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This paper proposes a new privacy-preserving framework to perform rare variant case-control association tests with information provided by two parties: a Genomic Research Unit (GRU) with sequencing data from individuals affected by a disease D (cases); a Genomic Research Center (GRC) with sequencing data from healthy individuals (controls). To identify genes with rare variants involved in D, GRU needs to compare cases against controls using association tests (genome-wide association study). The main originality of our proposal is twofold. First, it positions GRC as a proxy between GRU and the server. Doing so makes it possible to use classical cryptographic tools to securely conduct association tests with no computation complexity increase, contrarily to actual state of the art proposals which are of very high complexity being based on homomorphic encryption, for instance. In particular, we show how sensitive data confidentiality can be ensured with secret key based cryptographic hashing with no need to modify statistical algorithms. In our protocol the server simply conducts statistical analyses on partially hashed data. Secondly, we introduce a novel privacy constraint: GRU's identity should remain unknown to the server as this knowledge can give it clues about GRU's data (e.g., diseases and genes of interest). We exhibit how Pretty Good Privacy (PGP) can be used to solve this problem. We illustrate our protocol in the case of one rare variant association test, the Weighted-Sum Statistic (WSS) algorithm, carried out on real genetic data. This secure WSS achieves the same accuracy as its nonsecure version with no increase of complexity. Furthermore, we establish that our protocol can be extended to the different rare variant association tests available in the literature.

Privacy-Preserving Genome-Wide Association Study for Rare Mutations - A Secure FrameWork for Externalized Statistical Analysis