Testing for qualitative heterogeneity: An application to composite endpoints in survival analysis

Abderrahim Oulhaj, Anouar El Ghouch, Rury R. Holman

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


Composite endpoints are frequently used in clinical outcome trials to provide more endpoints, thereby increasing statistical power. A key requirement for a composite endpoint to be meaningful is the absence of the so-called qualitative heterogeneity to ensure a valid overall interpretation of any treatment effect identified. Qualitative heterogeneity occurs when individual components of a composite endpoint exhibit differences in the direction of a treatment effect. In this paper, we develop a general statistical method to test for qualitative heterogeneity, that is to test whether a given set of parameters share the same sign. This method is based on the intersection–union principle and, provided that the sample size is large, is valid whatever the model used for parameters estimation. We propose two versions of our testing procedure, one based on a random sampling from a Gaussian distribution and another version based on bootstrapping. Our work covers both the case of completely observed data and the case where some observations are censored which is an important issue in many clinical trials. We evaluated the size and power of our proposed tests by carrying out some extensive Monte Carlo simulations in the case of multivariate time to event data. The simulations were designed under a variety of conditions on dimensionality, censoring rate, sample size and correlation structure. Our testing procedure showed very good performances in terms of statistical power and type I error. The proposed test was applied to a data set from a single-center, randomized, double-blind controlled trial in the area of Alzheimer’s disease.

Original languageEnglish
Pages (from-to)151-169
Number of pages19
JournalStatistical Methods in Medical Research
Issue number1
Publication statusPublished - Jan 1 2019


  • Asymptotic test
  • Cox model
  • bootstrap
  • interaction-union principal
  • multivariate survival analysis
  • qualitative interaction
  • right-censoring

ASJC Scopus subject areas

  • Epidemiology
  • Statistics and Probability
  • Health Information Management


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