title: Comparing triage algorithms using HPV DNA genotyping, HPV E7 mRNA detection and cytology in high-risk HPV DNA-positive women.
abstract: BACKGROUND
  High-risk human papillomavirus (hrHPV) DNA positive women require triage testing to identify those with high-grade cervical intraepithelial neoplasia or cancer (≥CIN2).
  
  
  OBJECTIVE
  Comparing three triage algorithms (1) E7 mRNA testing following HPV16/18/31/33/45/52/58 genotyping (E7 mRNA test), (2) HPV16/18 DNA genotyping and (3) cytology, for ≥CIN2 detection in hrHPV DNA-positive women.
  
  
  METHODS
  hrHPV DNA-positive women aged 18-63 years visiting gynecology outpatient clinics were included in a prospective observational cohort study. From these women a cervical scrape and colposcopy-directed biopsies were obtained. Cervical scrapes were evaluated by cytology, HPV DNA genotyping by bead-based multiplex genotyping of GP5+6+-PCR-products, and presence of HPV16/18/31/33/45/52/58 E7 mRNA using nucleic acid sequence-based amplification (NASBA) in DNA positive women for respective HPV types. Sensitivities and specificities for ≥CIN2 were compared between E7 mRNA test and HPV16/18 DNA genotyping in the total group (n=348), and E7 mRNA test and cytology in a subgroup of women referred for non-cervix-related gynecological complaints (n=133).
  
  
  RESULTS
  Sensitivity for ≥CIN2 of the E7 mRNA test was slightly higher than that of HPV16/18 DNA genotyping (66.9% versus 60.9%; ratio 1.10, 95% CI: 1.0002-1.21), at similar specificity (54.8% versus 52.3%; ratio 1.05, 95% CI: 0.93-1.18). Neither sensitivity nor specificity of the E7 mRNA test differed significantly from that of cytology (sensitivity: 68.8% versus 75.0%; ratio 0.92, 95% CI: 0.72-1.17; specificity: 59.4% versus 65.3%; ratio 0.91, 95% CI: 0.75-1.10).
  
  
  CONCLUSIONS
  For detection of ≥CIN2 in hrHPV DNA-positive women, an algorithm including E7 mRNA testing following HPV16/18/31/33/45/52/58 DNA genotyping performs similar to HPV16/18 DNA genotyping or cytology.
authors.affiliation: VU University Medical Center, Department of Pathology, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Electronic address: r.luttmer@vumc.nl.
authors.forename: Roosmarijn
authors.initials: R
authors.lastname: Luttmer
authors.affiliation: VU University Medical Center, Department of Epidemiology & Biostatistics, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Electronic address: h.berkhof@vumc.nl.
authors.forename: Johannes
authors.initials: J
authors.lastname: Berkhof
authors.affiliation: VU University Medical Center, Department of Pathology, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Electronic address: mg.dijkstra@vumc.nl.
authors.forename: Maaike G
authors.initials: MG
authors.lastname: Dijkstra
authors.affiliation: VU University Medical Center, Department of Pathology, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Electronic address: f.vankemenade@erasmusmc.nl.
authors.forename: Folkert J
authors.initials: FJ
authors.lastname: van Kemenade
authors.affiliation: VU University Medical Center, Department of Pathology, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Electronic address: pjf.snijders@vumc.nl.
authors.forename: Peter J F
authors.initials: PJ
authors.lastname: Snijders
authors.affiliation: VU University Medical Center, Department of Pathology, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Electronic address: dam.heideman@vumc.nl.
authors.forename: Daniëlle A M
authors.initials: DA
authors.lastname: Heideman
authors.affiliation: VU University Medical Center, Department of Pathology, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Electronic address: cjlm.meijer@vumc.nl.
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000465:Algorithms; D003584:Cytological Techniques / Q000379:methods*; D005260:Female; D060005:Genotyping Techniques / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D021141:Nucleic Acid Amplification Techniques / Q000379:methods*; D027383:Papillomaviridae / Q000145:classification / Q000235:genetics / Q000302:isolation & purification*; D050725:Papillomavirus E7 Proteins / Q000032:analysis / Q000235:genetics; D030361:Papillomavirus Infections / Q000150:complications / Q000175:diagnosis* / Q000473:pathology; D011446:Prospective Studies; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D012680:Sensitivity and Specificity; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000473:pathology / Q000821:virology; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis* / Q000473:pathology / Q000821:virology
chemical_list: D050725:Papillomavirus E7 Proteins; D012333:RNA, Messenger; D012367:RNA, Viral
keywords: Cervical cancer; Cytology; E7 mRNA; Genotyping; Human papillomavirus; Triage