P.A.H. van Noord

Prospect-EPIC Utrecht: Study design and characteristics of the cohort population

The European Prospective Investigation into Cancer and Nutrition (EPIC), which has been established in order to investigate the relations between nutrition and cancer, was initiated in 1990 and involves 10 European countries with heterogeneous dietary patterns and differing cancer incidence rates. This manuscript presents the design, recruitment and baseline characteristics of the Prospect-EPIC cohort co-ordinated in Utrecht, The Netherlands. The cohort is based on volunteers recruited among women participating in a regional breast cancer screening program. It comprises of 17,357 subjects aged 50–69 years at enrolment from Utrecht and vicinity, who have consented to participate in the study and its follow-up. Each participant filled out a general questionnaire and a food frequency questionnaire. Participants were also physically examined and have donated a blood sample. Participation rate was 34.5%. Blood samples were donated by most participants (97.5%) and detailed informed consents were obtained from 87.4% of participants. Mean age at enrolment was 57 years. Anthropometric, lifestyle and morbidity characteristics of the cohort population did not differ largely from those of similar study populations in The Netherlands. Based on the Prospect-EPIC population, we intend to conduct prospective total cohort, nested case–control or case–cohort studies, in order to investigate relations between consumption of certain food groups or nutrients and chronic diseases, including hormone dependant cancers such as breast, colon, endometrial and ovary cancers.

Body mass index, waist circumference and waist-hip ratio and serum levels of IGF-I and IGFBP-3 in European women

Objective:To examine the relationship between body mass index (BMI) and waist–hip ratio (WHR) with serum levels of insulin-like growth factor-I (IGF-I), and its binding protein (IGFBP)-3.Design:Cross-sectional study on 2139 women participating in a case–control study on breast cancer and endogenous hormones. Data on lifestyle and reproductive factors were collected by means of questionnaires. Body height, weight, waist and hip circumferences were measured. Serum levels of IGF-I and insulin-like binding protein (IGFBP)-3 were measured by enzyme-linked immunosorbent assays. Adjusted mean levels of IGF-I and IGFBP-3 across quintiles of BMI, waist circumference, and WHR were calculated by linear regression. Results were adjusted for potential confounders associated with IGF-I and IGFBP-3.Results:Adjusted mean serum IGF-I values were lower in women with BMI<22.5 kg/m2 or BMI>29.2 kg/m2 compared to women with BMI within this range (Pheterogeneity<0.0001, Ptrend=0.35). Insulin-like growth factor-I was not related to WHR after adjustment for BMI. IGF-binding protein-3 was linearly positively related to waist and WHR after mutual adjustment. The molar ratio IGF-I/IGFBP-3 had a non-linear relation with BMI and a linear inverse relationship with WHR (P trend=0.005).Conclusions:Our data confirm the nonlinear relationship of circulating IGF-I to total adiposity in women. Serum IGFBP-3 was positively related to central adiposity. These suggest that bioavailable IGF-I levels could be lower in obese compared to non-obese women and inversely related to central adiposity.

Obesity and fat distribution in relation to hot flashes in Dutch women from the DOM-project

The authors studied obesity and fat distribution in relation to the occurrence of hot flashes in a population-based study comprising 2904 women aged 40-44 and 569 women aged 54-69 presenting for mammographic screening (the DOM-project). Women aged 40-44 in the upper tertiles of Quetelets index and waist/hip ratio reported hot flashes significantly more often than women in the respective lower tertiles. These associations were independent of each other and independent of age. After adjustment for age, waist/hip ratio and menopausal status, the odds ratio comparing the upper tertile of Quetelets index to the lower tertile was 1.70 (95% confidence interval, 1.30-2.21). After adjustment for age, Quetelets index and menopausal status, the odds ratio comparing the upper tertile of waist/hip ratio to the lower tertile was 1.37 (95% CI, 1.05-1.78). In women aged 54-69 no significant associations between Quetelets index and complaints of hot flashes were observed. Women in the upper tertile of waist/hip ratio reported hot flashes more often than women in the lower tertile, but this result was not significant (OR 1.38; 95% CI, 0.87-2.22).

Reliability of biomarkers of iron status, blood lipids, oxidative stress, vitamin D, C-reactive protein and fructosamine in two Dutch cohorts

Abstract Biomarkers are widely used in epidemiology, yet there are few reliability studies to assess the appropriateness of using these biomarkers for the assessment of exposure–disease relationships. The aim of the study was to assess the reliability of 20 biomarkers in serum collected from two Dutch centres (Utrecht and Bilthoven) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) at two points several years apart. Blood samples were collected from 30 men from Bilthoven and 35 women from Utrecht. Ferritin, total iron, total iron-binding capacity, transferrin saturation, transferrin, C-reactive protein, bilirubin, cholesterol, triglycerides, apo lipoprotein-A, apo lipoprotein-B, high-density lipoproteins, low-density lipoproteins, uric acid, creatinine, reactive oxygen metabolites, the ferric-reducing ability of plasma, protein thiol oxidation, fructosamine, and vitamin D biomarkers in serum were analysed from the blood samples at the two points of time. For all biomarkers, except C-reactive protein, there were no substantial changes in the mean levels over time. Uric acid, ferritin, creatinine, HDL, and apo lipoprotein-B levels consistently showed the highest reliability for men and women (intra-class correlation = 0.69–0.86). Among women, the ferric-reducing ability of plasma, and protein thiol oxidation had poor reliability; and among men iron-related biomarkers (except serum ferritin) had poor reliability. With the exception of a few gender-specific differences, most of the 20 biomarkers performed well and can be considered to have sufficient reliability to be used in future cohort studies.

Urinary endogenous sex hormone levels and the risk of postmenopausal breast cancer

To assess the relation between urinary endogenous sex steroid levels and the risk of postmenopausal breast cancer, a nested case–cohort study was conducted within a large cohort (the DOM cohort) in the Netherlands (n=9 349). Until the end of follow-up (1 January 1996), 397 postmenopausal breast cancer cases were identified and a subcohort of 424 women was then taken from all eligible women. Women using hormones were excluded, leaving 364 breast cancer cases and 382 women in the subcohort for the analyses. Concentrations of oestrone, oestradiol, testosterone, 5α-androstane-3α, 17β-diol and creatinine were measured in first morning urine samples, which had been stored since enrolment at −20°C. A Cox proportional Hazards model was used, with Barlows adjustment for case–cohort sampling, to estimate breast cancer risk in quartiles of each of the, creatinine corrected, hormone levels, the lowest quartile being the reference group. Women with higher levels of all four of the hormones were at increased risk for postmenopausal breast cancer (highest vs lowest quartile: incidence rate ratio for oestrone (IRRoestrone=2.5, 95% CI: 1.6–3.8; IRRoestradiol=1.5, 95% CI: 1.0–2.3; IRRtestosterone=1.6, 95% CI: 1.0–2.4; IRR5α-androstane-3α, 17β-diol=1.7, 95% CI: 1.1–2.7). In conclusion, women with higher excretion levels of both oestrogens and androgens have an increased risk of breast cancer.

Age at menopause, body mass index, and the risk of colorectal cancer mortality in the Dutch Diagnostisch Onderzoek Mammacarcinoom (DOM) cohort.

We investigated whether age at menopause is associated with subsequent mortality from colorectal cancer along with the possible modification of this association by body mass index. Our data are from the Diagnostisch Onderzoek Mammacarcinoom cohort of 10,671 postmenopausal women in the Netherlands, enrolled between 1974 and 1977, with a median follow-up of 18 years. During this follow-up, 95 women died of colorectal cancer. Women 49 years of age or older at menopause showed a lower risk of colorectal cancer mortality compared with women younger than 49 at menopause. This protective effect, however, was found only among nonoverweight women (< or =24 kg/m2), for whom the hazard ratio was 0.46 (95% confidence interval = 0.21-1.03). In larger women, the hazard ratio was 1.17 (95% confidence interval = 0.68-2.00).

Influence of estrogen receptor alpha and progesterone receptor polymorphisms on the effects of hormone therapy on mammographic density.

Postmenopausal hormone therapy increases mammographic density, a strong breast cancer risk factor, but effects vary across women. We investigated whether the effect of hormone therapy use is modified by polymorphisms in the estrogen receptor (ESR1) and progesterone receptor (PGR) genes in the Dutch Prospect-EPIC and the English EPIC-Norfolk cohorts. Information on hormone therapy use was obtained through questionnaires at recruitment and after 5 years. Blood samples were collected and consecutive mammograms were available through breast cancer screening programs. For 795 hormone therapy users, one mammogram before and a second mammogram during hormone therapy use was included. For 781 never hormone therapy users, mammograms with similar time intervals were included. Mammographic density was assessed using a computer-assisted method. Changes in density were analyzed using linear regression. A statistically significant difference in percentage density change between hormone therapy users and never users was seen in women with the ESR1 PvuII Pp or pp genotype (2.24%; P < 0.01), but not in those with the PP genotype (0.90%; P = 0.47). Similarly, effects of hormone therapy on percentage density were observed in women with the ESR1 XbaI Xx or xx genotype (2.20%; P < 0.01), but not in those with the XX genotype (−0.65%; P = 0.70). Also, effects were seen in women with the PGR +331 GG genotype (2.04%; P < 0.01), but not in those with the GA or AA genotype (0.98%; P = 0.53). The PGR PROGINS polymorphism did not seem to make women more susceptible to the effects of hormone therapy use. In conclusion, our results suggest that specific polymorphisms in the ESR1 and PGR genes may make women more susceptible to the effects of hormone therapy use on mammographic density. (Cancer Epidemiol Biomarkers Prev 2006;15(3):462–7)

Selenium and the risk of postmenopausal breast cancer in the DOM cohort

SummarySelenium has been claimed to have chemo-preventive properties. However, data showing that in humans selenium levels are already decreased prior to diagnosis of breast cancer were not available. Such information is mandatory before oral selenium supplementation in the primary prevention of (breast) cancer in humans is acceptable. This question of a ‘preventive-potential’ of selenium was evaluated in a case-control study nested in a cohort, because this design allows determination of the time-order of preceding selenium levels and subsequent cancer risk.The cohort consisted of 5577 women aged 55–70 years from the DOM project, a population based breast cancer screening program in the Netherlands. Instrumental Neutron Activation Analysis was used to measure the selenium content of toenail clippings. The 69 cases of breast cancer found during follow-up after screening represent ‘recent’ tumours since all women had a negative screening mammogram 3–5 years previously.No decreased selenium levels, as measured in nail clippings from the big toes, could be detected in cases-to-be, either when compared to 4 age matched controls per case or when compared with a random control group drawn from the entire cohort. On the contrary, a tendency for slightly higher selenium levels among ‘future’ cancer cases was observed.As to the sensitivity of detecting differences in selenium by nail clippings, lower selenium could be detected in nails of current smokers. The smoking-related decrease in nail selenium level was of the same order as the differences between breast cancer cases and controls, but was independent of the breast cancer risk.Results are similar to a comparable study on premenopausal breast cancer and argue against a preventive role for selenium on breast cancer risk.

Urinary endogenous sex hormone levels in postmenopausal women after caloric restriction in young adulthood

We investigated whether the 1944–1945 Dutch famine has affected postmenopausal sex hormone concentrations with data from 163 women (young adults during the famine). Urinary sex hormone concentrations showed modest elevations with increasing famine exposure. Effects were absent in parous women, but more pronounced in women who had never given birth.

Efficient use of biological banks for biochemical epidemiology: Exploratory hypothesis testing by means of a sequential t-test

In view of recent advances in molecular and biochemical epidemiology, there is growing interest in the creation of biological banks of blood, urine, tissue, or other biological specimens collected from participants in prospective cohort studies. The existence of biological banks may make it possible to study a multitude of etiologic hypotheses, by comparing biochemical parameters measured in the biological specimens of subjects who will eventually develop the disease of interest (“cases”) and of control subjects, using a nested case-control or a case-cohort design. In practice, however, the amount of biological material available per subject (in particular, that of cases) will limit the number of hypotheses that can be tested. The present paper discusses the use of a sequential t-test which, compared with an analogous fixed sample procedure, will on average require fewer biological specimens before a given study hypothesis can be accepted or rejected. The sequential test should thus facilitate an early decision on whether a new hypothesis is worth further investigation, while avoiding wasting too much biological material on testing hypotheses that may eventually prove unfruitful. If the test reveals an exposure difference of interest, the study may be extended so that relevant epidemiologic effect measures can be estimated more accurately.