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K Spencer

Publications and source records attributed to K Spencer.

At least 91 records · Page 5Linked to original sources
PubMed1999

Accuracy of Down's syndrome risks produced in a prenatal screening program.

Down's syndrome screening in the second trimester using a variety of combinations of maternal serum markers has become an established part of antenatal care over the past decade. The methodology of calculating Down's syndrome risk using statistical models based on the Gaussian distribution functions of the various markers used is often considered daunting, and many screening centres rely on specific screening computer software to undertake the relevant calculations. Such software is often a closed system which does not allow the user to check or change any of the parameters within the model. It is clear from a recent UK NEQAS survey of Down's syndrome screening laboratories (Spencer, Ellis, Seth, 1997, unpublished data) that many centres are unsure what method of calculating risk and what population parameters are used in their software, and how appropriate these are for the population being screened. This confusion has led to uncertainty over the reliability of the risk estimates produced in Down's syndrome screening programs.

Down Syndrome↗
PubMed1999

Urinary free beta hCG, beta core fragment and total oestriol as markers of Down syndrome in the second trimester of pregnancy.

In a study of 69 random urine samples from cases of Down syndrome and 405 samples from unaffected pregnancies, we have assessed the value of various candidate markers that have been proposed as tools for screening for Down syndrome. We found that the marker urine free beta hCG in Down syndrome had a median MoM of 3.53 (95 per cent confidence interval 2.48-4.68) and at a 5 per cent cut-off would have identified 49 per cent (34/69) of cases. Urine beta core had a median MoM of 4.95 (3.87-8.62) and at a 5 per cent cut-off would have identified 39 per cent (27/69) of cases. Total oestriol had a median MoM of 0.65 (0.55-0.80) and at a 5 per cent cut-off would have identified 35 per cent (24/69) of cases. In conjunction with maternal age, the modelled detection rate increased to 55.8 per cent for free beta hCG, 49.8 per cent for beta core and 48.8 per cent for total oestriol. In combination free beta hCG, total oestriol and maternal age would have detected 68 per cent of cases for a 5 per cent false-positive rate. Using analyte ratios to obviate the need to correct for urine dilution in our study (rather than correcting to a fixed creatinine concentration) was not shown to be as effective as correcting using urine creatinine. Urine markers on the whole are unlikely to be of practical screening value considering the 85 per cent to 90 per cent detection rates achievable in the first trimester using a combination of ultrasound and maternal serum biochemistry.

Adult↗
PubMed1999

Second trimester levels of pregnancy associated plasma protein-A in cases of trisomy 18.

In a study of 70 cases of trisomy 18 and 450 matched controls in the second trimester we have measured the maternal serum levels of the analytes alpha feto protein (AFP), free beta-human chorionic gonadotrophin (hCG) and pregnancy associated plasma protein-A (PAPP-A). We have found the median multiple of the median (MoM) of maternal serum free beta-hCG to be significantly lower (0.327) than normal, as was the level of AFP (0.600). Levels of PAPP-A were reduced even further (0.108). Of the markers associated with trisomy 18 at this time PAPP-A was the most discriminatory, being lower than the 5 per cent centile of normal in 93 per cent of cases, compared with 57 per cent of cases for free beta-hCG and 32 per cent of cases for AFP. Combining free beta-hCG and PAPP-A or all three markers with maternal age would have the ability to detect 74 per cent of cases at a 0.5 per cent false positive rate (or 64 per cent at a 0.1 per cent false positive rate). Unlike in cases of trisomy 21, the low PAPP-A values observed in the first trimester are continued into the second trimester. Whether the good discriminatory power of PAPP-A can be realized in second trimester screening programmes will depend on developing two stage screening algorithms. This approach is unlikely to be better than the excellent detection rates achievable with free beta-hCG, PAPP-A and nuchal translucency in the first trimester.

Adult↗
PubMed1998

The influence of smoking on maternal serum AFP and free beta hCG levels and the impact on screening for Down syndrome.

I have studied the impact of maternal smoking on the levels of maternal serum alpha-fetoprotein (AFP) and free beta human chorionic gonadotrophin (hCG) during the second trimester in a large series (30,727) of self-reported smokers and non-smokers whose pregnancy resulted in the birth of a normal fetus. I have confirmed in a smaller subset of this population that self-reporting is an accurate method of assessing smoking status as confirmed by biochemical (serum cotinine) assessment. In addition, I have investigated marker levels among 195 pregnancies affected by Down syndrome with smoking status confirmed by measurement of serum cotinine. In both unaffected and Down syndrome groups, the incidence of smoking was 19 per cent but a considerable variation was observed with maternal age when the incidence in younger women (under 25) was 32 per cent. AFP median levels in unaffected smokers were 3 per cent higher, whilst in the Down syndrome group smoker medians were increased by 10 per cent compared with the non-smoker group. Free beta hCG levels in unaffected smokers were reduced by 14 per cent, whilst in the Down syndrome group smoker median levels were decreased by 16 per cent. In the smoker group, the Down syndrome detection rate was 10 per cent lower than in the non-smoker group, whilst the false-positive rate was also 2 per cent lower. Correcting for smoking status would redress this inequality and produce an overall 2 per cent increase in the detection rate for a 0.4 per cent increase in the false-positive rate. This increase in screening performance may be worth building into screening programmes, particularly in populations with a high smoking incidence.

Adult↗
PubMed1998

Evolution of an inhibin A ELISA method: implications for Down's syndrome screening.

The development of a sensitive and specific enzyme-linked immunoassay (ELISA) for inhibin A stimulated the observation that inhibin A was a useful prenatal marker of Down's syndrome. Modifications of that ELISA, in terms of preassay sample treatment, detection methods and standard preparation, were subsequently introduced to improve assay performance and reduce costs. These modified formats have been validated and reported. We describe the modifications in detail, explaining the rationale for each, and report the results of a study directly comparing the various ELISA formats in terms of assay performance when applied to clinical samples and ability to differentiate between normal and Down's syndrome pregnancies. A format involving sample pretreatment with sodium dodecylsulphate at 100 degrees C was found to give better assay performance and a modest improvement in discrimination between Down's syndrome samples and controls, and we recommend this format for use by other investigators.

Down Syndrome↗
PubMed1997

Between-pregnancy biological variability of maternal serum alpha-fetoprotein and free beta hCG: implications for Down syndrome screening in subsequent pregnancies.

In women who have an increased Down syndrome risk in a first pregnancy there is a five-fold greater chance of also having an increased Down syndrome risk in a second subsequent pregnancy. Similarly, in women who have a high alpha-fetoprotein (AFP) level in the first pregnancy, suggesting an increased risk of a neural tube defect (NTD), there is also a five-fold greater chance of them also having a high result in a second subsequent pregnancy. Such a biological association of serum marker levels between pregnancies suggests that there are additional maternal or genetic factors influencing the levels of these serum markers, other than the physiological factors which in themselves are poorly understood. In theory, it is possible to correct for high/low marker results in a previous pregnancy and to do so, I estimate, would reduce the overall Down syndrome screening false-positive rate by about 0.2 per cent. There are insufficient data to make any prediction regarding the impact on detection rates. The small reduction in false-positive rate is unlikely to be a feature worth implementing in Down syndrome screening programmes.

Adult↗
PubMed1997

First-trimester urine free beta hCG, beta core, and total oestriol in pregnancies affected by Down's syndrome: implications for first-trimester screening with nuchal translucency and serum free beta hCG.

We have examined maternal urine concentrations of beta core, free beta human chorionic gonadotrophin (hCG), and total oestriol in 373 control pregnancies and 43 pregnancies affected by aneuploidy (including 22 cases of Down's syndrome) in an attempt to see if any of the analytes have a value in Down's syndrome screening between the tenth and 14th week of pregnancy. We have compared the performance of these analytes against nuchal translucency measurement combined with maternal serum free beta hCG at the same period of pregnancy. Our results show that levels of urine free beta hCG and beta core are increased in Down's syndrome with average multiple of the median levels of 1.81 and 2.91, respectively. Urine total oestriol was reduced (0.83) whilst maternal serum free beta hCG was increased (1.72). In trisomy 18 the levels of all analytes were reduced, although serum free beta hCG was the most discriminating. The spread of results in the control and the Down's group for urine beta core was more than three times than that for serum free beta hCG and with urine free beta hCG it was two times wider. In combination with maternal age, urine total oestriol had a 32 per cent detection rate at a fixed 5 per cent false-positive rate; urine beta core 34 per cent, urine free beta hCG 36 per cent, maternal serum free beta hCG 44 per cent, and nuchal translucency 82 per cent. In combination with nuchal translucency, urine total oestriol added an extra 1 per cent detection, urine beta core an extra 2 per cent, urine free beta hCG an extra 3 per cent, and serum free beta hCG an extra 5 per cent. It is unlikely that any of the urine markers will be of value in first-trimester screening. Optimal first-trimester screening programmes will rely for the foreseeable future on nuchal translucency, serum free beta hCG, and possibly pregnancy-associated plasma protein A.

Chorionic Gonadotropin, beta Subunit, Human↗
PubMed1997

Amniotic fluid and maternal serum levels of CA125 in pregnancies affected by Down syndrome: a re-evaluation of the role of CA125 in Down syndrome screening.

In a study of amniotic fluid from 91 Down syndrome cases and 240 controls, we have shown that the median value of CA125 in pregnancies affected by Down syndrome on the whole reflects those observed in the maternal serum from 106 affected cases and 238 controls. The median MOM for CA125 in amniotic fluid from Down syndrome pregnancies was 1.04 and in maternal serum 1.06, neither value being significantly different from that for the control population. We confirm our previous observation that CA125 is not a marker of Down syndrome and conclude that CA125 has no role to play in Down syndrome screening.

Amniotic Fluid↗
PubMed1997

Precise gaussian distribution functions of maternal serum alpha-fetoprotein and free beta-subunit of human chorionic gonadotropin for trisomy 21 screening: improved accuracy for patient counseling.

OBJECTIVE: Gaussian equation curves are used to generate baseline curves against which a priori maternal age Down syndrome risks are adjusted to develop likelihood ratios for individual patients. We sought to evaluate the accuracy of these calculations, minimize the affects of outliers, and to make improvements. STUDY DESIGN: Gaussian distribution functions were used to investigate the best model for alpha-fetoprotein and free beta-human chorionic gonadotropin multiples of the median with use of nonlinear regressions. Parameters from distribution functions can be used to compute a more precise likelihood ratio for the decision logic for trisomy 21. A total of 58,297 normal cases and 348 cases of trisomy 21 were computed. RESULTS: Log normal distribution functions generated by nonlinear regression produced excellent but exaggerated goodness of fit R2 to the frequency distributions of the data. For normal cases values were as follows (in mean, SD, and R2, respectively): log alpha-fetoprotein -0.07199, 0.15681, and 0.9970; log beta-human chorionic gonadotropin -0.15203, 0.24284, and 0.9987. For trisomy 21 cases the values were (in mean, SD, and R2, respectively) for log alpha-fetoprotein -0.19303, 0.15802, and 0.9828 and for log beta-human chorionic gonadotropin 0.19996, 0.29760, and 0.9669. Distributions reconstructed with use of statistical means and SDs generated goodness of fit R2 from 0.585 to 0.914. Use of means and SDs derived from distribution functions increased the R2 to 0.855 and 0.999. The change in the model produces, at a 5% false-positive rate, a sensitivity of 57.18% (199/348). A 1 in 113 cutoff point risk is obtained and is tighter than the 1 in 251 without the distribution functions, as versus 1 in 270 by age calculations alone. CONCLUSIONS: Our data suggest that (1) normality of log transforms of alpha-fetoprotein and normality of log transforms of beta-human chorionic gonadotropin are reasonable models, (2) distribution functions can minimize the effect of outliers, which produces more realistic risk estimates, and (3) the effect of distribution functions versus standard mean and SDs cannot automatically be extrapolated to other parameters, which must be tested individually.

Chorionic Gonadotropin, beta Subunit, Human↗
PubMed1997

Maternal serum alpha-fetoprotein in fetal neural tube and abdominal wall defects at 10 to 14 weeks of gestation.

Maternal serum alpha-fetoprotein concentration was determined in nine pregnancies with fetal anencephaly, seven with exomphalos containing liver, two with spina bifida and 100 normal controls at 10 to 14 weeks of gestation. The median alpha-fetoprotein in the group with fetal anencephaly and exomphalos was significantly higher than in normal fetuses but the sensitivity of this test is likely to be only about 30% for a false positive rate of 5%.

Abdominal Muscles↗
PubMed1997

Biochemical markers of trisomy 21 in amniotic fluid.

In a study of amniotic fluid from 91 Down's syndrome cases and 240 controls, we have shown that the median values of four biochemical markers (AFP, total hCG, free beta hCG, and unconjugated oestriol) in the amniotic fluid of pregnancies affected by Down's syndrome on the whole reflect those observed in the maternal serum of affected cases. The median MOM for AFP was lower than average (0.56), as was that for unconjugated oestriol (0.55), whilst those for total hCG (1.82) and free beta hCG (2.10) were increased on average. The width of the distribution of marker levels in amniotic fluid is similar to that in serum for free beta hCG and total hCG but between 1.5 and 2 times wider for unconjugated oestriol and AFP. Analysis of data by fetal sex showed a significantly higher median MOM in female control cases compared with male controls for the analytes free beta hCG, total hCG, and unconjugated oestriol, but not for AFP. Amongst the Down's syndrome cases, this trend was not statistically significant and we cannot confirm a previous study which reported that elevated levels of amniotic fluid total and free beta hCG were associated only with female fetuses.

Adult↗
PubMed1997

Comparison of Down's syndrome screening strategies in Asians combining serum free beta-hCG and alpha-fetoprotein with maternal age.

High free beta human chorionic gonadotropin (beta-hCG) and low alpha-fetoprotein (AFP) levels were found in 47 Asian Down's syndrome pregnancies (median values 2.79 and 0.77 MOM, respectively). At a 5 per cent false-positive rate, free beta-hCG alone would identify 46.8 per cent of Down's syndrome pregnancies, age alone detected 34.5 per cent of affected cases, whilst AFP alone detected 17 per cent and free beta-hCG/AFP MOM ratios detected 48.9 per cent of Down's syndrome cases. When combined with maternal age-specific risk, free beta-hCG could achieve a 59.6 per cent detection rate, with AFP achieving 42.6 per cent, free beta-hCG/AFP MOM ratios 61.7 per cent, and combined free beta-hCG and AFP a detection rate of 63.8 per cent for a 5 per cent false-positive rate. Down's syndrome screening at an early gestational age (before 18 weeks) could achieve a 68 per cent detection rate with a 5 per cent false-positive rate, compared with a 59.1 per cent detection rate for a 5.2 per cent false-positive rate when screening at a late gestational age. The use of free beta-hCG in Down's syndrome screening programmes can yield an improved efficacy in the detection of Down's syndrome in an Asian population.

Adolescent↗
PubMed1996

Age-independent indices in second-trimester serum screening for Down's syndrome are useless.

Serum screening for fetal Down's syndrome in the second trimester is far more efficient in older mothers than in younger ones because the risk calculation is based on maternal age. In recent publications, several authors have tried to better the 'classical' test for Down's syndrome screening by creating an age-independent index. This procedure, however, requires the assumption that at least for one parameter the mean MOM or the variance is not constant in relation to maternal age, leading to a smaller overlap in younger women. This study, based on almost 3000 normal cases and 161 cases with Down's syndrome, could not demonstrate any relationship between maternal age and MOM distribution for alpha-fetoprotein, unconjugated oestriol, total human chorionic gonadotropin (hCG), and free beta hCG. We conclude that for a constant false-positive rate, the detection rate of the 'classical' test for Down's syndrome screening in younger women cannot be bettered by creating an age-independent index.

Adult↗
PubMed1996

Urine free beta hCG and beta core in pregnancies affected by Down's syndrome.

Urine beta core was shown in recent studies to be markedly elevated in pregnancies affected by Down's syndrome in the late second trimester. Free beta human chorionic gonadotropin (hCG) has also been shown to be the most discriminatory maternal serum marker of Down's syndrome. Since free beta hCG is rapidly cleared from the maternal circulation, we have carried out a study to evaluate whether free beta hCG is elevated in the urine of pregnancies affected by Down's syndrome and to investigate whether urine beta core or urine free beta hCG may be used as possible screening markers. Urine samples from 29 cases of Down's syndrome, three cases of trisomy 18, and 400 control pregnancies were analysed for the two prospective markers. Results were corrected for urine concentration by expressing marker concentrations at a fixed creatinine concentration and then expressing the results as multiples of the median for unaffected pregnancies of the same gestation. The median value of beta core in the Down's syndrome pregnancies was 2.35 compared with 2.47 for free beta hCG. Free beta hCG distributions were closely similar to those in maternal serum. Using free beta hCG, we predict Down's syndrome detection rates of 58 per cent at a 5 per cent false-positive rate. Using beta core, however, this rate fell to 41 per cent. Measurement of free beta hCG in urine may present a feasible route for screening pregnant populations, particularly where community-based obstetric care is the norm and/or if early first-trimester screening becomes a reality.

Adult↗