Validating CALIPER pediatric reference intervals in a U.S. population using retrospective outpatient data and RefineR
Jillian Kodger1, Thomas J S Durant2, Nalan Yurtsever1
1Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA.
Insights
The RefineR method shows better alignment with Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) than CLSI guidelines for pediatric lab results. This approach is more accurate for diverse US pediatric outpatient populations.
Area of Science:
- Clinical Laboratory Medicine
- Pediatric Reference Interval Development
- Biostatistics in Healthcare
Background:
- Accurate pediatric reference intervals (RIs) are crucial for interpreting lab results but face challenges like physiological variation and limited sample sizes.
- This study assesses the applicability of Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) RIs in a diverse US pediatric outpatient setting.
- Two methods, RefineR inverse modeling and Clinical and Laboratory Standards Institute (CLSI) EP28-A3c, were used for evaluation.
Purpose of the Study:
- To evaluate the applicability of existing Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) to a US pediatric outpatient population.
- To compare the performance of the RefineR inverse modeling approach versus the CLSI EP28-A3c recommended approach for deriving pediatric reference intervals.
- To assess the accuracy and practicality of RefineR for developing population-specific pediatric reference intervals.
Main Methods:
- Collected outpatient laboratory data from 51,863 pediatric patients (under 19 years) between January 2023 and December 2024.
- Derived reference intervals (RIs) for nine common chemistry analytes using both RefineR and CLSI guidelines with bootstrap resampling.
- Compared derived RIs to CALIPER RIs using a flagging system based on 95% confidence intervals and total allowable error (TAE).
Main Results:
- RefineR-derived RIs aligned with CALIPER RIs in 86 out of 88 age- and gender-specific analyte groups.
- CLSI-derived RIs showed alignment in 77 out of 88 groups, indicating lower concordance.
- Discrepancies were noted for specific analytes (e.g., ALT, AST, ALP, BUN), influenced by factors like sample type, BMI, and hydration status.
Conclusions:
- RefineR demonstrated superior alignment with CALIPER RIs compared to CLSI guidelines in a US pediatric outpatient cohort.
- RefineR is a robust and practical method for deriving population-specific pediatric reference intervals, handling mixed data and skewed distributions effectively.
- The RefineR approach aids in verifying the implementation of external RIs, such as CALIPER, in diverse pediatric populations.
Background:
Accurate pediatric reference intervals (RIs) are critical for proper interpretation of laboratory results, yet their development is challenged by age-related physiological variation, limited sample sizes, and preanalytical variability. This study evaluates the applicability of the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) RIs to a US-based, diverse pediatric outpatient population using both the RefineR inverse modeling approach and the Clinical and Laboratory Standards Institute (CLSI) EP28-A3c recommended approach.
Methods:
Outpatient laboratory data from 51,863 patients under 19 years of age were collected from a single institution between January 2023 and December 2024. Nine commonly ordered chemistry analytes were evaluated. RIs were derived using both RefineR and CLSI guidelines with bootstrap resampling. These were compared to CALIPER RIs using a color-coded flagging system based on 95% confidence intervals and total allowable error (TAE).
Results:
RefineR-based RIs aligned with CALIPER values in 86 out of 88 age- and gender-specific analyte groups, whereas CLSI-derived RIs aligned in 79 out of 88. Notable discrepancies involved alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and blood urea nitrogen, often influenced by known preanalytical and physiological variables such as sample type, body mass index (BMI), and hydration status.
Conclusions:
RefineR demonstrated superior alignment with CALIPER RIs compared to CLSI guidelines, highlighting its robustness in outpatient pediatric populations. Given its tolerance to mixed data and skewed distributions, RefineR offers a more practical and accurate method for deriving population-specific RIs in pediatric laboratory medicine, and helps verify the implementation of external RIs, such as CALIPER.
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