Comparative optimism in models involving both classical clinical and gene expression information

BACKGROUND: In cancer research, most clinical variables have already been investigated and are now well established. The use of transcriptomic variables has raised two problems: restricting their number and validating their significance. Thus, their contribution to prognosis is currently thought to be overestimated. The aim of this study was to determine to what extent optimism concerning current transcriptomic models may lead to overestimation of the contribution of transcriptomic variables to survival prognosis. RESULTS: To achieve this goal, Cox proportional hazards models that adjust for clinical and transcriptomic variables were built. As the relevance of the clinical variables had already been established, they were not submitted to selection. As for genes, they were selected using both univariate and multivariate methods. Optimism and the contribution of clinical and transcriptomic variables to prognosis were compared through simulations and by using the Kent and O'Quigley ρ(2 )measure of dependence. We showed that the optimism relative to clinical variables was low because these are no longer submitted to selection of relevant variables. In contrast, for genes, the selection process introduced high optimism, which increased when the proportion of genes of interest decreased. However, this optimism can be decreased by increasing the number of samples. CONCLUSION: Two phenomena have to be taken into account by comparing the predictive power and optimism of clinical variables and those of genes: overestimation for genes due to the selection process and underestimation for clinical variables due to the omission of relevant genes. In comparison with genes, the predictive value of validated clinical variables is not overestimated, which should be kept in mind in future studies involving both clinical and transcriptomic variables.