A Prospective Study of Microalbuminuria and Incident Coronary Heart Disease and Its Prognostic Significance in a British Population

The EPIC-Norfolk Study

Matthew F. Yuyun1, Kay-Tee Khaw1, Robert Luben1, Ailsa Welch1, Sheila Bingham2, Nicholas E. Day1 and Nicholas J. Wareham1 

1 Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
2 Dunn Human Nutrition Unit, Medical Research Council, Cambridge, United Kingdom.

Received for publication June 2, 2003; accepted for publication July 31, 2003.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Microalbuminuria is associated with an increased risk of cardiovascular and renal disease in patients with diabetes and hypertension. The role of microalbuminuria as a predictor of coronary heart disease (CHD) has not been examined in large general-population cohorts, and its prognostic significance in persons with established CHD is uncertain. The authors examined the relation between microalbuminuria and incident CHD (1993–2002) in a population-based British cohort of 22,368 men and women aged 40–79 years without prevalent baseline CHD and evaluated its prognostic significance in 1,596 participants with baseline CHD. Participants were members of the Norfolk, United Kingdom, component of the European Prospective Investigation into Cancer and Nutrition (the EPIC-Norfolk Study). At baseline, participants were categorized into normoalbuminuria, microalbuminuria, and macroalbuminuria groups. During an average of 6.4 years of follow-up, 800 primary CHD events were registered. The age-adjusted incidence of CHD increased significantly across ordered categories of albuminuria (4.3, 4.4, and 5.6/1,000 person-years across tertiles of normoalbuminuria, 7.1/1,000 person-years for microalbuminuria, and 12.2/1,000 person-years for macroalbuminuria; p for trend < 0.001). The multivariate hazard ratio for incident primary CHD was 1.36 (95% confidence interval (CI): 1.12, 1.64) for microalbuminuria and 1.59 (95% CI: 1.10, 2.37) for macroalbuminuria. Among participants with established baseline CHD, the independent risk of all-cause mortality associated with microalbuminuria was 1.61 (95% CI: 1.19, 2.07). Microalbuminuria may be useful in identifying persons at increased risk of CHD and subsequent death in the general population.

albuminuria; cardiovascular diseases; coronary disease; diabetes mellitus; hypertension; proteinuria; risk factors

Abbreviations: Abbreviations: CHD, coronary heart disease; CI, confidence interval; EPIC, European Prospective Investigation into Cancer and Nutrition.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Although mortality from coronary heart disease (CHD) has declined since the late 1960s and 1970s in most industrialized countries, CHD is still the leading cause of death (1). The geographic and temporal patterns of CHD event rates correspond to trends in the prevalence of classical cardiovascular disease risk factors, with the residual variance in CHD attributable in part to unknown factors (2). This indicates that nonestablished CHD risk factors might be operational in CHD incidence and mortality and lends support to the continuous search for novel cardiovascular disease risk factors or risk markers that might predict CHD independently of the classical risk factors. Microalbuminuria is one of these possible predictive factors.

Microalbuminuria is associated with an increased risk of cardiovascular and renal disease in patients with diabetes mellitus (3, 4) and hypertension (5, 6). Although the role microalbuminuria plays in the general population is less well known, studies have shown that it is independently associated with prevalent cardiovascular disease in the general population (7, 8) and that it predicts all-cause and cardiovascular disease mortality in the general population and in nondiabetic persons (7, 912). Although the significance of albuminuria as a possible predictor of CHD in persons without diabetes has been suggested (1315), there has not been a report from a large population-based cohort study of albuminuria and incident CHD. The prognostic significance of albuminuria in persons with baseline CHD in the general population is also unknown. Therefore, we undertook this study to examine the etiologic significance of microalbuminuria for incident primary CHD and its prognostic significance among persons with established CHD in a British population.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
Participants in this study were men and women from the Norfolk, United Kingdom, component of the European Prospective Investigation into Cancer and Nutrition (the EPIC-Norfolk Study). Details on recruitment and test procedures have been published previously (16). Briefly, the EPIC-Norfolk Study is an ongoing population-based cohort study that is part of a 10-country European collaborative investigation of the relation between diet and cancer. The scope of the EPIC-Norfolk Study was broadened to include endpoints other than cancer and exposures other than diet.

Recruitment into EPIC-Norfolk began in March 1993 and was completed at the end of 1997. Participants were followed until March 31, 2002. Male and female residents of Norfolk aged 40–79 years were recruited using general-practice age-sex registers. Of the 77,630 mailed invitations, 30,447 persons consented to participate and completed a detailed baseline health and lifestyle questionnaire, and 25,633 underwent a health examination conducted by trained nurses using a standard protocol. A random spot urine sample was collected during the clinic visit, and urinary albumin:creatinine ratio was later determined.

A total of 25,112 persons who completed the health and lifestyle questionnaire, were examined by the nurses, and had their albumin:creatinine ratio calculated constituted our study population. We excluded participants with dipstick hematuria or leukocyturia (n = 1,148); this left 23,964 participants for our analyses. Of these, 1,596 persons had a baseline history of CHD and were used for prognostic analyses, while the remaining 22,368 persons without baseline CHD (12,216 women and 10,152 men) constituted the study population for incident primary CHD events. Ethical approval for this study was obtained from the Norwich District Ethics Committee.

Study design
Information on smoking status, prevalent physician-diagnosed diabetes, hypertension treatment, hyperlipidemia, CHD, and family history of CHD was obtained from a baseline health and lifestyle questionnaire that contained a section of the Rose angina questionnaire (17). Body mass index was calculated as weight in kilograms divided by height in meters squared, with height measured using a free-standing stadiometer and weight measured using digital scales (Salter, Tonbridge, United Kingdom). Blood pressure was measured using an Accutorr sphygmomanometer (Datascope Medical Company Ltd., Huntingdon, United Kingdom). Hypertension was defined as physician-diagnosed hypertension, systolic blood pressure >=140 mmHg, or diastolic blood pressure >=90 mmHg.

Nonfasting serum total cholesterol, high density lipoprotein cholesterol, and triglyceride levels were measured with an RA 1,000 Technicon analyzer (Bayer Diagnostics, Basingstoke, United Kingdom), and low density lipoprotein cholesterol level was calculated using the Friedewald formula (18). Dyslipidemia was defined as baseline treatment for hypercholesterolemia or a total cholesterol level >=6.2 mmol/liter. Urinary albumin concentration (mg/liter) was measured by immunonephelometry (19) using the Dade Behring Nephelometer II analyzer (Dade Behring Ltd., Milton Keynes, United Kingdom). Urinary creatinine concentration (mmol/liter) was measured by colorimetry (20) using the Dade-Behring Dimension AR analyzer (Dade Behring Ltd.). Urinary albumin:creatinine ratio (mg/mmol) was calculated. The use of urinary albumin:creatinine ratio (in random spot urine collection) as a measure of albuminuria has been validated against the "gold standard" of urinary albumin excretion rate measured in timed urine collections. In these studies, the correlation between the two methods has ranged from 0.81 to 0.99 (2125). The sensitivity for detection of albuminuria has ranged from 77 percent to 100 percent, with specificity ranging from 80 percent to 100 percent. Dipstick urinalysis was undertaken with the Multistix (Bayer Corporation, Newbury, United Kingdom) to detect hematuria and leukocyturia.

Endpoints
We identified incident fatal and nonfatal CHD events occurring between baseline and follow-up through March 31, 2002. Data on fatal endpoints were obtained from the Office for National Statistics. Data on nonfatal events were obtained from the National Health Service health district database of all hospital admissions for EPIC participants, using record linkage with the EPIC-Norfolk database. For these analyses, fatal CHD events were defined as deaths with an underlying cause of death coded 410–414 according to the International Classification of Diseases, Ninth Revision, or coded I20–I25 according to the International Classification of Diseases, Tenth Revision. For nonfatal events, we used the hospital codes for CHD hospital admissions, which were clinically defined by the attending consultant.

Statistical analyses
Normoalbuminuria was defined as an albumin:creatinine ratio less than 2.5 mg/mmol, microalbuminuria as an albumin:creatinine ratio of 2.5–25 mg/mmol, and macroalbuminuria (proteinuria) as an albumin:creatinine ratio greater than 25 mg/mmol (26). Persons with normoalbuminuria were further divided into tertiles, giving us five ordered categories of albuminuria. The normoalbuminuric population was not neatly divisible into tertiles because of the large numbers within each 0.1-mg/mmol increment of albumin:creatinine ratio. Testing for linear trends in continuous and categorical data across ordered categories of albuminuria was conducted by means of the nonparametric Cusick test and the {chi}2 test for trend with 1 df, respectively. Multivariate Cox regression analysis was used to determine the relation between CHD and albuminuria. Data on albumin:creatinine ratio were log-transformed to base 2 before we conducted any analyses involving the use of albumin:creatinine ratio as a continuous variable, because the distribution of values for the ratio was highly positively skewed. Kaplan-Meier estimates of survival for the three major categories of albuminuria were compared by means of the {chi}2 test for CHD survival trend. Statistical analyses were undertaken with Stata for Windows, version 7.0 (Stata Corporation, College Station, Texas), and GENSTAT 5 (Numerical Algorithms Group, Oxford, United Kingdom).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Baseline characteristics
The prevalence of microalbuminuria in the total study population was 11.5 percent. Prevalence was significantly lower in men (8.4 percent) than in women (14.1 percent) (p < 0.001). Table 1 shows baseline characteristics of the study population by ordered categories of albuminuria. Variables that showed a significant positive trend with increasing categories of albuminuria were age, smoking, diabetes mellitus, history of hypertension, systolic and diastolic blood pressure, history of dyslipidemia, total cholesterol level, and low density lipoprotein cholesterol level.


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TABLE 1. Baseline characteristics of the total study population used in analyses of coronary heart disease risk, by category of albuminuria (n = 22,368), EPIC*-Norfolk Study, United Kingdom, 1993–2002{dagger}
 
Incidence of CHD
A total of 800 fatal and nonfatal CHD events (531 in men and 269 in women) were registered among study participants during an average of 6.4 years of follow-up (142,037.4 person-years of follow-up), giving us a crude CHD incidence of 5.6 per 1,000 person-years in the total population. As is shown in table 2 and figure 1, part A, the age-adjusted incidence of CHD increased significantly across categories of baseline albuminuria in both men and women (p for trend < 0.001).


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TABLE 2. Age-adjusted incidence of coronary heart disease per 1,000 person-years and age-adjusted hazard ratios for coronary heart disease, by category of albuminuria, EPIC{dagger}-Norfolk Study, United Kingdom, 1993–2002
 


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FIGURE 1. Age-adjusted sex-stratified incidence of coronary heart disease (CHD) per 1,000 person-years (part A) and age-adjusted sex-stratified hazard ratios for CHD (part B), by category of baseline albuminuria (n = 22,368), EPIC-Norfolk Study, United Kingdom, 1993–2002. The p values for trend for the incidence and risk of CHD events were less than 0.001 in both men and women. The vertical lines above each bar in part A are the upper bounds of the 95% confidence intervals. Normo, normoalbuminuria (in tertiles); Micro, microalbuminuria (urinary albumin:creatinine ratio of 2.5–25.0 mg/mmol); Macro, macroalbuminuria. (EPIC, European Prospective Investigation into Cancer and Nutrition.)

 
Risk of CHD associated with albuminuria
Table 2 and figure 1, part B, show age-adjusted hazard ratios for CHD across ordered categories of albuminuria in comparison with the reference category. There was a significant positive trend of CHD risk across these degrees of albuminuria. Table 3 shows the multivariate hazard ratio for CHD associated with albuminuria. Taking albuminuria as a continuous variable (log2 albumin:creatinine ratio), the hazard ratios for CHD in multivariate analyses were 1.08 (95 percent confidence interval (CI): 1.03, 1.14; p = 0.009) in the total population, 1.11 (95 percent CI: 1.02, 1.18; p = 0.016) in women, and 1.07 (95 percent CI: 1.01, 1.12; p = 0.027) in men. These figures correspond to the risk associated with a doubling of the albumin:creatinine ratio or a twofold increase in albumin:creatinine ratio (i.e., from 2 mg/mmol to 4 mg/mmol or from 15 mg/mmol to 30 mg/mmol).


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TABLE 3. Hazard ratios for incident coronary heart disease associated with albuminuria as compared with normoalbuminuria (n = 22,368), EPIC{dagger}-Norfolk Study, United Kingdom, 1993–2002
 
Table 3 shows the results of multivariate subgroup analyses of some established cardiovascular disease risk factors. While, in subgroup analyses, the relation of microalbuminuria with CHD appeared to be slightly stronger among men and persons with established cardiovascular disease risk factors, the interactions were not statistically significant. When considered in isolation, the sensitivity of microalbuminuria and macroalbuminuria combined for CHD risk was 27.7 percent, and the specificity was 88.1 percent. The positive predictive value in this study was 6.3 percent, and the negative predictive value was 96.5 percent.

Recurrent CHD events and prognostic significance of microalbuminuria
In the 1,596 participants who were excluded from the original analysis because they had baseline CHD, microalbuminuria and proteinuria independently predicted secondary coronary events, with hazard ratios of 1.40 (95 percent CI: 1.13, 1.74) and 1.84 (95 percent CI: 1.16, 2.92), respectively, in men and women combined. There were 604 recurrent events altogether among participants with a baseline history of CHD, with an incidence of 65.8 per 1,000 person-years in all men and women. Therefore, the absolute risk of recurrent CHD events was very high in this group. To investigate the prognostic significance of albuminuria in the group with baseline CHD events, we calculated the multivariate adjusted hazard ratios for total mortality at follow-up and found them to be 1.61 (95 percent CI: 1.19, 2.07) for microalbuminuria and 1.73 (95 percent CI: 1.20, 2.81) for macroalbuminuria.

CHD-free survival
Figure 2 shows the Kaplan-Meier CHD-free survival curves by category of baseline albuminuria in women and men. There was a significant decreasing trend in CHD-free survival with increasing albuminuria in men and women (p for trend < 0.001).



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FIGURE 2. Kaplan-Meier survival curves for coronary heart disease (CHD), by category of baseline albuminuria, in the total population and in men and women (n = 22,368), EPIC-Norfolk Study, United Kingdom, 1993–2002. Results of the {chi}2 test for trend in CHD survival were 90.8 (p < 0.001) in the total population, 80.6 (p < 0.001) in men, and 32.3 (p < 0.001) in women. (EPIC, European Prospective Investigation into Cancer and Nutrition.)

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In these data, age-adjusted incidence of CHD increased significantly across categories of baseline albuminuria. Microalbuminuria and proteinuria predicted primary CHD events independently of other established cardiovascular disease risk factors. Both were equally predictive of recurrent events among participants with prevalent baseline CHD, in whom the absolute level of risk was much higher. In this report, we have also described the mortality experience of persons who have had a myocardial infarction. The prognostic significance of microalbuminuria in patients with acute myocardial infarction in unselected general coronary-care patients has previously been observed (27). A dose-response relation between the degree of albuminuria and the CHD hazard ratio was noted.

In the EPIC-Norfolk Study, only single random spot urine collections were made at baseline. Given the considerable day-to-day intraindividual variation in urinary albumin excretion when repeated measurements are made (28), it is possible that there might have been random misclassification in the different albuminuria categories. Collected urine specimens in the EPIC-Norfolk Study were stored at –20°C for 4–8 years before albumin and creatinine were assayed. Some studies have suggested that measurement of albumin concentration in frozen urine samples after long-term storage at –20°C results in underestimation of actual albumin values in comparison with storage at 4°C for up to 1–2 weeks prior to measurement or long-term storage at –70°C, and therefore limits the ability to diagnose borderline cases of microalbuminuria and macroalbuminuria (29). However, a few studies have found no difference (30). These random measurement errors in characterizing urinary albumin in an individual would tend to lead to regression dilution bias and underestimation of the size of the association between microalbuminuria and CHD incidence.

CHD was ascertained using death certification and hospital admission data, and it is possible that we may have missed nonfatal CHD events, including unrecognized (silent or atypical) myocardial infarction occurring in the community and not resulting in hospital admission. However, it is very unlikely that there was any systematic difference in the accession of CHD events occurring in the community with respect to albuminuria status.

The EPIC-Norfolk Study was designed as a prospective study, which required persons who were willing to participate and be followed up over the long term rather than a representative population sample. Nevertheless, comparison of the EPIC-Norfolk population with the population of the Health Survey for England suggests that this cohort was similar to the general population of England in terms of anthropometric measures, blood pressure, and serum lipid levels, though with fewer current smokers than the general population (16).

We did not measure blood glucose in this study, and cases of diabetes were defined according to clinical criteria using multiple sources of ascertainment. It is possible that persons with undiagnosed but biochemically prevalent diabetes would have been misclassified, given that approximately half of those with type 2 diabetes are undiagnosed in the general population (31). Therefore, residual confounding by diabetes is possible.

The prevalence of microalbuminuria was higher among women than among men in EPIC-Norfolk. This may be explained by the fact that urinary creatinine levels are higher in men than in women (32, 33), and therefore the albumin:creatinine ratio may be higher in women than in men with similar urinary albumin concentrations (26, 34). Because of this, it has been suggested that a higher threshold cutoff point (3.5 mg/mmol) be used to define microalbuminuria in women instead of 2.5 mg/mmol (26, 35). If women with normoalbuminuria were misclassified as having microalbuminuria because of the use of a lower cutpoint (2.5 mg/mmol instead of 3.5 mg/mmol), we would expect the hazard ratios for CHD in women to be biased towards the null. In EPIC-Norfolk, sex was not an effect modifier of the association between albuminuria and CHD.

Microalbuminuria is an independent predictor of all-cause mortality and cardiovascular disease endpoints in patients with diabetes (3, 4) and hypertension (5, 6). The possible predictive role of microalbuminuria in the general population, especially with regard to CHD, has not been well examined. Cross-sectional and case-control studies in the general population have found that microalbuminuria is independently associated with prevalent cardiovascular disease (8). Cross-sectional and case-control studies suffer from many potential biases, including biases associated with prevalent disease and their inability to define a temporal relation between an exposure and an outcome, as well as bias in selection of cases and controls. Investigators in prospective studies have observed that microalbuminuria predicts all-cause and cardiovascular disease mortality in the general population or in nondiabetic or elderly persons (7, 912). However, most of these studies either had small sample sizes (7, 9, 11), were conducted among persons with prevalent cardiovascular disease or at high risk of cardiovascular disease (10), or were limited by a high potential for residual confounding from inadequately measured covariates (12). Although the significance of microalbuminuria as a possible predictor of CHD in persons without diabetes has been suggested (1315), there has not been a report from a large general-population cohort study of microalbuminuria and incident CHD. For example, it has recently been suggested that an albumin:creatinine ratio above the 90th percentile of the distribution (>0.65 mg/mmol) predicts CHD in the Danish component of the MONICA Study, a population-based study of nondiabetic persons (13). This observation, which is consistent with the findings of an earlier population-based study of elderly nondiabetic persons in Kuopio, Finland (14), and a nested case-control analysis of postmenopausal women in the DOM Study, the Netherlands (15), underlines the significant role urinary albumin excretion might play in the estimation of CHD risk in the community. However, the use of nonconventional cutpoints for the definition of microalbuminuria in those studies limits the direct application of those findings in clinical settings. Depending on the units used, consensus conferences (26, 36) have defined microalbuminuria as a urinary albumin excretion rate >=20 µg/minute and <200 µg/minute in timed urine collection; a urinary albumin:creatinine ratio >=2.5 mg/mmol and <25 mg/mmol in spot urine collection; a 24-hour urinary albumin excretion rate >=30 mg/24 hours and <300 mg/24 hours; or a urinary albumin concentration >=30 mg/liter and <300 mg/liter. However, some authors have argued that this definition is too diabetes-focused and that cutpoints for nondiabetic persons should be lower, given the extension of cardiovascular disease risk down to high-normal levels of albuminuria (6, 10, 13). Therefore, to our knowledge, the EPIC-Norfolk Study is the first large study to have examined the predictive effect of microalbuminuria on incident CHD in the general population using the standard definition of microalbuminuria and including sex-stratified and subgroup analyses of other risk factors. In our data, the risk of CHD appeared to increase even below levels considered cutpoints for microalbuminuria, as has been observed by others (10).

The prognostic significance of microalbuminuria for early mortality after acute myocardial infarction in clinic-based patients has been demonstrated (27). Investigators in the HOPE Study made a similar observation in the general population (10), and the finding in EPIC-Norfolk that albuminuria is predictive of both recurrent CHD events and total mortality among persons with baseline CHD in the community adds to this. Randomized placebo-controlled trials such as the HOPE Study and the MicroHOPE substudy have shown that treatment of persons with baseline cardiovascular disease or persons at significant absolute risk of cardiovascular disease, based on a constellation of risk factors including microalbuminuria, offers significant primary and secondary prevention against cardiovascular disease (37, 38).

The underlying mechanism of the association between microalbuminuria and cardiovascular disease risk is unclear. A pathophysiologic link between microalbuminuria and atherosclerosis may be mediated through an increased generalized transvascular leakage of albumin. It is hypothesized that the systemic transvascular leakiness may also include lipoproteins, thus allowing for increased lipid penetration into the vessel walls (39). The leakiness might be due to hemodynamic factors or structural or functional perturbations of the endothelium or the intracellular matrix beneath (39).

In subgroup analyses of established cardiovascular disease risk factors, the CHD risk associated with microalbuminuria was highest among persons with established cardiovascular disease risk factors (sex, diabetes, hypertension, smoking, and dyslipidemia) in comparison with those without them, although there were non-statistically-significant interactions. Besides age and sex, the strongest correlates of microalbuminuria in the general population are hypertension, diabetes, and smoking (40). Regardless of whether microalbuminuria is a sensitive indicator of damage resulting from other CHD risk factors, our results suggest that microalbuminuria might be useful for identifying persons at increased risk of CHD who might benefit the most from treatment. However, given the low sensitivity and low positive predictive value of combined microalbuminuria and macroalbuminuria for CHD risk, albuminuria cannot be used in isolation to identify persons at increased risk. Development of new scores for prediction of absolute risk of primary CHD events along the lines of the Framingham Score (41), with the inclusion of microalbuminuria as one of the easily measured risk factors, might have clinical utility. Multiple-risk-factor assessment equations for primary prevention of CHD in the general population have been developed (41, 42), and it has been proposed that microalbuminuria status be included in these absolute risk equations among diabetic persons (43). Recently, in the Steno Diabetes Centre, it was shown that multifactorial intervention, including behavior modification and pharmacologic therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria in patients with diabetes and microalbuminuria, significantly lowered the risk of cardiovascular disease by more than 50 percent (44).

In this British population, the incidence of CHD increased significantly across categories of albuminuria, with microalbuminuria being independently associated with an approximately 40 percent increased risk of CHD in comparison with normoalbuminuria. Therefore, microalbuminuria may be a useful indicator, in addition to conventional risk factors such as smoking, dyslipidemia, hypertension, and diabetes, in identifying persons in the community who are at increased risk of primary CHD and subsequent mortality.


    ACKNOWLEDGMENTS
 
The EPIC-Norfolk Study is supported by program grants from the Cancer Research Campaign and the Medical Research Council, with additional support from the British Heart Foundation, the Stroke Association, the Department of Health, the Food Standard Agency, the Europe Against Cancer Program, the World Health Organization, and the Wellcome Trust.


    NOTES
 
Correspondence to Dr. Nicholas J. Wareham, Department of Public Health and Primary Care, Institute of Public Health, University Forvie Site, Robinson Way, Cambridge CB2 2SR, United Kingdom (e-mail: njw1004{at}medschl.cam.ac.uk). Back


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 RESULTS
 DISCUSSION
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