Table 1.

Considerations for experimental models and study designs commonly used in developmental programming research

Experimental Model	Considerations	Advantages	Disadvantages
Animal	Common species for study: rats, mice, non-human primates, sheep, and guinea pigs When translating findings: genetic similarities/differences to humans, polytocous and altricial species, proportional translation of intervention/exposure to humans Timing of exposure, e.g. initiation prior to conception, early in gestation, or throughout gestation? Include weaning?	Low genetic variability + genetic models (knockdowns, knockouts, transgenics) Highly controlled conditions (sleep cycle, diet, exercise, stress, etc.) Implementation of adverse intrauterine exposure Analysis of tissues Low cost Shorter gestation compared to human	Interpretation and translation for human relevance
Human	Timing of exposure, e.g. early, middle, late or all of gestation, breastfeeding Tissue specific epigenetic signatures	Translational findings Public health relevance	High interindividual variability Lifestyle (un/healthy) effects on development of disease and modifications of epigenome Ethical considerations for implementing/observing adverse intrauterine exposures and studying vulnerable populations Limited tissue access
Unknown Exposure  Retrospective	Availability of birth records Association of birth weight with adult onset diseases	Large sample size Low cost	Assumption of birth outcome correlating to adverse exposure Lack of causative evidence Reliance on medical records and/or self-report
Known Exposure  Retrospective	Availability of retrospective data e.g. birth records and documentation of intrauterine exposures	Large sample size Low cost Potential for causative correlations	Reliance on medical records and/or self-report
Prospective and Retrospective	Availability to associate retrospective prospective data	Ability for in vivo assessments such as body composition, insulin sensitivity, methylation patterns, etc.	Limited by the lack of data on or during the specific intrauterine environment exposures
Longitudinal	Feasibility and ethical considerations in vulnerable populations, e.g. naturally occurring adverse exposures through famine or other environmental disaster	Ability to evaluate intrauterine exposures in real time and respective fetal, infant and adolescent outcomes	High cost Difficulty with long-term retention
Interventional	Mendelian randomization Past exposures and current epigenome Parallel or crossover design Timing of intervention Intervention must be generally regarded as safe	Ability to control for covariates through randomization	High cost Resource intensive