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Received: 25 November 2018    Revised: 2 December 2019    Accepted: 13 December 2019
DOI: 10.1111/ijlh.13151
LETTER TO THE EDITOR
Establishment of common reference intervals for hematology
parameters in adults, measured in a multicenter study on the
Sysmex XN-series analyzer
Dear Editors,
Clinical laboratories are responsible for the reference intervals re-
ported on their laboratory reports, as specified by the International
Organization for Standardization standard 15  189. Although re-
quired by the directive on in vitro diagnostic medical devices in the
European Union (98/79/EC), manufacturers’ information about the
reference intervals is often very limited, is frequently based on pre-
vious generation analyzers and/or is not transferable to the patient
population that is served. This emphasizes the need for laboratories
to establish their own local reference intervals. However, produc-
ing reference intervals is expensive and a heavy task for most labo-
ratories. Therefore, the production of common reference intervals
for homogeneous populations shared by all laboratories within one
country or region has attracted a lot of interest. In this study, we
calculated multicentric reference intervals for hematology parame-
ters on the XN hematology analyzer (Sysmex). Although this class of
analyzers has already been launched in 2011, there are few studies
to report reference intervals for the reportable parameters on this
analyzer.1,2 To the best of our knowledge, no specific multicentric
reference intervals for the XN analyzer have been published so far.
The direct, a priori sampling technique was used to select the
reference individuals. Clear exclusion criteria were defined in a ques-
tionnaire. Volunteers (20 to 60  years old) were selected based on
their subjective healthy status, with female individuals being not
pregnant or breastfeeding. Biochemical tests to confirm the healthy
status (CRP, liver enzymes…) were not performed. Volunteers had
not been hospitalized or seriously ill in the previous 3 months and
did not use chronic medication (excluding oral contraceptives and
statins). Fasting prior to blood drawing was not required.
Reference individuals from ten hospital laboratories (H.
Hart Hospital Leuven, AZ Sint-Dimpna Hospital Geel, AZ Klina
Brasschaat, AZ Zeno, AZ Delta Roeselare, AZ Groeninge Kortrijk, AZ
Sint-Lucas Brugge, Imelda Hospital Bonheiden, AZ Alma Eeklo, and
Ghent University Hospital) using a XN hematology analyzer in daily
practice and operating in the narrow geographical area of Flanders,
Belgium (in a radius of maximum 75 km), were enrolled in this study.
Protocol, informed consent form and participant information sheet
were approved by the central and participating hospital ethic com-
mittees (Belgian registration number B670201317912). Written ap-
proval was obtained from all study participants.
Int J Lab Hematol. 2020;00:1–6. wileyonlinelibrary.com/journal/ijlh© 2020 John Wiley & Sons Ltd     1
Over a period of 12  weeks, venipunctures were performed by
skilled laboratory technicians or nurses using standard K2-EDTA col-
lection tubes (Sarstedt, Becton Dickinson, Terumo Europe, Greiner).
Samples were stored in an upright position at room temperature be-
fore analysis and were analyzed within 2 hours.
Complete blood count (CBC) including white blood cell (WBC)
differentiation and reticulocyte count were analyzed on an XN an-
alyzer by trained laboratory technicians. Platelet counts obtained
by the impedance method were used in this study. All XN analyzers
were calibrated and maintained according to the manufacturer's
instructions, but were not adjusted to each another, thereby mim-
icking at most daily practice. IPU software versions 00-13 or 00-15
were used and every laboratory performed multilevel IQC accord-
ing to local practice. As requested by Belgian government rule,
all laboratories participated in the Belgian National EQA program
(Sciensano) for CBC, WBC differentiation and reticulocyte count.
Results of the EQA rounds (n = 2) that were sent during the study
period were reviewed, with no Q-score results exceeding the max-
imum allowable deviation (as defined by Sciensano), with Q = (re-
ported value  −  assigned value)/assigned value and the assigned
value  =  median of all Belgian XN instruments that participated in
the EQA (n = 20 to 26).
All statistical analyses were performed using Medcalc software
version 15.6.1 (Medcalc, Mariakerke). The width of the 90% CI of
the lower/upper limit was evaluated against the recommendation
made in Clinical Laboratory Standards Institute (CLSI) document
EP28-A3C, 2010, that is being less than 0.2 times the width of the
reference interval.3
Three hundred and one reference individuals were included in
the study (female: 202; male: 99; median age: 41  years). After the
Tukey outlier rejection, the Kruskall-Wallis test was performed and
revealed significant differences (P  <  .05) between some laborato-
ries for a subset of parameters. However, exclusion of results from
these laboratories did not lead to statistically different reference in-
tervals (data not shown). Moreover, as age and gender distribution
also differed among the cohorts recruited by the participating lab-
oratories, no laboratories were excluded. Instead, imbalances in age
and sex distributions were adjusted (for age  ±  4  years) by random
deletion of 102 female results. The characteristics of this cohort are
shown in Table S1. Due to quality issues for reticulocyte count in
|
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2       LETTER TO THE EDITOR

one laboratory, data for reticulocytes from that laboratory were ex-
cluded from reference value calculation.
Testing for normality was done with the D’Agostino-Pearson
test for normal distribution. Since normality was not accepted
for all parameters, it was decided to calculate reference intervals
with the nonparametric method, according to the CLSI document
EP28-A3c. 3 95% nonparametric double-sided reference intervals
(2.5%-97.5%) and corresponding 90% confidence intervals (CI)
for the lower and upper limits were calculated for all pooled data
(males and females; n = 199) (Table 1). In addition, reference values
were calculated with gender stratification (Table 2). Calculations
for the reference intervals for men (n = 99) and women (n = 100)
separately were performed with the robust method, which is
recommended by the CLSI document EP28-A3c for sample sizes
smaller than 120. 3 The width of the 90% confidence intervals was
lower in the gender-specific groups than in the pooled population.
The 0.2 width criterium was reached for most parameters and
the threshold of 0.3 times the width of the reference interval was
never exceeded. Statistically significant differences in reference
values were found for 16 out of 24 parameters both for the fe-
male and male cohort versus the total cohort (upper and/or lower
reference value calculated for the gender-specific cohort was not
within the 90% confidence limit of the corresponding reference
value for all pooled data). Decisions whether reference intervals
for men and women could be pooled were based on calculating
z-scores, as described by Harris & Boyd. 3 Based on the calculated
z-scores, gender-specific reference intervals should be reported
for 10 parameters (ie, WBC, RBC, Hb, HCT, MCHC, PLT, NEU abs,
RET abs, NEU%, and MONO%). This is in line with the results of
other recent studies.4,5
According to the CLSI document EP28-A3c, transference check
of the newly calculated reference intervals was performed using
samples of presumably healthy individuals (24 men, 24 women with
exclusion criteria: not pregnant and no medication, except oral con-
traceptives) obtained from an independent hospital not involved
in the multicentric study (AZ Sint-Maarten, Mechelen, Flanders,
Belgium).3 Instead of the Tukey exclusion, the latent abnormal value
exclusion (LAVE) methodology 6 was used to exclude volunteers that

TA B L E 1   Reference intervals for all

Test (n) Units Low 90% CI low High 90% CI high
pooled data (n = 199; both males and
WBC (191) 109/L 4.3 3.67-4.69 9.64 9.03-10.16 females) for 24 hematological parameters
RBC (199) 1012/L 3.93 3.73-4.07 5.62 5.51-5.73 on the XN-1000 automated blood cell
analyzer, established according to CLSI
HGB (199) g/L 123 118-123 168 167-173
guideline EP28-A3
HCT (199) L/L 0.362 0.353-0.372 0.508 0.487-0.520
MCV (197) fL 83.9 83.1-84.5 98.0 96.6-98.4
MCH (197) pg 27.7 27.5-28.0 32.8 32.5-33.2
MCHC (194) g/L 317 313-318 354 350-356
RDW (186) % 11.5 11.3-11.7 13.9 13.7-14.3
9
PLT (194) 10 /L 163 150-174 347 323-357
NEU abs (193) 109/L 1.93 1.17-2.17 5.87 5.56-6.17
9
LYMPH abs 10 /L 1.23 1.07-1.30 3.42 3.23-3.57
(195)
MONO abs 109/L 0.26 0.21-0.31 0.78 0.75-0.82
(192)
EOS abs (190) 109/L 0.03 0.01-0.04 0.37 0.34-0.41
9
BASO abs (190) 10 /L 0.02 0.01-0.02 0.08 0.07-0.08
IG abs (189) 109/L 0.01 0.00-0.01 0.05 0.05-0.06
NEU % (196) % 39.2 37.1-41.8 71.5 69.1-73.0
LYMPH% (197) % 18.9 16.4-21.1 47.1 44.4-51.9
MONO% (187) % 4.8 3.8-5.3 11.5 11.2-11.9
EOS% (190) % 0.4 0.2-0.5 5.9 5.5-6.3
BASO% (195) % 0.2 0.2-0.3 1.4 1.2-1.5
IG% (192) % 0.0 0.0-0.1 0.8 0.7-0.9
RET % (174) % 0.64 0.45-0.73 2.0 1.8-2.2
RET abs (172) 109/L 30.0 21.4-34.4 93.0 87.9-96.7
RET-He (176) pg 28.3 27.8-29.6 36.1 35.5-37.2

Abbreviations: abs, absolute white blood cell differential count; CI low/high, 90% Confidence
Interval of the lower/upper reference limit; Low/High, lower/upper reference limit; n, number of
samples after the Tukey outlier exclusion.
LETTER TO THE EDITOR |
      3

had more than one parameter outside the 90% limits of the gen-
der-specific reference interval, with the outlying results not being
derived from the same measurement (as is the case for calculated
parameters). This resulted in exclusion of three females and three
males. For acceptance of results, no more than 10% of the obtained
values for the different parameters may fall out of the 95% reference
intervals. This criterion was met for all parameters for gender-spe-
cific as well as pooled reference values.
Our calculated reference intervals for the XN analyzer often
differed in a statistically significant way from the reference val-
ues calculated by Park et al1 and Arbiol-Roca et al2 for the XN
analyzer and the reference values proposed by Sysmex7 (Table 3).
However, these differences were not considered clinically signifi-
cant. For reticulocyte count however, we found higher results for
XN compared to XE. Moreover, the reticulocyte reference range
was shown to be lower in females than males, which is consistent
with previously published data 8 and may reflect the difference in
Hb levels between males and females and respective erythroid re-
generation rates.
This study showed some limitations, such as the limited number
of volunteers. However, as the width of the 90% CI of the lower/
upper limit resulted in a tolerable uncertainty in the gender-spe-
cific reference intervals, we believe adding more volunteers would
not have improved our reference intervals in a significant way.
Our calculated reference limits are based on an aged-matched and
gender-matched pooled dataset of all laboratories. This was done
to achieve a maximal number of participants in every subgroup.
We worked with volunteers that were feeling subjectively healthy,
without an objective measure of their health status. This might be a
limitation although Wu et al showed in an extensive study popula-
tion the association between self-rated health and objective health
status, exemplified by the prevalence of diseases, abnormalities in

TA B L E 2   Reference intervals for 24 hematological parameters on the XN-1000 automated blood cell analyzer, calculated separately for
males (n = 99), and females (n = 100), established with the CLSI robust method

Male Female

Test Units n Low 90% CI low High 90% CI high n Low 90% CI low High 90% CI high

WBC 109/L 94 3.64* 3.29-4.01 8.46* 8.04-8.82 96 3.80 3.35-4.19 9.39 8.94-9.84
12
RBC 10 /L 99 4.36* 4.26-4.47 5.78* 5.68-5.87 99 3.81 3.73-3.91 5.13* 5.03-5.22
HGB g/L 97 135* 133-138 170 167-172 99 117* 115-120 151* 149-154
HCT L/L 99 0.399* 0.391-0.407 0.510 0.502-0.518 100 0.354 0.347-0.362 0.461* 0.454-0.468
MCV fL 97 83.7 82.8-84.6 95.8* 94.9-96.6 100 83.3 82.3-84.3 98.5* 97.4-99.6
MCH pg 98 27.8 27.5-28.2 32.6 32.3-32.9 100 27.1* 26.7-27.5 33.1 32.7-33.5
MCHC g/L 97 316 313-319 355 352-358 98 313 310-315 348* 345-350
RDW % 90 11.4 11.3-11.6 13.6* 13.4-13.7 99 11.3 11.2-11.5 14.0 13.8-14.2
PLT 109/L 99 143* 130-157 325 312-338 99 175* 163-186 343 329-356
9
NEU abs 10 /L 94 1.53 1.30-1.77 4.90* 4.62-5.18 95 1.66 1.36-1.97 5.92 5.60-6.23
LYMPH 109/L 97 0.87* 0.73-1.02 3.12* 2.91-3.31 96 0.94* 0.83-1.11 3.25 3.08-3.48
abs
MONO 109/L 97 0.23 0.19-0.27 0.82 0.77-0.87 97 0.25 0.22-0.28 0.74* 0.70-0.77
abs
EOS abs 109/L 93 0.00 0.00-0.00 0.33* 0.30-0.37 95 0.00* 0.00-0.00 0.30* 0.26-0.33
BASO abs 109/L 98 0.00* 0.00-0.00 0.08 0.075-0.088 96 0.01 0.00-0.01 0.07 0.07-0.08
9
IG abs 10 /L 94 0.01 n.a. 0.05 n.a. 97 0.00 n.a. 0.06 n.a.
NEU% % 99 38.3 36.2-40.4 69.0* 66.7-71.2 97 41.6 39.2-44.1 73.7* 71.4-75.8
LYMPH% % 99 19.7 17.8-21.6 47.1 45.2-48.9 97 17.1 15.0-19.2 46.4 44.0-48.7
MONO% % 96 5.2 4.7-5.6 11.7 11.1-12.3 95 4.2 3.7-4.7 10.3* 9.8-10.7
EOS% % 93 0.0* 0.0-0.0 5.1* 4.6-5.7 98 0.0* 0.0-0.0 5.2* 4.5-5.7
BASO% % 96 0.0* 0.0-0.2 1.3 1.2-1.4 97 0.1* 0.0-0.2 1.1* 1.0-1.2
IG% % 94 0.0 n.a. 0.7 n.a. 98 0.0 n.a. 0.7 n.a.
RET% % 83 0.52 0.41-0.62 1.86 1.75-1.97 90 0.45 0.36-0.55 1.78* 1.66-1.90
RET abs 10 9/L 83 23.4 18.3-28.8 95.3* 88.5-101.5 91 16.0* 11.7-21.4 82.0* 75.8-89.0
RET-HE pg 82 30.1* 29.6-30.5 36.1 35.6-36.5 93 28.3 27.8-29.0 36.6 35.9-37.1

Abbreviations: abs, absolute white blood cell differential count; CI low/high, 90% Confidence Interval of the lower/upper reference limit; Low/High,
lower/upper reference limit; n.a., not applicable; n, number of samples after the Tukey outlier exclusion.
*Statistically significant difference with reference interval from all pooled data.
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4       LETTER TO THE EDITOR

TA B L E 3   Overview of calculated reference intervals and comparison with published reference intervals for other Sysmex hematology
analyzers

Arbiol- Sysmex
Pekelharing et Park et al Roca et al cooperation
Parameter Units Low CI Low High CI High al (XE-series) (XN-series) (XN-series) (XN-series)

WBC 109/L 4.3 3.67-4.69 9.64 9.03-10.16 M: 3.91-10.90 3.89-9.23 3.9-9.5 3.37*-8.38*
F: 4.49-12.68
RBC (Male) 1012/L 4.36 4.26-4.47 5.78 5.68-5.87 4.44-5.61 4.24*-5.65* 4.3-5.6* 4.29-5.70
RBC (Female) 1012/L 3.81 3.73-3.91 5.13 5.03-5.22 3.92-5.08 3.66*-4.76* 3.9-5.1 3.72*-5.06
HGB (Male) g/L 135* 133-138 170 167-172 135-169 131.9*-168.7 137.4-164.7* 133-166*
HGB (Female) g/L 117 115-120 151 149-154 119-146 118.5-142.0* 120.0-146.8* 110*-147*
HCT (Male) L/L 0.399* 0.391-0.407 0.510 0.502-0.518 0.400-0.494 0.3906-0.5127 0.40-0.50* 0.413*-0.521*
HCT (Female) L/L 0.354 0.347-0.362 0.461 0.454-0.468 0.366-0.440 0.3426*-0.4345* 0.36-0.45* 0.352-0.467
MCV fL 83.9 83.1-84.5 98.0 96.6-98.4 M: 81.8-95.5 86.50*-101.79* 83.6-97.0 86.7*-102.3*
F: 82.9-98.0
MCH pg 27.7 27.5-28.0 32.8 32.5-33.2 27.0-32.3 27.23*-33.60* 27*-32 27.1*-32.4*
MCHC g/L 317 313-318 354 350-356 M: 324-350 M: 314.5-347.4* 314-349a 297*-331*
F: 318-347 F: 305.9*-337.6*
RDW % 11.5 11.3-11.7 13.9 13.7-14.3 M: 12.0-13.6 11.40-15.29* 11.6-14.3 12.2*-14.8*
F: 12.1-14.3
PLT 109/L 163 150-174 347 323-357 M: 166-308 M: 146.6*-420.8* M: 149*-303* 172-378*
F: 173-390 F: 157.8-389.0* F: 153-368*
NEU abs 109/L 1.93 1.17-2.17 5.87 5.56-6.17 M: 1.8-6.98 1.78-6.04 1.5-5.7 1.49-4.67*
F: 2.1-8.89
LYMPH abs 109/L 1.23 1.07-1.30 3.42 3.23-3.57 1.26-3.35 1.24-3.05* 1.3-3.4 1.05*-2.88*
MONO abs 109/L 0.26 0.21-0.31 0.78 0.75-0.82 M: 0.29-0.95 M: 0.29-0.72* 0.31-0.92* 0.21-0.61*
F: 0.25-0.84 F: 0.24-0.72*
EOS abs 109/L 0.03 0.01-0.04 0.37 0.34-0.41 M: 0.03-0.59 M: 0.04-0.58* 0.03-0.39 0.03-0.28*
F: 0.01-0.40 F: 0.01-0.59*
BASO abs 109/L 0.02 0.01-0.02 0.08 0.07-0.08 0.01-0.07 0.01-0.09* 0.01-0.09* 0.02-0.07
IG abs 109/L 0.01 0.00-0.01 0.05 0.05-0.06 0.00-0.06 0.00-0.04* NR 0.00-0.00*
NEU% % 39.2 37.1-41.8 71.5 69.1-73.0 M: 41.0-70.7 40.8-70.4 37.1-68.4* 39.8-70.5
F: 41.9-74.3
LYM% % 18.9 16.4-21.1 47.1 44.4-51.9 M: 19.1-47.9 20.1-46.8 21-50 23.1*-49.9
F: 18.3-45.7
MON% % 4.8 3.8-5.3 11.5 11.2-11.9 M: 5.2-15.2 M: 4.91-10.38* 5.1-11.2 4.3-10.0*
F: 4.2-11.8 F: 4.83-11.15*
EOS% % 0.4 0.2-0.5 5.9 5.5-6.3 M: 0.6-7.6 M: 0.73*-8.86* 0.4-6.6* 0.6*-5.4*
F: 0.2-5.3 F: 0.24-10.24*
BASO% % 0.2 0.2-0.3 1.4 1.2-1.5 M: 0.1-1.2 0.2-1.5 0.2-1.3 0.3-1.4
F: 0.1-1.0
IG% % 0.0 0.0-0.1 0.8 0.7-0.9   0.00-0.50* NR 0.16*-0.61
RET% % 0.64 0.45-0.73 2.0 1.8-2.2 0.43-1.36 0.99*-2.11a 0.68-1.86 0.82*-2.25*
RET abs 109/L 30.0 21.4-34.4 93.0 87.9-96.7 M: 23.0-70.1 M: 40*-120*a 34-102* 36.3*-105.7*
F: 17.0-63.8 F: 40-110*a
RET-HE pg 28.3 27.8 −29.6 36.1 35.5-37.2 32.1-38.8 M: 31,61*-36,28* NR 30.3*-36.0
F: 28,36-35,68

Abbreviations: Age range, 41-60 y; CI low/high, Confidence interval of the lower/upper reference limit; F, female; Low/ High, lower/ upper reference
limit; M, male; NR, not reported.
a
Corrected value based on personal communication with author.
*Statistically significant difference with reference interval calculated in this manuscript.
LETTER TO THE EDITOR |
      5

4
laboratory test results (including some hematology parameters), and Department of Laboratory Medicine, Imelda Hospital,
9
health-related factors. Bonheiden, Belgium
5
This study focused on the XN hematology analyzer, the successor Department of Laboratory Medicine, Heilig Hart Ziekenhuis
of the XE analyzer series. Schoorl et al conducted a multicenter verifi- Leuven, Leuven, Belgium
6
cation study of the XN analyzer compared to the XE-2100 analyzer and Department of Laboratory Medicine, Algemeen Ziekenhuis
found an acceptable correlation between both analyzers.10 Recently, a Delta, Roeselare, Belgium
7
sigma-metric analysis was carried out using the data from the Schoorl Department of Laboratory Medicine, Algemeen Ziekenhuis Sint-
publication.11 They concluded that the high bias between the XN and Lucas, Brugge, Belgium
8
XE analyzer for some parameters exceeded the total allowable error, Department of Laboratory Medicine, Algemeen Ziekenhuis
leading to negative Sigma-metrics. In our study, this discrepancy be- Klina, Brasschaat, Belgium
9
tween both analyzers was most accentuated for the reference range Department of Laboratory Medicine, Algemeen Ziekenhuis
of the reticulocyte count (Table 3). Laboratories should be aware of Groeninge, Kortrijk, Belgium
10
the differences between both generation analyzers. Department of Laboratory Medicine, Algemeen Ziekenhuis
In conclusion, our study provides reference intervals that could Zeno, Knokke-Heist, Belgium
11
serve as a guide for clinical laboratories that use the Sysmex XN an- Department of Laboratory Medicine, Algemeen Ziekenhuis
alyzers and serve the same population as the one included in our Alma, Eeklo, Belgium
12
study. Department of Laboratory Medicine, Algemeen Ziekenhuis
Sint-Dimpna, Geel, Belgium
13
AC K N OW L E D G E M E N T Department of Diagnostic Sciences, Ghent University, Ghent,
The authors wish to thank Liesbeth Seaux for the analysis of samples Belgium
and the practical help during this study. The authors Matthijs Oyaert,
Veronique Stove, Marleen Vandevenne, Jan Van den Bossche and Correspondence
Lisa Florin provided samples from healthy volunteers from 3 different Veronique Stove, Department of Laboratory Medicine,
hospitals and were responsible for data analysis. The authors Marleen Ghent University Hospital, Corneel Heymanslaan 10, 9000
Vanden Driessche, Rowan Claeys, Ludo Marcelis, Johan Robbrecht, Gent, Belgium.
Nadia Jacobs, An Nijs, Karen Janssen, Annemie Van Ruymbeke and Email: veronique.stove@ugent.be
Guy de Mûelenaere contributed to this study by providing additional
datasets of samples from healthy volunteers from 8 other hospitals. ORCID
Lisa Florin  https://orcid.org/0000-0002-1374-4936
C O N FL I C T O F I N T E R E S T Matthijs Oyaert  https://orcid.org/0000-0002-0240-0679
The authors have no competing interests. Veronique Stove  https://orcid.org/0000-0002-2447-971X

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6       LETTER TO THE EDITOR

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S U P P O R T I N G I N FO R M AT I O N
Additional supporting information may be found online in the
Supporting Information section.