AJCP  / Original Article
CALIPER Hematology Reference Standards (II)
Improving Laboratory Test Interpretation in Children
(Beckman Coulter DxH 520–Physician Office
Hematology System) With Analytical Comparison to
the Beckman Coulter DxH 900
Victoria Higgins, PhD,1,2,*, Houman Tahmasebi, MSc,1,* Mary Kathryn Bohn,1,2 Alexandra Hall, MPH,1
and Khosrow Adeli, PhD1,2
From the 1CALIPER Program, Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada; and 2Department of Laboratory
Medicine & Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada.
Key Words: Hematology; Pediatric; Reference intervals; CALIPER; Beckman Coulter
Am J Clin Pathol September 2020;154:342-352
DOI: 10.1093/AJCP/AQAA057
ABSTRACT
Objectives:  The objective of this study was to establish
comprehensive age- and sex-specific reference intervals
for hematologic parameters in the CALIPER cohort of
healthy children and adolescents.
Methods:  A total of 536 healthy children and adolescents
(birth to 21 years) were recruited with informed consent,
and whole blood samples were analyzed for 27 hematologic
parameters on the Beckman Coulter DxH 520 system.
Age- and sex-specific pediatric reference standards were
established. Reference values obtained on the DxH
520 were also compared with data obtained on a larger
laboratory-based instrument (DxH 900).
Results:  Most hematologic parameters showed significant
age- and/or sex-specific changes during growth and
development. Of the 27 hematologic parameters, all
except four (mean corpuscular hemoglobin concentration,
basophil percentage, low hemoglobin density, immature cell
percentage) required age partitioning, and eight required
sex partitioning.
Conclusions:  This study establishes a robust pediatric
hematology reference database that will assist in more
accurate test result interpretation. Our data clearly
demonstrate significant variation in hematologic
parameter concentrations in children and adolescents,
necessitating the use of pediatric-specific reference
standards.
342 Am J Clin Pathol 2020;154:342-352
DOI: 10.1093/ajcp/aqaa057
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Key Points
• Although hematologic parameters are known to vary by age and sex,
critical gaps continue to exist in accurate reference standards for
pediatric test interpretation, compromising care.
• This study establishes robust pediatric reference intervals for 27
hematologic parameters on a modern physician’s office instrument and
assesses comparability with a laboratory-based platform.
• Established reference intervals will contribute to more accurate
hematologic test interpretation, improving clinical care.
Measurement of hematologic parameters in whole
blood aids in the clinical assessment of a wide array of
medical conditions (eg, anemia, infection, and leukemia).
Therefore, CBC is one of the most commonly ordered lab-
oratory tests. Hematologic test results are clinically inter-
preted using reference intervals (RIs), commonly defined
as the central 95% of test results expected in a healthy
population.1 Hematologic parameters are well known
to vary with age and sex in pediatric and adult popula-
tions,2,3 necessitating the consideration of these impor-
tant covariates in RI establishment. Due to physiologic
changes in childhood and adolescence, RIs developed in
adults cannot be broadly applied to pediatric patients.
Hematologic parameters are no exception as a result of
the transition from fetal to adult erythropoiesis,4 physio-
logic anemia of infancy,5 and the regulatory role of andro-
gens on erythropoiesis during puberty.6 However, several
challenges are encountered when establishing pediatric
RIs, including recruitment difficulties and small blood
© American Society for Clinical Pathology, 2020. All rights reserved.
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volume collection. Robust health-associated benchmarks
specific for pediatrics have thus largely been lacking,
potentially leading to misdiagnosis and patient harm.7
Several national initiatives have contributed to closing this
gap by establishing pediatric RIs based on healthy chil-
dren, including the Canadian Laboratory Initiative on
Pediatric Reference Intervals (CALIPER),8 the German
Health Interview and Examination Survey for Children
and Adolescents study,9 and the Lifestyle of Our Kids
program in Australia.10 In addition to the challenges of
recruiting a large healthy population, analyzing hemato-
logic parameters poses further challenge as samples must
be whole blood and rapidly analyzed following collection.
Few studies have established pediatric RIs for hemato-
logic parameters. Zierk et al11,12 established continuous in-
direct RIs for nine hematologic parameters using German
pediatric (0-18 years) patient laboratory data analyzed on
a Sysmex-XE 2100 (Sysmex). This same group later es-
tablished percentile charts and z scores for the same nine
parameters,13 offering a unique and valuable representa-
tion of test results. Some studies have used healthy pedi-
atric cohorts to develop hematologic RIs. Taylor et  al14
established RIs for 16 hematologic parameters analyzed on
the Coulter STKS and STKR analyzers using over 2,000
healthy Irish children aged 4 to 19  years. More recently,
Aldrimer et al3 developed RIs for 14 hematologic param-
eters using the Siemens Advia 2120 based on over 600
healthy participants aged 6 months to 18 years in Sweden.
Through collaboration with Statistics Canada, Adeli et al2
established RIs for several routine tests, including 15 he-
matologic parameters, on the Beckman Coulter HmX
analyzer using data from the Canadian Health Measures
Survey (CHMS) of healthy Canadians aged 3 to 79 years.
Nevertheless, robust pediatric RIs for a comprehensive
panel of hematologic parameters have yet to be developed
based on a large cohort of healthy Canadian children and
adolescents across the pediatric age.
Together with our accompanying publication,15 we
used the CALIPER cohort to address this important
evidence gap and established pediatric RIs for all hema-
tologic parameters available on both a physician’s office
instrument, the Beckman Coulter DxH 520 analyzer,
used for near patient testing and for low-volume labora-
tories, and the larger Beckman Coulter DxH 900 analyzer
for mid- to high-volume laboratories. The comprehensive
reference value database obtained will improve the clin-
ical interpretation of hematology tests in the pediatric
population by expanding the CALIPER database to in-
clude RIs for 27 parameters on the Beckman Coulter
DxH 520. A  method comparison analysis was also per-
formed between the DxH 520 and 900 to determine ana-
lytical comparability.
© American Society for Clinical Pathology
AJCP  / Original Article
Materials and Methods
Participant Recruitment and Sample Acquisition
This study was approved by the Research Ethics
Board at The Hospital for Sick Children (Toronto,
Canada). Participant recruitment, sample acquisition,
and inclusion/exclusion criteria are described in greater
detail in the accompanying publication.15 Briefly, 536
apparently healthy children and adolescents aged 0 to
less than  21  years (270 males and 266 females) were re-
cruited from blood collection clinics held at elementary
and high schools in the Greater Toronto Area (multi-
ethnic Canadian population), as well as from metaboli-
cally stable outpatient clinics at The Hospital for Sick
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Children. Blood samples were drawn into K2EDTA
plasma tubes, and whole blood was analyzed within 8
hours of collection.
Sample Analysis
Whole blood samples were consecutively analyzed
on the Beckman Coulter DxH 520 and 900 hematology
analyzers for 25 hematologic parameters: RBC count,
hemoglobin, hematocrit, mean corpuscular volume
(MCV), mean corpuscular hemoglobin (MCH), mean
corpuscular hemoglobin concentration (MCHC), RBC
distribution width (RDW), RBC distribution width–
standard deviation (RDW-SD), platelet count, mean
platelet volume (MPV), WBC count, lymphocyte per-
centage and absolute count, monocyte percentage and
absolute count, neutrophil percentage and absolute
count, eosinophil percentage and absolute count, ba-
sophil percentage and absolute count, and research
use only (RUO) parameters (low hemoglobin density
[LHD], microcytic anemia factor [MAF], plateletcrit
[PCT], and platelet distribution width [PDW]). Two ad-
ditional RUO hematologic parameters were analyzed
only on the Beckman Coulter DxH 520: immature cell
percentage and absolute count. Analytical methods were
controlled according to the manufacturer’s instructions
using preventative maintenance, function checks, cali-
bration, and internal quality control.
Reference Interval Establishment
RIs were determined for all 27 parameters on the
Beckman Coulter DxH 520 using Microsoft Excel and
R software (version 3.5.1; R Foundation for Statistical
Computing) in accordance with Clinical and Laboratory
Standards Institute (CLSI) EP28-A3c guidelines and sim-
ilar to previous CALIPER studies.16 The statistical proce-
dure for RI calculations is described in greater detail in the
accompanying publication.15 Briefly, extreme outliers were
Am J Clin Pathol 2020;154:342-352 343
DOI: 10.1093/ajcp/aqaa057
Higgins et al / CALIPER Hematology Reference Standards II
removed based on visual inspection of scatterplots. The
Harris and Boyd17 method was used to determine statis-
tically significant age and sex partitions. Outliers were re-
moved for each partition using the Tukey test18 and adjusted
Tukey test19 twice for normally distributed and skewed data,
respectively. The nonparametric rank and robust20 methods
were then used to calculate the 2.5th and 97.5th percentiles
for partitions with a sample size of more than 120 and fewer
than  120 but 40 or more participants, respectively. For each
reference limit, corresponding 90% confidence intervals
were calculated. For partitions with a sample size of fewer
than 40, maximum and minimum values were used as upper
and lower reference limits, respectively.
Method Comparison Analysis
A total of 536 samples were analyzed on both
the Beckman Coulter DxH 520 and 900 analyzers for
25 parameters, allowing a direct method comparison.
Statistical methods used to compare values obtained
on these two analytical platforms were selected to be
aligned with the CLSI EP09-A3 guidelines for meas-
urement procedure comparison and bias estimation.21
Extreme outliers were removed based on visual inspec-
tion. For each analyte, scatterplots were generated with
values obtained by the DxH 900 on the x-axis and by
the DxH 520 on the y-axis. Pearson’s correlation co-
efficient was calculated, and the line of best fit was
determined by Deming regression, with a slope of 1.0
and a y-intercept of 0 indicating perfectly concordant
methods. Difference plots were used to assess the ab-
solute bias between methods, with the average value
obtained by both analyzers on the x-axis and the differ-
ence (ie, DxH 520 − 900) on the y-axis. A mean differ-
ence of 0 with constant difference variability across the
concentration range indicates good agreement between
the two methods. The relative bias was also determined,
calculated as (DxH 520  − DxH 900)  / ((DxH 520  +
DxH900)/2). Last, residuals were plotted for each an-
alyte, with the predicted values for the DxH 520 on the
x-axis and the optimized residuals of the observed com-
pared with the predicted values on the y-axis. Residual
plots where data are randomly distributed around 0 in-
dicates minimal and constant scatter of points around
the regression line.
Results
Reference Interval Establishment
Age- and sex-specific RIs for 27 hematologic param-
eters on the Beckman Coulter DxH 520 are shown in
344 Am J Clin Pathol 2020;154:342-352
DOI: 10.1093/ajcp/aqaa057
❚Table 1❚. Scatterplots for all parameters are shown in
❚Figure 1❚, ❚Figure 2❚, and ❚Figure 3❚ and the supplemental
material (all supplemental materials can be found at
American Journal of Clinical Pathology online). All except
four parameters required age partitioning, while eight re-
quired sex partitioning. Method comparison analyses for
25 hematologic parameters between DxH 520 and 900 are
shown in the supplemental material and ❚Table 2❚.
RBC count, hemoglobin, and hematocrit required an
age partition for 0 to less than 1 year due to a slight de-
crease in variation at 1 year. All three parameters showed
a gradual rise with age, with levels in adolescent males
peaking higher than in females (Figures  1A-1C). The
RBC indices, MCV and MCH, were elevated during the
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first year of life and showed a gradual rise with age, al-
though neither exhibited sex differences (Figures 1D and
1E). In contrast, MCHC did not change with age or sex
and thus required only one RI (Figure 1F).
RDW (Figure  2A) gradually decreased, while
RDW-SD (Figure  2B) remained relatively stable with
age, and neither differed between sexes. Neither platelet
count nor MPV required sex partitioning (Figures 2C and
2D). Platelet count levels were elevated during the first
year of life. This was followed by a continuous decline,
necessitating another age partition at 12  years. On the
other hand, MPV levels increased with age, requiring two
age partitions.
WBC count decreased across the pediatric age range,
requiring three age partitions but no sex partitions
(Figure  3A). A  five-part differential was also obtained
for lymphocytes, monocytes, neutrophils, basophils, and
eosinophils. Lymphocyte percentage (Figure 3B) and ab-
solute count decreased with age, both requiring four age
partitions but no sex partitions. Monocyte percentage
slightly increased with age in males, requiring two age and
sex partitions (Figure 3C). In contrast, monocyte absolute
count decreased with age, requiring three age partitions
but no sex partitions. Neutrophil percentage (Figure 3D)
and absolute count both increased with age. Only neu-
trophil percentage exhibited a significant sex difference in
adolescents, with higher levels in males. Neither eosino-
phil percentage (Figure 3E) nor absolute count required
sex partitioning. Both parameters exhibited a relatively
high degree of variability across the pediatric age range
with no obvious trends. However, basophil percentage
(Figure 3F) and absolute count remained relatively stable
with age.
Last, pediatric RIs were also established for six RUO
parameters. LHD and immature cell percentage did not
change with age or sex and required only one RI. MAF
continuously increased with age, requiring five age par-
titions. MAF levels were higher in males than in females,
© American Society for Clinical Pathology
 ❚Table 1❚ 
Age- and Sex-Specific Reference Intervals for 27 Hematologic Parameters Analyzed on the Beckman DxH 520a
Male Reference Intervals Female Reference Intervals
Lower 90% Upper 90% Lower 90% Upper 90%
Lower Upper Confidence Confidence Lower Upper Confidence Confidence
Biomarker Units Age, y Limit Limit No. Interval Interval Age, y Limit Limit No. Interval Interval
RBC parameters
  RBC count 1012/L 0-<1 3.05 5.22 46 (2.78-3.26) (5.03-5.40) 0-<1 3.05 5.22 46 (2.78-3.26) (5.03-5.40)
1-≤14 4.22 5.21 151 (4.06-4.31) (5.12-5.32) 1-≤14 4.01 5.13 150 (3.90-4.10) (5.01-5.24)
14-≤21 4.36 5.74 85 (4.11-4.52) (5.67-5.81) 14-≤21 3.98 5.28 98 (3.87-4.07) (5.20-5.36)

© American Society for Clinical Pathology

 Hemoglobin g/L 0-<1 94.1 134.9 45 (89.7-97.9) (131.4-138.9) 0-<1 94.1 134.9 45 (89.7-97.9) (131.4-138.9)
1-<4 102.2 138.0 61 (96.8-107.0) (135.2-140.6) 1-<4 102.2 138.0 61 (96.8-107.0) (135.2-140.6)
4-<14 116.1 145.7 242 (111.0-117.9) (143.8-148.9) 4-<14 116.1 145.7 242 (111.0-117.9) (143.8-148.9)
14-≤21 133.1 168.6 87 (129.4-136.0) (166.2-170.8) 14-≤21 116.2 153.4 97 (112.6-119.3) (151.2-155.8)
 Hematocrit L/L 0-<1 0.288 0.410 44 (0.275-0.299) (0.396-0.421) 0-<1 0.288 0.410 44 (0.275-0.299) (0.396-0.421)
1-<4 0.313 0.417 61 (0.300-0.323) (0.407-0.425) 1-<4 0.313 0.417 61 (0.300-0.323) (0.407-0.425)
4-<14 0.349 0.437 242 (0.340-0.355) (0.430-0.446) 4-<14 0.349 0.437 242 (0.340-0.355) (0.430-0.446)
14-≤21 0.401 0.506 87 (0.391-0.410) (0.499-0.513) 14-≤21 0.362 0.459 96 (0.354-0.370) (0.453-0.465)
  Mean corpuscular volume fL 0-<1 72.8 98.9 46 (70.9-74.5) (96.0-102.5) 0-<1 72.8 98.9 46 (70.9-74.5) (96.0-102.5)
1-<4 75.5 85.3 55 (74.3-76.7) (84.6-86.1) 1-<4 75.5 85.3 55 (74.3-76.7) (84.6-86.1)
4-<14 77.9 90.5 237 (75.5-78.5) (90.0-92.7) 4-<14 77.9 90.5 237 (75.5-78.5) (90.0-92.7)
14-<21 79.8 97.3 185 (76.1-80.6) (95.7-98.8) 14-<21 79.8 97.3 185 (76.1-80.6) (95.7-98.8)
  Mean corpuscular hemoglobin pg 0-<1 23.5 32.7 46 (22.7-24.4) (31.8-33.5) 0-<1 23.5 32.7 46 (22.7-24.4) (31.8-33.5)
1-<3 23.3 28.7 43 (21.9-24.2) (28.3-29.2) 1-<3 23.3 28.7 43 (21.9-24.2) (28.3-29.2)
3-<6 25.6 29.5 73 (25.3-25.9) (29.1-29.9) 3-<6 25.6 29.5 73 (25.3-25.9) (29.1-29.9)
6-<13 25.4 30.6 161 (24.5-25.8) (30.2-31.3) 6-<13 25.4 30.6 161 (24.5-25.8) (30.2-31.3)
13-<21 26.0 32.2 206 (25.1-26.1) (31.8-32.6) 13-<21 26.0 32.2 206 (25.1-26.1) (31.8-32.6)
  Mean corpuscular hemoglobin g/L 0-<21 321 343 528 (319-322) (342-345) 0-<21 321 343 528 (319-322) (342-345)
 concentration
  RBC distribution width % 0-<2 12.9 17.2 75 (12.7-13.0) (16.8-17.7) 0-<2 12.9 17.2 75 (12.7-13.0) (16.8-17.7)
2-<21 12.6 15.4 459 (12.5-12.7) (15.1-15.6) 2-<21 12.6 15.4 459 (12.5-12.7) (15.1-15.6)
  RBC distribution width–standard fL 0-<1 36.0 54.9 44 (35.2-37.1) (52.1-58.0) 0-<1 36.0 54.9 44 (35.2-37.1) (52.1-58.0)
 deviation 1-<13 37.1 44.9 276 (36.5-37.6) (44.2-45.5) 1-<13 37.1 44.9 276 (36.5-37.6) (44.2-45.5)
13-<21 38.9 47.7 205 (38.6-39.2) (47.1-50.9) 13-<21 38.9 47.7 205 (38.6-39.2) (47.1-50.9)
Platelet parameters
  Platelet count 109/L 0-<1 276.2 646.7 46 (249.2-303.5) (599.6-696.1) 0-<1 276.2 646.7 46 (249.2-303.5) (599.6-696.1)
1-<12 206.4 434.3 251 (203.4-217.8) (410.9-462.6) 1-<12 206.4 434.3 251 (203.4-217.8) (410.9-462.6)
12-<21 172.1 371.4 233 (159.8-180.2) (349.1-397.1) 12-<21 172.1 371.4 233 (159.8-180.2) (349.1-397.1)
  Mean platelet volume fL 0-<7 7.16 10.08 187 (6.98-7.24) (9.76-11.26) 0-<7 7.16 10.08 187 (6.98-7.24) (9.76-11.26)
7-<21 7.39 10.59 349 (7.14-7.61) (10.47-11.00) 7-<21 7.39 10.59 349 (7.14-7.61) (10.47-11.00)
WBC parameters
  WBC count 109/L 0-<3 5.43 13.47 91 (4.80-5.95) (12.94-14.06) 0-<3 5.43 13.47 91 (4.80-5.95) (12.94-14.06)
3-<5 4.83 12.07 53 (4.46-5.18) (11.09-13.17) 3-<5 4.83 12.07 53 (4.46-5.18) (11.09-13.17)
5-<21 4.17 10.17 390 (3.98-4.24) (9.61-10.80) 5-<21 4.17 10.17 390 (3.98-4.24) (9.61-10.80)
  Lymphocyte percentage % 0-<2 34.35 84.03 75 (27.75-38.65) (80.06-86.97) 0-<2 34.35 84.03 75 (27.75-38.65) (80.06-86.97)
2-<4 25.54 72.53 33 NA NA 2-<4 25.54 72.53 33 NA NA

DOI: 10.1093/ajcp/aqaa057
4-<12 23.72 58.97 189 (19.33-26.79) (55.62-60.65) 4-<12 23.72 58.97 189 (19.33-26.79) (55.62-60.65)
12-<21 18.33 48.92 229 (17.16-21.75) (45.44-52.66) 12-<21 18.33 48.92 229 (17.16-21.75) (45.44-52.66)

Am J Clin Pathol 2020;154:342-352 345

AJCP  / Original Article

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 ❚Table 1❚  (cont)
Male Reference Intervals Female Reference Intervals
Lower 90% Upper 90% Lower 90% Upper 90%
Lower Upper Confidence Confidence Lower Upper Confidence Confidence
Biomarker Units Age, y Limit Limit No. Interval Interval Age, y Limit Limit No. Interval Interval
9
  Lymphocyte absolute count 10 /L 0-<1 3.43 8.96 46 (3.03-3.79) (8.33-9.59) 0-<1 3.43 8.96 46 (3.03-3.79) (8.33-9.59)

DOI: 10.1093/ajcp/aqaa057
1-<5 1.86 7.32 95 (1.65-2.08) (6.81-7.84) 1-<5 1.86 7.32 95 (1.65-2.08) (6.81-7.84)
5-<15 1.36 3.81 235 (1.17-1.54) (3.53-4.14) 5-<15 1.36 3.81 235 (1.17-1.54) (3.53-4.14)
15-<21 1.14 3.25 149 (1.06-1.26) (3.05-3.57) 15-<21 1.14 3.25 149 (1.06-1.26) (3.05-3.57)
  Monocyte percentage % 0-<15 3.52 10.62 377 (3.45-3.84) (10.19-11.16) 0-<15 3.52 10.62 377 (3.45-3.84) (10.19-11.16)

346 Am J Clin Pathol 2020;154:342-352

15-≤21 4.21 11.89 72 (3.92-4.54) (10.89-12.92) 15-≤21 3.54 10.56 77 (3.26-3.79) (9.72-11.40)
  Monocyte absolute count 109/L 0-<1 0.31 1.39 46 (0.25-0.37) (1.24-1.54) 0-<1 0.31 1.39 46 (0.25-0.37) (1.24-1.54)
1-<5 0.31 1.02 95 (0.28-0.33) (0.97-1.09) 1-<5 0.31 1.02 95 (0.28-0.33) (0.97-1.09)
5-<21 0.20 0.75 382 (0.19-0.23) (0.72-0.81) 5-<21 0.20 0.75 382 (0.19-0.23) (0.72-0.81)
  Neutrophil percentage % 0-<1 9.24 49.31 46 (7.65-10.99) (43.83-55.26) 0-<1 9.24 49.31 46 (7.65-10.99) (43.83-55.26)
1-<5 18.33 68.83 98 (16.12-20.73) (64.84-73.01) 1-<5 18.33 68.83 98 (16.12-20.73) (64.84-73.01)
5-<15 29.63 69.89 239 (28.67-33.69) (67.87-73.61) 5-<15 29.63 69.89 239 (28.67-33.69) (67.87-73.61)
15-≤21 43.00 76.75 71 (41.75-44.27) (72.83-80.76) 15-≤21 43.89 73.84 78 (41.27-46.53) (71.83-76.26)
  Neutrophil absolute count 109/L 0-<1 0.87 5.33 45 (0.73-1.04) (4.70-5.97) 0-<1 0.87 5.33 45 (0.73-1.04) (4.70-5.97)
1-<12 1.47 6.28 252 (1.41-1.62) (6.02-6.77) 1-<12 1.47 6.28 252 (1.41-1.62) (6.02-6.77)
Higgins et al / CALIPER Hematology Reference Standards II

12-<21 1.79 6.86 232 (1.42-2.11) (6.27-7.43) 12-<21 1.79 6.86 232 (1.42-2.11) (6.27-7.43)
  Eosinophil percentage % 0-<1 0.95 8.92 45 (0.69-1.28) (7.58-10.34) 0-<1 0.95 8.92 45 (0.69-1.28) (7.58-10.34)
1-<5 0.44 8.58 98 (0.33-0.56) (7.30-9.98) 1-<5 0.44 8.58 98 (0.33-0.56) (7.30-9.98)
5-<21 0.65 9.08 386 (0.56-0.69) (8.16-11.65) 5-<21 0.65 9.08 386 (0.56-0.69) (8.16-11.65)
  Eosinophil absolute count 109/L 0-<1 0.04 0.83 46 (0.01-0.07) (0.73-0.94) 0-<1 0.04 0.83 46 (0.01-0.07) (0.73-0.94)
1-<13 0.05 0.74 275 (0.04-0.05) (0.58-0.89) 1-<13 0.05 0.74 275 (0.04-0.05) (0.58-0.89)
13-<21 0.04 0.53 204 (0.03-0.05) (0.42-0.58) 13-<21 0.04 0.53 204 (0.03-0.05) (0.42-0.58)
  Basophil percentage % 0-<21 0.07 0.51 533 (0.06-0.08) (0.46-0.54) 0-<21 0.07 0.51 533 (0.06-0.08) (0.46-0.54)
  Basophil absolute count 109/L 0-<5 0.01 0.05 141 (0.00-0.01) (0.04-0.05) 0-<5 0.01 0.05 141 (0.00-0.01) (0.04-0.05)
5-<21 0.01 0.04 372 (0.01-0.01) (0.03-0.04) 5-<21 0.01 0.04 372 (0.01-0.01) (0.03-0.04)
Research use only parameters
  Low hemoglobin densityb % 0-<21 2.0 15.1 528 (1.7-2.2) (14.0-17.7) 0-<21 2.0 15.1 528 (1.7-2.2) (14.0-17.7)
  Microcytic anemia factorb NA 0-<2 7.7 11.4 74 (7.3-8.0) (11.1-11.7) 0-<2 7.7 11.4 74 (7.3-8.0) (11.1-11.7)
2-<5 8.9 11.7 65 (8.6-9.1) (11.4-11.9) 2-<5 8.9 11.7 65 (8.6-9.1) (11.4-11.9)
5-<12 9.3 12.9 156 (9.1-9.6) (12.6-13.5) 5-<12 9.3 12.9 156 (9.1-9.6) (12.6-13.5)
12-<15 9.8 13.5 83 (9.4-10.1) (13.3-13.8) 12-<15 9.8 13.5 83 (9.4-10.1) (13.3-13.8)
15-≤21 11.7 15.7 72 (11.4-12.0) (15.4-16.0) 15-≤21 10.2 14.2 75 (9.9-10.5) (13.9-14.5)
 Plateletcritb % 0-<2 0.190 0.471 74 (0.162-0.212) (0.449-0.493) 0-<2 0.190 0.471 74 (0.162-0.212) (0.449-0.493)
2-<15 0.177 0.335 307 (0.167-0.185) (0.329-0.354) 2-<15 0.177 0.335 307 (0.167-0.185) (0.329-0.354)
15-≤21 0.152 0.287 71 (0.143-0.161) (0.274-0.299) 15-≤21 0.163 0.331 79 (0.154-0.173) (0.315-0.348)
  Platelet distribution widthb NA 0-<2 18.8 22.7 71 (NA-NA) (22.2-23.1) 0-<2 18.8 22.7 71 (NA-NA) (22.2-23.1)
2-<15 16.7 21.6 304 (16.1-16.9) (21.3-21.7) 2-<15 16.7 21.6 304 (16.1-16.9) (21.3-21.7)
15-<21 15.5 21.4 152 (14.7-15.8) (21.0-22.8) 15-<21 15.5 21.4 152 (14.7-15.8) (21.0-22.8)
  Immature cell percentageb % 0-<21 0.35 1.20 529 (0.32-0.37) (1.17-1.29) 0-<21 0.35 1.20 529 (0.32-0.37) (1.17-1.29)
  Immature cell absolute countb 109/L 0-≤5 0.02 0.14 77 (0.02-0.03) (0.13-0.16) 0-≤5 0.02 0.12 64 (0.01-0.02) (0.11-0.13)
5-<21 0.02 0.11 387 (0.02-0.02) (0.10-0.14) 5-<21 0.02 0.11 387 (0.02-0.02) (0.10-0.14)

NA, not applicable; confidence intervals could not be estimated.

a
Italicized reference intervals indicate those with sex-specific differences. For partitions with a sample size of fewer than 40, maximum and minimum values were used as upper and lower reference limits, respectively.

© American Society for Clinical Pathology

b
Denotes research use only parameters.
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 AJCP  / Original Article

A B

C D

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E F

❚Figure 1❚  Age- and sex-specific scatterplots of pediatric reference values for RBC count (A), hemoglobin (B), hematocrit (C),
mean corpuscular volume (D), mean corpuscular hemoglobin (E), and mean corpuscular hemoglobin concentration (F). Males
are shown in blue and females are shown in pink.

requiring a sex partition for 15 to less than 21  years.
Conversely, PCT and PDW decreased with age, both re-
quiring three age partitions. While PDW did not differ
between sexes, PCT was higher in females than in males
aged 15 to less than 21 years. Also, while immature cell
absolute count appeared relatively stable throughout pe-
diatric age, levels were significantly higher in males than
in females aged 0 to less than 5 years (Table 1).
Comparability of Reference Values Obtained on DxH 520
and DxH 900
The majority of parameters correlated well between
the Beckman Coulter DxH 520 and 900, with 17 (68%)
parameters having a Pearson correlation coefficient (r)
of more than 0.90 (Table  2). Exceptions included mon-
ocyte percentage, monocyte absolute count, basophil
percentage, basophil absolute count, and MCHC, which
were negatively biased on the DxH 520, and LHD, PDW,
and RDW, which were positively biased on the DxH 520.
Discussion
Age- and sex-specific RIs were established for 27 he-
matologic parameters in a healthy pediatric cohort on the
Beckman Coulter DxH 520, a currently used physician’s
office instrument. Most parameters varied across the pe-
diatric age range during growth and development and
thus required age partitioning. This study complements
our accompanying study in which we established pediatric
RIs for 47 hematologic parameters on a larger laboratory-
based instrument, the Beckman Coulter DxH 900.15
Taken together, these two reports expand the CALIPER
database to include hematology RIs on two modern

© American Society for Clinical Pathology Am J Clin Pathol 2020;154:342-352 347

DOI: 10.1093/ajcp/aqaa057
Higgins et al / CALIPER Hematology Reference Standards II
A B
C D
❚Figure 2❚  Age- and sex-specific scatterplots of pediatric reference values for RBC distribution width (A), RBC distribution
width–standard deviation (B), platelet count (C), and mean platelet volume (D). Males are shown in blue and females are
shown in pink.
hematology analyzers. We also performed a method com-
parison analysis between DxH 520 and 900, in which the
majority of analytes exhibited high correlation.
RBC count, hemoglobin, and hematocrit increased
with age and were higher in males than in females at
the onset of puberty. These trends closely mirror those
of previous studies.2,3,12,14 Elevated levels in males during
puberty may be the result of elevations in testosterone,
which stimulates erythropoietin production, subse-
quently activating erythropoiesis.6,22 Furthermore, re-
duced metabolic demand, muscle mass, and iron stores
due to menstruation in females compared with males
likely contribute to lower levels in females. RBC indices
(MCV, MCH) also gradually increased with age but did
not differ between sexes, as was observed previously.2,12
Increased RBC indices reflect elevated erythropoiesis and
occur in parallel with rapid metabolic demand during
development. Slightly higher MCV in females has been
previously reported,3,14 although sex differences were not
observed in this study. In addition to increased concentra-
tions during puberty, similar to Zierk et al,12 we observed
elevated levels of RBC indices (MCV, MCH, and RDW)
in early life. Hemoglobin and RBC indices measured by
the DxH 520 and 900 correlated well (Pearson correlation
coefficient [r] ranged between 0.87 and 0.99), except for
MCHC (r = 0.65), and exhibited minimal bias.
348 Am J Clin Pathol 2020;154:342-352
DOI: 10.1093/ajcp/aqaa057
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Platelet levels rapidly declined during the first year
of life and continued to gradually decline throughout
childhood and adolescence. This rapid decline was not
previously observed in some studies,2,3,12,14 although Zierk
et  al12 similarly observed this decline throughout child-
hood and adolescence. Elevated platelet counts in early
childhood may be explained by elevated thrombopoietin,
the hormone that regulates platelet production, after
birth, which gradually declines until adulthood.23 A  sex
difference in platelet levels was previously observed with
higher counts in females compared with males,2,12,14 while
others reported no sex difference,3 in line with our study.
Comparing our RIs established to the latter study3 re-
vealed lower levels in our study. Differences may be due
to slightly different age partitions, analytical instruments
(ie, Beckman Coulter DxH 520 vs Siemens Advia 2120),
or populations (ie, Canadian vs Swedish). Conversely,
MPV increased with age but still exhibited no sex dif-
ference, further supporting observations from previous
studies.2,3,14 Platelet count and MPV exhibited a strong
correlation between the Beckman Coulter DxH 520 and
900 (r = 0.99 and 0.97, respectively).
Similar to Zierk et  al,12 we observed elevated WBC
in early life, subsequently declining through the pe-
diatric age range. Previously using CHMS data with
a cohort that started at 3  years of age, our group also
© American Society for Clinical Pathology
 AJCP  / Original Article

A B

C D

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E F

❚Figure 3❚  Age- and sex-specific scatterplots of pediatric reference values for WBC count (A), lymphocyte percentage (B),
monocyte percentage (C), neutrophil percentage (D), eosinophil percentage (E), and basophil percentage (F). Males are
shown in blue and females are shown in pink.

showed elevated WBC counts in early childhood, which
declined in older children.2 Elevated WBC counts early
in life may reflect immune system development, with de-
clining levels with age reflecting the increased exposure
to pathogens and development of adaptive immune re-
sponses. Most previous studies2,3,14 established RIs only
for absolute counts of the five-part differential, while here
we also examined percentage. Lymphocyte and monocyte
absolute count decreased with age and did not differ be-
tween sexes, similar to previous observations,2,3 although
Taylor et al14 reported higher monocyte counts in females.
In contrast, neutrophil absolute count slightly increased
throughout childhood and adolescence, as was observed
in CHMS.2 Previous studies reported no sex difference3 or
higher levels in females2,14,24 for neutrophils. Conversely,
we found higher neutrophil percentage in males. Last,
similar to CHMS,2 we saw low counts for eosinophils
and basophils. However, different reporting capabilities
for basophils made it more difficult to compare absolute
values and trends. Nevertheless, the observed decline in
eosinophils with age and lack of sex difference were con-
sistent with previous reports.2,3,14 WBC counts as well as
the absolute count and percentage of the five-part differ-
ential correlated well between the DxH 520 and 900 (r
range = 0.82-0.99), apart from basophil percentage and
absolute count (r = 0.120 and 0.246, respectively). In line
with these findings, a previous study comparing differ-
ential blood cell counts on other hematology analyzers
reported the largest discrepancy between instruments for
basophil counts.25

© American Society for Clinical Pathology Am J Clin Pathol 2020;154:342-352 349

DOI: 10.1093/ajcp/aqaa057
 ❚Table 2❚ 
Method Comparison Between Beckman DxH 520 and Beckman DxH 900 for 25 Hematology Parameters

DOI: 10.1093/ajcp/aqaa057
No. of Out- Sample Deming Regression Deming Regression Pearson Correla- Absolute Relative
Analyte Unit liers Removed Size, No. Slope (CI) Intercept (CI) tion Coefficient (r) Mean Biasa Mean Biasb
RBC count 1012/L 2 524 1.08 (1.06 to 1.10) –0.24 (–0.35 to –0.14) 0.978 0.11 0.02

350 Am J Clin Pathol 2020;154:342-352

Hemoglobin g/L 2 524 1.06 (1.04 to 1.07) –4.30 (–6.21 to –2.62) 0.990 3.16 0.02
Hematocrit L/L 2 524 1.09 (1.07 to 1.11) –0.02 (–0.03 to –0.01) 0.979 0.01 0.04
Mean corpuscular volume fL 0 526 1.00 (0.99 to 1.02) 0.62 (–0.36 to 1.55) 0.992 1.00 0.01
Mean corpuscular hemoglobin pg 0 526 0.95 (0.94 to 0.97) 1.27 (0.73 to 1.78) 0.978 –0.03 0.00
Mean corpuscular hemoglobin g/L 0 526 0.91 (0.82 to 1.00) 26.8 (–5.00 to 56.4) 0.650 –4.15 –0.01
concentration
RBC distribution width % 0 526 0.92 (0.87 to 0.96) 1.49 (0.88 to 2.08) 0.874 0.39 0.03
RBC distribution width– fL 0 526 1.08 (1.04 to 1.13) –1.31 (–3.27 to 0.34) 0.922 1.93 0.05
standard deviation
Platelet count 109/L 2 524 0.99 (0.97 to 1.01) –0.72 (–6.07 to 5.07) 0.985 –3.53 –0.01
Higgins et al / CALIPER Hematology Reference Standards II

Mean platelet volume fL 0 526 0.94 (0.92 to 0.97) 0.63 (0.42 to 0.82) 0.968 0.13 0.02
WBC count 109/L 0 526 1.02 (1.01 to 1.04) –0.15 (–0.29 to –0.030) 0.988 0.02 0.00
Lymphocyte percentage % 0 526 1.01 (1.00 to 1.02) –0.59 (–1.07 to –0.11) 0.991 –0.23 –0.01
Lymphocyte absolute count 109/L 0 526 1.00 (0.99 to 1.02) –0.03 (–0.07 to –0.02) 0.992 –0.02 –0.01
Monocyte percentage % 0 526 0.90 (0.85 to 0.95) –0.14 (–0.54 to 0.24) 0.823 –0.89 –0.12
Monocyte absolute count 109/L 0 526 0.92 (0.83 to 1.00) –0.02 (–0.06 to –0.03) 0.871 –0.06 –0.12
Neutrophil percentage % 0 526 1.01 (1.01 to 1.02) 0.62 (0.14 to 1.11) 0.992 1.32 0.03
Neutrophil absolute count 109/L 0 526 1.05 (1.04 to 1.08) –0.07 (–0.14 to –0.02) 0.990 0.11 0.03
Eosinophil percentage % 0 526 1.00 (0.98 to 1.03) 0.24 (0.18 to 0.31) 0.975 0.25 0.16
Eosinophil absolute count 109/L 0 526 0.98 (0.94 to 1.02) 0.02 (0.01 to 0.03) 0.966 0.02 0.30
Basophil percentage % 0 526 0.04 (0.02 to 0.08) 0.21 (0.18 to 0.23) 0.120 –0.45 –0.91
Basophil absolute count 109/L 0 526 0.05 (0.03 to 0.06) 0.02 (0.01 to 0.02) 0.246 –0.02 NAc
Low hemoglobin density % 0 526 1.72 (1.44 to 1.98) –1.33 (–2.36 to –0.24) 0.628 1.92 0.35
Microcytic anemia factor NA 2 524 1.05 (1.04 to 1.06) –0.16 (–0.29 to –0.02) 0.993 0.40 0.04
Plateletcrit % 2 524 1.03 (1.01 to 1.05) –0.01 (–0.01 to 0.00) 0.977 0.00 –0.01
Platelet distribution width NA 0 526 –17.5 (–37.5 to –11.3) 307 (205 to 638)  –0.170 2.89 0.16

CI, confidence interval; NA, not applicable.

a
Absolute bias calculated as Beckman 520 – Beckman 900.
b
Relative bias calculated as (Beckman 520 – Beckman 900) / ((Beckman 520 + Beckman 900) / 2).
c
Relative bias could not be calculated because the denominator ((Beckman 520 + Beckman 900) / 2) was equal to 0.

© American Society for Clinical Pathology

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Pediatric RIs were also established for six RUO
parameters. LHD (100 * √(1 – (1 / 1 + e–1.8(MCHC-30)))) and
MAF ((hemoglobin * MCV) / 100)  have been shown
to be a useful measure of iron status, with elevated
LHD and reduced MAF indicating low iron status.26-30
Ambayya et al24 previously established RIs for LHD and
MAF in a healthy multiethnic adult population. LHD
RIs established in the present study were slightly higher,
which may suggest that LHD is slightly higher in pedi-
atric populations compared with adults. While several
age and sex partitions were required in the present study
for MAF, the RIs for the oldest age group were similar
but slightly higher than those reported in adults. PCT
(MPV * PLT), which represents the volume occupied by
platelets in the blood, has been recognized for its poten-
tial as a biomarker for inflammation in hepatitis A  in-
fection31 and acute coronary syndrome.32 Similar to our
observations, PCT was previously shown to slightly de-
crease with age and exhibit higher levels in females at
the onset of puberty.14 PCT RIs established in a healthy
Indian adult population33 were higher than those estab-
lished in the present study for the oldest age group. PDW
represents the size distribution spread of platelets and
has been reported to be a useful inflammatory marker,
given morphologic changes upon platelet activation in
inflammatory environments such as acute pancreatitis,34
fibromyalgia,35 and chronic obstructive pulmonary di-
sease.36 PDW RIs also previously established in a healthy
Indian adult population33 were slightly lower and wider
than those established in the present study. Of the four
RUO parameters compared between the two analyzers,
two (ie, MAF and PCT) correlated well (r = 0.993 and
0.977, respectively), while the remaining two (ie, LHD
and PDW) correlated poorly (r = 0.628 and –0.170,
respectively).
To our knowledge, this is the first study to report RIs
for all hematologic parameters on the Beckman Coulter
DxH 520 in a healthy Canadian pediatric population.
This new data set contributes greatly to the well-estab-
lished CALIPER database,8 which lacked RIs for hema-
tologic parameters. A limitation to our study is that our
cohort comprised pediatric participants from the Greater
Toronto Area and was thus representative of its ethnic
distribution. Hematologic parameters are known to
vary between populations.24,37,38 It is therefore important
to validate RIs established in this study for use in other
populations.
In summary, the present study addresses an impor-
tant evidence gap in robust pediatric RIs for routine he-
matologic parameters as well as RUO parameters used for
research studies on the Beckman hematology analyzer.
© American Society for Clinical Pathology
AJCP  / Original Article
Furthermore, we demonstrate acceptable analytical com-
parability between the Beckman Coulter DxH 520 and
900 through method comparison analysis and similar
RIs. Following appropriate validation analysis by each
laboratory, as outlined by the CLSI,1 these RIs can be im-
plemented into laboratories for routine clinical use and
thus improve laboratory test interpretation and clinical
decision making in children and adolescents.
Corresponding author: Khosrow Adeli, PhD; khosrow.adeli@
sickkids.ca.
*First authors.
This work was supported by a Foundation Grant from the
Canadian Institutes of Health Research (CIHR) (grant
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353989), Beckman Coulter USA, CIHR doctoral award (to
V.H.), and Restracomp Scholarship (Hospital for Sick Children)
(to M.K.B.). The Beckman Coulter DxH 900 analyzers and
reagents used in the study were provided by Beckman Coulter.
Acknowledgments: This study would not have been possible
without the generous participation of children from the commu-
nity. We thank all participants, their families, and the numerous
CALIPER volunteers whose dedication and time commitment
made this study possible.
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