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Results: From initial assessments, the KSS used 2 corneal topography indices: average corneal power and root mean square (RMS)
error for higher-order Zernike terms derived from the first 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 specificities ranging from 0.93 to 0.98. The sensitivity and
specificity for determining nonkeratoconus from keratoconus were
both 1.00. Validation set 2 showed k statistics of 0.94 and 0.95 for
794
Severity Paper
Test Dataset
An initial test set of 1012 eyes was assembled to
determine the combination of data ranges for each classification criterion. The test set included subjects that clinically
could be classified into each of these categories. The set
included 130 normal eyes, 41 atypical eyes, 7 keratoconussuspect eyes, and 834 eyes with keratoconus. Keratoconus
suspects had corneal topography patterns suspicious for the
disease but no slit-lamp or other clinical findings. Using 95%
confidence 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 defined 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
Increased grade for density, size, number, and location near or on the line of
sight (LOS).
795
McMahon et al
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
796
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 defined 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 final 5 features assessed were slit-lamp signs, topography
q 2006 Lippincott Williams & Wilkins
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
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
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
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
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
Affectedsevere disease
Severity Paper
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 flows 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).
797
McMahon et al
TABLE 4. Summary Statistics for 2 Keratoconus Measures, by KSS Level, Obtained from Test Set
ACP
Mean
Min
Max
SD
95% CI
HORMSE
Mean
Min
Max
SD
95% CI
43.82
41.10
47.66
1.30
41.2246.42
44.10
40.00
47.01
1.60
40.9044.30
44.57
40.86
46.83
2.24
40.0949.05
47.10
39.47
51.97
2.74
41.6252.58
53.89
52.01
55.98
1.11
51.6756.11
62.81
56.08
90.38
6.52
49.7775.85
0.42
0.23
0.75
0.07
0.280.56
0.60
0.40
1.0
0.14
0.320.88
0.70
0.51
0.96
1.61
03.93
1.98
0.26
9.48
1.19
04.36
3.14
0.89
8.00
1.30
0.545.74
5.03
1.11
55.66
4.27
013.57
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 topography has proved valuable in identifying cases of subtle or
forme fruste keratoconus.4549 Several analytical, topographybased 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 significant shortcomings 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 artificial intelligence.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 al55,56 have used an ultrasound biomicroscope (UBM) technique for grading and tracking disease
severity in keratoconus that compares favorably with corneal
topographybased KSI readings. However, although less
95% CI
0.695
0.854
0.762
0.863
0.5980.792
0.7990.910
0.6780.847
0.8070.920
0.904
0.8620.946
proprietary, UBMs are uncommon instruments, and the transfer of the authors technique to the clinical environment has
not been reported.
Li et al38 have developed an index, the KISA%, to grade
the presence or absence of keratoconus. Although this index
has the potential to define disease severity in keratoconus, the
developers have described its role only in defining normals,
keratoconus suspects, and those with the disease. The KISA%
index has been used to monitor changes in normal eyes of
unilateral keratoconus patients38 and in genetic screening,
where KISA% was used to distinguish keratoconus from
normal individuals.11,57
Rabinowitz58 has described a classification 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 findings of disease are found, but scissoring of the
retroilluminated reflex 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 definite AB/SRAX pattern.
Indices only
Indices and manual read
Indices and scarring
Indices, manual read, and scarring
Indices, manual read, scarring,
and slit-lamp signs
798
Sensitivity Specificity
1.00
1.00
1.00
0.90
0.64
0.95
1.00
1.00
0.93
0.98
In other classification schemes, the shape of the conenipple (round), oval, or globus has been used to classify
keratoconus, although these do not lend themselves to grading
severity. Last, Hom59 classified keratoconus into 4 stages, with
stage 1 having such early disease that spectacles are the first
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 suggested. 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
defining disease severity. Other than a few proprietary topography 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. However, objective
reads of masked data, computer-derived indices, and ultimately, computer-driven classification assignments are also
incorporated, which make this scale beneficial for use in
multicenter studies relying on a quantitative classification
scheme of keratoconus.
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