Uncertainty-Guided Model Selection for Tabular Foundation Models in Biomolecule Efficacy Prediction

Jie Li, Andrew McCarthy, Zhizhuo Zhang

Keywords: in context learning, post hoc ensembe, siRNA efficacy predition

TL;DR: A TabPFN model's self-reported uncertainty can be used as a powerful label-free heuristic to select the best models for siRNA efficacy predictions.

Abstract: In-context learners like TabPFN are promising for biomolecule efficacy prediction, where established molecular feature sets and relevant experimental results can serve as powerful contextual examples. However, their performance is highly sensitive to the provided context, making strategies like post-hoc ensembling of models trained on different data subsets a common approach. An open question is how to select the best models for the ensemble without access to ground truth labels. In this study, we investigate an uncertainty-guided strategy for model selection. We demonstrate on an siRNA knockdown efficacy task that a TabPFN model using simple sequence-based features can surpass specialized state-of-the-art predictors. We also show that the model's predicted inter-quantile range (IQR), a measure of its uncertainty, strongly correlates with true prediction error. By selecting and averaging an ensemble of models with the lowest mean IQR, we achieve superior performance compared to naive ensembling or using a single model trained on all available data. This finding highlights model uncertainty as a powerful, label-free heuristic for optimizing biomolecule efficacy predictions.

Submission Number: 62