Medical mass spectrometrist (MMS) training and certification: A key step to expanding routine clinical mass spectrometry usage in Japan

Medical mass spectrometrist (MMS) training and certification: A key step to expanding routine clinical mass spectrometry usage in Japan

Journal Pre-proofs Medical mass spectrometrist (MMS) training and certification: a key step to expanding routine clinical mass spectrometry usage in J...

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Journal Pre-proofs Medical mass spectrometrist (MMS) training and certification: a key step to expanding routine clinical mass spectrometry usage in Japan Fumio Nomura, Toyofumi Nakanishi, Kazuo Igarashi, Seiji Yamaguchi, Mitsutoshi Setou, Toshimitsu Niwa PII: DOI: Reference:

S2376-9998(19)30058-3 https://doi.org/10.1016/j.clinms.2019.11.001 CLINMS 87

To appear in:

Clinical Mass Spectrometry

Received Date: Revised Date: Accepted Date:

7 May 2019 7 November 2019 7 November 2019

Please cite this article as: F. Nomura, T. Nakanishi, K. Igarashi, S. Yamaguchi, M. Setou, T. Niwa, Medical mass spectrometrist (MMS) training and certification: a key step to expanding routine clinical mass spectrometry usage in Japan, Clinical Mass Spectrometry (2019), doi: https://doi.org/10.1016/j.clinms.2019.11.001

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© 2019 Published by Elsevier B.V. on behalf of The Association for Mass Spectrometry: Applications to the Clinical Lab (MSACL).

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Medical mass spectrometrist (MMS) training and certification: a key step to expanding routine clinical mass spectrometry usage in Japan Fumio Nomuraa, Toyofumi Nakanishib, Kazuo Igarashic, Seiji Yamaguchid, Mitsutoshi Setoue, Toshimitsu Niwaf a

Division of Clinical Mass Spectrometry, Chiba University Hospital, Chiba, Japan b Department of Clinical Pathology, Osaka Medical College, Osaka, Japan c Association of Medicinal Analysis, Hyogo, Japan d Department of Pediatrics, Shimane University Faculty of Medicine, Shimane, Japan e International Mass Imaging Center and Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, Shizuoka, Japan. f Shubun University, Aichi, Japan Abstract Mass spectrometry (MS) is increasingly used in clinical medicine in Japan. In contrast to the successful application of MS in clinical microbiology, the adoption of MS-based assays for routine testing in clinical chemistry is very slow. In order to promote the significant benefits that MS platforms bring to laboratory medicine and patient care, the Japanese Society for Biomedical Mass Spectrometry (JSBMS) initiated a medical mass spectrometrist (MMS) certification program in 2013. As of Dec 2018, 308 persons from various medical specialties have been certified. We believe that they will play significant roles for expanding routine clinical MS usage in Japan. List of abbreviations IVD: in vitro diagnostics JSBMS: The Japanese Society for Biomedical Mass Spectrometry LDT: laboratory-developed test MMS: medical mass spectrometrist TAT: turnaround time

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Mass spectrometry (MS) is increasingly used in clinical medicine in Japan. A nationwide- and publicly-funded-expanded newborn screening by MS/MS has been conducted since 2014[1]. MS-based methods are widely used in forensic medicine [2], for therapeutic drug monitoring [3], and, more recently, in clinical microbiology [4] The Japanese Society for Biomedical Mass Spectrometry (JSBMS) was established in 1976. In 2013, the JSBMS initiated a medical mass spectrometrist (MMS) certification program to improve the awareness of the availability of MS-based methods and to provide educational training for medical professionals on the principles of MS-based laboratory medicine. Since the initiation of the MMS program, JSBMS membership has doubled from 300 to approximately 600, illustrating the success of the JSBMS outreach program. The JSBMS membership is comprised of medical professionals from diverse backgrounds. Some of them use MS exclusively for their biomedical research. Not all of the JSBMS members are directly involved in reporting results for patient care. The most successful application of MS in laboratory medicine has been the rapid identification of microorganisms using matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS). Indeed, there has been a revolutionary shift in clinical diagnostic microbiology in Japan [4]. As of August 2018, there were approximately 200 instruments (either Bruker’s MALDI Biotyper or bioMérieux’s VITEK®) in operation for routine clinical analysis in Japan. In sharp contrast, the adoption of MS-based assays for routine testing in clinical chemistry has been very slow, with the use of liquid chromatography-tandem mass spectrometry (LC/MS/MS) remaining limited. At present, the use of LC-MS in clinical chemistry laboratories in Japan is largely restricted to the measurement of biomolecules for which conventional in vitro diagnostics (IVDs) are not available (e.g., vitamin B1, homocysteine). Typically, mass spectrometer technicians are trained “on the job” by senior staff to learn key components of standard operating procedures of LC-MS and result interpretation. Additionally, the major LC-MS vendors in Japan provide one- or two-day educational services that include hands-on components; these are not only for customers, but are open to the public.

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However, there is no official process in Japan to certify technical competency of technicians performing LC-MS-based assays for routine clinical chemistry applications. There are several reasons for the limited use of LC-MS in the clinical chemistry field. (1)In Japan, the majority of clinical chemistry tests for outpatients are conducted as same-day tests in hospitals that have their own clinical laboratories, and who demand a turnaround time (TAT) of less than one hour; this TAT requirement impedes widespread use, (2)MS-based clinical chemistry tests are exclusively laboratory-developed tests (LDT) at the moment in Japan; LDT is generally not covered by the public health insurance system, (3)The advantages of MS-based assays over conventional methods are not well-recognized among laboratory personnel and physicians in Japan. Although the superiority of MS-based clinical applications is well recognized among MS experts, the historical perception of MS as complicated and expensive has still prevailed in medical society in general. (4)Finally, bench analysts competent enough to implement and run MS-based assays are limited. It was for these reasons that the JSBMS decided to establish Medical mass spectrometrist (MMS) certification program in 2013 with the following objectives: (ⅰ) to convey the message that MS-based clinical applications bring significant benefits to laboratory medicine and patient care, and (ⅱ) to educate new potential users on the fundamentals of MS-based clinical tests: with a modest amount of additional hands-on training, routine-use MS technology can be incorporated into virtually any medical laboratory. A one-day introductory course on clinical mass spectrometry is held on the last day of the annual meeting of the JSBMS; the main topics of educational talks in the intensive course are listed in Table 1. At the end of this course, there is a short written exam. The purpose of this exam is not to evaluate one’s technical competency of clinical MS, but to confirm that the student has a minimum essential knowledge of clinical MS. Technical competency is to be considered in an advanced program that is in the planning stages. To be certified as MMS, the participants must pass the exam and also become a member of JSBMS. As of Dec. 2018, a total of 308 persons

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have been certified. The mean age of those who completed the certification program is 43.4 years (ranging from 24 to 72). The positions and years of experiences are variable including 20 professors and 7 postdoctral fellows. The distribution of their subspecialties is shown in Figure.1; 96 persons (31% ) specialize in microbiology, followed by clinical chemistry, forensic toxicology and newborn screening. It is our expectation that they will play significant roles in expanding routine clinical MS usage in Japan. The initial certification is effective for 5 years. To be re-certified, one must present at least one paper at the annual JSBMS meeting and attend at least twice. We have initiated discussions regarding the establishment of an advanced program that will include technical training and certification of operational competency. We are planning to use the mass spectrometry section of the IFCC curriculum for Laboratory Medicine experts as a reference (http://www.ifcc.org/ifcc-news/archive-2018/2018-02-19-ifcc-curriculum/). The establishment and maintenance of an advanced certification program will require close collaboration between JSBMS and other MS-related academic societies. The majority of JSBMS members involved in reporting results for patient care have dual memberships with other societies related to MS, as exemplified in Table 2. Indeed, the current president of the Japanese Society for newborn Screening is a member of the committee for MMS of JSBMS. He has now announced in the newborn screening society that it is desirable, although not compulsory at this moment, that there is at least one MMS (basic program) in an institute conducting tandem mass screening of newborns. For specific fields such as clinical microbiology and newborn screening, the Japanese Society for Clinical Microbiology and the Japanese Society for Mass Screening, respectively, may have a priority to organize the advanced program and provide certification of hands-on competency. As a first step, the JSBMS has held hands-on training courses once a year since 2015, targeting one topic at a time (e.g., 25OH vitamin D, serum peptide). At the end of the course, the participants receive a certificate of completion, but it is not a certificate of technical competency. These hands-on seminars are made possible with the assistance of the major MS vendors and are held in their training labs. We are planning to rotate through several representative MS vendors in Japan as part of these educational courses.

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Attendance and completion of multiple hands-on seminars, together with satisfactory academic activity, documents to verify that one’s daily activity on clinical chemistry MS has met the institutional standard, and passing a written examination for the advanced program are tentative requirements to receive a JSBMS advanced certification for clinical chemistry LC-MS. In the future, it will be interesting to ascertain the impact of the certification programs (both basic and advanced) on the adoption of mass spectrometry and the quality of test results. References [1] Shibata N, Hasegawa Y, Yamada K et al: Newborn screening for carnitine palmitoyltransferase II deficiency using (C16+C18:1)/C2: Evaluation of additional indices for adequate sensitivity and lower false-positivity. Mol Genet Metab Rep. 2018; 16:5-10 [2] Hara K, Waters B, Ikematsu N et al: Development of a preparation method to produce a single sample that can be applied to both LC-MS/MS and GC-MS for the screening of postmortem specimens. Leg Med (Tokyo). 2016; 21: 85-92. [3] Mano N, Sato M, Nozawa M et al: An accurate quantitative LC/ESI-MS/MS method for sirolimus in human whole blood. J Chromatogr B Analyt Technol Biomed Life Sci 2011; 879:987-992. [4] Nomura F: Proteome-based bacterial identification using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS): A revolutionary shift in clinical diagnostic microbiology. Biochim Biophys Acta 2015; 1854: 528-537.

Acknowledgement The authors wish to thank Dr.D.B. Goodenowe (President/CEO, Prodrome Sciences Inc.) for his constructive comments and suggestions.

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Table 1: Representative topics covered in one-day extensive course introduction to clinical MS ・Successful examples of clinical applications ・Advantages of MS-based methods as compared with the conventional methods including immunoassays ・New applications of MS to laboratory medicine ・Assay standardization and harmonization ・Basic principles of mass spectrometry ・Roles of medical mass spectrometrist in laboratory medicine

Table 2 :Representative Academic Societies to which JSBMS members belong as dual memberships Clinical Microbiology The Japanese Society for Clinical Microbiology Newborn Screening Japanese Society for Mass Screening Clinical Chemistry Japan Society of Clinical Chemistry Therapeutic Drug Monitoring The Japanese Society of Therapeutic Drug Monitoring Forensic Toxicology Japanese Association for Forensic Toxicology MS Imaging Japanese Society for Molecular Imaging Proteomics HUPO (The Human Proteome Organization)

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Figure 1 Subspecialties of a total of 308 certified Medical Mass Spectrometrists in Japan 96 persons (31%) specialize in microbiology, followed by clinical chemistry, forensic toxicology and newborn screening.

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