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Private detection of relatives in forensic genomics using homomorphic encryption.

BACKGROUND: Forensic analysis heavily relies on DNA analysis techniques, notably autosomal Single Nucleotide Polymorphisms (SNPs), to expedite the identification of unknown suspects through genomic database searches. However, the uniqueness of an individual's genome sequence designates it as Personal Identifiable Information (PII), subjecting it to stringent privacy regulations that can impede data access and analysis, as well as restrict the parties allowed to handle the data. Homomorphic Encryption (HE) emerges as a promising solution, enabling the execution of complex functions on encrypted data without the need for decryption. HE not only permits the processing of PII as soon as it is collected and encrypted, such as at a crime scene, but also expands the potential for data processing by multiple entities and artificial intelligence services. METHODS: This study introduces HE-based privacy-preserving methods for SNP DNA analysis, offering a means to compute kinship scores for a set of genome queries while meticulously preserving data privacy. We present three distinct approaches, including one unsupervised and two supervised methods, all of which demonstrated exceptional performance in the iDASH 2023 Track 1 competition. RESULTS: Our HE-based methods can rapidly predict 400 kinship scores from an encrypted database containing 2000 entries within seconds, capitalizing on advanced technologies like Intel AVX vector extensions, Intel HEXL, and Microsoft SEAL HE libraries. Crucially, all three methods achieve remarkable accuracy levels (ranging from 96% to 100%), as evaluated by the auROC score metric, while maintaining robust 128-bit security. These findings underscore the transformative potential of HE in both safeguarding genomic data privacy and streamlining precise DNA analysis. CONCLUSIONS: Results demonstrate that HE-based solutions can be computationally practical to protect genomic privacy during screening of candidate matches for further genealogy analysis in Forensic Genetic Genealogy (FGG).

Humans

PRISM: privacy-preserving rare disease analysis using fully homomorphic encryption.

MOTIVATION: Rare diseases affect millions of people worldwide, yet their genomic foundations remain poorly understood due to limited patient data and strict privacy regulations, such as the General Data Protection Regulation (GDPR) (https://gdpr.eu/tag/gdpr/) in March 2025. These restrictions can hinder the collaborative analysis of genomic data necessary for uncovering disease-causing variants. RESULTS: We present PRISM, a novel privacy-preserving framework based on fully homomorphic encryption (FHE) that facilitates rare disease variant analysis across multiple institutions without exposing sensitive genomic information. To address the challenges of centralized trust, PRISM is built upon a Threshold FHE scheme. This approach decentralizes key management across participating institutions and ensures no single entity can unilaterally decrypt sensitive data. Our method filters disease-causing variants under recessive, dominant, and de novo inheritance models entirely on encrypted data. We propose two algorithmic variants: a multiplication-intensive (MUL-IN) approach and an addition-intensive (ADD-IN) approach. The ADD-IN algorithms minimize the number of costly multiplication operations, enabling up to a 17× improvement in runtime for recessive/dominant filtering and 22× for de novo filtering, compared to MUL-IN methods. While ADD-IN produces larger ciphertexts, efficient parallelization via SIMD and multithreading allows it to handle millions of variants in reasonable time. To the best of our knowledge, this is the first study that utilizes FHE for privacy-preserving rare disease analysis across multiple inheritance models, demonstrating its practicality and scalability in a single-cloud setting. AVAILABILITY AND IMPLEMENTATION: The source code and the data used in this work can be found in https://github.com/mdppml/PRISM.git.

Computer Security

Privacy-preserving framework for genomic computations via multi-key homomorphic encryption.

MOTIVATION: The affordability of genome sequencing and the widespread availability of genomic data have opened up new medical possibilities. Nevertheless, they also raise significant concerns regarding privacy due to the sensitive information they encompass. These privacy implications act as barriers to medical research and data availability. Researchers have proposed privacy-preserving techniques to address this, with cryptography-based methods showing the most promise. However, existing cryptography-based designs lack (i) interoperability, (ii) scalability, (iii) a high degree of privacy (i.e. compromise one to have the other), or (iv) multiparty analyses support (as most existing schemes process genomic information of each party individually). Overcoming these limitations is essential to unlocking the full potential of genomic data while ensuring privacy and data utility. Further research and development are needed to advance privacy-preserving techniques in genomics, focusing on achieving interoperability and scalability, preserving data utility, and enabling secure multiparty computation. RESULTS: This study aims to overcome the limitations of current cryptography-based techniques by employing a multi-key homomorphic encryption scheme. By utilizing this scheme, we have developed a comprehensive protocol capable of conducting diverse genomic analyses. Our protocol facilitates interoperability among individual genome processing and enables multiparty tests, analyses of genomic databases, and operations involving multiple databases. Consequently, our approach represents an innovative advancement in secure genomic data processing, offering enhanced protection and privacy measures. AVAILABILITY AND IMPLEMENTATION: All associated code and documentation are available at https://github.com/farahpoor/smkhe.

Computer Security

Secure bioinformatics: privacy-preserving federated analytics using homomorphic encryption.

MOTIVATION: Large-scale bioinformatics analyses increasingly require collaboration across multiple cohorts and institutions, yet existing workflows often rely on data co-localization, which is slow, difficult to scale, and raises privacy concerns. We present a privacy-preserving federated analytics framework that enables secure statistical analysis across distributed datasets without transferring raw data, by performing all computations on encrypted data via cryptographic methods. RESULTS: We evaluate the framework by validating polygenic risk scores and conducting meta-analyses on two real-world cohorts. The proposed solution achieves over 99.9% accuracy relative to plaintext analyses, while maintaining scalable runtime performance with increasing data size and number of participating sites. These results demonstrate the feasibility of secure federated analytics for practical bioinformatics applications involving sensitive data.

Computational Biology

Safeguarding biomedical AI: a critical scoping review of privacy-enhancing technologies, hybrid approaches, and deployment models.

BACKGROUND: Biomedical artificial intelligence (AI) requires the integration of privacy-enhancing technologies (PETs) to safeguard sensitive clinical, imaging, and genomic data while preserving analytical utility. OBJECTIVES: This review critically and systematically maps applications of PETs across the biomedical AI lifecycle in accordance with PRISMA-ScR guidelines and evaluates their technical trade-offs, deployment feasibility, and residual risks. METHODS: We systematically searched PubMed, IEEE Xplore, ACM Digital Library, and Scopus for studies published between 2015 and 2025. Eligible studies addressed differential privacy, federated learning, secure multiparty computation, homomorphic encryption, or hybrid approaches in biomedical AI. Data were charted on PET type, modality, lifecycle stage, utility metrics, privacy parameters, and deployment considerations. A critical appraisal rubric assessed threat-model adequacy, methodological clarity, reproducibility, privacy-utility transparency, and deployment realism. Additionally, we hand-searched major venues (USENIX Security, NeurIPS, AAAI) and screened Google Scholar for grey literature, applying de-duplication across sources. RESULTS: We identified 87 studies spanning clinical decision support, genomics, and medical imaging. From 25,761 initial records, 3,754 underwent title/abstract screening and 1,968 underwent full-text assessment. PETs demonstrated distinct strengths and limitations: differential privacy provided provable guarantees but reduced performance on imbalanced data; federated learning improved data access but remained vulnerable to gradient leakage; and cryptographic methods ensured confidentiality at high computational cost. Synthetic data generation supported privacy-conscious data sharing and benchmarking but remained sensitive to disclosure risk, fidelity loss, and subgroup representation. Hybrid and emerging approaches, including trusted execution environments, zero-knowledge proofs, and privacy-preserving transformer architectures, mitigated composability gaps yet lacked full end-to-end assurance. Case studies at hospital and biobank scale illustrated practical feasibility and infrastructure demands. CONCLUSIONS: Situating PETs within technical and operational contexts clarifies their capabilities, limitations, and deployment challenges. Residual risks persist, including fairness concerns, inference-time leakage, and overreliance on PETs as compliance proxies. Sustained technical innovation and institutional governance remain essential for the trustworthy integration of PETs in biomedical AI.

biomedical AI

bioETH-PRS: confidential polygenic risk scoring with smart contracts on an FHE-enabled blockchain.

Polygenic risk scores (PRSs) aggregate genetic effect estimates to predict disease susceptibility, yet calculating one through an external service can require exposing raw genotype data. Homomorphic encryption hides those data during the calculation but, in prior work, still places a designated evaluator in a position of trust. We present bioETH-PRS, a protocol that replaces the evaluator with publicly auditable smart contracts on a blockchain supporting Fully Homomorphic Ethereum Virtual Machine (fhEVM). Using integer-exact encrypted arithmetic, bioETH-PRS computes the PRS dot product entirely in the encrypted domain, so genotype dosages and, at the model provider's discretion, the GWAS weights stay hidden from the parties performing the computation. A fixed-point encoding represents signed weights as nonnegative integers within a bound that rules out overflow, recovering the score to the precision of the published weights. A four-contract architecture separates data custody, model publication, computation, and output release, and supports both a classic path that stores encrypted inputs and an appreciably cheaper streaming path that discards them. A release oracle can return a randomized risk category instead of the raw score, limiting what a repeated querier learns. Prototype evaluation on real GWAS fixtures, including a run on a public testnet, shows cost growing linearly with variant count and suggests the approach may be practical where transaction fees are low. Trust is redistributed rather than removed: the system still depends on the contracts, the blockchain, and the fhEVM services. We evaluate additive models of moderate size, not genome-wide or clinical use.

Blockchain