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The trends in incidence of lung cancer in never smokers are unclear as well as the significance of risk factors. We studied time trends in the incidence and risk factors of lung cancer in never smokers in Finland in a large, pooled cohort. We pooled data from seven Finnish health cohorts from the period between 1972 and 2015 with 106 193 never smokers. The harmonized risk factors included education, alcohol consumption, physical activity, height, and BMI. We retrieved incident lung cancers from the nation-wide Finnish Cancer Registry. We estimated average annual percent change (AAPC) and the effects of risk factors on cause-specific hazard ratios (HRs) of lung cancer using Poisson regression. We detected 47 lung cancers in never smoking men (n = 31 859) and 155 in never smoking women (n = 74 334). The AAPC of lung cancer incidence was -3.30% (95% confidence interval [CI]: -5.68% - -0.88%, P = 0.009) in never smoking men and 0.00% (95% CI: -1.57%-1.60%, P = 0.996) in never smoking women. Of the five studied risk factors only greater height in women had a statistically significant increased risk of lung cancer (multivariate HR = 1.84, 95%CI: 1.08-3.12). It is plausible that tobacco control measures focused on working places have reduced passive smoking among men more than among women, which could explain the declining trend in lung cancer incidence in never smoker men but not in never smoker women. As tobacco control measures have not been targeted to domestic environments, it is likely that women's exposure to passive smoking has continued longer. This article is protected by copyright. All rights reserved.

Tobacco smoke is a known carcinogen, but the magnitude of smoking-related cancer risk depends on country-specific, generational smoking patterns. We quantified cancer risk in relation to smoking in a population-based cohort, the 45 and Up Study (2006-2009) in New South Wales, Australia. Cox proportional hazards regressions estimated adjusted hazard ratios (HR) by self-reported smoking history at baseline (2006-2009) for incident, primary cancers via linkage to cancer registry data to 2013 and cancer death data to 2015. Among 229 028 participants aged ≥45 years, 18 475 cancers and 5382 cancer deaths occurred. Current-smokers had increased risks of all cancers combined (HR = 1.42, 95% confidence interval [CI], 1.34-1.51), cancers of the lung (HR = 17.66, 95%CI, 14.65-21.29), larynx (HR = 11.29, 95%CI, 5.49-23.20), head-and-neck (HR = 2.53, 95%CI, 1.87-3.41), oesophagus (HR = 3.84, 95%CI, 2.33-6.35), liver (HR = 4.07, 95%CI, 2.55-6.51), bladder (HR = 3.08, 95%CI, 2.00-4.73), pancreas (HR = 2.68, 95%CI, 1.93-3.71), colorectum (HR = 1.31, 95%CI, 1.09-1.57) and unknown primary site (HR = 3.26, 95%CI, 2.19-4.84) versus never-smokers. Hazards increased with increasing smoking intensity; compared to never-smokers, lung cancer HR = 9.22 (95%CI, 5.14-16.55) for 1-5 cigarettes/day and 38.61 (95%CI, 25.65-58.13) for >35 cigarettes/day. Lung cancer risk was lower with quitting at any age but remained higher than never-smokers for quitters aged >25y. By age 80y, an estimated 48.3% of current-smokers (41.1% never-smokers) will develop cancer, and 14% will develop lung cancer, including 7.7% currently smoking 1-5 cigarettes/day and 26.4% for >35 cigarettes/day (1.0% never-smokers). Cancer risk for Australian smokers is significant, even for 'light' smokers. These contemporary estimates underpin the need for continued investment in strategies to prevent smoking uptake and facilitate cessation, which remain key to reducing cancer morbidity and mortality worldwide.

Background: Estimates of future burden of cancer attributable to current modifiable causal exposures can guide cancer prevention. We quantified future head and neck cancer burden in Australia attributable to individual and joint causal exposures, and assessed whether these burdens differ between population subgroups. Methods: We estimated the strength of the associations between exposures and head and neck cancer using adjusted proportional hazards models from pooled data from seven Australian cohorts (N = 367,058) linked to national cancer and death registries and estimated exposure prevalence from the 2017 to 2018 Australian National Health Survey. We calculated population attributable fractions (PAF) with 95% confidence intervals (CI), accounting for competing risk of death, and compared PAFs for population subgroups. Results: Contemporary levels of current and former smoking contribute 30.6% (95% CI, 22.7%–37.8%), alcohol consumption exceeding two standard drinks per day 12.9% (95% CI, 7.6%–17.9%), and these exposures jointly 38.5% (95% CI, 31.1%–45.0%) to the future head and neck cancer burden. Alcohol-attributable burden is triple and smoking-attributable burden is double for men compared with women. Smoking-attributable burden is also at least double for those consuming more than two alcoholic drinks daily or doing less than 150 minutes of moderate or 75 minutes of vigorous activity weekly, and for those aged under 65 years, unmarried, with low or intermediate educational attainment or lower socioeconomic status, compared with their counterparts. Conclusions: Two-fifths of head and neck cancers in Australia are preventable by investment in tobacco and alcohol control. Impact: Targeting men and other identified high-burden subgroups can help to reduce head and neck cancer burden disparities.

Thyroid cancer incidence and the prevalence of overweight and obesity are increasing, but the future thyroid cancer burden attributable to contemporary levels of overweight and obesity has not been evaluated before. We quantified this burden in Australia, and assessed whether the overweight/obesity-attributable burden differed by sex or other population subgroupings. We estimated the strength of the associations of overweight and obesity with thyroid cancer with adjusted proportional hazards models using pooled data from seven Australian cohorts (N=367,058) with 431 thyroid cancer cases ascertained from linked national cancer registry data during a maximum 22-year follow-up. We combined these estimates with nationally representative 2017-2018 estimates of overweight and obesity prevalence to estimate Population Attributable Fractions (PAFs) of future thyroid cancers attributable to overweight and obesity, accounting for competing risk of death, and compared PAFs for population subgroups. Contemporary levels of overweight and obesity explain 18.6% (95%CI=5.2%-30.2%), and obesity alone 13.7% (95%CI=5.2%-21.4%), of the future thyroid cancer burden. The obesity-attributable thyroid cancer burden is 21.4% (95%CI=2.8%-36.5%) for men and 10.1% (95%CI=0.8%-18.6%) for women. Were the currently obese overweight instead, 9.9% (95%CI=1.0%-18.1%) of thyroid cancers could be avoided. The relative overweight/obesity-attributable burden is higher for those consuming on average more than two alcoholic drinks per day (63.4%) and for those who are not married/co-habiting (33.2%). In conclusion, avoiding excess weight, especially obesity, should be a priority for thyroid cancer prevention. Further studies, with findings stratified by tumour size, may reveal the potential role of overdiagnosis in our results. This article is protected by copyright. All rights reserved.

There is limited evidence for any dietary factor, except alcohol, in breast cancer (BC) risk. Therefore, studies on a whole diet, using diet quality indices, can broaden our insight. We examined associations of the Nordic Diet (mNDI), Mediterranean diet (mMEDI) and Alternative Healthy Eating Index (mAHEI) with postmenopausal BC risk. Five Finnish cohorts were combined including 6374 postmenopausal women with dietary information. In all, 8–9 dietary components were aggregated in each index, higher total score indicating higher adherence to a healthy diet. Cox proportional hazards regression was used to estimate the combined hazard ratio (HR) and 95% confidence interval (CI) for BC risk. During an average 10-year follow-up period, 274 incident postmenopausal BC cases were diagnosed. In multivariable models, the HR for highest vs. lowest quintile of index was 0.67 (95 %CI 0.48–1.01) for mNDI, 0.88 (0.59–1.30) for mMEDI and 0.89 (0.60–1.32) for mAHEI. In this combined dataset, a borderline preventive finding of high adherence to mNDI on postmenopausal BC risk was found. Of the indices, mNDI was more based on the local food culture than the others. Although a healthy diet has beneficially been related to several chronic diseases, the link with the etiology of postmenopausal BC does not seem to be that obvious.

There is a lack of tangible measures for directed public health action to halt the increase in weight and cancer. We estimated the fraction and preventable cases of all and major body fatness-related cancers attributable to 7-years weight gain (≥ 2 kg). We assessed validated self-reported anthropometrics from 44,114 women aged 34–49 years at the enrolment in 1991–1992 and from a second questionnaire in 1998, with follow-up through December 31, 2015. Over 18 years, 3216 body fatness-related cancers and 2041 deaths were reported. Nearly 70% of women experienced weight gain and the average weight change was 4 kg. We observed a substantial proportional impact of weight gain on pancreatic cancer with a population attributable fraction (PAF) of 41.8% (95% CI 8.1–63.1) and a high absolute impact on postmenopausal breast cancer with 4403 preventable cases (95% CI 1064–7299) and a PAF of 16.8% (95% CI 4.1–27.8), and colorectal cancer with 3857 preventable cases (95% CI 1313–5990) and a PAF of 22.6% (95% CI 7.7–35.1). Avoiding weight gain over seven years in middle adulthood could have prevented a considerable proportion of the cancer burden and thousands of cancer cases in women in Norway.

Cancer is among the leading non-communicable diseases in terms of morbidity and mortality [1]. In 2016, 24% of all deaths in Finland [2] and 16% of all deaths globally [3] were caused by neoplasms....

IntroductionWith almost 50% of cases preventable and the Australian National Bowel Cancer Screening Program in place, colorectal cancer (CRC) is a prime candidate for investment to reduce the cancer burden. The challenge is determining effective ways to reduce morbidity and mortality and their implementation through policy and practice. Pathways-Bowel is a multistage programme that aims to identify best-value investment in CRC control by integrating expert and end-user engagement; relevant evidence; modelled interventions to guide future investment; and policy-driven implementation of interventions using evidence-based methods.Methods and analysisPathways-Bowel is an iterative work programme incorporating a calibrated and validated CRC natural history model for Australia (Policy1-Bowel) and assessing the health and cost outcomes and resource use of targeted interventions. Experts help identify and prioritise modelled evaluations of changing trends and interventions and critically assess results to advise on their real-world applicability. Where appropriate the results are used to support public policy change and make the case for optimal investment in specific CRC control interventions. Fourteen high-priority evaluations have been modelled or planned, including evaluations of CRC outcomes from the changing prevalence of modifiable exposures, including smoking and body fatness; potential benefits of daily aspirin intake as chemoprevention; increasing CRC incidence in people aged Pathways-Bowel is a unique, comprehensive approach to evaluating CRC control; no prior body of work has assessed the relative benefits of a variety of interventions across CRC development and progression to produce a list of best-value investments.Ethics and disseminationEthics approval was not required as human participants were not involved. Findings are reported in a series of papers in peer-reviewed journals and presented at fora to engage the community and policymakers.

Background With the prevalence of cancer survivors increasing, their unique needs must be better understood. We examined the health, lifestyles and social circumstances of adults with and without a history of cancer. Methods We performed a cross-sectional study, using exposure and outcome data from the baseline survey (2006–2009) of participants in the 45 and Up Study, a prospective cohort study in New South Wales, Australia. We compared 20,811 cancer registry-verified adult cancer survivors with 207,148 participants without a history of cancer using propensity score weighting and accounting for multiple testing. The propensity weighting included age, sociodemographic factors and number of self-reported co-morbidities. Results Cancer survivors were more likely to report poorer physical and psychological health and quality of life compared to those without a cancer history, with most deficits still evident more than 10 years after cancer diagnosis. Cancer survivors were more likely to have a higher body mass index, but were less likely to smoke. Cancer survivors had greater functional limitations, including sexual, and were less likely to work full time, volunteer and spend time outdoors. Their social connectedness was, however, similar. Those with haematological cancer, lung cancer, or distant metastases, and those diagnosed at an older age, had the greatest health deficits and functional limitations. Conclusions A history of cancer is associated with poorer health and less paid and unpaid work. Our findings reinforce the importance of routine long-term, integrated multidisciplinary care for cancer survivors and indicate the subgroups with the greatest unmet needs.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, transethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N = 78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P

Substantial changes in the prevalence of the principal kidney and bladder cancer risk factors, smoking (both cancers) and body fatness (kidney cancer), have occurred but the contemporary cancer burden attributable to these factors has not been evaluated. We quantified the kidney and bladder cancer burden attributable to individual and joint exposures and assessed whether these burdens differ between population subgroups. We linked pooled data from seven Australian cohorts (N = 367,058) to national cancer and death registries and estimated the strength of the associations between exposures and cancer using adjusted proportional hazards models. We estimated exposure prevalence from representative contemporaneous health surveys. We combined these estimates to calculate population attributable fractions (PAFs) with 95% confidence intervals (CIs), accounting for competing risk of death, and compared PAFs for population subgroups. During the first 10‐year follow‐up, 550 kidney and 530 bladder cancers were diagnosed and over 21,000 people died from any cause. Current levels of overweight and obesity explain 28.8% (CI = 17.3–38.7%), current or past smoking 15.5% (CI = 6.0–24.1%) and these exposures jointly 39.6% (CI = 27.5–49.7%) of the kidney cancer burden. Current or past smoking explains 44.4% (CI = 35.4–52.1%) of the bladder cancer burden, with 24.4% attributable to current smoking. Ever smoking explains more than half (53.4%) of the bladder cancer burden in men, and the burden potentially preventable by quitting smoking is highest in men (30.4%), those aged 2 standard alcoholic drinks/day (41.2%). In conclusion, large fractions of kidney and bladder cancers in Australia are preventable by behavior change. Cancer Institute New South Wales, NHMRC, Ageing and Alzheimer's Institute, Cancer Council Victoria, VicHealth

Background The relationship between comorbid disease and health service use and risk of cancer of unknown primary site (CUP) is uncertain. Methods A prospective cohort of 266,724 people aged 45 years and over in New South Wales, Australia. Baseline questionnaire data were linked to cancer registration, health service records 4–27 months prior to diagnosis, and mortality data. We compared individuals with incident registry-notified CUP (n = 327; 90% C80) to two sets of randomly selected controls (3:1): (i) incident metastatic cancer of known primary site (n = 977) and (ii) general cohort population (n = 981). We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results In fully adjusted models incorporating sociodemographic and lifestyle factors, people with cancer registry-notified CUP were more likely to have fair compared with excellent self-rated overall health (OR 1.78, 95% CI 1.01–3.14) and less likely to self-report anxiety (OR 0.48, 95% CI 0.24−0.97) than those registered with metastatic cancer of known primary. Compared to general cohort population controls, people registered with CUP were more likely to have poor rather than excellent self-rated overall health (OR 6.22, 95% CI 1.35–28.6), less likely to self-report anxiety (OR 0.28, 95% CI 0.12−0.63), and more likely to have a history of diabetes (OR 1.89, 95% CI 1.15–3.10) or cancer (OR 1.62, 95% CI 1.03–2.57). Neither tertiary nor community-based health service use independently predicted CUP risk. Conclusion Low self-rated health may be a flag for undiagnosed cancer, and an investigation of its clinical utility in primary care appears warranted.

Background Little is known about the risk factors for cancer of unknown primary site (CUP). We examined the demographic, social and lifestyle risk factors for CUP in a prospective cohort of 266,724 people aged 45 years and over in New South Wales, Australia. Methods Baseline questionnaire data were linked to cancer registration, hospitalisation, emergency department admission, and mortality data. We compared individuals with incident cancer registry-notified CUP (n = 327) to two sets of controls randomly selected (3:1) using incidence density sampling with replacement: (i) incident cancer registry-notified metastatic cancer of known primary site (n = 977) and (ii) general cohort population (n = 981). We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results In a fully adjusted model incorporating self-rated overall health and comorbidity, people diagnosed with CUP were more likely to be older (OR 1.05, 95% CI 1.04–1.07 per year) and more likely to have low educational attainment (OR 1.77, 95% CI 1.24–2.53) than those diagnosed with metastatic cancer of known primary. Similarly, compared to general cohort population controls, people diagnosed with CUP were older (OR 1.10, 95% CI 1.08–1.12 per year), of low educational attainment (OR 1.69, 95% CI 1.08–2.64), and current (OR 3.42, 95% CI 1.81–6.47) or former (OR 1.95, 95% CI 1.33–2.86) smokers. Conclusion The consistent association with educational attainment suggests low health literacy may play a role in CUP diagnosis. These findings highlight the need to develop strategies to achieve earlier identification of diagnostically challenging malignancies in people with low health literacy.

Iatrogenic immunosuppression is a strong risk factor for non-Hodgkin lymphoma (NHL) but the dose-related association between individual immunosuppressive agents and NHL risk is unknown. We conducted a population-based cohort study of 4131 adult Australian liver, heart and lung transplant recipients (1984-2006). We ascertained NHL incidence by probabilistic record linkage between transplant registries and the Australian Cancer Database, and abstracted risk factor data at transplantation and at regular intervals thereafter from medical records. We estimated adjusted hazard ratios (HR) for early (

Objective Evidence on the endometrial and ovarian cancer burden preventable through modifications to current causal behavioural and hormonal exposures is limited. Whether the burden differs by population subgroup is unknown. Methods We linked pooled data from six Australian cohort studies to national cancer and death registries, and quantified exposure-cancer associations using adjusted proportional hazards models. We estimated exposure prevalence from representative health surveys. We then calculated Population Attributable Fractions (PAFs) with 95% confidence intervals (CIs), accounting for competing risk of death, and compared PAFs for population subgroups. Results During a median 4.9 years follow-up, 510 incident endometrial and 303 ovarian cancers were diagnosed. Overweight and obesity explained 41.9% (95% CI 32.3–50.1) of the endometrial cancer burden and obesity alone 34.5% (95% CI 27.5–40.9). This translates to 12,800 and 10,500 endometrial cancers in Australia in the next 10 years, respectively. The body fatness-related endometrial cancer burden was highest (49–87%) among women with diabetes, living remotely, of older age, lower socio-economic status or educational attainment and born in Australia. Never use of oral contraceptives (OCs) explained 8.1% (95% CI 1.8–14.1) or 2500 endometrial cancers. A higher BMI and current long-term MHT use increased, and long-term OC use decreased, the risk of ovarian cancer, but the burden attributable to overweight, obesity or exogenous hormonal factors was not statistically significant. Conclusions Excess body fatness, a trait that is of high and increasing prevalence globally, is responsible for a large proportion of the endometrial cancer burden, indicating the need for effective strategies to reduce adiposity.

Background Cancer of unknown primary (CUP) is a late-stage malignancy with poor prognosis, but we know little about what diagnostic tests and procedures people with CUP receive prior to diagnosis. The purpose of this study was to determine how health service utilisation prior to diagnosis for people with cancer-registry notified CUP differs from those notified with metastatic cancer of known primary. Methods We identified people with a cancer registry notification of CUP (n = 327) from the 45 and Up Study, a prospective cohort of 266,724 people ≥45 years in New South Wales, Australia, matched with up to three controls with a diagnosis of metastatic cancer of known primary (n = 977). Baseline questionnaire data were linked to population health data to identify all health service use, diagnostic tests, and procedures in the month of diagnosis and 3 months prior. We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results After adjusting for age and educational attainment, people with a cancer-registry notified CUP diagnosis were more likely to be an aged care resident (OR = 2.78, 95%CI 1.37–5.63), have an emergency department visit (OR = 1.65, 95%CI 1.23–2.21), serum tumor marker tests (OR = 1.51, 95%CI 1.12–2.04), or a cytology test without immunohistochemistry (OR = 2.01, 95%CI 1.47–2.76), and less likely to have a histopathology test without immunohistochemistry (OR = 0.43, 95%CI 0.31–0.59). Neither general practitioner, specialist, allied health practitioner or nurse consultations, hospitalisations, nor imaging procedures were associated with a CUP diagnosis. Conclusions The health service and diagnostic pathway to diagnosis differs markedly for people notified with CUP compared to those with metastatic cancer of known primary. While these differences may indicate missed opportunities for earlier detection and appropriate management, for some patients they may be clinically appropriate.

IntroductionThe cancer burden preventable through modifications to risk factors can be quantified by calculating their population attributable fractions (PAFs). PAF estimates require large, prospective data to inform risk estimates and contemporary population-based prevalence data to inform the current exposure distributions, including among population subgroups. Objectives and ApproachWe provide estimates of the preventable future cancer burden in Australia using large linked datasets. We pooled data from seven Australian cohort studies (N=367,058) and linked them to national registries to identify cancers and deaths. We estimated the strength of the associations between behaviours and cancer risk using a proportional hazards model, adjusting for age, sex, study and other behaviours. Exposure prevalence was estimated from contemporary National Health Surveys. We harmonised risk factor data across the data sources, and calculated PAFs and their 95% confidence intervals using a novel method accounting for competing risk of death and risk factor interdependence. ResultsDuring the first 10-years follow-up, there were 3,471 incident colorectal cancers, 640 premenopausal and 2,632 postmenopausal breast cancers, 2,025 lung cancers and 22,078 deaths. The leading preventable causes were current smoking (53.7% of lung cancers), body fatness or BMI ≥ 25kg/m2 (11.1% of colorectal cancers, 10.9% of postmenopausal breast cancers), and regular alcohol consumption (12.2% of premenopausal breast cancers). Three in five lung cancers, but only one in four colorectal cancers and one in five breast cancers, were attributable to modifiable factors, when we also considered physical inactivity, dietary and hormonal factors. The burden attributable to modifiable factors was markedly higher in certain population subgroups, including men (colorectal, lung), people with risk factor clustering (colorectal, breast, lung), and individuals with low educational attainment (breast, lung). Conclusion/ImplicationsEstimating PAFs for modifiable risk factors across cancers using contemporary exposure prevalence data can inform timely public health action to improve health and health equity. Testing PAF effect modification may identify population subgroups with the most to gain from programs that support behaviour change and early detection.

Background Knowledge of preventable disease and differences in disease burden can inform public health action to improve health and health equity. We quantified the future lung cancer burden preventable by behavioural modifications across Australia. Methods We pooled seven Australian cohort studies (n = 367 058) and linked them to national registries to identify lung cancers and deaths. We estimated population attributable fractions and their 95% confidence intervals (CIs) for modifiable risk factors, using risk estimates from the cohort data and risk factor exposure distribution from contemporary national health surveys. Results During the first 10-year follow-up, there were 2025 incident lung cancers and 20 349 deaths. Stopping current smoking could prevent 53.7% (95% CI, 50.0–57.2%) of lung cancers over 40 years and 18.3% (11.0–25.1%) in 10 years. The smoking-attributable burden is highest in males, those who smoke

Background Previous estimates of the colorectal cancer (CRC) burden attributed to behaviors have not considered joint effects, competing risk, or population subgroup differences. Methods We pooled data from seven prospective Australian cohort studies (n = 367 058) and linked them to national registries to identify CRCs and deaths. We estimated the strength of the associations between behaviors and CRC risk using a parametric piecewise constant hazards model, adjusting for age, sex, study, and other behaviors. Exposure prevalence was estimated from contemporary National Health Surveys. We calculated population attributable fractions for CRC preventable by changes to current behaviors, accounting for competing risk of death and risk factor interdependence. Statistical tests were two-sided. Results During the first 10 years of follow-up, there were 3471 incident CRCs. Overweight or obesity explained 11.1%, ever smoking explained 10.7% (current smoking 3.9%), and drinking more than two compared with two or fewer alcoholic drinks per day explained 5.8% of the CRC burden. Jointly, these factors were responsible for 24.9% (95% confidence interval [CI] = 19.7% to 29.9%) of the burden, higher for men (36.7%) than women (13.2%, Pdifference < .001). The burden attributed to these factors was also higher for those born in Australia (28.7%) than elsewhere (16.8%, Pdifference = .047). We observed modification of the smoking-attributable burden by alcohol consumption and educational attainment, and modification of the obesity-attributable burden by age group and birthplace. Conclusions We produced up-to-date estimates of the future CRC burden attributed to modifiable behaviors. We revealed novel differences between men and women, and other high–CRC burden subgroups that could potentially benefit most from programs that support behavioral change and early detection.

Background Most cohort studies investigating the effect of immunosuppression on transplant outcomes use drugs at first hospital discharge. We evaluated the extent of drug exposure misclassification and its impact on outcome prediction. Methods We retrospectively collected longitudinal immunosuppression data, at discharge and at 1, 5, 10, and 15 years after transplantation, and outcomes for solid organ transplant recipients 1984-2006 (n = 3133). We compared the risk of death from exposure to individual immunosuppressive drugs (cyclosporine, tacrolimus, azathioprine, and mycophenolate) and dual therapies, as defined by discharge only vs longitudinal immunosuppression data, using adjusted Cox proportional hazards models. Results During a median follow-up of 5.2 years, immunosuppressive drugs were altered for 947 (30%) recipients and 955 recipients died. Longitudinal receipt of cyclosporine and azathioprine were associated with an increased risk (HR 1.41, 95% CI 1.07-1.89, and HR 1.34, 95% CI 1.00-1.80), and mycophenolate with a reduced risk (HR 0.35, 0.16-0.78), of death. Recipients on mycophenolate and tacrolimus dual therapy had a lower risk of death compared to those on azathioprine and cyclosporine dual therapy (HR 0.30, 0.10-0.93). The increased risk of death associated with the receipt of cyclosporine or azathioprine was not shown in the analyses based on drugs allocated at discharge, and all of the associations between immunosuppressive regimens and death were strengthened in the analyses based on longitudinal immunosuppression data. Conclusions Cohort findings based on immunosuppressive drugs allocated at discharge should be interpreted with caution due to potential exposure misclassification. The use of granular, longitudinal data on immunosuppressive regimens could improve prediction.

Aim: To determine the monthly treatment costs for each element of cancer care in patients receiving chemotherapy and to apportion the burden of cost by financing agent (Commonwealth, State government, private health insurer, patient). Methods: A cohort of 478 patients (54% breast, 33% colorectal and 13% non-small-cell lung cancer) were recruited from 12 centers representing metropolitan and regional settings in public and private sectors. Primary data were linked to secondary data held in New South Wales state (Admitted Patients and Emergency Department Data) and Commonwealth (Medicare and Pharmaceutical Benefits) databases. The monthly treatment costs of each element of care and the funding agent were calculated from secondary health data. Results: Across all tumor types, the mean monthly treatment cost was $4162 (10%-90% quantiles $1018-$8098; range $2853 [adjuvant colorectal] to $5622 [metastatic lung]), with 54% of this cost borne by Commonwealth government, 26% by private health insurers, 14% by State government and 6% by patients. The mean monthly costs of treating metastatic disease were $1415 greater than those for adjuvant therapy. The mean monthly costs were contributed to by inpatient care ($1657, 40%), chemotherapy prescriptions ($1502, 36%), outpatient care ($452, 11%) and administration of chemotherapy ($364, 9%). Conclusion: All four funders have a shared incentive to reduce absolute monthly treatment costs since their proportional contribution is relatively constant for most tumor types and stages. There are opportunities to reduce cancer care costs by minimizing the risk of inpatient hospital admissions that arise from chemotherapy administration and by recognizing incentives for cost-shifting.

Background Early repolarization (ER) is defined as an elevation of the QRS-ST junction in at least two inferior or lateral leads of the standard 12-lead electrocardiogram (ECG). Our purpose was to create an algorithm for the automated detection and classification of ER. Methods A total of 6,047 electrocardiograms were manually graded for ER by two experienced readers. The automated detection of ER was based on quantification of the characteristic slurring or notching in ER-positive leads. The ER detection algorithm was tested and its results were compared with manual grading, which served as the reference. Results Readers graded 183 ECGs (3.0%) as ER positive, of which the algorithm detected 176 recordings, resulting in sensitivity of 96.2%. Of the 5,864 ER-negative recordings, the algorithm classified 5,281 as negative, resulting in 90.1% specificity. Positive and negative predictive values for the algorithm were 23.2% and 99.9%, respectively, and its accuracy was 90.2%. Inferior ER was correctly detected in 84.6% and lateral ER in 98.6% of the cases. Conclusions As the automatic algorithm has high sensitivity, it could be used as a prescreening tool for ER; only the electrocardiograms graded positive by the algorithm would be reviewed manually. This would reduce the need for manual labor by 90%.

OBJECTIVE Obesity, particularly visceral adiposity, is a major risk factor for type 2 diabetes. The commonly used obesity indicators, BMI, waist girth, and waist-to-hip ratio (WHR), have limited ability to measure the visceral adipose tissue. Sagittal abdominal diameter (SAD) has been shown to predict the amount of visceral fat. So far no study has been published on its ability to predict diabetes occurrence. RESEARCH DESIGN AND METHODS We assessed and compared the prediction of the four obesity indicators for diabetes incidence in a prospective study based on 5,168 participants from the nationally representative Health 2000 study. RESULTS During a mean follow-up lasting 8.1 years, 222 incident diabetes cases occurred. In multivariate models adjusted for lifestyle factors, BMI, waist girth, WHR, and SAD were significant predictors of diabetes incidence. The relative risks (95% CI) between high and low levels were 15.0 (6.94–32.6), 11.4 (5.39–23.8), 12.5 (6.47–24.2), and 14.7 (6.89–31.2), respectively. Pairwise interaction analysis showed that the co-occurrence of high BMI and high SAD was associated with the highest diabetes incidence, with a relative risk of 37.0 (11.2–122). After adjustment for waist girth and the components of the metabolic syndrome, the relative risk was 9.88 (2.81–34.7). The corresponding population-attributable fraction estimate was 84% (49–95). CONCLUSIONS The combination of SAD and BMI measurements yields a new predictor of diabetes incidence.

This study compares the effectiveness of solution-focused therapy (SFT) and short- and long-term psychodynamic psychotherapy (SPP and LPP) on self-concept during a 3-year follow-up. Altogether, 326 patients with mood or anxiety disorder were randomized to SFT, SPP, and LPP in the Helsinki Psychotherapy Study. Outcome was assessed using the Structural Analysis of Social Behavior questionnaire at baseline and 7, 12, 24, and 36 months after. Overall, during the first year of follow-up, self-concept improved more in both SFT and SPP than in LPP, indicated by the primary outcome indicators self-directed affiliation (AF) and self-directed autonomy, as well as by most of the eight secondary cluster scores. After the 3-year follow-up, LPP was more effective than SFT in AF and in the cluster scores self-affirm, self-blame, and self-neglect, whereas no difference was noted between LPP and SPP. Long duration and psychodynamic orientation of therapy may be beneficial for self-concept improvement.

Quantification of the impact of exposure to modifiable risk factors on a particular outcome at the population level is a fundamental public health issue. In cohort studies, the population attributable fraction (PAF) is used to assess the proportion of the outcome that is attributable to exposure to certain risk factors in a given population during a certain time interval. This is done by combining information about the prevalence of the risk factor in the population with estimates of the strength of the association between the risk factor and the outcome. In case of mortality, the PAF demonstrates what proportion of mortality can be delayed during the given follow-up time. However, literature on carrying out model-based estimation of PAF and its variance in cohort studies while properly taking follow-up time into account is still scarce. In this article, the authors present formulas for estimation of PAF, its variance, and its confidence interval using the piecewise constant hazards model and apply a SAS macro created for the estimation of PAF (SAS Institute Inc., Cary, North Carolina) to estimate the mortality attributable to some common risk factors.

Lifestyle factors predict type 2 diabetes occurrence, but their effect in high- and low-risk populations is poorly known. This study determines the prediction of low-risk lifestyle on type 2 diabetes in those with and without metabolic syndrome in a pooled sample of two representative Finnish cohorts, collected in 1978-1980 and 2000-2001. Altogether 8,627 individuals, aged 40-79 years, and free of diabetes and cardiovascular disease at baseline were included in this study. A low-risk lifestyle was defined based on body mass index, exercise, alcohol consumption, smoking, and serum vitamin D concentration. The metabolic syndrome was defined according to the International Diabetes Federation including obesity, blood pressure, serum HDL cholesterol, serum triglycerides, and fasting glucose. During a 10-year follow-up, altogether 226 type 2 diabetes cases occurred. Overweight was the strongest predictor of type 2 diabetes (population attributable fraction (PAF) = 77%, 95% confidence interval (CI): 53, 88%). Together with lack of exercise, unsatisfactory alcohol consumption, smoking, and low vitamin D concentration it explained 82% of the cases. Altogether 62% (CI: 47, 73%) of the cases were attributable to the metabolic syndrome and 92% (CI: 67, 98%) to the most unfavourable combination of its components. The metabolic syndrome did not modify the prediction of lifestyle factors but persons with normal blood pressure benefited more from positive changes in exercise, alcohol consumption, and smoking than those with elevated blood pressure (P for interaction = 0.01). In conclusion, modification of lifestyle factors apparently reduces type 2 diabetes risk, especially in persons with normal blood pressure.

Studies on the association between plant foods and cerebrovascular diseases have given contradictory results suggesting the existence of some effect-modifying factors. The present study determines whether the consumption of plant foods (i.e. fruits and berries, vegetables, and cereals) predicts a decreased cerebrovascular disease incidence in a population with low fruit and vegetable and high wholegrain intake. This cohort study on 3932 men and women was based on data from the Finnish Mobile Clinic Health Examination Survey, conducted in 1968–72. The participants were 40–74 years of age and free of cardiovascular diseases at baseline. Data on the plant food consumption were derived from a 1-year dietary history interview. During a 24-year follow-up 625 cases of cerebrovascular diseases occurred, leading to either hospitalisation or death. An inverse association was found between fruit consumption and the incidence of cerebrovascular diseases, ischaemic stroke and intracerebral haemorrhage. The adjusted relative risks (RR) between the highest and lowest quartiles of intake of any cerebrovascular disease, ischaemic stroke and intracerebral haemorrhage were 0·75 (95 % CI 0·59, 0·94), 0·73 (95 % CI 0·54, 1·00) and 0·47 (95 % CI 0·24, 0·92), respectively. These associations were primarily due to the consumption of citrus fruits and occurred only in men. Total consumption of vegetables or cereals was not associated with the cerebrovascular disease incidence. The consumption of cruciferous vegetables, however, predicted a reduced risk of cerebrovascular diseases (RR 0·79; 95 % CI 0·63, 0·99), ischaemic stroke (RR 0·67; 95 % CI 0·49, 0·92) and intracerebral haemorrhage (RR 0·49; 95 % CI 0·25, 0·98). In conclusion, the consumption of fruits, especially citrus, and cruciferous vegetables may protect against cerebrovascular diseases.

Low vitamin D status has been suggested as a risk factor for type 2 diabetes. Although the epidemiologic evidence is scarce, 2 recent studies have suggested an association. The present study investigated the relation of serum vitamin D with type 2 diabetes incidence using pooled data from these 2 cohorts.Two nested case-control studies, collected by the Finnish Mobile Clinic in 1973-1980, were pooled for analysis. The study populations consisted of men and women aged 40-74 years and free of diabetes at baseline. During a follow-up period of 22 years, 412 incident type 2 diabetes cases occurred, and 986 controls were selected by individual matching. Serum vitamin D (serum 25(OH)D) was determined from frozen samples, stored at baseline. Pooled estimates of the relationship between serum vitamin D concentration and type 2 diabetes incidence were calculated.Men had higher serum vitamin D concentrations than women and showed a reduced risk of type 2 diabetes in their highest vitamin D quartile. The relative odds between the highest and lowest quartiles was 0.28 (95% confidence interval = 0.10-0.81) in men and 1.14 (0.60-2.17) in women after adjustment for smoking, body mass index, physical activity, and education.The results support the hypothesis that high vitamin D status provides protection against type 2 diabetes. Residual confounding may contribute to this association.

To examine the prediction of coffee consumption on the incidence of Parkinson's disease. The study population comprised 6710 men and women, aged 50–79 years and free from Parkinson's disease at the baseline. At baseline, enquiries were made about coffee consumption in a self-administered questionnaire as the average number of cups per day. During a 22-year follow-up, 101 incident cases of Parkinson's disease occurred. Parkinson's disease cases were identified through a nationwide registry of patients receiving medication reimbursement, which is based on certificates from neurologist. After adjustments for age, sex, marital status, education, community density, alcohol consumption, leisure-time physical activity, smoking, body mass index, hypertension and serum cholesterol, the relative risk for subjects drinking 10 or more cups of coffee per day compared with non-drinkers was 0.26 (95% confidence interval 0.07–0.99, P-value for trend=0.18). The association was stronger among overweight persons and among persons with lower serum cholesterol level (P-value for interaction=0.04 and 0.03, respectively). The results support the hypothesis that coffee consumption reduces the risk of Parkinson's disease, but protective effect of coffee may vary by exposure to other factors.

Background Iatrogenic immunosuppression is a risk factor for lip cancer but the determinants are unknown. Objective We sought to quantify the association between the type, dose, and duration of iatrogenic immunosuppression and lip cancer risk in solid organ transplant recipients. Methods We conducted a population-based cohort study of all adult Australian liver, heart, and lung transplant recipients from 1984 to 2006 (n = 4141). We abstracted longitudinal data from medical records and ascertained incident lip cancer (n = 58) and deaths (n = 1434) by linkage with national registries. We estimated multivariable hazard ratios (HR) for lip cancer using the Fine and Gray proportional subdistribution hazards model, accounting for death as a competing risk. Results Lip cancer risk (n = 58) increased with high mean daily dose of azathioprine (HR 2.28, 95% confidence interval [CI] 1.18-4.38), longer duration of immunosuppression (HR 9.86, 95% CI 2.10-46.3), increasing year of age at transplantation (HR 1.14, 95% CI 1.04-1.25), earlier transplantation era (HR 8.73, 95% CI 1.11-68.7), and history of smoking (HR 2.71, 95% CI 1.09-6.70). Limitations Data on potential confounders such as personal solar ultraviolet radiation exposure were not available. Conclusion Higher doses of azathioprine increase lip cancer risk, with implications for managing immunosuppressed populations and our understanding of the relationship between solar ultraviolet radiation and lip cancer.

Unconfounded comparative data on the type and dose of immunosuppressive agents among solid organ transplant recipients are sparse, as are data on longitudinal immunosuppressive therapy since transplantation. We addressed this issue in a population-based cohort of Australian liver (n = 1895), heart (n = 1220), and lung (n = 1059) transplant recipients, 1984-2006. Data on immunosuppressive therapy were retrospectively collected at discharge, three months, and one, five, 10, and 15 yr after first transplant. We computed unadjusted and adjusted estimates for the association between the type and dose of immunosuppressive therapy and organ type. After adjustment for confounders, use of induction antibody and maintenance corticosteroids was more common in heart and lung compared to liver recipients (p < 0.001), and antibody therapy for rejection more common in liver recipients (p < 0.001). Liver recipients were more likely to receive calcineurin inhibitor monotherapy, with or without corticosteroids, compared to heart and lung recipients (p < 0.001). Liver recipients consistently received lower doses of azathioprine than heart and lung recipients (p < 0.001). These differences in immunosuppression may partly explain variations in immunosuppression-related morbidity by transplanted organ, for example, malignancy risk. Longitudinal changes in the type and the dose of immunosuppressive therapy over time since transplantation also demonstrate the need for time-dependent data in observational research.

Aim: To quantify the burden of colorectal cancer in Australia avoidable by modifications to established lifestyle-related risk factors: smoking, excess body weight, excessive red and processed meat consumption, excessive alcohol consumption and physical inactivity. Methods: Data on exposure to lifestyle-related risk factors from seven Australian cohort studies (N = 367,772) were harmonized and pooled. The cohorts were linked to the Australian Cancer Database and National Death Index to identify incident cancers and deaths. The strength of the exposure-cancer and exposure-death associations were estimated using a proportional hazards model, adjusting for age, sex and the other lifestyle exposures. Age- and sex-specific exposure prevalence was estimated from the Australian National Health Survey (NHS) 2011-2012 or from the latest 45 and Up cohort study when not available in the NHS. These estimates were then combined to calculate the Population Attributable Fractions (PAFs), i.e. fractions of cancer attributable to the lifestyle-related risk factors, and their 95% confidence intervals (CIs) using an advanced method accounting for competing risk of death. Results: During the first 10-years follow-up, 3,498 incident colorectal cancers and 20,135 deaths were ascertained as first events. Current or former smoking explained 9% (CI = 5-13%), BMI ≥ 25 kg/m2 9% (CI = 4-14%), red or processed meat consumption 3 or more times/week 6% (CI = 3-8%), and drinking more than 2 alcoholic drinks/day 4% (CI = 2-6%) of the colorectal cancer burden. PAF results for physical inactivity were not significant. The contribution of each factor was more pronounced in men than in women, with most of the burden attributable to excess weight in men (PAF = 15%, CI = 7-22%) and smoking in women (PAF = 7%, CI = 3-12%). Jointly the four significant lifestyle-related risk factors were responsible for 25% (CI = 19-30%) of the colorectal cancer burden, 33% (CI = 25-40%) in men and 15% (CI =7-23%) in women. Given the projected Australian incidence rates, this translates to 49,000 avoidable colorectal cancer cases, 35,000 in men and 14,000 in women, over the next 10 years. Conclusions: These first Australian and international colorectal cancer PAF estimates based on cohort studies and accounting for competing risk of death show that several modifiable risk factors contribute to the burden of colorectal cancer and their ranking differs by sex. Further analyses may identify subpopulations that would benefit from targeted intervention activities. Due to the high incidence of colorectal cancer, these PAF estimates translate into a significant number of avoidable cases. Citation Format: Claire M. Vajdic, Maria Arriaga, Peter Hull, Karen Canfell, Robert MacInnis, Emily Banks, Graham Giles, Paul Mitchell, Robert Cumming, Barbara-Ann Adelstein, Julie Byles, Dianna J. Magliano, Jonathan Shaw, Anne Taylor, Kay Price, Vasant Hirani, Maarit A. Laaksonen. Burden of colorectal cancer attributable to lifestyle-related risk factors: a pooled study of seven Australian cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2279. doi:10.1158/1538-7445.AM2017-2279

Aim: To estimate the proportion of exocrine pancreatic cancers in Australia that can be attributed to the established risk factors, smoking and excess body weight, and the suggested risk factors, excessive alcohol consumption and excessive red and processed meat consumption. Methods: The proportion of pancreatic cancers attributable to lifestyle-related risk factors was quantified using the Population Attributable Fraction (PAF) which combines estimates of the strength of the exposure-cancer association and the exposure prevalence in the population. The study population included seven Australian cohort studies (N=367,772) with comprehensive data on exposure to lifestyle-related risk factors and long-term follow-up. Pancreatic cancer incidence and all-cause mortality were identified through linkage with the Australian Cancer Database and National Death Index, respectively. A proportional hazards model was used to estimate the strength of exposure-cancer and exposure-death associations adjusting for age, sex and other lifestyle exposures. The age- and sex-specific exposure prevalence was calculated from the Australian National Health Survey (NHS) 2011-2012 except for red and processed meat consumption which was not available and was calculated from the latest 45 and Up study. A newly developed method that takes into account the competing risk of death was used to produce PAF estimates and their 95% confidence intervals (CIs). Results: During the first 10-years follow-up to incidence of pancreatic cancer, death or end of follow-up, there were 21,541 deaths and 613 incident exocrine pancreatic cancers. 10% (CI = 1-17%) of pancreatic cancers in Australia could be attributed to current or past smoking. Current smoking explained 8% (CI = 4-13%) of pancreatic cancers. Using cancer incidence projections estimated by the Australian Institute of Health and Welfare, a PAF of 8% translates to 2,700 potentially preventable pancreatic cancers over the next 10 years. The PAF results for excess body weight (≥ 25 kg/m2), excessive alcohol consumption (> 2 drinks/day) and excessive red and processed meat consumption (≥ 4 times/week) were not statistically significant. Conclusion: According to the first pancreatic cancer PAF results from cohort studies, and accounting for competing risk of death, smoking control could reduce the number of pancreatic cancers by one tenth. Further PAF studies should include confidence intervals for the estimates to allow an evaluation of their significance. Citation Format: Maria E. Arriaga, Maarit A. Laaksonen, Karen Canfell, Robert MacInnis, Emily Banks, Graham Giles, Paul Mitchell, Robert Cumming, Barbra-Ann Adelstein, Julie Byles, Dianna J. Magliano, Jonathan Shaw, Anne Taylor, Kay Price, Vasant Hirani, Claire M. Vajdic. Population-level relevance of lifestyle-related risk factors for pancreatic cancer in Australia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2283. doi:10.1158/1538-7445.AM2017-2283

Aim: The cancer burden avoidable through risk factor modification can be quantified using the Population Attributable Fraction (PAF) which combines estimates of the prevalence of the risk factor exposure in the population and the strength of the exposure-cancer association. PAF for risk factors causally related to cancer is most accurately estimated from cohort studies, using analytical approaches that account for death as a competing risk. We provide the first such estimates of the lifestyle-related avoidable lung cancer burden. Methods: Seven contemporary Australian cohort studies (N = 367,772), with comprehensive data on exposure to lifestyle-related risk factors, were linked to the Australian Cancer Database and National Death Index to identify lung cancers and deaths from any cause. The risk factors were harmonised across the studies and the data pooled. The strength of the exposure-cancer and exposure-death associations were estimated using a proportional hazards model, adjusting for age, sex and the other lifestyle exposures. Age- and sex-specific exposure prevalence was estimated from the Australian National Health Survey 2011-2012. These estimates were then combined to calculate the PAFs and their 95% confidence intervals (CI) using a newly developed method accounting for competing risk of death. Results: During the first 10-years follow-up, 2,030 incident lung cancers and 20,348 deaths were ascertained as first events. Smoking, physical inactivity and insufficient fruit intake were statistically significantly associated with both lung cancer incidence and death. Most of the lung cancer burden (PAF = 73%, CI = 69-76%) was attributable to current or past smoking, with 31% (CI = 27-35%) of the burden attributable to current smokers. Physical activity below Australian recommendations (< 150 minutes of moderate or 75 minutes of vigorous exercise per week) explained 14% (CI = 6-22%) and fruit intake below Australian recommendations (< 2 daily serves) explained 6% (CI = 0-12%) of the lung cancer burden. Each risk factor contributed more to the lung cancer burden in men than in women. Overall, 78% (CI = 74-81%) of the lung cancer burden was attributable to current or past smoking, physical inactivity and insufficient fruit intake. The combined contribution of modifiable risk factors (i.e. excluding past smoking) was 44% (CI = 37-50%). Based on projected Australian cancer incidence rates, this would translate to 59,000 avoidable lung cancers in the next 10 years. Conclusions: According to these joint PAF estimates, the current lung cancer burden in Australia could be reduced by up to half in 10 years by quitting smoking and increasing physical activity and fruit intake to the recommended levels. As the combined effect of risk factors is rarely additive, knowing both individual and joint effects of risk factors on cancer burden is essential in planning cancer interventions and public health policies and predicting their potential impact. Citation Format: Maarit A. Laaksonen, Maria Arriaga, Peter Hull, Karen Canfell, Robert MacInnis, Emily Banks, Graham Giles, Paul Mitchell, Robert Cumming, Barbara-Ann Adelstein, Julie Byles, Dianna J. Magliano, Jonathan Shaw, Anne Taylor, Kay Price, Vasant Hirani, Claire M. Vajdic. Burden of lung cancer in Australia avoidable by modifications to lifestyle-related risk factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2280. doi:10.1158/1538-7445.AM2017-2280

PurposeTo estimate the Australian cancer burden attributable to lifestyle-related risk factors and their combinations using a novel population attributable fraction (PAF) method that accounts for competing risk of death, risk factor interdependence and statistical uncertainty.Participants365 173 adults from seven Australian cohort studies. We linked pooled harmonised individual participant cohort data with population-based cancer and death registries to estimate exposure-cancer and exposure-death associations. Current Australian exposure prevalence was estimated from representative external sources. To illustrate the utility of the new PAF method, we calculated fractions of cancers causally related to body fatness or both tobacco and alcohol consumption avoidable in the next 10 years by risk factor modifications, comparing them with fractions produced by traditional PAF methods.Findings to dateOver 10 years of follow-up, we observed 27 483 incident cancers and 22 078 deaths. Of cancers related to body fatness (n=9258), 13% (95% CI 11% to 16%) could be avoided if those currently overweight or obese had body mass index of 18.5–24.9 kg/m2. Of cancers causally related to both tobacco and alcohol (n=4283), current or former smoking explains 13% (11% to 16%) and consuming more than two alcoholic drinks per day explains 6% (5% to 8%). The two factors combined explain 16% (13% to 19%): 26% (21% to 30%) in men and 8% (4% to 11%) in women. Corresponding estimates using the traditional PAF method were 20%, 31% and 10%. Our PAF estimates translate to 74 000 avoidable body fatness-related cancers and 40 000 avoidable tobacco- and alcohol-related cancers in Australia over the next 10 years (2017–2026). Traditional PAF methods not accounting for competing risk of death and interdependence of risk factors may overestimate PAFs and avoidable cancers.Future plansWe will rank the most important causal factors and their combinations for a spectrum of cancers and inform cancer control activities.

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

Many cancer predisposition syndromes are rare or have incomplete penetrance, and traditional epidemiological tools are not well suited for their detection. Here we have used an approach that employs the entire population based data in the Finnish Cancer Registry (FCR) for analyzing familial aggregation of all types of cancer, in order to find evidence for previously unrecognized cancer susceptibility conditions. We performed a systematic clustering of 878,593 patients in FCR based on family name at birth, municipality of birth, and tumor type, diagnosed between years 1952 and 2011. We also estimated the familial occurrence of the tumor types using cluster score that reflects the proportion of patients belonging to the most significant clusters compared to all patients in Finland. The clustering effort identified 25,910 birth name-municipality based clusters representing 183 different tumor types characterized by topography and morphology. We produced information about familial occurrence of hundreds of tumor types, and many of the tumor types with high cluster score represented known cancer syndromes. Unexpectedly, Kaposi sarcoma (KS) also produced a very high score (cluster score 1.91, p-value

Both non-alcoholic fatty liver (NAFL) and alcoholic fatty liver (AFL) are strongly associated with obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). Recently, also the vitamin D level has been associated with these and may also be associated with fatty liver (FL). Liver function tests (LFTs) are insensitive markers of FL, but use of scores may help in identifying subjects with FL. We studied how LFTs and the FL score predict the development of T2DM in subjects with AFL versus NAFL and low versus high vitamin D levels.A cohort study based on 4,517 participants, aged 40-79, from the representative Mini-Finland Health Survey was carried out. During a follow-up of 15 years, 217 T2DM cases occurred. LFTs were determined from serum samples, and the FL score was formed using BMI, fasting glucose, HDL cholesterol, and GGT concentrations.The risk of T2DM incidence in the highest versus lowest quartile was twofold for the LFTs and ninefold for the FL score. A total of 77 % (95 % confidence interval: 57-87 %) of the T2DM cases could have been prevented if all individuals' FL scores had been at the level of the first quartile. Heavy alcohol consumption and low serum vitamin D concentrations were associated with an increased risk of T2DM among individuals with high FL scores.The FL score is a useful tool for diagnosing FL in epidemiological studies. A high FL score predicts increased risk of T2DM, especially when combined with heavy alcohol consumption or low vitamin D levels.

Background The early repolarization pattern (ERP) is common and associated with risk of sudden cardiac death. ERP is heritable, and mutations have been described in syndromatic cases. Objective To conduct a meta-analysis of genome-wide association studies to identify common genetic variants influencing ERP. Methods We ascertained ERP on the basis of electrocardiograms in 3 large community-based cohorts from Europe and the United States: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed genome-wide association studies in participants with and without ERP by logistic regression assuming an additive genetic model and meta-analyzed individual cohort results. We then sought to strengthen support for findings that reached P ≤ 1 × 10 −5 in independent individuals by direct genotyping or in-silico analysis of genome-wide data. We meta-analyzed the results from both stages. Results Of 7482 individuals in the discovery stage, 452 showed ERP (ERP positive: mean age 46.9 ± 8.9 years, 30.3% women; ERP negative: 47.5 ± 9.4 years, 54.2% women). After meta-analysis, 8 single nucleotide polymorphisms reached P ≤ 1 × 10 −5 : The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95% confidence interval 0.36–0.61; P = 6.9 × 10 −9 ). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95% confidence interval 1.25–1.69; P = 8.5 × 10 −7 ). In the replication step (7151 individuals), none of the 8 variants replicated, and combined meta-analysis results failed to reach genome-wide significance. Conclusions In a genome-wide association study, we were not able to reliably identify genetic variants predisposing to ERP, presumably due to insufficient statistical power and phenotype heterogeneity. The reported heritability of ERP warrants continued investigation in larger well-phenotyped populations.

The population attributable fraction (PAF) is a useful measure for describing the expected change in an outcome if its risk factors are modified. Cohort studies allow researchers to assess the predictive value of the risk factor modification on the incidence of the outcome during a certain follow-up. Estimation of PAF for both mortality and morbidity in cohort studies with censored survival data has been developed in the recent years. So far, however, censoring due to death in the estimation of PAF for morbidity has been ignored, resulting in estimation of a quantity which is not relevant in practice as some people are likely to die during the follow-up. The risk factors related to the disease incidence may also be related to mortality, and modification of these risk factors is likely to delay the occurrence of both events. Thus, censoring due to death and the impact of risk factor modification must be considered when estimating PAF for disease incidence. We consider both and introduce two measures of disease burden: PAF for the incidence of disease during lifetime and PAF for the prevalence of disease in the population at a certain time. We demonstrate how consideration of censoring due to death changes the estimated PAF for disease incidence and its confidence interval. This underlines the importance of choosing a correct PAF measure depending on the outcome of interest and the risk factors of interest to obtain accurate and interpretable results.

It has been suggested that vitamin D reduces the risk of type 2 diabetes. The finding that vitamin D deficiency is associated with impaired -cell function and insulin resistance in animals (1,2) and humans (3,4) is in line with that hypothesis. In the only cohort study published, the intake of vitamin D supplements was inversely associated with the development of type 2 diabetes (5). Since vitamin D intake covers only a part of the total vitamin D available, the purpose of this study was to evaluate the prediction of serum 25-hydroxyvitaminD (25OHD) on