November 2014
Volume 55, Issue 11
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Glaucoma  |   November 2014
A Comprehensive Model for Correcting RNFL Readings of Varying Signal Strengths in Cirrus Optical Coherence Tomography
Author Notes
  • Naval Medical Center, San Diego, San Diego, California, United States 
  • Correspondence: David J. Russell, Department of Ophthalmology, 34800 Bob Wilson Drive, San Diego, CA 92134, USA; Russell_doc@yahoo.com
Investigative Ophthalmology & Visual Science November 2014, Vol.55, 7297-7302. doi:10.1167/iovs.14-14993
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      David J. Russell, Shamis Fallah, Christopher J. Loer, Robert H. Riffenburgh; A Comprehensive Model for Correcting RNFL Readings of Varying Signal Strengths in Cirrus Optical Coherence Tomography. Invest. Ophthalmol. Vis. Sci. 2014;55(11):7297-7302. doi: 10.1167/iovs.14-14993.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To develop a model for the Cirrus HD-OCT that allows for the comparison of retinal nerve fiber layer (RNFL) thickness measurements with dissimilar signal strengths (SS) and accounts for test–retest variability.

Methods.: Retinal nerve fiber layers were obtained in normals using the Cirrus optic disc cube 200 × 200 protocol during a single encounter. Five RNFL scans were obtained with a SS of 9 or 10. Diffusion lens filters were used to degrade SS to obtain five scans at each SS group of 7 or 8, 5 or 6, and 3 or 4. The relationship between average RNFL thickness and SS was established, and an equation was developed to allow for adjustment of an RNFL measurement had it been a SS of 7. Intravisit interclass correlation coefficient (ICC) and coefficient of variation (CV) parameter estimates for each SS group were calculated. Repeatability and upper tolerance limit were calculated as 1.96 × √2 × within-subject standard deviation (Sw) and 1.645 × √2 × Sw, respectively.

Results.: There was a linear relationship between average RNFL and SS. RNFLadj = RNFL − 1.03*SS + 7.21 allows for the adjustment of RNFL readings to the same SS. Interclass correlation coefficients and CVs were good for all measurements down to SS of 3 or 4. Repeatability and upper tolerance limit were 5.24 and 4.40 μm, respectively.

Conclusions.: Our model adjusts RNFL readings based on SS and includes an upper tolerance limit of 5 μm. If validated, this model could improve the detection of real RNFL changes. Further study to validate this model should be performed before widespread use is adopted.

Introduction
Optical coherence tomography (OCT) is a useful tool to follow patients with glaucoma or patients at risk for developing glaucoma. It is one of the few measures that practitioners can use to objectively quantify loss of retinal ganglion cells and hence glaucomatous damage. The Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA, USA) is a common OCT device currently used by many eye care professionals to follow these patients. It is necessary for practitioners to review OCT retinal nerve fiber layer (RNFL) changes in light of the inherent machine variability or risk misinterpreting a machine variation as a real change in the OCT RNFL. Repeated measures on HD-OCT have been shown to be less variable than on its predecessor, time-domain OCT.1,2 The reproducibility of measurements from the Cirrus OCT has been shown to be 4 to 5 μm for average RNFL thickness measurements.1,2 
In addition to the test–retest variability, other factors have been found to affect the variability of RNFL measurements. The Cirrus OCT generates a parameter called signal strength (SS), which combines the signal-to-noise ratio and the uniformity of the signal in the scan to provide an estimate of the quality of the scan ranging from 1 to 10 (1 being the worst quality, 10 being the best quality).3 Numerous studies have documented that RNFL measurements are positively correlated with SS.39 Most of these studies have been performed using time-domain technology and have shown that: RNFL measurement variability increases with decreasing SS, when SS is greater than 7, RNFL thickness is reproducible, and, if SS is less than 4, RNFL measurements may be considered unreliable. To better characterize this relationship, researchers have artificially changed the SS in patients by defocusing the image,9 by placing contact lenses during scans,10 and through introduction of optical filters in between the subject and the OCT machine.9,11,12 Simple formulas correcting for SS changes in average RNFL measurements have, at this time, shown limited predictive capability, in part due to not accounting for test–retest variability and being applied in unstable testing conditions.11 Although not specifically looking at RNFL values, more complex formulas analyzing reflectivity peaks in the macula have been developed to correct for changes due to SS12 and show potential, but as of now are too complicated and are not commercially available. 
In the clinical setting, repeated RNFL scans commonly show variation in SS as well as the actual RNFL measurement. As of yet, there is no clinically available tool that would allow eye care providers to directly compare RNFL scans from different SS. This study employed the use of diffusion lens filters to artificially decrease SS in an attempt to quantify the relationship between SS and RNFL thickness measurements. Additionally, repeated measures of RNFL thickness at each SS were performed. The goal was to develop a more comprehensive model that could account for both the variability due to changes in SS and the repeated measures variability. 
Methods
This study was approved by the Navy Medical Center, San Diego institutional review board and adhered to the tenets of the Declaration of Helsinki. Healthy adult subjects were recruited through use of fliers posted in public places in the hospital and by word of mouth to patients and employees of the department. All subjects consented to participation in the study after explanation of the nature and possible consequences of the study. All subjects received an ophthalmic examination including an undilated fundus exam. Exclusion criteria included patients with a history of ophthalmic disease of any kind, best-corrected visual acuity worse than 20/20, or evidence of ocular disease or pathology on examination (including but not limited to cataracts, glaucoma, or corneal pathology). 
A single experienced operator used the Cirrus HD 4000-6462 (version 5.1.0.96) OCT to obtain optic disc cube 200 × 200 scans for all measurements. A baseline OCT RNFL scan with a minimum SS of 9 was required to proceed with the study. Five OCT RNFL scans were taken at a SS of 9 or 10 (group A). In between each scan, subjects were asked to sit back for a moment and were then repositioned to obtain another scan. Tiffen Soft FX (Tiffen Company LLC, Hauppauge, NY, USA) diffusion lens filters of successively greater density were placed in between the eye and the OCT machine to artificially decrease the SS to obtain RNFL scans at SS of 7 or 8 (group B), 5 or 6 (group C), and 3 or 4 (group D). Filters with densities of ½, 1, 2, 3, and 4 and Light Loss: 0 f:stop were used. As an example, if a filter with a density of 2 dropped the SS too rapidly, a 1 was used. If a lens density of 1 did not lower the SS enough, a 1 and a ½ density filter were combined so that the appropriate SS could be reached. At least five more scans, with the appropriate filters in place, were obtained for each of SS groups B through D. Again, in between each scan, subjects were asked to sit back for a moment and were then repositioned to obtain another scan. Scans with incomplete imaging, motion artifact, or SS of less than 3 were discarded. The ONH and RNFL Analysis mode was examined to record the SS, the average RNFL thickness (μm), and the quadrant RNFL thickness (μm) measurements. All subjects had both eyes tested. 
Adjustment Equation Analysis
The goal was to develop a statistical model based on a correlation factor that would predict how much change in RNFL thickness measurement to expect based on SS changes between OCT scans. As such, the more subjects included, the stronger would be our correlation. We planned to collect only an adequate sample size for the purposes of this study. We aimed to collect data for approximately 60 eyes. 
The primary goal of this study was to develop a mathematical relationship between RNFL and SS so that if two RNFL readings arise from different SS readings, one RNFL reading can be adjusted to the RNFL it would have been at the SS of the other RNFL reading. In this way, a change in a patient's RNFL over time can be detected even if the two RNFL readings arose from measurements of different SS. 
The steps to accomplish this goal were as follows. (1) Establish the pattern of relationship between RNFL and SS as a mathematical equation. Any useful correction equation would be one of these types: linear, quadratic, cubic, logarithmic, or exponential. Any more complicated function would not be practical for clinical use. (2) Identify which parameters of this equation vary from patient to patient and which remain the same, and obtain estimates of the parameters that remain approximately constant. The equation then expresses the invariant RNFL-to-SS relationship. (3) Establish whether or not substitution of a patient's readings into the equation will allow an RNFL correction for varying SS values, and, if so, provide an algorithm for such a correction with confidence intervals on the corrected RNFL. (4) Illustrate the correction with the observed data. (5) Evaluate the accuracy and reliability of such corrections. 
Repeatability Analysis
The second goal of this study was to report the intravisit variability. The five scans for each eye at each SS, groups A through D, were used to calculate the intravisit variability. Statistical analysis was performed using Stata (version 12; StataCorp., College Station, TX, USA). Interclass correlation coefficient (ICC) and coefficient of variation (CV) parameter estimates were calculated. Intravisit repeatability was calculated as 1.96 × √2 × within-subject standard deviation (Sw),2 where Sw is the square root of the mean of within-subject variance. The repeatability equation implies that a true change could occur in either direction. For glaucoma patients, the only real change that could occur is deterioration. Thus a one-tailed statistical test is more appropriate and is defined as the intravisit upper tolerance limit and is 1.645 × √2 × Sw.1,13 
Results
Thirty subjects were recruited to participate. One was excluded due to findings on exam consistent with glaucoma, and two others were excluded due to inability to obtain a baseline RNFL OCT scan with a SS greater than 9. Fifty-four eyes of 27 subjects were analyzed. 
Adjustment Equation Derivation
The following is a derivation of a mathematical equation that explains the relationship between average RNFL thickness and SS. 
Pattern of Relationship.
Figure 1 shows the distribution of readings of RNFL on SS. Retinal nerve fiber layer appears to increase somewhat with SS, but no further effect is apparent. Testing for components by regression analysis yielded the following P values: degree 1, P < 0.001; degree 2, P = 0.620; degree 3, P = 0.527; logarithmic, P = 0.840; and exponential, P = 0.295. We concluded that only a linear relationship was significant and strong enough to be useful. We are left with an equation of the form    
Figure 1
 
Average RNFL thickness (μm) data for all 54 eyes by signal strength with regression line superposed showing a linear relationship.
Figure 1
 
Average RNFL thickness (μm) data for all 54 eyes by signal strength with regression line superposed showing a linear relationship.
Varying and Invariant Parameters.
We obtained the linear regression lines for each patient and examined the distributions of estimates of a and b. We noted the sources of variability: For any reading, a and b vary; for initial and corrected readings (say, t = 1 and 2) we have a1, b1, and a2, b2, each with its own variability. However, if SS changes, there is a change in RNFL, another source of variability, and the value we have set out to estimate. We found that b is similar throughout different SS values. As evidence, we note the following. The distribution of SS ranged from 3 to 10 in our data. The distribution of slopes was normal (Shapiro-Wilk normality test gives P = 0.144 and the Skewness-Kurtosis test's skewness component P = 0.098). Using the mean and its confidence interval for descriptive statistics, we found that the mean slope, that is, the value of b, was 1.03 with 95% confidence interval of 1.01 to 1.05, clinically negligible. Thus, the change in RNFL from reading 1 to reading 2 occurs primarily in a. Therefore, we base our correction on a revision of equation 1 as    
Making the Correction for RNFL Arising From Different Values of SS.
The subscripts 1 and 2 denote two separate readings. For the first, we read RNFL1 from SS1; and, for the second, we read RNFL2 from SS2. SS2 is different from SS1, so we do not know how much of the difference between RNFL2 and RNFL1 is due to a change in the patient's RNFL and how much to the change in SS. If we find and adjust for what RNFL2 would have been if that reading had arisen from SS1, then the difference would be due solely to a change in the patient's RNFL. Substituting RNFL2 and SS2 in Equation 2 and solving for a2, we find a2 = RNFL2 − 1.03 SS2. Substituting that in the equation for the first reading, we find that the adjusted RNFL (RNFLadj) is    
At this point, the equation allows one to compare two separate readings, but if more scans are performed, which should to be used as the baseline to compare the other results? To answer this question, we created an equation that adjusted all RNFL values to what they would have been at one particular SS. There is some evidence to suggest that OCT scans of high SS might overestimate true RNFL values and SS of low SS might underestimate true RNFL values.10 For this reason, we chose a SS of 7 as our adjustment SS value, which would allow some measurements to be adjusted positively and some negatively (in theory, providers could adjust it to whatever SS they desired, so long as they were consistent). When 7 is substituted for SS1 and the subscript 2 is removed to generalize the equation, we find that the adjustment equation reduces to    
This equation allows one to adjust any RNFL at any SS (≥3) to the RNFL it would have been had the SS been 7 simply by imputing the measured average RNFL and its associated SS. Figure 2 shows the group mean average RNFL measurements by SS and a superimposed adjusted mean average RNFL (using Equation 4) by SS. The adjusted RNFL measurements considerably reduce the variability that SS contributes to average RNFL measurements; that is, the slope of the regression line approaches zero. An example of how the equation works can be seen in Figure 3, which shows the data for a typical eye of one of the study subjects. The RNFL readings to the left of SS = 7 can be seen to increase and those to the right to decrease, so that all are adjusted to what they would have been had SS always been 7. Over the course of 7 SS units, the adjusted regression line varies by approximately 0.3 μm versus the nonadjusted regression line, which varies by 7.5 μm over the course of 7 SS units. 
Figure 2
 
Mean average RNFL thickness (μm) by signal strength. Circles show means for average RNFL data for all eyes. Xs show means for average RNFL thickness after adjustment using Equation 4. The shaded area shows the 95% confidence interval on the adjusted means. The variability in mean average RNFL thickness due to SS is substantially reduced after adjustment with Equation 4 as evidenced by the slope of the regression line approaching zero.
Figure 2
 
Mean average RNFL thickness (μm) by signal strength. Circles show means for average RNFL data for all eyes. Xs show means for average RNFL thickness after adjustment using Equation 4. The shaded area shows the 95% confidence interval on the adjusted means. The variability in mean average RNFL thickness due to SS is substantially reduced after adjustment with Equation 4 as evidenced by the slope of the regression line approaching zero.
Figure 3
 
Original and adjusted average RNFL thicknesses for a typical eye in the data set. The RNFL readings to the left of SS = 7 can be seen to increase and those to the right to decrease, so that all are adjusted to what they would have been had SS been 7 throughout. The end result is reduction in RNFL variability due to SS and a flattening of the slope of the regression line.
Figure 3
 
Original and adjusted average RNFL thicknesses for a typical eye in the data set. The RNFL readings to the left of SS = 7 can be seen to increase and those to the right to decrease, so that all are adjusted to what they would have been had SS been 7 throughout. The end result is reduction in RNFL variability due to SS and a flattening of the slope of the regression line.
Repeatability Analysis
Mean RNFL thickness decreased as SS decreased for average RNFL and in each of the quadrants (Table 1). The ICCs and CVs were good for average RNFL and each of the quadrants for all SS. Variability in repeated RNFL OCT measurements was greatest in the superior and inferior quadrants, with Sw being 5.23 and 5.29 μm, respectively, compared to 2.73 μm for average RNFL and 2.52 and 4.27 μm for the temporal and nasal quadrants, respectively. For average RNFL and each of the quadrants, the variability did not vary substantially as SS decreased. In fact, Sw was lower for SS group D compared to SS group C for all quadrants and group B for three quadrants. The intravisit repeatability and tolerance limit for all measurements were 7.57 and 6.35 μm, respectively (Table 2). After all the RNFL values were adjusted using Equation 4, repeatability and tolerance limit dropped to 5.24 and 4.40 μm, respectively. 
Table 1
 
Intravisit RNFL Means, ICCs, CVs, and Sws Sorted by SS Groups All, A, B, C, and D, Showing Average RNFL and Superior, Temporal, Inferior, and Nasal Quadrant Data
Table 1
 
Intravisit RNFL Means, ICCs, CVs, and Sws Sorted by SS Groups All, A, B, C, and D, Showing Average RNFL and Superior, Temporal, Inferior, and Nasal Quadrant Data
Parameter SS Group Mean, μm ICC, % ICC CIs CV, % Sw, μm
Average RNFL All 93.07 88.6 84.6–92.6 2.93 2.73
A 95.57 97.2 96.1–98.4 1.40 1.34
B 94.17 94.8 92.6–96.9 1.94 1.83
C 91.18 93.5 90.9–96.1 2.11 1.92
D 90.25 95.3 92.8–97.7 1.88 1.70
Superior All 117.72 86.6 82.0–91.2 4.44 5.23
A 121.31 90.2 86.2–94.1 3.55 4.31
B 118.97 89.9 86.0–93.9 3.64 4.33
C 115.21 89.1 85.0–93.3 5.20 4.63
D 114.01 93.4 90.0–96.8 4.33 4.04
Temporal All 63.28 90.3 86.8–93.8 3.98 2.52
A 63.93 89.7 85.5–93.8 3.75 2.40
B 63.80 92.8 89.8–95.7 3.50 2.23
C 62.60 92.2 89.2–95.3 3.61 2.26
D 62.44 93.2 89.7–96.7 3.56 2.22
Inferior All 122.72 84.4 79.2–89.7 4.31 5.29
A 124.84 90.2 86.2–94.1 3.41 4.26
B 124.13 91.8 88.5–95.1 3.13 3.88
C 120.55 82.6 76.4–88.9 4.42 5.33
D 120.39 88.3 82.6–94.0 3.53 4.25
Nasal All 68.53 83.6 78.2–89.1 6.23 4.27
A 72.11 91.9 88.6–95.2 4.41 3.18
B 69.73 88.9 84.6–93.3 4.99 3.48
C 66.35 90.3 86.5–94.1 4.37 2.90
D 64.26 95.1 92.5–97.6 3.41 2.19
Table 2
 
Cirrus HD OCT Intravisit Repeatability Parameters and Tolerance Limit After Adjustment With the Equation RNFLadj = RNFL − 1.03 SS + 7.21 Compared to Nonadjusted Parameter Estimates
Table 2
 
Cirrus HD OCT Intravisit Repeatability Parameters and Tolerance Limit After Adjustment With the Equation RNFLadj = RNFL − 1.03 SS + 7.21 Compared to Nonadjusted Parameter Estimates
SS Group Mean Avg RNFL, μm ICC, % ICC 95% CIs, % CV, % Sw, μm Repeatability, μm Tolerance Limit, μm
All-Adj 93.2 94.1 92.0–96.3 2.03 1.89 5.24 4.40
All 93.1 88.6 84.2–92.6 2.93 2.73 7.57 6.35
A 95.6 97.2 96.1–98.4 1.40 1.34 3.71 3.12
B 94.2 94.8 92.6–96.9 1.94 1.83 5.07 4.26
C 91.2 93.5 90.9–96.1 2.11 1.92 5.32 4.47
D 90.2 95.3 92.8–97.7 1.88 1.70 4.71 3.95
Discussion
Although other studies have independently investigated the relationship between SS and RNFL thickness measurements and the repeatability and reproducibility of the Cirrus HD-OCT, the findings of the current study add to the body of literature by proposing a more comprehensive prediction model that incorporates both concepts. The proposed model would function as follows: 
  1.  
    Apply the formula to RNFL OCT scans that have a SS greater than 3. To determine the adjusted RNFL value, one can use the formula directly or make an approximation by counting how many SS units away from 7 an OCT scan is and then either add, if less than 7, or subtract, if greater than 7, those units to or from the original average RNFL value. This will adjust the average RNFL thickness to what it would have been had the SS been 7. For example, if the original average RNFL thickness was 100 and the SS was 10, the adjusted RNFL value would be 97; and if the original average RNFL thickness was 90 and the SS was 5, the adjusted RNFL thickness would be 92.
  2.  
    For the model to work, it should be applied to all scans with SS from 3 to 10. This allows the practitioner to establish a more level and consistent baseline (Fig. 2).
  3.  
    A decrease in RNFL thickness greater than 5 μm (tolerance limit rounded up from 4.40) below baseline would suggest (with 95% confidence) pathologic loss of RNFL.
The relationship between SS and RNFL thickness has been studied previously, with some consistent results emerging. Cheung et al.9 artificially changed the SS of subjects by defocusing the image using the Stratus OCT and investigated how SS affected RNFL measurements. They showed that the superior, nasal, and average RNFL measurements were positively correlated to changes in SS. They did not, however, quantify the correlation or provide clinically useful recommendations as how to deal with interpreting differences in RNFL when SS is different. Observations by Lee et al.8 began to quantify this relationship. These investigators performed two OCT scans on participants and looked not only at repeatability of the measurement but also at whether SS affected the agreement of the two measurements. They found that if SS was the same, the average RNFL measurement was 2 μm different; it was 3.2 μm different if the difference in SS between the first and second measurement was 2. They did not differentiate between pairs of scans at different SS, making it difficult to interpret the results. Since their study used the time-domain Stratus OCT, their results are not directly comparable to ours. This same research team performed a similar study using the Cirrus OCT and showed that if there was no change in SS, the average RNFL did not change; if SS increased by 1 unit, then the average RNFL increased by 0.9 μm; and if SS increased by 2 units, then average RNFL increased by 1.7 μm.3 As in their previous study using the Stratus, they did not differentiate between pairs of scans at different SS. Even so, their results are comparable to ours, which showed a change between SS and average RNFL thickness of approximately 1 μm RNFL to 1 SS unit. An almost identical relationship was also observed by Kok et al.11 They measured average RNFL thickness using progressively denser reflective attenuation filters to artificially decrease SS in a group of four normal patients. They found that for every 0.1 change in optical density of the filter, there was a 1.07-μm change in average RNFL thickness (where a 0.1 change in optical density equals a 1.0 unit change in SS). 
Although this relationship seems to be relatively repeatable, the one attempt to try to validate this relationship yielded inconclusive results. When Kok et al.11 applied their derived model to a group of patients before and after cataract surgery to predict average RNFL changes due to changes in SS, their prediction was off by 3.71 ± 2.97 μm. They concluded that the predictive nature of their formula was “limited.” That conclusion may be premature for a number of reasons; and the relationship between RNFL and SS that they found, and that we confirmed, may still have predictive value. First, as they suggest in their discussion, RNFL thickness is affected by cataract surgery, likely via inflammatory mediators causing increased retinal vascular permeability and leakage. It has been shown that the average RNFL thickness 4 weeks following cataract surgery is approximately 4 μm greater than preoperative measurements14 and that thickening could potentially remain for up to 3 months following surgery.15 This transient thickening of the RNFL could account completely for the difference in their measured and predicted RNFL. Second, they cite that interindividual slopes between SS and average RNFL vary too much to be useful. That conclusion may be inaccurate, as it was based on a small sample size as well as an unstable testing environment, as noted above. In our sample of 54 eyes, we found the variability in the mean slope of a population to be very low (i.e., a mean of 1.03 and a 95% CI of 1.01–1.05). The interindividual variability was accounted for in the upper tolerance limit of 4.40 μm, which not only describes the variability due to repeated measures but also captures the individual variability between SS and RNFL. In our model, although individual slopes may not exactly match the group mean, the upper tolerance limit provides a means of accounting for this variability. Third, Kok et al.11 do not consider the confounding factor of repeated measures as a reason for the “limited” predictive value of their equation. Ours and other studies have shown that their “misprediction” could result almost entirely from test–retest variability (see more on this in the discussion below). Lastly, Kok et al.11 conclude that their derived relationship seems to hold only in the artificial environment of measuring RNFL with optical filters and did not persist in a real-life situation. Contrary to this line of reasoning, the same relationship between SS and RNFL was seen in the Kim et al.3 study, and their study included both glaucomatous patients and normals. It would be worthwhile to validate this relationship in a different setting, that is, a retrospective or prospective study of glaucoma and/or glaucoma suspect patients. 
Although not specifically looking at the relationship between SS and RNFL, others have attempted to develop a mechanism to account for the changes in OCT readings due to SS. Tappeiner et al.12 placed progressively denser neutral density filters between normal patients and the Stratus OCT machine to develop a mathematical correction formula to improve OCT imaging of the macula. By analyzing reflectivity peaks of the macula, they were able to develop a correction equation for diffusion filter–induced degradation in SS quality. Unfortunately, this complicated correction formula has not been validated outside of an artificially reduced SS condition, is not a part of the current OCT software, and is not commercially available, making it of little clinical value at this time. 
After applying our derived adjustment Equation 4 to all RNFL OCT scans, even down to SS of 3 or 4, we found a tolerance limit of 4.40 μm. This is consistent with previous reliability studies that have shown test–retest reliability to be between 4 and 5 μm.13 Notably, research using the Cirrus OCT looking at test–retest reliability have limited their samples to patients with SS greater than 5,3 greater than 6,1 or greater than 7.2,16 This is due, in part to the manufacturer's recommendation not to use scans with SS less than 5. The current study, however, demonstrated adequate ICCs, CVs, and Sws for SS even as low as 3 or 4 (Table 2), and it showed that the intravisit tolerance limit varied from 3.12 to 4.47 depending on the SS. A few others have suggested that RNFL measurements of lower SS may actually be acceptable. Ha et al.5 found that the lower limit of acceptable SS in the Stratus OCT was 4. In another study using the Stratus OCT, Wu et al.7 showed that in patients with an average SS of 4.3, there was only an average of a 5-μm difference between two separate readings. That 5-μm difference is similar to previously reported repeatability testing results for the Stratus.13 
In this study, the present authors report ICCs, CVs, Sws, repeatability, and tolerance limits for the average RNFL and the four quadrants but do not report the data for individual clock hours. Previous studies have already shown that reproducibility is the best for the average RNFL measurement,1,2 thus making it the most clinically relevant measure to follow. For that reason, the authors focused the current research on the average RNFL and included the quadrant data as a quality control measure to be verified for agreement with previous work on the Cirrus HD-OCT. Indeed, the current study, as well as those by both Mwanza et al.1 and Leung et al.,2 found the least variability in the average RNFL and temporal quadrant measurements; the nasal and inferior quadrant measurements showed the most variability. Kim et al.3 and Cremasco et al.16 also showed average RNFL to be the least variable, but found different patterns of variability in the quadrant RNFL measurements. 
There are a few notable limitations in this study. First, the model that the authors propose has not been validated. The current study was geared to be a preliminary study to produce the model. Validating the model would require following RNFLs of glaucoma and/or glaucoma suspect patients over time (prospectively or retrospectively) and seeing if the model predicts worsening glaucoma or development of glaucoma. Second, the results of this study should be taken with caution when one is trying to compare them to studies that investigated intervisit reproducibility (scans taken at different visits separated in time), as our study measured only intravisit repeatability (scans taken during the same visit). That being said, the difference between intervisit reproducibility and intravisit repeatability has been shown to be very small for average RNFL thickness,1,2 and not clinically significant. Third, our study included only healthy nonglaucomatous eyes. Since the main intent was to determine how varying the SS changes the RNFL thickness, we chose to include only healthy eyes so that every subject would be able to have a baseline SS of 9 or 10. The design of the study required normal subjects so that the authors could reproducibly decrease SS using diffusion filters. This may not have been possible had other media opacities or optic nerve abnormalities been present. This is an important point, as it is debatable whether the relationship between SS and RNFL thickness is the same in glaucoma and normal patients.3,17 Vermeer et al.17 found significant differences between the SS of glaucoma and normal patients, suggesting that glaucoma somehow directly affects the SS parameter on the OCT machine. On the other hand, Kim et al.3 found in their multivariate analysis that the presence of glaucoma was not associated with interscan SS differences, suggesting that there is a similar relationship between RNFL and SS for both glaucoma and nonglaucomatous patients. If it is determined that this relationship is different between glaucoma and normal patients, the model that we propose may potentially be better suited for the monitoring of glaucoma suspect patients until they actually develop glaucoma. 
In conclusion, the present authors have developed a comprehensive model that accounts for changes in RNFL thickness due to SS as well as differences due to test–retest variability. The model needs to be validated in a follow-up study on glaucoma and glaucoma suspect patients. If it is validated, eye care professionals could be more confident in following glaucoma and glaucoma suspect patients using RNFL scans with SS as low as 3 or 4, knowing that if a change of greater than 5 μm is realized, there is a 95% likelihood that that change represents a real change and possible glaucomatous progression. 
Acknowledgments
The views expressed herein are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the US government. 
Disclosure: D.J. Russell, None; S. Fallah, None; C.J. Loer, None; R.H. Riffenburgh, None 
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Figure 1
 
Average RNFL thickness (μm) data for all 54 eyes by signal strength with regression line superposed showing a linear relationship.
Figure 1
 
Average RNFL thickness (μm) data for all 54 eyes by signal strength with regression line superposed showing a linear relationship.
Figure 2
 
Mean average RNFL thickness (μm) by signal strength. Circles show means for average RNFL data for all eyes. Xs show means for average RNFL thickness after adjustment using Equation 4. The shaded area shows the 95% confidence interval on the adjusted means. The variability in mean average RNFL thickness due to SS is substantially reduced after adjustment with Equation 4 as evidenced by the slope of the regression line approaching zero.
Figure 2
 
Mean average RNFL thickness (μm) by signal strength. Circles show means for average RNFL data for all eyes. Xs show means for average RNFL thickness after adjustment using Equation 4. The shaded area shows the 95% confidence interval on the adjusted means. The variability in mean average RNFL thickness due to SS is substantially reduced after adjustment with Equation 4 as evidenced by the slope of the regression line approaching zero.
Figure 3
 
Original and adjusted average RNFL thicknesses for a typical eye in the data set. The RNFL readings to the left of SS = 7 can be seen to increase and those to the right to decrease, so that all are adjusted to what they would have been had SS been 7 throughout. The end result is reduction in RNFL variability due to SS and a flattening of the slope of the regression line.
Figure 3
 
Original and adjusted average RNFL thicknesses for a typical eye in the data set. The RNFL readings to the left of SS = 7 can be seen to increase and those to the right to decrease, so that all are adjusted to what they would have been had SS been 7 throughout. The end result is reduction in RNFL variability due to SS and a flattening of the slope of the regression line.
Table 1
 
Intravisit RNFL Means, ICCs, CVs, and Sws Sorted by SS Groups All, A, B, C, and D, Showing Average RNFL and Superior, Temporal, Inferior, and Nasal Quadrant Data
Table 1
 
Intravisit RNFL Means, ICCs, CVs, and Sws Sorted by SS Groups All, A, B, C, and D, Showing Average RNFL and Superior, Temporal, Inferior, and Nasal Quadrant Data
Parameter SS Group Mean, μm ICC, % ICC CIs CV, % Sw, μm
Average RNFL All 93.07 88.6 84.6–92.6 2.93 2.73
A 95.57 97.2 96.1–98.4 1.40 1.34
B 94.17 94.8 92.6–96.9 1.94 1.83
C 91.18 93.5 90.9–96.1 2.11 1.92
D 90.25 95.3 92.8–97.7 1.88 1.70
Superior All 117.72 86.6 82.0–91.2 4.44 5.23
A 121.31 90.2 86.2–94.1 3.55 4.31
B 118.97 89.9 86.0–93.9 3.64 4.33
C 115.21 89.1 85.0–93.3 5.20 4.63
D 114.01 93.4 90.0–96.8 4.33 4.04
Temporal All 63.28 90.3 86.8–93.8 3.98 2.52
A 63.93 89.7 85.5–93.8 3.75 2.40
B 63.80 92.8 89.8–95.7 3.50 2.23
C 62.60 92.2 89.2–95.3 3.61 2.26
D 62.44 93.2 89.7–96.7 3.56 2.22
Inferior All 122.72 84.4 79.2–89.7 4.31 5.29
A 124.84 90.2 86.2–94.1 3.41 4.26
B 124.13 91.8 88.5–95.1 3.13 3.88
C 120.55 82.6 76.4–88.9 4.42 5.33
D 120.39 88.3 82.6–94.0 3.53 4.25
Nasal All 68.53 83.6 78.2–89.1 6.23 4.27
A 72.11 91.9 88.6–95.2 4.41 3.18
B 69.73 88.9 84.6–93.3 4.99 3.48
C 66.35 90.3 86.5–94.1 4.37 2.90
D 64.26 95.1 92.5–97.6 3.41 2.19
Table 2
 
Cirrus HD OCT Intravisit Repeatability Parameters and Tolerance Limit After Adjustment With the Equation RNFLadj = RNFL − 1.03 SS + 7.21 Compared to Nonadjusted Parameter Estimates
Table 2
 
Cirrus HD OCT Intravisit Repeatability Parameters and Tolerance Limit After Adjustment With the Equation RNFLadj = RNFL − 1.03 SS + 7.21 Compared to Nonadjusted Parameter Estimates
SS Group Mean Avg RNFL, μm ICC, % ICC 95% CIs, % CV, % Sw, μm Repeatability, μm Tolerance Limit, μm
All-Adj 93.2 94.1 92.0–96.3 2.03 1.89 5.24 4.40
All 93.1 88.6 84.2–92.6 2.93 2.73 7.57 6.35
A 95.6 97.2 96.1–98.4 1.40 1.34 3.71 3.12
B 94.2 94.8 92.6–96.9 1.94 1.83 5.07 4.26
C 91.2 93.5 90.9–96.1 2.11 1.92 5.32 4.47
D 90.2 95.3 92.8–97.7 1.88 1.70 4.71 3.95
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