Practical strategies in contingent sequential screening for Down syndrome.
OBJECTIVE
To design and assess the performance of protocols for contingent sequential Down syndrome screening that can be implemented in practice.


METHODS
Protocols were designed in which all women received first-trimester measurement of nuchal translucency (NT) together with maternal serum pregnancy-associated plasma protein-A (PAPP-A) and either free beta- or total human chorionic gonadotrophin (hCG). Those women with borderline Down syndrome risks received follow-up second-trimester maternal serum involving double, triple, or quadruple serum screening markers: alpha-fetoprotein, free beta-hCG or total hCG, unconjugated estriol and inhibin-A. Specific ranges of risks were used to define the borderline group. Separate protocols were developed for the United Kingdom and the United States to reflect differences in commonly used tests, cut-offs, and the gestational age at testing. Detection rates and false-positive rates were estimated by multivariate Gaussian modelling with Monte Carlo simulation.


RESULTS
Proposed protocols based on first-trimester NT, PAPP-A and free beta-hCG or total hCG, followed by selective use of second-trimester quadruple markers can result in a 91% detection rate and 2.1% false-positive rate for the United Kingdom and a detection rate of 89% and false-positive rate of 3.1% for the United States. For both countries, over 60% of affected pregnancies would be detected in the first trimester and less than 20% of women would require a second-trimester Down syndrome risk assessment. Use of alternative cut-offs to define those with borderline risks or different combinations of second-trimester markers also yielded high detection rates and low false-positive rates.


CONCLUSIONS
With appropriate patient counselling, it should be possible to provide highly effective Down syndrome screening using contingent sequential protocols.
Benn
Peter
P
Department of Genetics and Developmental Biology, University of Connecticut, Health Center, Farmington, CT 06030-6140, USA. benn@nso1.uchc.edu
Wright
Dave
D
Cuckle
Howard
H
D015415:Biomarkers / Q000097:blood; D006063:Chorionic Gonadotropin / Q000097:blood; D018997:Chorionic Gonadotropin, beta Subunit, Human / Q000097:blood; D004314:Down Syndrome / Q000175:diagnosis*; D004964:Estriol / Q000097:blood; D005189:False Positive Reactions; D005260:Female; D006801:Humans; D007265:Inhibins / Q000097:blood; D008403:Mass Screening / Q000379:methods*; D048208:Nuchal Translucency Measurement / Q000295:instrumentation; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011266:Pregnancy-Associated Plasma Protein-A / Q000032:analysis; D011296:Prenatal Diagnosis; D012307:Risk Factors; D012680:Sensitivity and Specificity; D006113:United Kingdom; D014481:United States; D000509:alpha-Fetoproteins / Q000032:analysis
D015415:Biomarkers; D006063:Chorionic Gonadotropin; D018997:Chorionic Gonadotropin, beta Subunit, Human; D000509:alpha-Fetoproteins; D007265:Inhibins; D011266:Pregnancy-Associated Plasma Protein-A; D004964:Estriol