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  1. Abstract Motivation

    This article introduces Vivarium—software born of the idea that it should be as easy as possible for computational biologists to define any imaginable mechanistic model, combine it with existing models and execute them together as an integrated multiscale model. Integrative multiscale modeling confronts the complexity of biology by combining heterogeneous datasets and diverse modeling strategies into unified representations. These integrated models are then run to simulate how the hypothesized mechanisms operate as a whole. But building such models has been a labor-intensive process that requires many contributors, and they are still primarily developed on a case-by-case basis with each project starting anew. New software tools that streamline the integrative modeling effort and facilitate collaboration are therefore essential for future computational biologists.

    Results

    Vivarium is a software tool for building integrative multiscale models. It provides an interface that makes individual models into modules that can be wired together in large composite models, parallelized across multiple CPUs and run with Vivarium’s discrete-event simulation engine. Vivarium’s utility is demonstrated by building composite models that combine several modeling frameworks: agent-based models, ordinary differential equations, stochastic reaction systems, constraint-based models, solid-body physics and spatial diffusion. This demonstrates just the beginning of what is possible—Vivarium will be able to support future efforts that integrate many more types of models and at many more biological scales.

    Availability and implementation

    The specific models, simulation pipelines and notebooks developed for this article are all available at the vivarium-notebooks repository: https://github.com/vivarium-collective/vivarium-notebooks. Vivarium-core is available at https://github.com/vivarium-collective/vivarium-core, and has been released on Python Package Index. The Vivarium Collective (https://vivarium-collective.github.io) is a repository of freely available Vivarium processes and composites, including the processes used in Section 3. Supplementary Materials provide with an extensive methodology section, with several code listings that demonstrate the basic interfaces.

    Supplementary information

    Supplementary data are available at Bioinformatics online.

     
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  2. The extensive heterogeneity of biological data poses challenges to analysis and interpretation. Construction of a large-scale mechanistic model ofEscherichia colienabled us to integrate and cross-evaluate a massive, heterogeneous dataset based on measurements reported by various groups over decades. We identified inconsistencies with functional consequences across the data, including that the total output of the ribosomes and RNA polymerases described by data are not sufficient for a cell to reproduce measured doubling times, that measured metabolic parameters are neither fully compatible with each other nor with overall growth, and that essential proteins are absent during the cell cycle—and the cell is robust to this absence. Finally, considering these data as a whole leads to successful predictions of new experimental outcomes, in this case protein half-lives.

     
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