Describe the difference between reference intervals and decision limits.
Discuss the challenges in the establishment and verification of pediatric reference intervals.
Compare traditional and alternative strategies for determining or verifying reference intervals.
Summarize current initiatives with successful recruitment strategies of healthy children for reference interval studies.
Reference intervals are primordial to correctly interpret the laboratory data produced from biological samples. Comparison of laboratory test results to decision limits or reference intervals is an important part of medical decision making. Therefore, lack of accurate reference intervals can adversely impact patient care, by delaying diagnosis, treatment procedures, and/or modifying prognosis. Reference intervals need to be established for all age groups, as emphasized by quality standard requirements from various laboratory accreditation organizations, such as the College of American Pathologists (www.cap.org) and the Ontario Laboratory Accreditation, a division of the Institute for Quality Management in Healthcare (iqmh.org). For many laboratory tests, the pediatric reference intervals differ from the adult reference intervals. There is a serious risk to patient safety when reference intervals are not adequately evaluated for children. When attempting to conduct “classic” reference interval studies, laboratories face major challenges in accessing adequate numbers of specimens with sufficient volumes collected from healthy children ranging from the newborn period until past the adolescent years. Furthermore, reference intervals developed using one analytical platform cannot simply be transferred to another platform. The purpose of this chapter will be to review the most commonly encountered challenges and the statistical tools available to establish pediatric reference intervals. It will also highlight alternative approaches to establish or verify reference intervals with discussion of current initiatives that have been successful in conducting large-scale collection of specimens in healthy children for this purpose.
REFERENCE INTERVALS VERSUS DECISION LIMITS
A reference interval is generally defined as the central 95% (between the 2.5th and 97.5th percentiles) of measured analyte concentrations from a reference or “healthy” population.1 A reference population refers to a population of healthy individuals. Reference intervals should be calculated specifically for each laboratory method and should be calculated for specific populations.2 Clinicians use reference intervals to aid in interpreting patient quantitative test results to distinguish patients with results outside of the reference interval (ie, “abnormal”) from those with results within the reference interval that are typically considered “normal.” However, the reference interval should only be used as a guide, as patient analyte values must be interpreted in the context of the clinical situation.2,3 This is a very important point that is often misunderstood. Given the way in which reference intervals are calculated using statistical approaches, by design, 5% of analyte results from healthy individuals will fall outside of the reference interval. Figure 7-1 outlines a theoretical distribution of analyte values from a reference (healthy) population. The 2.5th and 97.5th percentile results are taken as the lower ...