Beyond Discrete Ancestry Groups: Distribution-Aware In-Context Learning for Cancer Outcome Prediction Across the Genetic Ancestry Continuum

Weizhi Li, Yan Cui

Machine learning models for omics-based prediction of cancer outcomes are commonly built on aggregated data without distinguishing ancestry groups, or under an ancestry-discrete design, which partitions samples into ancestry groups and fits a separate model within each group. Recent evidence shows that this approach is inherently limited: predictive accuracy declines with genetic distance from the training samples, even within a single ancestry group, because the data distribution shifts continuously rather than only between predefined categories. In this paper, we propose distribution-aware in-context learning (DA-ICL) for ancestry-continuum modeling. Our method extends conventional ancestry-discrete modeling to ancestry-continuum modeling, capturing the nonstationary omics-endpoint relationship across the genetic continuum while enabling efficient modeling through an in-context learning foundation model. We provide theoretical analysis demonstrating the superiority of the ancestry-continuum over ancestry-discrete modeling, along with empirical results supporting the proposed framework. Source code is available at https://github.com/ai4pm/DA-ICL-Continuum.