Nicholas E. Day

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.

Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and Nutrition (EPIC-Norfolk)

Abstract Objective: To examine the value of glycated haemoglobin (HbA1c) concentration, a marker of blood glucose concentration, as a predictor of death from cardiovascular and all causes in men. Design: Prospective population study. Setting: Norfolk cohort of European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk). Subjects: 4662 men aged 45-79 years who had had glycated haemoglobin measured at the baseline survey in 1995-7 who were followed up to December 1999. Main outcome measures: Mortality from all causes, cardiovascular disease, ischaemic heart disease, and other causes. Results: Men with known diabetes had increased mortality from all causes, cardiovascular disease, and ischaemic disease (relative risks 2.2, 3.3, and 4.2, respectively, P <0.001 independent of age and other risk factors) compared with men without known diabetes. The increased risk of death among men with diabetes was largely explained by HbA1c concentration. HbA1c was continuously related to subsequent all cause, cardiovascular, and ischaemic heart disease mortality through the whole population distribution, with lowest rates in those with HbA1c concentrations below 5%. An increase of 1% in HbA1c was associated with a 28% (P<0.002) increase in risk of death independent of age, blood pressure, serum cholesterol, body mass index, and cigarette smoking habit; this effect remained (relative risk 1.46, P=0.05 adjusted for age and risk factors) after men with known diabetes, a HbA1c concentration ≥7%, or history of myocardial infarction or stroke were excluded. 18% of the population excess mortality risk associated with a HbA1c concentration ≥5% occurred in men with diabetes, but 82% occurred in men with concentrations of 5%-6.9% (the majority of the population). Conclusions: Glycated haemoglobin concentration seems to explain most of the excess mortality risk of diabetes in men and to be a continuous risk factor through the whole population distribution. Preventive efforts need to consider not just those with established diabetes but whether it is possible to reduce the population distribution of HbA1c through behavioural means.

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%.

Association of Hemoglobin A1c with Cardiovascular Disease and Mortality in Adults: The European Prospective Investigation into Cancer in Norfolk

Context Several studies suggest that blood glucose levels are associated with cardiovascular disease, even at blood glucose values that do not meet diagnostic criteria for diabetes. Contribution Among adult residents of Norfolk, United Kingdom, there was a continuous relationship between hemoglobin A1c levels and cardiovascular disease and total mortality. This relationship was apparent even among persons without diabetes. Implications These observations justify the need for studies that address whether improvements in glycemic control might improve health outcomes in persons who do not have diabetes. The Editors Diabetes mellitus is of major and increasing global public health importance (1). Persons with diabetes are at increased risk for premature disability and death associated with vascular, renal, retinal, and neuropathic complications. Raised fasting and postchallenge blood glucose levels in an oral glucose tolerance test are used to diagnose diabetes. The diagnostic threshold is based on the shape of the risk curve between glucose levels and specific microvascular complications of diabetes (2-6). Diabetes also increases the risk for macrovascular diseases, such as coronary heart disease and stroke (7). In contrast to microvascular disease, increasing evidence suggests that the relationship between blood glucose level and macrovascular disease is continuous and does not have an obvious threshold (2, 8, 9). Hemoglobin A1c concentration is an indicator of average blood glucose concentrations over the preceding 3 months; it is useful for characterizing dysglycemia in population studies because it is simpler to perform than the oral glucose tolerance test (10). In a 3-year follow-up of men in a prospective study, we previously reported that hemoglobin A1c concentrations were related to cardiovascular disease and all-cause mortality (11). However, we had insufficient power to examine risk relationships at concentrations close to the diagnostic threshold of 7% or to examine the relationship in women. We report the relation between hemoglobin A1c concentrations and fatal and nonfatal coronary heart disease, cardiovascular disease events, and all-cause mortality in men and women after an average of 6 years of follow-up. Methods The European Prospective Investigation into Cancer in Norfolk (EPICNorfolk) is a prospective population study of 25 623 men and women who were between 40 and 79 years of age and who resided in Norfolk, United Kingdom. Participants were recruited from general practice registers. Information on the recruitment process is available elsewhere (12). Between 1993 and 1997, participants completed a health and lifestyle questionnaire. Participants were asked whether a doctor had ever told them that they have any of the conditions contained in a list that included diabetes, heart attack, and stroke. People with known diabetes were defined as those who responded yes to the diabetes option of this question. Smoking history was derived from responses (yes or no) to the questions: Have you ever smoked as much as 1 cigarette a day for as long as a year? and Do you smoke cigarettes now? At a clinic, trained nurses performed a health examination for each participant. Body mass index was estimated as weight (kg)/height (m2), and waist-to-hip ratio was determined by measurements of the circumference of the waist and hips. Blood pressure was measured by using an Accutorr (Datascope, Mahwah, New Jersey) noninvasive blood pressure monitor after the participant had been seated for 5 minutes. The mean of 2 readings was used for analysis. Nonfasting blood samples were taken; samples for assay were stored in a refrigerator at 4 C until transport within 1 week of sampling to the Department of Clinical Biochemistry, University of Cambridge. Starting in 1995, hemoglobin A1c was measured on fresh EDTA blood samples by using high-performance liquid chromatography (BioRad Diamat Automated Glycosylated Haemoglobin Analyser, Hemel Hempstead, United Kingdom). We report results for follow-up to January 2003, an average of about 6 years. All participants were flagged for death certification at the Office of National Statistics; vital status was obtained for the entire cohort. Trained nosologists coded death certificates according to the International Classification of Diseases, Ninth or Tenth Revisions (ICD-9 or ICD-10). Cardiovascular death (stroke, coronary heart disease, and other vascular causes) was defined as those whose underlying cause of death was coded as ICD-9 400448 or ICD-10 I10I79. Death from coronary heart disease was defined as those whose cause of death was coded as ICD-9 410414 or ICD-10 I22I25. Participants admitted to a hospital were identified by their National Health Service number. Hospitals were linked to the East Norfolk Health Authority database, which identifies all hospital contacts throughout England and Wales for Norfolk residents. We used the same ICD diagnostic codes described in the preceding paragraphs to ascertain hospital episodes of cardiovascular disease and coronary heart disease in our cohort. Participants were identified as having a coronary heart disease event during follow-up if they had a hospital admission or died with coronary heart disease as the cause of death. Of the coronary heart disease events identified, 21% (112 of 529) were fatal; of the cardiovascular disease events, 23% (197 of 806) were fatal. In men, 24% (76 of 321) of deaths were attributed to heart disease and 29% (117 of 321) were attributed to cardiovascular disease. In women, 18% (36 of 200) of deaths were attributed to heart disease and 35% (70 of 200) were attributed to cardiovascular causes. The Norwich Ethics Committee approved the study, and participants gave signed informed consent. Statistical Analysis These analyses, undertaken by using SPSS software, version 10.0 (SPSS, Inc., Chicago, Illinois), included 10 232 men and women age 45 to 79 years who completed the health and lifestyle questionnaire and had available hemoglobin A1c measurements. We divided the cohort into 7 categories on the basis of baseline data: known diabetes, high likelihood of previously undiagnosed diabetes (no personal history of diabetes but a hemoglobin A1c concentration 7%), and hemoglobin A1c concentrations in 0.5percentage point intervals (<5%, 5% to 5.4%, 5.5% to 5.9%, 6.0% to 6.4%, and 6.5% to 6.9%). We examined risk factor distributions and then coronary heart disease, cardiovascular disease, and all-cause mortality rates by hemoglobin A1c and diabetes category. Age-adjusted odds ratios were calculated by using logistic regression models. We used a Cox proportional hazards model to determine the independent contribution of hemoglobin A1c to total mortality and cardiovascular and coronary heart disease after adjustment for age, body mass index, waist-to-hip ratio, systolic blood pressure, blood cholesterol concentrations, cigarette smoking, and history of heart attack or stroke. Participants with missing baseline data for 1 or more risk factors (130 men and 186 women) were excluded from the multivariate analyses. Role of the Funding Sources The funding sources had no role in the design, conduct, and reporting of the study or in the decision to submit the manuscript for publication. Results Table 1 presents characteristics of the participants according to hemoglobin A1c concentration and self-reported diabetes. Those with known diabetes had higher mean (SD) hemoglobin A1c concentrations (8.0% 1.9%) than the rest of the study sample (5.3% 0.7%). They were older and had a higher body mass index, waist-to-hip ratio, and systolic blood pressure; they were also more likely to report having had a previous heart attack or stroke. Participants with probable but previously undiagnosed diabetes (hemoglobin A1c 7%) shared these characteristics. Mean risk factor levels rose with increasing concentration of hemoglobin A1c less than 7%. Table 1. Distribution of Variables by Hemoglobin A1c Concentration and Known Diabetes in 4662 Men and 5570 Women Age 45 to 79 Years (European Prospective Investigation into Cancer in Norfolk, 1995 to 1997) Table 2 shows adjusted odds ratios for hemoglobin A1c concentrations, diabetes status, and outcomes. Persons with known or undiagnosed diabetes had a greater risk for all-cause mortality and cardiovascular or coronary heart disease than those without diabetes. Risk for coronary heart or cardiovascular disease and total mortality increased throughout the whole range of hemoglobin A1c concentrations; those with hemoglobin A1c concentrations less than 5% had the lowest rates. For men, a gradient of increasing rates through the distribution was apparent for all end points. For women, odds ratios for cardiovascular or coronary heart disease did not increase significantly until the hemoglobin A1c concentration reached 6%; odds ratios were very high in women with concentrations greater than 7%. Table 2. Rates and Age-Adjusted Relative Risks for Total Coronary Heart Disease Events, Cardiovascular Disease Events, and All-cause Mortality by Category of Hemoglobin A1c Concentration and Known Diabetes in 4462 Men and 5570 Women Age 45 to 79 Years (European Prospective Investigation into Cancer in Norfolk, 1995 to 2003) Table 3 shows outcomes after adjustment for age alone and then after adjustment for age and other risk factors. In men, known diabetes predicted coronary heart and cardiovascular disease events and total mortality with approximate 2-fold relative risks. These relative risks were only slightly attenuated after adjustment for known risk factors. In women, known diabetes status predicted an approximate 5-fold increase in risk for coronary heart and 3-fold increase in risk for cardiovascular disease events; these increases were attenuated after adjustment for known risk factors to 3-fold and 2-fold risk, respectively. In men and women, hemoglobin A1c concentrations predicted an increased risk for coronar

Dietary effects on breast-cancer risk in Singapore

It is suspected that diet influences the risk of getting breast cancer. A study of diet and breast cancer was done among 200 Singapore Chinese women with histologically confirmed disease and 420 matched controls. A quantitative food-frequency questionnaire was used to assess intakes of selected nutrients and foods 1 year before interview. Daily intakes were computed and risk analysed after adjustment for concomitant risk factors. In premenopausal women, high intakes of animal proteins and red meat were associated with increased risk. Decreased risk was associated with high intakes of polyunsaturated fatty acids (PUFA), beta-carotene, soya proteins, total soya products, a high PUFA to saturated fatty acid ratio, and a high proportion of soya to total protein. In multiple analysis, the variables which were significant after adjustment for each other were red meat (p less than 0.001) as a predisposing factor, and PUFA (p = 0.02), beta-carotene (p = 0.003), and soya protein (p = 0.02) as protective factors. The analysis of dietary variables in postmenopausal women gave uniformly non-significant results. Our finding that soya products may protect against breast cancer in younger women is of interest since these foods are rich in phyto-oestrogens.

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.

Validity and repeatability of a simple index derived from the short physical activity questionnaire used in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

OBJECTIVE To assess the validity and repeatability of a simple index designed to rank participants according to their energy expenditure estimated by self-report, by comparison with objectively measured energy expenditure assessed by heart-rate monitoring with individual calibration. DESIGN Energy expenditure was assessed over one year by four separate episodes of 4-day heart-rate monitoring, a method previously validated against whole-body calorimetry and doubly labelled water. Cardio-respiratory fitness was assessed by four repeated measures of sub-maximum oxygen uptake. At the end of the 12-month period, participants completed a physical activity questionnaire that assessed past-year activity. A simple four-level physical activity index was derived by combining occupational physical activity together with time participating in cycling and other physical exercise (such as keep fit, aerobics, swimming and jogging). SUBJECTS One hundred and seventy-three randomly selected men and women aged 40 to 65 years. RESULTS The repeatability of the physical activity index was high (weighted kappa=0.6, ). There were positive associations between the physical activity index from the questionnaire and the objective measures of the ratio of daytime energy expenditure to resting metabolic rate and cardio-respiratory fitness As an indirect test of validity, there was a positive association between the physical activity index and the ratio of energy intake, assessed by 7-day food diaries, to predicted basal metabolic rate. CONCLUSIONS The summary index of physical activity derived from the questions used in the European Prospective Investigation into Cancer and Nutrition (EPIC) study suggest it is useful for ranking participants in terms of their physical activity in large epidemiological studies. The index is simple and easy to comprehend, which may make it suitable for situations that require a concise, global index of activity.

A pooled analysis of magnetic fields and childhood leukaemia

Previous studies have suggested an association between exposure to 50–60 Hz magnetic fields (EMF) and childhood leukaemia. We conducted a pooled analysis based on individual records from nine studies, including the most recent ones. Studies with 24/48-hour magnetic field measurements or calculated magnetic fields were included. We specified which data analyses we planned to do and how to do them before we commenced the work. The use of individual records allowed us to use the same exposure definitions, and the large numbers of subjects enabled more precise estimation of risks at high exposure levels. For the 3203 children with leukaemia and 10 338 control children with estimated residential magnetic field exposures levels < 0.4 μT, we observed risk estimates near the no effect level, while for the 44 children with leukaemia and 62 control children with estimated residential magnetic field exposures ≥ 0.4 μT the estimated summary relative risk was 2.00 (1.27–3.13), P value = 0.002). Adjustment for potential confounding variables did not appreciably change the results. For North American subjects whose residences were in the highest wire code category, the estimated summary relative risk was 1.24 (0.82–1.87). Thus, we found no evidence in the combined data for the existence of the so-called wire-code paradox. In summary, the 99.2% of children residing in homes with exposure levels < 0.4 μT had estimates compatible with no increased risk, while the 0.8% of children with exposures ≥ 0.4 μT had a relative risk estimate of approximately 2, which is unlikely to be due to random variability. The explanation for the elevated risk is unknown, but selection bias may have accounted for some of the increase.

Family history and the risk of breast cancer: A systematic review and meta‐analysis

An increased risk of breast cancer in women with a family history of breast cancer has been demonstrated by many studies using a variety of study designs. However, the extent of this risk varies according to the nature of the family history (type of relative affected, age at which relative developed breast cancer and number of relatives affected) and may also vary according to age of the individual. The aim of our study was to identify all the published studies which have quantified the risk of breast cancer associated with a family history of the disease, and to summarise the evidence from these studies, with particular emphasis on age‐specific risks according to subject and relative age. Seventy‐four published studies were identified. The pooled estimate of relative risk (RR) associated with various family histories was as follows: any relative, RR = 1.9 (95% CI, 1.7‐2.0); a first‐degree relative, RR = 2.1 (CI = 2.0, 2.2); mother, RR = 2.0 (CI = 1.8, 2.1); sister, RR = 2.3 (CI = 2.1, 2.4); daughter, RR = 1.8 (CI = 1.6, 2.0); mother and sister, RR = 3.6 (CI = 2.5, 5.0); and a second‐degree relative, RR = 1.5 (CI = 1.4, 1.6). Risks were increased in subjects under age 50 and when the relative had been diagnosed before age 50. Int. J. Cancer 71: 800‐809, 1997.

Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study

BACKGROUND Ascorbic acid (vitamin C) might be protective for several chronic diseases. However, findings from prospective studies that relate ascorbic acid to cardiovascular disease or cancer are not consistent. We aimed to assess the relation between plasma ascorbic acid and subsequent mortality due to all causes, cardiovascular disease, ischaemic heart disease, and cancer. METHODS We prospectively examined for 4 years the relation between plasma ascorbic acid concentrations and mortality due to all causes, and to cardiovascular disease, ischaemic heart disease, and cancer in 19 496 men and women aged 45-79 years. We recruited individuals by post using age-sex registers of general practices. Participants completed a health and lifestyle questionnaire and were examined at a clinic visit. They were followed-up for causes of death for about 4 years. Individuals were divided into sex-specific quintiles of plasma ascorbic acid. We used the Cox proportional hazard model to determine the effect of ascorbic acid and other risk factors on mortality. FINDINGS Plasma ascorbic acid concentration was inversely related to mortality from all-causes, and from cardiovascular disease, and ischaemic heart disease in men and women. Risk of mortality in the top ascorbic acid quintile was about half the risk in the lowest quintile (p<0.0001). The relation with mortality was continuous through the whole distribution of ascorbic acid concentrations. 20 micromol/L rise in plasma ascorbic acid concentration, equivalent to about 50 g per day increase in fruit and vegetable intake, was associated with about a 20% reduction in risk of all-cause mortality (p<0.0001), independent of age, systolic blood pressure, blood cholesterol, cigarette smoking habit, diabetes, and supplement use. Ascorbic acid was inversely related to cancer mortality in men but not women. INTERPRETATION Small increases in fruit and vegetable intake of about one serving daily has encouraging prospects for possible prevention of disease.