Case-crossover design: an alternative strategy for detecting drug-induced liver injury

J Clin Epidemiol. 2012 May;65(5):560-7. doi: 10.1016/j.jclinepi.2011.11.002.


Objective: Our observational study was conducted to assess if the case--crossover design could be applied to detect the risk of hepatoxic drugs on liver injury in the automated databases.

Study design and setting: The study was conducted on approximately 22 million people enrolled in Taiwan's National Health Insurance database from 1997 to 2004. We applied case--crossover and case--control designs to assess the estimated risks of liver injury related to well-known hepatoxic drugs, including isoniazid, rifampicin, erythromycin, and diclofenac. Using case--crossover and case--control designs, we analyzed to explore the association between hospitalization and our target drugs through a conditional logistic regression model.

Results: The adjusted odds ratios (ORs) of isoniazid, rifampicin, erythromycin, and diclofenac showed 24.4 (confidence interval [CI] =10.7-55.5), 30.8 (CI=14.1-67.1), 2.1 (CI=1.4-3.1), and 2.9 (CI=2.4-3.5) among 4,413 hospitalized liver injury patients during the 30-day exposure window by the case--crossover designs. Most adjusted ORs by case--crossover design were more conservative than ORs by case--control design.

Conclusions: In addition to a case--control design, the case--crossover design is a suitable method, for detecting the potential hepatotoxicity of drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-Bacterial Agents / adverse effects*
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Case-Control Studies
  • Chemical and Drug Induced Liver Injury / diagnosis
  • Chemical and Drug Induced Liver Injury / epidemiology*
  • Comorbidity
  • Cross-Over Studies
  • Databases as Topic
  • Diclofenac / adverse effects
  • Drug Prescriptions / statistics & numerical data
  • Drug-Related Side Effects and Adverse Reactions / diagnosis
  • Drug-Related Side Effects and Adverse Reactions / epidemiology*
  • Erythromycin / adverse effects
  • Female
  • Hospitalization / statistics & numerical data*
  • Humans
  • Isoniazid / adverse effects
  • Logistic Models
  • Male
  • Middle Aged
  • Odds Ratio
  • Pregnancy
  • Research Design
  • Rifampin / adverse effects
  • Risk Assessment
  • Taiwan / epidemiology
  • Time Factors
  • Young Adult


  • Anti-Bacterial Agents
  • Anti-Inflammatory Agents, Non-Steroidal
  • Diclofenac
  • Erythromycin
  • Isoniazid
  • Rifampin