Repeated measures screening for Trisomy 21 - results from a general population screening trial (the faster trial)


      To evaluate whether Repeated Measures Screening (RMS), a novel approach in which particularly highly correlated serum markers are measured repeatedly in both 1st and 2nd trimesters, will improve Trisomy 21 screening performance.

      Study design

      A nested case-control study was performed on 78 Trisomy 21 cases and 390 matched normal controls, with maternal blood obtained at 11-13 wks and 15-18 wks. Measurement of hCG was added to 1st trimester PAPP-A and NT, and PAPP-A was added to 2nd trimester Quad marker measurements. Multivariate Gaussian distribution of log MoM values in Trisomy 21 and unaffected pregnancies was assumed. Modeling was performed, based on samples of 500,000 observations drawn from these distributions. Likelihood ratios were computed and used to calculate detection rates (DRs) and false positive rates (FPRs) for each maternal age.


      Serum integrated screening (PAPP-A in 1st trimester; AFP/hCG/uE3/inhibin-A in 2nd trimester; single risk result provided) for Trisomy 21 has a 90% DR with a 4.9% FPR, when started at 11 wks. By repeating the assay for PAPP-A in the 2nd trimester, the FPR for serum integrated screening more than halves, to 1.9%, and decreases further to 1.4% by including an assay for hCG on the 1st trimester sample. Fully integrated screening (NT and PAPP-A in 1st trimester; AFP, total hCG, uE3, inhibin-A in 2nd trimester; single risk result provided) has a 90% DR with a 1.3% FPR, which decreases to <0.5% by repeating the assay for PAPP-A in the 2nd trimester and/or repeating the assay for hCG in the 1st trimester. Similar improved efficiency is seen for screening started at 12 or 13 wks.


      RMS is a highly efficient approach for Trisomy 21 screening, providing similarly high detection rates as serum or fully integrated screening, but with substantial further reductions in the overall FPR. The significant reduction in overall FPR should have a major impact on invasive testing rates, pregnancy loss rates and cost effectiveness of screening. Prospective studies to confirm these data are now warranted. (NIH-RO1-HD-38652)