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Biomedical subjects

Howard Cuckle

Publications and source records attributed to Howard Cuckle.

At least 19 recordsLinked to original sources
PubMed2006

Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years' follow-up: a randomised controlled trial.

BACKGROUND: The efficacy of screening by mammography has been shown in randomised controlled trials in women aged 50 years and older, but is less clear in younger women. A meta-analysis of all previous trials showed a 15% mortality reduction in invited women aged 40-49 years at study entry, but this finding could be due in part to screening of women after age 50 years. The Age trial was designed to study the effect on mortality of inviting women for annual mammography from age 40 years. METHODS: 160,921 women aged 39-41 years were randomly assigned in the ratio 1:2 to an intervention group of annual mammography to age 48 years or to a control group of usual medical care. The trial was undertaken in 23 NHS breast-screening units in England, Wales, and Scotland. The primary analysis was based on the intention-to-treat principle and compared mortality rates in the two groups at 10 years' follow-up. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN24647151. FINDINGS: At a mean follow-up of 10.7 years there was a reduction in breast-cancer mortality in the intervention group, in relative and absolute terms, which did not reach statistical significance (relative risk 0.83 [95% CI 0.66-1.04], p=0.11; absolute risk reduction 0.40 per 1000 women invited to screening [95% CI -0.07 to 0.87]). Mortality reduction adjusted for non-compliance in women actually screened was estimated as 24% (RR 0.76, 95% CI 0.51-1.01). INTERPRETATION: Although the reduction in breast-cancer mortality observed in this trial is not significant, it is consistent with results of other trials of mammography alone in this age-group. Future decisions on screening policy should be informed by further follow-up from this trial and should take account of possible costs and harms as well as benefits.

Adult↗
PubMed2006

Screening for Down syndrome using first-trimester combined screening followed by second-trimester ultrasound examination in an unselected population.

OBJECTIVE: Recent studies have reported the efficacy of first-trimester combined screening for Down syndrome based on maternal age, serum markers (human chorionic gonadotropin, pregnancy-associated plasma protein A), and ultrasound measurement of fetal nuchal translucency. However, those do not incorporate the value of the widely accepted routine 20-22 weeks' anomaly scan. STUDY DESIGN: We carried out a multicenter, interventional study in the unselected population of a single health authority in order to assess the performance of first-trimester combined screening, followed by routine second trimester ultrasound examination and/or screening by maternal serum markers (free beta-hCG and alpha-fetoprotein measurement or total hCG, alpha-fetoprotein, and unconjugated estriol measurement) when incidentally performed. Detection and screen positive rates were estimated using a correction method for nonverified issues. A cost analysis was also performed. RESULTS: During the study period, 14,934 women were included. Fifty-one cases of Down syndrome were observed, giving a prevalence of 3.4 per 1000 pregnancies. Of these, 46 were diagnosed through first (n = 41) or second (n = 5) trimester screening. Among the 5 screen-negative Down syndrome cases, all were diagnosed postnatally after an uneventful pregnancy. Detection and screen positive rates of first-trimester combined screening were 79.6% and 2.7%, respectively. These features reached 89.7%, and 4.2%, respectively, when combined with second-trimester ultrasound screening. The average cost of the full screening procedure was 108 euros (120 dollars) per woman and the cost per diagnosed Down syndrome pregnancy was 7,118 euros (7909 dollars). CONCLUSION: Our findings suggest that 1 pragmatic interventional 2-step approach using first-trimester combined screening followed by second-trimester detailed ultrasound examination is a suitable and acceptable option for Down syndrome screening in pregnancy.

Adult↗
PubMed2006

Maternal serum inhibin levels in twin and singleton pregnancies conceived by assisted reproduction.

BACKGROUND: To investigate whether second trimester serum inhibin levels differ in pregnancies conceived by assisted reproduction technology (ART). METHODS: In Israel, serum samples from twin pregnancies were obtained for inhibin testing from women either referred for routine ultrasound monitoring, follow up after multi-fetal reduction or amniocentesis, largely for advanced maternal age. In the UK, inhibin had been tested prospectively in singleton and twin pregnancies of women having routine Down's syndrome (DS) screening. Results were available from 207 ART pregnancies: 170 singletons and 37 twins. This includes 15 twins from Israel, known to have been reduced from triplets to twins. Comparison was made with 4384 spontaneous pregnancies: 4334 singletons and 50 twins. Results were expressed in multiples of the gestation-specific median (MoM) for normal spontaneous pregnancies. RESULTS: In ART singletons, the median maternal inhibin level was higher (1.11 MoM) than in spontaneous singletons (0.99 MoM, P < 0.001, two-tail Wilcoxon Rank Sum Test). In twins, there was no material difference between ART and spontaneous pregnancies with medians of 1.98 and 2.18 MoM, respectively (P = 0.62). There was no effect of multi-fetal reduction, with medians of 1.76 and 1.81 MoM in reduced and non-reduced twins, respectively (P = 0.46). CONCLUSION: It appears that serum inhibin levels are increased on average in ART singletons but not in ART twin pregnancies. More data will be needed before deciding whether risk calculation parameters need to be altered when using inhibin for DS screening in pregnancy.

Down Syndrome↗
PubMed2006

Three-stage contingent screening for Down syndrome.

OBJECTIVE: To demonstrate the potential value of three-stage sequential screening for Down syndrome. METHODS: Protocols were considered in which maternal serum pregnancy associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (hCG) measurements were taken on all women in the first trimester. Those women with very low Down syndrome risks were screened negative at that stage and nuchal translucency (NT) was measured on the remainder and the risk reassessed. Those with very low risk were then screened negative and those with very high risk were offered early diagnostic testing. Those with intermediate risks received second-trimester maternal serum alpha-fetoprotein, free beta-hCG, unconjugated estriol and inhibin-A. Risk was then reassessed and those with high risk were offered diagnosis. Detection rates and false-positive rates were estimated by multivariate Gaussian modelling using Monte-Carlo simulation. RESULTS: The modelling suggests that, with full adherence to a three-stage policy, overall detection rates of nearly 90% and false-positive rates below 2.0% can be achieved. Approximately two-thirds of pregnancies are screened on the basis of first-trimester biochemistry alone, five out of six women complete their screening in the first trimester, and the first-trimester detection rate is over 60%. CONCLUSION: Three-stage contingent sequential screening is potentially highly effective for Down syndrome screening. The acceptability of this protocol and its performance in practice, should be tested in prospective studies.

Algorithms↗
PubMed2006

Maternal serum ADAM12 levels in Down and Edwards' syndrome pregnancies at 9-12 weeks' gestation.

BACKGROUND: Maternal serum ADAM12 is reduced, on average, in early first-trimester Down and Edwards' syndrome pregnancies but the extent of reduction declines with gestation. Here we study levels at 9-12 weeks when the marker might be used concurrently with other established markers. METHODS: Samples from 16 Down and 2 Edwards' syndrome cases were retrieved from storage and tested together with 313 unaffected singleton pregnancies using a semi-automated time-resolved immuno-fluorometric assay. Results were expressed in multiples of the gestation-specific median (MoM) based on regression. RESULTS: The median in Down syndrome was 0.94 MoM with a 10th-90th centile range of 0.22-1.63 MoM compared with 1.00 and 0.33-2.24 MoM in unaffected controls (P = 0.21, one-side Wilcoxon Rank Sum Test). The two Edwards' syndrome cases had values 0.31 and 2.17 MoM. CONCLUSIONS: ADAM12 cannot be used concurrently with other markers in the late first trimester. However, it does have the potential to be used earlier in pregnancy either concurrently with other early markers or in a sequential or contingent protocol. More data will be required to reliably predict the performance of either approach.

ADAM Proteins↗
PubMed2005

First-trimester screening for Down syndrome with ductus venosus Doppler studies in addition to nuchal translucency and serum markers.

OBJECTIVE: To estimate the improvement in screening efficiency when fetal ductus venosus Doppler studies are added to existing first-trimester Down syndrome screening protocols. METHODS: Statistical modelling was used with parameters derived from prospective ductus venosus studies and from the published literature. The pulsatility index for veins (PIV), was determined in the fetal ductus venosus for 3706 unaffected and 25 Down syndrome pregnancies at 10-14 weeks' gestation. Concurrent nuchal translucency measurement and maternal serum pregnancy associated plasma protein A and free-beta human chorionic gonadotrophin were also measured. RESULTS: The median PIV in Down syndrome was 1.70 times higher than in unaffected pregnancies (95% confidence interval 1.36-2.12). PIV levels followed an approximately log Gaussian distribution with log(10) standard deviations of 0.193 and 0.076 in Down syndrome and unaffected pregnancies. There were no statistically significant correlations between PIV and the other markers. Modelling predicts that for a fixed 5% false-positive rate, the addition of PIV to nuchal translucency alone will increase the detection rate from 76 to 85%, and combined with serum markers, from 88 to 92%. For a fixed 85% detection rate, the false-positive rate reduced from 15 to 4.8% and from 3.2 to 1.2% respectively. CONCLUSION: Ductus venosus Doppler studies can substantially improve Down syndrome screening efficiency.

Chorionic Gonadotropin, beta Subunit, Human↗
PubMed2005

Second trimester ultrasound prenasal thickness combined with nasal bone length: a new method of Down syndrome screening.

OBJECTIVE: To evaluate ultrasound prenasal thickness (PT) as a way of enhancing the Down syndrome (DS) screening performance of second-trimester nasal bone (NB) length measurement. METHODS: Twenty-one DS and 500 normal fetuses were scanned at 14-27 weeks' gestation. The affected karyotype was known to the person performing the scan. Both PT and NB were measured in a mid-sagittal position and results were expressed in multiples of the normal gestation-specific median (MoM). Gaussian modelling was used to predict the performance of routine screening. RESULTS: Among DS fetuses, the PT median was 1.35 MoM, a highly statistically significant increase compared with the unaffected pregnancies (p < 0.0001, Wilcoxon Rank Sum Test, two-tailed). The NB median was 0.87 MoM (p < 0.0005) and the ratio PT/NB median was 1.51 MoM (p < 0.0001). In the normal fetuses, the two markers were positively correlated (0.25, p < 0.0001), whereas in the DS fetuses there was a non-significant negative correlation (-0.24, p = 0.33). For a 5% false-positive rate, the model predicted detection rate was 70% for PT and NB compared with 43% for NB alone. CONCLUSION: In the second trimester, PT is increased on average in DS fetuses. Combining PT and NB measurement could yield a higher screening detection rate than NB alone. Confirmation of our findings in a series of women scanned before the karyotype was known is needed before the method can be clinically implemented.

Down Syndrome↗
PubMed2005

Practical strategies in contingent sequential screening for Down syndrome.

OBJECTIVE: To design and assess the performance of protocols for contingent sequential Down syndrome screening that can be implemented in practice. METHODS: Protocols were designed in which all women received first-trimester measurement of nuchal translucency (NT) together with maternal serum pregnancy-associated plasma protein-A (PAPP-A) and either free beta- or total human chorionic gonadotrophin (hCG). Those women with borderline Down syndrome risks received follow-up second-trimester maternal serum involving double, triple, or quadruple serum screening markers: alpha-fetoprotein, free beta-hCG or total hCG, unconjugated estriol and inhibin-A. Specific ranges of risks were used to define the borderline group. Separate protocols were developed for the United Kingdom and the United States to reflect differences in commonly used tests, cut-offs, and the gestational age at testing. Detection rates and false-positive rates were estimated by multivariate Gaussian modelling with Monte Carlo simulation. RESULTS: Proposed protocols based on first-trimester NT, PAPP-A and free beta-hCG or total hCG, followed by selective use of second-trimester quadruple markers can result in a 91% detection rate and 2.1% false-positive rate for the United Kingdom and a detection rate of 89% and false-positive rate of 3.1% for the United States. For both countries, over 60% of affected pregnancies would be detected in the first trimester and less than 20% of women would require a second-trimester Down syndrome risk assessment. Use of alternative cut-offs to define those with borderline risks or different combinations of second-trimester markers also yielded high detection rates and low false-positive rates. CONCLUSION: With appropriate patient counselling, it should be possible to provide highly effective Down syndrome screening using contingent sequential protocols.

Biomarkers↗
PubMed2005

Predicting the result of additional second-trimester markers from a woman's first-trimester marker profile: a new concept in Down syndrome screening.

OBJECTIVE: To describe a method for deciding whether an individual's first-trimester Down syndrome screening test result justifies further testing in the second trimester. METHODS: Statistical modelling was used to estimate the distribution of second-trimester marker profiles for a given first-trimester profile and hence the probability of a final positive result, using a 1 in 250 term cut-off. A multi-variate log Gaussian model was used with published parameters. Markers were maternal serum pregnancy-associated plasma protein-A and free beta-human chorionic gonadotrophin (hCG) at 10 weeks, nuchal translucency at 11 weeks, and second-trimester maternal serum alpha-fetoprotein, total hCG, unconjugated estriol and inhibin-A. To illustrate the method, the model was applied to a published series of 24 Down syndrome and 367 unaffected pregnancies. RESULTS: Modelling predicts that for 63% Down syndrome and 0.4% unaffected pregnancies having first-trimester tests, there is a 50% or more probability of a final positive result. A step-wise sequential screening policy based on immediate prenatal diagnosis for those with high probability and second-trimester testing for the remainder would have a 90% detection rate and 1.7% false-positive rate. Modelling also predicts 8.0% Down syndrome and 89% unaffected pregnancies with probabilities below 3%. A contingent screening policy restricting second-trimester testing to those with 3-49% probabilities would have an 88% detection rate and 1.4% false-positive rate. CONCLUSION: Predicting the probability of a positive final result from the first-trimester marker profile has potential utility, either as a decision aide for individual women or as a formal part of screening policy in selecting a subset of women for second-trimester testing.

Adult↗
PubMed2005

Chromosomal abnormalities and birth defects among couples with colchicine treated familial Mediterranean fever.

OBJECTIVE: To determine whether colchicine prescribed for familial Mediterranean fever is teratogenic. STUDY DESIGN: Reproductive histories were analyzed from 326 couples referred for prenatal diagnosis because 1 partner was affected. Numbers of chromosomal abnormalities and birth defects were compared with numbers expected from published rates. RESULTS: There were 901 pregnancies, and amniocentesis had been performed in 566, all but 3 conceived while taking colchicine. Seven numerical chromosomal abnormalities were found, not statistically significantly greater than the 4.99 expected from maternal age and gestation of diagnosis (P = .24): unbalanced structural abnormalities were 6, compared with 3.22 expected (P = .11). There were 7 birth defects, a considerably lower rate than reported in local malformation registers. CONCLUSION: The current policy of routine amniocentesis in pregnancies of couples taking colchicine should not be changed until sufficient data accumulates to establish whether the higher number of chromosomal anomalies in this group is significant.

Abnormalities, Drug-Induced↗
PubMed2005

Down syndrome screening in the first and/or second trimester: model predicted performance using meta-analysis parameters.

OBJECTIVE: To predict the screening performance for 17 policies currently in use or being considered for the near future. METHODS: Multivariate Gaussian modeling using parameters derived from published meta-analyses and new meta-analyses for gestation-specific nuchal translucency and between trimester correlations. RESULTS: For a 1% to 5% false-positive rate, first trimester screening achieved detection rates up to 16% to 25% higher than the best second trimester combination. Screening in both trimesters sequentially could yield an even greater increase in detection of 24% to 35%. The most efficient sequential policy was contingent screening, which has a high detection rate with only 15% of women needing second trimester tests. CONCLUSION: Modeling with meta-analysis derived parameters provides a reliable guide for policy and favors a contingent screening policy. The widespread practice of calculating first and second trimester risks separately should be abandoned.

Chorionic Gonadotropin↗
PubMed2004

Contingent screening for Down syndrome is an efficient alternative to non-disclosure sequential screening.

OBJECTIVE: To present a first and second trimester Down syndrome screening strategy, whereby second-trimester marker determination is contingent on the first-trimester results. Unlike non-disclosure sequential screening ('the Integrated test'), which requires all women to have markers in both trimesters, this allows a large proportion of the women to complete screening in the first trimester. METHODS: Two first-trimester risk cut-offs defined three types of results: positive and referred for early diagnosis; negative with screening complete; and intermediate, needing second-trimester markers. Multivariate Gaussian modelling with Monte Carlo simulation was used to estimate the false-positive rate for a fixed 85% detection rate. The false-positive rate was evaluated for various early detection rates and early test completion rates. Model parameters were taken from the SURUSS trial. RESULTS: Completion of screening in the first trimester for 75% of women resulted in a 30% early detection rate and a 55% second trimester detected rate (net 85%) with a false-positive rate only 0.1% above that achievable by the Integrated test. The screen-positive rate was 0.1% in the first trimester and 4.7% for those continuing to be tested in the second trimester. If the early detection rate were to be increased to 45% or the early completion rate were to be increased to 80%, there would be a further 0.1% increase in the false-positive rate. CONCLUSION: Contingent screening can achieve results comparable with the Integrated test but with earlier completion of screening for most women. Both strategies need to be evaluated in large-scale prospective studies particularly in relation to psychological impact and practicability.

Biomarkers↗
PubMed2004

Age-standardisation when target setting and auditing performance of Down syndrome screening programmes.

OBJECTIVE: To describe and illustrate a method of setting Down syndrome screening targets and auditing performance that allows for differences in the maternal age distribution. METHODS: A reference population was determined from a Gaussian model of maternal age. Target detection and false-positive rates were determined by standard statistical modelling techniques, except that the reference population rather than an observed population was used. Second-trimester marker parameters were obtained for Down syndrome from a large meta-analysis, and for unaffected pregnancies from the combined results of more than 600,000 screens in five centres. Audited detection and false-positive rates were the weighted average of the rates in five broad age groups corrected for viability bias. Weights were based on the age distributions in the reference population. RESULTS: Maternal age was found to approximate reasonably well to a Gaussian distribution with mean 27 years and standard deviation 5.5 years. Depending on marker combination, the target detection rates were 59 to 64% and false-positive rate 4.2 to 5.4% for a 1 in 250 term cut-off; 65 to 68% and 6.1 to 7.3% for 1 in 270 at mid-trimester. Among the five centres, the audited detection rate ranged from 7% below target to 10% above target, with audited false-positive rates better than the target by 0.3 to 1.5%. CONCLUSION: Age-standardisation should help to improve screening quality by allowing for intrinsic differences between programmes, so that valid comparisons can be made.

Adolescent↗
PubMed2003

Frequency of Down's syndrome and neural-tube defects in the same family.

BACKGROUND: There is evidence that some mothers of infants with Down's syndrome have abnormal metabolism of folate and methyl, as well as mutations in folate genes, which are features that are also seen in neural-tube defects (NTD). We therefore investigated whether Down's syndrome and NTD arise more often in the same family than would be expected from the incidence of each disorder considered separately. METHODS: We studied two series of families using information obtained from medical records about maternal age, pregnancy outcome, congenital malformations, and karyotype: the first, 493 families from Israel who were at high risk of NTD (445 with a history of NTD and 48 with isolated hydrocephalus); and the second, 516 families from the Ukraine at high risk of Down's syndrome. FINDINGS: In the families at risk of NTD, there were a total of 11 pregnancies affected by Down's syndrome in 1492 at-risk pregnancies (compared with 1.87 expected on the basis of maternal age), which was a significant increase (p<0.00001). In the families at risk of Down's syndrome, there were seven NTD pregnancies in 1847 at risk, compared with 1.37 expected (p<0.001). INTERPRETATION: In this study, we provide direct evidence of a link between Down's syndrome and NTD. Folate supplementation before conception has the potential to reduce the frequency of Down's syndrome.

Adult↗