Yang 2021.

Study characteristics
Patient Sampling	Cross‐sectional, observational study that recruited participants at the Casey Eye Institute at Oregon Health and Science University (OHSU), Portland, Oregon. Age‐matched normal participants were recruited from volunteers and people seeking refractive surgery consultation. All participants were aged 18 years or older.
Patient characteristics and setting	A clinical diagnosis of keratoconus was established using a combination of corrected distance visual acuity (CDVA), slit‐lamp physical findings, topographic patterns, and the quantitative topography KISA%. Each keratoconic eye was assigned to 1 of the 3 keratoconic subgroups according to following classification scheme. Manifest keratoconus: slit‐lamp findings associated with keratoconus (Vogt's striae, Fleischer's ring, Munson's sign, iron ring, Rizzuti's sign, and apparent focal corneal bulging and thinning) or CDVA < 20/20; topography characteristic of keratoconus (asymmetric bowtie with a skewed radial axis, central or inferior steep zone, and claw shape); and KISA% > 100%. Subclinical keratoconus: CDVA ≥ 20/20; no slit‐lamp findings of keratoconus; topography characteristic of keratoconus or pellucid marginal degeneration; and KISA% > 100%. Forme fruste keratoconus: the better eye of people with asymmetric keratoconus (AKC) with CDVA ≥ 20/20; no slit‐lamp findings of keratoconus; and KISA% < 100%. Age‐matched normal participants were recruited from volunteers and people seeking refractive surgery consultation. All normal eyes had CDVA ≥ 20/20, no signs of keratoconus on slit‐lamp examination, regular axial power map topography pattern (round, oval, symmetric bowtie, etc.), KISA% < 100%, and no ocular pathology other than myopia or hyperopia. Exclusion criteria: previous corneal surgeries, recent contact lens usage (soft contact lens within 1 week or rigid gas‐permeable lens within 3 weeks), inability to give informed consent, or inability to maintain stable fixation for imaging. Severe keratoconus with corneal scarring has unpredictable corneal and epithelial thickness patterns and does not pose a challenge for clinical diagnosis.
Index tests	A 2‐step decision tree. Step 1 uses quantitative OCT pachymetric and epithelial thickness map parameters. If any of the 4 parameters listed in the previous section exceeds the cut‐off, the eye is suspicious for keratoconus and proceeds to step 2. If none of the 4 parameters exceeds the cut‐off, then the eye is considered normal and does not require step 2 examination. Step 2 requires a human grader to visually inspect the corneal and epithelial thickness maps and search for characteristic keratoconic map patterns of coincident thinning and concentric epithelial thinning.
Target condition and reference standard(s)	Unclear who made the diagnosis. All cases were diagnosed before the analysis with the 2‐step decision tree.
Flow and timing	Unclear if all cases were diagnosed by the same cornea specialists. All cases were included in the analysis.
Comparative	Not applicable
Notes	Supported by the National Institutes of Health, Bethesda, Maryland, USA (R01EY028755, R01EY029023, T32EY023211, and P30EY010572; E. Pavlatos, D. Huang, and Y. Li); a research grant and equipment support from OptoVue, Inc., Fremont, California (D. Huang and Y. Li); unrestricted grants to Casey Eye Institute from Research to Prevent Blindness, Inc., New York, New York (E. Pavlatos, W. Chamberlain, D. Huang, and Y. Li); National Natural Science Foundation of China, Beijing, China (81900830; Y. Yang). The sponsors did not participate in the data collection, data management, or data analysis in the study.
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient selection
Was a consecutive or random sample of patients enrolled?	No
Was a case‐control design avoided?	No
Did the study avoid inappropriate exclusions?	No
Could the selection of patients have introduced bias?		High risk
Are there concerns that the included patients and setting do not match the review question?			High
DOMAIN 2: Index test (All tests)
Were the index test results interpreted without knowledge of the results of the reference standard?	Yes
If a threshold was used, was it pre‐specified?	Unclear
Was the model designed in an appropriate manner?	Yes
Could the conduct or interpretation of the index test have introduced bias?		Low risk
Are there concerns that the index test, its conduct, or interpretation differ from the review question?			Low concern
DOMAIN 3: Reference standard
Is the reference standard likely to correctly classify the target condition?	Unclear
Were the reference standard results interpreted without knowledge of the results of the index tests?	Yes
Could the reference standard, its conduct, or its interpretation have introduced bias?		Unclear risk
Are there concerns that the target condition as defined by the reference standard does not match the question?			Low concern
DOMAIN 4: Flow and timing
Did all patients receive the same reference standard?	Unclear
Were all patients included in the analysis?	Yes
Could the patient flow have introduced bias?		Unclear risk
DOMAIN 5: Comparative