Mass Spectrometry Is Finding Larger Role in Clinical Labs

It’s a fast-growing trend in both the United States and Europe

CEO SUMMARY: Mass spectrometry is a diagnostic technology that is transforming clinical labs and improving care at a rapid pace. The current generation of instruments is capable of supporting a faster time-to-answer and provides improved accuracy and specificity over many existing methods. For certain clinical assays, mass spec also can cost less per test than conventional testing methods. Advocates of mass spectrometry predict a bright future for its use in clinical diagnostics.

BY PRODUCING BETTER RESULTS faster and cheaper than conventional diagnostic methods, mass spectrometry is displacing long-established technologies.

In many ways, mass spec has a legitimate claim as one of the next “big things” to happen in laboratory medicine. In fact, advocates of mass spectrometry predict that, at some future point, this method may become the dominant mode of testing in many labs.

Further, these same experts acknowledge that, although molecular and genetic testing will have growing and important roles in laboratory medicine, it is mass spectrometry that is poised to assume a large share of the workload in clinical labs.

If this proves true over time, it means that the adoption of mass spec for a growing number of clinical diagnostic purposes will be one of lab medicine’s essential trends. For these reasons, lab administrators and laboratory directors will want to be up-to-date on this rapidly-evolving technology.

“Already, mass spectrometry is becoming the pre-eminent technology in microbiology,” said David A. Herold, M.D., Ph.D., Chief of Clinical Chemistry at the VA San Diego Healthcare System and a Professor in the Department of Pathology at the University of California, San Diego. “Because it can deliver critical time-sensitive test results in a rapid manner, mass spectrometry is shortening test turnaround times in the microbiology lab.” (See sidebar below.)

“Mass spectrometry allows clinical labs to get answers more quickly than can be obtained from conventional testing methods for many assays,” Herold said. “When used appropriately, mass spec can significantly reduce the time needed to identify pathogens compared with more traditional laboratory testing methods. Thus, treating physicians can administer appropriate therapies confidently. In turn, appropriate therapies reduce costs and shorten length of stay.

“In fact, for microbiology, the earliest fully-automated mass spec systems specifically designed for use in clinical laboratories are already in beta testing,” Herold observed. “These are expected to earn FDA clearance over the next 6 to 18 months. As that happens, medical technologists will be using integrated mass spectrometry systems that are load-and-walk-away.

“In my view, these fully-automated mass spectrometry systems will trigger a fundamental change in microbiology, for example,” he said. “Additionally, pioneering work provides evidence that mass spectrometry could have a similarly dramatic effect on immunoassays as well.

“Currently, mass spectrometry is assuming a larger role in clinical testing, even though this method is manually intensive,” he noted. “What will accelerate acceptance by labs is the arrival of highly-automated mass spec systems into the clinical marketplace. Multiple vendors are poised to introduce such solutions.

Higher Accuracy

“More importantly, mass spec delivers results with higher accuracy, and at lower concentrations, than is possible with many immunoassays,” stated Herold. “Use of stable isotope labeled internal standards, sample preparation, high performance liquid chromatography, and specific mass spectrometry methods lead to increased confidence that the right answer is obtained.

“We regularly see instances in which mass spec is the only instrument that will produce the correct answer needed for precise diagnosis,” said Herold. “Testosterone is perhaps the poster child for mass spec testing. A growing number of endocrinologists view mass spec—rather than an immunoassay—as the most accurate method for measurement of testosterone in women and children.

“Physicians and lab medicine professionals seem to be moving in the direction of using mass spectrometry as the preferred method for all testosterone testing,” he continued. “Of course, in this stage of its clinical acceptance as a diagnostic technology, there are specific patient cases where mass spec is the best method for diagnosis. There are cases, however, where use of an immunoassay continues to be appropriate.”

Factors Supporting Adoption

Herold took care to explain some of the strategic factors supporting greater adoption of mass spectrometry for clinical testing. “As with any change in healthcare, there are multiple reasons for this shift,” he said. “At least four primary factors are driving this trend.

“First, the per-test cost for mass spec analysis tends to be less expensive (not including the initial capital investment for the instrument) when compared with other accepted methods,” Herold stated. “At a time when lab test reimbursement and lab budgets are shrinking, this becomes an important consideration.

“Second, results are more accurate with enhanced sensitivity when the mass spec assays are performed properly,” he continued. “Pathologists and laboratory scientists prefer such accuracy.

“Third, mass spectrometry can be faster—significantly so,” Herold noted. “The faster time-to-answer is one way that labs can deliver more value to clinicians, since the rapid delivery of test results can contribute to improved patient outcomes and reduced costs for the healthcare encounter.

“Fourth, mass spectrometry can analyze multiple analytes simultaneously without sacrificing analytical precision or accuracy,” he added. “This is another capability that is attractive to clinical labs.

“Take, for instance, the analysis of thyroid hormone levels” said Herold. “Using immunoassays, you would have to measure three thyroid hormones one at a time. However, with mass spec, it is possible to measure all three hormones simultaneously. The extension to steroid and pain clinic profiles are logical segues.”

To date, the adoption curve for mass spec in clinical diagnostics has proceeded in a step-wise fashion. “Mass spectrometry was quickly adopted for drugs-of- abuse testing and for inborn errors of metabolism,” he said. “Next, mass spec was adopted for use in testing for testosterone and vitamin D levels.

“These trends drove growth in the use of mass spec for clinical diagnostic purposes,” Herold explained. “This was particularly true after it became apparent that mass spec was a viable way to perform a vitamin D test rapidly.

“It was widely known that, in recent years, some of the national labs set up their mass spec instruments to do vitamin D tests at the rate of one sample per minute for 24 hours a day six days a week,” he recalled. “Typically on Sundays, these labs would perform maintenance on the instruments and then restart the machines again on Monday.”

Mass Spec and Vitamin D

This happened at a time between 2007 and 2011 when the volume of Vitamin D specimens was literally doubling every six months. It was common to see some of these national labs charge patient fees of as much as $225 to run each vitamin D 25(OH) D test.

“The surging volumes of vitamin D specimens during this time gave lab scientists the idea that this testing could be done quickly with mass spectrometry and the volume would generate substantial revenue at a reduced cost per analysis,” Herold observed. “Essentially, these labs were applying industrial pharmaceutical techniques to this area of medical laboratory testing.

“Here’s a good example of the type of cost/benefit analysis a laboratory would do for vitamin D testing,” he offered. “At our laboratory, we could perform the test here or send it out. “To do the analysis in our lab, the cost of consumables for each vitamin D test via mass spectrometry would be $2.75 to $3,” Herold said. “However, now in 2013, if we sent it out, the best price we’d get from a national lab is about $20 per test on our high-volume account.

“To this amount, it is necessary to add the time and labor required to package the specimens and get the test results into the LIS,” he stated. “If my lab can save $17 or more on each of 70,000 vitamin D tests every year, that reduces spending in my lab by almost $1.2 million.

“In turn, these savings would allow us to recover the cost of acquiring the mass spec equipment within the first four months of its use,” Herold said.

“Once a lab has put mass spectrometry equipment into operation, it makes clinical and economic sense to add other tests,” observed Herold. “That optimizes the return on the lab’s capital investment.

More Productivity

“For example, today it is common to see a lab use mass spec to run vitamin D tests,” he commented. “Then, that lab likely would add testosterone, drugs-of-abuse screens, and other tests. This makes sense because the more assays that are run on the mass spec, the greater the productivity attained from both lab personnel and instrumentation.

“There’s another advantage that mass spectrometry equipment has over immunoassay analyzers,” stated Herold. “Currently mass spec instruments tend to be more robust and hence have less down time for maintenance and repair than analyzers running immunoassays.

“Just a couple of years ago, that was not true,” he recalled. “During that period, uptime for mass spec equipment was often problematic. But manufacturers recognized and addressed this failing.

Auto Samplers

“In my view, the only apparent weak point for the current generation of mass spectrometry equipment now is that the auto samplers are not designed to handle hundreds of thousands of tests per month. Equipment operated at that workload will experience some breakdowns.

“Another important distinction between mass spec and immunoassay analyzers is the accuracy of mass spectrometry. With immunoassays, it is necessary to contend with the potential for interference where a detection agent (such as an antibody) cross-reacts and binds with other similar immune-reactive species,” he added. “This interference reduces the specificity of immunoassays, in general. Labs spend a lot of time addressing this problem.

“In contrast to immunoassay methods, mass spectrometry can identify the precise molecule in question,” stated Herold. “Now, for mass spectrometry there is also less sample preparation than has been required historically—even for difficult analyses.

“Today’s mass spec instrumentation supports running high-volume tests,” he said. “It can also perform assays that may analyze different types of specimens, including serum, plasma, cerebrospinal fluid, and blood spot cards.

Increased Specificity

“Mass spec permits isolation of a specific molecular ion that can be further fragmented to create daughter ions, and which, as a whole, represent the mass fingerprint of the molecule,” stated Herold. “This information can be used to specifically quantitate an analyte with high confidence. Compared with immunoassay this method increases the specificity of the analysis, which pathologists appreciate because it removes a level of uncertainty.

“Staffing to operate a mass spec testing program is another issue that labs must consider,” he stated. “The good news is that each generation of mass spec analyzers is smaller and more user friendly. At the same time, these lab instruments are also becoming more sophisticated.

“The staffing requirements needed for a lab to run a mass spec depend on what the lab aims to do with mass spec and how fast it wants to introduce this equipment or expand what exists,” said Herold. “The current state of mass spec instrumentation can be run by medical technologists who have been appropriately trained. As the next level of sophistication arrives for this equipment, a lab can continue running at the present level or it will be necessary to develop more sophisticated staff to use these instruments to their optimal limits.

“In fact, labs today would benefit from using lab staff willing to become more knowledgeable about mass spec as this
methodology and the associated technologies become more refined,” advised Herold. “It would be ideal to get personnel involved who have an interest not only in mass spec, but in data analysis as well, since mass spectrometry testing generates large quantities of data, especially with the emergence of metabolomic and proteomic analyses.

“Meanwhile, labs are moving quickly to adopt mass spectrometry,” noted Herold. “It is already in use at more than 600 hospitals in Europe. Academic and research hospitals here in the United States are actively using mass spectrometry as well.

“Currently, microbiology is leading the charge in getting mass spectrometry into the clinical lab,” stated Herold. “Several manufacturers have applied to the FDA for clearance of their diagnostics.

“These are the reasons mass spectrometry has expanded quickly over the past few years,” concluded Herold. “That it has gotten this far this fast is encouraging, and I believe it will continue to develop rapidly in the coming years.”

Houston’s Methodist Hospital Uses Mass Spec to Foster Lab and Pharmacy Collaboration

INNOVATIVE HEALTHCARE INSTITUTIONS are beginning to tap the capabilities of mass spectrometry in impressive ways. That was certainly the case when the results of a research study conducted by the departments of Pharmacy and Pathology and Genomic Medicine at the 1,000-bed Methodist Hospital in Houston, Texas, were reported.

The study showed that by using mass spectrometry, the pathology and pharmacy departments could collaborate to identify gram-negative bloodstream infec- tions quickly and get patients started on appropriate antibiotics. This testing method allowed the patients to leave the hospital sooner than if conventional lab testing methods were used.

By reducing length of stay, the researchers were able to slash costs by almost $20,000 per patient. From this intervention, the total annual savings for the hospital could be about $18 million, the researchers reported.

Study Used MALDI-TOF

This study was published online in the Archives of Pathology & Laboratory Medicine on December 6, 2012. The article, “Integrating Rapid Pathogen Identification and Antimicrobial Stewardship Significantly Decreases Hospital Costs,” explained that the researchers used matrix-assisted laser desorption ionization time- of-flight (MALDI-TOF) mass spectrometry to analyze microbial proteins in patients with blood stream infections (BSIs).

In clinical practice, use of MALDI-TOF technology for routine bacterial identification is in its infancy, the researchers reported. Therefore, their goal was to determine if mass spectrometry, in tandem with what they called antimicrobial stewardship, could substantially improve care for patients with BSIs compared with conventional testing.

Improved Patient Outcomes

“Early diagnosis of gram-negative BSIs, prompt identification of the infecting organism, and appropriate antibiotic therapy improved patient care outcomes and decreased health care expenditures,” the study authors wrote. “In an era of increasing antimicrobial resistance, methods to acquire and rapidly translate critical results into timely therapies for gram-negative BSIs are needed.”

By comparing outcomes for patients hospitalized before the intervention was implemented with the outcomes of those patients treated after implementation, the researchers reported decreased length of hospital stay (LOS) and lower costs.

After accounting for other factors that might affect LOS, they concluded that mean LOS in the preintervention group was 11.9 days versus 9.3 days in the intervention group. Mean hospital costs per patient were $45,709 in the preintervention group and $26,162 in the intervention group, representing a savings of $19,547 per patient, they reported.

“In our 1,000-bed quaternary care hospital, we project a cost savings of [about] $18 million annually with the implementation of this strategy for the management of gram-negative BSIs,” the researchers reported.

 

Mass Spectrometry Has a Long History, Now Gaining Acceptance for Clinical Testing

MASS SPECTROMETERS have been in use for over 100 years. The machines had their incarnation in the late 19th century.

Their first use for biological applications started in the mid-1950s. For most of their existence, however, they have been relegated to research applications as their characteristics made then incompatible with either unsophisticated users or high-throughput applications. New developments that make them more user-friendly and reliable are in the process of uncloaking a valued analytical tool that is now setting its sights on the clinical lab.

“Early on, mass spec equipment was both expensive and required operators with highly specialized training,” said David A. Herold, M.D., Ph.D., Chief of Clinical Chemistry at the VA San Diego Healthcare System and a Professor in the Department of Pathology at the University of California, San Diego. “If it ran for more than a week without needing troubleshooting and maintenance you were lucky. It was the perfect recipe for an esoteric research device, not a clinical analyzer.

“But after mass spec vendors identified clinical analysis as an attractive opportunity for this technology, they have made it their mission to hone these machines into pillars of reliability and ease of use,” continued Herold. “That process is ongoing, but without a doubt the technology has gained increased acceptance in the clinical lab over the past five to seven years.

“At least two advantages of mass spectrometry are the cost and precision of analysis,” Herold noted. “Once you make the capital investment in a mass spectrometer, the cost per test is near equivalent or significantly less than comparable immunoassays. Consider as well the increased accuracy, precision, and sensitivity, and you’ve got a powerful combination that addresses both economic- and healthcare-conscious interests.”

Herold also is the President and Scientific Chair of the Association for Mass Spectrometry: Applications to the Clinical Lab (www.mascl.org), which holds an annual conference covering topics that include the development and adoption of mass spectrometry for clinical analysis. The next conference will be March 1 to 5, 2014, in San Diego, California.

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