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Integrating personalized gene expression profiles intopredictive disease-associated gene pools

Gene expression data are routinely used to identify genes that on average exhibit different expression levels between a case and a control group. Yet, very few of such differentially expressed genes are detectably perturbed in individual patients. Here, we develop a framework to construct personalized perturbation profiles for individual subjects, identifying the set of genes that are significantly perturbed in each individual. This allows us to characterize the heterogeneity of the molecular manifestations of complex diseases
by quantifying the expression-level similarities and differences among patients with the same phenotype. We show that despite the high heterogeneity of the individual perturbation profiles, patients with asthma, Parkinson and Huntington’s disease share a
broad pool of sporadically disease-associated genes, and that individuals with statistically significant overlap with this pool have a 80–100% chance of being diagnosed with the disease. The developed framework opens up the possibility to apply gene expression
data in the context of precision medicine, with important implications for biomarker identification, drug development, diagnosis and treatment.

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Network-based in silico drug efficacy screening

 

The increasing cost of drug development together with a significant drop in the number of
new drug approvals raises the need for innovative approaches for target identification
and efficacy prediction. Here, we take advantage of our increasing understanding of the
network-based origins of diseases to introduce a drug-disease proximity measure that
quantifies the interplay between drugs targets and diseases. By correcting for the known
biases of the interactome, proximity helps us uncover the therapeutic effect of drugs, as well as to distinguish palliative from effective treatments. Our analysis of 238 drugs used in 78 diseases indicates that the therapeutic effect of drugs is localized in a small network
neighborhood of the disease genes and highlights efficacy issues for drugs used in Parkinson and several inflammatory disorders. Finally, network-based proximity allows us to predict novel drug-disease associations that offer unprecedented opportunities for drug repurposing and the detection of adverse effects.

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Developing New Drug Treatments in the Era of Network Medicine

Although impressive advances have been made in determining the genetic and molecular
causes of disease, treatment for many complex diseases remains inadequate. Despite
compelling unmet medical needs and new insights into disease pathobiology, new drug
approvals for complex diseases have stagnated. A new paradigm for drug development is
needed, and key concepts from network medicine and systems pharmacology may be
essential to this effort.

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A DIseAse MOdule Detection (DIAMOnD) Algorithm Derived from a Systematic Analysis of Connectivity Patterns of Disease Proteins in the Human Interactome

The observation that disease associated proteins often interact with each other has fueled
the development of network-based approaches to elucidate the molecular mechanisms of
human disease. Such approaches build on the assumption that protein interaction networks
can be viewed as maps in which diseases can be identified with localized perturbation within a certain neighborhood. The identification of these neighborhoods, or disease modules, is therefore a prerequisite of a detailed investigation of a particular pathophenotype. While numerous heuristic methods exist that successfully pinpoint disease associated modules, the basic underlying connectivity patterns remain largely unexplored. In this work we aim to fill this gap by analyzing the network properties of a comprehensive corpus of 70 complex diseases. We find that disease associated proteins do not reside within locally dense communities and instead identify connectivity significance as the most predictive quantity. This quantity inspires the design of a novel Disease Module Detection (DIAMOnD) algorithm to identify the full disease module around a set of known disease proteins. We study the performance of the algorithm using well-controlled synthetic data and systematically validate the identified neighborhoods for a large corpus of diseases.

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Endophenotype Network Models: Common Core of Complex Diseases 

Historically, human diseases have been differentiated and categorized based on the organ system in which they primarily manifest. Recently, an alternative view is emerging that emphasizes that different diseases often have common underlying mechanisms and shared intermediate pathophenotypes, or endo(pheno)types. Within this framework, a specific disease’s expression is a consequence of the interplay between the relevant endophenotypes and their local, organ-based environment. Important examples of such endophenotypes are inflammation, fibrosis, and thrombosis and their essential roles in many developing diseases. In this study, we construct endophenotype network models and
explore their relation to different diseases in general and to cardiovascular diseases in particular. We identify the local neighborhoods (module) within the interconnected map of molecular components, i.e., the subnetworks of the human interactome that represent the inflammasome, thrombosome, and fibrosome. We find that these neighborhoods are highly overlapping and significantly enriched with disease-associated genes. In particular they are also enriched with differentially expressed genes linked to cardiovascular disease (risk). Finally, using proteomic data, we explore how macrophage activation contributes to our understanding of inflammatory processes and responses. The results of our analysis show that inflammatory responses initiate from within the cross-talk of the three identified endophenotypic modules.

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A Proteome-Scale Map of the Human Interactome Network

Just as reference genome sequences revolutionized human genetics, reference maps of interactome networks will be critical to fully understand genotype-phenotype relationships. Here, we describe a systematic map of 14,000 high-quality human binary protein-protein interactions. At equal quality, this map is 30% larger than what is available from small-scale studies published in the literature in the last few decades. While currently available information is highly biased and only covers a relatively small portion of the proteome, our systematic map appears strikingly more homogeneous, revealing a ‘‘broader’’ human interactome network than currently appreciated. The map also uncovers significant interconnectivity between known and candidate cancer gene products, providing unbiased evidence for an expanded functional cancer landscape, while demonstrating how high-quality interactome models will help ‘‘connect the dots’’ of the genomic revolution.