Grantee Research Project Results

Final Report: Relating Cardiovascular Disease Risk to Ambient Air Pollutants Using Geographic Information Systems Technology and Bayesian Neural Networks: The AHSMOG Study

EPA Grant Number: R830547
Title: Relating Cardiovascular Disease Risk to Ambient Air Pollutants Using Geographic Information Systems Technology and Bayesian Neural Networks: The AHSMOG Study
Investigators: Knutsen, Synnove F. , Beeson, Larry , Ghamsary, Mark , Soret, Samuel
Institution: Loma Linda University
EPA Project Officer: Chung, Serena
Project Period: February 1, 2003 through December 31, 2006 (Extended to January 31, 2009)
Project Amount: $964,436
RFA: Epidemiologic Research on Health Effects of Long-Term Exposure to Ambient Particulate Matter and Other Air Pollutants (2002) RFA Text | Recipients Lists
Research Category: Particulate Matter , Human Health , Air

Objective:

Specific Objectives:

1. To assess the long-term effects of particulate and gaseous pollutants on risk of cardiovascular disease (CVD), including fatal and non-fatal coronary heart disease (CHD), during 23 years follow-up (1977-1999) using the unique data from the Adventist Health and Smog (AHSMOG) Study.

2. To assess the long-term effects of ambient air pollutants on risk of fatal and non-fatal CHD among sensitive subgroups (e.g., prevalent CVD, hypertensives, diabetics, elderly).

3. To assess the long-term effects of mixed pollutants on the endpoints in objectives 1 and 2.

4. To investigate the effect of lag-times on the ambient air pollution-CVD association.

Approach:

1. Utilize data from the existing AHSMOG Study, which has been updated through March 2000 through the current EPA STAR Grant (R827998). These data include monthly indices of air pollutants to zip code centroids, monthly residence and work location histories, outcome assessment (CHD, fatal and non-fatal) and assessment of relevant confounders (smoking, environmental tobacco smoke, diet, exercise, etc.).

2. Develop new indices of ambient air pollutants for the individual subjects in the AHSMOG Study using geographic information systems (GIS) technology and stochastic models that include error estimates of the indices.

3. Develop non-linear statistical models using Bayesian neural networks to develop alternative analytical strategies for modeling the relationship between different ambient air pollutants and risk of CHD where several pollutants and latent (unobserved) and missing values can be incorporated.

4. Compare new methods developed under approaches 2 and 3 to the classic or conventional methods previously used in the AHSMOG Study.

Summary/Accomplishments (Outputs/Outcomes):

The AHSMOG Study has been able to accomplish most of the objectives of this grant. However, for various reasons we were not able to assess the association between ambient air pollution and non-fatal CHD.

Monthly air pollution estimates for each subject were available since start of study in 1973 and for some pollutants (PM_2.5) back to 1966 and through 2000. These were developed using a deterministic method with interpolation to the centroid of each zip code. The AHSMOG study had used information from all relevant monitoring stations in California to develop their ambient air pollution estimates. Under this grant, we have developed individual mean estimates of the different air pollutants from 1977-2006 (or date of death) based on monthly residence history and monthly workplace zip code, which have been geocoded. In collaboration with the research team at Environmental Systems Research Institute (ESRI), we have developed a software program that can combine the geocoded residence and workplace information with the EPA air pollution database to assess subject-specific ambient air pollution estimates using geostatistical data analyses. Thus, we have subject- and residence-specific ambient air pollutant values for the entire AHSMOG cohort.

Unfortunately, we were not able to assess the association between ambient air pollution and incident CHD due to problems in obtaining medical records to verify incident cases of CHD. However, we have completed analyses for risk assessment of fatal CHD and a paper was published in 2005 (Chen LH, Knutsen SF, Shavlik D, Beeson WL, Petersen F, Ghamsary M, Abbey D. The association between fatal coronary heart disease and ambient particulate air pollution: are females at greater risk? Environmental Health Perspectives 2005;113:1723-1729). A significantly elevated risk of fatal CHD was found for each 10 µg/m³ increase in PM_2.5. The effect was mainly present in females and was strengthened when ozone was included in the model.

Under this funding, we also have assessed the risk between ambient particulate matter and fatal CHD in sensitive subgroups using three different cohorts: the AHSMOG-1 (with PM₁₀), the AHSMOG-2 (with PM_2.5) and a population of renal transplant recipients (with PM_2.5). The associations were of similar magnitude in the potentially sensitive subgroups and the total population cohorts. Thus, we cannot conclude that the sensitive subgroups tested are at higher risk than non-smokers in general. However, our risk estimates tend to be higher than what others have found, possibly due to the fact that our analyses are not confounded by smoking.

Under this grant, we also have continued general analyses on the association between ambient air pollution and other disease outcomes (cancer and respiratory disease). We find a moderate association with overall cancer mortality, lung cancer incidence and mortality and non-cancer respiratory mortality.

As part of this grant, we have explored different methods of assessing individual air pollutants, using inverse distance versus kriging. This has been presented at scientific meetings and the findings also are included in a paper that is soon to be submitted for publication. We have further assessed alternate statistical methods including Bayesian Neural Networks and Bayesian Cox (using BUGS software program). The findings have not been published yet.

1. Specific Objective I

“To assess the long-term effects of particulate and gaseous pollutants on risk of cardiovascular disease (CVD), including fatal and non-fatal coronary heart disease (CHD), during 23 years follow-up (1977-1999) using the unique data from the AHSMOG Study.”

1.A. Assessment of Non-fatal (incident) CHD

We have not been able to fulfill the objective of assessing risk of non-fatal CHD as associated with ambient air pollution.

From 1977-1982, we have information on and verification of incident myocardial infarctions (MI). However, the number of cases was too small for meaningful analyses. For the period 1983-1999, we have self-reported incidence of acute myocardial infarction with additional information on name and address of the hospital in which these were diagnosed. Validity of this information was planned through obtainment of medical records from the individual hospitals. However, this has proved impossible as hospitals do not keep medical records in-house for more than 5 years. After that they are put in remote storage and if records are older than 10 years, they often are destroyed. Thus, we have not been able to obtain more than 56% of the records or a total of 318 of 568.

To compensate for a lack of data for incident CHD, we requested permission from EPA to modify this part of the study and instead assess incident CHD in a new cohort, the Adventist Health Study 2 cohort. This cohort of 97,000 subjects recently has been assembled through funding from NCI to study the effect of lifestyle, especially diet, on cancer outcomes. We proposed to use the information from bi-annual hospitalization forms to study the association between particulate air pollution and incident CHD in the 6 western U.S. states using this population and a nested case-control design. Although we did engage a graduate student to work on this, it turned out to be more time consuming than expected. Therefore, it was decided to request separate funding and assess this in the entire AHS-2 population covering all 50 states of the United States and the 6 provinces of Canada. This will be a separate, stand-alone study once the datafile has been linked to air pollution estimates.

1.B. Fatal CHD

This objective has been more than fulfilled in that mortality has been completed through 2006 (instead of 1999 as stated in the objectives). We also have assessed the association between ambient air pollution and fatal CHD in both the AHSMOG-1 and AHSMOG-2 cohorts.

1.A.a. Fatal CHD and results from the AHSMOG-1

A total of 373 (6% of total cohort or 8% of total deaths) subjects died from coronary heart disease (CHD) during follow up (1977-2006).The paper on associations between fine particles (PM_2.5) and fatal CHD (through 1998) was published in December 2005 (Environment Health Perspectives 2005;113:1723-1729).

We found that women seemed to be at substantially higher risk for fatal CHD when living in areas with high PM_2.5 levels compared to men. This also was reflected in the observed associations with PM₁₀ in the geographic areas around airports, but not in other areas. The strong finding for women recently has been replicated in the larger cohort of the Womens Health Initiative study (Miller, et al., New England Journal of Medicine 2007;356(5):447-458).

We have tried, with the help of a graduate student, to assess whether our observed gender difference could be due to a greater degree of misclassification of exposure among males.

from the original AHSMOG study. However, it has been very difficult to separate the air pollution at residence and work location due to the way the data were set up and thus we are not able to assess this as planned.

1.A.b. Fatal CHD and Results from AHSMOG-2 (the AHS-2 cohort of 97,000)

As with the AHSMOG-1 study, we find a consistent association between ambient levels of PM_2.5 and fatal CHD. However, as opposed to the original AHSMOG Study, we also find an association among males. The magnitude of effect is relatively strong. After adjusting for age, education, past smoking history (all are non-smokers), race and exercise, the RR was 1.63 (0.92-2.9) in females and 2.19 (1.25-3.85) in males (Table 1.A.a. below). In runs not shown, we controlled additionally for BMI, vegetarian status, alcohol use, red meat consumption, high blood pressure, angina, diabetes, statin use, aspirin use, high blood pressure medicine use, and hormone replacement therapy. Controlling for these variables did not change the results.An abstract was presented at ISEE 2009 in Ireland.

Table 1.A.b. Risk of fatal CHD according to increments of PM_2.5 and ozone. Single- and two-pollutant models.
Model	Pollutant (increment)	Combined	Males	Females
		N=60,652 N (cases)=171	N=20,829 N (cases)=85	N=39,823 N (cases)=86
Single Pollutant Model	PM_2.5 (10 µg/m³)	1.9 (1.27-2.84)	2.19 (1.25-3.85)	1.63 (0.92-2.9)
Single Pollutant Model	Ozone (10 ppb)	1.26 (0.92-1.73)	1.2 (0.77-1.88)	1.37 (0.88-2.13)
Two Pollutant Model	PM_2.5 (10 µg/m³)	1.9 (1.27-2.84)	2.18 (1.24-3.83)	1.65 (0.93-2.93)
Two Pollutant Model	Ozone (10 ppb)	1.27 (0.92-1.75)	1.2 (0.75-1.9)	1.38 (0.88-2.17)

2. Specific Objective II

To assess the long-term effects of ambient air pollutants on risk of fatal and non-fatal CHD among sensitive subgroups (e.g., prevalent CVD, hypertensives, diabetics, elderly).

2. A. Sensitive subgroups in the original AHSMOG cohort

The following sensitive subgroups were identified:

· Older age (>64 yrs and > 74 yrs)

· Past smokers

· Prevalent CHD or stroke

· Prevalent diabetes

· Prevalent chronic obstructive pulmonary disease (COPD)

Only non-smokers were enrolled in the AHSMOG study. However, some of the subjects had been smokers before enrolling in the study and thus our study population was stratified on past smokers versus never smokers. For prevalent diabetes, information was only available at baseline (1977). Many may since that time have developed diabetes. Thus, any results could be biased towards the null.

For the groups with COPD or cardiovascular disease, this was assessed at each questionnaire (1977, 1982, 1992 and 2000). Therefore, we have used all this information and moved subjects into these sensitive subgroups as of the date they report having been diagnosed with the specific condition. Likewise, the sensitive subgroup of elderly has been put into this group as they aged throughout the study. Thus our final sensitive subgroups with the different outcomes are as follows:

Table 2.A. Number of total natural cause death, fatal CHD and cardio-pulmonary deaths during 30 year follow up of the AHSMOG-1 Study. 1977-2006. N=6,338.

Subgroup	N	All natural cause Mortality N	Fatal CHD N	Cardio-pulmonary death N
> 64 yrs	6,050	3,219	856	2,006
Prevalent CHD, stroke	906	679	285	518
Prevalent Diabetes	371*	279	97	187
Prevalent COPD	1,698	777	204	493
Past smokers	1,441	775	203	453

The results have been drafted into a paper. Briefly, the effect of PM₁₀ or gases on risk of CHD in sensitive subgroups seems to be small and of similar magnitude as those found in the entire cohort. However, among diabetic males, the risk of CHD, cardiopulmonary, and all natural cause mortality seems to be elevated. We have too few numbers to assess the effect of PM_2.5.

2.B. Sensitive Subgroups in the AHSMOG-2

The new AHSMOG-2 cohort of 97,000 non-smoking subjects gives much better power to assess the effect of ambient air pollution in sensitive subgroups. Thus, we have identified the following sensitive subgroups in this new cohort:

Older age: > 80 years

Past smokers

Prevalent diabetes (Type I and II)

Prevalent cardiovascular disease (CHD, hypertension, stroke)

Prevalent CHD (MI)

Prevalent COPD (asthma, bronchitis)

The analyses in the AHSMOG-2 are not yet completed as they are part of a doctoral dissertation. Analyses have so far been limited to the 60,652 who have not moved during follow-up. Preliminary results indicate similar magnitude of effect of PM_2.5 among different sensitive subgroups and they are similar to the overall effect in the full cohort. Thus, our preliminary conclusion is that the effect of various ambient air pollutants on fatal CHD in the potentially sensitive subgroups of this population, does not seem to be higher than among the population as a whole. Further analyses are needed in this new cohort before final conclusions can be made.

2.C. Sensitive Subgroup of Renal transplant recipients

To further assess the effect of air pollution in potentially sensitive subgroups, one of our doctoral students, has studied the effect of ambient air pollution on risk of fatal CHD in another sensitive subgroup, e.g., non-smoking renal transplant recipients. An abstract was accepted for presentation at the ISEE conference in Ireland in August 2009, and a paper is in the process of being submitted for publication.

3. Specific Objective III

“To assess the long-term effects of mixed pollutants on the endpoints in objectives 1 and 2.”

This criterion has been met and reported for each of the results reported under objectives 1 and 2 or in the respective appendices (which are not included with this report). In general, the effect of ozone is not affected to any significant degree by including either particulate or gaseous pollutants in a two-pollutant model one at a time. However, the effect of PM (especially PM_2.5) is clearly strengthened by adjusting for ozone in a two-pollutant model in the AHSMOG-1 and the renal transplant recipients. However, ozone does not seem to modify the PM effect to any great degree in the AHSMOG-2. This discrepancy warrants further investigation. The effect of other gaseous pollutants are smaller and do not modify the PM effect to any large extent.

4. Specific Objective IV

“To investigate the effect of lag-times on the ambient air pollution-CVD association.”

This criterion has been met. In our investigation of lag-times for the air pollution-CVD association, we tested out the effect of long lag-times versus more recent lag times. The original AHSMOG study only had a maximum of 4 years air pollution prior to a CHD death. Thus, we were limited in our ability to assess various lag-times. However, we were able to assess the effect of using the 4 years immediately prior to fatal CHD as the exposure window (with the exclusion of the last month before death to avoid short-term effects) and compare this with the use of a fixed time period immediately before the AHSMOG Study began (1973-1977). Of these two options, the moving 4 year average immediately prior to CHD death gave the strongest estimates with the most narrow confidence intervals (Table 4.A. below). This suggests that the effect of particulate air pollution on risk of CHD death is related to more recent ambient air pollution.

Table 4.A. The association between PM_2.5 and fatal CHD using different exposure estimates

Increment

Fixed time period, 1973-77

4-year moving average

95% CI

Single pollutant model

PM_2.5

10 µg/m³

1.10

0.93-1.31

1.42

1.11-1.81

Ozone*

10 ppb

1.01

0.99-1.04

0.97

0.71-1.32

Conclusions:

To date, one paper has been published, and 13 presentations have been given (including the two at ISEE in August 2009) at scientific meetings. Several papers are available in draft form or are being worked on by gradate students. Four doctoral students (Lie Hong Chen, David Shavlik, Rhonda Spencer Hwang and Shiva Metghalchi) are completing their dissertations addressing some of the aims of this study.

As mentioned earlier, the aim of assessing the relationship between ambient air pollution and incident CHD could not be fulfilled. Therefore, we are moving forward with plans to assess this in the newly established NCI-funded cohort of Adventists, the Adventist Health Study 2 cohort. The air pollution part of this study is being called the AHSMOG-2 study. We will use a nested case-control study design with four controls per case and obtain medical records for all cases after obtaining their approval using a HIPAA appropriate consent form. This proposed study has not yet been funded, but we are actively pursuing funding opportunities.

Journal Articles on this Report : 4 Displayed | Download in RIS Format

Publications Views
Other project views:	All 25 publications	4 publications in selected types	All 4 journal articles

Publications
Type	Citation	Project	Document Sources
Journal Article	Chen LH, Knutsen SF, Shavlik D, Beeson WL, Petersen F, Ghamsary M, Abbey D. The association between fatal coronary heart disease and ambient particulate air pollution:are females at greater risk? Environmental Health Perspectives 2005;113(12):1723-1729.	R830547 (2005) R830547 (2006) R830547 (2007) R830547 (Final) R827998 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: EHP-Full Text HTML Other: EHP-Full Text PDF
Journal Article	Gharibvand L, Lawrence Beeson W, Shavlik D, Knutsen R, Ghamsary M, Soret S, Knutsen SF. The association between ambient fine particulate matter and incident adenocarcinoma subtype of lung cancer. Environmental Health 2017;16(1):71 (9 pp.).	R830547 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: BMC-Full Text HTML Exit Other: BMC-Full Text PDF Exit
Journal Article	Gharibvand L, Shavlik D, Ghamsary M, Beeson WL, Soret S, Knutsen R, Knutsen SF. The association between ambient fine particulate air pollution and lung cancer incidence: results from the AHSMOG-2 study. Environmental Health Perspectives 2017;125(3):378-384.	R830547 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: EHP-Full Text HTML Other: EHP-Full Text PDF
Journal Article	Spencer-Hwang R, Knutsen SF, Soret S, Ghamsary M, Beeson WL, Oda K, Shavlik D, Jaipaul N. Ambient air pollutants and risk of fatal coronary heart disease among kidney transplant recipients. American Journal of Kidney Diseases 2011;58(4):608-616.	R830547 (Final)	Abstract from PubMed Abstract: AJKD-Abstract Exit

Supplemental Keywords:

Ambient air, ozone, particulate matter, exposure, risk, risk assessment, health effects, human health, sensitive populations, population, elderly, cumulative effects, susceptibility, epidemiology, modeling, monitoring, analytical, Bayesian neural networks, GIS, southwest, California, CA

, RFA, Health, Air, Scientific Discipline, ENVIRONMENTAL MANAGEMENT, Economic, Social, & Behavioral Science Research Program, Environmental Statistics, Susceptibility/Sensitive Population/Genetic Susceptibility, Health Risk Assessment, Risk Assessments, particulate matter, Biology, genetic susceptability, Biochemistry, Disease & Cumulative Effects, Risk Assessment, cumulative effects, health effects, environmental hazard exposures, sensitive populations, Bayesian method, age dependent response, Bayesian approach, mortality, elderly, respiratory, long term exposure, sensitive subgroups, health risk analysis, acute lung injury, human exposure, particulate exposure, cardiovascular vulnerability, susceptibility, statistical models, genetic susceptibility, Acute health effects, cardiopulmonery responses, cardiotoxicity, exposure, chronic health effects, air pollutants, toxics, air pollution, ambient air quality, elderly adults, GIS, human health risk, cardiovascular disease, exposure assessment, tobacco smoke, Bayesian neural networks

Relevant Websites:

Loma Linda University

Progress and Final Reports:

Original Abstract

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.