Charna Albert
June 2026—Despite elevated Lp(a) concentration having a high population prevalence of about 20 percent, the testing rate has been low, and that is about to change.
International guidelines have endorsed Lp(a) testing in every adult at least once per lifetime. In 2024, the National Lipid Association followed suit. Most recently, the American College of Cardiology and American Heart Association released new guidelines endorsing universal testing. “That’s huge for us in the United States. It’s going to increase our testing rates for sure,” says Leslie Donato, PhD, D(ABCC), co-director of the hospital clinical laboratory and the clinical specialty laboratory and associate professor in the Department of Laboratory Medicine and Pathology at Mayo Clinic in Rochester.
Dr. Donato will speak at the ADLM meeting next month, and she spoke in April with CAP TODAY. She will moderate and co-present “Lipoprotein(a) could be the next public health revolution: Are clinical laboratories ready for the challenge?”
Also on offer at ADLM, among other talks, will be pediatric reference intervals and vaccine-preventable diseases. Of the latter, Benjamin Bradley, MD, PhD, of ARUP Laboratories, and colleagues reported early this year that molecular testing for measles with the ability to differentiate wild-type strains from vaccine strains can be a helpful tool in the response to measles reemergence.
Data from the first of the phase three clinical trials for targeted therapies to lower Lp(a) are expected later this year. “They lower Lp(a) concentrations, and we’re talking dramatic lowering—80, 90, 95 percent lowering, which is not feasible with any other therapy we have,” Dr. Donato says.
For laboratories, these new therapies will bring the challenges of measuring and interpreting Lp(a)—her focus in the session—to the fore. Her co-presenters are Sotirios Tsimikas, MD, of the University of California San Diego, who will discuss the clinical trials and how the results will affect laboratory test expectations and demands, and Christa Cobbaert, PhD, EuSpLM, of Leiden University Medical Center, who will address International Federation of Clinical Chemistry and Laboratory Medicine efforts to standardize Lp(a) testing.
Dr. Donato recently wrote an editorial on the treatment trials and described the complexities of measuring and interpreting Lp(a) concentrations (Donato LJ. Clin Chem. 2026;72[2]:222–224). The immunoassays on the market use polyclonal antibodies specific for the apolipoprotein(a) protein on the Lp(a) particle. “They’re sensitive and specific,” she says. “There is no interference with other, off-target lipoproteins.” But the size of the Lp(a) particles varies widely from person to person owing to heterogeneity in the genetic sequence that encodes apolipoprotein(a). Because the particles vary in size, the apolipoprotein(a) protein has variable numbers of antigenic binding sites. “Your signal from a patient who has a small isoform of Lp(a) is going to be a little lower than the signal you get from a larger isoform particle because there will be more antigenic binding sites,” she says. “That can result in a bias in the concentration, depending on what calibrators are used in the assay.”
There’s no way to avoid the problem, she says, though assay manufacturers minimize the inaccuracies by using a mix of differently sized apolipoprotein(a) proteins in the calibrators and including five different calibration points. In addition, newer assay formulations use molar units for calibration, which aids accuracy. “Historically, these assays have been calibrated in mass-based units, which is problematic because the mass of the particle will change from patient to patient based on its size,” she says. Still, the fundamental mechanism of the detection method is affected by the varying particle sizes. Although the best assays are marketed as isoform-independent, “there is still some bias in there based on this phenomenon.”
That bias could affect measurements for patients whose results are at the borderline cutoffs of clinical decision-making, Dr. Donato says. Or if a patient switches hospital systems and gets retested with a newer assay reported in molar units, they or their physician might incorrectly assume their Lp(a) concentration has undergone significant change. “It certainly is a complication we need to figure out as a lab medicine community,” she says. But that shouldn’t discourage physicians from ordering Lp(a) testing. “You’re still going to pick up the high expressors with the assays we have now, even if you’re using an assay that’s calibrated in the older mass-based units.”
“The most important thing is to use the test available to your health care system,” she adds. “We need to get this test in everyone’s record moving forward.”
To add to the complications, the assays are not currently standardized across manufacturers. A once available international reference material for assay calibration has been exhausted, Dr. Donato says, though as Dr. Cobbaert will discuss in the session, an IFCC working group has utilized a new mass spectrometry-based reference measurement procedure and secondary serum-based reference materials (Dikaios I, et al. Clin Chem. 2023;69[3]:262–272).
What should clinical laboratories do to meet the moment?
If they run the test in-house, “I would certainly prepare for an increase in test demand,” Dr. Donato says. “Even if they don’t run it in their own clinical laboratory, I would suggest connecting with their reference laboratory to make sure they can handle increased demand.” Reagent shortages could occur, she notes. “My hope is assay manufacturers are also preparing for this increase in test demand and will scale up operations accordingly.”
One important note: Within some groups, the percentage of people with elevated Lp(a) concentrations is higher than the 20 percent populationwide average.
“There are quite strong ethnic and country of origin differences in concentrations,” Dr. Donato says. In the Black population, for instance, the median concentration is nearly three times that of the white population. Women, too, tend to express higher Lp(a) concentrations, particularly after menopause, when apolipoprotein(a) expression rises.
In these groups, she says, “it’s even more important to get the message out for universal testing and then risk reduction.”
When a disease absent for decades reemerges, what happens behind the scenes—in the doctor’s office, in the emergency department, in the laboratory—as the medical community comes to grips with the outbreak?
When measles cases in 2025 reached rates not seen in the U.S. since before the disease was declared eliminated in 2000, pathologists at ARUP Laboratories and the University of Utah acted, validating a laboratory-developed real-time measles PCR assay on the Hologic Panther Fusion Open Access system. IgM serology was once the primary testing method for acute measles infection; the Centers for Disease Control and Prevention now recommends dual IgM and PCR testing, given the potential for cross-reactivity of IgM between other common febrile rash illnesses and because a quarter of patients do not have detectable IgM antibodies within the first 72 hours after rash onset. When PCR testing is done, IgM offers added diagnostic certainty, as it can be positive for a longer period.
To understand testing trends, Benjamin Bradley, MD, PhD, medical director of high consequence pathogen response, virology, and molecular infectious diseases at ARUP Laboratories, examined with his colleagues three months of clinical testing data after bringing the PCR assay online (Anderson C, et al. J Clin Microbiol. 2026;64[1]:e01402-25). Over the study period, during which 525 tests from 491 patients were performed, IgM serology alone was the test most ordered for suspected measles, followed by IgM/IgG in combination. PCR made up a minority (nine percent), and only 4.2 percent of patients received paired serologic and molecular testing.
“PCR performs much better,” says Dr. Bradley, assistant clinical professor in the Department of Pathology at the University of Utah School of Medicine. “We see a lot of reliance on IgM because back in the 1950s and 1960s, when measles was last a problem, that was the only tool you had for diagnosing measles. PCR had not been invented.”
“We’ve been taught something for a long time about how to diagnose a pathogen, or how it presents,” he adds. “But in the intervening time that we haven’t seen it, the world has changed and technology has changed.”
Similarly, it would be unwise to assume anything from disease patterns seen long ago.
“Historically, measles has had a two- to three-year cycle,” Dr. Bradley says. “But now that we’re seeing the highest cases we’ve seen since the 1990s, we don’t quite know what that looks like in the future.” If vaccine hesitancy persists, “I think we’re going to see very local, very intense outbreaks that happen for six months to a year,” then retreat for several years and return. “From a national standpoint, we’ve seen big outbreaks in Texas, South Carolina, and Utah, but I think we need to be prepared to see something like this again in the near future in another state as well.”
In “The shot not taken: dangers of declining vaccination rates and impacts to the lab,” Dr. Bradley will discuss how the clinical laboratory can help to identify and contain reemerging vaccine-preventable disease outbreaks. His co-presenters are Denver Niles, MD, D(ABMM), of Texas Children’s Hospital, who will offer the pediatrician’s perspective, and Anthony Tran, DrPH, D(ABMM), MT(ASCP), of the California Department of Public Health, who will address cooperation between public health and the clinical laboratory amid growing gaps in the nation’s public health infrastructure.
Utah’s measles outbreak began in earnest after Dr. Bradley and his colleagues published their testing data. As of early May, 441 cases in 2026 had been recorded, compared with 197 in 2025. “Originally it was located in the southwest corner of the state where we have lower vaccine coverage, but now we’ve seen lots of cases within the city [Salt Lake] as well,” he says. “Our pediatric clinics and pediatric hospitals have been relying on this testing a lot.” With limited time for prophylactic vaccination after exposure, the laboratory has made turnaround time a priority. “We’ve had exposures in our pediatric ED,” he says. “By knowing sooner, we’re able to potentially offer prophylactic treatment or start contact tracing.”
Because about five percent of people present with a rash after measles vaccination and may test positive without being contagious, Dr. Bradley and his colleagues included in the PCR test a target to detect the vaccine strain of the virus in addition to true wild-type measles. “We brought on the vaccine target to lower the burden for our infection control group,” he says. “If someone gets vaccinated and then they’re tested using an assay that does not differentiate wild-type from vaccine strain and they’re positive, public health may have to investigate that, may have to send follow-up testing to the CDC to determine if it was vaccine strain or not, and that can divert resources from where they need to go.”
Shades of the pandemic can be seen in the current crisis, he says. There are no FDA-cleared molecular assays for measles, for instance. Laboratories can bring on their own tests, as ARUP did—some companies manufacture pre-synthesized primers and probes for purchase—but a full validation would be required, tough for many laboratories. On the public health side, individual states may vary in their capacity to support large testing volumes and genotyping. “Fortunately, Utah has been well resourced for doing pathogen sequencing,” Dr. Bradley says. But that doesn’t mean the public health infrastructure in the next state to see a large outbreak will be up to speed.
Data sharing poses similar difficulties. He cites the 2025 government shutdown, when the CDC stopped updating its tallies for some pathogens. “When you see a system malfunction like that, to me it signals we need to have more redundancy,” he says. “I think it falls on clinical laboratories who haven’t always done this work to start asking themselves, ‘What more could I do to contribute to strengthening this infrastructure that I might not have had to do in the past?’” (ARUP announced post-interview the launch of its National Infectious Disease Test Positivity Trends Dashboard. See page 66.)
Even as measles gets the lion’s share of attention, other vaccine-preventable diseases have had higher case counts in the U.S. About 6,000 measles cases have been documented in the U.S. since 2000. In contrast, from the start of 2024 to September 2025, the U.S. saw about 55,000 cases of pertussis—almost 10 times more, “but with maybe 10 times less media attention,” Dr. Bradley says.
Access to standalone testing for pertussis is limited. If a physician wants the testing, they typically order a large syndromic panel, Dr. Bradley says. “And for clinical laboratories, they may not be getting reimbursed for that because the payer says, ‘If you were worried about pertussis, why did you order seasonal coronaviruses and RSV and whatever else?’” As demand increases, the laboratory has to decide if anticipated volumes justify bringing on a new test.
When panel testing is costly for hospitals and patients, the bill itself is not the only downside, he says.
Vaccine-preventable diseases are spreading in communities skeptical of health care providers and the medical system. “If they get tested for pertussis and they get hit with a $300 bill for a multi-syndromic panel, that’s going to further erode that trust.”
In pediatric patients, the difficulties associated with reference interval studies are considerable.
“Getting specimens from healthy children is a large lift and it’s very challenging,” says Kelly Doyle, PhD, D(ABCC), who will co-present “Pediatric reference intervals: progress, challenges, and future perspectives.” Dr. Doyle is medical director of special chemistry, endocrinology, and mass spectrometry at ARUP Laboratories. He and others at ARUP saw in its sizable testing data set an opportunity: use statistical modeling to generate pediatric ranges.
In the session, Dr. Doyle will discuss the strengths, limitations, and clinical applications of the indirect approach to generating pediatric reference intervals—in other words, modeling the distributions of test results in different age brackets to determine the range of results that indicate normal or abnormal. Co-presenting will be Khosrow Adeli, PhD, D(ABCC), principal investigator of the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER), and Dennis Dietzen, PhD, D(ABCC), of Phoenix Children’s Hospital, who will address advocating in Congress for improved pediatric reference intervals.
At ARUP, Dr. Doyle and his colleagues have validated pediatric reference intervals for glucose-6-phosphate dehydrogenase deficiency. “G6PD is an ideal candidate marker for these studies because there’s good separation between affected and unaffected individuals,” he says. The algorithms they use require being able to model the pathological results from the nonpathological, he explains. When too many pathological results make their way into the data, it can introduce bias. “Even though we have a lot of data, it’s generally from pediatric patients who are unwell,” he says. For G6PD, he and his colleagues verified the accuracy of the proposed ranges using genetic data. “On a subset of the patients we used for indirect reference interval testing,” he says, “we could then overlay the genetic test results, which also had a phenotype result, with our ranges to ensure we’re categorizing them properly.”
The indirect reference interval approach has analytical advantages, Dr. Doyle says, such as scalability for rare age groups like neonates. “I’m going to highlight some of our work where we have modeled test result distributions for multiple hematological biomarkers in neonates,” he says. “These analyses are from very large data sets that also include information about gestational age, because we know a lot of these markers are influenced not only by how old they [patients] are post-delivery but also by the length of the gestational period.”
As he continues this work, Dr. Doyle anticipates a role for machine learning. One use would be to evaluate proxy markers of pubertal development that could prove useful in modeling growth markers such as IGF-1, which are influenced by Tanner Stage development, or sexual maturity, rather than age alone. “Age isn’t the only factor we need to be looking at in children,” he says. “They’re developing and going through puberty at different age stages, and that can be confounding if you’re looking at these markers based on age only.” Multicenter data sharing is another potential direction, he says, noting that the IFCC is now permitting indirect reference interval data to be incorporated into some of its reference interval databases.
The statistical methods Dr. Doyle and his colleagues use can complement conventional reference interval studies that involve collecting samples from healthy children, says Dr. Adeli, who started the Canadian CALIPER initiative in 2008. A laboratory can use the indirect approach to verify reference interval data for its local patient population, “or even a manufacturer-recommended reference interval from the package insert,” he says.
Dr. Adeli and his CALIPER collaborators have established pediatric reference intervals for more than 200 biochemical, immunochemical, and hematological markers, now compiled in a free online database and mobile application. In the session, Dr. Adeli, division head of clinical biochemistry in the Department of Pediatric Laboratory Medicine at the Hospital for Sick Children in Toronto and full professor in the Department of Laboratory Medicine and Pathobiology at the University of Toronto, will share some of the initiative’s recent work.
Updating and expanding the database are a focus now. CALIPER ensures that all pediatric reference interval data added to the database is first peer-reviewed and published, Dr. Adeli says, noting two key publications among many (Adeli K, et al. BMJ. 2018;361:k1950; Adeli K, et al. Crit Rev Clin Lab Sci. 2017; 54[6]:358–413).
Another focus is expanding the CALIPER database to include platforms widely used both within and outside North America. Close collaboration with the IVD industry in North America has led to development and publication of pediatric reference interval data on all major clinical chemistry platforms including Abbott, Beckman Coulter, Quidel-Ortho, Roche, Siemens Healthineers, Diasorin, and others. Recent collaborative studies with Chinese IVD companies including Mindray and Snibe are expanding the database to platforms used outside North America. “We’ve been doing studies on those systems and adding data to the database,” he says. They’re also exploring the potential for harmonization across different systems. “Our data supports the idea that many assays could be harmonized in terms of reference intervals, not just for adults but also for children in some cases,” he says. Whether ethnic origin can influence reference values is being studied, too. With the exception of a handful of assays, like vitamin D and ferritin, “there isn’t a significant influence.”
Dr. Adeli also will talk about continuous reference intervals, which are generated by combining direct sampling and continuous modeling of laboratory values with age.
How has generating pediatric reference intervals contributed to medical knowledge of children and adolescents?
Dr. Doyle speculates that the more appropriate reference intervals will affect downstream use of blood products and other therapies. “One of our recent studies has shown that perhaps we’re defining thrombocytopenia based on a lower platelet cutoff that’s too high for neonates,” he says.
Another example is the cutoff established for alkaline phosphatase, for which most laboratories in the past used an upper cutoff only, Dr. Adeli says. “Our data showed age-specific lower cutoffs that are also essential in pediatrics.” For example, hypophosphatasia is a genetic metabolic bone disease caused by mutations in the ALPL gene, leading to low ALP enzyme activity. “CALIPER data helped to reveal the importance of the lower cutoff,” he says, and pharmaceutical companies with drugs to treat hypophosphatasia have advised clinical laboratories worldwide to use the CALIPER data to diagnose the condition.
Dr. Adeli also cites an older finding that’s changed medical understanding of cardiac tissue development in the early days of life. In generating pediatric reference intervals for the cardiac biomarkers troponin and NT-proBNP, CALIPER collaborators found extremely high levels in very young children, and in neonates in particular. “Initially we thought there was something wrong with the data,” he recalls. But when they repeated the studies on other instruments, they found the same phenomenon.
It’s understood now that in cardiac tissue development in the initial days of life, “there is a significant release of these proteins,” he says. “After about a few months it normalizes to the very low level you see in older children.” The cardiologists they consulted were initially just as surprised by their findings.
“Now, it’s well accepted.”
Charna Albert is CAP TODAY senior editor.