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Exploring novel mechanistic insights in Alzheimer's disease by assessing reliability of protein interactions.

ABSTRACT: Protein interaction networks are widely used in computational biology as a graphical means of representing higher-level systemic functions in a computable form. Although, many algorithms exist that seamlessly collect and measure protein interaction information in network models, they often do not provide novel mechanistic insights using quantitative criteria. Measuring information content and knowledge representation in network models about disease mechanisms becomes crucial particularly when exploring new target candidates in a well-defined functional context of a potential disease mechanism. To this end, we have developed a knowledge-based scoring approach that uses literature-derived protein interaction features to quantify protein interaction confidence. Thereby, we introduce the novel concept of knowledge cliffs, regions of the interaction network where a significant gap between high scoring and low scoring interactions is observed, representing a divide between established and emerging knowledge on disease mechanism. To show the application of this approach, we constructed and assessed reliability of a protein-protein interaction model specific to Alzheimer's disease, which led to screening, and prioritization of four novel protein candidates. Evaluation of the identified candidates showed that two of them are already followed in clinical trials for testing potential AD drugs.

SUBMITTER: Malhotra A

PROVIDER: S-EPMC4562155 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Exploring novel mechanistic insights in Alzheimer's disease by assessing reliability of protein interactions.

Malhotra Ashutosh A Younesi Erfan E Sahadevan Sudeep S Zimmermann Joerg J Hofmann-Apitius Martin M

Scientific reports 20150908

Protein interaction networks are widely used in computational biology as a graphical means of representing higher-level systemic functions in a computable form. Although, many algorithms exist that seamlessly collect and measure protein interaction information in network models, they often do not provide novel mechanistic insights using quantitative criteria. Measuring information content and knowledge representation in network models about disease mechanisms becomes crucial particularly when ex ...[more]

PMID: 26346705

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Project description:BackgroundProtein-protein interactions play vital roles in nearly all cellular processes and are involved in the construction of biological pathways such as metabolic and signal transduction pathways. Although large-scale experiments have enabled the discovery of thousands of previously unknown linkages among proteins in many organisms, the high-throughput interaction data is often associated with high error rates. Since protein interaction networks have been utilized in numerous biological inferences, the inclusive experimental errors inevitably affect the quality of such prediction. Thus, it is essential to assess the quality of the protein interaction data.ResultsIn this paper, a novel Bayesian network-based integrative framework is proposed to assess the reliability of protein-protein interactions. We develop a cross-species in silico model that assigns likelihood scores to individual protein pairs based on the information entirely extracted from model organisms. Our proposed approach integrates multiple microarray datasets and novel features derived from gene ontology. Furthermore, the confidence scores for cross-species protein mappings are explicitly incorporated into our model. Applying our model to predict protein interactions in the human genome, we are able to achieve 80% in sensitivity and 70% in specificity. Finally, we assess the overall quality of the experimentally determined yeast protein-protein interaction dataset. We observe that the more high-throughput experiments confirming an interaction, the higher the likelihood score, which confirms the effectiveness of our approach.ConclusionThis study demonstrates that model organisms certainly provide important information for protein-protein interaction inference and assessment. The proposed method is able to assess not only the overall quality of an interaction dataset, but also the quality of individual protein-protein interactions. We expect the method to continually improve as more high quality interaction data from more model organisms becomes available and is readily scalable to a genome-wide application.

Dataset Information

Exploring novel mechanistic insights in Alzheimer's disease by assessing reliability of protein interactions.

Publications

Exploring novel mechanistic insights in Alzheimer's disease by assessing reliability of protein interactions.

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