What is a major difficulty in an epidemiologic experiment comparing exposed and control city populations?

The major difficulty in an epidemiologic experiment comparing exposed and control city populations stems from the issue of comparability between the case and control groups, especially when considering confounding factors. In such studies, it's crucial that both groups are similar in terms of demographics, socio-economic status, health behaviors, and other relevant characteristics to ensure that any differences observed are attributed to the exposure under investigation rather than other variables.

If the case and control groups are not comparable on these factors, the results can be misleading. For example, if one city's population has higher rates of smoking or different access to healthcare compared to another, these variables could confound the results, making it difficult to ascertain the true impact of the exposure being studied. Hence, addressing and ensuring comparability is essential to enhancing the validity and reliability of epidemiological findings.