A fully featured COMBINE archive of a simulation study on syncytial mitotic cycles in Drosophila embryos

Introduction

In systems biology and systems medicine, the steadily increasing size and complexity of simulation studies pose additional challenges to sharing reproducible results¹. Repeated mentions of problems with replication and reproducibility^2–4 led to new standards, tools, and methods for the transfer of reproducible simulation studies^5–9. Several projects and initiatives already deal with reproducibility issues, such as COMBINE (co.mbine.org), FAIRDOM (fair-dom.org), and the Reproducibility Initiative (reproducibilityinitiative.org).

The Computational Modeling in Biology Network (COMBINE) coordinates the development of standard formats for various aspects of a simulation study: The Systems Biology Markup Language (SBML)¹⁰ and CellML¹¹ encode the mathematical models; the Systems Biology Graphical Notation (SBGN)¹² encodes the visual representation of models; the Simulation Experiment Description Markup Language (SED-ML)¹³ encodes the simulation recipes; and the Systems Biology Result Markup Language (SBRML)¹⁴ encodes numerical data and simulation results.

Today’s studies consist of multiple, heterogeneous, and sometimes distributed data files, leading to the challenge of exchanging complete and thus reproducible results. To close this gap, the COMBINE community developed the COMBINE archive⁸. A COMBINE archive is a single file that aggregates all data files and information necessary to reproduce a simulation study in computational biology. The skeleton of a COMBINE archive consists of a manifest and a metadata file, specified by the Open Modeling EXchange format (OMEX).

Here we describe a fully featured COMBINE archive, which encodes an investigation of the syncytial mitotic cycles in Drosophila embryos¹⁵. The study published by Calzone et al. proposes a dynamical model for the molecular events underlying rapid, synchronous, syncytial nuclear division cycles in Drosophila embryos. This particular study was chosen for several reasons. Firstly, the paper, the documentation, and the related data are openly accessible. Secondly, the model is available in two standard formats: The CellML encoding is available from the Physiome Model Repository¹⁶ at models.cellml.org/exposure/1a3f36d015121d5596565fe7d9afb332 and the SBML encoding is available from BioModels¹⁷ at www.ebi.ac.uk/biomodels-main/BIOMD0000000144. Thirdly, both model files are already curated, which increases the level of trust. Fourthly, the model describes a common biological system (cell cycle). Thus, the basic mechanisms of the encoded biology should be familiar to many researchers, reducing the effort of understanding the example.

This archive contains files that are openly available for download, as well as previously unpublished files that were generated using COMBINE-compliant software tools (see Section Materials and methods). When executed, it reproduces the original findings by Calzone et al.

Materials and methods

The fully featured COMBINE archive was created in three subsequent steps. Firstly, all available materials relating to the study were automatically retrieved from an online resource (initial archive). Secondly, the data files were organised into subdirectories, following the different aspects of a simulation study (documentation, model, experiment, result). Thirdly, missing files were manually retrieved from web resources or created using COMBINE-compliant software tools. The three steps are described in the following.

Extending the COMBINE archive

To make the encoded study reproducible, the COMBINE archive needs to be extended with additional files.

The article is typically the central object of a research study. For this study, the original publication by Calzone et al., together with available supplementary information, was retrieved from the homepage of the journal Molecular Systems Biology (msb.embopress.org/content/3/1/131). Using WebCAT, the files were uploaded to the documentation/directory of the archive. The automatically added metadata was adjusted to attribute the authors of the publication and to state when and where the files were downloaded. In the background, WebCAT encoded the metadata in RDF/XML and added it to the archive.

The model is not only available in CellML format, but also in SBML format. The SBML file was retrieved from BioModels (www.ebi.ac.uk/biomodels-main/download?mid=BIOMD0000000144, SBML Level 2 Version 1) and uploaded to the model/directory. Again, the metadata was corrected to attribute the original authors, curators, and contributors, as stated on the BioModels website (www.ebi.ac.uk/biomodels-main/BIOMD0000000144) and in the model document.

The simulation description is essential to run the experiment. It defines the simulation environment and the output of the in silico execution. As no simulation description was found in any of the open repositories, an initial version was created using the SED-ML Web Tools (SWT) Version 2.1 (bqfbergmann.dyndns.org/SED-ML_Web_Tools). SWT takes the model files and creates a default simulation description with standard settings. For this study, a default SED-ML file encodes instructions to generate 66 plots and a data table. Each plot describes the change of concentration in one species of the model. The data table contains all numerical values. Based on the default script, a second SED-ML file (Calzone2007-simulation-figure-1B.xml) was generated to reassemble Figure 1B of the original publication. Using WebCAT, both SED-ML scripts were added to the experiment/directory of the archive. The metadata for the new files was added.

Figure 1. Visualisation of the model.

This figure shows the SBGN-PD compliant reaction network, as encoded in the SBML model obtained from BioModels. The figure was generated and modified using SBGN-ED.

The simulation results reflect the behaviour of a model under certain conditions. The script defined in Calzone2007-simulation-figure-1B.xml was loaded into SWT and into the stand-alone software program COPASI Version 4.15 Build 95¹⁹. The plots generated by both tools show that the developed in silico experiment reproduces the results from the paper. Using WebCAT, the figures produced by SWT and COPASI were uploaded and added to the result/ directory of the archive. Metadata, such as the versions of the software tools, was added accordingly.

The visualisation of a model helps to understand the encoded biological system. For this study, an SBGN-compliant visualisation of the model was created using SBGN-ED Version 1.5.1²⁰ together with VANTED Version 2.1.0²¹. SBGN-ED generated an automatic layout of the uploaded SBML model, which was then improved manually. The resulting Figure 1 was exported in different formats (GraphML²², GML (www.fim.uni-passau.de/index.php?id=17297&L=1), PNG image, PDF, and SBGN-ML²³). Using WebCAT the files were uploaded to the model/sbgn directory and metadata was provided.

Data description

The archive consists of 21 files (Table 1). Among these files are the manifest.xml and the metadata.rdf, which form the skeleton of the archive. The manifest lists the files included in the archive. The metadata file contains additional information about the files in the archive, such as creators and descriptions. A third file, README.md, contains a description for visitors of the GitHub repository, where the archive is being developed (github.com/SemsProject/CombineArchiveShowCase). The remaining 18 files are organised in four directories, cmp. Section Organising the COMBINE archive. The original publication (PDF) is stored in the documentation/ directory. The encodings of the model (CellML, SBML, graph formats) are stored in the model/ directory. The simulation descriptions (SED-ML) are stored in the experiment/ directory. The simulation results (SVG, PNG) are stored in the result/ directory.

The latest version of the compiled COMBINE archive can be accessed through our web server at scripts.sems.uni-rostock.de/getshowcase.php.

Data validation

The COMBINE archive described in this data note reproduces the results of the study published by Calzone et al. To validate the reproducibility, we executed the archive in different simulation tools. For example, the encoded simulation study can be executed in COPASI, cmp. Figure 2(b). The archive can also be loaded to the SWT by opening a specific URL (bqfbergmann.dyndns.org/SED-ML_Web_Tools/Home/SimulateUrl?url=http://scripts.sems.uni-rostock.de/getshowcase.php). The simulation results will immediately be shown in the web browser, cmp. Figure 2(c). Moreover, users reported a successful reproduction of the simulation results using Tellurium²⁴ (github.com/SemsProject/CombineArchiveShowCase/pull/2).

Figure 2. Comparison of simulation results.

The figure shows the simulation results included in the original publication (2(a)). Furthermore, the results generated by COPASI (2(b)) and the SWT (2(c)), using the SED-ML script Calzone2007-simulation-figure-1B.xml, are shown.

Conclusions

The presented COMBINE archive provides a reproducible simulation study for a previously published model on syncytial mitotic cycles in Drosophila embryos¹⁵. The archive contains several files that were collected from online resources, e. g. the CellML model from the Physiome Model Repository or the scientific publication from the publisher’s website. It also provides new files that did not exist previously, e. g. a SED-ML file to encode the simulation setup for Figure 1B of the original publication.

This fully featured archive allows scientists to reproduce the results obtained by Calzone et al. in software tools that can read COMBINE archives. For example, the archive was successfully executed in the SED-ML Web Tools and Tellurium. Figure 2 shows that the developed study is able to reproduce the original results.

This data note describes the fully featured COMBINE Archive as published on Figshare²⁵. However, we expect the archive to evolve further. The latest version of the archive is available from GitHub at github.com/SemsProject/CombineArchiveShowCase. It can also be downloaded from our website at scripts.sems.uni-rostock.de/getshowcase.php. Extensions, refinements, and comments are very welcome. Please fork the project on GitHub and contribute pull requests.

Data availability

The latest version of the COMBINE archive: github.com/SemsProject/CombineArchiveShowCase/ (latest commit at the time of submission: a469197)

The fully featured COMBINE archive as at the time of publication: Figshare: COMBINE Archive Show Case, 10.6084/m9.figshare.3427271.v1²⁴