CLSI C62-A: A New Standard for Clinical Mass Spectrometry.

Until recently, there existed minimal guidance on the use of LC-MS for clinical diagnostics. The Clinical and Laboratory Standards Institute (CLSI) has now presented a standardized approach for LC-MS assay development and verification in its new guidance document, CLSI C62-A. This document should aid in the harmonization of LC-MS methods and thus have significant ramifications for the evolution of this technology in the clinical laboratory. The ability to accurately identify and quantify a measurand with high sensitivity and specificity by use of selective reaction monitoring has been the driving force for the adoption of LC-MS in the clinical laboratory. LC-MS offers analytical specificity superior to that of widespread diagnostic methodologies such as immunoassays and enzymatic assays. Whereas immunoassays are commonplace in the clinical laboratory, they are not available for all analytes of interest, are plagued by specificity issues, and require the time-consuming production and evaluation of antibodies during development. Just as immunoassays have evolved since their development 50 years ago and have found their place as the leading automated technological approach to diagnostic testing, mass spectrometry (MS) will continue to progress and influence the clinical laboratory landscape. Therefore, standardization of the use of LC-MS is essential. Mass spectrometers were initially used in clinical laboratories only for specialized testing by highly trained and experienced operators. Today they are essential for the diagnosis of metabolic disorders, screening of diseases, quantification of hormone concentrations, monitoring of drug therapies, identification of microbial organisms, and recognition of drug toxicity and poisonings. Without the current clinical quantitative LC-MS methods, metabolic disorders would go undetected at birth, the accuracy of testosterone measurements for women and children would be equivalent to an educated guess, and monitoring of a variety of chemotherapeutics and immunosuppressants would be limited. Despite its widespread use, there is only 1 quantitative LC-MS assay approved by the US Food and Drug Administration (FDA); all other assays fall under the FDA classification of laboratory-developed test (LDT). An LDT is defined as an in vitro diagnostic test that is designed, manufactured, validated, and used within a single laboratory. Therefore, no 2 LC-MS methods for the same analyte are alike. The number of variables that could exist between any 2 LC-MS methods developed for the same purpose are too numerous to list, but include sample preparation method, instrumentation used, liquid chromatography stationary and mobile phases, MS sourceand compound-dependent parameters, ion transitions monitored, and most importantly, calibrators used.