Predicting Fetal Chromosome Anomalies in the First Trimester Using Pregnancy Associated Plasma Protein-A: A Comparison of Statistical Methods

Abstract:

The analysis of the clinical efficiency of a biochemical parameter in the prediction of chromosome anomalies is described, using a database of 475 cases including 30 abnormalities. A comparison was made of two different approaches to the statistical analysis: the use of Gaussian frequency distributions and likelihood ratios, and logistic regression. Both methods computed that for a 5% false-positive rate approximately 60% of anomalies are detected on the basis of maternal age and serum PAPP-A. The logistic regression analysis is appropriate where the outcome variable (chromosome anomaly) is binary and the detection rates refer to the original data only. The likelihood ratio method is used to predict the outcome in the general population. The latter method depends on the data or some transformation of the data fitting a known frequency distribution (Gaussian in this case). The precision of the predicted detection rates is limited by the small sample of abnormals (30 cases). Varying the means and standard deviations (to the limits of their 95% confidence intervals) of the fitted log Gaussian distributions resulted in a detection rate varying between 42% and 79% for a 5% false-positive rate. Thus, although the likelihood ratio method is potentially the better method in determining the usefulness of a test in the general population, larger numbers of abnormal cases are required to stabilise the means and standard deviations of the fitted log Gaussian distributions.

Key-Words

First Trimester - Screening - Pregnancy-Associated Plasma Protein-A (PAPP-A) - Logistic Regression

• REFERENCES

• 1 Cuckle HS, Wald NJ, Thompson SG. Estimating a woman’s risk of having a pregnancy associated with Down’s syndrome using her age and serum alpha-fetoprotein level. Brit J Obstet Gynaecol 1987; 94: 387-402.
• 2 Canick JC, Knight GJ, Palomaki GE, Haddow JE, Cuckle HS, Wald NJ. Low second trimester maternal serum unconjugated oestriol in pregnancies with Down’s syndrome. Brit J Obstet Gynaecol 1988; 95: 330-3.
• 3 Wald NJ, Cuckle HS, Densem JW. et al. Maternal serum screening for Down’s syndrome in early pregnancy. BMJ 1988; 297: 883-87.
• 4 Lewis M, Faed MJW, Howie PW. Screening for Down’s syndrome based on individual risk. BMJ 1991; 303: 551-3.
• 5 Brambati B, Simoni G, Bonacchi I, Piceni L. Fetal chromosomal aneuploides and maternal serum alpha fetoprotein levels in the first trimester. Lancet 1986; ii: 165-6.
• 6 Barkai G, Shaki R, Pariente C, Goldman B. First trimester alpha fetoprotein levels in normal and chromosomally abnormal pregnancies (letter). Lancet 1987; ii: 389.
• 7 Cuckle HS, Wald NJ, Barkai G. et al. First trimester biochemical screening for Down syndrome (letter). Lancet 1988; ii: 851-2.
• 8 Mantingh A, Marrink J, De Wolf B, Breed AS, Beekhuis JR, Visser GH. Low maternal serum alpha fetoprotein at 10 weeks gestation and fetal Down’s syndrome. Brit J Obstet Gynaecol 1989; 96 (04) 499-500.
• 9 Milunsky A, Wands J, Brambati B, Bonacchi I, Currie K. First trimester maternal serum alpha fetoprotein screening for chromosome defects. Am J Obstet Gynecol 1988; 159 (05) 1209-13.
• 10 Brambati B, Macintosh MCM, Teisner B. et al. Low maternal serum levels of pregnancy-associated plasma protein A (PAPP-A) in the first trimester in association with abnormal fetal karyotype. Accepted for publication. Brit J Obstet Gynaecol. 1993 (in press).
• 11 Sinosich MJ, Teisner B, Folkersen J, Saunders DM, Grudzinskas JG. Radioimmunoassay for pregnancy-associated plasma protein A. Clin Chem 1982; 05: 777-86.
• 12 Chard T, Lilford RJ. In: How Useful is a Test?: Progress in Obstetrics and Gynaecology. Studd J. (ed). Churchill Livingstone Publ; 1991: 9.
• 13 Hook EB, Cross PK, Jackson L, Pergament E, Brambati B. Maternal age specific rates of 47, +21 and other cytogenetic abnormalities diagnosed in the first trimester of pregnancy in chorionic villus biopsy specimens: comparison with rates expected from observations at amniocentesis. Am J Hum Genet 1988; 42: 797-807.
• 14 Ferguson-Smith MA, Yates JRW. Maternal age specific rates for chromosome aberrations and factors influencing them: report of a collaborative European study on 52,965 amniocentesis. Prenat Diagn 1984; 04: 5-44.
• 15 Birth Statistics (England and Wales). London: HMSO. Office of Population Censuses and Surveys FM1 No. 16, 1987
• 16 Cuckle HS. Measuring unconjugated estriol in maternal serum to screen for fetal Down’s syndrome. Clin Chem 1992; 38: 1687-9.
• 17 Thornton JG, Lilford RJ. Prenatal diagnosis of Down’s syndrome; a method for measuring the consistency of women’s decisions. Med Decision Making 1990; 10: 288-93.
• 18 Haddow JE, Palomaki GE, Knight GJ. et al. Prenatal screening for Down’s syndrome with use of maternal serum markers. New Engl J Med 1992; 327: 588-93.
• 19 Wald NJ, Kennard A, Densem JW, Cuckle HS, Chard T, Butler L. Antenatal maternal serum screening for Down’s syndrome: results of a demonstration project. BMJ 1992; 305: 391-3.