{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:50:05Z","timestamp":1792173005491,"version":"4.4.0"},"reference-count":14,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The Clinical Pharmacogenetics Implementation Consortium (CPIC) bases its drug\u2010gene recommendations on the assignment of star alleles, which map known genotypes to defined functional categories and corresponding drug dosage guidelines. The star allele framework, first proposed in 1996 for the\n                    <jats:italic>CYP<\/jats:italic>\n                    gene family and later formalized with CPIC's establishment in 2010, remains foundational to pharmacogenomics. However, this system has notable limitations. Its dependence on a restricted set of benchmark single nucleotide polymorphisms (SNPs) excludes rare or novel pathogenic variants that can invalidate a star allele call and lead to incorrect dosing recommendations. Furthermore, nearby non\u2010pathogenic variants can interfere with haplotype interpretation, introducing additional risk of misclassification. To explore how these gaps might be addressed at the analytical layer, we describe PHARMWATCH, a proposed multilayer pharmacogenomics framework that couples standard star\u2010allele assignment with two additional analyses: (1) germline variant screening using the ACMG\u2010based BIAS\u20102015 classifier and (2) variant interpretation in context (VIIC), which reconstructs the observed amino acid sequence at each star\u2010allele\u2010defining locus for comparison against the sequence predicted by the assigned star allele (3). We describe the framework's architecture, specify the flag thresholds and translation rules used by each layer, and illustrate its behavior on a documented DPYD case in which a rare pathogenic variant fell outside the tag\u2010SNP panel used for pre\u2010treatment genotyping. We present PHARMWATCH as an exploratory framework; cohort\u2010scale performance characterization and extension to additional SNP\u2010driven pharmacogenes are identified as priority future work.\n                  <\/jats:p>","DOI":"10.1111\/cts.70745","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T08:01:53Z","timestamp":1792051313000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>PHARMWATCH<\/scp>\n                    : A Proposed Multilayer Pharmacogenomics Framework for Contextual Star Allele Interpretation"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2866-7181","authenticated-orcid":false,"given":"Chris","family":"Eisenhart","sequence":"first","affiliation":[{"name":"Bitscopic, Inc.  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5209-4710","authenticated-orcid":false,"given":"Rachel","family":"Brickey","sequence":"additional","affiliation":[{"name":"Bitscopic, Inc.  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9527-6533","authenticated-orcid":false,"given":"Joel","family":"Mewton","sequence":"additional","affiliation":[{"name":"Bitscopic, Inc.  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,15]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"CBC News This Commonly Prescribed Cancer Drug was Supposed to Help Save this Doctor's Life Instead it Killed him \u201d(2023) https:\/\/www.cbc.ca\/news\/canada\/toronto\/cancer\u2010drug\u20105fu\u2010genetic\u2010variant\u2010testing\u20101.7039145."},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1568"},{"key":"e_1_2_10_4_1","unstructured":"ClinPGx \u201cPharmacogenomics Clinical Annotation \u201d (2025) https:\/\/pharmcat.clinpgx.org\/."},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073\u2010025\u201001581\u2010y"},{"key":"e_1_2_10_6_1","unstructured":"UCSC Genome Browser \u201cCCDS Gene Track Schema in GRCh38\/hg38 \u201d (2025) https:\/\/genome.ucsc.edu\/cgi\u2010bin\/hgTables?db=hg38&hgta_group=genes&hgta_track=ccdsGene&hgta_table=ccdsGene&hgta_doSchema=describe+table+schema."},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.911"},{"key":"e_1_2_10_8_1","unstructured":"UCSC Genome Browser \u201cDPYD Gene Coordinates in GRCh38\/hg38 \u201d (2023) https:\/\/genome.ucsc.edu\/cgi\u2010bin\/hgTracks?db=hg38&position=chr1%3A97077743\u201097921034."},{"key":"e_1_2_10_9_1","unstructured":"ClinVar \u201cDPYD Variants \u201d (2025) https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/?term=DPYD[gene]."},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-2151"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-015-1779-7"},{"key":"e_1_2_10_12_1","volume-title":"PraediGene: Clinical Genomic Interpretation and Visualization Platform","author":"Bitscopic, Inc","year":"2026"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.37"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn8197"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.01.004"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70745","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.70745","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70745","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:18:01Z","timestamp":1792171081000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.70745"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":14,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1111\/cts.70745"],"URL":"https:\/\/doi.org\/10.1111\/cts.70745","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"2026-04-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70745"}}