PRENATAL DIAGNOSIS, VOL.
12,545-552 (1992)
LETTERS TO THE EDITOR Aneuploidy indices in biochemical screening In recent years, several different maternal blood markers of fetal Down’s syndrome have been discovered and biochemical screening for this disorder is now routine in many centres. When screening with more than one marker, a method is needed to combine information o n the individual marker levels in order to classify each result as positive or negative. One approach is to estimate the risk of a Down’s syndrome pregnancy for the given combination of marker levels and maternal age, regarding any risk exceeding, say, the 95th centile (usually about 1 in 250) as positive. A second approach, advocated in two recent Prenatal Diagnosis articles (Kratzer et al., 1991; Bogart and Jones, 1991) and originally suggested by White et al. (1989), is to form an ‘aneuploidy index’ by taking the product of the marker levels or the ratio between them and regarding the result as positive if the index is extreme. The index approach makes it easier to determine whether a result is positive or negative but this is likely to be achieved at the cost of a loss of detection. There are two reasons for this. Firstly, the index is arbitrary and may not take full account of the relative discriminatory power of the individual markers and the correlation between them. For example, the index of White et al. (human chorionic gonadotrophin (hCG) divided by alphafetoprotein (AFP)) gives equal weight to both hCG and A F P (e.g., the index is 3 if hCG is elevated to 3 multiples of the median (MOM) but A F P is 1 MOM, and if h C G is 1 MOM but A F P is reduced to 0.33 MOM), whereas h C G is more discriminatory than A F P and should be given more weight. Secondly, the index ignores maternal age. That may not be important if screening is restricted to young women but if it is used across all ages the loss of detection will be substantial. It has been estimated that using the 95th centile of the hCG/AFP index as a cut-off level, the detection rate would be 38 per cent compared with 44 per cent using the 95th centile of risk based on hCG and A F P without maternal age and 55 per cent 0
1992 by John Wiley & Sons, Ltd.
including maternal age (Cuckle et al., 1989). The two recently published indices are ways of combining information on hCG, and free alpha-subunit of glycoprotein together with progesterone to screen for Down’s syndrome in the first trimester or A F P in the second. Until sufficient data have been published on the multivariate frequency distribution of these markers, potential screening efficiency cannot be adequately judged. When such data become available, it will also be possible to compare the indices with formulae for Down’s syndrome risk based on the same markers derived by standard logistic regression or possibly multivariate Gaussian analysis. HOWARD CUCKLE Institute of Epidemiology and Health Services Research, Department of Clinical Medicine, University of Leeds. 34 f f y d e Terrace, Leeds LS2 9LN. U . K . REFERENCES Bogart, M.H., Jones, O.W. (1991). Invited Editorial Response: Prenatal screening for fetal Down’s syndrome, Prenal. Diagn., 11,763-765. Cuckle, H.S., Densem, J.W., Wald, N.J. (1989). Simplification of biochemical screening for Down syndrome, Am. J . Hum. Genet., 45, 979-980. Kratzer, P.G., Golbus, M.S., Monroe, S.E., Finkelstein, D.E., Taylor, R.N. (1991). First trimester aneuploidy screening using serum human chorionic gonadotrophin (hCG), free ahCG, and progesterone, Prenat. Diagn., 11, 75 1-763.
White, I., Papiha, S.S., Magnay, D. (1989). Improving methods of screening for Down’s syndrome, N . Engl. J . Med., 320,401402.
Low maternal serum human chorionic gonadotrophin and unconjugated oestriol in a triploidy pregnancy The recent case reports from Kohn el al. (1991) prompted us to report a further case of triploidy where the maternal levels of both
12,545-552 (1992)
LETTERS TO THE EDITOR Aneuploidy indices in biochemical screening In recent years, several different maternal blood markers of fetal Down’s syndrome have been discovered and biochemical screening for this disorder is now routine in many centres. When screening with more than one marker, a method is needed to combine information o n the individual marker levels in order to classify each result as positive or negative. One approach is to estimate the risk of a Down’s syndrome pregnancy for the given combination of marker levels and maternal age, regarding any risk exceeding, say, the 95th centile (usually about 1 in 250) as positive. A second approach, advocated in two recent Prenatal Diagnosis articles (Kratzer et al., 1991; Bogart and Jones, 1991) and originally suggested by White et al. (1989), is to form an ‘aneuploidy index’ by taking the product of the marker levels or the ratio between them and regarding the result as positive if the index is extreme. The index approach makes it easier to determine whether a result is positive or negative but this is likely to be achieved at the cost of a loss of detection. There are two reasons for this. Firstly, the index is arbitrary and may not take full account of the relative discriminatory power of the individual markers and the correlation between them. For example, the index of White et al. (human chorionic gonadotrophin (hCG) divided by alphafetoprotein (AFP)) gives equal weight to both hCG and A F P (e.g., the index is 3 if hCG is elevated to 3 multiples of the median (MOM) but A F P is 1 MOM, and if h C G is 1 MOM but A F P is reduced to 0.33 MOM), whereas h C G is more discriminatory than A F P and should be given more weight. Secondly, the index ignores maternal age. That may not be important if screening is restricted to young women but if it is used across all ages the loss of detection will be substantial. It has been estimated that using the 95th centile of the hCG/AFP index as a cut-off level, the detection rate would be 38 per cent compared with 44 per cent using the 95th centile of risk based on hCG and A F P without maternal age and 55 per cent 0
1992 by John Wiley & Sons, Ltd.
including maternal age (Cuckle et al., 1989). The two recently published indices are ways of combining information on hCG, and free alpha-subunit of glycoprotein together with progesterone to screen for Down’s syndrome in the first trimester or A F P in the second. Until sufficient data have been published on the multivariate frequency distribution of these markers, potential screening efficiency cannot be adequately judged. When such data become available, it will also be possible to compare the indices with formulae for Down’s syndrome risk based on the same markers derived by standard logistic regression or possibly multivariate Gaussian analysis. HOWARD CUCKLE Institute of Epidemiology and Health Services Research, Department of Clinical Medicine, University of Leeds. 34 f f y d e Terrace, Leeds LS2 9LN. U . K . REFERENCES Bogart, M.H., Jones, O.W. (1991). Invited Editorial Response: Prenatal screening for fetal Down’s syndrome, Prenal. Diagn., 11,763-765. Cuckle, H.S., Densem, J.W., Wald, N.J. (1989). Simplification of biochemical screening for Down syndrome, Am. J . Hum. Genet., 45, 979-980. Kratzer, P.G., Golbus, M.S., Monroe, S.E., Finkelstein, D.E., Taylor, R.N. (1991). First trimester aneuploidy screening using serum human chorionic gonadotrophin (hCG), free ahCG, and progesterone, Prenat. Diagn., 11, 75 1-763.
White, I., Papiha, S.S., Magnay, D. (1989). Improving methods of screening for Down’s syndrome, N . Engl. J . Med., 320,401402.
Low maternal serum human chorionic gonadotrophin and unconjugated oestriol in a triploidy pregnancy The recent case reports from Kohn el al. (1991) prompted us to report a further case of triploidy where the maternal levels of both
