A New Method for Grading the Severity of Keratoconus
The Keratoconus Severity Score (KSS) Timothy T. McMahon, OD,* Loretta Szczotka-Flynn, OD, MS, Joseph T. Barr, OD, MS, Robert J. Anderson, PhD, Mary E. Slaughter, Jonathan H. Lass, MD, Sudha K. Iyengar, PhD and the CLEK Study Group Purpose: To dene a new method for grading severity of keratoconus, the Keratoconus Severity Score (KSS). Methods: A rationale for grading keratoconus severity was developed using common clinical markers plus 2 corneal topographic indices, creating a 0 to 5 severity score. An initial test set of 1012 eyes, including normal eyes, eyes with abnormal corneal and topo- graphic ndings but not keratoconus, and eyes with keratoconus having a wide range of severity, was used to determine cutpoints for the KSS. Validation set 1, comprising data from 128 eyes, was assigned a KSS and compared with a clinicians ranking of severity termed the gold standard to determine if the scale fairly represented how a clinician would grade disease severity. k statistics, sensitivity, and specicity were calculated. A program was developed to auto- mate the determination of the score. This was tested against a manual assignment of KSS in 2121 (validation set 2) eyes from the Collabo- rative Longitudinal Evaluation of Keratoconus (CLEK) Study, as well as normal eyes and abnormal eyes without keratoconus. Ten percent of eyes underwent repeat manual assignment of KSS to determine the variability of manual assignment of a score. Results: From initial assessments, the KSS used 2 corneal topo- graphy indices: average corneal power and root mean square (RMS) error for higher-order Zernike terms derived from the rst corneal surface wavefront. Clinical signs including Vogt striae, Fleischer rings, and corneal scarring were also included. Last, a manual interpretation of the map pattern was included. Validation set 1 yielded a k statistic of 0.904, with sensitivities ranging from 0.64 to 1.00 and specicities ranging from 0.93 to 0.98. The sensitivity and specicity for determining nonkeratoconus from keratoconus were both 1.00. Validation set 2 showed k statistics of 0.94 and 0.95 for right and left eyes, respectively. Testretest analysis yielded k statistics of 0.84 and 0.83 for right and left eyes, respectively. Conclusion: A simple and reliable grading system for keratoconus was developed that can be largely automated. Such a grading scheme could be useful in genetic studies for a complex trait such as keratoconus requiring a quantitative measure of disease presence and severity. Key Words: keratoconus, severity, corneal topography, grading scale (Cornea 2006;25:794800) K eratoconus is a bilateral noninammatory corneal thinning disorder leading to protrusion, distortion, and scarring of the cornea. 1 It is an uncommon disorder with widely variable estimates of its annual incidence ranging from 50 to 230 per 100,000. 2 Previous studies performed more than 20 years ago estimate the prevalence to be 54 per 100,000. 36 The origin of keratoconus is unclear, although there is a growing body of literature suggesting that in some cases keratoconus is determined through heredity. 730 Modern statistical genetics uses a variety of both model- based and model-free methods to link genetic similarity to phenotypic or clinical similarity. Phenotypes can simply be classied as dichotomous variables (eg, affected vs. un- affected), or a more detailed characterization of a trait, such as a severity index, can be used. Use of multiple discrete features in an ordinal scale reduces the probability of misclassication that is associated with simply classifying individuals as affected versus unaffected to examine differences in the genome of siblings and/or other relatives within a family. If this type of technique is to be used in searching for a gene(s) for keratoconus, a valid and easily applied severity scale is needed. This requires that a scale be based on a variety of phenotypic keratoconus features, broad enough to span the range of disease severity from normal to severe, and be shown as accurate with this categorization. This report details the development of a new severity scale, the Keratoconus Severity Score (KSS), based on slit- lamp ndings (including apical scarring), corneal topography map characteristics, and 2 easily determined topographic indices: average corneal power (ACP) 31 and higher-order rst corneal surface wavefront root mean square (RMS) error (HORMSE). 3234 Such a severity scale could be applied to a variety of circumstances, including genetic studies of Received for publication November 8, 2005; revision received March 22, 2006; accepted March 25, 2006. From the Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL; the Department of Ophthalmology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH; the Ohio State University College of Optometry, Columbus, OH; the Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, IL; and the {Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH. Reprints: Timothy T. McMahon, OD, Department of Ophthalmology and Visual Sciences University of Illinois at Chicago, Suite 3.164 (M/C 648), 1855 W. Taylor Street, Chicago, IL 60612 (e-mail: timomcma@uic.edu). Copyright 2006 by Lippincott Williams & Wilkins 794 Cornea
Volume 25, Number 7, August 2006 keratoconus, that require knowledge of disease severity measured on an ordinal scale. MATERIALS AND METHODS Developing the Severity Score Many indices derived from corneal topography were initially evaluated as potential candidates for inclusion in the new scale to meet the above-mentioned criteria. Simulated indices were computed and incorporated in the Ohio State Corneal Topography Tool (OSUCTT). 35 These indices are simulated because they were initially derived from descriptions in the published literature and compared with the results provided by the proprietary instrument using them. For example, ACP was developed for the TMS-1 instrument (Tomey Technologies, Nagoya, Japan). 31 In our previous studies, when ACP was compared with the simulated ACP, there were discrepancies that could be explained only by manufacturer modications to the published formulas (unpublished data). In fact, this was the rule rather than the exception across instrument manufacturers for other simulated indices as well. These discrepancies required reverse engineering to improve the correlations between the native instrument output and that derived from the OSUCTT. Hence, for consistency across platforms, we used simulated indices in this study. The rst set of analyses to identify candidate topo- graphic indices examined the correlation for several pairs of indices. This analysis grouped 17 indices into 4 major groups: those associated with corneal power, corneal asymmetry, corneal irregularity, and corneal cylinder (orthogonal astig- matism). Among the corneal power measures, the correlations were very high. ACP was chosen because the simulations were closest to the native machine output. Corneal asymmetry and irregularity essentially represent higher-order optical aberra- tions, so we selected the third-order and higher RMS error (HORMSE; through the 27th term) to describe these features collectively. HORMSE was derived from raw corneal topography data by VOL-CT software (version 6.58; Sarver and Associates, Carbondale, IL). Corneal astigmatism was not used in this scale. In previous studies (unpublished data), the cylinder was not a very powerful diagnostic tool either in identifying keratoconus or in tracking its severity. In addition to these 2 topographic indices, the KSS also used an analysis of topographic patterns. One observer (T.T.M.) subjectively classied the topographic patterns using an axial algorithm-displayed map as either normal, atypical (but not keratoconus), or whether it exhibited an isolated area of steepening characteristic for keratoconus. Finally, the KSS used clinical assessments of keratoconic slit-lamp signs, specically the presence or absence of Fleischer rings, Vogt striae, and corneal scarring characteristic for keratoconus. The scaling of scarring for KSS followed the protocol used for gestalt scarring in the Collaborative Longitudinal Evalua- tion of Keratoconus (CLEK) Study. 36 Gestalt scarring is a measure of the total scarring observed in the central cornea in CLEK Study corneal photographs. In a previous study, masked CLEK Photography Reading Center readers assessed the number, size, density, and shape of corneal opacities in corneas of keratoconus patients. 36 In the Gestalt scarring assessment, the reader takes into ac- count how close the scarring as a whole is to the line of sight and how large and dense is the scarring to estimate the overall (gestalt) scarring. Table 1 denes the gestalt scarring scale. Intraclass correlation coefcients for readers reading the same slides of corneal scarring (masked) on a repeated basis indicate very good reliability. 37 The testretest reliability for gestalt grading for random rereads for all readers for each year from 1998 to 2004 were 0.77, 0.49, 0.80, 0.71, 0.54, 0.72, and 0.61, respectively. Over this 6-year period, the testretest reliability was 0.66, which is typically considered very good (un- published data). A scale suitable for segregation analysis requires a range of quantitative classications from normal to severely affected cases. Our scale includes values for normal eyes, keratoconus suspects, and mild, moderate, and severe keratoconus. Un- usual corneas not caused by keratoconus referred to as atypical corneas were also included. Atypical eyes consisted of contact lensinduced warpage, penetrating keratoplasty, myopic refractive surgery, and corneal scarring from disease or trauma not associated withkeratoconus. This resultedina 5-point scale, with 0 being normal and 5 indicating severe disease. Testing of data consisted of 3 steps: evaluating a test dataset and validating the scale results using 2 validation sets. Test Dataset An initial test set of 1012 eyes was assembled to determine the combination of data ranges for each classi- cation criterion. The test set included subjects that clinically could be classied into each of these categories. The set included 130 normal eyes, 41 atypical eyes, 7 keratoconus- suspect eyes, and 834 eyes with keratoconus. Keratoconus suspects had corneal topography patterns suspicious for the disease but no slit-lamp or other clinical ndings. Using 95% condence intervals (CIs), possible demarcation points were determined for HORMSE for each level. The cutpoints for ACP were determined through clinical experience and 95% CI and were dened as less than 52.00 D = mild, 52.00 to 56.00 D = moderate, and more than 56.00 D = severe. Validation Set 1 A set of 128 right eyes, referred to as validation set 1, was subjected to ranking and compared with a clinicians TABLE 1. Descriptors for Overall (Gestalt) Scarring (0.04.0 in 0.5 Steps) Grade 1.0 Trace and not on LOS, ,1.5 mm total size Grade 2.0 Easily noticeable and approaching LOS, 1.52.5 mm total size Grade 3.0 Dense but translucent and impinging on LOS, total size 2.5 mm or greater Grade 4.0 Opaque and on LOS, size 2.5 mm or greater Increased grade for density, size, number, and location near or on the line of sight (LOS). q 2006 Lippincott Williams & Wilkins 795 Cornea
Volume 25, Number 7, August 2006 Severity Paper grading of severity used in clinical practice, which we refer to as the gold standard. The gold standard was determined in validation set 1 by one of the authors (L.S.-F.) using clinical chart data including slit-lamp ndings, best-corrected visual acuity, color corneal topography maps from the Keratron or Humphrey Atlas systems, and keratometry. The 2 topograph- ically derived indices, ACP and HORMSE, were not available for the gold standard grading. One hundred eyes from CLEK Study subjects were examined at the Department of Oph- thalmology at the Case Western Reserve University CLEK site. Also, 10 normals, 10 atypical normals, and 8 suspect cases (not in the CLEK Study) were also provided by the Case Western University, Department of Ophthalmology clinic. Because there is no uniformly accepted severity classication scheme for keratoconus using a combination of objective and subjective assessments, the gold standard grading criterion was independently developed by the examiner (L.S.-F.) using clinical experience in combination with published recom- mendations. 3842 The gold standard grading system is de- scribed in Table 2. These gold standard grades were compared with the KSS determined for this same group of patients at the Corneal Topography Reading Center (CTRC) at the University of Illinois at Chicago. Corneal topography data, computed indices, and corneal slit-lamp signs including the corneal scarring grade provided by the CLEK Study database were used by the CTRC to establish a KSS. Cohen k statistics were calculated. Also, 2 3 2 contingency tables were constructed to calculate the sensitivity and specicity for determining the screening capability of the model in differentiating keratoconus from normals and atypical normals and identifying the different levels of keratoconus severity. To automate the classication of KSS, a cascading classication algorithm was written using the SAS statistical software package (version 9.1). The algorithm used the structure and criteria of the KSS (Table 3). The decision process within the algorithm owed down the 6 grades, assigning the largest KSS score possible with all required criteria within a grade satised. A KSS score was not assigned for an eye that underwent a corneal transplant or if any data needed to assign a score were missing. Validation Set 2 To validate the assignment of a KSS score, a second validation set (validation set 2) was assembled. This set consisted of a cohort of CLEK Study subjects with keratoconus plus keratoconus suspects, normals, and atypical normals. 43 For those CLEK eyes with no missing data, a manual KSS was determined using a combination of the CLEK data, topographical scans, and clinical expertise from the grader (T.T.M.). The agreement between the algorithm and the manual KSS was evaluated with k statistics. Also, to assess testretest reliability of the observer (T.T.M.) in manually assigning a KSS, a random sample of approximately 10% of validation set 2 eyes (138 total) was assessed again in a masked manner, both manually and with a second pass (retest) of the KSS scoring algorithm. k statistics, evaluating the agreement between the manual observerassigned and the calculated KSS, were determined. These validations were performed to assess variability of the observer and algorithm to accurately assign a KSS score to the CLEK cohort. RESULTS Table 4 shows the mean, range, SD, and 95% CIs for ACP and HORMSE for each level for the initial test set. The KSS scale is dened in Table 3. It is derived largely from the data found in Table 2 and the application of judicious clinical opinion. The strategy to rank an eye is dependent on the worst feature of any of the data types in the scale algorithm. The nal 5 features assessed were slit-lamp signs, topography TABLE 2. Gold Standard Grading Scheme Normal Regular axial topography pattern (round, oval, symmetric bow tie, etc) Normal slit-lamp exam Spectacle corrected acuity P55 letters at 4 m on Log Mar chart (with no other ocular pathology) Atypical normal Unusual axial topography explained by slit-lamp exam or history (contact lens warpage, corneal scars not typical of keratoconus, history of refractive surgery) Normal or diminished spectacle acuity Keratoconus suspect Suspicious axial topography for keratoconus (isolated area of steepening, central steepening .48 D) Normal slit-lamp exam Spectacle corrected acuity P55 letters at 4 m on Log Mar chart (with no other ocular pathology) Mild keratoconus Axial topography consistent with keratoconus Flat keratometry reading ,51.00 D Fleischer ring or Vogt striae No corneal scarring Reduced spectacle acuity (,55 letters at 4 m on Log Mar chart) (with no other ocular pathology) Moderate keratoconus Axial topography consistent with keratoconus Flat keratometry reading between 51.25 and 56.00 D or astigmatism P8 D Fleischer ring or Vogt striae May have corneal scarring up to and including CLEK grade 3.0 (any scarring up to well-dened stromal scarring consistent with keratoconus) Reduced spectacle acuity ( 645 letters at 4 m on Log Mar chart) (with no other ocular pathology) Severe keratoconus Axial topography consistent with keratoconus with marked areas of steepening Flat keratometry reading .56.01 D Fleischer ring or Vogt striae May have corneal scarring up to and including CLEK grade 4.0 (any scarring up to a dense/opaque stromal scar consistent with keratoconus) Reduced spectacle acuity (,30 letters at 4 m on Log Mar chart) (with no other ocular pathology) 796 q 2006 Lippincott Williams & Wilkins McMahon et al Cornea
Volume 25, Number 7, August 2006 pattern, corneal scarring, ACP, and HORMSE. For normals and atypical normals, all of the features of the category must have been met for an eye to assume the KSS score for that category. At the suspect level in the scale, the decision-making was bifurcated. To be placed in the suspect category, an eye must have had no scarring, no other slit-lamp ndings for keratoconus, and have had an axial topography pattern with an isolated area of steepening typical for keratoconus. In addition, the worse of ACP or HORMSE dened the KSS category. This bifurcated decision tree extended to all the higher levels, with changing criteria as the severity increased. k statistics were calculated for the components of the model to determine the relative value of each component (Table 5). As can be seen, the addition of each successive component to the model increases the k statistic, thus enhanc- ing the t to the gold standard evaluation. Table 6 denes the sensitivity and specicity of KSS to segregate eyes into the proper score. This analysis was set up for each grade level computed for the KSS and compared with the gold standard by using validation set 1. The eyes in validation set 2, including the CLEK Study cohort, were assigned a KSS by using the algorithm in Table 5. These eyes encompassed the entire range of the scale; 57 normal eyes, 8 atypical eyes, 49 keratoconus suspects, 927 eyes with mild keratoconus, 682 with moderate disease, and 398 with severe keratoconus. To determine the consistency with which the algorithm assigned KSS compared with a manually assigned KSS, weighted k statistics were calculated using CicchettiAllison weights. 44 For right eyes, the weighted k was 0.94 (95% CI: 0.920.96); for left eyes, it was 0.95 (95% CI: 0.940.97). Both of these statistics indicate very high agreement and give condence to the use of an automated approach for assigning a KSS score. A random sample of validation set 2 comprising ap- proximately 10% of the overall sample was used to assess the testretest reliability of assigning a severity score. There were 69 right eyes and 69 left eyes in the sample (eyes with a corneal transplant were excluded). These maps were rescored weeks after their initial score assignment. Eyes used in this sample had initial KSS ranging from 1 through 5. Weighted k statistics were 0.84 (95% CI: 0.730.95) for right eyes and 0.83 (95% CI: 0.710.94) for left eyes. TABLE 3. Keratoconus Severity Score Ranking Scheme 0 Unaffectednormal topography Required features: No corneal scarring consistent with keratoconus No slit-lamp signs for keratoconus Typical axial pattern Average corneal power (ACP) #47.75 D Higher-order RMS error #0.65 1 Unaffectedatypical topography Required features: No corneal scarring consistent with keratoconus No slit-lamp signs for keratoconus Atypical axial pattern Irregular pattern or Asymmetric superior bowtie or Asymmetric inferior bowtie or Inferior or superior steepening no more than 3.00 D steeper than ACP ACP #48.00 D Higher-order RMS error #1.00 2 Suspect topography Required features: No corneal scarring consistent with keratoconus No slit-lamp signs for keratoconus Axial pattern with isolated area of steepening Inferior steep pattern or Superior steep pattern or Central steep pattern Additional features: ACP #49.00 D or Higher-order RMS error .1.00, #1.50 3 Affectedmild disease Required features: Axial pattern consistent with KCN May have positive slit-lamp signs No corneal scarring consistent with keratoconus Additional features: ACP #52.00 D or Higher-order RMS error .1.50, #3.50 4 Affectedmoderate disease Required features: Axial pattern consistent with KCN Must have positive slit-lamp signs Additional features: ACP .52.00 D, #56.00 D or Higher-order RMS error .3.50, #5.75 or Corneal scarring and overall CLEK grade up to 3.0 5 Affectedsevere disease TABLE 3. (Continued) Required features: Axial pattern consistent with KCN Must have positive slit-lamp signs Additional features: ACP .56.00 D or Higher-order RMS error .5.75 or Corneal scarring CLEK grade 3.5 or greater overall Rules: The decision process ows down each grade. For grades 01, all of the parameters in a category must be met. For all grades, the required features must be met. The worst of the additional features is then assessed, with the worst of the features carrying the greater weight (as long as the required features are met). q 2006 Lippincott Williams & Wilkins 797 Cornea
Volume 25, Number 7, August 2006 Severity Paper DISCUSSION The detection of keratoconus has received a great deal of attention in the past 15 years, concomitant with the rise in popularity of refractive surgery. The development of Placido disk-based videokeratography was stimulated largely by the desire to screen out patients with keratoconus from the group of prospective refractive surgery candidates. 45 Corneal topog- raphy has proved valuable in identifying cases of subtle or forme fruste keratoconus. 4549 Several analytical, topography- based screening tools have been developed to detect eyes with signs of keratoconus. 31,5052 These tools have limited use as screening tools in most cases and suffer signicant short- comings in actually tracking the severity of keratoconus as it progresses. 53,54 There are a few techniques that have been developed for tracking disease severity in keratoconus. Smolek and Klyce have developed a Keratoconus Severity Index (KSI) using previously developed expert systems and articial intelli- gence. 31 This system is proprietary to 1 instrument and to use it with corneal topography data from other instruments would not be prudent until appropriate model training and validation has been accomplished. To date, this has not been available. Avitabile et al 55,56 have used an ultrasound biomicro- scope (UBM) technique for grading and tracking disease severity in keratoconus that compares favorably with corneal topographybased KSI readings. However, although less proprietary, UBMs are uncommon instruments, and the trans- fer of the authors technique to the clinical environment has not been reported. Li et al 38 have developed an index, the KISA%, to grade the presence or absence of keratoconus. Although this index has the potential to dene disease severity in keratoconus, the developers have described its role only in dening normals, keratoconus suspects, and those with the disease. The KISA% index has been used to monitor changes in normal eyes of unilateral keratoconus patients 38 and in genetic screening, where KISA% was used to distinguish keratoconus from normal individuals. 11,57 Rabinowitz 58 has described a classication scheme of 3 distinct categories: keratoconus, early keratoconus, and keratoconus suspect. In his most advanced categorization (keratoconus), disease can be detected by slit-lamp evaluation and an asymmetric bowtie/skewed radial axis pattern (AB/SRAX) on videokeratography. In early keratoconus, no slit-lamp ndings of disease are found, but scissoring of the retroilluminated reex and an AB/SRAX pattern are present. In keratoconus suspects, no clinical signs of keratoconus on either slit-lamp evaluation or retroillumination assessment are found, but there is an AB/SRAX pattern. In our experience, there are frequent occasions (eg, an isolated area of inferior steepening) where eyes with keratoconus did not have a denite AB/SRAX pattern. TABLE 4. Summary Statistics for 2 Keratoconus Measures, by KSS Level, Obtained from Test Set 0 1 2 3 4 5 ACP Mean 43.82 44.10 44.57 47.10 53.89 62.81 Min 41.10 40.00 40.86 39.47 52.01 56.08 Max 47.66 47.01 46.83 51.97 55.98 90.38 SD 1.30 1.60 2.24 2.74 1.11 6.52 95% CI 41.2246.42 40.9044.30 40.0949.05 41.6252.58 51.6756.11 49.7775.85 HORMSE Mean 0.42 0.60 0.70 1.98 3.14 5.03 Min 0.23 0.40 0.51 0.26 0.89 1.11 Max 0.75 1.0 0.96 9.48 8.00 55.66 SD 0.07 0.14 1.61 1.19 1.30 4.27 95% CI 0.280.56 0.320.88 03.93 04.36 0.545.74 013.57 Scores: 0, normal; 1, atypical normal; 2, keratoconus suspect; 3, keratoconusmild; 4, keratoconusmoderate; 5, keratoconussevere. ACP, average corneal power; HORMSE, higher-order root mean square (Wavefront) error. TABLE 5. Agreement (Computed With Cohen k Statistic) Between KSS and the Gold Standard Evaluation Weighted k 95% CI Indices only 0.695 0.5980.792 Indices and manual read 0.854 0.7990.910 Indices and scarring 0.762 0.6780.847 Indices, manual read, and scarring 0.863 0.8070.920 Indices, manual read, scarring, and slit-lamp signs 0.904 0.8620.946 TABLE 6. Sensitivity and Specificity for Screening for Assignment of Proper Grade Level Grade Description (Grade Number) Sensitivity Specicity Normal (0) vs. atypical normal (1) 1.00 0.95 Atypical normal (1) vs. keratoconus suspect (2) 1.00 1.00 Keratoconus suspect (2) vs. mild keratoconus (3) 1.00 1.00 Mild keratoconus (3) vs. moderate keratoconus (4) 0.90 0.93 Moderate keratoconus (4) vs. severe keratoconus (5) 0.64 0.98 798 q 2006 Lippincott Williams & Wilkins McMahon et al Cornea
Volume 25, Number 7, August 2006 In other classication schemes, the shape of the cone- nipple (round), oval, or globus has been used to classify keratoconus, although these do not lend themselves to grading severity. Last, Hom 59 classied keratoconus into 4 stages, with stage 1 having such early disease that spectacles are the rst form of treatment, and stage 4 has corneal steepening .55 D, apical opacities, and Munson sign. As previously mentioned, there is a growing body of evidence that keratoconus has a hereditary component or is fully an inherited disease. Despite many studies, there is little concordance of results as to the location of a gene or genes for keratoconus. 11,12,14,20,21,60,61 In fact, it is remarkable how dissimilar the regions of the genome are that have been sug- gested. One potential explanation would be that the composite keratoconus trait is a complex genetic trait. A good model to discover complex genetic traits includes a reliable means of dening disease severity. Other than a few proprietary topog- raphy instruments (based solely on topography data), no such method currently exists. We present a severity rating scale, based on common clinical signs and easily obtained corneal topography indices, that corresponds well with clinician grading of severity, has very good reproducibility, and has a strong ability to separate normal corneas and those with abnormal but nonkeratoconic topographic features (such as refractive surgery or trauma) from those with keratoconus. This method also is not tied to any 1 particular topography instrument. It requires a skilled observer to detect clinical slit-lamp signs of keratoconus and an observer competent in reviewing topography maps for some segregation into the proper severity score. 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