Threshold labeled private set intersection protocol for human genetic testing

Abstract Recent breakthroughs in genome sequencing have revolutionized genetic diagnostics, yet secure sharing of sensitive genomic data remains a critical barrier to clinical collaboration.We address this challenge through Threshold Labeled Private Set Intersection (TLPSI), a novel cryptographic protocol without using computation-heavy homomorphic encryption. enabling confidential diagnostic label exchange between a client with private variants and a server hosting pathogenic variant databases–disclosing labels only when matched variants surpass clinical threshold t . TLPSI integrates three key innovations: threshold-bound label recovery via ( t , n )-Shamir sharing, genomic marker protection through VOLE-based oblivious polynomial evaluation, and optimized O ( n ) complexity operations. Provably secure under the Decisional Diffie–Hellman assumption in semi-honest settings, TLPSI guarantees no leakage of unmatched variants or labels. In BRCA1/2 breast cancer testing, TLPSI processes 65k comparisons in 1.35 s with 53.5% (16-Thread) lower computational overhead than sequential threshold-plus-labeled PSI baselines, confirming clinical readiness. Our source code is available at https://anonymous.4open.science/r/TLPSI-CD5B .