{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T18:34:37Z","timestamp":1789929277672,"version":"4.0.1"},"reference-count":55,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2015,6,5]],"date-time":"2015-06-05T00:00:00Z","timestamp":1433462400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico - CNPq","award":["no. 238194\/2012-4"],"award-info":[{"award-number":["no. 238194\/2012-4"]}]},{"name":"NIEHS Research Supplement to Promote Diversity in Health-Related Research","award":["PA-08-190"],"award-info":[{"award-number":["PA-08-190"]}]},{"name":"Thomas Luechtefeld by an NIEHS training","award":["T32 ES007141"],"award-info":[{"award-number":["T32 ES007141"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Supervised learning methods promise to improve integrated testing strategies (ITS), but must be adjusted to handle high dimensionality and dose\u2013response data. ITS approaches are currently fueled by the increasing mechanistic understanding of adverse outcome pathways (AOP) and the development of tests reflecting these mechanisms. Simple approaches to combine skin sensitization data sets, such as weight of evidence, fail due to problems in information redundancy and high dimensionality. The problem is further amplified when potency information (dose\/response) of hazards would be estimated. Skin sensitization currently serves as the foster child for AOP and ITS development, as legislative pressures combined with a very good mechanistic understanding of contact dermatitis have led to test development and relatively large high\u2010quality data sets. We curated such a data set and combined a recursive variable selection algorithm to evaluate the information available through <jats:italic>in silico<\/jats:italic>, <jats:italic>in chemico<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> assays. Chemical similarity alone could not cluster chemicals' potency, and <jats:italic>in vitro<\/jats:italic> models consistently ranked high in recursive feature elimination. This allows reducing the number of tests included in an ITS. Next, we analyzed with a hidden Markov model that takes advantage of an intrinsic inter\u2010relationship among the local lymph node assay classes, i.e. the monotonous connection between local lymph node assay and dose. The dose\u2010informed random forest\/hidden Markov model was superior to the dose\u2010naive random forest model on all data sets. Although balanced accuracy improvement may seem small, this obscures the actual improvement in misclassifications as the dose\u2010informed hidden Markov model strongly reduced \" false\u2010negatives\" (i.e. extreme sensitizers as non\u2010sensitizer) on all data sets. Copyright \u00a9 2015 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/jat.3172","type":"journal-article","created":{"date-parts":[[2015,6,5]],"date-time":"2015-06-05T09:27:04Z","timestamp":1433496424000},"page":"1361-1371","source":"Crossref","is-referenced-by-count":30,"title":["Probabilistic hazard assessment for skin sensitization potency by dose\u2013response modeling using feature elimination instead of quantitative structure\u2013activity relationships"],"prefix":"10.1002","volume":"35","author":[{"given":"Thomas","family":"Luechtefeld","sequence":"first","affiliation":[{"name":"Johns Hopkins University Bloomberg School of Public Health, Center for Alternatives to Animal Testing  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Maertens","sequence":"additional","affiliation":[{"name":"Johns Hopkins University Bloomberg School of Public Health, Center for Alternatives to Animal Testing  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"McKim","sequence":"additional","affiliation":[{"name":"Iontox Kalamazoo  MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Hartung","sequence":"additional","affiliation":[{"name":"Johns Hopkins University Bloomberg School of Public Health, Center for Alternatives to Animal Testing  Baltimore MD USA"},{"name":"University of Konstanz Center for Alternatives to Animal Testing Europe  Konstanz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre","family":"Kleensang","sequence":"additional","affiliation":[{"name":"Johns Hopkins University Bloomberg School of Public Health, Center for Alternatives to Animal Testing  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"S\u00e1\u2010Rocha","sequence":"additional","affiliation":[{"name":"Johns Hopkins University Bloomberg School of Public Health, Center for Alternatives to Animal Testing  Baltimore MD USA"},{"name":"Natura Inova\u00e7\u00e3o  Cajamar Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,6,5]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-011-0693-2"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2005.10.012"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/026119290703500124"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2012.05.013"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1214\/aoms\/1177699147"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1574-1400(08)00012-1"},{"key":"e_1_2_7_8_1","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1023\/A:1010933404324","article-title":"Random Forests","volume":"45","author":"Breiman L.","year":"2003","journal-title":"Machine Learning"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/026119290503300108"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1039\/9781849732093-00385"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/10915810591000631"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2010.03.009"},{"key":"e_1_2_7_13_1","volume-title":"EUR 26383 \u2013 EURL ECVAM Recommendation on the Direct Peptide Reactivity Assay (DPRA) for Skin Sensitisation Testing. Publications Office of the European","author":"European Commission Joint Research Centre","year":"2013"},{"key":"e_1_2_7_14_1","volume-title":"EUR 26427 \u2013 EURL ECVAM Recommendation on the KeratinoSensTM Assay for Skin Sensitisation Testing. Publications Office of the European","author":"European Commission Joint Research Centre","year":"2014"},{"key":"e_1_2_7_15_1","first-page":"59","article-title":"Regulation (EC) No 1223\/2009 of the European Parliament and of the Council of 30 November 2009 on Cosmetic Products","volume":"342","author":"Union European","year":"2009","journal-title":"Off. J. Eur. Union"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-1873.2004.00290.x"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.2310\/6620.2005.05040"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfm064"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfp059"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/460208a"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.14573\/altex.2013.1.003"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/4601080a"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2013.02.013"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.2869"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.14573\/altex.2011.3.211"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2005.09.006"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btn479"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2013.10.013"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/occmed\/kql039"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.3109\/15569527.2010.483869"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.3109\/15569527.2012.667031"},{"key":"e_1_2_7_32_1","volume-title":"Toxicity Testing in the 21st Century: A Vision and a Strategy","author":"Council National Research","year":"2007"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfn204"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.2868"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2012.11.006"},{"key":"e_1_2_7_36_1","volume-title":"Test No. 406: Skin Sensitisation","author":"OECD","year":"1992"},{"key":"e_1_2_7_37_1","volume-title":"Test No.429: Skin Sensitisation","author":"OECD","year":"2010"},{"key":"e_1_2_7_38_1","volume-title":"Test No.442C: In Chemico Skin Sensitisation","author":"OECD","year":"2015"},{"key":"e_1_2_7_39_1","volume-title":"Test No. 442D: In Vitro Skin Sensitisation","author":"OECD","year":"2015"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2014.06.001"},{"key":"e_1_2_7_41_1","first-page":"2825","article-title":"Scikit\u2010learn: Machine Learning in Python","volume":"12","author":"Pedregosa F","year":"2011","journal-title":"J. Machine Learning Res."},{"key":"e_1_2_7_42_1","first-page":"763","article-title":"Allergic contact dermatitis: epidemiology, molecular mechanisms, in vitro methods and regulatory aspects. Current knowledge assembled at an international workshop at BfR, Germany. Cell Mol","volume":"69","author":"Peiser M","year":"2012","journal-title":"Life Sci."},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2006.12.026"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.14573\/altex.1411011"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.14573\/altex.2009.3.187"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2005.10.014"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1177\/096032719101000405"},{"key":"e_1_2_7_48_1","unstructured":"SIDS OECD.2005.PHTHALIC ANHYDRIDE CAS N: 85\u201044\u20109.UNEP Publications:Paris France."},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10822-005-8694-y"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0536.2006.01058.x"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0536.2007.01220.x"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/9783527628766"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2014.09.009"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2014.12.008"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1109\/TIT.1967.1054010"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1097\/DER.0b013e318273a3b8"}],"container-title":["Journal of Applied Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjat.3172","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jat.3172","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T11:28:47Z","timestamp":1760527727000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/jat.3172"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,6,5]]},"references-count":55,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2015,11]]}},"alternative-id":["10.1002\/jat.3172"],"URL":"https:\/\/doi.org\/10.1002\/jat.3172","archive":["Portico"],"relation":{},"ISSN":["0260-437X","1099-1263"],"issn-type":[{"value":"0260-437X","type":"print"},{"value":"1099-1263","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,6,5]]}}}