Referent selection in case-crossover analyses of acute health effects of air pollution

Epidemiology. 2001 Mar;12(2):186-92. doi: 10.1097/00001648-200103000-00010.


The case-crossover design was proposed for the study of a transient effect of an intermittent exposure on the subsequent occurrence of a rare acute-onset disease. This design can be an alternative to Poisson time series regression for studying the health effects of fine particulate matter air pollution. Characteristics of time-series of particulate matter, including long-term time trends, seasonal trends, and short-term autocorrelations, require that referent selection in the case-crossover design be considered carefully and adapted to minimize bias. We performed simulations to evaluate the bias associated with various referent selection strategies for a proposed case-crossover study of associations between particulate matter and primary cardiac arrest. Some a priori reasonable strategies were associated with a relative bias as large as 10%, but for most strategies the relative bias was less than 2% with confidence interval coverage within 1% of the nominal level. We show that referent selection for case-crossover designs raises the same issues as selection of smoothing method for time series analyses. In addition, conditional logistic regression analysis is not strictly valid for some case-crossover designs, introducing further bias.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acute Disease
  • Air Pollutants / adverse effects
  • Air Pollution / adverse effects*
  • Cross-Over Studies
  • Heart Arrest / epidemiology
  • Heart Arrest / etiology*
  • Humans
  • Research Design
  • Retrospective Studies
  • Selection Bias*
  • Washington / epidemiology


  • Air Pollutants