title: Diagnostic accuracy and cost-effectiveness of different strategies to triage women with adnexal masses: a prospective study.
abstract: OBJECTIVE
  Transvaginal sonography (TVS) and serum biomarkers are used widely in clinical practice to triage women with adnexal masses, but the effectiveness of current biomarkers is weak. The aim of this study was to determine the best method of diagnosing patients with adnexal masses, in terms of diagnostic accuracy and economic costs, among four triage strategies: (1) the International Ovarian Tumor Analysis group's simple rules (SR) for interpretation of TVS with subjective assessment (SA) by an experienced ultrasound operator when TVS results are inconclusive (referred to hereafter as SR ± SA), (2) SR ± SA and cancer antigen 125 (CA 125), (3) SR ± SA and human epididymis protein 4 (HE4) and (4) SR ± SA and the risk of malignancy algorithm (ROMA). Our main hypothesis was that the addition of the biomarkers to SR ± SA could improve triaging of these patients in terms of diagnostic accuracy (i.e. malignant vs benign). As secondary analyses, we estimated the cost effectiveness of the four strategies and the diagnostic accuracy of SR ± SA at the study hospitals.
  
  
  METHODS
  Between February 2013 and January 2015, 447 consecutive patients who were scheduled for surgery for an adnexal mass at the S. Anna and Mauriziano Hospitals in Turin were enrolled in this multicenter prospective cohort study. Preoperative TVS was performed and preoperative CA 125 and HE4 levels were measured. Pathology reports were used to assess the diagnostic accuracy of the four triage strategies and the cost of each strategy was calculated.
  
  
  RESULTS
  A total of 391 patients were included in the analysis: 57% (n = 221) were premenopausal and 43% (n = 170) were postmenopausal. The overall prevalence of malignancy was 21%. SR were conclusive in 89% of patients and thus did not require SA; the overall performance of SR ± SA showed a sensitivity of 82%, specificity of 92% and positive and negative predictive values and positive and negative likelihood ratios of 74%, 95%, 10.5 and 0.19, respectively. In premenopausal women, mean cost among the four triage strategies varied from €36.41 for SR ± SA to €70.12 for SR ± SA + ROMA. The addition of biomarkers to SR ± SA showed no diagnostic advantage compared with SR ± SA alone and was more costly. Among postmenopausal women, mean cost among the four triage strategies varied from €39.52 for SR ± SA to €73.23 for SR ± SA + ROMA. Among these women, SR ± SA + CA 125 and SR ± SA + ROMA had a higher sensitivity (both 92% (95% CI, 85-99%)) than SR ± SA (81% (95% CI, 71-91%)), but SR ± SA had a higher specificity (84% (95% CI, 77-91%)). SR ± SA + CA 125 and SR ± SA + ROMA improved diagnostic accuracy, each diagnosing a third more malignant adnexal masses. In postmenopausal women, compared with SR ± SA alone, SR ± SA + CA 125 showed a net reclassification improvement (NRI) of 28.8% at an extra cost of €13.00, while the extra cost for SR ± SA + ROMA was €33.71, with a comparable gain, in terms of NRI, as that of SR ± SA + CA 125.
  
  
  CONCLUSIONS
  In our study sample, SR ± SA seems to be the best strategy to triage women with adnexal masses for surgical management. Among postmenopausal women, SR ± SA + CA 125 increased the NRI at a reasonable extra cost. Our data do not justify the use of HE4 and ROMA in the initial triage of women with adnexal masses. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.
authors.affiliation: Department of Surgical Sciences, University of Turin, Turin, Italy.|Obstetrics & Gynecology Unit, Ospedale Martini, Turin, Italy.
authors.forename: E
authors.identifier: http://orcid.org/0000-0002-5629-703X
authors.initials: E
authors.lastname: Piovano
authors.affiliation: Department of Surgical Sciences, University of Turin, Turin, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Cavallero
authors.affiliation: Obstetrics & Gynecology Academic Unit, Ospedale Mauriziano, Turin, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Fuso
authors.affiliation: Department of Gynecology and Obstetrics, Division of Ultrasound and Prenatal Diagnosis, 'Città della Salute e della Scienza di Torino' University Hospital, Turin, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Viora
authors.affiliation: Obstetrics & Gynecology Academic Unit, Ospedale Mauriziano, Turin, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Ferrero
authors.affiliation: Department of Gynecology and Obstetrics, Obstetrics & Gynecology Unit no. 3, 'Città della Salute e della Scienza di Torino' University Hospital, Turin, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Gregori
authors.affiliation: Department of Lab Medicine, Clinical Biochemistry Unit, 'Città della Salute e della Scienza di Torino' University Hospital, Turin, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Grillo
authors.affiliation: Department of Surgical Sciences, University of Turin, Turin, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Macchi
authors.affiliation: Department of Lab Medicine, Clinical Biochemistry Unit, 'Città della Salute e della Scienza di Torino' University Hospital, Turin, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Mengozzi
authors.affiliation: Department of Surgical Sciences, University of Turin, Turin, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mitidieri
authors.affiliation: Unit of Clinical Epidemiology, 'Città della Salute e della Scienza di Torino' University Hospital and CPO Piemonte, Turin, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Pagano
authors.affiliation: Department of Surgical Sciences, University of Turin, Turin, Italy.|Department of Gynecology and Obstetrics, Obstetrics & Gynecology Academic Unit no. 2, 'Città della Salute e della Scienza di Torino' University Hospital, Turin, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Zola
mesh_terms: D000291:Adnexal Diseases / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000191:economics / Q000453:epidemiology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood; D018394:CA-125 Antigen / Q000097:blood; D015331:Cohort Studies; D003362:Cost-Benefit Analysis; D005260:Female; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008875:Middle Aged; D009313:National Health Programs; D011446:Prospective Studies; D011506:Proteins / Q000378:metabolism; D012680:Sensitivity and Specificity; D014218:Triage; D000081102:WAP Four-Disulfide Core Domain Protein 2; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; D011506:Proteins; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human
keywords: CA 125; HE4; diagnostic algorithm; ovarian cancer; preoperative evaluation; simple rules; triage; ultrasonography