Comments on "PM2.5 and mortality in long-term prospective cohort studies: cause-effect or statistical associations?".

The lengthy commentary by Gamble (1) is rife with inaccuracies, all ofwhich cannot be commented on in the context of this reply. However, because Gamble's critique largely is directed toward ecological studies, we wish to focus on a number ofwidespread misconceptions to which his critique has succumbed. We have discussed these issues at length in a recent publication in EHP (2). Contrary to his assertion, none of the major studies (cohort, times-series or cross-sectional) cited and criticized by Gamble truly are ecological studies. Having incorrectly categorized the studies, he then proceeded to cite commentaries (3,4) that point out the significant limitations of ecological studies when the target ofinference is individual risk. The hallmark of ecological studies is the lack of individual-level measurements. Thus, the ecological study merely relies on a comparison of aggregate (group)-level prevalence or incidences of outcomes with some aggregate level of exposure. For example , in a paper cited by Gamble, Brenner et al. (3) used county-specific mortality rates for lung cancer and estimates of the prevalence ofsmoking for each county to demonstrate the pitfalls of the use of group data to make inferences about individual risk. The cohort and several of the large multicenter cross-sectional studies cited by Gamble differ from Brenner's example on two crucial points: 1) they contain large sets of individual data (as acknowledged by Gamble), which indude most of the relevant risk factors and potential confounders for which adjustment might be necessary; and 2) exposure is not an average proportion of the population that is exposed (as was the case in the Brenner example), but rather a crude average ambient concentration measured in a particular city. It is this second characteristic of what we have called the semi-individual study design (2) that often leads to the misapplication of the term ecological to the study design. Brenner et al. (3) noted that exposure prevalence in a truly ecological study suffers from the fact that the unknown sensitivity and specificity of the exposure assignment has a substantial impact on the potential distortion of the ecological exposure-outcome association relative to the "true" individual-level association. Moreover, prevalence (ofsmoking, for example), an inherently group-level concept, has no interpretation at the level of the individual. In contrast, in a semi-individual study of the type critiqued by Gamble, the exposure (ambient particle concentration) clearly is of relevance for all individuals who live in a particular region. The ambient levels …