Efficient and Privacy-Preserving Biomedical AI: From Precision Therapeutics Design to Private Clinical Prediction

Accurate protein characterization, precision therapeutics design, and privacy-preserving clinical modeling are important challenges in biomedical artificial intelligence (AI). Addressing these challenges requires computational frameworks that are not only accurate and scalable but also capable of supporting reliable decision-making. This dissertation develops efficient, scalable, and reliable computational frameworks across three areas: Computational characterization of proteins, precision therapeutics design, and privacy-aware clinical representation learning. The first part of this dissertation focuses on efficient protein characterization at both the sequence and residue levels. GPCR-SLM, a knowledge-distilled small protein language model, classifies G-protein-coupled receptors (GPCRs), a family targeted by approximately 35% of FDA-approved drugs. Across 86 families, GPCR-SLM achieves 99% accuracy, outperforming BLAST (86.4%) and HMMER (91%), with a 33.5-fold speedup over large protein language models. Extending characterization to the residue level, a protein-metal-ion binding site prediction framework evaluates five protein language models and incorporates positional encoding to capture long-range dependencies. Under 10-fold cross-validation, it achieves a Matthews correlation coefficient of 0.89, with precision, recall, and F1 scores exceeding 95% across six metal ions.

Building on these protein characterization methods, the second part advances precision therapeutics design through uncertainty quantification and generative learning for therapeutic antibodies. NbBayesLM combines protein language model embeddings and physicochemical descriptors in a Bayesian neural network to predict nanobody thermostability. Evaluated on 10,630 VHH sequences, it achieves a mean absolute error of 1.89C and an R2 of 0.67 while estimating epistemic and aleatoric uncertainty to support candidate prioritization. CIgFlow employs classifier-free guidance to generate de novo, antigen-conditioned antibody sequences without fixed scaffolds or paired structural data. Generated sequences achieve a median OASis humanness score of 0.90 and mean predicted local distance difference test (pLDDT) score of 85.0, demonstrating promising novelty and diversity. The third part addresses privacy-aware clinical modeling using electrocardiograms (ECGs), which encode diagnostic information and sensitive demographic attributes. A variational autoencoder with dual discriminators suppresses demographic information while preserving clinically relevant representations.

Collectively, this dissertation advances efficient protein representation learning, computational antibody design, and privacy-preserving clinical AI, contributing methodological foundations for trustworthy biomedical applications.