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Biomedical subjects

N J Wald

Publications and source records attributed to N J Wald.

At least 127 records · Page 7Linked to original sources
PubMed1995

Risk-based prenatal screening for trisomy 18 using alpha-fetoprotein, unconjugated oestriol and human chorionic gonadotropin.

Nine centres collaborated to examine the feasibility of a screening method for trisomy 18 that was based on assigning individual risk, using a combination of maternal age and measurements of alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotropin (hCG). Second-trimester measurements of these analytes were obtained from 94 trisomy 18 pregnancies. In the 89 pregnancies without an associated open defect, the median levels for AFP, uE3, and hCG were 0.65, 0.43 and 0.36 multiples of the unaffected population median, respectively. The strongest individual predictor of risk for trisomy 18 was uE3, followed by hCG, AFP, and maternal age, in that order. Using a method of individual risk estimation that is based on the three markers and maternal age, 60 per cent of pregnancies associated with trisomy 18 would be detected at a risk cut-off level of 1:100, with a false-positive rate of about 0.2 per cent. One in nine pregnancies identified as being at increased risk for trisomy 18 would be expected to have an affected pregnancy. This risk-based screening method is more efficient than an existing method that is based on fixed analyte cut-off levels. Even though the birth prevalence of trisomy 18 is low, prenatal screening can be justified when performed in conjunction with Down syndrome screening and when a high proportion of women offered amniocentesis have an affected fetus.

Adult↗
PubMed1995

Repeat maternal serum testing for Down's syndrome screening using multiple markers with special reference to free alpha and free beta-hCG.

To determine the effect of routine repeat testing in serum screening for Down's syndrome, we compared estimates of the detection and false-positive rates. Five serum markers were measured--alpha-fetoprotein (AFP), unconjugated oestriol (uE3), human chorionic gonadotrophin (hCG), and its two subunits, free alpha and free beta-hCG. First and repeat test marker levels were available from 142 women whose samples had been routinely collected and stored in an antenatal serum bank. Different repeat testing policies were compared for various combinations of the markers. If all women had repeat tests using the four markers AFP, uE3, and free alpha and free beta-hCG, the detection rate for a 5 per cent false-positive rate was 69 per cent compared with 65 per cent if no women were repeated. Policies of repeating selected women gave similar results. The small gain in screening performance with repeat testing performed routinely is not worthwhile. If a woman does happen to have a repeat test, her risk estimate should, however, be based on both results, not just the second.

Biomarkers↗
PubMed1995

First trimester serum screening for Down's syndrome.

Screening for Down's Syndrome has been shown to be effective at 10 weeks of pregnancy. A multicentre study (the first trimester serum screening study) has shown that there are two biochemical markers of choice at this time in pregnancy, namely pregnancy associated placental protein A (PAPP-A) and the free beta-sub-unit of human chorionic gonadotrophin (free beta-hCG). When used together with maternal age these two biochemical markers have an estimated detection rate of 62% and a 5% false-positive rate. The results are consistent with those obtained from a systematic review of the world literature. Other markers are less predictive of Down's syndrome though there is still some uncertainty over the value of dimeric inhibin-A at 10 weeks of pregnancy. Nuchal translucency measurement, from an ultrasound examination performed at about 10 weeks of pregnancy, is associated with Down's syndrome and is emerging as an important potential screening marker. At present there is uncertainty over its quantitative performance and performance when combined with biochemical markers. The resolution of these issues is currently the subject of active research. Ten week screening for Down's syndrome is an advance that is now technically possible though there is still insufficient information to justify its use in routine screening practice.

Biomarkers↗
PubMed1995

Selective miscarriage of Down's syndrome fetuses in women aged 35 years and older.

OBJECTIVE: To estimate the fetal loss of Down's syndrome fetuses between the time of chorionic villus sampling (10 weeks gestation) and the time of amniocentesis (16 weeks gestation) and term in women aged 35 years and older. DESIGN: The age specific prevalence rates in the first trimester of Down's syndrome were estimated using the Danish cytogenetic register in combination with results from four published studies. These were compared with the reported prevalence at the time of amniocentesis and at birth. SUBJECTS: 5927 singleton pregnancies undergoing chorionic villus sampling (71 cases of Down's syndrome and 5856 unaffected cases). This was combined with published data on a further 231 cases of Down's syndrome and 16,620 unaffected cases. MAIN OUTCOME MEASURES: Age specific prevalences at the time of chorionic villus sampling. Proportion of pregnancies lost between the time of chorionic villus sampling and the time of amniocentesis and term. RESULTS: Thirty-two percent of Down's syndrome pregnancies are lost between the time of chorionic villus sampling (10 weeks) and the time of amniocentesis (16 weeks) and 54% are lost by term. CONCLUSIONS: The high fetal loss rates of Down's syndrome between the time of chorionic villus sampling and term introduce problems when evaluating first trimester screening tests with respect to their effective detection rates at term. A recommendation for quoting term risks is made.

Abortion, Spontaneous↗
PubMed1995

Occupational exposure to hydrazine and subsequent risk of cancer.

OBJECTIVES: The aim was to examine the cause specific mortality of men exposed to hydrazine. METHODS: Hydrazine was produced at a factory in the east midlands between 1945 and 1971. The cohort of all 427 men who were employed there for at least six months with varying degrees of occupational exposure to hydrazine were followed up until the end of January 1992. RESULTS: By the end of July 1982 49 deaths had occurred and the observed mortality was found to be close to that expected at each level of exposure. By the end of January 1992 a further 37 deaths had occurred. Again the observed mortality was close to that expected for all causes and also for lung cancer, cancers of the digestive system, other cancers, and all other causes, irrespective of the level of exposure. CONCLUSIONS: The results weigh against there having been any material hazard of occupational exposure to hydrazine. The small number of men studied means, however, that a relative risk as high as 3.5 for lung cancer cannot confidently be excluded.

Cause of Death↗
PubMed1995

The tar reduction study: randomised trial of the effect of cigarette tar yield reduction on compensatory smoking.

BACKGROUND: Observational and short term intervention studies have reported that smokers of low tar cigarettes inhale more deeply (that is, compensate) than those who smoke high tar cigarettes. To quantify this effect a long term randomised trial was conducted on the effects of switching to low tar cigarettes. METHODS: The trial was carried out between April 1985 and March 1988 among cigarette smokers in the British Civil Service, measuring blood carboxyhaemoglobin (COHb) levels and serum cotinine levels as markers of tobacco smoke intake. Volunteers first switched to a cigarette brand yielding around 10% less tar than their usual brand to identify smokers able to change brand. The 434 subjects who successfully switched were then randomly allocated to one of three groups: (a) "fast reduction" group which changed to a brand of cigarettes with a tar yield of about half that of their usual brand; (b) "slow reduction" group which reduced to the same level in steps over several months; and (c) a control group which continued smoking cigarettes with a tar yield 10% lower than their usual brand. RESULTS: Over the course of the trial cigarette consumption declined slightly in all three groups. In both the "fast reduction" and the "slow reduction" groups, intake of COHb and cotinine was reduced, though not to the same extent as the yield reduction. Comparison of the results before randomisation with those at the end of the trial showed that a reduction in carbon monoxide yield of 45% was associated with a decrease in carbon monoxide intake of 19% (95% confidence interval 14% to 24%) and that a reduction in nicotine yield of 40% was associated with an 11% (6% to 16%) reduction in nicotine intake, reflecting relative intakes of about 1.5 for both carbon monoxide and nicotine in the "fast reduction" group. Results were similar in the "slow reduction" group with a 42% reduction in carbon monoxide yield, a 16% (11% to 22%) reduction in carbon monoxide intake, a 37% reduction in nicotine yield, and a 6% (0% to 13%) reduction in nicotine intake. Estimates of compensation derived from these results were 65% for carbon monoxide, 79% for nicotine, and 62% for tar. CONCLUSIONS: Compensation, demonstrated when switching from a high tar cigarette to a low tar one, was incomplete. Advising people who have failed to give up smoking to switch to low tar cigarettes will reduce the intake of smoke constituents to a small extent. This would be expected to decrease their risk of smoking-related diseases, although by a smaller amount than would be achieved by giving up smoking altogether.

Adaptation, Psychological↗
PubMed1995

Antenatal screening for Down syndrome.

Antenatal screening for Down syndrome was introduced a quarter of a century ago. The risk of fetal loss due to amniocentesis and the costs of the procedure restrict antenatal diagnosis to women who are at high risk of having an affected pregnancy. Initially the only method of screening women to identify older women for the diagnostic test. In 1988, the introduction of antenatal serum screening using various biochemical markers together with maternal age improved the performance of screening considerably - the proportion of affected pregnancies identified in the 5% of women of highest risk increased from about 30% to over 60%. Current research is continuing to refine the screening methods to improve screening performance by the addition of new markers, by the combination of serum and ultrasound markers, and by carrying out screening earlier in pregnancy. Improvements in the technical quality of screening needs to be matched by continuing attention to the quality of the screening service and ensuring that the public are satisfied with the service.

Biomarkers↗
PubMed1995

Serum cholesterol and ischaemic heart disease.

A systematic examination of the evidence on the relationship between serum cholesterol and ischaemic heart disease shows conclusively that serum cholesterol reduction in populations with high rates of heart disease is an effective and safe method of reducing ischaemic heart disease rates. The relative protective effect is greater at younger ages (50% reduction at age 40 for a 0.6 mmol/l reduction in serum cholesterol declining to about 20% at age 70 or more). The absolute protective effect is greater if the disease is common because the effect of a give serum cholesterol reduction is proportional to the prevailing heart disease rate. The full effect of a serum cholesterol reduction is evident after about 5 years. The use of drugs of the 'statin' type can lower serum cholesterol by about 1.8 mmol/l, yielding a reduction in risk of about 60% at age 60. A diet typical in Japan would lower serum cholesterol by about 1.2 mmol/l and lead to a halving of the risk. Only modest serum cholesterol reductions (about 0.3 mmol/l) are generally achievable by individuals altering their diet independently of others and this is expected to lead to a 15% reduction in the risk of ischaemic heart disease at age 60. Larger reductions (about 0.6 mmol/l) require collective action over the supply and preparation of food which could reduce the risk by about 30%. Achieving the full impact of serum cholesterol reduction in a population will require a national nutritional policy. It is not something that can be effectively left to individual action.

Adult↗
PubMed1994

Systematic underestimation of association between serum cholesterol concentration and ischaemic heart disease in observational studies: data from the BUPA study.

OBJECTIVE: To estimate the size of the association between serum concentration of low density lipoprotein cholesterol and mortality from ischaemic heart disease. DESIGN: Prospective study of total serum cholesterol concentration and mortality from ischaemic heart disease in 21,515 men (538 deaths) and study of total cholesterol concentration measured on two occasions an average of three years apart in 5696 men in whom low density lipoprotein cholesterol concentration was also measured on the second occasion. SUBJECTS: Men who attended the medical centre of the British United Provident Association (BUPA) in London between 1975 and 1982. MAIN OUTCOME MEASURE: The difference in mortality from ischaemic heart disease for a 0.6 mmol/l difference in concentration of low density lipoprotein cholesterol after adjustment for, firstly, regression dilution bias, which arises from the random fluctuation of serum cholesterol concentration in people over time, and, secondly, the surrogate dilution effect, which arises because differences in total cholesterol concentration between people reflect smaller differences in low density lipoprotein cholesterol concentration. RESULTS: The observed difference in mortality from ischaemic heart disease associated with a difference of 0.6 mmol/l in total serum cholesterol concentration was 17% but increased to 24% after correction for the regression dilution bias and to 27% (95% confidence interval 21% to 33%) after adjustment for both sources of underestimation, which provides an estimate of the difference in mortality for a true difference of 0.6 mmol/l in low density lipoprotein cholesterol concentration. The association was greater at younger ages. The estimated decrease in mortality from all causes was 6% before and 10% (1% to 17%) after adjustment for the two sources of underestimation. There was no excess mortality from any cause associated with low cholesterol concentration. CONCLUSIONS: The association between serum cholesterol concentration and ischaemic heart disease is materially stronger than directly inferred from prospective studies. This has important implications for the health benefit of achieving low cholesterol concentrations.

Adult↗
PubMed1994

By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease?

OBJECTIVE: To estimate by how much and how quickly a given reduction in serum cholesterol concentration will reduce the risk of ischaemic heart disease. DESIGN: Data on the incidence of ischaemic heart disease and serum cholesterol concentration were analysed from 10 prospective (cohort) studies, three international studies in different communities, and 28 randomised controlled trials (with mortality data analysed according to allocated treatment to ensure the avoidance of bias). MAIN OUTCOME MEASURE: Decrease in incidence of ischaemic heart disease or mortality for a 0.6 mmol/l (about 10%) decrease in serum cholesterol concentration. RESULTS: For men results from the cohort studies showed that a decrease of serum cholesterol concentration of 0.6 mmol/l (about 10%) was associated with a decrease in incidence of ischaemic heart disease of 54% at age 40 years, 39% at age 50, 27% at 60, 20% at 70, and 19% at 80. The combined estimate from the three international studies (for ages 55-64 years) was 38% (95% confidence interval 33% to 42%), somewhat greater than the cohort study estimate of 27%. The reductions in incidence of ischaemic heart disease in the randomised trials (for ages 55-64 years) were 7% (0 to 14%) in the first two years, 22% (15% to 28%) from 2.1-5 years, and 25% (15% to 35%) after five years, the last estimate being close to the estimate of 27% for the long term reduction from the cohort studies. The data for women are limited but indicate a similar effect. CONCLUSIONS: The results from the cohort studies, international comparisons, and clinical trials are remarkably consistent. The cohort studies, based on half a million men and 18,000 ischaemic heart disease events, estimate that a long term reduction in serum cholesterol concentration of 0.6 mmol/l (10%), which can be achieved by moderate dietary change, lowers the risk of ischaemic heart disease by 50% at age 40, falling to 20% at age 70. The randomised trials, based on 45,000 men and 4000 ischaemic heart disease events show that the full effect of the reduction in risk is achieved by five years.

Adult↗
PubMed1994

Assessing possible hazards of reducing serum cholesterol.

OBJECTIVE: To assess whether low serum cholesterol concentration increases mortality from any cause. DESIGN: Systematic review of published data on mortality from causes other than ischaemic heart disease derived from the 10 largest cohort studies, two international studies, and 28 randomised trials, supplemented by unpublished data on causes of death obtained when necessary. MAIN OUTCOME MEASURES: Excess cause specific mortality associated with low or lowered serum cholesterol concentration. RESULTS: The only cause of death attributable to low serum cholesterol concentration was haemorrhagic stroke. The excess risk was associated only with concentrations below about 5 mmol/l (relative risk 1.9, 95% confidence interval 1.4 to 2.5), affecting about 6% of people in Western populations. For noncirculatory causes of death there was a pronounced difference between cohort studies of employed men, likely to be healthy at recruitment, and cohort studies of subjects in community settings, necessarily including some with existing disease. The employed cohorts showed no excess mortality. The community cohorts showed associations between low cholesterol concentration and lung cancer, haemopoietic cancers, suicide, chronic bronchitis, and chronic liver and bowel disease; these were most satisfactorily explained by early disease or by factors that cause the disease lowering serum cholesterol concentration (depression causes suicide and lowers cholesterol concentration, for example). In the randomised trials nine deaths (from a total of 687 deaths not due to ischaemic heart disease in treated subjects) were attributed to known adverse effects of the specific treatments, but otherwise there was no evidence of an increased mortality from any cause arising from reduction in cholesterol concentration. CONCLUSIONS: There is no evidence that low or reduced serum cholesterol concentration increases mortality from any cause other than haemorrhagic stroke. This risk affects only those people with a very low concentration and even in these will be outweighed by the benefits from the low risk of ischaemic heart disease.

Accidents↗
PubMed1994

Apolipoproteins and ischaemic heart disease: implications for screening.

Apolipoproteins and lipids are established risk factors of ischaemic heart disease (IHD) but their efficacy as screening tests is not known. We therefore examined the mortality from IHD and serum concentrations of lipids and apolipoproteins in a prospective study of 21,520 men aged 35-64 years. Serum apo B was the apolipoprotein most strongly associated with IHD risk; a decrease in apo B of 10% was associated with 22% lower risk of IHD. However, measurement of apo B alone detected only 17% of all IHD deaths at the cost of a 5% false-positive rate. Combining apo B with apo AI and apo (a) increased the detection rate to 19%. With systolic blood pressure, smoking, and family history of IHD the detection rate increased to 28%. We conclude that screening for IHD by measuring apo B alone or with apo AI and apo (a) is too poor to discriminate between recommending drug therapy or lifestyle change for some and not others. It is not advisable to screen for IHD by measuring any combination of cholesterol, apo B, apo AI, apo (a) and the other risk factors. The primary aim in prevention of ischaemic heart disease should be to lower the risk factors in the population.

Adult↗