title: Testing for carryover effects after cessation of treatments: a design approach.
abstract: Recently, trials addressing noisy measurements with diagnosis occurring by exceeding thresholds (such as diabetes and hypertension) have been published which attempt to measure carryover - the impact that treatment has on an outcome after cessation. The design of these trials has been criticised and simulations have been conducted which suggest that the parallel-designs used are not adequate to test this hypothesis; two solutions are that either a differing parallel-design or a cross-over design could allow for diagnosis of carryover.
  
  
  
  We undertook a systematic simulation study to determine the ability of a cross-over or a parallel-group trial design to detect carryover effects on incident hypertension in a population with prehypertension. We simulated blood pressure and focused on varying criteria to diagnose systolic hypertension.
  
  
  
  Using the difference in cumulative incidence hypertension to analyse parallel-group or cross-over trials resulted in none of the designs having acceptable Type I error rate. Under the null hypothesis of no carryover the difference is well above the nominal 5 % error rate.
  
  
  
  When a treatment is effective during the intervention period, reliable testing for a carryover effect is difficult. Neither parallel-group nor cross-over designs using the difference in cumulative incidence appear to be a feasible approach. Future trials should ensure their design and analysis is validated by simulation.
authors.affiliation: The Department of Statistics, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand. sstu011@aucklanduni.ac.nz.
authors.forename: S Gwynn
authors.initials: SG
authors.lastname: Sturdevant
authors.affiliation: The Department of Statistics, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lumley
mesh_terms: D001794:Blood Pressure; D018592:Cross-Over Studies; D006801:Humans; D006973:Hypertension / Q000628:therapy*; D012107:Research Design; D016896:Treatment Outcome; D028761:Withholding Treatment
keywords: Carryover; Cumulative incidence; Prehypertension; Prevention; Randomized trials; Survival analysis