Abstract
purpose. To compare the diagnostic accuracy of the Matrix frequency-doubling technology (FDT) 24-2, first-generation FDT N-30 (FDT N-30), and standard automated perimetry (SAP) tests of visual function.
methods. One eye of each of 85 glaucoma patients and 81 healthy controls from the Diagnostic Innovations in Glaucoma Study was included. Evidence of glaucomatous optic neuropathy on stereophotographs was used to classify the eyes. Matrix FDT 24-2, first-generation FDT N-30, and SAP-SITA 24-2 tests were performed on all participants within 3 months. Receiver operating characteristic (ROC) curves were generated and used to determine sensitivity levels at 80% and 90% specificity for mean deviation (MD), pattern standard deviation (PSD), number of total deviation (TD), and pattern deviation (PD) points triggered at less than 5% and 1%. The tests were compared using the best parameter for each test (that with the highest area under the ROC curve) and with the PSD.
results. The best parameters were MD for SAP (0.680), PSD for FDT N-30 (0.733), and number of TD less than 5% points for FDT 24-2 (0.774). Using the best parameter, the area under the ROC curve was significantly larger for FDT 24-2 than for SAP (P = 0.01). No statistically significant differences were observed between SAP and FDT N-30 (P = 0.21) and FDT N-30 and FDT 24-2 (P = 0.26). Similar results were obtained when the PSD was used to compare the tests, with the exception that the area under the ROC curve for the FDT N-30 test (0.733) was significantly larger than that of the SAP-SITA (0.641; P = 0.03).
conclusions. The performance of the Matrix FDT 24-2 was similar to that of the first-generation FDT N-30. The Matrix FDT 24-2 test was consistently better than SAP at discriminating between healthy and glaucomatous eyes. Further studies are needed to evaluate the ability of the Matrix FDT 24-2 to monitor glaucoma progression.
Frequency-doubling technology (FDT) perimetry measures contrast sensitivity. Although participants are not asked to assess the spatial frequency of the FDT stimuli, the test is based on the frequency-doubling illusion first described by Kelly
1 and later proposed as a sensitive measure of glaucomatous visual field loss.
2 3 This illusion occurs when a sinusoidal grating of low spatial frequency undergoes counterphase flickering at a high temporal frequency. Under these conditions, the sinusoidal grating is perceived to have twice its physical spatial frequency. It was originally believed that the FDT test isolates the spatially nonlinear M
y cells,
2 4 a subset of the magnocellular retinal ganglion cells. However, more recent evidence suggests that the magnocellular pathway is isolated as a whole by the FDT stimulus.
5 6 This isolation reduces redundancy within the visual system and is responsible for the greater sensitivity to glaucoma achieved by function-specific tests.
7 Several reports suggest that FDT perimetry in both the screening
8 9 10 11 and the thresholding
12 modes is sensitive to glaucomatous visual losses. Medeiros et al.
13 showed that FDT is also able to predict future visual loss on standard automated perimetry (SAP). Furthermore, the variability of FDT is independent of visual field loss,
14 and its test-retest variability is more uniform than that of SAP over the dynamic range of the instrument.
15 16
The proliferation of new tests and instruments to assess vision requires frequent reevaluations, comparing each new test with its precursors and with other tests. Frequency-doubling technology is a useful clinical tool that sensitively detects glaucoma and is robust to blur, pupil size, and refractive errors.
17 The FDT instrument is also relatively inexpensive and easy to transport. Although several studies have reported better diagnostic accuracy for FDT than for SAP, most were performed using the first-generation FDT perimeter.
18 19 The original FDT perimeter allowed testing of the central 30° of the visual field with screening and thresholding strategies. Targets were relatively large, and a maximum of 19 locations could be tested. Johnson et al.
20 showed that the sensitivity of FDT to glaucomatous loss was maintained using smaller targets distributed in a pattern similar to that of the SAP 24-2 test. The Humphrey Matrix was commercially introduced in 2003, offering the following tests: macula, 10-2; N-30-F, 24-2 and 30-2. The Glaucoma Hemifield Test (GHT) is available for the FDT 24-2 and 30-2 tests. The purpose of the present study was to compare the ability of the Matrix FDT 24-2, first-generation FDT N-30, and SAP-SITA 24-2 tests to discriminate between healthy and glaucoma eyes.
Participants underwent complete ophthalmologic examinations, including slit lamp biomicroscopy, intraocular pressure measurement, and dilated stereoscopic fundus examination. Simultaneous stereoscopic photographs with good clarity and stereopsis were obtained for all participants. At study entry, all participants had open angles, best-corrected acuity of 20/40 or better, spherical refraction within ±5.0 diopters (D), and cylinder correction within ±3.0 D. A family history of glaucoma was allowed.
Participants were excluded if they had a history of intraocular surgery except for uncomplicated cataract or glaucoma surgery. We also excluded all participants with secondary causes of elevated IOP (e.g., iridocyclitis, trauma), other intraocular eye disease, other diseases affecting the visual field (e.g., pituitary lesions, demyelinating diseases, HIV or AIDS, or diabetic retinopathy), those taking medications known to affect visual field sensitivity, and those with problems other than glaucoma that affected color vision.
Healthy Controls.
Glaucoma Patients.
The appearance of the optic disc of each participant was assessed with simultaneous stereophotographs (TRC-SS; Topcon, Paramus, NJ). Stereoscopic sets of slides were examined using a stereoscopic viewer (Asahi; Pentax, Golden, CO) by two trained graders who determined whether the optic disc appeared to be normal or glaucomatous. The graders were masked to the identity of the participants and to the assessment of the other grader. When the two graders disagreed, a third experienced grader served as an adjudicator.
Standard Automated Perimetry.
FDT N-30.
FDT 24-2.
Table 3shows the area under the ROC curves for each parameter of each test, the SE associated with the area under the ROC curves, the sensitivities at set specificities of approximately 80% and 90%, and the criteria that yielded these values. The statistical power to detect a difference of 0.1 between the areas under the ROC curves was 0.80. Within each test, no statistically significant differences were observed between any of the parameters.
The best parameter (that with the highest area under the ROC curve) was MD for SAP (area under the ROC curve, 0.680), PSD for FDT N-30 (area under the ROC curve, 0.733), and the number of TD points triggered at less than 5% for FDT 24-2 (area under the ROC curve, 0.774). The ROC curves for the best parameter of each test are presented in
Figure 3 . A statistical comparison of the areas under the ROC curves for the best parameter of each test was performed and shows a significant difference between SAP and FDT 24-2 (
P = 0.01; 95% CI, 0.02 to 0.17). No significant differences were observed between the areas under the ROC curves for the best parameters of SAP and FDT N-30 (
P = 0.21; 95% CI, −0.03 to 0.14) and between FDT N-30 and FDT 24-2 (
P = 0.26; 95% CI, −0.03 to 0.11). At a set specificity of 80%, the sensitivity associated with the best parameter of each test was 46% for SAP, 56% for FDT N-30, and 60% for FDT 24-2. At a set specificity of 90%, sensitivity was 38% for SAP, 40% for FDT N-30, and 44% for FDT 24-2.
Using the PSD to compare all tests, we obtained areas under the ROC curve of 0.641 for SAP, 0.733 for FDT N-30, and 0.755 for the FDT 24-2 test. Significant differences were observed between the areas under the ROC curves of SAP and FDT 24-2 (P = 0.002; 95% CI, −0.19 to −0.04) and between SAP and FDT N-30 (P = 0.03; 95% CI, −0.17 to −0.01). The difference between FDT N-30 and FDT 24-2 (P = 0.51; 95% CI, −0.09 to 0.04) was not significant.
Figure 4shows the relationship between the mean deviation (
R 2 = 0.76; slope = 0.63) and pattern standard deviation (
R 2 = 0.78; slope = 1.14) of the FDT N-30 and FDT 24-2. Scatter plots, similar to those reported by Brusini et al.,
26 showing the relationship between the MD and PSD values for the glaucoma patients (
n = 85) for SAP-SITA, FDT N-30, and FDT 24-2 are presented in
Figure 5 . The agreement between the three tests in classifying the glaucoma eyes (
n = 85) is presented in the Venn diagram shown in
Figure 6 . This figure is based on the criteria for the best parameter of each test at 80% specificity.
Table 4presents the kappa statistic and the strength of agreement between each test combination using the best parameter and the PSD for the glaucoma group (
n = 85). Fair agreement was found between the participant classification based on the stereophotographs and the Glaucoma Hemifield Test (GHT) for both the FDT 24-2 (kappa = 0.364) and SAP (kappa = 0.237) (
n = 166).
A histogram depicting the distribution of test durations for each test is presented in
Figure 7 . An analysis of variance (ANOVA) and Tukey post hoc test show a significant difference in test duration between the three tests (
P < 0.001), with the FDT N-30 (272 ± 21 seconds) taking on average less time to perform than both SAP-SITA (318 ± 54 seconds) and FDT 24-2 (315 ± 14 seconds). No difference in mean test duration was observed between SAP-SITA and FDT 24-2.
With only a few reports available in the literature, there is no consensus on whether the Matrix FDT 24-2 test is more sensitive to glaucoma than SAP-SITA. Our results suggest that the FDT 24-2 is better able to discriminate between healthy and glaucomatous eyes than SAP-SITA, a finding consistent with the results reported by Brusini et al.,
27 Leeprechanon et al.,
28 and Medeiros et al.
29 Two other studies, however, have reported similar performance between the FDT 24-2 and SAP.
30 31 A direct comparison between our results and those reported by Spry et al.
30 is complicated by their inclusion of patients with several types of glaucoma (pseudoexfoliation, primary open-angle glaucoma, normal tension), patients with ocular hypertension, and glaucoma suspects and by their use of the SITA-Fast strategy for SAP. Selection bias is likely responsible for the finding reported by Patel et al.
31 that the FDT 24-2 failed to detect 36% of abnormal SAP-SITA test results in their sample because only patients with abnormal results on SAP-SITA were included.
The best parameter for each test in this study was selected because it produced the highest area under the ROC curve. From a clinical perspective, however, the usefulness of the pattern standard deviation for early detection of glaucomatous visual field loss is solidly established.
32 33 Given that no significant differences were found between the best parameter for each test and all other parameters, we also compared the tests using the PSD. Similar to when the best parameter was used, the FDT 24-2 performed significantly better than SAP, and no difference was observed between the FDT 24-2 and FDT N-30 tests. The comparison between the SAP and FDT N-30 tests, however, differed depending on which parameter was used to compare the tests. When the best parameter for each test was used, no difference was observed between the two tests. Consistent with previous reports,
19 33 however, significantly better performance was observed for the FDT N-30 test compared to SAP-SITA when the PSD was used to compare the tests. Better agreement between the tests was also observed when the PSD was used to compare the tests.
Differences were observed in the relationship between the mean deviation and pattern standard deviation within each test for patients with glaucoma
(Fig. 5) . A much tighter distribution was observed for SAP compared with the FDT N-30 and FDT 24-2 tests. SAP tended to cluster patients with glaucomatous optic neuropathy within the normal range of MD and PSD values, and this may explain the poorer ability of SAP to discriminate between healthy and glaucomatous eyes. Patients were more evenly distributed along the severity continuum for both FDT tests, resulting in better diagnostic accuracy.
We did not find any difference between the performance of the FDT 24-2 and FDT N-30 tests in discriminating between healthy and glaucomatous eyes. When plotting the mean deviations for the FDT N-30 and FDT 24-2 tests against each other, however, the slope (0.63) was not equal to 1, as might have been expected. A 1-unit reduction in the MD of the FDT N-30 test resulted in a greater decrease in the MD of the FDT 24-2 MD test. This is likely because of the eccentricity and the smaller size of the stimulus used in the FDT 24-2 test, consistent with reports showing a reduction in sensitivity with increasing eccentricity when smaller stimuli are used.
20 34
The level of agreement observed between the tests could be better interpreted if we knew the level of agreement achieved when the same test is performed twice. Although no study has directly compared the intertest and intratest agreement within the same cohort, the Ocular Hypertension Treatment Study has shown that normal visual field test results can occur in patients who previously had two and even three abnormal visual field results.
35 This highlights the considerable variability associated with current perimetric techniques. The Venn diagram presented in
Figure 6shows that though 28 patients were classified with an abnormality by all three tests, 19 were classified with normal results by all three tests. It is possible that these 19 patients experienced detectable structural changes before any evidence of visual loss showed. It is also possible that some participants were misclassified by the criteria used in this study (i.e., evidence of glaucomatous optic neuropathy on stereophotographs). Ideally, we would have classified our participants based on a more definitive diagnosis, such as evidence of progressive glaucomatous optic neuropathy.
36 Unfortunately, this information was not available for all the participants included in this study.
Important strengths of the present study include the comparison of the three visual field tests in the same sample and the use of a classification criterion (glaucomatous optic neuropathy on stereophotographs) independent of visual function. A fair comparison of the three visual function tests, which use different stimuli and assess different visual pathways, was achieved by setting their respective specificity at equal levels with the use of the ROC analysis. In conclusion, the results of the present study suggest that the Matrix FDT 24-2 and FDT N-30 tests are better able than SAP-SITA to discriminate between healthy and glaucomatous eyes. No differences were observed between the Matrix FDT 24-2 and the FDT N-30 tests. Future studies are needed to determine whether the Matrix FDT 24-2 will be useful to monitor glaucoma progression.
Supported by National Eye Institute Grants EY 08208 (PAS) and EY 11008 (LMZ). Participant retention incentive grants in the form of glaucoma medication at no cost: Alcon Laboratories Inc, Allergan, Pfizer Inc, and Santen Inc.
Submitted for publication April 23, 2007; revised July 12 and November 11, 2007; accepted January 16, 2008.
Disclosure:
L. Racette, None;
F.A. Medeiros, Carl Zeiss Meditec (F, R), Heidelberg Engineering (R);
L.M. Zangwill, Carl Zeiss Meditec (F), Heidelberg Engineering (F, R);
D. Ng, None;
R.N. Weinreb, Carl Zeiss Meditec (F, R), Heidelberg Engineering (F, R);
P.A. Sample, Carl Zeiss Meditec (F), Haag-Streit (F), Heidelberg Engineering (F), Welch-Allyn (F)
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “
advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Corresponding author: Lyne Racette, Hamilton Glaucoma Center, Department of Ophthalmology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0946;
[email protected].
Table 1. Percentages of Fixation Losses, False-Positive, and False-Negative Errors for the SAP, FDT N-30, and FDT 24-2 Tests
Table 1. Percentages of Fixation Losses, False-Positive, and False-Negative Errors for the SAP, FDT N-30, and FDT 24-2 Tests
| Fixation Losses | False-Positive Errors | False-Negative Errors |
SAP-SITA | 5.77 ± 7.01 | 1.98 ± 2.57 | 0.81 ± 8.36 |
FDT N-30 | 2.71 ± 7.41 | 1.88 ± 4.89 | 1.81 ± 8.76 |
FDT 24-2 | 4.76 ± 6.67 | 2.65 ± 5.43 | 2.01 ± 7.29 |
Table 2. Descriptive Measures for Each Study Group
Table 2. Descriptive Measures for Each Study Group
| Controls (n = 81) | Glaucoma (n = 85) | P |
Age, mean ± SD (years) | 59.0 ± 10.7 | 61.2 ± 12.2 | 0.22 |
Eye (% right eye) | 54.3 | 51.8 | 0.74 |
Sex (% male) | 33.3 | 52.9 | 0.03 |
Cataract extraction before study (%) | 3 (3.7) | 15 (17.7) | 0.003 |
SAP MD, mean ± SD (dB) | −0.96 ± 1.51 | −3.82 ± 6.12 | <0.001 |
SAP MD, range (dB) | −5.98–1.50 | −30.63–1.19 | — |
SAP PSD, mean ± SD (dB) | 1.84 ± 0.82 | 3.82 ± 3.75 | <0.001 |
SAP PSD, range (dB) | 1.05–6.93 | 1.02–16.11 | — |
Table 3. Area under the Receiver Operating Characteristic Curve and Associated SE Are Presented for Each Parameter for Each Test (N = 166)
Table 3. Area under the Receiver Operating Characteristic Curve and Associated SE Are Presented for Each Parameter for Each Test (N = 166)
| AUC | SE | Sensitivity/Specificity (%) | Criteria for 80% Specificity | Sensitivity/Specificity (%) | Criteria for 90% Specificity |
SAP-SITA | | | | | | |
MD | 0.680 | 0.041 | 46/80 | −1.98 | 38/90 | −2.49 |
PSD | 0.641 | 0.043 | 45/80 | 2.10 | 30/90 | 2.28 |
TD <5% | 0.668 | 0.042 | 46/81 | 13 | 27/91 | 20 |
TD <1% | 0.640 | 0.043 | 49/83 | 3 | 33/90 | 6 |
PD <5% | 0.645 | 0.043 | 51/79 | 9 | 31/90 | 13 |
PD <1% | 0.622 | 0.011 | 45/83 | 3 | 33/89 | 4 |
FDT N-30 | | | | | | |
MD | 0.660 | 0.042 | 44/80 | −3.75 | 33/90 | −4.74 |
PSD | 0.733 | 0.038 | 56/80 | 4.91 | 40/90 | 5.72 |
TD <5% | 0.662 | 0.042 | 44/79 | 9 | 24/91 | 13 |
TD <1% | 0.689 | 0.041 | 54/78 | 2 | 40/90 | 4 |
PD <5% | 0.728 | 0.039 | 59/79 | 5 | 47/89 | 7 |
PD <1% | 0.690 | 0.041 | 56/73 | 1 | 42/90 | 2 |
FDT 24-2 | | | | | | |
MD | 0.763 | 0.037 | 55/80 | −3.69 | 45/89 | −5.09 |
PSD | 0.755 | 0.037 | 56/80 | 3.39 | 38/90 | 4.07 |
TD <5% | 0.774 | 0.036 | 60/78 | 9 | 44/90 | 19 |
TD <1% | 0.761 | 0.037 | 64/78 | 2 | 46/90 | 6 |
PD <5% | 0.731 | 0.038 | 52/80 | 8 | 44/90 | 12 |
PD <1% | 0.756 | 0.037 | 62/75 | 3 | 47/90 | 5 |
Table 4. Agreement between Each Test Combination (Kappa Statistic and Strength of Agreement) for the Glaucoma Patients (n = 85) Using the Best Parameter for Each Test and the PSD Criteria
Table 4. Agreement between Each Test Combination (Kappa Statistic and Strength of Agreement) for the Glaucoma Patients (n = 85) Using the Best Parameter for Each Test and the PSD Criteria
| | Kappa Statistic | Strength of Agreement |
Best parameter | SAP and FDT 24-2 | 0.444 | Moderate |
| SAP and FDT N-30 | 0.371 | Fair |
| FDT 24-2 and FDT N-30 | 0.396 | Fair |
PSD | SAP and FDT 24-2 | 0.628 | Substantial |
| SAP and FDT N-30 | 0.489 | Moderate |
| FDT 24-2 and FDT N-30 | 0.617 | Substantial |
The authors thank Madhusudhanan Balasubramanian for assistance with graphics and Chris A. Johnson for helpful comments during the revision process.
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