Gene-Specific Variant Classifier (DPYD-Varifier) to Identify Deleterious Alleles of Dihydropyrimidine Dehydrogenase

Shikshya Shrestha, Cheng Zhang, Calvin R. Jerde, Qian Nie, Hu Li, Steven M. Offer, Robert B. Diasio

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Deleterious variants in dihydropyrimidine dehydrogenase (DPD, DPYD gene) can be highly predictive of clinical toxicity to the widely prescribed chemotherapeutic 5-fluorouracil (5-FU). However, there are very limited data pertaining to the functional consequences of the >450 reported no-synonymous DPYD variants. We developed a DPYD-specific variant classifier (DPYD-Varifier) using machine learning and in vitro functional data for 156 missense DPYD variants. The developed model showed 85% accuracy and outperformed other in silico prediction tools. An examination of feature importance within the model provided additional insight into functional aspects of the DPD protein relevant to 5-FU toxicity. In the absence of clinical data for unstudied variants, prediction tools like DPYD-Varifier have great potential to individualize medicine and improve the clinical decision-making process.

Original languageEnglish (US)
Pages (from-to)709-718
Number of pages10
JournalClinical pharmacology and therapeutics
Volume104
Issue number4
DOIs
StatePublished - Oct 2018

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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