title: Assessing the incremental value of diagnostic and prognostic markers: a review and illustration.
abstract: BACKGROUND
  New markers may improve prediction of diagnostic and prognostic outcomes. We review various measures to quantify the incremental value of markers over standard, readily available characteristics.
  
  
  METHODS
  Widely used traditional measures include the improvement in model fit or in the area under the receiver operating characteristic (ROC) curve (AUC). New measures include the net reclassification index (NRI) and decision-analytic measures, such as the fraction of true-positive classifications penalized for false-positive classifications [net benefit (NB)]. For illustration, we discuss a case study on the presence of residual tumour vs. benign tissue in 544 patients with testicular cancer. We assessed three tumour markers [Alpha-fetoprotein (AFP), Human chorionic gonadotropin (HCG) and Lactate dehydrogenase (LDH)] for their incremental value over currently standard clinical predictors.
  
  
  RESULTS
  AUC and R(2) values suggested adding continuous LDH and AFP whereas NB only favoured HCG as a potentially promising marker at a clinically defendable decision threshold of 20% risk. The NRI suggested reclassification potential of all three markers.
  
  
  CONCLUSIONS
  The improvement in standard discrimination measures, which focus on finding variables that might be promising across all decision thresholds, may not detect the most informative markers at a specific threshold of particular clinical relevance. When a marker is intended to support decision-making, calculation of the improvement in a decision-analytic measure, such as NB, is preferable over an overall judgment as obtained from the AUC in ROC analysis.
authors: Department of Public Health, Erasmus MC, Rotterdam, The Netherlands. e.steyerberg@erasmusmc.nl
authors: Ewout W
authors: EW
authors: Steyerberg
authors: Michael J
authors: MJ
authors: Pencina
authors: Hester F
authors: HF
authors: Lingsma
authors: Michael W
authors: MW
authors: Kattan
authors: Andrew J
authors: AJ
authors: Vickers
authors: Ben
authors: B
authors: Van Calster
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D006801:Humans; D008297:Male; D015233:Models, Statistical; D009373:Neoplasms, Germ Cell and Embryonal / Q000175:diagnosis*; D011237:Predictive Value of Tests; D011379:Prognosis; D015203:Reproducibility of Results; D013736:Testicular Neoplasms / Q000175:diagnosis*
chemical_list: D014408:Biomarkers, Tumor