Engineering simulations for cancer systems biology

Computer simulation can be used to inform in vivo and in vitro experimentation, enabling rapid, low-cost hypothesis generation and directing experimental design in order to test those hypotheses. In this way, in silico models become a scientific instrument for investigation, and so should be developed to high standards, be carefully calibrated and their findings presented in such that they may be reproduced. Here, we outline a framework that supports developing simulations as scientific instruments, and we select cancer systems biology as an exemplar domain, with a particular focus on cellular signalling models. We consider the challenges of lack of data, incomplete knowledge and modelling in the context of a rapidly changing knowledge base. Our framework comprises a process to clearly separate scientific and engineering concerns in model and simulation development, and an argumentation approach to documenting models for rigorous way of recording assumptions and knowledge gaps. We propose interactive, dynamic visualisation tools to enable the biological community to interact with cellular signalling models directly for experimental design. There is a mismatch in scale between these cellular models and tissue structures that are affected by tumours, and bridging this gap requires substantial computational resource. We present concurrent programming as a technology to link scales without losing important details through model simplification. We discuss the value of combining this technology, interactive visualisation, argumentation and model separation to support development of multi-scale models that represent biologically plausible cells arranged in biologically plausible structures that model cell behaviour, interactions and response to therapeutic interventions

Supporting the automated generation of modular product line safety cases

Abstract The effective reuse of design assets in safety-critical Software Product Lines (SPL) would require the reuse of safety analyses of those assets in the variant contexts of certification of products derived from the SPL. This in turn requires the traceability of SPL variation across design, including variation in safety analysis and safety cases. In this paper, we propose a method and tool to support the automatic generation of modular SPL safety case architectures from the information provided by SPL feature modeling and model-based safety analysis. The Goal Structuring Notation (GSN) safety case modeling notation and its modular extensions supported by the D-Case Editor were used to implement the method in an automated tool support. The tool was used to generate a modular safety case for an automotive Hybrid Braking System SPL

Disruptive Innovations and Disruptive Assurance: Assuring Machine Learning and Autonomy

Autonomous and machine learning-based systems are disruptive innovations and thus require a corresponding disruptive assurance strategy. We offer an overview of a framework based on claims, arguments, and evidence aimed at addressing these systems and use it to identify specific gaps, challenges, and potential solutions

Validation of Ultrahigh Dependability for Software-Based Systems

Modern society depends on computers for a number of critical tasks in which failure can have very high costs. As a consequence, high levels of dependability (reliability, safety, etc.) are required from such computers, including their software. Whenever a quantitative approach to risk is adopted, these requirements must be stated in quantitative terms, and a rigorous demonstration of their being attained is necessary. For software used in the most critical roles, such demonstrations are not usually supplied. The fact is that the dependability requirements often lie near the limit of the current state of the art, or beyond, in terms not only of the ability to satisfy them, but also, and more often, of the ability to demonstrate that they are satisfied in the individual operational products (validation). We discuss reasons why such demonstrations cannot usually be provided with the means available: reliability growth models, testing with stable reliability, structural dependability modelling, as well as more informal arguments based on good engineering practice. We state some rigorous arguments about the limits of what can be validated with each of such means. Combining evidence from these different sources would seem to raise the levels that can be validated; yet this improvement is not such as to solve the problem. It appears that engineering practice must take into account the fact that no solution exists, at present, for the validation of ultra-high dependability in systems relying on complex software

Reasoning About the Reliability of Multi-version, Diverse Real-Time Systems

This paper is concerned with the development of reliable real-time systems for use in high integrity applications. It advocates the use of diverse replicated channels, but does not require the dependencies between the channels to be evaluated. Rather it develops and extends the approach of Little wood and Rush by (for general systems) by investigating a two channel system in which one channel, A, is produced to a high level of reliability (i.e. has a very low failure rate), while the other, B, employs various forms of static analysis to sustain an argument that it is perfect (i.e. it will never miss a deadline). The first channel is fully functional, the second contains a more restricted computational model and contains only the critical computations. Potential dependencies between the channels (and their verification) are evaluated in terms of aleatory and epistemic uncertainty. At the aleatory level the events ''A fails" and ''B is imperfect" are independent. Moreover, unlike the general case, independence at the epistemic level is also proposed for common forms of implementation and analysis for real-time systems and their temporal requirements (deadlines). As a result, a systematic approach is advocated that can be applied in a real engineering context to produce highly reliable real-time systems, and to support numerical claims about the level of reliability achieved