Parallel to the progress in next-generation and whole genome sequencing, major developments in mass spectrometry (MS) and bioinformatics are now offering complementary data for the drive toward precision medicine. This signals the dawning of what we call next-generation clinical MS. An influential 2012 Institute of Medicine report outlined the forces behind this advancement in MS. Titled The Evolution of Translational Omics: Lessons Learned and the Path Forward, this document characterized molecular disciplines to include genomics, proteomics, metabolomics, and other omics biomarkers. Further, a 2012 National Institutes of Health (NIH) announcement about new metabolomics programs described the metabolome as the sum of all metabolites in an organism—both endogenous and exogenous—at any given moment. These expression markers are essential to providing clues in disease etiology.
Metabolomic and proteomic technologies include many innovative MS applications, both with and without liquid chromatography (LC) or gas chromatography. A game-changer in microbiology has been clinical application of matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF). MALDI-TOF’s ease of sample preparation and rapid, automated analysis and informatics have set the standard for new MS clinical applications.
Next generation MS will deliver faster turnaround times and increased sensitivity and specificity. These technologies will be easier for laboratories to apply with improved automation, and eventually, integrated online automation within clinical core laboratories. Online automation will use cloud computing to enable result and data harmonization, and data portability.
Next Generation MS in Action
At AACC’s 5th Annual Mass Spectrometry and Separation Sciences for Laboratory Medicine Conference, held October 1–2, 2015, distinguished speakers offered a glimpse into next-generation clinical MS. In the opening address, Hans Maurer, PhD, a professor of pharmacology and toxicology and head of the department of experimental and clinical toxicology at Saarland University in Germany, focused on the use of high resolution mass spectrometry (HRMS) in toxicology. Current HRMS technologies such as time-of-flight and Orbitrap for accurate mass detection bring greater accuracy to drug screening, drug metabolism studies, and drug quantitation and monitoring. HRMS also enables laboratories to use smaller samples with less preparation time, easier MS optimization, higher sensitivity and selectivity, and a full scan analysis that delivers retrospective interpretation and more comprehensive quantitation.
AACC President-Elect Michael Bennett, PhD, a professor of pathology at the University of Pennsylvania and director of the clinical chemistry and metabolic disease laboratory at The Children’s Hospital of Philadelphia, discussed using MS to assess metabolic disorders for newborn screening. Bennett explored how MS is improving screening and diagnosis for certain diseases, such as ornithine transcarbamylase deficiency. He also explained how targeted organic acid profiling is being used to diagnose a variety of metabolic disorders, with complicating issues related to secondary metabolites from the microbiome and xenobiotics.
Brent Dixon, PhD, chief scientist at Physician’s Choice Laboratory Services, illustrated how pain management is being transformed through use of complementary pharmacogenomics data and conventional toxicology testing. For example, cytochrome P450 allele analysis can affect an individual’s pharmacokinetics and inform drug dosing for warfarin, methadone, and clopidogrel.
Another emerging technology profiled during the conference was tissue imaging using MS. Richard Caprioli, PhD, the Stanford Moore Chair in Biochemistry and Director of the Mass Spectrometry Research Center at Vanderbilt University School of Medicine in Nashville, described how, using a tissue biopsy and laser ablation, an advanced pixel array offers images at single mass-to-charge values. Laboratories might perform this technique using single cells or even whole animal sections, such as a mouse kidney. Researchers have used MS-based tissue imaging to study the effect of diabetes on renal glomerulus, to perform histology-directed analysis from frozen section and paraffin embedded tissue, and to diagnose malignant melanoma. Caprioli’s lab is advancing clinical application of this technique with a new pathology interface. He predicted that high-throughput imaging MS will be complementary to other imaging technologies.
Another example of next-generation MS is single cell proteomics. Sean Bendall, PhD, an assistant professor of pathology at Stanford University School of Medicine in California, noted that single cell analysis by mass cytology will present many opportunities for diagnostics. For example, this technique might be used for profiling immune system response and predicting a patient’s recovery after surgery. Other potential applications include identifying phenotype versus function in diseases such as acute myeloid leukemia.
Ultimately, the velocity of next-generation MS will depend on the ability of laboratory medicine professionals to translate emerging biomarkers from bench to bedside. Yan Victoria Zhang, PhD, director of the clinical mass spectrometry and toxicology lab and associate professor of pathology and laboratory medicine at the University of Rochester in New York, shared her experience translating omics biomarkers. On this front, laboratories face many challenges, including the complexity of the human proteome, lack of coherent research pipelines, and lack of standardization in sample collection. In moving biomarkers from bench to bedside, mass spectrometists have made integral contributions using MALDI and electro-spray platforms. Candidate biomarkers have to be validated extensively, and laboratorians must ensure sample quality by dealing with pre-analytic issues as well as intra- and inter-individual variability.
As next-generation MS advances, the contributions of MS in proteomics must be married to those of genomics. At the conference, Henry Rodriquez, PhD, director of the office of cancer clinical proteomics research at the National Cancer Institute (NCI), gave examples of how this is occurring with regard to colorectal, ovarian, and breast cancer. One group leading the proteogenomics effort is NCI’s Clinical Proteomic Tumor Analysis Consortium. This consortium works to identify proteins that derive from alterations in cancer genomes. These proteins could lead to new assays and new insights into cancer biology. In ovarian cancer, for example, deep proteomic analysis has identified biomarkers that correlate with survival.
In addition to these conference presentations, the January 2016 special issue of AACC’s Clinical Chemistry journal focused on cutting-edge MS. Interestingly, one of the issue co-editors, Graham Cooks, PhD, is researching miniaturized MS using three-dimensional printing. This issue of Clinical Chemistry also highlighted pre-analytic advances in paper spray and dry blood spot analyses.
Another on-going development is the use of alternate samples such as oral fluid for drug screening and confirmation. The Substance Abuse and Mental Health Services Administration has published a draft document about the use of oral fluid as a complement to current urine drug testing for the workplace. If this program were to be approved, MS, especially LC-MS/MS, would be vital in offering drug confirmation.
Advancing the Next Generation
AACC’s Mass Spectrometry and Separation Science (MSSS) Division is dedicated to building a community that advances next-generation clinical MS. This community will include contributions from laboratory scientists with clinical, basic research, and corporate research and development backgrounds. We aim to educate all laboratory medicine professionals—from bench-level scientists to laboratory directors. In September 2016, the AACC/MSSS: Mass Spectrometry and Separation Sciences for Laboratory Medicine conference will focus on some of the key areas explored during the 2016 conference. It also will emphasize educational outreach to both clinical and anatomic pathology. In addition, AACC’s MSSS division will be hosting hands-on workshops for pathology residents and laboratory scientists during the upcoming 68th AACC Annual Scientific Meeting & Clinical Lab Expo in Philadelphia.
As next-generation MS progresses, simply knowing all the technical ins-and-outs won’t be enough. Laboratory medicine professionals also must stay engaged with regulators and payers. In fact, the Food and Drug Administration is hosting a workshop on May 2 titled Mass Spectrometry in the Clinic: Regulatory Considerations Surrounding Validation of Liquid Chromatography-Mass Spectrometry Based Devices. This event will cover analytical and clinical study designs and considerations for validation and use of LC/MS-based tests. Since MS-based tests are mostly regarded as laboratory-developed tests, this workshop could have important implications for future MS assays. Zhang will offer public comments on behalf of AACC at this workshop.
Harmonization of clinical and translational assays also will be important as next-generation MS matures. Harmonization and other goals for next-generation MS will require collaboration among laboratorians in government agencies such as NCI, other NIH Institutes, and the Centers for Disease Control and Prevention, to name a few. Growing news coverage of pharmacogenomics and personalized medicine shows the public is gaining a better awareness of and appreciation for new disciplines related to laboratory medicine. Now is the time for laboratorians to keep our commitment to patient care and patient safety by driving the next steps in clinical MS testing.
Ultimately, the velocity of next-generation MS will depend on the ability of laboratory medicine professionals to translate emerging biomarkers from bench to bedside.
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