Do We Need Pakistan-Specific Reference Ranges in Laboratory Medicine?

Abstract

Evidence-based laboratory medicine is indispensable for health care practices. Reference values or reference ranges are necessary for the interpretation of clinical laboratory tests and subsequent patient care. Nearly 70% of medical decisions by physicians are solely based on information provided by laboratory test results.1 As a preliminary investigation into the topic of reference ranges, Gräsbeck and Fellman published a study in 1968 titled “Normal Value and Statistics”.2 The term “reference values” was used as a result of the realization that the concept of “normal values” was insufficient and even partially inaccurate in later years. A test result by itself is of little significance exceptwhen it is reported with adequate information for its interpretation. Classically, this information is delivered in the form of a reference range or reference interval or normal value. According to the recommendations by International Federation of Clinical Chemistry (IFCC), the term “interval” is preferred to “range.”3 The term “range” should only relate to the difference between an interval’s upper and lower limits. For instance, the sodium content in serum would have a reference range of 10mmol/L and a reference interval of 135 to 145mmol/L. Comparison of a patient’s laboratory test result versus a reference or “normal” range is vital to medical decisionmaking. Physicians compare laboratory report values to specified reference ranges tomake decisions about a person’s health status in clinical diagnosis, treatment, and monitoring. Reference ranges are also required by professional accreditation and regulatory bodies such as International Organization for Standardization 15189 which recommends that each laboratory should reevaluate its own reference interval on a regular basis.3 Likewise, in the European Directive 98/79 on in vitro diagnostic medical devices, diagnostic kit producers are required to give their customers the proper reference intervals to use with their assay kit reagents.4 Unfortunately, due to the challenges involved in obtaining a sufficient number of healthy people and the high cost of sample analysis, the majority of clinical laboratories are unable to develop their own reference ranges.5 For reference range formulation, a preselected reference population is sampled, measurements are taken, and then reference ranges are calculated according to the direct approach, a classic way to produce reference values.6 The use of normal laboratory data recorded in the laboratory information system to derive reference intervals in an indirect one has, however, become more and more popular. The study to compare the traditional (direct) and alternative (indirect) methodologies for the determination of reference intervals is now being worked on by the IFCC and Laboratory Medicine CommitteeonReference Intervals andDecision Limits.Mostof the reference intervals in use refer to the central 95% of the reference population of study subjects. By definition, 5% of all findings from “healthy” individuals will deviate from the published reference value and be marked as abnormal.6,7 Clinical and Laboratory Standards Institute guidelines advise establishing a reference valueby choosing a statistically significantgroupwith aminimumof120healthy reference subjects. International organizations also endorse population-specific clinical laboratory reference intervals, asgender, age, ethnicity, race, diet, geographic location, and other factors can affect the physiological value of a biochemical parameter.8