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Making standardization simple

Mass spectrometry (MS) is a well-known and broadly used analytical technique, and one that is particularly effective when coupled with liquid chromatography (LC). LC-MS/MS operates by analyte separation, ionization, mass analysis and detection, and lends itself as an ideal technique to meet the needs of a range of laboratory types. Over the past decade, LC-MS/MS has been applied across several different fields of clinical diagnostics and has become commonplace for forensic and clinical toxicology. However, until now it has only been used across a limited number of specialities, including endocrinology and therapeutic drug monitoring.

By Professor Brian Keevil and Dr Sarah Robinson

Such a powerful technique has the potential to bring significant advantages to the clinical setting, and would enable clinicians to analyse multiple analytes at greater specificities than immunoassay-based methods. It has the potential to supersede alternative methods since it avoids the issues surrounding interferences and the subsequent generation of unreliable data. Even with such advantages, LC-MS/MS has not yet been further adopted by the clinical community. The lack of an automated system has limited its suitability to routine clinical use, while also presenting challenges to laboratories under pressures to standardize and harmonize their practices. Current LC-MS/MS systems involve multiple and complex manual stages that are open to human error while being both time- and labour-intensive. Furthermore, the lack of standardization of LC-MS/MS methods is deterring clinical labs from benefiting from their advantages.

Standardization is critical in clinical laboratories since it is necessary to ensure the correct results are obtained and they are in accordance with results from other labs, especially for therapeutic drug monitoring and endocrine applications.

The challenge of standardization
One of the barriers to more widespread LC-MS/MS use is the lack of properly standardized methods and different laboratories will often use a wide range of techniques, equipment and internal standards. Together, these factors may mean that different results are generated from the same sample.

This level of variation makes it challenging to obtain proper standardization of LC-MS/MS results and is highly problematic. Not only does it become difficult to control results within a lab and ensure they remain comparable year on year, but it can create discrepancies between labs. This could ultimately lead to incorrect patient diagnoses and clinicians recommending the wrong treatment programmes.

The drive for change
Until now, LC-MS/MS systems have been designed with the research laboratory in mind and, as such, are highly configurable making them great for developing methods. However, the needs of the clinical lab are different from those of the research community. The clinical setting requires a dedicated system that not only promotes, but also facilitates standardization. Studies have shown that, through careful use of the same instrument, column and methods, it is possible to generate consistent and reliable resulting data from LC-MS/MS systems based at different laboratories. There is currently a drive from organizations, such as the International Federation of Clinical Chemistry (IFCC), the Centers for Disease Control and Prevention (CDC), and the Endocrine Society, to harmonize assays across laboratories to improve levels of quality. The adoption of one dedicated system among an entire network of laboratories would not only satisfy this organizational drive, but also help clinicians be confident that the data across their entire network is standardized, and thus comparable and repeatable.

The availability of a dedicated system with standardized methods and procedures would make this process significantly easier and remove one of the primary barriers to uptake of this gold standard technique. A dedicated system would need to be optimized for the specific methods run by each laboratory, and available with columns, reagents, calibrators and controls that are consistent and designed specifically for the system. This would help to ensure all data generated is both reproducible and accurate – paramount to patient diagnosis and care. In addition, a clinical LC-MS/MS system would need to be automated and easy to use. Clinical labs are extremely busy so even the most junior members of the staff must be able to operate the instrument and walk away with the confidence that samples are being analysed without error or the need for manual intervention. A system such as this would help to ensure patients were properly diagnosed and appropriate treatment plans devised.

Breaking through the barrier
If a network of laboratories decided to start using a dedicated clinical analyser, it would be able to adopt common reference ranges and reagents, which would provide much greater confidence in the consistency of results. For example, if a patient was transferred to a different hospital mid-way through treatment then there would be a level of assurance that the test results would be the same from both facilities. The data would therefore be directly comparable as long as both labs were using the same dedicated LC-MS/MS system.

Proper standardization is extremely important, yet challenging, and is a key consideration when deciding on an analytical method for implementation. An automated, dedicated clinical LC-MS/MS system would enable inter-laboratory standardization, while allowing interference-prone immunoassay-based tests to be phased out and replaced by clinical LC-MS/MS analysers. The results obtained from one laboratory would then be consistent over many years, and match those results generated from the same patient samples in other labs using the same system. Furthermore, such a system could be operated by the entire laboratory team, removing the need for in-depth and specialist training. This ease of use would decrease the investment required in training, while freeing up more experienced team members to focus on their research.

Analytical techniques are a core component to clinical workflow to ensure accurate patient diagnosis and treatment. LC-MS/MS has clear advantages over alternative immunoassay-based methods, with the ability to analyse multiple analytes at greater specificities. However, its uptake across the clinical community has been slow. This is because LC-MS/MS systems to date have been developed for use in research laboratories, and although the data have been demonstrated to be of high quality, the technology does not simply translate to the needs of the clinical lab.

With analytical needs that directly correlate to patient treatment plans, analytical methods within the clinical lab need to be automated, standardized, reliable and provide walk-away capabilities. This clear need for a dedicated analytical technique has driven the development of the new Thermo Scientific™ Cascadion™ SM Clinical Analyzer*. This dedicated clinical LC-MS/MS system is accurate, easy to use, and has been designed specifically for the clinical laboratory, facilitating standardization both on an inter- and intra-laboratory level to enable clinicians to fully leverage the power of this technique. The impact of this system would help laboratories and laboratory networks to meet their clinical needs.

To find out more, visit www.thermofisher.com/cascadion
*This product is in development and not available for sale. This product is not CE marked or FDA 510(k) cleared.

The authors
Professor Brian Keevil1 and Dr Sarah Robinson2
1Consultant Clinical Scientist and Head of the Clinical Biochemistry Department, University Hospital of South Manchester
2Market Development Specialist, Thermo Fisher Scientific