Developing the Applicability Domain of In Silico Models: Relevance, Importance and Methods

Abstract

The past two decades has seen the rapid growth in the development and utilisation of computational technologies to predict the toxicity of chemicals. Most notably, widespread pressure to both reduce and replace current animal testing regimes has led to in silico modelling becoming a widely utilised tool in toxicological screening. Unfortunately, given that computational models are open to misuse, there has been, and still is, significant reluctance to accept them for regulatory use. In an effort to combat this, the validation of both model and predictions is now at the forefront of research, with the concept of applicability domain being central to the validation process. In this chapter the applicability domain concept is defined and numerous methods for its characterisation are detailed and explored with the aid of a case study example. These approaches are shown to span from relatively simple descriptor-based methods to more complex approaches based upon structural similarity or mechanism of action. Given the wealth of differing approaches available and the different information each method yields about the model, a stepwise scheme which considers numerous methods is recommended. With appreciation of model architecture and subsequent utilisation, this chapter shows that a robust and multifaceted applicability domain can be generated. Once defined, the applicability domain serves as a critical screening stage ensuring that a model is fit-for-purpose and predictions are made with maximal confidence.