N. J. Wald

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

Abstract 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 lose 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.

Assessing possible hazards of reducing serum cholesterol

Abstract 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 non-circulatory 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 diseases; 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.

Detection in life of confirmed Alzheimer's disease using a simple measurement of medial temporal lobe atrophy by computed tomography

The medial temporal lobe of the brain is important for normal cognitive function, notably for memory, and is the region with the most extensive pathological change in Alzheimers disease (AD). We wanted to find out if atrophy of the medial temporal lobe could be detected in life in patients in whom a diagnosis of AD was subsequently established histopathologically. The minimum width of the medial temporal lobe, measured by temporal-lobe-oriented computed tomography (CT) about one year before death, in 44 patients with a histopathological diagnosis of AD (cases) was nearly half (0.56 of the median) that in 75 controls of the same age with no clinical evidence of dementia (95% confidence interval 0.51-0.61). There was little overlap between the distributions of measurements in cases and controls. A cut-off (< 0.79 MoM) selected to yield a 5% false-positive rate gave an expected detection rate of 92%. A cut-off selected to yield a false-positive rate of 1% (< 0.70 MoM) yielded a 79% detection rate. 20 of the 44 patients with histopathologically diagnosed AD had been scanned more than once before death, and the test (cut-off < 0.79 MoM) was positive in all 20 more than a year before and in 9/10 more than 2 years before death. In 10 subjects with dementia but with histopathology excluding AD, the mean minimum width of the medial temporal lobe was significantly greater than that in the cases with AD, but was not significantly different from that in controls. Medial temporal lobe CT is a non-invasive, rapid, simple and effective test for AD which could have immediate application firstly in improving the accuracy of prevalence and incidence studies and, secondly, for the identification of groups of high-risk patients in the evaluation of novel treatments for AD. In the future, it could be applied as a screening test.

Maternal serum unconjugated oestriol as an antenatal screening test for Down's syndrome

Summary. The median maternal serum unconjugated oestriol level between 13 and 27 weeks gestation in 77 pregnancies associated with Downs syndrome was lower than the median level in 385 unaffected control pregnancies matched for maternal age, gestational age, and duration of serum sample storage (P<0·001). The median level for the affected pregnancies was 73% of that in the controls. Low unconjugated oestriol levels can be used to detect fetal Downs syndrome; at cut‐off levels selected to detect at least 35% of affected pregnancies, unconjugated serum oestriol was a better screening test than either maternal age or serum alpha‐fetoprotein (AFP). The use of all three variables in combination to select women with a 1:250 or greater risk of a Downs syndrome term pregnancy would yield a 45% detection rate with a falsepositive rate of 5.2%. The same detection rate using maternal age alone or using age and serum AFP in combination would yield higher falsepositive rates, 15% and 9.8% respectively. The addition of unconjugated oestriol to a Downs syndrome screening programme would therefore be more efficient than the use of age and AFP alone; for a given detection rate fewer women would need an amniocentesis or, for a given percentage of women having an amniocentesis, more pregnancies with Downs syndrome would be detected.

AMNIOTIC-FLUID ACETYLCHOLINESTERASE AS A POSSIBLE DIAGNOSTIC TEST FOR NEURAL-TUBE DEFECTS IN EARLY PREGNANCY

Raised levels (greater than or equal to 4.5 munits/ml) of acetylcholinesterase (AChE) activity in amniotic fluid at 14--23 weeks of pregnancy were significantly associated with open fetal neural-tube defects. Out of 72 pregnancies correctly classified by the amniotic-fluid alpha-fetoprotein (A.F.P.) test, 2 of 56 without neural-tube defects and all 16 with open neural-tube defects (8 with anencephaly and 8awith open spina bifida) had raised levels of AChE. Out of 5 pregnancies misclassified by the A.F.P. test (4 without neural-tube defects and 1 with open spina bifida), only 1 was misclassified by the AChE test--namely, one of those without a neural-tube defect. Thus, only 3 of the 77 pregnancies tested were misclassified by the quantitative AChE test. A qualitative test for an isoenzyme of AChE found in cerebrospinal fluid correctly classified these 3 pregnancies. These findings suggest that the analysis of AChE in amniotic fluid may be a useful test in the diagnosis of open neural-tube defects.

Serum beta-carotene and subsequent risk of cancer: results from the BUPA Study.

In the BUPA Study, a prospective study of 22,000 men attending a screening centre in London, serum samples were collected and stored. The concentration of beta-carotene was measured in the stored serum samples from 271 men who were subsequently notified as having cancer and from 533 unaffected controls, matched for age, smoking history and duration of storage of the serum samples. The mean beta-carotene level of the cancer subjects was significantly lower than that of their matched controls (198 and 221 micrograms l-1 respectively, P = 0.007). The difference was apparent in subjects from whom blood was collected several years before the diagnosis of the cancer, indicating that the low beta-carotene levels in the cancer subjects were unlikely to have been simply a consequence of pre-clinical disease. Men in the top two quintiles of serum beta-carotene had only about 60% of the risk of developing cancer compared with men in the bottom quintile. The study was not large enough to be able to indicate with confidence the sites of cancer for which the inverse association between serum beta-carotene and risk of cancer applied, though the association was strongest for lung cancer. The association may be due to beta-carotene affecting the risk directly or it may reflect an indirect association of cancer risk with some other component of vegetables or with a nonvegetable component of diet that is itself related to vegetable consumption.

Serum vitamin E and subsequent risk of cancer

In a prospective study of about 22,000 men attending a screening centre, serum samples were collected and stored. The concentration of vitamin E (alpha-tocopherol) was measured in the stored serum samples from 271 men subsequently notified as having cancer and from 533 unaffected controls, matched for age, smoking history and duration of storage of the serum samples. The mean vitamin E level of the cancer subjects was not significantly different from that of their matched controls. The mean level in the cancer subjects who were diagnosed as having cancer before the elapse of one year from the date of blood collection was, however, significantly lower than the mean concentration of their matched controls (10.0 and 11.5 mgl-1 respectively, P = 0.003). For subjects whose cancers were diagnosed one or more years after blood collection the difference was not statistically significant either for all cancers or for cancers of six sites considered separately, viz. lung, colon and rectum, stomach, bladder, central nervous system and skin. The most likely explanation for these results is that the low vitamin E levels observed in these subjects were a metabolic consequence, rather than a precursor, of the cancer. This would explain, at least in part, the overall inverse association between serum vitamin E and risk of cancer observed in the published epidemiological studies on serum vitamin E and cancer.

How should urinary cotinine concentrations be adjusted for urinary creatinine concentration

The correlation between cotinine concentrations in a single specimen of urine and in serum collected on the same occasion from 279 male smokers was 0.83. This was significantly increased, to 0.91, by adjusting the urinary cotinine levels for urinary creatinine concentration to take account of variations in urinary dilution between people. The adjustment used was based on the observed regression relationship between urinary cotinine and urinary creatinine concentrations. Expressing urinary cotinine values as a ratio to urinary creatinine, which has been used as a method of adjustment by others, did not improve the correlation between serum and urinary cotinine levels. The method of adjusting urinary cotinine for urinary creatinine is, therefore, important. The principle of such adjustment should apply not only to cotinine but also to other urinary biochemical measurements.

SMALL BIPARIETAL DIAMETER OF FETUSES WITH SPINA BIFIDA: IMPLICATIONS FOR ANTENATAL SCREENING

The biparietal diameter of 20 fetuses with spina bifida was measured during pregnancy by ultrasound scanning, mainly in the second trimester. The mean result was 0.83 cm smaller than the value based on 186 unaffected pregnancies at the same gestational ages (P<0.001), suggesting that spina bifida fetuses are growth retarded. The practical consequence of this finding is that the routine use of ultrasound in pregnancy will increase the sensitivity of AFP screening for open spina bifida at 16 to 18 weeks gestation from 79 per cent as estimated by the UK Collaborative AFP Study to about 90 per cent or more.

SERUM COTININE LEVELS IN PIPE SMOKERS: EVIDENCE AGAINST NICOTINE AS CAUSE OF CORONARY HEART DISEASE

Serum levels of cotinine (a principal metabolite of nicotine) were studied in men who did not smoke (28), and in men who smoked cigarettes only (150), cigars only (70), and pipes only (56). The mean cotinine level for pipe smokers was 389 ng/ml, significantly higher than the mean level for cigarette and cigar smokers (306 and 121 ng/ml, respectively); no cotinine was detected in the serum from any of the non-smokers. Large prospective studies have shown that pipe smokers have no material excess risk of coronary heart disease but cigarette smokers do, so that our observations indicate that nicotine is unlikely to be the major cause of the excess coronary heart disease mortality in cigarette smokers.