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PURPOSE: Understanding seasonal variation in physical activity is important for informing public health surveillance and intervention design. The aim of the current study was to describe seasonal variation in children's objectively measured physical activity and sedentary time. METHODS: Data are from the UK Millennium Cohort Study. Participants were invited to wear an accelerometer for 7 d on five occasions between November 2008 and January 2010. Outcome variables were sedentary time (2241 counts per minute, min·d(-1)). The season was characterized using a categorical variable (spring, summer, autumn, or winter) and a continuous function of day of the year. Cross-classified linear regression models were used to estimate the association of each of these constructs with the outcome variables. Modification of the seasonal variation by sex, weight status, urban/rural location, parental income, and day of the week (weekday/weekend) was examined using interaction terms in regression models. RESULTS: At least one wave of valid accelerometer data was obtained from 704 participants (47% male; baseline age, 7.6 (0.3) yr). MVPA was lower in autumn and winter relative to spring, with the magnitude of this difference varying by weekday/weekend, sex, weight status, urban/rural location, and family income (P for interaction <0.05 in all cases). Total sedentary time was greater in autumn and winter compared with spring; the seasonal effect was stronger during the weekend than during the weekday (P for interaction <0.01). CONCLUSIONS: Lower levels of MVPA and elevated sedentary time support the implementation of intervention programs during autumn and winter. Evidence of greater seasonal variation in weekend behavior and among certain sociodemographic subgroups highlights targets for tailored intervention programs. ; The co-operation of the participating families is gratefully acknowledged. The fourth sweep of the Millennium Cohort Study was funded by grants to Professor Health Joshi, former director of the study, from the Economic and Social Research Council and a consortium of government funders. The current director is Professor Lucinda Platt. The authors acknowledge: the Centre for Longitudinal Studies, Institute of Education for the use of these data; the UK Data Service for making them available; the MRC Centre of Epidemiology for Child Health (Grant reference G0400546), Institute of Child Health, University College London for creating the accelerometer data resource which was funded by the Wellcome Trust (grant reference 084686/Z/08/A). The institutions and funders acknowledged bear no responsibility for the analysis or interpretation of these data. The work of Andrew J Atkin, Flo Harrison, and Esther M F van Sluijs was supported, wholly or in part, by the Centre for Diet and Activity Research (CEDAR), a UKCRC Public Health Research Centre of Excellence (RES-590-28-0002). Funding from the British Heart Foundation, Department of Health, Economic and Social Research Council, Medical Research Council, and the Wellcome Trust, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged. The work of Soren Brage, Stephen Sharp and Esther MF van Sluijs was supported by the Medical Research Council (MC_UU_12015/7, MC_UU_12015/3, MC_UU_12015/1). ; This is the final version of the article. It first appeared from Wolters Kluwer via http://dx.doi.org/10.1249/MSS.0000000000000786

Abstract Background: The disease or mortality burdens of unhealthy lifestyle behaviours are often reported. The positive side of the story, the burden that existing levels have averted, is rarely discussed. We present what we believe to be global application of the Prevented Fraction for the Population to obtain estimates of the percentage of premature mortality and number of premature deaths averted by total physical activity levels for 168 countries. Methods: We combined previously published activity prevalence data (2001-2016) and relative risks of mortality in Monte-Carlo simulations to estimate country-specific Prevented Fractions for the Population (percentage of mortality averted) and their 95% confidence intervals. Higher Prevented Fractions indicate a greater proportion of deaths averted due to physical activity. Using mortality data for 40-74 year olds, we estimated the number of premature deaths averted due to activity levels for all adults and by sex. We presented the median and range of the Prevented Fractions globally, by region, and by income classification. Results: The global median Prevented Fraction for the Population was 15.0% (range 6.6-20.5%), conservatively equating to 3.9 million (95% confidence interval: 2.5-5.6) premature deaths averted annually. The African region had the highest median (16.6%, range 12.1-20.5%), the Americas had the lowest (13.1%, range 10.8-16.6%). Low income countries tended to have higher median Prevented Fractions (17.9%, range 12.3-20.5%) than high income countries (14.1%, range 6.6-17.8%). Globally, the median Prevented Fraction was higher for men than women (16.0% (range 7.8-20.7% and 14.1% (range 5.0-20.4%), respectively). Interpretation: Existing physical activity levels have contributed to averting premature mortality across all countries. The Prevented Fraction for the Population has utility as an advocacy tool to promote healthy lifestyle behaviours as, by making the case of what has been achieved, it could demonstrate the value of current investment and services. This may be more conducive to political support. ; TS, SJS, and SB are funded by the UK Medical Research Council (MC_UU_12015/1 and MC_UU_12015/3). DD is funded by a Future Leader Fellowship by Heart Foundation Australia (No. 101234). At the time of this work, MT was a member of the Centre for Diet and Activity Research (MR/K023187/1), a UKCRC Public Health Research Centre of Excellence. Funding from the British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, National Institute for Health Research (NIHR), and Wellcome Trust, under the auspices of the UKClinical Research Collaboration, is gratefully acknowledged. MT was also funded on the METAHIT project (Medical Research Council grant MR/P02663X/1).

BACKGROUND: Disease and mortality burdens of unhealthy lifestyle behaviours are often reported. In contrast, the positive narrative around the burdens that an existing behaviour have averted is rarely acknowledged. We aimed to estimate the prevented fraction for the population (PFP) for premature mortality averted by physical activity on a global scale. METHODS: In this descriptive study, we obtained previously published data on physical activity prevalence (2001–16) and relative risks of all-cause mortality for 168 countries. We combined the data in Monte-Carlo simulations to estimate country-specific, mean PFP values, corresponding to percentage of mortality averted, and their 95% CIs. High prevented fractions indicated an increased proportion of deaths averted due to physical activity. Using mortality data for all people in a country aged 40–74 years, we estimated the number of premature deaths averted for all adults and by gender. We present the median and range of the prevented fractions globally, by WHO region, and by World Bank income classification. FINDINGS: The global median PFP was 15·0% (range 6·6–20·5), conservatively equating to 3·9 million (95% CI 2·5–5·6) premature deaths averted annually. The African region had the highest median prevented fraction (16·6% [range 12·1–20·5]) and the Americas had the lowest (13·1% [10·8–16·6]). Low-income countries tended to have higher prevented fractions (group median 17·9% [12·3–20·5]) than high-income countries (14·1% [6·6–17·8]). Globally, the median prevented fraction was higher for men (16·0% [7·8–20·7] than women (14·1% [5·0–20·4]). INTERPRETATION: Existing physical activity prevalence has contributed to averting premature mortality across all countries. PFP has utility as an advocacy tool to promote healthy lifestyle behaviours. By making the case of what has been achieved, the prevented fraction can show the value of current investment and services, which might be conducive to political support. FUNDING: UK Medical Research Council, British Heart ...

BACKGROUND: The World Health Organization has advocated for sugar-sweetened beverage (SSB) taxes as part of a broader non-communicable disease prevention strategy, and these taxes have been recently introduced in a wide range of settings. However, much is still unknown about how SSB taxes operate in various contexts and as a result of different tax designs. In 2015, the Government of Barbados implemented a 10% ad valorem (value-based) tax on SSBs. It has been hypothesized that this tax structure may inadvertently encourage consumers to switch to cheaper sugary drinks. We aimed to assess whether and to what extent there has been a change in sales of SSBs following implementation of the SSB tax. METHODS: We used electronic point of sale data from a major grocery store chain and applied an interrupted time series (ITS) design to assess grocery store SSB and non-SSB sales from January 2013 to October 2016. We controlled for the underlying time trend, seasonality, inflation, tourism and holidays. We conducted sensitivity analyses using a cross-country control (Trinidad and Tobago) and a within-country control (vinegar). We included a post-hoc stratification by price tertile to assess the extent to which consumers may switch to cheaper sugary drinks. RESULTS: We found that average weekly sales of SSBs decreased by 4.3% (95%CI 3.6 to 4.9%) compared to expected sales without a tax, primarily driven by a decrease in carbonated SSBs sales of 3.6% (95%CI 2.9 to 4.4%). Sales of non-SSBs increased by 5.2% (95%CI 4.5 to 5.9%), with bottled water sales increasing by an average of 7.5% (95%CI 6.5 to 8.3%). The sensitivity analyses were consistent with the uncontrolled results. After stratifying by price, we found evidence of substitution to cheaper SSBs. CONCLUSIONS: This study suggests that the Barbados SSB tax was associated with decreased sales of SSBs in a major grocery store chain after controlling for underlying trends. This finding was robust to sensitivity analyses. We found evidence to suggest that consumers may have changed their behaviour in response to the tax by purchasing cheaper sugary drinks, in addition to substituting to untaxed products. This has important implications for the design of future SSB taxes. ; MA is funded through a Gates Cambridge PhD Scholarship, and received travel funding from Robinson College, the Global Food Security Fund, the Luca D'Agliano Scholarship, the Yates Unilever Fund and the Smuts Memorial Fund. JA is funded by the Centre for Diet and Activity Research (CEDAR), a UKCRC Public Health Research Centre of Excellence. Funding from the British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, the National Institute for Health Research, and the Wellcome Trust, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged.

BACKGROUND: Low circulating concentrations of 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, are associated with an increased risk of type 2 diabetes, but whether this association is causal remains unclear. We aimed to estimate the unconfounded, causal association between 25(OH)D concentration and risk of type 2 diabetes using a mendelian randomisation approach. METHODS: Using several data sources from populations of European descent, including type 2 diabetes cases and non-cases, we did a mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) within or near four genes related to 25(OH)D synthesis and metabolism: DHCR7 (related to vitamin D synthesis), CYP2R1 (hepatic 25-hydroxylation), DBP (also known as GC; transport), and CYP24A1 (catabolism). We assessed each SNP for an association with circulating 25(OH)D concentration (5449 non-cases; two studies), risk of type 2 diabetes (28 144 cases, 76 344 non-cases; five studies), and glycaemic traits (concentrations of fasting glucose, 2-h glucose, fasting insulin, and HbA1c; 46 368 non-cases; study consortium). We combined these associations in a likelihood-based mendelian randomisation analysis to estimate the causal association of 25(OH)D concentration with type 2 diabetes and the glycaemic traits, and compared them with that from a meta-analysis of data from observational studies (8492 cases, 89 698 non-cases; 22 studies) that assessed the association between 25(OH)D concentration and type 2 diabetes. FINDINGS: All four SNPs were associated with 25(OH)D concentrations (p0·25). INTERPRETATION: The association between 25(OH)D concentration and type 2 diabetes is unlikely to be causal. Efforts to increase 25(OH)D concentrations might not reduce the risk of type 2 diabetes as would be expected on the basis of observational evidence. These findings warrant further investigations to identify causal factors that might increase 25(OH)D concentration and also reduce the risk of type 2 diabetes. FUNDING: UK Medical Research Council Epidemiology Unit and European Union Sixth Framework Programme. ; This is the final published version. It is available from Elsevier in The Lancet Diabetes & Endocrinology here: http://www.sciencedirect.com/science/article/pii/S2213858714701846.

Background: The World Health Organization has advocated for sugar-sweetened beverage (SSB) taxes as part of a broader non-communicable disease prevention strategy, and these taxes have been recently introduced in a wide range of settings. However, much is still unknown about how SSB taxes operate in various contexts and as a result of different tax designs. In 2015, the Government of Barbados implemented a 10% ad valorem (value-based) tax on SSBs. It has been hypothesized that this tax structure may inadvertently encourage consumers to switch to cheaper sugary drinks. We aimed to assess whether and to what extent there has been a change in sales of SSBs following implementation of the SSB tax. Methods: We used electronic point of sale data from a major grocery store chain and applied an interrupted time series (ITS) design to assess grocery store SSB and non-SSB sales from January 2013 to October 2016. We controlled for the underlying time trend, seasonality, inflation, tourism and holidays. We conducted sensitivity analyses using a cross-country control (Trinidad and Tobago) and a within-country control (vinegar). We included a post-hoc stratification by price tertile to assess the extent to which consumers may switch to cheaper sugary drinks. Results: We found that average weekly sales of SSBs decreased by 4.3% (95%CI 3.6 to 4.9%) compared to expected sales without a tax, primarily driven by a decrease in carbonated SSBs sales of 3.6% (95%CI 2.9 to 4.4%). Sales of non-SSBs increased by 5.2% (95%CI 4.5 to 5.9%), with bottled water sales increasing by an average of 7.5% (95%CI 6.5 to 8.3%). The sensitivity analyses were consistent with the uncontrolled results. After stratifying by price, we found evidence of substitution to cheaper SSBs. Conclusions: This study suggests that the Barbados SSB tax was associated with decreased sales of SSBs in a major grocery store chain after controlling for underlying trends. This finding was robust to sensitivity analyses. We found evidence to suggest that consumers may have ...

OBJECTIVE: To evaluate the association between physical distancing interventions and incidence of coronavirus disease 2019 (covid-19) globally. DESIGN: Natural experiment using interrupted time series analysis, with results synthesised using meta-analysis. SETTING: 149 countries or regions, with data on daily reported cases of covid-19 from the European Centre for Disease Prevention and Control and data on the physical distancing policies from the Oxford covid-19 Government Response Tracker. PARTICIPANTS: Individual countries or regions that implemented one of the five physical distancing interventions (closures of schools, workplaces, and public transport, restrictions on mass gatherings and public events, and restrictions on movement (lockdowns)) between 1 January and 30 May 2020. MAIN OUTCOME MEASURE: Incidence rate ratios (IRRs) of covid-19 before and after implementation of physical distancing interventions, estimated using data to 30 May 2020 or 30 days post-intervention, whichever occurred first. IRRs were synthesised across countries using random effects meta-analysis. RESULTS: On average, implementation of any physical distancing intervention was associated with an overall reduction in covid-19 incidence of 13% (IRR 0.87, 95% confidence interval 0.85 to 0.89; n=149 countries). Closure of public transport was not associated with any additional reduction in covid-19 incidence when the other four physical distancing interventions were in place (pooled IRR with and without public transport closure was 0.85, 0.82 to 0.88; n=72, and 0.87, 0.84 to 0.91; n=32, respectively). Data from 11 countries also suggested similar overall effectiveness (pooled IRR 0.85, 0.81 to 0.89) when school closures, workplace closures, and restrictions on mass gatherings were in place. In terms of sequence of interventions, earlier implementation of lockdown was associated with a larger reduction in covid-19 incidence (pooled IRR 0.86, 0.84 to 0.89; n=105) compared with a delayed implementation of lockdown after other physical distancing interventions were in place (pooled IRR 0.90, 0.87 to 0.94; n=41). CONCLUSIONS: Physical distancing interventions were associated with reductions in the incidence of covid-19 globally. No evidence was found of an additional effect of public transport closure when the other four physical distancing measures were in place. Earlier implementation of lockdown was associated with a larger reduction in the incidence of covid-19. These findings might support policy decisions as countries prepare to impose or lift physical distancing measures in current or future epidemic waves.

OBJECTIVE: To evaluate the association between physical distancing interventions and incidence of coronavirus disease 2019 (covid-19) globally. DESIGN: Natural experiment using interrupted time series analysis, with results synthesised using meta-analysis. SETTING: 149 countries or regions, with data on daily reported cases of covid-19 from the European Centre for Disease Prevention and Control and data on the physical distancing policies from the Oxford covid-19 Government Response Tracker. PARTICIPANTS: Individual countries or regions that implemented one of the five physical distancing interventions (closures of schools, workplaces, and public transport, restrictions on mass gatherings and public events, and restrictions on movement (lockdowns)) between 1 January and 30 May 2020. MAIN OUTCOME MEASURE: Incidence rate ratios (IRRs) of covid-19 before and after implementation of physical distancing interventions, estimated using data to 30 May 2020 or 30 days post-intervention, whichever occurred first. IRRs were synthesised across countries using random effects meta-analysis. RESULTS: On average, implementation of any physical distancing intervention was associated with an overall reduction in covid-19 incidence of 13% (IRR 0.87, 95% confidence interval 0.85 to 0.89; n=149 countries). Closure of public transport was not associated with any additional reduction in covid-19 incidence when the other four physical distancing interventions were in place (pooled IRR with and without public transport closure was 0.85, 0.82 to 0.88; n=72, and 0.87, 0.84 to 0.91; n=32, respectively). Data from 11 countries also suggested similar overall effectiveness (pooled IRR 0.85, 0.81 to 0.89) when school closures, workplace closures, and restrictions on mass gatherings were in place. In terms of sequence of interventions, earlier implementation of lockdown was associated with a larger reduction in covid-19 incidence (pooled IRR 0.86, 0.84 to 0.89; n=105) compared with a delayed implementation of lockdown after other physical ...

INTRODUCTION: Adolescent physical activity promotion is rarely effective, despite adolescence being critical for preventing physical activity decline. Low adolescent physical activity is likely to last into adulthood, increasing health risks. The Get Others Active (GoActive) intervention is evidence-based and was developed iteratively with adolescents and teachers. This intervention aims to increase physical activity through increased peer support, self-efficacy, group cohesion, self-esteem and friendship quality, and is implemented using a tiered-leadership system. We previously established feasibility in one school and conducted a pilot randomised controlled trial (RCT) in three schools. METHODS AND ANALYSIS: We will conduct a school-based cluster RCT (CRCT) in 16 secondary schools targeting all year 9 students (n=2400). In eight schools, GoActive will run for two terms: weekly facilitation support from a council-funded intervention facilitator will be offered in term 1, with more distant support in term 2. Tutor groups choose two weekly activities, encouraged by older adolescent mentors and weekly peer leaders. Students gain points for trying new activities; points are entered into a between-class competition. Outcomes will be assessed at baseline, interim (week 6), postintervention (week 14-16) and 10-month follow-up (main outcome). The primary outcome will be change from baseline in daily accelerometer-assessed moderate-to-vigorous physical activity. Secondary outcomes include accelerometer-assessed activity intensities on weekdays/weekends; self-reported physical activity and psychosocial outcomes; cost-effectiveness and cost-utility analyses; mixed-methods process evaluation integrating information from focus groups and participation logs/questionnaires. ETHICS AND DISSEMINATION: Ethical approval for the conduct of the study was gained from the University of Cambridge Psychology Research Ethics Committee. Given the lack of rigorously evaluated interventions, and the inclusion of objective measurement of physical activity, long-term follow-up and testing of causal pathways, the results of a CRCT of the effectiveness and cost-effectiveness of GoActive are expected to add substantially to the limited evidence on adolescent physical activity promotion. Workshops will be held with key stakeholders including students, parents, teachers, school governors and government representatives to discuss plans for wider dissemination of the intervention. TRIAL REGISTRATION NUMBER: ISRCTN31583496.

ACKNOWLEDGEMENTS We would like to thank Keith Summerhill, Laura Wang, and Stephen Young for the measurement of plasma phospholipid fatty acids. We also want to thank all the participants in the EPIC-Norfolk study. Medical Research Council Epidemiology Unit MC_UU_12015/1 and MC_UU_12015/5; Medical Research Council Human Nutrition Research MC_UP_A090_1006; Cambridge Lipidomics Biomarker Research Initiative G0800783; NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014). Dr Ju-Sheng Zheng has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 701708. ; Peer reviewed ; Publisher PDF

Introduction: Adolescent physical activity promotion is rarely effective, despite adolescence being critical for preventing physical activity decline. Low adolescent physical activity is likely to last into adulthood, increasing health risks. The Get Others Active (GoActive) intervention is evidence-based and was developed iteratively with adolescents and teachers. This intervention aims to increase physical activity through increased peer support, self-efficacy, group cohesion, self-esteem and friendship quality, and is implemented using a tiered-leadership system. We previously established feasibility in one school and conducted a pilot randomised controlled trial (RCT) in three schools. Methods and analysis: We will conduct a school-based cluster RCT (CRCT) in 16 secondary schools targeting all year 9 students (n=2400). In eight schools, GoActive will run for two terms: weekly facilitation support from a council-funded intervention facilitator will be offered in term 1, with more distant support in term 2. Tutor groups choose two weekly activities, encouraged by older adolescent mentors and weekly peer leaders. Students gain points for trying new activities; points are entered into a between-class competition. Outcomes will be assessed at baseline, interim (week 6), postintervention (week 14-16) and 10-month follow-up (main outcome). The primary outcome will be change from baseline in daily accelerometer-assessed moderate-to-vigorous physical activity. Secondary outcomes include accelerometer-assessed activity intensities on weekdays/weekends; self-reported physical activity and psychosocial outcomes; cost-effectiveness and cost-utility analyses; mixed-methods process evaluation integrating information from focus groups and participation logs/questionnaires. Ethics and dissemination: Ethical approval for the conduct of the study was gained from the University of Cambridge Psychology Research Ethics Committee. Given the lack of rigorously evaluated interventions, and the inclusion of objective measurement of physical activity, long-term follow-up and testing of causal pathways, the results of a CRCT of the effectiveness and cost-effectiveness of GoActive are expected to add substantially to the limited evidence on adolescent physical activity promotion. Workshops will be held with key stakeholders including students, parents, teachers, school governors and government representatives to discuss plans for wider dissemination of the intervention.

BACKGROUND: Insulinemia and type 2 diabetes (T2D) have been associated with endometrial cancer risk in numerous observational studies. However, the causality of these associations is uncertain. Here we use a Mendelian randomization (MR) approach to assess whether insulinemia and T2D are causally associated with endometrial cancer. METHODS: We used single nucleotide polymorphisms (SNPs) associated with T2D (49 variants), fasting glucose (36 variants), fasting insulin (18 variants), early insulin secretion (17 variants), and body mass index (BMI) (32 variants) as instrumental variables in MR analyses. We calculated MR estimates for each risk factor with endometrial cancer using an inverse-variance weighted method with SNP-endometrial cancer associations from 1287 case patients and 8273 control participants. RESULTS: Genetically predicted higher fasting insulin levels were associated with greater risk of endometrial cancer (odds ratio [OR] per standard deviation = 2.34, 95% confidence internal [CI] = 1.06 to 5.14, P = .03). Consistently, genetically predicted higher 30-minute postchallenge insulin levels were also associated with endometrial cancer risk (OR = 1.40, 95% CI = 1.12 to 1.76, P = .003). We observed no associations between genetic risk of type 2 diabetes (OR = 0.91, 95% CI = 0.79 to 1.04, P = .16) or higher fasting glucose (OR = 1.00, 95% CI = 0.67 to 1.50, P = .99) and endometrial cancer. In contrast, endometrial cancer risk was higher in individuals with genetically predicted higher BMI (OR = 3.86, 95% CI = 2.24 to 6.64, P = 1.2x10(-6)). CONCLUSION: This study provides evidence to support a causal association of higher insulin levels, independently of BMI, with endometrial cancer risk. ; This study was supported by MRC grant MC_UU_12015/1 and by the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n° 115372 (contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies). ANECS recruitment was supported by project grants from the National Health and Medical Research Council of Australia (ID#339435), The Cancer Council Queensland (ID#4196615) and Cancer Council Tasmania (ID#403031 and ID#457636). SEARCH recruitment was funded by a programme grant from Cancer Research UK [C490/A10124]. Case genotyping was supported by the National Health and Medical Research Council (ID#552402). Control data was generated by the Wellcome Trust Case Control Consortium (WTCCC), and a full list of the investigators who contributed to the generation of the data is available from the WTCCC website. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. Funding for this project was provided by the Wellcome Trust under award 085475. Recruitment of the QIMR controls was supported by the National Health and Medical Research Council of Australia (NHMRC). The University of Newcastle, the Gladys M Brawn Senior Research Fellowship scheme, The Vincent Fairfax Family Foundation, the Hunter Medical Research Institute and the Hunter Area Pathology Service all contributed towards the costs of establishing the Hunter Community Study. K.T.N. was supported by the Gates Cambridge Trust. R.K.S. is supported by the Wellcome Trust (grant number WT098498). A.B.S. is supported by the National Health and Medical Research Council (NHMRC) Fellowship Scheme. D.F.E. is a Principal Research Fellow of Cancer Research UK. A.M.D is supported by the Joseph Mitchell Trust. ; This is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/jnci/djv178