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Abstract Because alcohol consumption is an established cause of female breast cancer, understanding whether cessation affects risk is of public health importance. In a recent meta-analysis, compared with continuing consumption, the relative risk (RR) for cessation was 0.95 (95% confidence interval [CI] 0.88–1.01). Because intake of alcohol is more consistently associated with estrogen receptor positive (ER+) than negative (ER-) subtypes, we conducted a meta-analysis of alcohol cessation for ER-specific breast cancer risk using data from three cohort studies and one population-based case-control study (ER + n = 3,793; ER- n = 627) with information reported on cessation and ER status. Compared with continuing consumption, cessation was associated with lower risk of ER+ (RR = 0.88, 95%CI, 0.79–0.98) but not ER- (RR = 1.23, 95%CI, 0.98–1.55) breast cancer. These results suggest that, compared with continuing consumption, alcohol cessation may reduce ER + but not ER- breast cancer risk. However, research that considers duration of cessation is warranted.

Abstract Background Quantifying the benefits and harms of breast cancer screening accurately is important for planning and evaluating screening programs and for enabling women to make informed decisions about participation. However, few cohort studies have attempted to estimate benefit and harm simultaneously. Aims We aimed to quantify the impact of mammographic screening on breast cancer mortality and overdiagnosis using a cohort of women invited to attend Australia's national screening program, BreastScreen. Methods In a cohort of 41,330 women without prior breast cancer diagnosis, screening, or diagnostic procedures invited to attend BreastScreen Western Australia in 1994‐1995, we estimated the cumulative risk of breast cancer mortality and breast cancer incidence (invasive and ductal carcinoma in situ) from age 50 to 85 years for attenders and non‐attenders. Data were obtained by linking population‐based state and national health registries. Breast cancer mortality risks were estimated from a survival analysis that accounted for competing risk of death from other causes. Breast cancer risk for unscreened women was estimated by survival analysis, while accounting for competing causes of death. For screened women, breast cancer risk was the sum of risk of being diagnosed at first screen, estimated using logistic regression, and risk of diagnosis following a negative first screen estimated from a survival analysis. Results For every 1,000 women 50 years old at first invitation to attend BreastScreen, there were 20 (95% CI 12‐30) fewer breast cancer deaths and 25 (95% CI 15‐35) more breast cancers diagnosed for women who attended than for non‐attendees by age 85. Of the breast cancers diagnosed in screened women, 21% (95% CI 13%‐27%) could be attributed to screening. Discussion The estimated ratio of benefit to harm was consistent with, but slightly less favourable to screening than most other estimates from cohort studies. Conclusion Women who participate in organised screening for breast cancer in Australia have substantially lower breast cancer mortality, while some screen‐detected cancers may be overdiagnosed.

ABSTRACTObservational studies suggest a link between vitamin D and the composition of the gut microbiome, but there is little evidence from randomized controlled trials of vitamin D supplementation. We analyzed data from the D-Health Trial, a randomized, double-blind, placebo-controlled trial. We recruited 21,315 Australians aged 60–84 y and randomized them to 60,000 IU of vitamin D3 or placebo monthly for 5 y. Stool samples were collected from a sample of 835 participants (417 in the placebo and 418 in the vitamin D group) approximately 5 y after randomization. We characterized the gut microbiome using 16S rRNA gene sequencing. We used linear regression to compare alpha diversity indices (i.e. Shannon index (primary outcome), richness, inverse Simpson index), and the ratio of Firmicutes to Bacteroidetes between the two groups. We analyzed between-sample (beta) diversity (i.e. Bray Curtis distance and UniFrac index) using principal coordinate analysis and used PERMANOVA to test for significant clustering according to randomization group. We also assessed the difference in the abundance of the 20 most abundant genera between the two groups using negative binomial regression model with adjustment for multiple testing. Approximately half the participants included in this analysis were women (mean age 69.4 y). Vitamin D supplementation did not alter the Shannon diversity index (mean 3.51 versus 3.52 in the placebo and vitamin D groups, respectively, p = 0.50). Similarly, there was little difference between the groups for other alpha diversity indices, the abundance of different genera, and the Firmicutes-to-Bacteroidetes ratio. We did not observe clustering of bacterial communities according to randomization group. In conlusion, monthly doses of 60,000 IU of vitamin D supplementation for 5 y did not alter the composition of the gut microbiome in older Australians.

Lifestyle-related phenotypes have been shown to be heritable and associated with DNA methylation. We aimed to investigate whether genetic predisposition to tobacco smoking, alcohol consumption, and higher body mass index (BMI) moderates the effect of these phenotypes on blood DNA methylation. We calculated polygenic scores (PGS) to quantify genetic predisposition to these phenotypes using training (N = 7,431) and validation (N = 4,307) samples. Using paired genetic-methylation data (N = 4,307), gene–environment interactions (i.e., PGS × lifestyle) were assessed using linear mixed-effects models with outcomes: 1) methylation at sites found to be strongly associated with smoking (1,061 CpGs), alcohol consumption (459 CpGs), and BMI (85 CpGs) and 2) two epigenetic ageing measures, PhenoAge and GrimAge. In the validation sample, PGS explained ~1.4% (P = 1 × 10−14), ~0.6% (P = 2 × 10−7), and ~8.7% (P = 7 × 10−87) of variance in smoking initiation, alcohol consumption, and BMI, respectively. Nominally significant interaction effects (P

Abstract Background Higher levels of time spent sitting (sedentary behavior) contribute to adverse health outcomes, including earlier death. This effect may be modified by other lifestyle factors. We examined the association of television viewing (TV), a common leisure-time sedentary behavior, with all-cause mortality, and whether this is modified by body mass index (BMI), physical activity, smoking, alcohol intake, soft drink consumption, or diet-associated inflammation. Methods Using data from participants in the Melbourne Collaborative Cohort Study, flexible parametric survival models assessed the time-dependent association of self-reported TV time (three categories: 3 h/day) with all-cause mortality. Interaction terms were fitted to test whether there was effect modification of TV time by the other risk factors. Results From 19,570 participants, 4,417 deaths were reported over a median follow up of 14.5 years. More TV time was associated with earlier mortality; however, this relationship diminished with increasing age. The hazard ratio (HR) and 95% confidence interval (95% CI) for > 3 h/day compared with 0.16). Conclusions The relationship between TV time and all-cause mortality may change with age. It may also be more pronounced in those who are otherwise inactive or who have a pro-inflammatory diet.

Abstract Multiple myeloma (MM) is the second most common hematological cancer and causes significant mortality and morbidity. Knowledge regarding modifiable risk factors for MM remains limited. This analysis of an Australian population‐based case–control family study investigates whether smoking or alcohol consumption is associated with risk of MM and related diseases. Incident cases (n = 789) of MM were recruited via cancer registries in Victoria and New South Wales. Controls (n = 1,113) were either family members of cases (n = 696) or controls recruited for a similarly designed study of renal cancers (n = 417). Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional multivariable logistic regression. Heavy intake (>20 g ethanol/day) of alcohol had a lower risk of MM compared with nondrinkers (OR = 0.68, 95% CI: 0.50–0.93), and there was an inverse dose–response relationship for average daily alcohol intake (OR per 10 g ethanol per day = 0.92, 95% CI: 0.86–0.99); there was no evidence of an interaction with sex. There was no evidence of an association with MM risk for smoking‐related exposures (p > 0.18). The associations between smoking and alcohol with MM are similar to those with non‐Hodgkin lymphoma. Further research into potential underlying mechanisms is warranted.

Abstract Background Mechanisms underlying the adiposity–cancer relationship are incompletely understood. We quantified the mediating roles of C‐reactive protein (CRP), leptin, fasting insulin, and estradiol in the effect of adiposity on estrogen receptor (ER)‐positive breast, endometrial, and colorectal cancer risk in postmenopausal women. Methods We used a case–cohort study within the Women's Health Initiative Observational Study, analyzed as a cumulative sampling case–control study. The study included 188 breast cancer cases, 98 endometrial cancer cases, 193 colorectal cancer cases, and 285 controls. Interventional indirect and direct effects on the risk ratio (RR) scale were estimated using causal mediation analysis. Results For breast cancer, the total effect RR for BMI ≥30 versus ≥18.5–

Abstract Background Falls cause considerable morbidity and mortality in older people. It is unclear how vitamin D supplementation affects falls risk, particularly when taken at high doses. We sought to determine whether monthly high‐dose vitamin D supplementation reduces risk and incidence of falls. Methods We used data from the randomized, double‐blind, placebo‐controlled D‐Health Trial conducted in Australia. Between February 2014 and May 2015, 21 315 participants aged 60–84 years were randomized (1:1) to monthly doses of either 60 000 IU of colecalciferol or placebo for a maximum of 5 years. People who reported a history of osteomalacia, sarcoidosis, hyperparathyroidism, hypercalcaemia or kidney stones or who were taking >500 IU/day supplementary vitamin D were ineligible. Each year, we collected blood samples from ~450 randomly sampled participants from each trial arm and measured 25‐hydroxyvitamin D [25(OH)D]. Falls, a prespecified tertiary outcome, were ascertained using annual surveys and, for a subset of participants, 3‐month falls diaries. The primary outcome for this analysis was any fall in the month before completing an annual survey. As part of our process to maintain blinding, we used random samples of participants (surveys, n = 16 000; diaries, n = 2400), with equal numbers per group. Participants with no outcome data were excluded. Following an intention‐to‐treat approach, we analysed outcomes using logistic, ordinal and negative binomial regression. Registration: Australian New Zealand Clinical Trials Registry (ACTRN12613000743763); registered 4 July 2013. Results Mean treatment duration was 4.3 years (standard deviation [SD] = 1.4 years). Mean serum 25(OH)D concentrations during the trial were 114.8 (SD 30.3) nmol/L and 77.5 (SD 25.2) nmol/L in the vitamin D and placebo groups, respectively. Survey and diary analytic sets included 15 416 and 2200 participants, respectively; approximately half were randomized to vitamin D (surveys: 50.1%; diaries: 50.4%). Vitamin D had no effect on falling in the past month (odds ratio [OR] 1.02, 95% confidence interval [CI] 0.95–1.10). There was an interaction with body mass index (BMI) (P‐interaction = 0.001); vitamin D increased risk in participants with BMI

Abstract Background To examine the association between circulating 25(OH)D concentrations and incidence of total hip replacement for osteoarthritis in a prospective cohort study. Methods This study examined a random sample of 2651 participants in the Melbourne Collaborative Cohort Study who had 25(OH)D concentrations measured from dried blood spots collected in 1990-1994. Participants who underwent total hip replacement for osteoarthritis between January 2001 and December 2018 were identified by linking the cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of total hip replacement for osteoarthritis in relation to 25(OH)D concentrations, adjusted for confounders. Results Eighty-six men and eighty-seven women had a total hip replacement for osteoarthritis. Compared with men in the lowest (1st) quartile of 25(OH)D concentration, the HR for total hip replacement was 2.32 (95% CI 1.05, 5.13) for those in the 2nd quartile, 2.77 (95% CI 1.28, 6.00) for those in the 3rd quartile, and 1.73 (95% CI 0.75, 4.02) for those in the highest quartile of 25(OH)D concentrations (p for trend 0.02). There was little evidence of an association in women. Conclusions Higher circulating 25(OH)D concentrations were associated with an increased risk of total hip replacement for osteoarthritis in men but not in women. Although the underlying mechanism warrants further investigation, our findings highlight the need to determine the optimal levels of circulating 25(OH)D to reduce the risk of hip osteoarthritis.

We conducted a genome-wide association study of blood DNA methylation and smoking, attempted replication of previously discovered associations, and assessed the reversibility of smoking-associated methylation changes. DNA methylation was measured in baseline peripheral blood samples for 5,044 participants in the Melbourne Collaborative Cohort Study. For 1,032 participants, these measures were repeated using blood samples collected at follow-up, a median of 11 years later. A cross-sectional analysis of the association between smoking and DNA methylation and a longitudinal analysis of changes in smoking status and changes in DNA methylation were conducted. We used our cross-sectional analysis to replicate previously reported associations for current (N = 3,327) and former (N = 172) smoking. A comprehensive smoking index accounting for the biological half-life of smoking compounds and several aspects of smoking history was constructed to assess the reversibility of smoking-induced methylation changes. This measure of lifetime exposure to smoking allowed us to detect more associations than comparing current with never smokers. We identified 4,496 cross-sectional associations at P

Abstract Objective: Length of hospital stay (LOS) is considered a vital component for successful colorectal surgery treatment. Evidence of an association between hospital surgery volume and LOS has been mixed. Data modelling techniques may give inconsistent results that adversely impact conclusions. This study applied techniques to overcome possible modelling drawbacks. Method: An additive quantile regression model formulated to isolate hospital contextual effects was applied to every colorectal surgery for cancer conducted in Victoria, Australia, between 2005 and 2015, involving 28,343 admissions in 90 Victorian hospitals. The model compared hospitals’ operational efficiencies regarding LOS. Results: Hospital LOS operational efficiencies for colorectal cancer surgery varied markedly between the 90 hospitals and were independent of volume. This result was adjusted for pertinent patient and hospital characteristics. Conclusion: No evidence was found that higher annual surgery volume was associated with lower LOS for patients undergoing colorectal cancer surgery. Our model showed strong evidence that differences in LOS efficiency between hospitals was driven by hospital contextual effects that were not predicted by provider volume. Further study is required to elucidate these inherent differences between hospitals. Implications for public health: Our model indicated improved efficiency would benefit the patient and medical system by lowering LOS and reducing expenditure by more than $3 million per year.

Abstract Background Adherence to a traditional Mediterranean diet has been associated with lower mortality and cardiovascular disease risk. The relative importance of diet compared to other lifestyle factors and effects of dietary patterns over time remains unknown. Methods We used the parametric G-formula to account for time-dependent confounding, in order to assess the relative importance of diet compared to other lifestyle factors and effects of dietary patterns over time. We included healthy Melbourne Collaborative Cohort Study participants attending a visit during 1995–1999. Questionnaires assessed diet and physical activity at each of three study waves. Deaths were identified by linkage to national registries. We estimated mortality risk over approximately 14 years (1995–2011). Results Of 22,213 participants, 2163 (9.7%) died during 13.6 years median follow-up. Sustained high physical activity and adherence to a Mediterranean-style diet resulted in an estimated reduction in all-cause mortality of 1.82 per 100 people (95% confidence interval (CI): 0.03, 3.6). The population attributable fraction was 13% (95% CI: 4, 23%) for sustained high physical activity, 7% (95% CI: − 3, 17%) for sustained adherence to a Mediterranean-style diet and 18% (95% CI: 0, 36%) for their combination. Conclusions A small reduction in mortality may be achieved by sustained elevated physical activity levels in healthy middle-aged adults, but there may be comparatively little gain from increasing adherence to a Mediterranean-style diet.

Background: There is strong and well-documented evidence that socio-economic inequality in cancer survival exists within and between countries, but the underlying causes of these differences are not well understood. Methods: We systematically searched the Ovid Medline, EMBASE, and CINAHL databases up to 31 May 2020. Observational studies exploring pathways by which socio-economic position (SEP) might causally influence cancer survival were included. Results: We found 74 eligible articles published between 2005 and 2020. Cancer stage, other tumor characteristics, health-related lifestyle behaviors, co-morbidities and treatment were reported as key contributing factors, although the potential mediating effect of these factors varied across cancer sites. For common cancers such as breast and prostate cancer, stage of disease was generally cited as the primary explanatory factor, while co-morbid conditions and treatment were also reported to contribute to lower survival for more disadvantaged cases. In contrast, for colorectal cancer, most studies found that stage did not explain the observed differences in survival by SEP. For lung cancer, inequalities in survival appear to be partly explained by receipt of treatment and co-morbidities. Conclusions: Most studies compared regression models with and without adjusting for potential mediators; this method has several limitations in the presence of multiple mediators that could result in biased estimates of mediating effects and invalid conclusions. It is therefore essential that future studies apply modern methods of causal mediation analysis to accurately estimate the contribution of potential explanatory factors for these inequalities, which may translate into effective interventions to improve survival for disadvantaged cancer patients.

Despite overall improvements in cancer survival due to earlier diagnosis and better treatment, socio-economically disadvantaged people have lower cancer survival than more advantaged people. We aimed to examine differences in cancer survival by area-level socio-economic disadvantage in Victoria, Australia and assess whether these inequalities varied by year of diagnosis, age at diagnosis, time since diagnosis and sex. Cases diagnosed with a first primary cancer in 2001-2015 were identified using the Victorian Cancer Registry and followed to the end of 2016. Five-year net survival and the excess risk of death due to a cancer diagnosis were estimated. People living in more disadvantaged areas had lower five-year survival than residents of less disadvantaged regions for 21 of 29 cancer types: head and neck, oesophagus, stomach, colorectum, anus/anal canal, liver, gallbladder/biliary tract, pancreas, lung, melanoma, connective/soft tissue, female breast, ovary, prostate, kidney, bladder, brain and central nervous system, unknown primary, non-Hodgkin lymphoma, multiple myeloma and leukemia. The observed lower survival in more deprived regions persisted over time, except head and neck cancer, for which the gap in survival has widened. Socio-economic inequalities in survival decreased with increasing age at diagnosis for cancers of connective/soft tissue, bladder and unknown primary. For colorectal cancer, the observed survival disadvantage in lower socio-economic regions was greater for men than for women, while for brain and central nervous system tumours, it was larger for women. Cancer survival is generally lower for residents of more socio-economically disadvantaged areas. Identifying the underlying reasons for these inequalities is important and may help to identify effective interventions to increase survival for underprivileged cancer patients.

Abstract Background Case–control studies show that mammographic density is a better risk factor when defined at higher than conventional pixel-brightness thresholds. We asked if this applied to interval and/or screen-detected cancers. Method We conducted a nested case–control study within the prospective Melbourne Collaborative Cohort Study including 168 women with interval and 422 with screen-detected breast cancers, and 498 and 1197 matched controls, respectively. We measured absolute and percent mammographic density using the Cumulus software at the conventional threshold (Cumulus) and two increasingly higher thresholds (Altocumulus and Cirrocumulus, respectively). Measures were transformed and adjusted for age and body mass index (BMI). Using conditional logistic regression and adjusting for BMI by age at mammogram, we estimated risk discrimination by the odds ratio per adjusted standard deviation (OPERA), calculated the area under the receiver operating characteristic curve (AUC) and compared nested models using the likelihood ratio criterion and models with the same number of parameters using the difference in Bayesian information criterion (ΔBIC). Results For interval cancer, there was very strong evidence that the association was best predicted by Cumulus as a percentage (OPERA = 2.33 (95% confidence interval (CI) 1.85–2.92); all ΔBIC > 14), and the association with BMI was independent of age at mammogram. After adjusting for percent Cumulus, no other measure was associated with risk (all P > 0.1). For screen-detected cancer, however, the associations were strongest for the absolute and percent Cirrocumulus measures (all ΔBIC > 6), and after adjusting for Cirrocumulus, no other measure was associated with risk (all P > 0.07). Conclusion The amount of brighter areas is the best mammogram-based measure of screen-detected breast cancer risk, while the percentage of the breast covered by white or bright areas is the best mammogram-based measure of interval breast cancer risk, irrespective of BMI. Therefore, there are different features of mammographic images that give clinically important information about different outcomes.

Abstract Background Physical activity reduces the risk of colorectal cancer (CRC), but the relevant evidence derives primarily from self-reported recreational and occupational activity. Less is known about the contribution of other domains of physical activity, such as transport and household. We examined associations between domain-specific physical activities and CRC risk within the Melbourne Collaborative Cohort Study. Methods Analyses included 23,586 participants who were free from invasive colorectal cancer and had completed the International Physical Activity Questionnaire-Long Form at follow-up 2 (2003–2007). Cox regression, with age as the time metric, was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for ordinal categories of each physical activity domain. Results Adjusted HRs for the highest versus the lowest categories of physical activity were 0.71 (95% CI: 0.51–0.98; p trend = 0.03) for recreational activity; 0.80 (95% CI: 0.49–1.28; p trend = 0.38) for occupational activity; 0.90 (95% CI: 0.68–1.19; p trend = 0.20) for transport activity; and 1.07 (95% CI: 0.82–1.40; p trend = 0.46) for household activity. Conclusions Recreational activity was associated with reduced CRC risk. A non-significant, inverse association was observed for occupational activity, whereas no association was found for transport or household domains.

Abstract Background In a previous paper, we had assumed that the risk of screen-detected breast cancer mostly reflects inherent risk, and the risk of whether a breast cancer is interval versus screen-detected mostly reflects risk of masking. We found that inherent risk was predicted by body mass index (BMI) and dense area (DA) or percent dense area (PDA), but not by non-dense area (NDA). Masking, however, was best predicted by PDA but not BMI. In this study, we aimed to investigate if these associations vary by tumor characteristics and mode of detection. Methods We conducted a case-control study nested within the Melbourne Collaborative Cohort Study of 244 screen-detected cases matched to 700 controls and 148 interval cases matched to 446 controls. DA, NDA and PDA were measured using the Cumulus software. Tumor characteristics included size, grade, lymph node involvement, and ER, PR, and HER2 status. Conditional and unconditional logistic regression were applied as appropriate to estimate the Odds per Adjusted Standard Deviation (OPERA) adjusted for age and BMI, allowing the association with BMI to be a function of age at diagnosis. Results For screen-detected cancer, both DA and PDA were associated to an increased risk of tumors of large size (OPERA ~ 1.6) and positive lymph node involvement (OPERA ~ 1.8); no association was observed for BMI and NDA. For risk of interval versus screen-detected breast cancer, the association with risk for any of the three mammographic measures did not vary by tumor characteristics; an association was observed for BMI for positive lymph nodes (OPERA ~ 0.6). No associations were observed for tumor grade and ER, PR and HER2 status of tumor. Conclusions Both DA and PDA were predictors of inherent risk of larger breast tumors and positive nodal status, whereas for each of the three mammographic density measures the association with risk of masking did not vary by tumor characteristics. This might raise the hypothesis that the risk of breast tumours with poorer prognosis, such as larger and node positive tumours, is intrinsically associated with increased mammographic density and not through delay of diagnosis due to masking.

Objective Limited research has assessed the association between patterns of body mass index (BMI) change across adulthood and mortality. We aimed to identify groups of individuals who followed specific group-based BMI trajectories across adulthood, using weight collected on three occasions and recalled data from early adulthood, and to examine associations with all-cause and cause-specific mortality.Design Prospective cohort study.Setting Melbourne, Australia.Participants Adults (n=29 881) enrolled in the Melbourne Collaborative Cohort Study, who were aged from 40 to 70 years between 1990 and 1994, and had BMI data for at least three time points.Outcome Deaths from any cause before 31 March 2017 and deaths from obesity-related cancers, cardiovascular diseases (CVDs) and other causes before 31 December 2013.Results We identified six group-based BMI trajectories: lower-normal stable (TR1), higher-normal stable (TR2), normal to overweight (TR3), chronic borderline obesity (TR4), normal to class I obesity (TR5) and overweight to class II obesity (TR6). Generally, compared with maintaining lower-normal BMI throughout adulthood, the lowest mortality was experienced by participants who maintained higher-normal BMI (HR 0.90; 95% CI 0.84 to 0.97); obesity during midlife was associated with higher all-cause mortality even when BMI was normal in early adulthood (HR 1.09; 95% CI 0.98 to 1.21) and prolonged borderline obesity from early adulthood was also associated with elevated mortality (HR 1.16; 95% CI 1.01 to 1.33). These associations were stronger for never-smokers and for death due to obesity-related cancers. Being overweight in early adulthood and becoming class II obese was associated with higher CVD mortality relative to maintaining lower-normal BMI (HR 2.27; 95% CI 1.34 to 3.87).Conclusion Our findings highlight the importance of weight management throughout adulthood to reduce mortality.

Background: Many observational studies have reported an association between vitamin D and non-skeletal health outcomes. The D-Health Trial was launched to determine if supplementing the older population with high monthly doses of Vitamin D can prevent cancer and premature mortality. The intervention is ongoing but here we provide a detailed statistical analysis plan for the primary and secondary outcomes of the D-Health Trial. Methods/design: The D-Health Trial is a double-blind, randomized, placebo-controlled trial. Between February 2014 and May 2015, 21,315 people were randomized in a 1:1 ratio to receive monthly doses of either 60,000 IU of cholecalciferol (vitamin D3) or placebo for five years. The primary outcome is all-cause mortality and the secondary outcomes are total cancer incidence and colorectal cancer incidence. These will be ascertained via linkage to death and cancer registries. The primary analysis for each outcome will follow an intention-to-treat approach; we will use flexible parametric survival models to investigate the association between supplementation and time to an event. We describe in detail sophisticated secondary analyses that consider non-compliance and contamination due to off-study supplementation. Conclusions: Publication of this statistical analysis plan in advance of the intervention's completion, and adherence to it, will avoid data-driven analyses of the primary and secondary outcomes and ensure robust reporting of outcomes. Clinical trial registration number: Australian New Zealand Clinical Trials Registry: ACTRN12613000743763. Registered on 4 July 2013. Keywords: Statistical analysis plan, Randomized controlled trial, Vitamin D, Mortality, Cancer

Homozygosity for the p.C282Y substitution in the HFE protein encoded by the hemochromatosis gene on chromosome 6p (HFE) is a common genetic trait that increases susceptibility to iron overload. McLaren et al. used bivariate mixture modeling to analyze the joint population distribution of transferrin saturation (TS) and serum ferritin concentration (SF) measured for participants in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. They identified four components (C1, C2, C3, and C4) with successively increasing means for TS and SF. They demonstrated that bivariate mixture modeling in TS and SF reflect the genetic locus of HFE and may isolate p.C282Y homozygotes from the general population. In the current study we used data from the another large cohort, the Australian HealthIron study of genetic and environmental modifiers of hereditary hemochromatosis, to validate the component analysis approach, to examine stability of component proportions over time and to determine if TS and SF values from an individual move between components at baseline and follow-up. Because sampling fractions from each p.C282Y / p.H63D genotype stratum are not equal, we used frequency weights based on the inverse of the probability of selection for invitation to participate. In the weighted female analytic cohorts, C4 captured most of C282Y homozygotes, and C2 was the largest component. We identified four components from the weighted male analytic cohort and C4 captured most of p.C282Y homozygotes. The bivariate mixture modeling approach suggested that the model is transferable from one white population to another, although estimated means within components may differ.

Abstract We are very pleased to introduce Ten to Men, the Australian Longitudinal Study on Male Health. Ten to Men is, to our knowledge, the largest national all-male cohort study in the world. It involves 15,988 males who were aged between 10 and 55 years when we recruited them in 2013/14. Together, the articles in this collection provide an overview of the study’s methods, examples of some of the key questions it can answer, and guidance for researchers wishing to use it. Perhaps most importantly, the articles demonstrate the enormous potential Ten to Men has to make a real difference to our understanding of male health and the factors that influence it.

Abstract Background The Australian Longitudinal Study on Male Health (Ten to Men) was established in 2011 to build the evidence base on male health to inform policy and program development. Methods Ten to Men is a national longitudinal study with a stratified multi-stage cluster random sample design and oversampling in rural and regional areas. Household recruitment was conducted from October 2013 to July 2014. Males who were aged 10 to 55 years residing in private dwellings were eligible to participate. Data were collected via self-completion paper questionnaires (participants aged 15 to 55) and by computer-assisted personal interview (boys aged 10 to 14). Household and proxy health data for boys were collected from a parent via a self-completion paper-based questionnaire. Questions covered socio-demographics, health status, mental health and wellbeing, health behaviours, social determinants, and health knowledge and service use. Results A cohort of 15,988 males aged between 10 and 55 years was recruited representing a response fraction of 35 %. Conclusion Ten to Men is a unique resource for investigating male health and wellbeing. Wave 1 data are available for approved research projects.