Table 3.

Checklist of elements to consider as part of an expert review of results from expert rule-based

Expert 4review elements	Considerations
A. Alert score or qualitative output	The results from the alert system might include information related to the likelihood of a positive outcome (e.g., precision of the alert). The reliability of the prediction may be increased when such a score can be justified through an expert review of the information provided.
B. Justification of negative prediction	Additional considerations may be important where no alerts are identified in the test chemical. Such analysis may focus on similar analogs as well as other chemicals containing the different structural elements of the test chemical to verify there is no potential toxicity attributable to these fragments, such as additional reactive features. Such analysis may be used to evaluate the reliability of the negative prediction. If a negative prediction has a structure of concern, a further inspection of the rules may determine why the compound was not included to elucidate the underlying cause for firing no alert. Is the prediction really negative, equivocal, or not in of the applicability domain of the model?.
C. Reliability of the mechanism of toxicity	Although the presence of a structural alert increases the potential of the chemical to exert a toxicological effect or mechanism, this effect may depend on other features of the molecule. If a mechanism of toxicity is proposed for the structural alert, then an expert may assess the plausibility of the mechanism for the query compound. For example, the presence of other substituents in the molecule may impact the activity, potentially deactivating the alerting structure. This may include metabolism considerations.
D. Inspection of chemicals and experimental data matching the alert	The reliability of the prediction can be assessed by the quality of the experimental data of the reference set substances used to make the prediction (e.g., if a guideline study to generate these data). The structural diversity of the matching chemical may also be considered. For example, alerts that match diverse structures may increase the reliability over alerts where the matching chemicals are from a tight congeneric series. This is especially true when the reference set examples are structurally dissimilar from the query chemical. Review of the scientific literature to support the alert to understand the strengths and limitations of the experimental data supporting it.