title: Discrimination-based sample size calculations for multivariable prognostic models for time-to-event data.
abstract: BACKGROUND
  Prognostic studies of time-to-event data, where researchers aim to develop or validate multivariable prognostic models in order to predict survival, are commonly seen in the medical literature; however, most are performed retrospectively and few consider sample size prior to analysis. Events per variable rules are sometimes cited, but these are based on bias and coverage of confidence intervals for model terms, which are not of primary interest when developing a model to predict outcome. In this paper we aim to develop sample size recommendations for multivariable models of time-to-event data, based on their prognostic ability.
  
  
  METHODS
  We derive formulae for determining the sample size required for multivariable prognostic models in time-to-event data, based on a measure of discrimination, D, developed by Royston and Sauerbrei. These formulae fall into two categories: either based on the significance of the value of D in a new study compared to a previous estimate, or based on the precision of the estimate of D in a new study in terms of confidence interval width. Using simulation we show that they give the desired power and type I error and are not affected by random censoring. Additionally, we conduct a literature review to collate published values of D in different disease areas.
  
  
  RESULTS
  We illustrate our methods using parameters from a published prognostic study in liver cancer. The resulting sample sizes can be large, and we suggest controlling study size by expressing the desired accuracy in the new study as a relative value as well as an absolute value. To improve usability we use the values of D obtained from the literature review to develop an equation to approximately convert the commonly reported Harrell's c-index to D. A flow chart is provided to aid decision making when using these methods.
  
  
  CONCLUSIONS
  We have developed a suite of sample size calculations based on the prognostic ability of a survival model, rather than the magnitude or significance of model coefficients. We have taken care to develop the practical utility of the calculations and give recommendations for their use in contemporary clinical research.
authors.affiliation: MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London, WC2B 6NH, UK. rcjinks@gmail.com.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Jinks
authors.affiliation: MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London, WC2B 6NH, UK. j.royston@ucl.ac.uk.
authors.forename: Patrick
authors.initials: P
authors.lastname: Royston
authors.affiliation: MRC Clinical Trials Unit at UCL, Aviation House, 125 Kingsway, London, WC2B 6NH, UK. m.parmar@ucl.ac.uk.
authors.forename: Mahesh K B
authors.initials: MK
authors.lastname: Parmar
mesh_terms: D000465:Algorithms; D003657:Decision Making; D006801:Humans; D008113:Liver Neoplasms / Q000401:mortality*; D008962:Models, Theoretical; D011379:Prognosis; D012107:Research Design; D018401:Sample Size