RESUMO
The clinical burden of mental illness, in particular schizophrenia and bipolar disorder, are driven by frequent chronic courses and increased mortality, as well as the risk for comorbid conditions such as cardiovascular disease and type 2 diabetes. Evidence suggests an overlap of molecular pathways between psychotic disorders and somatic comorbidities. In this study, we developed a computational framework to perform comorbidity modeling via an improved integrative unsupervised machine learning approach based on multi-rank non-negative matrix factorization (mrNMF). Using this procedure, we extracted molecular signatures potentially explaining shared comorbidity mechanisms. For this, 27 case-control microarray transcriptomic datasets across multiple tissues were collected, covering three main categories of conditions including psychotic disorders, cardiovascular diseases and type II diabetes. We addressed the limitation of normal NMF for parameter selection by introducing multi-rank ensembled NMF to identify signatures under various hierarchical levels simultaneously. Analysis of comorbidity signature pairs was performed to identify several potential mechanisms involving activation of inflammatory response auxiliarily interconnecting angiogenesis, oxidative response and GABAergic neuro-action. Overall, we proposed a general cross-cohorts computing workflow for investigating the comorbid pattern across multiple symptoms, applied it to the real-data comorbidity study on schizophrenia, and further discussed the potential for future application of the approach.
RESUMO
The past decades have brought a steady growth of pathway databases and enrichment methods. However, the advent of pathway data has not been accompanied by an improvement in interoperability across databases, hampering the use of pathway knowledge from multiple databases for enrichment analysis. While integrative databases have attempted to address this issue, they often do not account for redundant information across resources. Furthermore, the majority of studies that employ pathway enrichment analysis still rely upon a single database or enrichment method, though the use of another could yield differing results. These shortcomings call for approaches that investigate the differences and agreements across databases and methods as their selection in the design of a pathway analysis can be a crucial step in ensuring the results of such an analysis are meaningful. Here we present DecoPath, a web application to assist in the interpretation of the results of pathway enrichment analysis. DecoPath provides an ecosystem to run enrichment analysis or directly upload results and facilitate the interpretation of results with custom visualizations that highlight the consensus and/or discrepancies at the pathway- and gene-levels. DecoPath is available at https://decopath.scai.fraunhofer.de, and its source code and documentation can be found on GitHub at https://github.com/DecoPath/DecoPath.
