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

Objectives 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%. Conclusion 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. © 2015 John Wiley & Sons, Ltd.