“2 out of 3” weight of evidenceSummary of defined approach
This method uses a weight of evidence approach by taking a majority of two congruent results of the first 3 key events (represented by the results of the DPRA, KeratinoSens™, and h-CLAT assays). This method returns a simple prediction of the compound being a sensitiser or non-sensitiser. Our implementation of this model performs an overall assessment using a 2 out of 3 majority voting approach, where if 2 out of the 3 assays are positive for a tested compound, then the substance is rated to be a skin sensitiser, and a substance is rated as a non-sensitiser if 2 out of the 3 tests are negative. The details of how each test is deemed positive or negative are described in the corresponding OECD guidelines for each of the 3 in vitro tests [1-3]. The accuracy of this model (based on the dataset of 213 compounds from the Bausch et al ) is 79% when compared to LLNA and 90% when compared to human data (see Table 1 below).
Table 1. Cooper statistics for the “2 out of 3” majority voting method compared to the LLNA or human reference data, respectively.
|Compared to LLNA data||Compared to human data|
|Positive predictive value||89%||96%|
|Negative predictive value||59%||79%|
Advantages of the “2 out of 3” weight of evidence approach include:
- This approach could be customised for users as it is flexible enough to allow for the inclusion of new assays as the need arises.
- Prediction can be made on any compound as long as the results of three in vitro assays are provided and the compound is within the applicability domain of the 3 assays.
- It offers quick prioritisation as it returns a simple sensitiser/non-sensitiser prediction.
- Prediction for a given compound is independent of the others (i.e. there is no training/fitting)
Experimental values used in SaferSkin™
|Input parameters||Provided by user||Calculated by application|
|DPRA assay: DPRACys, DPRALys|
|KeratinoSens™ assay: KEC1.5|
|h-CLAT: CD54 and CD86 (positive/negative)|
(1) OECD,Test No. 442C: In Chemico Skin Sensitisation: Direct Peptide Reactivity Assay (DPRA) 2015
(2) OECD,Test No. 442D: In Vitro Skin Sensitisation: ARE-Nrf2 Luciferase Test Method 2018
(3) OECD,Test. No. 442E: In Vitro Skin Sensitisation: In Vitro Skin Sensitisation assays addressing the Key Event on activation of dendritic cells on the Adverse Outcome Pathway for Skin Sensitisation 2018
(4) C. Bausch, S. N. Kolle, T. Ramirez, T. Eltze, E. Fabian, A. Mehling, W. Teubner, B. van Ravenzwaay and R. Landsiedel;Regul. Toxicol. Pharmacol. 2012