5-year outcome of an interventional strategy in non-ST-elevation acute coronary syndrome: the British Heart Foundation RITA 3 randomised trial.

BACKGROUND: The long-term outcome of an interventional strategy in patients with non-ST-elevation acute coronary syndrome is unknown. We tested whether an interventional strategy (routine angiography followed by revascularisation) was better than a conservative strategy (ischaemia-driven or symptom-driven angiography) over 5 years' follow-up. METHODS: In a multicentre randomised trial, 1810 patients (from 45 hospitals in England and Scotland, UK) with non-ST-elevation acute coronary syndrome were randomly assigned to receive an early intervention (n=895) or a conservative strategy (n=915) within 48 h of the index episode of cardiac pain. In each group, the aim was to provide the best medical treatment, and also to undertake coronary arteriography within 72 h in the interventional strategy with subsequent management guided by the angiographic findings. Analysis was by intention to treat and the primary outcome (composite of death or non-fatal myocardial infarction) had masked independent adjudication. RITA 3 has been assigned the International Standard Randomised Control Trial Number ISRCTN07752711. FINDINGS: At 1-year follow-up, rates of death or non-fatal myocardial infarction were similar. However, at a median of 5 years' follow-up (IQR 4.6-5.0), 142 (16.6%) patients with intervention treatment and 178 (20.0%) with conservative treatment died or had non-fatal myocardial infarction (odds ratio 0.78, 95% CI 0.61-0.99, p=0.044), with a similar benefit for cardiovascular death or myocardial infarction (0.74, 0.56-0.97, p=0.030). 234 (102 [12%] intervention, 132 [15%] conservative) patients died during follow-up (0.76, 0.58-1.00, p=0.054). The benefits of an intervention strategy were mainly seen in patients at high risk of death or myocardial infarction (p=0.004), and for the highest risk group, the odds ratio of death or non-fatal myocardial infarction was 0.44 (0.25-0.76). INTERPRETATION: In patients with non-ST-elevation acute coronary syndrome, a routine invasive strategy leads to long-term reduction in risk of death or non-fatal myocardial infarction, and this benefit is mainly in high-risk patients. The findings provide support for national and international guidelines in the need for more robust risk stratification in acute coronary syndrome.

Quality of life after coronary angioplasty or continued medical treatment for angina: three-year follow-up in the RITA-2 trial. Randomized Intervention Treatment of Angina.

OBJECTIVES: We sought to evaluate the impact of percutaneous transluminal coronary angioplasty (PTCA) and medical treatment on self-perceived quality of life among patients with angina. BACKGROUND: The second Randomized Intervention Treatment of Angina trial (RITA-2) implemented initial policies of PTCA or continued medical treatment in patients with angina, allowing assessment of long-term health consequences. METHODS: A total of 1,018 patients were randomly assigned (504 to PTCA and 514 to medical treatment). The short form 36 (SF-36) self-administered quality-of-life questionnaire was completed at randomization and three months, one year and three years later. To date, 98% of patients reached one year and 67% reached three years. RESULTS: The PTCA group had significantly greater improvements in physical functioning, vitality and general health at both three months and one year, but not at three years. These quality-of-life scores were strongly related to breathlessness, angina grade and treadmill exercise time both at baseline and at one year. The treatment differences in quality of life are explained by the PTCA group's improvements in breathlessness, angina and exercise time. The attenuation of treatment difference at three years is partly attributed to 27% of medically treated patients receiving nonrandomized interventions in the interim. For both groups, there were also improvements in ratings of physical role functioning, emotional role functioning, social functioning, pain and mental health, but for these the superiority of PTCA over medical treatment was less pronounced. After one year, 33% and 22% of the PTCA and medical groups, respectively, rated their health much better. CONCLUSIONS: Coronary angioplasty substantially improves patient-perceived quality of life, especially physical functioning and vitality, as compared with continued medical treatment. These differences are attributed to alleviation of cardiac symptoms (specifically, breathlessness and angina), but must be balanced against the small procedure-related risks of PTCA.

Issues in data monitoring and interim analysis of trials.

OBJECTIVES: To address issues about data monitoring committees (DMCs) for randomised controlled trials (RCTs). DATA SOURCES: Electronic databases. Handsearching of selected books. Personal contacts with experts in the field. REVIEW METHODS: Systematic literature reviews of DMCs and small group processes in decision-making; sample surveys of: reports of RCTs, recently completed and ongoing RCTs and policies of major organisations involved in RCTs; case studies of four DMCs; and interviews with experienced DMC members. All focused on 23 prestated questions. RESULTS: Although still a minority, RCTs increasingly have DMCs. There is wide agreement that nearly all trials need some form of data monitoring. Central to the role of the DMC is monitoring accumulating evidence related to benefit and toxicity; variation in emphasis has been reflected in the plethora of names. DMCs for trials performed for regulatory purposes should be aware of any special requirements and regulatory consequences. Advantages were identified for both larger and smaller DMCs. There is general agreement that a DMC should be independent and multidisciplinary. Consumer and ethicist membership is controversial. The chair is recognised as being particularly influential, and likely to be most effective if he or she is experienced, understands both statistical and clinical issues, and is facilitating in style and impartial. There is no evidence available to judge suggested approaches to training. The review suggested that costs should be covered, but other rewards must be so minimal as to not affect decision-making. It is usual to have a minimum frequency of DMC meetings, with evidence that face-to-face meetings are preferable. It is common to have open sessions and a closed session. A report to a DMC should cover benefits and risks in a balanced way, summarised in an accessible style, avoiding excessive detail, and be as current as possible. Disadvantages of blinded analyses seem to outweigh advantages. Information about comparable studies should be included, although interaction with the DMCs of similar ongoing trials is controversial. A range of formal statistical approaches can be used, although this is only one of a number of considerations. DMCs usually reach decisions by consensus, but other approaches are sometimes used. The general, but not unanimous, view is that DMCs should be advisory rather than executive on the basis that it is the trial organisers who are ultimately responsible for the conduct of the trial. CONCLUSIONS: Some form of data monitoring should be considered for all RCTs, with reasons given where there is no DMC or when any member is not independent. An early DMC meeting is helpful, determining roles and responsibilities; planned operations can be agreed with investigators and sponsors/funders. A template for a DMC charter is suggested. Competing interests should be declared. DMC size (commonly three to eight people) is chosen to optimise performance. Members are usually independent and drawn from appropriate backgrounds, and some, particularly the chair, are experienced. A minimum frequency of meetings is usually agreed, with flexibility for more if needed. The DMC should understand and agree the statistical approach (and guidelines) chosen, with both the DMC statistician and analysis statistician competent to apply the method. A DMC's primary purpose is to ensure that continuing a trial according to its protocol is ethical, taking account of both individual and collective ethics. A broader remit in respect of wider ethical issues is controversial; arguably, these are primarily the responsibility of research ethics committees, trial steering committees and investigators. The DMC should know the range of recommendations or decisions open to it, in advance. A record should be kept describing the key issues discussed and the rationale for decisions taken. Errors are likely to be reduced if a DMC makes a thorough review of the evidence and has a clear understanding of how it should function, there is active participation by all members, differences are resolved through discussion and there is systematic consideration of the various decision options. DMCs should be encouraged to comment on draft final trial reports. These should include information about the data monitoring process and detail the DMC membership. It is recommended that groups responsible for data monitoring be given the standard name 'Data Monitoring Committee' (DMC). Areas for further research include: widening DMC membership beyond clinicians, trialists and statisticians; initiatives to train DMC members; methods of DMC decision-making; 'open' data monitoring; DMCs covering a portfolio of trials rather than single trials; DMC size and membership, incorporating issues of group dynamics; empirical study of the workings of DMCs and their decision-making, and which trials should or should not have a DMC.

Predictive value of repeated measurements of CD4 lymphocyte counts on progression to AIDS.

OBJECTIVE: Description of the relationship between repeated measurements of CD4 lymphocyte count and development of AIDS in asymptomatic HIV-infected patients. DESIGN: Repeated measurements of CD4 lymphocyte counts over an AIDS-free period in asymptomatic HIV-infected patients, and follow-up of the cohort to record subsequent clinical progression to AIDS. METHODS: The cohort was studied in a double-blind randomized clinical trial. CD4 lymphocyte counts were measured on three occasions over 8 months in 851 patients. RESULTS: Eighty subsequent clinical progressions to AIDS were recorded during a median follow-up period of 15.3 months. Each of the three measurements of CD4 lymphocyte count were separately predictive of subsequent progression to AIDS. However, when the three measurements were included simultaneously in a predictive model only the last measurement showed a significant predictive value. Change in individual CD4 count was also related to the risk of developing AIDS, but was no longer significant when the most recent measurement was included in the model. CONCLUSION: These results indicate the closeness of the relationship between the actual state of the immune system and subsequent progression to AIDS.

Long-term survival in patients with advanced immunodeficiency.

OBJECTIVE: To identity prognostic factors associated with survival time in HIV-infected patients with advanced immunodeficiency. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 1284 HIV-infected patients with serial CD4 count measurements and at least one CD4 cell count < or = 50 x 10(6)/I (CD4 < or = 50). MAIN OUTCOME MEASURE: Survival from initial CD4 cell count < or = 50 x 10(6)/l. RESULTS: The median survival from initial CD4 < or = 50 x 10(6)/l was 17.1 months. The risk of death increased by 2% 195% confidence interval (Cl), 1-31 for each year of age, by 10% (95% Cl, 3-16) for each 10 x 10(6)/l decrease in CD4 count, and by 14% (95% Cl, 9-18) for each 1 g/dl decrease in haemoglobin level. Compared to AIDS-free patients with CD4 < or = 50 x 10(6) cells/l, the risk of dying was 1.5-fold (95% Cl, 1.2-1.9) that of patients who had an AIDS diagnosis for fewer than 3 months prior to CD4 < or = 50, 1.8-fold for patients with an AIDS diagnosis for 4-11 months prior to CD4 < or = 50, and twice that of patients with AIDS for > or = 12 months prior to CD4 < or = 50. The risk of dying for patients whose rate of CD4 cell decline was > 40 x 10(6)/l per 6 months was 1.7-fold (95% Cl, 1.3-2.3) that of patients with an average CD4 cell loss < 40 x 10(6)/l per 6 months, after adjusting for age, haemoglobin and duration of AIDS prior to CD4 < or = 50 x 10(6) cells/l. A prognostic score was developed from the final multivariate model, based on age at CD4 < or = 50, haemoglobin at CD4 < or = 50, duration of AIDS and rate of CD4 decline prior to CD4 < or = 50. CONCLUSIONS: Routinely available clinical and laboratory data including haemoglobin level, rate of CD4 decline and duration of AIDS can be readily translated into a prognostic score and then used to predict the survival experience of an HIV-infected patient with advanced immunodeficiency.

Blood pressure and hypertension in middle-aged British men.

Blood pressure measurements in 7735 middle-aged men from general practices in 24 towns in England, Wales and Scotland provide information on the prevalence of hypertension and its management in Great Britain. Despite a substantial correlation (r = 0.70) between systolic and diastolic blood pressures, individuals can show considerable discrepancies between these two measurements; they are not interchangeable. This observation has important implications for the choice of criteria used to define hypertension. However defined, the prevalence of hypertension increases markedly with age, increasing body mass index and with heavy alcohol consumption. It is not related to smoking and only to a small extent to social class. Diastolic hypertension (greater than or equal to 90 mmHg) was present in 26% and systolic hypertension (greater than or equal to 160 mmHg) in 22% of these men. In both systolic and diastolic hypertension, only one quarter of affected men could recall having been diagnosed as hypertensive by a doctor, and only one third of these were on regular antihypertensive treatment. There is a threefold variation in the prevalence of measured hypertension in the 24 towns with a trend towards higher rates in Northern England and Scotland. No relationship was seen between the prevalence rates of measured hypertension in the towns and the rates of doctor diagnosis of hypertension. Cardiovascular mortality rates in the towns were correlated with the measured prevalence rates for systolic and diastolic hypertension (r = 0.70 and r = 0.57, respectively). The geographic variations in blood pressure and hypertension in Great Britain provide a major opportunity for research into the causes of 'essential' hypertension.

The relationship between blood lead, blood pressure, stroke, and heart attacks in middle-aged British men.

The relationship between blood lead concentration and blood pressure is examined in a survey of 7371 men aged 40 to 59 from 24 British towns. After allowance for relevant confounding variables, including town of residence and alcohol consumption, there exists a very weak but statistically significant positive association between blood lead and both systolic and diastolic blood pressure. These cross-sectional data indicate that an estimated mean increase of 1.45 mm Hg in systolic blood pressure occurs for every doubling of blood lead concentration with a 95% confidence interval of 0.47 to 2.43 mm Hg. After 6 years of follow-up, 316 of these men had major ischemic heart disease, and 66 had a stroke. After allowance for the confounding effects of cigarette smoking and town of residence there is no evidence that blood lead is a risk factor for these cardiovascular events. However, as the blood lead-blood pressure association is so weak, it is unlikely that any consequent association between lead and cardiovascular disease could be demonstrated from prospective epidemiological studies. An overview of data from this and other large epidemiological surveys provides reasonably consistent evidence on lead and blood pressure. While NHANES II data on 2254 U.S. men indicate a slightly stronger association between blood lead and systolic blood pressure, data from two Welsh studies on over 2000 men did not show a statistically significant association. However, the overlapping confidence limits for all these studies suggest that there may be a weak positive statistical association whereby systolic blood pressure is increased by about 1 mm Hg for every doubling of blood lead concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

The variability of serum cholesterol measurements: implications for screening and monitoring.

The reliability of screening for high serum total cholesterol is adversely affected by the variability of cholesterol levels over time. This problem is investigated using data on repeated cholesterol measurements for 14,600 men and women in the MRC Mild Hypertension Trial. For measurements 1 year apart, the within-person coefficient of variation (CV) is 7%, which is substantial compared with the between-person CV of 15%. In a screening programme, this within-person variability may lead to the misclassification of individuals and inappropriate intervention. For example, 28% of middle-aged British men with a single cholesterol measurement above 6.9 mmol/l have a long-term average cholesterol below that value even without intervention. Using averages of several cholesterol measurements reduces, but does not eliminate, these problems. Furthermore, monitoring the effect of interventions in individuals by sequential cholesterol measurement may be unhelpful or even misleading. These problems cast serious doubt on the value of general population screening for high cholesterol levels.

Within-subject diastolic blood pressure variability: implications for risk assessment and screening.

Because of variability in diastolic blood pressure within an individual, repeated measurements increase precision in assessing an individual's underlying mean pressure and so also aid risk classification. Data from a cohort of 11,299 middle-aged men is used to model the variability in diastolic pressure between annual measurements. A simple model with pressure normally distributed about an underlying mean with standard deviation increasing with level fits the data very well. In modelling risk of cardiovascular mortality, a strong association is found with observed diastolic pressure level but not to trends in or variability between observed values. The effect of regression dilution is clear with the risk relationship appearing greater as one uses the mean of an increasing number of measurements. A method of adjusting for this regression dilution is described so giving an estimate of the relationship with underlying mean diastolic pressure. Using this survival model and the model for blood pressure variability, a method is presented for estimating both underlying mean pressure and absolute risk of cardiovascular disease given a sequence of blood pressure measurements from screening. This allows a sequential strategy for determining whether (a) antihypertensive intervention is desirable, (b) no further screening is necessary, or (c) further screening would aid the assessment, and emphasizes the need to consider blood pressure in the context of multiple risk factors.

Sample size requirements for prospective studies, with examples for coronary heart disease.

Methods of determining the required number of disease cases for estimation of relative odds in prospective studies are evaluated, with examples from coronary heart disease. Data from a British prospective study of coronary heart disease are used in simulation exercises to assess the reliability of estimation formulae for both continuous and categorical risk factors. For continuous risk factors, a univariate formula based on estimation of the standardized relative odds (Whittemore A. S. JAMA 1981; 76: 27-32 [1]), gives reliable estimation of the required number of disease cases, provided the risk factor has a near normal distribution. An extension of the formula to adjustment for other risk factors, was less satisfactory, perhaps because of departures from multivariate normality. For categorical risk factors, an adaption of a univariate method for case control studies (Smith PG, Day NE. Int J Epidemiol 1984; 13: 356-365 [2]), gives reliable estimates of the number of cases required. However, this depends on approximate prior knowledge of the relative odds. In general, prospective studies of coronary heart disease risk factors should aim for at least 400 cases to enable sufficient accuracy of estimation.

Lead exposure and children's intellectual performance.

The Institute of Child Health/Southampton study is the largest cross-sectional survey of lead exposure and children's intelligence. 402 six year olds in London with tooth lead concentration in three pre-defined ranges were selected for neuropsychological testing. This paper presents new findings on the relationship between child IQ and tooth lead levels which build on previous findings in four respects: Rather than simply classifying children into high, medium and low lead groups the actual concentrations of lead in each child's tooth have been used to provide a more powerful assessment of the association between IQ and body lead burden. The influence of parental and social factors on child IQ is explored in detail in order to see if any residual lead-IQ association exists after allowance for such confounders. The methods of multiple regression, including an 'optimal' statistical policy, are more fully described. The possibility of interactions between lead and confounders is explored. Findings are that parental IQ is the most important influence on child IQ, though several other factors (eg: family size, social class and quality of marital relationships) were also significantly related. There was no overall evidence that tooth lead concentrations were related to child IQ once these other factors were taken into account. However, a significant interaction between tooth lead and sex of child indicates that the lead-IQ association appears much more pronounced in boys. This unexpected finding needs cautious interpretation and further exploration in other studies.

Short-term effects of air pollution on daily mortality in Athens: a time-series analysis.

BACKGROUND: Athens has a serious air pollution problem which became evident in the early 1970s. Studies for the years 1975-1982 have indicated a positive association of sulphur dioxide (SO2) with total daily mortality. Since 1983 the pollution profile in Athens has gradually changed but the levels of smoke, SO2 and carbon monoxide (CO) remain relatively high. METHODS: The association of air pollution with daily all-cause mortality in Athens for the years 1984-1988 was investigated using daily values of SO2, smoke and CO. Autoregressive models with log-transformed daily mortality as the dependent variable, were used to adjust for temperature and relative humidity (both lagged by 1 day), year, season and day of week, as well as for serial correlations in mortality. RESULTS: Graphic analysis revealed non-linear monotonically increasing relationships between total mortality and SO2, smoke and CO, with steeper exposure-response slopes at lower air pollution levels. Air pollution data lagged by 1 day had the strongest association with daily mortality. In three separate autoregression models for log(SO2), log(smoke) and log(CO) the regression coefficients for each were highly statistically significant (P < 0.001). Further multiple regression modelling showed that SO2 and smoke are both independent predictors of daily mortality, though to a lesser extent than temperature and relative humidity. The inclusion of CO in the model did not further improve the prediction of daily mortality. The magnitude of association is small, for instance, a 10% reduction in smoke is estimated to decrease daily mortality by 0.75% (95% confidence interval [CI]: 0.51-0.99). However, it cannot be accounted for by climatic and seasonal effects, so that a causal influence of air pollution on daily mortality seems plausible. CONCLUSIONS: These findings suggest that current air pollution levels in Athens (and many other industrialized cities) may be responsible for substantial numbers of premature deaths, and hence remain an important public health issue.

Diurnal variations in serum biochemical and haematological measurements.

Twenty five biochemical and haematological measurements were determined on nonfasting blood and serum samples collected between 9 am and 7 pm from a representative group of 7685 British middle-aged men. Most measurements showed significant diurnal variations, but only for bilirubin, phosphate, and triglyceride did time of day account for more than 5% of the between subject variance. Serum bilirubin concentrations showed a pronounced downward trend in the afternoon, the mean value after 6 pm being 30% lower than the mean value in the morning. Mean serum triglyceride and phosphate concentrations increased steadily through the day. Mean concentrations of potassium, haemoglobin, and haematocrit and red cell count were higher in the morning, while urea and creatinine concentrations and white cell count had higher means in the afternoon. Glucose showed a pattern consistent with short term response to meals. The effects of these diurnal trends on routine use of biochemical tests needs careful consideration, and a greater understanding of their biological mechanisms is required.

Risk factors for ischaemic heart disease: the prospective phase of the British Regional Heart Study.

Risk factors for major ischaemic heart disease (acute myocardial infarction or sudden death) have been investigated in a prospective study of 7735 men aged 40-59 years drawn from general practices in 24 British towns. After a mean follow-up of 4.2 years, there have been 202 cases of major ischaemic heart disease. Univariate estimates of the risk of ischaemic heart disease show that serum total cholesterol, HDL-cholesterol and triglyceride concentrations, systolic and diastolic blood pressures, cigarette smoking, and body mass index are all associated with increased risk of ischaemic heart disease. Evidence of ischaemic heart disease at initial examination is also strongly associated with increased risk of subsequent ischaemic heart disease. All these factors were then considered simultaneously using multiple logistic models. Definite myocardial infarction on electrocardiogram and recall of a doctor diagnosis of ischaemic heart disease remained predictive of subsequent major ischaemic heart disease, after allowance for all other risk factors. Serum total cholesterol, blood pressure, and cigarette smoking each remained as highly significant independent risk factors whereas overweight, above average levels of HDL-cholesterol and serum triglyceride were not predictive of risk after allowance for the above factors. Men with and without pre-existing ischaemic heart disease were examined separately in the same way (using multiple logistic models). The strength of association between the principal risk factors and subsequent major ischaemic heart disease was reduced in the men with pre-existing ischaemic heart disease, only age and serum total cholesterol remaining highly significant. Overall the levels of the major risk factors commonly encountered in British men have a marked effect on the risk of ischaemic heart disease. Modification of these risk factors in the general population constitutes an important national priority.

Effects of tap water lead, water hardness, alcohol, and cigarettes on blood lead concentrations.

A survey of middle-aged men in 24 British towns has found pronounced geographical variation in blood lead concentrations. Towns with the highest mean blood lead concentrations have soft water supplies and have the highest water lead concentrations. Individual blood lead can be considerably increased by raised household tap water lead concentrations. Mean blood lead is estimated to be 43% higher for men when the concentration of lead in first-draw domestic tap water is 100 micrograms/l compared with a zero concentration. Individual blood lead is also affected by alcohol consumption and cigarette smoking, such that on average these two life-style habits together contribute an estimated 17% to the blood concentration of lead in middle-aged men. Lead in water should be given greater priority in any national campaign to reduce lead exposure.

The contribution of drinking water lead to maternal blood lead concentrations.

The association between domestic water lead concentrations and blood lead concentrations has been examined in 232 mothers at delivery. The blood lead was found to vary significantly with the cube root of the water lead. This association was stronger for first flush water lead rather than for running water lead. This study emphasises the danger to mothers and to their children of environmental lead over-exposure in areas of soft acid plumbosolvent water.

Biochemical and haematological response to alcohol intake.

In a clinical survey of 7735 middle-aged men, alcohol consumption has been related to 25 biochemical and haematological measurements obtained from a single blood sample. Most measurements showed some association with alcohol consumption, gamma-glutamyl transferase (GGT) being the most strongly associated. Lead, mean corpuscular haemoglobin (MCH), mean corpuscular volume, high-density lipoprotein-cholesterol (HDL-C), urate and aspartate transaminase also showed substantial associations with alcohol intake. Using a discriminant analysis technique, a simple score based on five variables (GGT, HDL-C, urate, MCH and lead) provided the best discrimination between heavy drinkers (e.g. more than three pints of beer daily) and occasional drinkers, but still failed to identify more than half of the heavy drinkers. This combined score may prove a useful measure of an individual's biochemical/haematological response to alcohol consumption for use in epidemiological and clinical studies of alcohol related disorders. The use of such indices should complement but not replace measures of alcohol intake derived from questionnaires.

Studies of water quality and cardiovascular disease in the United Kingdom.

The British Regional Heart Study aims at determining factors responsible for the marked regional variations in cardiovascular disease in Great Britain. PHASE I is a retrospective study of cardiovascular mortality with water quality (hardness and more than 20 other water parameters have been studied), climate, air pollution, socio-economic and genetic factors. An association between water hardness and cardiovascular mortality is reaffirmed, towns with soft water tending to have higher death rates than towns with hard water. This relationship is somewhat weakened after allowing for climatic and socio-economic factors but remains statistically significant for both coronary heart disease and stroke. After adjustment for other factors, soft water areas (around 0.25 mmol/l) have a 10-15% higher cardiovascular mortality that areas of medium hardness (around 1.70 mmol/l) whereas any further increase beyond 1.70 mmol/l has little extra lowering effect on cardiovascular mortality.

Factors influencing household water lead: a British national survey.

From a survey of 2,831 households in Great Britain, a quantitive assessment was made of the combined influence of lead piping, acidity of water supply, and other factors on houselhold water lead levels. Estimates are provided of the effects that remedial measures would have on blood lead levels in the population.

Environmental lead and children's intelligence: a systematic review of the epidemiological evidence.

OBJECTIVE: To quantify the magnitude of the relation between full scale IQ in children aged 5 or more and their body burden of lead. DESIGN: A systematic review of 26 epidemiological studies since 1979: prospective studies of birth cohorts, cross sectional studies of blood lead, and cross sectional studies of tooth lead. SETTING: General populations of children > or = 5 years. MAIN OUTCOME MEASURES: For each study, the regression coefficient of IQ on lead, after adjustment for confounders when possible, was used to derive the estimated change in IQ for a specific doubling of either blood or tooth lead. RESULTS: The five prospective studies with over 1100 children showed no association of cord blood lead or antenatal maternal blood lead with subsequent IQ. Blood lead at around age 2 had a small and significant inverse association with IQ, somewhat greater than that for mean blood lead over the preschool years. The 14 cross sectional studies of blood lead with 3499 children showed a significant inverse association overall, but showed more variation in their results and their ability to allow for confounders. The seven cross sectional studies of tooth lead with 2095 children were more consistent in finding an inverse association, although the estimated magnitude was somewhat smaller. Overall synthesis of this evidence, including a meta-analysis, indicates that a typical doubling of body lead burden (from 10 to 20 micrograms/dl (0.48 to 0.97 mumol/l) blood lead or from 5 to 10 micrograms/g tooth lead) is associated with a mean deficit in full scale IQ of around 1-2 IQ points. CONCLUSION: While low level lead exposure may cause a small IQ deficit, other explanations need considering: are the published studies representative; is there inadequate allowance for confounders; are there selection biases in recruiting and following children; and do children of lower IQ adopt behaviour which makes them more prone to lead uptake (reverse causality)? Even if moderate increases in body lead burden adversely affect IQ, a threshold below which there is negligible influence cannot currently be determined. Because of these uncertainties, the degree of public health priority that should be devoted to detecting and reducing moderate increases in children's blood lead, compared with other important social detriments that impede children's development, needs careful consideration.