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PERSPECTIVEProtein biomarker discovery and validation:
the long and uncertain path to clinical utility.com/naturebiotechnology Nature Publishing Group Nader Rifai1, Michael A Gillette2 & Steven A Carr2Better biomarkers are urgently needed to improve diagnosis,
guide molecularly targeted therapy and monitor activity and
therapeutic response across a wide spectrum of disease.
Proteomics methods based on mass spectrometry hold special
promise for the discovery of novel biomarkers that might
form the foundation for new clinical blood tests, but to date
their contribution to the diagnostic armamentarium has been
disappointing. This is due in part to the lack of a coherent
pipeline connecting marker discovery with well-established
methods for validation. Advances in methods and technology
now enable construction of a comprehensive biomarker pipeline
from six essential process components: candidate discovery,
qualification, verification, research assay optimization,
biomarker validation and commercialization. Better
understanding of the overall process of biomarker discovery
and validation and of the challenges and strategies inherent
in each phase should improve experimental study design, in
turn increasing the efficiency of biomarker development and
facilitating the delivery and deployment of novel clinical tests.A biomarker is a measurable indicator of a specific biological state, particularly one relevant to the risk of contraction, the presence or the stage
of disease. Though historically often a physical trait or physiological
metric, the term is now typically shorthand for a molecular biomarker.
Molecular biomarkers can take many forms, and as a consequence a variety of strategies have been adopted for their discovery. Transcriptional
profiling and DNA methylation studies have shown strong potential for
biomarker discovery in cancer1, and metabolomics approaches are beginning to show promise for metabolic disease, drug and toxicity studies2.
The protein domain is likely the most ubiquitously affected in disease,
response and recovery, however, and proteomics holds special promise
for biomarker discovery. The development of novel protein biomarkers
is the focus of this perspective.Biomarkers can be used clinically to screen for, diagnose or monitor the activity of diseases and to guide molecularly targeted therapy
or assess therapeutic response3. In the biopharmaceutical industry,
biomarkers define molecular taxonomies of patients and diseases and
serve as surrogate endpoints in early-phase drug trials. The utility and
importance of biomarkers has been recognized by substantial public and
private funding, and biomarker discovery efforts are now commonplace
in...