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To apply this evidence to the clinical setting, we compared the cost-effectiveness of the proposed \u201cHLA-guided treatment schedule\u201d and the \u201ccurrent schedule\u201d being used in Japan and the United Kingdom (UK) (absolute neutrophil count (ANC) cutoff at 1500\/mm<jats:sup>3<\/jats:sup>); in the \u201cHLA-guided treatment schedules,\u201d we considered a situation wherein the HLA test performed before clozapine initiation could provide \u201ca priori information\u201d by detecting patients harboring risk of HLA variants (HLA-B*59:01 and \u201cHLA-B 158T\/HLA-DQB1 126Q\u201d for Japanese and Caucasian populations, respectively), a part of whom can then avoid CIAG onset (assumed 30% \u201cprevention rate\u201d). For the primary analysis, we estimated the incremental cost-effectiveness ratio (ICER) of \u201cHLA-guided treatment schedule\u201d and \u201ccurrent schedule\u201d used in Japan and the UK, using a Markov model to calculate the cost and quality-adjusted life years (QALYs) over a 10-year time period. Furthermore, as an explorative analysis, we simulated several situations with various ANC cutoffs (1000\/mm<jats:sup>3<\/jats:sup> and 500\/mm<jats:sup>3<\/jats:sup>) and plotted the cost\/QALYs for each option to identify the best, or estimate the next best candidate option applicable in actual clinical settings. The primary probabilistic analysis showed that the \u201cHLA-guided treatment schedule\u201d was more cost effective than the \u201ccurrent schedule\u201d; the ICER was \u00a320,995 and \u00a321,373 for the Japanese and the UK populations, respectively. Additional simulation revealed that the treatment option of ANC cutoff at 500\/mm<jats:sup>3<\/jats:sup> without HLA screening was the most cost-effective option; however, several options may be candidates to break away from the \u201ccurrent schedule\u201d of ANC cutoff at 1500\/mm<jats:sup>3<\/jats:sup>. Owing to its cost-effectiveness, we propose such pharmacogenetic-guided\/pharmacogenomic-guided clozapine treatment for use in the real-world setting, which provides key information for optimization of clinical guidelines for high-risk patients for gradual change of clozapine treatment schedule under the safety consideration.<\/jats:p>","DOI":"10.1038\/s41398-021-01487-4","type":"journal-article","created":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T23:05:19Z","timestamp":1625612719000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Cost effectiveness of pharmacogenetic-guided clozapine administration based on risk of HLA variants in Japan and the UK"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6232-0008","authenticated-orcid":false,"given":"Kohei","family":"Ninomiya","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeo","family":"Saito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomo","family":"Okochi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoru","family":"Taniguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayu","family":"Shimasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rei","family":"Aoki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeo","family":"Hata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taisei","family":"Mushiroda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3781-297X","authenticated-orcid":false,"given":"Tetsufumi","family":"Kanazawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6237-2449","authenticated-orcid":false,"given":"Masashi","family":"Ikeda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3189-6076","authenticated-orcid":false,"given":"Nakao","family":"Iwata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,7,7]]},"reference":[{"key":"1487_CR1","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1136\/bmj.39227.616447.BE","volume":"335","author":"MM Picchioni","year":"2007","unstructured":"Picchioni MM, Murray RM. 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Iwata has received research support or speakers\u2019 honoraria from, or has served as a consultant to Jansen, Glaxo SmithKline, Eli Lilly, Otsuka, Shionogi, Dainippon Sumitomo, Tanabe Mitsubishi, Daiichi-Sankyo. For the remaining authors none were declared.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Written informed consent was obtained from each subject after the procedures had been fully explained. This study was performed in accordance with the World Medical Association\u2019s Declaration of Helsinki, and approved by the Ethics Committees of Fujita Health University and Osaka Medical College.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}}],"article-number":"362"}}