Strength of evidence for paternal influence on offspring epigenome in observational human studies: a systematic review and risk-of-bias appraisal for non-randomized exposures

. SES) or had clearly defined timing produced more consistent results. Notably, studies with clearly defined timing of paternal smoking suggested preconception exposure may influence offspring epigenetic pathways related to innate immunity but not pregnancy exposure. In contrast, paternal factors with poorly defined experimental analogues, such as BMI, provided inconsistent results. Aligning study design more closely with clinical trials or animal models, by clearly defining populations and exposures, may result in more reliable and replicable findings. Frameworks like 'target trial emulation,' offer a promising approach to improve reproducibility and interpretability of future research on paternal effects on offspring epigenome.