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Frank T. Bergmann

Publications and source records attributed to Frank T. Bergmann.

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Making Models That Matter: How to Build Trustworthy and Useful Systems Biology Models

Computational models supporting mechanistic understanding of (complex) biological systems, systems behaviour prediction, and experimental design are becoming more and more embedded in research on complex biological systems. Reuse and refinement of models, rather than continuous reinvention, is becoming increasingly important as models' demands on computational infrastructure increase. However published models - despite the variety of efforts taken so far - are frequently difficult to reproduce or reuse, substantially limiting their scientific value. Here we address the requirements for model reusability in the light of the field-specific CURE framework (Credible, Understandable, Reproducible, Extensible) and the more general FAIR principles (Findable, Accessible, Interoperable, Reusable). Considering published guidance we identify broad agreement on requirements for findability, accessibility, and interoperability, but continued lack of clarity and consensus around reusability. Focusing on the scientific quality and usability of computational models we discuss six key practices underpinning model sharing and re-use. Mapping the FAIR and CURE principles onto the model lifecycle we propose ten recommendations for building and sharing systems biology models that are both FAIR- and CURE-compliant.

q-bio.OT

EFECT: A Method to Quantify the Reproducibility of Stochastic Simulations

Reproducibility is a fundamental requirement for validating scientific claims in computational research. Stochastic computational models are widely used in fields such as systems biology, financial modeling and environmental sciences. However, achieving reproducibility in stochastic simulations remains challenging, as each run can produce different outcomes. Existing infrastructure and software tools do not address independent reproduction of simulation results. Without independent reproducibility, results and conclusions lack credibility, as it remains unclear whether observed findings reflect model behavior or are artifacts of stochastic variation or an underpowered study. To bridge this gap, we introduce the Empirical Characteristic Function Equality Convergence Test (EFECT), a data-driven method to quantify the reproducibility of stochastic simulation results. EFECT employs empirical characteristic functions to compare reported results with those independently generated by assessing distributional inequality, termed EFECT error. Additionally, we establish the EFECT convergence point, a quantitative metric for determining the required number of simulation runs to achieve an EFECT error value of a priori significance. EFECT is applicable to all bounded, real-valued outputs, regardless of the model type or simulation method that produced them. We tested EFECT with over 40 use cases to demonstrate its broad applicability and effectiveness. EFECT standardizes stochastic simulation reproducibility, establishing a workflow that guarantees reliable results, supporting a wide range of stakeholders, and thereby enhancing validation of stochastic simulation studies, across a model's lifecycle. To promote standardization, we are developing the open-source software library libSSR in multiple programming languages for easy integration of EFECT.

stat.ME

BioSimulators: a central registry of simulation engines and services for recommending specific tools

Computational models have great potential to accelerate bioscience, bioengineering, and medicine. However, it remains challenging to reproduce and reuse simulations, in part, because the numerous formats and methods for simulating various subsystems and scales remain siloed by different software tools. For example, each tool must be executed through a distinct interface. To help investigators find and use simulation tools, we developed BioSimulators (https://biosimulators.org), a central registry of the capabilities of simulation tools and consistent Python, command-line, and containerized interfaces to each version of each tool. The foundation of BioSimulators is standards, such as CellML, SBML, SED-ML, and the COMBINE archive format, and validation tools for simulation projects and simulation tools that ensure these standards are used consistently. To help modelers find tools for particular projects, we have also used the registry to develop recommendation services. We anticipate that BioSimulators will help modelers exchange, reproduce, and combine simulations.

q-bio.QM

SED-ML Validator: tool for debugging simulation experiments

Summary: More sophisticated models are needed to address problems in bioscience, synthetic biology, and precision medicine. To help facilitate the collaboration needed for such models, the community developed the Simulation Experiment Description Markup Language (SED-ML), a common format for describing simulations. However, the utility of SED-ML has been hampered by limited support for SED-ML among modeling software tools and by different interpretations of SED-ML among the tools that support the format. To help modelers debug their simulations and to push the community to use SED-ML consistently, we developed a tool for validating SED-ML files. We have used the validator to correct the official SED-ML example files. We plan to use the validator to correct the files in the BioModels database so that they can be simulated. We anticipate that the validator will be a valuable tool for developing more predictive simulations and that the validator will help increase the adoption and interoperability of SED-ML. Availability: The validator is freely available as a webform, HTTP API, command-line program, and Python package at https://run.biosimulations.org/utils/validate and https://pypi.org/project/biosimulators-utils. The validator is also embedded into interfaces to 11 simulation tools. The source code is openly available as described in the Supplementary data. Contact: karr@mssm.edu

q-bio.QM

PEtab -- interoperable specification of parameter estimation problems in systems biology

Reproducibility and reusability of the results of data-based modeling studies are essential. Yet, there has been -- so far -- no broadly supported format for the specification of parameter estimation problems in systems biology. Here, we introduce PEtab, a format which facilitates the specification of parameter estimation problems using Systems Biology Markup Language (SBML) models and a set of tab-separated value files describing the observation model and experimental data as well as parameters to be estimated. We already implemented PEtab support into eight well-established model simulation and parameter estimation toolboxes with hundreds of users in total. We provide a Python library for validation and modification of a PEtab problem and currently 20 example parameter estimation problems based on recent studies. Specifications of PEtab, the PEtab Python library, as well as links to examples, and all supporting software tools are available at https://github.com/PEtab-dev/PEtab, a snapshot is available at https://doi.org/10.5281/zenodo.3732958. All original content is available under permissive licenses.

q-bio.QM

Reducing local minima in fitness landscapes of parameter estimation by using piecewise evaluation and state estimation

Ordinary differential equations (ODE) are widely used for modeling in Systems Biology. As most commonly only some of the kinetic parameters are measurable or precisely known, parameter estimation techniques are applied to parametrize the model to experimental data. A main challenge for the parameter estimation is the complexity of the parameter space, especially its high dimensionality and local minima. Parameter estimation techniques consist of an objective function, measuring how well a certain parameter set describes the experimental data, and an optimization algorithm that optimizes this objective function. A lot of effort has been spent on developing highly sophisticated optimization algorithms to cope with the complexity in the parameter space, but surprisingly few articles address the influence of the objective function on the computational complexity in finding global optima. We extend a recently developed multiple shooting for stochastic systems (MSS) objective function for parameter estimation of stochastic models and apply it to parameter estimation of ODE models. This MSS objective function treats the intervals between measurement points separately. This separate treatment allows the ODE trajectory to stay closer to the data and we show that it reduces the complexity of the parameter space. We use examples from Systems Biology, namely a Lotka-Volterra model, a FitzHugh-Nagumo oscillator and a Calcium oscillation model, to demonstrate the power of the MSS approach for reducing the complexity and the number of local minima in the parameter space. The approach is fully implemented in the COPASI software package and, therefore, easily accessible for a wide community of researchers.

q-bio.QM

One file to share them all: Using the COMBINE Archive and the OMEX format to share all information about a modeling project

Background: With the ever increasing use of computational models in the biosciences, the need to share models and reproduce the results of published studies efficiently and easily is becoming more important. To this end, various standards have been proposed that can be used to describe models, simulations, data or other essential information in a consistent fashion. These constitute various separate components required to reproduce a given published scientific result. Results: We describe the Open Modeling EXchange format (OMEX). Together with the use of other standard formats from the Computational Modeling in Biology Network (COMBINE), OMEX is the basis of the COMBINE Archive, a single file that supports the exchange of all the information necessary for a modeling and simulation experiment in biology. An OMEX file is a ZIP container that includes a manifest file, listing the content of the archive, an optional metadata file adding information about the archive and its content, and the files describing the model. The content of a COMBINE Archive consists of files encoded in COMBINE standards whenever possible, but may include additional files defined by an Internet Media Type. Several tools that support the COMBINE Archive are available, either as independent libraries or embedded in modeling software. Conclusions: The COMBINE Archive facilitates the reproduction of modeling and simulation experiments in biology by embedding all the relevant information in one file. Having all the information stored and exchanged at once also helps in building activity logs and audit trails. We anticipate that the COMBINE Archive will become a significant help for modellers, as the domain moves to larger, more complex experiments such as multi-scale models of organs, digital organisms, and bioengineering.

cs.DL

TinkerCell: Modular CAD Tool for Synthetic Biology

Synthetic biology brings together concepts and techniques from engineering and biology. In this field, computer-aided design (CAD) is necessary in order to bridge the gap between computational modeling and biological data. An application named TinkerCell has been created in order to serve as a CAD tool for synthetic biology. TinkerCell is a visual modeling tool that supports a hierarchy of biological parts. Each part in this hierarchy consists of a set of attributes that define the part, such as sequence or rate constants. Models that are constructed using these parts can be analyzed using various C and Python programs that are hosted by TinkerCell via an extensive C and Python API. TinkerCell supports the notion of a module, which are networks with interfaces. Such modules can be connected to each other, forming larger modular networks. Because TinkerCell associates parameters and equations in a model with their respective part, parts can be loaded from databases along with their parameters and rate equations. The modular network design can be used to exchange modules as well as test the concept of modularity in biological systems. The flexible modeling framework along with the C and Python API allows TinkerCell to serve as a host to numerous third-party algorithms. TinkerCell is a free and open-source project under the Berkeley Software Distribution license. Downloads, documentation, and tutorials are available at www.tinkercell.com.

q-bio.MN

Athena: Modular CAM/CAD Software for Synthetic Biology

Synthetic biology is the engineering of cellular networks. It combines principles of engineering and the knowledge of biological networks to program the behavior of cells. Computational modeling techniques in conjunction with molecular biology techniques have been successful in constructing biological devices such as switches, oscillators, and gates. The ambition of synthetic biology is to construct complex systems from such fundamental devices, much in the same way electronic circuits are built from basic parts. As this ambition becomes a reality, engineering concepts such as interchangeable parts and encapsulation will find their way into biology. We realize that there is a need for computational tools that would support such engineering concepts in biology. As a solution, we have developed the software Athena that allows biological models to be constructed as modules. Modules can be connected to one another without altering the modules themselves. In addition, Athena houses various tools useful for designing synthetic networks including tools to perform simulations, automatically derive transcription rate expressions, and view and edit synthetic DNA sequences. New tools can be incorporated into Athena without modifying existing program via a plugin interface, IronPython scripts, Systems Biology Workbench interfacing and the R statistical language. The program is currently for Windows operating systems, and the source code for Athena is made freely available through CodePlex, www.codeplex.com/athena.

q-bio.QM

Enumeration and Online Library of Mass-Action Reaction Networks

The aim of this work is to make available to the community a large collection of mass-action reaction networks of a given size for further research. The set is limited to what can be computed on a modern multi-core desktop in reasonable time (< 20 days). We have currently generated over 47 million unique reaction networks. All currently generated sets of networks are available and as new sets are completed they will also be made available. Also provided are programs for translating them into different formats, along with documentation and examples. Source code and binaries for all the programs are included. These can be downloaded from (http://www.sys-bio.org/networkenumeration). This library of networks will allow for thorough studies of the reaction network space. Additionally, these methods serve as an example for future work on enumerating other types of biological networks, such as genetic regulatory networks and mass-action networks that include regulation.

q-bio.MN