Reproductive and hormonal factors and risk of renal cell carcinoma among women in the European Prospective Investigation into Cancer and Nutrition

PurposeThe incidence of small intestinal cancer (SIC) is increasing, however, its aetiology remains unclear due to a lack of data from large-scale prospective cohorts. We examined modifiable risk factors in relation to SIC overall and by histological subtype.MethodsWe analysed 450,107 participants enrolled in the European Prospective Investigation into Cancer and Nutrition cohort. Cox proportional hazards models were used to estimate univariable and multivariable hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsDuring an average of 14.1 years of follow-up, 160 incident SICs (62 carcinoids, 51 adenocarcinomas) were identified. Whilst univariable models revealed a positive association for current versus never smokers and SIC (HR, 95% CI: 1.77, 1.21-2.60), this association attenuated in multivariable models. In energy-adjusted models, there was an inverse association across vegetable intake tertiles for SIC overall (HRT3vsT1, 95% CI: 0.48, 0.32-0.71, p-trend: < 0.001) and for carcinoids (HRT3vsT1, 95% CI: 0.44, 0.24-0.82, p-trend: 0.01); however, these attenuated in multivariable models. Total fat was also inversely associated with total SIC and both subtypes but only in the second tertile (SIC univariable HRT2vsT1, 95% CI: 0.57, 0.38-0.84; SIC multivariable HRT2vsT1, 95% CI: 0.55, 0.37-0.81). Physical activity, intake of alcohol, red or processed meat, dairy products, or fibre were not associated with SIC.ConclusionThese exploratory analyses found limited evidence for a role of modifiable risk factors in SIC aetiology. However, sample size was limited, particularly for histologic subtypes; therefore, larger studies are needed to delineate these associations and robustly identify risk factors for SIC

Reproductive and hormonal factors and risk of renal cell carcinoma among women in the European Prospective Investigation into Cancer and Nutrition

Background - Renal cell carcinoma (RCC) is twice as common among men compared with women, and hormonal factors have been suggested to partially explain this difference. There is currently little evidence on the roles of reproductive and hormonal risk factors in RCC aetiology. Materials & Methods - We investigated associations of age at menarche and age at menopause, pregnancy-related factors, hysterectomy and ovariectomy and exogenous hormone use with RCC risk among 298,042 women in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Results - During 15 years of follow-up, 438 RCC cases were identified. Parous women had higher rates of RCC compared with nulliparous women (HR = 1.71, 95% CI 1.18, 2.46), and women who were older at age of first pregnancy had lower rates of RCC (30 years + vs. Conclusion - Our results suggest that parity and reproductive organ surgeries may play a role in RCC aetiology

The implications of three major new trials for the effect of water, sanitation and hygiene on childhood diarrhea and stunting: a consensus statement

BACKGROUND: Three large new trials of unprecedented scale and cost, which included novel factorial designs, have found no effect of basic water, sanitation and hygiene (WASH) interventions on childhood stunting, and only mixed effects on childhood diarrhea. Arriving at the inception of the United Nations' Sustainable Development Goals, and the bold new target of safely managed water, sanitation and hygiene for all by 2030, these results warrant the attention of researchers, policy-makers and practitioners. MAIN BODY: Here we report the conclusions of an expert meeting convened by the World Health Organization and the Bill and Melinda Gates Foundation to discuss these findings, and present five key consensus messages as a basis for wider discussion and debate in the WASH and nutrition sectors. We judge these trials to have high internal validity, constituting good evidence that these specific interventions had no effect on childhood linear growth, and mixed effects on childhood diarrhea. These results suggest that, in settings such as these, more comprehensive or ambitious WASH interventions may be needed to achieve a major impact on child health. CONCLUSION: These results are important because such basic interventions are often deployed in low-income rural settings with the expectation of improving child health, although this is rarely the sole justification. Our view is that these three new trials do not show that WASH in general cannot influence child linear growth, but they do demonstrate that these specific interventions had no influence in settings where stunting remains an important public health challenge. We support a call for transformative WASH, in so much as it encapsulates the guiding principle that - in any context - a comprehensive package of WASH interventions is needed that is tailored to address the local exposure landscape and enteric disease burden

A comparison of complementary measures of vitamin B6 status, function, and metabolism in the European Prospective Investigation into Cancer and Nutrition (EPIC) study

Background: Vitamin B6 insufficiency has been linked to increased risk of cancer and other chronic diseases. The circulating concentration of pyridoxal 5'-phosphate (PLP) is a commonly used measure of vitamin B6 status. Ratios of substrates indicating PLP coenzymatic function and metabolism may be useful complementary measures to further explore the role of vitamin B6 in health. Objectives: We explored the sensitivity of 5 outcomes, namely PLP concentration, homocysteine:cysteine (Hcy:Cys), cystathionine:cysteine (Cysta:Cys), the 3´-hydroxykynurenine ratio (HKr), and the 4-pyridoxic acid ratio (PAr) to vitamin B6 intake as well as personal and lifestyle characteristics. Medthods: Dietary intake and biomarker data were collected from participants from 3 nested case-control studies within the European Prospective Investigation into Cancer and Nutrition (EPIC). Bayesian regression models assessed the associations of the 5 biomarker outcomes with vitamin B6 intake and personal and lifestyle covariates. Analogous models examined the relations of Hcy:Cys, Cysta:Cys, and HKr with PLP. Results: In total, 4608 participants were included in the analyses. Vitamin B6 intake was most strongly associated with PLP, moderately associated with Hcy:Cys, Cysta:Cys, and HKr, and not associated with PAr (fold change in marker given a doubling of vitamin B6 intake: PLP 1.60 [95% credible interval (CrI): 1.50, 1.71]; Hcy:Cys 0.87 [95% CrI: 0.84, 0.90]; Cysta:Cys 0.89 [95% CrI: 0.84, 0.94]; HKr 0.88 [95% CrI: 0.85, 0.91]; PAr 1.00 [95% CrI: 0.95, 1.05]). PAr was most sensitive to age, and HKr was least sensitive to BMI and alcohol intake. Sex and menopause status were strongly associated with all 5 markers. Conclusions: We found that 5 different markers, capturing different aspects of vitamin B6-related biological processes, varied in their associations with vitamin B6 intake and personal and lifestyle predictors

Adherence to oral glucose tolerance testing in children in stage 1 of type 1 diabetes : The TEDDY study

Objective: To examine adherence to the oral glucose tolerance test (OGTT) in multiple islet autoantibody children in stage 1 of developing type 1 diabetes (T1D). Methods: Children are followed from birth in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Completion of an OGTT is recommended every 6 months in children ≥3 years of age who are multiple islet autoantibody positive. Factors associated with adherence to the OGTT protocol were examined. Results: The average subject level adherence with the OGTT protocol was 62% although there were large differences across countries; Finnish participants and older children from Sweden were more adherent than participants from the United States and Germany. Factors associated with nonadherence included having a first-degree relative with T1D, using a local laboratory rather than a TEDDY center for the OGTT, and maternal underestimation of the child's risk for T1D. Children were more adherent to the OGTT if their mothers: were more satisfied with TEDDY participation, reported monitoring the child for T1D by checking blood glucose levels at home, and viewed participating in TEDDY as the primary way they were monitoring the child for T1D. Conclusions: In a study of children in stage 1 of T1D, adherence to an OGTT protocol was suboptimal despite extensive efforts to communicate the child's high risk to parents. These findings provide important guidance for development of strategies to improve methods for detecting progression or the development of T1D in high-risk pediatric populations

Methodological approaches to compile and validate a food composition database for methyl-group carriers in the European Prospective Investigation into Cancer and Nutrition (EPIC) study

A standardised methodology was used to compile and validate a methyl-group carrier database (MGDB) including folate, choline, betaine and methionine, for use in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Compilation was performed by following structured guidelines to match the EPIC dietary intake data to food items from four food composition databases, according to their assigned priority of use. To assess relative validity, calculated dietary folate intakes were compared between the MGDB and the EPIC nutrient database (ENDB), used as the reference database. Folate intakes based on the MGDB and those generated using the ENDB showed good agreement (weighted κ = 0.63) and were strongly correlated (r = 0.81). This MGDB can be used for investigating potential associations between methyl-group carrier intakes and risk or prognosis of cancer and other diseases in the EPIC study population.status: publishe

Methodological approaches to compile and validate a food composition database for methyl-group carriers in the European Prospective Investigation into Cancer and Nutrition (EPIC) study

International audienceA standardised methodology was used to compile and validate a methyl-group carrier database (MGDB) including folate, choline, betaine and methionine, for use in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Compilation was performed by following structured guidelines to match the EPIC dietary intake data to food items from four food composition databases, according to their assigned priority of use. To assess relative validity, calculated dietary folate intakes were compared between the MGDB and the EPIC nutrient database (ENDB), used as the reference database. Folate intakes based on the MGDB and those generated using the ENDB showed good agreement (weighted κ = 0.63) and were strongly correlated (r = 0.81). This MGDB can be used for investigating potential associations between methyl-group carrier intakes and risk or prognosis of cancer and other diseases in the EPIC study population

Dietary Methyl-Group Donor Intake and Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)

We thank the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands, for their contribution to, and ongoing support of, the EPIC Study. We thank Aude De Bruycker for her graphical support.(1) Background: Methyl-group donors (MGDs), including folate, choline, betaine, and methionine, may influence breast cancer (BC) risk through their role in one-carbon metabolism; (2) Methods: We studied the relationship between dietary intakes of MGDs and BC risk, adopting data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort; (3) Results: 318,686 pre- and postmenopausal women were followed between enrolment in 1992–2000 and December 2013–December 2015. Dietary MGD intakes were estimated at baseline through foodfrequency questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary intake of MGDs, measured both as a calculated score based on their sum and individually, and BC risk. Subgroup analyses were performed by hormone receptor status, menopausal status, and level of alcohol intake. During a mean follow-up time of 14.1 years, 13,320 women with malignant BC were identified. No associations were found between dietary intakes of the MGD score or individual MGDs and BC risk. However, a potential U-shaped relationship was observed between dietary folate intake and overall BC risk, suggesting an inverse association for intakes up to 350 µg/day compared to a reference intake of 205 µg/day. No statistically significant differences in the associations were observed by hormone receptor status, menopausal status, or level of alcohol intake; (4) Conclusions: There was no strong evidence for an association between MGDs involved in one-carbon metabolism and BC risk. However, a potential U-shaped trend was suggested for dietary folate intake and BC risk. Further research is needed to clarify this association.Research Foundation Flanders (FWO, 189019N)Research Foundation Flanders (FWO, V427019N)International Agency for Research on Cancer (IARC)Department of Epidemiology and Biostatistics, School of Public Health, Imperial College LondonNIHR Imperial Biomedical Research Center (BRC)Danish Cancer Society (Denmark)Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France)German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany)Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy)Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands)Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology—ICO (Spain)Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden)Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford), (United Kingdom

Predicting progression to type 1 diabetes from ages 3 to 6 in islet autoantibody positive TEDDY children

Abstract Objective: The capacity to precisely predict progression to type 1 diabetes (T1D) in young children over a short time span is an unmet need. We sought to develop a risk algorithm to predict progression in children with high‐risk human leukocyte antigen (HLA) genes followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Methods: Logistic regression and 4‐fold cross‐validation examined 38 candidate predictors of risk from clinical, immunologic, metabolic, and genetic data. TEDDY subjects with at least one persistent, confirmed autoantibody at age 3 were analyzed with progression to T1D by age 6 serving as the primary endpoint. The logistic regression prediction model was compared to two non‐statistical predictors, multiple autoantibody status, and presence of insulinoma‐associated‐2 autoantibodies (IA‐2A). Results: A total of 363 subjects had at least one autoantibody at age 3. Twenty‐one percent of subjects developed T1D by age 6. Logistic regression modeling identified 5 significant predictors ‐ IA‐2A status, hemoglobin A1c, body mass index Z‐score, single‐nucleotide polymorphism rs12708716_G, and a combination marker of autoantibody number plus fasting insulin level. The logistic model yielded a receiver operating characteristic area under the curve (AUC) of 0.80, higher than the two other predictors; however, the differences in AUC, sensitivity, and specificity were small across models. Conclusions: This study highlights the application of precision medicine techniques to predict progression to diabetes over a 3‐year window in TEDDY subjects. This multifaceted model provides preliminary improvement in prediction over simpler prediction tools. Additional tools are needed to maximize the predictive value of these approaches

The implications of three major new trials for the effect of water, sanitation and hygiene on childhood diarrhea and stunting: a consensus statement.

BackgroundThree large new trials of unprecedented scale and cost, which included novel factorial designs, have found no effect of basic water, sanitation and hygiene (WASH) interventions on childhood stunting, and only mixed effects on childhood diarrhea. Arriving at the inception of the United Nations' Sustainable Development Goals, and the bold new target of safely managed water, sanitation and hygiene for all by 2030, these results warrant the attention of researchers, policy-makers and practitioners.Main bodyHere we report the conclusions of an expert meeting convened by the World Health Organization and the Bill and Melinda Gates Foundation to discuss these findings, and present five key consensus messages as a basis for wider discussion and debate in the WASH and nutrition sectors. We judge these trials to have high internal validity, constituting good evidence that these specific interventions had no effect on childhood linear growth, and mixed effects on childhood diarrhea. These results suggest that, in settings such as these, more comprehensive or ambitious WASH interventions may be needed to achieve a major impact on child health.ConclusionThese results are important because such basic interventions are often deployed in low-income rural settings with the expectation of improving child health, although this is rarely the sole justification. Our view is that these three new trials do not show that WASH in general cannot influence child linear growth, but they do demonstrate that these specific interventions had no influence in settings where stunting remains an important public health challenge. We support a call for transformative WASH, in so much as it encapsulates the guiding principle that - in any context - a comprehensive package of WASH interventions is needed that is tailored to address the local exposure landscape and enteric disease burden