title: Cell-free DNA analysis for noninvasive examination of trisomy.
abstract: BACKGROUND
  Cell-free DNA (cfDNA) testing for fetal trisomy is highly effective among high-risk women. However, there have been few direct, well-powered studies comparing cfDNA testing with standard screening during the first trimester in routine prenatal populations.
  
  
  METHODS
  In this prospective, multicenter, blinded study conducted at 35 international centers, we assigned pregnant women presenting for aneuploidy screening at 10 to 14 weeks of gestation to undergo both standard screening (with measurement of nuchal translucency and biochemical analytes) and cfDNA testing. Participants received the results of standard screening; the results of cfDNA testing were blinded. Determination of the birth outcome was based on diagnostic genetic testing or newborn examination. The primary outcome was the area under the receiver-operating-characteristic curve (AUC) for trisomy 21 (Down's syndrome) with cfDNA testing versus standard screening. We also evaluated cfDNA testing and standard screening to assess the risk of trisomies 18 and 13.
  
  
  RESULTS
  Of 18,955 women who were enrolled, results from 15,841 were available for analysis. The mean maternal age was 30.7 years, and the mean gestational age at testing was 12.5 weeks. The AUC for trisomy 21 was 0.999 for cfDNA testing and 0.958 for standard screening (P=0.001). Trisomy 21 was detected in 38 of 38 women (100%; 95% confidence interval [CI], 90.7 to 100) in the cfDNA-testing group, as compared with 30 of 38 women (78.9%; 95% CI, 62.7 to 90.4) in the standard-screening group (P=0.008). False positive rates were 0.06% (95% CI, 0.03 to 0.11) in the cfDNA group and 5.4% (95% CI, 5.1 to 5.8) in the standard-screening group (P<0.001). The positive predictive value for cfDNA testing was 80.9% (95% CI, 66.7 to 90.9), as compared with 3.4% (95% CI, 2.3 to 4.8) for standard screening (P<0.001).
  
  
  CONCLUSIONS
  In this large, routine prenatal-screening population, cfDNA testing for trisomy 21 had higher sensitivity, a lower false positive rate, and higher positive predictive value than did standard screening with the measurement of nuchal translucency and biochemical analytes. (Funded by Ariosa Diagnostics and Perinatal Quality Foundation; NEXT ClinicalTrials.gov number, NCT01511458.).
authors.affiliation: From the University of California, San Francisco, San Francisco (M.E.N.), University of California, San Diego, San Diego (L.C.L.), Perinatal Diagnostic Center, Riverside (H.B.), and Ariosa Diagnostics, San Jose (D.H., T.J.M.) - all in California; Sahlgrenska University Hospital, Gothenburg, Sweden (B.J.); Duke University, Durham, NC (G.K.S.); Saint Peter's University Hospital, New Brunswick, NJ (A.C.R.); Northwest Perinatal Center (M.W.T.) and Oregon Health and Science University (L.P.) - both in Portland; Perinatal Quality Foundation, Oklahoma City (J.L.S.); and Columbia University, New York (H.C., R.J.W.).
authors.forename: Mary E
authors.initials: ME
authors.lastname: Norton
authors.forename: Bo
authors.initials: B
authors.lastname: Jacobsson
authors.forename: Geeta K
authors.initials: GK
authors.lastname: Swamy
authors.forename: Louise C
authors.initials: LC
authors.lastname: Laurent
authors.forename: Angela C
authors.initials: AC
authors.lastname: Ranzini
authors.forename: Herb
authors.initials: H
authors.lastname: Brar
authors.forename: Mark W
authors.initials: MW
authors.lastname: Tomlinson
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pereira
authors.forename: Jean L
authors.initials: JL
authors.lastname: Spitz
authors.forename: Desiree
authors.initials: D
authors.lastname: Hollemon
authors.forename: Howard
authors.initials: H
authors.lastname: Cuckle
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Musci
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Wapner
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002869:Chromosome Aberrations; D004247:DNA / Q000032:analysis* / Q000097:blood; D004314:Down Syndrome / Q000175:diagnosis* / Q000235:genetics; D005189:False Positive Reactions; D005260:Female; D005333:Fetus / Q000002:abnormalities; D006801:Humans; D008875:Middle Aged; D048208:Nuchal Translucency Measurement; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011296:Prenatal Diagnosis / Q000379:methods*; D011446:Prospective Studies; D012680:Sensitivity and Specificity; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: D004247:DNA