Table 1.

Basic study designs for epigenetic research vary in their ability to detect different types of epigenetic responses.

Study design	Ability of study design to detect types of epigenetic differences
	Epigenetic differences related to exposure	Epigenetic differences related to exposure in past generations	Epigenetic differences not a consequence of the disease of interest
Case–control studies	Cannot be determined by this study design	Can be established if exposures in past generations are known and DNA samples collected at birth can be assessed†	Cannot be determined by this study design
Cross-sectional studies	Can be established only if healthy individuals are analyzed or sampling is conducted before the disease developed (e.g., at birth)	Can be established if exposures in past generations are known and DNA samples collected at birth can be assessed†	Due to disease misclassification using one point in time, it is uncertain whether epigenetic differences are also responses to the disease
Follow-up studies	Can be established only if healthy individuals are analyzed or sampling is conducted before the disease developed (e.g., at birth)	Exploit exposure information and samples from more than one generation	Can be established if healthy subjects are followed-up and the disease developed after onset of epigenetic changes (time order)
Randomized intervention trials (experimental study) with follow-up	An experimental change of exposure (e.g., smoking cessation) can demonstrate whether the intervention results in an epigenetic response	Can differentiate between epigenetic inheritance and epigenetic responses due to intervention in exposures	Can differentiate whether a disease is a response to epigenetic changes or due to epigenetic inheritance

^†Some states in the USA (e.g., CA, MI, NY) and some countries store blood spots collected at birth (Guthrie cards) that can be used for epigenetic studies.