LC-MS/MS in the clinical laboratory - Where to from here?

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has seen enormous growth in clinical laboratories during the last 10-15 years. It offers analytical specificity superior to that of immunoassays or conventional high performance/pressure liquid chromatography (HPLC) for low molecular weight analytes and has higher throughput than gas chromatography-mass spectrometry (GC-MS). Drug/Toxicology and Biochemical Genetics/Newborn Screening laboratories were at the vanguard of clinical LC-MS/MS use, but have been eclipsed by Endocrine laboratories. In USA reference/referral laboratories, most steroids and biogenic amines are now assayed by LC-MS/MS, and the technology has started to penetrate into smaller laboratories. Assays for mineralo- and gluco-corticoids and their precursors, sex steroids, metanephrines and 25-hydroxy vitamin D highlight the advantages of LC-MS/MS. However, several limitations of LC-MS/MS have become apparent, centring on the interacting triangle of sensitivity - specificity - throughput. While sample throughput is higher than for conventional HPLC or GC-MS, it lags behind automated immunoassays. Techniques which improve throughput include direct sample injection, LC-multiplexing and samplemultiplexing. Measures to improve specificity and sensitivity include sample clean-up and optimising chromatography to avoid interferences and ion suppression due to sample-matrix components. Next generation instrumentation may offer additional benefits. The next challenge for clinical LC-MS/MS is peptide/protein analysis. The quest for multi-biomarker profiles for various diseases has largely failed, but targeted peptide and protein testing by LC-MS/MS, directed at analytical and clinical questions that need to be answered, is proving highly successful. We anticipate that this will result in similar growth of clinical protein/peptide LC-MS/MS as has been seen for low molecular weight applications.