Design the strongest feasible human study to test the thrifty gene hypothesis and identify a critical confounder that must be controlled. Which study design and confounder pairing is best?

• A. A case series of extreme obesity patients treated surgically, assuming surgical cohorts represent general population genetic selection dynamics
• B. A single small cross-sectional survey asking people whether they feel thrifty, without genetic data or historical context; no confounders are relevant because feelings fully determine outcomes
• C. A lab-based short-term overfeeding trial in students with no genetic data, assuming short-term responses prove ancient selection pressures
• D. A multi-ethnic longitudinal cohort combining deep genomic sequencing, historical famine exposure data, and careful contemporary measures of diet/physical activity with statistical controls for socioeconomic status and migration; critical confounder to control: recent environmental exposure (diet changes) that mimic genetic effects

Answer: (D)