Mark S. Goldberg

Overview of the Reanalysis of the Harvard Six Cities Study and American Cancer Society Study of Particulate Air Pollution and Mortality

This article provides an overview of the Reanalysis Study of the Harvard Six Cities and the American Cancer Society (ACS) studies of particulate air pollution and mortality. The previous findings of the studies have been subject to debate. In response, a reanalysis team, comprised of Canadian and Amercian researchers, was invited to participate in an independent reanalysis project to address the concerns. Phase I of the reanalysis involved the design of data audits to determine whether each study conformed to the consistency and accuracy of their data. Phase II of the reanalysis involved conducting a series of comprehensive analyses using alternative statistical methods. Alternative models were also used to identify covariates that may confound or modify the association of particulate air pollution as well as identify sensitive population subgroups. The audit demonstrated that the data in the original analyses were of high quality, as were the risk estimates reported by the original investigators. The sensitivity analysis illustrated that the mortality risk estimates reported in both studies were found to be robust against alternative Cox models. Detailed investigation of the covariate effects found a significant modifying effect of education and a relative risk of mortality associated with fine particles and declining education levels. The study team applied spatial analytic methods to the ACS data, resulting in various levels of spatial autocorrelations supporting the reported association for fine particles mortality of the original investigators as well as demonstrating a significant association between sulfur dioxide and mortality. Collectively, our reanalysis suggest that mortality may be attributable to more than one component of the complex mixture of ambient air pollutants for U.S. urban areas.

ASSOCIATION BETWEEN PARTICULATE- AND GAS-PHASE COMPONENTS OF URBAN AIR POLLUTION AND DAILY MORTALITY IN EIGHT CANADIAN CITIES

Although some consensus has emerged among the scientific and regulatory communities that the urban ambient atmospheric mix of combustion related pollutants is a determinant of population health, the relative toxicity of the chemical and physical components of this complex mixture remains unclear. Daily mortality rates and concurrent data on sizefractionated particulate mass and gaseous pollutants were obtained in eight of Canadas largest cities from 1986 to 1996 inclusive in order to examine the relative toxicity of the components of the mixture of ambient air pollutants to which Canadians are exposed. Positive and statistically significant associations were observed between daily variations in both gas- and particulate-phase pollution and daily fluctuations in mortality rates. The association between air pollution and mortality could not be explained by temporalvariation in either mortality rates or weather factors. Fine particulate mass (less than 2.5 μm in average aerometric diameter) was a stronger predictor of mortality than coarse mass (between 2.5 and 10 μm). Size-fractionated particulate mass explained 28% of the total health effect of the mixture, with the remaining effects accounted for by the gases. Forty-seven elemental concentrations were obtained for the fine and coarse fraction using nondestructive x-ray fluorescence techniques. Sulfate concentrations were obtained by ion chromatography. Sulfate ion, iron, nickel, and zinc from the fine fraction were most strongly associated with mortality. The total effect of these four components was greater than that for fine mass alone, suggesting that the characteristics of the complex chemical mixture in the fine fraction maybe a better predictor of mortality than mass alone. However,the variation in the effects of the constituents of the fine fraction between cities was greater than the variation in the mass effect, implying that there are additional toxic components of fine particulate matter not examined in this study whose concentrations and effects vary between locations. One of these components, carbon, represents half the mass of fine particulate matter. We recommend that measurements of elemental and organiccarbon be undertaken in Canadian urban environments to examine their potential effects on human health.

Statistical assessment of ordinal outcomes in comparative studies

Ordinal regression is a relatively new statistical method developed for analyzing ranked outcomes. In the past, ranked scales have often been analyzed without making full use of the ordinality of the data or, alternatively, by assigning arbitrary numerical scores to the ranks. While ordinal regression models are now available to make full use of ranked data, they are not used widely. This article, directed to clinical researchers and epidemiologists, provides a description of the properties of these methods. Using ordinal measures of back pain in a follow-up study of adolescent idiopathic scoliosis, we illustrate the advantages of those methods and describe how to interpret the estimated parameters. Comparisons with binary logistic regression are made to show why a single dichotomization of the ordinal scale may lead to incorrect inferences. Two ordinal models (the proportional odds and the continuation ratio models) are discussed, and the goodness-of-fit of these models is examined. We conclude that ordinal regression is a tool that is powerful, simple to use, and produces an interpretable parameter that summarizes the effect between groups over all levels of the outcome.

Risk of nonaccidental and cardiovascular mortality in relation to long-term exposure to low concentrations of fine particulate matter: a Canadian national-level cohort study.

Background: Few cohort studies have evaluated the risk of mortality associated with long-term exposure to fine particulate matter [≤ 2.5 μm in aerodynamic diameter (PM2.5)]. This is the first national-level cohort study to investigate these risks in Canada. Objective: We investigated the association between long-term exposure to ambient PM2.5 and cardiovascular mortality in nonimmigrant Canadian adults. Methods: We assigned estimates of exposure to ambient PM2.5 derived from satellite observations to a cohort of 2.1 million Canadian adults who in 1991 were among the 20% of the population mandated to provide detailed census data. We identified deaths occurring between 1991 and 2001 through record linkage. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for available individual-level and contextual covariates using both standard Cox proportional survival models and nested, spatial random-effects survival models. Results: Using standard Cox models, we calculated HRs of 1.15 (95% CI: 1.13, 1.16) from nonaccidental causes and 1.31 (95% CI: 1.27, 1.35) from ischemic heart disease for each 10-μg/m3 increase in concentrations of PM2.5. Using spatial random-effects models controlling for the same variables, we calculated HRs of 1.10 (95% CI: 1.05, 1.15) and 1.30 (95% CI: 1.18, 1.43), respectively. We found similar associations between nonaccidental mortality and PM2.5 based on satellite-derived estimates and ground-based measurements in a subanalysis of subjects in 11 cities. Conclusions: In this large national cohort of nonimmigrant Canadians, mortality was associated with long-term exposure to PM2.5. Associations were observed with exposures to PM2.5 at concentrations that were predominantly lower (mean, 8.7 μg/m3; interquartile range, 6.2 μg/m3) than those reported previously.

A review of the association between cigarette smoking and the development of nonspecific back pain and related outcomes.

Study Design. A structured review of the epidemiologic literature was performed. Thirty-eight studies published in peer-reviewed journals were reviewed. The methodologic strengths and weaknesses of the studies were described and assessed qualitatively. Four studies were excluded because of difficulties in design or interpretation. Objectives. To provide a systematic analysis of the literature to assess the evidence as to whether smoking is associated with the prevalence and incidence of nonspecific back pain and related outcomes. Summary of Background Data. Evidence has been gathering regarding the association of smoking with nonspecific back pain and other back disorders, but a comprehensive summary and evaluation of the data have not been published. Results. Positive associations between current smoking and nonspecific back pain were found in 18 of 26 studies in men and 18 of 20 studies in women. For sciatica and herniated discs, there were four of eight and one of five positive studies in men and women, respectively. The majority of these studies were cross-sectional (18 in men and 16 in women), with only a handful of prospective studies. Positive associations between past smoking and nonspecific back pain were reported in five of nine studies in men and five of six studies in women. In addition, increases in the prevalence and/or incidence of nonspecific back pain were found in the majority of studies in which level of consumption was analyzed and reported. An attempt was made to assess whether these results could be artifactual arising from selection bias, confounding bias, publication bias, or errors in measurement. As well, the biologic mechanisms were summarized that have been suggested by various investigators. Conclusions. The available data are consistent with the notion that smoking is associated with the incidenceand prevalence of nonspecific back pain, but there are too few studies to make any conclusions for the other end points (e.g., sciatica, herniated discs). It cannot be ruled out that the association is a statistical artifact arising from either selection or confounding factors, because the evidence for nonspecific low back pain derives mostly from cross-sectional studies. In addition, it cannot be stated unequivocally that smoking preceded back pain. Long-term follow-up studies are needed to eliminate the possibility that chronic back pain preceded smoking, to better estimate dose–response correlations, and to perform biologic measurements to elucidate possible mechanisms.

A systematic review of the relation between long-term exposure to ambient air pollution and chronic diseases.

We conducted a systematic review of all studies published between 1950 and 2007 of associations between long-term exposure to ambient air pollution and the risks in adults of nonaccidental mortality and the incidence and mortality from cancer and cardiovascular and respiratory diseases. We searched bibliographic databases for cohort and case-control studies, abstracted characteristics of their design and conduct, and synthesized the quantitative findings in tabular and graphic form. We assessed heterogeneity, estimated pooled effects for specific pollutants, and conducted sensitivity analyses according to selected characteristics of the studies. Our analysis showed that long-term exposure to PM2.5 increases the risk of nonaccidental mortality by 6% per a 10 microg/m3 increase, independent of age, gender, and geographic region. Exposure to PM2.5 was also associated with an increased risk of mortality from lung cancer (range: 15% to 21% per a 10 microg/m3 increase) and total cardiovascular mortality (range: 12% to 14% per a 10 microg/m3 increase). In addition, living close to busy traffic appears to be associated with elevated risks of these three outcomes. Suggestive evidence was found that exposure to PM2.5 is positively associated with mortality from coronary heart diseases and exposure to SO2 increases mortality from lung cancer. For the other pollutants and health outcomes, the data were insufficient data to make solid conclusions.

Assessing Spatial Variability of Ambient Nitrogen Dioxide in Montréal, Canada, with a Land-Use Regression Model

Abstract The purpose of this study was to derive a land-use regression model to estimate on a geographical basis ambient concentrations of nitrogen dioxide (NO2) in Montréal, Quebec, Canada. These estimates of concentrations of NO2 will be subsequently used to assess exposure in epidemiologic studies on the health effects of traffic-related air pollution. In May 2003, NO2 was measured for 14 consecutive days at 67 sites across the city using Ogawa passive diffusion samplers. Concentrations ranged from 4.9 to 21.2 ppb (median 11.8 ppb). Linear regression analysis was used to assess the association between logarithmic concentrations of NO2 and land-use variables derived using the ESRI Arc 8 geographic information system. In univariate analyses, NO2 was negatively associated with the area of open space and positively associated with traffic count on nearest highway, the length of highways within any radius from 100 to 750 m, the length of major roads within 750 m, and population density within 2000 m. Industrial land-use and the length of minor roads showed no association with NO2. In multiple regression analyses, distance from the nearest highway, traffic count on the nearest highway, length of highways and major roads within 100 m, and population density showed significant associations with NO2; the best-fitting regression model had a R2 of 0.54. These analyses confirm the value of land-use regression modeling to assign exposures in large-scale epidemiologic studies.

Reducing the lifetime risk of cancer from spinal radiographs among people with adolescent idiopathic scoliosis.

Study Design Data from a retrospective cohort study of people with adolescent idiopathic scoliosis were combined with information on full‐spinal radiographs to estimate contemporary x‐ray doses and lifetime risks for development of cancer. Objectives To project the lifetime risk for development of cancer from diagnostic radiographs for people with adolescent idiopathic scoliosis. Summary of Background Data Although a twofold excess risk for breast cancer has been reported for women treated for scoliosis between 1925 and 1965, information on the cancer risks associated with scoliosis management today is sparse. Specifically, there is a lack of up‐to‐date information on the number of spinal radiographs taken, the organ‐specific x‐ray doses from current radiographic techniques, and the projected cancer risks. Methods The cohort consisted of subjects with adolescent idiopathic scoliosis who were referred to the scoliosis clinic of a large pediatric hospital between 1965 and 1979 in Montreal, Quebec, Canada. Based on radiographic equipment and practices implemented in 1982, organ‐specific x‐ray doses to the thyroid gland, female breast, respiratory organs, digestive organs, and bone marrow were calculated using Monte Carlo methods. These doses were incorporated into a life table procedure to calculate theoretic lifetime cancer risks. For all organs except the thyroid gland, dose‐response models from the United States National Academy of Sciences Fifth Committee on the Biological Effects of lonizing Radiation were used. For thyroid cancer, a risk model was derived from a study of thyroid cancer incidence after x‐ray treatment for tinea capitis. Results The average number of spinal radiographs was 12 for women (80% anteroposterior or posteroanterior) and 10 for men (78% anteroposterior or posteroanterior). Cumulative x‐ray doses were in general higher in adolescents who were referred as younger teenagers than at later ages, and doses increased with the size of the spinal curve. Depending on the age at referral and curve size, the total excess lifetime cancer risks were calculated to range from 42 to 238 cases per 100,000 women and 14 to 79 cases per 100,000 men. For subjects who underwent surgery (those exposed to the highest doses), the lifetime number of cancer cases over and above background was almost as great as the number of thyroid cancers that would occur in the absence of radiation exposure. If the anteroposterior view was replaced by the posteroanterior view, a three‐ to sevenfold reduction in cumulative doses to the thyroid gland and the female breast would be achieved, yielding three‐ to fourfold reductions in the lifetime risk of breast cancer and a halving of the lifetime risk of thyroid cancer. Conclusions The cancer risks from full‐spinal radiographs for scoliosis are not negligible and can be reduced from one half to three quarters if the anteroposterior view is replaced with the posteroanterior view.

Risk of Incident Diabetes in Relation to Long-term Exposure to Fine Particulate Matter in Ontario, Canada

Background: Laboratory studies suggest that fine particulate matter (≤ 2.5 µm in diameter; PM2.5) can activate pathophysiological responses that may induce insulin resistance and type 2 diabetes. However, epidemiological evidence relating PM2.5 and diabetes is sparse, particularly for incident diabetes. Objectives: We conducted a population-based cohort study to determine whether long-term exposure to ambient PM2.5 is associated with incident diabetes. Methods: We assembled a cohort of 62,012 nondiabetic adults who lived in Ontario, Canada, and completed one of five population-based health surveys between 1996 and 2005. Follow-up extended until 31 December 2010. Incident diabetes diagnosed between 1996 and 2010 was ascertained using the Ontario Diabetes Database, a validated registry of persons diagnosed with diabetes (sensitivity = 86%, specificity = 97%). Six-year average concentrations of PM2.5 at the postal codes of baseline residences were derived from satellite observations. We used Cox proportional hazards models to estimate the associations, adjusting for various individual-level risk factors and contextual covariates such as smoking, body mass index, physical activity, and neighborhood-level household income. We also conducted multiple sensitivity analyses. In addition, we examined effect modification for selected comorbidities and sociodemographic characteristics. Results: There were 6,310 incident cases of diabetes over 484,644 total person-years of follow-up. The adjusted hazard ratio for a 10-µg/m3 increase in PM2.5 was 1.11 (95% CI: 1.02, 1.21). Estimated associations were comparable among all sensitivity analyses. We did not find strong evidence of effect modification by comorbidities or sociodemographic covariates. Conclusions: This study suggests that long-term exposure to PM2.5 may contribute to the development of diabetes.

Postmenopausal breast cancer is associated with exposure to traffic-related air pollution in Montreal, Canada: a case-control study.

Background Only about 30% of cases of breast cancer can be explained by accepted risk factors. Occupational studies have shown associations between the incidence of breast cancer and exposure to contaminants that are found in ambient air. Objectives We sought to determine whether the incidence of postmenopausal breast cancer is associated with exposure to urban air pollution. Methods We used data from a case–control study conducted in Montreal, Quebec, in 1996–1997. Cases were 383 women with incident invasive breast cancer, and controls were 416 women with other incident, malignant cancers, excluding those potentially associated with selected occupational exposures. Concentrations of nitrogen dioxide (NO2) were measured across Montreal in 2005–2006. We developed a land-use regression model to predict concentrations of NO2 across Montreal for 2006, and developed two methods to extrapolate the estimates to 1985 and 1996. We linked these estimates to addresses of residences of subjects at time of interview. We used unconditional logistic regression to adjust for accepted and suspected risk factors and occupational exposures. Results For each increase of 5 ppb NO2 estimated in 1996, the adjusted odds ratio was 1.31 (95% confidence interval, 1.00–1.71). Although the size of effect varied somewhat across periods, we found an increased risk of approximately 25% for every increase of 5 ppb in exposure. Conclusions We found evidence of an association between the incidence of postmenopausal breast cancer and exposure to ambient concentrations of NO2. Further studies are needed to confirm whether NO2 or other components of traffic-related pollution are indeed associated with increased risks.