Pediatric reference interval verification for 16 biochemical markers on the Alinity ci system in the CALIPER cohort of healthy children and adolescents

Mary Kathryn Bohn; Randal Schneider; Benjamin Jung; Khosrow Adeli

doi:10.1515/cclm-2023-0256

. 2023 May 1;61(11):2033–2040. doi: 10.1515/cclm-2023-0256

Pediatric reference interval verification for 16 biochemical markers on the Alinity ci system in the CALIPER cohort of healthy children and adolescents

Mary Kathryn Bohn ^1,², Randal Schneider ³, Benjamin Jung ^1,², Khosrow Adeli ^1,^2,^✉

PMCID: PMC10695436 PMID: 37114851

Abstract

Objectives

Special chemistry parameters are useful in the diagnosis and management of inherited disorders, liver disease, and immunopathology. Evidence-based pediatric reference intervals (RIs) are required for appropriate clinical decision-making and need to be verified as new assays are developed. This study aimed to evaluate the applicability of pediatric RIs established for biochemical markers on the ARCHITECT for use on newer Alinity assays.

Methods

An initial method validation was completed for 16 assays, including precision, linearity, and method comparison. Sera collected from approximately 100 healthy children and adolescents as part of the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) were also analyzed on the Alinity c system. Percentage of results within established ARCHITECT RIs were calculated and considered verified if ≥90 % fell within established limits. New RIs were established for three electrolytes, glucose, and lactate wherein no data were previously reported.

Results

Of the 11 assays for which CALIPER pediatric RIs were previously established on ARCHITECT assays, 10 met the verification criteria. Alpha-1-antitrypsin did not meet verification criterion and a new RI was established. For the other 5 assays, de novo RIs were derived following analysis of 139–168 samples from healthy children and adolescents. None required age- and sex-partitioning.

Conclusions

Herein, pediatric RIs were verified or established for 16 chemistry markers in the CALIPER cohort on Alinity assays. Findings support excellent concordance between ARCHITECT and Alinity assays with one exception (alpha-1-antitrypsin) as well as robustness of age- and sex-specific patterns originally reported by CALIPER in healthy Canadian children and adolescents.

Keywords: pediatrics, reference intervals, special chemistry

Introduction

Disease diagnosis, monitoring, and prognostication rely on clinical laboratory testing for various biomarkers of health and disease. Evidence-based reference intervals are required to support accurate test result interpretation and inform clinical decision-making [1]. Reference interval establishment requires consideration of key covariates that may influence reference values of measured biomarkers, including age and sex [1]. This is particularly important in pediatric populations wherein dynamic growth and development and sexual differentiation necessitate the determination of age- and sex-stratified reference intervals throughout childhood and adolescence. The Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) aims to address gaps in evidence-based pediatric reference intervals to support improved healthcare delivery from birth to adulthood. Initial studies in the CALIPER cohort were completed using ARCHITECT assays (Abbott Diagnostics) in approximately 2000 healthy children and adolescents [2], [3], [4], [5], [6]. Clinical biomarkers evaluated included enzymes, proteins, and metabolites [3], thyroid hormones, peptides, and vitamins [5] in addition to sex hormones [4], cancer antigens [7], and other specialized biomarkers [6]. To broaden and enhance the clinical utility of CALIPER data, a series of transference and de novo reference interval studies were completed for other widely used commercial assay methodologies, including the Beckman AU, DxC and DxI, Ortho VITROS, Roche Cobas and Modular P, and Siemens Vista, Advia, Dimension, and Atellica [1, 8], [9], [10], [11]. The rigorous process undertaken to partition reference intervals by age and sex on several analytical assays has resulted in a dataset of unprecedented richness, underscoring the importance of growth and development on circulating biomarkers. Additional global initiatives in other populations have also contributed significantly to the field, improving laboratory test result interpretation in pediatric institutions worldwide [12], [13], [14], [15]. However, it is important to continue these efforts when novel or newer assay methodologies are introduced to replace older ones to ensure reproducibility and validate performance in contemporary populations.

The Alinity c system (Abbott Diagnostics) is an automated chemistry module that applies various analytical methodologies for the quantitative detection of clinical biomarkers. It is the new generation of the ARCHITECT assay system and is currently being implemented by clinical laboratories in healthcare institutions globally. Recent studies from our group have verified previously established pediatric reference intervals on ARCHITECT assays in the CALIPER cohort for use on the Alinity, including routine biochemical [16], routine immunochemical [17], and specialized immunochemical assays [18]. Findings demonstrated excellent comparability of Alinity and ARCHITECT assays in most cases, suggesting both tightly controlled assay performance as well as the robustness of CALIPER data and reproducibility of age- and sex-specific patterns. However, there were exceptions that required new Alinity-specific reference interval establishment (e.g., free thyroxine, prolactin, magnesium, calcium). Further, specialized chemistry parameters (e.g., immune proteins) and electrolytes were not evaluated.

The current study aims to verify pediatric reference intervals previously established in the CALIPER cohort for an additional 11 chemistry ARCHITECT assays for use on the new Alinity c system. Furthermore, de novo reference interval establishment was also completed for three electrolytes, glucose, and lactate in the CALIPER cohort using Abbott Diagnostics assays for the first time in order to further increase coverage of the assay menu available on this platform.

Materials and methods

Analytical validation

An initial analytical validation was completed for each chemistry assay on the Alinity c system following Clinical and Laboratory Standard Institute (CLSI) guidelines. Internal quality controls were assayed five times per day over a period of five days. Mean and coefficient of variation for each level were determined. A five level linearity series was created by spiking a high patient specimen in a low patient pool. All levels were measured in triplicate and linear regression was applied to determine slope, intercept, and correlation coefficient [19]. After establishment of acceptable performance, 20–40 patient samples were analyzed on an ARCHITECT system (Abbott Diagnostics) at The Hospital for Sick Children (Toronto, ON, Canada), University Hospital Network (Toronto, ON, Canada), or Nova Scotia Health (Halifax, NS, Canada), depending on the assay, and compared to the Alinity system at The Hospital for Sick Children (Toronto, ON, Canada). Deming regression and Pearson R correlation were used to determine line of best fit and degree of correlation [16], [17], [18] (Supplemental Figures 1–10).

Participant and sample acquisition

Approximately 100 serum samples from healthy children and adolescents (birth to 18 years) were collected as part of the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) [1]. Participation required completion of informed consent, health questionnaire, and blood donation. Participants were excluded if they were pregnant or had a history of chronic illness, acute illness within 7 days of collection, and/or regular use of prescribed medication. Blood samples were collected in serum separator tubes (SST, BD Vacutainer), centrifuged at 4,000 rpm for 10 min, and stored at −80 °C prior to analysis. All procedures were approved by the Research Ethics Board at The Hospital for Sick Children (Toronto, ON, Canada).

Sample analysis

Samples were analyzed on the Alinity c system (Abbott Diagnostics) at The Hospital for Sick Children (Toronto, ON, Canada). The following assays were evaluated: alpha-1-antitrypsin, alpha-1-glycoprotein, ceruloplasmin, cholinesterase, chloride, complement C3, complement C4, glucose (random), haptoglobin, immunoglobulin A (IgA), immunoglobulin E (IgE), immunoglobulin G (IgG), immunoglobulin M (IgM), lactic acid, potassium, and sodium. Sample size varied slightly across parameters due to sample volume, reagent availability, and/or panel description. Analyzer diagnostics, calibration, and quality control for all assays passed specifications prior to sample testing (Supplemental Tables 1 and 2).

Statistical analysis

Statistical analysis was completed using R Statistical Programming and Excel, as previously described [16], [17], [18]. Reference value distributions were plotted by age, and separated by sex when previous ARCHITECT data reported statistically significant sex-specific differences [3, 6, 20]. Reference values were superimposed with previously published data on ARCHITECT assays to evaluate concordance. Extreme outliers were assessed visually and removed manually. The percentage of test results falling within previously established CALIPER reference and confidence limits on ARCHITECT assays were calculated [3, 6, 20]. The percentage within the reference limits was calculated as the number of samples falling within the previously established ARCHITECT lower and upper limits divided by the total sample size per partition. The percentage within the confidence limits was calculated as the number of samples falling within the lower and upper bounds of the previously established ARCHITECT 90 % confidence intervals. An example is provided in Supplemental Table 3. If ≥90 % of samples fell within the confidence limits, the reference intervals were considered verified.

For assays where CALIPER reference intervals were not available, approximately 150 samples were assayed and reference intervals were established per CLSI EP-28A3c guidelines [21]. Briefly, data were plotted by age- and color-coded by sex. Age- and sex-specific partitions were assessed using the method of Harris and Boyd [22]. Outliers were then removed using the Tukey or adjusted Tukey method twice for Gaussian and non-Gaussian distributions [1]. Reference intervals were then established using the robust method of Horn and Pesce [23] or the nonparametric method, depending on sample size, as previously described [1].

Results

Of the 11 chemistry assays for which pediatric reference intervals were previously derived on the Abbott ARCHITECT system by CALIPER, 10 met the verification criteria (Table 1). De novo reference interval establishment was completed for six biochemical parameters (Table 2). Reference value distributions for all assays are provided in Figures 1–3.

Table 1:

Pediatric reference interval verification for Alinity chemistry assays in the CALIPER cohort.

Assay	Units	n	Percent verification within CALIPER ARCHITECT reference limits	Percent verification within CALIPER ARCHITECT confidence limits	Reference
Alpha-1-antitrypsin	g/L	143	80 %	81 %	[6]
Alpha-1-glycoprotein	g/L	99	86 %	91 %	[6]
Ceruloplasmin	mg/L	94	95 %	96 %	[6]
Cholinesterase	U/L	85	89 %	91 %	[6]
Complement C3	g/L	123	89 %	91 %	[3]
Complement C4	g/L	104	91 %	94 %	[3]
Haptoglobin	g/L	104	94 %	95 %	[3]
IgA	g/L	121	90 %	93 %	[3]
IgE	IU/mL	118	99 %	100 %	[6]
IgG	g/L	100	98 %	99 %	[3]
IgM	g/L	116	84 %	91 %	[3]

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Green/bold, met verification criterion; reference, publication wherein initial ARCHITECT reference interval was derived.

Table 2:

Pediatric reference intervals for new Alinity chemistry assays in the CALIPER cohort.

Assay	Units	Partition	Lower limit	Upper limit	n	Lower limit 90 % CI	Upper limit 90 % CI
Glucose (random)	mmol/L	0 to <19 years	3.5	5.9	146	(3.5, 3.8)	(5.6, 6.2)
Lactate	mmol/L	0 to <19 years	1.1	3.6	156	(1.0, 1.2)	(3.2, 4.1)
Chloride	mmol/L	0 to <19 years	100	111	160	(98, 101)	(110, 112)
Potassium	mmol/L	0 to <19 years	3.7	5.3	168	(3.7, 3.9)	(5.2, 5.4)
Sodium	mmol/L	0 to <19 years	136	145	142	(136, 136)	(145, 148)
Alpha-1-antitrypsin	g/L	0 to <19 years	0.8	1.6	139	(0.8, 1.0)	(1.5, 1.7)

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CI, confidence limit.

Figure 1: — Reference value concentrations plotted by age on the Abbott Alinity assays and overlaid with previously published data (depicted in light grey) from the Abbott ARCHITECT assays in the CALIPER cohort [3, 6]. Assays with known significant sex-specific differences are graphed separately. (A) Alpha-1 antitrypsin, (B) alpha-1 glycoprotein, (C) ceruloplasmin (female), (D) ceruloplasmin (male), (E) cholinesterase (female), (F) cholinesterase (male), (G) immunoglobulin M (female), (H) immunoglobulin M (male). Alinity-specific values are graphed in green (both), pink (female), and blue (male).

Figure 2: — Reference value concentrations plotted by age on the Abbott Alinity assays (depicted in green) and overlaid with previously published data (depicted in light grey) from the Abbott ARCHITECT assays in the CALIPER cohort [3, 6]. (A) Complement C3, (B) complement C4, (C) immunoglobulin A, (D) immunoglobulin G, (E) immunoglobulin E, (F) haptoglobin.

Figure 3: — Reference value concentrations plotted by age and sex on the Abbott Alinity assays in the CALIPER cohort (blue: male, pink: female). (A) Sodium, (B) chloride, (C) potassium, (D) lactate, (E) glucose.

Alpha-1-antitrypsin did not meet verification criteria with 81 % of reference values falling within previously established CALIPER ARCHITECT confidence limits (Figure 1A). Concentrations were lower relative to ARCHITECT values, warranting de novo reference interval establishment (Table 2). No age and/or sex-specific differences were observed in alpha-1-antitrypsin concentrations across the pediatric age continuum. A single reference interval of 0.8–1.6 g/L was thus established (Table 2). Alpha-1-glycoprotein, cholinesterase, and ceruloplasmin all demonstrated above 90 % verification, observing excellent concordance with ARCHITECT values (Figure 1B–F). Cholinesterase and ceruloplasmin required sex-specific consideration with higher and lower concentrations observed in males relative to females, respectively (Figure 1C–F).

Reference value distributions for complement C3, complement C4, IgA, IgG, IgE, and haptoglobin are provided in Figure 2. All met the verification criterion, demonstrating reproducible age- and sex-specific patterns relative to ARCHITECT data. Specifically, both complement C3 and complement C4 demonstrated consistent concentrations throughout the pediatric age range (Figure 2A and B), while IgA and IgG increased significantly (Figure 2C and D). IgE concentrations were low with 52 % of result values reporting concentrations lower than the assay limit of detection (LoD) (<15.7 IU/mL, n=61/118) (Figure 2E). The reporting interval of 15.7 to 10,000 IU/mL was applied in measuring IgE concentrations per manufacturer recommendations. Haptoglobin concentrations were variable from birth to adolescence, decreasing initially in early childhood followed by subsequent increases in adolescence (Figure 2F). 95 % of reference values fell within CALIPER ARCHITECT confidence limits (Table 1). Only four results were equal to or below the assay LoD of 0.08 g/L (4 %, n=4/104). IgM was the only immune protein that required sex-specific consideration with 91 % of reference values falling within CALIPER ARCHITECT confidence limits (Figure 1G and H). No reference values for IgA, IgM, or IgG demonstrated values equal to or below the assay LoD.

No pediatric reference value data were available in the CALIPER cohort for sodium, chloride, potassium, lactate, and glucose on ARCHITECT assays thus de novo reference interval establishment was pursued by analyzing 139–168 healthy children serum samples (Table 2). Concentrations were tightly regulated across the pediatric age range and no age- and/or sex-specific differences were observed (Figure 3).

Discussion

The current study verified previously established reference intervals in the CALIPER cohort on 12 specialized chemistry ARCHITECT assays on the Alinity c system. Findings support excellent concordance between assays, with one exception (i.e., alpha-1-antitrypsin). De novo reference intervals were also established for three electrolytes, glucose, and lactate. Key findings are discussed below.

Serum immunoglobulin and complement measurement in children have diverse applications in the identification of primary and secondary innate and adaptive immune disorders, including autoimmune disease, as well as in the follow-up of immunosuppressive therapies. Circulating concentrations of serum proteins from birth to adolescence are known to be impacted by physiological adaptations occurring concomitantly with growth and development [24], [25], [26]. Our data support previously established reference value distributions for immunoglobulins and complement proteins in healthy children and adolescents in the CALIPER cohort and other populations [3, 6, 24], [25], [26]. Specifically, IgG and IgA concentrations increased significantly throughout childhood. This may be due to repeated and increased exposure to various pathogens and antigens throughout childhood, which has been reported to stimulate B-cell production of immunoglobulins and promote class-switch recombination from IgM to IgA and IgG production [24, 27]. IgE was relatively constant throughout the pediatric age continuum with low levels observed (52 % of results were below the assay LoD of 15.7 IU/mL), reflecting its highly regulated role as a mediator of allergic immunological response. Comparative CALIPER Architect IgE data was published by Kelly et al. in 2015. At the time of publication, the Architect IgE assay had a LoD of 25 IU/mL and 61 % of CALIPER reference values fell below this limit. This comparable but increased percentage can be explained by the change in IgE LoD [6]. It is important to note that for assays wherein the lower limit of the RI is equal to or less than the assay LoD (e.g., IgE, haptoglobin), no lower limit should be reported in clinical test interpretation as flagging of low values as pathological is not appropriate. Alinity complement C3, C4, IgA, IgG, and IgM assays were measured using an immunoturbidimetric method that is referenced against IFCC serum reference protein material (ERM-DA470). IgE was also measured using an immunoturbidimetric method but calibrated against the 3rd International Standard for serum IgE (World Health Organization). Measurement traceability further highlight concordance between assay systems.

Additional specialized chemistry markers assessed included alpha-1-antitrypsin, alpha-1-glycoprotein, cholinesterase, and ceruloplasmin. Alpha-1-antitrypsin demonstrated the lowest verification performance at 81 %. Result values were lower for the Alinity assay relative to ARCHITECT, but overlapped well visually. Alpha-1-antitrypsin is a hepatic protease inhibitor that circulates in the plasma and diffuses into the lungs [28, 29]. It is primarily measured to detect alpha-1-antitrypsin deficiency, which occurs at relatively high prevalence due to genetic variation of more than 100 different alleles that can be classified as normal, deficient, null, or dysfunctional [30]. In pediatrics, clinical indications are primarily patients with family history of deficiency or evidence of significant liver disease as opposed to pulmonary obstructive defects which commonly trigger testing in adults [31]. Few studies have reported alpha-1-antitrypsin values in children. A report by Donato et al. established reference intervals for normal adult and pediatric populations with the MM phenotype of 1.0–2.73 g/L and 0.93–2.51 g/L on a Siemens Nephelometer II (Siemens Healthcare Diagnostics, Tarrytown, NJ) [32]. This suggests slightly lower concentrations observed in children relative to adults; however, quantitative values were higher relative to our estimate of 0.8–1.6 g/L. This is not surprising considering the lack of standardization for this assay. The expected range provided by the manufacturer is 0.9–2.0 g/L; however, this is based on recommendations from 1996 [33]. A common cut-off applied to assess deficiency is 1.0 g/L. The past CALIPER ARCHITECT reference interval derived from 675 children from birth to adolescence was 1.1–1.8 g/L [6]. It is unclear whether small changes in reference limits are clinically significant. Changes in calibration as well as use of different sample sets may explain observed differences, especially considering method comparison performance (Supplemental Material). Alpha-1-glycoprotein, cholinesterase, and ceruloplasmin demonstrated excellent verification. Verified reference intervals will therefore be useful in the diagnosis, monitoring, and prognostication of inherited metabolic disorders, liver dysfunction, and/or inflammatory conditions for pediatric clinical laboratories using Alinity c instrumentation [6, 34, 35].

De novo Alinity reference intervals were also established for glucose, lactate, chloride, potassium, and sodium. No age- and/or sex-specific differences were observed in study cohort. Samples were collected non-fasting and therefore derived glucose reference intervals represent a random measurement. The glucose reference interval was 3.5–5.9 mmol/L, which was similar to findings determined on other analytical platforms in the CALIPER cohort, including Siemens Advia (4.05–6.22 mmol/L) [10], Atellica (3.60–5.80 mmol/L) [9], and Dimension (4.22–6.66 mmol/L) [10] in serum as well as Nova StatStrip (3.70–6.20 mmol/L) [36] and Radiometer ABL90 (4.00–6.20 mmol/L) [37] in whole blood. Quantitative variations in established reference intervals may be due to known sampling variation in random glucose measurement as well as analytical differences (e.g., enzymatic vs amperometric). Established reference intervals for electrolytes were similar to the expected ranges observed in adult populations. It is important to note that sample size was not sufficient to assess age-specific differences in the first year of life. Distinct concentration patterns during this period are expected due to changes in water and electrolyte balance [38]. Additional studies should be completed to address this evidence gap.

To conclude, the current study verified pediatric reference intervals previously established for 12 specialized chemistry assays on the ARCHITECT for use on the Alinity and established new reference intervals for three electrolytes, glucose, and lactate. Findings support excellent concordance between ARCHITECT and Alinity Chemistry assays with one exception (i.e., alpha-1-antitrypsin) as well as robustness of age- and sex-specific patterns reported by CALIPER in healthy Canadian children and adolescents. Findings will be useful to laboratories globally transitioning to the Alinity c system; however, local verification is strongly encouraged as per CLSI guidelines. Together with previously published CALIPER pediatric reference intervals on the Alinity c system [16], [17], [18], the majority of the test menu is now covered.

Supplementary Material

Click here for additional data file.^{(25.3KB, docx)}

Supplementary Material

Click here for additional data file.^{(619.9KB, pdf)}

Acknowledgments

We would like to thank CALIPER participants without whom this work would not be possible.

Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/cclm-2023-0256).

Footnotes

Research funding: This work was supported by a Canadian Institutes for Health Research (CIHR) foundation grant to Khosrow Adeli. Mary Kathryn Bohn was supported by a CIHR Doctoral Award. Abbott Diagnostics also supported the study and provided all reagents at no cost.

Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

Competing interests: Authors state no conflict of interest.

Informed consent: Informed consent was obtained from all individuals included in this study.

Ethical approval: The local Institutional Review Board approved all study procedures.

References

1.Adeli K, Higgins V, Trajcevski K, White-Al Habeeb N. The Canadian laboratory initiative on pediatric reference intervals: a CALIPER white paper. Crit Rev Clin Lab Sci. 2017;54:358–413. doi: 10.1080/10408363.2017.1379945. [DOI] [PubMed] [Google Scholar]
2.Karbasy K, Lin DCC, Stoianov A, Chan MK, Bevilacqua V, Chen Y, et al. Pediatric reference value distributions and covariate-stratified reference intervals for 29 endocrine and special chemistry biomarkers on the Beckman Coulter Immunoassay Systems: a CALIPER study of healthy community children. Clin Chem Lab Med. 2015;54:643–57. doi: 10.1515/cclm-2015-0558. [DOI] [PubMed] [Google Scholar]
3.Colantonio DA, Kyriakopoulou L, Chan MK, Daly CH, Brinc D, Venner AA, et al. Closing the gaps in pediatric laboratory reference intervals: a caliper database of 40 biochemical markers in a healthy and multiethnic population of children. Clin Chem. 2012;58:854–68. doi: 10.1373/clinchem.2011.177741. [DOI] [PubMed] [Google Scholar]
4.Konforte D, Shea JL, Kyriakopoulou L, Colantonio D, Cohen AH, Shaw J, et al. Complex biological pattern of fertility hormones in children and adolescents: a study of healthy children from the CALIPER cohort and establishment of pediatric reference intervals. Clin Chem. 2013;59:1215–27. doi: 10.1373/clinchem.2013.204123. [DOI] [PubMed] [Google Scholar]
5.Bailey D, Colantonio D, Kyriakopoulou L, Cohen AH, Chan MK, Armbruster D, et al. Marked biological variance in endocrine and biochemical markers in childhood: establishment of pediatric reference intervals using healthy community children from the CALIPER cohort. Clin Chem. 2013;59:1393–405. doi: 10.1373/clinchem.2013.204222. [DOI] [PubMed] [Google Scholar]
6.Kelly J, Raizman JE, Bevilacqua V, Chan MK, Chen Y, Quinn F, et al. Complex reference value distributions and partitioned reference intervals across the pediatric age range for 14 specialized biochemical markers in the CALIPER cohort of healthy community children and adolescents. Clin Chim Acta. 2015;450:196–202. doi: 10.1016/j.cca.2015.08.020. [DOI] [PubMed] [Google Scholar]
7.Bevilacqua V, Chan MK, Chen Y, Armbruster D, Schodin B, Adeli K. Pediatric population reference value distributions for cancer biomarkers and covariate-stratified reference intervals in the CALIPER cohort. Clin Chem. 2014;60:1532–42. doi: 10.1373/clinchem.2014.229799. [DOI] [PubMed] [Google Scholar]
8.Bohn MK, Horn P, League D, Steele P, Hall A, Adeli K. Pediatric reference intervals for endocrine markers and fertility hormones in healthy children and adolescents on the Siemens Healthineers Atellica immunoassay system. Clin Chem Lab Med. 2021;59:1421–30. doi: 10.1515/cclm-2021-0050. [DOI] [PubMed] [Google Scholar]
9.Bohn MK, Horn P, League D, Steele P, Hall A, Adeli K. Pediatric reference intervals for 32 routine biochemical markers using the siemens healthineers atellica® CH assays in healthy children and adolescents. Clin Biochem. 2021;99:69–77. doi: 10.1016/j.clinbiochem.2021.10.006. [DOI] [PubMed] [Google Scholar]
10.Tahmasebi H, Higgins V, Woroch A, Asgari S, Adeli K. Pediatric reference intervals for clinical chemistry assays on Siemens ADVIA XPT/1800 and Dimension EXL in the CALIPER cohort of healthy children and adolescents. Clin Chim Acta. 2019;490:88–97. doi: 10.1016/j.cca.2018.12.011. [DOI] [PubMed] [Google Scholar]
11.Bohn MK, Higgins V, Asgari S, Leung F, Hoffman B, MacRi J, et al. Paediatric reference intervals for 17 Roche cobas 8000 e602 immunoassays in the CALIPER cohort of healthy children and adolescents. Clin Chem Lab Med. 2019;57:1968–79. doi: 10.1515/cclm-2019-0707. [DOI] [PubMed] [Google Scholar]
12.Kohse KP. KiGGS – the German survey on children’s health as data base for reference intervals and beyond. Clin Biochem. 2014;47:742–3. doi: 10.1016/j.clinbiochem.2014.05.039. [DOI] [PubMed] [Google Scholar]
13.Hoq M, Matthews S, Karlaftis V, Burgess J, Cowley J, Donath S, et al. Reference values for 30 common biochemistry analytes across 5 different analyzers in neonates and children 30 days to 18 years of age. Clin Chem. 2019;65:1317–26. doi: 10.1373/clinchem.2019.306431. [DOI] [PubMed] [Google Scholar]
14.Ni X, Song W, Peng X, Shen Y, Peng Y, Li Q, et al. Pediatric reference intervals in China (PRINCE): design and rationale for a large, multicenter collaborative cross-sectional study. Sci Bull. 2018;63:1626–34. doi: 10.1016/j.scib.2018.11.024. [DOI] [PubMed] [Google Scholar]
15.Zierk J, Baum H, Bertram A, Boeker M, Buchwald A, Cario H, et al. High-resolution pediatric reference intervals for 15 biochemical analytes described using fractional polynomials. Clin Chem Lab Med. 2021;59:1267–78. doi: 10.1515/cclm-2020-1371. [DOI] [PubMed] [Google Scholar]
16.Bohn MK, Wilson S, Hall A, Massamiri Y, Randell E, Adeli K. Pediatric reference interval verification for common biochemical assays on the Abbott Alinity system. Clin Chem Lab Med. 2021;59:1554–62. doi: 10.1515/cclm-2021-0336. [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Bohn MK, Wilson S, Hall A, Adeli K. Pediatric reference interval verification for endocrine and fertility hormone assays on the Abbott Alinity system. Clin Chem Lab Med. 2021;59:1680–7. doi: 10.1515/cclm-2021-0337. [DOI] [PubMed] [Google Scholar]
18.Bohn MK, Wilson S, Schneider R, Massamiri Y, Randell EW, Adeli K. Pediatric reference interval verification for 17 specialized immunoassays and cancer markers on the Abbott Alinity i system in the CALIPER cohort of healthy children and adolescents. Clin Chem Lab Med. 2022;61:123–32. doi: 10.1515/cclm-2022-0709. [DOI] [PMC free article] [PubMed] [Google Scholar]
19.EP06-A evaluation of the linearity of quantitative measurement procedures: a statistical approach. Approved Guideline; 2003. [Google Scholar]
20.Higgins V, Asgari S, Chan MK, Adeli K. Pediatric reference intervals for calculated LDL cholesterol, non-HDL cholesterol, and remnant cholesterol in the healthy CALIPER cohort. Clin Chim Acta. 2018;486:129–34. doi: 10.1016/j.cca.2018.07.028. [DOI] [PubMed] [Google Scholar]
21.Horowitz GL, Altaie S, Boyd JC. Defining, establishing, and verifying reference intervals in the clinical laboratory; approved guideline. 3rd ed. Wayne, PA, USA: CLSI; 2010. [Google Scholar]
22.Harris EK, Boyd JC. On dividing reference data into subgroups to produce separate reference ranges. Clin Chem. 1990;36:265–70. doi: 10.1093/clinchem/36.2.265. [DOI] [PubMed] [Google Scholar]
23.Horn PS, Pesce AJ. Reference intervals: an update. Clin Chim Acta. 2003;334:5–23. doi: 10.1016/s0009-8981(03)00133-5. [DOI] [PubMed] [Google Scholar]
24.Garcia-Prat M, Vila-Pijoan G, Martos Gutierrez S, Gala Yerga G, García Guantes E, Martínez-Gallo M, et al. Age‐specific pediatric reference ranges for immunoglobulins and complement proteins on the OptiliteTM automated turbidimetric analyzer. J Clin Lab Anal. 2018;32:e22420. doi: 10.1002/jcla.22420. [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Lepage N, Huang SHS, Nieuwenhuys E, Filler G. Pediatric reference intervals for immunoglobulin G and its subclasses with Siemens immunonephelometric assays. Clin Biochem. 2010;43:694–6. doi: 10.1016/j.clinbiochem.2010.02.003. [DOI] [PubMed] [Google Scholar]
26.Khan SR, van der Burgh AC, Peeters RP, van Hagen PM, Dalm VASH, Chaker L. Determinants of serum immunoglobulin levels: a systematic Review and meta-analysis. Front Immunol. 2021;12:664526. doi: 10.3389/fimmu.2021.664526. [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Durandy A, Kracker S. Immunoglobulin class-switch recombination deficiencies. Arthritis Res Ther. 2012;14:218. doi: 10.1186/ar3904. [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency. Lancet. 2005;365:2225–36. doi: 10.1016/s0140-6736(05)66781-5. [DOI] [PubMed] [Google Scholar]
29.Tanash HA, Nystedt-Duzakin M, Montero LC, Sveger T, Piitulainen E. The Swedish alpha1-antitrypsin screening study: health status and lung and liver function at age 34. Ann Am Thorac Soc. 2015;12:807–12. doi: 10.1513/annalsats.201410-452oc. [DOI] [PubMed] [Google Scholar]
30.Strnad P, McElvaney NG, Lomas DA. Alpha1-Antitrypsin deficiency. N Engl J Med. 2020;382:1443–55. doi: 10.1056/NEJMra1910234. [DOI] [PubMed] [Google Scholar]
31.American Thoracic Society/European Respiratory Society Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168:818–900. doi: 10.1164/rccm.168.7.818. [DOI] [PubMed] [Google Scholar]
32.Donato LJ, Jenkins SM, Smith C, Katzmann JA, Snyder MR. Reference and interpretive ranges for α1-antitrypsin quantitation by phenotype in adult and pediatric populations. Am J Clin Pathol. 2012;138:398–405. doi: 10.1309/ajcpmeejk32acyfp. [DOI] [PubMed] [Google Scholar]
33.Dati F, Baudner S, Schumann G, Thomas L, Aguzzi F, Bienvenu J, et al. Consensus of a group of professional societies and diagnostic companies on guidelines for interim reference ranges for 14 proteins in serum based on the standardization against the IFCC/BCR/CAP reference material (CRM 470) Clin Chem Lab Med. 1996;34:517–20. [PubMed] [Google Scholar]
34.Primhak RA, Tanner MS. Alpha-1 antitrypsin deficiency. Arch Dis Child. 2001;85:2–5. doi: 10.1136/adc.85.1.2. [DOI] [PMC free article] [PubMed] [Google Scholar]
35.Kim JA, Kim HJ, Cho JM, Oh SH, Lee BH, Kim GH, et al. Diagnostic value of ceruloplasmin in the diagnosis of pediatric Wilson’s disease. Pediatr Gastroenterol Hepatol Nutr. 2015;18:187–92. doi: 10.5223/pghn.2015.18.3.187. [DOI] [PMC free article] [PubMed] [Google Scholar]
36.Wilson S, Earle H, Bohn MK, Hall A, Adeli K. Pediatric reference intervals for point-of-care random glucose in healthy children and adolescents. J Appl Lab Med. 2022;7:582–8. doi: 10.1093/jalm/jfab155. [DOI] [PubMed] [Google Scholar]
37.Bohn MK, Hall A, Wilson S, Henderson T, Adeli K. Pediatric reference intervals for critical point-of-care whole blood assays in the CALIPER cohort of healthy children and adolescents. Am J Clin Pathol. 2021;156:1030–7. doi: 10.1093/ajcp/aqab064. [DOI] [PubMed] [Google Scholar]
38.Dodd A, El-Farhan N, Moat S. Are commonly used paediatric reference intervals for water and electrolyte balance appropriate for clinical use? Ann Clin Biochem. 2015;52:44–52. doi: 10.1177/0004563214531557. [DOI] [PubMed] [Google Scholar]

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[j_cclm-2023-0256_ref_001] 1.Adeli K, Higgins V, Trajcevski K, White-Al Habeeb N. The Canadian laboratory initiative on pediatric reference intervals: a CALIPER white paper. Crit Rev Clin Lab Sci. 2017;54:358–413. doi: 10.1080/10408363.2017.1379945. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_002] 2.Karbasy K, Lin DCC, Stoianov A, Chan MK, Bevilacqua V, Chen Y, et al. Pediatric reference value distributions and covariate-stratified reference intervals for 29 endocrine and special chemistry biomarkers on the Beckman Coulter Immunoassay Systems: a CALIPER study of healthy community children. Clin Chem Lab Med. 2015;54:643–57. doi: 10.1515/cclm-2015-0558. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_003] 3.Colantonio DA, Kyriakopoulou L, Chan MK, Daly CH, Brinc D, Venner AA, et al. Closing the gaps in pediatric laboratory reference intervals: a caliper database of 40 biochemical markers in a healthy and multiethnic population of children. Clin Chem. 2012;58:854–68. doi: 10.1373/clinchem.2011.177741. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_004] 4.Konforte D, Shea JL, Kyriakopoulou L, Colantonio D, Cohen AH, Shaw J, et al. Complex biological pattern of fertility hormones in children and adolescents: a study of healthy children from the CALIPER cohort and establishment of pediatric reference intervals. Clin Chem. 2013;59:1215–27. doi: 10.1373/clinchem.2013.204123. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_005] 5.Bailey D, Colantonio D, Kyriakopoulou L, Cohen AH, Chan MK, Armbruster D, et al. Marked biological variance in endocrine and biochemical markers in childhood: establishment of pediatric reference intervals using healthy community children from the CALIPER cohort. Clin Chem. 2013;59:1393–405. doi: 10.1373/clinchem.2013.204222. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_006] 6.Kelly J, Raizman JE, Bevilacqua V, Chan MK, Chen Y, Quinn F, et al. Complex reference value distributions and partitioned reference intervals across the pediatric age range for 14 specialized biochemical markers in the CALIPER cohort of healthy community children and adolescents. Clin Chim Acta. 2015;450:196–202. doi: 10.1016/j.cca.2015.08.020. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_007] 7.Bevilacqua V, Chan MK, Chen Y, Armbruster D, Schodin B, Adeli K. Pediatric population reference value distributions for cancer biomarkers and covariate-stratified reference intervals in the CALIPER cohort. Clin Chem. 2014;60:1532–42. doi: 10.1373/clinchem.2014.229799. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_008] 8.Bohn MK, Horn P, League D, Steele P, Hall A, Adeli K. Pediatric reference intervals for endocrine markers and fertility hormones in healthy children and adolescents on the Siemens Healthineers Atellica immunoassay system. Clin Chem Lab Med. 2021;59:1421–30. doi: 10.1515/cclm-2021-0050. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_009] 9.Bohn MK, Horn P, League D, Steele P, Hall A, Adeli K. Pediatric reference intervals for 32 routine biochemical markers using the siemens healthineers atellica® CH assays in healthy children and adolescents. Clin Biochem. 2021;99:69–77. doi: 10.1016/j.clinbiochem.2021.10.006. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_010] 10.Tahmasebi H, Higgins V, Woroch A, Asgari S, Adeli K. Pediatric reference intervals for clinical chemistry assays on Siemens ADVIA XPT/1800 and Dimension EXL in the CALIPER cohort of healthy children and adolescents. Clin Chim Acta. 2019;490:88–97. doi: 10.1016/j.cca.2018.12.011. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_011] 11.Bohn MK, Higgins V, Asgari S, Leung F, Hoffman B, MacRi J, et al. Paediatric reference intervals for 17 Roche cobas 8000 e602 immunoassays in the CALIPER cohort of healthy children and adolescents. Clin Chem Lab Med. 2019;57:1968–79. doi: 10.1515/cclm-2019-0707. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_012] 12.Kohse KP. KiGGS – the German survey on children’s health as data base for reference intervals and beyond. Clin Biochem. 2014;47:742–3. doi: 10.1016/j.clinbiochem.2014.05.039. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_013] 13.Hoq M, Matthews S, Karlaftis V, Burgess J, Cowley J, Donath S, et al. Reference values for 30 common biochemistry analytes across 5 different analyzers in neonates and children 30 days to 18 years of age. Clin Chem. 2019;65:1317–26. doi: 10.1373/clinchem.2019.306431. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_014] 14.Ni X, Song W, Peng X, Shen Y, Peng Y, Li Q, et al. Pediatric reference intervals in China (PRINCE): design and rationale for a large, multicenter collaborative cross-sectional study. Sci Bull. 2018;63:1626–34. doi: 10.1016/j.scib.2018.11.024. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_015] 15.Zierk J, Baum H, Bertram A, Boeker M, Buchwald A, Cario H, et al. High-resolution pediatric reference intervals for 15 biochemical analytes described using fractional polynomials. Clin Chem Lab Med. 2021;59:1267–78. doi: 10.1515/cclm-2020-1371. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_016] 16.Bohn MK, Wilson S, Hall A, Massamiri Y, Randell E, Adeli K. Pediatric reference interval verification for common biochemical assays on the Abbott Alinity system. Clin Chem Lab Med. 2021;59:1554–62. doi: 10.1515/cclm-2021-0336. [DOI] [PMC free article] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_017] 17.Bohn MK, Wilson S, Hall A, Adeli K. Pediatric reference interval verification for endocrine and fertility hormone assays on the Abbott Alinity system. Clin Chem Lab Med. 2021;59:1680–7. doi: 10.1515/cclm-2021-0337. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_018] 18.Bohn MK, Wilson S, Schneider R, Massamiri Y, Randell EW, Adeli K. Pediatric reference interval verification for 17 specialized immunoassays and cancer markers on the Abbott Alinity i system in the CALIPER cohort of healthy children and adolescents. Clin Chem Lab Med. 2022;61:123–32. doi: 10.1515/cclm-2022-0709. [DOI] [PMC free article] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_019] 19.EP06-A evaluation of the linearity of quantitative measurement procedures: a statistical approach. Approved Guideline; 2003. [Google Scholar]

[j_cclm-2023-0256_ref_020] 20.Higgins V, Asgari S, Chan MK, Adeli K. Pediatric reference intervals for calculated LDL cholesterol, non-HDL cholesterol, and remnant cholesterol in the healthy CALIPER cohort. Clin Chim Acta. 2018;486:129–34. doi: 10.1016/j.cca.2018.07.028. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_021] 21.Horowitz GL, Altaie S, Boyd JC. Defining, establishing, and verifying reference intervals in the clinical laboratory; approved guideline. 3rd ed. Wayne, PA, USA: CLSI; 2010. [Google Scholar]

[j_cclm-2023-0256_ref_022] 22.Harris EK, Boyd JC. On dividing reference data into subgroups to produce separate reference ranges. Clin Chem. 1990;36:265–70. doi: 10.1093/clinchem/36.2.265. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_023] 23.Horn PS, Pesce AJ. Reference intervals: an update. Clin Chim Acta. 2003;334:5–23. doi: 10.1016/s0009-8981(03)00133-5. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_024] 24.Garcia-Prat M, Vila-Pijoan G, Martos Gutierrez S, Gala Yerga G, García Guantes E, Martínez-Gallo M, et al. Age‐specific pediatric reference ranges for immunoglobulins and complement proteins on the OptiliteTM automated turbidimetric analyzer. J Clin Lab Anal. 2018;32:e22420. doi: 10.1002/jcla.22420. [DOI] [PMC free article] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_025] 25.Lepage N, Huang SHS, Nieuwenhuys E, Filler G. Pediatric reference intervals for immunoglobulin G and its subclasses with Siemens immunonephelometric assays. Clin Biochem. 2010;43:694–6. doi: 10.1016/j.clinbiochem.2010.02.003. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_026] 26.Khan SR, van der Burgh AC, Peeters RP, van Hagen PM, Dalm VASH, Chaker L. Determinants of serum immunoglobulin levels: a systematic Review and meta-analysis. Front Immunol. 2021;12:664526. doi: 10.3389/fimmu.2021.664526. [DOI] [PMC free article] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_027] 27.Durandy A, Kracker S. Immunoglobulin class-switch recombination deficiencies. Arthritis Res Ther. 2012;14:218. doi: 10.1186/ar3904. [DOI] [PMC free article] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_028] 28.Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency. Lancet. 2005;365:2225–36. doi: 10.1016/s0140-6736(05)66781-5. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_029] 29.Tanash HA, Nystedt-Duzakin M, Montero LC, Sveger T, Piitulainen E. The Swedish alpha1-antitrypsin screening study: health status and lung and liver function at age 34. Ann Am Thorac Soc. 2015;12:807–12. doi: 10.1513/annalsats.201410-452oc. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_030] 30.Strnad P, McElvaney NG, Lomas DA. Alpha1-Antitrypsin deficiency. N Engl J Med. 2020;382:1443–55. doi: 10.1056/NEJMra1910234. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_031] 31.American Thoracic Society/European Respiratory Society Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168:818–900. doi: 10.1164/rccm.168.7.818. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_032] 32.Donato LJ, Jenkins SM, Smith C, Katzmann JA, Snyder MR. Reference and interpretive ranges for α1-antitrypsin quantitation by phenotype in adult and pediatric populations. Am J Clin Pathol. 2012;138:398–405. doi: 10.1309/ajcpmeejk32acyfp. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_033] 33.Dati F, Baudner S, Schumann G, Thomas L, Aguzzi F, Bienvenu J, et al. Consensus of a group of professional societies and diagnostic companies on guidelines for interim reference ranges for 14 proteins in serum based on the standardization against the IFCC/BCR/CAP reference material (CRM 470) Clin Chem Lab Med. 1996;34:517–20. [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_034] 34.Primhak RA, Tanner MS. Alpha-1 antitrypsin deficiency. Arch Dis Child. 2001;85:2–5. doi: 10.1136/adc.85.1.2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_035] 35.Kim JA, Kim HJ, Cho JM, Oh SH, Lee BH, Kim GH, et al. Diagnostic value of ceruloplasmin in the diagnosis of pediatric Wilson’s disease. Pediatr Gastroenterol Hepatol Nutr. 2015;18:187–92. doi: 10.5223/pghn.2015.18.3.187. [DOI] [PMC free article] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_036] 36.Wilson S, Earle H, Bohn MK, Hall A, Adeli K. Pediatric reference intervals for point-of-care random glucose in healthy children and adolescents. J Appl Lab Med. 2022;7:582–8. doi: 10.1093/jalm/jfab155. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_037] 37.Bohn MK, Hall A, Wilson S, Henderson T, Adeli K. Pediatric reference intervals for critical point-of-care whole blood assays in the CALIPER cohort of healthy children and adolescents. Am J Clin Pathol. 2021;156:1030–7. doi: 10.1093/ajcp/aqab064. [DOI] [PubMed] [Google Scholar]

[j_cclm-2023-0256_ref_038] 38.Dodd A, El-Farhan N, Moat S. Are commonly used paediatric reference intervals for water and electrolyte balance appropriate for clinical use? Ann Clin Biochem. 2015;52:44–52. doi: 10.1177/0004563214531557. [DOI] [PubMed] [Google Scholar]

PERMALINK

Pediatric reference interval verification for 16 biochemical markers on the Alinity ci system in the CALIPER cohort of healthy children and adolescents

Mary Kathryn Bohn

Randal Schneider

Benjamin Jung

Khosrow Adeli