Papi 2006.

Study characteristics
Patient sampling	Design: cohort study of consecutive participants Inclusion criteria: (1) male & female participants > 18 years (2) palpable nodules (3) non‐palpable nodules > 10 mm (4) non palpable nodule < 10 mm with malignant features on US Exclusion criteria: (1) participants < 18 years (2) non palpable nodules < 10 mm without malignant US features (3) participants previously evaluated for nodular goitre by FNA and/or CT measurement (4) participants reporting familial history of MEN and participants with known MTC (5) participants with hyper‐ and hypothyroidism without thyroid nodules (6) participants in follow‐up for thyroid disease (7) participants not confirmed as having thyroid diseases
Patient characteristics and setting	Number of participants: 1474 participants Number with NTD: 1474 participants Number with NTD and calcitonin testing: 1425 participants Sex (female%)(N): 80% (1144) Age (mean/SD): 49.6(+ 6.8) years range: 18‐91 years MTC: 9 participants Type of thyroid nodules: euthyroid nodular thyroid disease (N = 1369), hypothyroid nodular thyroid disease (N = 32), sub acute de Quervain's thyroiditis (N = 1), Graves' disease (N = 2), toxic nodular goitre (N = 21). Multinodular disease (N = 1024), uninodular disease (N = 401) Thyroid nodules detected by palpation or US: both Nodule size: 21.8 + 4 mm Number of nodules: — Sonographic morphology of thyroid nodules: — FNA procedures performed through ultrasound guidance or palpation: ultrasound Setting: — Country: Italy
Index tests	Index test: basal and stimulated calcitonin Calcitonin as a triage or add‐on test: — Used calcitonin assay: two‐site chemiluminescence assay, Nichols institute diagnostics, San Juan Capristano, CA92675, USA) Sensitivity: 1 pg/mL Stimulated calcitonin: yes Indication: when basal serum CT concentrations exceeded 5 pg/mL, but not exceeded 100 pg/mL Stimulative: pentagastrin (Cambridge laboratories, Walsend, Tyne and Wear, NE289NX) Dose: 0.5 ug/kg Time: before, 2, 5 and 10 minutes after injection Reported and extracted cut‐off values Basal: reported: 5 pg/mL extracted: 5, 10, 15, 20, 30, 50,100 pg/mL Stimulated: reported: 100 pg/mL extracted: 100, 200 pg/mL
Target condition and reference standard(s)	Target condition: MTC Reference standards: FNAC and in selected participants, histopathological examination after surgical treatment Indication surgical treatment: basal serum CT concentrations > 5 pg/mL < 100 pg/mL and Pg‐stimulated CT levels > 100 pg/mL or basal serum CT concentrations > 100 pg/mL; participants with a suspicious or repeatedly non‐diagnostic FNAC and participants with a benign FNAC and compressive symptoms Type: in participants with benign FNAC and compressive symptoms a lobectomy or near‐total thyroidectomy. In participants with suspicious or non‐diagnostic FNAC, surgical extent depended on histological examination of frozen sections. In participants with malignancy other than MTC a total thyroidectomy and in case of lymph node involvement a lymphadenectomy. In MTC patients a total thyroidectomy and a systematic microdissection of both central neck and bilateral neck compartments. Contralateral lymph node dissection was omitted in MTC patients with a unilateral thyroid tumour and no ipsilateral and central lymph node involvement Calcitonin negative (N = 1402) Number FNAC: 1402 participants Number operated: 292 participants Calcitonin positive: (N = 23) Number FNAC: 23 participants Number operated: 23 participants
Flow and timing	Follow‐up calcitonin negative: — Type: — Duration: — Follow‐up calcitonin positive: — Type: — Duration: —
Comparative
Publication details	Language of publication: English Funding: — Publication status: full article
Stated aim of study	Quote from publication: "To assess the prevalence of hypercalcitoninemia and MTC in NTD patients, to compare the ability of CT measurement and fine needle aspiration cytology (FNAC) to predict MTC, to identify age groups of NTD patients who should be better candidates than others to undergo routine measurement of CT."
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
		Low	Low
DOMAIN 2: Index Test All tests
If a threshold was used, was it pre‐specified?	Yes
		Low	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Unclear
Were the reference standard results interpreted without knowledge of the results of the index tests?	Unclear
		Unclear	Low
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Unclear
Did all patients receive the same reference standard?	No
Were all patients included in the analysis?	Yes
Did all patients receive the reference standard?	No
		High