If you have a child under 25, he or she is likely the beneficiary of the first clinical application of mass spectrometry. In the early 1990s mass spec was introduced to hospital or clinical laboratories for newborn screening of inborn errors of metabolism.

Since then clinical applications of mass spec have expanded to the infectious disease field, drug toxicology testing (such as opioid testing), endocrinological testing, and therapeutic drug monitoring. These are all situations where a few different types of related molecules (or lack thereof) need to be measured accurately and quickly in one test—an application that mass spectrometers are especially well suited for.

Why mass spec

Traditional techniques for detecting and measuring the presence or absence of proteins such as immunoassays have drawbacks of cross reactivity, less sensitivity, and not being able to detect all the “proteforms”, variations of the proteins with its post-translational modifications. Additionally, immunoassays can only be used to detect proteins whereas mass spectrometers can detect any type of biological molecule by separating molecules based on their mass/charge ratio. So mass spec allows biomarker research to expand beyond just proteins.

Workflow enhancements are one of the main reasons for increasing adoption of mass spectrometers in the clinical lab.

Donald Mason, global scientific affairs manager at Waters, cites workflow enhancements as one of the main reasons for increasing adoption of mass spectrometers in the clinical lab (hospitals, reference labs such as Quest, and private testing labs). The advances include pre-analytic improvements in sample prep, more high-performing chromatography options coupled to the mass spec instrument, and at the back end, better software that allows transfer of data to a hospital’s information system.

Home grown mass spec kits: LDTs

In order for a clinical laboratory to use mass spec for a clinical application such as drug testing or vitamin D testing, they need to create a laboratory developed test (LDT). “There are specific CLIA guidelines that need to be followed to demonstrate that the LDT is reliable enough for the diagnosis purposes. The LDTs have to be properly calibrated, controlled, and validated. LDTs require highly trained staff such as an LC/MS specialist with a Ph.D.”, explains Aaron Hudson, senior director & general manager of SCIEX Diagnostics.

Clinical labs find it worth the effort though because of the efficiency afforded by mass spec in being able to measure more than one type of molecule in a single experiment. For example, according to Mason, multiple metabolites of vitamin D may be measured from the same sample, or in the case of an estrogen test, one test might reveal estrone, estradiol, and estriol levels.

Another big incentive to mass spec adoption in the clinical lab is the fact that much of biomarker research is accomplished with mass spectrometers, so it’s easy to move that to clinical applications. Mass spec also provides costs savings in cases where it’s being used to replace radio isotope-based assays.

Newest trend—Mass spec made easy

The most recent trend in the clinical mass spec arena is a new kind of “almost anyone can use” mass spectrometer. Within the past year, two regulatory agency-cleared, more user-friendly mass spec kits have become available in the U.S. and Europe. The first mass spec kit approved for use was in Europe and developed by Waters for measuring the presence of an immunosuppressant, tacrolimus, in samples from kidney and liver transplant patients.

The second mass spec kit within the past year was by SCIEX for vitamin D assays. It was cleared by the FDA in May 2017 via the de novo regulatory pathway.

While this is not an easy process for the developer, it’s worth it to the end-user because it enables nonheavily trained personnel to perform the test. Another key advantage is that it allows hospital labs to avoid the LDT process. “Hospital core labs are very busy and many don’t have the time to develop their own assays. I could see this trend of instrument companies developing FDA-cleared kits accelerating the adoption of mass spec for clinical lab testing.” Hudson also believes that by reducing the the time and effort required to develop CLIA-compliant LDTs hospital lab can save money.

However launching a mass spec kit is not an easy process for a mass spec company. According to Hudson, it took SCIEX two to three years to develop and then get FDA clearance for its vitamin D kit. They had to compare it to standard vitamin D programs run by the CDC to prove its accuracy. But for an application like vitamin D testing, which is one of the top five assays reimbursed by Medicare according to the Office of Inspector General, it’s worth the development costs for the company, Hudson says.

What were the innovations?

There haven’t been many mass spec instrument innovations in the past 10 years. Clinical applications rely on “targeted” mass spec assays where you know what you’re looking for and you adjust the mass spec to “look” in that range. The tandem quadrupole mass spec is the workhorse for “targeted” applications of mass spec. Rather, innovations have been in the peripheral areas of mass spec that enhance key requirements for a clinical lab such as accuracy, speed, reproducibility, and multiplexing.

Lisa Thomas, senior director of marketing, chromatography and mass spectrometry at Thermo Fisher Scientific, delineates these peripheral advances as automated, multichannel sample prep; the ability to add more sophisticated HPLC units to handle more samples at once; more automation in middle steps for accuracy and speed; and more intuitive software at the backend. Mason and Hudson also cite software advances that enable easier use and integration with other systems as key improvements.

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Jennifer Van Eyk, director, Advanced Clinical Biosystems Institute in the department of biomedical sciences at Cedars-Sinai, concurs about automation playing a central role to adoption of mass spec in the clinical arena. But she also cites advances in discovery. “Knowing the types of proteins you should look at for different conditions is important for ‘targeted assays’ so that you know the parameters to input to mass spec. We are in unprecedented times with everything congealing: on the research side we know more markers, on the technological side, companies have made significant advances with automated sample preparation and then on the hospital side we have the e-health initiative that dovetails with the companies’ software advances.”

The future

Dr. Van Eyk believes remote patient monitoring is another near-term application of mass spec in the clinical field. Because of improvements in sensitivity, less sample is needed, which allows a patient to simply put blood from a finger prick onto filter paper and mail it for mass spec analysis. Soon physicians may be able to monitor their patients for long periods of time for example by analyzing their finger pricks two years after surgery to measure various markers—helping achieve a goal of personalized medicine. Companies such as Neoterix have already sprung up to help with such sample collection. But all scientist interviewed agreed that the next frontier is bringing mass spec to the people analyzing a patient’s sample right there in the doctor’s office. According to Dr. Van Eyk , the DOD is investing in this. Mason believes mass spec in direct patient care is probably at least five to ten years away. Once the instrument is no longer considered a high-complexity instrument, he could envision it being used for rapid testing of parameters related to diabetes, for example, in the doctor’s office. As Hudson explains, innovations in software cannot be underestimated for making mass spec usable by a broader base.

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