Methodological considerations for epidemiological studies of air pollution and the sars and COVID-19 coronavirus outbreaks

BACKGROUND: Studies have reported that ambient air pollution is associated with an increased risk of developing or dying from coronavirus-2 (COVID-19). Methodological approaches to investigate the health impacts of air pollution on epidemics should differ from those used for chronic dis-eases, but the methods used in these studies have not been appraised critically. OBJECTIVES: Our study aimed to identify and critique the methodological approaches of studies of air pollution on infections and mortality due to COVID-19 and to identify and critique the methodological approaches of similar studies concerning severe acute respiratory syndrome (SARS). METHODS: Published and unpublished papers of associations between air pollution and developing or dying from COVID-19 or SARS that were reported as of 10 May 2020 were identified through electronic databases, internet searches, and other sources. RESULTS: All six COVID-19 studies and two of three SARS studies reported positive associations. Two were time series studies that estimated associations between daily changes in air pollution, one was a cohort that assessed associations between air pollution and the secondary spread of SARS, and six were ecological studies that used area-wide exposures and outcomes. Common shortcomings included possible cross-level bias in ecological studies, underreporting of health outcomes, using grouped data, the lack of highly spatially resolved air pollution measures, inadequate control for confounding and evaluation of effect modification, not accounting for regional variations in the timing of outbreaks’ temporal changes in at-risk popu-lations, and not accounting for nonindependence of outcomes. DISCUSSION: Studies of air pollution and novel coronaviruses have relied mainly on ecological measures of exposures and outcomes and are suscepti-ble to important sources of bias. Although longitudinal studies with individual-level data may be imperfect, they are needed to adequately address this topic. The complexities involved in these types of studies underscore the need for careful design and for peer review

Associations between incident breast cancer and ambient concentrations of nitrogen dioxide from a national land use regression model in the Canadian National Breast Screening Study

Background: Air pollution has been classified as a human carcinogen based largely on epidemiological studies of lung cancer. Recent research suggests that exposure to ambient air pollution increases the risk of female breast cancer especially in premenopausal women. Methods: Our objective was to determine the association between residential exposure to ambient nitrogen dioxide (NO2) and newly diagnosed cases of invasive breast cancer in a cohort of 89,247 women enrolled in the Canadian National Breast Screening Study between 1980 and 1985.

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, <0.1 µm) 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 gr

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

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

Ambient PM2.5, O3, and NO2 exposures and associations with mortality over 16 years of follow-up in the canadian census health and environment cohort (CanCHEC)

Background: Few studies examining the associations between long-term exposure to ambient air pollution and mortality have considered multiple pollutants when assessing changes in exposure due to residential mobility during follow-up. Objective: We investigated associations between cause-specific mortality and ambient concentrations of fine particulate matter (≤ 2.5 μm; PM2.5), ozone (O3), and nitrogen dioxide (NO2) in a national cohort of about 2.5 million Canadians. Methods: We assigned estimates of annual concentrations of these pollutants to the residential postal codes of subjects for each year during 16 years of follow-up. Historical tax data allowed us to track subjects’ residential postal code annually. We estimated hazard ratios (HRs) for each pollutant separately and adjusted for the other pollutants. We also estimated the product of the three HRs as a measure of the cumulative association with mortality for several causes of death for an increment of the mean minus the 5th percentile of each pollutant: 5.0 μg/m3 for PM2.5, 9.5 ppb for O3, and 8.1 ppb for NO2. Results: PM2.5, O3, and NO2 were associated with nonaccidental and cause-specific mortality in single-pollutant models. Exposure to PM2.5 alone was not sufficient to fully characterize the toxicity of the atmospheric mix or to fully explain the risk of mortality associated with exposure to ambient pollution. Assuming additive associations, the estimated HR for nonaccidental mortality corresponding to a change in exposure from the mean to the 5th percentile for all three pollutants together was 1.075 (95% CI: 1.067, 1.084). Accounting for residential mobility had only a limited impact on the association between mortality and PM2.5 and O3, but increased associa-tions with NO2. conclusions: In this large, national-level cohort, we found positive associations between several common causes of death and exposure to PM2.5, O3, and NO2