Knowledge-Driven Feature Selection and Engineering for Genotype Data with Large Language Models.

Predicting phenotypes with complex genetic bases based on a small, interpretable set of variant features remains a challenging task. Conventionally, data-driven approaches are used for this task, yet the high dimensional nature of genotype data makes the analysis and prediction difficult. Motivated by the biomedical knowledge encoded in pre-trained LLMs and the emerging applications for genetics, we set to examine the ability of LLMs in feature selection and engineering for tabular genotype data, with a novel knowledge-driven framework. We develop FREEFORM, Free-flow Reasoning and Ensembling for Enhanced Feature Output and Robust Modeling, designed with chain-of-thought and ensembling principles, to select and engineer features with the intrinsic knowledge of LLMs. Evaluated on two distinct genotype-phenotype datasets, genetic ancestry and hereditary hearing loss, we find this framework outperforms several data-driven methods, particularly on low-data regimes. FREEFORM is available as open-source framework at GitHub: https://github.com/PennShenLab/FREEFORM.