title: Validation of a second-generation multivariate index assay for malignancy risk of adnexal masses.
abstract: BACKGROUND
  Women with adnexal mass suspected of ovarian malignancy are likely to benefit from consultation with a gynecologic oncologist, but imaging and biomarker tools to ensure this referral show low sensitivity and may miss cancer at critical stages.
  
  
  OBJECTIVE
  The multivariate index assay (MIA) was designed to improve the detection of ovarian cancer among women undergoing surgery for a pelvic mass. To improve the prediction of benign masses, we undertook the redesign and validation of a second-generation MIA (MIA2G).
  
  
  METHODS
  MIA2G was developed using banked serum samples from a previously published prospective, multisite registry of patients who underwent surgery to remove an adnexal mass. Clinical validity was then established using banked serum samples from the OVA500 trial, a second prospective cohort of adnexal surgery patients. Based on the final pathology results of the OVA500 trial, this intended-use population for MIA2G testing was high risk, with an observed cancer prevalence of 18.7% (92/493). Coded samples were assayed for MIA2G biomarkers by an external clinical laboratory. Then MIA2G results were calculated and submitted to a clinical statistics contract organization for decoding and comparison to MIA results for each subject. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated, among other measures, and stratified by menopausal status, stage, and histologic subtype.
  
  
  RESULTS
  Three MIA markers (cancer antigen 125, transferrin, and apolipoprotein A-1) and 2 new biomarkers (follicle-stimulating hormone and human epididymis protein 4) were included in MIA2G. A single cut-off separated high and low risk of malignancy regardless of patient menopausal status, eliminating potential for confusion or error. MIA2G specificity (69%, 277/401 [n/N]; 95% confidence interval [CI], 64.4-73.4%) and PPV (40%, 84/208; 95% CI, 33.9-47.2%) were significantly improved over MIA (specificity, 54%, 215/401; 95% CI, 48.7-58.4%, and PPV, 31%, 85/271; 95% CI, 26.1-37.1%, respectively) in this cohort. Sensitivity and NPV were not significantly different between the 2 tests. When combined with physician assessment, MIA2G correctly identified 75% of the malignancies missed by physician assessment alone.
  
  
  CONCLUSIONS
  MIA2G specificity and PPV were significantly improved compared with MIA, while sensitivity and NPV were unchanged. The second-generation test significantly improved the predicted efficiency of triage vs MIA without sacrificing high sensitivity and NPV, which are essential for effectiveness.
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.affiliation: Obstetrics and Gynecology, University of Cincinnati Cancer Institute, Cincinnati, OH.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Herzog
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Chan
authors.affiliation: Vermillion Inc, Austin, TX.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Munroe
authors.affiliation: Vermillion Inc, Austin, TX.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Pappas
authors.affiliation: Applied Clinical Intelligence LLC, Bala Cynwyd, PA.
authors.forename: Alan
authors.initials: A
authors.lastname: Smith
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Vermillion Inc, Austin, TX. Electronic address: jwolf@Vermillion.com.
authors.forename: Judith
authors.initials: J
authors.lastname: Wolf
mesh_terms: D000291:Adnexal Diseases / Q000097:blood / Q000175:diagnosis*; D000328:Adult; D000465:Algorithms; D014408:Biomarkers, Tumor / Q000097:blood; D005260:Female; D006801:Humans; D008875:Middle Aged; D015999:Multivariate Analysis; D010051:Ovarian Neoplasms / Q000097:blood / Q000175:diagnosis*; D012042:Registries; D018570:Risk Assessment; D012680:Sensitivity and Specificity
chemical_list: D014408:Biomarkers, Tumor
keywords: diagnostic; ovarian cancer; protein; referral; serum