Flexible modeling of the cumulative effects of time-dependent exposures on the hazard

Stat Med. 2009 Nov 30;28(27):3437-53. doi: 10.1002/sim.3701.


Many epidemiological studies assess the effects of time-dependent exposures, where both the exposure status and its intensity vary over time. One example that attracts public attention concerns pharmacoepidemiological studies of the adverse effects of medications. The analysis of such studies poses challenges for modeling the impact of complex time-dependent drug exposure, especially given the uncertainty about the way effects cumulate over time and about the etiological relevance of doses taken in different time periods. We present a flexible method for modeling cumulative effects of time-varying exposures, weighted by recency, represented by time-dependent covariates in the Cox proportional hazards model. The function that assigns weights to doses taken in the past is estimated using cubic regression splines. We validated the method in simulations and applied it to re-assess the association between exposure to a psychotropic drug and fall-related injuries in the elderly.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Accidental Falls
  • Cohort Studies
  • Dose-Response Relationship, Drug*
  • Flurazepam / adverse effects
  • Flurazepam / therapeutic use
  • Humans
  • Hypnotics and Sedatives / adverse effects
  • Hypnotics and Sedatives / therapeutic use
  • Models, Biological*
  • Pharmacoepidemiology / methods*
  • Proportional Hazards Models*
  • Sleep Initiation and Maintenance Disorders / drug therapy


  • Hypnotics and Sedatives
  • Flurazepam