Dataset Information

Repeat-dose toxicity prediction with Generalized Read-Across (GenRA) using targeted transcriptomic data: A proof-of-concept case study.

ABSTRACT: Read-across is a data gap filling technique utilized to predict the toxicity of a target chemical using data from similar analogues. Recent efforts such as Generalized Read-Across (GenRA) facilitate automated read-across predictions for untested chemicals. GenRA makes predictions of toxicity outcomes based on "neighboring" chemicals characterized by chemical and bioactivity fingerprints. Here we investigated the impact of biological similarities on neighborhood formation and read-across performance in predicting hazard (based on repeat-dose testing outcomes from US EPA ToxRefDB v2.0). We used targeted transcriptomic data on 93 genes for 1060 chemicals in HepaRG^™ cells that measure nuclear receptor activation, xenobiotic metabolism, cellular stress, cell cycle progression, and apoptosis. Transcriptomic similarity between chemicals was calculated using binary hit-calls from concentration-response data for each gene. We evaluated GenRA performance in predicting ToxRefDB v2.0 hazard outcomes using the area under the Receiver Operating Characteristic (ROC) curve (AUC) for the baseline approach (chemical fingerprints) versus transcriptomic fingerprints and a combination of both (hybrid). For all endpoints, there were significant but only modest improvements in ROC AUC scores of 0.01 (2.1%) and 0.04 (7.3%) with transcriptomic and hybrid descriptors, respectively. However, for liver-specific toxicity endpoints, ROC AUC scores improved by 10% and 17% for transcriptomic and hybrid descriptors, respectively. Our findings suggest that using hybrid descriptors formed by combining chemical and targeted transcriptomic information can improve in vivo toxicity predictions in the right context.

SUBMITTER: Tate T

PROVIDER: S-EPMC10259651 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Repeat-dose toxicity prediction with Generalized Read-Across (GenRA) using targeted transcriptomic data: A proof-of-concept case study.

Tate Tia T Wambaugh John J Patlewicz Grace G Shah Imran I

Computational toxicology (Amsterdam, Netherlands) 20210801

Read-across is a data gap filling technique utilized to predict the toxicity of a target chemical using data from similar analogues. Recent efforts such as Generalized Read-Across (GenRA) facilitate automated read-across predictions for untested chemicals. GenRA makes predictions of toxicity outcomes based on "neighboring" chemicals characterized by chemical and bioactivity fingerprints. Here we investigated the impact of biological similarities on neighborhood formation and read-across performa ...[more]

PMID: 37309449

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Project description:Read-across is a useful data gap filling technique used within category and analogue approaches in regulatory hazard and risk assessment. Recently we developed an algorithmic, approach called Generalised Read-Across (GenRA) (Shah et al., 2016) which makes read-across predictions of toxicity effects using a similarity weighted average of source analogues characterised by their chemical and/or bioactivity descriptors. A default GenRA approach (termed baseline GenRA) relies on identifying 10 source analogues relative to a target substance that are structurally similar based on Morgan chemical fingerprints and computing an activity score to estimate presence or absence of in vivo toxicity. This current study investigated the impact that similarity in bioavailability plays in altering the local neighbourhood of source analogues as well as read-across performance relative to baseline GenRA using physicochemical property information as a surrogate for bioavailability. Two approaches were evaluated: 1) a filtering approach which restricted structurally related analogues based on their physicochemical properties; and 2) a search expansion approach which included additional analogues based on a combined structural and physicochemical similarity index. Filtering minimally improved performance, and was very dependent on the similarity threshold selected. The search expansion approach performed at least as well as the baseline GenRA, and showed up to a 9% improvement in read-across performance for at least 10 of the 50 organs considered. We summarise the overall impact that physicochemical information plays on GenRA performance, illustrate the improvement for a specific case study substance and describe how to select the most appropriate physicochemical similarity threshold to achieve optimal read-across performance depending on the toxicity effect and chemical of interest. The analyses show that physicochemical property information does result in a modest (up to 9% increase) improvement in structural based read-across predictions.

Dataset Information

Repeat-dose toxicity prediction with Generalized Read-Across (GenRA) using targeted transcriptomic data: A proof-of-concept case study.

Publications

Repeat-dose toxicity prediction with Generalized Read-Across (GenRA) using targeted transcriptomic data: A proof-of-concept case study.

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