title: Development of a multiple marker test for ectopic pregnancy.
abstract: OBJECTIVE
  Many serum markers have been proposed to aid in the identification of an ectopic pregnancy, but few have been validated. Most studies have been limited by sample size and design. The goal of this study was to assess putative markers to identify which can be optimally combined.
  
  
  METHODS
  We conducted a case-control study using sera from 100 patients with ectopic pregnancy and 100 patients with intrauterine pregnancy who presented to three urban academic centers between September 2000 and April 2009 with first-trimester pain or bleeding. Samples were analyzed for 12 promising biomarkers. Classification tree analysis was used to examine markers simultaneously with the goal of optimizing the accuracy of ectopic pregnancy diagnosis, and validation was performed using bootstrapping.
  
  
  RESULTS
  Six of the 12 markers were differentially expressed between those with ectopic pregnancy and intrauterine pregnancy (P<.001) with fair diagnostic properties (area under the curve greater than 0.6) when examined individually (inhibin A, progesterone, activin A, vascular endothelial growth factor [VEGF], pregnancy-specific β-1-glycoprotein, and pregnancy-associated plasma protein-A). Six additional markers were found to have limited value. Using a two-step diagnostic algorithm with four markers (progesterone, VEGF, inhibin A, activin A), we diagnosed 42% of the sample with perfect specificity and 98% (93-100%) sensitivity. Overall, a single ectopic pregnancy was misclassified, achieving 99% (96-100%) accuracy.
  
  
  CONCLUSIONS
  Evaluating a large number of biomarkers simultaneously demonstrates that most of the putative markers of ectopic pregnancy are not useful. However, a select few can distinguish ectopic pregnancy from intrauterine pregnancy with superior accuracy as part of a multiple marker test.
  
  
  BACKGROUND
  : ClinicalTrials.gov, www.clinicaltrials.gov, NCT00194168.
authors.affiliation: From the Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania; the Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; the Department of Obstetrics and Gynecology, University of Miami School of Medicine, Miami, Florida; and the Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Rausch
authors.forename: Mary D
authors.initials: MD
authors.lastname: Sammel
authors.forename: Peter
authors.initials: P
authors.lastname: Takacs
authors.forename: Karine
authors.initials: K
authors.lastname: Chung
authors.forename: Alka
authors.initials: A
authors.lastname: Shaunik
authors.forename: Kurt T
authors.initials: KT
authors.lastname: Barnhart
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D011237:Predictive Value of Tests; D011247:Pregnancy; D011271:Pregnancy, Ectopic / Q000097:blood* / Q000175:diagnosis*; D055815:Young Adult
chemical_list: D015415:Biomarkers