Translational mass spectrometry in clinical chemistry

Current mass-spectrometry-based strategies will allow us to understand the molecular phenotypes of disease, which will drastically improve the diagnostic power of new clinical tests. In this interview, Professor Cobbaert [head of the Department of Clinical Chemistry and Laboratory Medicine at the Leiden University Medical Center (LUMC), Leiden, The Netherlands] and Dr Van der Burgt (associate professor at the Center for Proteomics and Metabolomics, LUMC) give us their expert opinions on how a strong collaboration between biomarker researchers, clinicians and medical laboratory specialists is necessary to make the development process more efficient. Professor Cobbaert is driven to innovate the field of laboratory medicine: “The clinical lab will change from a care-relevant to a system-relevant cross-sectoral discipline which will greatly affect the development of the entire healthcare system”.
About us
The clinical chemistry lab at the Leiden University Medical Center (LUMC) works closely together with researchers at the Center for Metabolomics and Proteomics (CPM) to develop new bioanalytical tests. The goal is to contribute to Precision Medicine through improved, molecular characterization of health and disease, for the sake of better patient management and patient outcome.
Christa Cobbaert heads the Department of Clinical Chemistry and Laboratory Medicine at LUMC, which encompasses clinical chemistry, hematology, coagulation and blood transfusion.
“In addition to regular patient diagnostics, our department also has responsibility for the hospital-wide central receipt of patient and research specimens. Our department supports research and biobanking from a large variety of clinical groups that want to use our services. Another core task is training and education of lab specialists and medical technicians.
“Some current numbers? Our routine lab works 24/7, we do about 4000 specimens per day, and produce over 4 million tests per year. We have 180 employees, about 140 full time equivalents. The majority are phlebotomists, who collect blood, and medical technologists, who run the analyses. We have an academic staff encompassing multiple laboratory specialists, who are responsible for the lab policy, lab organization, for state-of-the-art test menus, clinical consulting and post-academic training of lab specialists. Head medical technicians, quality control officers, as well as information and communication technology specialists and administrative personnel are a coaching layer between the academics and the operational co-workers.
“Since we are an academic institute, we are responsible for the traineeship of new lab specialists. We also contribute to the education of medical doctors. Teaching future medical doctors about the targeted use of lab diagnostics is key because approximately 70% of medical decisions in hospitals are based on lab results. We further provide teaching contributions in new disciplines such as clinical technology, and contribute to different Masters programmes.”
Dr Yuri van der Burgt is an associate professor at the CPM. “Trained as a chemist, I did a PhD in bioorganic chemistry and moved to the clinical field. At the LUMC I joined pioneering ‘omics’ research for medical care and patient research. For 50% of my time I work for the clinical chemistry lab, and from that position I bridge to the CPM research aiming for improved biomarker translation. CPM has approximately 50 researchers (PhD students postdocs, senior scientists, assistants and associates) and is headed by Manfred Wuhrer. We explore promising biomarkers that are discovered in basic research and aim to verify their potential for translation to the clinic. Mass-spectrometry (MS)-based omics studies have reported a wide variety of biomarkers or signatures, but only a few of these have been translated into a laboratory test. This limited translation is partly due to the lack of standardized protocols, robustness and reproducibility, but more importantly ill-defined or flawed study designs.”
Cobbaert: “We are happy with the cooperation with CPM because it’s very important to have analytical chemists connected to our lab. Once that lab specialists and clinicians have identified unmet clinical needs, analytical chemists support us with the assay development for molecular phenotyping of disease and health using MS-based technology. Together we attempt to bring promising biomarkers from the research field into the clinical arena. We believe that this collaboration should lead to a more robust and effective pipeline for developing medical tests. We also support research from various clinical groups at the LUMC, especially in the domains of Cardiovascular Diseases, Cancer Diagnosis and Kidney Diseases.”
Improving effectiveness
Van der Burgt: “One of the main activities at CPM is the elucidation of modifications on existing protein biomarkers, with emphasis on glycosylation analysis. As we want to make sure that these biomarkers can be of use for the clinic, we do not only report discoveries, but rather aim for further development of our findings into something clinically useful. Therefore we first make an inventory of the unmet needs from the clinicians, and what is actually needed for improved patient care. Hence, the clinical need guides our -omics research. And it is my task to bring these two worlds together. My goal is not just to publish papers on new discoveries, but to contribute to finding more effective solutions: clinically effective, cost effective and safe tests for patient care.”
Cobbaert: “The current pipeline and the current process of financing research is in my perception a wasteful process because there is insufficient attention to the downstream consequences (utility) of the research findings for patient care. Currently the number of papers and citation indices are rewarded, rather than the impact for patient care. Subsidizers should stimulate the translation and implementation of newly discovered biomarkers by making the funding of translation and implementation research inclusive.
“To counteract this inefficient pipeline from discovery to application researchers, clinicians, biostatisticians and lab specialists should collaborate closely. The clinical needs should be the driver of the test development process, rather than the technological push. Once these needs are identified a more informed decision can be made with regard to priorities: ‘This is what we are setting up together and this is where we go for’. The European Federation of Laboratory Medicine (EFLM) Test Evaluation framework provides guidance and encompasses key elements for creating evidence regarding the clinical and cost-effectiveness of new medical tests.
“Our mantra is that our research efforts should lead to precision diagnostics and clinically effective medical tests. In our collaboration with CPM we aim to contribute to better patient management and patient outcome with a targeted approach. As it is essential to add value to clinical pathways and patient management, we need actionable results for better patient care.”
International initiatives
Cobbaert: “We try to educate stakeholders of the biomarkers-medical test pipeline about the usefulness of the Test Evaluation framework for guiding this development process.
“We have asked ourselves: Why is the process from research to application such a wasteful process? What should we do? Last November we organized a precision diagnostics symposium in which we shared our experiences on quantitative proteomics and proposed our solutions [‘Prime time for precision diagnostics driven by unmet clinical needs’ (LUMC, Leiden, The Netherlands, November 2019)]. We also shared our struggles: developing specific molecular tests for proteins is not an easy road. Several barriers had to be alleviated. And that’s difficult to do, sometimes we failed, sometimes we felt that it doesn’t go quick enough. But we all are dedicated to make it a success together.
“Once a medical test is available, and evidence regarding its clinical utility and value has been generated, medical tests have to be implemented in clinical practice, either as a Lab-Developed-Test (rare) or as a Conformité Européene in vitro diagnostic (CE-IVD) test (often). To be successful, clear guidance should be given to doctors regarding its intended use in the clinical care pathway of interest. As a rule of thumb, the average trajectory from promising biomarker to applied medical test in the clinic takes about 10 years.
“In the current curriculum of medical students limited education is given regarding medical test use, notwithstanding the 70% rule (medical decisions are to a large extent based on lab test results). Laboratory specialists have to demonstrate medical leadership by educating physicians on proper test use.
“Collaborations are necessary to innovate laboratory medicine. We all start to understand the need for cooperation between different areas of expertise. A smooth and fruitful interaction between different types of laboratory specialists (e.g. microbiology, pathology, geneticists, immunologists…), researchers and clinicians should help to overcome the old boundaries.”
Collaboration is key
Van der Burgt: “An example of such a collaboration between CPM and clinical chemistry is our work on glycoprotein markers that we recently presented at the symposium on precision diagnostics, ‘Prime time for precision diagnostics driven by unmet clinical needs’ (LUMC, Leiden, The Netherlands, November 2019).
“Structure refinement of the biomarker for prostate cancer, the prostate specific antigen (PSA) demonstrated the importance of glycosylation for further development. We have worked on PSA at the CPM together with the clinical chemistry lab and in that collaborative effort we have seen that we can add extra information on the PSA test readout. Additionally, we aim to discover novel biomarkers for early detection of cancers. We see an enormous worldwide effort there and the result is hundreds, if not thousands, of new markers without any clinical pre-knowledge or knowledge of urgent clinical needs, it was technology-driven.”
Cobbaert: “It should be the opposite, clinical needs and sustainable and affordable health care should be the drivers of the test menu. In that context, our quantitative proteomics based activities for precision diagnostics are becoming more and more appreciated. To make translational research more effective, the funding agencies should also be concerned that the research they support will be applied in the clinical lab and will improve patient care.”
Paradigm shift
Cobbaert: “In the 20th century, our technology did not enable molecular characterization of disease, at least not in the high-throughput manner that is needed in clinical practice. Now we live in the 21st century and technology and medical insights have evolved. I expect a paradigm shift whereby traditional diagnostic tests will be complemented with precision diagnostic tests which enable Predictive, Preventive, Personalized Medicine, with Participation of the patient.
“As we drill down to the molecular level of health and disease, we should be able to provide more refined diagnoses and treatments. In 10 or 20 years, we may expect to read out a patient’s complete molecular phenotype or ‘proteotype’ and we will be able to monitor changes from a personal baseline.
“To innovate lab medicine and to realize the ambitions for Precision Medicine, we also need to find interoperable information technology (IT)-solutions. To that end, we need strategically thinking people who align the different stakeholders of the test pipeline, strive to improve health and patient care and know how to find advanced technical ,IT and organizational solutions to disclose the billions of data. Standardization of IT and making databases interoperable will be key. Unfortunately, we seem to be very far away from standardized interoperable solutions owing to a very fragmented IT-landscape across and even within health institutions.”