title: Evaluating first trimester maternal serum screening combinations for Down syndrome suitable for use with reflexive secondary screening via sequencing of cell free DNA: high detection with low rates of invasive procedures.
abstract: OBJECTIVE
  Examine primary Down syndrome screening using combinations of first trimester serum markers, with and without sequencing of cell free DNA as a secondary reflexive test.
  
  
  METHODS
  Samples from 40 Down syndrome cases were matched with five control samples and tested for PAPP-A, free β, AFP, inhibin-A and PlGF. Results were converted to weight-adjusted multiples of the median (MoM) and population parameters computed. Monte Carlo simulation modeled Down syndrome detection and false positive rates for various marker combinations. After reflexive DNA testing, the revised detection and false positive rates were also computed.
  
  
  RESULTS
  At a primary false positive rate of 20%, the baseline combination (maternal age, PAPP-A and free β) detected 86.9%. Adding AFP or PlGF increased detection to 89.8% and 89.5%, respectively. Adding AFP and PlGF, AFP and inhibin-A, or all three markers, detected 93.7%, 94.1% and 95.5%, respectively. Modeling reflexive cf DNA testing results in little loss in detection (1%), but false positive rates fall to 0.2%.
  
  
  CONCLUSIONS
  First trimester reflexive testing does not require nuchal translucency measurements, and has high detection and very low rates of invasive procedures. However, timing of DNA sample collection and the costs of sample collection and DNA testing need to be considered before implementation.
authors.affiliation: Division of Medical Screening and Special Testing, Department of Pathology and Laboratory Medicine, Women and Infants Hospital, Providence, RI, USA.|Department of Pathology and Laboratory Medicine, Alpert School of Medicine, Brown University, Providence, RI, USA.
authors.forename: Glenn E
authors.initials: GE
authors.lastname: Palomaki
authors.affiliation: Division of Medical Screening and Special Testing, Department of Pathology and Laboratory Medicine, Women and Infants Hospital, Providence, RI, USA.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Eklund
authors.affiliation: Division of Medical Screening and Special Testing, Department of Pathology and Laboratory Medicine, Women and Infants Hospital, Providence, RI, USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Neveux
authors.affiliation: Division of Medical Screening and Special Testing, Department of Pathology and Laboratory Medicine, Women and Infants Hospital, Providence, RI, USA.|Department of Pathology and Laboratory Medicine, Alpert School of Medicine, Brown University, Providence, RI, USA.
authors.forename: Geralyn M
authors.initials: GM
authors.lastname: Lambert Messerlian
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002474:Cell-Free System; D004247:DNA / Q000097:blood; D004314:Down Syndrome / Q000175:diagnosis* / Q000235:genetics; D005189:False Positive Reactions; D005260:Female; D006801:Humans; D062145:Maternal Serum Screening Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000097:blood*
chemical_list: D015415:Biomarkers; D004247:DNA