Journal of Medical Screening > Volume 15, Number 2 > Pp. 55-61

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Original Articles

Multiple-marker screening for Down's syndrome: a method of assessing the statistical robustness of proposed tests

J K Morris, Reader in Medical Statistics  , Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Barts and the London Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK

J Bestwick, Statistician , Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Barts and the London Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK

N J Wald, Professor , Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Barts and the London Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK

Correspondence to: J K Morris, Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Barts and the London Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK; j.k.morris{at}qmul.ac.uk

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Objectives Antenatal screening for Down's syndrome relies on the use of multiple markers in combination. Markers that are highly correlated can cause statistical instability. We used the maximum variance inflation factor (VIF_max) to determine whether a screening test using multiple markers was robust to imprecision in the estimation of the marker distribution parameters.

Methods The VIF_max for a specified screening test was calculated from the correlations between markers in Down's syndrome pregnancies for six tests: integrated and serum integrated tests without repeat measurements, both tests with repeat measurements across trimesters analysed in the standard way, and both tests with repeat measurements analysed as cross-trimester (CT) marker ratios. The screening performance of each test using published parameter values, in terms of the false-negative rates for a 3% false-positive rate (FN₃), were calculated for simulated populations with medians 0.2 standard deviations (SD) higher or lower than the published values (to reflect imprecision in parameter estimation) for pregnancy-associated plasma protein A and unconjugated oestriol in affected pregnancies. For each test, the VIF_max value was compared with the coefficient of variation of the FN₃ (FN₃ CV). An independent set of 27 Down's syndrome pregnancies was used to determine how many had meaningless low risks (<1 in 10,000) with each test.

Results Tests with VIF_max values greater than 5 had FN₃CV values over 50%, but those with VIF_max values less than 5 had FN₃ CV values less than 21%. The numbers of Down's syndrome pregnancies with meaningless low risk estimates in the independent set were 18 (64%) in tests with VIF_max values 5 and none for those with values <5.

Conclusion VIF_max values of 5 or more suggest instability. The tests using CT marker ratios were stable (VIF_max < 3), but the tests using repeat measurements in the standard manner were not (VIF_max > 5).

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