Clinical Chemistry 67:2 374–384 (2021)

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BACKGROUND: The concept of personalized medicine has received widespread attention in the last decade. However, personalized medicine depends on correct diagnosis and monitoring of patients, for which personalized reference intervals for laboratory tests may be beneficial. In this study, we propose a simple model to generate personalized reference intervals based on historical, previously analyzed results, and data on analytical and within-subject biological variation.
METHODS: A model using estimates of analytical and within-subject biological variation and previous test results was developed. We modeled the effect of adding an increasing number of measurement results on the estimation of the personal reference interval. We then used laboratory test results from 784 adult patients (>18 years) considered to be in a steady-state condition to calculate personalized reference intervals for 27 commonly requested clinical chemistry and hematology measurands.
RESULTS: Increasing the number of measurements had little impact on the total variation around the true homeostatic set point and using 3 previous measurement results delivered robust personalized reference intervals. The personalized reference intervals of the study participants were different from one another and, as expected, located within the common reference interval. However, in general they made up only a small proportion of the population-based reference interval.
CONCLUSIONS: Our study shows that, if using results from patients in steady state, only a few previous test results and reliable estimates of within-subject biological variation are required to calculate personalized reference intervals. This may be highly valuable for diagnosing patients as well as for follow-up and treatment.

Biochemia Medica 2016;26(1):5–16

Reliable and accurate reference intervals (RIs) for laboratory analyses are an integral part of the process of correct interpretation of clinical laboratory test results. RIs given in laboratory reports have an important role in aiding the clinician in interpreting test results in reference to values for healthy populations. Since the 1980s, the International Federation of Clinical Chemistry (IFCC) has been proactive in establishing recommendations to clarify the true significance of the term ‘RIs, to select the appropriate reference population and statistically analyse the data. The C28-A3 guideline published by the Clinical and Laboratory Standards Institute (CLSI) and IFCC is still the most widely-used source of reference in this area. In recent years, protocols additional to the Guideline have been published by the IFCC, Committee on Reference Intervals and Decision Limits (C-RIDL), including all details of multicenter studies on RIs to meet the requirements in this area. Multicentric RIs studies are the most important development in the area of RIs. Recently, the C-RIDL has performed many multicentric studies to obtain common RIs. Confusion of RIs and clinical decision limits (CDLs) remains an issue and pediatric and geriatric age groups are a significant problem. For future studies of RIs, the genetic effect would seem to be the most challenging area.
The aim of the review is to present the current theory and practice of RIs, with special emphasis given to multicenter RIs studies, RIs studies for pediatric and geriatric age groups, clinical decision limits and partitioning by genetic effects on RIs.

Biochem Med (Zagreb). 2016 Feb 15; 26(1): 5–11.

Reliable and accurate reference intervals (RIs) for laboratory analyses are an integral part of the process of correct interpretation of clinical laboratory test results. RIs given in laboratory reports have an important role in aiding the clinician in interpreting test results in reference to values for healthy populations. Since the 1980s, the International Federation of Clinical Chemistry (IFCC) has been proactive in establishing recommendations to clarify the true significance of the term ‘RIs, to select the appropriate reference population and statistically analyse the data. The C28-A3 guideline published by the Clinical and Laboratory Standards Institute (CLSI) and IFCC is still the most widely-used source of reference in this area. In recent years, protocols additional to the Guideline have been published by the IFCC, Committee on Reference Intervals and Decision Limits (C-RIDL), including all details of multicenter studies on RIs to meet the requirements in this area. Multicentric RIs studies are the most important development in the area of RIs. Recently, the C-RIDL has performed many multicentric studies to obtain common RIs. Confusion of RIs and clinical decision limits (CDLs) remains an issue and pediatric and geriatric age groups are a significant problem. For future studies of RIs, the genetic effect would seem to be the most challenging area.
The aim of the review is to present the current theory and practice of RIs, with special emphasis given to multicenter RIs studies, RIs studies for pediatric and geriatric age groups, clinical decision limits and partitioning by genetic effects on RIs.

Ann Lab Med. Sep 2012; 32(5): 345–354.

Abstract
Background

Many laboratories use 4 delta check methods: delta difference, delta percent change, rate difference, and rate percent change. However, guidelines regarding decision criteria for selecting delta check methods have not yet been provided. We present new decision criteria for selecting delta check methods for each clinical chemistry test item.

Methods

We collected 811,920 and 669,750 paired (present and previous) test results for 27 clinical chemistry test items from inpatients and outpatients, respectively. We devised new decision criteria for the selection of delta check methods based on the ratio of the delta difference to the width of the reference range (DD/RR). Delta check methods based on these criteria were compared with those based on the CV% of the absolute delta difference (ADD) as well as those reported in 2 previous studies.

Results

The delta check methods suggested by new decision criteria based on the DD/RR ratio corresponded well with those based on the CV% of the ADD except for only 2 items each in inpatients and outpatients. Delta check methods based on the DD/RR ratio also corresponded with those suggested in the 2 previous studies, except for 1 and 7 items in inpatients and outpatients, respectively.

Conclusions

The DD/RR method appears to yield more feasible and intuitive selection criteria and can easily explain changes in the results by reflecting both the biological variation of the test item and the clinical characteristics of patients in each laboratory. We suggest this as a measure to determine delta check methods.

Clin Biochem Rev Vol 29 November 2008

Screening, diagnosis and monitoring of paediatric diseases relies on the measurement of a spectrum of disease biomarkers in clinical laboratories to guide important clinical decisions. Physicians rely on the availability of suitable and reliable reference intervals to accurately interpret laboratory test results with data collected during medical history and physical examination. However, critical gaps currently exist in accurate and up-to-date reference intervals (normal values) for accurate interpretation of laboratory tests performed in children and adolescents. These gaps in the available paediatric laboratory reference intervals have the clear potential of contributing to erroneous diagnosis or misdiagnosis of many diseases of childhood and adolescence.
Most of the available reference intervals for laboratory tests were determined over two decades ago on older instruments and technologies, and are no longer relevant considering the current testing technology used by clinical laboratories. It is thus critical and of utmost urgency that a more acceptable and comprehensive database be established. There are however many challenges when attempting to establish paediatric reference intervals.
Paediatric specimen collection is a major concern for health care providrs as it is frequently difficult to obtain sufficient volumes of blood or urine from paediatric patients. Common reference intervals have not been widely implemented due to lack of harmonisation of methods and differences in patient populations. Consequently, clinical laboratory accreditation organisations and licensing agencies require that each laboratory verify or establish reference intervals for each method. To provide such reference intervals requires selection criteria for suitable reference individuals, defined conditions for specimen collection and analysis, method selection to determine reference limits and validation of the reference interval. The current review will provide a brief introduction to the current approach to establishment of reference intervals, will highlight the current gaps in data available in paediatric populations, and review a recent Canadian initiative, CALIPER (Canadian Laboratory Initiative on Paediatric Reference Intervals), to establish a comprehensive database for both traditional and emerging biomarkers of paediatric disease.