{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T03:22:29Z","timestamp":1790652149742,"version":"4.1.0"},"reference-count":16,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T00:00:00Z","timestamp":1582761600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:p>Dihydropyrimidine dehydrogenase (DPD)\u2010deficient patients might only become aware of their genotype after exposure to dihydropyrimidines, if testing is performed. Case reports to pharmacovigilance databases might only contain phenotypical manifestations of DPD, without information on the genotype. This poses a difficulty in estimating the cases due to DPD. Auto machine learning models were developed to train patterns of phenotypical manifestations of toxicity, which were then used as a surrogate to estimate the number of cases of DPD\u2010related toxicity. Results indicate that between 8,878 (7.0%) and 16,549 (13.1%) patients have a profile similar to DPD deficient status. Results of the analysis of variable importance\u00a0match the known end\u2010organ damage of DPD\u2010related toxicity, however, accuracies in the range of 90% suggest presence of overfitting, thus, results need to be interpreted carefully. This study shows the potential for use of machine learning in the regulatory context but additional studies are required\u00a0to better understand regulatory applicability.<\/jats:p>","DOI":"10.1002\/cpt.1789","type":"journal-article","created":{"date-parts":[[2020,1,19]],"date-time":"2020-01-19T10:34:45Z","timestamp":1579430085000},"page":"944-947","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["An Application of Machine Learning in Pharmacovigilance: Estimating Likely Patient Genotype From Phenotypical Manifestations of Fluoropyrimidine Toxicity"],"prefix":"10.1111","volume":"107","author":[{"given":"Luis","family":"Correia Pinheiro","sequence":"first","affiliation":[{"name":"European Medicines Agency Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Durand","sequence":"additional","affiliation":[{"name":"European Medicines Agency Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Michel","family":"Dogn\u00e9","sequence":"additional","affiliation":[{"name":"University of Namur Namur Belgium"},{"name":"Belgian Federal Agency for Medicines and Health Products Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,2,27]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(196011\/12)13:6<1230::AID-CNCR2820130612>3.0.CO;2-D"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3109\/07357909909032859"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/1559325818803042"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3816\/CCC.2004.n.018"},{"key":"e_1_2_9_5_1","unstructured":"Genetic and Rare Diseases Information Center Dihydropyrimidine dehydrogenase deficiency<https:\/\/rarediseases.info.nih.gov\/diseases\/19\/dihydropyrimidine-dehydrogenase-deficiency>. Accessed September 15 2019."},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-0747"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2003.12.004"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1517\/14740338.2010.511610"},{"key":"e_1_2_9_9_1","unstructured":"European Medicines Agency Fluorouracil and fluorouracil related substances (capecitabine tegafur and flucytosine) containing medicinal products<https:\/\/www.ema.europa.eu\/en\/medicines\/human\/referrals\/fluorouracil-fluorouracil-related-substances-capecitabine-tegafur-flucytosine-containing-medicinal> (2019). Accessed September 15 2019."},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40264-018-0647-1"},{"key":"e_1_2_9_11_1","unstructured":"Meddra.org MedDRA|Medical Dictionary for Regulatory Activities<http:\/\/www.meddra.org\/> (2015). Accessed September 15 2019."},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.2165\/00002018-200730070-00009"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12874-019-0681-4"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.9778\/cmajo.20180142"},{"key":"e_1_2_9_15_1","unstructured":"H2O. Open source leader in AI and ML <https:\/\/www.h2o.ai\/>. Accessed September 15 2019."},{"key":"e_1_2_9_16_1","unstructured":"European Medicines Agency.EMA regulatory science to 2025\u2014strategic reflection<https:\/\/www.ema.europa.eu\/en\/documents\/regulatory-procedural-guideline\/ema-regulatoryscience-2025-strategic-reflection_en.pdf> (2018)."}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.1789","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.1789","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.1789","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T13:37:19Z","timestamp":1699364239000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.1789"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,27]]},"references-count":16,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2020,4]]}},"alternative-id":["10.1002\/cpt.1789"],"URL":"https:\/\/doi.org\/10.1002\/cpt.1789","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,27]]},"assertion":[{"value":"2019-09-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-01-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-02-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}