In recent years, liquid chromatography-tandem mass spectrometry (LC-MS/MS) has seen a huge uptake in clinical laboratories. This is thought to be attributable to its improved specificity over other techniques such as immunoassays or conventional HPLC for low-molecular-weight analytes.1 Sex steroids, mineralocorticoids, glucocorticoids and 25-hydroxy vitamin D are all examples of such analytes that have seen improvements in clinical testing from the introduction of this technology.2
However, as uptake increases, the limitations of LC-MS/MS have become apparent. For example, when compared to automated immunoassays, particularly those which incorporate multiplexing technology, sample throughput is often lacking. As a key limitation of the technology, manufacturers have focused on improving throughput and, as a result, have sought to automate LC-MS/MS systems.3
In this SelectScience interview, we speak with Victoria McKnight, Senior Biomedical Scientist and Dr. Andrew Davison, Consultant Clinical Scientist and clinical lead for research at Liverpool Clinical Laboratories, part of the Royal Liverpool University Hospital, under the University Hospital Foundation Trust, to explore the impact a new automated LC-MS/MS system has had on their diagnostic services and day-to-day routine.
VM: As a supervisor in the laboratory, I'm responsible for making sure that the work is processed in a timely manner. We have lots of quality documents and standard operating procedures that need to be followed and updated. I'm also one of the training officers within the department, so I’m heavily involved with training and developing staff. We have around 3,000 - 4,000 samples a day that run through our routine automation in chemistry. In our non-automated specialist section, we run mass specs to test steroid hormones, immunosuppressants and vitamin D.
AD: My role as a Consultant Clinical Scientist is complementary to Victoria’s. An essential part of my role, along with other clinical colleagues, is liaising with patient-facing healthcare professionals to ensure we deliver the best clinical laboratory service for patients. I have a special link with the endocrinology and the adrenal multi-disciplinary team here providing expert advice to help the investigation and management of patients. Additionally, I am heavily focused on research and development trying to deliver new mass spectrometry-based assays, and to use high-resolution mass spectrometry for translational research projects. Both of these are key to providing personalized medicine to patients. I also lecture at the Universities of Manchester and Liverpool teaching master’s and Ph.D. students. Audit, quality, and clinical governance are integral to my role, as they are to Victoria’s.
VM: A large part of it was to do with the number of samples that we were receiving for our vitamin D service - we receive over 5,000 vitamin D samples a month on this site. As you can imagine, to process these manually takes a lot of time and it is really a two-person job. Also, because it's quite new technology, I think we also wanted to be new and pivotal, and a little bit dynamic with our testing. We were one of the first people in the country to run the Thermo Scientific™ Cascadion™ SM Clinical analyzer.
AD: One of the drivers for our purchase of the Cascadion analyzer was the high throughput, to get a quality mass spec result and to deliver the result to patients that need it quickly. For example, cancer patients who are waiting for certain treatments do need a result quickly. When we were looking into this technology, there were some people who said you don't need a rapid vitamin D result, but there are situations where you actually do. Now we have the Liverpool Clatterbridge Oncology Center across the road from us, it's important that we do deliver that service.
VM: Initially Thermo Fisher Scientific provided us with a week-long training course, and there were five members of staff on that training course. That was really in-depth and hands-on, and everyone thoroughly enjoyed the course. In terms of instrument verification, we have a defined protocol that we follow within our lab, but it was really quick to perform because the Cascadion analyzer is nice to use and it's quite intuitive. Overall, the verification itself took us around three weeks with all the sample testing that we have to do.
For a lot of our new staff who have come from the automated laboratory, it's an easier transition for them than coming straight into something like a mass spec. It’s a lot like a routine automated platform and people are finding it quite nice to use. Also, those who attended the original training course find it easy to pick up even if they haven’t been near the instrument for a couple of weeks, and that’s a huge positive. However, we do still expect people to understand the methodology behind the instruments.
AD: In November this year, the lab should start moving to a new hospital – with an aim to complete the move by March 2022 (these dates are proposed of course). Due to the ease of using the instrument, and its similarity to other automated equipment, our plan is to move the Cascadion analyzer to the automated lab so it can become part of the routine job for someone working in this lab.
VM: Thermo Fisher Scientific has been very supportive as well. We had some problems with the instrument a couple of months ago and they were on hand straight away. They've only got a small team of engineers, but they are very approachable and were very helpful.
AD: It certainly made the Cascadion analyzer an easier choice because with a conventional mass spec where you want to do a laboratory-developed test, it takes a lot longer. With the Cascadion analyzer, a lot of the work is already done for you. As Victoria said, it's just a case of doing a verification like you would on any automated platform. From getting the kit to going live, it could take around a month, which is really, really good.
AD: To get a quality mass spec result that's traceable to a standard is always appealing, particularly where you have to have little intervention for method development. I think one of the challenges with Cascadion analyzer is, to make it work, you always need high volume, you need a lot of samples. I think you'd need the sample numbers to justify a business case to get one, but if you can transfer work for certain assays, it will release staff to work on more esoteric assays on more conventional mass spec platforms. I do think the technology has legs. I think in time, maybe 10 years' time, it might be a case of it's a routine place to see automated mass spec. You'll probably see far less conventional mass specs.
AD: From the vitamin D point of view, to get a result before a patient is given bisphosphonates, for example in our oncology or metabolic bone disease patients, is very important. If you can get a fast result, then you can give treatment faster, and of course, you can then tailor that treatment. For example, you could give a patient vitamin D if they're vitamin D deficient.
I think the other important area that automated LC-MS/MS can help is with transplant patients that require immunosuppressants. To have a 24-hour service for immunosuppressants would be highly unique. There aren't any labs in the UK that I'm aware of that can offer that service, seven days a week. In patients who are at risk of graft rejection or toxicity for a variety of reasons, who are taking immunosuppressants, a rapid result would mean the doctor can look at reviewing a patient’s medication and altering it to enable graft survival. It would be a huge change in the way we can deliver that mass spec quality result to a patient.
Zhang YV, Wei B, Zhu Y, et al. Liquid Chromatography-Tandem Mass Spectrometry: An Emerging Technology in the Toxicology Laboratory. Clin Lab Med. 2016; 36 (4): 635-661 (2016).
Grebe SKG and Singh RJ. LC-MS/MS in the Clinical Laboratory – Where to From Here? Clin Biochem Rev. 2011; 32 (1): 5-31.
Scott K. The Road to Automation in Clinical Mass Spectrometry. AACC Clinical Laboratory News. September 1, 2020.