Small area disease mapping of cancer incidence in British Columbia using Bayesian spatial models and the smallareamapp R Package.

Introduction: There is an increasing interest in small area analyses in cancer surveillance; however, technical capacity is limited and accessible analytical approaches remain to be determined. This study demonstrates an accessible approach for small area cancer risk estimation using Bayesian hierarchical models and data visualization through the smallareamapp R package. Materials and methods: Incident lung (N = 26,448), female breast (N = 28,466), cervical (N = 1,478), and colorectal (N = 25,457) cancers diagnosed among British Columbia (BC) residents between 2011 and 2018 were obtained from the BC Cancer Registry. Indirect age-standardization was used to derive age-adjusted expected counts and standardized incidence ratios (SIRs) relative to provincial rates. Moran's I was used to assess the strength and direction of spatial autocorrelation. A modified Besag, York and Mollie model (BYM2) was used for model incidence counts to calculate posterior median relative risks (RR) by Community Health Service Areas (CHSA; N = 218), adjusting for spatial dependencies. Integrated Nested Laplace Approximation (INLA) was used for Bayesian model implementation. Areas with exceedance probabilities (above a threshold RR = 1.1) greater or equal to 80% were considered to have an elevated risk. The posterior median and 95% credible intervals (CrI) for the spatially structured effect were reported. Predictive posterior checks were conducted through predictive integral transformation values and observed versus fitted values. Results: The proportion of variance in the RR explained by a spatial effect ranged from 4.4% (male colorectal) to 19.2% (female breast). Lung cancer showed the greatest number of CHSAs with elevated risk (Nwomen = 50/218, Nmen = 44/218), representing 2357 total excess cases. The largest lung cancer RRs were 1.67 (95% CrI = 1.06-2.50; exceedance probability = 96%; cases = 13) among women and 2.49 (95% CrI = 2.14-2.88; exceedance probability = 100%; cases = 174) among men. Areas with small population sizes and extreme SIRs were generally smoothed towards the null (RR = 1.0). Discussion: We present a ready-to-use approach for small area cancer risk estimation and disease mapping using BYM2 and exceedance probabilities. We developed the smallareamapp R package, which provides a user-friendly interface through an R-Shiny application, for epidemiologists and surveillance experts to examine geographic variation in risk. These methods and tools can be used to estimate risk, generate hypotheses, and examine ecologic associations while adjusting for spatial dependency.

Association of the CPT1A p.P479L Metabolic Gene Variant With Childhood Respiratory and Other Infectious Illness in Nunavut.

Objective: Infectious illness, including lower respiratory tract infection (LRTI), is a leading cause of childhood morbidity and infant mortality in Inuit children in Nunavut Canada. The carnitine palmitoyltransferase 1A (CPT1A) p.P479L variant is common in arctic Indigenous populations of Alaska, Canada, and Greenland. CPT1A is a fatty acid oxidation enzyme expressed in the liver, immunocytes and other tissues, and is needed to use fats for energy during fasting. Previous association of the variant with early childhood infectious illness and infant death has been challenged because of sample size and limited adjustment for confounders. We evaluated whether the p.P479L variant is associated with infectious illness in Inuit children of Nunavut, Canada. Methods: We conducted a retrospective clinical chart review of 2,225 Inuit children (0-5 years) for infectious illness (including otitis media, gastroenteritis, and hospital admission for LRTI), prenatal, perinatal, and socioeconomic indicators, subsequently linking to CPT1A genotype. Multivariable logistic regression adjusted for birth characteristics, breastfeeding, maternal smoking, food insecurity, and socioeconomic indicators. Results: Overall, 27% of children were hospitalized for LRTI, 86% had otitis media and 50% had gastroenteritis. The p.P479L allele frequency was 0.82. In multivariable analysis, p.P479L homozygosity was associated with LRTI admission (aOR:2.88 95%CI:1.46-5.64), otitis media (aOR:1.83, 95%CI:1.05-3.21), and gastroenteritis (aOR:1.74, 95%CI:1.09-2.77), compared to non-carriers. Conclusion: Children homozygous for the p.P479L variant were more likely to experience infectious illness than non-carriers, including hospitalization for respiratory tract infections. Given the role of CPT1A in immunocytes, our findings indicate that more study is needed to determine if there is a role of the variant in immune response. Continued Inuit involvement is essential when considering next steps.

Stomach Cancer Incidence and Mortality Trends among Circumpolar Nations.

BACKGROUND: Stomach cancer incidence and mortality rates are declining across circumpolar nations, but the burden may not be distributed equally across subpopulations, including Indigenous peoples. Our objective was to examine stomach cancer incidence and mortality trends across circumpolar populations. METHODS: Cancer incidence and mortality data from 1999-2016 were obtained from the Canadian Cancer Registry, Canadian Vital Statistics, CDC WONDER, NORDCAN, Northwestern Russian cancer registries, and National Cancer Reports. The direct method was used to calculate 10-year rolling age-standardized incidence and mortality rates to the world (WHO 2000-2025) and 2011 Canadian standard populations. Standardized incidence rate ratios (SRR) were calculated. Data were stratified by sex, year, and region. U.S. data were broken down by race [White; American Indian/Alaska Native (AIAN)]. Race data were not available from non-U.S. cancer registries. RESULTS: Most populations showed declining incidence and mortality rates over time. Incidence rates among Greenland males and females, Alaska AIAN males and females, and Northern Canadian both sexes were elevated compared with regional counterparts and remained stable. The largest male SRR was observed among Alaska AIAN versus Alaska Whites [SRR = 3.82; 95% confidence interval (95% CI), 2.71-5.37]. The largest female SRR was observed among Alaska AIAN versus Alaska Whites (SRR = 4.10; 95% CI, 2.62-6.43). CONCLUSIONS: Despite stomach cancer incidence and mortality rates declining overall, some northern and Indigenous populations experience elevated and stable incidence and mortality rates. IMPACT: There is a need to address disparities observed among circumpolar subpopulations. Given similarities in incidence, mortality, and risk factor prevalence across circumpolar regions, addressing disparities could benefit from coordinated international action.

Disease assimilation: The mortality impacts of fine particulate matter on immigrants to Canada.

BACKGROUND: Immigrants make up 20% of the Canadian population; however, little is known about the mortality impacts of fine particulate matter (PM2.5) air pollution on immigrants compared with non-immigrants, or about how impacts may change with duration in Canada. DATA AND METHODS: This study used the 2001 Canadian Census Health and Environment Cohort, a longitudinal cohort of 3.5 million individuals, of which 764,000 were classified as immigrants (foreign-born). Postal codes from annual income tax files were used to account for mobility among respondents and to assign annual PM2.5 concentrations from 1998 to 2016. Exposures were estimated as a three-year moving average prior to the follow-up year. Cox survival models were used to determine hazard ratios (HRs) for cause-specific mortality, comparing the Canadian and foreign-born populations, with further stratification by year of immigration grouped into 10-year cohorts. RESULTS: Differences in urban-rural settlement patterns resulted in greater exposure to PM2.5 for immigrants compared with non-immigrants (mean = 9.3 vs. 7.5 µg/m3), with higher exposures among more recent immigrants. In fully adjusted models, immigrants had higher HRs per 10 µg/m3 increase in PM2.5 concentration compared with Canadian-born individuals for cardiovascular mortality (HR [95% confidence interval] = 1.22 [1.12 to 1.34] vs. 1.12 [1.07 to 1.18]) and cerebrovascular mortality (HR = 1.25 [1.03 to 1.52] vs. 1.03 [0.93 to 1.15]), respectively. However, tests for differences between the two groups were not significant when Cochran's Q test was used. No significant associations were found for respiratory outcomes, except for lung cancer in non-immigrants (HR = 1.10 [1.02 to 1.18]). When stratified by year of immigration, differences in HRs across varied by cause of death. DISCUSSION: In Canada, PM2.5 is an equal-opportunity risk factor, with immigrants experiencing similar if not higher mortality risks compared with non-immigrants for cardiovascular-related causes of death. Some notable differences also existed with cerebrovascular and lung cancer deaths. Continued reductions in air pollution, particularly in urban areas, will improve the health of the Canadian population as a whole.

Current State of Geospatial Methodologic Approaches in Canadian Population Oncology Research.

Geospatial analyses are increasingly used in population oncology. We provide a first review of geospatial analysis in Canadian population oncology research, compare to international peers, and identify future directions. Geospatial-focused peer-reviewed publications from 1992-2020 were compiled using PubMed, MEDLINE, Web of Science, and Google Scholar. Abstracts were screened for data derived from a Canadian cancer registry and use of geographic information systems. Studies were classified by geospatial methodology, geospatial unit, location, cancer site, and study year. Common limitations were documented from article discussion sections. Our search identified 71 publications using data from all provincial and national cancer registries. Thirty-nine percent (N = 28) were published in the most recent 5-year period (2016-2020). Geospatial methodologies included exposure assessment (32.4%), identifying spatial associations (21.1%), proximity analysis (16.9%), cluster detection (15.5%), and descriptive mapping (14.1%). Common limitations included confounding, ecologic fallacy, not accounting for residential mobility, and small case/population sizes. Geospatial analyses are increasingly used in Canadian population oncology; however, efforts are concentrated among a few provinces and common cancer sites, and data are over a decade old. Limitations were similar to those documented internationally, and more work is needed to address them. Organized efforts are needed to identify common challenges, develop leading practices, and identify shared priorities.

Evaluating the Sensitivity of PM2.5-Mortality Associations to the Spatial and Temporal Scale of Exposure Assessment.

BACKGROUND: The temporal and spatial scales of exposure assessment may influence observed associations between fine particulate air pollution (PM2.5) and mortality, but few studies have systematically examined this question. METHODS: We followed 2.4 million adults in the 2001 Canadian Census Health and Environment Cohort for nonaccidental and cause-specific mortality between 2001 and 2011. We assigned PM2.5 exposures to residential locations using satellite-based estimates and compared three different temporal moving averages (1, 3, and 8 years) and three spatial scales (1, 5, and 10 km) of exposure assignment. In addition, we examined different spatial scales based on age, employment status, and urban/rural location, and adjustment for O3, NO2, or their combined oxidant capacity (Ox). RESULTS: In general, longer moving averages resulted in stronger associations between PM2.5 and mortality. For nonaccidental mortality, we observed a hazard ratio of 1.11 (95% CI = 1.08, 1.13) for the 1-year moving average compared with 1.23 (95% CI = 1.20, 1.27) for the 8-year moving average. Respiratory and lung cancer mortality were most sensitive to the spatial scale of exposure assessment with stronger associations observed at smaller spatial scales. Adjustment for oxidant gases attenuated associations between PM2.5 and cardiovascular mortality and strengthened associations with lung cancer. Despite these variations, PM2.5 was associated with increased mortality in nearly all of the models examined. CONCLUSIONS: These findings support a relationship between outdoor PM2.5 and mortality at low concentrations and highlight the importance of longer-exposure windows, more spatially resolved exposure metrics, and adjustment for oxidant gases in characterizing this relationship.

Low concentrations of fine particle air pollution and mortality in the Canadian Community Health Survey cohort.

BACKGROUND: Approximately 2.9 million deaths are attributed to ambient fine particle air pollution around the world each year (PM2.5). In general, cohort studies of mortality and outdoor PM2.5 concentrations have limited information on individuals exposed to low levels of PM2.5 as well as covariates such as smoking behaviours, alcohol consumption, and diet which may confound relationships with mortality. This study provides an updated and extended analysis of the Canadian Community Health Survey-Mortality cohort: a population-based cohort with detailed PM2.5 exposure data and information on a number of important individual-level behavioural risk factors. We also used this rich dataset to provide insight into the shape of the concentration-response curve for mortality at low levels of PM2.5. METHODS: Respondents to the Canadian Community Health Survey from 2000 to 2012 were linked by postal code history from 1981 to 2016 to high resolution PM2.5 exposure estimates, and mortality incidence to 2016. Cox proportional hazard models were used to estimate the relationship between non-accidental mortality and ambient PM2.5 concentrations (measured as a three-year average with a one-year lag) adjusted for socio-economic, behavioural, and time-varying contextual covariates. RESULTS: In total, 50,700 deaths from non-accidental causes occurred in the cohort over the follow-up period. Annual average ambient PM2.5 concentrations were low (i.e. 5.9 µg/m3, s.d. 2.0) and each 10 µg/m3 increase in exposure was associated with an increase in non-accidental mortality (HR = 1.11; 95% CI 1.04-1.18). Adjustment for behavioural covariates did not materially change this relationship. We estimated a supra-linear concentration-response curve extending to concentrations below 2 µg/m3 using a shape constrained health impact function. Mortality risks associated with exposure to PM2.5 were increased for males, those under age 65, and non-immigrants. Hazard ratios for PM2.5 and mortality were attenuated when gaseous pollutants were included in models. CONCLUSIONS: Outdoor PM2.5 concentrations were associated with non-accidental mortality and adjusting for individual-level behavioural covariates did not materially change this relationship. The concentration-response curve was supra-linear with increased mortality risks extending to low outdoor PM2.5 concentrations.

Evaluation of a method to indirectly adjust for unmeasured covariates in the association between fine particulate matter and mortality.

BACKGROUND: Indirect adjustment via partitioned regression is a promising technique to control for unmeasured confounding in large epidemiological studies. The method uses a representative ancillary dataset to estimate the association between variables missing in a primary dataset with the complete set of variables of the ancillary dataset to produce an adjusted risk estimate for the variable in question. The objective of this paper is threefold: 1) evaluate the method for non-linear survival models, 2) formalize an empirical process to evaluate the suitability of the required ancillary matching dataset, and 3) test modifications to the method to incorporate time-varying exposure data, and proportional weighting of datasets. METHODS: We used the association between fine particle air pollution (PM2.5) with mortality in the 2001 Canadian Census Health and Environment Cohort (CanCHEC, N = 2.4 million, 10-years follow-up) as our primary dataset, and the 2001 cycle of the Canadian Community Health Survey (CCHS, N = 80,630) as the ancillary matching dataset that contained confounding risk factor information not available in CanCHEC (e.g., smoking). The main evaluation process used a gold-standard approach wherein two variables (education and income) available in both datasets were excluded, indirectly adjusted for, and compared to true models with education and income included to assess the amount of bias correction. An internal validation for objective 1 used only CanCHEC data, whereas an external validation for objective 2 replaced CanCHEC with the CCHS. The two proposed modifications were applied as part of the validation tests, as well as in a final indirect adjustment of four missing risk factor variables (smoking, alcohol use, diet, and exercise) in which adjustment direction and magnitude was compared to models using an equivalent longitudinal cohort with direct adjustment for the same variables. RESULTS: At baseline (2001) both cohorts had very similar PM2.5 distributions across population characteristics, although levels for CCHS participants were consistently 1.8-2.0 µg/m3 lower. Applying sample-weighting largely corrected for this discrepancy. The internal validation tests showed minimal downward bias in PM2.5 mortality hazard ratios of 0.4-0.6% using a static exposure, and 1.7-3% when a time-varying exposure was used. The external validation of the CCHS as the ancillary dataset showed slight upward bias of -0.7 to -1.1% and downward bias of 1.3-2.3% using the static and time-varying approaches respectively. CONCLUSIONS: The CCHS was found to be fairly well representative of CanCHEC and its use in Canada for indirect adjustment is warranted. Indirect adjustment methods can be used with survival models to correct hazard ratio point estimates and standard errors in models missing key covariates when a representative matching dataset is available. The results of this formal evaluation should encourage other cohorts to assess the suitability of ancillary datasets for the application of the indirect adjustment methodology to address potential residual confounding.

Red blood cell folate levels in Canadian Inuit women of childbearing years: influence of food security, body mass index, smoking, education, and vitamin use.

BACKGROUND: The benefits of folic acid for prevention of congenital anomalies are well known. For the Inuit of Canada, where vitamin use is low and access to folate-rich foods limited, fortification is likely a major source of intake. We sought to determine whether red blood cell folate (RBCF) levels of Inuit women reached accepted target levels. METHODS: The Inuit Health Survey, 2007-2008, included evaluation of RBCF levels among 249 randomly selected non-pregnant women of reproductive age. Using descriptive statistics and linear regression analyses, RBCF levels were assessed and compared across several socio-demographic variables to evaluate the characteristics associated with RBCF status. RESULTS: Mean (SD) RBCF levels of 935.5 nmol/L (± 192) reached proposed target levels (> 906 nmol/L); however, 47% of women had lower than target levels. In bivariate analysis, non-smoking, higher education, higher income, food security, increased body mass index, and vitamin use were each significantly associated with higher RBCF. Increased levels of smoking had a negative association with RBCF levels (- 5.8 nmol/L per cigarette smoked per day (p = 0.001)). A total of 6.8% of women reported taking vitamin supplements, resulting in a 226 nmol/L higher RBCF level on average compared to non-users (p < 0.001). CONCLUSION: While mean levels of folate reached target levels, this was largely driven by the small number of women taking vitamin supplements. Our results suggest that folate status is often too low in Inuit women of childbearing years. Initiatives to improve food security, culturally relevant education on folate-rich traditional foods, vitamin supplements, and smoking cessation/reduction programs may benefit Inuit women and improve birth outcomes.

Air pollution, neighbourhood and maternal-level factors modify the effect of smoking on birth weight: a multilevel analysis in British Columbia, Canada.

BACKGROUND: Maternal smoking during pregnancy negatively impacts fetal growth, but the effect is not homogenous across the population. We sought to determine how the relationship between cigarette use and fetal growth is modified by the social and physical environment. METHODS: Birth records with covariates were obtained from the BC Perinatal Database Registry (N = 232,291). Maternal smoking status was self-reported as the number of cigarettes smoked per day usually at the first prenatal care visit. Census dissemination areas (DAs) were used as neighbourhood-level units and linked to individual births using residential postal codes to assign exposure to particulate air pollution (PM2.5) and neighbourhood-level attributes such as socioeconomic status (SES), proportion of post-secondary education, immigrant density and living in a rural place. Random coefficient models were used with cigarettes/day modeled with a random slope to estimate its between-DA variability and test cross-level interactions with the neighbourhood-level variables on continuous birth weight. RESULTS: A significant negative and non-linear association was found between maternal smoking and birth weight. There was significant between-DA intercept variability in birth weight as well as between-DA slope variability of maternal smoking on birth weight of which 68 and 30 % respectively was explained with the inclusion of DA-level variables and their cross-level interactions. High DA-level SES had a strong positive association with birth weight but the effect was moderated with increased cigarettes/day. Conversely, heavy smokers showed the largest increases in birth weight with rising neighbourhood education levels. Increased levels of PM2.5 and immigrant density were negatively associated with birth weight, but showed positive interactions with increased levels of smoking. Older maternal age and suspected drug or alcohol use both had negative interactions with increased levels of maternal smoking. CONCLUSION: Maternal smoking had a negative and non-linear dose-response association with birth weight which was highly variable between neighbourhoods and evidence of effect modification with neighbourhood-level factors. These results suggest that focusing exclusively on individual behaviours may have limited success in improving outcomes without addressing the contextual influences at the neighbourhood-level. Further studies are needed to corroborate our findings and to understand how neighbourhood-level attributes interact with smoking to affect birth outcomes.

The reduction of birth weight by fine particulate matter and its modification by maternal and neighbourhood-level factors: a multilevel analysis in British Columbia, Canada.

BACKGROUND: The purpose of this research was to determine the relationship between modeled particulate matter (PM2.5) exposure and birth weight, including the potential modification by maternal risk factors and indicators of socioeconomic status (SES). METHODS: Birth records from 2001 to 2006 (N = 231,929) were linked to modeled PM2.5 data from a national land-use regression model along with neighbourhood-level SES and socio-demographic data using 6-digit residential postal codes. Multilevel random coefficient models were used to estimate the effects of PM2.5, SES and other individual and neighbourhood-level covariates on continuous birth weight and test interactions. Gestational age was modeled with a random slope to assess potential neighbourhood-level differences of its effect on birth weight and whether any between-neighbourhood variability can be explained by cross-level interactions. RESULTS: Models adjusted for individual and neighbourhood-level covariates showed a significant non-linear negative association between PM2.5 and birth weight explaining 8.5 % of the between-neighbourhood differences in mean birth weight. A significant interaction between SES and PM2.5 was observed, revealing a more pronounced negative effect of PM2.5 on birth weight in lower SES neighbourhoods. Further positive and negative modification of the PM2.5 effect was observed with maternal smoking, maternal age, gestational diabetes, and suspected maternal drug or alcohol use. The random intercept variance indicating between-neighbourhood birth weight differences was reduced by 75 % in the final model, while the random slope variance for between-neighbourhood gestational age effects remained virtually unchanged. CONCLUSION: We provide evidence that neighbourhood-level SES variables and PM2.5 have both independent and interacting associations with birth weight, and together account for 49 % of the between-neighbourhood differences in birth weight. Evidence of effect modification of PM2.5 on birth weight across various maternal and neighbourhood-level factors suggests that certain sub-populations may be more or less vulnerable to relatively low doses PM2.5 exposure.

The shared pathoetiological effects of particulate air pollution and the social environment on fetal-placental development.

Exposure to particulate air pollution and socioeconomic risk factors are shown to be independently associated with adverse pregnancy outcomes; however, their confounding relationship is an epidemiological challenge that requires understanding of their shared etiologic pathways affecting fetal-placental development. The purpose of this paper is to explore the etiological mechanisms associated with exposure to particulate air pollution in contributing to adverse pregnancy outcomes and how these mechanisms intersect with those related to socioeconomic status. Here we review the role of oxidative stress, inflammation and endocrine modification in the pathoetiology of deficient deep placentation and detail how the physical and social environments can act alone and collectively to mediate the established pathology linked to a spectrum of adverse pregnancy outcomes. We review the experimental and epidemiological literature showing that diet/nutrition, smoking, and psychosocial stress share similar pathways with that of particulate air pollution exposure to potentially exasperate the negative effects of either insult alone. Therefore, socially patterned risk factors often treated as nuisance parameters should be explored as potential effect modifiers that may operate at multiple levels of social geography. The degree to which deleterious exposures can be ameliorated or exacerbated via community-level social and environmental characteristics needs further exploration.

Heavy smoking during pregnancy as a marker for other risk factors of adverse birth outcomes: a population-based study in British Columbia, Canada.

BACKGROUND: Smoking during pregnancy is associated with known adverse perinatal and obstetrical outcomes as well as with socio-economic, demographic and other behavioural risk factors that independently influence outcomes. Using a large population-based perinatal registry, we assess the quantity of cigarettes smoked for the magnitude of adverse birth outcomes and also the association of other socio-economic and behavioural risk factors documented within the registry that influence pregnancy outcomes. Our goal was to determine whether number of cigarettes smoked could identify those in greatest need for comprehensive intervention programs to improve outcomes. METHODS: Our population-based retrospective study of singleton births from 2001 to 2006 (N = 237,470) utilized data obtained from the BC Perinatal Database Registry. Smoking data, self reported at the earliest prenatal visit, was categorized as: never, former, light (1 to 4), moderate (5 to 9), or heavy smoker (10 or more per day). Crude and adjusted odds ratios (AOR) with 95% confidence intervals (95% CI) were calculated using logistic regression models for smoking frequency and adverse birth outcomes. A partial proportional odds (pp-odds) model was used to determine the association between smoking status and other risk factors. RESULTS: There were 233,891 singleton births with available smoking status data. A significant dose-dependent increase in risk was observed for the adverse birth outcomes small-for-gestational age, term low birth weight and intra-uterine growth restriction. Results from the pp-odds model indicate heavy smokers were more likely to have not graduated high school: AOR (95% CI) = 3.80 (3.41-4.25); be a single parent: 2.27 (2.14-2.42); have indication of drug or alcohol use: 7.65 (6.99-8.39) and 2.20 (1.88-2.59) respectively, attend fewer than 4 prenatal care visits: 1.39 (1.23-1.58), and be multiparous: 1.59 (1.51-1.68) compared to light, moderate and non-smokers combined. CONCLUSION: Our data suggests that self reports of heavy smoking early in pregnancy could be used as a marker for lifestyle risk factors that in combination with smoking influence birth outcomes. This information may be used for planning targeted intervention programs for not only smoking cessation, but potentially other support services such as nutrition and healthy pregnancy education.