Cited by 1,867Advanced Proteomics Techniques and ApplicationsAdvanced Biosensing Techniques and ApplicationsBiomarkers in Disease Mechanisms

Protein biomarker discovery and validation: the long and uncertain path to clinical utility

Rifai, Nader, Gillette, Michael A, Carr, Steven A·2006·Nature Biotechnology

Abstract

Better 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.

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Crossref · 10.1038/nbt1235

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116 of 116 references verified0 citation errors · 0 not checkable

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  • MS detection of low-abundance proteins from blood remains an unsolved challenge due to the extraordinary dynamic range of the blood proteome.

    “However, the MS detection of low-abundance proteins remains an unsolved challenge due to high dynamic range of the human proteome8–10.”
  • Front-end protein enrichment strategies are required to specifically capture and enrich low-abundance proteins from complex biological milieu prior to MS analysis.

    “Front-end protein enrichment strategies are therefore required to specifically capture and enrich low-abundance proteins from the complex biological milieu prior to MS analysis9,11.”
  • The human blood proteome has a huge dynamic range (~10^12) dominated by highly abundant proteins such as human serum albumin (HSA), making detection of low-abundance proteins extremely difficult.

    “In particular, the human blood proteome, a circulating representation of all pathophysiological processes, is immensely complex and the huge dynamic range of the blood proteome (1012) dominated by the presence of numerous highly abundant proteins, such as human serum albumin (HSA), makes the detection of low-abundance proteins extremely difficult9,10.”
  • Additional sources of uncertainty may arise from processes such as protein quantification in bottom-up proteomics because measurements are made at the peptide level and isoforms can be difficult to identify.

    “additional sources of uncertainty may arise from processes such as protein quantification in bottom-up proteomics (Rifai et al., 2006; Plubell et al., 2022) as measurements are made at the peptide level and isoforms can be difficult to identify (Forshed et al., 2011; Webb-Robertson et al., 2014).”

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Authors
Rifai, N., Gillette, M. A., & Carr, S. A.
Affiliations
  • Boston Children's Hospital (US)
  • Broad Institute (US)
Corresponding author
Carr, Steven A
Venue
Nature Biotechnology
Published
2006-08
Volume
24
Issue
8
Pages
971-983
ISSN
  • 0733-222X (ISSN-L)
  • 1087-0156
  • 1546-1696
OpenAlex
W2094229819
Cited by
1,867
References
118
Citations by year
2026: 56 · 2025: 70 · 2024: 75 · 2023: 66 · 2022: 69 · 2021: 85 · 2020: 74 · 2019: 88 · 2018: 91 · 2017: 96 · 2016: 99 · 2015: 130 · 2014: 131 · 2013: 116 · 2012: 138
FWCI
7.25
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Biotechnology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Advanced Biosensing Techniques and Applications
  • Life Sciences › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
Keywords
protein biomarkers, biomarker discovery, biomarker validation, mass spectrometry-based proteomics, diagnostic biomarkers, biomarker qualification, research design
MeSH terms
Animals, Blood Chemical Analysis, Blood Proteins, Humans, Peptide Mapping, Sensitivity and Specificity, Mass Spectrometry, Biomarkers, Protein Array Analysis

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