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As a developmental outcome, it presents a challenging, mechanistically complex endpoint for predictive modeling. A data set of 500 chemicals evaluated for their ability to induce cleft palate in animal prenatal developmental studies was compiled from Toxicity Reference Database and the biomedical literature, which included 63 cleft palate active and 437 inactive chemicals. To characterize the potential molecular targets for chemical\u2010induced cleft palate, we mined the ToxCast high\u2010throughput screening database for patterns and linkages in bioactivity profiles and chemical structural descriptors. ToxCast assay results were filtered for cytotoxicity and grouped by target gene activity to produce a \u201cgene score.\u201d Following unsuccessful attempts to derive a global prediction model using structural and gene score descriptors, hierarchical clustering was applied to the set of 63 cleft palate positives to extract local structure\u2010bioactivity clusters for follow\u2010up study. Patterns of enrichment were confirmed on the complete data set, that is, including cleft palate inactives, and putative molecular initiating events identified. The clusters corresponded to ToxCast assays for cytochrome P450s, G\u2010protein coupled receptors, retinoic acid receptors, the glucocorticoid receptor, and tyrosine kinases\/phosphatases. These patterns and linkages were organized into preliminary decision trees and the resulting inferences were mapped to a putative adverse outcome pathway framework for cleft palate supported by literature evidence of current mechanistic understanding. This general data\u2010driven approach offers a promising avenue for mining chemical\u2010bioassay drivers of complex developmental endpoints where data are often limited.<\/jats:p>","DOI":"10.1002\/bdr2.1581","type":"journal-article","created":{"date-parts":[[2019,8,31]],"date-time":"2019-08-31T05:30:38Z","timestamp":1567229438000},"page":"19-39","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Characterizing cleft palate toxicants using ToxCast data, chemical structure, and the biomedical literature"],"prefix":"10.1002","volume":"112","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8351-9435","authenticated-orcid":false,"given":"Nancy C.","family":"Baker","sequence":"first","affiliation":[{"name":"Leidos  Research Triangle Park North Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nisha S.","family":"Sipes","sequence":"additional","affiliation":[{"name":"NIEHS Division of the National 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