Volume 40 Number 2 | April 2026
Summary

The article argues that traditional reference intervals based on younger adults often misclassify normal age‑related changes in older patients as disease. Age‑adjusted intervals improve diagnostic accuracy, reduce over diagnosis, and support ethical, patient‑centered care. While challenging to develop, they help prevent harm, reduce anxiety, and promote more equitable, clinically meaningful interpretation of laboratory results.

Sean Witt, MLS(ASCP)CMMBCM,SHCM, Volunteer Contributor

Introduction

Sean WittReference intervals (RIs) define the expected range of laboratory test results and provide clinicians with a framework to interpret values as normal or indicative of pathology. Clinical laboratories bear the responsibility of establishing or validating RIs that accurately reflect the demographic and clinical characteristics of their patient populations. With the global population aged 60 years and older projected to grow from 1.1 to 1.4 billion by 2030 (WHO, 2025), the prevalence of age-related physiological changes and comorbidities is increasing, complicating the interpretation of standard laboratory tests.

RIs for quantitative tests are traditionally derived from healthy adult populations and represent the central 95 percent of measured values, consistent with the methodology outlined in the Clinical and Laboratory Standards Institute (CLSI) EP28 guideline (CLSI, 2020). This approach overlooks important population differences, including age-related physiological changes, comorbidity prevalence, and medication use. Efforts in pediatric populations highlight the utility of population-specific RIs. The Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) established age- and sex-specific RIs to account for normal physiological variation throughout childhood and adolescence (Adeli et al., 2017). Similarly, age-adjusted RIs in older adults can provide a more accurate framework for interpreting laboratory results in the context of age-related changes.

Clinical laboratories must implement age-adjusted RIs and interpretation guidelines for common biochemical testing in older adult populations to improve diagnostic accuracy, support precise clinical decision-making, and minimize inappropriate testing. Such measures will decrease misdiagnoses and reduce unnecessary interventions, ultimately helping to mitigate the growing healthcare burden associated with an aging U.S. population. 

“From both ethical and clinical perspectives, the establishment of age-adjusted RIs aligns with the fundamental aim of laboratory medicine: improving health and improving lives through accurate and reliable diagnostic tests.”

Improved Diagnostic Accuracy

Physiological aging affects the kidneys, liver, heart, endocrine organs, and immune system. Subtle functional changes can influence laboratory test values even in the absence of disease (Stefanacci, 2024). Given that normal aging can modify laboratory values, it is essential to establish RIs that distinguish between expected physiological changes and true pathology.

Ma et al. (2020), Ni et al. (2022), and Helmersson-Karlqvist et al. (2016) aimed to establish RIs for common biochemical tests in older adults. Ma et al. (2020) established RIs for 22 analytes using data from 97,220 adults without chronic disease, abnormal weight, or blood pressure, compared with a similar cohort under 65. Except for alanine transaminase (AST) and high-density lipoprotein cholesterol (HDL-C), all other common biochemical analytes showed statistically significant differences between the two groups. When stratified by sex, significant differences were observed in ALT and HDL-C levels.

Ni et al. (2022) aimed to establish age-adjusted thyrotropin (TSH) RIs for individuals aged 65 and older to assess the prevalence of subclinical hypothyroidism (SCH). TSH concentration gradually rises with age, however, this observation is not linked to impaired quality of life, cardiovascular events, or mortality in older adults (Leng & Razvi, 2019). Applying age-specific TSH RIs reduced the prevalence of subclinical hypothyroidism from 10.3 percent to 3.7 percent, thereby demonstrating how age-adjusted RIs can avoid overdiagnosis. Helmersson-Karlqvist et al. (2016) showed that in comparison to the population in the Nordic Reference Interval Project (NORIP), creatinine and urea limits were higher, and iron and albumin limits were lower in 80-year-old participants without diabetes and cardiovascular disease.

Collectively, these studies demonstrated that RIs established using younger adult populations cannot be reliably applied to older adults. When interpreted in the wrong context, results of routine biochemical testing may lead to incorrect diagnoses and care planning strategies. Establishing accurate, age-adjusted RIs is therefore essential to distinguishing normal age-related changes from pathological conditions, ensuring appropriate management and more accurate prognostic assessment in older adults. The implications of misapplied RIs extend beyond misdiagnosis, posing ethical and safety concerns for patients.

Protecting Patients from Harm

Failure to establish RIs specific to older adults may jeopardize patient safety. This situation presents an ethical challenge for both laboratory professionals and clinicians. Edvardsson et al. (2017) and Tannenbaum et al. (2025) highlight that applying standard RIs to older adults can produce misleading results. Edvardsson provided tangible evidence, showing that many biomarker differences in frail elderly adults had weak associations with disease, suggesting that pathology may be falsely diagnosed.

A substantial portion of the variability in albumin and creatinine levels could not be explained by patient sex and clinical condition alone. Thyroid disease and a history of stroke accounted for 11 percent of the variance in albumin concentrations, while kidney disease, sex, cognitive status, and asthma explained only 34 percent of the variation in creatinine levels (Edvardsson, 2017). These findings emphasize that inaccurate RIs can affect not only clinical decision-making but also patient perceptions and understanding of their own health data.

Under the CURES Act, patients now have immediate electronic access to their health information, including detailed clinical laboratory results with accompanying interpretations. As a result, older adults whose test results fall outside reference ranges established from younger populations are confronted with alarming flags on laboratory reports. This can create unnecessary anxiety and confusion for patients who may interpret these abnormalities as evidence of disease. Tennenbaum’s (2025) argument highlights the ethical responsibility of laboratorians to ensure that data are both accurate and meaningful in the context of the patients age, sex, comorbidities, and medication use. Although protecting patients from harm demands accurate RIs, laboratories face considerable obstacles in designing intervals that truly represent the older adult population

Practical Challenges of Establishing Age-Adjusted RIs

Tannenbaum et al. (2025) and Edvardsson et al. (2014) highlight challenges in establishing RIs for older adults, including defining a truly healthy population and recruiting representative samples amid high rates of chronic disease and polypharmacy. Additional barriers to consider are reduced mobility and limited access to care (Office of Disease Prevention and Health Promotion, 2025). Sampling bias toward inpatients or older adults with greater resources may limit the representativeness of RIs, thereby reducing their applicability. Even after addressing these practical challenges, interpreting laboratory results in older adults remains complex, as multiple demographic and physiological factors can influence values beyond what reference intervals alone can capture

Edvardsson et al. (2018) examined the clinical complexity of interpreting laboratory tests in individuals over 80 years-of-age, finding that even optimal RIs are insufficient without clinical context. The findings of Ma et al. (2020), Mohammed Hashim Harka et al. (2024), and Ni et al. (2022), support this conclusion, showing that gender differences contribute to age-related changes. These studies suggest that variance is multifactorial, influenced by both demographic and physiological factors. Such challenges raise questions about the practical necessity of establishing multiple, age-adjusted RIs, given the potential for added complexity without substantial clinical benefit.

Challenging the Need for Multiple Age-Adjusted RIs

Carefully designed study populations can provide valuable evidence for developing age-adjusted reference intervals. However, the resulting cutoffs from such studies may only slightly differ from those derived from younger adult populations. Consequently, laboratory reports may include multiple reference intervals that add complexity without meaningful benefit to patient care. Furthermore, overcomplicated reports may be harder to interpret and easier to misread (Gandhi et al., 2006).

To avoid these potential pitfalls, laboratorians should rigorously evaluate any proposed RIs before they are implemented. This requires a close, collaborative partnership between the laboratory and clinical teams, ensuring that only those adjustments to RIs that meaningfully influence patient management are adopted. Additionally, the laboratory information system (LIS) or electronic medical record (EMR) may be configured to display only the reference interval that applies to a patient’s demographics.

Clinical Judgement vs. Age-Adjusted RIs

Providers may argue that clinical judgement may be equal to or exceed the performance of clinical prediction models (Luis Enrique Colunga-Lozano et al., 2024). However, not all clinicians have the same level of expertise. Relying solely on individual clinical judgement can introduce variability and subjectivity when interpreting laboratory data. Standardized, age-adjusted RIs could help reduce this variability by providing an objective view of diagnostic test results across clinicians and care settings. Furthermore, age-adjusted RIs could provide a safety net for misinterpretation, which only serves to benefit the patient by reducing the potential for harmful or unnecessary interventions.

Resource Considerations

Developing accurate, age-adjusted RIs requires large, well characterized study populations, which can be costly and time-consuming for laboratories to recruit participants and reduce data (Ozarda et al., 2018; Płaczkowska et al., 2020). Conducting a comprehensive analysis of every analyte on the test menu to identify age- and sex-related differences within existing RIs may be a highly resource intensive endeavor. While the upfront cost of establishing age-adjusted RIs is something to consider, this initiative can be viewed as a strategic investment rather than a burden on the clinical laboratory and health system.

Establishing accurate, population specific RIs can improve patient care long-term. Furthermore, failing to optimize result interpretation guidelines could lead to inappropriate interventions, delayed diagnoses, and poor patient experiences. Taken together, these potential outcomes undermine the credibility of the health system and diminish public trust in the quality of care delivered.

Conclusion

With an aging global population on the horizon, it is imperative that diagnostic test results are accurate and reliable for screening, diagnosis, treatment planning, and prognosis. The present evidence clearly demonstrates that RIs derived from younger adults often fail to capture the biochemical variability inherent to older adults. When these traditional RIs are applied indiscriminately, they risk producing misleading results, contributing to overdiagnosis, unnecessary treatments, and patient anxiety. From both ethical and clinical perspectives, the establishment of age-adjusted RIs aligns with the fundamental aim of laboratory medicine: improving health and improving lives through accurate and reliable diagnostic tests.

References

Sean Witt is a DCLS Resident at the University of Kansas Medical Center, Department of Clinical Laboratory Sciences in Kansas City, Kansas.