How can we improve? Understanding new clinical pathology paradigms for better interpretation of results

Current paradigms and practices impede the ability of practitioners to fully utilise clinical pathology results from blood and other body fluids to recognise and manage disease in veterinary patients. These issues include analyser bias, the suitability of population reference intervals, and "grey areas" around individual results. Analyser bias gives rise to different results for the same sample determined on different analysers (even of the same model at commercial laboratories). Such bias is often not accurately accounted for by using reference intervals specific for the different analysers. The ideal solution would be harmonising analysers so that results are equivalent regardless of the analyser they were determined on. Without harmonisation, results from different analysers should not be compared. Population-based reference intervals may not reflect the local population and, for most analytes, are much wider than an individual patient's normal fluctuation of results. This means that clinically relevant changes that remain within the population reference interval may be missed. Rather than assessing results in relation to a patient's cohort, results can be assessed in relation to a patient's prior results, expected analyser variation and expected physiological fluctuation. Such fluctuations are known as biological variation. Biological variation enables individualised reference intervals to be determined from prior results obtained when a patient is clinically stable. Such reference intervals are not yet readily available; however, assessing prior results and comparing them to expected variation (see Supplementary Tables 1 and 2) to recognise the significance of any change could be used as an interim measure. A single laboratory result represents a range of possible values. This range is known as dispersion and is also determined from biological and analyser variation. Dispersion creates grey areas around individual results and thresholds such as reference interval limits and staging of disease. Therefore, any threshold should not be taken as definitive and apparent changes may be within expected physiological fluctuation and therefore not significant.This review assesses the background and science behind these issues and offers ideal solutions for how they may be addressed in the future and practical approaches that can be immediately incorporated by clinicians into daily practice. Addressing these issues can help improve clinical pathology acuity and thus improve outcomes for veterinary patients.Abbreviations: CKD: Chronic kidney disease; CV_A: Analyser variation; CV_G: Inter-individual (group) variation; CV_I: Intra-individual variation; HSP: Homeostatic set point; IRIS: International Renal Interest Society; RCV: Reference change value; SDMA: Symmetric dimethylarginine.