• Division of Population Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
• Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, California, United States of America.

Self-identified race/ethnicity is a correlate of both genetic ancestry and socioeconomic factors, both of which may contribute to racial disparities in mortality. Investigators often hold a priori assumptions, rarely made explicit, regarding the relative importance of these factors. We studied 2,239 self-identified African Americans (SIAA) from the Prostate, Lung, Colorectal and Ovarian screening trial enrolled from 1993-1998 and followed prospectively until 2019 or until death, whichever came first. Percent African genetic ancestry was estimated using the GRAF-Pop distance-based method. A neighborhood socioeconomic status (nSES) index was estimated using census tract measures of income, housing, and employment and linked to participant residence in 2012. We used Directed Acyclic Graphs (DAGs) to represent causal models favoring (1) biomedical and (2) social causes of mortality. Hazard ratios were estimated using Cox models adjusted for sociodemographic, behavioral, and neighborhood covariates guided by each DAG. 901 deaths occurred over 40,767 person-years of follow-up. In unadjusted (biomedical) models, a 10% increase in percent African ancestry was associated with a 7% higher rate of all-cause mortality (HR: 1.07, 95% CI: 1.02, 1.12). This effect was attenuated in covariate adjusted (social) models (aHR: 1.01, 95% CI: 0.96, 1.06). Mortality was lower comparing participants in the highest to lowest nSES quintile following adjustment for covariates and ancestry (aHR: 0.74, 95% CI: 0.57, 0.98, Ptrend = 0.017). Higher African ancestry and lower nSES were associated with higher mortality, but African ancestry was not associated with mortality following covariate adjustment. Socioeconomic factors may be more important drivers of mortality in African Americans.