title: Impact of bias in serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A multiples of the median levels on first-trimester screening for trisomy 21.
abstract: OBJECTIVE
  To examine the effect of bias in median multiples of the median (MoM) levels of pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (β-hCG) on first-trimester combined screening for trisomy 21.
  
  
  METHODS
  The effects of deviations in the MoM levels of free β-hCG and PAPP-A were investigated by simulating nuchal translucency (NT) at 12 weeks and MoM values for PAPP-A and free β-hCG for 500 000 euploid and 500 000 trisomy 21 pregnancies at 9 and at 12 weeks of gestation. Likelihoods were calculated using the mixture model for NT and the standard Gaussian model for log MoM PAPP-A and free β-hCG values. Deviations in MoM marker levels were simulated by applying percentage changes of 5% to 20% to MoM values. Detection and false-positive rates were calculated with and without adjustments of the maternal serum marker levels by taking the proportion of euploid and aneuploid cases above given thresholds for each maternal age and then taking a weighted average with respect to the maternal age distribution.
  
  
  RESULTS
  With median MoM levels on target, the modeled detection and false-positive rates in combined screening for trisomy 21 at 12 weeks of gestation with a fixed risk cut-off of 1 in 100 were 85% and 2.5%, respectively. For median MoM levels of free β-hCG and PAPP-A between 0.8 and 1.2 MoM, detection rates ranged from 77% to 91%, with corresponding false-positive rates ranging from 1.0% to 6.1%.
  
  
  CONCLUSIONS
  In first-trimester screening for trisomy 21, biases in the serum marker MoM levels of 10% can increase false-positive rates by over 50%, whilst biases of 20% can more than double false-positive rates.
authors.affiliation: Department of Mathematics and Statistics, University of Plymouth, Plymouth, UK. D.Wright@plymouth.ac.uk
authors.forename: D
authors.initials: D
authors.lastname: Wright
authors.forename: H
authors.initials: H
authors.lastname: Abele
authors.forename: A
authors.initials: A
authors.lastname: Baker
authors.forename: K O
authors.initials: KO
authors.lastname: Kagan
mesh_terms: D015982:Bias; D015415:Biomarkers / Q000378:metabolism; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000378:metabolism*; D003718:Denmark / Q000453:epidemiology; D004314:Down Syndrome / Q000175:diagnosis / Q000453:epidemiology / Q000378:metabolism*; D005260:Female; D005865:Gestational Age; D006801:Humans; D008423:Maternal Age; D048208:Nuchal Translucency Measurement; D011237:Predictive Value of Tests; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011266:Pregnancy-Associated Plasma Protein-A / Q000378:metabolism*; D012372:ROC Curve; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D015415:Biomarkers; D018997:Chorionic Gonadotropin, beta Subunit, Human; D011266:Pregnancy-Associated Plasma Protein-A