Department of Public Health and Caring Sciences/Geriatrics, PO Box 609, SE 751 25, Uppsala, Sweden.
Dr Lena Kilander. E-mail: lena.kilander{at}geriatri.uas.lul.se
Abstract
Background There is a well-established inverse relation between education and mortality from cardiovascular disease and cancer. The reasons for this are still in part unclear. We aimed to investigate whether differences in traditional vascular risk factors, adult height, physical activity, and biomarkers of fatty acid and antioxidant intake, could explain this association.
Methods In all, 2301 50-year-old men in Uppsala, Sweden (82% of the background population) were examined with regard to educational level, blood pressure, blood glucose, body mass index, serum lipids, smoking, body height, physical activity, serum beta carotene, alpha tocopherol, selenium, and serum fatty acids in cholesterol esters. Cause-specific mortality was registered 25 years later.
Results Low education was associated with a higher rate of mortality from cardiovascular disease (crude relative risk [RR] = 1.67, 95% CI : 1.172.39), and from cancer (crude RR = 1.94, 95% CI : 1.213.10), compared to high educational attainment. Men with high education had an overall more beneficial risk factor profile concerning traditional cardiovascular risk factors, physical activity, and biomarkers of dietary intake of antioxidants and fat. After adjustment for all examined risk factors, the inverse gradient between education and cardiovascular mortality disappeared (RR in low education = 1.01. 95% CI : 0.671.52). Controlling for smoking, physical activity and dietary biomarkers explained less than half of the excess cancer mortality in the lower educational groups. Smoking (adjusted RR = 1.89, 95% CI : 1.372.61), and high proportions of palmitoleic acid in serum cholesterol esters (adjusted RR per 1 SD = 1.39, 95% CI : 1.071.82) predicted cancer mortality, independently of all other factors. There were no independent relations between serum antioxidants and mortality.
Conclusions These data indicate that modifiable lifestyle factors mediate the inverse gradient between education and death from cerebro- and cardiovascular disease. Smoking, physical activity and dietary factors explained half of the excess cancer mortality in lower educated groups. Further studies are needed to explore the proposed association between palmitoleic acid, a marker of high intake of animal and dairy fat, and cancer.
Keywords Mortality, education, cardiovascular disease, cancer
Accepted 19 February 2001
There is a well-established inverse relation between education, and other markers of socioeconomic status (SES), and mortality.13 Low SES is associated with a higher mortality from cardiovascular disease (CVD),1,2,4 as well as from cancer.1,2 The reason for this is still in part unclear. Low education has been linked to traditional cardiovascular risk factors, such as smoking,1,57 hypertension,1,6 and overweight with associated metabolic disturbances.1,68 These factors contribute to, but do not fully explain, the excess incidence of coronary heart disease, or CVD mortality, associated with low SES.1,4,9 Regarding low SES and cancer, the relationship is still more complex. Additional explanations may be sought among several lifestyle factors. Factors operating early in life may be of importance in this context, since biological markers of adverse socioeconomic conditions during childhood have been associated with adult poor health and increased mortality.10,11 A low degree of leisure time physical activity has been associated both with low SES,6,7,12 and with a higher mortality from CVD12 and cancer.13,14 Further, dietary factors may play a role in the explanation of SE inequalities in mortality, since a low educational attainment has been associated with an unhealthy' diet, such as a high intake of saturated fat and a low intake of antioxidants.5,15,16 We aimed to investigate whether traditional cardiovascular risk factors, adult body height, leisure-time physical activity level, and biomarkers of fatty acid (FA) and antioxidant intakes, together could explain the relation between low education and cause-specific mortality.
Population and Methods
In 19701973, all 2841 men born in 19201924 and living in Uppsala, Sweden, were invited to a health survey, in which 82% (n = 2322) participated. Data on socioeconomic factors were available for 2301 men, who were 48.6 to 51.1 years old at the examination. Men who died within 2 years of baseline (n = 16) were excluded from the analyses; thus, the analyses in this study involves data from 2285 men. Systolic (SBP) and diastolic blood pressure (DBP) in the supine condition, fasting concentrations of blood glucose, serum cholesterol and triglycerides, and body weight and height, were measured under standardized conditions.17 Body mass index (BMI) was calculated as the quotient between body weight (kg) and body height (m2). Adult body height was chosen as a marker of early life conditions, since data on birthweight were available for only 60% of the cohort, and since educational level was more closely associated with adult height than with birthweight. Serum concentrations of beta carotene and alpha tocopherol (n = 2028) were measured by high-performance liquid chromatography after storage in liquid nitrogen.18 Lipid-adjusted alpha tocopherol, calculated as the quotient between alpha tocopherol (mmol/l) and the sum of serum total cholesterol and triglycerides (mmol/l), was used in the analyses.19 Selenium was determined in serum using the graphite-furnace atomic absorption spectrometric method.20 Measurements of serum proportions of FA in cholesterol esters (n = 1990) included palmitic acid (16:0), palmitoleic acid (16:1 n-7), stearic acid (18:0), oleic acid (18:1 n-9), linoleic acid (18:2 n-6), alpha-linolenic acid (18:3 n-3), gamma-linolenic acid (18:3 n-6), dihomogamma-linolenic acid (20:3 n-6), arachidonic acid (20:4 n-6), EPA (eicosapentaenoic acid, 20:5 n-3) and DHA (docosahexaenoic acid, 22:6 n-3), as previously described.21 Values are expressed as percentages of total FA in cholesterol esters. Smoking habits (current daily smoking yes/no) were obtained in an interview with the physician in charge of the study. In a questionnaire, leisure-time physical activity was asked as: Do you spend most of your time reading, watching TV, or in other mostly sedentary activities?' (yes = low); Do you often go walking or cycling for pleasure?' (yes = medium); and Do you do any active sport or heavy gardening for 3 hours every week?' (yes = high). Educational levels, stratified as low (
7 years of schooling), medium (810 years) or high (high school or university studies), and marital status were collected from the Swedish census in 1970. The main outcome measurement was mortality by the end of December 1995, according to the Swedish death register. Causes of death were coded according to the International Classification of Diseases (Eighth or Ninth Revision). Codes 390448 defined mortality from cardio- and cerebrovascular disease, and 140209 defined cancer mortality. The loss of follow-up of mortality was very low since the 10-digit social security number allows matching with the nation-wide Causes of Death Register. According to the homepage of the Swedish National Board of Health and Welfare, only 0.36% of all deaths in 1996 lacked a diagnosis, and the ICD code (first three figures) was miscoded in 2.2% of cases. All analyses were adjusted for age. Tests for trend between level of education (low, medium, high) and risk factors were performed according to Spearman's correlation. A Cox's proportional hazards model was used to examine the associations between risk factors and mortality. Continuous variables were entered, standardized to SD = 1. The highest educational level was used as the reference category. The results are shown as relative risks (RR) (95% CI) per one standard deviation or per category, and with two-sided P-values. The SAS statistical analysis computer package (Version 6.12) was used. Informed consent was obtained from the participants after the nature of the procedure had been fully explained. The study was approved by the Ethics Committee at Uppsala University.
Results
By December 1995, corresponding to a maximum follow-up time of 25.7 years, 630 men (27.6%) had died. Death from CVD had occurred in 301 men, and 216 men had died from cancer (72 men from gastrointestinal cancer, 43 from lung cancer and 28 from prostate cancer). Age-adjusted RR of mortality, setting men with high education as reference group, was 1.77 (95% CI : 1.362.29) in the least educated men, and 1.57 (95% CI : 1.182.10) in those with medium-long education (Table 1). Regarding CVD mortality, there was a similar inverse gradient; the RR in low and medium-long education being 1.67 (95% CI : 1.172.39), and 1.26 (95% CI : 0.831.90), respectively. Compared to highly educated men, the risk of dying from cancer was approximately twice as high in those with low (RR = 1.94, 95% CI : 1.213.10) or medium education (RR = 2.16, 95% CI : 1.303.58).
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Cardio- and cerebrovascular mortality: multivariate analyses
Table 4a shows the RR of CVD mortality according to educational level in five different multivariate models. Adjustment for serum cholesterol, and smoking, respectively, decreased the RR only slightly from 1.67 (95% CI : 1.172.39) to 1.50 (95% CI : 1.052.16), and to 1.47 (95% CI : 1.022.11); the other separate traditional risk factors had a smaller impact. Adjustment for all traditional risk factors further reduced the risk in those least educated to 1.31 (95% CI : 0.911.89). After controlling for all variables, i.e. traditional risk factors, body height, physical activity, serum FA and antioxidants, the higher risk in the least educated disappeared (RR = 1.01, 95% CI : 0.671.52). In this model, blood glucose, serum cholesterol, and smoking remained as independent predictors of CVD mortality (Table 4b
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In this population of 50-year-old men, follow-up after 25 years confirmed the association between a low educational level and a higher rate of mortality from cardio- and cerebrovascular disease (crude RR = 1.67, 95% CI : 1.172.39), as well as from cancer (crude RR = 1.94, 95% CI : 1.213.10). Men with a high educational attainment had an overall more beneficial risk factor profile: the rate of smoking was lower, and concentrations of serum lipids, palmitoleic acid, oleic acid, and serum antioxidants, were higher than in low- or medium-long educated subjects. Differences in traditional cardiovascular risk factors, i.e. blood pressure, BMI, blood glucose, serum lipids and smoking, explained more than half of the excess CVD mortality in the low education category (adjusted RR = 1.31, 95% CI : 0.911.89). After controlling also for physical activity, body height, serum FA and antioxidants, CVD mortality was similar between the three educational strata. Regarding cancer mortality, adjustment for smoking, physical activity, serum antioxidants and fatty acids, explained approximately half of the increased risk in the low or medium-long education groups.
The participation rate was 82%, thus, the results should be reasonably representative for middle-aged men in Uppsala. The impact of low SES may possibly be even greater in the general population, since Uppsala is a university city with few industries. Our study was limited to men, and no conclusions regarding women may be drawn. Other studies have described similar associations between SES and the risk factor profile in men and women, i.e. low education being associated with smoking and overweight,7 impaired glucose tolerance,8 and a higher dietary intake of saturated fat and cholesterol.15 However, in a Finnish cohort, traditional cardiovascular risk factors explained less of the higher risk in the lower socioeconomic groups in women than in men.1
One strength of our study was that biomarkers of dietary intake were available. Most other cohort studies have analysed data collected from dietary registrations, such as semi-quantative food frequency questionnaires. However, measurements of FA in serum cholesterol esters provide only indirect evidence of diet, since the numbers are relative proportions, and give no information on the true intake. Further, it is not possible to discriminate between the effects of high dietary intake, and the effects of increased endogenous synthesis, or decreased utilization. In the Swedish diet, palmitic acid, palmitoleic acid and oleic acid are commonly linked together, originating mainly from animal fat. In contrast, in a Mediterranean population, high proportions of oleic acid in cholesterol esters would imply a high intake of olive oil. In a US population, levels of monounsaturated FA in cholesterol esters reflected the intake of saturated FA, rather than that of monounsaturated FA.22 For example, palmitoleic acid (16:1 n-7) is mainly endogenously synthesized from palmitic acid (16:0), reflecting the intake of dairy products, meat and hard margarines. However, the major advantage of using biomarkers of FA and antioxidants is that the problem with reporting bias is avoided. This matter is of special relevance in this context, since low SES has been associated with an underestimation of the true intake.23
Cerebro- and cardiovascular mortality
Our findings regarding CVD are in concordance with some other studies: controlling for traditional risk factors explained not more than half of the excess risk in subjects with low education.1,4,9,24 In our cohort, social inequalities in the other lifestyle factors provided further explanation to the excess mortality in the least educated group. Interestingly, none of the untraditional' risk factors, i.e. serum antioxidants, biomarkers of fat intake, or physical activity level, was independently associated with CVD mortality. Thus, we found no support for the hypothesis that antioxidants per se protect from atherosclerotic disease. This is in concordance with the negative results from trials comparing beta carotene and/or alpha tocopherol supplementation with placebo.2527 In our cohort, serum concentrations of beta carotene, alpha tocopherol, and selenium, were all strongly linked to educational level. Probably, the inverse relation between reported intake of single antioxidants, such as alpha tocopherol and beta carotene, and coronary heart disease, described by others, may be explained by residual confounding of education, or rather the overall risk factor pattern associated with educational level.
Concerning dietary fat intake, the relation between high serum cholesterol and CVD is well established. The net effects of linoleic acid are debated; it has been suggested that the beneficial effects on serum lipids may be counteracted by an increase of the oxidation of low density lipoprotein. In our cohort, neither linoleic acid, alpha-linolenic acid, nor long-chain n-3 FA, were linked to mortality from CVD. Further, the association between high proportions in serum cholesterol esters of saturated and monounsaturated FA, and CVD mortality, disappeared in the multivariate analyses. These results can be compared to those from the Health Professionals' follow-up study, and the Physicians' Health Study, i.e. two large homogeneous cohorts of highly educated subjects, where no clear relations between intake of saturated fat,28 or intake of fish fatty acids,29 and coronary heart disease, were found.
In our study, being physically active was related to a decreased risk of CVD mortality, but this association disappeared after controlling for other factors. There were close interrelationships between physical activity and markers of a healthy diet, such as high serum beta carotene, and low levels of palmitoleic acid. Thus, as previously discussed by others,30 the link between physical activity and low mortality may partly be mediated by different dietary habits in active subjects. Adult body height is partly determined by genetic factors, but is also a marker of childhood socioeconomic position. This was reflected by the strong positive relation between education and body height in our cohort. In univariate analyses, body height was inversely related to CVD mortality, but this relation disappeared when controlling for other factors. The results from other studies are not clear-cut. In the Whitehall Study, coronary death was inversely related to adult height, irrespective of employment grade.31 In the Physicians' Health Study, taller men had a lower risk of myocardial infarction, but not of stroke and cardiovascular death.32 In NHANES I, height was inversely associated with fatal and non-fatal CVD; however, this relation disappeared after adjusting for years of education.33
Cancer mortality
The higher RR of cancer mortality in men with low or medium-long education was reduced by less than half when smoking, physical activity and dietary biomarkers were adjusted for. The risk of cancer connected with smoking was twice as high, even when education and other variables were taken into account. Regarding antioxidants, serum beta carotene was inversely related to cancer mortality after adjusting for education, alpha tocopherol and selenium, but not when all the other risk factors were controlled for. This is consistent with the negative results from trials comparing beta carotene and/or alpha tocopherol supplementation with placebo.25,27 On the other hand, high levels of palmitoleic acid remained as an independent predictor of death in cancer, suggesting that the FA composition of the diet, or the capacity to metabolize FA, may be a causal determinant of malignant disease. A high proportion of palmitoleic acid in serum cholesterol esters is a marker of a high intake of meat, dairy products, and hard margarines. To our knowledge, there is only one previous longitudinal study that has analysed the relations between FA in serum cholesterol esters and death from cancer.34 These results were in concordance with those in our study. In a French population of middle-aged men, cancer mortality was preceded by high levels of palmitoleic acid and oleic acid, and decreased levels of linoleic acid, however, socioeconomic factors were not controlled for. The results from experimental studies35 and case-control studies on relations between cancer and the FA spectrum in cholesterol esters or phospholipids are inconsistent,36,37 but in one study a relation between increased proportions of palmitoleic acid and prostate cancer was described.37
Although it is a crude measurement, current daily smoking was the strongest predictor of cancer in all multivariate models. Concerning the other risk factors, the question of which intermediate factor is most important' or most explanatory', is certainly not solved. The strength of risk factors measured in different ways, for instance physical activity level, and relative proportions of fatty acids in serum cholesterol esters, cannot easily be compared in multivariate models. Further, there were close intercorrelations between the different unhealthy lifestyle factors', which is why there may be residual effects of confounding. Hence, it cannot be concluded from our results that a low intake of animal fat is beneficial, but a high intake of antioxidants is of no importance. In general, diets low in animal fat contain more vegetable oils, fruits and vegetables, and thus a high amount of antioxidants, linoleic acid and fibre.38,39 Our data gave only partial explanation of the higher cancer mortality in lower educational groups. Probably, other dietary factors, including excessive alcohol intake, and adverse physical and psychological work environmental factors, are important in this context. To conclude, our results stress that potentially modifiable lifestyle factors are strong mediators of social inequalities in CVD mortality. Further research is needed to explore the association between low education and cancer, including dietary factors.
KEY MESSAGES
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Acknowledgments
Supported by grants from the Swedish Medical Research Council and the Swedish Council for Social Research.
References
1
Pekkanen J, Tuomilehto J, Uutela A, Vartiainen E, Nissinen A. Social class, health behaviour, and mortality among men and women in eastern Finland. Br Med J 1995;311:58993.
2 Davey Smith G, Neaton JD, Wentworth D, Stamler R, Stamler J. Mortality differences between black and white men in the USA: contribution of income and other risk factors among men screened for the MRFIT. Lancet 1998;351:93439.[ISI][Medline]
3
Lantz PM, House JS, Lepkowski JM, Williams DR, Mero RP, Chen J. Socioeconomic factors, health behaviors, and mortality: results from a nationally representative prospective study of US adults. JAMA 1998; 279:170308.
4 Kaplan GA, Keil JE. Socioeconomic factors and cardiovascular disease: a review of the literature. Circulation 1993;88:197398.[Abstract]
5 Jacobsen BK, Thelle DS. Risk factors for coronary heart disease and level of education. The Tromso Heart Study. Am J Epidemiol 1988;127: 92332.[Abstract]
6 Hoeymans N, Smit HA, Verkleij H, Kromhout D. Cardiovascular risk factors in relation to educational level in 36,000 men and women in the Netherlands. Eur Heart J 1996;17:51825.[Abstract]
7 Choiniere R, Lafontaine P, Edwards AC. Distribution of cardiovascular disease risk factors by socioeconomic status among Canadian adults. Can Med Assoc J 2000;162(Suppl.):S1324.[Medline]
8 Brunner EJ, Marmot MG, Nanchahal K et al. Social inequality in coronary risk: central obesity and the metabolic syndrome. Evidence from the Whitehall II Study. Diabetologia 1997;40:134149.[ISI][Medline]
9 Diez-Roux AV, Nieto FJ, Tyroler HA, Crum LD, Szklo M. Social inequalities and atherosclerosis. The atherosclerotic risk in community study. Am J Epidemiol 1995;141:96072.[Abstract]
10
Davey Smith G, Hart C, Blane D et al. Adverse socioeconomic conditions in childhood and cause specific adult mortality: prospective observational study. Br Med J 1998;316:163135.
11 van de Mheen H, Stronks K, Looman CW et al. Does childhood socioeconomic status influence adult health through behavioural factors? Int J Epidemiol 1998;27:43137.[Abstract]
12 Rosengren A, Wilhelmsen L. Physical activity protects against coronary death and deaths from all causes in middle-aged men. Ann Epidemiol 1997;7:6975.[ISI][Medline]
13 Lee IM, Sesso HD, Paffenbarger RS Jr. Physical inactivity and risk of lung cancer. Int J Epidemiol 1999;28:62025.[Abstract]
14 Thune I, Lund E. The influence of physical activity on lung-cancer risk: A prospective study of 81 516 men and women. Int J Cancer 1997;70:5762.[ISI][Medline]
15 Shimakawa T, Sorlie P, Carpenter MA et al. Dietary intake patterns and sociodemographic factors in the atherosclerosis risk in communities study. Prev Med 1994;23:76980.[ISI][Medline]
16 Bolton-Smith C, Smith WC, Woodward M, Tunstall-Pedoe H. Nutrient intake of different social-class groups: results from the Scottish Heart Health Study. Br J Nutr 1991;65:32135.[ISI][Medline]
17 Skarfors ET, Selinus KI, Lithell HO. Risk factors for developing non-insulin dependent diabetes: a 10 year follow-up of men in Uppsala. Br Med J 1991;303:75560.[ISI][Medline]
18
Milne DB, Botnen J. Retinol, alpha-tocopherol, lycopene, and alpha- and beta-carotene simultaneously determined in plasma by isocratic liquid cromotography. Clin Chem 1986;32:87476.
19 Thurnham DI, Davies JA, Crump BJ, Situnayake RD, Davis M. The use of different lipids to express serum tocopherol:lipid ratios for the measurements of vitamin E status. Ann Clin Biochem 1986;23:51420.[ISI][Medline]
20 Salonen JT, Alfthan G, Huttunen JK, Pikkarainen J, Puska P. Association between cardiovascular deaths and myocardial infarction and serum selenium in a matched-pair longitudinal study. Lancet 1982;Jul.24:17579.
21 Vessby B, Aro A, Skarfors E, Berglund L, Salminen I, Lithell H. The risk to develop NIDDM is related to the fatty acid composition of the serum cholesterol esters. Diabetes 1994;43:135357.[Abstract]
22 Ma J, Folsom AR, Shahar E, Eckfeldt JH. Plasma fatty acid composition as an indicator of habitual dietary fat intake in middle-aged adults. Am J Clin Nutr 1995;62:56471.[Abstract]
23 Stallone DD, Brunner EJ, Bingham SA, Marmot MG. Dietary assessment in Whitehall II: the influence of reporting bias on apparent socioeconomic variation in nutrient intakes. Eur J Clin Nutr 1997; 51:81525.[ISI][Medline]
24 Suadicani P, Hein HO, Gyntelberg F. Strong mediators of social inequalities in risk of ischaemic heart disease: a six-year follow-up in the Copenhagen Male Study. Int J Epidemiol 1997;26:51622.[Abstract]
25
Hennekens CH, Buring JE, Manson JE et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;334: 114549.
26
Virtamo J, Rapola JM, Ripatti S et al. Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Arch Intern Med 1998;158:66875.
27
Omenn GS, Goodman GC, Thornquist MD et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:115055.
28
Ascherio A, Rimm EB, Giovannucci EL, Spiegelman D, Stampfer M, Willett WC. Dietary fat and risk of coronary heart disease in men: cohort follow up study in the United States. Br Med J 1996;313:8490.
29 Morris MC, Manson JE, Rosner B, Buring JE, Willett WC, Hennekens CH. Fish consumption and cardiovascular disease in the physicians' health study: a prospective study. Am J Epidemiol 1995;142:16675.[Abstract]
30 Eaton CB, McPhillips JB, Gans KM et al. Cross-sectional relationship between diet and physical activity in two south eastern New England communities. Am J Prev Med 1995;11:23844.[ISI][Medline]
31 Leon DA, Davey Smith G, Shipley M, Strachan D. Adult height and mortality in London: early life, socioeconomic confounding or shrinkage? J Epidemiol Community Health 1995;49:59.[Abstract]
32 Hebert PR, Rich-Edwards JW, Manson JE et al. Height and incidence of cardiovascular disease in male physicians. Circulation 1993;88: 143743.[Abstract]
33 Liao Y, McGee DL, Cao G, Cooper RS. Short stature and risk of mortality and cardiovascular disease: negative findings from the NHANES I epidemiologic follow-up study. J Am Coll Cardiol 1996;27: 67882.[ISI][Medline]
34
Zureik M, Ducimetière P, Warnet J-M, Orssaud G. Fatty acid proportions in cholesterol esters and risk of premature death of cancer in middle aged French men. Br Med J 1995;311:125154.
35 Rose DP, Connolly JM. Effects of fatty acids and eicosanoid synthesis inhibitors on the growth of two human prostate cancer cell lines. Prostate 1991;18:24354.[ISI][Medline]
36 Simon JA, Fong J, Bernert JT Jr, Browner WS. Serum fatty acids and the risk of fatal cancer. Am J Epidemiol 1998;148:85458.[Abstract]
37 Harvei S, Bjerve KS, Tretli S, Jellum E, Robsahm TE, Vatten L. Prediagnostic level of fatty acids in serum phospholipids: omega-3 and omega-6 fatty acids and the risk of prostate cancer. Int J Cancer 1997;71:54551.[ISI][Medline]
38 Baghurst KI, Baghurst PA, Record SJ. Demographic and dietary profiles of high and low fat consumers in Australia. J Epidemiol Community Health 1994;48:2632.[Abstract]
39 Ursin G, Ziegler RG, Subar AF, Graubard BI, Haile RW, Hoover R. Dietary patterns associated with low-fat diet in the national health examination follow-up study: identification of potential confounders for epidemiological analyses. Am J Epidemiol 1993;137:91627.[Abstract]