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      Case-Crossover Analysis of Air Pollution Health Effects: A Systematic Review of Methodology and Application


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          Case-crossover is one of the most used designs for analyzing the health-related effects of air pollution. Nevertheless, no one has reviewed its application and methodology in this context.


          We conducted a systematic review of case-crossover (CCO) designs used to study the relationship between air pollution and morbidity and mortality, from the standpoint of methodology and application.

          Data sources and extraction

          A search was made of the MEDLINE and EMBASE databases. Reports were classified as methodologic or applied. From the latter, the following information was extracted: author, study location, year, type of population (general or patients), dependent variable(s), independent variable(s), type of CCO design, and whether effect modification was analyzed for variables at the individual level.

          Data synthesis

          The review covered 105 reports that fulfilled the inclusion criteria. Of these, 24 addressed methodological aspects, and the remainder involved the design’s application. In the methodological reports, the designs that yielded the best results in simulation were symmetric bidirectional CCO and time-stratified CCO. Furthermore, we observed an increase across time in the use of certain CCO designs, mainly symmetric bidirectional and time-stratified CCO. The dependent variables most frequently analyzed were those relating to hospital morbidity; the pollutants most often studied were those linked to particulate matter. Among the CCO-application reports, 13.6% studied effect modification for variables at the individual level.


          The use of CCO designs has undergone considerable growth; the most widely used designs were those that yielded better results in simulation studies: symmetric bidirectional and time-stratified CCO. However, the advantages of CCO as a method of analysis of variables at the individual level are put to little use.

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          Most cited references101

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          Increased particulate air pollution and the triggering of myocardial infarction.

          Elevated concentrations of ambient particulate air pollution have been associated with increased hospital admissions for cardiovascular disease. Whether high concentrations of ambient particles can trigger the onset of acute myocardial infarction (MI), however, remains unknown. We interviewed 772 patients with MI in the greater Boston area between January 1995 and May 1996 as part of the Determinants of Myocardial Infarction Onset Study. Hourly concentrations of particle mass <2.5 microm (PM(2.5)), carbon black, and gaseous air pollutants were measured. A case-crossover approach was used to analyze the data for evidence of triggering. The risk of MI onset increased in association with elevated concentrations of fine particles in the previous 2-hour period. In addition, a delayed response associated with 24-hour average exposure 1 day before the onset of symptoms was observed. Multivariate analyses considering both time windows jointly revealed an estimated odds ratio of 1.48 associated with an increase of 25 microg/m(3) PM(2.5) during a 2-hour period before the onset and an odds ratio of 1.69 for an increase of 20 microg/m(3) PM(2.5) in the 24-hour period 1 day before the onset (95% CIs 1.09, 2.02 and 1.13, 2.34, respectively). The present study suggests that elevated concentrations of fine particles in the air may transiently elevate the risk of MIs within a few hours and 1 day after exposure. Further studies in other locations are needed to clarify the importance of this potentially preventable trigger of MI.
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            Case-crossover analyses of air pollution exposure data: referent selection strategies and their implications for bias.

            The case-crossover design has been widely used to study the association between short-term air pollution exposure and the risk of an acute adverse health event. The design uses cases only; for each individual case, exposure just before the event is compared with exposure at other control (or "referent") times. Time-invariant confounders are controlled by making within-subject comparisons. Even more important in the air pollution setting is that time-varying confounders can also be controlled by design by matching referents to the index time. The referent selection strategy is important for reasons in addition to control of confounding. The case-crossover design makes the implicit assumption that there is no trend in exposure across the referent times. In addition, the statistical method that is used-conditional logistic regression-is unbiased only with certain referent strategies. We review here the case-crossover literature in the air pollution context, focusing on key issues regarding referent selection. We conclude with a set of recommendations for choosing a referent strategy with air pollution exposure data. Specifically, we advocate the time-stratified approach to referent selection because it ensures unbiased conditional logistic regression estimates, avoids bias resulting from time trend in the exposure series, and can be tailored to match on specific time-varying confounders.
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              Ischemic heart disease events triggered by short-term exposure to fine particulate air pollution.

              Recent evidence suggests that long-term exposure to particulate air pollution contributes to pulmonary and systemic oxidative stress, inflammation, progression of atherosclerosis, and risk of ischemic heart disease and death. Short-term exposure may contribute to complications of atherosclerosis, such as plaque vulnerability, thrombosis, and acute ischemic events. These findings are inconclusive and controversial and require further study. This study evaluates the role of short-term particulate exposure in triggering acute ischemic heart disease events. A case-crossover study design was used to analyze ischemic events in 12,865 patients who lived on the Wasatch Front in Utah. Patients were drawn from the cardiac catheterization registry of the Intermountain Heart Collaborative Study, a large, ongoing registry of patients who underwent coronary arteriography and were followed up longitudinally. Ambient fine particulate pollution (particles with an aerodynamic diameter < or = 2.5 microm; PM2.5) elevated by 10 microg/m3 was associated with increased risk of acute ischemic coronary events (unstable angina and myocardial infarction) equal to 4.5% (95% confidence interval, 1.1 to 8.0). Effects were larger for those with angiographically demonstrated coronary artery disease. Short-term particulate exposures contributed to acute coronary events, especially among patients with underlying coronary artery disease. Individuals with stable presentation and those with angiographically demonstrated clean coronaries are not as susceptible to short-term particulate exposure.

                Author and article information

                Environ Health Perspect
                Environmental Health Perspectives
                National Institute of Environmental Health Sciences
                August 2010
                31 March 2010
                : 118
                : 8
                : 1173-1182
                [1 ] Department of Preventive Medicine and Public Health, University of Santiago de Compostela, Santiago de Compostela, Spain
                [2 ] Santiago of Compostela Health Area, Galician Health Service [Servizo Galego de Saúde (SERGAS)], Santiago de Compostela, Spain
                [3 ] Consortium for Biomedical Research in Epidemiology and Public Health [CIBER en Epidemiología y Salud Pública (CIBERESP)], Spain
                [4 ] Institute of Environmental Analysis and Water Research [Instituto de Diagnóstico Ambiental y Estudios del Agua (IDAEA)], Spanish Scientific Research Council [Consejo Superior de Investigaciones Científicas (CSIC)], Barcelona, Spain
                [5 ] Research Group on Statistics, Applied Economics and Health [Grup de Recerca en Estadística, Economia Aplicada i Salut (GRECS)], University of Girona, Girona, Spain
                Author notes
                Address correspondence to A. Figueiras, Departamento de Medicina Preventiva y Salud Pública, Facultad de Medicina, c/San Francisco s/n, 15786 Santiago de Compostela (A Coruña), Spain. Telephone: 34-981-581-237/34-981-951-192. Fax: 34-981-572-282. E-mail: adolfo.figueiras@ 123456usc.es

                The authors declare they have no actual or potential competing financial interests.

                This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.

                Public health
                crossover studies,health,epidemiologic methods,air pollution,systematic review
                Public health
                crossover studies, health, epidemiologic methods, air pollution, systematic review


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