Jeffrey Perkel has been a scientific writer and editor since 2000. He holds a PhD in Cell and Molecular Biology from the University of Pennsylvania, and did postdoctoral work at the University of Pennsylvania and at Harvard Medical School.
It’s no secret that mass spectrometry (mass spec) has emerged as a key tool in life science research. Proteomics and metabolomics, in particular, owe much of their recent success to advances in mass spec. But the technique has value outside the research lab, too, including in the clinic.
On some level, of course, a mass spec is a mass spec, whether it’s intended to reside in either a research or a clinical lab.
But clinical mass spectrometers typically are less flexible in terms of application, simpler to operate and specially certified for use in a regulated environment.
To learn how clinical mass spectrometers are used and what to look for in making a purchase, Biocompare spoke with Dr. Scott Kuzdzal, general manager of marketing at Shimadzu Scientific Instruments; Lisa Thomas, senior director for clinical, forensic and toxicology markets, chromatography and mass spectrometry at Thermo Fisher Scientific; and Jim Langridge, director of health sciences at Waters Corp. Here are the responses they shared with us.
What classes of mass spectrometer are typically used in the clinic?
Jim Langridge: The clinical environment today is really dominated by tandem quadrupoles. They’re absolutely perfect for the environment: They’re very robust, very rugged. You can get high-throughput on them when LC-MS/MS is combined with good sample preparation. And those are the types of things that really drive the clinical lab—productivity, robustness and confidence in the results. Often, though, these labs also have associated labs performing research activities. That’s obviously more exploratory, so there you see different types of mass spectrometers being used, like time-of-flight systems and other higher-resolution analyzers.
What are the most popular assays in the clinical environment?
Jim Langridge: There are a variety of different assays, but Vitamin D and immunosuppressant drug-dosage monitoring—those two are the big ones. And use of tandem mass spectrometry for neonatal screening also has a lot of interest: profiling amino acids and acyl-carnitines in neonatal blood to ensure babies don’t have any metabolic disorders.
Scott Kuzdzal: Questions are frequently aimed at the microheterogeneity of a class of compounds, such as glycoproteins in proteomics. Clinical researchers may investigate the effects of diseases on such heterogeneity and look for surrogates to actively monitor diseases, or they may wish to elucidate a biochemical pathway. We are seeing more and more questions regarding biological function. Mass spectrometry is best positioned to answer these questions due to its inherent speed and sensitivity.
Why use mass spectrometry rather than ELISA in the clinic?
Scott Kuzdzal: ELISA remains a powerful tool today due to the fact that it is rapid, scalable and specific. Its specificity, however, is also a limitation. Because an ELISA assay is dependent upon binding of the analyte by an antibody, it cannot distinguish between antigenically identical analytes. Also, ELISA assays take time to develop in commercial, kit form, and antibodies are expensive. Mass spectrometers coupled with chromatography can distinguish between different isoforms, and have the advantage that new analytes can be added to a compound list as soon as methods are developed.
Jim Langridge: In the clinical mass spectrometry area, we see a lot of interest in developing LC-MS assays where there are issues with the immunoassay. A good example is Waters’ MassTrak Immunosuppressant Kit for LC-MS/MS, where there are known issues with the immunoassay in terms of cross-reactivity of the antibody for [the immunosuppressant] tacrolimus, and therefore that gives poor precision and accuracy. So LC-MS is very much used as an orthogonal technique to that, to provide more reliable results.
What key challenges do would-be mass spec users face in clinical laboratories?
Lisa Thomas: There are several, including technology expertise. The health-care market is accustomed to purchasing “push button analyzers,” so the expertise to onboard mass spectrometry for some institutions remains a challenge. Laboratories continue to desire FDA or locally approved tests to reduce their risk, however market approval continues to be a lengthy endeavor. Additionally, the lack of standardized reference materials for certain drugs (i.e., immunosuppressants) means results may vary from lab to lab. Other challenges include automation, cost of ownership and fear of workflow downtime. (The most common source of downtime is the HPLC.)
What advice would you offer those in the market for a clinical mass spec?
Jim Langridge: Amazingly, performance per se is not the overriding factor. The research world is all about performance and pushing the boundaries. In the clinical world, it’s about ensuring you get the right result and are confident in what you’re doing. The same is true, I think, with purchasing decisions, where you see people wanting to deal with someone that can provide the complete solution—not just hardware but software, making sure the system is robust, reliable, and that you have good post-sale support. All of those variables that might be called ‘soft factors’ in the research world really are critical to the clinical laboratory.
What trends and/or unmet needs are you seeing in the clinical mass spectrometry marketplace?
Lisa Thomas: The next “big thing” in the application of mass spectrometry to clinical research is the integration of genomics, mass spectrometry “omics” and exogenous drug measurements to enable diagnosticians and physicians to answer common questions such as: “Is this the right treatment, at the right time, in the right amount for the right person?” Mass spectrometry provides more precise knowledge of a patient’s disease, enabling targeted treatment approaches, re-introduction of drugs that are specific to certain patient populations, rapid validation of new drugs and health-care industry cost savings.
Scott Kuzdzal: Full clinical-laboratory automation remains one of the greatest challenges in clinical MS. While mass spectrometers are exceptionally fast, the sample-preparation steps are frequently manual and tedious. Another issue: Quantitative protein assays on triple-quadrupole LC-MS/MS typically require synthetic or expressed peptide/protein standards, but preparing those can be time consuming and expensive. Researchers at the University of Arkansas have developed a method that requires no standards; instead, proteins of interest are targeted and quantified using MRM methods developed using Skyline software and a Shimadzu triple-quad LC-MS/MS, based on retention time and sequence-specific fragment ions.
What mass spec systems would you recommend for clinical laboratories?
Scott Kuzdzal: Ultra-fast triple-quadrupole mass spectrometers in multiple reaction mode remain the gold standard for accurate, targeted quantitative, clinical assays. Our newly developed UF-Qarray ion guide increases LC-MS/MS sensitivity by enhancing ion signal intensity and reducing noise. By improving the ion-sampling device, the ion guide and the vacuum efficiency, our Shimadzu LCMS-8060 delivers a new vision of sensitivity and makes a real difference in increasing the throughput of clinical research laboratories.
Jim Langridge: Waters has several triple quads for clinical mass spectrometry, including the ACQUITY® TQD, Xevo® TQD, Xevo TQ-S and most recently, the Xevo TQ-S micro. The difference comes down to sensitivity: In a lot of cases, we find the Xevo TQD has the right blend of sensitivity and performance to be able to solve the problems in the clinical lab. But there are assays—for instance, for estradiol—that are more challenging in terms of sensitivity, where you need the ultimate performance.
The Xevo TQ-S micro is a more compact and less expensive version of the Xevo TQ-S, our top-of-the-line clinical mass spectrometer, for laboratories where space is at a premium. In January of this year, the UPLC I-Class Xevo TQ-S micro system, comprising both the UPLC system and mass spectrometer, was IVD-marked, which allows it to be used in the clinical environment.
Lisa Thomas: Thermo Fisher Scientific has developed several instruments for general use in clinical mass spectrometry workflows that are listed as medical devices with the U.S. FDA: The Endura MD™ triple quadrupole mass spectrometer, Prelude MD™ sample cleanup and liquid chromatography system and Prelude LX-4 MD™ HPLC.
The Thermo Scientific™ Prelude MD automated multichannel HPLC enables automated sample cleanup using patented Thermo Scientific Turboflow™ technology and two channels of HPLC separation to simplify sample cleanup while also improving productivity and certainty from laboratory-developed clinical mass spectrometry diagnostic tests. For complex biological samples, TurboFlow improves mass spectrometry detector response to analytes of interest by removal of non-analyte matrix interferences, such as phospholipids, that can interfere with the measurement of the analyte, subsequently improving signal-to-noise ratio. The Thermo Scientific Prelude LX-4 MD automated multichannel HPLC delivers up to four different separations to a single mass spectrometer.
Researchers as well as clinicians continue to push the boundaries on the utilities and applications of mass spec in the lab. Mass spectrometry brings greater detail and sensitivity when characterizing target proteins, and this will ultimately translate to researchers and clinicians obtaining a better understanding of disease states and devising potentially better treatments.
These comments have been edited for length and clarity.
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