Lynne M. George

PRENATAL SCREENING FOR DOWN'S SYNDROME USING INHIBIN-A AS A SERUM MARKER

The value of measuring inhibin‐A (αβA dimer) with human chorionic gonadotrophin (total or the sub‐units free α‐hCG and free β‐hCG separately), alpha‐fetoprotein (AFP), and unconjugated oestriol (uE3) was examined to determine the effect on the performance of serum screening for Downs syndrome between 15 and 22 weeks of pregnancy. The study was based on stored serum samples from 77 Downs syndrome singleton pregnancies and 385 unaffected singleton pregnancies, matched for maternal age, gestational age, and duration of storage of the sample, supplemented by data from 970 white women with unaffected pregnancies. Inhibin‐A was elevated in the serum of women with Downs syndrome pregnancies with a median of 1·79 multiples of the median (MOM). Using the four serum markers AFP, uE3, total hCG, and inhibin‐A, in addition to maternal age, 70 per cent of Downs syndrome pregnancies were detected for a 5 per cent false‐positive rate compared with 59 per cent with the conventional triple test (AFP, uE3, and total hCG with maternal age). If the estimate of gestational age were based on an ultrasound scan examination, the detection rate would be 77 per cent [95 per cent confidence interval (CI) 69–85 per cent] using the four serum markers including inhibin‐A, compared with 67 per cent with the triple test or 79 per cent (95 per cent CI 71–87 per cent) if marker values were adjusted for maternal weight. If the detection rate were kept at 70 per cent and the gestational age were estimated by an ultrasound scan examination, the four‐marker test would reduce the false‐positive rate from 6·1 per cent using the triple test to 2·9 per cent. The results were virtually the same if free β‐hCG was used instead of total hCG. The inhibin‐A‐based four‐marker test is the most effective method of prenatal screening for Downs syndrome suitable for routine use. If the extra cost required to carry out the inhibin‐A test were less than about £3 per woman screened, the four‐marker test including inhibin‐A would be financially cost‐effective.

Serum screening for Down's syndrome between 8 and 14 weeks of pregnancy

Objective To determine the value of serum screening for Downs syndrome at 8–14 weeks of pregnancy using seven potential serum markers (alpha‐fetoprotein, unconjugated oestriol, total human chorionic gonadotrophin (hCG), free α‐hCG, free P‐hCG, pregnancy associated plasma protein A (PAPP‐A), and dimeric inhibin A).

Maternal serum unconjugated oestriol and human chorionic gonadotrophin levels in twin pregnancies: implications for screening for Down's syndrome

Objective— To investigate maternal serum unconjugated oestriol (uE3) and human chorionic gonadotrophin (hCG) levels in twin pregnancies and to consider the implications of the results for antenatal screening for Downs syndrome.

Prospective observational study to assess value of prostate specific antigen as screening test for prostate cancer

Abstract Objective: To evaluate measurement of serum prostate specific antigen as a potential screening test for future clinical prostate cancer among healthy men. Design: Nested case-control study with stored serum samples collected from 49261 men with follow up using national death and cancer registration systems. Subjects: 265 asymptomatic men who subsequently developed clinical prostate cancer and 1055 controls matched for age, study centre, and duration of storage of samples. Main outcome measures: Distribution of concentrations of the antigen in men who developed prostate cancer and in controls. Results: Prostate specific antigen concentrations were significantly higher in men who subsequently developed prostate cancer than in controls. In the first three years after blood collection the median concentration was 23 times greater in cases than in controls of the same age at the same centre (that is, 23 multiples of the median). A smaller difference persisted thereafter; 4.0 multiples of the median 3-6 years after blood collection, 3.6 6-10 years, and 1.8 after 10 years. In the first three years the proportion of men who developed prostate cancer and had raised levels of the antigen (>/=12 multiples of the median) (detection rate or sensitivity) was 81% (95% confidence interval 54% to 96%). The proportion of men who did not develop prostate cancer but had levels this high (false positive rate) was only 0.5%. Conclusion: Prostate specific antigen measurement is a highly discriminatory screening test for prostate cancer among healthy men. In the general population, 60-74 year old men who had >/=12 times the normal median level would have about a 50% chance of developing clinical prostate cancer in the next three years. Measurement of this antigen is a good enough screening test to justify a randomised controlled trial to determine any reduction in mortality from prostate cancer.

Insulin-like growth factors and cancer : no role in screening. Evidence from the BUPA study and meta-analysis of prospective epidemiological studies

Insulin-like growth factor-1 (IGF-1), insulin-like growth factor-2 (IGF-2), and insulin-like growth factor binding protein-3 (IGFBP-3) were measured in frozen serum samples from 1051 men with cancer and 3142 controls in a nested case–control study from the British United Provident Association (BUPA) study cohort and associations with 14 cancers were examined, including prostate, colorectal, and lung. A meta-analysis of studies on these three cancer sites was also conducted. In the meta-analysis the odds ratio between the highest quartile IGF-1 group and the lowest quartile group was 1.31 (95% confidence interval (CI): 1.03–1.67) for prostate, 1.37 (1.05–1.78) for colorectal and 1.02 (0.80–1.31) for lung cancer, and for IGF-2 it was 0.72 (0.36–1.44) for prostate and 1.95 (1.26–3.00) for colorectal cancer. Results from the BUPA study were consistent with the estimates from the other studies. There were no statistically significant associations with IGFBP-3 and any of the cancer sites considered. Our results suggest that IGF-1, IGF-2, and IGFBP-3 measurements have no value in cancer screening, although IGF-1 and IGF-2 may be of aetiological significance in relation to colorectal and prostate cancer.

Assay precision of serum α fetoprotein in antenatal screening for neural tube defects and Down's syndrome

Objectives To assess the impact of current serum α fetoprotein (AFP) assays on the performance of screening for open neural tube defects and Downs syndrome. Methods Maternal serum samples, collected between weeks 15 and 22 from 470 singleton pregnancies without neural tube defects or Downs syndrome, were assayed for AFP using an automated fluorometric immunoassay. The samples had been assayed for AFP using an in house radioimmunoassay with a lower precision ten years before. The variance of AFP using the radioimmunoassay was compared with that using the current fluorometric assay and then used to estimate the detection rates and false positive rates for neural tube defect and Downs syndrome screening. Results Current serum AFP assays are more precise. Using a cut off level of 2.5 multiples of the median, the false positive rate in screening for anencephaly and open spina bifida was 0.8% with the new assay compared with 2% using the previous assay. When screening for Downs syndrome, the false positive rate is reduced by about one percentage point without loss of detection. Conclusion Improvements in the precision of maternal serum AFP measurement have led to small but useful improvements in screening for open neural tube defects and Downs syndrome. Published estimates of screening performance using such modern assays can be revised accordingly.

MATERNAL SERUM INHIBIN-A LEVELS IN TWIN PREGNANCIES: IMPLICATIONS FOR SCREENING FOR DOWN'S SYNDROME

A nested case–control study using stored serum samples collected as part of a prospective study of the outcome of pregnancy was performed to investigate concentrations of (dimeric) inhibin‐A in maternal serum between 15 and 22 weeks of pregnancy in 200 twin pregnancies and 600 singleton control pregnancies. Each twin pregnancy was matched with three singleton pregnancies for gestational age (same completed week) and duration of sample storage (same calendar year), although for one twin there was insufficient serum. The median inhibin‐A level in the twin pregnancies was 1·99 multiples of the median (MOM) for singleton pregnancies (P<0·001) [95 per cent confidence interval (CI) 1·83–2·16]. These results enable inhibin‐A values to be adjusted so that prenatal screening for Downs syndrome can be performed using this marker in twin pregnancies as well as in singleton pregnancies.

MATERNAL SERUM INHIBIN‐A IN PREGNANCIES WITH INSULIN‐DEPENDENT DIABETES MELLITUS: IMPLICATIONS FOR SCREENING FOR DOWN'S SYNDROME

A nested case–control study using stored serum samples collected as part of a prospective study of the outcome of pregnancy was performed to investigate concentrations of (dimeric) inhibin‐A in maternal serum between 15 and 22 weeks of pregnancy in 126 pregnancies among 92 women with insulin‐dependent diabetes mellitus (IDDM). Each IDDM pregnancy was matched with two control singleton pregnancies for gestational age (same completed week) and duration of sample storage (same calendar quarter). The median inhibin‐A level in the IDDM pregnancies was 0·88 multiples of the median (MOM) for pregnancies without IDDM at the same gestational age (P=0·05) (95 per cent confidence interval 0·78–1·00) or 0·91 MOM after adjustment for maternal weight. These results enable inhibin‐A values to be adjusted so that prenatal screening for Downs syndrome can be performed using this marker in IDDM pregnancies as well as in non‐diabetic pregnancies.

The value of early second trimester PAPP-A and ADAM12 in screening for pre-eclampsia

Objective To estimate the pre-eclampsia screening performance of PAPP-A (pregnancy-associated plasma protein-A) and ADAM12 (A Disintegrin And Metalloprotease 12) in the early second trimester of pregnancy. Methods Stored frozen serum samples from a previously published nested case-control study comprising 77 women who developed pre-eclampsia and 224 unaffected controls were thawed and assayed for PAPP-A and ADAM12. Levels were converted into multiple of the unaffected median (MoM) values. Results Neither PAPP-A or ADAM12 were significantly different in women who developed pre-eclamspia compared with unaffected controls (PAPP-A: 0.97 MoM [95% confidence interval 0.73 to 1.25], ADAM12: 1.01 MoM [0.91 to 1.13]). Conclusion Our results do not support the use of PAPP-A or ADAM12 in early second trimester antenatal screening for pre-eclampsia

Antenatal Screening for Down Syndrome Using Serum Placental Growth Factor with the Combined, Quadruple, Serum Integrated and Integrated Tests

Objective To estimate the value of first or second trimester placental growth factor (PlGF) as an additional antenatal screening marker for Down syndrome. Design Nested case-control study. Setting Antenatal screening service. Population or Sample 532 Down syndrome pregnancies and 1,155 matched unaffected pregnancies. Methods Stored maternal serum samples (−40°C) were assayed for PlGF. Monte Carlo simulation was used to estimate the screening performance of PlGF with the Combined, Quadruple, serum Integrated and Integrated tests. Main Outcome Measures Median PlGF levels in affected and unaffected pregnancies and screening performance (detection rates [DR] for specified false-positive rates [FPR] and vice versa). Results First trimester median PlGF was 15%, 28% and 39% lower in Down syndrome than unaffected pregnancies at 11, 12 and 13 completed weeks’ gestation respectively (all p<0.001). Second trimester median PlGF was 31% lower at 14 weeks (p<0.001), and the difference decreased (6% lower at 17 weeks). At a 90% DR with first trimester markers measured at 13 weeks, adding PlGF decreased the FPR from 11.1 to 5.1% using the Combined test, 9.3% to 4.5% using the serum Integrated test, and 3.4% to 1.5% using the Integrated test (or 1.5 to 1.4% with first trimester markers measured at 11 weeks). Adding PlGF to the Quadruple test (measured at 15 weeks) decreased the FPR from 10.0% to 9.6% at a 90% DR. Conclusions First trimester PlGF measurements improve the performance of antenatal screening for Down syndrome using the Combined, serum Integrated and Integrated tests. Second trimester PlGF measurements are of limited value.