Home >> ALL ISSUES >> 2018 Issues >> New accreditation program checklist section: Imaging mass spec scores its own quality standards

New accreditation program checklist section: Imaging mass spec scores its own quality standards

image_pdfCreate PDF
Anne Paxton

October 2018—It happened for next-generation sequencing. It was an important step for in vivo microscopy. And now it’s taking place with imaging mass spectrometry. The milestone: development and adoption of a set of specialized checklist requirements for laboratories that want CAP accreditation.

Dr. Lehman

Imaging mass spectrometry, an adjunct methodology to help pathologists analyze areas of interest in tissue specimens, is, at this point, used in a small number of research laboratories in the U.S., says CAP Checklists Committee member Christopher M. Lehman, MD, clinical professor of pathology, University of Utah College of Medicine, and medical director of the University of Utah Hospital Laboratory. But the technology is swiftly moving toward clinical use, and the CAP decided it was time to set standards that laboratories could adopt for the use of imaging mass spec (IMS). The new checklist requirements, released in August, are part of the 2018 chemistry and toxicology checklist.

“IMS gives you the ability to do mass spectrometry on a slide or a piece of tissue, and then overlay the MS results onto, say, an H&E-stained slide, so you can see not only the morphology of the tissue but also where the molecules of interest are showing up. With IMS, you can actually look at the lipids, proteins, and peptides of interest that are associated with specific pathological or histological traits on the slide,” Dr. Lehman explains.

Since the subject-matter experts consulted by the Checklists Committee were not familiar with the creation of checklists, “to help them we supplied them with existing checklists including the molecular, microbiology, and chemistry checklists,” Dr. Lehman says. “Many of the IMS checklist items were derived from these checklists.”

Obviously, the experts doing research on IMS know how they do it. But to develop the checklist, he says, they had to create a mental process map and think through the steps and the quality control points. “We said to them, ‘If you were going into another researcher’s lab to evaluate how they performed mass spectrometry imaging, what would you want to see to be assured that they were doing it correctly.’”

Most of the checklist requirements will make sense to people who operate mass spectrometers or who already do microscopy. They include how to operate the instrument, what would be a proper control, and how to identify an area you are interested in analyzing, Dr. Lehman says. “Those already exist in the checklist but had to be adapted for IMS.” He expects the checklist to be revised as more is learned about how to use IMS.

IMS has become a mainstream research tool in certain circles all over the world, says Jeremy L. Norris, PhD, managing director of the National Research Resource for Imaging Mass Spectrometry at Vanderbilt University School of Medicine. He and Richard Caprioli, PhD, director of Vanderbilt’s Mass Spectrometry Research Center, were the two IMS experts consulted by the Checklists Committee.

There are many R&D applications of IMS in the pharmaceutical industry, including use of IMS to characterize drug distribution and drug metabolism in animal studies. However, “The use of IMS to look at biological tissue is something that originated with Dr. Caprioli,” Dr. Norris says. “It’s becoming apparent that there are going to be real applications for diagnosis of human disease and use in the clinical lab.”

The Mass Spectrometry Research Center is already at that stage. “IMS is a pretty robust R&D tool. Now that experience is being applied to develop a new clinical diagnostics lab with IMS as the core technology.” Dr. Norris is also CEO of Frontier Diagnostics, which he co-founded with Dr. Caprioli in 2014 expressly to develop some of the diagnostic capabilities of the technologies the MSRC has developed and to eventually launch commercially available clinical assays.

IMS has advantages over traditional MS assays, which often homogenize the sample, then extract the proteins, then do the analysis. “In that process, you’ve lost all of the sample’s spatial information,” Dr. Norris points out. By contrast, IMS is part of a unique combination of tools that preserves that spatial information. With IMS, “what we do is collect molecular information from vivisections, like those the pathologists are looking at under a microscope, but we preserve the spatial information from the samples. So we are using MALDI MS, which already has a toehold in the clinical laboratory through several applications, to add a molecular dimension to microscopy.”

Dr. Norris

“We can work collaboratively with pathologists to identify groups of cells that potentially might be diseased, then we can collect unique signatures from each of those. Within one section, you can do multiple areas of analysis and you can accomplish that very quickly. Then you use that data to ask: Are these specific cells cancerous, or not? Tissues are heterogeneous, and this allows us to collect that additional molecular data while preserving that heterogeneity.”

Dr. Norris views IMS as building on the existing knowledge base in pathology. “With this application, we’re not necessarily claiming we’re going to replace what pathologists do, but we are adding the capability to get an extra dimension of information that can help in the areas of the tissue that might be too ambiguous to make a definitive call.” Much of what is unique about the assays Frontier is developing has to do with how the sample is prepared, Dr. Norris says. “The software systems tie the sample preparation in together with the instrumentation and the data analysis to get the job done efficiently. The innovation is less the instrument itself and more about how you integrate it into the workflow.”

In many ways the IMS work at Vanderbilt is bringing the molecular age to the field of anatomic pathology, in his view. That’s how he thinks it will be revolutionary. “There certainly are molecular assays that are done in AP. What we have the opportunity to do is, on a single platform, develop methodologies that can be applicable in many areas of AP without making a lot of change in the reagents we use. So we can potentially have one instrument platform that can serve many different subspecialties using a common analytical method.”

In helping to create the checklist, he and Dr. Caprioli saw their role as identifying the unique areas for which IMS requires special consideration and making sure the checks and balances are in place. “We try to think through what are all the possible ways that one might prepare or set up the instrument and to make sure that the checklist items are general enough to cover those possibilities—without being so loose that they aren’t effective.”

In addition to the more standard checklist elements such as the need to tune and calibrate the instrument, use appropriate consumables, and retain data, the new IMS checklist addresses those unique areas. “We’re detecting a rather broad number of peptides in each analysis we do,” Dr. Norris points out. “And so we had additional instrument QA or QC in the checklist to make sure the instrument is sensitive, plus steps for identifying the region of interest within the tissue, steps for data analysis, and protocols to ensure we are able to pick up a false-negative or false-positive.”

Frontier plans to launch its IMS platform in its own CLIA-certified laboratory first, Dr. Norris says. “Over time, there is an opportunity to provide labs with an FDA-approved platform, with kits suited to certain assays, and reagents and protocols to do the assay correctly.” He expects the platform will be able to perform multiple assays because “you have to have critical mass with the number of applications to justify purchasing the instrument and having it in the lab.” For example, since there are many types of skin cancer, the company plans to have multiple assays in the area of skin cancer, each with its own assay label.

CAP TODAY
X