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Elevated blood homocysteine levels appear to be a risk factor for atherosclerosis. A study of 750 people with atherosclerosis and 800 without found that those with the highest blood homocysteine levels had twice the risk of atherosclerosis compared to those with lower levels. This risk was independent of other risks but also seemed to magnify other risks such as smoking and hypertension. Those who took vitamins had lower homocysteine levels and a lower risk of atherosclerosis, but this group was relatively small. Several B vitamins are involved in the metabolism of homocysteine., Context. -- Elevated plasma homocysteine is a known risk factor for atherosclerotic vascular disease, but the strength of the relationship and the interaction of plasma homocysteine with other risk factors are unclear. Objective. -- To establish the magnitude of the vascular disease risk associated with an increased plasma homocysteine level and to examine interaction effects between elevated plasma homocysteine level and conventional risk factors. Design. -- Case-control study. Setting. -- Nineteen centers in 9 European countries. Patients. -- A total of 750 cases of atherosclerotic vascular disease (cardiac, cerebral, and peripheral) and 800 controls of both sexes younger than 60 years. Measurements. -- Plasma total homocysteine was measured while subjects were fasting and after a standardized methionine-loading test, which involves the administration of 100 mg of methionine per kilogram and stresses the metabolic pathway responsible for the irreversible degradation of homocysteine. Plasma cobalamin, pyridoxal 5'-phosphate, red blood cell folate, serum cholesterol, smoking, and blood pressure were also measured. Results. -- The relative risk for vascular disease in the top fifth compared with the bottom four fifths of the control fasting total homocysteine distribution was 2.2 (95% confidence interval, 1.6-2.9). Methionine loading identified an additional 27% of atrisk cases. A dose-response effect was noted between total homocysteine level and risk. The risk was similar to and independent of that of other risk factors, but interaction effects were noted between homocysteine and these risk factors; for both sexes combined, an increased fasting homocysteine level showed a more than multiplicative effect on risk in smokers and in hypertensive subjects. Red blood cell folate, cobalamin, and pyridoxal phosphate, all of which modulate homocysteine metabolism, were inversely related to total homocysteine levels. Compared with nonusers of vitamin supplements, the small number of subjects taking such vitamins appeared to have a substantially lower risk of vascular disease, a proportion of which was attributable to lower plasma homocysteine levels. Conclusions. -- An increased plasma total homocysteine level confers an independent risk of vascular disease similar to that of smoking or hyperlipidemia. It powerfully increases the risk associated with smoking and hypertension. It is time to undertake randomized controlled trials of the effect of vitamins that reduce plasma homocysteine levels on vascular disease risk.

The incidence of neural tube defects could be reduced significantly by fortifying food with folic acid through a population approach. Researchers found that a large sample of Irish women who gave birth to babies with neural tube defects had much lower levels of plasma and red cell folate at 15 weeks' gestation. Among pregnant women whose red cell folate levels were less than 340 nmol/L, the risk of having a baby with neural tube defects was eight times greater than among women who with levels of 906 nmol/L or higher. A strategy that would increase red cell folate levels for women before pregnancy appears to be the optimum approach. With a population intake of 0.4 mg per day of folic acid, a reduction of 48% in the rate of neural tube defects is estimated to be possible., Using data from a recent case-control study, a woman's risk of having a child with a neural tube defect (NTD) was found to be Associated with early pregnancy red cell folate levels in a continuous dose-response relationship. These findings were used to calculate the reduction in NTD cases that would be expected under two different strategies to raise folate levels. Targeting high-risk individuals has a small effect on the population prevalence but can substantially change an individual's risk. Targeting the population produces a small change in individual risk but has a large effect on the population prevalence. Supplementation of high-risk women would be the most efficient method to implement the high-risk strategy, while food fortification would be preferable for the population approach. The current guidelines for the prevention of NTD are for an increased folic acid intake of 0.4 mg per day. This would result in a 48% reduction in NTDs, which may be near optimal. The two intervention strategies should be considered complementary in prevention of NTDs.

A randomised trial was initiated in Ireland in 1981 to determine if periconceptional supplementation with either folic acid alone or a multivitamin preparation alone could reduce the recurrence risk of neural tube defects (NTDs) in women with a previously affected pregnancy from 5.0% to 1.0% or less. The trial was concluded before the initial target number of study subjects was reached and without a clear treatment effect being observed. A total of 354 women were randomised to receive one of three treatments: folic acid, multivitamins without folic acid, and folic acid plus multivitamins. At the end of the trial 257 women had had a first trial pregnancy outcome (261 infants/fetuses) where the presence or absence of NTDs was ascertainable. There was one NTD recurrence in the 89 infants/fetuses of women in the multivitamin group and no recurrence in the 172 infants/fetuses of women in the folic acid groups, a non-significant difference. Otherwise eligible women who were pregnant when first contacted constituted a non-randomised control group; there were three recurrences among the 103 infants in this group. The difference in the recurrence rate between the folic acid groups and the non-randomised controls was statistically significant but we have reservations about the validity of this comparison. Although our findings do not provide clear evidence of a protective effect of folic acid supplementation they are consistent with those of the Medical Research Council (MRC) trial which demonstrated the efficacy of folic acid in preventing recurrence of NTDs and they raise the possibility that folic acid may be protective at a much lower dosage than that used in the MRC trial. [ABSTRACT FROM AUTHOR]

The use of confidence intervals has become standard in the presentation of statistical results in medical journals. Calculation of confidence limits can be straightforward using the normal approximation with an estimate of the standard error, and in particular cases exact solutions can be obtained from published tables. However, for a number of commonly used measures in epidemiology and clinical research, formulae either are not available or are so complex that calculation is tedious. The author describes how an approach to confidence interval estimation which has been used in certain specific instances can be generalized to obtain a simple and easily understood method that has wide applicability. The technique is applicable as long as the measure for which a confidence interval is required can be expressed as a monotonic function of a single parameter for which the confidence limits are available. These known confidence limits are substituted into the expression for the measure—giving the required interval. This approach makes fewer distributional assumptions than the use of the normal approximation and can be more accurate. The author illustrates his technique by calculating confidence intervals for Levin's attributable risk, some measures in population genetics, and the “number needed to be treated” in a clinical trial. Hitherto the calculation of confidence intervals for these measures was quite problematic. The substitution method can provide a practical alternative to the use of complex formulae when performing interval estimation, and even in simpler situations it has major advantages. Am J Epidemiol 1998; 147: 783–90. [ABSTRACT FROM PUBLISHER]

Presents several letters concerning medicine. Effect of nicotine chewing gum as an adjunct to general practitioner's advice against smoking; Health effects of smoking cessation after unstable angina and myocardial infarction; Role of radiation in the etiology of Down's syndrome.

A response is presented from the author of the article "Confidence limits made easy: interval estimation using a substitution method," from a volume 147, 1998 issue.