Selection bias is unlikely to fully explain the protective effect of childhood adiposity on breast cancer risk.

BackgroundHigher adiposity in early life has consistently been associated with a reduced risk of breast cancer in later life, with Mendelian randomization (MR) studies supporting a potential causal effect. However, concerns have been raised that selection bias, particularly collider stratification due to selective participation or survival, may induce spurious protective effects. MethodsWe used a triangulation framework combining empirical analyses and simulations to evaluate whether selection-induced bias could plausibly explain the inverse effect of early life body size on breast cancer risk. First, we re-examined proxy-genotype MR analyses and conducted family-based simulations to assess whether attenuation in relative-based estimates could arise without selection bias. Second, we performed multivariable MR analyses of parental survival to evaluate survival-related selection mechanisms. Third, we conducted extensive simulations under a null causal model to quantify the magnitude of bias introduced by selection under a range of plausible and extreme scenarios, including interaction-driven selection. ResultsAttenuation in proxy-genotype MR estimates was reproduced in simulations without selection bias, indicating that this pattern does not provide evidence for selection bias. Multivariable MR analyses of parental survival indicated that survival differences are primarily driven by adulthood, not childhood, adiposity, providing little support for survival-related selection acting through childhood body size. In simulation analyses, additive selection produced minimal bias, while interaction-driven selection generated increasing distortion; however, even under extreme scenarios, the magnitude of bias was insufficient to replicate the observed protective effect. When selection operated through adulthood body size, bias was confined largely to adulthood estimates. Across all scenarios, the joint pattern of univariable and multivariable MR findings was not reproduced under selection alone. ConclusionsAlthough selection bias can influence MR estimates, our findings suggest that plausible selection mechanisms are unlikely to fully explain the observed inverse effect of early life adiposity on breast cancer risk. These results support a causal interpretation of the protective effect and highlight the value of triangulating evidence across complementary approaches when evaluating bias in lifecourse MR.