There is evidence that schizophrenia is characterized by activation of the immune-inflammatory response (IRS) and compensatory immune-regulatory systems (CIRS) and lowered neuroprotection. Studies performed on antipsychotic-naïve first episode psychosis (AN-FEP) and schizophrenia (FES) patients are important as they may disclose the pathogenesis of FES. However, the protein–protein interaction (PPI) network of FEP/FES is not established. The aim of the current study was to delineate a) the characteristics of the PPI network of AN-FEP and its transition to FES; and b) the biological functions, pathways, and molecular patterns, which are over-represented in FEP/FES. Toward this end, we used PPI network, enrichment, and annotation analyses. FEP and FEP/FES are strongly associated with a response to a bacterium, alterations in Toll-Like Receptor-4 and nuclear factor-κB signaling, and the Janus kinases/signal transducer and activator of the transcription proteins pathway. Specific molecular complexes of the peripheral immune response are associated with microglial activation, neuroinflammation, and gliogenesis. FEP/FES is accompanied by lowered protection against inflammation, in part attributable to dysfunctional miRNA maturation, deficits in neurotrophin and Wnt/catenin signaling, and adherens junction organization. Multiple interactions between reduced brain derived neurotrophic factor, E-cadherin, and β-catenin and disrupted schizophrenia-1 (DISC1) expression increase the vulnerability to the neurotoxic effects of immune molecules, including cytokines and complement factors. In summary: FEP and FES are systemic neuro-immune disorders that are probably triggered by a bacterial stimulus which induces neuro-immune toxicity cascades that are overexpressed in people with reduced anti-inflammatory and miRNA protections, cell–cell junction organization, and neurotrophin and Wnt/catenin signaling.

Categorizing human diseases provides higher efficiency and accuracy for disease diagnosis, prognosis, and treatment. Disease-disease association (DDA) is a precious information that indicates the large-scale structure of complex relationships of diseases. However, the number of known and reliable associations is very small. Therefore, identification of DDAs is a challenging task in systems biology and medicine. Here, we developed a novel network-based scoring algorithm called DDA to identify the relationships between diseases in a large-scale study. Our method is developed based on a random walk prioritization in a protein-protein interaction network. This approach considers not only whether two diseases directly share associated genes but also the statistical relationships between two different diseases using known disease-related genes. Predicted associations were validated by known DDAs from a database and literature supports. The method yielded a good performance with an area under the curve of 71% and outperformed other standard association indices. Furthermore, novel DDAs and relationships among diseases from the clusters analysis were reported. This method is efficient to identify disease-disease relationships on an interaction network and can also be generalized to other association studies to further enhance knowledge in medical studies.

Disease-related gene prioritization is one of the most well-established pharmaceutical techniques used to identify genes that are important to a biological process relevant to a disease. In identifying these essential genes, the network diffusion (ND) approach is a widely used technique applied in gene prioritization. However, there is still a large number of candidate genes that need to be evaluated experimentally. Therefore, it would be of great value to develop a new strategy to improve the precision of the prioritization. Given the efficiency and simplicity of centrality measures in capturing a gene that might be important to the network structure, herein, we propose a technique that extends the scope of ND through a centrality measure to identify new disease-related genes. Five common centrality measures with different aspects were examined for integration in the traditional ND model. A total of 40 diseases were used to test our developed approach and to find new genes that might be related to a disease. Results indicated that the best measure to combine with the diffusion is closeness centrality. The novel candidate genes identified by the model for all 40 diseases were provided along with supporting evidence. In conclusion, the integration of network centrality in ND is a simple but effective technique to discover more precise disease-related genes, which is extremely useful for biomedical science.

Characterizing the activating and inhibiting effect of protein-protein interactions (PPI) is fundamental to gain insight into the complex signaling system of a human cell. A plethora of methods has been suggested to infer PPI from data on a large scale, but none of them is able to characterize the effect of this interaction. Here, we present a novel computational development that employs mitotic phenotypes of a genome-wide RNAi knockdown screen and enables identifying the activating and inhibiting effects of PPIs. Exemplarily, we applied our technique to a knockdown screen of HeLa cells cultivated at standard conditions. Using a machine learning approach, we obtained high accuracy (82% AUC of the receiver operating characteristics) by cross-validation using 6,870 known activating and inhibiting PPIs as gold standard. We predicted de novo unknown activating and inhibiting effects for 1,954 PPIs in HeLa cells covering the ten major signaling pathways of the Kyoto Encyclopedia of Genes and Genomes, and made these predictions publicly available in a database. We finally demonstrate that the predicted effects can be used to cluster knockdown genes of similar biological processes in coherent subgroups. The characterization of the activating or inhibiting effect of individual PPIs opens up new perspectives for the interpretation of large datasets of PPIs and thus considerably increases the value of PPIs as an integrated resource for studying the detailed function of signaling pathways of the cellular system of interest. Mathematical models which aim to describe cellular signaling start from constructing an interaction network of effectors, mediators and their effected target proteins. Several developments came up making it easier to put these links together. Besides tediously assembling knowledge from textbooks and research articles, experimental high-throughput methods were established like Yeast-2-Hybrid assays or Fluorescence Emission Resonance Transfer. However, these methods do not elucidate the effect of such interactions. We aimed inferring if an interaction in a specific cellular context is rather activating or inhibiting. We used cellular phenotypes of a genome-wide RNAi knockdown screen of live cells to identify such activating and inhibiting effects of protein interactions. The rationale behind it is that activating protein interactions should lead to similar phenotypes when their respective genes are knocked down, whereas an inhibiting protein interaction should lead to dissimilar phenotypes. Exemplarily, we applied our method to a phenotype screen of perturbed HeLa cells. Our predictions effectively reproduced textbook relationships between proteins or domains when comparing the predicted effects with pairs of effectors, receptors, kinases, phosphatases and of general signalling modules. The presented computational approach is generic and may enable elucidating the effects of studied interactions also of other cellular systems under more specific conditions.

Protein-protein interactions integrated with disease-gene associations represent important information for revealing protein functions under disease conditions to improve the prevention, diagnosis, and treatment of complex diseases. Although several studies have attempted to identify disease-gene associations, the number of possible disease-gene associations is very small. High-throughput technologies have been established experimentally to identify the association between genes and diseases. However, these techniques are still quite expensive, time consuming, and even difficult to perform. Thus, based on currently available data and knowledge, computational methods have served as alternatives to provide more possible associations to increase our understanding of disease mechanisms. Here, a new network-based algorithm, namely, Disease-Gene Association (DGA), was developed to calculate the association score of a query gene to a new possible set of diseases. First, a large-scale protein interaction network was constructed, and the relationship between two interacting proteins was calculated with regard to the disease relationship. Novel plausible disease-gene pairs were identified and statistically scored by our algorithm using neighboring protein information. The results yielded high performance for disease-gene prediction, with an F-measure of 0.78 and an AUC of 0.86. To identify promising candidates of disease-gene associations, the association coverage of genes and diseases were calculated and used with the association score to perform gene and disease selection. Based on gene selection, we identified promising pairs that exhibited evidence related to several important diseases, e.g., inflammation, lipid metabolism, inborn errors, xanthomatosis, cerebellar ataxia, cognitive deterioration, malignant neoplasms of the skin and malignant tumors of the cervix. Focusing on disease selection, we identified target genes that were important to blistering skin diseases and muscular dystrophy. In summary, our developed algorithm is simple, efficiently identifies disease–gene associations in the protein-protein interaction network and provides additional knowledge regarding disease-gene associations. This method can be generalized to other association studies to further advance biomedical science.

Drug repositioning, discovering new indications for existing drugs, is known to solve the bottleneck of drug discovery and development. To support a task of drug repositioning, many in silico methods have been proposed for predicting drug-disease associations. A meta-path based approach, which extracts network-based information through paths from a drug to a disease, can produce comparable performance with less required information when compared to other approaches. However, existing meta-path based methods typically use counts of extracted paths and discard information of intermediate nodes in those paths although they are very important indicators, such as drug- and disease-associated proteins. Herein, we propose an ensemble learning method with Meta-path based Gene ontology Profiles for predicting Drug-Disease Associations (MGP-DDA). We exploit gene ontology (GO) terms to link drugs and diseases to their associated functions and act as intermediate nodes in a drug-GO-disease tripartite network. For each drug-disease pair, MGP-DDA utilizes meta-paths to generate novel profiles of GO functions, termed as meta-path based GO profiles. We train bagging and boosting classifiers with those novel features to recognize known (positive) from unknown (unlabeled) drug-disease associations. Consequently, MGP-DDA outperforms the state-of-the-art methods and yields the precision of 88.6%. By MGP-DDA, the eminent number of new drug-disease associations with supporting evidence in ClinicalTrials.gov (37.7%) ensures the practicality of our method in drug repositioning.