February 2012
Volume 53, Issue 2
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Cornea  |   February 2012
Progression of Keratoconus by Longitudinal Assessment with Corneal Topography
Author Affiliations & Notes
  • Jin A Choi
    From Department of Ophthalmology, St. Vincent's Hospital, and
  • Man-Soo Kim
    Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of Medicine, Catholic University of Korea, Seoul, Korea.
  • Corresponding author: Man-Soo Kim, Department of Ophthalmology and Visual Science, Seoul St. Mary's, Hospital, College of Medicine, Catholic University of Korea, 505 Banpo-dong, Seocho-ku, Seoul, 137–701, Korea; mskim@catholic.ac.kr
Investigative Ophthalmology & Visual Science February 2012, Vol.53, 927-935. doi:10.1167/iovs.11-8118
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      Jin A Choi, Man-Soo Kim; Progression of Keratoconus by Longitudinal Assessment with Corneal Topography. Invest. Ophthalmol. Vis. Sci. 2012;53(2):927-935. doi: 10.1167/iovs.11-8118.

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

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Abstract

Purpose.: To investigate the longitudinal changes in corneal topographic indices over time in patients with mild keratoconus (KC) and to determine predictive factors for the increase in corneal curvature.

Methods.: The authors retrospectively reviewed the data of 94 eyes of patients with mild KC who had undergone computerized videokeratography (Orbscan IIz; Bausch & Lomb Surgical, Rochester, NY) at least twice at an interval of ≥1 year. Patients with an increase of ≥1.50 diopters (D) in the central keratometry (K) were placed in the progression group, and the others were placed in the nonprogression group. In each group, the quantitative topographic parameters were compared and tested as predictive factors for KC progression. Additionally, corneal astigmatic changes were evaluated by means of vector analysis.

Results.: In total, 94 eyes of 85 patients were included. Twenty-five of 94 (26.5%) eyes showed progression of the central K ≥1.50 D; progression took 3.5 years on average. Median time to progression by Kaplan-Meier analysis was 12 years. Significant predictors for KC progression were as follows: highest point on the anterior elevation from the anterior best-fit sphere (BFS), ≥0.04 mm; irregularity index at 3 mm, ≥6.5 D; irregularity index at 5 mm, ≥6.0 D; thinnest pachymetry, <350 μm at baseline examination; yearly change rate of anterior BFS, ≥0.1 D/y; central K, ≥0.1 D/y; simulated K in maximum, ≥0.15 D/y; simulated K in minimum, ≥0.2 D/y; and anterior chamber depth, ≥0.0 mm/y. The dominant with-the-rule pattern of astigmatism at the baseline examination was changed to an oblique pattern of astigmatism at the last examination.

Conclusions.: Mild KC tended to be progressive in approximately 25% of patients, and progression lasted 3.5 years on average. Longitudinal changes in the corneal topography quantitative indices can be used as predictors of KC progression.

Keratoconus (KC) is a progressive disorder in which the cornea assumes a conical shape as a result of noninflammatory thinning and protrusion. This corneal thinning induces irregular astigmatism, myopia, and protrusion, which leads to mild to marked impairment in vision quality. 1 KC becomes manifested during the second decade of life and during puberty, 1 and it progresses over 10 to 20 years until the progression gradually stops. 2,3 The severity of the disorder at the time when the progression stops can range from very mild irregular astigmatism to severe thinning, protrusion, and scarring that requires keratoplasty. 4 The major concern of patients is how much deterioration the disease causes in the years after diagnosis. 
Other than studies on the classification of KC by severity, 3,5 several studies have been conducted regarding the natural course of KC. However, most of these studies dealt with advanced cases of KC in which penetrating keratoplasty was required, 6,7 or they considered the natural course of suspected KC. 8 10 Few data are available regarding the natural history of clinical KC without intervention. Thus, information regarding the natural course of KC and its progression would be helpful to clinicians for guiding patients with KC after the diagnosis is made. 
Computer-assisted corneal topography devices have become indispensable for diagnosing subclinical/clinical KC and for evaluating disease progression. 4 Because KC progresses, contour and thickness measurements by corneal topography taken over time can help track the disease course. 
In the present study, we investigated the longitudinal changes in corneal topographic indices over time and particularly focused on corneal curvature in patients with mild KC. We also determined the characteristics of the patients who showed progression of corneal curvature and identified the topographic parameters associated with disease progression. 
Materials and Methods
Study Samples
The subjects of this retrospective study included patients with mild KC of grade I or II by the Amsler-Krumeich classification 11,12 (Table 1) and who were seen at Seoul St. Mary's Hospital, Seoul, Korea. A strict definition of KC 13 15 was used to exclude patients with irregular corneal astigmatism resulting from other nonkeratoconic causes. Patients had to be 12 years of age or older; have an irregular cornea determined by distortion of the keratometric mires, the retinoscopic reflex, and/or the “red” reflex on direct ophthalmoscopy; and have one of the following biomicroscopic signs in at least one eye: Vogt's striae, Fleischer's ring with at least a 2-mm arc, corneal scarring consistent with KC. 
Table 1.
 
Amsler-Krumeich Classification for Grading Keratoconus
Table 1.
 
Amsler-Krumeich Classification for Grading Keratoconus
Stage 1
Eccentric steepening
Myopia, induced astigmatism, or both <5.00 D
Mean central K readings <48.00 D
Stage 2
Myopia, induced astigmatism, or both from 5.00 to 8.00 D
Mean central K readings <53.00 D
Absence of scarring
Minimum corneal thickness >400 μm
Stage 3
Myopia, induced astigmatism, or both from 8.00 to 10.00 D
Mean central K readings >53.00 D
Absence of scarring
Minimum corneal thickness 300 to 400 μm
Stage 4
Refraction not measurable
Mean central K readings >55.00 D
Central corneal scarring
Minimum corneal thickness 200 μm
In total, 201 clinical records were reviewed. Eyes with advanced grade III KC or more by the Amsler-Krumeich classification (keratometric astigmatism >8.00 diopters [D], mean central K reading >53.00 D, central corneal scarring, or minimum corneal thickness <400 μm) were excluded. Patients who did not undergo at least two videokeratography examinations with an interval of 1 year or longer between each examination were excluded. Ninety-four eyes from 85 patients met the criteria and were finally included in the study. This study was approved by the institutional review board of Seoul St. Mary's Hospital and was conducted in adherence to the tenets of the Declaration of Helsinki. 
Corneal Topography Assessment
Videokeratographic data were obtained by computerized videokeratography (Orbscan IIz; Bausch & Lomb Surgical, Rochester, NY), which is a three-dimensional slit-scanning topography system that is used to analyze the corneal anterior and posterior surfaces and for performing pachymetry. Computerized videokeratography uses a slit-scanning system to measure 18,000 data points and a Placido-based system to make the necessary adjustments to produce the topography data. 16,17  
Measurements were repeated at least three times for each eye to obtain a well-focused, properly aligned image of the eye and one measurement with the most proper centration and focusing. The least eyelid shadow was chosen for the following analysis. 
At each visit, the following quantitative indices (directly available from the Quad Map display mode of Orbscan IIz [Bausch & Lomb Surgical]) were recorded: central power (D) and radius (mm) in both the anterior best-fit sphere (BFS) and the posterior BFS; highest point on the anterior elevation from the anterior BFS (anterior difference) and highest point on the posterior elevation from the posterior BFS (posterior difference); simulated keratometry in maximum (SKmax), minimum (SKmin), and astigmatism (SimK'sAstig); central keratometry (K) at the 3-mm zone in the dioptric values; irregularity index at 3 and 5 mm; central pachymetry; thinnest pachymetry; difference between central pachymetry and thinnest pachymetry; magnitude of decentration of the thinnest corneal point from the corneal geometric center (DTP); horizontal vector of the DTP (DTPx); vertical vector of the DTP (DTPy); and anterior chamber depth (ACD). The degrees of skewed radial axes (SRAX) from the principal meridian were also measured. For each index of each eye, the yearly rate of change was quantified using the slope of the within-eye regression line that described the changes from baseline to the last follow-up. 
Characteristics of Progressive KC
The Kaplan-Meier method was used to evaluate the cumulative incidence rate of substantial progression of KC. In the analysis, an event (deterioration) was defined as an increase of at least 1.50 D in the central K during the follow-up period, and the time of the event was the length of time from the first visit of the patient to the time when the central K increased >1.50 D from the baseline central K. Patients who showed an increase of ≥1.50 D in the central K were considered the progression group, and the other patients were considered the nonprogression group. 
To evaluate factors that might predict KC progression, we compared the topographic indices and the demographic parameters between the progression group and the nonprogression group. Student's t-test was conducted for quantitative traits, and χ2 test was used to compare proportions of qualitative traits between groups. The predictive value of each factor that had statistical significance in the Student's t-test or the χ2 test for KC progression was determined by analysis of the area under the receiver operating-characteristic (ROC) curve. The significance of the selected variables was analyzed by the log-rank test in a univariate analysis. 
Finally, multivariate analysis was conducted using the Cox proportional hazard model to identify a set of independent predictors for determining progression of the central K ≥1.50 D. An “event” was the same as that for the survival analysis, and the “time” variable was defined as the period from the baseline examination to the last examination. Parameters that had significance in the log-rank test were entered into the Cox proportional model as independent variables. We studied each topographic index separately because topographic values might be related. 
Astigmatism Vector Analysis
The astigmatic vector values at the initial examination and the last examination were plotted as a doubled-angle polar plot, as proposed by Holladay et al., 18 to evaluate the longitudinal changes in astigmatism. SimK'sAstig, suggested by Orbscan IIz (Bausch & Lomb Surgical), was used to measure the amount and axis of the astigmatic vector. In addition, the proportions of eyes with SRAX greater than 21°, suggested by Rabinowitz et al. 19 as one of the parameters for screening KC, were analyzed at the initial examination and the last examination. 
Furthermore, keratometric changes using a vector analysis (difference vector [DV]) between the initial examination and the last examination were compared in the progression group and the nonprogression group. 
Statistical analyses were performed (SPSS for Windows, version 14.0; SPPS, Inc., Chicago, IL). All data are mean ± SD. P < 0.05 was considered statistically significant. All mathematical analyses were performed using commercial statistical software (Oriana 3; Kovach Computing Services, Wales, UK) and ImageJ software (developed by Wayne Rasband, National Institutes of Health, Bethesda, MD; available at http://rsb.info.nih.gov/ij/index.html). 
Results
Ninety-four eyes of 85 patients were included in the study. The follow-up period ranged from 5 to 14 years (mean, 7.76 ± 2.86 years). None of the eyes had undergone penetrating keratoplasty during the follow-up period. 
Twenty-five (26.5%) of 94 eyes showed KC progression with an increase of ≥1.5 D of the central K (the progression group), and 69 of 94 eyes showed nonprogression of KC (the nonprogression group.) In the progression group, 48% (12), 44% (11), and 8% (2) eyes were followed up for 5, 10, and 15 years, respectively. In the nonprogression group, 46.4% (32), 50.7% (35), and 2.8% (2) were followed up for 5, 10, and 15 years, respectively. 
Figure 1 illustrates the number of years to progression in the eyes in the progression group. Twenty-five (76%) eyes in the progression group had progressed within the first 5 years. A representative case of topographic changes in progressive KC is shown in Figure 2. During the 5 years, many topographic parameters (e.g., anterior/posterior elevation indices, irregularity indices, pachymetry, ACD, and central K) changed compared with the initial examination with progression of the disease. Figure 3 shows the survival curve for KC progression. The median time from the first diagnosis of KC to progression with an increase of ≥1.50 D of the central K was 12 years (95% confidence interval, 9.12–14.88 years). 
Figure 1.
 
Number of years to progression in the progression group. Nineteen of 25 (76%) eyes in this group experienced progression within the first 5 years.
Figure 1.
 
Number of years to progression in the progression group. Nineteen of 25 (76%) eyes in this group experienced progression within the first 5 years.
Figure 2.
 
Orbscan IIz (Bausch & Lomb Surgical) Quad map of an eye with progressive keratoconus at the initial examination (upper) and at the examination 5 years later (lower). During 5 years, many topographic parameters such as anterior/posterior elevation indices, irregularity indices, pachymetry, anterior chamber depth, and central K changed compared to those at the initial examination.
Figure 2.
 
Orbscan IIz (Bausch & Lomb Surgical) Quad map of an eye with progressive keratoconus at the initial examination (upper) and at the examination 5 years later (lower). During 5 years, many topographic parameters such as anterior/posterior elevation indices, irregularity indices, pachymetry, anterior chamber depth, and central K changed compared to those at the initial examination.
Figure 3.
 
Survival curve of the eyes from the first diagnosis of mild keratoconus to progression, with an increase of ≥1.50 D of the central K. Top line: upper 95% confidence intervals of the survival curve; middle line: survival curve of the estimated progression time and proportions; bottom line: lower 95% confidence intervals of the survival curve.
Figure 3.
 
Survival curve of the eyes from the first diagnosis of mild keratoconus to progression, with an increase of ≥1.50 D of the central K. Top line: upper 95% confidence intervals of the survival curve; middle line: survival curve of the estimated progression time and proportions; bottom line: lower 95% confidence intervals of the survival curve.
When we evaluated the demographic and refractive variables, the mean age of the progression group (21.5 ± 4.5 years) was significantly lower than that in the nonprogression group (25.8 ± 7.6 years) (P = 0.001). The mean baseline best-corrected visual acuity (BCVA) in the progression group (0.49 ± 0.27) was also significantly lower than the mean baseline BCVA in the nonprogression group (0.63 ± 0.28) (P = 0.045). The other patient characteristics were not significantly different between the groups (Table 2). 
Table 2.
 
Patient Characteristics in the Progression and Nonprogression Groups
Table 2.
 
Patient Characteristics in the Progression and Nonprogression Groups
Characteristics Group P
Progression Nonprogression
Eyes, n 25 69
Age, y, mean ± SD 21.5 ± 4.5 25.8 ± 7.6 0.001
Males, n (%) 18 (72) 45 (65) 0.537
OD, n (%) 10 (40) 34 (49) 0.426
History of atopy, n (%) 13 (52) 41 (59) 0.520
BCVA (decimal) 0.49 ± 0.27 0.63 ± 0.28 0.045
Refractive sphere, D ± SD (range) −4.84 ± 4.06 (−16.00 to +0.00) −4.34 ± 3.78 (−14.00 to +7.25) 0.615
Refractive cylinder, D ± SD (range) −3.98 ± 2.60 (−8.00 to −0.75) −4.16 ± 2.31 (−11.00 to −0.50) 0.771
We evaluated the baseline topographic variables and the yearly changes in those variables to identify factors that predict KC progression. The mean ± SD of the topographic factors at the baseline examination and an intergroup comparison are shown in Table 3. No significant differences were observed in anterior BFS and posterior BFS between the two groups. However, significantly larger anterior differences and posterior differences were found (P = 0.023 and 0.013, respectively) in the progression group. Significantly more 3- and 5-mm irregularities were observed in the progression group (P = 0.033, P = 0.010, respectively). Significantly thinner central pachymetry and the thinnest pachymetry were found in the progression group (P = 0.037, P = 0.014, respectively). However, the differences between central pachymetry and thinnest pachymetry and the decentration parameters were not significant. A significantly deeper ACD was found in the progression group than in the nonprogression group. The amount of SRAX was not significantly different between the two groups (P = 0.359). 
Table 3.
 
Topographic Factors and Comparisons between Groups at the Baseline Examination
Table 3.
 
Topographic Factors and Comparisons between Groups at the Baseline Examination
Variable Group P
Progression Nonprogression
n 25 69
Anterior BFS, D 43.54 ± 1.95 43.64 ± 1.60 0.809
Posterior BFS, D 6.15 ± 0.32 6.19 ± 0.26 0.590
Anterior BFS, mm 7.77 ± 0.35 7.74 ± 0.28 0.736
Posterior BFS, mm 6.18 ± 0.32 6.19 ± 0.26 0.513
Ant. diff, mm 0.0392 ± 0.0238 0.0271 ± 0.0132 0.023
Post. diff, mm 0.1034 ± 0.0576 0.0711 ± 0.0348 0.013
SimK's Astig, D 6.22 ± 3.86 4.56 ± 2.25 0.051
SKmax, D 52.42 ± 6.41 49.66 ± 3.69 0.051
SKmin, D 46.23 ± 3.93 45.10 ± 2.88 0.132
Central K (3-mm zone), D 47.43 ± 3.73 46.63 ± 2.22 0.324
Irreg 3 mm, D 6.60 ± 2.93 5.20 ± 1.89 0.033
Irreg 5 mm, D 6.80 ± 2.90 5.13 ± 1.60 0.010
CP, μm 428.2 ± 76.0 465.0 ± 59.1 0.037
TP, μm 415.4 ± 69.2 450.7 ± 56.4 0.014
Difference CP − TP, μm 12.8 ± 22.0 12.1 ± 26.0 0.909
Decentration of TPx, μm 0.560 ± 0.652 −0.010 ± 0.531 0.618
Decentration of TPy, μm −0.280 ± 0.335 −0.394 ± 0.434 0.240
Decentration of TP, ( TP x ) 2 + ( TP y ) 2 , μm 0.696 ± 0.343 0.684 ± 0.367 0.888
ACD, mm 3.52 ± 0.23 3.36 ± 0.35 0.009
Skewed radial axis, deg 14.80 ± 18.62 10.97 ± 14.38 0.359
Table 4 shows the yearly change rates in the topographic factors and a comparison between the progression and nonprogression groups. The progression group showed a significantly higher yearly change rate in the anterior BFS (D). Significantly higher yearly change rates for SKmax, SKmin, and the central K (3 mm) were also found. Additionally, the yearly change rate in the ACD was significantly deeper in the progression group than in the nonprogression group. The yearly change rate of the SRAX was not significantly different between the two groups (P = 0.772). 
Table 4.
 
Annual Change Rates in Topographic Factors and Comparison between Groups
Table 4.
 
Annual Change Rates in Topographic Factors and Comparison between Groups
Variable Group P
Progression Nonprogression
n 25 69
Rate of anterior BFS, D/y 0.23 ± 0.23 0.03 ± 0.12 <0.001
Rate of posterior BFS, D/y 0.08 ± 0.48 −0.03 ± 0.60 0.389
Rate of anterior BFS, mm/y −0.08 ± 0.21 −0.00 ± 0.03 0.079
Rate of posterior BFS, mm/y −0.02 ± 0.04 −0.00 ± 0.04 0.075
Rate of ant. diff, mm/y 0.0023 ± 0.0045 −0.0040 ± 0.0341 0.355
Rate of post. diff, mm/y 0.0006 ± 0.0081 −0.0020 ± 0.0040 0.127
Rate of SimK's Astig, D/y 0.17 ± 2.54 −0.10 ± 0.36 0.607
Rate of SKmax, D/y 0.49 ± 0.87 −0.03 ± 0.32 <0.001
Rate of SKmin, D/y 0.57 ± 0.82 0.16 ± 0.70 0.021
Rate of central K (3-mm zone), D/y 0.43 ± 0.60 0.02 ± 0.16 0.002
Rate of irreg 3 mm, D/y 0.09 ± 0.47 −0.04 ± 0.28 0.201
Rate of irreg 5 mm, D/y 0.14 ± 0.59 0.04 ± 0.41 0.474
Rate of CP, μm/y 0.42 ± 7.08 2.44 ± 6.85 0.215
Rate of TP, μm/y −1.41 ± 10.43 2.18 ± 0.75 0.071
Rate of difference CP - TP, μm/y 0.847 ± 0.292 1.089 ± 8.311 0.892
Rate of decentration TPx, μm/y 0.006 ± 0.077 0.013 ± 0.082 0.686
Rate of decentration TPy, μm/y −0.025 ± 0.068 −0.001 ± 0.101 0.355
Rate of decentration of TP, ( TP x ) 2 + ( TP y ) 2 , μm/y 0.002 ± 0.077 0.018 ± 0.086 0.421
Rate of ACD, mm/y 0.00 ± 0.34 −0.04 ± 0.08 0.012
Rate of skewed radial axes, deg/y 3.39 ± 4.93 3.72 ± 4.84 0.772
ROC curves for the parameters that had statistical significance in the Student's t-test or the χ2 test were analyzed. AUCs of the parameter are shown in Table 5; the predictive powers were significant. Optimal cutoff values for the parameters are also presented in Table 5
Table 5.
 
Factors Associated with Progression of Central K ≥1.50 D in Univariate Analysis
Table 5.
 
Factors Associated with Progression of Central K ≥1.50 D in Univariate Analysis
Variable AUC Cutoff Value P, Log-Rank Test
Age, y 0.676 <30 or ≥30 0.004
BCVA, decimal 0.647 <0.5 or ≥0.5 0.518
Baseline topographic variables
    Ant. diff, mm 0.662 <0.04 or ≥0.04 0.017
    Post. diff, mm 0.675 <0.095 or ≥0.095 0.091
    Irreg 3 mm, D 0.633 <6.5 or ≥6.5 0.008
    Irreg 5 mm, D 0.676 <6.0 or ≥6.0 0.002
    CP, μm 0.628 <400 or ≥400 0.159
    TP, μm 0.635 <350 or ≥350 0.021
    ACD, mm 0.644 <3.1 or ≥3.1 0.018
Rate topographic variables
    Rate of anterior BFS, D/y 0.814 <0.1 or ≥0.1 <0.001
    Rate of SKmax, D/y 0.734 <0.15 or ≥0.15 <0.001
    Rate of SKmin, D/y 0.794 <0.2 or ≥0.2 <0.001
    Rate of central K, D/y 0.827 <0.1 or ≥0.1 <0.001
    Rate of ACD, mm/y 0.744 <0.0 or ≥0.0 <0.001
In the univariate analysis using the log-rank test, the factors that correlated significantly with KC progression were age younger than 30 years, anterior difference ≥0.04 mm, irregularity index 3 mm ≥6.5 D, irregularity index 5 mm ≥6.0 D, thinnest pachymetry <350 μm, ACD ≥3.1 mm at the baseline examination, and yearly change rate of anterior BFS ≥0.1 D/y, SKmax ≥0.15 D/y, SKmin ≥0.2 D/y, central K ≥0.1 D/y, and ACD ≥0.0 mm/y (Table 5). 
Multivariate analysis controlling for age revealed that anterior difference ≥0.04 mm, irregularity index 3 mm ≥6.5 D, irregularity index 5 mm ≥6.0 D, thinnest pachymetry <350 μm at baseline examination, and yearly change rate of anterior BFS ≥0.1 D/y, SKmax ≥0.15 D/y, SKmin ≥0.2 D/y, central K ≥0.1 D/y, and ACD ≥0.0 mm/y proved to be independent factors for KC progression. Variables associated with KC progression in the multivariate analysis are shown in Table 6 with the relative risk ratios. 
Table 6.
 
Independent Predictors of Progression of Central K ≥1.50 D in Multivariate Analysis
Table 6.
 
Independent Predictors of Progression of Central K ≥1.50 D in Multivariate Analysis
Model Variable Associated with Progression of Keratoconus Risk Ratio 95% Confidence Interval P
1 Age 3.961 1.546–10.148 0.004
2 Baseline ant. diff 4.122 1.699–10.004 0.002
3 Baseline irreg 3 mm 3.134 1.412–6.952 0.005
4 Baseline irreg 5 mm 4.348 1.892–9.991 0.001
5 Baseline TP 3.327 1.227–9.019 0.018
6 Rate of ant. BFS 7.379 2.516–21.643 <0.001
7 Rate of SKmax 3.312 1.454–7.546 0.004
8 Rate of SKmin 6.819 2.796–16.629 <0.001
9 Rate of central K 6.482 2.204–19.067 0.001
10 Rate of ACD 4.103 1.785–9.431 0.006
Baseline astigmatic vectors of all patients are represented as a doubled-angle polar plot in Figure 4. At the baseline examination, the refractive centroid, which is the mean calculated with coordinates of both axes for each patient, was +2.52 × 91.4°, with an SD of ± 2.84 D, and the shape factor, which provides the shape of the area of the SD, was ρ = 0.48. The shape factor is drawn as a horizontal elliptical, indicating that a higher percentage of patients have with-the-rule (WTR) or against-the-rule (ATR) astigmatism rather than an oblique astigmatism at the initial examination. 
Figure 4.
 
Double-angle plot of the baseline astigmatism in patients at the initial examination. The centroid of the baseline keratometric astigmatism was +2.52 × 91.4° ± 2.84 D, ρ = 0.48. The centroid is in the WTR area, and the shape factor is horizontally elliptical, indicating that a higher percentage of patients have WTR or ATR astigmatism rather than oblique astigmatism at the initial examination.
Figure 4.
 
Double-angle plot of the baseline astigmatism in patients at the initial examination. The centroid of the baseline keratometric astigmatism was +2.52 × 91.4° ± 2.84 D, ρ = 0.48. The centroid is in the WTR area, and the shape factor is horizontally elliptical, indicating that a higher percentage of patients have WTR or ATR astigmatism rather than oblique astigmatism at the initial examination.
We plotted the final astigmatism at the last examination with the initial astigmatism in the same polar plot for convenience of the comparison (Fig. 5). At the last examination, the refractive centroid was +3.69 × 120.0°, with an SD of ± 2.50 D, and the shape factor was ρ = 1.12, indicating that a higher percentage of patients had oblique astigmatism rather than WTR or ATR astigmatism. The horizontally oriented ellipse-shape factor (ρ = 0.48) at the initial examination changed to a circular shape (ρ = 1.12), indicating a change toward oblique astigmatism over time. Additionally, the refractive centroid at the last examination changed to an oblique astigmatism area. 
Figure 5.
 
Double-angle plot scattergram of the initial keratometric astigmatism versus the final astigmatism at the last examination. The centroid of the keratometric astigmatism at the last examination was +3.689 × 120° ± 2.50 D, ρ = 1.12. The horizontally oriented ellipse factor at the initial examination (upper circle) changed to a circle, indicating a higher percentage of oblique astigmatism. Lower circle: the centroid at the last examination changed to the oblique astigmatism area.
Figure 5.
 
Double-angle plot scattergram of the initial keratometric astigmatism versus the final astigmatism at the last examination. The centroid of the keratometric astigmatism at the last examination was +3.689 × 120° ± 2.50 D, ρ = 1.12. The horizontally oriented ellipse factor at the initial examination (upper circle) changed to a circle, indicating a higher percentage of oblique astigmatism. Lower circle: the centroid at the last examination changed to the oblique astigmatism area.
At the baseline examination, the proportion of eyes with SRAX greater than 21° was 21.3% (20 eyes of 94 eyes), which was increased to 52.1% (49 eyes of 94 eyes) at the last examination. The increase was statistically significant by χ2 test (P < 0.001). 
Last, we calculated the DV for each eye between the initial examination and the last examination in the progression group and the nonprogression group (Fig. 6). The mean absolute value of the DV for the progression group (7.98 ± 3.62 D) was significantly larger than that for the nonprogression group (6.09 ± 4.73 D) (P = 0.04). Vectorial changes over time in each group showed that the keratometric centroid of the progression group was +5.80 × 24° ± 4.73 D, ρ = 0.96 (upper circle), and that the keratometric centroid of the nonprogression group was +4.20 × 179° ± 3.62 D, ρ = 0.65 (lower circle). The centroid in the progression group was in an oblique astigmatism area, and the centroid of the nonprogression group was in the ATR area. The shape factor was a horizontally oriented ellipse in the nonprogression group (ρ = 0.65), whereas it was more circular in the progression group (ρ = 0.96), indicating that the change toward the oblique astigmatism rate was dominant when KC progressed. 
Figure 6.
 
Double-angle plot of the DVs between the baseline examination and the last examination in the progression and nonprogression groups. The keratometric centroid of the progression group was +5.80 × 24° ± 4.73 D, ρ = 0.96 (upper circle), and the keratometric centroid of the nonprogression group was +4.20 × 179° ± 3.62 D, ρ = 0.65 (lower circle). The shape factor was a horizontally oriented ellipse in the nonprogression group, whereas it was more of a circle in the progression group, indicating that the oblique astigmatism rate is higher when keratoconus shows progression.
Figure 6.
 
Double-angle plot of the DVs between the baseline examination and the last examination in the progression and nonprogression groups. The keratometric centroid of the progression group was +5.80 × 24° ± 4.73 D, ρ = 0.96 (upper circle), and the keratometric centroid of the nonprogression group was +4.20 × 179° ± 3.62 D, ρ = 0.65 (lower circle). The shape factor was a horizontally oriented ellipse in the nonprogression group, whereas it was more of a circle in the progression group, indicating that the oblique astigmatism rate is higher when keratoconus shows progression.
Discussion
The present study tracked the longitudinal changes in the topographic findings in patients with mild KC. Oshika et al. 20 reported changes in the corneal refractive parameters over several years in patients with KC who had no history of penetrating keratoplasty. In their study, 20 the subjects were not adjusted for disease stage. Because KC is a progressive disease with various stages according to its natural course, mild KC and advanced KC may have different progression rates. Therefore, we set the inclusion criteria as mild KC of grade I or II by the Amsler-Krumeich classification, 11,12 which is based on disease evolution, and we tracked the progression of mild KC. 
Corneal curvature is the clinical variable most commonly used to monitor the change in KC disease severity. 3,5,13 Several index-based classification methods based on corneal topography systems 3,13 as well as the Amsler-Krumeich classification system use the central K value for grading KC severity. In the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study, 13 whether the first definitive apical clearance lens and the flatter keratometric reading increased ≥3.00 D was used to evaluate definitive disease progression. In our study, only nine patients showed ≥3.00 D increase in the central K during the follow-up period. Therefore, we modified the criteria to ≥1.50 D increase in the central K, and we expanded the number of patients in the progression group for a more detailed statistical evaluation. 
Kaplan-Meier analysis revealed that progression occurred in approximately 50% of patients with mild KC, with an increase in the central K of ≥1.50 D during 12 years (Fig. 3). In the study by Shirayama-Suzuki et al., 8 who investigated the progression of suspected KC compared with true KC, progression to true KC occurred in >20% of the eyes over 6 years. Li et al. 9 reported that 50% of the clinically normal fellow eyes progressed to clinical KC within 16 years. Holland et al. 21 stated that bilateral disease would be found in most patients if they were observed for a sufficient period. Thus, longer follow-ups may result in finding more progression to severe KC, although the natural course of KC appeared to be slow in most of the patients in our study. 
Patients who showed increases ≥1.50 D in central K were considered the progression group, and the characteristics of this group were analyzed. Mean age and baseline BCVA were significantly lower in the progression group than in the nonprogression group (P = 0.001 and P = 0.045, respectively; Table 2) In the univariate analysis, age younger than 30 years was a significant predictor for KC progression. This was consistent with the results of the CLEK study, 13 in which younger age and poorer high-contrast manifest refraction visual acuity at baseline predicted the rate of corneal curvature change. However, other demographic parameters, such as sex, history of atopy, and refractive sphere/cylinder, were not significantly different from the parameters in the nonprogression group. Many studies have demonstrated a link between KC and atopic disease during the past half century. 22 24 The largest controlled study also found that the proportion of patients with a history of atopic disease was significantly higher in those with KC. 25,26 However, a history of atopic disease may not be associated with KC progression, though it has a positive impact on disease development. In accordance with our study, McMahon et al. 13 showed that a history of atopic disease is not associated with the rate of corneal curvature change in patients with KC. Additionally, in a study by Davis et al., 14 a history of atopy was not involved in the changes in visual acuity in patients with KC. 
Among the elevation topographic indices, anterior difference ≥0.04 mm, irregularity index 3 mm ≥6.5 D, and irregularity index 5 mm ≥6.0 D at the baseline examination and annual change rate of anterior BFS ≥0.1 D/y were significant independent predictors of KC progression. Nilforoushan et al. 27 showed that patients with suspected KC had multiple distinguishing characteristics on the anterior and posterior corneal surfaces according to the elevation topography and that they had a higher anterior maximum elevation and larger differences between the highest and lowest points on the Orbscan IIz (Bausch & Lomb Surgical) posterior elevation. 
Irregularity indices at 3 and 5 mm reflect optical surface irregularities, which are proportional to the SD of the axis-independent surface curvature. 16 Irregularity indices are calculated automatically by the Orbscan IIz (Bausch & Lomb Surgical) software, based on a statistical combination of the standard deviations of the mean and toric curvatures. 28 Several studies have demonstrated that these irregularity indices are significantly higher in corneas with suspected KC than in normal corneas. 29,30  
Among the corneal thickness topographic variables, thinnest pachymetry <350 μm at the baseline examination was a significant predictor for KC progression, which is in agreement with the definition of KC as noninflammatory thinning and protrusion (Table 6). However, the difference between central pachymetry and thinnest pachymetry or decentration of the thinnest pachymetry (horizontal and vertical displacement) was not associated with KC progression. This may be related to the fact that horizontal and vertical displacement of the thinnest pachymetry on the pachymetry map is commonly associated with poor patient fixation or operator centration during acquisition of the Orbscan IIz (Bausch & Lomb Surgical) image. 27  
Among keratometric variables, the yearly change rate of SKmax ≥0.15 D/y, SKmin ≥0.2 D/y, and central K ≥0.1 D/y predicted KC progression. However, baseline keratometric values were not associated with KC progression. 
Additionally, significantly deeper ACD was found at the baseline examination in the progression group than in the nonprogression group. The yearly change rate of ACD was also larger in the progression group, and it was significant in the multivariate analysis. In agreement with our study results, Emre et al. 31 reported that significantly increased anterior chamber parameters, including ACD, were found according to KC severity. Kovacs et al. 32 also reported that the ACD increased significantly in a KC group compared with a control group. The increased ACD in patients with KC may be explained by the fact that the most specific changes in KC curvature are steepening and protrusion of the cornea; this deformation occurs in both the anterior and the posterior corneal surfaces of KC eyes. 
In this study, we also evaluated longitudinal changes in astigmatism using vector analysis. We plotted the astigmatism of patients at baseline and at the last examination using a double-angle plot, as was done in the study of de Toledo et al., 33 who evaluated the long-term progression of astigmatism after penetrating keratoplasty for treating patients with KC. 18,33 To the best of our knowledge, ours is the first study to evaluate the characteristics of astigmatic changes by vector analysis in patients with progressive KC. 
A higher percentage of patients had astigmatism in the WTR area at the baseline examination (Fig. 4) that changed to an oblique astigmatism area at the last examination (Fig. 5). Considering the finding that the progression group showed more changes toward oblique astigmatism (Fig. 6) with a larger mean absolute value of the DV than the nonprogression group (P = 0.04), progression of KC seems to accompany the axial changes in the steep meridian from WTR astigmatism to oblique astigmatism over time. In addition, these axial changes toward oblique astigmatism may to be associated with the increase of SRAX because the proportions of patients with SRAX greater than 21° was significantly increased at the last examination compared with the baseline examination (P < 0.001). 
In agreement with our findings, de Toledo et al. 33 also stated that increasing oblique astigmatism after penetrating keratoplasty suggests recurrent KC. Significant variability in the orientation and magnitude of evolving astigmatism was observed in the study of Piñero et al., 34 who evaluated corneal astigmatic changes by vector analysis occurring in KC corneas during a 3-year follow-up period, although the magnitude of the refractive and corneal astigmatism increased. Further studies with longer follow-up are needed to confirm the direction of vectorial changes of astigmatism in patients with KC. 
In summary, mild KC tended to progress in approximately 25% of patients, and this progression lasted 3.5 years on average. Kaplan-Meier analysis revealed that the median time to increase the central K by ≥1.50 D was 12 years. Among the topographic indices, anterior difference ≥0.04 mm, irregularity index 3 mm ≥6.5 D, irregularity index 5 mm ≥6.0 D, thinnest pachymetry <350 μm at the baseline examination, and yearly change rate of anterior BFS ≥0.1 D/y, central K ≥0.1 D/y, SKmax ≥0.15 D/y, SKmin ≥0.2 D/y, and ACD ≥0.0 mm/y were significant predictors for KC progression. Additionally, the axial changes in the steep meridian from WTR astigmatism toward oblique astigmatism were associated with KC progression. These indices may be used as parameters to assess KC progression and diagnose KC. Further studies are needed to determine the cutoff criteria of these parameters for distinguishing subclinical KC and the different stages of clinical KC. 
Footnotes
 Disclosure: J. Choi, None; M.-S. Kim, None
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Figure 1.
 
Number of years to progression in the progression group. Nineteen of 25 (76%) eyes in this group experienced progression within the first 5 years.
Figure 1.
 
Number of years to progression in the progression group. Nineteen of 25 (76%) eyes in this group experienced progression within the first 5 years.
Figure 2.
 
Orbscan IIz (Bausch & Lomb Surgical) Quad map of an eye with progressive keratoconus at the initial examination (upper) and at the examination 5 years later (lower). During 5 years, many topographic parameters such as anterior/posterior elevation indices, irregularity indices, pachymetry, anterior chamber depth, and central K changed compared to those at the initial examination.
Figure 2.
 
Orbscan IIz (Bausch & Lomb Surgical) Quad map of an eye with progressive keratoconus at the initial examination (upper) and at the examination 5 years later (lower). During 5 years, many topographic parameters such as anterior/posterior elevation indices, irregularity indices, pachymetry, anterior chamber depth, and central K changed compared to those at the initial examination.
Figure 3.
 
Survival curve of the eyes from the first diagnosis of mild keratoconus to progression, with an increase of ≥1.50 D of the central K. Top line: upper 95% confidence intervals of the survival curve; middle line: survival curve of the estimated progression time and proportions; bottom line: lower 95% confidence intervals of the survival curve.
Figure 3.
 
Survival curve of the eyes from the first diagnosis of mild keratoconus to progression, with an increase of ≥1.50 D of the central K. Top line: upper 95% confidence intervals of the survival curve; middle line: survival curve of the estimated progression time and proportions; bottom line: lower 95% confidence intervals of the survival curve.
Figure 4.
 
Double-angle plot of the baseline astigmatism in patients at the initial examination. The centroid of the baseline keratometric astigmatism was +2.52 × 91.4° ± 2.84 D, ρ = 0.48. The centroid is in the WTR area, and the shape factor is horizontally elliptical, indicating that a higher percentage of patients have WTR or ATR astigmatism rather than oblique astigmatism at the initial examination.
Figure 4.
 
Double-angle plot of the baseline astigmatism in patients at the initial examination. The centroid of the baseline keratometric astigmatism was +2.52 × 91.4° ± 2.84 D, ρ = 0.48. The centroid is in the WTR area, and the shape factor is horizontally elliptical, indicating that a higher percentage of patients have WTR or ATR astigmatism rather than oblique astigmatism at the initial examination.
Figure 5.
 
Double-angle plot scattergram of the initial keratometric astigmatism versus the final astigmatism at the last examination. The centroid of the keratometric astigmatism at the last examination was +3.689 × 120° ± 2.50 D, ρ = 1.12. The horizontally oriented ellipse factor at the initial examination (upper circle) changed to a circle, indicating a higher percentage of oblique astigmatism. Lower circle: the centroid at the last examination changed to the oblique astigmatism area.
Figure 5.
 
Double-angle plot scattergram of the initial keratometric astigmatism versus the final astigmatism at the last examination. The centroid of the keratometric astigmatism at the last examination was +3.689 × 120° ± 2.50 D, ρ = 1.12. The horizontally oriented ellipse factor at the initial examination (upper circle) changed to a circle, indicating a higher percentage of oblique astigmatism. Lower circle: the centroid at the last examination changed to the oblique astigmatism area.
Figure 6.
 
Double-angle plot of the DVs between the baseline examination and the last examination in the progression and nonprogression groups. The keratometric centroid of the progression group was +5.80 × 24° ± 4.73 D, ρ = 0.96 (upper circle), and the keratometric centroid of the nonprogression group was +4.20 × 179° ± 3.62 D, ρ = 0.65 (lower circle). The shape factor was a horizontally oriented ellipse in the nonprogression group, whereas it was more of a circle in the progression group, indicating that the oblique astigmatism rate is higher when keratoconus shows progression.
Figure 6.
 
Double-angle plot of the DVs between the baseline examination and the last examination in the progression and nonprogression groups. The keratometric centroid of the progression group was +5.80 × 24° ± 4.73 D, ρ = 0.96 (upper circle), and the keratometric centroid of the nonprogression group was +4.20 × 179° ± 3.62 D, ρ = 0.65 (lower circle). The shape factor was a horizontally oriented ellipse in the nonprogression group, whereas it was more of a circle in the progression group, indicating that the oblique astigmatism rate is higher when keratoconus shows progression.
Table 1.
 
Amsler-Krumeich Classification for Grading Keratoconus
Table 1.
 
Amsler-Krumeich Classification for Grading Keratoconus
Stage 1
Eccentric steepening
Myopia, induced astigmatism, or both <5.00 D
Mean central K readings <48.00 D
Stage 2
Myopia, induced astigmatism, or both from 5.00 to 8.00 D
Mean central K readings <53.00 D
Absence of scarring
Minimum corneal thickness >400 μm
Stage 3
Myopia, induced astigmatism, or both from 8.00 to 10.00 D
Mean central K readings >53.00 D
Absence of scarring
Minimum corneal thickness 300 to 400 μm
Stage 4
Refraction not measurable
Mean central K readings >55.00 D
Central corneal scarring
Minimum corneal thickness 200 μm
Table 2.
 
Patient Characteristics in the Progression and Nonprogression Groups
Table 2.
 
Patient Characteristics in the Progression and Nonprogression Groups
Characteristics Group P
Progression Nonprogression
Eyes, n 25 69
Age, y, mean ± SD 21.5 ± 4.5 25.8 ± 7.6 0.001
Males, n (%) 18 (72) 45 (65) 0.537
OD, n (%) 10 (40) 34 (49) 0.426
History of atopy, n (%) 13 (52) 41 (59) 0.520
BCVA (decimal) 0.49 ± 0.27 0.63 ± 0.28 0.045
Refractive sphere, D ± SD (range) −4.84 ± 4.06 (−16.00 to +0.00) −4.34 ± 3.78 (−14.00 to +7.25) 0.615
Refractive cylinder, D ± SD (range) −3.98 ± 2.60 (−8.00 to −0.75) −4.16 ± 2.31 (−11.00 to −0.50) 0.771
Table 3.
 
Topographic Factors and Comparisons between Groups at the Baseline Examination
Table 3.
 
Topographic Factors and Comparisons between Groups at the Baseline Examination
Variable Group P
Progression Nonprogression
n 25 69
Anterior BFS, D 43.54 ± 1.95 43.64 ± 1.60 0.809
Posterior BFS, D 6.15 ± 0.32 6.19 ± 0.26 0.590
Anterior BFS, mm 7.77 ± 0.35 7.74 ± 0.28 0.736
Posterior BFS, mm 6.18 ± 0.32 6.19 ± 0.26 0.513
Ant. diff, mm 0.0392 ± 0.0238 0.0271 ± 0.0132 0.023
Post. diff, mm 0.1034 ± 0.0576 0.0711 ± 0.0348 0.013
SimK's Astig, D 6.22 ± 3.86 4.56 ± 2.25 0.051
SKmax, D 52.42 ± 6.41 49.66 ± 3.69 0.051
SKmin, D 46.23 ± 3.93 45.10 ± 2.88 0.132
Central K (3-mm zone), D 47.43 ± 3.73 46.63 ± 2.22 0.324
Irreg 3 mm, D 6.60 ± 2.93 5.20 ± 1.89 0.033
Irreg 5 mm, D 6.80 ± 2.90 5.13 ± 1.60 0.010
CP, μm 428.2 ± 76.0 465.0 ± 59.1 0.037
TP, μm 415.4 ± 69.2 450.7 ± 56.4 0.014
Difference CP − TP, μm 12.8 ± 22.0 12.1 ± 26.0 0.909
Decentration of TPx, μm 0.560 ± 0.652 −0.010 ± 0.531 0.618
Decentration of TPy, μm −0.280 ± 0.335 −0.394 ± 0.434 0.240
Decentration of TP, ( TP x ) 2 + ( TP y ) 2 , μm 0.696 ± 0.343 0.684 ± 0.367 0.888
ACD, mm 3.52 ± 0.23 3.36 ± 0.35 0.009
Skewed radial axis, deg 14.80 ± 18.62 10.97 ± 14.38 0.359
Table 4.
 
Annual Change Rates in Topographic Factors and Comparison between Groups
Table 4.
 
Annual Change Rates in Topographic Factors and Comparison between Groups
Variable Group P
Progression Nonprogression
n 25 69
Rate of anterior BFS, D/y 0.23 ± 0.23 0.03 ± 0.12 <0.001
Rate of posterior BFS, D/y 0.08 ± 0.48 −0.03 ± 0.60 0.389
Rate of anterior BFS, mm/y −0.08 ± 0.21 −0.00 ± 0.03 0.079
Rate of posterior BFS, mm/y −0.02 ± 0.04 −0.00 ± 0.04 0.075
Rate of ant. diff, mm/y 0.0023 ± 0.0045 −0.0040 ± 0.0341 0.355
Rate of post. diff, mm/y 0.0006 ± 0.0081 −0.0020 ± 0.0040 0.127
Rate of SimK's Astig, D/y 0.17 ± 2.54 −0.10 ± 0.36 0.607
Rate of SKmax, D/y 0.49 ± 0.87 −0.03 ± 0.32 <0.001
Rate of SKmin, D/y 0.57 ± 0.82 0.16 ± 0.70 0.021
Rate of central K (3-mm zone), D/y 0.43 ± 0.60 0.02 ± 0.16 0.002
Rate of irreg 3 mm, D/y 0.09 ± 0.47 −0.04 ± 0.28 0.201
Rate of irreg 5 mm, D/y 0.14 ± 0.59 0.04 ± 0.41 0.474
Rate of CP, μm/y 0.42 ± 7.08 2.44 ± 6.85 0.215
Rate of TP, μm/y −1.41 ± 10.43 2.18 ± 0.75 0.071
Rate of difference CP - TP, μm/y 0.847 ± 0.292 1.089 ± 8.311 0.892
Rate of decentration TPx, μm/y 0.006 ± 0.077 0.013 ± 0.082 0.686
Rate of decentration TPy, μm/y −0.025 ± 0.068 −0.001 ± 0.101 0.355
Rate of decentration of TP, ( TP x ) 2 + ( TP y ) 2 , μm/y 0.002 ± 0.077 0.018 ± 0.086 0.421
Rate of ACD, mm/y 0.00 ± 0.34 −0.04 ± 0.08 0.012
Rate of skewed radial axes, deg/y 3.39 ± 4.93 3.72 ± 4.84 0.772
Table 5.
 
Factors Associated with Progression of Central K ≥1.50 D in Univariate Analysis
Table 5.
 
Factors Associated with Progression of Central K ≥1.50 D in Univariate Analysis
Variable AUC Cutoff Value P, Log-Rank Test
Age, y 0.676 <30 or ≥30 0.004
BCVA, decimal 0.647 <0.5 or ≥0.5 0.518
Baseline topographic variables
    Ant. diff, mm 0.662 <0.04 or ≥0.04 0.017
    Post. diff, mm 0.675 <0.095 or ≥0.095 0.091
    Irreg 3 mm, D 0.633 <6.5 or ≥6.5 0.008
    Irreg 5 mm, D 0.676 <6.0 or ≥6.0 0.002
    CP, μm 0.628 <400 or ≥400 0.159
    TP, μm 0.635 <350 or ≥350 0.021
    ACD, mm 0.644 <3.1 or ≥3.1 0.018
Rate topographic variables
    Rate of anterior BFS, D/y 0.814 <0.1 or ≥0.1 <0.001
    Rate of SKmax, D/y 0.734 <0.15 or ≥0.15 <0.001
    Rate of SKmin, D/y 0.794 <0.2 or ≥0.2 <0.001
    Rate of central K, D/y 0.827 <0.1 or ≥0.1 <0.001
    Rate of ACD, mm/y 0.744 <0.0 or ≥0.0 <0.001
Table 6.
 
Independent Predictors of Progression of Central K ≥1.50 D in Multivariate Analysis
Table 6.
 
Independent Predictors of Progression of Central K ≥1.50 D in Multivariate Analysis
Model Variable Associated with Progression of Keratoconus Risk Ratio 95% Confidence Interval P
1 Age 3.961 1.546–10.148 0.004
2 Baseline ant. diff 4.122 1.699–10.004 0.002
3 Baseline irreg 3 mm 3.134 1.412–6.952 0.005
4 Baseline irreg 5 mm 4.348 1.892–9.991 0.001
5 Baseline TP 3.327 1.227–9.019 0.018
6 Rate of ant. BFS 7.379 2.516–21.643 <0.001
7 Rate of SKmax 3.312 1.454–7.546 0.004
8 Rate of SKmin 6.819 2.796–16.629 <0.001
9 Rate of central K 6.482 2.204–19.067 0.001
10 Rate of ACD 4.103 1.785–9.431 0.006
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