Prevalent occupational exposures and risk of lung cancer among women: Results from the application of the Canadian Job-Exposure Matrix (CANJEM) to a combined set of ten case-control studies.

BACKGROUND: Worldwide, lung cancer is the second leading cause of cancer death in women. The present study explored associations between occupational exposures that are prevalent among women, and lung cancer. METHODS: Data from 10 case-control studies of lung cancer from Europe, Canada, and New Zealand conducted between 1988 and 2008 were combined. Lifetime occupational history and information on nonoccupational factors including smoking were available for 3040 incident lung cancer cases and 4187 controls. We linked each reported job to the Canadian Job-Exposure Matrix (CANJEM), which provided estimates of probability, intensity, and frequency of exposure to each selected agent in each job. For this analysis, we selected 15 agents (cleaning agents, biocides, cotton dust, synthetic fibers, formaldehyde, cooking fumes, organic solvents, cellulose, polycyclic aromatic hydrocarbons from petroleum, ammonia, metallic dust, alkanes C18+, iron compounds, isopropanol, and calcium carbonate) that had lifetime exposure prevalence of at least 5% in the combined study population. For each agent, we estimated lung cancer risk in each study center for ever-exposure, by duration of exposure, and by cumulative exposure, using separate logistic regression models adjusted for smoking and other covariates. We then estimated the meta-odds ratios using random-effects meta-analysis. RESULTS AND CONCLUSIONS: None of the agents assessed showed consistent and compelling associations with lung cancer among women. The following agents showed elevated odds ratio in some analyses: metallic dust, iron compounds, isopropanol, and organic solvents. Future research into occupational lung cancer risk factors among women should prioritize these agents.

Male-Pattern Vertex Baldness Trajectories, Chest Hair Patterns, and Odds of Overall and Aggressive Prostate Cancer.

BACKGROUND: The link between hormones and hair growth is well established. Inconsistent associations have been found between hair patterns and cancer of the prostate, a hormone-dependent organ. We assessed vertex baldness trajectories, chest hair amount, and their relationships with the odds of developing prostate cancer in a large case-control study in Montreal, Canada. METHODS: In-person interviews were conducted with 1,931 incident prostate cancer cases and 1,994 population-based age-matched (±5 years) controls. Participants reported their hair patterns using the validated Hamilton-Norwood scale of baldness for 10-year increments starting at age 30, and their current amount of chest hair. Group-based trajectories were used to identify men sharing similar patterns of vertex baldness severity over adulthood. Multivariable logistic regression assessed associations between indicators of baldness (frontal, vertex, age at onset, severity, and trajectories), chest hair, and odds of prostate cancer. RESULTS: Vertex balding onset at age 30 was associated with increased odds of overall prostate cancer [Odds ratio (OR), 1.30; 95% confidence interval (CI), 1.03-1.64]. Men in the trajectory characterized by early moderate vertex baldness and developing severe baldness had increased odds of overall (OR, 1.42; 95% CI, 1.03-1.96) and especially aggressive prostate cancer (OR, 1.98; 95% CI, 1.21-3.22) compared with men without baldness. Men with little chest hair had higher odds of aggressive tumors than those with a moderate amount/a lot of chest hair. CONCLUSIONS: Early-onset moderate vertex baldness that progresses and having little chest hair may be useful biomarkers of aggressive prostate cancer. IMPACT: Integration of early-onset vertex balding patterns into risk prediction models of aggressive prostate cancer should be envisaged.

Ascertaining asthma status in epidemiologic studies: a comparison between administrative health data and self-report.

BACKGROUND: Studies have suggested that agreement between administrative health data and self-report for asthma status ranges from fair to good, but few studies benefited from administrative health data over a long period. We aimed to (1) evaluate agreement between asthma status ascertained in administrative health data covering a period of 30 years and from self-report, and (2) identify determinants of agreement between the two sources. METHODS: We used administrative health data (1983-2012) from the Quebec Birth Cohort on Immunity and Health, which included 81,496 individuals born in the province of Quebec, Canada, in 1974. Additional information, including self-reported asthma, was collected by telephone interview with 1643 participants in 2012. By design, half of them had childhood asthma based on health services utilization. Results were weighted according to the inverse of the sampling probabilities. Five algorithms were applied to administrative health data (having ≥ 2 physician claims over a 1-, 2-, 3-, 5-, or 30-year interval or ≥ 1 hospitalization), to enable comparisons with previous studies. We estimated the proportion of overall agreement and Kappa, between asthma status derived from algorithms and self-reports. We used logistic regression to identify factors associated with agreement. RESULTS: Applying the five algorithms, the prevalence of asthma ranged from 49 to 55% among the 1643 participants. At interview (mean age = 37 years), 49% and 47% of participants respectively reported ever having asthma and asthma diagnosed by a physician. Proportions of agreement between administrative health data and self-report ranged from 88 to 91%, with Kappas ranging from 0.57 (95% CI: 0.52-0.63) to 0.67 (95% CI: 0.62-0.72); the highest values were obtained with the [≥ 2 physician claims over a 30-year interval or ≥ 1 hospitalization] algorithm. Having sought health services for allergic diseases other than asthma was related to lower agreement (Odds ratio = 0.41; 95% CI: 0.25-0.65 comparing ≥ 1 health services to none). CONCLUSIONS: These findings indicate good agreement between asthma status defined from administrative health data and self-report. Agreement was higher than previously observed, which may be due to the 30-year lookback window in administrative data. Our findings support using both administrative health data and self-report in population-based epidemiological studies.

Evaluating Approaches for Constructing Polygenic Risk Scores for Prostate Cancer in Men of African and European Ancestry.

Genome-wide polygenic risk scores (GW-PRS) have been reported to have better predictive ability than PRS based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer risk variants from multi-ancestry GWAS and fine-mapping studies (PRS 269 ). GW-PRS models were trained using a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls used to develop the multi-ancestry PRS 269 . Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California/Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI=0.635-0.677) in African and 0.844 (95% CI=0.840-0.848) in European ancestry men and corresponding prostate cancer OR of 1.83 (95% CI=1.67-2.00) and 2.19 (95% CI=2.14-2.25), respectively, for each SD unit increase in the GW-PRS. However, compared to the GW-PRS, in African and European ancestry men, the PRS 269 had larger or similar AUCs (AUC=0.679, 95% CI=0.659-0.700 and AUC=0.845, 95% CI=0.841-0.849, respectively) and comparable prostate cancer OR (OR=2.05, 95% CI=1.87-2.26 and OR=2.21, 95% CI=2.16-2.26, respectively). Findings were similar in the validation data. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the multi-ancestry PRS 269 constructed with fine-mapping.

Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry.

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.

Neighbourhood social deprivation and risk of prostate cancer.

BACKGROUND: Striking geographic variations in prostate cancer incidence suggest an aetiological role for spatially-distributed factors. We assessed whether neighbourhood social deprivation, which can reflect limited social contacts, unfavourable lifestyle and environmental exposures, is associated with prostate cancer risk. METHODS: In 2005-2012, we recruited 1931 incident prostate cancer cases and 1994 controls in a case-control study in Montreal, Canada. Lifetime residential addresses were linked to an area-based social deprivation index around recruitment (2006) and about 10 years earlier (1996). Logistic regression estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Men residing in areas characterised by greater social deprivation had elevated prostate cancer risks (ORs of 1.54 and 1.60 for recent and past exposures, respectively; highest vs lowest quintiles), independently from area- and individual-level confounders and screening patterns. The increase in risk with recent high social deprivation was particularly elevated for high-grade prostate cancer at diagnosis (OR 1.87, 95% CI 1.32-2.64). Associations were more pronounced for neighbourhoods with higher proportions of separated/divorced or widowed individuals in the past, and with higher percentages of residents living alone recently. CONCLUSIONS: These novel findings, suggesting that neighbourhood-level social deprivation increases the risk of prostate cancer, point out to potential targeted public health interventions.

Family structure and living arrangements as indicators of social isolation, and prostate cancer risk.

Social isolation has been linked to a poorer prostate cancer prognosis. Little is known about how it could also influence its incidence. We investigated the association between family structure and living arrangements as potential indicators of social isolation, and prostate cancer risk, globally and according to disease aggressiveness. Data from the Prostate Cancer & Environment Study (PROtEuS), a case-control population-based study conducted between 2005 and 2012 in Montreal, Canada, were used. The study population comprised 1931 incident cases of prostate cancer, aged ≤75 years, and 1994 age-matched (±5 years) population controls. In-person interviews collected information on family composition and living arrangements recently and at age 40. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for potential confounders. Single men had an increased risk of high-grade prostate cancer at diagnosis (OR 1.80; 95% CI 1.29-2.51), compared to men currently married or with a partner. Having at least one daughter was associated with a lower risk of aggressive cancer (OR 0.76; 95% CI 0.61-0.96) while no association was found with having son(s). An inverse dose-response relationship was observed between the number of people living with the subject 2 years before diagnosis/interview and prostate cancer risk (p-trend<0.001). These results suggest a protective role of a rich personal environment on the risk of developing prostate cancer. As several of the associations studied here are novel, replication is required.

Occupational heat exposure and prostate cancer risk: A pooled analysis of case-control studies.

BACKGROUND: Heat exposures occur in many occupations. Heat has been linked to key carcinogenic processes, however, evidence for associations with cancer risk is sparse. We examined potential associations between occupational heat exposure and prostate cancer risk in a multi-country study. METHODS: We analysed a large, pooled dataset of 3142 histologically confirmed prostate cancer cases and 3512 frequency-matched controls from three countries: Canada, France, and Spain. Three exposure indices: ever exposure, lifetime cumulative exposure and duration of exposure, were developed using the Finnish Job-Exposure Matrix, FINJEM, applied to the lifetime occupational history of participants. We estimated odds ratios (ORs) and 95% confidence intervals (CIs), using conditional logistic regression models stratified by 5-year age groups and study, adjusting for potential confounders. Potential interactions with exposure to other occupational agents were also explored. RESULTS: Overall, we found no association for ever occupational heat exposure (OR 0.97; 95% CI 0.87, 1.09), nor in the highest categories of lifetime cumulative exposure (OR 1.04; 95% CI 0.89, 1.23) or duration (OR 1.03; 95% CI 0.88, 1.22). When using only the Spanish case-control study and a Spanish Job Exposure Matrix (JEM), some weakly elevated ORs were observed. CONCLUSIONS: Findings from this study provide no clear evidence for an association between occupational heat exposure and prostate cancer risk.

Occupational exposure to nickel and hexavalent chromium and the risk of lung cancer in a pooled analysis of case-control studies (SYNERGY).

There is limited evidence regarding the exposure-effect relationship between lung-cancer risk and hexavalent chromium (Cr(VI)) or nickel. We estimated lung-cancer risks in relation to quantitative indices of occupational exposure to Cr(VI) and nickel and their interaction with smoking habits. We pooled 14 case-control studies from Europe and Canada, including 16 901 lung-cancer cases and 20 965 control subjects. A measurement-based job-exposure-matrix estimated job-year-region specific exposure levels to Cr(VI) and nickel, which were linked to the subjects' occupational histories. Odds ratios (OR) and associated 95% confidence intervals (CI) were calculated by unconditional logistic regression, adjusting for study, age group, smoking habits and exposure to other occupational lung carcinogens. Due to their high correlation, we refrained from mutually adjusting for Cr(VI) and nickel independently. In men, ORs for the highest quartile of cumulative exposure to CR(VI) were 1.32 (95% CI 1.19-1.47) and 1.29 (95% CI 1.15-1.45) in relation to nickel. Analogous results among women were: 1.04 (95% CI 0.48-2.24) and 1.29 (95% CI 0.60-2.86), respectively. In men, excess lung-cancer risks due to occupational Cr(VI) and nickel exposure were also observed in each stratum of never, former and current smokers. Joint effects of Cr(VI) and nickel with smoking were in general greater than additive, but not different from multiplicative. In summary, relatively low cumulative levels of occupational exposure to Cr(VI) and nickel were associated with increased ORs for lung cancer, particularly in men. However, we cannot rule out a combined classical measurement and Berkson-type of error structure, which may cause differential bias of risk estimates.

Ambient exposures to selected volatile organic compounds and the risk of prostate cancer in Montreal.

Little is known about environmental factors that may increase the risk of prostate cancer. We estimated associations between incident prostate cancer and environmental concentrations of five ambient volatile organic compounds (VOCs): benzene; n-decane; ethylbenzene; hexane; and 1,2,4-trimethylbenzene. Methods: This study is based on a population-based case-control study of incident prostate cancer (PROtEuS) in men ≤ 75 years of age living in Montreal, Canada, in 2005 to 2012. We included 1172 cases and 1177 population controls. We had personal information, lifetime residential addresses, occupational exposures, and a variety of area-wide covariables. We inferred concentrations of the five VOCs using Bayesian geostatistical models using data from a dense environmental survey conducted in Montreal in 2005 to 2006. We used different sets of adjustments to estimate odds ratios (OR) and confidence intervals. Results: We found nonlinear associations such that the ORs increased monotonically and then either flattened or fell off with increased exposures. The model that contained other environmental variables and contextual variables led to lower ORs and results were similar when we restricted analyses to controls recently screened or tested for prostate cancer or cases with low- or high-grade tumors. A change from the 5th to 25th percentile in mean environmental benzene levels led to an adjusted OR of 2.00 (95% confidence interval = 1.47, 2.71). Conclusion: We found positive associations between prostate cancer and concentrations of benzene and ethylbenzene, independently of previous testing for prostate cancer or tumor grade, suggesting that exposure to certain ambient VOCs may increase incidence.

Spatial modeling of ambient concentrations of volatile organic compounds in Montreal, Canada.

Volatile organic compounds (VOCs) are components of the complex mixture of air pollutants within cities and can cause various adverse health effects. Therefore, it is necessary to understand their spatial distribution for exposure assessment in epidemiological studies. Objectives: The objective was to model measured concentrations of five VOCs within the city of Montreal, Canada, developing spatial prediction models that can be used in health studies. Methods: We measured concentrations using 3M 3500 Organic Vapor Monitors, over 2-week periods, for three monitoring campaigns between 2005 and 2006 in over 130 locations in the city. Using GC/MSD (Gas Chromatography/Mass Selective Detector), we measured concentrations of benzene, n-decane, ethylbenzene, hexane, and trimethylbenzene. We fitted four different models that combine land-use regression and geostatistical methods to account for the potential spatial structure that remains after accounting for the land-use variables. The fitted models also accounted for possible variations in the concentration of air pollutants across campaigns. Results: The highest concentrations for all VOCs were found in December with hexane being the most abundant followed by ethylbenzene. We obtained predicted surfaces for the VOCs for the three campaigns and mean surfaces across campaigns. We found higher concentrations of some VOCs along highways and in the Eastern part of Montreal, which is a highly industrialized area. Conclusions: Each of the fitted models captured the spatial and across-campaigns variability for each VOC, and we found that different VOCs required different model structures.

Ambient air pollution and prostate cancer risk in a population-based Canadian case-control study.

Ambient air pollution is a human carcinogen and a possible risk factor for prostate cancer. Methods: We investigated associations between ambient concentrations particulate matter 2.5 (PM2.5) and nitrogen dioxide (NO2) and incident prostate cancer in a Canadian case-control study. Between 1994 and 1997, cases were identified from provincial cancer registries, and a population-based series of controls was recruited. Among men 50 years of age or older, risk factor and residential history data (1975 to 1994) were collected from 1,420 prostate cancer cases and 1,424 controls. Three methods were used to estimate the residential mean exposure to PM2.5 and NO2 during this period: (1) satellite-derived observations; (2) satellite-derived observations scaled with historical fixed-site measurements; and (3) a national land-use regression (LUR) model. Odds ratios (ORs) and their 95% confidence intervals (CIs) in relation to interquartile range (IQR) increases in PM2.5 and NO2 were estimated using logistic regression, adjusting for personal and contextual factors. Results: We found positive associations between exposure to PM2.5 and NO2 over the previous 20 years and prostate cancer. An IQR increase in PM2.5 (3.56 µg/m3 for satellite and 4.48 µg/m3 for scaled satellite observations) yielded ORs of 1.28 (95% CI = 1.07, 1.52) and 1.20 (95% CI = 1.03, 1.40), respectively. For NO2, IQR increases (1.45 ppb for satellite, 15.18 ppb for scaled satellite-derived information, and 15.39 ppb for the national LUR) were associated with ORs of 1.09 (95% CI = 0.95, 1.24), 1.21 (95% CI = 1.02, 1.43), and 1.19 (95% CI = 1.03, 1.38), respectively. Conclusions: Our findings support the hypothesis that ambient air pollution increases the risk of prostate cancer.

Appendectomy and risk for inflammatory bowel disease: effect of age and time post appendectomy - a cohort study.

BACKGROUND AND OBJECTIVE: Appendectomy may modulate the risk of inflammatory bowel disease through an effect on the gut microbiota. This study investigated the associations between appendectomy and incidence of Crohn's disease (CD) or ulcerative colitis (UC), with an emphasis on the influence of age and time post appendectomy. METHODS: This cohort study included 400 520 subjects born in Québec in 1970-1974 and followed until 2014. Administrative health data were used to ascertain appendectomy and cases of CD and UC. Cox proportional hazards models with time-dependent variables (appendectomy and time elapsed post appendectomy) allowed for the estimation of HRs and 95% CIs. RESULTS: A total of 2545 (0.6%) CD cases and 1134 (0.3%) UC cases were identified during follow-up. Appendectomy increased the risk of CD (HR=2.02; 95% CI: 1.66 to 2.44), especially when performed at 18-29 years of age. The risk of CD was increased in the first 2 years, and decreased significantly after ≥15 years post appendectomy. Appendectomy appeared to protect against UC (HR=0.39; 95% CI: 0.22 to 0.71). The risk of UC was not associated with age at appendectomy, but decreased with time elapsed post appendectomy (HR=0.21; 95% CI: 0.06 to 0.72, comparing ≥5 with 0-4 years after appendectomy). CONCLUSIONS: The increased risk of CD related to appendectomy in young adults may result from detection bias, but physicians should have a low threshold for suspicion of CD in young symptomatic adults with a history of appendectomy. A strong protective effect of appendectomy against UC was observed after 5 years.

Early life Bacillus Calmette-Guerin vaccination and incidence of type 1, type 2, and latent autoimmune diabetes in adulthood.

AIMS: Bacillus Calmette-Guerin (BCG) vaccination limits blood sugar elevations and autoimmunity. Previous studies focused on type 1 diabetes among children, despite possible effects on other phenotypes later in life. We studied associations between BCG vaccination and type 1, type 2 and latent autoimmune diabetes (LADA) in adulthood. METHODS: A 1970-1974 birth cohort was linked with the BCG vaccination registry and administrative health data of Quebec. 396,118 people aged 22-44 years were followed-up for diabetes mellitus (DM) onset. Incident DM cases were subjects with ≥1 hospitalization or ≥2 physician claims related to DM over a 2-year period. Type 1 diabetes, type 2 diabetes, and LADA cases were individuals with ≥1 reimbursement of insulin, oral antidiabetic agent, or both. Cox proportional regressions were used to estimate hazard ratios (HR), adjusting for potential confounders. RESULTS: Forty-four percent of subjects were BCG vaccinated, 88% of these before age 1. For type 1 diabetes, no association was found before 30 years old, but vaccinated subjects had a lower risk of this phenotype after age 30 (HRadj= 0.65, 95% CI: 0.44-0.95). BCG vaccination was associated with a lower risk of type 2 diabetes (HRadj=0.85, 95% CI: 0.79-0.92), whereas no association was observed for LADA (HRadj=1.30, 95% CI: 0.71-2.38). Results did not differ by sex. CONCLUSIONS: Early life BCG vaccination was associated with lower risks of both type 1 and type 2 diabetes from early to middle adulthood, but not of LADA. Future studies should explore these long-term associations, while distinguishing diabetes phenotypes.

Association of allergic diseases and epilepsy with risk of glioma, meningioma and acoustic neuroma: results from the INTERPHONE international case-control study.

We investigated the association of allergic diseases and epilepsy with risk of brain tumours, in Interphone, a 13-country case-control study. Data were obtained from 2693 glioma cases, 2396 meningioma cases, and 1102 acoustic neuroma cases and their 6321 controls. Conditional logistic regression models were used to estimate pooled odds ratios (ORs) and their respective 95% confidence intervals (CIs), adjusted for education and time at interview. Reduced ORs were observed for glioma in relation to physician-diagnosed asthma (OR = 0.73; CI 0.58-0.92), hay fever (OR 0.72; CI 0.61-0.86), and eczema (OR 0.78, CI 0.64-0.94), but not for meningioma or acoustic neuroma. Previous diagnosis of epilepsy was associated with an increased OR for glioma (2.94; CI 1.87-4.63) and for meningioma (2.12; CI 1.27-3.56), but not for acoustic neuroma. This large-scale case-control study adds to the growing evidence that people with allergies have a lower risk of developing glioma, but not meningioma or acoustic neuroma. It also supports clinical observations of epilepsy prior to the diagnosis of glioma and meningioma.

Bacillus Calmette-Guerin vaccination and multiple sclerosis: A population-based birth cohort study in Quebec, Canada.

BACKGROUND AND PURPOSE: The bacillus Calmette-Guerin (BCG) vaccine could reduce the incidence of multiple sclerosis (MS) through immunomodulation. Previous studies, presenting some limitations, reported no association. We re-examined this association in a large cohort focusing on relapsing-remitting MS (RRMS). METHODS: The cohort included 400,563 individuals, and was linked with the Quebec provincial BCG vaccination registry and administrative health data. Individuals were followed up from 1983 to 2014 and then within Period 1 (1983-1996) and Period 2 (1997-2014), for the occurrence of MS. Incident MS cases were defined as those with ≥3 hospital or physician claims for MS. Subjects with ≥1 drug reimbursement for MS disease-modifying therapies were classified as RRMS. Cox proportional hazards regression was used to estimate hazard ratios (HRs) over the follow-ups, adjusting for potential confounders. Possible effect modification due to sex was assessed. RESULTS: A total of 178,335 (46%) individuals were BCG vaccinated. There were 274 (0.06%) incident MS cases identified in 1983-1996, and 1433 (0.4%) in 1997-2014. No association was found with RRMS, either in Period 1 (adjusted HR [HRadj ] = 0.96, 95% confidence interval [CI] = 0.63-1.45; 96 cases) or in Period 2 (HRadj  = 1.02, 95% CI = 0.85-1.23; 480 cases). The remaining MS cases, for whom the phenotype was unknown, were positively associated with BCG over the entire follow-up (HRadj  = 1.25, 95% CI = 1.10-1.41; 1131 cases) and in Period 2 (HRadj  = 1.33, 95% CI = 1.17-1.52; 953 cases). No interaction with sex was found. CONCLUSIONS: Findings suggest that BCG vaccination does not decrease the risk of RRMS, and that future studies should consider phenotypes of MS.

Comparison of mixed model based approaches for correcting for population substructure with application to extreme phenotype sampling.

BACKGROUND: Mixed models are used to correct for confounding due to population stratification and hidden relatedness in genome-wide association studies. This class of models includes linear mixed models and generalized linear mixed models. Existing mixed model approaches to correct for population substructure have been previously investigated with both continuous and case-control response variables. However, they have not been investigated in the context of extreme phenotype sampling (EPS), where genetic covariates are only collected on samples having extreme response variable values. In this work, we compare the performance of existing binary trait mixed model approaches (GMMAT, LEAP and CARAT) on EPS data. Since linear mixed models are commonly used even with binary traits, we also evaluate the performance of a popular linear mixed model implementation (GEMMA). RESULTS: We used simulation studies to estimate the type I error rate and power of all approaches assuming a population with substructure. Our simulation results show that for a common candidate variant, both LEAP and GMMAT control the type I error rate while CARAT's rate remains inflated. We applied all methods to a real dataset from a Québec, Canada, case-control study that is known to have population substructure. We observe similar type I error control with the analysis on the Québec dataset. For rare variants, the false positive rate remains inflated even after correction with mixed model approaches. For methods that control the type I error rate, the estimated power is comparable. CONCLUSIONS: The methods compared in this study differ in their type I error control. Therefore, when data are from an EPS study, care should be taken to ensure that the models underlying the methodology are suitable to the sampling strategy and to the minor allele frequency of the candidate SNPs.

A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry.

A rare African ancestry-specific germline deletion variant in HOXB13 (X285K, rs77179853) was recently reported in Martinican men with early-onset prostate cancer. Given the role of HOXB13 germline variation in prostate cancer, we investigated the association between HOXB13 X285K and prostate cancer risk in a large sample of 22 361 African ancestry men, including 11 688 prostate cancer cases. The risk allele was present only in men of West African ancestry, with an allele frequency in men that ranged from 0.40% in Ghana and 0.31% in Nigeria to 0% in Uganda and South Africa, with a range of frequencies in men with admixed African ancestry from North America and Europe (0-0.26%). HOXB13 X285K was associated with 2.4-fold increased odds of prostate cancer (95% confidence interval [CI] = 1.5-3.9, p = 2 × 10-4), with greater risk observed for more aggressive and advanced disease (Gleason ≥8: odds ratio [OR] = 4.7, 95% CI = 2.3-9.5, p = 2 × 10-5; stage T3/T4: OR = 4.5, 95% CI = 2.0-10.0, p = 2 × 10-4; metastatic disease: OR = 5.1, 95% CI = 1.9-13.7, p = 0.001). We estimated that the allele arose in West Africa 1500-4600 yr ago. Further analysis is needed to understand how the HOXB13 X285K variant impacts the HOXB13 protein and function in the prostate. Understanding who carries this mutation may inform prostate cancer screening in men of West African ancestry. PATIENT SUMMARY: A rare African ancestry-specific germline deletion in HOXB13, found only in men of West African ancestry, was reported to be associated with an increased risk of overall and advanced prostate cancer. Understanding who carries this mutation may help inform screening for prostate cancer in men of West African ancestry.

Diagnostic radiological examinations and risk of intracranial tumours in adults-findings from the Interphone Study.

BACKGROUND: Exposure to high doses of ionizing radiation is among the few well-established brain tumour risk factors. We used data from the Interphone study to evaluate the effects of exposure to low-dose radiation from diagnostic radiological examinations on glioma, meningioma and acoustic neuroma risk. METHODS: Brain tumour cases (2644 gliomas, 2236 meningiomas, 1083 neuromas) diagnosed in 2000-02 were identified through hospitals in 13 countries, and 6068 controls (population-based controls in most centres) were included in the analysis. Participation across all centres was 64% for glioma cases, 78% for meningioma cases, 82% for acoustic neuroma cases and 53% for controls. Information on previous diagnostic radiological examinations was obtained by interviews, including the frequency, timing and indication for the examinations. Typical brain doses per type of examination were estimated based on the literature. Examinations within the 5 years before the index date were excluded from the dose estimation. Adjusted odds ratios were estimated using conditional logistic regression. RESULTS: No materially or consistently increased odds ratios for glioma, meningioma or acoustic neuroma were found for any specific type of examination, including computed tomography of the head and cerebral angiography. The only indication of an elevated risk was an increasing trend in risk of meningioma with the number of isotope scans, but no such trends for other examinations were observed. No gradient was found in risk with estimated brain dose. Age at exposure did not substantially modify the findings. Sensitivity analyses gave results consistent with the main analysis. CONCLUSIONS: There was no consistent evidence for increased risks of brain tumours with X-ray examinations, although error from selection and recall bias cannot be completely excluded. A cautious interpretation is warranted for the observed association between isotope scans and meningioma.