Using argument notation to engineer biological simulations with increased confidence

The application of computational and mathematical modelling to explore the mechanics of biological systems is becoming prevalent. To significantly impact biological research, notably in developing novel therapeutics, it is critical that the model adequately represents the captured system. Confidence in adopting in silico approaches can be improved by applying a structured argumentation approach, alongside model development and results analysis. We propose an approach based on argumentation from safety-critical systems engineering, where a system is subjected to a stringent analysis of compliance against identified criteria. We show its use in examining the biological information upon which a model is based, identifying model strengths, highlighting areas requiring additional biological experimentation and providing documentation to support model publication. We demonstrate our use of structured argumentation in the development of a model of lymphoid tissue formation, specifically Peyer's Patches. The argumentation structure is captured using Artoo (www.york.ac.uk/ycil/software/artoo), our Web-based tool for constructing fitness-for-purpose arguments, using a notation based on the safety-critical goal structuring notation. We show how argumentation helps in making the design and structured analysis of a model transparent, capturing the reasoning behind the inclusion or exclusion of each biological feature and recording assumptions, as well as pointing to evidence supporting model-derived conclusions

Systems analysis of auxin transport in the Arabidopsis root apex

Auxin is a key regulator of plant growth and development. Within the root tip, auxin distribution plays a crucial role specifying developmental zones and coordinating tropic responses. Determining how the organ-scale auxin pattern is regulated at the cellular scale is essential to understanding how these processes are controlled. In this study, we developed an auxin transport model based on actual root cell geometries and carrier subcellular localizations. We tested model predictions using the DII-VENUS auxin sensor in conjunction with state-of-the-art segmentation tools. Our study revealed that auxin efflux carriers alone cannot create the pattern of auxin distribution at the root tip and that AUX1/LAX influx carriers are also required. We observed that AUX1 in lateral root cap (LRC) and elongating epidermal cells greatly enhance auxin’s shootward flux, with this flux being predominantly through the LRC, entering the epidermal cells only as they enter the elongation zone. We conclude that the nonpolar AUX1/LAX influx carriers control which tissues have high auxin levels, whereas the polar PIN carriers control the direction of auxin transport within these tissues

Simulation validation: exploring the suitability of a simulation of cell division and differentiation in the prostate

Individual or agent-based simulation is an important tool for research involving understanding of complex systems. For a research tool to be useful, its use must be understood, and it must be possible to interpret the results of using the tool in the context of the research. This paper presents the partial validity argument for ongoing work on prostate cell simulation (a companion paper describes the models and implementation of the simulation). This is the basis for a discussion of issues in the validation of complex systems simulations used as scientific research tools

Reflections on the Simulation of Complex Systems for Science

In studying complex systems, agent-based simulations offer the possibility of directly modelling components in an environment. However, the scientific value of agent-based simulations has been limited by inadequate scientific rigour. The paper focuses on agent-based simulations that are used in biological and bio-medical research. Starting from a review of best practice in simulation engineering, the paper identifies some of the key activities in developing complex systems simulations that support scientific research, and how these contribute to the essential development of mutual trust among developers and scientists. Examples from the authors' own experience illustrate how a range of studies have manifested these key activities, and identifies some successes and problems encountered