We introduce a reproducible, bias-resistant machine learning framework that integrates domain-informed feature engineering, nested cross-validation, and calibrated decision-threshold optimization for small-sample neuroimaging data. Conventional cross-validation frameworks that reuse the same folds for both model selection and performance estimation yield optimistically biased results, limiting reproducibility and generalization. Demonstrated on a high-dimensional structural MRI dataset of deep brain stimulation cognitive outcomes, the framework achieved a nested-CV balanced accuracy of 0.660\,±\,0.068 using a compact, interpretable subset selected via importance-guided ranking. By combining interpretability and unbiased evaluation, this work provides a generalizable computational blueprint for reliable machine learning in data-limited biomedical domains.
@article{arxiv.2602.02920,
title = {A Reproducible Framework for Bias-Resistant Machine Learning on Small-Sample Neuroimaging Data},
author = {Jagan Mohan Reddy Dwarampudi and Jennifer L Purks and Joshua Wong and Renjie Hu and Tania Banerjee},
journal= {arXiv preprint arXiv:2602.02920},
year = {2026}
}