The growth of mass spectrometry and more specifically liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS)2 continues to accelerate in the clinical laboratory. A recent publication (1) provides readers with the opportunity to see where we have been, offering examples of how LC-MS/MS has impacted diagnostic care (steroids and clinical toxicology); where we are (pain management, peptide hormones, and single proteins); and where we are going (protein panels, increased throughput and automation). The techniques and technologies discussed posit 3 conclusions. First, the potential scope of mass spectrometry testing in clinical chemistry is prospectively limitless. Second, the tools and technologies being deployed will require further refinement for mass spectrometers to become established automated clinical analyzers. Third, the promise of reference interval measurement in support of clinical measurement has been practically realized for some applications and is feasible for others. Two central tenets are evident in each application. First, the “killer app” of mass spectrometry incorporates the use of a stable labeled isotope of the analyte(s) being measured with various isotope dilution strategies for calibration. An ideal internal standard is both physiologically unique relative to the composition of the test specimen and physicochemically identical to the analyte, such that recovery, separation, and ionization in each specimen are controlled and corrected: the perfect analytical control for each specimen. Second, multiconcentration calibrators defining the analytical range, often bracketing QCs and samples, control for instrument response drift and deviations from detection linearity over the course of analysis. The combination of these two principles, coupled with the specificity of measurement that LC-MS/MS affords, provides the opportunity for reference level measurement. This, however, comes with historical baggage; LC-MS/MS is almost exclusively deployed in a batch mode of analysis in clinical laboratories. In this issue of Clinical Chemistry , Olson et al. (2) illuminate, illustrate, and iterate …
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