The interface between biomarker discovery and clinical validation: The tar pit of the protein biomarker pipeline

Abstract

The application of "omics" technologies to biological samples generates hundreds to thousands of biomarker candidates; however, a discouragingly small number make it through the pipeline to clinical use. This is in large part due to the incredible mismatch between the large numbers of biomarker candidates and the paucity of reliable assays and methods for validation studies. We desperately need a pipeline that relieves this bottleneck between biomarker discovery and validation. This paper reviews the requirements for technologies to adequately credential biomarker candidates for costly clinical validation and proposes methods and systems to verify biomarker candidates. Models involving pooling of clinical samples, where appropriate, are discussed. We conclude that current proteomic technologies are on the cusp of significantly affecting translation of molecular diagnostics into the clinic.

Figure 1

Current and desired flux of candidates through the biomarker discovery pipeline. Note that despite our ability to generate long lists of candidate biomarkers using omics approaches, a mere 0–2 per year are achieving FDA approval (across all diseases). Our immediate goal is to improve this process 100-fold, which may be possible using a staged approach with sequential, cost-effective credentialing of candidate biomarkers. If conventional proteomics is to meet its promise for delivering molecular diagnostics, we must hone our ability to credential candidates in the most cost-effective manner. One approach is to stage candidate credentialing such that a small amount of resources are invested in early testing of a very large number of candidates, whereas greater resources are invested for assay development in only the subset of candidates showing greatest promise for clinical utility.