Reference Intervals: Strengths, Weaknesses, and Challenges

Abstract

A reference interval (RI) 10 is a standard component of reporting a laboratory result and is important to transform a numerical value into clinically meaningful information. An RI is intended to inform the clinical care provider that laboratory values within the interval indicate a nondiseased condition. The most common approach is to base an RI on the central 95% of laboratory test values observed for a reference population that is free of diseases that influence that laboratory test result. Because many diseases are asymptomatic, it becomes difficult to qualify people for a nondiseased condition, thus biasing the selection of reference individuals. Furthermore, information on the full complement of disease conditions that influence a laboratory test may be unknown. Thus, RIs may be influenced by inappropriately selected reference populations.Another limitation in determining an RI is obtaining an adequate sample of a reference population to make an estimate of the central 95% of results with suitable uncertainty to be meaningful for interpreting a test result. The sample size requirement becomes even larger when partitioning by sex, age, ethnicity, menstrual cycle, and other parameters is necessary for meaningful RIs. CLSI Guideline EP28-A3c describes consensus approaches and some limitations for establishing and verifying RIs. However, some of the approaches in this guideline are statistically underpowered such that uncertainties in the RIs may not be appreciated.A particularly challenging situation is the requirement for laboratories to establish an RI for a laboratory developed measurement procedure (MP) or to verify the RIs proposed by the manufacturer of an in vitro diagnostic (IVD) MP. Identifying a suitable reference population for either requirement can be very challenging.Evolution in laboratory practice is needed to enable appropriate RIs to be adopted by laboratories. We asked experts with different perspectives to address issues we all face in establishing or verifying RIs. How can an IVD device manufacturer get a suitable sample of a reference population to establish an RI?Ferruccio Ceriotti: "The RIs for the quantities being determined" are required from an IVD manufacturer to comply with the European Directive on in vitro diagnostic medical devices. Moreover, the RIs provided by the manufacturer are probably those most commonly used on clinical laboratory reports. There is not a single answer to this critical question, it depends on the measurand. If a reference system exists for calibration traceability and there are published well-characterized RIs obtained with a well-standardized MP ("traceable RIs"), the manufacturer can provide those RIs without the need of a new RI study provided that its MP has the same level of standardization. For nonstandardized measurands, I do not see alternatives to an RI study performed according to CLSI

Reference intervals for selected haematological and biochemical parameters among apparently healthy adults in different eco-geographical zones in Ghana

“…Reference intervals (RIs) are threshold values within which a specified proportion of measurements from a healthy population would fall [2,3]. They provide the basis of interpretation of laboratory results [4][5][6] and are thus an essential component of reporting laboratory test results [7].…”

The concurrence of the current postanalytical phase management with the national recommendations

“…The obstacles for the verification of the RI mentioned by the laboratories in this survey ( e.g. , availability of referent population and time-consuming process) are the same ones discussed by several prominent laboratory experts ( 12 ). Establishing own RI is even more challenging work for many reasons, such as selecting the representative population ( e.g.…”

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

“…Reference intervals describe the percentile values of a biomarker measured in a reference population [ 1 , 2 ]. Ideally, the reference population should be selected from a representative population free of any pathological conditions that are known to affect the biomarker, with samples handled under standardized pre-analytical conditions.…”