Ann Lab Med.  2023 Sep;43(5):408-417. 10.3343/alm.2023.43.5.408.

Functional Reference Limits: Describing Physiological Relationships and Determination of Physiological Limits for Enhanced Interpretation of Laboratory Results

• Chuah TY
• Lim CY
• Tan RZ
• Pratumvinit B
• Loh TP
• Vasikaran S
• Markus C
• for the APFCB Harmonization of Reference Intervals Working Group

• KMID: 2551988
• DOI: http://doi.org/10.3343/alm.2023.43.5.408

Abstract

Functional reference limits describe key changes in the physiological relationship between a pair of physiologically related components. Statistically, this can be represented by a significant change in the curvature of a mathematical function or curve (e.g., an observed plateau). The point at which the statistical relationship changes significantly is the point of curvature inflection and can be mathematically modeled from the relationship between the interrelated biomarkers. Conceptually, they reside between reference intervals, which describe the statistical boundaries of a single biomarker within the reference population, and clinical decision limits that are often linked to the risk of morbidity or mortality and set as thresholds. Functional reference limits provide important physiological and pathophysiological insights that can aid laboratory result interpretation. Laboratory professionals are in a unique position to harness data from laboratory information systems to derive clinically relevant values. Increasing research on and reporting of functional reference limits in the literature will enhance their contribution to laboratory medicine and widen the evidence base used in clinical decision limits, which are currently almost exclusively contributed to by clinical trials. Their inclusion in laboratory reports will enhance the intellectual value of laboratory professionals in clinical care beyond the statistical boundaries of a healthy reference population and pave the way to them being considered in shaping clinical decision limits. This review provides an overview of the concepts related to functional reference limits, clinical examples of their use, and the impetus to include them in laboratory reports.

Keyword

Reference values; Threshold limit values; Homeostasis

Figure

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  Fig. 1 Relationship between plasma osmolality and plasma antidiuretic hormone concentration. Not drawn to scale.

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  Fig. 2 Relationship between serum vitamin D and plasma parathyroid hormone concentrations represented by a regression line (solid line) and its 95% confidence interval (dashed lines). Not drawn to scale.

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  Fig. 3 Inclusion of subclinical/pathological populations may inappropriately broaden lower and upper reference limits. The dashed lines represent the distribution of the healthy population while the solid line represents the broadened distribution when subclinical/pathological populations are included.

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  Fig. 4 Relationship between two interrelated biomarkers in different overlapping populations, normal subjects (gray circles), and pathological subjects (open triangles). The concentrations of biomarkers A and B both increase until a point where they start to plateau (change in curvature, dashed vertical line), which is considered the functional reference limit.

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