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

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.

Hemoglobin A1c Levels Are Slightly but Significantly Lower in Normoglycemic Subjects With the Hemoglobin E Phenotype

Hb mutations can alter the structure, behavior, stability, or quantity of the globin chain produced. Some Hb variants shorten the erythrocyte life span, resulting in physiologically lower hemoglobin A1c (HbA1c) levels. The hemoglobin E (HbE) phenotype involves a single-nucleotide polymorphism that reduces β-globin chain synthesis. We compared the HbA1c levels of subjects with normal Hb (HbAA; N=131) and HbE (N=148) phenotypes, examining potential hematological and biochemical factors contributing to differences in HbA1c levels. All had normal fasting plasma glucose ( < 5.6 mmol/L), AST, ALT, and creatinine levels. Mean±SD HbA1c levels differed between HbAA and HbE subjects: 5.5±0.3% and 5.3±0.3% (P < 0.001) according to an immunoassay, and 5.5±0.3% and 5.3±0.3% (P < 0.001) according to cation-exchange HPLC, respectively. In multiple logistic regression, only mean corpuscular volume (P < 0.001) contributed to the difference in HbA1c levels between groups. Although a 0.2% difference in HbA1c is relatively small and unlikely to alter clinical decisions, epidemiologically, this can lead to misclassification of a significant proportion of the population, especially since the threshold of non-diabetes HbA1c (≤5.6%) falls very close to the HbA1c median of the general population.

The Effect of Vitamin D Status on Pediatric Asthma at a University Hospital, Thailand

PURPOSE: In the USA and Europe, hypovitaminosis D is associated with increased asthma severity, emergency department (ED) visit, and impaired pulmonary function in asthmatic patients. However, in tropical countries, data on the effect of vitamin D status on asthma is limited. This study evaluates the relationship between vitamin D status and the level of asthma control as well as other asthmatic parameters. METHODS: Asthmatic children were evaluated for serum 25-hydroxyvitamin D, pulmonary function tests, a skin prick test, and the level of asthma control. RESULTS: A total of 125 asthmatic children were recruited (boys, 66.4%). Their mean age+/-SD was 10.8+/-3.0 years. Vitamin D statuses were: deficiency (30 ng/mL) in 36%. The vitamin D levels were 25.9+/-9.4 ng/mL in uncontrolled patients, 29.2+/-8.6 ng/mL in partly controlled patients, and 27.9+/-8.0 ng/mL in controlled patients (P>0.05). There were no significant differences in pulmonary function, asthma exacerbation, inhaled-corticosteroid (ICS) dose, anti-inflammatory drugs, or ED visit or hospitalization between different vitamin D statuses. Vitamin D deficiency patients were older and had a delayed onset of asthma than insufficiency or sufficiency patients. There was no significant correlation between serum vitamin D and pulmonary function/doses of ICS. CONCLUSIONS: High prevalences of vitamin D deficiency and insufficiency were found in asthmatic children in Thailand; however, there was no significant relationship between vitamin D status and the level of asthma control or other asthma parameters.