Wald 2003.

Clinical features and settings	Routine screening.
Participants	606 participants: 101 cases, 505 controls matched for gestation, duration of storage and centre. UK and Austria ‐ multicentre trial. September 1996 ‐ April 2000. Pregnant women. 9‐13 and 14‐20 weeks' gestation.
Study design	Case‐control study.
Target condition and reference standard(s)	Down's syndrome: 101 cases. Reference standards: invasive testing (following second trimester screening) or follow‐up to birth.
Index and comparator tests	First trimester NT (midsagittal section, optimal magnification of thickness of translucent space between inner skin surface and fascia covering cervical spine (white black interface (outer) ‐ black white interface (inner), 41 models of ultrasound machine, 20 minutes allotted scanning time). First and second trimester serum AFP, hCG, uE3, PAPP‐A, free beta hCG (time resolved fluoroimmunoassay, AutoDELFIA). First and second trimester inhibin A (Sandwich enzyme‐linked immunosorbent assay, Oxford Bio‐innovation). First and second trimester urinary beta core fragment, total hCG, ITA and free beta hCG (ITA and beta core fragment, Quest diagnostics USA).
Follow‐up	Follow‐up by: 1) Staff at local hospitals completed a study outcome form at, or just after. delivery, 2) Study records of CVS, amniocentesis or karyotype at birth linked to information from cytogenic laboratories, 3) Study records linked to records of cases of Down's syndrome from the National Down's Syndrome Cytogenetic Register, 4) Information obtained from local obstetrical outcome records, 5) Forms sent to all women with a request to return details of the outcome of their pregnancy, 6) Individual searches in respect of women whose outcomes of pregnancy had not been obtained by any of the previous methods. 4% of women in the total cohort did not have a documented outcome of pregnancy. Unclear if any of these women were included in this nested case‐control study.
Aim of study	To identify the most effective, safe and cost‐effective strategy for antenatal screening for Down's syndrome using NT, maternal serum and urine markers in the first and second trimesters of pregnancy and maternal age in various combinations.
Notes	Performance of screening assessed at 17 weeks' gestation. Study tried to be non‐interventional in the first trimester ‐ second trimester testing was aimed to be used as the basis for any referral for invasive testing.
Table of Methodological Quality
Item	Authors' judgement	Description
Representative spectrum? All tests	Yes	Routine screening of typical pregnant population.
Acceptable reference standard? All tests	Yes	Karyotyping or follow‐up to birth.
Partial verification avoided? All tests	Unclear	Unclear if all women received a reference standard.
Differential verification avoided? All tests	No	Women received different reference standards.
Incorporation avoided? All tests	Yes	Reference standard was independent of the index test.
Reference standard results blinded? All tests	No	Reference standard interpreted with knowledge of index test results.
Index test results blinded? All tests	Unclear	Serum testing conducted after reference standard and unclear if interpreted without knowledge of reference standard results.
Relevant clinical information? All tests	Yes	Information available as would be in standard clinical practice.
Uninterpretable results reported? All tests	Yes	Rates of NT failure on average 9%. Pre‐10 weeks' gestation, > 33% failure rate, declined to 7% at 12 weeks.
Withdrawals explained? All tests	No	No details of withdrawals given.