Timothy J. Key

General and Abdominal Adiposity and Risk of Death in Europe

BACKGROUND Previous studies have relied predominantly on the body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) to assess the association of adiposity with the risk of death, but few have examined whether the distribution of body fat contributes to the prediction of death. METHODS We examined the association of BMI, waist circumference, and waist-to-hip ratio with the risk of death among 359,387 participants from nine countries in the European Prospective Investigation into Cancer and Nutrition (EPIC). We used a Cox regression analysis, with age as the time variable, and stratified the models according to study center and age at recruitment, with further adjustment for educational level, smoking status, alcohol consumption, physical activity, and height. RESULTS During a mean follow-up of 9.7 years, 14,723 participants died. The lowest risks of death related to BMI were observed at a BMI of 25.3 for men and 24.3 for women. After adjustment for BMI, waist circumference and waist-to-hip ratio were strongly associated with the risk of death. Relative risks among men and women in the highest quintile of waist circumference were 2.05 (95% confidence interval [CI], 1.80 to 2.33) and 1.78 (95% CI, 1.56 to 2.04), respectively, and in the highest quintile of waist-to-hip ratio, the relative risks were 1.68 (95% CI, 1.53 to 1.84) and 1.51 (95% CI, 1.37 to 1.66), respectively. BMI remained significantly associated with the risk of death in models that included waist circumference or waist-to-hip ratio (P<0.001). CONCLUSIONS These data suggest that both general adiposity and abdominal adiposity are associated with the risk of death and support the use of waist circumference or waist-to-hip ratio in addition to BMI in assessing the risk of death.

European prospective investigation into cancer and nutrition (EPIC): study populations and data collection

The European Prospective Investigation into Cancer and Nutrition (EPIC) is an ongoing multi-centre prospective cohort study designed to investigate the relationship between nutrition and cancer, with the potential for studying other diseases as well. The study currently includes 519 978 participants (366 521 women and 153 457 men, mostly aged 35-70 years) in 23 centres located in 10 European countries, to be followed for cancer incidence and cause-specific mortality for several decades. At enrollment, which took place between 1992 and 2000 at each of the different centres, information was collected through a non-dietary questionnaire on lifestyle variables and through a dietary questionnaire addressing usual diet. Anthropometric measurements were performed and blood samples taken, from which plasma, serum, red cells and buffy coat fractions were separated and aliquoted for long-term storage, mostly in liquid nitrogen. To calibrate dietary measurements, a standardised, computer-assisted 24-hour dietary recall was implemented at each centre on stratified random samples of the participants, for a total of 36 900 subjects. EPIC represents the largest single resource available today world-wide for prospective investigations on the aetiology of cancers (and other diseases) that can integrate questionnaire data on lifestyle and diet, biomarkers of diet and of endogenous metabolism (e.g. hormones and growth factors) and genetic polymorphisms. First results of case-control studies nested within the cohort are expected early in 2003. The present paper provides a description of the EPIC study, with the aim of simplifying reference to it in future papers reporting substantive or methodological studies carried out in the EPIC cohort.

Epidemiology of breast cancer

Breast cancer is the commonest cause of cancer death in women worldwide. Rates vary about five-fold around the world, but they are increasing in regions that until recently had low rates of the disease. Many of the established risk factors are linked to oestrogens. Risk is increased by early menarche, late menopause, and obesity in postmenopausal women, and prospective studies have shown that high concentrations of endogenous oestradiol are associated with an increase in risk. Childbearing reduces risk, with greater protection for early first birth and a larger number of births; breastfeeding probably has a protective effect. Both oral contraceptives and hormonal therapy for menopause cause a small increase in breast-cancer risk, which appears to diminish once use stops. Alcohol increases risk, whereas physical activity is probably protective. Mutations in certain genes greatly increase breast-cancer risk, but these account for a minority of cases.

Dietary fibre in food and protection against colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC): an observational study

BACKGROUND Dietary fibre is thought to protect against colorectal cancer but this view has been challenged by recent prospective and intervention studies that showed no protective effect. METHODS We prospectively examined the association between dietary fibre intake and incidence of colorectal cancer in 519978 individuals aged 25-70 years taking part in the EPIC study, recruited from ten European countries. Participants completed a dietary questionnaire in 1992-98 and were followed up for cancer incidence. Relative risk estimates were obtained from fibre intake, categorised by sex-specific, cohort-wide quintiles, and from linear models relating the hazard ratio to fibre intake expressed as a continuous variable. FINDINGS Follow-up consisted of 1939011 person-years, and data for 1065 reported cases of colorectal cancer were included in the analysis. Dietary fibre in foods was inversely related to incidence of large bowel cancer (adjusted relative risk 0.75 [95% CI 0.59-0.95] for the highest versus lowest quintile of intake), the protective effect being greatest for the left side of the colon, and least for the rectum. After calibration with more detailed dietary data, the adjusted relative risk for the highest versus lowest quintile of fibre from food intake was 0.58 (0.41-0.85). No food source of fibre was significantly more protective than others, and non-food supplement sources of fibre were not investigated. INTERPRETATION In populations with low average intake of dietary fibre, an approximate doubling of total fibre intake from foods could reduce the risk of colorectal cancer by 40%.

Validity of self-reported height and weight in 4808 EPIC-Oxford participants.

OBJECTIVE To assess the validity of self-reported height and weight by comparison with measured height and weight in a sample of middle-aged men and women, and to determine the extent of misclassification of body mass index (BMI) arising from differences between self-reported and measured values. DESIGN Analysis of self-reported and measured height and weight data from participants in the Oxford cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Oxford). SUBJECTS Four thousand eight hundred and eight British men and women aged 35-76 years. RESULTS Spearman rank correlations between self-reported and measured height, weight and BMI were high (r > 0.9, P < 0.0001). Height was overestimated by a mean of 1.23 (95% confidence interval (CI) 1.11-1.34) cm in men and 0.60 (0.51-0.70) cm in women; the extent of overestimation was greater in older men and women, shorter men and heavier women. Weight was underestimated by a mean of 1.85 (1.72-1.99) kg in men and 1.40 (1.31-1.49) kg in women; the extent of underestimation was greater in heavier men and women, but did not vary with age or height. Using standard categories of BMI, 22.4% of men and 18.0% of women were classified incorrectly based on self-reported height and weight. After correcting the self-reported values using predictive equations derived from a 10% sample of subjects, misclassification decreased to 15.2% in men and 13.8% in women. CONCLUSIONS Self-reported height and weight data are valid for identifying relationships in epidemiological studies. In analyses where anthropometric factors are the primary variables of interest, measurements in a representative sample of the study population can be used to improve the accuracy of estimates of height, weight and BMI.

Comparison of dietary assessment methods in nutritional epidemiology : weighed records v. 24 h recalls, food-frequency questionnaires and estimated-diet records

Women (n 160) aged 50 to 65 years were asked to weigh their food for 4 d on four occasions over the period of 1 year, using the PETRA (Portable Electronic Tape Recorded Automatic) scales. Throughout the year, they were asked to complete seven other dietary assessment methods: a simple 24 h recall, a structured 24 h recall with portion size assessments using photographs, two food-frequency questionnaires, a 7 d estimated record or open-ended food diary, a structured food-frequency (menu) record, and a structured food-frequency (menu) record with portion sizes assessed using photographs. Comparisons between the average of the 16 d weighed records and the first presentation of each method indicated that food-frequency questionnaires were not appreciably better at placing individuals in the distribution of habitual diet than 24 h recalls, due partly to inaccuracies in the estimation of frequency of food consumption. With a 7 d estimated record or open-ended food diary, however, individual values of nutrients were most closely associated with those obtained from 16 d weighed records, and there were no significant differences in average food or nutrient intakes.

Endogenous Sex Hormones and Prostate Cancer: A Collaborative Analysis of 18 Prospective Studies

BACKGROUND Sex hormones in serum have been hypothesized to influence the risk of prostate cancer. We performed a collaborative analysis of the existing worldwide epidemiologic data to examine these associations in a uniform manner and to provide more precise estimates of risks. METHODS Data on serum concentrations of sex hormones from 18 prospective studies that included 3886 men with incident prostate cancer and 6438 control subjects were pooled by the Endogenous Hormones and Prostate Cancer Collaborative Group. Relative risks (RRs) of prostate cancer by fifths of serum hormone concentration were estimated by use of conditional logistic regression with stratification by study, age at recruitment, and year of recruitment. All statistical tests were two-sided. RESULTS No associations were found between the risk of prostate cancer and serum concentrations of testosterone, calculated free testosterone, dihydrotestosterone, dehydroepiandrosterone sulfate, androstenedione, androstanediol glucuronide, estradiol, or calculated free estradiol. The serum concentration of sex hormone-binding globulin was modestly inversely associated with prostate cancer risk (RR in the highest vs lowest fifth = 0.86, 95% confidence interval = 0.75 to 0.98; P(trend) = .01). There was no statistical evidence of heterogeneity among studies, and adjustment for potential confounders made little difference to the risk estimates. CONCLUSIONS In this collaborative analysis of the worldwide data on endogenous hormones and prostate cancer risk, serum concentrations of sex hormones were not associated with the risk of prostate cancer.

Modified Mediterranean diet and survival: EPIC-elderly prospective cohort study.

Abstract Objective To examine whether adherence to the modified Mediterranean diet, in which unsaturates were substituted for monounsaturates, is associated with longer life expectancy among elderly Europeans. Design Multicentre, prospective cohort study. Setting Nine European countries (Denmark, France, Germany, Greece, Italy, the Netherlands, Spain, Sweden, United Kingdom). Participants 74 607 men and women, aged 60 or more, without coronary heart disease, stroke, or cancer at enrolment and with complete information about dietary intake and potentially confounding variables. Main outcome measures Extent of adherence to a modified Mediterranean diet using a scoring system on a 10 point scale, and death from any cause by time of occurrence, modelled through Cox regression. Results An increase in the modified Mediterranean diet score was associated with lower overall mortality, a two unit increment corresponding to a statistically significant reduction of 8% (95% confidence interval 3% to 12%). No statistically significant evidence of heterogeneity was found among countries in the association of the score with overall mortality even though the association was stronger in Greece and Spain. When dietary exposures were calibrated across countries, the reduction in mortality was 7% (1% to 12%). Conclusion The Mediterranean diet, modified so as to apply across Europe, was associated with increased survival among older people.

Air pollution and lung cancer incidence in 17 European cohorts: prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE)

BACKGROUND Ambient air pollution is suspected to cause lung cancer. We aimed to assess the association between long-term exposure to ambient air pollution and lung cancer incidence in European populations. METHODS This prospective analysis of data obtained by the European Study of Cohorts for Air Pollution Effects used data from 17 cohort studies based in nine European countries. Baseline addresses were geocoded and we assessed air pollution by land-use regression models for particulate matter (PM) with diameter of less than 10 μm (PM10), less than 2·5 μm (PM2·5), and between 2·5 and 10 μm (PMcoarse), soot (PM2·5absorbance), nitrogen oxides, and two traffic indicators. We used Cox regression models with adjustment for potential confounders for cohort-specific analyses and random effects models for meta-analyses. FINDINGS The 312 944 cohort members contributed 4 013 131 person-years at risk. During follow-up (mean 12·8 years), 2095 incident lung cancer cases were diagnosed. The meta-analyses showed a statistically significant association between risk for lung cancer and PM10 (hazard ratio [HR] 1·22 [95% CI 1·03-1·45] per 10 μg/m(3)). For PM2·5 the HR was 1·18 (0·96-1·46) per 5 μg/m(3). The same increments of PM10 and PM2·5 were associated with HRs for adenocarcinomas of the lung of 1·51 (1·10-2·08) and 1·55 (1·05-2·29), respectively. An increase in road traffic of 4000 vehicle-km per day within 100 m of the residence was associated with an HR for lung cancer of 1·09 (0·99-1·21). The results showed no association between lung cancer and nitrogen oxides concentration (HR 1·01 [0·95-1·07] per 20 μg/m(3)) or traffic intensity on the nearest street (HR 1·00 [0·97-1·04] per 5000 vehicles per day). INTERPRETATION Particulate matter air pollution contributes to lung cancer incidence in Europe. FUNDING European Communitys Seventh Framework Programme.

Lung cancer susceptibility locus at 5p15.33

We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P = 2 × 10−7 and P = 4 × 10−6) and replicated by the independent study series (P = 7 × 10−5 and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.