Building confidence in quantitative systems pharmacology models: An engineer's guide to exploring the rationale in model design and development

Abstract

This tutorial promotes good practice for exploring the rationale of systems pharmacology models. A safety systems engineering inspired notation approach provides much needed rigor and transparency in development and application of models for therapeutic discovery and design of intervention strategies. Structured arguments over a model's development, underpinning biological knowledge, and analyses of model behaviors are constructed to determine the confidence that a model is fit for the purpose for which it will be applied.

Figure 1

Description of the notation used in the creation of an argument. To show how these components are linked together, we present the description of each component within the format of an argument structure.

Figure 2

Top‐level argument in the process of arguing that the leishmaniasis simulation is fit for purpose. Black diamonds indicate the strategies in this figure are expanded upon below.

Figure 3

Arguing appropriateness of evidence used as a basis for the Leishmaniasis simulation in Ref. 11.

Figure 4

Argument that the biological abstractions introduced in the model are suitable. In this case, the approach is exemplified by focusing on abstractions of cell type to be included in the model.

Figure 5

Subset of the argument that supports the rationale for abstracting modeling abstractions.

Figure 6

Argument that the adopted modeling approach is adequate given the research context. In this case, the approach is exemplified by focusing on the choice of modeling paradigm: Petri net, agent‐based model, or ordinary differential equations.

Figure 7

Subset of the argumentation structure used to argue that the implementation of the model is adequate for meeting the purpose specified in Figure 2.

Figure 8

Subset of the argumentation structure for the design of the experimental analysis.