title: ADAM 12 as a first-trimester maternal serum marker in screening for Down syndrome.
abstract: BACKGROUND
  A Disintegrin And Metalloprotease 12 (ADAM 12) is a glycoprotein synthesised by placenta and it has been shown to be a potential first-trimester maternal serum marker for Down syndrome (DS) in two small series. Here we analyse further, the potential of ADAM 12 as a marker for DS in a large collection of first-trimester serum samples.
  
  
  METHODS
  The concentration of ADAM 12 was determined in 10-14-week pregnancy sera from 218 DS pregnancies and 389 gestational age-matched control pregnancies, which had been collected as part of routine prospective first-trimester screening programs (DS = 105) or as part of previous research studies (DS = 113). ADAM 12 was measured using a semi-automated time resolved immunofluorometric assay and median values for normal pregnancies were established by polynomial regression. These medians were then used to determine population distribution parameters for DS and normal pregnancy groups. Correlation with previously established PAPP-A and free beta-hCG multiple of the medians (MoMs) and delta nuchal translucency (NT) were determined and used to model the performance of first-trimester screening with ADAM 12 in combination with other first-trimester markers at various time periods across the first trimester. The benefits of a contingent testing model incorporating early measurement of PAPP-A and ADAM 12 were also explored.
  
  
  RESULTS
  The maternal serum concentration of ADAM 12 was significantly reduced (p = 0.0049) with an overall median MoM of 0.79 in the DS cases and a log(10) MoM SD of 0.3734 in the DS cases and 0.3353 in the controls. There was a significant correlation of ADAM 12 MoM in DS cases with gestational age (r = 0.375) and the median MoM increased from 0.50 at 10-11 weeks to 1.38 at 13 weeks. ADAM 12 was correlated with maternal weight (r(controls) = 0.283), PAPP-A (r(controls) = 0.324, r(DS) = 0.251) but less so with free beta-hCG (r(controls) = 0.062, r(DS) = 0.049) and delta NT (r(controls) = 0.110, r(DS) = 0.151). ADAM 12 was significantly (p = 0.026) lower in smokers (0.87 vs 1.00) and elevated in Afro-Caribbean women compared to Caucasian women (1.34 vs 1.00). Population modelling using parameters from this and an earlier study showed that a combination of ADAM 12 and PAPP-A measured at 8-9 weeks and combined with NT and free beta-hCG measured at 12 weeks could achieve a detection rate of 97% at a 5% false-positive rate or 89% at a 1% false-positive rate. PAPP-A and ADAM 12 alone at 8-9 weeks could identify 91% of cases at a 5% false-positive rate. Using this as part of a contingent-screening model to select an intermediate risk group of women for NT and free beta-hCG at 11-12 weeks would enable the detection of 92% of cases with a 1% false-positive rate at a cost of providing NT and free beta-hCG for 6% of women with 94% of women having completed screening by the 10th week of pregnancy.
  
  
  CONCLUSIONS
  ADAM 12 in early first trimester is a very efficient marker of DS. In combination with existing markers, it offers enhanced screening efficiency in a two-stage sequential first-trimester screening program or in a contingent-screening model, which may have benefits in health economies where universal access to high quality ultrasound is difficult. More data on early first-trimester cases with DS are required to establish more secure population parameters by which to assess further the validity of these models.
authors.affiliation: Department of Clinical Biochemistry, Statens Serum Institut, Copenhagen, Denmark.
authors.forename: Jennie
authors.initials: J
authors.lastname: Laigaard
authors.forename: Kevin
authors.initials: K
authors.lastname: Spencer
authors.forename: Michael
authors.initials: M
authors.lastname: Christiansen
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Cowans
authors.forename: Severin Olesen
authors.initials: SO
authors.lastname: Larsen
authors.forename: Bent Norgaard
authors.initials: BN
authors.lastname: Pedersen
authors.forename: Ulla M
authors.initials: UM
authors.lastname: Wewer
mesh_terms: D051722:ADAM Proteins / Q000097:blood*; D000072199:ADAM12 Protein; D015415:Biomarkers / Q000097:blood; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000097:blood; D019483:Disintegrins / Q000097:blood*; D004314:Down Syndrome / Q000175:diagnosis*; D005260:Female; D005865:Gestational Age; D006801:Humans; D008565:Membrane Proteins / Q000097:blood*; D016011:Normal Distribution; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011266:Pregnancy-Associated Plasma Protein-A / Q000032:analysis
chemical_list: D015415:Biomarkers; D018997:Chorionic Gonadotropin, beta Subunit, Human; D019483:Disintegrins; D008565:Membrane Proteins; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human; D011266:Pregnancy-Associated Plasma Protein-A