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Qualification and Verification of Protein Biomarker Candidates

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Modern Proteomics – Sample Preparation, Analysis and Practical Applications

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 919))

Abstract

The importance of biomarkers has long been recognized by the public, scientific community, and industry. Yet despite extensive efforts and funding investments in biomarker discovery, only 109 protein biomarkers in plasma or serum were approved by the US Food and Drug Administration throughout 2008 (Anderson NL. Clin Chem 56:177–185, 2010), and even fewer protein biomarkers are currently used routinely in the clinic. In recent years, the introduction of new protein biomarkers approved by the US Food and Drug Administration has fallen to an average of 1.5 per year (a median of only 1 per year) (Anderson NL. Clin Chem 56:177–185, 2010). The low efficiency of biomarker development is due to several reasons, including the poor quality of clinical samples, the gap between subjective clinical definition of a disease and objective protein measurements, and high false discovery rate of differentially expressed proteins identified in the initial discovery phase (Rifai N, Gillette MA, Carr SA. Nat Biotechnol 24:971–983, 2006). It has become clear that the vast majority of differentially expressed proteins identified in the discovery phase will ultimately fail as useful clinical biomarkers, and only few true positive candidates can move through the biomarker development pipeline. Isolation of true biomarkers from the large pool of differentially expressed proteins identified in the discovery phase becomes the greatest challenge and the bottleneck in most biomarker pipelines. To succeed, after the initial discovery study (see Chap. 20), the authenticity of biomarker candidates need to be tested in a pilot study with high throughput, high accuracy and reasonable cost. This essential process is addressed by qualification and verification phase of the biomarker development pipeline.

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Abbreviations

AIF:

All-ion fragmentation

AIMS:

Accurate inclusion mass screening

AQUA:

absolute quantification peptides standard

CART:

classification and regression trees

CE:

capillary electrophoresis

CFD:

complement factor D

CV:

coefficient of variation

DDA-MS/MS:

data-dependent MS/MS acquisition

DIA-MS/MS:

Data-independent MS/MS acquisition

ELISA:

Enzyme-linked immunosorbent assay

FDR:

false positive rate

FWHM:

full width at half maximum

HCD:

higher energy C-trap dissociation

HPLC:

high performance liquid chromatography

HR/AM:

high resolution and mass accuracy

IPed:

immuno-precipitated

LC:

liquid chromatography

LLOQ:

lower limit of quantification

LOD:

limit of detection

MARS:

multivariate adaptive regression splines

MS:

mass spectrometry

MS/MS:

tandem mass spectrometry

PAcIFIC:

Precursor acquisition independent from ion count

PRM:

parallel reaction monitoring

QCAT:

concatemer of standard peptides

QQQ-MS:

triple quadrupole mass spectrometry

SAM:

significance analysis of microarray

SEC:

size-exclusive chromatography

SID:

stable isotope dilution

SISCAPA:

stable isotope-labeled standards with capture by anti-peptide antibodies

SOPs:

standard operating protocols

SRM:

selected reaction monitoring

SWATH:

Sequential window acquisition of all theoretical mass spectra.

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Authors and Affiliations

  1. The University of Texas Medical Branch, 301 University Blvd, 77555, Galveston, TX, USA

    Yingxin Zhao & Allan R. Brasier

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  1. Yingxin Zhao
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  2. Allan R. Brasier
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Correspondence to Yingxin Zhao .

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  1. UT Southwestern Medical Center, Dallas, Texas, USA

    Hamid Mirzaei

  2. Biotech Division, Neurophagy Therapeutics, INC, Odessa, Texas, USA

    Martin Carrasco

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Zhao, Y., Brasier, A.R. (2016). Qualification and Verification of Protein Biomarker Candidates. In: Mirzaei, H., Carrasco, M. (eds) Modern Proteomics – Sample Preparation, Analysis and Practical Applications. Advances in Experimental Medicine and Biology, vol 919. Springer, Cham. https://doi.org/10.1007/978-3-319-41448-5_23

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