A New Normal: The Quest for Age-Related Reference Ranges for Children

A lack of accurate reference standards can often prove challenging when it comes to treating pediatric patients. A coalition is seeking a federal effort to establish better pediatric reference intervals for medical tests could make treating these patients less problematic.   

“Children are not small adults” is an admonition to remind clinicians that they should not rely on adult reference intervals of diagnostic tests for treating pediatric patients. The problem is that adequate age-related reference intervals do not exist for a wide range of hormones and other analytes.

The need for this information has led the Endocrine Society to join a coalition urging Congress to provide funds to the Centers for Disease Control and Prevention (CDC) for a major program to better establish these intervals.

The Endocrine Society has long been active in efforts to improve testing through the consortium it developed and leads, the Partnership for Accurate Testing of Hormones (PATH), an alliance of some 20 organizations that started as an advisory group to the CDC to promote efforts to harmonize and standardize various hormone assays.

“The Endocrine Society agrees with the need to get accurate reference ranges for children as well as adults,” says Mila Becker, chief policy officer at the Endocrine Society.

To that end, the Society signed on to a letter recommending that “Congress provide the CDC Environmental Health Laboratory with an additional $10 million in fiscal year 2020 to initiate and coordinate” the work of improving pediatric reference intervals. The letter was drafted by the American Association for Clinical Chemistry (AACC), which also sponsored a presentation on the issue to congressional staff earlier this year.

At press time, 23 organizations had added their names to the effort, including the Pediatric Endocrine Society, College of American Pathologists, and American Society for Bone and Mineral Research.

The long-term goal would be to create “a national repository to collect and store pediatric samples from healthy children that can be used to develop more precise age, developmental, ethnic, and gender-specific reference intervals. The repository should also maintain a comprehensive database of existing pediatric reference intervals and make them readily accessible by healthcare providers and patients,” according to an AACC position paper.

The Problem with Children

“To establish reference intervals, you have to analyze a large number of specimens from a ‘healthy’ population,” says Dennis Dietzen, AACC past president and professor of pathology and immunology as well as pediatrics at Washington University in St. Louis. “It is relatively easy to do that with adults because they don’t mind when you stick a needle in their arm, and you can draw relatively large amounts of blood.”

It’s a different story with children because parental permission can be difficult to obtain and the smallest have a limited blood volume. Historically, most pediatric data has come from samples taken during clinic or hospital visits, which suggests they are not from a healthy population, Dietzen says.

“You rarely see age-specific reference intervals provided for thyroid hormones, even though newborns, babies, and toddlers commonly have higher thyroid hormone levels than adults.” –  John S. Fuqua, MD, professor of clinical pediatrics, Indiana University School of Medicine, Indianapolis, Ind.

In addition, as children grow through various developmental stages, their normal concentrations can change quickly, requiring a series of age- or developmentally matched ranges. That has led to “considerable inconsistency and large gaps in the ranges provided for children,” he says.

Markers Change with Age

The marker of renal function, creatinine, exemplifies how concentrations can change with age. “The circulating concentration of creatinine is a function of muscle mass,” Dietzen says. “When babies are born they have high water content compared to lean muscle mass, so their creatinine concentrations are very low. As they get older, their creatinine concentrations tend to rise. When puberty hits, male muscle mass becomes larger than female muscle mass, so then you have a gender difference in addition. So the major challenge is rapid developmental change, and to be able to collect and analyze enough data to define biochemically each one of those developmental changes,” Dietzen says.

Alkaline phosphatase is another example — a high level in an adult can indicate bone or liver disease, whereas the same level in young children and infants may be normal and simply represent growth and development.

John S. Fuqua, MD, professor of clinical pediatrics at the Indiana University School of Medicine in Indianapolis, says that he commonly encounters misunderstandings about thyroid hormones: “You rarely see age-specific reference intervals provided for thyroid hormones, even though newborns, babies, and toddlers commonly have higher thyroid hormone levels than adults.”

He often has children referred to him because of “high” thyroid hormone levels that are  completely normal for their age. “The parents are worried, the patient has to come to the appointment, which in our area sometimes requires a three-hour drive, and then they hear it is normal. The parents took a day off work, incurred the expense of getting here, and had all that anxiety induced because someone told them they had an abnormal test that really was fine.”

Why the CDC?

The groups are asking Congress to fund a program in which the CDC would gather large numbers of samples from a diverse population to establish pediatric reference intervals for a wide variety of analytes because the task would be an extension of work the agency is already doing.

“The major challenge is rapid developmental change, and to be able to collect and analyze enough data to define biochemically each one of those developmental changes.” – Dennis Dietzen, PhD, professor of pathology and immunology, professor of pediatrics, Washington University, St. Louis, Mo.

“The CDC has experience measuring disease biomarkers and collecting reliable health data from people,” says Hubert  W. Vesper, PhD, director of the clinical standardization programs at the CDC National Center for Environmental Health, and one of the presenters at the educational session AACC organized for congressional staff earlier this year. “CDC currently works to improve the accuracy and reliability of laboratory tests, assists with generating generally accepted reference intervals for adults, and provides the intervals to laboratories, physicians, and researchers. CDC also conducts the National Health and Nutrition Examination Survey (NHANES), which collects blood, urine, and comprehensive health status information from its participants. This expertise in recruiting participants, collecting health information, and generating data could be useful in creating reference intervals for other populations,” including children.

The CDC has led harmonization programs for cholesterol, triglyceride, vitamin D, testosterone, and estradiol assays.

Dietzen says that NHANES has the capability to “go out into every geographic corner of the U.S. and find kids who fit our inclusion/exclusion criteria and draw samples from them. They can annotate physical characteristics and developmental characteristics of these kids, to create a very good clinically annotated data set. The CDC has a rich concentration of different analytic platforms, so it will be the central analytic outfit that will measure the analytes that we want to measure and begin to do the data analysis that we need.”

The groups are working to persuade members of Congress to include the funding for the effort, but given the current climate in Washington, there are no assurances of success.

“This is a work in progress,” Fuqua says. “It is going to take some time. But it is great that we have this effort to advocate for kids.”

— Seaborg is a freelance writer based in Charlottesville, Va. He wrote about how in-house diabetes treatment teams could be helpful in improving patient outcomes in hospital settings in the September issue.

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