Marinka Zitnik

Fusing bits and DNA

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PSB 2018: Large-Scale Analysis of Disease Pathways in the Human Interactome

Our paper on large-scale analysis of disease pathways in the human interactome will appear at Pacific Symposium on Biocomputing.

Discovering disease pathways, which can be defined as sets of proteins associated with a given disease, is an important problem that has the potential to provide clinically actionable insights for disease diagnosis, prognosis, and treatment. Computational methods aid the discovery by relying on protein-protein interaction (PPI) networks. They start with a few known disease-associated proteins and aim to find the rest of the pathway by exploring the PPI network around the known disease proteins.

However, the success of such methods has been limited, and failure cases have not been well understood. In the paper we study the PPI network structure of disease pathways. We find that pathways do not correspond to single well-connected components in the PPI network. These results counter one of the most frequently used assumptions in network medicine, which posits that disease pathways are likely to correspond to highly interconnected groups of proteins. Instead, we show that proteins associated with a single disease tend to form many separate connected components/regions in the network.

Furthermore, we show that state-of-the-art disease pathway discovery methods perform especially poorly on diseases with disconnected pathways. These results suggest that integration of disconnected regions of disease proteins into a broader disease pathway will be crucial for a holistic understanding of disease mechanisms.

In addition to new insights into the PPI network connectivity of disease proteins, our analysis leads to important implications for future disease protein discovery that can be summarized as:

  • We move away from modeling disease pathways as highly interlinked regions in the PPI network to modeling them as loosely interlinked and multi-regional objects with two or more regions distributed throughout the PPI network.
  • Higher-order connectivity structure provides a promising direction for disease pathway discovery.

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