular ring around the optic disk
(for RNFL scans). For macula and ONH scans, the radial
scans had to be centered on the fovea and optic disk,
respectively. RNFL scans were also evaluated as to the
adequacy of the algorithm for detection of the RNFL. Only
scans without overt algorithm failure in detecting the
retinal borders were included in the study. If one type ofscan was classified as unacceptable, the patient was ex-
cluded from the study. From an initial group of 189 eligible
patients, 23 (12%) had unacceptable Stratus OCT scans
and were excluded from further analysis.
RNFL THICKNESS MEASUREMENTS: The fast RNFL
algorithm was used to obtain RNFL thickness measure-
ments with Stratus OCT. Three images were acquired from
each subject, with each image consisting of 256 A-scans
along a 3.4-mm-diameter circular ring around the optic
disk. A mean image was automatically created by the
Stratus OCT software.Parapapillary RNFL thickness parameters automati-
cally calculated by existing Stratus OCT software (version
3.1) and evaluated in this study were average thickness
(360-degree measure), temporal quadrant thickness (316
degrees to 45 degrees), superior quadrant thickness (46
degrees to 135 degrees), nasal quadrant thickness (136
degrees to 225 degrees), inferior quadrant thickness (226
degrees to 315 degrees), and thickness for each of 12
clock-hour positions with the 3-oclock position as nasal,
6-oclock position as inferior, 9-oclock position as tempo-
ral, and 12-oclock position as superior. Other parameters
evaluated included superior maximum (Smaxthickestpoint in the superior quadrant), inferior maximum
(Imaxthickest point in the inferior quadrant), and rela-
tional parameters such as Imax/Smax, Smax/Imax, Imax/
Tavg (inferior maximum/temporal quadrant thickness),
Smax/Navg (Superior maximum/Nasal quadrant thick-
ness), and Max-min (difference between the thickest and
thinnest points along the measurement circle).
OPTIC NERVE HEAD MEASUREMENTS: The Fast Opti-
cal Disk scanning protocol was used to obtain ONH
measurements with Stratus OCT. The ONH scan consists
of six radial scans in a spoke like pattern centered on theONH. The OCT interpolates between the scans to provide
measurements throughout the ONH. In optic nerve head
scans, the device automatically determines the disk margin
as the end of the retinal pigment epithelium/choriocapil-
laris layer. One can manually adjust the demarcation of the
edge of the retinal pigment epithelium to improve the
outlining of the disk margin. However, to minimize sub-
jectivity, the automatically determined default disk margin
was used in this study. A straight line connects the edges
of the retinal pigment epithelium/choriocapillaris, and a
parallel line is constructed 150 m anteriorly. Structures
below this line are defined as the disk cup and above this
line as the neuroretinal rim.
ONH parameters automatically calculated by existing
Stratus OCT software (version 3.1) and evaluated in this
study were vertically integrated rim area (total volume of
rim tissue calculated by multiplying the average of indi-
vidual rim areas times the circumference of the disk),
horizontally integrated rim width (estimate of total rimarea calculated by multiplying the average of individual
rim widths times the circumference of the disk), disk area,
cup area, rim area, cup/disk area ratio (ratio of cup area to
disk area), horizontal cup/disk ratio (ratio of the longest
horizontal line across the cup to the longest horizontal line
across the disk), and vertical cup/disk ratio (ratio of the
longest vertical line across the cup to the longest vertical
line across the disk).
MACULAR THICKNESS MEASUREMENTS: The Fast
Macular Thickness protocol was used to obtain macular
thickness measurements with Stratus OCT. The macularscans consist of six radial scans in a spokelike pattern
centered on the fovea with each radial scan spaced 30
degrees from one to another. To fill the gaps between the
scans, OCT uses interpolation.
Stratus OCT software calculates retinal thickness as
the distance between the vitreoretinal interface and the
junction between the inner and outer segment of photo-
receptors, which is just above the retinal pigment epithe-
lium. Three concentric circles divide the macular
thickness map into three zones: fovea, inner macula, and
outer macula. The inner and outer zones are further
divided in four quadrants by two diagonal lines. Thus, atotal of nine areas (fovea, superior outer, superior inner,
inferior outer, inferior inner, temporal outer, temporal
inner, nasal outer, and nasal inner) are available for
analysis. For this study, concentric circles with default
diameters of 1 mm, 3 mm, and 6 mm were used to divide
the macular thickness map.
Macular thickness parameters automatically calculated
by existing Stratus OCT software (version 3.1) and eval-
uated in this study were foveal thickness, superior outer
macular thickness, inferior outer macular thickness (IOM),
temporal outer macular thickness, nasal outer macular
thickness, superior inner macular thickness, inferior innermacular thickness, temporal inner macular thickness, and
nasal inner macular thickness. Average macular thickness
was calculated as the weighted average of the sectoral
macular thickness measurements excluding the fovea.
STATISTICAL ANALYSIS: Student t tests were used to
evaluate optic nerve head, RNFL thickness, and macular
thickness measurement differences between glaucomatous
and healthy eyes. Results of statistical significance were
also provided after Bonferronis correction based on the
number of comparisons within each analysis. Pearsons
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correlation coefficients were used to assess the correlations
between continuous variables. Bland and Altman plotswere constructed to assess agreement between optic disk
stereophotograph assessment and Stratus OCT ONHmeasurements.17,18
Receiver operating characteristic (ROC) curves wereused to describe the ability to differentiate glaucomatous
from healthy eyes of each Stratus OCT software-providedparameter. The ROC curve shows the trade-off between
sensitivity and 1-specificity. An area under the ROC curveof 1.0 represents perfect discrimination, whereas an area of
0.5 represents chance discrimination. The method ofDeLong and associates19 was used to compare areas under
the ROC curve.A discriminant analysis was performed to develop a
classification function (linear discriminant functionLDF) designed to identify and combine the best Stratus
OCT measures to differentiate glaucomatous from normaleyes. A principal component analysis was initially per-
formed to select a reduced set of variables that accountedfor most of the variance of the original data set.20,21 The
central idea of PCA is to reduce the dimensionality of a
data set consisting of a large number of interrelatedvariables while retaining as much as possible of the
variation present in the data set.20 Thirteen principalcomponents explaining 91% of the variance of the data set
were selected according to Jollifes criterion.22 After vari-max rotation, the variables with highest loadings in each
component were selected for further analysis and possibleinclusion in the discriminant function.21 LDFs were then
constructed using all possible subsets from the reduced set
of variables. The bias-corrected area under the ROC curvewas used as a measure of the performance of each LDF. Biascorrection was performed using 10-fold cross-validation.
The model that maximized the bias-corrected ROC curvearea was selected as best.
To evaluate model stability, 1,000 bootstrap randomsamples were drawn with replacement from the original
sample. The model selection procedure was then applied toeach of the 1,000 bootstrap resamples, and the best model
was selected in each resample. The frequency of inclusionof the variables in the selected models was reported.
Important variables should be included in most of thereplications, and the inclusion frequencies may be used as
a criterion for the importance of a variable.23
EXTERNAL VALIDATION ANALYSIS: To determinegeneralizability of the derived Stratus OCT LDF to new
patients, the final LDF was applied to an external inde-pendent sample from a different geographic area.24 Patients
in this sample were not used in any of the steps of modeldevelopment. This validation set included 63 eyes of 63
subjects (27 glaucomatous and 36 normals) evaluated atthe Glaucoma Center of the University of So Paulo,
Brazil. Informed consent was obtained from all subjects,and the appropriate regulatory and ethics committees
approved all protocols. The inclusion and exclusion crite-
ria were identical to those used for the derivation set.Mean age (SD) of glaucoma patients and healthy sub-
jects was 59 15 years and 56 10 years, respectively(P .36). Average MD of the glaucomatous eyes on the
visual field test nearest the imaging date was 6.58 dB.According to the Hodapp-Parrish-Anderson16 grading
scale of severity of visual field defects, 16 patients (59%)were classified as having early visual field defects, 4
patients (15%) had moderate defects, and 7 patients(26%) had severe visual field defects.
A P value less than .05 was considered statisticallysignificant. Statistical analyses were performed using soft-
ware SPSS v.10.0 (SPSS Inc., Chicago, Illinois, USA) andS-PLUS 2000 (Mathsoft Inc., Seattle, Washington, USA).
RESULTS
RNFL THICKNESS MEASUREMENTS: Table 1 showsmean values of Stratus OCT RNFL parameters in glauco-
matous and normal eyes. After Bonferronis correction ( 0.002; 25 comparisons), statistical significant differenceswere found for all parameters except thickness at 9-oclock,
Imax/Smax, Smax/Tavg, and Smax/Navg. Table 1 alsoshows ROC curve areas and sensitivities at fixed specific-
ities. The 3 Stratus OCT RNFL parameters with largestareas under the ROC curves were inferior thickness (0.91),
average thickness (0.91), and inferior maximum (0.90).There were no statistically significant differences in the
ROC curve areas for these parameters (P .05 for all
comparisons).
OPTIC NERVE HEAD MEASUREMENTS: Table 2 shows
mean values of Stratus OCT ONH parameters in glauco-matous and normal eyes. After Bonferronis correction ( 0.006; 8 comparisons), statistical significant differenceswere found for all parameters except disk area. Table 2 also
shows ROC curve areas and sensitivities at fixed specific-ities. The 3 Stratus OCT ONH parameters with largest
areas under the ROC curves were cup/disk area ratio(0.88), vertical cup/disk ratio (0.88), and HIRW (0.88).
Vertical and horizontal cup/disk ratio measurementsobtained by the Stratus OCT also were compared with
those obtained by stereophotograph assessment. There wasno statistically significant difference between mean Stratus
OCT vertical cup/disk ratio and stereophotograph verticalcup/disk ratio [0.59 0.20 vs 0.58 0.24; P .59, paired
t test). There was a statistically significant correlationbetween the two measurements (r .87; P .001). Figure
1 shows a Bland and Altman plot of the agreement invertical cup/disk ratio between Stratus OCT and stereo-
photograph assessment. The difference (stereophotographvertical cup/disk ratioStratus OCT vertical cup/disk
ratio) was plotted against the average of the two measure-ments. Although no significant fixed bias was observed, a
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statistically significant proportional bias was detected (r
.34; P .001). For lower values of vertical cup/disk ratio,Stratus OCT measurements tended to be higher than
stereophotograph measurements; whereas for higher valuesof vertical cup/disk ratio, Stratus OCT measurements
tended to be lower than stereophotograph measurements.For the horizontal cup/disk ratio, Stratus OCT measure-
ments were significantly larger than stereophotograph-basedsubjective assessment (0.64 0.22 vs 0.54 0.22; P .001;
paired t test). A significant correlation was obtained between
the two measures (r .84; P .001). The Bland and Altmanplot (Figure 2) showed the presence of fixed bias, but no
proportional bias was detected (r .01; P .87).
MACULAR THICKNESS MEASUREMENTS: Table 3shows mean values of Stratus OCT macular thickness
parameters in glaucomatous and normal eyes. AfterBonferronis correction ( 0.005; 10 comparisons),
TABLE 1. Mean ( SD) Values of Stratus OCT Retinal Nerve Fiber Layer Parameters With Areas Under the Receiver Operating
Characteristic (ROC) Curves and Sensitivities (Sn) at Fixed Specificities (Sp)
Parameter
Glaucoma
(n 88)
Normal
(n 78) P* ROC (SE)
Sn/Sp
(Sp 95%)
Sn/Sp
(Sp 80%)
Inferior thickness (m) 84.6 23.2 123.8 16.5 .0001 0.91 (0.02) 65/96 89/80
Average thickness (m) 74.2 13.3 96.5 9.90 .0001 0.91 (0.02) 71/95 86/80Imax (m) 112.3 30.5 159.3 21.1 .0001 0.90 (0.03) 63/95 85/80
Thickness at 6-oclock (m) 90.2 29.6 133.8 24.5 .0001 0.87 (0.03) 56/95 78/80
Thickness at 7-oclock (m) 87.7 32.0 132.4 21.2 .0001 0.87 (0.03) 64/95 81/80
Max-min (m) 94.0 25.1 124.5 18.6 .0001 0.85 (0.03) 55/95 81/80
Superior thickness (m) 92.2 22.5 118.6 16.0 .0001 0.83 (0.03) 52/96 73/81
Smax (m) 120.4 26.6 149.8 19.5 .0001 0.81 (0.03) 50/95 68/80
Thickness at 11-oclock (m) 96.1 29.5 124.9 19.0 .0001 0.78 (0.04) 47/95 68/80
Imax/Tavg 1.92 0.54 2.43 0.51 .0001 0.76 (0.04) 38/95 50/81
Thickness at 5-oclock (m) 75.8 23.5 105.2 25.5 .0001 0.80 (0.03) 34/95 63/80
Nasal thickness (m) 59.5 15.8 76.1 19.6 .0001 0.76 (0.04) 13/95 61/80
Thickness at 3-oclock (m) 49.5 12.5 62.2 19.2 .0001 0.70 (0.04) 10/96 34/81
Thickness at 4-oclock (m) 59.1 16.8 75.2 19.9 .0001 0.74 (0.04) 22/95 55/81
Thickness at 2-oclock (m) 69.9 23.1 91.1 25.2 .0001 0.74 (0.04) 21/95 52/80
Thickness at 1-oclock (m) 86.0 26.0 109.2 21.9 .0001 0.75 (0.04) 39/95 50/80
Thickness at 12-oclock (m) 94.4 27.4 121.8 26.7 .0001 0.76 (0.04) 31/95 58/80
Smax/Tavg 2.08 0.61 2.28 0.48 .019 0.64 (0.04) 27/96 43/80
Thickness at 10-oclock (m) 69.0 20.6 80.9 18.4 .0001 0.68 (0.04) 26/96 46/81
Imax/Smax 0.97 0.31 1.08 0.17 .004 0.65 (0.04) 33/95 44/81
Thickness at 8-oclock (m) 60.7 17.9 69.7 16.2 .0001 0.67 (0.04) 24/95 49/81
Temporal thickness (m) 60.5 15.2 67.6 13.1 .002 0.65 (0.04) 22/95 38/81
Thickness at 9-oclock (m) 51.8 13.6 52.4 11.2 .760 0.51 (0.05) 11/95 22/82
Smax/Navg 2.16 1.01 2.10 0.63 .634 0.48 (0.05) 5/95 17/80
Smax/Imax 1.15 0.39 0.95 0.15 .0001 0.35 (0.04) 7/95 16/80
TABLE 2. Mean ( SD) Values of Stratus OCT Optic Nerve Head Parameters With Areas Under the Receiver OperatingCharacteristic (ROC) Curves and Sensitivities (Sn) at Fixed Specificities (Sp)
Parameter
Glaucoma
(n 88)
Normal
(n 78) P* ROC (SE)
Sn/Sp
(Sp 95%)
Sn/Sp
(Sp 80%)
Cu p/disk:are a ratio 0.55 0.19 0.26 0.14 .0001 0.88 (0.03) 69/95 80/80
Vertical C/D ratio 0.70 0.14 0.45 0.16 .0001 0.88 (0.03) 65/95 81/80
HIRW (mm2) 1.23 0.28 1.69 0.28 .0001 0.88 (0.03) 55/95 77/80
Rim area (mm2) 1.02 0.42 1.74 0.45 .0001 0.88 (0.03) 51/95 81/80
VIRA (mm2) 0.17 0.16 0.48 0.34 .0001 0.87 (0.03) 58/95 82/80
Horizontal C/D rat io 0.76 0.16 0.50 0.19 .0001 0.86 (0.03) 59/95 74/80
Cup area (mm2) 1.31 0.60 0.61 0.39 .0001 0.84 (0.03) 50/95 74/80
Disk area (mm2) 2.34 0.47 2.35 0.51 .847 0.51 (0.05) 6/95 19/80
*HIRW horizontal integrated rim width; VIRA vertical integrated rim area.
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statistically significant differences were found for allparameters except NIM thickness and foveal thick-
ness. Table 3 also shows ROC curve areas and sensitiv-ities at fixed specificities. The 3 Stratus OCT macular
thickness parameters with the largest areas under theROC curves were IOM thickness (0.81), Macular thick-
ness average (0.75), and TOM thickness (0.75). Therewere no statistically significant differences in the ROC
curve areas for these parameters (P .05 for allcomparisons).
COMPARISON OF RNFL, ONH, AND MACULAR THICK-
NESS MEASUREMENTS: No statistically significant differ-ence was found between the areas under the ROC curves
(AUC) for the RNFL thickness parameter with largestAUC (inferior thickness; AUC 0.91) and the ONH
parameter with largest AUC (cup/disk area ratio; AUC 0.88) (P .28). The RNFL parameter inferior thickness
had a significantly larger AUC than the macular thicknessparameter with largest AUC (IOM; AUC 0.81) (P
.004). The AUC of the ONH parameter cup/disk area ratiowas higher than that of the macular thickness parameter
IOM, but the difference did not reach statistical signifi-cance (P .09).
We evaluated whether a combination of Stratus OCTmeasures improved the discrimination between glaucoma
and healthy subjects. The best discriminant functionresulting from the combination of Stratus OCT parameters
had the following formula:LDF 3.023 (2.659 cup/disk area ratio)
(0.035 average thickness) (0.013 thickness at7-oclock) (0.011 thickness at 11-oclock) (0.031 thickness at 9-oclock)
This LDF had an AUC of 0.97 (SE 0.01) with an
estimated bias of 0.011. The AUC of the LDF wassignificantly larger than that of the single Stratus OCT
software-provided parameter with largest AUC (inferiorthickness) (0.97 vs 0.91; P .012). Figure 3 shows the
ROC curves for the two parameters of RNFL, ONH, andmacular analyses with largest AUCs and also for the
Stratus OCT LDF. For specificity at 95%, the LDF hada sensitivity of 90% (cut-off of 0.284). For specificity at
81%, the LDF had a sensitivity of 94% (cut-off of0.683).
Although there were several LDFs that were competi-tive with the above formula, the variables included in the
final LDF had the highest frequencies of inclusion in themodels selected in the bootstrap samples. Figure 4 illus-
FIGURE 1. Bland and Altman plot of the agreement on vertical cup/disk ratio between stereophotograph assessment and Stratus
OCT measurements. The difference (stereophotograph Stratus OCT) is plotted vs the average (stereophotograph Stratus
OCT)/2. The existence of proportional bias is indicated by the significant slope of the line regressing the difference on the average
(r .34; P < .001). The regression line is shown with 95% individual confidence limits bands.
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trates the frequency of inclusion of the variables in the
final models selected in the 1,000 bootstrap replications.The variables included in the final LDF were selected in
59% to 88% of the final models, whereas the othervariables were included in no more than 32% of the
models. The full model containing all 13 variables had abias-corrected AUC of 0.96.
When applied to the independent validation sample
(n 63), the LDF had an AUC of 0.97 (SE 0.02).Figure 5 shows the ROC curves for the LDF when
applied to the independent sample and for the twoparameters with largest AUC for RNFL (average thick-
ness; AUC 0.93 and RNFL thickness at 6-oclock;AUC 0.92), ONH (VIRA; AUC 0.92 and cup/disk
FIGURE 2. Bland and Altman plot of the agreement on horizontal cup/disk ratio between stereophotograph assessment and Stratus
OCT measurements. The difference (stereophotograph Stratus OCT) is plotted vs the average (stereophotograph Stratus
OCT)/2. The continuous line represents the mean difference and 95% limits of agreement. The existence of fixed bias is indicated
by the significant deviation from zero of the mean difference between stereophoto and Stratus OCT measurements.
TABLE 3. Mean ( SD) Values of Stratus OCT Macular Thickness Parameters With Areas Under the Receiver Operating
Characteristic (ROC) Curves and Sensitivities (Sn) at Fixed Specificities (Sp)
Parameter
Glaucoma
(n 88)
Normal
(n 78) P* ROC (SE)
Sn/Sp
(Sp 95%)
Sn/Sp
(Sp 80%)
Inferior outer macula (m) 205 16 224 16 .0001 0.81 (0.03) 47/95 73/82
Macula average (m) 216 13 231 15 .0001 0.75 (0.04) 35/95 50/80
Temporal outer macula (m) 202 15 218 18 .0001 0.75 (0.04) 32/95 51/80
Superior outer macula (m) 220 18 236 17 .0001 0.73 (0.04) 36/95 48/80
Nasal outer macula (m) 235 18 247 18 .0001 0.68 (0.04) 21/95 39/80
Temporal inner macula (m) 246 18 257 19 .0001 0.67 (0.04) 22/95 42/80
Inferior inner macula (m) 254 19 265 19 .0001 0.65 (0.04) 26/96 34/80
Superior inner macula (m) 259 21 269 19 .002 0.63 (0.04) 18/95 34/80
Nasal inner macula (m) 264 21 269 21 .12 0.55 (0.05) 14/95 31/80
Fovea (m) 202 25 201 28 .83 0.47 (0.05) 6/95 18/80
*Macula average thickness is calculated from the weighted average of all sectors excluding the fovea. SE standard error.
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area ratio; AUC 0.91), and macular thickness anal-yses (IOM; AUC 0.79 and SOM; AUC 0.78) on
the independent sample.
DISCUSSION
THE ANALYSIS OF STRATUS OCT SOFTWARE-PROVIDED PA-
rameters showed that parapapillary RNFL measures and
ONH topographic parameters had the highest power todiscriminate glaucomatous from healthy eyes. Areas under
the ROC curves and sensitivities at moderate and highspecificities were similar for the best parameters from each
of these two methods of analysis. We also found that acombination of selected RNFL and ONH parameters in a
linear discriminant function resulted in further improve-ment of the diagnostic accuracy of OCT.
The ROC curve areas for the Stratus OCT RNFLmeasurements were similar to those obtained with the
previous versions of this technology. The areas under theROC curves for the earlier OCT models have been
reported to range from 0.79 to 0.94, depending on the
parameter and characteristics of the population evaluat-
ed.911,15,2527 In studies evaluating the diagnostic ability of
several OCT parameters, the RNFL thickness in the
inferior region often had the best performance to discrim-
inate healthy eyes from eyes with early to moderate
glaucoma with sensitivities between 67% and 79% for
specificities 90%.9,11,26 In our study, the parameter
inferior thickness also had the highest area under the
ROC curve, with sensitivity of 65% for specificity at95%. The parameter average thickness also had a similar
performance.
The RNFL thicknesses at 7-oclock and at 11-oclock
were included as RNFL parameters in our discriminant
function, along with RNFL thickness at 9-oclock and
average thickness. The high discriminating ability of
RNFL thickness at 7- and 11-oclock is readily understand-
able, as these variables represent the inferior temporal and
superior temporal sectors of the optic disk, respectively,
which are the sectors most commonly affected in glauco-
ma.28 The inclusion of these variables may also be related
FIGURE 3. Receiver operating characteristic (ROC) curves of the two parameters with largest areas under the ROC curves from
the Stratus OCT retinal nerve fiber layer (inferior thickness and average thickness), optic nerve head (cup/disk area ratio and
vertical cup/disk ratio), macular thickness analysis (inferior outer macular thickness [IOM] and macula average), and of the lineardiscriminant function (LDF) obtained from the combination of selected parameters.
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to the detection of localized nerve fiber layer defects that
are most commonly seen in these sectors.29 The average
RNFL thickness is a measurement of global thickness ofthe RNFL and, therefore, is presumably important in thedifferentiation of glaucoma from healthy eyes. The inclu-
sion of the RNFL thickness at 9-oclock in the discrimi-nant function is more difficult to explain. This variable
corresponds to the thickness at the most temporal sector,in the region of the papilomacular bundle. No significant
difference was observed in the mean RNFL thicknessvalues at 9-oclock between glaucomatous and healthy
eyes. This is in agreement with previous studies demon-strating that the RNFL is usually preserved in the region of
the papilomacular bundle until late in the course of thedisease. It is well known that RNFL thickness can vary
widely among healthy subjects limiting the usefulness ofabsolute thickness values to separate glaucomatous from
healthy subjects. Conversely, the evaluation of the modu-lation of the RNFL thickness may provide a useful tool for
detection of relative loss of nerve fibers in glaucoma.30 Themodulation represents the difference between the thickest
and the thinnest parts of the RNFL around the optic disk.The RNFL thickness difference between the 9-oclock
sector and the 7- and 11-oclock sectors could provide anindication of the modulation of RNFL thickness around
the optic disk. The negative sign of this variable in theLDF formula indicates that, all other variables being equal,
a subject with thicker RNFL at 9-oclock (and lower
modulation) will have a higher chance of having glauco-
matous visual field loss than a subject with thinner RNFLin this sector (and higher modulation). In a recent study,Nouri-Mahdavi27 and associates found that the thickness
at 7-, 10-, and 11-oclock provided the best combination ofOCT RNFL parameters to discriminate patients with
glaucomatous visual field loss from healthy subjects. Intheir study, the thickness at 10-oclock had a positive
correlation with the presence of glaucomatous visual fieldloss, that is, higher values indicated a higher chance of
glaucoma. Thus, it is possible that the RNFL thickness at10-oclock in their discriminant function had the same role
as the RNFL thickness at 9-oclock in our study. This issupported by the high correlation existing between these
two variables (r .77, P .001 in our study).Stratus OCT ONH parameters also performed well for
glaucoma detection in our study. Areas under the ROCcurves were similar for all ONH parameters except disk
area. The parameter cup/disk area ratio had the highestsensitivity with specificity at 95%, and this parameter was
also included in the final LDF developed in our study.Highly significant correlations were found between Stratus
OCT and stereophotograph assessment of vertical andhorizontal cup/disk ratios. However, important disagree-
ments were detected between these two methods whenBland and Altman plots (Figures 1 and 2) were analyzed,
FIGURE 4. Frequency of inclusion of the 13 different variables in the best models selected in each of the 1,000 bootstrap
replications.
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indicating the low utility of correlation coefficients toassess agreement between methods of measurement, an
issue that has already been extensively acknowledged inthe literature.17,18,31 The limited agreement with stereo-
photographic assessment does not preclude the use ofStratus OCT ONH parameters for glaucoma diagnosis.
Stereophotographic assessment of cup/disk ratio is a sub-jective measure and has a large interobserver variability.32
In contrast, Stratus OCT ONH assessment provides ob-jective measures of optic disk topography using an auto-
mated process of optic disk edge detection and cupdelimitation, and a recent study has found these measures
to be highly reproducible.33 In fact, the discriminatingabilities of Stratus OCT ONH parameters were similar to
those of the best RNFL measures, and the combination ofan ONH parameter (cup/disk area ratio) with RNFL
thickness parameters resulted in the best discriminantfunction for glaucoma detection in our study.
The utility of the topographical evaluation of the ONHwith OCT for glaucoma diagnosis still needs further
evaluation. As the automatic algorithm for detection ofthe disk margin is based on the determination of the end
of the retinal pigment epithelium/choriocapillaris layer, itis possible that the evaluation of the disk margin will be
influenced by changes in these layers such as with progres-sive parapapillary atrophy in glaucoma.34 A manual algo-
rithm for disk margin determination is also available.However, we did not use the manual algorithm to avoid
introducing a subjective component to our analysis. Fur-thermore, the manual and automatic algorithms have been
demonstrated to have comparable performance in a previ-ous work.12
Stratus OCT macular thickness measurements had alimited ability to differentiate glaucomatous from healthy
eyes in our investigation. Although mean macular thick-ness parameters of glaucomatous eyes were significantly
lower than that of normal control eyes, the macularthickness parameter with largest AUC had a sensitivity of
only 47% for a specificity set at 95%, with an AUC of 0.81.This agrees with a previous investigation where a maxi-
FIGURE 5. Receiver operating characteristic (ROC) curve of the linear discriminant function when applied to the independent
sample and of the two parameters with the largest areas under the ROC curves for RNFL (average thickness and RNFL thicknessat 6 oclock), ONH (vertically integrated rim area [VIRA] and cup/disk area ratio), and macular thickness analyses (inferior outer
macula thickness [IOM] and superior outer macula thickness [SOM]) on the independent sample.
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mum ROC curve area of 0.77 for macular thickness
parameters was obtained for the discrimination betweenearly glaucoma and normal subjects, whereas peripapillary
RNFL thickness parameters had maximum ROC curvearea of 0.94 in the same situation.15 In contrast to RNFL
and ONH measures, macular thickness parameters werenot included in the final LDF developed in our study. The
low frequency of inclusion of macular thickness parameterswhen the model building process was replicated in the
bootstrap samples provides an indication that these vari-ables had at most a weak influence on the discrimination
between glaucomatous and healthy eyes when severalStratus OCT parameters were combined. However, it
should be noted that we have only investigated the currentmacular thickness parameters provided by the standard
Stratus OCT printout, and it is possible that advances inthe software designed to extract data from the macular area
would improve detection of retinal ganglion cell loss in theposterior pole.
Our study has limitations. Although the generalizabilityof the discriminant function combining several Stratus
OCT parameters was good when applied to an indepen-
dent population, the size of the validation sample wasrelatively small. However, the sample size of the validation
group provided 79% power to detect a decrease in perfor-mance of 0.05 in the ROC curve area in the validation
sample compared with the performance in the develop-ment sample.35 The validation sample contained a higher
proportion of moderate and advanced cases compared withthe development sample. However, even when patients
with moderate and advanced glaucomatous visual field loss
were excluded from the validation sample, the LDF stillperformed well, with an area under the ROC curve of 0.96.Another limitation of our study was that the inclusion
criteria for normal subjects required a normal optic nerveappearance at the clinical examination. This was required
to avoid the inclusion of subjects with glaucomatous opticneuropathy but normal visual fields in the control group. It
might be argued that these inclusion criteria could haveoverestimated the diagnostic accuracy of OCT parameters,
especially of ONH parameters. However, this is a limita-tion common to case-control studies of this type, and no
practical solution to this problem is available at this time.In conclusion, RNFL and ONH measurements had the
best performance for glaucoma detection among the sev-eral Stratus OCT parameters examined in our study. A
combination of ONH and RNFL parameters seems to bepromising for glaucoma diagnosis using OCT.
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