Exploring the evolution of biochemical models at the network level.

The evolution of biochemical models is difficult to track. At present, it is not possible to inspect the differences between model versions at the network level. Biochemical models are often constructed in a distributed, non-linear process: collaborators create model versions on different branches from novel information, model extensions, during curation and adaption. To discuss and align the versions, it is helpful to abstract the changes to the network level. The differences between two model versions can be detected by the software tool BiVeS. However, it cannot show the structural changes resulting from the differences. Here, we present a method to visualise the differences between model versions effectively. We developed a JSON schema to communicate the differences at the network level and extended BiVeS accordingly. Additionally, we developed DiVil, a web-based tool to represent the model and the differences as a standardised network using D3. It combines an automatic layout with an interactive user interface to improve the visualisation and to inspect the model. The network can be exported in standardised formats as images or markup language. Our method communicates the structural differences between model versions. It facilitates the discussion of changes and thus supports the collaborative and non-linear nature of model development. Availability and implementation: DiVil prototype: https://divil.bio.informatik.uni-rostock.de, Code on GitHub: https://github.com/Gebbi8/DiVil, licensed under Apache License 2.0. Contact: url="tom.gebhardt@uni-rostock.de.

Computational Models for Clinical Applications in Personalized Medicine-Guidelines and Recommendations for Data Integration and Model Validation.

The future development of personalized medicine depends on a vast exchange of data from different sources, as well as harmonized integrative analysis of large-scale clinical health and sample data. Computational-modelling approaches play a key role in the analysis of the underlying molecular processes and pathways that characterize human biology, but they also lead to a more profound understanding of the mechanisms and factors that drive diseases; hence, they allow personalized treatment strategies that are guided by central clinical questions. However, despite the growing popularity of computational-modelling approaches in different stakeholder communities, there are still many hurdles to overcome for their clinical routine implementation in the future. Especially the integration of heterogeneous data from multiple sources and types are challenging tasks that require clear guidelines that also have to comply with high ethical and legal standards. Here, we discuss the most relevant computational models for personalized medicine in detail that can be considered as best-practice guidelines for application in clinical care. We define specific challenges and provide applicable guidelines and recommendations for study design, data acquisition, and operation as well as for model validation and clinical translation and other research areas.

Evolution of computational models in BioModels Database and the Physiome Model Repository.

BACKGROUND: A useful model is one that is being (re)used. The development of a successful model does not finish with its publication. During reuse, models are being modified, i.e. expanded, corrected, and refined. Even small changes in the encoding of a model can, however, significantly affect its interpretation. Our motivation for the present study is to identify changes in models and make them transparent and traceable. METHODS: We analysed 13734 models from BioModels Database and the Physiome Model Repository. For each model, we studied the frequencies and types of updates between its first and latest release. To demonstrate the impact of changes, we explored the history of a Repressilator model in BioModels Database. RESULTS: We observed continuous updates in the majority of models. Surprisingly, even the early models are still being modified. We furthermore detected that many updates target annotations, which improves the information one can gain from models. To support the analysis of changes in model repositories we developed MoSt, an online tool for visualisations of changes in models. The scripts used to generate the data and figures for this study are available from GitHub https://github.com/binfalse/BiVeS-StatsGenerator and as a Docker image at https://hub.docker.com/r/binfalse/bives-statsgenerator/ . The website https://most.bio.informatik.uni-rostock.de/ provides interactive access to model versions and their evolutionary statistics. CONCLUSION: The reuse of models is still impeded by a lack of trust and documentation. A detailed and transparent documentation of all aspects of the model, including its provenance, will improve this situation. Knowledge about a model's provenance can avoid the repetition of mistakes that others already faced. More insights are gained into how the system evolves from initial findings to a profound understanding. We argue that it is the responsibility of the maintainers of model repositories to offer transparent model provenance to their users.

Unveiling network-based functional features through integration of gene expression into protein networks.

Decoding health and disease phenotypes is one of the fundamental objectives in biomedicine. Whereas high-throughput omics approaches are available, it is evident that any single omics approach might not be adequate to capture the complexity of phenotypes. Therefore, integrated multi-omics approaches have been used to unravel genotype-phenotype relationships such as global regulatory mechanisms and complex metabolic networks in different eukaryotic organisms. Some of the progress and challenges associated with integrated omics studies have been reviewed previously in comprehensive studies. In this work, we highlight and review the progress, challenges and advantages associated with emerging approaches, integrating gene expression and protein-protein interaction networks to unravel network-based functional features. This includes identifying disease related genes, gene prioritization, clustering protein interactions, developing the modules, extract active subnetworks and static protein complexes or dynamic/temporal protein complexes. We also discuss how these approaches contribute to our understanding of the biology of complex traits and diseases. This article is part of a Special Issue entitled: Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.