Guitera 2012.

Study characteristics
Patient sampling	Study design: case series Data collection: NR Period of data collection: NR Country: Australia and Italy Test set derived: randomly split into training and test sets
Patient characteristics and setting	Inclusion criteria: consecutive participants presenting or found with suspicious lesions, including all macules of the face and neck suspicious for LM, and which would be subjected to biopsy or excision to rule out an epithelial tumour or an MM following conventional clinical and dermoscopy diagnosis and with lesion location amenable to RCM; described as predominantly melanocytic or suspicious for BCC. Setting: mixed, lesions recruited from Modena (general dermatology) and Sydney (skin cancer/pigmented lesions clinic) Prior testing: clinical or dermatoscopic suspicion, or both Exclusion criteria: location/site of lesion keratotic, sole, and palm lesions were excluded. Sample size (participants): number eligible: 663 Sample size (lesions): number eligible: 710 / number included: 356 in test set, 253 melanocytic Participant characteristics: median age (full sample): 53, IQR 39 to 66 (for full sample), range: 6–90; male: 354 (53.4%) (of full sample) Lesion characteristics: NR
Index tests	RCM: RCM score and Segura algorithm; also derived own independently significant features for MM and BCC. Vivascope 1500 Method of diagnosis: confocal images (remote) Prior test data: lesion site or participant age only, or both: "RCM features were described by two expert observers (GP and PG), blinded from any clinical information, dermoscopy, and clinical aspects, but not for the location and age of the patient." Diagnostic threshold: 2 established algorithms assessed: Pellacani scoring system for melanoma (Pellacani 2007), score > 3; and Segura 2‐step algorithm (Segura 2009), score of 0; own new 2‐step model identified 7 independently significant features for MM (assume presence of any one indicated T+): cerebriform nests, atypical cobblestone pattern with small nucleated cells in the epidermis, marked cytological atypia, pagetoid cells, disarranged epidermal layer with no honeycomb, large inter‐papillae spaces filled with honeycomb, dense nest. 8 independently significant features for BCC: polarised in the honeycomb, linear telangiectasia‐like horizontal vessels, basaloid cord or nodule, epidermal shadow, convoluted glomerular‐like vessels, non‐visible papillae, cerebriform nests, disarray of the epidermal layer. Derivation aspect to study: lesion characteristics assessed a series of 48 features, corresponding to previous observations (Pellacani 2007; Guitera 2009), and new descriptors were considered at 3 different depth levels. Descriptions and definitions provided. Selection of characteristics indicative of skin cancer by multivariate discriminant analysis performed on the training set. Diagnosis based on: single observer (n = 2) Observer qualifications: dermatologist Experience in practice: high experience or 'expert' Experience with index test: high experience/'expert' users
Target condition and reference standard(s)	Type of reference standard: histological diagnosis alone Details: not further described; full sample Disease positive: 335/disease negative: 375 Target condition (final diagnoses): test set only; melanoma (in situ and invasive, or NR): 105; BCC: 52; cSCC: 9 benign nevus 132; Spitz nevus 16; AK 8; 31 benign macule of the face; and 3 dermatofibroma
Flow and timing	No exclusions Imaged prior to biopsy
Comparative
Notes	—
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Yes
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	Yes
Are the included participants and chosen study setting appropriate?	Unclear
Did the study avoid including participants with multiple lesions?	No
		Low	High
DOMAIN 2: Index Test Reflectance confocal microscopy
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?	Yes
For studies reporting the accuracy of multiple diagnostic thresholds, was each threshold or algorithm interpreted without knowledge of the results of the others?
Was the test applied and interpreted in a clinically applicable manner?	Unclear
Were thresholds or criteria for diagnosis reported in sufficient detail to allow replication?	Yes
Was the test interpretation carried out by an experienced examiner?	Unclear
		Low	Unclear
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Were the reference standard results interpreted without knowledge of the results of the index tests?	Unclear
Expert opinion (with no histological confirmation) was not used as a reference standard	Yes
Was histology interpretation carried out by an experienced histopathologist or by a dermatopathologist?	Unclear
Were the reference standard results interpreted without knowledge of the referral diagnosis?	Unclear
		Unclear	Unclear
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Yes
Did all patients receive the same reference standard?	Yes
Were all patients included in the analysis?	Yes
Was the minimum clinical follow‐up after application of index test(s) adequate?
If more than one algorithm evaluated for the same test, was the interval between application of the different algorithms 1 month or less?
		Low