title: Preoperative sensitivity and specificity for early-stage ovarian cancer when combining cancer antigen CA-125II, CA 15-3, CA 72-4, and macrophage colony-stimulating factor using mixtures of multivariate normal distributions.
abstract: OBJECTIVE
  In CA-125-based ovarian cancer screening trials, overall specificity and screening sensitivity of ultrasound after an elevated CA-125 exceeded 99.6% and 70%, respectively, thereby yielding a positive predictive value (PPV) exceeding 10%. However, sensitivity for early-stage disease was only 40%. This study aims to increase preoperative sensitivity for early-stage ovarian cancer while maintaining the annual referral rate to ultrasound at 2% by combining information across CA-125II, CA 15-3, CA 72-4, and macrophage colony-stimulating factor (M-CSF). For direct comparisons between marker panels, all sensitivity results correspond to a 98% fixed first-line specificity (referral rate 2%).
  
  
  METHODS
  Logistic regression, classification tree, and mixture discriminant analysis (MDA) models were fit to a training data set of preoperative serum measurements (63 patients, 126 healthy controls) from one center. Estimates from the training set applied to an independent validation set (60 stage I to II patients, 98 healthy controls) from two other centers provided unbiased estimates of sensitivity.
  
  
  RESULTS
  Preoperative sensitivities for early-stage disease of the optimal panels were 45% for CA-125II; 67% for CA-125II and CA 72-4; 70% for CA-125II, CA 72-4, and M-CSF; and 68% for all four markers (latter two results using MDA).
  
  
  CONCLUSIONS
  Efficiently combining information on CA-125II, CA 72-4, and M-CSF significantly increased preoperative early-stage sensitivity from 45% with CA-125II alone to 70%, while maintaining 98% first-line specificity. Screening trials with these markers using MDA followed by referral to ultrasound may maintain previously high levels of specificity and PPV, while significantly increasing early-stage screening sensitivity. MDA is a useful, biologically justified method for combining biomarkers.
authors.affiliation: Massachusetts General Hospital, 50 Stanford St, Suite 560, Boston, MA 02114, USA. sskates@partners.org
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Skates
authors.forename: Nora
authors.initials: N
authors.lastname: Horick
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Yu
authors.forename: Feng-Ji
authors.initials: FJ
authors.lastname: Xu
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Havrilesky
authors.forename: Henk W A
authors.initials: HW
authors.lastname: de Bruijn
authors.forename: Ate G J
authors.initials: AG
authors.lastname: van der Zee
authors.forename: Robert P
authors.initials: RP
authors.lastname: Woolas
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jacobs
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bast
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood*; D018394:CA-125 Antigen / Q000097:blood*; D016002:Discriminant Analysis; D005260:Female; D006801:Humans; D016015:Logistic Models; D016173:Macrophage Colony-Stimulating Factor / Q000097:blood*; D018396:Mucin-1 / Q000097:blood*; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000000981:diagnostic imaging; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D014463:Ultrasonography
chemical_list: D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; D018396:Mucin-1; D016173:Macrophage Colony-Stimulating Factor