Sequential testing strategies in prenatal screening for down's syndrome

Down’s syndrome is a classic chromosomal disorder with an incidence rate of one in every 750 live births. Early detection of Down’s syndrome pregnancies through screening will provide the option of early termination of pregnancy and better obstetric care to women with affected pregnancies. Some of the screening policies which have been implemented in the UK are second trimester double, triple or quadruple marker tests, first trimester combined ultrasound and biochemical (CUB) screening, and integrated screening. Screening performance can be optimized by applying appropriate correction factors for variables such as maternal smoking, ethnicity and assisted conception. Typical screening performance is around 70% detection of Down’s syndrome pregnancies at a 5% false positive rate for second trimester quadruple marker screening, 90% detection at a 5% false positive rate for CUB screening and 90% detection at a 1-2% false positive rate for integrated screening. The NHS Fetal Anomaly Screening Programme Committee has set a current performance target for Down’s syndrome screening of at least 75% detection at a 3% or lower false positive rate and this can be achieved by CUB or integrated testing by setting a threshold (cut-off) risk of 1 in 150 at term. However, further improvements in performance proposed by the Committee to meet a detection rate of 90% at a false positive rate of 2% or less are unlikely to be reached by single stage testing, and protocols which include some element of sequential testing are required. The Health Technology Assessment Programme is currently reviewing two new approaches to screening, namely, repeated measure and cross trimester testing to evaluate their potential to meet the more challenging standard. In the present study, using various combinations of maternal serum marker and ultrasound measurements, several screening strategies and refinements are explored to establish their potential for improving detection rates and reducing false positive rates in Down’s syndrome screening. Extensive use has been made of routinely collected screening data from the west of Scotland Regional Screening programme for retrospective analysis using standard Gaussian methods, statistical modeling and SPSS and S-PLUS statistical software. The performance of within- and across-trimester contingent screening programmes have been evaluated and the effects of ethnicity, maternal smoking habit and assisted reproductive technology (ART) on screening markers has been assessed using first and second trimester samples. Screening within the first trimester The standard approach to CUB screening is to carry out maternal serum marker measurements (PAPP-A and fβhCG) and ultrasound Nuchal Translucency measurements at 11-13+6 weeks of gestation. This study had also shown that in the CUB screened population in the west of Scotland, adopting a within-trimester contingent screening protocol where all women have serum marker testing but only those women with intermediate risks from the serum markers are offered NT, would have achieved a detection rate of 88.7% at a false positive rate of 5.8% with 29% of women requiring an NT measurement. Using LMP based gestational age this screening protocol would have achieved a detection rate of 83.3% at a false positive rate of 7.4% with 25.9% of women requiring an NT measurement. When analysis was performed only on pregnancies with certain LMP dates, the contingent screening protocol would have achieved a detection rate of 88.9% at a false positive rate of 7.0% with 25.3% of women requiring an NT measurement. Where ultrasound resources are scarce within-trimester contingent screening has the potential to maintain screening performance whilst reducing the number of NT scans required. Across –trimester screening Evidence suggests that sequential testing strategies can improve screening performance. This has been explored in this study by statistical modelling using S-PLUS. Various combinations of markers were tested. It was estimated that optimal performance could be achieved by a cross-trimester contingent screening protocol with repeat measures of PAPP-A (NT, PAPP-A, fβhCG in the first trimester followed by AFP, hCG, InhA, uE3, PAPP-A in the second trimester in a sub-set of women with intermediate risks). This could achieve a detection rate of 92.2% at a false positive rate of 1.4% but with only 9.7% of women requiring a second trimester screening test. This meets the aspirational performance standard proposed by the UK NSC. Without NT measurements (i.e. serum only screening), the model indicates that this screening protocol would achieve a detection rate of 86.2% at a false positive rate of 3.0% with 22.3% of women requiring a second trimester screening test. Therefore, the inclusion of NT measurement at the first stage of testing is necessary to achieve the desired performance. The Effects of Smoking and Ethnicity Many maternal and pregnancy factors are known to affect serum marker concentrations and small but useful improvements in screening performance can be made by correcting for these. Changes however, vary between trimesters and in this study paired first and second trimester samples have been used to measure the changes in serum marker levels in smokers and between different ethnic groups at each stage of pregnancy. In this study, the AFP level in smokers was increased in the first trimester by 16.3% when compared with the non-smokers. The hCG level in smokers was decreased by 27.6% and 30.5% in the first and second trimesters respectively. The fβhCG level was decreased in smokers in the second trimester by 17.1% when compared with non-smokers. The PAPP-A level was decreased by 14% and 22.8% in first and second trimesters respectively when compared with non-smokers. These results demonstrate that the effect of smoking is gestation dependant and without appropriate correction factors being applied, these serum marker changes would result in inappropriate risks being estimated for individual women. The study on the effect of ethnicity on screening markers has shown that South Asian women had higher hCG levels in the first trimester compared with Caucasian women. They also had lower fβhCG and PAPP-A in the second trimester. Oriental women had higher first and second trimester hCG levels when compared with Caucasian women. They also had higher fβhCG and PAPP-A levels in the first trimester. Middle East women had lower first trimester AFP when compared with Caucasian women. Black women had higher hCG in the first trimester when compared with Caucasian women. In Black women, the PAPP-A level was also elevated in both trimesters. While this study confirms that correction for ethnicity is clearly indicated, appropriate correction factors are difficult to derive as there is likely to be some variation in the classification of ethnicity between studies. Assisted Reproductive Technology The growing use of ART in developed countries and the variety of different methods employed make accurate correction factors desirable but difficult to derive. In this study, women pregnant after ART had larger NT measurements compared with women who had conceived spontaneously. The PAPP-A level was lower in the IVF or ICSI with fresh eggs group when compared with the controls. Among the ART treatment groups, the NT was higher in the IVF or ICSI with fresh eggs group when compared with the controls. The AFP level was higher in the IVF with donor’s egg group when compared with the controls. The hCG level was higher in the ART group overall when compared with the controls. Women pregnant after IVF or ICSI with fresh eggs and frozen eggs had higher hCG level. Smoking frequency, birthweight and prematurity In addition to its effects on serum marker concentrations, smoking in pregnancy is known to be associated with low birth weight and prematurity. It is important therefore that maternal smoking is accurately recorded on screening request forms and in this study, the accuracy of self reported smoking status was assessed by analysis of cotinine in serum. Results showed that the percentage of self-reported smokers (24.1%) at booking was significantly lower than the cotinine-validated estimate of 30.1%. Also, smoking was associated with low birth weight, delivery prior to 39 weeks, increased AFP level (3.1%) and reduced hCG level (28.7%) in the second trimester. An increasing AFP level (but not hCG level) was associated with lower birth weight and delivery prior to 39 weeks in both smokers and non smokers but the effect was most marked in smokers. The difference in birth weight between the highest and the lowest AFP category for non-smokers was 448.3g and for smokers was 619.2g, suggesting that smoking exacerbates the effect of an elevated AFP on birth weight. Overall the difference in birth weight between the lowest AFP category in non smokers and the highest AFP category in smokers was 931.6g. Summary In summary, this study has shown that a cross-trimester contingent screening protocol with repeat measures has the potential to meet the UK NSC aspirational standard of 90% detection of Down’s syndrome pregnancies with a screen positive rate of less than 2%. Around 90% of women would complete screening in the first trimester without the need for a second stage sequential test. Correcting for factors such as maternal smoking habits, ethnicity and ART would further improve screening performance. Also it has been shown that where ultrasound resources are scarce, within-trimester and across-trimester protocols can reduce the need for NT measurement in all women and still deliver excellent screening performance although this falls short of the higher performance standard. The potential of these new screening protocols now need to be tested in prospective multicentre trials to confirm their performance in prospective practice

Image Segmentation With Cyclic Load Balanced Parallel Fuzzy C - Means.

Fuzzy C - Means (FCM) ialah satu daripada algoritma pengelompokan yang paling kerap digunakan dalam segmentasi imej. Fuzzy C - Means (FCM) is one of the most popular clustering algorithm that has been used in image segmentation

Effects Of Camptothecin On Pichia Pastoris Strain Smd1168h Expressing Dna Topoisomerase I On Agar Plates

DNA topoisomerase I (TopoI) is a ubiquitous enzyme, that is responsible for releasing topological stress by introducing a temporary nick in one strand of the DNA helix and later, resealing the single-stranded DNA. TopoI is involved in cell proliferation; therefore, overexpression of this enzyme in a cell often mimics cancer cells. Hence, this enzyme plays a major role in molecular biology studies for developing various types of antineoplastic agents, such as camptothecin. Camptothecin exhibits strong anti-inhibitory properties towards the catalytic activity of TopoI by preventing the re-ligation of the nicked DNA, resulting in shear stress and eventually, cell death. Pichia pastoris expression system is well-known for its ability to produce human-like endogenous TopoI compared to other expression systems, e.g. Escherichia coli, Saccharomyces cerevisiae and baculovirus. Currently, searching for more effective compounds to reduce the toxicity of cancer treatments, while still producing similar effects as current chemotherapy regimens is required. As such, this research aims to investigate the inhibitory properties of camptothecin on the growth of recombinant clones of multi-copy number insert of P. pastoris transformants expressing human DNA topoisomerase I (SMD1168H-pPICZαA-hTopoI) grown on yeast extract agar and microbiological agar plates, respectively. The agar plates contained different concentrations of camptothecin (25 µM, 50 µM, 75 µM and 100 µM) and were left to incubate for 3 days. In conclusion, the highest inhibitory activity of camptothecin was observed when both the recombinant clones were grown in microbiological agar plate that contained 100 µM of camptothecin

Perceived weight discrimination and 10-year risk of allostatic load among US adults

Background Discrimination promotes multisystem physiological dysregulation termed allostatic load, which predicts morbidity and mortality. It remains unclear whether weight-related discrimination influences allostatic load. Purpose The aim of this study was to prospectively examine 10-year associations between weight discrimination, allostatic load, and its components among adults 25–75 years in the Midlife Development in the US Biomarker Substudy. Methods Participants with information on weight discrimination were analyzed (n=986). At both timepoints, participants self-reported the frequency of perceived weight discrimination across nine scenarios as “never/rarely” (scored as 0), “sometimes” (1), or “often” (2). The two scores were averaged and then dichotomized as “experienced” versus “not experienced” discrimination. High allostatic load was defined as having ≥3 out of 7 dysregulated systems (cardiovascular, sympathetic/parasympathetic nervous systems, hypothalamic pituitary axis, inflammatory, lipid/metabolic, and glucose metabolism), which collectively included 24 biomarkers. Relative risks (RR) were estimated from multivariate models adjusted for sociodemographic and health characteristics, other forms of discrimination, and BMI. Results Over 41% of the sample had obesity, and 6% reported weight discrimination at follow-up. In multivariable-adjusted analyses, individuals who experienced (versus did not experience) weight discrimination had twice the risk of high allostatic load (RR, 2.07; 95 % CI, 1.21; 3.55 for baseline discrimination; 2.16, 95 % CI, 1.39; 3.36 for long-term discrimination). Weight discrimination was associated with lipid/metabolic dysregulation (1.56; 95 % CI 1.02, 2.40), glucose metabolism (1.99; 95 % CI 1.34, 2.95), and inflammation (1.76; 95 % CI 1.22, 2.54), but no other systems. Conclusions Perceived weight discrimination doubles the 10-year risk of high allostatic load. Eliminating weight stigma may reduce physiological dysregulation, improving obesity-related morbidity and mortality

Understanding the Relationship between Food Variety, Food Intake, and Energy Balance

Purpose of Review: In accordance with US dietary guidance, incorporating variety into the diet can align with energy balance, though greater food variety in some categories may make energy balance more challenging. Thus, experimental and epidemiologic evidence is summarized on the relationship between food variety, food and energy intake, and energy balance. Recent Findings: Lab-based, experimental research consistently demonstrates that greater variety within foods or sensory characteristics of food increases food and energy intake within an eating occasion. Epidemiologic evidence is less consistent, potentially driven by differing methodologies, particularly in defining and measuring food variety. Moreover, the effect of variety on energy balance appears to be moderated by food energy density. Summary Integrating insights from experimental and epidemiologic research are essential for strengthening food variety guidance including developing evidence-based definitions of food variety, understanding moderators of the relationship, and developing practical guidance interpretable to consumers

Increasing low-energy-dense foods and decreasing high-energy-dense foods differently influence weight loss trial outcomes

Background/Objective: Although reducing energy density (ED) enhances weight loss, it is unclear whether all dietary strategies that reduce ED are comparable, hindering effective ED guidelines for obesity treatment. This study examined how changes in number of low-energy-dense (LED) (\u3c4.186 kJ/1.0 kcal g–1) and high-energy-dense (HED) (\u3e12.56 kJ/3.0 kcal g–1) foods consumed affected dietary ED and weight loss within an 18-month weight loss trial. Methods: This secondary analysis examined data from participants randomized to an energy-restricted lifestyle intervention or lifestyle intervention plus limited non-nutrient dense, energy-dense food variety (n=183). Number of daily LED and HED foods consumed was calculated from three, 24-h dietary recalls and anthropometrics were measured at 0, 6 and 18 months. Multivariable-adjusted generalized linear models and repeated-measures mixed linear models examined associations between 6-month changes in number of LED and HED foods and changes in ED, body mass index (BMI), and percent weight loss at 6 and 18 months. Results: Among mostly female (58%), White (92%) participants aged 51.9 years following an energy-restricted diet, increasing number of LED foods or decreasing number of HED foods consumed was associated with 6- and 18-month reductions in ED (β=−0.25 to −0.38 kJ g–1 (−0.06 to −0.09 kcal g–1), P\u3c0.001). Only increasing number of LED foods consumed was associated with 6- and 18-month reductions in BMI (β=−0.16 to −0.2 kg m–2, P\u3c0.05) and 6-month reductions in percent weight loss (β=−0.5%, P\u3c0.05). Participants consuming ⩽2 HED foods per day and ⩾6.6 LED foods per day experienced better weight loss outcomes at 6- and 18-month than participants only consuming ⩽2 HED foods per day. Conclusion: Despite similar reductions in ED from reducing number of HED foods or increasing number of LED foods consumed, only increasing number of LED foods related to weight loss. This provides preliminary evidence that methods used to reduce dietary ED may differentially influence weight loss trajectories. Randomized controlled trials are needed to inform ED recommendations for weight loss

SOME RESULTS ON OPTIMUM PREMIUM PAYMENT PLANS

Any insurance plan consists of a sequence of payments every year (or some other fixed time interval) in return for certain death benefits. The benefits may take the form of a wide variety of insurances or annuities. For simplicity, we will assume that premiums and benefits are paid annually. In this paper, we investigate the appropriateness of this type of plan. Naturally, appropriateness of any plan cannot be measured without an optimality criteria. Three such criteria, which are statistical in nature, are introduced in this paper. For the principal safety criterion which we use, the optimal premium are those which minimize a certain profit variance subject to a familiar profit constraint. We also develop a profitability criterion and then solve an associated optimality problem. Our main results state that if the sequence of present values of total benefits is nonincreasing, then the profit variance is minimum when the insured pays a net single premium at once, and if this cannot be done, the insured should pay off the policy as early as possible

Integration of teaching strategies and resources in a multicultural school environment.

Thesis (M.Ed.)-University of Durban-Westville, 1998.This research is an example of a multiple case study. It investigates the teaching strategies and resources currently being utilised in culturally diverse classrooms, ascertains the reasons for the use of such strategies and resources, and recommends strategies and resources that could be integrated and utilized in order to cater for a culturally diverse pupil population in the classroom. The research was conducted in five purposely-selected secondary schools in the Verulam-Phoenix area. The schools selected were former predominantly Indian schools in order to facilitate the work of the researcher with regard to data collection. The schools also had a pupil population composed of different cultural groups (in terms of religion, race and language) since the study was concerned with an emerging multicultural school situation. The study focused on the teaching strategies and resources utilised in five subject areas - English, Mathematics, Biology, Geography and Accounting. The subjects selected gave the researcher a cross-curricular perspective of the strategies and resources used. Data was collected primarily by engaging in non-participant and participant observation of school resource centres, teachers' centres, and actual teaching in the classrooms. The researcher also conducted structured and unstructured interviews with school principals, subject teachers, pupils, staff at school resource centres and teachers' centres, and also lecturers from universities and colleges of education. Questionnaires were used to supplement the data collected from teachers and pupils. Data was then analysed qualitatively and quantitatively to determine the strategies and resources most commonly utilised by teachers. The data gathered was analysed in terms of the present education system and current thinking regarding teaching strategies and use of resources in teaching. The outcomes of this analysis formed the basis for the recommendations made at the end of the study

Boron Removal Through Precipitation Process in Produced Water

The amount of boron in the water generated is quite high. When oil and gas are drilled, they bring water with them, which is known as "produced water." As a result, it comprises both the formation's characteristics and the hydrocarbon itself. Simply put, if the boron content in the generated water is not appropriately eliminated, the water will be useless