A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: application to BRCA1 and BRCA2.

A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.

Polymorphisms in genes of melatonin biosynthesis and signaling support the light-at-night hypothesis for breast cancer.

Light-at-night triggers the decline of pineal gland melatonin biosynthesis and secretion and is an IARC-classified probable breast-cancer risk factor. We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at genes of melatonin biosynthesis/signaling using a study population of 44,405 women from the Breast Cancer Association Consortium (22,992 cases, 21,413 population-based controls). Genotype data of 97 candidate single nucleotide polymorphisms (SNPs) at 18 defined gene regions were investigated for breast-cancer risk effects. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) by logistic regression for the main-effect analysis as well as stratified analyses by estrogen- and progesterone-receptor (ER, PR) status. SNP-SNP interactions were analyzed via a two-step procedure based on logic regression. The Bayesian false-discovery probability (BFDP) was used for all analyses to account for multiple testing. Noteworthy associations (BFDP < 0.8) included 10 linked SNPs in tryptophan hydroxylase 2 (TPH2) (e.g. rs1386492: OR = 1.07, 95% CI 1.02-1.12), and a SNP in the mitogen-activated protein kinase 8 (MAPK8) (rs10857561: OR = 1.11, 95% CI 1.04-1.18). The SNP-SNP interaction analysis revealed noteworthy interaction terms with TPH2- and MAPK-related SNPs (e.g. rs1386483R ∧ rs1473473D ∧ rs3729931D: OR = 1.20, 95% CI 1.09-1.32). In line with the light-at-night hypothesis that links shift work with elevated breast-cancer risks our results point to SNPs in TPH2 and MAPK-genes that may impact the intricate network of circadian regulation.

Translocation of bacterial LPS is associated with self-reported cognitive abilities in men living with HIV receiving antiretroviral therapy.

BACKGROUND: Gut damage allows translocation of bacterial lipopolysaccharide (LPS) and fungal ß-D-glucan (BDG) into the blood. This microbial translocation contributes to systemic inflammation and risk of non-AIDS comorbidities in people living with HIV, including those receiving antiretroviral therapy (ART). We assessed whether markers of gut damage and microbial translocation were associated with cognition in ART-treated PLWH. METHODS: Eighty ART-treated men living with HIV from the Positive Brain Health Now Canadian cohort were included. Brief cognitive ability measure (B-CAM) and 20-item patient deficit questionnaire (PDQ) were administered to all participants. Three groups were selected based on their B-CAM levels. We excluded participants who received proton pump inhibitors or antiacids in the past 3 months. Cannabis users were also excluded. Plasma levels of intestinal fatty acid binding protein (I-FABP), regenerating islet-derived protein 3 α (REG3α), and lipopolysaccharides (LPS = were quantified by ELISA, while 1-3-ß-D-glucan BDG) levels were assessed using the Fungitell assay. Univariable, multivariable, and splines analyses were performed. RESULTS: Plasma levels of I-FABP, REG3α, LPS and BDG were not different between groups of low, intermediate and high B-CAM levels. However, LPS and REG3α levels were higher in participants with PDQ higher than the median. Multivariable analyses showed that LPS association with PDQ, but not B-CAM, was independent of age and level of education. I-FABP, REG3α, and BDG levels were not associated with B-CAM nor PDQ levels in multivariable analyses. CONCLUSION: In this well characterized cohort of ART-treated men living with HIV, bacterial but not fungal translocation was associated with presence of cognitive difficulties. These results need replication in larger samples.

The association between the incidence of postmenopausal breast cancer and occupational exposure to selected organic solvents, Montreal, Canada, 2008-2011.

BACKGROUND: Breast cancer is the most diagnosed cancer among women and recognized risk factors explain 25%-47% of cases. Organic solvents are used widely in the workplace and exposure may increase the risk of developing breast cancer, yet there are insufficient data to confirm this hypothesis. We sought to determine whether past occupational exposures to selected organic solvents were associated with the incidence of invasive breast cancer in postmenopausal women in Montréal, Canada. METHODS: From a population-based case-control study (2008-2011), using in-depth interviews we elicited information on risk factors and lifetime occupational histories. Industrial hygienists and chemists translated job descriptions into specific chemical and physical exposures. We assessed 11 individual solvents and four solvent groups. Unconditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for metrics of past exposures to selected solvents. Exposure metrics included any previous exposure, average frequency in hours per week, duration in years, and average cumulative concentration weighted by hours per workweek exposed. RESULTS: We enrolled 695 cases and 608 controls. We found increased ORs for average cumulative concentration of exposure to mononuclear aromatic hydrocarbons (OR: 1.52, 95% CI: 1.04, 2.28), chlorinated alkanes (OR: 2.42, 95% CI: 1.23, 5.68), toluene (OR: 1.59, 95% CI: 1.02, 2.59), and a group of organic solvents with reactive metabolites (OR: 1.53, 95% CI: 1.08, 2.24). Positive associations were found across all exposure metrics and were higher among women with estrogen-positive/progesterone-negative tumors. CONCLUSION: Our findings suggest occupational exposure to certain organic solvents may increase the risk of incident postmenopausal breast cancer.

Household determinants of biocontaminant exposures in Canadian homes.

Exposure to biocontaminants, such as dust mites, animal dander, bacteria, and mold, is associated with a range of health effects. This study identified household characteristics associated with indoor biocontaminant loadings in four Canadian cities. Floor dust was collected in 290 Canadian homes in Edmonton, Halifax, Montreal, and Windsor. The dust samples were analyzed for house dust mite allergens (Der f 1 and Der p 1), cat allergen (Fel d 1), cockroach allergen (Bla g 1), beta-(1,3)-D-glucan, and endotoxin. Household information was obtained through questionnaires and home inspections. We performed univariate and multivariate analyses to identify household determinants of biocontaminant loadings and mold odor presence. We observed large regional variations for all biocontaminants, except for cockroach allergen. The ranges of the contaminants measured in loadings and concentrations were similar to that of previous Canadian studies. Household characteristics including presence of carpeting, low floor cleaning frequency, older home age, presence of pets, and indoor relative humidity above 45% were positively associated with the presence of multiple indoor biocontaminants. High floor cleaning frequency and use of dehumidifiers were negatively associated with the presence of multiple indoor biocontaminants. Mold odor was positively associated with older home age, past water damage, and visible mold growth.

Exposure to ambient air pollution and the incidence of lung cancer and breast cancer in the Ontario Population Health and Environment Cohort.

Lung and female breast cancers are highly prevalent worldwide. Although the association between exposure to ambient fine particulate matter (PM2.5 ) and lung cancer has been recognized, there is less evidence for associations with other common air pollutants such as nitrogen dioxide (NO2 ) and ozone (O3 ). Even less is known about potential associations between these pollutants and breast cancer. We conducted a population-based cohort study to investigate the associations of chronic exposure to PM2.5 , NO2 , O3 and redox-weighted average of NO2 and O3 (Ox ) with incident lung and breast cancer, using the Ontario Population Health and Environment Cohort (ONPHEC), which includes all long-term residents aged 35-85 years who lived in Ontario, Canada, 2001-2015. Incident lung and breast cancers were ascertained using the Ontario Cancer Registry. Annual estimates of exposures were assigned to the residential postal codes of subjects for each year during follow-up. We used Cox proportional-hazards models adjusting for personal- and neighborhood-level covariates. Our cohorts for lung and breast cancer analyses included ~4.9 million individuals and ~2.5 million women, respectively. During follow-up, 100,146 incident cases of lung cancer and 91,146 incident cases of breast cancer were diagnosed. The fully adjusted analyses showed positive associations of lung cancer incidence with PM2.5 (hazard ratio [HR] = 1.02 [95% CI: 1.01-1.05] per 5.3 µg/m3 ) and NO2 (HR = 1.05 [95% CI: 1.03-1.07] per 14 ppb). No associations with lung cancer were observed for O3 or Ox . Relationships between PM2.5 and NO2 with lung cancer exhibited a sublinear shape. We did not find compelling evidence linking air pollution to breast cancer.

Long-term exposure to air pollution and the incidence of multiple sclerosis: A population-based cohort study.

BACKGROUND: Evidence of the adverse neurological effects of exposure to ambient air pollution is emerging, but little is known about its effect on the development of multiple sclerosis (MS), the most common autoimmune disease of the central nervous system. OBJECTIVES: To investigate the associations between MS incidence and long-term exposures to fine particles (PM2.5), nitrogen dioxide (NO2), and ozone (O3) METHODS: We conducted a population-based cohort study to investigate the associations between long-term exposures to PM2.5, NO2, and O3 and the incidence of MS. Our study population included all Canadian-born residents aged 20-40 years who lived in the province of Ontario, Canada from 2001 to 2013. Incident MS was ascertained from a validated registry. We assigned estimates of annual concentrations of these pollutants to the residential postal codes of subjects for each year during the 13 years of follow-up. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for each pollutant separately using random-effects Cox proportional hazards models. We conducted various sensitivity analyses, such as lagging exposure up to 5 years and adjusting for access to neurological care, annual average temperature, and population density. RESULTS: Between 2001 and 2013, we identified 6203 incident cases of MS. The adjusted HR of incident MS was 0.96 (95% CI: 0.86-1.07) for PM2.5, 0.91(95% CI: 0.81-1.02) for NO2, and 1.09 (95% CI: 0.98-1.23) for O3. These results were robust to various sensitivity analyses conducted. CONCLUSIONS: In this large population-based cohort, we did not observe significant associations between MS incidence and long-term exposures to PM2.5, NO2, and O3 in adults in Ontario, 2001-2013.

Gene-environment interactions involving functional variants: Results from the Breast Cancer Association Consortium.

Investigating the most likely causal variants identified by fine-mapping analyses may improve the power to detect gene-environment interactions. We assessed the interplay between 70 single nucleotide polymorphisms identified by genetic fine-scale mapping of susceptibility loci and 11 epidemiological breast cancer risk factors in relation to breast cancer. Analyses were conducted on up to 58,573 subjects (26,968 cases and 31,605 controls) from the Breast Cancer Association Consortium, in one of the largest studies of its kind. Analyses were carried out separately for estrogen receptor (ER) positive (ER+) and ER negative (ER-) disease. The Bayesian False Discovery Probability (BFDP) was computed to assess the noteworthiness of the results. Four potential gene-environment interactions were identified as noteworthy (BFDP < 0.80) when assuming a true prior interaction probability of 0.01. The strongest interaction result in relation to overall breast cancer risk was found between CFLAR-rs7558475 and current smoking (ORint = 0.77, 95% CI: 0.67-0.88, pint = 1.8 × 10-4 ). The interaction with the strongest statistical evidence was found between 5q14-rs7707921 and alcohol consumption (ORint =1.36, 95% CI: 1.16-1.59, pint = 1.9 × 10-5 ) in relation to ER- disease risk. The remaining two gene-environment interactions were also identified in relation to ER- breast cancer risk and were found between 3p21-rs6796502 and age at menarche (ORint = 1.26, 95% CI: 1.12-1.43, pint =1.8 × 10-4 ) and between 8q23-rs13267382 and age at first full-term pregnancy (ORint = 0.89, 95% CI: 0.83-0.95, pint = 5.2 × 10-4 ). While these results do not suggest any strong gene-environment interactions, our results may still be useful to inform experimental studies. These may in turn, shed light on the potential interactions observed.

Spatial variations in ambient ultrafine particle concentrations and the risk of incident prostate cancer: A case-control study.

BACKGROUND: Diesel exhaust contains large numbers of ultrafine particles (UFPs, <0.1µm) and is a recognized human carcinogen. However, epidemiological studies have yet to evaluate the relationship between UFPs and cancer incidence. METHODS: We conducted a case-control study of UFPs and incident prostate cancer in Montreal, Canada. Cases were identified from all main Francophone hospitals in the Montreal area between 2005 and 2009. Population controls were identified from provincial electoral lists of French Montreal residents and frequency-matched to cases using 5-year age groups. UFP exposures were estimated using a land use regression model. Exposures were assigned to residential locations at the time of diagnosis/recruitment as well as approximately 10-years earlier to consider potential latency between exposure and disease onset. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated per interquartile range (IQR) increase in UFPs (approximately 4000 particles/cm3) using logistic regression models adjusting for individual-level and ecological covariates. RESULTS: Ambient UFP concentrations were associated with an increased risk of prostate cancer (OR=1.10, 95% CI: 1.01, 1.19) in fully adjusted models when exposures were assigned to residences 10-years prior to diagnosis. This risk estimate increased slightly (OR=1.17, 95% CI; 1.01, 1.35) when modeled as a non-linear natural spline function. A smaller increased risk (OR=1.04, 95% CI: 0.97, 1.11) was observed when exposures were assigned to residences at the time of diagnosis. CONCLUSIONS: Exposure to ambient UFPs may increase the risk of prostate cancer. Future studies are needed to replicate this finding as this is the first study to evaluate this relationship.

The association between the incidence of postmenopausal breast cancer and concentrations at street-level of nitrogen dioxide and ultrafine particles.

BACKGROUND: There is scant information as to whether traffic-related air pollution is associated with the incidence of breast cancer. Nitrogen dioxide (NO2) and ultrafine particles (UFPs, <0.1µm), are two pollutants that capture intra-urban variations in traffic-related air pollution and may also be associated with incidence. METHODS: We conducted a population-based, case-control study of street-level concentrations of NO2 and UFPs and incident postmenopausal breast cancer in Montreal, Canada. Incident cases were identified between 2008 and 2011 from all but one hospital that treated breast cancer in the Montreal area. Population controls were identified from provincial electoral lists of Montreal residents and frequency-matched to cases using 5-year age groups. Concentrations of NO2 and UFPs were estimated using two separate land-use regression models. Exposures were assigned to residential locations at the time of recruitment, and we identified residential histories of women who had lived in these residences for 10 years or more. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models adjusting for individual-level and ecological covariates. We assessed the functional form of NO2 and UFP exposures using natural cubic splines. RESULTS: We found that the functional form of the response functions between incident postmenopausal breast cancer and concentrations of NO2 and UFPs were consistent with linearity. For NO2, we found increasing risks of breast cancer for all subjects combined and stronger associations when analyses were restricted to those women who had lived at their current address for 10 years or more. Specifically, the OR, adjusted for personal covariates, per increase in the interquartile range (IQR=3.75 ppb) of NO2 was 1.08 (95%CI: 0.92-1.27). For women living in their homes for 10 years or more, the adjusted OR was 1.17 (95%CI: 0.93-1.46; IQR=3.84 ppb); for those not living at that home 10 years before the study, it was 0.93 (95%CI: 0.64, 1.36; IQR=3.65 ppb). For UFPs, the ORs were lower than for NO2, with little evidence of association in any of the models or sub-analyses and little variability in the ORs (about 1.02 for an IQR of ~3500cm-3). On the other hand, we found higher ORs amongst cases with positive oestrogen and progesterone receptor status; namely for NO2, the OR was 1.13 (95%CI: 0.94-1.35) and for UFPs it was 1.05 (95%CI: 0.96-1.14). CONCLUSIONS: Our findings suggest that exposure to ambient NO2 and UFPs may increase the risk of incident postmenopausal breast cancer especially amongst cases with positive oestrogen and progesterone receptor status.

Comparison of spatiotemporal prediction models of daily exposure of individuals to ambient nitrogen dioxide and ozone in Montreal, Canada.

BACKGROUND: In previous studies investigating the short-term health effects of ambient air pollution the exposure metric that is often used is the daily average across monitors, thus assuming that all individuals have the same daily exposure. Studies that incorporate space-time exposures of individuals are essential to further our understanding of the short-term health effects of ambient air pollution. OBJECTIVES: As part of a longitudinal cohort study of the acute effects of air pollution that incorporated subject-specific information and medical histories of subjects throughout the follow-up, the purpose of this study was to develop and compare different prediction models using data from fixed-site monitors and other monitoring campaigns to estimate daily, spatially-resolved concentrations of ozone (O3) and nitrogen dioxide (NO2) of participants' residences in Montreal, 1991-2002. METHODS: We used the following methods to predict spatially-resolved daily concentrations of O3 and NO2 for each geographic region in Montreal (defined by three-character postal code areas): (1) assigning concentrations from the nearest monitor; (2) spatial interpolation using inverse-distance weighting; (3) back-extrapolation from a land-use regression model from a dense monitoring survey, and; (4) a combination of a land-use and Bayesian maximum entropy model. We used a variety of indices of agreement to compare estimates of exposure assigned from the different methods, notably scatterplots of pairwise predictions, distribution of differences and computation of the absolute agreement intraclass correlation (ICC). For each pairwise prediction, we also produced maps of the ICCs by these regions indicating the spatial variability in the degree of agreement. RESULTS: We found some substantial differences in agreement across pairs of methods in daily mean predicted concentrations of O3 and NO2. On a given day and postal code area the difference in the concentration assigned could be as high as 131ppb for O3 and 108ppb for NO2. For both pollutants, better agreement was found between predictions from the nearest monitor and the inverse-distance weighting interpolation methods, with ICCs of 0.89 (95% confidence interval (CI): 0.89, 0.89) for O3 and 0.81 (95%CI: 0.80, 0.81) for NO2, respectively. For this pair of methods the maximum difference on a given day and postal code area was 36ppb for O3 and 74ppb for NO2. The back-extrapolation method showed a higher degree of disagreement with the nearest monitor approach, inverse-distance weighting interpolation, and the Bayesian maximum entropy model, which were strongly constrained by the sparse monitoring network. The maps showed that the patterns of agreement differed across the postal code areas and the variability depended on the pair of methods compared and the pollutants. For O3, but not NO2, postal areas showing greater disagreement were mostly located near the city centre and along highways, especially in maps involving the back-extrapolation method. CONCLUSIONS: In view of the substantial differences in daily concentrations of O3 and NO2 predicted by the different methods, we suggest that analyses of the health effects from air pollution should make use of multiple exposure assessment methods. Although we cannot make any recommendations as to which is the most valid method, models that make use of higher spatially resolved data, such as from dense exposure surveys or from high spatial resolution satellite data, likely provide the most valid estimates.

A structured review of panel studies used to investigate associations between ambient air pollution and heart rate variability.

INTRODUCTION: Dysfunction of the autonomic nervous system is one of the postulated pathways linking short-term exposure to air pollution to adverse cardiovascular outcomes. A hypothesis is that exposure to air pollution decreases heart rate variability, a recognized independent predictor of poorer cardiovascular prognosis. METHODS: We conducted a structured review of panel studies published between 1946 and July 2015 of the association between ambient air pollution and parameters of heart rate variability reflecting autonomic nervous function. We focused on exposure to mass concentrations of fine particles (PM2.5), nitrogen dioxide (NO2), and ozone (O3), and four commonly used indices of heart rate variability (HRV): standard deviation of all normal-to-normal intervals (SDNN); root mean square of successive differences in adjacent normal-to-normal intervals (RMSSD); high frequency power (HF); and low frequency power (LF). We searched bibliographic databases and references of identified articles and abstracted characteristics of their design and conduct, and synthesized the quantitative findings in graphic form according to health condition of the study population and the functional form of the HRV indices used in the regression analyses. RESULTS: A total of 33 panel studies were included: 31, 12, and 13 studies were used to investigate ambient exposure to PM2.5, NO2 and O3, respectively. We found substantial variation across studies in terms of design characteristics and statistical methodologies, and we identified some studies that may have had methodological and statistical issues. Because many panel studies were not comparable to each other, meta-analyses were not generally possible, although we were able to pool the results obtained amongst older adults who had cardiovascular disease for the 24-h average concentrations of PM2.5 prior to the heart rate variability measurements. In studies of PM2.5 among older adults with cardiovascular disease, logarithmic transformations of the HRV indices were used in ten studies. Negative associations across all HRV indices were found in 60-86% of these studies for periods of exposures ranging from 5-min to 5-days. The pooled percent changes for an increase of 10µg/m(3) in the 24-h prior to the measurements of HRV were: -2.11% for SDNN (95% confidence interval (95%CI): -4.00, -0.23%), -3.29% for RMSSD (95%CI: -6.32, -0.25%), -4.76% for LF (95%CI: -12.10, 2.58%), and -1.74% for HF (95%CI: -7.79, 4.31%). No transformations were used in seven studies of PM2.5 among older adults with cardiovascular disease, and we found for absolute differences pooled changes in the HRV indices, for an increase of 10µg/m(3), of -0.31ms for SDNN (95%CI: -1.02, 0.41ms) and -1.22ms for RMSSD (95%CI: -2.37; -0.07ms). For gaseous pollutants, negative associations over periods of exposure ranging from 5-min or to 5-days prior to the heart rate variability measurements were reported in 71-83% of studies of NO2 and 57-100% of studies of O3, depending of the indices of heart rate variability. However, many of these studies had statistical or methodological issues, and in the few studies without these issues the confidence intervals were relatively wide and mostly included the null. CONCLUSIONS AND DISCUSSION: We were not persuaded by the results that there was an association between PM2.5 and any of the four indices of heart rate variability. For NO2 and O3 the number of high-quality studies was insufficient to draw any definite conclusions. Further panel studies with improved design and methodologies are needed to help establish or refute an association between ambient exposure to air pollution and heart rate variability.

A panel study of the acute effects of personal exposure to household air pollution on ambulatory blood pressure in rural Indian women.

BACKGROUND: Almost half the world's population is exposed to household air pollution from biomass and coal combustion. The acute effects of household air pollution on the cardiovascular system are poorly characterized. We conducted a panel study of rural Indian women to assess whether personal exposures to black carbon during cooking were associated with acute changes in blood pressure. METHODS: We enrolled 45 women (ages 25-66 years) who cooked with biomass fuels. During cooking sessions in winter and summer, we simultaneously measured their personal real-time exposure to black carbon and conducted ambulatory blood pressure measurements every 10min. We recorded ambient temperature and participants' activities while cooking. We assessed body mass index, socioeconomic status, and salt intake. Multivariate mixed effects regression models with random intercepts were used to estimate the associations between blood pressure and black carbon exposure, e.g., average exposure in the minutes preceding blood pressure measurement, and average exposure over an entire cooking session. RESULTS: Women's geometric mean (GM) exposure to black carbon during cooking sessions was lower in winter (GM: 40µg/m(3); 95% CI: 30, 53) than in summer (GM: 56µg/m(3); 95% CI: 42, 76). Interquartile range increases in black carbon were associated with changes in systolic blood pressure from -0.4mm Hg (95% CI: -2.3, 1.5) to 1.9mm Hg (95% CI: -0.8, 4.7), with associations increasing in magnitude as black carbon values were assessed over greater time periods preceding blood pressure measurement. Interquartile range increases in black carbon were associated with small decreases in diastolic blood pressure from -0.9mm Hg (95% CI: -1.7, -0.1) to -0.4mm Hg (95% CI: -1.6, 0.8). Associations of a similar magnitude were estimated for cooking session-averaged values. CONCLUSIONS: We found some evidence of an association between exposure to black carbon and acute increases in systolic blood pressure in Indian women cooking with biomass fuels, which may have implications for the development of cardiovascular diseases.

Trace metal exposure is associated with increased exhaled nitric oxide in asthmatic children.

BACKGROUND: Children with asthma experience increased susceptibility to airborne pollutants. Exposure to traffic and industrial activity have been positively associated with exacerbation of symptoms as well as emergency room visits and hospitalisations. The effect of trace metals contained in fine particulate matter (aerodynamic diameter 2.5 µm and lower, PM2.5) on acute health effects amongst asthmatic children has not been well investigated. The objective of this panel study in asthmatic children was to determine the association between personal daily exposure to ambient trace metals and airway inflammation, as measured by fractional exhaled nitric oxide (FeNO). METHODS: Daily concentrations of trace metals contained on PM2.5 were determined from personal samples (n = 217) collected from 70 asthmatic school aged children in Montreal, Canada, over ten consecutive days. FeNO was measured daily using standard techniques. RESULTS: A positive association was found between FeNO and children's exposure to an indicator of vehicular non-tailpipe emissions (8.9 % increase for an increase in the interquartile range (IQR) in barium, 95 % confidence interval (CI): 2.8, 15.4) as well as exposure to an indicator of industrial emissions (7.6 % increase per IQR increase in vanadium, 95 % CI: 0.1, 15.8). Elevated FeNO was also suggested for other metals on the day after the exposure: 10.3 % increase per IQR increase in aluminium (95 % CI: 4.2, 16.6) and 7.5 % increase per IQR increase in iron (95 % CI: 1.5, 13.9) at a 1-day lag period. CONCLUSIONS: Exposures to ambient PM2.5 containing trace metals that are markers of traffic and industrial-derived emissions were associated in asthmatic children with an enhanced FeNO response.

Spatial association between ambient fine particulate matter and incident hypertension.

BACKGROUND: Laboratory studies suggest that exposure to fine particulate matter (≤2.5 µm in diameter) (PM2.5) can trigger a combination of pathophysiological responses that may induce the development of hypertension. However, epidemiological evidence relating PM2.5 and hypertension is sparse. We thus conducted a population-based cohort study to determine whether exposure to ambient PM2.5 is associated with incident hypertension. METHODS AND RESULTS: We assembled a cohort of 35 303 nonhypertensive adults from Ontario, Canada, who responded to 1 of 4 population-based health surveys between 1996 and 2005 and were followed up until December 31, 2010. Incident diagnoses of hypertension were ascertained from the Ontario Hypertension Database, a validated registry of persons diagnosed with hypertension in Ontario (sensitivity=72%, specificity=95%). Estimates of long-term exposure to PM2.5 at participants' postal-code residences were derived from satellite observations. We used Cox proportional hazards models, adjusting for various individual and contextual risk factors including body mass index, smoking, physical activity, and neighbourhood-level unemployment rates. We conducted various sensitivity analyses to assess the robustness of the effect estimate, such as investigating several time windows of exposure and controlling for potential changes in the risk of hypertension over time. Between 1996 and 2010, we identified 8649 incident cases of hypertension and 2296 deaths. For every 10-µg/m(3) increase of PM2.5, the adjusted hazard ratio of incident hypertension was 1.13 (95% confidence interval, 1.05-1.22). Estimated associations were comparable among all sensitivity analyses. CONCLUSIONS: This study supports an association between PM2.5 and incident hypertension.

Methodological issues related to pooling results from panel studies of heart rate variability and its association with ambient air pollution.

Reviews of observational studies and subsequent meta-analyses are challenging to interpret because of potential methodological issues and biases inherent in studies. In reviewing panel studies of the association between heart rate variability and ambient air pollution we identified a number of methodological issues that make difficult interpreting and pooling findings from longitudinal studies, notably issues related to associations arising from different type of designs, differences in design characteristics, including study populations, measurements of heart rate variability (e.g., duration and condition of the electrocardiogram recordings), exposure assessment (e.g., types of monitoring), metrics of exposure used, and parameters estimated from regression models. We conclude that many panel studies of the association between heart rate variability and ambient air pollution may not be comparable to each other, and thus caution must be exercised to avoid misleading conclusions.

Investigating the role of transportation models in epidemiologic studies of traffic related air pollution and health effects.

In two earlier case-control studies conducted in Montreal, nitrogen dioxide (NO2), a marker for traffic-related air pollution was found to be associated with the incidence of postmenopausal breast cancer and prostate cancer. These studies relied on a land use regression model (LUR) for NO2 that is commonly used in epidemiologic studies for deriving estimates of traffic-related air pollution. Here, we investigate the use of a transportation model developed during the summer season to generate a measure of traffic emissions as an alternative to the LUR model. Our traffic model provides estimates of emissions of nitrogen oxides (NOx) at the level of individual roads, as does the LUR model. Our main objective was to compare the distribution of the spatial estimates of NOx computed from our transportation model to the distribution obtained from the LUR model. A secondary objective was to compare estimates of risk using these two exposure estimates. We observed that the correlation (spearman) between our two measures of exposure (NO2 and NOx) ranged from less than 0.3 to more than 0.9 across Montreal neighborhoods. The most important factor affecting the "agreement" between the two measures in a specific area was found to be the length of roads. Areas affected by a high level of traffic-related air pollution had a far better agreement between the two exposure measures. A comparison of odds ratios (ORs) obtained from NO2 and NOx used in two case-control studies of breast and prostate cancer, showed that the differences between the ORs associated with NO2 exposure vs NOx exposure differed by 5.2-8.8%.

Indirect adjustment for multiple missing variables applicable to environmental epidemiology.

OBJECTIVES: Develop statistical methods for survival models to indirectly adjust hazard ratios of environmental exposures for missing risk factors. METHODS: A partitioned regression approach for linear models is applied to time to event survival analyses of cohort study data. Information on the correlation between observed and missing risk factors is obtained from ancillary data sources such as national health surveys. The relationship between the missing risk factors and survival is obtained from previously published studies. We first evaluated the methodology using simulations, by considering the Weibull survival distribution for a proportional hazards regression model with varied baseline functions, correlations between an adjusted variable and an adjustment variable as well as selected censoring rates. Then we illustrate the method in a large, representative Canadian cohort of the association between concentrations of ambient fine particulate matter and mortality from ischemic heart disease. RESULTS: Indirect adjustment for cigarette smoking habits and obesity increased the fine particulate matter-ischemic heart disease association by 3%-123%, depending on the number of variables considered in the adjustment model due to the negative correlation between these two risk factors and ambient air pollution concentrations in Canada. The simulations suggested that the method yielded small relative bias (<40%) for most cohort designs encountered in environmental epidemiology. CONCLUSIONS: This method can accommodate adjustment for multiple missing risk factors simultaneously while accounting for the associations between observed and missing risk factors and between missing risk factors and health endpoints.

Associations between personal exposure to air pollutants and lung function tests and cardiovascular indices among children with asthma living near an industrial complex and petroleum refineries.

OBJECTIVE: The acute cardiorespiratory effects of air quality among children living in areas with considerable heavy industry have not been well investigated. We conducted a panel study of children with asthma living in proximity to an industrial complex housing two refineries in Montreal, Quebec, in order to assess associations between their personal daily exposure to air pollutants and changes in pulmonary function and selected indicators of cardiovascular health. METHODS: Seventy-two children with asthma age 7-12 years in 2009-2010 participated in this panel study for a period of 10 consecutive days. They carried a small backpack for personal monitoring of sulphur dioxide (SO2), benzene, fine particles (PM2.5), nitrogen dioxide (NO2) and polycyclic aromatic hydrocarbons (PAHs) and underwent daily spirometry and cardiovascular testing (blood pressure, pulse rate and oxygen saturation). To estimate these associations, we used mixed regression models, adjusting for within-subject serial correlation, and for the effects of a number of personal and environmental variables (e.g., medication use, ethnicity, temperature). RESULTS: Children with asthma involved in the study had relatively good pulmonary function test results (mean FEV1 compared to standard values: 89.8%, mean FVC: 97.6%, mean FEF25-75: 76.3%). Median diastolic, systolic blood pressures and oxygen saturation were 60/94 mmHg and 99%, respectively. Median personal concentrations of pollutants were NO2, 5.5 ppb; benzene, 2.1 µg/m(3); PM2.5, 5.7 µg/m(3); and total PAH, 130 µg/m(3). Most personal concentrations of SO2 were below the level of detection. No consistent associations were observed between cardio-pulmonary indices and personal exposure to PM2.5, NO2 and benzene, although there was a suggestion for a small decrease in respiratory function with total concentrations of PAHs (e.g., adjusted association with FVC: -9.9 ml per interquartile range 95%CI: -23.4, 3.7). CONCLUSIONS: This study suggests that at low daily average levels of exposure to industrial emissions, effects on pulmonary and cardiovascular functions in children with asthma may be difficult to detect over 10 consecutive days.