Reflection on modern methods: building causal evidence within high-dimensional molecular epidemiological studies of moderate size.

This commentary provides a practical perspective on epidemiological analysis within a single high-dimensional study of moderate size to consider a causal question. In this setting, non-causal confounding is important. This occurs when a factor is a determinant of outcome and the underlying association between exposure and the factor is non-causal. That is, the association arises due to chance, confounding or other bias rather than reflecting that exposure and the factor are causally related. In particular, the influence of technical processing factors must be accounted for by pre-processing measures to remove artefact or to control for these factors such as batch run. Work steps include the evaluation of alternative non-causal explanations for observed exposure-disease associations and strategies to obtain the highest level of causal inference possible within the study. A systematic approach is required to work through a question set and obtain insights on not only the exposure-disease association but also the multifactorial causal structure of the underlying data where possible. The appropriate inclusion of molecular findings will enhance the quest to better understand multifactorial disease causation in modern observational epidemiological studies.