Biography as the dark matter of treatment response

Modern medicine faces a crisis of predictive failure. Despite unprecedented molecular knowledge and substantial investment in genome-based personalized medicine, treatment responses remain highly heterogeneous and effect sizes modest. This paper argues that "biographical dark matter", a person's lived experience including trauma, chronic stress, and social factors, powerfully shapes treatment response through measurable biological mechanisms, yet remains systematically unmeasured in clinical trials. By averaging responses across unmeasured biographical heterogeneity, we may be obscuring substantial effects within specific biology-biography mechanisms, producing the appearance of weak or absent efficacy. Integrating biographical and biological predictors into trial design offers a path toward improved predictive matching and escape from the current paradigm's diminishing returns.