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Background: The shape of the exposure-response curve for long-term ambient fine particulate (PM2.5) exposure and cause-specific mortality is poorly understood, especially for rural populations and underrepresented minorities.Methods: We used hybrid machine learning and Cox proportional hazard models to assess the association of long-term PM2.5 exposures on specific causes of death for 53 million U.S. Medicare beneficiaries (aged ≥65) from 2000 to 2008. Models included strata for age, sex, race, and ZIP code and controlled for neighborhood socio-economic status (SES) in our main analyses, with approximately 4 billion person-months of follow-up, and additionally for warm season average of 1-h daily maximum ozone exposures in a sensitivity analysis. The impact of non-traffic PM2.5 on mortality was examined using two stage models of PM2.5 and nitrogen dioxide (NO2).Results: A 10 μg /m3 increase in 12-month average PM2.5 prior to death was associated with a 5% increase in all-cause mortality, as well as an 8.8, 5.6, and 2.5% increase in all cardiovascular disease (CVD)-, all respiratory-, and all cancer deaths, respectively, in age, gender, race, ZIP code, and SES-adjusted models. PM2.5 exposures, however, were not associated with lung cancer mortality. Results were not sensitive to control for ozone exposures. PM2.5-mortality associations for CVD- and respiratory-related causes were positive and significant for beneficiaries irrespective of their sex, race, age, SES and urbanicity, with no evidence of a lower threshold for response or of lower Risk Ratios (RRs) at low PM2.5 levels. Associations between PM2.5 and CVD and respiratory mortality were linear and were higher for younger, Black and urban beneficiaries, but were largely similar by SES. Risks associated with non-traffic PM2.5 were lower than that for all PM2.5 and were null for respiratory and lung cancer-related deaths.Conclusions: PM2.5 was associated with mortality from CVD, respiratory, and all cancer, but not lung cancer. PM2.5-associated risks of CVD and respiratory mortality were similar across PM2.5 levels, with no evidence of a threshold. Blacks, urban, and younger beneficiaries were most vulnerable to the long-term impacts of PM2.5 on mortality. [ABSTRACT FROM AUTHOR]

[Display omitted] Our understanding of the impact of long-term exposures to PM 2.5 constituents and sources on mortality is limited. To examine associations between long-term exposures to PM 2.5 constituents and sources and cause-specific mortality in US older adults. We obtained demographic and mortality data for 15.4 million Medicare beneficiaries living within the conterminous United States (US) between 2000 and 2008. We assessed PM 2.5 constituents exposures for each beneficiary and used factor analysis and residual-based methods to characterize PM 2.5 sources and mixtures, respectively. In age-, sex-, race- and site- stratified Cox proportional hazard models adjusted for neighborhood socio-economic status (SES), we assessed associations of individual PM 2.5 constituents, sources, and mixtures and cause-specific mortality and examined modification of these associations by participant demographics and location of residence. We assessed the robustness of our findings to additional adjustment for behavioral risk factors and to alternate exposure definitions and exposure windows. Hazard ratios (HR) were highest for all causes of death, except COPD, for PM 2.5 constituents and the coal combustion-related PM 2.5 components, with no evidence of confounding by behavioral covariates. We further found Pb and metal-related PM 2.5 components to be significantly associated with increased HR of all causes of death, except COPD and lung cancer mortality, and nitrate (NO 3 –) and silicon (Si) and associated source-related PM 2.5 components (traffic and soil, respectively) to be significantly associated with increased all-cause, CVD, respiratory and all cancer-related mortality HR. Associations for other examined constituents and mortality were inconsistent or largely null. Our analyses of mixtures were generally consistent with these findings. Mortality HRs were greatest for minority, especially Black, low-income urban, younger, and male beneficiaries. PM 2.5 components related to coal combustion, traffic, and to a lesser extent, soil were strongly associated with mortality from CVD, respiratory disease, and cancer. [ABSTRACT FROM AUTHOR]