MSACL: MS and Clinical Diagnostics
The eighth annual Association for Mass Spectrometry: Applications to the Clinical Laboratory conference (MSACL) was held in Palm Springs, California, from February 21 to February 25, its first year outside of San Diego, California. Selected presentations on Thursday evidenced both optimism about MS’s future in clinical diagnostics and the need for greater progress. The conference also marked the organization’s official launch of a new journal, Clinical Mass Spectrometry.
Attendance totaled approximately 980, the same as last year. However, the number of exhibitors increased from 43 to 55 and included all of the major MS vendors: Agilent Technologies, Bruker, SCIEX, Shimadzu, Thermo Fisher Scientific and Waters. Among the conference topics were metabolomics, tissue imaging and cancer biomarkers.
In his plenary lecture, Graham Cooks, PhD, of Purdue University laid out what he called “current tasks” for MS: ambient ionization, using no or minimum sample preparation; miniature MS with “just adequate” performance, enabling fast analysis in the field; and MS in situ and at point of care (POC). Discussing current progress in these areas, he highlighted the use of paper spray ambient ionization for quantitative analysis as well as the need for automated ambient ionization. For POC applications, he discussed the use of MS for surgical diagnostics, specifically an ambient imaging approach for the analysis of diseased brain tissue in the operating room. He also advocated for the routine use of MS in organic synthesis.
The session presented by Timothy S. Collier, PhD, of ClevelandHeartLab provided an introduction to clinical proteomics, defining clinical proteomics as “the analysis of proteins/peptides in biological fluids, tissues and cells to provide diagnostic/prognostic insight into a patient’s state of health.” The talk gave an overview of how MS works and current challenges for it. Dr. Collier listed several constraints of clinical proteome diagnostics. Preanalytical constraints are prefractionation and enzymatic digestion. Analytical constraints are reproducibility, robustness, limits of detection; internal/external quality control; and reference intervals, target ranges, cutoffs. Postanalytical constraints are quantification strategies and software.
Dr. Collier also discussed success stories for the use of MS for clinical diagnostics, such the measurement of thyroglobin as a marker for the recurrence of thyroid cancer. MS provides a direct measurement, addressing issues with immunoassay tests, such as interference from autoantibodies. He also highlighted that there are MS-based tests for Apolipoprotein A-I and ApoB for cardiovascular risk assessment whose precision and accuracy are “on par” with the immunoassay tests. Future developments in the field listed by him were increased multiplex capabilities (pseudo multiple reaction monitoring [MRM], parallel MRM, data independent acquisition), evolving calibration strategies, increased sensitivity and dynamic range in mass analyzers, and miniaturization.
Reviewing the history of MS-based protein tests in the US, Dobrin Nedelkov, PhD, of the Biodesign Institute at Arizona State University presented a summary of commercially available MS-based protein tests. Multiple tests on the list are offered by Quest Diagnostics, Nuclea Biotechnologies and Intrinsic Bioprobes. He stressed that only 8 of the 15 commercialized tests, about which the earliest publication was in 2001, are still available.
Characterizing the eight tests, he noted they all are LDTs, developed and characterized under CLIA requirements and not cleared by the FDA. Most of them are focused on already known protein biomarkers and utilize top-down methods, primarily LC-MS/MS. In addition, they are so-called “esoteric” tests, meaning nonroutine, and for each of them the results are presented either as a concentration of the proteins or as yes/no answers. He noted that some of the tests face little or sporadic consumer demand. Emphasizing that sample preparation remains the bottleneck for MS-based protein tests, he proposed that a single sample preparation approach is needed.
He also listed factors to consider in future MS protein test development, including the level of demand, the complexity of using LC/MS, the need for simpler sample preparation and the need for FDA submissions.
Among the commercialized tests listed by Dr. Nedelkov, there are three using MALDI-TOF MS, including Biodesix’s VeriStrat, a multiplex test using MALDI-TOF profiling for guidance of treatment for advanced non–small cell lung cancer. As Mark W. Duncan, PhD, of the School of Medicine at the University of Colorado examined in his talk, improvements in MALDI-TOF instrumentation have made the technique more advantageous for clinical diagnostics, including faster analysis speeds, improved sensitivity, higher throughput (thousands of samples per day) and greater quantification (a linear dynamic range up to 100,000).
A presentation by Melanie Yarbrough, PhD, of Washington University in St. Louis discussed the use of MALDI-TOF for clinical microbiology and its broad application to organism identification, including gram positive bacteria, gram negative bacteria, mycobacteria, fungi and yeast. She noted that one limitation of MALDI-TOF for such testing is that it cannot differentiate between e. coli and shingella. She also provided an overview of the two different software analyses that Bruker’s MALDI Biotyper and bioMérieux’s VITEK systems use.
Also raising the profile of MALDI-TOF at the show was SimulTOF’s launch of its benchtop SimulTOF ONE system, a linear MALDI-TOF MS. The company told IBO that this system replaces its current product line and features a faster laser and more competitive price. The company noted the new instrument’s increased sensitivity, ease of use and reliability as well as increased reproducibility for quantitation. In the future, the company will release a reflectron version.
The company’s work in advancing clinical MALDI -TOF MS applications include an assay for the testing of glycated hemoglobin for more accurate diagnoses of type 2 diabetes. Other tests that have been developed by the company for MALDI-TOF MS include a test for the measurement of albumin and creatinine in urine.