2007 Progress 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 Period Covered by this Report: February 1, 2007 through January 31,2008
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: Health Effects , Particulate Matter , Air

Objective:

The primary objective of this project is to determine the association between cardiovascular disease and long term particulate ambient pollutants in 6,338 non-smoking California Seventh-day Adventists. The outcomes include both fatal and non-fatal coronary heart disease as well as other cardiovascular disease during 22 years of follow-up. Additional objectives are to assess the same effects in sensitive subgroups (e.g., prevalent CVD, hypertensives, diabetics, elderly).

Further, this study aims to assess whether other pollutants (specifically gaseous pollutants) modify the association between particulate pollution and CVD.

Approach:

  1. Utilize data from the existing AHSMOG Study, which has been updated through March 2000 through the current EPA STAR Grant (R-82799801-0). This data includes 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.

Progress Summary:

Air Pollution Estimates
The AHSMOG study already had monthly air pollution estimates for each subject since start of study in 1973 and for some pollutants (PM2.5) back to 1966. These were developed using a deterministic method with interpolation to the centroid of each zipcode. The AHSMOG study had used information from all relevant monitoring stations in California to develop their ambient air pollution estimates. However, in meetings between the STAR grantees and EPA, it was decided to use a common air pollution database from EPA. This will allow a comparison of estimated ambient air pollution values by the four studies. For AHSMOG, this will also allow a comparison with our previous, comprehensive methods for estimation of ambient air pollution. However, this decision has also delayed the progress of the study in obtaining air pollution estimates using geostatistical methods.

To date, we have developed individual mean estimates of the different air pollutants for 1977 to 1999 (or date of death) based on monthly residence history and monthly workplace zipcode 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 analysis. Thus we have subject-specific ambient air pollutant values for the entire AHSMOG cohort.

In addition, we have analyzed the risk of fatal CHD and total mortality using alternate statistical methods including Bayesian Neural Networks and Bayesian Cox (using BUGS software program). A paper has been written and is being revised for re-submission. A doctoral student is further elaborating on measurements and measurement errors and will complete his dissertation in August 2009.

Assessment of outcome
Incident CHD and respiratory disease. From 1977-1982, we have information on and verification of incident myocardial infarctions (MI). 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 usually for more than 5 years in-house. After that they are put in remote storage and if records are older than 10 years, they are often destroyed. Thus, we have not been able to obtain more than 56% of the records or a total of 318 of 568.

Incident emphysema and asthma are being assessed for 22 –year follow-up by a doctoral student who finds increased risk of emphysema with increasing levels of PM10. Findings are presented at the SER in Chicago, June 2008.

Mortality
All death certificates have been coded by a certified nosologist and all mortality outcomes have thus been updated. A total of 2,462 deaths have occurred in the cohort since 1977. Of these, 2,393 are natural cause deaths (ICD-9 < 800) and 644 are due to ischemic heart disease (ICD-9: 410-414). We hope to have 7 more years of follow-up through our no-cost extension.

Analyses and Results:

Coronary Heart Disease mortality
A paper has been published (Environ Health Perspect 2005;113:1723-9) assessing the effect of fine particles on the risk of CHD in males and females and finding a stronger effect in females than in males. This surprising finding of a strong effect in females has since been replicated by others using data from the larger cohort of the WHI study (Miller et al. N Engl J Med, 2007;356(5):447-58).

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

Outcomes in sensitive subgroups –

The following sensitive subgroups have been identified:

  • Older age (>64 yrs and > 74 yrs)
  • Prevalent CHD of stroke
  • Prevalent diabetes
  • Past smokers
  • Prevalent chronic obstructive pulmonary disease (COPD)

Preliminary analyses of sensitive subgroups using previously estimated ambient air pollution do not indicate any increased risk associated with PM10 in sensitive subgroups, except for persons with diabetes where the risk of ANC, cardiopulmonary and CHD mortality seems to be elevated among males. We have limited numbers to assess the health effects of fine PM except for possibly all natural cause mortality. We are therefore requesting a one year extension to extend follow-up.

Outcomes in the full AHSMOG study

Cancer
With regards to total cancer mortality, we find, as in an earlier report, an elevated risk of total cancer among females that persists in the 22 year follow-up. These data were presented at ISEA, 2007. For individual cancers, we find, in two-pollutant models with ozone, elevated risk of both lung cancer and non-Hodgkin Lymphoma associated with particulate matter (PM10). But, again, the number of outcomes is limited and we are requesting a one-year extension to obtain 7 more years of follow-up to increase our numbers.

Total mortality outcomes
Our findings are in broad agreement with other studies. In two-pollutant models with ozone, we find 5% increased, although not statistically significant, risk of ANC associated with a 10 μg/m3 mean incremental increase in PM10 for both genders. For cardiopulmonary and CHD mortality as well as non-malignant respiratory mortality, we find that the effect is somewhat stronger in females than in males. A poster was presented at ISEE, 2007 on the non-malignant respiratory mortality.

Progress

To date, one paper has been published, and 9 presentations have been given (including the one at SER in June, 2009) at scientific meetings. Several papers are available in draft form or being worked on (see below). Several graduate students are working on different aspects and three doctoral students (Lie Hong Chen, David Shavlik and Shiva Metghalchi) are completing their dissertation addressing some of the aims of this study.

As mentioned earlier, the aim of assessing the relationship between ambient air pollution and incident CHD cannot be fulfilled. We are therefore moving forward with plans to assess this in a newly established NCI funded cohort of Adventists, the Adventist Health Study 2 cohort. We will use a nested case-control study design with 4 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.

The development of GIS based individual ambient air pollution estimates has been completed for PM10, PM2.5, NO2, SO2 and ozone. We have worked in close collaboration with ESRI and have developed an automated program that can estimate individual and time specific measures based on GIS krieging of the air pollutant and the subject’s residence and work location. One of the co-investigators, Dr. Samuel Soret, is continuing to work on two papers, one cross-validating air pollution estimates using GIS based krieging versus a deterministic model. In the second paper, he is estimating the errors introduced, if any, by using zipcode centroids versus actual street address of residence to estimate individual measures of air pollution.

Using GIS, we are also pursuing two papers related to mobile sources of PM by:

  1. relating risk of fatal CHD to time spent on freeways and high traffic roads and
  2. relating risk of fatal CHD to how distance of residence from freeways/highways.

One of our investigators and a doctoral student, David Shavlik, is pursuing further work evaluating spatial interpolation methods on PM10 and assessing and adjusting for bias in RRs using spatial interpolation methods. He is also working closely with Dr. Soret on papers where he will adjust AHSMOG data for spatial auto correlation using generalized mixed models as well as deal with measurement errors. The topics for his 3 papers are:

  1. Cross-validation of ozone exposure estimates for alternative spatial resolutions of subjects in air pollution studies
  2. Cross-validation of PM10 exposure estimates for alternative spatial resolutions of subjects in air pollution studies
  3. Correcting measurement error in PM10 exposure estimates for a California cohort.

The development of statistical models using neural networks and Bayesian neural networks is completed. The first paper on this work was presented at the Hawaii International Conference on Statistics in Honolulu in June, 2004. Three MSPH students have worked on one thesis each:

  1. developing a model using survival neural network analysis based on a method developed by Drs. Dipley of University of Oxford, UK;
  2. developing a model using Bayesian Neural Network using an approach described by Dr. Rad Neill of Univ. of Ontario, Canada.
  3. developing a new model for dealing with missing values.

We have also been able to use the BUGS statistical software to do Bayesian Cox analyses. Dr. Ghamsary has worked closely with the developers of this software in order to make it run with large datasets such as ours. Comparing the risk estimates using BUGS with estimates using traditional COX analysis, was reassuring as they gave virtually the same estimates. A paper describing these analyses was submitted to Statistics in Medicine. However, the paper was rejected and we are now revising the paper and pursuing other suitable journals.

Mortality/Morbidity
One paper has been published, on particulate matter and fatal CHD. Lie Hong Chen, who published this paper, is working on completing the other two papers for her DrPH degree:

  1. All-cause, cardiopulmonary and non-cancer respiratory mortality as they relate to PM10, PM2.5 and PM10-2.5.
  2. Ambient air pollution and mortality in sensitive subgroups.

Shiva Metghalchi, another of our doctoral students, is currently writing two papers for her doctoral dissertation:

  1. Particulate and gaseous ambient air pollution and incidence of emphysema. Results from 24 years follow-up in the AHSMOG study.
  2. Particulate and gaseous ambient air pollution and incidence of asthma. Results from 24 years follow-up in the AHSMOG study.

Dr. Beeson is working with a MPH student on writing a paper on hospitalizations for cardiovascular disease and respiratory disease in relation to air pollution.

Cancer outcomes
The paper on risk of Non-Hodgkin’s lymphoma and particulate matter has been difficult to publish due to small number of events. A total of 4 journals (Environmental Health Perspectives (ENP); Cancer, Causes and Control (CCC); Epidemiology and Am J Epid) have rejected the manuscript with one main reason being that we have too few cases. Our paper on lung cancer (Shavlik and Knutsen) has the same problem – too few lung cancer cases. We are therefore requesting another year extension to be able to update our mortality and incidence data byt 7 years and thus increase the numbers.

Expenditures to date
As of February 28, 2007, the grant had spent $ 853,860.38. Because of the challenges of being able to publish (low number of outcomes), progress has been slow. We have now decided to update linkage with the mortality and cancer incidence data in the large new Adventist Health Study (AHS-2), where many of the AHSMOG cohort also are participants. For those who are not part of the AHS-2, we will link to the National Death Index and tumor registries. This will update our records for another 7 years (throught 2005) and thus increase our number of endpoints and the power of our study. The remaining funds will be used for these linkages and for finalizing the papers.

Future Activities:

During 2007, we have repeatedly received feedback from journals that we have marginal number of outcomes. This is the main reason why our interesting NHL paper has not been accepted for publication. Therefore, we have decided to request a 1-year no-cost extension and update our mortality data and cancer incidence data through 2005 (adding another 7 years of follow-up). To be cost-efficient, this was to be done in coordination with the large new cohort study of Adventists, the AHS-2, of which some of the AHSMOG subjects also are enrolled in. The timing of linkage in the AHS-2 study was planned for Fall 2007. However, the timeline kept being pushed back and only in January and February were these linkages actually done. Cleaning of these data is still ongoing. Thus, our grant has been delayed waiting for updated mortality and cancer incidence. We have therefore asked for another no-cost extension in order to get higher number of outcome data. As soon as our request for extension is approved, we will be able to link the non-AHS-2 subjects in the AHSMOG study with NDI and get a complete updated number of new deaths.

During this last year (2008), we expect to update the numbers in the many manuscripts that are available in draft form. Thus, we hope to submit them all for publication before the end of the January, 2009.


Journal Articles on this Report : 1 Displayed | Download in RIS Format

Other project views: All 25 publications 4 publications in selected types All 4 journal articles
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
  • 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, Economic, Social, & Behavioral Science Research Program, Health, Scientific Discipline, Air, ENVIRONMENTAL MANAGEMENT, particulate matter, Health Risk Assessment, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Disease & Cumulative Effects, Biochemistry, Environmental Statistics, genetic susceptability, Biology, Risk Assessment, ambient air quality, elderly adults, health effects, sensitive populations, health risk analysis, air pollutants, long term exposure, acute lung injury, Bayesian approach, cardiovascular vulnerability, exposure, Bayesian method, Bayesian neural networks, air pollution, chronic health effects, human exposure, statistical models, susceptibility, particulate exposure, sensitive subjects, Acute health effects, elderly, GIS, sensitive subgroups, cardiotoxicity, mortality, tobacco smoke, age dependent response, cardiovascular disease, cumulative effects, exposure assessment, human health risk, respiratory, genetic susceptibility, cardiopulmonery responses, toxics

    Relevant Websites:

    http://www.llu.edu/llu/health/ahsmog.htm Exit

    Progress and Final Reports:

    Original Abstract
  • 2003 Progress Report
  • 2004 Progress Report
  • 2005 Progress Report
  • 2006 Progress Report
  • Final Report