by Lisa Thomas and Bradley Hart AL


The Growth of Mass Spectrometry in the Clinic


Mass spectrometry (MS) is increasingly being adopted by clinical labora- tories for an expanding range of healthcare applications, from forensic toxicology to precision medicine. Faster, more precise and often more cost-effective MS-based workflows and laboratory-developed tests are enabling clinical researchers to obtain results with improved confidence using smaller sample volumes. Yet some healthcare testing labs are late to adopt this technology due to concerns over upfront equipment cost and the time and resources required to develop and validate protocols. To address these challenges, MS systems are becoming more intuitive, allowing operation by nonspecialists, and emerging technologies are set to eliminate sample preparation steps.


Benefits in precision, throughput and affordability Early clinical MS applications were, for the most part, limited to drugs-


of-abuse testing using gas chromatography/mass spectrometry (GC/ MS). The use of MS in the clinical laboratory really took off with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Its adoption over the last 15 years has been driven by the need for greater immuno- assay accuracy, faster results and a desire for cost reduction.


The high specificity and sensitivity of LC-MS/MS overcomes many of the limitations associated with traditional immunoassays, such as nonspecific antibody binding and cross-reactivity,1


giving clinical scientists increased


confidence in results. Immunoassay-based analyses of thyroid cancer pa- tients, for example, are often unable to differentiate disease progression biomarkers such as thyroglobin and autoantibodies produced in the body, resulting in false readings.2


sirolimus, no immunoassays exist, leaving clinical researchers with no choice but to investigate LC-MS/MS for this therapeutic monitoring application.3


LC-MS/MS also allows clinical research laboratories to develop or rep- licate tests for disease biomarkers more quickly than is possible with traditional immunoassays. For instance, many immunosuppressants have a narrow therapeutic index (a measure of the difference between therapeutic and toxic dose), necessitating post-treatment monitoring of drug distribution over extended periods. Therapeutic drug monitor- ing panels are capable of evaluating toxicokinetic response to dosing in addition to monitoring real-time biological response through anti- body production. Advances in full-scan MS technology enable clinical research laboratories to screen for multiple analytes simultaneously, which is beneficial for monitoring individuals taking multiple therapies.


Affordability is another reason clinical laboratories are turning to LC-MS/ MS. Conventional hospital diagnostic assays have largely been based on clinical chemistry and immunoassay techniques, which require


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analyte-specific reagents and antibodies. LC-MS/MS-based approaches are considered reagent-free, which means there is less waste and running costs are approximately one-fifth those of immunoassays.4


Combined


with the expense associated with sending samples externally when spe- cific immunoassays are unavailable in-house, the cost over equipment lifetime can be considerably less.


Trends in MS LC/MS is the dominant technology for clinical research, ’omics and the


discovery and targeted quantitation of protein-based and small-molecule biomarkers. Hybrid MS technology, such as quadrupole-Orbitrap systems (Thermo Fisher Scientific, Sunnyvale, Calif.), couple high-resolution ion- trap instruments with a front-end quadrupole component that allow analytes to be identified with high precision through analyte fragmenta- tion in a more affordable benchtop design. These full-scan techniques enable clinical researchers to scan for highly mass-resolved structures more quickly. Such technology can be employed for “shotgun” proteomics, where proteins are digested to peptides and sequenced by their MS/MS spectra, and for metabolite screening.


In some cases, such as for the immunosuppressant


Advances in clinical multi-’omics show promise to enable noninvasive liquid biopsies for early detection of diseases such as cancer in patients who otherwise present no symptoms. Researchers are leveraging highly sensitive LC-MS/MS for targeted analysis of protein biomarkers in donor samples, providing oncologists with information in minutes. Future ap- proaches may allow greater patient stratification, leading to more targeted treatment, while potentially facilitating improved patient monitoring.


Other MS-based techniques, such as inductively coupled plasma/mass spectrometry (ICP/MS), have undergone intensive development in recent years. With detection limits for most elements about 100 times greater than those achieved by graphite furnace atomic analysis (GFAA) and its multielement capability, ICP/MS has become the standard technique for trace elemental analysis of donor samples. For heavy-metal forensic toxicology, for instance, ICP/MS not only offers more precise quantifica- tion, but also the ability to perform isotopic tracer, dilution and ratio measurements. Such isotopic fingerprinting can help identify the external metal source. Medical scientists are researching the application of this technique to understand an individual’s “personal” ability to absorb es- sential elements, as well as select therapeutics to enable more effective treatment programs in the future.


Advances in ionization techniques such as laser ablation (LA) are enabling clinical researchers to move beyond the ability to merely quan- tify the amount of metal in tissue and to employ proteomic approaches


JANUARY/FEBRUARY 2017


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