77 Diagnostic utility of molecular and imaging biomarkers 2 Supplementary material and methods Literature search and study selection The review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [344]. The main research question was defined using the target Population (including previous tests), Index test, Comparator (reference) test, Target condition, and Study (PICTS) design strategy [345]. In collaboration with a trained academic librarian, a search query was composed containing a combination of Medical Subject Headings (MeSH) and truncated synonyms of the population “thyroid nodule” AND “indeterminate cytology” AND synonyms for all index tests under investigation combined with the Boolean operator “OR” (Table 1). On 15 March 2016 a systematic literature search using this query was performed in the PubMed, Embase and Cochrane libraries. Indeterminate cytology was defined as Bethesda III and Bethesda IV cytology, as well as the equivalent Thy3a, Thy3f and TIR3A and TIR3B categories from the respective British Thyroid Association Thy system and Italian SIAPEC-IAP classification [16, 45, 46]. Studies that did not apply one of these cytology classification systems, were still eligible if they defined indeterminate cytology in accordance with definitions of one of these cytology classifications systems. If the study population also included patients with cytology corresponding to ‘nondiagnostic’ (Bethesda I, Thy1 or TIR1), ‘benign’ (Bethesda II, Thy2 or TIR2), ‘suspicious for malignancy’ (Bethesda V, Thy4 or TIR4) or ‘malignant’ (Bethesda VI, Thy5 or TIR5) categories and data for the defined indeterminate population could not be extracted, the study was excluded. The diagnostic techniques under investigation in this review – to be referred to as the index tests – were determined by expert opinion and included the following: various gene mutation, fusion and expression analyses, microRNA, immunocytochemistry (ICC), ultrasonography (US), elastosonography (USE), computed tomography (CT), technetium 99m Tc sestamibi ([99mTc]Tc-MIBI), fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) and diffusion-weighted magnetic resonance imaging (DW-MRI). Original articles that investigated any of the selected index tests as an additional diagnostic procedure in cytologically indeterminate thyroid nodules and used histopathology as a reference test were eligible for inclusion in our systematic review. After removing duplicate references, titles and abstracts and retrieved full text articles were subsequently screened for eligibility by two authors (DV and EJK) using predefined inclusion and exclusion criteria (Figure 1). Reviews, meta-analyses, letters to the editor, author commentaries, opinion papers, studies including less than 10 patients, case-control studies, articles written in languages other than English, German, French or Dutch, studies not involving humans and studies using ex-vivo FNAC samples were excluded. Studies were excluded if the patient population overlapped with either previously published patient data (e.g., follow-up or spin-off studies) or
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