Ultrahigh Performance Mass Spectrometry in Clinical Chemistry: A Taste of the Future?

The application of mass spectrometry (MS)-based methods for the analysis of proteins in clinical chemistry has been a source of inspiration for many years (1, 2). Today, however, despite substantial advances in methodology and instrumentation, protein MS is still far from being the standard in clinical chemistry laboratories. MS's ability to generate complex protein or peptide profiles that can be compared among samples was initially recognized as a powerful approach for characterizing pathophysiological states and therefore a promising tool for disease diagnosis and prognosis. This strategy works well with low-complexity proteomes of simple organisms and has allowed MALDI-TOF MS protein profiling to revolutionize the identification of bacteria and fungi in clinical microbiology laboratories (3). However, when applied to more complex samples, such as human blood or urine, the lack of reproducibility of MS proteomic profiling methods and the difficulty in extracting useful information from a vast background of nonmeaningful data were soon considered insurmountable obstacles to clinical application. Because of these limitations, the prevailing view became that, to integrate clinical laboratories, MS protein assays should rely on simpler analytical work flows and straightforward data analysis processes. In other words, rather than comparing long protein lists as done in discovery proteomics, clinical proteomics should focus on the quantification of specific protein biomarkers of relevant clinical interest, taking advantage of the higher analytical performance MS can offer over traditional immunoassays (4, 5). Such targeted MS assays typically combine a protein digestion step, the fractionation of the resulting peptides by liquid chromatography, and the quantification of signature peptides by MS. An immuno-enrichment step of proteins or peptides can be added to increase …