Breaking the Bottleneck in the Protein Biomarker Pipeline

Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Francisco, San Francisco, CA, USA.
Clinical Chemistry (Impact Factor: 7.91). 12/2011; 58(2):321-3. DOI: 10.1373/clinchem.2011.175034
Source: PubMed
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    • "or MS - based analysis Collection and preservation of samples in biobanks is crucial * Very complex proteomes need fractionation Separation of proteins in multiple dimensions Working with subproteomes potential to speed up the validation of candidate biomarkers due to their large multiplex capabilities combined with excellent limits of detection ( Witkowska et al . , 2012 ) . Development of MS - based targeted methods however still take several months for a specific type of biomarker . Furthermore , the production of stable isotope - labeled standards ( SIS ) peptides that allow absolute quantification is still costly ( Parker and Borchers , 2014a ) . An overview of all mass spectrometry - based proteomi"
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    Critical reviews in oncology/hematology 08/2015; DOI:10.1016/j.critrevonc.2015.07.006 · 4.03 Impact Factor
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    • "Biomarker verification is the bottleneck of the biomarker pipeline [9] [10]. It is at this stage that hundreds of candidate markers need to be screened against hundreds to thousands of patient cohorts for evaluation of their true clinical utility [11]. "
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    ABSTRACT: Accurate and rapid protein quantitation is essential for screening biomarkers for disease stratification and monitoring, and to validate the hundreds of putative markers in human biofluids, including blood plasma. An analytical method that utilizes stable isotope-labeled standard (SIS) peptides and selected/multiple reaction monitoring-mass spectrometry (SRM/MRM-MS) has emerged as a promising technique for determining protein concentrations. This targeted approach has analytical merit, but its true potential (in terms of sensitivity and multiplexing) has yet to be realized. Described herein is a method that extends the multiplexing ability of the MRM method to enable the quantitation 142 high-to-moderate abundance proteins (from 31 mg/mL to 44 ng/mL) in undepleted and non-enriched human plasma in a single run. The proteins have been reported to be associated to a wide variety of non-communicable diseases (NCDs), from cardiovascular disease (CVD) to diabetes. The concentrations of these proteins in human plasma are inferred from interference-free peptides functioning as molecular surrogates (2 peptides per protein, on average). A revised data analysis strategy, involving the linear regression equation of normal control plasma, has been instituted to enable the facile application to patient samples, as demonstrated in separate nutrigenomics and CVD studies. The exceptional robustness of the LC/MS platform and the quantitative method, as well as its high throughput, makes the assay suitable for application to patient samples for the verification of a condensed or complete protein panel. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge.
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    ABSTRACT: Perhaps paradoxically, we argue that the biological sciences are "data-limited". In contrast to the glut of DNA sequencing data available, high-throughput protein analysis is expensive and largely inaccessible. Hence, we posit that access to robust protein-level data is inadequate. Here, we use the framework of the formal engineering design process to both identify and understand the problems facing measurement science in the 21st century. In particular, discussion centers on the notable challenge of realizing protein analyses that are as effective (and transformative) as genomics tools. This Perspective looks through the lens of a case study on protein biomarker validation and verification, to highlight the importance of iterative design in realizing significant advances over currently available measurement capabilities in the candidate or targeted proteomics space. The Perspective follows a podium presentation given by the author at The 16th International Conference on Miniaturized Systems for Chemistry and Life Sciences (μTAS 2012), specifically focusing on novel targeted proteomic measurement tools based in microfluidic design. The role of unmet needs identification, iteration in concept generation and development, and the existing gap in rapid prototyping tools for separations are all discussed.
    Analytical Chemistry 08/2013; 85(16). DOI:10.1021/ac4010887 · 5.64 Impact Factor
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