Accepted Manuscript

Keratoconus screening indices and their Diagnostic ability to Distinguish Normal from
Ectatic Corneas

Rohit Shetty, Harsha Rao, Pooja Khamar, Kanchan Sainani, Krishnapoojita Vunnava,
Chaitra Jayadev, Luci Kaweri

PII: S0002-9394(17)30286-6
DOI: 10.1016/j.ajo.2017.06.031
Reference: AJOPHT 10190

To appear in: American Journal of Ophthalmology

Received Date: 16 March 2017

Revised Date: 24 June 2017
Accepted Date: 27 June 2017

Please cite this article as: Shetty R, Rao H, Khamar P, Sainani K, Vunnava K, Jayadev C, Kaweri L,
Keratoconus screening indices and their Diagnostic ability to Distinguish Normal from Ectatic Corneas,
American Journal of Ophthalmology (2017), doi: 10.1016/j.ajo.2017.06.031.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.
 ACCEPTED MANUSCRIPT
Abstract:
Purpose: To compare the diagnostic ability of three Scheimpflug devices in
differentiating normal from ectatic corneas.

Design: Comparison of diagnostic instrument accuracy

Methods: This study included 42 normal eyes, 37 subclinical and 51

keratoconic eyes, seen in a tertiary eye care institute. Keratoconus-screening
indices were evaluated using the Pentacam, Galilei and Sirius. Sensitivity,

PT
specificity and area under receiver operating characteristic curve (AUC) were
calculated.

RI
Results: Highest sensitivity (100%) to diagnose keratoconus was seen for six
parameters on Pentacam and one in Galilei. None of the indices in Sirius
reached 100% sensitivity. For subclinical keratoconus, the highest sensitivity

SC
(100%) was seen for two parameters on Pentacam but for none of them in
Galilei and Sirius.

All parameters were strong enough to differentiate keratoconus (AUC

U
>0.9). On comparing the best parameters of all three machines, the AUC of
the Belin/Ambrosio enhanced ectasia total derivation (BAD-D) and the
AN
inferior-superior value (ISV) of Pentacam were statistically similar to that of
the Keratoconus Prediction Index (KPI) and Keratoconus probability (Kprob)
of Galilei (p =0.27) and 4.5 mm root mean square per unit area (RMS/A) back
M

of Sirius (p=0.55). When differentiating subclinical from normals, BAD-D was

similar to the surface regularity index (SRI) of Galilei (p=0.78) but was
significantly greater than the 8mm RMS/A back of Sirius (p=0.002).
D

Conclusion: Keratoconus indices measured by all three machines can

TE

effectively differentiate keratoconus from normal corneas. However, new cut

off values might be needed to differentiate subclinical from normal corneas.
C EP
AC
 ACCEPTED MANUSCRIPT

Keratoconus screening indices and their Diagnostic ability to Distinguish Normal

from Ectatic Corneas

(1) Authors: Rohit Shetty

Harsha Rao

PT
Pooja Khamar
Kanchan Sainani
Krishnapoojita Vunnava

RI
Chaitra Jayadev
Luci Kaweri

SC
(2) Affiliation:
Narayana Nethralaya Eye Institute
121/C Chord Road, Rajajinagar 1st R Block,

U
Bangalore 560010, India.
AN
(3) Short title: Diagnostic ability of keratoconus screening devices.

(4) Presented earlier: No

M
D

(5) Corresponding author:

Dr Luci Kaweri
TE

Cataract and Refractive Services,

Narayana Nethralaya Eye Hospital
121/C Chord Road, Rajaji nagar 1st R Block,
Bangalore 560010, India.
EP

Phone: +91-08066121400
e-mail:dr.lucikaweri@gmail.com
C
AC

1
 ACCEPTED MANUSCRIPT

Introduction:
Keratoconus is a disorder characterized by thinning and anterior protrusion of the
cornea.1 Prevalence of keratoconus varies from 4-60/100000 due to several definitions
and diagnostic criteria.2 Routine screening before myopic refractive surgery detects 1-
6% cases of subclinical and clinical keratoconus.3 Early diagnosis of these cases is of

PT
utmost importance as surgery on an undiagnosed keratoconic cornea may cause
unsatisfactory postoperative outcome and complications.4 Besides, the economic
burden of keratoconus treatment is high to the patients and their caretakers.5 Hence, it is

RI
important to identify those with the disease timely and accurately.

Clinical diagnosis of keratoconus in eyes with biomicroscopic, keratometric and

retinoscopic signs is not difficult.6 Corneal topography represents a true revolution in the

SC
diagnosis and management of keratoconus as it can detect subtle changes in the
anterior corneal surface that occur prior to the loss of corrected distance visual acuity
and the development of typical slit-lamp microscopy findings.7 Scheimpflug based

U
cameras, such as the Pentacam rotating Scheimpflug camera (Oculus, Wetzlar,
Germany), Galilei (Ziemer, Biel, Switzerland) and Sirius (Costruzione Strumenti
AN
Oftalmici, Florence, Italy) have shown promise in early detection of keratoconus.2 As the
Scheimpflug principle works with maximal possible depth of focus and minimal image
distortion, it provides valuable information from the anterior corneal surface to the
posterior lens surface.8 Further advances have led to the generation of a variety of
M

indices that allow quantification of the severity of corneal irregularity.9,10 The sensitivity
and specificity of keratoconus screening indices for Pentacam and Galilei have been
reported earlier but these were done as two separate studies in different population
D

groups.7, 11
TE

The purpose of this study was to determine the diagnostic ability of the indices of
these three Scheimpflug machines in distinguishing between keratoconus, subclinical
keratoconus and normal corneas and ascertain the strongest parameter of each device.
Study subjects underwent scans using all three machines, so that we could compare the
EP

keratoconus screening indices of each of them.

Methods:
C

Patient Inclusion:
AC

This study of diagnostic instrument accuracy was carried out at a tertiary eye care
center in Bangalore, India, with the approval of the Institutional ethics committee. The
study was carried out in accordance with the guidelines laid down by the Declaration of
Helsinki.

Fifty-one keratoconic eyes, 37 sub clinical keratoconus cases and 42 normal

volunteers were included in this study. A diagnosis of keratoconus was made6 if there
was (1) an irregular cornea determined by distorted keratometry mires, distortion of the
retinoscopic or ophthalmoscopic red reflex (or a combination of the two) and (2) at least
1 of the following biomicroscopic signs: Vogt’s striae; a 2 mm arc of Fleischer’s ring;

2
 ACCEPTED MANUSCRIPT

corneal scarring consistent with keratoconus. Only one eye was included if both eyes
had frank ectasia. Subclinical keratoconus12 was labeled if it was the fellow eye of a
patient with keratoconus or showed all the following features: (1) normal-appearing
cornea on slit-lamp biomicroscopy, keratometry, retinoscopy, and ophthalmoscopy; (2)
inferior–superior asymmetry and/or bow-tie pattern with skewed radial axes on the
tangential map of the Pentacam and (3) no history of contact lens use, ocular surgery, or
trauma. Normal volunteers were also scanned on all three machines and only one eye

PT
selected by randomization was included in the study.

Exclusion criteria were previous ocular surgery, corneal scarring, trauma,

RI
pregnancy or lactation, glaucoma and non-corneal causes of ocular astigmatism. For
contact lens wearing patients, they were asked to stop wearing contact lenses for 3
weeks in case of rigid contact lenses and 1 week for soft contact lenses before

SC
assessment.

Topography and data collection: All patients underwent topographic examinations

using the Pentacam, Galilei and Sirius in random order.

U
The Pentacam system uses a monochromatic blue light-emitting diode (LED) at
AN
475 nm and a Scheimpflug camera (180°) that rotates around the optical axes of the eye
to analyze the anterior segment. While the Pentacam has the option of 25 or 50 three-
dimensional scans, the Sirius has only a 25-scan setting with one Placido image option.
Hence, for better comparability, a scan setting of 25 was chosen in the Pentacam as
M

well. A total of 25 images are captured within 2 seconds, with each slit image composed
of 25,000 points including 500 true elevation points. Keratoconus indices from the
refractive and Belin Ambrosio Displays (BAD) of the Pentacam included the index of
D

surface variance (ISV), index of height asymmetry (IHA), index of vertical asymmetry
(IVA), index of height decentration (IHD), keratoconus index (KI), minimum sagittal
TE

curvature (Rmin), central keratoconus index (CKI), average pachymetric progression

index (RPIavg), maximum Ambrosio relation thickness (ARTmax) and Belin/Ambrosio
enhanced ectasia total derivation value (BAD-D)
EP

The Galilei G6 has a dual Scheimpflug rotating camera and an integrated

Placido’s disk. It uses a monochromatic slit-light source (blue LED at 470 nm). The
whole scan usually takes less than a minute to complete and gives information of more
C

than 122,000 data points. Placido and Scheimpflug images of the cornea are
simultaneously obtained in a single scan and used for anterior corneal measurements.
AC

Parameters used for our analyses were the keratoconus prediction index (KPI),
keratoconus probability (Kprob), cone location and magnitude index (CLMI), percentage
probability of keratoconus (PPK), inferior-superior index (IS), differential sector index
(DSI), surface asymmetry index (SAI), opposite sector index (OSI), surface regularity
index (SRI), center/surround index (CSI), irregular astigmatism index (IAI), and standard
deviation of corneal power (SDP).

The Sirius has a single Scheimpflug rotating camera combined with a Placido’s
disk. The 22 rings additionally provide height, slope, and curvature data, which are
obtained by an arc-step method with conic curves. The camera acquires a series of 25

3
 ACCEPTED MANUSCRIPT

Scheimpflug images, which provide data about the anterior cornea, posterior cornea,
anterior lens, and iris. Utilizing a proprietary method, information of the anterior cornea is
collated using data from both the Placido’s disk and Scheimpflug images. Data for the
posterior cornea, anterior lens, and iris are obtained from the Scheimpflug images.
Parameters studied were symmetry index front (SIf), symmetry Index back (SIb),
Baiocchi-Calossi-Versaci index (BCV) front, back and total, and 4.5 and 8 mm zone root
mean square values per unit area (RMS/A) front and back.

PT
A standard methodology was used to obtain measurements on each device with
the eye aligned to the visual axis by a central fixation light of the machine. Patients were

RI
asked to blink before each scan was taken. Scans with a quality specification of ‘‘OK’’
were taken for the analysis; low-quality or unacceptable scans were deleted and the
measurements retaken.

SC
Statistical Analyses:

Statistical analyses were performed using the Stata version 13.1 (StataCorp, College

U
Station, TX, USA) statistical software. As most of the continuous variables were non-
normally distributed, quantitative data were expressed as medians and quartiles and
AN
Kruskal Wallis test was used to compare the variables between the groups. Receiver-
operating characteristics (ROC) curves were used to distinguish clinical and subclinical
keratoconus from normal eyes. These curves are obtained by plotting sensitivity against
1-specificity, calculated for each value observed. The area under the ROC curves (AUC)
M

measures discrimination, which is the ability of the test to accurately classify eyes with
and without disease. An area of 1.0 represents a perfect test while an area of 0.5
represents a worthless test.13 The superiority of one parameter over the other was
D

tested by comparing the AUCs using the Z test.14

TE

In order to determine sensitivity, specificity, positive likelihood ratio (sensitivity/ [1-

specificity]), negative likelihood ratio ([1-sensitivity]/specificity), positive predictive value,
and negative predictive value for all keratoconus screening indices, the cut off values
provided by previous studies and company based parameters were used.7,11
EP

Results:
C

The mean patient age was 24.25 ± 6.18 years (range 12-37, males 30, females 22) in
AC

patients with keratoconus, 26.02 ± 7.01 years (range 14-60, males 8, females 29) in
subclinical keratoconus and 25.5 ± 4.9 years (range 19-44, males 14, females 28) in the
controls. There were 78 right eyes and 59 left eyes. Table I gives the median and
quartiles of all the parameters used for the analysis.

Tables II and III demonstrates the sensitivity, specificity, positive and negative
likelihood ratios, and positive and negative predictive values of different parameter sets
to differentiate eyes with keratoconus and subclinical keratoconus from normal eyes
based on the cut offs provide in earlier published studies and company based cut offs. In

4
 ACCEPTED MANUSCRIPT

order to distinguish keratoconus from controls, the highest sensitivity (100%) was seen
for ISV, IHA, IHD, KI, ARTmax and BAD-D on Pentacam, PPK on Galilei (100%) and
SIf, BCVf and 4.5mm RMS/A back (84.6%) on Sirius. The highest specificity was seen
for IHA (80%) on Pentacam, SRI and AAI on Galilei (100% each) and Slb, BCV and
8mm RMS/A back (100% each) on Sirius.

To distinguish subclinical keratoconus from controls, the highest sensitivity was

PT
seen for ISV and IHA (100%) on Pentacam, CSI (97.3%) on Galilei, and Slf (29.7%) on
Sirius, with the highest specificity seen for IHA and curvature radius (100%) on
Pentacam, OSI on Galilei (95.3 %) and SIb (100%) on Sirius.

RI
Table IV shows the AUCs. As indicated, all parameters were strong enough to
differentiate keratoconus (AUC > 0.9) and the highest strength was seen for ISV and

SC
BAD-D on Pentacam (0.972), KPI and Kprob on Galilei (0.993) and 4mm RMS/Aback
(0.983) on Sirius. The parameters with the best AUC to differentiate subclinical
keratoconus from normal eyes were BAD-D on Pentacam (0.887), SRI on Galilei (0.875)
and 8 mm RMS/A back on Sirius (0.730).

U
Figure 1 compares the parameters that showed the best AUC to differentiate
AN
keratoconus from normal eyes. AUC of BAD-D and ISV of Pentacam was statistically
similar to that of KPI of Galilei (p =0.27) and 4.5 mm RMS/A back of Sirius (p=0.55).
When differentiating subclinical from normals, BAD-D was similar to SRI of Galilei
(p=0.78) but was significantly greater than 8mm RMS/A back of Sirius (p=0.002). AUC
M

of SRI of Galilei was also significantly greater than 8 mm RMS/A back of Sirius
(p=0.026, Figure 2).
D

Discussion:
TE

Several technologies have been introduced to evaluate features of the corneal

surface in normal and keratoconic corneas including Placido disk-based topography, slit
scanning topography (Orbscan), and Scheimpflug system analyzer (Pentacam, Sirius
and Galilei). The Scheimpflug placido imaging technology has been reported to be
EP

highly reproducible and repeatable.8 The range and normal values of corneal
tomographic parameters obtained by the Pentacam and Galilei have previously been
reported.7,11 Our study reports the characteristics of keratoconus indices measured with
Pentacam, Galilei and Sirius corneal topographers in eyes with keratoconus, subclinical
C

keratoconus and controls to determine their their predictive ability to differentiate normal
corneas from ectatic ones. As each of these machines use different indices for
AC

keratoconus screening, direct comparison is not possible.

Sensitivity and specificity vary with the cut-off chosen for each diagnostic test and
are not intrinsic to the test but critically dependent upon the clinical context.15 The ROC
curve graphically displays the trade-off between sensitivity and specificity. The overall
accuracy can be expressed as the AUC and provides a useful parameter for comparing
the test performance.15

Majority of parameters had sufficient strength (AUC > 0.90) to differentiate

5
 ACCEPTED MANUSCRIPT

keratoconus from normal corneas (Table IV). The same was not true when
distinguishing subclinical keratoconus from controls. An earlier study by Feizi S et al7
showed similar findings while determining the predictive ability of Galilei in distinguishing
subclinical keratoconus and keratoconus from normal corneas. These screening indices
had sufficient strength (AUC > 0.8) in distinguishing keratoconus from normal but could
not differentiate between subclinical keratoconus and controls (AUC<0.8). Hashemi et
al11 found that BAD-D on Pentacam was the strongest indicator to detect both subclinical

PT
and clinical keratoconus. They found ISV and IVA to be strong indicators as well but the
same was not true in our study probably due to differing diagnostic criteria for subclinical
keratoconus. A literature search did not reveal any previous studies comparing

RI
keratoconus screening indices of the Sirius topographer.

Pentacam’s BAD-D was found to be strong parameter to differentiate both

SC
keratoconus and subclinical keratoconus from normals (Figure 1 and 2). A possible
reason for this is that BAD-D is a combination of anterior elevation at the minimum
thickness point, posterior elevation at the minimum thickness point, change in anterior
elevation, change in posterior elevation, corneal thickness at minimum thickness point,

U
location of thinnest point, pachymetric progression, Ambrósio relational thickness and
Kmax.16 Each parameter is displayed individually as a standard deviation and then a
AN
final overall reading is obtained based on a regression analysis to maximize the
separation of normal corneas from those with keratoconus.17

Inferior-superior value on Pentacam is the power difference between five points

M

of the inferior hemisphere and five points of the superior hemisphere of the corneal
region located at 3 mm from the corneal apex at spatial intervals of 30°. 16 A positive
value indicates higher inferior curvature while a negative value indicates higher superior
D

curvature. This index also showed a good strength in diagnosing keratoconus.

TE

Galile’s KPI is also a multivariate index like BAD-D of Pentacam and is calculated
by a combination of 8 topographic indices using a linear discriminant function. These
indices are: Sim K1, Sim K2, SAI, DSI, OSI, CSI, IAI and AA. Kprob is the probability
that a keratoconic pattern was detected based on the anterior surface axial curvature.
EP

The SRI on the Galilei is an index of regularity in the central 4.5 mm diameter of the
cornea (it comprises the central ten rings of the Placido Disc) and quantifies power
gradient differences between successive pairs of rings in 256 equidistant
C

semi-meridians. SDP is the value of the standard deviation of the total corneal power.
AC

Root Mean Square on the Sirius represents the deviation of the surface being
examined from the asphero-toric best-fit surface characterized by a flat radius, steep
radius, asphericity and axis. If the RMS is low, the surface of the cornea in the area
delimited by the given diameter is very regular; higher the RMS, the more irregular the
corneal surface is. RMS/A: Root Mean Square per unit of area.

For all machines, the multivariate indices i.e those which were combination of
different topographic indices, were found to have the best diagnostic capability. The
main deterrent to the direct comparison of these topographic indices is the fact that each

6
 ACCEPTED MANUSCRIPT

index has a high degree of specificity for the corneal topographer for which it has been
developed and cannot be directly extrapolated to other corneal topographers.16

Therefore we compared the AUC for the best parameters of each machine. For
keratoconus screening, BAD-D and ISV of Pentacam were similar to KPI and Kprob of
Galilei and 4mm RMS/Aback of Sirius whereas for subclinical keratoconus screening
BAD-D was similar in strength to SRI and both were stronger than 8mmRMS/A back.

PT
Topographic screening tests help reduce to a minimum the number of incorrectly
classified corneal anomalies. Conditions like corneal warpage can have topographic

RI
changes similar to ectasia and some healthy corneas can present with isolated
topographic findings mimicking early keratoconus. The need of the hour is an objective
method, which can accurately differentiate normal from abnormal. Therefore,

SC
determining the predictive ability of these indices is of importance. In the current study,
we have not compared the instruments across different grades of keratoconus and only
those parameters of each machine that can be used as keratoconus screening indices
have been included.

U
In conclusion, screening indices from all three Scheimpflug devices can be used
AN
for the diagnosis of keratoconus with good strength but the cut offs provided in earlier
studies and by companies are not adequate to differentiate subclinical keratoconus from
normals. A combination of various indices may help to distinguish and diagnose
subclinical keratoconus.
M
D
TE

Acknowledgements:
EP

This study received no funding from any source

None of the authors have any financial interests to disclose

C
AC

References:

1. Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998;42:297– 319.

2. Finis D, Ralla B, Karbe M, Borrelli M, Schrader S, Geerling G. Comparison of two
different scheimpflug devices in the detection of keratoconus, regular
astigmatism, and healthy corneas. J Ophthalmol. 2015;2015:315281.
3. Varssano D, Kaiserman I, Hazarbassanov R. Topographic patterns in refractive
surgery candidates. Cornea 2004;23:602‐607.
4. Seiler T, Quurke AW. Iatrogenic keratectasia after LASIK in a case of forme fruste
keratoconus. J Cataract Refract Surg 1998;24:1007‐1009.

7
 ACCEPTED MANUSCRIPT

5. Rebenitsch RL, Kymes SM, Walline JJ, Gordon MO. The lifetime economic
burden of keratoconus: a decision analysis using a markov model. Am J
Ophthalmol. 2011 May;151(5):768-773.e2.
6. de Sanctis U, Loiacono C, Richiardi L, Turco D, Mutani B, Grignolo FM.
Sensitivity and specificity of posterior corneal elevation measured by Pentacam in
discriminating keratoconus/subclinical keratoconus. Ophthalmology. 2008
Sep;115(9):1534-9.

PT
7. Feizi S, Yaseri M, Kheiri B. Predictive Ability of Galilei to Distinguish Subclinical
Keratoconus and Keratoconus from Normal Corneas. J Ophthalmic Vis Res.
2016 Jan-Mar;11(1):8-16.

RI
8. Shetty R, Arora V, Jayadev C, Nuijts RM, Kumar M, Puttaiah NK, Kummelil MK.
Repeatability and agreement of three Scheimpflug-based imaging systems for
measuring anterior segment parameters in keratoconus. Invest Ophthalmol Vis

SC
Sci. 2014 Jul 29;55(8):5263-8.
9. Maeda N, Klyce SD, Smolek MK, Thompson HW. Automated keratoconus
screening with corneal topography analysis. Invest Ophthalmol Vis Sci
1994;35:2749 –57.

U
10. Rabinowitz YS, Rasheed K. KISA% index: a quantitative videokeratography
algorithm embodying minimal topographic criteria for diagnosing keratoconus. J
AN
Cataract Refract Surg 1999;25:1327–35.
11. Hashemi H, Beiranvand A, Yekta A, Maleki A, Yazdani N, Khabazkhoob M.
Pentacam top indices for diagnosing subclinical and definite keratoconus. J Curr
Ophthalmol. 2016 Mar 29;28(1):21-6.
M

12. Serdarogullari H, Tetikoglu M, Karahan H, Altin F, Elcioglu M. Prevalence of

keratoconus and subclinical keratoconus in subjects with astigmatism using
pentacam derived parameters. J Ophthalmic Vis Res. 2013 Jul;8(3):213-9.
D

13. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver
operating characteristic (ROC) curve. Radiology. 1982;143(1): 29–36.
TE

14. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the ares under two or
more correlated receiver operating characteristic curves: a nonparametric
approach, Biometrics 1988;44:837-845
EP

15. Florkowski CM. Sensitivity, specificity, receiver-operating characteristic (ROC)

curves and likelihood ratios: communicating the performance of diagnostic tests.
Clin Biochem Rev. 2008 Aug;29 Suppl 1:S83-7.
16. Cavas-Martínez F, De la Cruz Sánchez E, Nieto Martínez J, Fernández Cañavate
C

FJ, Fernández-Pacheco DG. Corneal topography in keratoconus: state of the art.

Eye Vis (Lond). 2016 Feb 22;3:5.
AC

17. Belin MW, Ambrósio R. Scheimpflug imaging for keratoconus and ectatic

Figure Legends:
Figure 1 compares the parameters that showed the best AUCs to differentiate
keratoconus from normal eyes

Figure 2 compares the parameters that showed the best AUCs to differentiate
subclinical keratoconus from normal eyes

8
 ACCEPTED MANUSCRIPT

Table of Contents Statement

In this retrospective, observational study, the diagnostic ability of keratoconus screening
indices of Pentacam, Galilei and Sirius in distinguishing between Keratoconus,
Subclinical keratoconus and normal corneas is determined. The strongest parameter of
each device is ascertained and compared to that of other machines.

PT
RI
U SC
AN
M
D
TE
C EP
AC

9
 ACCEPTED MANUSCRIPT

PENTACAM GALILEI SIRIUS

Median (25%, 75%) Median (25%, 75%) Median (25%, 75%)
Normal Subclinical KC p- p- Normal Subclinical KC p- p-value2 Normal Subclinical KC KC p- p-value2
KC value1 value2 KC value1 valu
e1
ISV 16 23 77 .0002 .0001 KPI 2.55 8.81 98.35 .048 <.0001 Slf 0.335 0.43 6.24 .626 <.0001
(13,19) (17,26) (49.5,103) (0,9.51) (1.02,13.6) (58.2,100) (0.05,0.48) (-0.08, 0.85) (2.65,8.44)
IHA 4.3 5.2 24.9 .0876 .0001 Kprob 3.07 7.43 100 .052 <.0001 Slb -0.005 0.04 1.275 .085 <.0001
(1.3,8) (2.9,9.4) (12.7,44)

PT
(1.75,8.18) (2.45,14.2) (99.2, 100) (-.08,0.07) (-0.05, 0.1) (0.66,2.04)

IVA 0.13 0.16 0.74 .0934 .0001 CLMI 0.69 0.47 5.93 .004 <.0001 BCVf 0.235 0.34 2.93 .198 <.0001
(0.1,0.17) (0.11,0.21) (0.40,1.02) aa (0.4,1) (0.25,0.62) (3.61,10.12) (.08, 0.44) (0.19, 0.59) (1.5, 4.72)

RI
IHD 0.01 0.02 0.09 .0504 .0001 PPK 0.69 0.43 99.8 .005 <.0001 BCVb 0 0.14 2.87 .010 <.0001
(0.01,0.02) (0.01,0.02) (0.51,0.16) (0.37,1.31) (0.27,0.6) (77.25, 100) (0, 0.22) (0.01, 0.44) (1.54,4.10)

SC
KI 1.02 1.04 1.185 .0418 .0001 IS 0.52 0.72 6.65 .014 <.0001 BCV 0.13 0.18 2.68 .257 <.0001
(1.01, .03) (1.02,1.05) (1.1,1.27) (0.29,0.88) (0.47,1.12) (3.68, 10.82) (0.04, (0.09, 0.37) (1.48,4.77)
0.35)
R 7.58 7.34 6.29 .0001 .0001 DSI 1.54 1.85 7.99 .050 <.0001 4.5mm 0.02 0.03 0.22 .487 <.0001

U
(7.43,7.86) (7.2,7.55) (5.97,6.8) (1.06,1.85) (1.34,2.53) (4.63, 11.21) RMS/A (0.02, (0.02, 0.03) (0.11, 0.3)
Front 0.03)

AN
CKI 1.01 1.01 1.05 SAI 0.65 0.78 3.69 .017 <.0001 4.5mm 0.09 0.12 0.50 .003 <0.0001
(1, .01) (1.01,1.01) (1.03,1.08) (0.4,0.77) (0.59,1.01) (2.22, 5.48) RMS/A (0.07, (0.09, 0.16) (0.31,0.78)
back 0.12)

M
RPI 0.98 1.17 1.74 .0001 .0001 OSI 1.1 1.2 7.42 .873 <.0001 8mm 0.045 0.05 0.22 .375 <0.0001
avg (0.88,1.07) (1.12,1.25) (1.47,2.19) (0.78,1.38) (0.78,1.56) (4.10, 10.44) RMS/A (0.03, (0.04, 0.07) (0.11,0.29)
Front 0.07)
ART 434.5 333 183 .0001 .0001 SRI 0.34 0.79 1.69 .0001 <.0001 8mm 0.11 (0.1, 0.155 (0.12, 0.34 (0.23, .004 <0.0001

D
max (379,489) (305, 376) (134, 215) (0.18,0.55) (0.71,0.95) (1.45, 1.91) RMS/A 0.145) 0.19) 0.50)
back

TE
BAD- 0.98 2.03 6.97 .0001 .0001 CSI 0.47 0.52 2.56 .390 <.0001
D (0.62,1.34) (1.72,2.49) (5.47, (0.28,0.62) (0.39, (1.57, 3.53)
9.78) 0.63)
EP
IAI 0.35 0.45 0.66 .0001 <.0001
(0.34, 0.4) (0.44,0.49) (0.55, 0.78)
SDP 0.68 1.40 2.98 <0.00 <0.0001
(0.55, (1.25,1.64) (1.95,4.11) 01
C

0.98)
AC

Table I gives the median and quartiles of all the parameters used for statistical analysis. Kruskal Wallis test was used to compare
the variables between the groups.
 ACCEPTED MANUSCRIPT

p-value1- shows the comparison between normal and subclinical keratoconus.

p-value2- shows the comparison between normal and keratoconus.

PT
Pentacam: Index of surface variance (ISV), Index of height asymmetry (IHA), Index of vertical asymmetry (IVA), Index of height decentration (IHD), Keratoconus index (KI), Minimum sagittal
curvature (Rmin), Central keratoconus index (CKI), Average pachymetric progression index (RPIavg), Maximum Ambrosio relation thickness (ARTmax) and Belin/Ambrosio enhanced ectasia total

RI
derivation value (BAD-D)

Galilei: Keratoconus prediction index (KPI), Keratoconus probability (Kprob), Cone location and magnitude index (CLMI), Percentage probability of keratoconus (PPK), Inferior-superior index (IS),

SC
Differential sector index (DSI), Surface asymmetry index (SAI), Opposite sector index (OSI), Surface regularity index (SRI), Centre/surround index (CSI), Irregular astigmatism index (IAI), Standard
deviation of corneal power (SDP).

Sirius: Symmetry index front (SIf), Symmetry Index back (Sib), Baiocchi-Calossi-Versaci index (BCV) front, back and total, 4.5 and 8mm zone root mean square values per unit area (RMS/A) front

U
and back

AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT
Table II demonstrates the sensitivity (with ±95% confidence interval),
specificity (with ±95% confidence interval), positive and negative likelihood
ratios (LR), positive and negative predictive value (PPV and NPV) for different
parameter sets to differentitate eyes with keratoconus from normal eyes
PENTACAM
Cut off Sensitivity Specificity LR+ LR- PPV NPV
(95% CI) (95%CI)
ISV >41 100 (85.8-100) 70 (57.9-80.4) 3.24 0.0287 53.3 100
IHA >21 70.8 (48.9-87.4) 80 (68.7-88.6) 3.54 0.365 54.8 88.9

PT
IVA >0.32 100 (85.8-100) 70 (57.9- 80.4) 3.24 0.0287 53.3 100
IHD >0.016 100 (85.8-100) 45.7 (33.7-58.1) 1.84 0.0437 38.7 100
KI >1.07 100 (85.8-100) 65.7(53.4-76.7) 2.84 0.0305 50 100
R <6.71 91.7 (73-99) 77.1 (65.6-86.3) 4.01 0.108 57.9 96.4

RI
CKI >1.03 79.2 (57.8-92.9) 68.6 (56.4-79.1) 2.52 0.304 46.3 90.6
RPIavg >1.06 95.8 (78.9-99.9) 47.1 (35.1-59.4) 1.81 0.0884 38.3 97.1
ARTmax < 390 100 (85.5-100) 55.7 (43.3-67.6) 2.21 0.0359 43.6 100
BAD-D >2.6 100 (85.8-100) 61.4 (49-72.8) 2.53 0.0326 47.1 100

SC
GALILEI
Cut off Sensitivity Specificity LR+ LR- PPV NPV
(95% CI) (95%CI)
KPI >18.55 96.2 (86.8-99.5) 95.2 (83.8-99.4) 20.2 0.0404 96.2 95.2

U
KPROB >25.55 96.2 (86.8-99.5) 95.2 (83.8-99.4) 20.2 0.0404 96.2 95.2
PPK >45 100 (93.2-100) 28.6 (15.7-44.6) 1.4 0.0325 63.4 100
AN
IS >2.33 88.5 (76.6-95.6) 95.2 (83.8-99.4) 18.6 0.121 95.8 87
DSI >3.26 90.4 (79-96.8) 97.6 (87.4-99.9) 25.7 0.108 97.9 89.1
SAI >1.25 92.3 (81.5-97.9) 95.2 (83.8-99.4) 19.4 0.0808 96 90.9
OSI >2.04 92.3 (81.5-97.9) 95.2 (83.8-99.4) 19.4 0.0808 96 90.9
SRI >1.52 65.4 (50.9-78) 100 (91.6-100) 56 0.353 100 70
M

CSI <0.7 13.5 (5.59-25.8) 14.3 (5.43-28.5) 0.157 6.06 16.3 11.8
IAI >0.58 67.3 (52.9-79.7) 100 (91.6-100) 57.6 0.334 100 71.2
SDP >1.93 98.1 (89.7-100) 83.3 (68.6-93) 5.88 0.0231 87.9 97.2
D

SIRIUS
Cut off Sensitivity Specificity LR+ LR- PPV NPV
(95% CI) (95%CI)
TE

Slf >1.172 84.6 (71.9-93.1) 95.2 (83.8-99.4) 17.8 0.162 95.7 83.3
Slb >0.324 88.5 (76.6-95.6) 100 (91.6-100) 75.5 0.124 100 87.5
BCVf >1.2 84.6 (71.9-93.1) 95.2 (83.8-99.4) 17.8 0.162 95.7 83.3
BCVb >1.2 78.8 (65.3-88.9) 100 (91.6-100) 67.3 0.22 100 79.2
EP

BCV >1.2 78.8 (65.3-88.9) 97.6 (87.4-99.9) 33.1 0.217 97.6 78.8
4mm >0.131 63.5 (49-76.5) 95.2 (83.8-99.4) 13.3 0.384 94.3 67.8
RMSF/A
4mmRM >0.269 84.6 (71.9-93.1) 97.6 (87.4-99.9) 35.5 0.158 97.8 83.7
C

Sb/A
8mmRM >0.131 69.2 (54.9-81.3) 95.2 (83.8-99.4) 14.5 0.323 94.7 71.4
S/A
AC

Front
8mmRM >0.269 78.8 (65.3-88.9) 100 (91.6-100) 67.3 0.22 100 79.2
S/Aback
Pentacam: Index of surface variance (ISV), Index of height asymmetry (IHA), Index of vertical asymmetry (IVA),
Index of height decentration (IHD), Keratoconus index (KI), Minimum sagittal curvature (Rmin), Central keratoconus
index (CKI), Average pachymetric progression index (RPIavg), Maximum Ambrosio relation thickness (ARTmax) and
Belin/Ambrosio enhanced ectasia total derivation value (BAD-D)

Galilei: Keratoconus prediction index (KPI), Keratoconus probability (Kprob), Cone location and magnitude index
(CLMI), Percentage probability of keratoconus (PPK), Inferior-superior index (IS), Differential sector index (DSI),
Surface asymmetry index (SAI), Opposite sector index (OSI), Surface regularity index (SRI), Centre/surround index
(CSI), Irregular astigmatism index (IAI), Standard deviation of corneal power (SDP).

Sirius: Symmetry index front (SIf), Symmetry Index back (Sib), Baiocchi-Calossi-Versaci index (BCV) front, back and
total, 4.5 and 8mm zone root mean square values per unit area (RMS/A) front and back
 ACCEPTED MANUSCRIPT
Table III demonstrates the sensitivity (with ±95% confidence interval),
specificity (with ±95% confidence interval), positive and negative likelihood
ratios, positive and negative predictive value for different parameter sets to
differentiate eyes with subclinical keratoconus from normal eyes

PENTACAM
Cut off Sensitivity Specificity LR+ LR- PPV NPV
(95% CI) (95%CI)
ISV >37 100 (2.5-100) 96.2 (89.3-99.2) 17.1 0.261 25 100
IHA >19 100(2.5-100) 100 (95.4-100) 120 .252 100 100

PT
IVA >0.28 10.8(3.03-25.4) 95.3(84.2-99.4) 2.32 0.935 66.7 55.4
IHD >0.014 43.2(27.1-60.5) 67.4(51.5-80.9) 1.33 .842 53.3 58
KI >1.07 100 0 . . . .
R <6.71 2.7(.0684-14.2) 100(91.8-100) 3.47 0.972 100 54.4
CKI >1.03 2.7(0.684-14.2) 97.7 (87.7-99.9) 1.16 0.996 50 53.8

RI
RPIavg >1.06 83.8(68-93.8) 74.4(58.8-86.5) 3.28 0.218 73.8 84.2
ARTmax <340 86.5(71.2-95.5) 69.8(53.9-82.8) 2.86 .194 71.1 85.7
BAD-D >1.6 83.8(68-93.8) 86(72.1-94.7) 6 .188 .089 86
GALILEI
Cut off Sensitivity Specificity LR+ LR- PPV NPV

SC
(95% CI) (95%CI)
KPI >5 56.8(39.5-72.9) 58.1(42.1-73) 1.36 .744 53.8 61
KPROB >11.6 29.7(15.9-47) 86(72.1-94.7) 2.13 .817 64.7 58.7
PPK >25 81.1(64.8-92) 9.3(2.59-22.1) .894 2.03 43.5 36.4
IS >1.6 10.8(3.03-25.4) 90.7(77.9-97.4) 1.16 .983 50 54.2

U
DSI >1.73 54.1(36.9-70.5) 69.8(53.9-82.8) 1.79 .659 60.6 63.8
SAI >0.895 43.2(27.1-60.5) 90.7(77.9-97.4) 4.65 .626 80 65
OSI >1.85 21.6(9.83-38.2) 95.3(84.2-99.4) 4.65 .822 80 58.6
AN
SRI >0.735 67.6(50.2-82) 86(72.1-94.7) 4.84 .377 80.6 75.5
CSI <0.9 97.3(85.8-99.9) 4.65(.568-15.8) 1.02 .581 46.8 66.7
IAI >0.45 54.1(36.9-70.5) 81.4(66.6-91.6) 2.91 .564 71.4 67.3
SDP >1.065 89.2(74.6-97) 81.4(66.6-91.6) 4.79 .133 80.5 89.7
SIRIUS
M

Cut off Sensitivity Specificity LR+ LR- PPV NPV

(95% CI) (95%CI)
Slf >0.757 29.7(15.9-47) 79.1(64-90) 1.42 .889 55 56.7
Slb >0.214 16.2(6.19-32) 100(91.8-100) . .838 100 58.1
D

BCVf >0.8 10.8(3.03-25.5) 83.7(69.3-93.2) .66 1.07 36.4 52.2

BCVb >0.8 5,41(.661-18.2) 97.7(87.7-99.9) 2.32 .968 66.7 54.5
BCV >0.8 8.11(1.7-21.9) 97.7(87.7-99.9) 3.49 .941 75 55.3
4mm >0.088 8.11(1.7-21.9) 93(80.9-98.5) 1.16 .988 50 54.1
TE

RMSF/A
4mmRM >0.212 13.5(4.54-28.8) 97.7(87.7-99.9) 5.81 .885 83.3 56.8
Sb/A
8mmRM >0.088 10.8(3.03-25.4) 79.1(64-90) .517 1.13 30.8 50.7
S/A
EP

Front
8mmRM >0.212 16.2(6.19-32) 100(91.8-100) . .838 100 58.1
S/Aback
C

Pentacam: Index of surface variance (ISV), Index of height asymmetry (IHA), Index of vertical asymmetry (IVA),
Index of height decentration (IHD), Keratoconus index (KI), Minimum sagittal curvature (Rmin), Central keratoconus
AC

index (CKI), Average pachymetric progression index (RPIavg), Maximum Ambrosio relation thickness (ARTmax) and
Belin/Ambrosio enhanced ectasia total derivation value (BAD-D)

Galilei: Keratoconus prediction index (KPI), Keratoconus probability (Kprob), Cone location and magnitude index
(CLMI), Percentage probability of keratoconus (PPK), Inferior-superior index (IS), Differential sector index (DSI),
Surface asymmetry index (SAI), Opposite sector index (OSI), Surface regularity index (SRI), Centre/surround index
(CSI), Irregular astigmatism index (IAI), Standard deviation of corneal power (SDP).

Sirius: Symmetry index front (SIf), Symmetry Index back (Sib), Baiocchi-Calossi-Versaci index (BCV) front, back and
total, 4.5 and 8mm zone root mean square values per unit area (RMS/A) front and back
 ACCEPTED MANUSCRIPT

KERATOCONUS
PENTACAM GALILEI SIRIUS

PT
ROC 95% CI SE ROC 95% CI SE ROC 95% CI SE

RI
ISV 0.972 0.934 1.000 0.019 KPI 0.993 0.984 1.000 0.004 Slf 0.921 0.856 0.983 0.031

IHA 0.892 0.826 0.958 0.033 KPROB 0.993 0.984 1.000 0.004 Slb 0.941 0.879 1.000 0.031

SC
IVA 0.955 0.913 0.996 0.0212 CLMIaa 0.966 0.931 1.000 0.017 BCVf 0.940 0.885 0.994 0.027

U
IHD 0.968 0.935 1.000 0.016 PPK 0.968 0.936 1.000 0.016 BCVb 0.969 0.930 1.000 0.019

AN
KI 0.954 0.910 1.000 0.024 ISD 0.980 0.959 1.000 0.010 BCV 0.957 0.906 1.000 0.026

R 0.978 0.948 1.00 0.015 DSI 0.983 0.964 1.000 0.009 4.5mm RMSF/A 0.954 0.906 1.000 0.024

M
CKI 0.900 0.828 0.971 0.036 SAI 0.984 0.965 1.000 0.009 4.5mmRMSb/A back 0.983 0.962 1.000 0.010

D
RPIavg 0.962 0.921 1.000 0.021 OSI 0.983 0.961 1.000 0.011 8mmRMSF/A Front 0.919 0.861 0.977 0.029

TE
ARTma 0.958 0.910 1.000 0.022 SRI 0.992 0.979 1.000 0.006 8mmRMSb/A 0.965 0.927 1.000 0.019

BAD-D 0.972 0.932 1.000 0.020 CSI 0.906 0.834 0.977 0.036
EP
IAI 0.973 0.948 0.997 0.012
C

SDP 0.986 0.966 1.000 0.010

AC

SUBCLINICAL KERATOCONUS
PENTACAM GALILEI SIRIUS

ROC 95% CI SE ROC 95% CI SE ROC 95% CI SE

 ACCEPTED MANUSCRIPT

ISV 0.739 0.629 0.848 0.058 KPI 0.629 0.51 0.75 0.062 Slf 0.531 0.40 0.66 0.066

IHA 0.611 0.48 0.73 0.063 KPROB 0.626 0.50 0.75 0.064 Slb 0.612 0.48 0.73 0.064

PT
IVA 0.609 0.48 0.73 0.065 CLMIaa 0.314 0.19 0.43 0.062 BCVf 0.583 0.45 0.71 0.064

RI
IHD 0.627 0.50 0.75 0.063 PPK 0.318 0.19 0.44 0.062 BCVb 0.668 0.55 0.78 0.059

KI 0.631 0.50 0.75 0.064 ISD 0.595 0.64 0.72 0.046 BCV 0.573 0.44 0.70 0.064

SC
R 0.771 0.66 0.88 0.053 DSI 0.627 0.50 0.75 0.064 4.mm RMSF/A 0.545 0.42 0.66 0.062

CKI 0.576 0.47 0.68 0.052 SAI 0.656 0.53 0.77 0.062 4mmRMSb/A 0.692 0.57 0.80 0.059

U
RPIavg 0.883 0.804 0.963 0.040 OSI 0.510 0.37 0.64 0.067 8mmRMSF/A Front 0.557 0.43 0.68 0.064

AN
ARTmax 0.850 0.765 0.934 0.043 SRI 0.875 0.79 0.95 0.040 8mmRMSb/A 0.730 0.61 0.84 0.056

M
BAD-D 0.887 0.810 0.964 0.039 CSI 0.556 0.42 0.68 0.065

IAI 0.858 0.77 0.94 0.043

D
SDP 0.916 0.85 0.98 0.033

TE
EP
Table IV shows the receiver operating characteristics (ROC) area under the curve (AUC) (with ±95% confidence interval) and
C

standard error.
AC

Pentacam: Index of surface variance (ISV), Index of height asymmetry (IHA), Index of vertical asymmetry (IVA), Index of height decentration (IHD), Keratoconus index (KI), Minimum sagittal
curvature (Rmin), Central keratoconus index (CKI), Average pachymetric progression index (RPIavg), Maximum Ambrosio relation thickness (ARTmax) and Belin/Ambrosio enhanced ectasia total
derivation value (BAD-D)

Galilei: Keratoconus prediction index (KPI), Keratoconus probability (Kprob), Cone location and magnitude index (CLMI), Percentage probability of keratoconus (PPK), Inferior-superior index (IS),
Differential sector index (DSI), Surface asymmetry index (SAI), Opposite sector index (OSI), Surface regularity index (SRI), Centre/surround index (CSI), Irregular astigmatism index (IAI), Standard
 ACCEPTED MANUSCRIPT

deviation of corneal power (SDP).

Sirius: Symmetry index front (SIf), Symmetry Index back (Sib), Baiocchi-Calossi-Versaci index (BCV) front, back and total, 4.5 and 8mm zone root mean square values per unit area (RMS/A) front

PT
and back

RI
U SC
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC
 ACCEPTED MANUSCRIPT

PT
RI
U SC
AN
M
D
TE
EP
C
AC