MOTIVATION: As most proteins interact with other proteins to perform their respective functions, methods to computationally predict these interactions have been developed. However, flawed evaluation schemes and data leakage in test sets have obscured the fact that sequence-based protein-protein interaction (PPI) prediction is still an open problem. Recently, methods achieving better-than-random performance on leakage-reduced PPI data have been proposed. RESULTS: Here, we show that the use of ESM-2 protein embeddings explains this performance gain irrespective of model architecture. We compared the performance of models with varying complexity, per-protein, and per-token embeddings, as well as the influence of self- or cross-attention, where all models plateaued at an accuracy of 0.65. Moreover, we show that the tested sequence-based models cannot implicitly learn a contact map as an intermediate layer. These results imply that other input types, such as structure, might be necessary for producing reliable PPI predictions. AVAILABILITY AND IMPLEMENTATION: All code for models and execution of the models is available at https://github.com/daisybio/PPI_prediction_study. Python version 3.8.18 and PyTorch version 2.1.1 were used for this study. The environment containing the versions of all other packages used can be found in the GitHub repository. The used data are available at https://doi.org/10.6084/m9.figshare.21591618.v3.

Abstract Federated learning (FL) is emerging as a privacy-aware alternative to classical cloud-based machine learning. In FL, the sensitive data remains in data silos and only aggregated parameters are exchanged. Hospitals and research institutions which are not willing to share their data can join a federated study without breaching confidentiality. In addition to the extreme sensitivity of biomedical data, the high dimensionality poses a challenge in the context of federated genome-wide association studies (GWAS). In this article, we present a federated singular value decomposition algorithm, suitable for the privacy-related and computational requirements of GWAS. Notably, the algorithm has a transmission cost independent of the number of samples and is only weakly dependent on the number of features, because the singular vectors corresponding to the samples are never exchanged and the vectors associated with the features are only transmitted to an aggregator for a fixed number of iterations. Although motivated by GWAS, the algorithm is generically applicable for both horizontally and vertically partitioned data.

Federated learning (FL) is a privacy-aware data mining strategy keeping the private data on the owners’ machine and thereby confidential. The clients compute local models and send them to an aggregator which computes a global model. In hybrid FL, the local parameters are additionally masked using secure aggregation, such that only the global aggregated statistics become available in clear text, not the client specific updates. In this context, we investigate the data leakage of three popular algorithms for QR decomposition, Gram-Schmidt orthonormalization, the Householder algorithm and Givens rotation. We show that, even when using additive SMPC, Givens rotation and the Householder matrix leak raw data and are therefore not suited for this computation paradigm. Gram-Schmidt orthonormalization relies on inner vector products and does not leak raw data points.

Federated learning (FL) has emerged as a privacy-aware alternative to centralized data analysis, especially for biomedical analyses such as genome-wide association studies (GWAS). The data remains with the owner, which enables studies previously impossible due to privacy protection regulations. Principal component analysis (PCA) is a frequent preprocessing step in GWAS, where the eigenvectors of the sample-by-sample covariance matrix are used as covariates in the statistical tests. Therefore, a federated version of PCA suitable for vertical data partitioning is required for federated GWAS. Existing federated PCA algorithms exchange the complete sample eigenvectors, a potential privacy breach. In this paper, we present a federated PCA algorithm for vertically partitioned data which does not exchange the sample eigenvectors and is hence suitable for federated GWAS. We show that it outperforms existing federated solutions in terms of convergence behavior and scalability. Additionally, we provide a user-friendly privacy-aware web tool to promote acceptance of federated PCA among GWAS researchers.