SAS Macros for Calculation of Population Attributable Fraction in a Cohort Study Design

The population attributable fraction (PAF) is a useful measure for quantifying the impact of exposure to certain risk factors on a particular outcome at the population level. Recently, new model-based methods for the estimation of PAF and its confidence interval for different types of outcomes in a cohort study design have been proposed. In this paper, we introduce SAS macros implementing these methods and illustrate their application with a data example on the impact of different risk factors on type 2 diabetes incidence.

The burden of colon cancer attributable to modifiable factors—The Norwegian Women and Cancer Study

Colon cancer is the second most frequently diagnosed cancer in women in Norway, where incidence rates of colon cancer increased 3-fold between 1955 and 2014, for unknown reasons. We aimed to assess the burden of colon cancer attributable to modifiable risk factors in Norwegian women using the data from the Norwegian Women and Cancer (NOWAC) study. Self-reported information from 35 525 women from the NOWAC study were available. These included the following exposures: smoking status, alcohol consumption, body mass index, physical activity, intake of calcium, fibers, and red and processed meat. Colon cancer cases were identified from the Cancer Registry of Norway. A parametric piecewise constant hazards model was used to estimate the strength of exposure-cancer associations. Population attributable fractions with 95% confidence intervals (CIs) were calculated considering competing risk of death. The fraction of incident colon cancer attributable to ever smoking was 18.7% (95% CI 4.7%-30.6%), low physical activity 10.8% (95% CI −0.7% to 21.0%), alcohol consumption 14.5% (95% CI −2.8% to 28.9%), and low intake of calcium 10.0% (95% CI −7.8% to 24.8%). A small proportion of colon cancer cases was attributable to combined intake of red and processed meat over 500 g/week, overweight/obesity, and low intake of fibers. Jointly, these seven risk factors could explain 46.0% (95% CI 23.0%-62.4%) of the colon cancer incidence burden. Between 23% and 62% of the colon cancer burden among women in Norway was attributable to modifiable risk factors, indicating an important preventive potential of a healthy lifestyle

Association between overall diet quality and postmenopausal breast cancer risk in five Finnish cohort studies

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.Peer reviewe

Incidence trends and risk factors of lung cancer in never smokers : Pooled analyses of seven cohorts

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 harmonised 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% to -0.88%, P = .009) in never smoking men and 0.00% (95% CI: -1.57% to 1.60%, P = .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 to 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.Peer reviewe

Incidence trends and risk factors of lung cancer in never smokers : Pooled analyses of seven cohorts

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 harmonised 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% to -0.88%, P = .009) in never smoking men and 0.00% (95% CI: -1.57% to 1.60%, P = .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 to 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.Peer reviewe

Nationwide Registry-Based Analysis of Cancer Clustering Detects Strong Familial Occurrence of Kaposi Sarcoma

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 <0.0001). We verified from population records that many of the KS patients forming the clusters were indeed close relatives, and identified one family with five affected individuals in two generations and several families with two first degree relatives. Our approach is unique in enabling systematic examination of a national epidemiological database to derive evidence of aberrant familial aggregation of all tumor types, both common and rare. It allowed effortless identification of families displaying features of both known as well as potentially novel cancer predisposition conditions, including striking familial aggregation of KS. Further work with high-throughput methods should elucidate the molecular basis of the potentially novel predisposition conditions found in this study.Peer reviewe

The Future Colorectal Cancer Burden Attributable to Modifiable Behaviors: A Pooled Cohort Study

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 ¼ 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] ¼ 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 ¼ .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.This work was supported by the Australian National Health and Medical Research Council (NHMRC; ID1060991). The Australian NHMRC also supported Dr. Laaksonen (ID1053642), Prof. Canfell (ID1082989), Prof. Banks (ID1042717), Prof. Shaw (ID1079438), and Prof. Magliano (ID1118161). Dr. Laaksonen was additionally supported by the Cancer Institute of New South Wales (ID13/ECF/1-07). Ms. Arriaga was supported by an Australian Postgraduate Award and a Translational Cancer Research Network PhD Scholarship Top-up Award

The burden of cancer attributable to modifiable risk factors: The Australian cancer-PAF cohort consortium

Purpose To 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. Participants 365 173 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 date Over 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 plans We will rank the most important causal factors and their combinations for a spectrum of cancers and inform cancer control activities.This study was funded by the National Health and Medical Research Council (ID1060991; ID1053642 to MAL; ID1082989 to KC; ID1042717 to EB) and a Cancer Institute New South Wales Fellowship (ID13/ECF/1-07 to MAL). Maria Arriaga was supported by Australian Postgraduate Award and a Translational Cancer Research Network (TCRN) PhD Scholarship Top-up Award

A Large Linked Study to Evaluate the Future Burden of Cancer in Australia Attributable to Current Modifiable Behaviours

Introduction The 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 Approach We 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. Results During 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/Implications Estimating 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

Genes Involved in Systemic and Arterial Bed Dependent Atherosclerosis - Tampere Vascular Study

BACKGROUND: Atherosclerosis is a complex disease with hundreds of genes influencing its progression. In addition, the phenotype of the disease varies significantly depending on the arterial bed. METHODOLOGY/PRINCIPAL FINDINGS: We characterized the genes generally involved in human advanced atherosclerotic (AHA type V-VI) plaques in carotid and femoral arteries as well as aortas from 24 subjects of Tampere Vascular study and compared the results to non-atherosclerotic internal thoracic arteries (n=6) using genome-wide expression array and QRT-PCR. In addition we determined genes that were typical for each arterial plaque studied. To gain a comprehensive insight into the pathologic processes in the plaques we also analyzed pathways and gene sets dysregulated in this disease using gene set enrichment analysis (GSEA). According to the selection criteria used (>3.0 fold change and p-value <0.05), 235 genes were up-regulated and 68 genes down-regulated in the carotid plaques, 242 genes up-regulated and 116 down-regulated in the femoral plaques and 256 genes up-regulated and 49 genes down-regulated in the aortic plaques. Nine genes were found to be specifically induced predominantly in aortic plaques, e.g., lactoferrin, and three genes in femoral plaques, e.g., chondroadherin, whereas no gene was found to be specific for carotid plaques. In pathway analysis, a total of 28 pathways or gene sets were found to be significantly dysregulated in atherosclerotic plaques (false discovery rate [FDR] <0.25). CONCLUSIONS: This study describes comprehensively the gene expression changes that generally prevail in human atherosclerotic plaques. In addition, site specific genes induced only in femoral or aortic plaques were found, reflecting that atherosclerotic process has unique features in different vascular beds