Personalization of medicine requires better observational evidence

Abstract

Rutger A Middelburg,1,2 M Sesmu Arbous,2,3 Judith G Middelburg,4 Johanna G van der Bom1,2 1Center for Clinical Transfusion Research, Sanquin Research, Leiden, the Netherlands; 2Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; 3Department of Intensive Care Medicine, Leiden University Medical Center, Leiden, the Netherlands; 4Department of Radiation Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands Abstract: Evidence-based medicine has become associated with a preference for randomized trials. Randomization is a powerful tool against both known and unknown confounding. However, due to cost-induced constraints in size, randomized trials are seldom able to provide the subgroup analyses needed to gain much insight into effect modification. To apply results to an individual patient, effect modification needs to be considered. Results from randomized trials are therefore often difficult to apply in daily clinical practice. Confounding by indication, which randomization aims to prevent, is caused by more severely ill patients being less or more likely to be treated. Therefore, the prognostic indicators that physicians use to make treatment decisions become confounders. However, these same prognostic indicators are also effect modifiers. This is in fact exactly why they are relevant to decision-making. We use simple, fictive numerical examples to illustrate these concepts. Then we argue that if we would record all relevant variables, it would simultaneously solve the problem of confounding by indication and allow quantification of effect modification. It has previously been argued that it is practically more feasible to “simply” randomize treatment allocation, than to adequately correct for confounding by indication. We will argue that, in the current age of evidence-based medicine and highly regulated randomized trials, this balance has shifted. We therefore call for better observational clinical research. However, careless acceptance of results from poorly performed observational research can lead clinicians seriously astray. Therefore, a more interactive approach toward the medical literature might be needed, where more room is made for scientific discussion and interpretation of results, instead of one-way reporting. Keywords: treatment, personalized, effectiveness, effect modification, risk factors, confounding by indicatio