Biostatistics, Epidemiology and Research Design

Welcome to the Biostatistics, Epidemiology and Research Design (BERD)

The importance of biomarker discovery, and later validation, to progress in translational research is underlined by the large numbers of Requests for Applications each year that specifically include a biomarker component. Although there is a large literature on biomarker validation in general, much of this was originally developed in the context of developing diagnostic tests, particularly in cancer screening, and there remains a large need to extend these methods to other clinical areas. For example, a screening marker intended to detect the presence or absence of disease, may not be valuable in prediction of disease progression or response to therapy within individuals with the disorder. For example, in chronic kidney disease, monitoring of disease status is often based monitoring of longitudinal changes of estimates of glomerular filtration rate (GFR), a continuous measure. It is also not always necessary to apply the classical methods of, say, receiver operating characteristic (ROC) analysis, to define cut points for novel biomarkers; a biomarker may contribute useful information to risk stratification models, even if a cut point is not strictly defined.

Furthermore, biomarker validation efforts must take into account available clinical data, as well as assay and analyte characteristics. A valuable biomarker must contribute information above and beyond existing clinical data to risk prediction models. Biomarkers may predict disease progression and inform individual-level treatment decisions. Risk estimates can be improved through the use of novel biomarkers, and in some cases, re-classify those at intermediate risk into high or low risk groups and directly impact treatment decisions.

Since biomarkers might eventually serve as "surrogate markers" for clinical endpoints, particularly in clinical trials, further research on statistical methods for the validation of surrogate markers, as related to endpoint identification, is also needed. As illustrated with the experience with HDL, interpretation and prediction of the surrogate value of biomarkers may prove quite complex. While a biomarker that is strongly associated with a definitive disease outcome has the potential to move a therapeutic field forward, biomarkers may be highly informative, even if they do not meet the criteria for surrogacy.


Response to COVID-19 

The rapid arrival of large numbers infected patients and the need rapidly to assess the safety and efficacy of potential therapeutics provides an opportunity for the development and application of novel and diversified approaches to trial design, statistical analysis ( e.g. “basket trials of multiple therapies; Bayesian analyses) and regulatory approval, all of which will rely on the BERD and RKS teams. We anticipate that prioritization of access to resource – from ventilators to entry into clinical trials to compassionate use approvals - will present complex ethical challenges that will engage Dr. Joffe and his team. This pandemic promises to alter substantially our approach to trial design and approval of therapeutics and highlight the need for a transparent and ethical approach to triaging resources that are in short supply relative to demand.