Schneider 2012.

Study characteristics
Patient sampling	Design: cohort study Inclusion criteria: participants diagnosed with thyroid nodules > 2 mm based on the spatial resolution of ultrasound equipment Exclusion criteria: participants referred with elevated or previously determined CT values, MTC or a family history of MTC, renal insufficiency, bacterial infection, alcohol abuse, proton‐pump inhibitor therapy, Graves'disease or autoimmune thyroid disease
Patient characteristics and setting	Number of participants: 11270 participants Number with NTD: 11,270 participants Number with NTD and calcitonin testing: 11,270 participants Sex (female%)(N): — Age (mean/SD): — range: — MTC: 12 participants Type of thyroid nodules: — Thyroid nodules detected by palpation or US: ultrasound Nodule size: only reported of MTC and PTC participants Number of nodules: — Sonographic morphology of thyroid nodules: only reported of participants with elevated basal CT levels FNA procedures performed through ultrasound guidance or palpation: — Setting: — Country: Germany
Index tests	Calcitonin as a triage or add‐on test: — Index test: basal and stimulated calcitonin Used calcitonin assay: solid‐phase, enzyme labelled, two‐site chemiluminescent assay with Immulite 2000 (Siemens Immulite 2000, Munich, Germany) Sensitivity: — Stimulated calcitonin: yes Indication: bCT > 13 and < 100 pg/mL (if PG was available and the participants physical condition allowed testing) Stimulative: pentagastrin (pentagastrin injection BP, Ireland, UK) Dose: 0.5 ug/kg bodyweight Time: 2 and 5 minutes after injection Reported and extracted cut‐off values Basal: reported 13 pg/mL; extracted: 13, 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: histopathological examination after thyroid surgery, follow‐up Indication surgical treatment: 1) basal CT > 100 pg/mL, PG‐stimulated CT > 100 pg/mL, 3) suspicious thyroid nodules based on the participants history, sonography (hypoechogenicity, irregular margins, microcalcifications) or scintigraphy (cold nodules have been consistently associated with malignancy) Type: — Calcitonin negative (N = 11238) Number FNAC: — Number operated: — Calcitonin positive: (N = 32) Number FNAC: — Number operated: 18 participants
Flow and timing	Follow‐up calcitonin negative: — Type: — Duration: — Follow‐up calcitonin positive: participants with no sCT > 100 pg/mL, participants with no sCT performed Type: repeated bCT testing Number with follow‐up: 10 participants Duration: mean 7 months
Comparative
Publication details	Language of publication: English Funding: no conflicts of interest Publication status: full article
Stated aim of study	Quote from publication: "The positive predictive value (PPV) of a slightly elevated basal calcitonin for the diagnosis of medullary thyroid cancer is still under debate."
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