Reconstruction of host-pathogen protein interaction networks is of great significance to reveal the underlying microbic pathogenesis. However, the current experimentally-derived networks are generally small and should be augmented by computational methods for less-biased biological inference. From the point of view of computational modelling, data scarcity, data unavailability and negative data sampling are the three major problems for host-pathogen protein interaction networks reconstruction. In this work, we are motivated to address the three concerns and propose a probability weighted ensemble transfer learning model for HIV-human protein interaction prediction (PWEN-TLM), where support vector machine (SVM) is adopted as the individual classifier of the ensemble model. In the model, data scarcity and data unavailability are tackled by homolog knowledge transfer. The importance of homolog knowledge is measured by the ROC-AUC metric of the individual classifiers, whose outputs are probability weighted to yield the final decision. In addition, we further validate the assumption that only the homolog knowledge is sufficient to train a satisfactory model for host-pathogen protein interaction prediction. Thus the model is more robust against data unavailability with less demanding data constraint. As regards with negative data construction, experiments show that exclusiveness of subcellular co-localized proteins is unbiased and more reliable than random sampling. Last, we conduct analysis of overlapped predictions between our model and the existing models, and apply the model to novel host-pathogen PPIs recognition for further biological research.

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BackgroundPrediction of protein subcellular localization generally involves many complex factors, and using only one or two aspects of data information may not tell the true story. For this reason, some recent predictive models are deliberately designed to integrate multiple heterogeneous data sources for exploiting multi-aspect protein feature information. Gene ontology, hereinafter referred to as GO, uses a controlled vocabulary to depict biological molecules or gene products in terms of biological process, molecular function and cellular component. With the rapid expansion of annotated protein sequences, gene ontology has become a general protein feature that can be used to construct predictive models in computational biology. Existing models generally either concatenated the GO terms into a flat binary vector or applied majority-vote based ensemble learning for protein subcellular localization, both of which can not estimate the individual discriminative abilities of the three aspects of gene ontology.ResultsIn this paper, we propose a Gene Ontology Based Transfer Learning Model (GO-TLM) for large-scale protein subcellular localization. The model transfers the signature-based homologous GO terms to the target proteins, and further constructs a reliable learning system to reduce the adverse affect of the potential false GO terms that are resulted from evolutionary divergence. We derive three GO kernels from the three aspects of gene ontology to measure the GO similarity of two proteins, and derive two other spectrum kernels to measure the similarity of two protein sequences. We use simple non-parametric cross validation to explicitly weigh the discriminative abilities of the five kernels, such that the time & space computational complexities are greatly reduced when compared to the complicated semi-definite programming and semi-indefinite linear programming. The five kernels are then linearly merged into one single kernel for protein subcellular localization. We evaluate GO-TLM performance against three baseline models: MultiLoc, MultiLoc-GO and Euk-mPLoc on the benchmark datasets the baseline models adopted. 5-fold cross validation experiments show that GO-TLM achieves substantial accuracy improvement against the baseline models: 80.38% against model Euk-mPLoc 67.40% with 12.98% substantial increase; 96.65% and 96.27% against model MultiLoc-GO 89.60% and 89.60%, with 7.05% and 6.67% accuracy increase on dataset MultiLoc plant and dataset MultiLoc animal, respectively; 97.14%, 95.90% and 96.85% against model MultiLoc-GO 83.70%, 90.10% and 85.70%, with accuracy increase 13.44%, 5.8% and 11.15% on dataset BaCelLoc plant, dataset BaCelLoc fungi and dataset BaCelLoc animal respectively. For BaCelLoc independent sets, GO-TLM achieves 81.25%, 80.45% and 79.46% on dataset BaCelLoc plant holdout, dataset BaCelLoc plant holdout and dataset BaCelLoc animal holdout, respectively, as compared against baseline model MultiLoc-GO 76%, 60.00% and 73.00%, with accuracy increase 5.25%, 20.45% and 6.46%, respectively.Conclusions...

Pathogen-host protein-protein interaction (PPI) plays an important role in revealing the underlying pathogenesis of viruses and bacteria. The need of rapidly mapping proteome-wide pathogen-host interactome opens avenues for and imposes burdens on computational modeling. For Salmonella typhimurium, only 62 interactions with human proteins are reported to date, and the computational modeling based on such a small training data is prone to yield model overfitting. In this work, we propose a multi-instance transfer learning method to reconstruct the proteome-wide Salmonella-human PPI networks, wherein the training data is augmented by homolog knowledge transfer in the form of independent homolog instances. We use AdaBoost instance reweighting to counteract the noise from homolog instances, and deliberately design three experimental settings to validate the assumption that the homolog instances are effective to address the problems of data scarcity and data unavailability. The experimental results show that the proposed method outperforms the existing models and some predictions are validated by the findings from recent literature. Lastly, we conduct gene ontology based clustering analysis of the predicted networks to provide insights into the pathogenesis of Salmonella.