title: An approach to identifying preclinical biomarkers of susceptibility to drug-induced toxicity.
abstract: OBJECTIVE
  Drug-induced toxicity that leads to termination of candidate drugs or postmarketing removal of approved drugs can potentially be explained by the existence of susceptible subpopulations. If the susceptible subpopulations are identified in advance, the drug's benefits could be maximized by optimal treatment decisions. This article presents a statistical model and an approach for identifying pharmacogenomic biomarkers of susceptibility to drug-induced toxicity for detecting the susceptible subpopulations.
  
  
  METHODS
  Biomarkers are categorized into three disjoint sets: biomarkers of both susceptibility and exposure (A); biomarkers of susceptibility only (B); and biomarkers of exposure only (C). Set B contains the most useful biomarkers to identify susceptible subpopulations prior to drug exposure; these markers demonstrate no change in response before and after drug exposure. We present a sample size analysis to illustrate the issues and challenges facing identifying biomarker set B.
  
  
  RESULTS
  The required sample size increases as the proportion of the susceptible subpopulation decreases. The examples demonstrated that at least 75 subjects per group are needed for a population with a 5% susceptible subpopulation and more than 1000 are often necessary.
  
  
  CONCLUSIONS
  This study demonstrates that the biomarkers identified by common methods are a mixture of biomarkers of exposure and susceptibility (A and C), it further demonstrates that the proposed approach could be used to identify biomarkers of susceptibility (B), where a large sample size may be required for adequate power and low false-positive rate. Original submitted 14 October 2010; Revision submitted 8 December 2010.
authors.affiliation: Division of Personalized Nutrition & Medicine, National Center for Toxicological Research, US FDA, Jefferson, AR 72079, USA.
authors.forename: Wei-Jiun
authors.initials: WJ
authors.lastname: Lin
authors.forename: James J
authors.initials: JJ
authors.lastname: Chen
mesh_terms: D054316:Biomarkers, Pharmacological / Q000032:analysis*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics*; D005819:Genetic Markers; D006801:Humans; D015233:Models, Statistical; D020411:Oligonucleotide Array Sequence Analysis; D018401:Sample Size
chemical_list: D054316:Biomarkers, Pharmacological; D005819:Genetic Markers