Spectra-first feature analysis in clinical proteomics - A case study in renal cancer.
In proteomics, useful signal may be unobserved or lost due to the lack of confident peptide-spectral matches. Selection of differential spectra, followed by associative peptide/protein mapping may be a complementary strategy for improving sensitivity and comprehensiveness of analysis (spectra-first paradigm). This approach is complementary to the standard approach where functional analysis is performed only on the finalized protein list assembled from identified peptides from the spectra (protein-first paradigm). Based on a case study of renal cancer, we introduce a simple spectra-binning approach, MZ-bin. We demonstrate that differential spectra feature selection using MZ-bin is class-discriminative and can trace relevant proteins via spectra associative mapping. Moreover, proteins identified in this manner are more biologically coherent than those selected directly from the finalized protein list. Analysis of constituent peptides per protein reveals high expression inconsistency, suggesting that the measured protein expressions are in fact, poor approximations of true protein levels. Moreover, analysis at the level of constituent peptides may provide higher resolution insight into the underlying biology: Via MZ-bin, we identified for the first time differential splice forms for the known renal cancer marker MAPT. We conclude that the spectra-first analysis paradigm is a complementary strategy to the traditional protein-first paradigm and can provide deeper level insight.
* School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Tianjin 300072, P. R. China.
Wilson Wen Bin
WW
Goh
† Department of Computer Science, National University of Singapore, 13 Computing Drive, 117417 Singapore.
Limsoon
L
Wong
D014408:Biomarkers, Tumor / Q000032:analysis; D005189:False Positive Reactions; D000066506:Heuristics; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods*; D007680:Kidney Neoplasms / Q000378:metabolism*; D013058:Mass Spectrometry / Q000379:methods*; D010449:Peptide Mapping / Q000379:methods; D010455:Peptides / Q000032:analysis / Q000378:metabolism; D020033:Protein Isoforms; D040901:Proteomics / Q000379:methods*; D015203:Reproducibility of Results
D014408:Biomarkers, Tumor; D010455:Peptides; D020033:Protein Isoforms
Mass spectrometry; SWATH; data independent acquisition; feature-selection; proteomics