Pediatric reference intervals are key to medical decisionmaking, but suffer from errors and large information gaps. In an AACC-sponsored congressional briefing on February 27, leaders in clinical laboratory medicine from the federal and private sectors discussed ways to counter these issues, including increasing access to samples of healthy children covering all ages and developmental ranges, expanding biomarker measurements, and ensuring that clinical laboratories use the same reference intervals.

AACC, which has long advocated for harmonizing test results, and the Centers for Disease Control and Prevention (CDC) are looking into a partnership to improve upon and expand reference intervals for children. “Our goal is to make Congress aware that we need funding” to make these improvements happen, said moderator David Koch, PhD, DABCC, FADLM, director of clinical chemistry, toxicology, and point-of-care testing at Grady Memorial Hospital in Atlanta and chair of AACC’s Policy and External Affairs Core Committee.

Intervals define normal biomarker levels in healthy children, said Hubert Vesper, PhD, CDC’s director of clinical standardization programs. However, the intervals labs currently use aren’t consistent and accurate enough to reliably diagnose and treat children in a cost-effective manner, Vesper said. Laboratories generally haven’t had widespread access to samples from healthy children to develop more precise intervals for most pediatric lab tests. Pediatric cohorts and reference ranges often vary from lab to lab. “Labs can only work with the systems available to them, and the information they have is very limited,” added Vesper.

Many tests still don’t have a well-defined, accurate pediatric reference interval. Using adult reference intervals in children could result in a misdiagnosis. “Children are not little adults,” said Patrick Mason, MD, PhD, a regional medical director at Quest Diagnostics in Chantilly, Virginia. Certain biomarkers such as thyroid abnormalities are going to present much differently in an adult than in an infant, for example, Mason said.

Avoiding harm to patients, not to mention unnecessary medical costs, are key issues for labs, said Dennis Dietzen, PhD, DABCC, FADLM, medical director of laboratory services at St. Louis Children’s Hospital in Missouri and immediate past president of AACC. “If we miss a diagnosis in a child, that has lifelong consequences for the patient and associated costs.” The same outcomes can happen if an overdiagnosis leads to treatments and procedures a patient didn’t need.

But pediatric reference intervals are hard to build. Laboratories need large numbers of healthy children from birth through adulthood, said Dietzen, citing one example in which more than 1,000 specimens were required for developing a reference interval for creatinine. “Other biomarkers may exhibit seasonal, ethnic, or geographic variability. This requires even bigger numbers,” he told CLN Stat. Not only that, but parents have to give their consent for their children to volunteer, and undergo phlebotomy. “Depending on the age of the child, he or she also has to agree to phlebotomy even if Mom or Dad says it’s okay. The child can overrule. This is an incredibly difficult hurdle to overcome,” Dietzen emphasized.

Labs need to acquire as much blood as possible to study large numbers of lab parameters. However, the volume of blood a lab can collect in the youngest children is limited. “This situation also dictates the need for more participants,” Dietzen said. Once a lab acquires all of these specimens, it has to process, store, and analyze the specimens. “This is a labor-intensive, expensive proposition,” he added.

Solutions involve creating well-characterized pediatric cohorts and measuring these children with reliable and accurate tests, Vesper said. The bottom line is “labs all need to use the same reference ranges,” he stressed.

CDC already has an infrastructure in place for developing and applying accurate and reliable lab tests in well-characterized pediatric populations, Vesper noted. The agency’s National Health and Nutrition Examination Survey (NHANES) provides data on more than 30 health and disease biomarkers in children and adolescents, including hormones, lipids, and iron status. The problem is CDC doesn’t have this information for children in all age groups. In addition, the NHANES biomarker data doesn’t cover all of the needs of clinical labs—which routinely measure more than 30 biomarkers, he said. More biomarker measurements are needed, in addition to more reference ranges in children at all stages of development.

Data on children ages 3 years or younger is needed in particular, according to Vesper.

AACC in a policy brief has called on Congress to fund an initiative within CDC to establish more comprehensive, reliable pediatric reference intervals, expanding NHANES’ survey to include additional children ages 0-18 and build a more robust sample pool. CDC’s Environmental Health Laboratory could perform testing on the samples to produce more accurate intervals based on age, ethnicity, gender, and stages of development. In a letter to the Senate and House Appropriations Subcommittees on Labor, Health and Human Services, Education, and Related Agencies, AACC and 19 other major healthcare organizations also urged Congress to provide funding so that the Centers for Disease Control and Prevention (CDC) can fill a crucial gap in children’s medical testing by developing accurate pediatric reference intervals. 

AACC would play a role in this effort, partnering with CDC to distribute these improved reference intervals to the laboratory community.

Searching for the perfect interval will be “an ongoing process” as instruments continue to evolve, said Mason. “Technology is getting better and more specific. A reference interval for an immunoassay is not going to be the same as the interval used for a tandem mass spectrometry assay.”

To address the consent issue, some organizations have taken gradual, multistep approaches to gain parental trust. The CALIPER (Canadian Laboratory Initiative on Paediatric Reference Intervals Database) group, for example, talks to assemblies of students and parents at schools about the importance of reference intervals, Dietzen said. “They make themselves available to answer questions and once they reach a level of comfort, they come in and set up consenting and phlebotomy sessions.” Seeing the family doctor is another good setting to address this issue. “Coming at naive patients with a consent form in one hand and a needle in the other is not effective,” Dietzen said.