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In cancer patients, plasma often contains mutant DNA released by cancer cells. We have assessed the significance of plasma DNA mutations for subsequent cancer development in healthy subjects in a large longitudinal prospective study. The European Prospective Investigation into Cancer and Nutrition study was analyzed with a nested case-control design. Cases were nonsmokers or ex-smokers for >10 years and newly diagnosed with lung, bladder, or upper aerodigestive tract cancers or leukemia accrued after a median follow-up of 6.3 years. Controls were matched 2:1 for follow-up, age, sex, area of recruitment, and smoking status. KRAS2 mutations were detected by mutant-enriched PCR and sequencing (n = 1,098). TP53 mutations were detected by denaturing high-performance liquid chromatography, temporal temperature gradient electrophoresis, and sequencing (n = 550). KRAS2 or TP53 mutations were detected in 13 of 1,098 (1.2%) and 20 of 550 (3.6%) subjects, respectively, 16 of whom developed cancer on average after 18.3 months of follow-up. Among 137 subjects who developed bladder cancer, 5 had KRAS2 mutations [odds ratio (OR), 4.25; 95% confidence interval (95% CI), 1.27-14.15] and 7 had TP53 mutations (OR, 1.81; 95% CI, 0.66-4.97). There was a nonsignificant trend for association between TP53 mutations and bulky adducts in lymphocyte DNA (OR, 2.78; 95% CI, 0.64-12.17). This is the first report of TP53 or KRAS2 mutations in the plasma of healthy subjects in a prospective study, suggesting that KRAS2 mutation is detectable ahead of bladder cancer diagnosis. TP53 mutation may be associated with environmental exposures. These observations have implications for monitoring early steps of carcinogenesis. (Cancer Res 2006; 66(13): 6871-6)

Supplementary Table 1 from TP53 and KRAS2 Mutations in Plasma DNA of Healthy Subjects and Subsequent Cancer Occurrence: A Prospective Study

AimsTens of millions of people worldwide use opiates but little is known about their potential role in causing cardiovascular diseases. We aimed to study the association of long-term opiate use with cardiovascular mortality and whether this association is independent of the known risk factors.Methods and resultsIn the population-based Golestan Cohort Study—50 045 Iranian participants, 40–75 years, 58% women—we used Cox regression to estimate hazard ratios and 95% confidence intervals (HRs, 95% CIs) for the association of opiate use (at least once a week for a period of 6 months) with cardiovascular mortality, adjusting for potential confounders—i.e. age, sex, education, wealth, residential place, marital status, ethnicity, and tobacco and alcohol use. To show independent association, the models were further adjusted for hypertension, diabetes, waist and hip circumferences, physical activity, fruit/vegetable intake, aspirin and statin use, and history of cardiovascular diseases and cancers. In total, 8487 participants (72.2% men) were opiate users for a median (IQR) of 10 (4–20) years. During 548 940 person-years—median of 11.3 years, >99% success follow-up—3079 cardiovascular deaths occurred, with substantially higher rates in opiate users than non-users (1005 vs. 478 deaths/100 000 person-years). Opiate use was associated with increased cardiovascular mortality, with adjusted HR (95% CI) of 1.63 (1.49–1.79). Overall 10.9% of cardiovascular deaths were attributable to opiate use. The association was independent of the traditional cardiovascular risk factors.ConclusionLong-term opiate use was associated with an increased cardiovascular mortality independent of the traditional risk factors. Further research, particularly on mechanisms of action, is recommended.

Summary: Background: Evidence is emerging for a role of opiates in various cancers. In this study, we aimed to investigate the association between regular opium use and cancer incidence. Methods: This study was done in a population-based cohort of 50 045 individuals aged 40–75 years from northeast Iran. Data on participant demographics, diet, lifestyle, opium use, and different exposures were collected upon enrolment using validated questionnaires. We used proportional hazards regression models to estimate hazard ratios (HRs) and corresponding 95% CIs for the association between opium use and different cancer types. Findings: During a median 10 years of follow-up, 1833 participants were diagnosed with cancer. Use of opium was associated with an increased risk of developing all cancers combined (HR 1·40, 95% CI 1·24–1·58), gastrointestinal cancers (1·31, 1·11–1·55), and respiratory cancers (2·28, 1·58–3·30) in a dose-dependent manner (ptrend

Previous studies have reported an association between hot tea drinking and risk of esophageal cancer, but no study has examined this association using prospectively and objectively measured tea drinking temperature. We examined the association of tea drinking temperature, measured both objectively and subjectively at study baseline, with future risk of esophageal squamous cell carcinoma (ESCC) in a prospective study. We measured tea drinking temperature using validated methods and collected data on several other tea drinking habits and potential confounders of interest at baseline in the Golestan Cohort Study, a population-based prospective study of 50,045 individuals aged 40-75 years, established in 2004-2008 in northeastern Iran. Study participants were followed-up for a median duration of 10.1 years (505,865 person-years). During 2004-2017, 317 new cases of ESCC were identified. The objectively measured tea temperature (HR 1.41, 95% CI 1.10-1.81; for >= 60 degrees C vs. = 6 min) were all associated with ESCC risk. In analysis of the combined effects of measured temperature and amount, compared to those who drank less than 700 ml of tea/day at = 60 degrees C) was consistently associated with an about 90% increase in ESCC risk. Our results substantially strengthen the existing evidence supporting an association between hot beverage drinking and ESCC.

Background & Aims: Northeast Iran has one of the highest reported rates of esophageal squamous cell carcinoma (ESCC) worldwide. Decades of investigations in this region have identified some local habits and environmental exposures that increase risk. We analyzed data from the Golestan Cohort Study to determine the individual and combined effects of the major environmental risk factors of ESCC. Methods: We performed a population-based cohort of 50,045 individuals, 40 to 75 years old, from urban and rural areas across Northeast Iran. Detailed data on demographics, diet, lifestyle, socioeconomic status, temperature of drinking beverages, and different exposures were collected using validated methods, questionnaires, and physical examinations, from 2004 through 2008. Participants were followed from the date of enrollment to the date of first diagnosis of esophageal cancer, date of death from other causes, or date of last follow-up, through December 31, 2017. Proportional hazards regression models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the association between different exposures and ESCC. Results: During an average 10 years of follow-up, 317 participants developed ESCC. Opium smoking (HR 1.85; 95% CI 1.18–2.90), drinking hot tea (≥60°C) (HR 1.60; 95% CI 1.15–2.22), low intake of fruits (HR 1.48; 95% CI 1.07–2.05) and vegetables (HR 1.62; 95% CI 1.03–2.56), excessive tooth loss (HR 1.66; 95% CI 1.04–2.64), drinking unpiped water (HR 2.04; 95% CI 1.09–3.81), and exposure to indoor air pollution (HR 1.57; 95% CI 1.08–2.29) were significantly associated with increased risk of ESCC, in a dose-dependent manner. Combined exposure to these risk factors was associated with a stepwise increase in the risk of developing ESCC, reaching a more than 7-fold increase in risk in the highest category. Approximately 75% of the ESCC cases in this region can be attributed to a combination of the identified exposures. Conclusions: Analysis of data from the Golestan Cohort Study in Iran identified multiple risk factors for ESCC in this population. Our findings support the hypothesis that the high rates of ESCC are due to a combination of factors, including thermal injury (from hot tea), exposure to polycyclic aromatic hydrocarbons (from opium and indoor air pollution), and nutrient-deficient diets. We also associated ESCC risk with exposure to unpiped water and tooth loss.

Objectives were to investigate prospectively the ability of DNA adducts to predict cancer and to study the determinants of adducts, especially air pollutants. DNA adducts were measured in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) investigation. Cases included newly diagnosed lung cancer (n = 115), upper respiratory cancers (pharynx and larynx; n = 82), bladder cancer (n = 124), leukemia (n = 166), and chronic obstructive pulmonary disease or emphysema deaths (n = 77) accrued after a median follow-up of 7 years among the EPIC former smokers and never-smokers. Three controls per case were matched for questionnaire analyses and two controls per case for laboratory analyses. Matching criteria were gender, age, smoking status, country of recruitment, and follow-up time. Individual exposure to air pollution was assessed using concentration data from monitoring stations in routine air quality monitoring networks. Leukocyte DNA adducts were analyzed blindly using 32P postlabeling technique. Adducts were associated with the subsequent risk of lung cancer, with an odds ratio (OR) of 1.86 [95% confidence interval (95% CI), 0.88-3.93] when comparing detectable versus nondetectable adducts. The association with lung cancer was stronger in never-smokers (OR, 4.04; 95% CI, 1.06-15.42) and among the younger age groups. After exclusion of the cancers occurring in the first 36 months of follow-up, the OR was 4.16 (95% CI, 1.24-13.88). A positive association was found between DNA adducts and ozone (O3) concentration. Our prospective study suggests that leukocyte DNA adducts may predict lung cancer risk of never-smokers. Besides, the association of DNA adduct levels with O3 indicates a possible role for photochemical smog in determining DNA damage.

Background: Current evidence suggests that high red meat intake is associated with increased colorectal cancer risk. High fish intake may be associated with a decreased risk, but the existing evidence is less convincing. Methods: We prospectively followed 478 040 men and women from 10 European countries who were free of cancer at enrollment between 1992 and 1998. Information on diet and lifestyle was collected at baseline. After a mean follow-up of 4.8 years, 1329 incident colorectal cancers were documented. We examined the relationship between intakes of red and processed meat, poultry, and fish and colorectal cancer risk using a proportional hazards model adjusted for age, sex, energy (nonfat and fat sources), height, weight, work-related physical activity, smoking status, dietary fiber and folate, and alcohol consumption, stratified by center. A calibration substudy based on 36 994 subjects was used to correct hazard ratios (HRs) and 95% confidence intervals (CIs) for diet measurement errors. All statistical tests were two-sided. Results: Colorectal cancer risk was positively associated with intake of red and processed meat (highest [>160 g/day] versus lowest [80 g/day versus

CIFXML applies the XML strategies and technologies to create a general interface for processing CIF documents that conform to the CIF syntax and DDL1. Both a DTD and an XML schema for CIFs are presented. CIFs can be read, edited, validated syntactically, sorted, normalized, filtered, stored as an XML document object model, transformed and output.CIFXOMprovides an easy way of converting CIFs to XML andvice versausing Java.

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Methods for assessing diet are prone to measurement error, which may be substantial in large cohort investigations. Biomarkers can be used as objective measures with which to compare estimates of nutritional exposure using different methodsCross sectional comparisons in 12 474 men and women of regression between biomarkers for vitamin C, sodium, potassium, fibre, carbohydrate, fat and phytoestrogens with intakes derived from food diaries and food frequency questionnaires (FFQ), and odds ratios for risk of ischaemic heart disease (IHD) by dietary and plasma vitamin C.There were strong (P0.001) associations between biomarkers and intakes as assessed by food diary. Coefficients were markedly attenuated for data obtained from the FFQ, especially so for vitamin C, potassium and phytoestrogens (Z P0.05). Risk of IHD was associated with plasma vitamin C (P0.001) and intake of vitamin C and fruit and vegetables assessed by food diary (P quintile trends0.001, 0.001) but not by the FFQ (P quintile trends 0.923, 0.186).Nutritional data that reflect the findings from biomarkers reduce measurement error and will thus improve statistical power in studies of gene nutrient interactions in cohort studies.

BACKGROUND: International multicentre studies on diet and cancer are relatively new in epidemiological research. They offer a series of challenging methodological issues for the evaluation of the association between dietary exposure and disease outcomes, which can both be quite heterogeneous across different geographical regions. This requires considerable work to standardize dietary measurements at the food and the nutrient levels. METHODS: Within the European Prospective Investigation into Cancer and Nutrition (EPIC), a calibration study was set up to express individual dietary intakes according to the same reference scale. A linear regression calibration model was used to correct the association between diet and disease for measurement errors in dietary exposures. In the present work, we describe an approach for analysing the EPIC data, using as an example the evaluation of the association between fish intake and colorectal cancer incidence. RESULTS: Sex- and country-specific attenuation factors ranged from 0.083 to 0.784, with values overall higher for men compared with women. Hazard ratio estimates of colorectal cancer for a 10 g/day increase in fish intake were 0.97 [95% confidence interval (CI): 0.95-0.99] and 0.93 (0.88-0.98), before and after calibration, respectively. CONCLUSIONS: In a multicentre study, the diet/disease association can be evaluated by exploiting the whole variability of intake over the entire study. Calibration may reduce between-centre heterogeneity in the diet-disease relationship caused by differential impact of measurement errors across cohorts. Udgivelsesdato: 2008-Apr

Although breast cancer screening has been shown to work in randomised trials, there is a need to evaluate service screening programmes to ensure that they are delivering the benefit indicated by the trials. We carried out a case–control study to investigate the effect of mammography service screening, in the NHS breast screening programme, on breast cancer mortality in the East Anglian region of the UK. Cases were deaths from breast cancer in women diagnosed between the ages of 50 and 70 years, following the instigation of the East Anglia Breast Screening Programme in 1989. The controls were women (two per case) who had not died of breast cancer, from the same area, matched by date of birth to the cases. Each control was known to be alive at the time of death of her matched case. All women were known to the breast screening programme and were invited, at least once, to be screened. There were 284 cases and 568 controls. The odds ratio (OR) for risk of death from breast cancer in women who attended at least one routine screen compared to those who did not attend was 0.35 (CI: 0.24, 0.50). Adjusting for self-selection bias gave an estimate of the breast cancer mortality reduction associated with invitation to screening of 35% (OR=0.65, 95% CI: 0.48, 0.88). The effect of actually being screened was a 48% breast cancer mortality reduction (OR=0.52, 95% CI: 0.32, 0.84). The results suggest that the National Breast Screening Programme in East Anglia is achieving a reduction in breast cancer deaths, which is at least consistent with the results from the randomised controlled trials of mammographic screening.

Rana JS, Boekholdt SM, Ridker PM, Jukema JW, Luben R, Bingham SA, Day NE, Wareham NJ, Kastelein JJP, Khaw K-T. (Academic Medical Center, Amsterdam, The Netherlands; University of Pittsburgh, Pittsburgh, PA, USA; Leiden University Medical Center, The Netherlands; and Institute of Public Health, University of Cambridge, Cambridge, UK). Differential leucocyte count and the risk of future coronary artery disease in healthy men and women: the EPIC-Norfolk Prospective Population Study. J Intern Med 2007; 262: 678–689. Background: We examined the relationship between granulocyte, lymphocyte and monocyte counts and risk of coronary heart disease (CHD) and cardiovascular disease (CVD) in men and women. There is paucity of data on the differential leucocyte count and its relationship with the risk of CHD and CVD. Methods: This prospective study comprised 7073 men and 9035 women who were 45–79 years of age and were residents of Norfolk. United Kingdom. Results: During an average of 8 years of follow-up we identified 857 incident CHD events and 2581 CVD incident events. Increased total leucocyte count was associated with increased risk for both CHD and CVD. The highest quartile of granulocyte count was associated with increased risk when compared to lowest quartile for CHD (men HR 1.70 95% CI: 1.30–2.21; women HR 1.24 95% CI: 0.91–1.69) and for CVD (men HR 1.46 95% CI: 1.24–1.71; women HR 1.20 95% CI: 1.02–1.42). The association remained unchanged when the analyses were restricted to nonsmokers and when risk was assessed for every 1000 cells L−1 increase in cell count. In multivariable models, despite adjusting for C-reactive protein (CRP), the granulocyte count remained an independent predictor of CHD and CVD risk, especially amongst men. Lymphocyte or monocyte counts were not significantly associated with increased risk. In all analyses, additionally adjusting for CRP did not affect the results materially. Conclusions: In conclusion, we found that the higher risk for CHD and CVD associated with increased total leucocyte count seems to be accounted for by the increased granulocyte count.

Since the early 1970’s, Norman Breslow has made enormous contributions to statistical theory and its applications in epidemiology, and he was a founding member and principal statistician of the Wilms Tumor Study Group, which is credited with great improvements in the treatment and understanding of this disease. Applications of the biostatistical methods that Norm developed have been concentrated on two of the most important areas of biomedical science where statistical thinking is fundamental, clinical trials and chronic disease epidemiology. In these two areas, much of the applied statistical work over the past three decades is based on the conceptual framework of which he was a principal architect. Biostatistics is a pluripotential discipline with a multitude of possible careeravenues.Manybiostatisticiansloosentheirtieswiththecoredisciplineto become, for example, epidemiologists, or to manage clinical trial data centers or move into population genetics, to name just some of the options. This Norm never did. Although he became deeply involved in a range of biomedical applications, in particular his extremely productive commitment over the decades to theWilmsTumorStudyGroup,describedinthelaterarticlebyGiulioD’Angio, The U.S. Government’s right to retain a non-exclusive, royalty-free license in and to any copyright is acknowledged.

Recent research has suggested that brain-derived neurotrophic factor (BDNF) may be implicated in the aetiology of mood-related phenotypes. Here we report an investigation of the association between a BDNF coding variant (Val66Met, rs6265) and mood status in a large non-clinical sample of men and women. We genotyped 7389 adult men and women, aged 41-80 years, selected from participants in the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk, United Kingdom). Evidence of past year prevalent, lifetime and recurrent episodic major depressive disorder (MDD) and of past year prevalent and lifetime generalised anxiety disorder (GAD), defined by DSM-IV diagnostic criteria, was assessed through questionnaire together with a five-item version of the Mental Health Inventory (MHI-5). A total of 1214 (16.4%) participants reported lifetime MDD and 355 (4.8%) reported lifetime GAD. In this population based study we found no evidence to support an association between the BDNF gene Val66Met polymorphism and mood status.

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2 > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P

ObjectivesTo investigate the association between fruit and vegetable consumption and self-reported physical and mental functional health measured by an anglicised short-form 36-item questionnaire (UK SF-36).DesignPopulation-based cross-sectional study.SettingGeneral community in Norfolk, UK.SubjectsA total of 16 792 men and women aged 40–79 years recruited from general practice population registers as part of the European Prospective Investigation into Cancer (EPIC)–Norfolk study, who completed food-frequency questionnaires in 1993–1997 and Health and Life Experiences Questionnaires 18 months later, were enrolled in the study.ResultsMean SF-36 physical component summary scores increased significantly with increasing total fruit and vegetable consumption in both men and women (P ConclusionHigher fruit and vegetable consumption is associated with better self-reported physical functional health within a general population. Increasing daily intake by two portions of fruit and vegetables was associated with an 11% higher likelihood of good functional health. Since the current average consumption of fruit and vegetables in the UK is about three portions, the recommended ‘five a day’ strategy may have additional benefit for functional as well as other health outcomes in the population.

Biomarkers of individual susceptibility: field studiesBiomarker: single-nucleotide polymorphisms in COMT, CYP19, ESR1, and SHBG genesEffect studied: cancer riskTissue/biological material/sample size: urine, bloodMethod of analysis: genotypingStudy design: nested case-control studyStudy size: 89 cases and 178 controlsImpact on outcome (including dose-response): Odds ratios for phytoestrogen exposure, as assessed using the four methods, were not significantly associated with prostate cancer risk (P = 0.15-0.94). Men with the CC genotype for the ESRI PvuII polymorphism had significantly higher risk for prostate cancer compared with men with the TT genotype [adjusted odds ratio = 4.65 (1.60-13.49); P = 0.005]. Prospective phytoestrogen exposure was assessed using both biomarkers and estimates of intake in 89 British men recruited into the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition study, men who subsequently developed prostate cancer. Results were compared with those from 178 healthy men matched by age and date of recruitment. Levels of seven phytoestrogens (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) were measured in spot urine and serum samples. Five single-nucleotide polymorphisms in COMT, CYP19, ESR1, and SHBG genes were genotyped. Urinary levels of all phytoestrogens correlated strongly with serum levels. Correlation coefficients ranged from 0.63 (glycitein) to 0.88 (daidzein) (P < 0.001). Urinary and serum levels correlated significantly with isoflavone intake assessed from food diaries (R = 0.15-0.20; P < 0.05) but not with that from a food-frequency questionnaire. Odds ratios for phytoestrogen exposure, as assessed using the four methods, were not significantly associated with prostate cancer risk (P = 0.15-0.94). Men with the CC genotype for the ESRI PvuII polymorphism had significantly higher risk for prostate cancer compared with men with the TT genotype [adjusted odds ratio = 4.65 (1.60-13.49); P = 0.005]. Our results utilizing a combined prospective exposure provide no evidence that phytoestrogens alter prostate cancer risk in British men, whereas the C allele for the PvuII polymorphism may be associated with increased risk.

In cancer patients, plasma often contains mutant DNA released by cancer cells. We have assessed the significance of plasma DNA mutations for subsequent cancer development in healthy subjects in a large longitudinal prospective study. The European Prospective Investigation into Cancer and Nutrition study was analyzed with a nested case-control design. Cases were nonsmokers or ex-smokers for >10 years and newly diagnosed with lung, bladder, or upper aerodigestive tract cancers or leukemia accrued after a median follow-up of 6.3 years. Controls were matched 2:1 for follow-up, age, sex, area of recruitment, and smoking status. KRAS2 mutations were detected by mutant-enriched PCR and sequencing (n = 1,098). TP53 mutations were detected by denaturing high-performance liquid chromatography, temporal temperature gradient electrophoresis, and sequencing (n = 550). KRAS2 or TP53 mutations were detected in 13 of 1,098 (1.2%) and 20 of 550 (3.6%) subjects, respectively, 16 of whom developed cancer on average after 18.3 months of follow-up. Among 137 subjects who developed bladder cancer, 5 had KRAS2 mutations [odds ratio (OR), 4.25; 95% confidence interval (95% CI), 1.27-14.15] and 7 had TP53 mutations (OR, 1.81; 95% CI, 0.66-4.97). There was a nonsignificant trend for association between TP53 mutations and bulky adducts in lymphocyte DNA (OR, 2.78; 95% CI, 0.64-12.17). This is the first report of TP53 or KRAS2 mutations in the plasma of healthy subjects in a prospective study, suggesting that KRAS2 mutation is detectable ahead of bladder cancer diagnosis. TP53 mutation may be associated with environmental exposures. These observations have implications for monitoring early steps of carcinogenesis. (Cancer Res 2006; 66(13): 6871-6)

Purpose To explore the relationship between self-reported physical functional health and mortality. Methods A cohort of 17,777 men and women aged 41–80 years who completed the anglicised 36-item short-form questionnaire (UK SF-36) in 1996–2000 were followed prospectively until 2004, average 6.5 years, for mortality from all causes, from cardiovascular disease, from cancer, and from all other causes. Results During 115,527 person-years of follow-up, 1065 deaths occurred. After adjusting for age, body mass index, systolic blood pressure, cholesterol, smoking, diabetes, and social class, the relative risks (RR) for all cause mortality were 2.15 (95% CI: 1.54, 2.99) and 2.42 (1.57, 3.74), cardiovascular mortality were RR = 2.71 (1.47, 4.98) and 3.09 (1.30, 7.33), and death from other causes excluding cancer RR = 2.88 (1.43, 5.79) and 5.22 (1.21, 22.53) in men and women respectively for those who were in the lowest compared to top quintile of SF-36 scores. These associations remained unchanged after exclusion of deaths during the first two years of follow-up and were also consistent in different age groups. Conclusions Poor self-reported physical functional health in men and women without known instances of prevalent cardiovascular disease or cancer predicts total and cardiovascular disease mortality in the general population independently of known risk factors.

The health benefits of physical activity are well established, but the overall amount of physical activity associated with cardiovascular and other health outcomes, and whether the relationships are similar in men and women and at different ages is still debated. This may be partly related to different methods for assessing physical activity. Most studies have focused on leisure time physical activity.We examined the prospective relationship between usual physical activity, taking into account both leisure and work activity, using a simple, pragmatic, four-point rating scale validated against heart rate monitoring, and cardiovascular disease incidence and total mortality after an average 8 years follow-up in 22,191 community living men and women aged 45-79 years with no known cardiovascular disease or cancer at baseline.The relative risks (95% confidence interval) for all-cause mortality (1,553 deaths) for men and women who were moderately inactive, moderately active, and active compared with those who were inactive were 0.83 (0.73-0.95), 0.68 (0.58-0.80), and 0.68 (0.57-0.81), respectively, after adjusting for age, sex, systolic blood pressure, blood cholesterol, cigarette smoking, alcohol intake, diabetes, body mass index, and social class. The relationships were also consistent for cardiovascular disease incidence (3,079 events), in subgroups stratified by age, sex, body mass index, smoking status and social class, and after excluding deaths in the first 2 years. The combined scale was more consistently associated with mortality than the individual work and leisure time components separately.When both work and leisure time physical activity patterns are taken into account, using a simple, pragmatic, validated questionnaire feasible for use in clinical and public health practice, even very moderate levels of usual physical activity are associated with significantly reduced risk of mortality and cardiovascular disease in men and women in the general population and potential population attributable impact of 14% for inactive compared with active levels. These findings may encourage efforts to increase physical activity levels not only in leisure time but also in usual daily working life.

Background— Lipoprotein lipase (LPL) is associated with coronary artery disease (CAD) risk, but prospective population data are lacking. This is mainly because of the need for cumbersome heparin injections, which are necessary for LPL measurements. Recent retrospective studies, however, indicate that LPL concentration can be reliably measured in serum that enabled evaluation of the prospective association between LPL and future CAD. Methods and Results— LPL concentration was determined in serum samples of men and women in the EPIC-Norfolk population cohort who developed fatal or nonfatal CAD during 7 years of follow-up. For each case (n=1006), 2 controls, matched for age, sex, and enrollment time, were identified. Serum LPL concentration was lower in cases compared with controls (median and interquartile range: 61 [43–85] versus 66 [46–92] ng/mL; P P P =0.02). As expected from LPL biology, additional adjustments for either high-density lipoprotein cholesterol (HDL-C) or triglyceride (TG) levels rendered loss of statistical significance. Of interest, serum LPL concentration was positively linear correlated with HDL and LDL size. Conclusions— Reduced levels of serum LPL are associated with an increased risk for future CAD. The data suggest that high LPL concentrations may be atheroprotective through decreasing TG levels and increasing HDL-C levels.

Background. While the relationship between risk factors and stroke is well established, there is less information about the risk factors and survival after stroke. We examined the independent association between cardiovascular and modifiable lifestyle risk factors and subsequent mortality in people with stroke. Methods. 308 free-living men and women with stroke at baseline survey in 1993–1997 participating in the European Prospective Investigation into Cancer (EPIC)-Norfolk were followed up for long-term mortality (average follow-up 7.5 years). Using Cox's proportional hazards model, we assessed the relationships between an individual's age, sex, cardiovascular risk profile including systolic blood pressure, body mass index, cholesterol, history of diabetes and lifestyle behaviors smoking and alcohol consumption and subsequent mortality up to July 2004. Results. There were a total of 100 deaths during follow-up (total person years = 2318). Advancing age (RR 1.72, 95%CI: 1.42, 2.09) and current smoking (RR 2.27, 95%CI: 1.12, 4.57) predicted higher risk while female sex was associated with reduced risk (RR 0.51, 95%CI; 0.31, 0.84) of subsequent mortality after stroke independently of other risk factors investigated. Conclusions. Our findings may provide further empirical encouragement for smoking cessation after stroke.

INTRODUCTION: Measurement of C-reactive protein (CRP) levels has been proposed as a useful marker to improve the prediction of future coronary artery disease (CAD) risk, but this notion has been challenged recently. METHODS AND RESULTS: We performed a prospective case-control study among apparently healthy men and women. The odds ratio (OR) for future CAD incidence was 2.49 (95% CI=2.02-3.08, p for linearity

Most studies to date support a protective role of physical activity in reducing stroke risk. However, they were not able to take into account combined work and leisure activity. We prospectively followed up 22,602 men and women aged 40–79 years, who had no history of stroke and myocardial infarction at baseline, participating in the European Prospective Investigation into Cancer-Norfolk. Participants were categorized into four levels of physical activity based on a validated self-reported questionnaire, which assesses combined work and leisure activities, at baseline during the period from 1993 to 1997. Stroke incidence was ascertained by death certificate and hospital record linkage data up to 2004, average 8.6 years of follow-up. We used the Cox proportional hazards model. There were 361 incident strokes during follow-up (total person years = 195,092). After adjusting for age, sex, systolic blood pressure, body mass index, cholesterol, history of diabetes and smoking, men and women who were physically active were less likely to have a stroke (relative risk = 0.70, 95% CI: 0.49–0.99, p = 0.024) compared to those who were inactive. This highlights the fact that efforts to increase physical activity in both the work place and in leisure time should be encouraged.

Background: Antioxidants, such as ascorbic acid, play a role in scavenging free radicals to protect against oxidative endothelial damage. Excess fat may promote fatty acid oxidation and increase free radical concentrations, which could result in increased antioxidant use. Whether plasma ascorbic acid concentrations are associated with fat distribution remains unclear. Objective: Our aim was to examine the association between abdominal obesity, as measured by the waist-to-hip ratio, and plasma ascorbic acid concentrations in the general population. Design: We examined the cross-sectional relation between anthropometric measurements of fat distribution and plasma ascorbic acid concentrations in 19 068 men and women aged 45-79 y without known chronic illness. Dietary ascorbic acid intake was estimated for a subgroup of 8178 men and women who kept 7-d food diaries coded for nutrient intake. Results: The waist-to-hip ratio was inversely related to plasma ascorbic acid concentrations in both men and women. This association was independent of body mass index, age, vitamin supplement use, cigarette smoking, and socioeconomic group. Waist and hip circumferences showed separate and opposite associations with plasma ascorbic acid concentrations, independent of body mass index and other covariates. Dietary ascorbic acid intake only partly explained the observed associations. Conclusions: Plasma ascorbic acid was associated with fat distribution independent of body mass index. Differences in dietary intake and lifestyle habits, underlying systemic oxidative stress, or both may explain the inverse relation between fat distribution and plasma ascorbic acid concentrations. Additional studies are needed to determine the underlying explanation of these observations.

Phytoestrogens have been hypothesized to protect against prostate cancer via modulation of circulating androgen concentrations. We conducted a cross-sectional study of 267 men in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with 2 aims: first, to investigate the association between phytoestrogen exposure (measured from diet, urine, and serum) and plasma concentrations of sex hormone-binding globulin (SHBG), androstanediol glucuronide, testosterone and Free Androgen Index (FAI); and second, whether the association may be modified by polymorphisms in CYP19 and SHBG genes. Dietary daidzein and genistein intakes were obtained from food diaries and computed using an in-house food composition database. Urinary and serum concentrations of 3 isoflavones (daidzein, genistein, glycitein), 2 daidzein metabolites O-desmethylangolensin (O-DMA) and 2 lignan metabolites (enterodiol and enterolactone) were measured using mass spectrometry. There was no association between dietary, urinary, and serum phytoestrogens and plasma SHBG concentrations. Enterolactone was positively associated with plasma androstanediol glucuronide concentrations (urinary enterolactone: r = 0.127, P = 0.043; serum enterolactone: r = 0.172, P = 0.006) and FAI (urinary enterolactone: r = 0.115, P = 0.067; serum enterolactone: r = 0.158, P = 0.011). Both urinary and serum equol were associated with plasma testosterone (urinary equol: r = 0.332, P = 0.013; serum equol: r = 0.318, P = 0.018) and FAI (urinary equol: r = 0.297, P = 0.027; serum equol: r = 0.380, P = 0.004) among men with the TT genotype but not the CC or CT genotypes (r = -0.029 to -0.134, P = 0.091-0.717) for the CYP19 3'untranslated region (UTR) T-C polymorphism. Urinary and serum enterolactone showed similar genotype-dependent associations with testosterone but not with FAI. In this first study on phytoestrogen-gene associations in men, we conclude that enterolactone and equol are positively associated with plasma androgen concentrations, and interactions with CYP19 gene may be involved.

A substantial proportion of the familial risk of breast cancer may be due to genetic variants, each contributing a small effect. The protein encoded by ERCC2 is a key enzyme involved in nucleotide excision repair, in which gene defects could lead to cancer prone syndromes such as Xeroderma pigmentosum D. We have examined the association between single nucleotide polymorphisms in the ERCC2 gene and the incidence of invasive breast cancer in three case-control series, with a maximum of 3,634 patients and of 3,340 controls. None of the three single nucleotide polymorphisms were significantly associated with the incidence of breast cancer.

Measurement error can have an important impact on the estimation of the true relation between diet and disease. The authors examined the performance of models regressing plasma vitamin C level on fruit and vegetable consumption and the effect of categorization of fruit and vegetable consumption on the association with plasma vitamin C. They used diet information reported by 4,487 participants in the Norfolk, United Kingdom, portion of the European Prospective Investigation into Cancer and Nutrition by means of a 7-day diet diary and a food frequency questionnaire (FFQ) (1993–1998). The authors found substantial differences in mean fruit and vegetable consumption assessed by the two diet instruments. Consumption estimated with the FFQ was about twice as high as that obtained with the 7-day diary, and the ranking of individuals according to estimates of fruit and vegetable consumption from the 7-day diary and the FFQ differed substantially. When fruit and vegetable consumption were categorized into quintiles, the two questionnaires produced similar associations of relative intake with plasma vitamin C, but estimation of the association of absolute intake with plasma vitamin C differed.

Background Recent literature reviews have questioned hostility as a risk factor for heart disease. However, controversy persists due to the rarity of large-scale prospective cohort studies of initially healthy populations. Methods We prospectively investigated the association between hostility and cardiovascular (and all-cause) mortality among 20,550 men and women, 41–80 years of age, participating in the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk), United Kingdom study. Participants were recruited by post from general practice age–sex registers and subsequently attended health checks that included the assessment of coronary disease risk factors. Hostility assessment was completed by postal questionnaire. Results During mean follow-up of 6 years, 1284 deaths were recorded including 481 from cardiovascular disease (CVD). Hostility was not associated with CVD mortality, after adjustment for age and prevalent disease, in either men (rate ratio for a 1 SD decrease in hostility score, representing increased hostility, 1.09; 95% confidence interval 0.98–1.22) or in women (rate ratio 1.00; 95% confidence interval 0.86–1.26). Subgroup analysis suggested hostility may be associated with CVD mortality (independent of age, prevalent disease and cigarette smoking) for participants reporting very high hostility and for those aged less than 60 years. Conclusions Hostility was not associated with an increased risk of cardiovascular mortality in this population study of older adults.

Plasma fibrinogen may be an independent risk factor for cardiovascular disease. Cigarette smoking is a well-recognized determinant of plasma fibrinogen however it remains unclear how fibrinogen levels relate to the degree and duration of smoking, or to time since smoking cessation.In a population-based study of 11 059 men and women aged 45-74 years, we examined the cross-sectional relationship between plasma fibrinogen and cigarette smoking habit.Mean fibrinogen concentrations were higher in current smokers compared to non-current smokers (men: 3.13+/-0.77 versus 2.80+/-0.71 g/l, P0.0001; women: 3.03+/-0.72 versus 2.95+/-0.71 g/l, P=0.01), independent of age, body mass index and hormone replacement therapy in women In men, fibrinogen concentrations declined with years since stopping smoking but remained higher than in life-long non-smokers for 15 years. No relationship between fibrinogen and duration of smoking cessation was observed in women. On multivariate analysis, age, body mass index, use of hormone-replacement therapy, smoking status and pack-years of smoking were independent predictors of plasma fibrinogen.Plasma fibrinogen is strongly associated with cigarette smoking with a dose-response relationship with total pack-years of smoking. In men who stop smoking plasma fibrinogen may remain elevated for several years after cessation.

INTRODUCTION: About two-thirds of the excess familial risk associated with breast cancer is still unaccounted for and may be explained by multiple weakly predisposing alleles. A gene thought to be involved in low-level predisposition to the disease is ERBB2 (HER2). This gene is involved in cell division, differentiation, and apoptosis and is frequently amplified in breast tumours. Its amplification correlates with poor prognosis. Moreover, the coding polymorphism I655V has previously been associated with an increased risk of breast cancer. METHODS: We aimed to determine if common polymorphisms (frequency >or= 5%) in ERBB2 were associated with breast cancer risk in a white British population. Five single-nucleotide polymorphisms (SNPs) were selected for study: SNP 1 near the promoter, SNP 2 in intron 1, SNP 3 in intron 4, SNP 4 in exon 17 (I655V), and SNP 5 in exon 27 (A1170P). We tested their association with breast cancer in a large case-control study (n = 2192 cases and 2257 controls). RESULTS: There were no differences in genotype frequencies between cases and controls for any of the SNPs examined. To investigate the possibility that a common polymorphism not included in our study might be involved in breast cancer predisposition, we also constructed multilocus haplotypes. Our set of SNPs generated all existing (n = 6) common haplotypes and no differences were seen in haplotype frequencies between cases and controls (P = 0.44). CONCLUSIONS: In our population, common ERBB2 polymorphisms are not involved in predisposition to breast cancer.

Martin Claridge1, Simon Hobbs1, Clive Quick2, Nick Day3, Andrew Bradbury1, Teun Wilmink11Department of Vascular Surgery, University of Birmingham, Birmingham Heartlands Hospital Birmingham, UK; 2Department of Surgery, Hinchingbrooke Hospital, Huntingdon, UK; 3Department of Epidemiology and Biostatistics, University of Cambridge, Cambridge, UKObjectives: Nonsteroidal antiinflammatory drugs (NSAIDS) have been shown to retard aneurysm growth in animal models. In vitro studies have shown an inhibitory effect of NSAIDS on matrix metalloproteinase-9, interleukin-1β, and IL-6 mediated arterial wall elastolysis. The aim of this study was to investigate the effects of NSAIDs on arterial stiffness, a surrogate marker of elastolysis.Methods: 447 subjects enrolled in a community-based abdominal aortic aneurysm (AAA) screening program were assessed for age, blood pressure, smoking status, and drug history. Aortic diameter and stiffness were measured by M-Mode ultrasound. The concentration of the amino-terminal propeptide of type III procollagen was used as a proxy measurement of type III collagen turnover.Results: NSAID ingestion was significantly (p = 0.006) associated with increased aortic wall stiffness after adjusting for age, aortic diameter, blood pressure, and smoking status. No such effect was seen for β-blockers, calcium channel antagonists, nitrates, angiotensin-converting enzyme inhibitors, diuretics, or antiplatelet agents.Discussion: These novel data show that NSAIDS are associated with increased aortic stiffness, possibly through the effects of cytokine mediated elastolysis. This in turn may prevent aortic expansion and the development of AAA.Keywords: nonsteroidal antiinflammatory drugs, abdominal aortic aneurysm, aortic stiffness, elastolysis

Objectives— To study the prospective relationship between serum levels of type II secretory phospholipase A2 (sPLA2) and the risk of future coronary artery disease (CAD) in apparently healthy men and women. Methods and Results— We conducted a prospective nested case-control study among apparently healthy men and women aged 45 to 79 years. Cases (n=1105) were people in whom fatal or nonfatal CAD developed during follow-up. Controls (n=2209) were matched by age, sex, and enrollment time. sPLA2 levels were significantly higher in cases than controls (9.5 ng/mL; interquartile range [IQR], 6.4 to 14.8 versus 8.3 ng/mL; IQR, 5.8 to 12.6; P P =0.02) for people in the highest sPLA2 quartile, compared with those in the lowest ( P for linearity=0.03). Conclusion— Elevated levels of sPLA2 were associated with an increased risk of future CAD in apparently healthy individuals. The magnitude of the association was similar to that observed between CRP and CAD risk, and both associations were independent.

Methods Volunteer sub-study of 97 men and women (mean ages 54 and 51 years respectively) within the European Investigation into Cancer (EPIC) study in Norfolk (UK). Dietary assessment of energy intake and physical activity was by self-report and weight was measured using standard techniques. Energy expenditure was assessed objectively by recording heart rate for 4 days following a calibration of the relationship between heart rate and oxygen consumption. Results Self-reported energy intake by 7-day diary (mean 8.5 MJ/day) and food frequency questionnaire (FFQ) (mean 8.8 MJ/day) were significantly lower than objectively measured total energy expenditure (mean 11.2 MJ/day). The deattenuated partial correlations between total energy expenditure were 0.33 (7-day diary), 0.34 (FFQ), 0.50 (physical activity), and 0.56 (weight). Weight accounted for 31% (deattenuated) of the sum of squares about the mean of true energy intake after adjusting for age and sex. With the addition of self-reported physical activity, the model was significantly improved (R 2 = 0.57). Adding energy either assessed by the diary or FFQ did not improve the model. Conclusions The results presented here indicate that to adjust for energy intake, for the

Background In nutritional epidemiology, it is common to fit models in which several dietary variables are included. However, with standard instruments for dietary assessment, not only are the intakes of many nutrients often highly correlated, but the errors in the estimation of the intake of different nutrients are also correlated. The effect of this error correlation on the results of observational studies has been little investigated. This paper describes the effect on multivariate regression coefficients of different levels of correlation, both between the variables themselves and between the errors of estimation of these variables. Methods Using a simple model for the multivariate error structure, we examine the effect on the estimates of bivariate linear regression coefficients of (1) differential precision of measurement of the two independent variables, (2) differing levels of correlation between the true values of the two variables, and (3) differing levels of correlation between the errors of measurement of the two variables. As an example, the prediction of plasma vitamin C levels by dietary intake variables is considered, using data from the European Prospective Investigation of Cancer (EPIC) Norfolk study in which dietary intake was estimated using both a food frequency questionnaire (FFQ) and a 7-day diary (7DD). The dietary variables considered are vitamin C, fat, and energy, with different approaches taken to energy adjustment. Results When the error correlation is zero, the estimates of the bivariate regression coefficients reflect the precision of measurement of the two variables and mutual confounding. The sum of the observed regression coefficients is biased towards the null as in univariate regression. When the error correlation is non-zero but below about 0.7, the effect is minor. However, as the error correlation increases beyond 0.8 the effect becomes large and highly dependent on the relative precision with which the two variables are measured. At the extreme, the bivariate estimates can become indefinitely large. In the example, the error correlation between fat and energy using the FFQ appears to be over 0.9, the corresponding value for the 7DD being approximately 0.85. The error correlation between vitamin C and fat, and vitamin C and energy, appears to be below 0.5 and smaller for the 7DD than for the FFQ. The impact of these error correlations on bivariate regression coefficients is large. The effect of energy adjustment differs widely between vitamin C and fat. Conclusion High levels of error correlation can have a large effect on bivariate regression estimates, varying widely depending on which two variables are considered. In particular, the effect of energy adjustment will vary widely. For vitamin C, the effect of energy adjustment appears negligible, whereas for fat the effect is large indicating that error correlation close to one can partially remove regression dilution due to measurement error. If, for fat intake, energy adjustment is performed by using energy density, the partial removal of regression dilution is achieved at the expense of substantial reduction in the true variance.

Background: Abundant evidence indicates that a high sodium intake is causally related to high blood pressure, but debate over recommendations to reduce dietary sodium in the general population continues. A key issue is whether differences in usual sodium intake within the range feasible in free-living populations have clinical or public health relevance. Objective: We examined the relation between blood pressure and urinary sodium as a marker of dietary intake. Design: This was a study of 23 104 community-living adults aged 45-79 y. Results: Mean systolic and diastolic blood pressure increased as the ratio of urinary sodium to creatinine increased (as estimated from a casual urine sample), with differences of 7.2 mm Hg for systolic blood pressure and 3.0 mm Hg for diastolic blood pressure (P < 0.0001) between the top and bottom quintiles. This trend was independent of age, body mass index, urinary potassium:creatinine, and smoking and was consistent by sex and history of hypertension. The prevalence of those with systolic blood pressure ≥ 160 mm Hg halved from 12% in the top quintile to 6% in the bottom quintile; the odds ratio for having systolic blood pressure ≥ 160 mm Hg was 2.48 (95% CI: 1.90, 3.22) for men and 2.67 (95% CI: 2.08, 3.43) for women in the top compared with the bottom quintile of urinary sodium. Estimated mean sodium intakes in the lowest and highest quintiles were 80 and 220 mmol/d, respectively. Conclusions: Within the usual range found in a free-living population, differences in urinary sodium, an indicator of dietary sodium intake, are associated with blood pressure differences of clinical and public health relevance. Our findings reinforce recommendations to lower average sodium intakes in the general population.

Vegetarian diets have been suggested to be beneficial for bone health due to increased consumption of plant foods, including soya, or reduced consumption of meat. However, meat may also be beneficial for bone health. The evidence relating diet to bone health is based largely on studies of women, often in those at high risk of osteoporosis. Few studies have investigated dietary inter-relationships in men as well as women from general populations. We examined broadband ultrasound attenuation (BUA) of the calcaneum, using a CUBA clinical instrument, in 6,369 men and 5,379 postmenopausal women. The population was divided into four groups according to vegetarian status and frequency of soya consumption, which was defined by response to a food frequency questionnaire that estimates frequency of consumption of food types over the year prior to completion. Regular soya consumers were defined as those who ate soya products with a frequency of between once a day and once a week. Calcaneum BUA in vegetarian men was significantly lower than omnivores by approximately 6% (5 dB/MHz) and was 15% (13.6 dB/MHz) lower in those who were also regular soya consumers. This difference remained after adjustment for age, height, weight, smoking habit, physical activity, selected foods and nutrients and exclusion of those with a prior history of osteoporosis, fractures or cancer. Calcaneum BUA in omnivorous men with regular soya consumption was not lower than the remaining population. In women, there were no significant differences by usual dietary pattern. This surprising finding indicates that regular soya intake is not associated with better bone indices in vegetarian men. The difference in BUA was not explained by the known common covariates; however, it is possible that other aspects of lifestyle associated with these eating behaviors might explain this observation. Plausible mechanisms exist for our findings; soya contains phytoestrogens, likened to naturally occurring estrogens, and meat has been shown to influence levels of IGF-1 and sex hormone binding globulin, which may be related to bone health. Our findings emphasize the need for further research and investigation into dietary inter-relationships and bone health and the effects of vegetarian status, including consumption of soya-based foods, in men as well as women.

To assess whether starting to smoke in childhood increases the risk of obstructive airways disease (OAD) in adult life.A retrospective cohort analysis was undertaken of 12 504 current and ex-smokers in the EPIC-Norfolk cohort. The main exposure was starting to smoke during childhood (age16 years). Three definitions of OAD were used: doctor diagnosed asthma, doctor diagnosed bronchitis/emphysema, and "any OAD" (doctor diagnosed asthma or bronchitis/emphysema, or taking medication used in the treatment of OAD).Childhood smokers had significantly more pack years of exposure and poorer lung function than subjects who started to smoke in adulthood (/=16 years). Compared with starting in adulthood, starting to smoke in childhood was associated with a greater risk of bronchitis/emphysema in female smokers (OR 1.79, 95% CI 1.25 to 2.56) and ex-smokers of both sexes (OR 1.29, 95% CI 1.07 to 1.55 in men and OR 1.40, 95% CI 1.05 to 1.85 in women), and of "any OAD" in female smokers (OR 1.72, 95% CI 1.24 to 2.38) and male and female ex-smokers (OR 1.20, 95% CI 1.03 to 1.40 in men and 1.34, 95% CI 1.07 to 1.57 in women). After adjustment for pack years, childhood smoking was associated with poorer lung function (FEV(1) 92.3% predicted in adult smokers and 89.5% in childhood smokers, p = 0.03) and a greater risk of bronchitis/emphysema (adjusted OR 1.55, 95% CI 1.08 to 2.24) and for "any OAD" (OR 1.54, 95% CI 1.10 to 2.13) in female smokers but not in male and female ex-smokers.Starting to smoke in childhood is associated with an increased risk of airways disease because of the extra pack years smoked. In women, childhood smoking is itself an independent risk factor for the development of airways disease.

Data suggest that soy protein, a source of isoflavones, may have favorable effects on cardiovascular risk factors. Women (n = 205), ages 49-65 y, were randomized into this double blind, placebo-controlled trial of 43.5 mg red clover-derived isoflavones/d. A total of 177 women completed the trial. There were no differences between treatments for changes from baseline to 12 mo in total cholesterol, LDL cholesterol, triglycerides, HDL cholesterol, systolic and diastolic blood pressures, fibrinogen, and plasminogen activator inhibitor type 1 (PAI-1) (P >/= 0.1). Interactions between treatment and menopausal status were significant for changes in triglycerides and PAI-1 (P = 0.02 and P = 0.01), and changes were significant among perimenopausal women. In the isoflavone and placebo groups, changes in triglycerides were -0.2 +/- 0.6 and 0.4 +/- 0.6 mmol/L, P = 0.02, and changes in PAI-1 were -3.06 +/- 5.88 and 4.95 +/- 6.25 IU/L, P = 0.004, respectively. Interactions between apolipoprotein E (apoE) genotype and treatment tended to be significant for changes in total and LDL cholesterol (P = 0.06 and P = 0.05), and differences between treatments were significant in E2/E3 women. In the isoflavone and placebo groups, changes in total cholesterol were -0.61 +/- 0.79 and 0.18 +/- 0.79 mmol/L, P = 0.03, and changes in LDL cholesterol were -0.84 +/- 0.79 and -0.04 +/- 0.69 mmol/L, P = 0.02, respectively. Although there were potentially beneficial changes in triglycerides and PAI-1 among perimenopausal women consuming isoflavones, this study suggests that isoflavones alone are not responsible for the well-documented effects of soy protein on blood lipids. A larger study is required to confirm the effect modification by apoE genotype.

Self-reported diet is prone to measurement error. Analytical models of diet may include several foods or nutrients to avoid confounding. Such multivariate models of diet may be affected by errors correlated among the dietary covariates, which may introduce bias of unpredictable direction and magnitude. The authors used 1993-1998 data from the European Prospective Investigation into Cancer and Nutrition in Norfolk, United Kingdom, to explore univariate and multivariate regression models relating nutrient intake estimated from a 7-day diet record or a food frequency questionnaire to plasma levels of vitamin C. The purpose was to provide an empirical examination of the effect of two different multivariate error structures in the assessment of dietary intake on multivariate regression models, in a situation where the underlying relation between the independent and dependent variables is approximately known. Emphasis was put on the control for confounding and the effect of different methods of controlling for estimated energy intake. The results for standard multivariate regression models were consistent with considerable correlated error, introducing spurious associations between some nutrients and the dependent variable and leading to instability of the parameter estimates if energy was included in the model. Energy adjustment using regression residuals or energy density models led to improved parameter stability.

Microalbuminuria is independently associated with increased cardiovascular risk and renal function deterioration in diabetes and hypertension, but the clinical relevance of raised albuminuria in the general population is less certain. We examined the prevalence of microalbuminuria and its relationship to cardiovascular risk factors and cardiovascular morbidity in the UK general population.Cross-sectional population-based study of 23,964 individuals, aged 40-79 years recruited in 1993-1997 for the EPIC-Norfolk Study. Smoking status, prevalent physician diagnosed diabetes, hypertension, cardiovascular disease and cancer were derived from a health and lifestyle questionnaire. Albumin-to-creatinine ratios were estimated from random spot urine specimens collected at the survey visit, and using these ratios participants were categorized into normoalbuminuria, microalbuminuria (2.5-25 mg/mmol), and macroalbuminuria.The prevalence of microalbuminuria and macroalbuminuria was 11.8% and 0.9% respectively in the total population and significantly higher in women (14.4%) compared with men (8.9%) (P0.001). Independent determinants of microalbuminuria were age, sex, systolic blood pressure and current smoking. Microalbuminuria was independently associated with cardiovascular morbidity, after adjusting for known cardiovascular risk factors, with odds ratio (95% confidence interval) for prevalent cardiovascular disease of 1.30 (1.12-1.51) in all men and women.Microalbuminuria was present in approximately 12% of this population. It was independently associated with cardiovascular risk factors and prevalent cardiovascular disease. Microalbuminuria may be a useful indicator of high absolute cardiovascular risk in the community but prospective data are needed to establish its independent predictive value for future events.

Objectives:To assess whether the amount of fruits and vegetables consumed depends on the serving size or on how often fruits and vegetables are eaten.Design:Estimation of the weight of serving sizes and the number of fruits and vegetables eaten daily, using a validated food diary method.Setting:Free-living men and women participating in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC).Subjects:Two hundred and sixty-nine men and women sampled from EPIC–Norfolk to participate in a study of simple methods of assessing fruit and vegetable intakes.Results:The average portion of all fruits and vegetables measured was 87 g, close to the standard portion size of 80 g used as the basis of ‘5-a-day’ recommendations. There was a wide variation; the average portion size for baked beans was 147 g while for lettuce it was 26 g. The 20th and 80th percentiles also showed a large range, e.g. 39–72 g for carrots and 60–150 g for strawberries. Women ate more fruit than did men but fewer vegetables, so the total amount of fruit and vegetables eaten by men and women was the same. High consumers of fruits and vegetables (≥400 g day-1) ate them ~5 times a day whilst low consumers (-1) ate them less often (~3 servings per day,PConclusions:Frequency of intake is more important than portion size when distinguishing between high and low consumption of fruits and vegetables. Therefore, to increase intakes, low consumers should eat fruits and vegetables more often. This endorses the ‘5-a-day’ healthy eating message.

Objective: To investigate the independent association between three different measures of socioeconomic status and plasma ascorbic acid level. Design: Cross-sectional population based study. Setting and participants: 20 292 men and women aged 39–79 y who participated in the EPIC-Norfolk study. Results: Individuals in manual social classes, who had no educational qualifications or those who lived in the most deprived areas had significantly lower levels of plasma ascorbic acid compared to those in nonmanual social classes, with at least O-level qualifications or who lived in less deprived areas. The magnitude of effect for each measure of socioeconomic status was greater in current smokers compared to current nonsmokers. Conclusion: Education and social class were stronger predictors of differences in ascorbic acid levels, an indicator of dietary health behaviour, than a deprivation index based on the Townsend score. This suggests that education could be particularly important in influencing large socioeconomic differentials in health related behaviours and potentially, health outcomes in the UK.

The design of studies aimed at identifying the interaction between genetic and environmental determinants in disease risk is attracting increased attention. In this paper, we study the effect of errors on measuring exposures and the effect of assessing genotype at one locus on the association of a continuous outcome measure with continuous exposures and genotype. The estimation of misclassification errors in assessing genotypes from a separate study is proposed. If the exposure measurement error is substantial, then even relatively small errors in genotyping within limits that are often quoted can have an appreciable effect on interaction estimates. We, thus, consider a method for correcting the measurement errors when the interaction between the exposures and the genetic factor is significant. Finally, we present an epidemiological example to demonstrate the importance of correcting measurement errors.

Yuyun MF, Khaw K-T, Luben R, Welch A,Bingham S, Day NE, Wareham NJ (University ofCambridge and Medical Research Council DunnHuman Nutrition Unit, Cambridge, UK).Microalbuminuria and stroke in a Britishpopulation: the European Prospective Investigationinto Cancer in Norfolk (EPIC-Norfolk) populationstudy. J Intern Med 2004; 255: 247–256.Objectives. To examine the relationship betweenmicroalbuminuria and incident stroke in the generalpopulation.Design. Population-based prospective cohort study.Setting. Participants were recruited in a primarycare setting from 35 participating general practiceunits in Norfolk, UK.Subjects and main outcome measures. The studypopulation consisted of 23 630 individuals aged 40–79 years recruited between 1993 and 1997 for theEPIC-Norfolk Study and followed up for an averageof 7.2 years. Random spot urine specimens werecollected at baseline and albumin-to-creatinine ratiomeasured. Participants were categorized into nor-moalbuminuria, microalbuminuria and macroalbu-minuria groups. During follow-up, the main endpoint was stroke incidence (fatal and nonfatal),ascertained from the UK Office for National Statisticsand from the National Health Service Health Districtdatabase of all hospital admissions.Results. A total of 246 stroke events occurred duringfollow-up [crude incidence rate of stroke, 1.5 per1000 person years (pyrs)]. The age-adjustedincidence of stroke increased significantly acrosscategories of baseline albuminuria (0.9, 1.1 and 1.4/1000 pyrs for tertiles of normoalbuminuria, 2.6/1000 pyrs for microalbuminuria, and 6/1000 pyrsfor macroalbuminuria in the total population,P < 0.001 for trend). In all women and men, themultivariate hazard ratio [95% confidence interval(CI)] for stroke associated with microalbuminuriawas 1.49 (1.13–2.14) and macroalbuminuria 2.43(1.11–6.26). After stratifying by stroke subtype,microalbuminuria was only independentlypredictive of ischaemic stroke, with hazard ratio(95% CI) of 2.01 (1.29–3.31).Conclusion. Microalbuminuria is independentlyassociated with approximately 50% increasedrisk of stroke in the general population. Micro-albuminuria may be useful in identifying thoseat increased risk of stroke in the general pop-ulation.Keywords: albuminuria, cardiovascular diseases,cerebrovascular accident, proteinuria, risk factor.

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

The effects of phytoestrogen isoflavones on bone density in women: a double-blind, randomized, placebo-controlled trial Background: Isoflavone phytoestrogen therapy has been proposed as a natural alternative to hormone replacement therapy (HRT). HRT has a beneficial effect on bone, but few trials in humans have investigated the effects of isoflavones on bone. Objective: The objective of the study was to determine the effect on bone density of a red clover-derived isoflavone supplement that provided a daily dose of 26 mg biochanin A, 16 mg formononetin, I mg genistein, and 0.5 mg daidzein for 1 y. Effects on biochemical markers of bone turnover and body composition were also studied. Design: Women aged 49-65 y (n = 205) were enrolled in a double-blind, randomized, placebo- controlled trial; 177 completed the trial. Bone density, body composition, bone turnover markers, and diet were measured at baseline and after 12 mo. Results: Loss of lumbar spine bone mineral content and bone mineral density was significantly (P = 0.04 and P = 0.03, respectively) lower in the women taking the isoflavone supplement than in those taking the placebo. There were no significant treatment effects on hip bone mineral content or bone mineral density, markers of bone resorption, or body composition, but bone formation markers were significantly increased (P = 0.04 and P = 0.01 for bone-specific alkaline phosphatase and N-propeptide of collagen type 1, respectively) in the intervention group compared with placebo in postmenopausal women. Interactions between treatment group and menopausal status with respect to changes in other outcomes were not significant. Conclusion: These data suggest that, through attenuation of bone loss, isoflavones have a potentially protective effect on the lumbar spine in women.