Background: In a previous study we examined the changes in the median
multiple of the median (MoM) with gestation of free beta human chorionic
gonadotrophin (Fβ-hCG), total human chorionic gonadotrophin (ThCG), α-fetoprotein
(AFP) and pregnancy-associated plasma protein A (PAPP-A) in a large series of Down's
syndrome pregnancies. Results showed that there was a significant temporal variation
of the MoM for each marker. In this paper, we assess the impact of this temporal
shift on the estimation of patient-specific risks and the detection rates (DRs) for
Down's syndrome pregnancies.
Methods: Individual patient-specific risks, DRs and false positive rates
were estimated using statistical modelling techniques and computer simulations. The
data for these simulations were the regressed mean log10 analyte MoMs,
marker standard deviations (as log10 MoM) and correlation coefficients
derived from the analysis of over 1000 cases of Down's syndrome and 150 000
unaffected pregnancies between 6 and 20 weeks of gestation reported in our previous
study. Two models were compared: the classical constant median separation model,
which assumes no variation in median shift with gestation (model 1), and a variable
median separation model (model 2), which takes account of the changes in median shift
with gestation as described in our previous study.
Results: When individual patient-specific risks calculated for various
MoM values using model 1 were compared with those derived from model 2, considerable
differences in risk estimates were observed for all marker combinations, particularly
in the first trimester. Using a 1 in 250 cut-off risk, DRs at each gestation in the
second trimester for the AFP+Fβ-hCG combination were maximized at 14-17 weeks of
gestation and were virtually identical at 63-65% for model 1 and model 2. A similar
trend was observed for the AFP+ThCG combination, with an optimum gestational range of
15-18 weeks and DRs of 66-68%. In the first trimester, using a 1 in 250 cut-off risk,
DRs were more variable with gestation for the prime marker combination of
Fβ-hCG+PAPP-A, varying from 73% at 8 weeks to 65% at 13 weeks with model 1 and from
75% to 66% with model 2.
Conclusion: Risk algorithms should take into account temporal variation
in marker MoMs in order to produce accurate patient-specific risks. This also helps
to maximize DRs, particularly when samples are taken outwith the optimal gestational
range.
