Medical Laboratory Observer - February 2024

MLO-online.com

February 2024

Vol 56, No. 2

™ The Peer-Reviewed Management Source for Lab Professionals since 1969

CMS’ coverage of HbA1c testing for diabetes screening Page 22

CE:

The changing respiratory testing landscape Why the value of flexibility is key Page 6

PLUS

Overcoming data management challenges Page 18

Advancing standards through credentials Page 32

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IN THIS ISSUE...

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February 2024 | Vol. 56, No. 2

4

From the editor

CONTINUING EDUCATION

6

The changing respiratory testing landscape: Why the value of flexibility is key

By Ayaz Majid, PhD and Chris Gardner

CLINICAL ISSUES

6

10

Revealing the therapeutic potential of novel drugs for HPV-positive head and neck cancer

By Ashesh Saraiya, PhD

INFECTION DIAGNOSTICS

14

HIV epidemic: From the origin towards the end

By Rajasri Chandra, MS, MBA

LAB MANAGEMENT

10

18

Overcoming data management challenges: The biggest challenge of all is…us

By Robert F. Moran, PhD, FCCM, FACB

EDUCATION

22

CMS’ coverage of HbA1c testing for diabetes screening is a good start — But we can do more

By Michael J. McPhaul, MD

PRODUCT FOCUS

14

29

Antibody tests

MOLECULAR DIAGNOSTICS

30

A new twist: How the COVID-19 pandemic paved the way for increased molecular testing of hepatitis

By Erica Frew

BEST PRACTICES

22

32

Advancing standards in laboratory medicine and pathology through professional credentials

By Joseph B. Baker, MS and Amy Spiczka, MS, HTL(ASCP)CMSCT, MBCM, CPHQ LAB INNOVATOR

35

Details from AMP on LDTs/LDPs

By Christina Wichmann

DEPARTMENTS

36 32 2 | FEBRUARY 2024 MLO-ONLINE.COM

Index of advertisers

ON THE COVER: Petmal / iStock / Getty Images Plus / Getty Images

F ROM T HE EDITOR

CLIA Updates

O

n December 28, 2023, the Centers for Medicare & Medicaid Services published a final rule in the Federal Register that updated CLIA fees and regulations. Specifically, the final rule adjusts laboratory fees to provide sustainable funding for the CLIA program; revises certain requirements for both the histocompatibility test specialty as well as personnel qualifications and responsibilities for CLIA laboratories; and provides additional discretion to CMS by allowing it to impose alternative sanctions against noncompliant Certificate of Waiver laboratories, rather

By Christina Wichmann than being limited only to imposing principal sanctions of revocation, suspension, or limitation of a laboratory’s Editor in Chief CLIA certificate. Some of the regulatory changes were made effective January 27, 2024, and others will be effective December 28, 2024.

By statute, the CLIA program is funded through user fees assessed on certified laboratories. CMS said the increased fees were necessary as the program will not be self-supporting by the end of FY 2023 without an additional fee increase.

CMS says that the one-time 18% across-the-board increase would generate approximately 12.1 million dollars annually while the inflation factor would generate approximately 4.6 million dollars. The updated CLIA user fees are as follows: 1. Imposing an 18% across-the-board increase to existing fees 2. Fees to cover program costs for the following: • Performing follow-up/validation surveys to determine correction of deficient practices • Adding a specialties survey fee when necessary to determine compliance of one or more specialties outside a survey cycle • Performing a substantiated complaint survey • Performing a desk review of unsuccessful proficiency testing performance • Issuing a revised or replacement certificate 3. Increasing the certificate fee for Certificate of Waiver laboratories by $25 to offset program obligations to the FDA 4. Increasing fees every two years based on a two-part calculation of the Consumer Price Index-Urban (CPI-U) inflation adjustment, and, if applicable, an additional across the board increase.

Other regulatory updates include CLIA personnel requirements, which will necessitate updates to laboratories’ policies and procedures as follows: 1. Removed the proposed addition of a nursing degree qualification for high-complexity testing personnel 2. Revised the language of the regulations addressing laboratory director qualifications to specify that an individual qualifying under the doctoral degree algorithm must have an earned doctoral degree 3. Require lab directors to be on site at each laboratory they direct at least once every six months, with at least a fourmonth interval between the two on-site visits 4. Revised regulations providing additional educational/ qualification options, technical updates, reformatting of regulatory citations, and updating regulatory cross references The full final rule can be viewed at: https://www.govinfo.gov/content/pkg/FR2023-12-28/pdf/2023-28170.pdf.

I welcome your comments and questions — please send them to me at cwichmann@mlo-online.com.

4 | FEBRUARY 2024 MLO-ONLINE.COM

Vol.56, No. 2 PUBLISHER Chris Driscoll

cdriscoll@endeavorb2b.com EDITOR IN CHIEF Christina Wichmann

cwichmann@mlo-online.com MANAGING EDITOR Erin Brady ebrady@endeavorb2b.com PRODUCTION MANAGER Edward Bartlett ART DIRECTOR Kermit Mulkins AUDIENCE DEVELOPMENT/LIST RENTALS

Laura Moulton | lmoulton@endeavorb2b.com ADVERTISING SERVICES MANAGER

Karen Runion | krunion@endeavorb2b.com ADVERTISING DIRECTOR OF SALES EAST COAST/MIDWEST SALES, CLASSIFIEDS

Carol Vovcsko (941) 321-2873 | cvovcsko@mlo-online.com SOUTH/WEST COAST/ILLINOIS SALES

Lora Harrell (941) 328-3707 | lharrell@mlo-online.com MLO EDITORIAL ADVISORY BOARD John Brunstein, PhD, Biochemistry (Molecular Virology) President & CSO PathoID, Inc., British Columbia, Canada Lisa-Jean Clifford, COO & Chief Strategy Officer Gestalt, Spokane, WA Barbara Strain, MA, SM(ASCP), CVAHP Principal, Barbara Strain Consulting LLC, Formerly Director, Value Management, University of Virginia Health System, Charlottesville, VA Jeffrey D. Klausner, MD, MPH Professor of Preventive Medicine in the Division of Disease Prevention, Policy and Global Health, Department of Preventive Medicine at University of Southern California Keck School of Medicine.

Donna Beasley, DLM(ASCP), Director, Huron Healthcare, Chicago, IL Anthony Kurec, MS, H(ASCP)DLM, Clinical Associate Professor, Emeritus, SUNY Upstate Medical University, Syracuse, NY Suzanne Butch, MLS(ASCP)CM, SBBCM, DLMCM Freelance Consultant, Avon, OH Paul R. Eden, Jr., MT(ASCP), PhD, Lt. Col., USAF (ret.), (formerly) Chief, Laboratory Services, 88th Diagnostics/Therapeutics Squadron, Wright-Patterson AFB, OH Daniel J. Scungio, MT (ASCP), SLS, CQA (ASQ), Consultant at Dan the Lab Safety Man and Safety Officer at Sentara Healthcare, Norfolk, VA CORPORATE TEAM

CEO Chris Ferrell PRESIDENT June Griffin COO Patrick Rains CRO Reggie Lawrence CHIEF DIGITAL OFFICER Jacquie Niemiec CHIEF ADMINISTRATIVE AND LEGAL OFFICER

Tracy Kane

EVP CITY SERVICES & HEALTHCARE Kylie Hirko

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CONTINUING EDUCATION :: RESPIRATORY TESTING

The changing respiratory testing landscape: Why the value of flexibility is key

By Ayaz Majid, PhD and Chris Gardner

I

n the post-pandemic era of respiratory testing, laboratories need to consolidate platforms and assays to accomplish more with less all while ensuring sufficient testing menus for meeting clinical needs.1 At the same time, there is growing pressure to align testing procedures with a changing land-

Earning CEUs

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LEARNING OBJECTIVES

Upon completion of this article, the reader will be able to: 1. Identify the goal of developing appropriate diagnostic respiratory testing panels.

2. Differentiate the key factors in the development of testing workflows for diagnosing respiratory illness.

3. Identify the goals of creating a diagnostic stewardship program for respiratory illnesses.

4. Discuss the different options in choosing the right testing algorithms for the diagnosis of respiratory illness.

6 | FEBRUARY 2024 MLO-ONLINE.COM

scape of diagnostic stewardship protocols and ensure that each patient gets the right test at the right time to generate meaningful information that influences appropriate clinical decisions. Ultimately, the goal is to lead to both better patient outcomes and reduce unnecessary testing that increases healthcare costs without producing actionable results. 2 Achieving these goals simultaneously will be a significant challenge for the clinical laboratory community. However, it’s never too early to begin planning for seasonal respiratory testing as a year-round strategy. This is key for ensuring flexible testing algorithms. The most important factor in today’s respiratory testing is flexibility in workflows. Fixed testing products such as broad syndromic panels make it far more difficult to tailor testing to each patient’s needs, and their fixed costs are not conducive to lowering laboratory bills.

Given the multitude of respiratory pathogens as well as clinical, epidemiological, and economic factors, testing for respiratory infections involves a high degree of complexity and burden. Differences in seasons, patient demographics, severity of disease, specimen type, suspected pathogen type, and more can influence the testing process.1,3 Several key factors4,5 that must be considered for respiratory testing workflows include the following:

CONTINUING EDUCATION :: RESPIRATORY TESTING Seasonality: Respiratory testing algorithms are highly influenced by co-circulating respiratory pathogens that may follow a seasonal pattern, such as influenza viruses and respiratory syncytial virus (RSV), while other With many different types of respiratory test formats available, it can respiratory infections may present opprove challenging to know which test to use in which scenario. Here portunistically in season following a flu is a quick overview of the most common types of diagnostic tools for infection, such as bacterial pneumonia respiratory infections. caused by Staphylococcus aureus or HeRapid antigen testing: Also known as lateral flow testing, rapid antigen mophilus influenzae. In these seasonal tests moved into physicians’ offices years ago and more recently became scenarios, typical outpatients with less widely used for at-home COVID-19 testing. Their benefits include rapid severe symptoms may require stanresults (generally 15 minutes or less) and ease of use (even an untrained dard targeted flu A/B and RSV testing; consumer can typically use the test properly); they also tend to be fairly hospitalized patients with more severe inexpensive. However, rapid antigen tests are generally less sensitive symptoms could require a broader than molecular options, often requiring confirmation of negative results panel-based test. Conversely, a comby PCR when symptoms persist.

Targeted molecular laboratory tests: Molecular tests are known for their bination of targeted seasonal testing and reflex testing to a panel-based accuracy, with high sensitivity and specificity. Also called nucleic acid syndromic approach for patients with amplification tests, these targeted assays can be used to detect a single ongoing disease or pediatric patients pathogen at a time (such as group A Streptococcus (GAS) or SARS-CoV-2) may be warranted. or a small number of pathogens that make sense to test together (such Out-of-season testing is largely driven as flu A/B and RSV). Molecular tests may be performed with automated by symptoms and etiological risk factors sample-to-answer platforms that require very little hands-on time, as is the case of many commercial in-vitro diagnostic assays, or they may such as travel and/or exposure. As exrequire a more traditional, higher level of laboratory expertise with amples, targeted testing for COVID-19, more complex workflows. These typically require sample preparation group A streptococcus, and Bordetella (manual or automated) prior to running on a separate thermocycler or pertussis might be warranted in some reader. Results are produced fairly quickly, generally in about 2–3 hours cases, while a syndromic panel approach depending upon the system. might be needed based on disease risk Syndromic molecular tests: These test panels share all the benefits of other or severity. molecular tests — including accuracy and fairly rapid results — but provide Patient needs: Regardless of season or results for a much broader group of pathogens per sample. Since these tests the regional epidemiological landscape, cover many more targets, syndromic panels can be more expensive than their patient demographics can require different levels of testing. The presence of targeted molecular counterparts and are frequently reserved for in-patient and critical care testing. If flexible testing options are available, syndromic common respiratory pathogens may be molecular assays can be equally cost-effective as other solutions by only affected by age (e.g., RSV for children or resulting and paying for the pathogens needed to drive clinical action. the elderly), health status (e.g., immunocompromised or severe pneumonia), and vaccination status. Single-pathogen tests or targeted mini-panels might be appropriate for an otherwise healthy adult, but an immu- sions today are based on diagnostic tests. This is a testament nocompromised patient, an elderly patient, or a child might to the importance of clinical laboratories in patient care, but require a broader approach — and typically a different broader it also puts laboratory testing front and center in efforts to approach for each of these types of patients depending on reduce healthcare costs by ensuring appropriate testing and their exact clinical situation. prompting the right healthcare actions.

Pathogen type: In some situations, such as during a For respiratory testing, where symptoms in many cases are COVID-19 community surge, it may be safe to assume that very similar, diagnostic stewardship aims to deliver approprithe pathogen responsible for a patient’s respiratory infection ate testing algorithms in order to fast-track clinical decisions is the SARS-CoV-2 virus, so starting with a targeted test would and facilitate appropriate treatments for patients while reducbe justified. However, for immunosuppressed individuals or ing the unnecessary use of antibiotics or antivirals. Another patients with, or at risk for, critically ill respiratory disease, a aim, less important for patient care but just as important for syndromic approach makes for better clinical utility given the the responsible management of healthcare costs on behalf multitude of potential pathogens causing similar symptoms. of patients, is to get the right clinical information quickly Identifying the correct pathogen is essential for ensuring ap- at the lowest possible price point. A lab that relies on fixed propriate therapy and avoiding prolonged disease or mortality. syndromic panels for all suspected respiratory infections, regardless of patient demographics or seasonality, might offer Diagnostic stewardship a comprehensive testing approach but fail to meet the goals Applying appropriate clinical and epidemiological factors to of diagnostic stewardship. select the right test for the right patient at the right time allows laboratory medicine specialists to align with the principles Choosing the right test of diagnostic and antimicrobial stewardship.2,6 Going forward, post-pandemic respiratory testing algorithms Laboratory interventions to guide clinical testing and are already taking shape based on clinical, epidemiological, patient management are key, given that most healthcare deci- and economic factors. Appropriate strategies will enable

Respiratory test options

MLO-ONLINE.COM FEBRUARY 2024 | 7

CONTINUING EDUCATION :: RESPIRATORY TESTING optimal patient outcomes without wasteful and costly testing or treatment while facilitating laboratory profitability and alleviating hospital burdens. In addition, simplicity and flexibility in testing algorithms will help reduce the burden on ordering physicians and laboratory staff.

While many labs have adopted targeted testing for differential diagnosis of common respiratory pathogens, others have adopted flexible testing approaches based on syndromic panels. A flexible syndromic method allows for the creation of targeted custom panels as subsets of the broader syndromic panel. In this model, labs pay only for the results they select from the broader test.7,8 Should all results of an initial grouping come back negative, staff may choose to view results for more targets on the syndromic panel without re-running the assay. This is accomplished through software manipulation rather than as part of the assay workflow. This flexible approach makes it possible for laboratory staff to use a streamlined syndromic algorithm for their unique test situations, minimizing the need for training and validation while meeting the diagnostic stewardship goal to avoid over-testing.

For example, some laboratories begin with syndromic panels of about 20 respiratory pathogens, from which they select targeted groupings that can be used for a more customized testing approach. One grouping might include viral and bacterial pathogens that cause similar symptoms. Others might represent the full range of testing needs based on patient demographics, such as a targeted panel of influenza A/B and RSV for a pediatric patient, or a broader group of viral targets for an immunocompromised patient. These groups can also be used as a reflex when singleplex testing is negative either on the same platform or a different platform.

Alternatively, a successful approach for clinical labs is to run respiratory tests on one platform, eliminating the need to bring in multiple platforms to handle all pathogens, all throughputs, and all price points.

What’s next

Test selection by patient demographics For respiratory infections, clinical laboratory testing algorithms can become quite complex. Broadly, a few key categories based on patient demographics can help guide selection of the most appropriate test. The information below is gleaned from typical algorithms at many clinical laboratories.

Otherwise healthy adults: The clinical utility of respiratory antigen testing was exemplified with at-home COVID-19 antigen tests to facilitate rapid and low-cost testing for patient isolation and prevent spread. Other respiratory pathogen antigen tests are performed by health care providers (e.g., GAS, flu, and RSV) in symptomatic individuals. However, those negative by antigen testing yet clearly symptomatic benefit from more sensitive targeted molecular testing based on viruses in circulation (e.g., COVID-19 and flu A/B or COVID-19, flu A/B, and RSV) or differentiated patient symptoms (e.g., GAS). Syndromic panel-based testing is beneficial especially when the predicted targeted molecular testing was negative and symptoms persist.

Outside of the typical respiratory season, clinicians may recommend targeted tests based on signs and symptoms or regional epidemiology. However, based on severity of disease, a syndromic test may be warranted to effectively treat and or track out-of-season respiratory outbreaks.

Otherwise healthy children: The youngest kids — typically below age five — are at high risk for RSV and typically require a molecular test covering COVID-19, flu A/B, and RSV.9 Kids over the age of five might need that same test with the addition of group A strep (antigen or molecular test). In those children presenting with additional symptoms like a persistent cough, a syndromic test will enable appropriate management without delay and help rule out causative viruses and bacteria not captured in the initial screening assays.

Elderly: The elderly can be particularly vulnerable to respiratory infections due to underlying disease and/or compromised immune systems. Careful clinical evaluation can direct appropriate ordering for targeted molecular testing to rule out select viruses that may be circulating concurrently (i.e., COVID-19/, flu A/B, and RSV) or based on the severity of disease and underlying risk, then immediate syndromic testing may be warranted to initiate appropriate clinical action and patient treatment.

Immunocompromised adults or children: These vulnerable patients are susceptible to more severe respiratory infections and may become hospitalized. Patients in this group likely need a broad syndromic panel covering all pathogens typically responsible for respiratory infections.

The confluence of endemic COVID-19, diagnostic stewardship programs, and rising healthcare costs has led to more complexity than ever in the world of respiratory testing.

Laboratories must decide when to test which patients for which pathogens, and then be prepared to justify the costs of those decisions — all on a patient-by-patient basis.

Regardless of which diagnostic platforms a clinical laboratory chooses to implement, the most important factors in meeting these different goals should be simplicity, flexibility, and test appropriateness. In planning for future respiratory testing, laboratory leaders will want to prioritize testing options based on clinical and epidemiological factors that align with their institutional needs and allow for the championing of the quest for diagnostic stewardship and optimized

8 | FEBRUARY 2024 MLO-ONLINE.COM

healthcare. Targeted respiratory testing or flexible syndromic panel testing can fit nicely into this approach, addressing reimbursement concerns, and managing costs without an overly complicated workflow.

Ultimately, clinical laboratories have a unique opportunity within the changing post-pandemic respiratory landscape to ensure diagnostic stewardship principles for respiratory testing practice and beyond. Collectively, these initiatives will drive appropriate clinical and economic outcomes against ongoing healthcare challenges.

REFERENCES 1. Wichmann C. (2023, July 13). Right patient, right test, and lab efficiency.

Medical Lab Observer, 55 (8), 42. https:// www.mlo-online.com/management/ careers/article/53063478/right-patientright-test-and-lab-efficiency.

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2. World Health Organization. (2016). Diagnostic stewardship: A guide to implementation in antimicrobial resistance surveillance sites [Technical document]. https://www.who.int/publications/i/item/ WHO-DGO-AMR-2016.3.

WHY SWITCH?

3. Chow EJ, Uyeki TM, Chu HY. The effects of the COVID-19 pandemic on community respiratory virus activity. Nat Rev Microbiol. 2023;21, 195–210. https://doi. org/10.1038/s41579-022-00807-9.

Better performance Lower cost

4. Calderaro A, Buttrini M, Farina B, Montecchini S, De Conto F, Chezzi C. Respiratory Tract Infections and Laboratory Diagnostic Methods: A Review with A Focus on Syndromic Panel-Based Assays. Microorganisms.

2022; 10(9):1856. https://doi.org/10.3390/ microorganisms10091856.

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5. Albert C. (2023, October). Looking ahead to respiratory virus season.

CAP Today, 37 (10), 1,24. https://www. captodayonline.com/looking-aheadto-respiratory-virus-season/.

6. Claeys KC, Johnson MD. Leveraging diagnostic stewardship within antimicrobial stewardship programmes. Drugs Context. 2023;12:2022-9-5. Published 2023 Feb 20. doi:10.7573/dic.2022-9-5.

7.

Silva A. (2016). Flexible Respiratory Pathogen Testing: Why Clinical Laboratories No Longer Have to Settle [White paper]. Luminex. https://us.diasorin.com/sites/default/ files/products-documentation-tool/ WP103759.VERIGENE.RPFlex.Silva. v2.WR.pdf.

8. Lopansri B. (2016). Expert Commentary: A Clinician’s Perspective on Flexible Testing [Case study]. Luminex. https://us.diasorin.com/sites/default/ files/products-documentation-tool/ CASE147747.Clin.FlexTesting-CASE9181.

WR.pdf.

9. Centers for Disease Control and Prevention. (2023). RSV in Infants and Young Children. U.S. Department of Health and Human Services, National Center for Immunization and Respiratory Diseases. https://www.cdc.gov/rsv/high-risk/ infants-young-children.html.

Ayaz Majid, PhD and Chris Gardner are Directors of Product Management at Diasorin, responsible for targeted and syndromic in vitro diagnostic molecular technologies respectively. They each have extensive experience in molecular diagnostics for a wide range of infectious disease applications.

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CLINICAL ISSUES :: HPV INFECTION

Revealing the therapeutic potential of novel drugs for HPV-positive head and neck cancer

By Ashesh Saraiya, PhD

H

uman papillomavirus (HPV) is a viral infection that has well-known oncogenic effects. The virus is predominantly associated with the onset of cervical cancer, but its role in other malignancies has more recently been established. Effective antiviral therapies for HPV infection are lacking, and exciting new treatments may lie in the use of novel epigenetic drugs — bromodomain and extra-terminal domain inhibitors (BETis) — in combination with radiotherapy. This article describes recent research into the relevance and specificity of bromodomain-driven transcription in HPV-induced head and neck cancers and outlines the intriguing findings that have been revealed through next generation sequencing (NGS).

The HPV family includes more than 170 different viral strains that infect stratified epithelium, the protective layer of tissue covering all internal and external surfaces of the

10 | FEBRUARY 2024 MLO-ONLINE.COM

body.1 Approximately 18 percent of all human cancers have a viral etiology,2 and HPV has been identified as a key player in malignancies such as cervical cancer, anogenital tumors, and a subset of head and neck carcinomas. In particular, head and neck squamous cell carcinomas (HNSCCs) — HPV16-derived malignancies that develop from the mucosal epithelium in the oral cavity, pharynx and larynx — are responsible for more than 650,000 new cases of cancer annually, in addition to over 350,000 deaths.1 The frequency and severity of these carcinomas have led to a research surge in this field in recent years, driven by advancing technologies such as automated NGS library preparation. This has improved access to sequencing, leading to the identification of genomic and epigenetic factors involved in cancer progression, as well as the characterization of viral integration sites into the human genome.2

CLINICAL ISSUES :: HPV INFECTION The biology of HPV infection in head and neck cancer

All papillomaviruses have a circular, double-stranded DNA genome of approximately eight kilobases that encodes eight or nine open reading frames (ORFs) — genes enabling viral genome replication and particle assembly during infection.3 These ORFs are organized and named based on the timing of expression; genes are either expressed early or late in the viral life cycle. Of the proteins encoded by the early expression genes, E1 and E2 are responsible for replication of the viral genome, while E4 to E7 are accessory proteins that coordinate viral genome amplification and virulence. The late Figure 1: The initiation of HPV infection and subsequent tumorigenesis in cells of the tonsillar crypt.6 expression genes — known as L1 and L2 — encode two coat proteins that make up the viral shell An epigenetic target and enable its entry into host cells.3,4 The initiation and progression of HNSCC and other cancers To establish an infection, papillomavirus virion must gain occur due to both genetic changes, such as genome instability access to the epithelial basal layer of cells in the tonsillar and mutation, and dysregulation of the epigenome.7,8 Reverscrypt, entering the dividing basal keratinocytes and deliver- ible epigenetic modifications —including DNA methylation, ing their DNA into the nucleus of the cells (Figure 1).5,6 Viral histone modification, chromatin remodeling and noncoding DNA normally exists separately to the host genome in the RNAs — regulate various cellular responses, and disrupnucleus as an episome, employing enzymes in the host cell tions to these processes can lead to heightened expression to replicate its genome, along with host chromosomes, in a of oncogenes, playing an important role in tumorigenesis. A carefully regulated manner.3,4 Tight regulation of the repli- classic example of this is the acetylation of lysine residues, cation process keeps copy numbers of the viral DNA low, a process mediated by histone acetyltransferases (HATs), at helping the virus to evade the host immune system. However, enhancer regions of oncogenes, such as c-MYC, BCL2 and in oncogenic HPV genotypes, E6 and E7 oncoproteins enable CDK6. Histone acetylation can be recognized by proteins the integration of HPV into the host genome, dysregulating carrying bromodomains (BRDs) and, in turn, these epigenetic the normal cell cycle of keratinocytes in favor of viral replica- readers can recruit chromatin complexes to modulate trantion. These oncoproteins control expression of p53 and Rb scription and activate the expression of oncogenes – such as tumor suppressor genes, boosting cellular proliferation while E6 and E7 – that play an important role in cancer initiation preventing normal repair of chance mutations in the cellular and progression (Figure 2).9,10 genome, and driving HPV-related carcinogenesis.3 The human genome encodes 46 diverse proteins containing BRDs, which are structurally clustered into eight distinct subfamilies.10 The second subfamily — consisting of BRD2, BRD3, BRD4 and BRDT — is known as bromodomain and extra-terminal domain (BET) proteins. This group of epigenetic readers has recently emerged as a promising target for cancer therapeutics, with the development of small molecule inhibitors to prevent the transcription of key genes involved in cancer pathogenesis.

NGS developments

Figure 2: Bromodomains recognize acetylation markers in histone tails and recruit transcriptional machinery and epigenetic protein complexes to modulate transcription, activating the expression of oncogenes.9,10

Understanding the potential of BET inhibitors to mediate cancer requires in-depth knowledge of the role of BET oncoproteins, and this has been the focus of multiple genomic and epigenetic studies, as well as more than 39 clinical trials around the world. For example, researchers in the Department of Human Oncology at the University of Wisconsin-Madison have conducted extensive investigations into the specific functions of these oncoproteins.

MLO-ONLINE.COM FEBRUARY 2024 | 11

CLINICAL ISSUES :: HPV INFECTION HPV treatments, which combine cisplatin administration and radiation therapy. Although cisplatin is an effective chemotherapeutical agent, its administration often leads to multiple side effects — including nephrotoxicity12 — and the onset of additional comorbidities. These adverse effects occur because cisplatin is a non-specific DNA cross-linking agent; it binds randomly to genetic material and activates multiple signaling pathways in host cells, resulting in excessive inflammation, oxidative stress, and damage in healthy cells.

Conclusion

Researchers at the University of Wisconsin-Madison plan to continue their research into BET inhibitors, using the new automated library preparation system to accelerate NGS workflows and enhance the reproducibility of their results.

They are currently exploring new bromodomain-specific inhibitors targeted at BRD1 or BRD2 and optimizing the effectiveness of this new class of non-toxic anticancer drugs.

In the long term, BET inhibition holds significant clinical potential as part of combination treatment regimens for HPV HNSCC, and for a variety of other HPV-related cancers.

Figure 3: A phylogenetic representation of the 61 human bromodomains and their inhibitors.10

The team characterized a panel of HPV-infected cell lines for their full integration status and examined the distinct roles of BRD2 and BRD4 in regulating viral-host transcription machinery. Determining the downstream effects of these proteins on DNA repair, cell cycle control, and oncogenic signaling pathways required a combination of NGS and biochemistry techniques.

DNA sequencing technologies have evolved rapidly over the last few decades, and NGS enables the analysis of millions to billions of DNA or RNA sequences in parallel.11 This offers many advantages over traditional sequencing methods — including higher throughput, reduced costs, and easier data interpretation — but also requires advanced equipment and information technology to handle upstream and downstream processes, such as library preparation and analysis of the large amounts of data that are generated.

Researchers in the Department of Human Oncology have therefore introduced a number of new technologies into their lab, including a robust and reliable benchtop library preparation solution that streamlines all the steps required to prepare nucleic acid libraries. The introduction of this equipment reduces the time and effort required for sample preparation, allowing researchers to focus on understanding the biological underpinnings of HPV-induced HNSCC. Automated library preparation platforms, such as Tecan’s MagicPrep™ NGS system, has improved the consistency of data generated by the laboratory, and enhanced the researchers’ confidence in the accuracy of the transcriptional data that they produce.

Improving treatment for HPV-related cancers

The University of Wisconsin-Madison team has focused its efforts on answering several questions related to HPV HNSCC, such as why oncogenic HPV genotypes integrate into the genome, whether BRD4 coregulates viral and host genes in the presence of a BET inhibitor, and whether the antitumorigenic effects of BTE inhibitors occur independently or in the presence of radiation. The results are yet to be published, but they could potentially lead to improvements to conventional

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REFERENCES 1. Sabatini ME, Chiocca S. Human papillomavirus as a driver of head and neck cancers. Br J Cancer. 2020;122(3):306-314. doi:10.1038/ s41416-019-0602-7.

2. Tuna M, Amos CI. Next generation sequencing and its applications in HPV-associated cancers. Oncotarget. 2017;31;8(5):8877-8889. doi:10.18632/oncotarget.12830.

3. Faraji F, Zaidi M, Fakhry C, Gaykalova DA. Molecular mechanisms of human papillomavirus-related carcinogenesis in head and neck cancer. Microbes Infect. 2017;19(9-10):464-475. doi:10.1016/j. micinf.2017.06.001.

4. Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci (Lond). 2006;110(5):525-41. doi:10.1042/ CS20050369.

5. Aksoy P, Gottschalk EY, Meneses PI. HPV entry into cells. Mutat Res Rev Mutat Res. 2017;772:13-22. doi:10.1016/j.mrrev.2016.09.004.

6. Faraji F, Zaidi M, Fakhry C, Gaykalova DA. Molecular mechanisms of human papillomavirus-related carcinogenesis in head and neck cancer. Microbes Infect. 2017;19(9-10):464-475. doi:10.1016/j. micinf.2017.06.001.

7.

Kanwal R, Gupta K, Gupta S. Cancer epigenetics: an introduction.

Methods Mol Biol. 2015;1238:3-25. doi:10.1007/978-1-4939-1804-1_1.

8. Cheng Y, He C, Wang M, et al. Targeting epigenetic regulators for cancer therapy: Mechanisms and advances in clinical trials. Signal Transduct Target Ther. 2019;17;4:62. doi:10.1038/s41392-019-0095-0.

9. Suarez-Alvarez B, Rodriguez RM, Ruiz-Ortega M, Lopez-Larrea C. BET Proteins: An Approach to Future Therapies in Transplantation. Am J Transplant. 2017;17(9):2254-2262. doi:10.1111/ajt.14221.

10. Pérez-Salvia M, Esteller M. Bromodomain inhibitors and cancer therapy: From structures to applications. Epigenetics. 2017;4;12(5):323-339. doi:10.1080/15592294.2016.1265710.

11. Hess JF, Kohl TA, Kotrová M, et al. Library preparation for Next generation sequencing: A review of automation strategies. Biotechnol Adv. 2020;41:107537. doi:10.1016/j.biotechadv.2020.107537.

12. Sun L, Liu J, Yuan Y, Zhang X, Dong Z. Protective effect of the BET protein inhibitor JQ1 in cisplatin-induced nephrotoxicity. Am J Physiol Renal Physiol. 2018;1;315(3):F469-F478. doi:10.1152/ajprenal.00527.2017.

Ashesh Saraiya, PhD is the Associate Director of Product Management at Tecan Genomics. He completed his PhD in molecular biology at Wayne State University, specializing in ribosomal RNA genetics, and followed this up with postdoctoral work examining miRNA and gene translation in protozoan parasites at University of California, San Francisco. Ashesh began his Tecan career as a Field Application Scientist, before moving to product management, where he continues to leverage his experience to help develop innovative solutions to address the challenges associated with NGS sample preparation.

Best Practices for Managing

Sepsis and Septic Shock Including the Use of ePV Sepsis is a life-threatening condition marked by organ dysfunction and other physiologic changes caused by a host response to infection. Although the prognosis of patients with sepsis has improved through advances in critical care management, mortality from sepsis remains high. Devang Sanghavi, MD, Vice Chair of Practice, Critical Care Medicine, Mayo Clinic, will review key considerations and controversies surrounding sepsis identification and resuscitation.

He will review clinical studies of estimated plasma volume (ePV), an important new tool for managing the volume status of sepsis patients.

Learning Objectives: Sepsis identification and definition The Sep1 metric. Does it really matter?

• Early and appropriate antibiotic administration • Markers of perfusion: Lactate vs central venous oxygen saturation (SCVO2) • Fluid management: Crystalloids 30 cc/kg or less • Volume assessment • Timing of pressor initiation Role of AI in inpatient identification of sepsis Use of ePV for managing volume status of sepsis patients

Primary Speaker Devang Sanghavi, MD, MHA, FCCP Vice Chair of Practice, Critical Care Medicine Director, MICU; Chair, Sepsis Work Group Associate Professor of Medicine Mayo Clinic

ePV Assessment in Critical Illness Fluid resuscitation is a mainstay in the treatment of sepsis. However, as reported in previous studies, a positive fluid balance may be associated with a worse prognosis. Dennis Begos, MD, Senior Director of Medical and Scientific Affairs for Nova Biomedical, will review the use of ePV status to assess fluid balance in critical illnesses including sepsis.

A comprehensive blood gas/critical care analyzer that now includes ePV as part of its 22-test profile will be described.

Speaker Dennis Begos, MD, FACS, FACRS Senior Director Medical and Scientific Affairs Nova Biomedical

Webinar Dates: Wednesday, March 20, 3 pm Eastern Time Thursday, March 28, 1 pm Eastern Time

Register Now: novabiomedical.com/sepsis-mlo This program offers 1 hour of P.A.C.E. continuing education credits. Nova Biomedical is approved as a provider of continuing education programs in the clinical laboratory sciences by the ASCLS P.A.C.E.® Program.

This program has been approved by the American Association of Critical-Care Nurses (AACN), for 1.00 CERPs, Synergy CERP Category A, File Number 24839. Approval refers to recognition of continuing education only and does not imply AACN approval or endorsement of the content of this educational activity, or the products mentioned.

Nemes Laszlo / iStock / Getty Images Plus / Getty Images

INFECTION DIAGNOSTICS :: HIV

HIV epidemic

From the origin towards the end

By Rajasri Chandra, MS, MBA

H

uman immunodeficiency virus (HIV) is an RNA (ribonucleic acid) virus that infects human immune cells, in particular CD4 T lymphocytes and is acquired through mucosal or intravenous exposure to infected bodily fluids such as blood, semen, and genital tract secretions. Infection from HIV was first reported in 1981 in the Morbidity and Mortality Weekly Report (MMWR), a publication of the Centers for Disease Control and Prevention (CDC), when doctors discovered clusters of Kaposi’s sarcoma and pneumocystis pneumonia in homosexual men in Los Angeles, New York City, and San Francisco having weakened immune systems. In 1982, the CDC named the disease caused by HIV as acquired immune deficiency syndrome, AIDS.1 If left untreated, HIV infections progress from acute through chronic to AIDS. Excepting a small proportion of untreated persons infected with HIV who remain asymptomatic and show little evidence of progressive immune suppression after 10 or more years of infection, nearly all eventually develop AIDS. The number of AIDS cases grew in epidemic proportion and per the latest United Nations AIDS factsheet, 85.6 million people have become infected with HIV, and 40.4 million people have died from AIDS-related illnesses since the start of the epidemic. 2 HIV has two subtypes – HIV-1 and HIV-2. HIV-1 has 3 major phylogenetic groups – M (major), O (outlier) & N (non-M, non-O), all of which can cause AIDS.3,4,5 HIV-1 M infections are common worldwide, O is restricted to West Central Africa and N is least spreading and was found in Cameroon.3 HIV-1 group N is a mosaic of divergent HIV-1

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and simian immunodeficiency virus (SIV) found in chimpanzees.4,5 The HIV strains reported in the United States in 1981 were of HIV-1 subtype. Serologic evidence of another human immunodeficiency virus subtype (HIV-2) was discovered in 1985 in Senegal,6 which was subsequently isolated in 1986 from a Cape Verdean patient.7 Around 95% of the people infected with HIV are infected with HIV-1 subtype. HIV-2 is mainly present in West Africa, but it is slowly starting to appear in other regions, including the United States, Europe, and India.8

Situations that necessitate testing

HIV testing is needed as follows: • To determine the human immunodeficiency virus (HIV) infection status of a person • To test or screen blood products before donation • To evaluate the progression of disease • To monitor the effectiveness of antiretroviral therapy (ART)

Tests for HIV detection

HIV infection can be detected in the following ways: 9 • Direct visualization of HIV virus by electron microscopy • Cultivation by lymphocyte culture • Measurement of HIV-specific serologic responses • Detection of viral antigens • Detection of viral nucleic acids However, the most common tests use the immunological method or the molecular method.10

INFECTION DIAGNOSTICS :: HIV Enzyme-linked immunosorbent assays (ELISA)

The first-generation HIV test was an immunological test that became available in 1985 — the enzyme-linked immunosorbent assay (ELISA) detected IgG antibody of HIV-1 only in patients 6 to 12 weeks after infection. False-positive results occurred; so positive results needed to be confirmed using a second test — western blot or an immunofluorescence test. The second-generation HIV test became available in 1987 and had increased specificity and positive predictive value as it had a recombinant HIV-1 p24 antigen. Some tests included HIV-1 group O protein and an HIV-2 protein to enable detection of both HIV-1 and HIV-2 antibodies. The second-generation tests also reduced the antibody-negative window to 4 to 6 weeks post-infection infection. The thirdgeneration HIV tests added an IgM antibody and reduced the antibody-negative window further to three weeks postinfection. In the late 1990s, the fourth-generation HIV screening assays were launched that detected both antibody and p24 antigen for HIV-1 and HIV-2 combined and reduced the test-negative to two weeks. In 2015, the fifth-generation HIV screening assay was launched that not only detected both antibody and antigen for HIV-1 and HIV-2 but also differentiated between HIV-1 and HIV-2.11 Table 1 summarizes the evolution of HIV detection assays.

Eclipse Period

IgG

p24

IgM

X

0

10

20

30 40 50 60 Days After Infection

70

80

90

NAT p24/IgM/IgG sensitive IgM/IgG sensitive IgG sensitive Western blot*

Molecular method/nucleic acid test (NAT)

Nucleic acid tests can be used as follows: • To diagnose HIV patients • To determine disease progression and enable antiretroviral treatment monitoring • Determine drug resistance characterization A nucleic acid test for HIV-1 was first demonstrated in blood specimens from HIV-1 infected individuals in 1988.13 It detects the HIV RNA and has the shortest window period of 10 to 33 days post-infection. NAT is considered more accurate than

RNA (NAT)

*Western blot is no longer used for HIV

Figure 1: Window period for NAT, antigen/antibody, and antibody test for HIV.14

ELISA tests and hence used as confirmatory tests. However, NATs are more expensive than ELISA tests. The graph in Figure 1 depicts the window period for the different types of tests — the NAT detects HIV the earliest post-infection, followed by the antigen/antibody test, and lastly, the antibody test.14

Generation

1st

2nd

3rd

4th

5th

Year of launch

1985

1987

1991

1997

2015

Antigen (Ag) source

Virus infected cell lysate

Lysate and recombinant protein

Recombinant and synthetic protein

Recombinant and synthetic protein

Recombinant and synthetic protein

Sensitivity

99%

>99.5%

>99.5%

>99.8%

100%

Specificity

95-98%

>99%

>99.5%

99.5%

99.5%

Negative window

8–10 weeks

4–6 weeks

2–3 weeks

2 weeks

2 weeks

Detects antibody (Ab) and Ag

IgG Anti-HIV-1

IgG Anti-HIV-1 and IgG Anti-HIV-2

IgG and IgM Anti-HIV-1, HIV-2 and Group O

IgG and IgM AntiHIV-1, HIV-2. Group O and HIV-1 p24 Ag

IgG and IgM AntiHIV-1, HIV-2. Group O and HIV-1 p24 Ag

Results

Single result

Single result

Single result

Single result

Separate results for HIV-1 and HIV-2 Ab and Ag

HIV-1 western blot or immunofluorescence

HIV-1 western blot or immunofluorescence; HIV-2 ELI-SA and western blot if HIV-1 is confirmed negative

HIV-1 western blot or immunofluorescence; HIV-2 ELI-SA and western blot if HIV-1 is confirmed negative

HIV-1/HIV-2 differentia-tion assay followed

by HIV-1 nucle-ic acid test (NAT) to confirm neg-ative8

HIV-1/HIV-2 differentia-tion assay followed

by HIV-1 nucle-ic acid test (NAT) to confirm neg-ative12

Confirming tests

Table 1: Human immunodeficiency virus diagnostic testing.11 MLO-ONLINE.COM FEBRUARY 2024 | 15

INFECTION DIAGNOSTICS :: HIV HIV Screening and testing guidelines

In the United States, screening of blood donors for HIV-1 and HIV-2 started in March 1985 and June 1992 respectively.15 At present, the CDC recommends that everyone between the ages of 13 and 64 should get tested for HIV at least once as part of their routine healthcare. Those with certain ongoing risk factors — such as having more than one sex partner since their last HIV test or having sex with someone whose sexual history they don’t know — should get tested annually.

Some sexually active gay and bisexual men may benefit from more frequent testing (e.g., every three to six months).16 Specimen types for HIV testing include blood from a finger stick or in the form of serum, plasma, or dried blood spots (DBS). Oral fluid and urine specimens can also be used for HIV testing.17

Before HIV Infection

Acute HIV Infection

Chronic HIV Infection

Weeks to Months

Years

Infection

CD4 cell

AIDS

HIV

Figure 2: HIV viral load and CD4 cell count as HIV progresses.18

Disease progression and evaluation

There are three stages of HIV infection, including acute, chronic, and AIDS.18 Acute HIV infection: Develops within two to four weeks after infection. Some people get flu-like symptoms, such as fever, headache, and rash. HIV multiplies rapidly and spreads throughout the body. The virus attacks and destroys the CD4 T lymphocytes. As the level of HIV in the blood is very high, the risk of transmission is also very high during this stage.

Chronic HIV infection: Is the next stage when HIV continues to multiply in the body but at very low levels and hence the individuals are mostly asymptomatic. They can transmit HIV to others but if the viral load is maintained at an undetectable level taking antiretroviral therapy (ART), risk of HIV transmission is minimal.

Acquired immune deficiency syndrome (AIDS): The most severe stage when the individual’s immune system is damaged and cannot fight off infections from opportunistic organisms.

There are two types of tests to evaluate disease progression: HIV viral load and CD4 count. HIV viral load tests are

The initiative focuses on four key strategies:

quantitative nucleic acid tests that determine the number of copies of HIV RNA per milliliter of blood. They can be used to diagnose acute HIV infection, guide treatment choices, and monitor response to antiretroviral therapy (ART).19 CD4 count determination by immunofluorescence analysis using flow cytometer is considered the gold standard. The normal range is between 500 to 1500 cells/cubic millimeter.

For AIDS patients CD4 cell count drops below 200 cells/cubic millimeter.20 Figure 2 depicts the HIV viral load and CD4 count during HIV progression.

Ending the HIV Epidemic Initiative

With various developments in HIV testing and treatment options, the HIV epidemic has seen a decline with new infections declining. In 2019, the U.S. Department of Health and Human Services (HHS) launched an initiative that aims to reduce new HIV infections in the United States by 90 percent by 2030 (See Figure 3).23 However, the emergence of drug resistant HIV strains has posed a great challenge to successful antiretroviral therapy (ART).21 The HIV-1 pol gene is generally used to identify mutations associated with drug resistance and also for HIV-1 subtyping.22

Conclusion DIAGNOSE all people with HIV as early as possible.

TREAT people with HIV rapidly and effectively to reach sustained viral suppression.

PREVENT new HIV transmissions using proven interventions, including PrEP and syringe service programs (SSPs).

RESPOND quickly to potential HIV outbreaks to get needed prevention and treatment services to people who need them.

Figure 3: Four pillars of End the HIV Epidemic (EHE) initiative by HHS.23

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It is often said that “Where there is a will, there is a way.”

Tackling the HIV epidemic proves that point. The menace from the devastating HIV epidemic is now under control, thanks to the efforts by the various sections of society. Now, HIV testing is not restricted to clinical labs and is available to the public as point-of-care at-home tests. Hence by following the tenets of EHE, one can prevent infection from HIV, and if by chance get infected, individuals should get diagnosed and treated immediately to prevent development into AIDS. REFERENCES 1. Gov H. Timeline of the HIV and AIDS epidemic. Hiv.gov. Published November 15, 2023. Accessed December 14, 2023. https://www.hiv. gov/hiv-basics/overview/history/hiv-and-aids-timeline/.

2. Global HIV & AIDS statistics — Fact sheet. Unaids.org. Accessed December 14, 2023. https://www.unaids.org/en/resources/fact-sheet.

INFECTION DIAGNOSTICS :: HIV 3. Yang C, Dash B, Hanna SL, et al. Predominance of HIV type 1 subtype G among commercial sex workers from Kinshasa, Democratic Republic of Congo. AIDS Res Hum Retroviruses. 2001;1;17(4):361-5. doi:10.1089/08892220150503726.

15. U.S. public health service guidelines for testing and counseling blood and plasma donors for human immunodeficiency virus type 1 antigen.

Cdc.gov. Published March 1, 1996. Accessed December 14, 2023. https://www.cdc.gov/mmwr/preview/mmwrhtml/00040546.htm.

4. Yang C, Dash BC, Simon F, et al. Detection of diverse variants of human immunodeficiency virus-1 groups M, N, and O and simian immunodeficiency viruses from chimpanzees by using generic pol and env primer pairs. J Infect Dis. 2000;181(5):1791-5. doi:10.1086/315439.

16. Gov HIV. Resources for 2023 national HIV Testing Day. Hiv.gov.

Published June 15, 2023. Accessed December 14, 2023. https://www. hiv.gov/blog/resources-for-2023-national-hiv-testing-day/.

5. Fonjungo PN, Dash BC, Mpoudi EN, et al. Molecular screening for HIV-1 group N and simian immunodeficiency virus cpz-like virus infections in Cameroon. AIDS. 2000;14;14(6):750-2. doi:10.1097/00002030-200004140-00018.

17. Women and HIV: Get the Facts on HIV Testing, Prevention, and treatment. U.S. Food and Drug Administration.

Published October 30, 2023. Accessed December 14, 2023. https://www.fda.gov/consumers/womens-health-topics/ women-and-hiv-get-facts-hiv-testing-prevention-and-treatment.

6. Barin F, M’Boup S, Denis F, et al. Serological evidence for virus related to simian T-lymphotropic retrovirus III in residents of west Africa. Lancet. 1985;21-28;2(8469-70):1387-9. doi:10.1016/s0140-6736(85)92556-5.

18. The stages of HIV infection. Nih.gov. Accessed December 14, 2023. https://hivinfo.nih.gov/understanding-hiv/fact-sheets/ stages-hiv-infection.

7.

Clavel F, Guétard D, Brun-Vézinet F, et al. Isolation of a new human retrovirus from West African patients with AIDS. Science.

1986;18;233(4761):343-6. doi:10.1126/science.2425430.

19. Viral load test. Hiv.gov. Accessed December 14, 2023. https://clinicalinfo.hiv.gov/en/glossary/viral-load-test.

20. Battistini Garcia SA, Guzman N. Acquired Immune Deficiency Syndrome CD4+ Count. StatPearls Publishing; 2023.

8. Burgess L. HIV-1 vs. HIV-2: Differences and similarities. Medicalnewstoday.com. Published December 5, 2018. Accessed December 14, 2023. https://www.medicalnewstoday.com/articles/323893.

21. Chimukangara B, Samuel R, Naidoo K, de Oliveira T. Primary HIV-1 Drug Resistant Minority Variants. AIDS Rev. 2017;19(2):89-96.

9. Tang YW, Ou CY. Past, present and future molecular diagnosis and characterization of human immunodeficiency virus infections. Emerg Microbes Infect. 2012;1(8):e19. doi:10.1038/emi.2012.15.

22. Pasquier C, Millot N, Njouom R, et al. HIV-1 subtyping using phylogenetic analysis of pol gene sequences. J Virol Methods.

2001;94(1-2):45-54. doi:10.1016/s0166-0934(01)00272-5.

10. HIV testing. Cdc.gov. Published June 9, 2022. Accessed December 14, 2023. https://www.cdc.gov/hiv/testing/.

23. Introduction. Cdc.gov. Published August 9, 2021. Accessed December 14, 2023. https://www.cdc.gov/hiv/policies/strategic-priorities/mobilizing/introduction.html.

11. Alexander TS. Human Immunodeficiency Virus Diagnostic Testing: 30 Years of Evolution. Clin Vaccine Immunol. 2016;4;23(4):249-53. doi:10.1128/CVI.00053-16.

12. 2018 Quick reference guide: Recommended laboratory HIV testing algorithm for serum or plasma specimens. Published online 2018.

Accessed December 14, 2023. https://stacks.cdc.gov/view/cdc/50872.

13. Ou CY, Kwok S, Mitchell SW, et al. DNA amplification for direct detection of HIV-1 in DNA of peripheral blood mononuclear cells. Science.

1988;15;239(4837):295-7. doi:10.1126/science.3336784.

14. Which HIV tests should I use? Cdc.gov. Published June 1, 2023.

Accessed December 14, 2023. https://www.cdc.gov/hiv/clinicians/ screening/tests.html.

2402MLO_AdvancedDataSystems.indd 1

Rajasri Chandra, MS, MBA is a global marketing leader with expertise in managing upstream, downstream, strategic, tactical, traditional, and digital marketing in biotech, in vitro diagnostics, life sciences, and pharmaceutical industries. Raj is an orchestrator of go-to-market strategies driving complete product life cycle from ideation to commercialization.

| 1:33 PM MLO-ONLINE.COM FEBRUARY 2024 1/3/24 17

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LAB MANAGEMENT :: OVERCOMING DATA MANAGEMENT CHALLENGES

Overcoming data management challenges: The biggest challenge of all is…us

By Robert F. Moran, PhD, FCCM, FACB

N

ew or newly engineered analytical technology has brought about an array of analytical systems for laboratory testing just as information technology has brought faster and more innovative ways of displaying the information for clinicians. All are great advances for facilitating patient care, but this author’s experience over the decades has shown that to make it all work together most effectively, providers, laboratorians, and information technology professionals, both institutional and external, must work as an integral unit with a mutual professional respect for each other’s operational needs and perspectives.

A recent article in the October issue of MLO by J.S. Tony1 really piqued this author’s interest, since over a long professional career, managing information/data has too frequently emerged as an issue that surpassed many technical and operational challenges.2-6 However, the writer began to reflect on its apparent simplicity as being the panacea for the ills of communicating critical information from a wide range of laboratory sources. Not taking away from the concept of an all-in-one LIMS as described by the article’s author, which he stated clearly and with appropriate enthusiasm — an enthusiasm I share — although with expanding the scope to meet laboratory and provider needs more fully.

Despite this ‘operational’ enthusiasm, attention should be drawn to some serious concerns about implementation and enthusiastic acceptance by the end user of any such system.

This concern is based on issues related to getting the correct information to the end-user/provider in a rapid and unambiguous manner appropriate to the need.7

Salient points: Critical and point-of-care patients

Many analyses are performed not only in the central laboratory but in POC systems that are controlled by the lab and in systems that are internal but independent of the central lab. All data/information should go to the patient record, which gives

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rise to inevitable comparisons and potential for confusion especially when analysis is with different instrumentation and report nomenclature. Consequently, we will use some examples from POC testing. While POC testing may be the best example of the needs as concluded here, other areas of lab testing and reporting undoubtedly have analogous issues.

The usual issues of integrating information from disparate sources is even more significant in POC and critical care testing since immediate critical decisions may be made, and the accuracy of communication of both quantitative results and their specific meaning is crucial. Optimally that meaning must include the nature, source, and collection time of the specimen as well as the quantitative and qualitative characteristics of what is being reported. The information must be understandable to and among the various professional providers — not just the scientists who developed the measurements, protocols, and the naming/symbols used. To bring this about, our experience shows that significant pre-work is necessary, especially including the information technology (IT) professionals who develop and maintain both analytical and reporting systems. I could also cite examples of reports and formats we thought would be ‘great’ but when put into practice were totally rejected by medical staff, because we did not consult with them on their needs or wants.

While some of these concerns are obvious and primarily technical issues with solutions already made available by the various technical or professional organizations, the real integration of systems goes beyond the technical. We believe that dialog between central laboratory and IT professionals is only the beginning. Direct providers and central laboratory as well as ‘independent’ POC testing areas must all be part of the design and implementation of the final output of any such system, including the inevitable compromises. This may be a challenge, since each group may speak a different professional/technical dialect, if not at times a different language,

LAB MANAGEMENT :: OVERCOMING DATA MANAGEMENT CHALLENGES and quite possibly have a different view of intrapersonal communication on the clinical and analytical aspects. Based on this writer’s experience, successful implementation of useful information reporting systems is less likely or will take longer if these different dialects and communication styles are not acknowledged and accommodations made by both the direct participants and their management. The associated issues are not resolved by one or two mega-meetings, each group identifying their requirements, IT implementation, and then voila-success! Success only results from a lot of arduous work (sometimes boring and repetitive but still challenging). Repeated explanations and discussions within small and large groups and reflection in between are all part of an effective process. Once believed complete, one finds that it is not complete: test/evaluate the results, make corrections, and then try again, putting it into effect one related piece at a time.

Attempting any such program requires a real and long-term commitment on the part of not only those clinical and technical specialists but more importantly of their direct and high-level management. The developer/supplier of an ‘all-in-one’ LIMS must recognize this and then facilitate the process as needed.

Communication and complete ID of results exemplified in POC

An example shared from POC testing and reporting results may help understand the generalities stated above. (And we would expect that other specialty areas may have other similar specimen and reporting that might be added to this.) A specific example of a situation in which analytical/clinical ambiguity may exist, and consequently impact patient care, is that of the enhanced blood gas analyzer (eBGA) (i.e., the blood gas systems that also measure electrolytes, CO-oximetry, glucose, etc. or any similar multi-measurand system.) The software/ firmware is already in place and data/information available to the provider. Since clinical action may take place before the full system reports are available, subsequent confusion will be reduced if the reports from different devices are similar in appearance and detail.

Basic identification: 1) Identifying patient and specimen type/source and collection time/date clearly. Recall that a ‘blood gas,’ or an ‘enhanced blood gas’ is done on blood, but the blood can be from various sources — arterial, capillary, venous, etc., and each with different clinical meaning. 2) Identifying the measurand’s entity/quantity type (i.e., analyte or parameter). For example, carbon dioxide tension in venous whole blood. -pCO2(vB), mmHg/kPa. [Kind of quantity ‘p’ (tension); measurand identity –‘CO2;’ specimen source –‘v,’ venous; and specimen type – ‘B’ (blood).] All International Federation for Clinical Chemistry (IFCC) / International Union of Pure and Applied Chemistry (IUPAC) symbols.

Technology effect identification: Specific technologies impact reported results. (Are all tests performed on ‘whole blood’ in fact, concentrations in whole blood? No, they are not!) What does a sodium concentration mean? Is the central lab value different from the eBGA value? The symbol set for molar concentration of sodium from an eBGA should be cNa(aBpu). [‘c’ molar concentration; Na’–sodium; ‘a’– arterial; ’B’-Blood; ’pu’ – plasma, undiluted.] The symbols are all IFCC/IUPAC, but with the subscripted ‘u’ referring to the Clinical and Laboratory Standards Institute (CLSI) / National Institute of Standards and Technology (NIST) calibration protocol. Similarly, is a ‘bicarbonate’ the same thing as a ‘plasma bicarbonate’? The symbol set for bicarbonate from an eBGA should be cHCO3(aBpu).

With the specific identifying symbols as a part of the name, there is no question, in each case is a concentration (molar) of the ion from an arterial blood specimen reported from undiluted plasma. The central lab would ideally report for example cNa(vBpd), with collection time included in an unambiguous report. Use of these established symbols reduces the size of the name on the report while providing the most complete information to the provider.

External sequelae: Some laboratory system/POC reports may be used in other (non-lab) computations). Consequently, expect this, and label results as part of the name accordingly.

Thus, as one example, a ’mixed’ venous blood gas would report -cO2(vmBt) representing the concentration of oxygen in the mixed venous whole blood specimen as a total of the dissolved and that bound to hemoglobin — clear and unambiguous both analytically and clinically.

Thus, clear, timely, and unambiguous reporting to the clinical provider of direct patient care involves a complex interaction among users and providers within the institution and within the relevant parts of the institution as well as with the manufacturers of the analytical systems and LIMS vendors. Many, if not most, of the technical solutions are already available to central laboratories, especially through the International Federation for Clinical Chemistry (IFCC) for complete and unambiguous nomenclature and symbols, and by CLSI and NIST for standards (material and paper).8,9 Symbols as names on patient record/information management display: The question might be, are these technical solutions widely known and applied by laboratory staff, to say nothing of the medical professionals who use the information? An example of existing symbols as prescribed by IFCC/IUPAC or proposed to them13 is shown in the table below. These symbols also include designations that identify specimen treatment effects by the analysis according to the CLSI/NIST guidelines, thus making the significance of values immediately obvious (See Table 1).

Result source

Bicarbonate

Sodium

1

POCT

cHCO3 (aBpu)

cNa(aBpu)

2

Central lab (best symbol)

cHCO3 (vBpd)

cNa(vBpd)

3

Central lab (acceptable)

cHCO3 (vB)

cNa(vB)

4

Central lab (?)

cHCO3

cNa

Table 1: Unambiguous reporting: Detailed symbols as names on patient record with only a few added characters. Incorporate this into analytical system information management (ASIM), laboratory information management system (LIMS), and hospital information management system (HIMS).

Other regulatory requirements for having certain information available on the laboratory report make sense, but is the information where it is really needed, or does the provider have to hunt for it? Does the hunt for essential information frustrate the provider to the extent that they contact the lab for information, thus wasting both provider and lab staff time?

Other specimen characteristics may also need to be identified for clearer documentation and for both clinical and analytical use. Consider: 1) ‘arterialized’ capillary specimens as collected, are different from both arterial specimen and untreated capillary specimens; 2) venous or mixed venous MLO-ONLINE.COM FEBRUARY 2024 | 19

LAB MANAGEMENT :: OVERCOMING DATA MANAGEMENT CHALLENGES specimens are also different and may be Information sources, flow, & reports: Actionable* report proliferation used differently. Finally, POC systems, (standalone and multicomponent), measure and report other quantities on ASIM Reports ASIM Reports an undiluted specimen in the plasma fraction of the whole blood-potentially ASIM affecting result value. These and other ASIM POC 1,2,3 collection and measurement-related POC 1,2,3 LIMS-1 conditions can affect results and their Lab-Linked POCs Non-Lab interpretation.

Institutional POCs Reporting issues have been exacerH.A.L.-MML bated as more testing has been done AS-1,2,n (HIMS/IIMS) using ‘enhanced’ blood gas analyzers’ Off-site (eBGA’s) since many of these systems Affiliated LIMS-2 also have been simplified to the extent Labs that professional staff operating them Integrated are not as familiar with the symbology System + AS-1,2,n that can be used or the significance of Reports the technology on clinical practice. *Available to MD + AS-Analytical System Not only is it important to label specimens as to type/nature and source, but in reporting and setting requirements Figure 1: A more encompassing solution. for instrumentation and reporting/ charting system used. Those responsible for measuring, as 2. Moran RF, Lesica JP. An automated data management system for blood gas quality control. New Zealand J Med Lab Tech. 1983;37:28-55. well as integrating the measurement devices output with 3.

Moran RF. A Centralized Quality Control Data Processing and system wide reporting must make provisions for complete Management System for the Critical Care Laboratory. Market Issues specimen-result characterization. Testing experts may need and Operational Alternatives Leading to a Strategic Decision. Pacific Western University,1987. to get together with IT and other clinical experts to assure that what is reported is identified/reported unambiguously. 4. Moran, RF. Computer Standards, Healthcare Management Briefs. 1990.

A more encompassing solution

To accomplish the overall goal of better and more efficiently provided information to providers, it is essential to have a developed rapport among the medical and measuring professionals by, for example, constructively participating in each other’s staff meetings/professional committees,8,9 as well as the more traditional in-service training. With the central lab taking the lead in organizing the discussions and using the symbols and protocols already available through IFCC13/ IUPAC, CLSI, and NIST, the output of various information management systems can be enhanced and operational management clearly improved (See Figure 1).

For the many institutions now using both traditional measuring methods and eBGA’s, accurate and complete specimen measurement differentiation will enable the diagnostic/therapeutic/operational advantage of the various technologies that are now analytically fully integrated. This ensures proper comparison of numeric values when viewed on patient’s charts, which may have the same measurand reported using other non-direct systems — making more work for the IT professionals in set-up — but important for both analytical accuracy and clinical application.

The mantra might be to conceive, design, adopt, adapt, integrate, educate, and communicate to enhance improved patient care for these most critical of tests performed in point(s) of care. That involves not just a great all-in-one LIMS, but one fully integrated with the HIMS/LIMS and designed/ put together by a total and collegial healthcare team.10,11 REFERENCES 1. Tony JS. Overcoming data management challenges with an all-inone LIMS. Medical Laboratory Observer. Published September 21, 2023. Accessed December 18, 2023. https://www.mlo-online. com/information-technology/data-management/article/53070653/ overcoming-data-management-challenges-with-an-all-in-one-lims.

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5. Vanderlinde RE, Schaffer R. Development of certified reference materials for the National Reference System for the Clinical Laboratory, Nat Comm Clin Lab Standards NRSCL3-A. Nat Comm Clin Lab Standards NRSCL3-A. Published online 1991.

6. Moran RF. Implications for the intensivist in relating pre-analytical treatment of patient blood samples to clinical reliability of electrolytes, PCO2 and total hemoglobin. West Pac Cong Crit Care Med. Published online 1993.

7.

Howard, M and Moran, RF Implementing a complete laboratory information system (MediTech®, inc.) to ensure faster and more usable data in the right place and time. Unpublished, 1975.

8. Orazio D. Standardization of sodium and potassium ion-selective electrode systems to the flame photometric reference method - Approved Standard. Nat Comm Clin Lab Standards NCCLS: C29-A. Published online 1995.

9. Burnett R, Ehrmeyer SS, Moran RF. Blood gas and pH analysis and related measurements; Approved Guideline. Nat Comm Clin Lab Standards NCCLS C46-A. Published online 2001.

10. Moran RF. Point of Care vs. In: Central Lab Discrepancies: Getting the Message Across. JALM,1:05. ; 2017:595-597.

11. Podcast- Point of Care vs. In: Central Lab Discrepancies: Getting the Message Across. JALM. ; 2017.

12. Moran RF, Liesching TN. The ABC’s of ABG’s¿: A Cyclopedic Dictionary of the Testing Terms Used in Critical Care.; 2018.

13. Moran, RF, POC testing and reporting of sodium, and other small molecules need modified IFCC source/type designations to improve operational efficacy and for clinically accurate, unambiguous reporting. eJIFCC, December 2023.

Robert F. Moran, PhD, FCCM, FACB is the Principal Scientist at mviSciences, a consulting and educational services organization and President of AccuTest™ Proficiency Testing Services. Dr. Moran served multiple terms on the NCCLS (Now CLSI) Board of Directors and was an active participant or chairholder in several of their blood gas and electrolyte standards-writing teams. Also active in clinical chemistry internationally, he is an appointed Fellow of the International Union of Pure and Applied Chemistry (FIUPAC). He is a retired professor of chemistry and physics from Wentworth Institute of Technology but remains active in consulting work and writing.

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1. Wiwanitkit, V. Types and frequency of preanalytical mistakes in the first Thai ISO 9002:1994 certified clinical laboratory, a 6 – month monitoring. BMC Clin Pathol 1, 5 (2001).

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EDUCATION :: HBA1C

CMS’ coverage of HbA1c testing for diabetes screening is a good start — But we can do more

By Michael J. McPhaul, MD

I

n November, the Centers for Medicare & Medicaid Services (CMS) announced policy changes for Medicare payments under its Physician Fee Schedule (PFS). Included in these changes was an update countless experts believe was a long time coming: the new proposal now includes coverage of hemoglobin A1C (HbA1c) testing for diabetes and prediabetes screening.1 Lauded by many, the American Medical Association called the addition “a significant step forward.”2 The change was in response to concerns raised by medical groups, including the Diabetes Advocacy Alliance.

What is HbA1c, and why is it important for diabetes screening?

HbA1c testing is a single non-fasting blood test that assesses a patient’s average blood sugar levels over time, and has long been used as a measure of disease management for individuals who have been diagnosed with diabetes. Patients with known diabetes typically have their HbA1c measured

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twice yearly to assess the level of control of their disease.3 However, beginning in 2010, HbA1c was recognized by the American Diabetes Association (ADA) guidelines as an accepted method by which diabetes can be diagnosed and to identify patients with prediabetes.4 Since it can be measured in a single non-fasting specimen, HbA1c is a powerful screening tool to diagnose diabetes – particularly type 2, which often

Although recognized by the ADA as an accepted means to diagnose diabetes and prediabetes, HbA1c was not recognized or reimbursed for this purpose by CMS until November of 2023.

EDUCATION :: HBA1C develops in adulthood and affects the majority of (90-95%) that prevent them from accessing screenings. Research has America’s 38 million individuals with diabetes.5 Although shown racial and ethnic minority and low-income adult recognized by the ADA as an accepted means to diagnose populations consistently remain at a higher risk of type 2 diabetes and prediabetes, HbA1c was not recognized or diabetes.9 These populations are also impacted by social reimbursed for this purpose by CMS until November of 2023. determinants of health, like economic instability or lack of insurance coverage, which can make receiving needed care While a fasting blood sugar test has long been a primary difficult to obtain. In this way, CMS’ coverage of HbA1c and method of screening for diabetes and prediabetes, HbA1c and other screening tests is an extremely fasting glucose may give somewhat 65+ years positive change. Additional coverage different answers in specific individu18-44 years 27.2% 32.8% als and the measurement of both proCDC65+National Diabetes Statistics may stop these patients from living years 18-44 years with an undiagnosed condition for vides a better view of an individual’s 27.2% 32.8% metabolic state.6 Other studies have years, allowing them to receive treatdemonstrated additional utility ment and begin lifestyle changes 45-64 years in HbA1c testing, such as the to improve their health sooner.

65+ years 37.5% 27.2% 45-64 years 18-44 years ability to predict costly micro32.8% 37.5% and macro-vascular clinical Identifying at-risk complications that may maniindividuals before a fest in patients down the line, prediabetes diagnosis 45-64 years ultimately allowing for earlier Yet there is still more that can 37.5% interventions and therefore lowbe done. While HbA1c testing ering the cost of care over time.7 has been commonplace for years Though it can be as effective as when diagnosing and treating fasting blood sugar testing, HbA1c diabetes and other metabolic contesting as a screening measure for diaditions, certain other markers have shown to be effective in not only Figure 1: An estimated 97.6 million adults aged betes is not a replacement for this test.To 18 years or older had prediabetes in 2021. provide the most comprehensive look at identifying risk of diabetes, but other a patient’s health, and craft an effective related conditions, like cardiovascular treatment plan, a physician should order disease and chronic kidney disease. both tests. CMS’ coverage of HbA1c These markers may not yet be Women testing as a screening measure for mainstream lab tests, despite 44.3% Men diabetes and prediabetes is still a being widely prevalent among Women 53.2% step forward — so long as it takes individuals.

44.3% Men care not to minimize the imporOne such test is insulin re53.2% tant role fasting blood sugar sistance. Insulin resistance is a condition that prevents the testing plays in patient care. Both Women tests have clinical utility and are body from responding correctly 44.3% Men vital in getting patients diagnosed to insulin, making a person 53.2% unable to use glucose from the and treatment provided as soon as possible. blood for energy. It is often the first stage in metabolic abnormalities that Figure 2: A higher percentage of men (53.2%) How diabetes screening eventually may evolve, with age and than women (44.3%) had prediabetes, based weight gain, to prediabetes and then evolves disease management on their fasting glucose or A1C level.

Diabetes is a condition that is manto type 2 diabetes. A recent analysis of ageable with lifestyle changes and, in 6,000 young adults, ages 18–44, found some cases, reversible. Certain modi40% have insulin resistance.10 Among fications to a person’s diet or exerexperts, it is thought to be a precurHispanic cise regimen can greatly impact sor not only to the development of 15% their health. But patients cannot diabetes, but also other cardioAsian 5.8% Hispanic 15% manage what they don’t know vascular events, like potentially White Black they have. While approximately fatal heart attacks or strokes.

Asian 5.8% 61.8% 12.3% 98 million American adults have Certain new studies have emWhite Black Hispanic prediabetes – an elevation of phasized the ability of insulin 61.8% 12.3% 15% blood sugar levels not yet high resistance to identify a patient’s Asian 5.8% enough to be diagnosable as risk of diabetes, even when their type 2 diabetes – more than 80% fasting blood sugar test is reported White Black of these individuals do not know in a normal range.11,12 This research 61.8% 12.3% 8 they have it. As prediabetes can put also found that the combination of Figure 3: Prevalence of prediabetes (based on a person at increased risk of type 2 HbA1c testing with insulin resistance fasting glucose or A1C level) was similar among diabetes, heart disease, or stroke, it is can be a powerful prognostic tool for all racial and ethnic groups and education levels. important to ensure these individuals risk assessment, effectively identifying are aware of their high blood sugar patients likely to develop prediabetes Reference: National Diabetes Statistics Report. levels as soon as possible. and diabetes before these conditions Cdc.gov. Published November 29, 2023.

Some of these patients may be have become evident by laboratory Accessed January 5, 2024. https://www.cdc.gov/ testing. Furthermore, a number of unaware because of barriers to care diabetes/data/statistics-report/index.html.

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EDUCATION :: HBA1C

other studies have examined (and Conclusion Result A1C continue to examine) the value of using With diabetes impacting so many Normal Less than 5.7% combinations of glycemic biomarkers individuals across America, it is hard like fasting blood sugar, HbA1c, and to see greater availability of screenPrediabetes 5.7% to 6.4% others to improve risk assessment of ing tools as anything but a net posiDiabetes 6.5% or higher cardiometabolic outcomes.13 tive. However, we can and should do As certain biomarkers and, more more. Providing diagnostic insights Table 1: The A1C test measures your average to patients is extremely important. blood glucose for the past two to three months. importantly, combinations of biomarkThe A1C test can be used to diagnose diabetes Without the knowledge provided by ers can lead to improvements in risk or help patients know how their treatment lab testing, physicians will lack the prediction for cardiovascular disease plan is working. From American Diabetes complete picture of an individual’s and diabetes, expanding coverage and Association: Diabetes Diagnosis & Tests | ADA availability of testing beyond HbA1c will health needed to craft a care plan. And be key to improving the health of Ameripatients may lack the motivation to seek cans nationwide. While the inclusion of care if they are unaware of their risk, HbA1c testing is a step in the right direction, there is so much potentially worsening underlying conditions and making more that can be done. Maintaining the availability of fasting it more likely they will suffer irreversible harm. blood sugar testing in combination with HbA1c, and widening The inclusion of HbA1c testing as a diabetic screening the adoption of other tests to assess insulin resistance, will be measure by CMS will certainly benefit many at-risk individucritical to identifying individuals in need of treatment as early als. But broadening coverage to include biomarkers like insulin as possible. And the sooner these people become aware of resistance will allow physicians to test for combinations with their conditions, the sooner they can begin managing them. the best ability to predict future risk, including of other cardiometabolic conditions. Like with so many diseases, providing treatment as soon as possible is critical to giving patients the best care. Testing early provides the insight needed to embark on the next steps of a care journey some at-risk individuals With diabetes impacting so many may be unable to prolong. individuals across America, it is hard to see The research has been clear. The tools to predict risk are greater availability of screening tools as here, and growing in sensitivity and specificity. Why not utilize them to the best of their ability, and get more Americans anything but a net positive. with undiagnosed prediabetes screened to encourage them to take action?

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When it comes to diabetes quality controls, independent Liquichek Diabetes Control* delivers exceptional quality to any successful HbA1c QC testing strategy. Featuring a 45-day open-vial stability, you can save time and money by minimizing QC waste. Plus, take advantage of the advanced formulation with optimized shelf life and three distinct levels to help address HbA1c precision monitoring for diabetes testing. With expert service and support, Bio-Rad empowers your diabetes testing, allowing you to deliver quality to patient care.

• 45-day open-vial stability saves lab time, money, and storage costs • 36-month shelf-life reduces reagent costs and time • 3 distinct HbA1c levels helps monitor the precision of diabetes testing • Connect to over 29,000 labs worldwide with Unity Peer Program Learn more about Bio-Rad Diabetes Quality Controls by visiting: qcnet.com/diabetes. *Available with catalog number: 12011343, 12011344, 12011345, 12011334 Bio-Rad and Liquichek are registered trademarks of Bio-Rad Laboratories, Inc. in certain jurisdictions.

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EDUCATION :: HBA1C

REFERENCES 1. Calendar year (CY) 2024 Medicare Physician Fee Schedule final rule. Cms.gov. Accessed December 14, 2023. https://www.cms.gov/newsroom/fact-sheets/ calendar-year-cy-2024-medicare-physician-fee-schedule-final-rule.

2. American Medical Association. Pay schedule contains AMA advocacy wins on telehealth, diabetes. American Medical Association.

Published September 29, 2023. Accessed December 14, 2023. https:// www.ama-assn.org/practice-management/medicare-medicaid/ pay-schedule-contains-ama-advocacy-wins-telehealth-diabetes.

News. Published September 20, 2021. Accessed December 14, 2023. https://www.uab.edu/news/research/item/12289-uab-researchers-findthat-40-percent-of-young-american-adults-have-insulin-resistanceand-cardiovascular-risk-factors.

11. Rooney MR, Daya NR, Leong A, et al. Prognostic value of insulin resistance and hyperglycemia biomarkers for long-term risks of cardiometabolic outcomes. J Diabetes Complications. 2023;37(9):108583. doi:10.1016/j.jdiacomp.2023.108583.

3. CDC. All about your A1C. Centers for Disease Control and Prevention.

Published September 19, 2023. Accessed December 14, 2023. https:// www.cdc.gov/diabetes/managing/managing-blood-sugar/a1c.html.

12. Meigs JB, Porneala B, Leong A, et al. Simultaneous Consideration of HbA1c and Insulin Resistance Improves Risk Assessment in White Individuals at Increased Risk for Future Type 2 Diabetes. Diabetes Care.

2020;43(8):e90-e92. doi:10.2337/dc20-0718.

4. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33 Suppl 1(Suppl 1):S62-9. doi:10.2337/dc10-S062.

13. Bachmann KN, Wang TJ. Biomarkers of cardiovascular disease: contributions to risk prediction in individuals with diabetes. Diabetologia.

2018;61(5):987-995. doi:10.1007/s00125-017-4442-9.

5. CDC. Type 2 diabetes. Centers for Disease Control and Prevention.

Published November 12, 2023. Accessed December 14, 2023. https:// www.cdc.gov/diabetes/basics/type2.html.

6. Hilborne LH, Bi C, Radcliff J, Kroll MH, Kaufman HW. Contributions of Glucose and Hemoglobin A1c Measurements in Diabetes Screening.

Am J Clin Pathol. 2022;6;157(1):1-4. doi:10.1093/ajcp/aqab106.

7.

Jesudason DR, Dunstan K, Leong D, Wittert GA. Macrovascular risk and diagnostic criteria for type 2 diabetes: implications for the use of FPG and HbA(1c) for cost-effective screening. Diabetes Care.

2003;26(2):485-90. doi:10.2337/diacare.26.2.485.

8. CDC. Prediabetes - your chance to prevent type 2 diabetes. Centers for Disease Control and Prevention. Published November 12, 2023.

Accessed December 14, 2023. https://www.cdc.gov/diabetes/basics/ prediabetes.html.

9. Connecting SDOH and HRSN to prediabetes and type 2 diabetes. National DPP Coverage Toolkit. Published July 14, 2022. Accessed December 14, 2023. https:// coveragetoolkit.org/health-equity-and-the-national-dpp/ connecting-sdoh-and-hrsns-to-prediabetes-and-type-2-diabetes/.

10. Jones A. UAB researchers find that 40 percent of young American adults have insulin resistance and cardiovascular risk factors. UAB

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Michael J. McPhaul, MD is a Medical Advisor at Quest Diagnostics and an expert on the interconnection of cardiometabolic disorders such as insulin resistance, diabetes and CVD. In his role at Quest, Dr. McPhaul drives the development of new tools and diagnostic tests that assist in the comprehensive care of patients with prediabetes, metabolic syndrome, and diabetes mellitus, as well as the early identification of these ailments. Dr. McPhaul earned his medical degree from the University of Texas Southwestern Medical School. He completed his internship and residency in internal medicine at Parkland Memorial Hospital, followed by a research fellowship in biochemistry at Stanford University Medical Center. Dr. McPhaul is board-certified by American Board of Internal Medicine. He is an active member of several professional societies, including the American Society of Clinical Investigation, American Association of Clinical Endocrinology, Endocrine Society, American Diabetes Association, Southern Society for Clinical Investigation, and the American Federation for Medical Research.

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MOLECULAR DIAGNOSTICS :: HEPATITIS TESTING

A new twist

How the COVID-19 pandemic paved the way for increased molecular testing of hepatitis

By Erica Frew

S

ARS-CoV-2 and hepatitis might not seem to have much in common, but in the world of clinical laboratory testing, they have become intertwined.

After the unprecedented infrastructure scale-up that occurred in clinical labs during the COVID-19 pandemic, demand for SARS-CoV-2 testing has now fallen to a fraction of its peak volumes. Laboratory teams around the world have extra capacity thanks to the higher-throughput platforms or additional instruments they implemented to handle pandemic testing.

With all of that investment, labs are now in the unusual position of figuring out how to best utilize it in a post-pandemic era. While the typical approach is to adopt new testing platforms reactively when demand for a certain assay or capability is obvious, many lab teams now have surplus instrument capacity — and the unfamiliar luxury of being able to use this capacity to proactively select the most impactful new tests for their patient population.

Fortunately, many of the molecular diagnostic platforms that were implemented by labs for the pandemic surge can run a broad menu of tests, giving labs real flexibility and choice in how they use these instruments going forward. Di-

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agnostic reagent manufacturers are continuously innovating to develop products that best serve laboratories and deliver on the promise of this increased capability.

This is where hepatitis comes into play. Back in 2016, the World Health Organization (WHO) announced its intention to prioritize public health efforts to reduce the incidence and impact of viral hepatitis. The goal is to slash the number of cases by 90 percent and the number of deaths by 65 percent by the year 2030 (with all numbers based on 2015 global statistics for hepatitis).1 The WHO’s top targets are hepatitis B and C, the viral strains associated with a high risk of mortality due to their ability to cause cirrhosis and liver cancer.

If these goals can be met in that ambitious timeline, the WHO predicts that it would prevent approximately 4.5 million deaths.2 The hepatitis elimination program includes a number of broad recommendations that public health leaders in each country can choose from based on their own population’s status. For example, the use of vaccinations, therapies, and diagnostic tools is recommended in a variety of ways, as are means of monitoring progress over the years. The initiative also aims to rein in vertical transmission of hepatitis, which is a particularly dangerous mode of infection. When mothers infect

MOLECULAR DIAGNOSTICS :: HEPATITIS TESTING their babies in utero or during birth, there is very high risk for those children to suffer chronic, possibly lifelong infections.

Laboratories may not have had the opportunity to prioritize hepatitis B and C testing before the pandemic, but now these targets have become popular choices for how to make use of the extra testing capacity that is currently available. Molecular diagnostic tests typically cover both hepatitis B and C, and some broader panel tests include rare strains, which makes it easy to add hepatitis testing to a lab’s menu using the same platforms that were brought in for COVID-19 testing. When performed with high-quality synthetic controls for safety, this approach delivers accurate results that will help labs contribute to the global goal of eliminating hepatitis.

How to test for hepatitis

The Centers for Disease Control and Prevention (CDC) has developed a useful set of recommendations to help guide providers and clinical lab professionals in knowing when to use hepatitis screening or testing for their patients. Here’s a brief summary.

In general, all adults aged 18 or older should be screened at least once for each type of hepatitis. For hepatitis B, the CDC advises using a triple panel serology test that detects the surface antigen and antibody, as well as the IgM antibody and total antibody to the hepatitis B core antigen.3 This represents more comprehensive coverage than the agency’s older testing guidelines, which focused on detection of the surface antigen only. For hepatitis C, the CDC calls for near-universal screening but allows for exceptions in areas where the prevalence of this virus is vanishingly low, at 0.1 percent or less.4 Pregnant women should get increased attention to prevent transmission from mother to child. The CDC recommends screening all pregnant women for hepatitis B using a surface antigen test, ideally during the first trimester. For women who are positive for the virus, their newborns should also be tested with an assay designed to detect the surface antigen or antibodies to it. For hepatitis C, the recommendation is similar: screening should be performed in every pregnancy unless the woman lives in a region where hepatitis C is quite rare.

For patients at higher risk, the CDC advises more frequent testing. Hepatitis B tests should be performed periodically for patients who have previously tested positive for sexually transmitted infections, people who were born in areas with a high incidence of the virus, people who were or are incarcerated, men who have sex with men, patients on dialysis, and people who have a history of using drugs by injection, along with a few other high-risk groups. Routine hepatitis C testing is recommended for dialysis patients as well as for people who inject themselves with drugs or share needles with other drug users. In addition, one-time hepatitis testing is advised for anyone with HIV, people who have received blood transfusions or organ transplants, medical professionals who are exposed to hepatitis C, or children of women found to have the virus.

Why synthetic controls matter

While there is a good selection of molecular diagnostic tests for hepatitis B and hepatitis C to be considered by clinical lab professionals, one component is often overlooked in the evaluation phase. Assays perform best when paired with safe, high-quality controls. Some diagnostic manufacturers include appropriate controls in the test kit, but in many cases, lab teams are left to their own devices for acquiring the right controls.

Unfortunately, many labs turn to controls that may seem easier to acquire but confer high risks. Remnant patient samples or attenuated viral strains are used all too often but are known for being unsafe. Both options put lab staff at risk of infection as the hepatitis virus is noted for its extreme transmissibility and durability. In addition, patient samples make a suboptimal control because of their unpredictable supply. To ensure their ability to meet demand for hepatitis tests, clinical labs need a control type that is readily available.

Synthetic molecular controls offer a safer, cost-effective approach that allows for high-quality results without risking the health of lab members. Designed to mirror the viral genome of hepatitis B or C, they can be customized quickly for various targets. Synthetic controls are produced in carefully controlled laboratories with rigorous manufacturing practices.

Because they are not infectious, they are easier to ship and store compared to other types of controls.

One type of synthetic control comes with the added advantage of a viral-like coating making it ideal for monitoring the entire testing workflow. These controls are encased in a protein layer that serves as a kind of armor, stabilizing the control and protecting its nucleic acids. Adding the layer of armor reduces the risk of RNA or DNA degradation in most biological matrices, so the controls can be used from the time the sample is extracted, riding along through most DNA or RNA isolation techniques. When used as an exogenous control throughout the sample’s entire journey, these armored controls allow laboratorians to evaluate the performance of each step of the diagnostic workflow to ensure reliable results.

Armored controls for hepatitis C are compatible with a variety of clinical assay types and can also be useful for developing new molecular tests for this family of viruses.5

In conclusion

The elimination of hepatitis is an ambitious and worthy public health goal. Clinical laboratories will be essential to this work by performing robust and reliable diagnostic testing for hepatitis B and C. Now that many labs have extra capacity available on their molecular testing platforms as COVID-19 testing demand eases, deploying some of that infrastructure to join in the global fight to end hepatitis will be an important step to improve care for many patient populations.

REFERENCES 1. WHO releases first-ever global guidance for country validation of viral hepatitis B and C elimination. Who.int. Accessed December 14, 2023. https://www.who.int/news/item/25-06-2021-whoreleases-first-ever-global-guidance-for-country-validation-of-viralhepatitis-b-and-c-elimination.

2. Hepatitis. Who.int. Accessed December 14, 2023. https://www.who.int/ health-topics/hepatitis/elimination-of-hepatitis-by-2030.

3. Screening and testing recommendations for chronic hepatitis B virus infection (HBV). Cdc.gov. Published May 3, 2023. Accessed December 14, 2023. https://www.cdc.gov/hepatitis/hbv/testingchronic.htm.

4. Testing recommendations for hepatitis C virus infection. Cdc.gov.

Published October 30, 2023. Accessed December 14, 2023. https:// www.cdc.gov/hepatitis/hcv/guidelinesc.htm.

5. WalkerPeach CR, Winkler M, DuBois DB, Pasloske BL. Ribonuclease-resistant RNA controls (Armored RNA) for reverse transcription-PCR, branched DNA, and genotyping assays for hepatitis C virus. Clin Chem. 1999;45(12):2079-85.

Erica Frew is a product manager at Asuragen, a Bio-Techne brand, where she specializes in molecular controls for clinical tests.

MLO-ONLINE.COM FEBRUARY 2024 | 31

Photo 86207011 © Auremar | Dreamstime.com

BEST PRACTICES :: PROFESSIONAL CREDENTIALS

Advancing standards in laboratory medicine and pathology through professional credentials

By Joseph B. Baker, MS and Amy Spiczka, MS, HTL(ASCP)CMSCT, MBCM, CPHQ

H

ealthcare is experiencing a dire need for medical professionals. The shortage in the workforce is particularly concerning given their essential role in healthcare.

Laboratory professionals are responsible for conducting a wide range of tests that inform 70% of medical decisions, from the diagnosis of diseases to the determination of treatment plans.1 The lack of sufficient and competent laboratory professionals leads to delays in diagnosis and treatment, impacting patient care and outcomes. 2 Due in part to the ongoing impacts of the COVID-19 pandemic, an aging workforce, recruitment and retention challenges, evolving technological advancements in laboratory medicine, and other factors, significant shortages of personnel in the global medical laboratory workforce has become prominent.2 As challenging as these issues are, they also present prospects for growth and innovation in laboratory medicine and pathology. As decision-makers at all levels seek and implement multi-faceted solutions, leveraging credentials such as those offered by the American Society for Clinical Pathology, Board of Certification (ASCP BOC) is emerging as a key strategy.3 This strategy not only enhances professional skills but opens new avenues for recruitment and retention.

Using professional credentials as a solution to these issues ensures the maintenance of high standards in laboratory medicine and aids in enhancing the profession’s appeal and recognition. As the healthcare landscape continues to evolve, addressing this shortage is imperative for maintaining the efficacy and quality of global health systems.

32 | FEBRUARY 2024 MLO-ONLINE.COM

The role of the ASCP BOC

The ASCP BOC is a laboratory professional credentialing agency with nearly a century’s legacy, having been established in 1928. Over this period, the ASCP BOC has credentialed more than 625,000 laboratory professionals worldwide, upholding its mission to provide excellence in certification of laboratory professionals on behalf of patients globally.

The credentialing portfolio offered by the ASCP BOC spans 26 unique examinations for laboratory leaders at all levels, supporting phlebotomists who have direct interactions with patients through PhD scientists who lead high complexity laboratories. In 2006, the ASCP BOC began certifying laboratory professionals with an international “ASCPi” designation.

The ASCPi initiative has seen widespread adoption, with applicants spanning 130 countries and, to date, more than 22,000 individuals from 117 countries earning ASCPi credentials.4

The importance of credentials for medical laboratory professionals

Credentials for medical laboratory professionals are a testament to their competence and proficiency. They demonstrate that individuals have undergone rigorous education, training, and experiential assessments and have met established standards of knowledge and skills. This is particularly crucial in a field where precision and accuracy are paramount. Laboratory errors can have dire consequences on patient diagnosis and treatment, making the role of credentialed professionals indispensable.5 Credentialed laboratory professionals ensure

BEST PRACTICES :: PROFESSIONAL CREDENTIALS that laboratory tests, which form the basis of a significant portion of clinical decisions, are accurate and reliable.

Moreover, in the realm of healthcare, trust is a vital commodity. When medical staff and patients are aware that laboratory professionals are credentialed, it instills confidence in the test results and diagnoses derived from these laboratories.

This trust is not only essential for patient care but also for the smooth functioning of the entire healthcare system.6 Another aspect where credentials play a pivotal role is in regulatory compliance and quality assurance. Many healthcare regulations and standards mandate that individuals performing laboratory tests be properly credentialed. This compliance is critical for laboratories not just to operate legally but also to participate in insurance programs, including those funded by the government.3 Furthermore, credentialing can significantly impact dynamics of the medical laboratory professional workforce. It provides a clear pathway for career advancement and professional growth, which is crucial for attracting and retaining talent in the field. It also mandates continuous education and professional development, ensuring that laboratory professionals stay abreast of the latest technologies and procedures.3 This continuous learning environment fosters professional pride and job satisfaction, which are essential in reducing turnover rates.

U.S. & global workforce challenges

According to the ASCP BOC’s 2022 ASCPi Survey, many laboratories around the world report difficulties in filling open positions.7 In the United States, the Bureau of Labor Statistics of the Department of Labor forecasts an 11% growth in employment for medical laboratory scientists, technologists, and technicians from 2020 to 2030, surpassing the average growth rate for all occupations.2 Despite this optimistic job outlook, a recent report by the ASCP and the University of Washington Center for Health Workforce Studies warns of an impending increase in laboratory workforce shortages.2 This anticipated rise is attributed to growing demand for laboratory services, limited opportunities for education and training, and challenges in recruiting and retaining laboratory personnel.2 Challenges such as these impact the overall quality of patient care and the effectiveness of laboratory operations.

These credential examinations are a cost-effective way to ensure that laboratory professionals who pass are competent, knowledgeable, and focused on delivering high-quality, safe patient care. The ASCP BOC’s examinations are constantly being reviewed by ASCP BOC team members to ensure examination content reflects the rigor of current practice and is fair for all test takers.

To address the shortage in the United States and globally, the article“Severe Shortages of Qualified Medical Laboratory Professionals” suggests that hiring qualified, board-certified laboratory professionals is crucial.8 For emerging U.S. laboratory professionals, this involves taking a credential examination upon graduation to achieve board certification. Many medical and pathology laboratory employers also provide on-the-job training, which enhances the formal credentialing process.

This blend of practical experience and credentials offers a solid foundation for career success, improving skills, knowledge, and contributing to the expansion of the laboratory workforce.

The contribution of professional credentials to the laboratory field is further evidenced by a 2019 survey by the Institute for Credentialing Excellence (ICE). This extensive survey, involving more than 12,000 credential holders from six organizations, aimed to assess attitudes and experiences

regarding certification examinations and credentialing.3 The findings revealed that the respondents view certification (i.e., credentials) as highly valuable to their profession, with certification requirements seen as appropriate, and the ethics and code of conduct set by certifying bodies as beneficial.

Moreover, credentialing is considered crucial for enhancing competence and performance in the profession.3 Internationally, the ASCP BOC also champions competencybased exams by recognized credentialing bodies. Its credentials are acknowledged in various regions, including the Middle East & North Africa, Latin America, and Asia.9 Developing global standards in credentialing helps guarantee that laboratory practices meet international safety and accuracy benchmarks, which is essential for effective disease diagnosis and management. It also aids in responding to global health workforce shortages by ensuring the availability and distribution of highly skilled professionals across various geographical regions, thereby contributing significantly to maintaining global health standards and effectively delivering healthcare services.

Inclusion, diversity, equity, and access (IDEA)

In the medical laboratory and pathology professions, sustainability transcends mere ecological considerations. It crucially includes the dimension of social sustainability, which is central to cultivating a resilient, competent workforce amidst prevalent challenges such as workforce migration and talent deficits. Effective laboratories are those that integrate strategies such as continual professional development, career progression pathways anchored in specialist or additional qualifications, the nurturing of a positive workplace culture, and the encouragement of a harmonious work-life balance.10 These strategies are instrumental in not only retaining adept personnel but also in attracting new talent, thereby enhancing overall employee contentment.

The pillars of inclusion, diversity, equity, and access (IDEA) are imperative for the cultivation of a sustainable workforce in laboratories. By fostering an environment that embraces diversity and ensures accessibility, laboratories can access a wider spectrum of talent, reflective of the diverse communities and patient populations they serve. The implementation of equitable practices, such as equal remuneration for comparable work and equal opportunities for career progression, is pivotal in maintaining a diverse and talented workforce.

Credentials play an indispensable role in advancing IDEA within the laboratory workforce. By offering a uniform assessment of professional skills and knowledge, these credentials ensure that all practitioners are evaluated solely on their expertise, irrespective of their background. This system of objective evaluation upholds the principles of equity, accessibility, and fairness within the workplace, fostering a more inclusive and equitable environment.

Moving forward

Laboratory professional credentials provided by the ASCP BOC play a pivotal role in addressing the global workforce shortage in medical and pathology laboratories. Through its credentials, the ASCP BOC not only standardizes and enhances the professional skills of laboratory workers but also opens new avenues for recruitment and retention.

Key strategies for effective laboratory operations include continuous professional development and clear career progression paths linked to credentials, such as those offered by the ASCP BOC. Stacking, or gaining additional credentials, including becoming certified as a specialist in a particular area, MLO-ONLINE.COM FEBRUARY 2024 | 33

BEST PRACTICES :: PROFESSIONAL CREDENTIALS can lend to these clear pathways. These strategies help foster a positive workplace culture and promote a work-life balance and are essential for retaining skilled staff and attracting new talent, ultimately leading to greater employee satisfaction.

Additionally, the principles of IDEA are integral to creating a sustainable, resilient workforce. By providing a uniform assessment of skills and knowledge, the ASCP BOC’s credentials promote fairness and equity in the laboratory profession, ensuring that professionals are evaluated based on their expertise, irrespective of their background. In summary, the advancement of standards in laboratory medicine and pathology through professional credentials not only addresses immediate workforce challenges but also sets the foundation for a globally competent, diverse, and sustainable healthcare system in the future.

REFERENCES 1. Strengthening clinical laboratories. Cdc.gov. Published November 15, 2018. Accessed December 20, 2023. https://www.cdc.gov/csels/dls/ strengthening-clinical-labs.html.

2. Garcia E, Kundu I, Fong K. The American Society for Clinical Pathology’s 2021 Wage Survey of Medical Laboratories in the United States.

Am J Clin Pathol. 2022;1;158(6):702-722. doi:10.1093/ajcp/aqac116.

3. Value of Certification: Multi-Organization Survey of Credential Holders.

Institute for Credentialing Excellence.; 2019.

4. Spiczka A, Sreckovic A. Biannual Report on Examinees and Certifications for ASCPi. American Society for Clinical Pathology, Board of Certification. 2023.

5. Mrazek C, Lippi G, Keppel MH, et al. Errors within the total laboratory testing process, from test selection to medical decision-making - A review of causes, consequences, surveillance and solutions. Biochem Med (Zagreb). 2020;15;30(2):020502. doi:10.11613/BM.2020.020502.

6. Cope EL, Khan M, Millender S. Trust In Health Care: Insights From Ongoing Research. Health Affairs Published. Published online 2022.

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t Source anagemen iewed M Peer-Rev

Baker J, Spiczka A. ASCPi Survey. American Society for Clinical Pathology, Board of Certification.

8. Robinson AT. Healthcare: Severe shortages of qualified medical laboratory professionals. Biomed J Sci Tech Res. 2023;48(3):39710-39713. doi:10.26717/bjstr.2023.48.007651.

9. Board of Certification. Countries with ASCP BOC Government Recognition. American Society for Clinical Pathology, Board of Certification.

2023.

10. Garcia E, Kundu I, Kelly M, et al. The American Society for Clinical Pathology’s Job Satisfaction, Well-Being, and Burnout Survey of Laboratory Professionals. Am J Clin Pathol. 2020;9;153(4):470-486. doi:10.1093/ajcp/aqaa008.

Joseph B. Baker, MS is the Director, Engagement & Experience for ASCP Board of Certification (BOC). He leads the ASCP BOC’s constituent and stakeholder outreach activities. He has diverse experience, including roles with the Indianapolis Mayor’s Office, Indiana State Department of Health, and a background in quantitative historical analysis, communication, and journalism, with academic expertise related to the social and economic impact of chronic disease on Indigenous American populations.

Amy Spiczka, MS, HTL(ASCP)CMSCT, MBCM, CPHQ currently serves as the American Society of Clinical Pathology (ASCP) Board of Certification (BOC) Executive Director. Ms. Spiczka provides oversight of and engagement for 26 credentials provided globally in 130 countries spanning the entire laboratory medicine and pathology spectrum. She is a patient-centric advocate for the laboratory professional workforce, as the ASCP BOC collaboratively provides examinations and credentials across the entirety of the laboratory-specific healthcare continuum.

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LABORATORY

INNOVATOR

Details from AMP on LDTs/LDPs

By Christina Wichmann

Eric Konnick, MD is an Associate Professor in the Genetics and Solid Tumors division of the Department of Laboratory Medicine and Pathology at the University of Washington. He has developed, validated, and verified numerous manufactured and laboratory-developed tests during his 25-year career. He is board-certified in Anatomic and Clinical Pathology and Molecular Genetic Pathology. Dr. Konnick is an Associate Clinical Laboratory Director for the Seattle Coronavirus Assessment Network and was extensively involved in Emergency Use Authorization regulatory submissions of SARS-CoV-2. He is Chair of the Professional Relations committee for the Association for Molecular Pathology, Chair of the CAP Genomic Medicine Committee, and is President of the Washington State Society of Pathologists.

So all understand, would you please explain what laboratory-developed tests (LDTs) are and provide examples of these types of tests?

First, AMP prefers to use the term laboratory developed testing procedures (LDPs) instead of LDTs since these tests are essential clinical services. LDPs are vital laboratory services that are designed, developed, validated, performed, and interpreted by board-certified professionals in regulated clinical laboratories. They are being used across a range of applications including oncology, rare disease diagnosis, newborn screening, infectious disease testing, and more.

Additionally, laboratories often modify FDA-cleared or approved test kits to improve performance or expand the utility of the tests to their specific patient populations. LDPs are not commercially manufactured, nor boxed and shipped

as medical devices, and should not be regulated that way. The licensed and board-certified individuals involved in using LDPs are highly trained professionals, not manufacturers.

The proposed rule threatens the ability of professionals in clinical laboratories to create, adapt, and modify LDPs to meet patients’ needs, account for supply chain issues, reflect advances in scientific understanding and practice standards, and improve performance characteristics.

Would you please describe why AMP and other organizations disagree with the FDA’s proposed rule to regulate LDTs as medical devices?

AMP strongly opposes FDA’s proposal to regulate these testing services as medical devices. As detailed in our comments,1 the FDA’s proposed changes to the definition of an in vitro diagnostic product, and its plan to end what it refers to as “enforcement discretion,”would result in laboratory professionals being treated as manufacturers. Laboratory professionals are board-certified healthcare providers who develop and rigorously ensure the analytic and clinical validity of their LDPs and who interpret their results within the context of available patient clinical information and other relevant test results.

Treating laboratory professionals as product manufacturers is inappropriate and unjustified, and it will unequivocally hinder and harm patient care.

Do you think that current laboratory test validation and quality management requirements are sufficient, or would improvements by other means be beneficial?

AMP and our members have consistently advocated for up-to-date regulations and continuous quality improvement of the field. We have spent the past 10 years collaborating with many professional societies, patient advocates, diagnostic companies, hospitals, academic centers, independent laboratories, regulators, and other stakeholders from across the country to help educate lawmakers on alternative proposals.

We have long maintained that the involvement of appropriately trained and qualified laboratory professionals is critical to the development of accurate and reliable LDPs, as well as for correct utilization, interpretation, and appropriate application of molecular test results.

The AMP proposal2 modernizes the current Clinical Laboratory Improvement Amendments (CLIA) regulatory program and provides assurance of quality, analytical validity, and clinical validity. Our approach would provide a far more appropriate and efficient regulatory framework that ensures access to necessary patient care while continuing to foster rapid innovation and the promise of new diagnostic technologies.

Patient safety has been identified as a concern with LDTs by the FDA. What are your patient care concerns if these tests have to undergo FDA review?

All LDPs should be accurate, precise, clinically relevant, and monitored for continued quality performance, and patients should receive the most appropriate tests and procedures for their medical evaluation and/or clinical condition. It is unacceptable when any test does not meet these standards, and it is important that this country continues to have a federal regulatory approach that works toward ensuring that patients receive the appropriate and effective level of care.

It is irresponsible of the FDA to make broad claims asserting that LDPs are low quality and harm patients when, in fact, the data support that the vast majority of LDPs produce accurate results that successfully contribute to the management of patient care. If there are any systematic concerns about the quality of the majority of LDPs used for patient care, that information would be available based on information acquired by third-party accrediting organizations who must verify that CLIA standards are met, test the proficiency of laboratories at least on a biannual basis, and report to CMS when patients and/or the public are in immediate jeopardy as a result of a laboratory error.

MLO-ONLINE.COM FEBRUARY 2024 | 35

LABORATORY INNOVATOR :: DETAILS FROM AMP ON LDTS/LDPS It is also disingenuous to convey to the public that FDA authorization would deter all harm, and indeed, no single entity could. It is for this reason that AMP instead advocates for a multi-layered approach where CLIA, state, and third-party requirements work in concert with a peer-review-based system and the interest of appropriately trained professionals to provide the best care possible for their patients.

The American public saw firsthand how inappropriate FDA medical regulations are for LDPs during the early days of the COVID-19 pandemic. FDA enforcement, allowed under the Public Health Emergency declaration, prevented many laboratory professionals from mitigating the flaw in the first test kit provided by the Centers for Disease Control and Prevention. FDA’s use of the emergency use authorization process overwhelmed the agency, contributed to testing scarcity, and eliminated the opportunity to immediately contain and slow the spread of this highly transmissible virus in those critical first weeks of the pandemic in this country.

This same entity should not be responsible for regulating all LDPs for conditions ranging from infectious diseases to cancer.

The shortages in the laboratory workforce are well known. How could the proposed regulation impact an already overburdened healthcare community?

If the proposed rule is finalized, there would be numerous immediate and long-term consequences that would decimate the clinical laboratory community, disrupt patient care, and restrict training opportunities. Hospital-based clinical laboratories may have no choice but to outsource clinical testing. As these centers are critical for training pathologists, residents, medical students, clinical laboratory scientists, technicians, PhDs, and clinical fellows, there will be limited ability for the future of our workforce to be trained in areas that are vitally important to general laboratory medicine, let alone personalized medicine. While the effects will be felt in every region of the United States, AMP is especially concerned about the impacts on underserved populations and rural communities that already struggle with adequate staffing by qualified personnel.

Regarding molecular diagnostics, the Government Accountability Office found the medical genetic workforce to be quite limited with only approximately 4,700 genetic counselors and 1,240 medical geneticists certified to provide care in the United States in 2020.3 In addition, the GAO reports an average of only seven genetic counselors for every 500,000 people and only two medical geneticists per every 500,000 people. To address the looming 20% retirement rate in laboratory personnel, plus the current 13% vacancy rate, over 25 professional organizations formed the Medical and Public Health Laboratory Workforce Coalition this year.4 There are also well publicized shortages of medical laboratory scientists, histotechs, and laboratory physicians (pathologists). Policymakers need to invest in expanding the diagnostic and molecular laboratory workforce to meet the demands of our healthcare system, which will only grow as precision medicine utilization increases, not implement rules that will reduce training opportunities for these professionals.

If the FDA’s proposed rule is finalized, it is likely that the Agency, companies, and other organizations will also be looking to hire individuals with laboratory expertise to review submissions and perform other regulatory functions.

Given the current shortages and limited training programs, it is hard to envision how both the clinical and regulatory functions will be accommodated. While the FDA could hire non-laboratory professionals for some functions, that would be much less effective and efficient, and would likely lead to numerous delays.

REFERENCES 1. Califf RM. Amp.org. Published 2023. Accessed December 19, 2023. https://www.amp.org/AMP/assets/File/advocacy/AMP_LDT_Proposed_ Rule_Comments_FINAL_12_2_23.pdf?pass=49.

2. Definitions “. Section 2. Definitions. Amp.org. Accessed December 19, 2023. https://www.amp.org/AMP/assets/File/advocacy/Amendments%20to%20CLIA%20modernization%20legislative%20text%20 11_7_23%20FINAL.pdf?pass=42.

3. U.S. Government Accountability Office. Genetic services: Information on genetic counselor and medical geneticist workforces. Gao.gov. Accessed December 19, 2023. https://www.gao.gov/products/gao-20-593.

4. Medical and public health laboratory workforce coalition. Mphlcoalition.org. Accessed December 19, 2023. https://www.mphlcoalition.org/.

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