title: Molecular Testing for miRNA, mRNA, and DNA on Fine-Needle Aspiration Improves the Preoperative Diagnosis of Thyroid Nodules With Indeterminate Cytology.
abstract: BACKGROUND
  Molecular testing for oncogenic mutations or gene expression in fine-needle aspirations (FNAs) from thyroid nodules with indeterminate cytology identifies a subset of benign or malignant lesions with high predictive value.
  
  
  OBJECTIVE
  This study aimed to evaluate a novel diagnostic algorithm combining mutation detection and miRNA expression to improve the diagnostic yield of molecular cytology.
  
  
  METHODS
  Surgical specimens and preoperative FNAs (n = 638) were tested for 17 validated gene alterations using the miRInform Thyroid test and with a 10-miRNA gene expression classifier generating positive (malignant) or negative (benign) results.
  
  
  METHODS
  Cross-sectional sampling of thyroid nodules with atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) or follicular neoplasm/suspicious for a follicular neoplasm (FN/SFN) cytology (n = 109) was conducted at 12 endocrinology centers across the United States. Qualitative molecular results were compared with surgical histopathology to determine diagnostic performance and model clinical effect.
  
  
  RESULTS
  Mutations were detected in 69% of nodules with malignant outcome. Among mutation-negative specimens, miRNA testing correctly identified 64% of malignant cases and 98% of benign cases. The diagnostic sensitivity and specificity of the combined algorithm was 89% (95% confidence interval [CI], 73-97%) and 85% (95% CI, 75-92%), respectively. At 32% cancer prevalence, 61% of the molecular results were benign with a negative predictive value of 94% (95% CI, 85-98%). Independently of variations in cancer prevalence, the test increased the yield of true benign results by 65% relative to mRNA-based gene expression classification and decreased the rate of avoidable diagnostic surgeries by 69%.
  
  
  CONCLUSIONS
  Multiplatform testing for DNA, mRNA, and miRNA can accurately classify benign and malignant thyroid nodules, increase the diagnostic yield of molecular cytology, and further improve the preoperative risk-based management of benign nodules with AUS/FLUS or FN/SFN cytology.
authors.affiliation: Asuragen, Inc (E.L., B.A., D.W., S.B.H.), Austin, Texas 78744; Jersey Shore University Medical Center (A.S.), Center for Thyroid, Parathyroid and Adrenal Diseases, Neptune, New Jersey 07753; Metropolitan Fine Needle Aspiration Service (A.E.B.), Washington, District of Columbia 20037 and Bethesda, Maryland 20814; Thyroid & Endocrine Center of Florida (M.A.L.), Sarasota, Florida 34231; and (M.L.M.) San Diego, California 92103.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Labourier
authors.affiliation: Asuragen, Inc (E.L., B.A., D.W., S.B.H.), Austin, Texas 78744; Jersey Shore University Medical Center (A.S.), Center for Thyroid, Parathyroid and Adrenal Diseases, Neptune, New Jersey 07753; Metropolitan Fine Needle Aspiration Service (A.E.B.), Washington, District of Columbia 20037 and Bethesda, Maryland 20814; Thyroid & Endocrine Center of Florida (M.A.L.), Sarasota, Florida 34231; and (M.L.M.) San Diego, California 92103.
authors.forename: Alexander
authors.initials: A
authors.lastname: Shifrin
authors.affiliation: Asuragen, Inc (E.L., B.A., D.W., S.B.H.), Austin, Texas 78744; Jersey Shore University Medical Center (A.S.), Center for Thyroid, Parathyroid and Adrenal Diseases, Neptune, New Jersey 07753; Metropolitan Fine Needle Aspiration Service (A.E.B.), Washington, District of Columbia 20037 and Bethesda, Maryland 20814; Thyroid & Endocrine Center of Florida (M.A.L.), Sarasota, Florida 34231; and (M.L.M.) San Diego, California 92103.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Busseniers
authors.affiliation: Asuragen, Inc (E.L., B.A., D.W., S.B.H.), Austin, Texas 78744; Jersey Shore University Medical Center (A.S.), Center for Thyroid, Parathyroid and Adrenal Diseases, Neptune, New Jersey 07753; Metropolitan Fine Needle Aspiration Service (A.E.B.), Washington, District of Columbia 20037 and Bethesda, Maryland 20814; Thyroid & Endocrine Center of Florida (M.A.L.), Sarasota, Florida 34231; and (M.L.M.) San Diego, California 92103.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lupo
authors.affiliation: Asuragen, Inc (E.L., B.A., D.W., S.B.H.), Austin, Texas 78744; Jersey Shore University Medical Center (A.S.), Center for Thyroid, Parathyroid and Adrenal Diseases, Neptune, New Jersey 07753; Metropolitan Fine Needle Aspiration Service (A.E.B.), Washington, District of Columbia 20037 and Bethesda, Maryland 20814; Thyroid & Endocrine Center of Florida (M.A.L.), Sarasota, Florida 34231; and (M.L.M.) San Diego, California 92103.
authors.forename: Monique L
authors.initials: ML
authors.lastname: Manganelli
authors.affiliation: Asuragen, Inc (E.L., B.A., D.W., S.B.H.), Austin, Texas 78744; Jersey Shore University Medical Center (A.S.), Center for Thyroid, Parathyroid and Adrenal Diseases, Neptune, New Jersey 07753; Metropolitan Fine Needle Aspiration Service (A.E.B.), Washington, District of Columbia 20037 and Bethesda, Maryland 20814; Thyroid & Endocrine Center of Florida (M.A.L.), Sarasota, Florida 34231; and (M.L.M.) San Diego, California 92103.
authors.forename: Bernard
authors.initials: B
authors.lastname: Andruss
authors.affiliation: Asuragen, Inc (E.L., B.A., D.W., S.B.H.), Austin, Texas 78744; Jersey Shore University Medical Center (A.S.), Center for Thyroid, Parathyroid and Adrenal Diseases, Neptune, New Jersey 07753; Metropolitan Fine Needle Aspiration Service (A.E.B.), Washington, District of Columbia 20037 and Bethesda, Maryland 20814; Thyroid & Endocrine Center of Florida (M.A.L.), Sarasota, Florida 34231; and (M.L.M.) San Diego, California 92103.
authors.forename: Dennis
authors.initials: D
authors.lastname: Wylie
authors.affiliation: Asuragen, Inc (E.L., B.A., D.W., S.B.H.), Austin, Texas 78744; Jersey Shore University Medical Center (A.S.), Center for Thyroid, Parathyroid and Adrenal Diseases, Neptune, New Jersey 07753; Metropolitan Fine Needle Aspiration Service (A.E.B.), Washington, District of Columbia 20037 and Bethesda, Maryland 20814; Thyroid & Endocrine Center of Florida (M.A.L.), Sarasota, Florida 34231; and (M.L.M.) San Diego, California 92103.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Beaudenon-Huibregtse
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D044963:Biopsy, Fine-Needle; D003430:Cross-Sectional Studies; D004247:DNA / Q000032:analysis / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000032:analysis / Q000235:genetics*; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D057234:Preoperative Period; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics*; D012680:Sensitivity and Specificity; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology / Q000601:surgery; D016606:Thyroid Nodule / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D055815:Young Adult
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D004247:DNA