Thyroid Test Reference Intervals Guide
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Alejandro MarquezThyroid Test Reference Intervals Guide
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Alejandro MarquezReference Intervals for Children
and Adults
Elecsys Thyroid Tests
TSH, FT4, FT3, T4, T3, T-Uptake, FT4-index, Anti-TPO, Anti-Tg, Tg
Elecsys systems 1010/2010
MODULAR ANALYTICS E170
cobas e 411 and cobas e 601 analysers
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
Contents Page
1 Introduction 4
2 Summary 4–5
3 Subjects, Materials and Methods 6–11
3.1 Description of the reference population 6
3.1.1 Newborns, infants, children and adolescents 0–20 years, 2004/2007 6
3.1.2 Adults (20–69 years), Leipzig, Germany, 2003/2004 6–7
3.1.3 Pregnant women, Essen and Hamburg, Germany, 2004 7
3.1.4 Reference population mentioned in the package inserts,
1995/96 up to 2001 8
3.1.5 Local reference intervals, groups for fT3, partly also for TSH and fT4 8–9
3.2 Analytical methods 9
3.3 Statistical evaluation, Terminology 9–11
4 Results and Discussion 12–47
4.1 Cross-parameter results and explanations on the following chapters 12
4.2 Thyrotropin, Thyroid stimulating hormone – TSH 13–15
4.3 Free thyroxine – fT4 15–19
4.4 Free triiodothyronine – fT3 20–23
4.5 Total triiodothyronine – T3 24–28
4.6 Total thyroxine – T4 29–33
4.7 Thyroxine-binding capacity – or TBC, T-uptake / Free T4-index – fT4I (T4/TBI) 34–40
4.8 Antibodies to thyroid peroxidase – anti-TPO 40–42
4.9 Antibodies to thyroglobulin – anti-Tg 43–44
4.10 Thyroglobulin – Tg 45–47
5 Conclusion 48
6 References 49
Significant additions or changes are indicated by a change bar in the margin.
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Reference Intervals Elecsys and cobas e analyzers
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1 Introduction
The introduction of a new Elecsys FT3 test in the year 2003 was an opportunity to retest
reference intervals for all of the thyroid tests that Roche offers for the Elecsys 1010/2010/
MODULAR ANALYTICS E170 automated immunoassay analyzer for children and adults
in order to close some of the gaps that have appeared due to product improvements. This
applies especially to the values for children, adolescents, and pregnant women.
In this context, the reference values given in the product package inserts have been
summarized together with the newly determined values and others from laboratories in
different countries. All available information on the composition of the population
groups is given. Explanations for some the differences found can be valued in the light of
this information.
The latest discussions on the diagnosis and treatment of subclinical thyroid disorders 1–10
prompted us to analyze the adult population in particular. In this context we have looked
into the necessity of having different reference ranges for different patient groups.
To update and complete the reference range values for children a new study was per-
formed in 2007.
2 Summary
Reference ranges for all Elecsys thyroid parameters are available for the following groups:
s #HILDREN AND ADOLESCENTS FROM %RLANGEN AND ,EIPZIG 'ERMANY FROM BIRTH TO YEARS
characterized as clinically healthy with respect to thyroid disorders.
s !DULTS FROM ,EIPZIG 'ERMANY TO YEARS
A dependency on age, sex, thyroid volume and density, body mass index, thyroglobulin,
albumin and contraceptives was tested in the adult group and, if noticeable, identified.
This group was evaluated in three steps:
)NCLUSION OF ALL BLOOD DONORS CONSIDERED HEALTHY
%XCLUSION OF PERSONS WITH NOTICEABLE SONOGRAPHIC RESULTS THYROID VOLUME AND
DENSITY AND 43( CONCENTRATIONS OUTSIDE THE REFERENCE LIMITS !$6)! #ENTAUR
"AYER 'ERMANY
)NCLUSION AND EXCLUSION CRITERIA ACCORDING TO THE GUIDELINES OF THE .ATIONAL !CADEMY
OF #LINICAL "IOCHEMISTRY .!#" FOR THE DETERMINATION OF REFERENCE INTERVALS FOR
43( CRITERIA APPLIED TO ALL PARAMETERS EXCEPT ANTI 40/ ANTI 4G AND 4G EVALUATED
ACCORDING TO THE CORRESPONDING SPECIlC CRITERIA OF THE .!#" GUIDELINES
s (EALTHY PREGNANT WOMEN FROM %SSEN AND (AMBURG 'ERMANY ST ND AND RD
TRIMESTER
Additional reference groups used by clinical centers or commercial labs in various
COUNTRIES FOR %LECSYS THYROID PARAMETERS SELECTION CRITERIA WERE 43( F4 PARTLY AUTOANTI-
BODIES ANTI 40/ OR A CLINICAL CHARACTERIZATION ARE AVAILABLE
s .ORWAY FROM -OLDE AND 3ANDEFJORD FOR F4
s !USTRIA FROM 6IENNA FOR 43( F4 AND F4
s 'ERMANY FROM (AMBURG (EIDELBERG FOR 43( F4 AND F4
s 3WEDEN RESULTS FROM A STUDY ON %1!,)3 FOR 43( F4 AND ANTI 40/
!DDITIONAL RESULTS FOR PATIENTS WITH SERIOUS NONTHYROIDAL ILLNESSES .4)S AND DIALYSIS
patients and for hypo- and hyperthyroid patients for fT3 and fT4 are available.
All groups are described in greater detail in chapter 3.1, analytical methods in chapter 3.2,
and the statistical methods used in chapter 3.3. Chapters 4.2–4.10 show the individual
RESULTS OF ALL GROUPS AND THE CORRESPONDING CONlDENCE RANGES AND THE DEPENDENCIES
on potentially influencing factors for all thyroid tests.
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Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
7ITH RESPECT TO CONCENTRATIONS STANDARDIZATION AND ASSAY PERFORMANCE THE CUR-
rently available Elecsys thyroid tests have not been changed since launch. The refer-
ENCE INTERVALS EXPECTED VALUES GIVEN IN THE PACKAGE INSERTS WERE CONlRMED BY THE
current respective reference groups and continue to be valid. This is due to the fact
THAT THE CURRENT REFERENCE RANGE LIMITS ARE COVERED BY THE CONlDENCE INTERVAL OF
THE EXPECTED VALUES AND OR QUANTILE OF THE CORRESPONDING GROUPS
from the well characterized Leipzig data.
Differences to the reference intervals listed in the Elecsys package inserts and those
provided by clinical centers and commercial labs are most likely due to the differing
composition of the reference groups – see chapter 3.1.
An analysis in the adult group using multivariate methods to account for the factors age
and sex as well as age and contraceptives, gave the following results for the below listed
parameters:
s $EPENDENCY OF THE VALUES FROM SEX OVER ALL AGE GROUPS
3IGNIlCANT P F4 F4 4 UPTAKE
.OT SIGNIlCANT 43( 4 4 F4 INDEX
s $EPENDENCY OF THE VALUES FROM CONTRACEPTIVES OVER ALL AGE GROUPS
3IGNIlCANT P 4 4 4 UPTAKE
.OT SIGNIlCANT 43( F4 F4 F4 INDEX
Using alle data the multivariate analysis assesses in how far the combined effect of the
factors age, gender, medication take influence on the assay result. Even if there is no such
connection, the univariate statistics may well exhibit a statistically significant difference
for individual group comparisons.
The following overview shows the effects of influencing factors on the concentration of
the thyroid test parameters in the various groups evaluated by univariate analysis.
Legend: SIGNIlCANTLY ELEVATED VALUES P AND LOWER = significantly depressed
VALUES P AND LOWER NO SIGNIlCANT DIFFERENCE BETWEEN VALUES -EDIAN TEST AND
-EDIAN #HI 3QUARE TEST OR 4UKEYS 3TUDENTIZED 2ANGE (3$ TEST
TSH fT4 fT3 T3 T4 T-upt. fT4I A-TPO A-Tg Tg
Sex m. vs. f.
Age 20 up to 69 years
Males 40–49 vs. 20–39 y.
Females 40–49 vs. 20–39 y.
Contraceptives w vs. w/o
TBG
Albumin
Obesity, BMI
Pregnancy
2nd trim. vs. 1st trim.
3rd trim. vs. 2nd trim.
Reference groups
NACB (GL3/4/5) vs. all
GL2 TSH+Sono NAD vs. all
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
3 Subjects, Materials and Methods
3.1 Description of 4HE INFORMATION ON THE SUBJECTS AND PATIENT GROUPS TESTED FOR THE REFERENCE INTERVALS
reference population information is summarized below. In addition to the populations tested for the latest
groups STUDIES IN %RLANGEN AND ,EIPZIG %SSEN AND (AMBURG THE SUMMARY AGAIN INCLUDES THE
groups mentioned in the package inserts of the respective test parameters.
3.1.1 Newborns, infants, The reference range calculation for the thyroid parameters was made using remaining
children and adoles- SAMPLE MATERIAL SERUM AND PLASMA COLLECTED IN %RLANGEN BETWEEN -AY AND !UGUST
cents 0-20 years AND IN ,EIPZIG BETWEEN *ANUARY AND *UNE 4HIS COMBINED COLLECTIVE IS REFERRED TO AS
Erlangen and Leipzig, Group GEL in the brochure. In the subgroup Erlangen a total of 420 specimen and in the
'ERMANY subgroup Leipzig a total of 1004 specimen of newborns, children and adolescents of both
2003/2004/2007 sexes between the ages of 0 and > 20 was included. Depending on the parameter between
n SPECIMENS IN EACH OF THE '%, SUBGROUPS ARE SHOWN
The exclusion and inclusion criteria for both groups were similarly applied:
s .O PREVIOUS OR ACUTE THYROID DISORDER
s .OT IN INTENSIVE CARE
s .O POST OPERATIVE CARE
s .O FAMILY HISTORY OF THYROID DISORDER %RLANGEN
s .O ENDOCRINE DISORDERS OR SEVERE NON ENDOCRINE DISEASES THAT MAY INmUENCE THE
4HYROID FUNCTION ,EIPZIG
The general presence of autoantibodies was not an exclusion criterion.
-EASUREMENTS WERE TAKEN FOR 43( F4 F4 4 4 4 UPTAKE ANTI 40/ ANTI 4G AND 4G
4HE F4 INDEX WAS DETERMINED FROM THE 4 AND 4 UPTAKE 4") RATIO
3.1.2 Adults Leipzig, To determine the reference ranges of all thyroid parameters, in 2003/2004, at the
'ERMANY u5NIVERSITØTSKLINIKUM ,EIPZIGh 'ERMANY FROM -AY TO !UGUST SERUM SPECIMENS WERE
USED FROM A TOTAL OF BLOOD DONORS BETWEEN THE AGES OF AND YEARS
Information is available for these specimens as to: Age, sex, height, weight, personal and
family history of thyroid disorders, contraceptive use and cigarette use.
Measurement results are available for: Thyroid volume and structure, blood pressure,
heart rate, blood count, lipid metabolism parameters, protein, albumin and all thyroid
parameters including autoantibodies and thyroglobulin.
4HE 43( INCLUSION OR EXCLUSION CRITERIA WERE ENSURED BASED ON THE RESULTS OF A COMMER-
CIALLY AVAILABLE TEST !$6)! #ENTAUR "AYER 'ERMANY
The following groups were formed – assessment for all thyroid test parameters
s Group GL1: Blood donors, all men and women: all tested blood donors – no exclusions
s Group GL2: .ORMAL THYROID ULTRASOUND VOLUME AND STRUCTURE !$6)! #ENTAUR 43(
within reference range.
s Group GL3: )NCLUSION AND EXCLUSION CRITERIA ACCORDING TO 'UIDELINE OF THE .ATIONAL
!CADEMY OF #LINICAL "IOCHEMISTRY .!#" 53! n 2ECOMMENDATIONS ON DETER-
MINING REFERENCE INTERVALS OF 43(2 .O VISIBLE OR PALPABLE GOITER ANTI 40/ ANTI 4G
NEGATIVE DETERMINED FROM %LECSYS RESULTS SUBJECTS WITH PERSONAL OR FAMILY HISTORY OF
THYROID DYSFUNCTION EXCLUDED NO MEDICATIONS EXCEPT CONTRACEPTIVES 4HERE ARE NO
others labotatory parameter covered except for the autoantibodies!
Additionally for thyroglobulin:
s Group GL4: )NCLUSION AND EXCLUSION CRITERIA ACCORDING TO 'UIDELINE OF THE .!#"
53! n 2ECOMMENDATIONS ON DETERMINING REFERENCE INTERVALS OF 4G 43( BETWEEN
n M)5, AGE YEARS NON SMOKER ANTI 40/ ANTI 4G NEGATIVE DETERMINED
FROM %LECSYS RESULTS SUBJECTS WITH PERSONAL OR FAMILY HISTORY OF THYROID DYSFUNCTION
excluded.
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
Additionally for antibodies to thyroid peroxidase and thyroglobulin:
s Group GL5: )NCLUSION AND EXCLUSION CRITERIA ACCORDING TO 'UIDELINE OF THE .!#"
53! n 2ECOMMENDATIONS ON DETERMINING REFERENCE INTERVALS OF ANTI 40/ AND
ANTI 4G -EN 43( BETWEEN n M)5, AGE YEARS NO GOITER NO NON THYROID
AUTOIMMUNE DISEASES EG LUPUS ERYTHEMATHODES OR DIABETES
0REGNANT WOMEN Group P: Women in their 1st, 2nd and 3rd trimester of pregnancy.
%SSEN(AMBURG 4HE GROUP CONSISTS OF SAMPLES OF HEALTHY PREGNANT WOMEN FROM %SSEN AND
'ERMANY SAMPLES FROM HEALTHY PREGNANT WOMEN YEARS FROM (AMBURG WITH A NORMAL
pregnancy without known complications.
Exclusion criteria for this group were:
A known or supposed thyroid dysfunction or history, substitution of thyroid hormones,
F4 CONCENTRATIONS PMOL, AND F4 CONCENTRATIONS PMOL, 3AMPLES WITH 43(
concentrations outside a range of 0.1 to 10 µIU/mL were excluded in both groups.
Number of individu- 4HE FOLLOWING TABLE COMBINES THE NEWLY INVESTIGATED THREE POPULATION GROUPS CHILDREN
als of the reference from Erlangen, adults, children from Leipzig and pregnant women from Essen and
population tested (AMBURG AND SHOWS THE DISTRIBUTION OF THE SUBJECTS BY AGE AND SEX FOR THE PARAMETERS
tested. The data shown in the table provide the basis for the data in the figures depicting
the age-dependency for the individual thyroid tests.
FT3 FT4 T3 T4 A-TG TG A-TPO TSH TUP FTI
n n n n n n n n n n
Male
0 6 Days 51 57 49 43 28 44 27 49 29 25
6 Days 3 Months 55 58 50 51 51 50 35 62 35 30
3 12 Months 69 69 59 61 55 73 48 76 52 47
1 6 Years 203 203 202 201 198 200 192 205 197 193
6 11 Years 139 137 139 137 134 130 131 138 133 131
11 20 Years 227 225 229 226 224 221 221 227 225 221
20 30 Years 201 201 201 201 201 201 201 201 200 201
30 40 Years 110 110 110 110 110 110 110 110 110 110
40 50 Years 91 91 91 91 91 91 91 91 91 91
50 60 Years 48 48 48 48 48 48 48 48 48 48
60 70 Years 31 31 31 31 31 31 31 31 31 31
Female
0 6 Days 58 55 51 50 29 41 27 54 31 28
6 Days 3 Months 51 53 45 48 32 46 22 57 29 25
3 12 Months 46 48 42 44 36 45 24 47 36 34
1 6 Years 144 141 140 140 139 139 135 141 138 137
6 11 Years 126 126 128 127 119 119 116 127 120 118
11 20 Years 243 244 244 244 239 233 236 244 237 234
20 30 Years 224 224 224 224 224 224 224 224 224 224
30 40 Years 118 118 118 118 118 118 118 118 118 118
40 50 Years 105 105 105 105 105 105 105 105 104 105
50 60 Years 45 45 45 45 45 45 45 45 45 45
60 70 Years 22 22 22 22 22 22 22 21 22 22
Total
0 6 Days 109 112 100 93 57 85 54 103 60 53
6 Days 3 Months 106 111 95 99 83 96 57 119 64 55
3 12 Months 115 117 101 105 91 118 72 123 88 81
1 6 Years 347 344 342 341 337 339 327 346 335 330
6 11 Years 265 263 267 264 253 249 247 265 253 249
11 20 Years 470 469 473 470 463 454 457 471 462 455
20 30 Years 425 425 425 425 425 425 425 424 423 425
30 40 Years 228 228 228 228 228 228 228 228 228 228
40 50 Years 196 196 196 196 196 196 196 196 195 196
50 60 Years 93 93 93 93 93 93 93 93 93 93
60 70 Years 53 53 53 53 53 53 53 52 53 53
Table 1
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Reference Intervals Elecsys and cobas e analyzers
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3.1.4 Reference population Description of the reference population used as the basis of the reference interval given in
given for the data in the package inserts for the Elecsys thyroid parameters see below:
the package inserts s 4HE STUDY WAS CONDUCTED IN LATE EARLY TO INTRODUCE A REVISED 4 TEST AND TO
UP TO VALIDATE THE REFERENCE INTERVALS WHICH WERE ESTABLISHED IN AT THE TIME OF THE
fT4, T3, T4, T-uptake, introduction of the Elecsys systems or in some cases adopted from the previous tests –
fT4-index 2000 / 2001 the Enzymun-Test parameters.
ANTI 40/ ANTI 4G 4G The reference population which is the basis for the information in the current package
INSERTS CONSISTED OF WOMEN AND MEN BETWEEN AND YEARS OF AGE WHOSE SERUM
samples were measured in routine tests in clinical centers in Belgium, Japan and
'ERMANY
The groups consisted of blood donors in addition to hospital inpatients and outpa-
TIENTS 4HE 43( RESULTS WERE WITHIN THE NORMAL RANGE FOR THE RESPECTIVE ROUTINE METHOD
for all specimens. No information was available on any medication taken by the test
SUBJECTS .O INFORMATION ON POSSIBLE PREGNANCIES WAS AVAILABLE IN THE FEMALE GROUPS
4HE NUMBER OF SAMPLES WHICH VARIED FROM TO DEPENDING ON THE TEST PARA
meter, is given in the tables in the chapters on the individual tests.
Measurements were taken for fT4, T3, T4 and T-uptake. The fT4 index was determined
from the T4 and T-uptake ratio.
'ROUP 5 2EFERENCE POPULATION 53! FOR 4 AND F4 INDEX 0ITTSBURGH 53! 3PECIMENS
FROM APPARENTLY HEALTHY HOSPITAL EMPLOYEES AND FROM SUBJECTS CHARACTERIZED AS
CLINICALLY HEALTHY ,EXINGTON +9 53! ROUTINE SPECIMENS WITH 43( CONCENTRATIONS
within 0.27 to 4.2 µIU/mL and free T4 values within 12.0 to 23.0 pmol/L.
4HE REFERENCE POPULATION TESTED FOR ANTI 40/ ANTI 4G AND 4G IN CONSISTED OF
SUBJECTS WHOSE 43( AND F4 CONCENTRATIONS WERE WITHIN THE EUTHYROID RANGE AND THE
clinical appearance was without any signs for thyroid dysfunction.
2EFERENCE POPULATION $URING THE PRODUCT LAUNCH OF THE %LECSYS &4 TEST #AT NO IN *ULY LOCAL
for fT3, partly also for REFERENCE INTERVALS WERE DETERMINED IN CLINICAL CENTERS IN .ORWAY !USTRIA AND 'ERMANY
43( F4 which have kindly been provided to us for publication.
Local reference s Group N: #OMBINED POPULATION N Molde and Sandefjord, Norway: inclusion
intervals CRITERIA 43( CONCENTRATIONS BETWEEN n M)5, ;RESULTS PUBLISHED BY "JORO ET AL
u(EALTH 3TUDY OF .ORD 4RONDELAGh (5.4 3TUDY=12 and fT4 concentrations
between 11–22 pmol/L. This fT4 reference interval has been used in Norway for the
%LECSYS METHOD SINCE &OR SOME SPECIMENS THE CRITERION ANTI 40/ NEGATIVE WAS
APPLIED (OWEVER ANTI 40/ MEASUREMENTS ARE NOT AVAILABLE FOR ALL SAMPLES 4HE SAME IS
TRUE FOR AGE INFORMATION )N 3ANDEFJORD THERE WERE OUTPATIENTS IN -OLDE THE
TEST SUBJECTS WERE APPROX OUTPATIENTS AND INPATIENTS
s Group GHH: Hamburg, Germany, POPULATION FOR F4 AND F4 n N 4HESE
samples came from a large commercial community laboratory. The criterion for
INCLUSION WAS A 43( CONCENTRATION FROM n M)5, .O OTHER INFORMATION ON THE
patients was analyzed. This corresponds to a socalled “routine collective” as was also
used for earlier reference interval determinations.
s Group GHD: Heidelberg, Germany, POPULATION FOR F4 N AND F4 N 4HE
INCLUSION EXCLUSION CRITERIA AND THE TYPE OF LABORATORY SEE GROUP '(( &OR 43(
Routine samples. Reference range based on personal communication.
s Group A: Vienna, Austria, POPULATION FOR F4 F4 AND 43( 3PECIMENS FROM
clinically characterized euthyroid patients were used. The main criteria were: no history
OF THYROID MEDICATION THYROID PALPATION NEGATIVE 43( CONCENTRATIONS WITHIN THE
reference range of the routine method.
8
Reference Intervals Elecsys and cobas e analyzers
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s Group SE: 2EFERENCE RANGE DETERMINED USING %1!,)3 Helsingborg/Boras and
Västeras, Sweden, FOR F4 43( AND ANTI 40/ 4HE REFERENCE POPULATION IS COMPOSED
OF AND BLOOD DONORS IN 6ØSTERAS UND "ORAS RESPECTIVELY WOMEN AGE n
YEARS MEN AGE n YEARS IN (ELSINGBORG AND HEALTHY HOSPITAL STAFF N
Inclusion criteria for this group were: no family history of thyroid disorder, no goiter,
NO MEDICATION EXCEPT CONTRACEPTIVES 4HE ANALYSIS FOR ANTI 40/ WAS MADE ACCORDING TO
THE .!#" GUIDELINES 43( AND F4 WERE ANALYZED IN AN ANTI 40/ NEGATIVE POPULATION
Thailand: SPECIMENS FROM EUTHYROID SUBJECTS .O OTHER INFORMATION ON THE SUBJECTS
was given.
3.2 Analytical methods To determine the reference intervals, the Roche Electro-ChemiLuminescence Immuno-
ASSAYS h%#,)! v %LECSYS 43( &4 &4 4 4 4 5PTAKE !NTI 40/ !NTI 4G AND 4G
were used on the Elecsys 2010 and the MODULAR ANALYTICS E170 immunoassay
ANALYZERS FOLLOWING THE OPERATING INSTRUCTIONS PROVIDED AND THE STANDARD LOCAL QUALITY
control guidelines.
4HE PERFORMANCE DATA OF THE TESTS ARE DESCRIBED IN THE PACKAGE INSERTS 4HE %LECSYS 43(
test is a 3rd GENERATION 43( TEST ACCORDING TO THE DElNITION BY # 3PENCER20
The measurement methodology for the samples taken from children and adults in
Erlangen and Leipzig in 2003 and 2007 as well as for the samples taken from pregnant
WOMEN FROM %SSEN AND (AMBURG ARE DEALT WITH BELOW
43( MEASUREMENTS WERE USED IN THE CLASSIlCATION OF THE SPECIMENS IN ,EIPZIG WITH THE
TEST ON THE !$6)! #ENTAUR SYSTEM FROM "AYER 'ERMANY
The clinical-chemical laboratory parameters were measured with the Roche Diagnostics
tests.
4HYROID ULTRASONOGRAPHY WAS PERFORMED ON ALL SUBJECTS BY TRAINED PHYSICIANS USING AN
%5" PLUS DEVICE EQUIPPED WITH A -(Z LINEAR TRANSDUCER (ITACHI
4HYROID VOLUME WAS CALCULATED AS LENGTH X WIDTH X DEPTH X M, FOR EACH LOBE
'OITER WAS DElNED AS A THYROID VOLUME EXCEEDING M, IN WOMEN AND M, IN MEN
The normal thyroid echo was classified as homogeneous. If the echo pattern was not
homogeneous, showing small lesions or distinct abnormalities in the echo texture of the
GLAND IT WAS CLASSIlED AS INHOMOGENEOUS 6ISUAL NODULAR CHANGES WERE DElNED AS
nodules.
"ODY MASS INDEX "-) WAS CALCULATED USING THE FORMULA "-) WEIGHT ;KG=
height2 ;M=2 .
3.3 Statistical methods 3TUDY 0OPULATION
&REQUENCY TABLES AND BAR CHARTS PROVIDE AN OVERVIEW OF THE STUDY POPULATION
Assay data:
4HE DEPENDENCY OF ASSAY RESULTS ON CLINICAL PARAMETERS AGE GENDER MEDICATION AND
MEASUREMENT CONDITIONS STUDY SITE IS VISUALIZED IN SCATTER AND DOT PLOTS
0OOLING OF DATA
4O ACHIEVE A BROAD DATA BASIS IN PARTICULAR FOR THE JUVENILE AGE CLASSES DATA FROM TWO
sources, Leipzig and Erlangen, have been combined. A Wilcoxon rank sum test to evaluate
the statistical significance of differences in assay results between the two centers was
EXECUTED !BOUT OF THE ASSAYS TIMES AGEGROUPS CENTER COMPARISONS HAVE BEEN
found statistically significant different. Boxplots to investigate the relevance of the
observed differences have been generated, too. It has been decided that the situation
observed for these two study centers reflect the real world target population very well. As a
CONSEQUENCE QUANTILES ARE DERIVED FROM THE POOLED DATA
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
3.3 Statistical methods !GE DEPENDENT QUANTILE CURVES
CONTD !GE DEPENDENT AND PERCENT REFERENCE LIMITS HAVE BEEN DETERMINED AS SMOOTH
CURVES BY MEANS OF QUANTILE REGRESSION USING THE 3!3 6 SYSTEM 1UANTILE REGRESSION IS A
STATISTICAL TECHNIQUE TO ESTIMATE AND CONDUCT INFERENCE ABOUT CONDITIONAL QUANTILE
functions.23,24 A linear model utilizing non-integer powers of the explanatory variable age
HAS BEEN USED FOR ALL ASSAYS 4HE ESTIMATION IS BASED ON A WEIGHTED SUM WITH WEIGHTS
DEPENDING ON THE ORDER OF THE QUANTILES OF ABSOLUTE VALUES OF RESIDUALS ACCORDINGLY
extreme values are smoothed out. When surveying the whole age span of the thyroidal
assays the largest amount of variation takes place at the infant and early stages of adoles-
CENCE )N THIS REGIME WE PROlT MOST FROM THE SMOOTHING OF THE QUANTILE REGRESSION CURVES
1UANTILES
!CCORDING TO THE RECOMMENDATION OF THE )&## NONPARAMETRIC QUANTILES ARE USED AS
reference values.13,14 4O EVALUATE THE RELIABILITY OF THESE QUANTILES ADDITIONALLY THE COMPUTA-
tion of respective confidence limits is recommended. In this broschure two approaches
HAVE BEEN USED FOR THE DERIVATION OF THE QUANTILES AND THEIR CORRESPONDING TWO SIDED
CONlDENCE LIMITS I 4HE NONPARAMETRIC PROCEDURES INTRODUCED BY (AHN AND -EEKER
WITH 3!3 6 II 1UANTILES WERE OBTAINED AS READINGS FROM AGE DEPENDENT QUANTILE
REGRESSION CURVES )N PARTICULAR FOR THE JUVENILE AGEGROUP CLASSES THE AGE CLASS MIDPOINTS
ARE USED TO DERIVE THE RESPECTIVE AND PERCENT REFERENCE LIMITS AND THEIR RESPECTIVE
CONlDENCE LIMITS (OWEVER TO MINIMIZE UPDATING EFFORT THE (AHN -EEKER CLASS SPECIlC
QUANTILES ARE KEPT FOR THE ELDER AGE CLASSES AS THESE HAVE BEEN PROVEN USEFUL OVER A COUPLE
OF YEARS ! CROSSCHECK HAS DEMONSTRATED THAT FOR THESE CLASSES THE QUANTILE REGRESSION CURVE
DERIVED QUANTILES AND THE (AHN -EEKER QUANTILES CLOSELY AGREE
Comparison of clinical groups:
For the evaluation of the significance of the differences in assay results between clinically
DElNED GROUPS EITHER A 7ILCOXON 2ANK 3UM A -EDIAN #HI 3QUARE OR A +RUSKAL 7ALLIS
TEST HAS BEEN APPLIED AS APPROPRIATE (OWEVER AS SAMPLE SIZES HAVE NOT BEEN DESIGNED
BIOSTATISTICALLY P VALUES ARE DESCRIPTIVE 'RAPHICALLY DIFFERENT CLINICAL GROUPS ARE REPRE-
SENTED BY DOT PLOTS &OR MULTIPLE PAIR WISE COMPARISONS A 4UKEYS 3TUDENTIZED 2ANGE (3$
test has been used.
Multivariate methods:
Multivariate methods have been used to investigate the combined influence of age and
taking contraceptives on the test results. In particular the situation corresponds to a
RANDOMIZED COMPLETE BLOCK DESIGN WITH A lXED BLOCK FACTOR AGE CLASS AND A lXED
TREATMENT FACTOR CONTRACEPTIVE 4HE ERROR TERM FOR TESTING THE SIGNIlCANCE OF THE
treatment effect is the block-treatment-interaction. The generalized linear model ap-
PROACH THUS CORRECTS FOR THE EFFECTS OF AN AGE DEPENDENT FREQUENCY OF SUBJECTS WHO DO OR
do not take contraceptives, and the true impact of contraceptives on the result level of the
test parameters has been assessed.
The combined influence of age and gender on the assay results has also been investigated
by means of multivariate methods. Again the situation corresponds to a randomized
COMPLETE BLOCK DESIGN WITH A lXED BLOCK FACTOR AGE CLASS AND A TREATMENT FACTOR SEX
4HE ERROR TERM FOR TESTING THE TREATMENT EFFECT SEX IS THE BLOCK TREATMENT INTERACTION
The generalized linear model approach thus corrects for the effects of an age-dependent
FREQUENCY OF SAMPLES FROM EITHER GENDER AND SHOWS THE TRUE IMPACT OF GENDER ON THE
result level of the test.
For a statistical evaluation of the pregnancy data, the differences between the trimesters
ARE INVESTIGATED BY USING THE -EDIAN #HI SQUARE TEST &OR THE RESPECTIVE PAIR WISE COMPARI-
SONS A 4UKEYS 3TUDENTIZED 2ANGE (3$ TEST ALPHA HAS BEEN EXECUTED ! DIFFERENCE
IS CONSIDERED STATISTICALLY SIGNIlCANT IF THE SIMULTANEOUS CONlDENCE LIMITS OF THE
difference between means does not include zero.
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Reference Intervals Elecsys and cobas e analyzers
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Terminology Reference population / reference group: Random sample from the population of
asymptomatic patient specimens. The reference population provides the basis for deter-
mining reference intervals. The reference population is also called reference group.
Reference intervals / reference range / reference values / expected values: In accor-
dance with IFCC recommendations, the reference intervals or reference ranges are the
NON PARAMETRICALLY ESTIMATED AND QUANTILES PERCENTILES OF THE REFERENCE
POPULATION 4HE QUANTILE DESIGNATES THE VALUE FOR WHICH OF THE DATA ARE SMALLER
OR EQUAL THAN THIS VALUE THE QUANTILE DESIGNATES THE VALUE FOR WHICH OF THE
DATA ARE SMALLER OR EQUAL THAN THE QUANTILE VALUE /CCASIONALLY THE REFERENCE VALUES ARE ALSO
called reference limits because they bracket the reference range. Reference ranges are
FURTHERMORE SOMETIMES ALSO REFERRED TO AS CENTRAL RANGE EG OF ALL DATA ARE BELOW
AND ABOVE THIS RANGE n &IGURE
Elecsys package inserts contain the term expected values instead of reference values or
reference intervals.
Confidence interval: )N THE GIVEN CONTEXT THE RANGE AROUND THE ESTIMATED QUANTILE WHICH
INCLUDES THE TRUE VALUE OF THE QUANTILE WITH A GIVEN COVERAGE PROBABILITY 4HE CONlDENCE
interval decreases in size as the sample size increases. Figure 1 shows the position of the
CONlDENCE INTERVALS OF THE THE MEDIAN AND QUANTILE
Coverage probability: 0ROBABILITY TYPICALLY A VALUE OF IS SELECTED IF POSSIBLE THAT THE
TRUE QUANTILE VALUE IS COVERED BY THE CONlDENCE INTERVAL 3AMPLES THAT ARE TOO SMALL LEAD TO
insufficient coverage probabilities. Note that the IFCC recommends at least n = 120.
Frequency
Reference interval (corresponds in this case to the 95% central range)
min max
Concentration of the
analyte
2.5% 50% (median) 97.5%
quantile quantile quantile
Confidence interval Confidence interval Confidence interval
Figure 1
11
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4 Results and Discussion
4.1 Cross-parameter For the Leipzig blood donor group, the scatter plots of figure 2 show the age-dependent
results DISTRIBUTION OF ALBUMIN 4"' AND THYROID VOLUME IN ADDITION TO THE THYROID PARAMETERS
SEE CHAPTERS n 4HERE IS NO CORRELATION BETWEEN THYROID PARAMETERS AND PROTEIN
concentration or body mass index. Information on a correlation between the concentra-
tion in the thyroid tests and other parameters not described here is given in the individual
chapters on the tests.
All blood donors - Leipzig All blood donors - Leipzig
53
53 60
60
50
50 50
50
Tthyroid volume [mL]
48
48
40
40
Albumin [g/L]
45
45
30
30
43
43
20
20
40
40
10
10
38
38
Pearson’s r = 0.381
35
35 00
1616 2222 2828 3434 4040 45
46 52
52 58
58 64
64 70
70 20
20 25
25 30
30 35
35 40
40 45
45 50
50 55
55 60
60 65
65 70
70
Age [Years ] Age [Years ]
All blood donors - Leipzig Females
Thyroxin binding globulin (TBG) [mg/L]
50
50 50
Thyroxin binding globulin (TBG) [mg/L]
50
40
40 40
40
30
30 30
30
20
20 20
20
10
10 10
10
00 00
15
15 20
20 25
25 30
30 35
35 40
40 45
45 50
50 55
55 60
60 65
65 70
70 15
15 20
20 25
25 30 35 40 45
45 50 55
55 60
60 65
65 70
70
Age [Years ] Age [Years ]
Females With contraceptives
% Males W/o contraceptives
Figure 2
Explanation on the The following details apply to each of the parameters tested:
following chapters s !GE DEPENDENCY FROM BIRTH TO YEARS
Each figure shows an age-dependent representation of the individual data of the
Erlangen and Leipzig reference group for children, adolescents and young grown-ups
n AGE BIRTH TO YEARS n AND THE INDIVIDUAL DATA OF THE ,EIPZIG ADULT GROUP n AGE n
4HE LINES CONNECT THE MEDIANS AND THE AND QUANTILES OF THE SELECTED AGE
groups of children, youths, and adults.
s 4ABLES WITH DATA FROM ALL EVALUATED TEST GROUPS
! TABLE SHOWS THE VALUES FOR ALL ANALYZED GROUPS OF THE RESPECTIVE CENTRAL RANGES
AND THE CORRESPONDING CONlDENCE INTERVALS FOR THE MEDIAN AND
QUANTILES EXCEPTION ANTI 40/ ANTI 4G AND 4G MEDIAN AND QUANTILES
12
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.2 Thyrotropin, RD GENERATION 43( TESTS ARE USED AS lRST LINE PARAMETERS TO IDENTIFY THYROID DYSFUNCTION
Thyroidstimulating- OF PATIENTS THAT ARE NOT HOSPITALIZED 43( IS USED TO DETECT A SLIGHT SUBCLINICAL HYPER OR
HORMONE n 43( HYPOFUNCTION OF THE THYROID 4HE PREVALENCE OF PATHOLOGICAL 43( CONCENTRATIONS IN
combination with fT4 concentrations in the reference range, which are associated with a
subclinical thyroid hyper- or hypofunction is in various studies described as being approx.
AND ! CONSENSUS DECISION ON UNIFORM AND APPROPRIATE DIAGNOSIS ALGORITHMS AND
therapeutic measures is still open.n
4ABLE SHOWS DETAILED RESULTS FOR ADULTS INCLUDING PREGNANT WOMEN AND CHILDREN OF
VARIOUS AGE GROUPS SEPARATED ACCORDING TO SEX WOMEN TAKING CONTRACEPTIVES ARE IDENTIlED
separately.
&OR 43( LITERATURE REFERENCES DESCRIBE DIFFERENT REFERENCE LIMITS FOR MEN AND WOMEN18
4HESE DIFFERENCES WERE ALSO FOUND IN THE PRESENT STUDIES THEY WERE HIGHLY SIGNIlCANT IN THE
NON SELECTED GROUP ', P AND SLIGHTLY SIGNIlCANT IN GROUP ', P BUT
NOT IN GROUP ', P WHICH WAS EVALUATED ACCORDING TO THE .!#" CRITERIA FOR
43( 4HE PRESENT DATA DOES NOT SUGGEST THE USE OF SEX SPECIlC REFERENCE INTERVALS
Marginally significant differences were found in the group of women which did or did not
TAKE CONTRACEPTIVES P
4HE REFERENCE INTERVAL CURRENTLY GIVEN IN THE PACKAGE INSERT IS WITHIN THE CONlDENCE
INTERVAL FOR THE AND QUANTILE AND AS SUCH IN LINE WITH THE NEW RESULTS
The selection of inclusion and exclusion criteria influences the width of the range
CONSIDERABLY IN SOME CASES "ASED ON THE EXCLUSION CRITERIA USED 43( !$6)! #ENTAUR IN
THE RESPECTIVE REFERENCE RANGE LOWER LIMIT OF THE REFERENCE INTERVAL OF THE GROUPS TESTED IS
HIGHER FOR GROUP ', !S A CONSEQUENCE THIS GROUP DIFFERS SIGNIlCANTLY FROM GROUP ',
P
13
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.2 Thyrotropin, The so determined reference ranges correspond to those obtained in 2000 in a multicenter
Thyroidstimulating- REFERENCE VALUE STUDY DONE IN 3PAIN WITH %LECSYS 43( §)5M, n §)5M,
HORMONE n 43( TO §)5M, n §)5M, CENTRAL RANGE CONlDENCE INTERVAL OF THE
CONTD AND QUANTILES N (ERE TOO THE SAMPLES WERE SELECTED OVER 43(
concentrations in the reference range of another method.17
4HE GROUP ', SELECTED ACCORDING TO .!#" CRITERIA WHERE NO LABORATORY PARAMETERS WERE
included except for the autoantibodies and the patient history on personal and familiar
thyroid disorders shows correspondingly low limit values. There is no significant differ-
ENCE AS COMPARED TO GROUP ', P
4HE ,EIPZIG GROUP DID NOT REVEAL ANY DEPENDENCIES ON 4"' ALBUMIN AND "-)
Over trimester 1 to 3, pregnant women show a tendency in the upper limits towards lower
43( CONCENTRATIONS 4HERE IS NO SIGNIlCANT DIFFERENCE BETWEEN THE MEDIANS
Figure 3 SHOWS ALL DATA FOR CHILDREN AND ADULTS FROM BIRTH TO YEARS USING SEPARATE
SYMBOLS TO DISTINGUISH BETWEEN MALE AND FEMALE SUBJECTS
4HE HIGH 43( CONCENTRATIONS IN THE lRST DAYS AFTER BIRTH CONTINUOUSLY DECREASE WITH AGE
4HE MEDIANS OF THE AGE GROUPS SHOWN IN GROUP ', DIFFER SIGNIlCANTLY AMONG MEN AND
WOMEN P n 4ABLE
TSH (µlU/ml)
age
%%%male female
Figure 3
14
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.2 Thyrotropin, 95p 95p CI
95 p CI 50% 95p CI
95p 95p CI
CI low 2.5% high CI low 97.5% high Year of
Thyroidstimulating- (2.5% quant. (2.5%
low quant. high
(97.5% quant. (97.5%
n
publ.
(median) median (median)
HORMONE n 43( quant.) quant.) quant.) quant.)
µIU/mL µIU/mL µIU/mL µIU/mL µIU/mL µIU/mL µIU/mL µIU/mL µIU/mL
CONTD Elecsys TSH – package insert 0.27 1.16 4.20 516 96/‘97
Adults 20–69 years
Group GL1 (all blood donors) 0.21 0.30 0.37 1.25 1.31 1.35 3.35 3.69 4.32 869 2004
L1 Males all 0.24 0.30 0.40 1.21 1.25 1.32 3.01 3.18 4.32 445 2004
L1 Males 20–39 y 0.29 0.46 0.58 1.32 1.42 1.55 3.04 3.25 4.66 286 2004
L1 Males 40–69 y 0.18 0.21 0.30 0.87 0.96 1.07 2.09 2.52 4.32 150 2004
L1 Females all 0.12 0.30 0.39 1.31 1.38 1.47 3.54 3.94 7.18 424 2004
L1 Females 20–39 y 0.10 0.44 0.58 1.35 1.46 1.58 3.36 3.63 6.15 269 2004
L1 Females 40–69 y 0.05 0.16 0.37 1.01 1.21 1.37 2.86 3.94 66.83 128 2004
L1 Females with contracept. 0.10 0.39 0.60 1.34 1.47 1.59 3.36 3.82 11.19 236 2004
L1 Fem. with contracept. 20–39 y 0.10 0.52 0.62 1.38 1.51 1.60 3.49 5.09 11.19 181 2004
L1 Fem. with contracept. 40–69 y 0.30 0.30 0.37 0.75 1.20 1.59 2.68 2.88 2.88 33 2004
L1 Fem. w/o contracept. 0.05 0.16 0.37 1.18 1.30 1.42 3.22 4.25 66.8 187 2004
L1 Fem. w/o contracept. 20–39 y 0.05 0.22 0.60 1.18 1.36 1.67 2.80 3.05 4.47 87 2004
L1 Fem. w/o contracept. 40–69 y 0.05 0.14 0.37 1.01 1.27 1.42 3.22 4.25 66.8 95 2004
Group GL2 (TSH+SD–Sono NAD) 0.54 0.60 0.65 1.36 1.44 1.52 3.35 3.69 4.32 631 2004
L2 Males 0.52 0.58 0.64 1.29 1.37 1.46 3.04 3.44 4.66 332 2004
L2 Females 0.51 0.63 0.72 1.40 1.52 1.64 3.49 3.82 5.29 299 2004
Group GL3 org (NACB crit. for TSH) 0.29 0.44 0.47 1.29 1.36 1.44 3.14 3.77 4.47 447 2004
L4 Males 0.20 0.36 0.46 1.24 1.34 1.43 3.01 3.44 5.12 274 2004
L4 Females 0.12 0.44 0.63 1.30 1.42 1.59 3.14 3.94 5.29 173 2004
Group P (Pregnancy)
1st Trimester 0.21 0.33 0.48 1.37 1.48 1.61 3.99 4.59 5.80 418 2004
2nd Trimester 0.21 0.35 0.41 1.38 1.52 1.60 4.10 4.10 4.80 369 2004
3rd Trimester 0.11 0.21 0.29 1.32 1.42 1.59 2.78 3.15 7.08 170 2004
Group GEL Children, Adolescents
0–6 Days 0.11 0.70 4.62 3.51 4.41 5.55 8.49 15.2 27.0 103 2007
6 Days 3 Months 0.09 0.72 5.81 2.88 3.72 4.79 5.79 11.0 20.9 119 2007
3 12 Months 0.08 0.73 7.03 2.43 3.19 4.21 4.16 8.35 16.8 123 2007
1 6 Years 0.06 0.70 8.52 1.89 2.58 3.50 2.75 5.97 13.0 346 2007
6 11 Years 0.04 0.60 9.02 1.53 2.14 2.99 2.07 4.84 11.3 265 2007
11 20 Years 0.03 0.51 8.89 1.30 1.86 2.66 1.75 4.30 10.6 471 2007
Results from various locations
Group A (euthyroid indiv.) 0.3 1.5 3.3 128 2003
Group GHD (routine samples) 0.27 4.20
Group N (HUNT Study) females 0.30 3.60 70000 2000
Group N (HUNT Study) males 0.30 3.40 2000
Group SE (EQALIS) 0.59 3.72 2003
Table 2
Applying the given inclusion and exclusion criteria, the ranges for the groups from
various locations in different countries that were available for evaluation correspond
BASICALLY TO THE RANGES GIVEN IN THE PACKAGE INSERT EG '($ GROUP OR TO THE CORRESPOND-
ING COLLECTIVES OF THE BLOOD DONATORS FROM ,EIPZIG EG 3% GROUP WHERE ONLY ANTI 40/
NEGATIVE SAMPLES WERE USED
4.3 Free thyroxin – fT4 4ABLES A AND B SHOW DETAILED RESULTS FOR ADULTS INCLUDING PREGNANT WOMEN AND
CHILDREN OF VARIOUS AGE GROUPS SEPARATED ACCORDING TO SEX WOMEN TAKING CONTRACEPTIVES
are identified separately.
!S FOR 43( LITERATURE REFERENCES DESCRIBE DIFFERENT REFERENCE LIMITS FOR MEN AND WOMEN
also for fT4. These differences were also found in the present studies for the different
groups. The publications are reporting higher values as well as lower values for males
compared to those of women. )N OUR STUDY DIFFERENCES WERE HIGHLY SIGNIlCANT P
IN ALL GROUPS ', ', AND ', -ALES SHOW HIGHER VALUES COMPARED TO WOMEN
ESPECIALLY FOR THE QUANTILE AND THE MEDIAN 4HESE lNDINGS ARE ALSO CONlRMED BY THE
GROUP 3% %1!,)3 FROM 3WEDEN
For fT4 the reference interval currently given in the Elecsys FT4 package insert is basically
CONlRMED TAKING THE CONlDENCE INTERVAL OF THE RESPECTIVE QUANTILE ESTIMATORS FOR
males into account.
4HE GROUP , SELECTED ACCORDING TO .!#" CRITERIA FOR 43( WHERE NO LABORATORY PARAM-
eters were included except for the autoantibodies and the patient history on personal and
familial thyroid disorders shows correspondingly narrowed reference limits.
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.3 Free thyroxin – fT4 There is no significant difference between the groups from Leipzig.
CONTD No significant differences were found in the group of women which did or did not take
CONTRACEPTIVES P AND NO DEPENDENCIES ON THE 4"' CONCENTRATIONS MEASURED IN
THE SUBJECTS OF THE GROUP FROM ,EIPZIG n SEE &IGURE
As expected, pregnant women have lower fT4 concentrations correlated with the gesta-
TIONAL AGE 4HE MEDIAN VALUES IN THE ST ND AND RD TRIMESTER DIFFER SIGNIlCANT P
between each other.
95p CI 95p 95p CI
95p CI 95 p CI 50% 95p CI
2.5% high CI low 97.5% high Year of
low (2.5% low quant. high n
quant. (2.5% (97.5% quant. (97.5% publ.
quant.) (median) median (median)
quant.) quant.) quant.)
pmol/L pmol/L pmol/L pmol/L pmol/L pmol/L pmol/L pmol/L pmol/L
Elecsys FT4 package insert 12.0 16.0 22.0 801 1998
Adults 20–69 years
Group GL1 (all blood donors) 12.3 12.7 13.0 16.0 16.2 16.5 20.4 20.8 21.4 870 2004
L1 Males all 12.8 13.1 13.4 16.7 16.9 17.2 20.8 21.3 22.2 445 2004
L1 Males 20–39 y 12.9 13.4 14.0 16.9 17.1 17.5 20.7 21.3 23.0 286 2004
L1 Males 40–69 y 10.3 12.5 13.2 15.8 16.2 16.8 19.9 21.2 22.2 150 2004
L1 Females all 11.5 12.3 12.7 15.4 15.6 15.9 20.0 20.2 20.1 425 2004
L1 Females 20–39 y 11.7 12.4 12.9 15.4 15.7 16.0 19.9 20.4 21.7 270 2004
L1 Females 40–69 y 8.24 11.5 13.3 15.2 15.6 15.9 18.9 19.6 21.0 128 2004
L1 Fem. with contracept. 11.5 12.4 12.8 15.3 15.6 16.0 19.6 20.0 21.7 230 2004
L1 Fem. with contracept. 20–39 y 11.5 12.4 12.8 15.3 15.7 16.1 19.4 19.9 21.7 181 2004
L1 Fem. with contracept. 40–69 y 12.3 12.3 13.2 14.1 14.9 16.1 17.1 19.0 19.0 33 2004
L1 Fem. w/o contracept. 8.2 11.7 13.3 15.4 15.7 15.9 20.0 20.4 28.6 188 2004
L1 Fem. w/o contracept. 20–39 y 11.7 13.0 13.6 15.3 15.7 16.7 20.0 20.5 28.6 88 2004
L1 Fem. w/o contracept. 40–69 y 8.2 9.30 13.4 15.3 15.7 16.1 19.0 20.1 21.0 95 2004
Group GL2 (TSH+SD–Sono NAD) 12.3 12.8 13.0 15.9 16.2 16.5 20.2 20.7 21.4 632 2004
L2 Males 12.7 13.1 13.4 16.7 17.0 17.3 20.4 21.3 23.0 332 2004
L2 Females 11.5 12.3 12.8 15.3 15.6 15.8 19.6 20.1 20.8 300 2004
Group GL3 (NACB crit. for TSH) 12.2 12.8 13.0 15.9 16.2 16.6 20.2 20.4 21.5 448 2004
L4 Males 10.3 12.9 13.2 16.7 17.0 17.4 20.4 21.4 24.7 274 2004
L4 Females 9.30 12.2 12.8 15.3 15.5 15.8 19.2 20.1 20.7 174 2004
Group P (Pregnancy)
1st Trimester 11.8 12.1 12.4 15.1 15.4 15.7 19.2 19.6 21.4 418 2004
2nd Trimester 9.18 9.63 10.0 12.6 12.9 13.1 16.1 17.0 18.0 369 2004
3rd Trimester 6.95 8.39 9.31 11.6 11.9 12.3 14.8 15.6 17.8 169 2004
Group GEL Children, Adolescents
0–6 Days 7.70 11.0 15.8 16.0 17.7 19.6 26.4 32.0 38.9 112 2007
6 Days 3 Months 7.73 11.5 17.1 15.6 17.4 19.4 22.8 28.3 35.1 111 2007
3 12 Months 7.75 11.9 18.2 15.3 17.2 19.3 20.3 25.6 32.3 117 2007
1 6 Years 7.71 12.3 19.7 14.8 16.9 19.2 17.6 22.8 29.5 344 2007
6 11 Years 7.58 12.5 20.7 14.4 16.6 19.2 16.2 21.5 28.4 263 2007
11 20 Years 7.44 12.6 21.3 14.2 16.5 19.1 15.6 21.0 28.2 469 2007
Results from various locations
Group A (euthyroid indiv. 2003) 9.75 21.3 127 2003
Group GHD (routine samples) 10.6 22.7 8608 2002
Group GHH (routine samples) 11.2 11.4 11.5 15.7 21.7 22.0 22.4 5365 2004
Group SE (EQALIS) Males 12.0 13.0 13.0 19.0 20.0 20.0 2003
Group SE (EQALIS) Females 11.0 12.0 13.0 18.0 19.0 21.0 2003
Table 3a – SI units
Applying the given inclusion and exclusion criteria, the ranges for the groups from
various locations in different countries that were available for evaluation correspond
BASICALLY TO THE RANGES GIVEN IN THE PACKAGE INSERT EG '(( GROUP ,OCAL DIFFERENCES CAN
be observed.
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.3 Free thyroxin – fT4 95p CI
95p CI
95 p CI 50% 95p CI
95p 95p CI
2.5% high CI low 97.5% high Year of
CONTD low (2.5%
quant. (2.5%
low quant. high
(97.5% quant. (97.5%
n
publ.
quant.) (median) median (median)
quant.) quant.) quant.)
ng/dL ng/dL ng/dL ng/dL ng/dL ng/dL ng/dL ng/dL ng/dL
Elecsys FT4 package insert 0.93 1.24 1.71 801 1998
Adults 20–69 years
Group GL1 (all blood donors) 0.95 0.99 1.01 1.24 1.26 1.28 1.58 1.62 1.67 870 2004
L1 Males all 0.99 1.01 1.04 1.30 1.31 1.34 1.62 1.65 1.72 445 2004
L1 Males 20–39 y 1.00 1.04 1.09 1.31 1.33 1.36 1.61 1.65 1.79 286 2004
L1 Males 40–69 y 0.80 0.97 1.02 1.23 1.25 1.30 1.55 1.65 1.72 150 2004
L1 Females all 0.89 0.95 0.99 1.20 1.21 1.23 1.55 1.57 1.56 425 2004
L1 Females 20–39 y 0.91 0.97 1.00 1.20 1.22 1.25 1.55 1.58 1.68 270 2004
L1 Females 40–69 y 0.64 0.89 1.03 1.18 1.21 1.24 1.47 1.52 1.63 128 2004
L1 Fem. with contracept. 0.90 0.97 0.99 1.19 1.21 1.24 1.52 1.56 1.68 230 2004
L1 Fem. with contracept. 20–39 y 0.90 0.97 0.99 1.19 1.22 1.25 1.51 1.55 1.68 181 2004
L1 Fem. with contracept. 40–69 y 0.95 0.95 1.03 1.10 1.16 1.25 1.33 1.48 1.48 33 2004
L1 Fem. w/o contracept. 0.64 0.91 1.03 1.20 1.22 1.24 1.55 1.58 2.22 188 2004
L1 Fem. w/o contracept. 20–39 y 0.91 1.01 1.05 1.19 1.22 1.30 1.55 1.59 2.22 88 2004
L1 Fem. w/o contracept. 40–69 y 0.64 0.72 1.04 1.18 1.22 1.25 1.47 1.56 1.63 95 2004
Group GL2 (TSH+SD–Sono NAD) 0.95 0.99 1.01 1.23 1.26 1.28 1.57 1.61 1.67 632 2004
L2 Males 0.99 1.01 1.04 1.30 1.32 1.34 1.59 1.65 1.79 332 2004
L2 Females 0.90 0.95 0.99 1.19 1.21 1.23 1.52 1.56 1.62 300 2004
Group GL3 (NACB crit. for TSH) 0.94 0.99 1.01 1.23 1.26 1.29 1.57 1.59 1.67 448 2004
L4 Males 0.80 1.00 1.02 1.30 1.32 1.35 1.58 1.67 1.92 274 2004
L4 Females 0.72 0.94 0.99 1.19 1.20 1.23 1.49 1.56 1.61 174 2004
Group P (Pregnancy)
1st Trimester 0.92 0.94 0.96 1.17 1.20 1.22 1.49 1.52 1.66 418 2004
2nd Trimester 0.71 0.75 0.78 0.98 1.00 1.02 1.25 1.32 1.40 369 2004
3rd Trimester 0.54 0.65 0.72 0.90 0.93 0.95 1.15 1.21 1.38 169 2004
Group GEL Children, Adolescents
0–6 Days 0.60 0.86 1.23 1.25 1.38 1.52 2.05 2.49 3.02 112 2007
6 Days 3 Months 0.60 0.89 1.33 1.21 1.35 1.51 1.77 2.20 2.72 111 2007
3 12 Months 0.60 0.92 1.41 1.19 1.33 1.50 1.58 1.99 2.51 117 2007
1 6 Years 0.60 0.96 1.53 1.15 1.31 1.49 1.37 1.77 2.29 344 2007
6 11 Years 0.59 0.97 1.61 1.12 1.29 1.49 1.26 1.67 2.20 263 2007
11 20 Years 0.58 0.98 1.65 1.10 1.28 1.49 1.21 1.63 2.19 469 2007
Results from various locations
Group A (euthyroid indiv. 2003) 0.76 1.65 127 2003
Group GHD (routine samples) 0.82 1.77 8608 2002
Group GHH (routine samples) 0.87 0.89 0.90 1.22 1.69 1.71 1.74 5365 2004
Group SE (EQALIS) Males 0.93 1.01 1.01 1.48 1.55 1.55 2003
Group SE (EQALIS) Females 0.85 0.93 1.01 1.40 1.48 1.63 2003
Table 3b – conventional units
17
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.3 Free thyroxin – fT4 Figure 4 SHOWS ALL DATA FOR CHILDREN AND ADULTS FROM BIRTH TO YEARS USING SEPARATE
CONTD SYMBOLS TO DISTINGUISH BETWEEN MALE AND FEMALE SUBJECTS
The dependency of the fT4 concentration levels on sex is statistically significant for all age
groups.
4HE MEDIANS OF THE AGE GROUPS SHOWN IN GROUP ', DIFFER SIGNIlCANTLY ONLY AMONG MEN
P n 4ABLES AB
fT4 (pmol/l)
age
%%%male female
Figure 4
,EIPZIG AND 0REGNANT )N lGURE F4 RESULTS FOR THE SUBJECTS OF THE INDIVIDUAL GROUPS ', ', AND ', OF THE
Women: POPULATION F ROM ,EIPZIG AS WELL AS FOR THE PREGNANT WOMEN WERE PLOTTED AGAINST THE 43(
43( VERSUS F4 RESULTS OF THE SAME SAMPLES 4HE DASHED LINES CORRESPOND TO THE AND QUANTILES
OF THE VALID REFERENCE INTERVALS AS LISTED IN THE PACKAGE INSERTS 4HE CORRESPONDING
central range is identified by grey areas. The continuous lines and the white areas corre-
SPOND TO THE CENTRAL RANGE FOR 43( AND F4 OF THE INDIVIDUAL GROUPS ', ', AND
', AS STATED IN THE LEGENDS &OR THE RESULTS OF PREGNANT WOMEN THE LINES AND THE GREY
AREA CORRESPOND TO GROUP ', THE WHITE AREA CORRESPONDS TO THE LOWEST QUANTILE AND
TO THE HIGHEST QUANTILE DURING PREGNANCY
The dependency of the reference values on the applied inclusion/exclusion criteria
BECOMES QUITE APPARENT
18
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.3 Free thyroxin – fT4 Group GL1 - all blood donors Group GL2 - TSH+Sono NAD
CONTD 100
(n = 870: 445 males %, 425 females ) (n = 632: 332 males %, 300 females )
100 100
100
10
10 1010
Ref. interval 0.3-3.69
Ref. interval 0.6-3.69
TSH [mU/L] log
TSH [mU/L] log
11 11
0,1
0.1 0.1
0,1
0,01
0.01 0.01
0,01
00 55 10
10 15
15 20
20 25
25 30
30 35 00 55 10
10 15
15 20
20 25
25 30
30 35
35
fT4 [pmol/L] fT4 [pmol/L]
Ref. interval 12.7-20.8 Ref. interval 12.8-20.7
Group GL3 - (TSH-NACB) Pregnant women
(n = 447: 274 males %, 173 females ) ( 1st trim. n = 417, % 2nd trim. n = 368, 3rd trim. 169)
100
100 100
100
10
10 10
10
TSH [mU/L] log - lines GL1
Ref. interval 0.40-3.8-GL1
TSH [mU/L] log
11 11
c
0.1
0,1 0,1
0.1
0.01
0,01 0.01
0,01
00 55 10
10 15
15 20
20 25
25 30
30 35
35 00 55 15
15 25
25 35
35
fT4 [pmol/L] fT4 [pmol/L] - lines GL1
Ref. interval 12.8-20.4
Figure 5
! NON RELEVANT DEPENDENCY 0EARSONS R n WAS OBSERVED BETWEEN 4"' AND F4
n SEE &IGURE
Leipzig Blood Group GL1 Females
Donors - fT4 versus 3030 30
30
4"' 2525
2020 20
20
fT4 [pmol/L]
fT4 [pmol/L]
1515
1010 10
10
55
Pearson’s r = - 0.243 Pearson’s r = - 0.184
00 00
00 10
10 20
20 30
30 40
40 50
50 00 10
10 20
20 30
30 40
40 50
50
Frauen With contraceptives
Females
% Males TBG [mg/L] W/o contraceptives
Figure 6
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.4 Free triiodo- Establishing values in reference range studies is based primarily on samples obtained from
thyronine – fT3 OUTPATIENT CLINICS HOSPITALS AND COMMERCIAL LABORATORIES 43( AND F4 LEVELS ARE FOUND TO
be in the euthyroid range in these samples. The patients often have non-thyroid diseases
which might influence the thyroid function in general, and especially the fT3 level. This
may explain the differences observed when comparing the reference ranges based on
different population groups using the same fT3 method. Beside local differences in iodine
intake the overall health status of the individuals involved is decisive for the outcome of
the reference intervals.
Due to the new assay formulation in 2003 reference ranges for the Elecsys FT3 were
established based on reference population selected by differing criteria. The width is
differing for these ranges see tables 4a and 4b.
4ABLES A AND B SHOW DETAILED RESULTS FOR ADULTS INCLUDING PREGNANT WOMEN AND
CHILDREN OF VARIOUS AGE GROUPS SEPARATED ACCORDING TO SEX WOMEN TAKING CONTRACEPTIVES
are identified separately. Results of routine samples from community labs located in
various regions and results from following characterized patient groups are also listed in
the tables: dialysis patients and NTI patients.
4HE MEDIAN F4 RESULTS OF THE GROUPS FROM ,EIPZIG DO NOT DIFFER SIGNIlCANTLY P
95p CI 95p 95p CI
95p CI 95 p CI 50% 95p CI
2.5% high CI low 97.5% high Year of
low (2.5% low quant. high n
quant. (2.5% (97.5% quant. (97.5% publ.
quant.) (median) median (median)
quant.) quant.) quant.)
pmol/L pmol/L pmol/L pmol/L pmol/L pmol/L pmol/L pmol/L pmol/L
Group GHH (routine samples), ins. 3.07 3.13 4.64 6.65 6.76 6.87 5366 2004
Group GHD (Dialysis patients), insert 2.37 6.30 211 2003
MCE, NTI patients, insert 1.26 3.15 6.26 94 2003
Adults 20–69 years
Group GL1 (all blood donors) _ins. final 3.67 3.89 3.99 5.02 5.10 5.15 6.54 6.66 7.00 870 2004
L1 Males all 4.02 4.09 4.29 5.23 5.30 5.36 6.54 6.65 7.21 445 2004
L1 Males 20–39 y 4.04 4.36 4.54 5.22 5.29 5.37 6.54 6.74 7.21 286 2004
L1 Males 40–69 y 2.52 3.98 4.09 5.17 5.30 5.45 6.24 6.54 9.47 150 2004
L1 Females all 3.34 3.71 3.84 4.71 4.76 4.82 6.18 6.70 7.27 425 2004
L1 Females 20–39 y 3.13 3.66 3.89 4.72 4.78 4.88 6.10 6.72 7.94 270 2004
L1 Females 40–69 y 3.52 3.74 3.97 4.54 4.69 4.81 5.94 6.11 6.85 128 2004
L1 Fem. with contracept. 3.18 3.91 4.03 4.74 4.82 4.94 6.20 6.85 9.96 236 2004
L1 Fem. with contracept. 20–39 y 3.18 3.91 4.08 4.72 4.80 4.91 6.02 6.31 9.96 181 2004
L1 Fem. with contracept. 40–69 y 3.97 3.97 4.02 4.52 4.82 5.11 5.55 6.85 6.85 33 2004
L1 Fem. w/o contracept. 3.01 3.55 3.74 4.61 4.70 4.80 6.10 6.37 7.94 188 2004
L1 Fem. w/o contracept. 20–39 y 3.01 3.34 3.80 4.63 4.74 4.91 5.67 6.87 7.94 88 2004
L1 Fem. w/o contracept. 40–69 y 3.52 3.71 3.92 4.47 4.63 4.77 5.94 6.11 6.37 95 2004
Group GL2 (TSH+SD–Sono NAD) 3.67 3.92 4.03 4.99 5.08 5.15 6.54 6.65 7.00 632 2004
L2 Males 3.85 4.07 4.28 5.21 5.25 5.35 6.54 6.66 7.21 332 2004
L2 Females 3.13 3.80 3.92 4.70 4.76 4.82 6.12 6.31 7.27 300 2004
Group GL3 (NACB crit. for TSH) 3.71 3.92 4.07 5.03 5.12 5.19 6.54 6.74 7.21 448 2004
L4 Males 2.52 4.09 4.28 5.19 5.25 5.36 6.57 6.79 8.46 274 2004
L4 Females 3.01 3.80 3.89 4.70 4.77 4.85 6.10 6.70 9.96 174 2004
Group P (Pregnancy)
1st Trimester 3.60 3.78 3.87 4.75 4.80 4.87 5.84 5.97 6.22 416 2004
2nd Trimester 3.08 3.21 3.28 4.02 4.09 4.18 5.25 5.45 5.75 368 2004
3rd Trimester 2.44 3.09 3.19 3.80 3.90 3.99 4.73 5.03 6.36 169 2004
Group GEL Children, Adolescents
0–6 Days 1.50 2.65 4.69 4.76 5.50 6.36 8.05 9.68 11.6 109 2007
6 Days 3 Months 1.60 3.00 5.61 4.97 5.82 6.83 7.57 9.28 11.4 106 2007
3 12 Months 1.68 3.30 6.48 5.12 6.07 7.21 7.19 8.95 11.1 115 2007
1 6 Years 1.76 3.69 7.75 5.19 6.27 7.59 6.64 8.46 10.8 347 2007
6 11 Years 1.75 3.88 8.59 5.04 6.18 7.58 6.20 8.02 10.4 265 2007
11 20 Years 1.71 3.93 9.03 4.81 5.96 7.39 5.88 7.70 10.1 470 2007
Results from various locations
Group A (euthyroid indiv. 2003) 3.30 6.30 127 2003
Group GHD (routine samples) 3.40 4.79 6.80 374 2003
Group N, all 2.80 3.10 3.30 6.20 6.30 6.80 604 2003
Group N, SKKL+Molde 3.00 4.50 6.30 367 2003
Group N, SKKL (outpatients) 3.60 4.80 6.50 237 2003
Table 4a: SI units
20
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.4 Free triiodo- 3IGNIlCANT DIFFERENCES BETWEEN MALES AND FEMALES IN GROUP ', WERE OBSERVED ESPECIALLY
thyronine – fT3 FOR THE LOWER LIMIT OF THE CENTRAL RANGE ,ITERATURE REFERENCES DESCRIBE BOTH SIGNIl-
CONTD cant and nonsignificant differences between the sex groups. In our study differences
WERE HIGHLY SIGNIlCANT P IN ALL GROUPS ', ', AND ', -ALES SHOW HIGHER
VALUES AS COMPARED TO WOMEN ESPECIALLY FOR THE QUANTILE AND THE MEDIAN
Slightly higher values were seen in the group of women which did take contraceptives
COMPARED TO THE GROUP OF WOMEN WHICH DID NOT TAKE CONTRACEPTIVES P
As expected, pregnant women have lower fT3 concentrations correlated with the gesta-
TIONAL AGE 4HE MEDIAN VALUES IN THE ST ND AND RD TRIMESTER DIFFER SIGNIlCANT P
between each other.
Applying the given inclusion and exclusion criteria, the ranges for the groups from
various locations in different countries that were available for evaluation correspond
BASICALLY TO THE RANGES GIVEN FOR THE '(( GROUP LISTED ALSO IN THE PACKAGE INSERT
Local differences as well as differences caused by the composition of the groups can be
observed.
95p CI 95p 95p CI
95p CI 95 p CI 50% 95p CI
2.5% high CI low 97.5% high Year of
low (2.5% low quant. high n
quant. (2.5% (97.5% quant. (97.5% publ.
quant.) (median) median (median)
quant.) quant.) quant.)
pg/mL pg/mL pg/mL pg/mL pg/mL pg/mL pg/mL pg/mL pg/mL
Group GHH (routine samples), ins. 2.00 2.04 2.08 3.02 4.33 4.40 4.47 5366 2004
Group GHD (Dialysis patients), insert 1.54 4.10 211 2003
MCE, NTI patients, insert 0.82 2.05 4.08 94 2003
Adults 20–69 years
Group GL1 (all blood donors) _ins. final 2.39 2.53 2.60 3.27 3.32 3.35 4.26 4.34 4.56 870 2004
L1 Males all 2.62 2.66 2.79 3.40 3.45 3.49 4.26 4.33 4.69 445 2004
L1 Males 20–39 y 2.63 2.84 2.96 3.40 3.44 3.50 4.26 4.39 4.69 286 2004
L1 Males 40–69 y 1.64 2.59 2.66 3.37 3.45 3.55 4.06 4.26 6.16 150 2004
L1 Females all 2.17 2.42 2.50 3.07 3.10 3.14 4.02 4.36 4.73 425 2004
L1 Females 20–39 y 2.04 2.38 2.53 3.07 3.11 3.18 3.97 4.37 5.17 270 2004
L1 Females 40–69 y 2.29 2.43 2.58 2.96 3.05 3.13 3.87 3.98 4.46 128 2004
L1 Fem. with contracept. 2.07 2.55 2.62 3.09 3.14 3.22 4.04 4.46 6.48 236 2004
L1 Fem. with contracept. 20–39 y 2.07 2.55 2.66 3.07 3.12 3.20 3.92 4.11 6.48 181 2004
L1 Fem. with contracept. 40–69 y 2.58 2.58 2.62 2.94 3.14 3.33 3.61 4.46 4.46 33 2004
L1 Fem. w/o contracept. 1.96 2.31 2.43 3.00 3.06 3.12 3.97 4.15 5.17 188 2004
L1 Fem. w/o contracept. 20–39 y 1.96 2.17 2.47 3.01 3.09 3.20 3.69 4.47 5.17 88 2004
L1 Fem. w/o contracept. 40–69 y 2.29 2.42 2.55 2.91 3.01 3.11 3.87 3.98 4.15 95 2004
Group GL2 (TSH+SD–Sono NAD) 2.39 2.55 2.62 3.25 3.31 3.35 4.26 4.33 4.56 632 2004
L2 Males 2.51 2.65 2.79 3.39 3.42 3.48 4.26 4.34 4.69 332 2004
L2 Females 2.04 2.47 2.55 3.06 3.10 3.14 3.98 4.11 4.73 300 2004
Group GL3 (NACB crit. for TSH) 2.42 2.55 2.65 3.27 3.33 3.38 4.26 4.39 4.69 448 2004
L4 Males 1.64 2.66 2.79 3.38 3.42 3.49 4.28 4.42 5.51 274 2004
L4 Females 1.96 2.47 2.53 3.06 3.10 3.16 3.97 4.36 6.48 174 2004
Group P (Pregnancy)
1st Trimester 2.34 2.46 2.52 3.09 3.12 3.17 3.80 3.89 4.05 416 2004
2nd Trimester 2.01 2.09 2.14 2.62 2.66 2.72 3.42 3.55 3.74 368 2004
3rd Trimester 1.59 2.01 2.08 2.47 2.54 2.60 3.08 3.27 4.14 169 2004
Group GEL Children, Adolescents
0–6 Days 0.98 1.73 3.05 3.10 3.58 4.14 5.24 6.30 7.58 109 2007
6 Days 3 Months 1.04 1.95 3.65 3.23 3.79 4.44 4.93 6.04 7.40 106 2007
3 12 Months 1.10 2.15 4.22 3.33 3.95 4.69 4.68 5.83 7.25 115 2007
1 6 Years 1.15 2.41 5.05 3.38 4.08 4.94 4.33 5.50 7.01 347 2007
6 11 Years 1.14 2.53 5.59 3.28 4.02 4.93 4.03 5.22 6.76 265 2007
11 20 Years 1.11 2.56 5.88 3.13 3.88 4.81 3.82 5.01 6.56 470 2007
Results from various locations
Group A (euthyroid indiv. 2003) 2.15 4.10 127 2003
Group GHD (routine samples) 2.21 3.12 4.43 374 2003
Group N, all 1.82 2.02 2.15 4.04 4.10 4.43 604 2003
Group N, SKKL+Molde 1.95 2.93 4.10 367 2003
Group N, SKKL (outpatients) 2.34 3.12 4.23 237 2003
Table 4b: conventionell units
21
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.4 Free triiodo- Figure 7 SHOWS ALL DATA FOR CHILDREN AND ADULTS FROM BIRTH TO YEARS USING SEPARATE
thyronine – fT3 SYMBOLS TO DISTINGUISH BETWEEN MALE AND FEMALE SUBJECTS
CONTD The dependency of the fT3 concentration levels on sex is statistically significant for all age
groups.
4HE MEDIANS OF THE AGE GROUPS SHOWN IN GROUP ', DO NOT DIFFER SIGNIlCANTLY MALES P
FEMALES P n 4ABLES AB
fT3 (pmol/l)
age
%%%male female
Figure 7
,EIPZIG AND 0REGNANT )N lGURE F4 RESULTS FOR THE SUBJECTS OF THE INDIVIDUAL GROUPS ', ', AND ', OF THE
Women: POPULATION FROM ,EIPZIG AS WELL AS FOR THE PREGNANT WOMEN WERE PLOTTED AGAINST THE 43(
43( VERSUS F4 RESULTS OF THE SAME SAMPLES 4HE DASHED LINES CORRESPOND TO THE AND QUANTILES
OF THE VALID REFERENCE INTERVALS AS LISTED IN THE PACKAGE INSERTS 4HE CORRESPONDING
central range is identified by grey areas. The continuous lines and the white areas corre-
SPOND TO THE CENTRAL RANGE FOR 43( AND F4 OF THE INDIVIDUAL GROUPS ', ', AND
', AS STATED IN THE LEGENDS &OR THE RESULTS OF PREGNANT WOMEN THE LINES AND THE GREY
AREA CORRESPOND TO GROUP ', THE WHITE AREA CORRESPONDS TO THE LOWEST QUANTILE AND
TO THE HIGHEST QUANTILE DURING PREGNANCY
22
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.4 Free triiodo- The dependency of the reference values on the applied inclusion/exclusion criteria
thyronine – fT3 BECOMES QUITE APPARENT
CONTD
Group GL1 - all blood donors Group GL2 - TSH+Sono NAD
(n = 870: 445 males %, 425 females ) (n = 632: 332 males %, 300 females )
100
100 100
100
10
10 10
10
Ref. interval 0.2-3.69
Ref. interval 0.6-3.69
TSH [mU/L] log
TSH [mU/L] log
11 11
0,1
0.1 0,1
0.1
0,01
0.01 0,01
0.01
0 2 4 6 88 10
10 12
12 00 2 44 66 88 10
10 12
12
fT3 [pmol/L] fT3 [pmol/L]
Ref. interval 3.89-6.66 Ref. interval 3.92-6.65
Group GL3 - (TSH-NACB) Pregnant women
(n = 447: 274 males %, 173 females ) ( 1st trim. n = 416, % 2nd trim. n = 368, 3rd trim. 169)
100
100 100
100
10
10 10
10
Ref. interval 0.40-3.8 - all
TSH [mU/L] log
TSH [mU/L] log
lines GL1
11 11
0.1
0,1 0,1
0.1
0,01
0.01 0.01
0,01
00 22 44 66 88 10
10 12
12 00 22 4 66 88 10
10 12
12
fT3 [pmol/L]
fT3 [pmol/L]- lines GL1
Ref. interval 3.92-6.74
Figure 8
Leipzig Blood Donors -.O DEPENDENCY OF F4 0EARSONS R n WAS OBSERVED ON THE 4"' CONCENTRATIONS
F4 VERSUS 4"' MEASURED IN THE ,EIPZIG GROUP ', n SEE &IGURE
Group GL1 Females
1010 12
10
88
Elecsys FT3 [pmol/L]
Elecsys FT3 [pmol/L]
8
66
44
4
22
2
00 0
00 10
10 20
20 30
30 40
40 50
50 0 10 20 30 40 50
Females TBG [mg/L] With contraceptives
% Males W/o contraceptives
Figure 9
23
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4RIIODOTHYRONINE n 4 The total thyroid hormone levels, T3 and T4, are more commonly influenced as a result of
BINDING PROTEIN VARIANCES THAN RESULT FROM TRUE THYROID DYSFUNCTION !S WITH 4 OVER
OF 4 IS BOUND TO TRANSPORT PROTEINS (OWEVER THE AFlNITY OF 4 TO THEM IS AROUND
10-fold lower.
0ATIENTS WITH ABNORMAL 4"' EG DURING PREGNANCY ESTROGEN THERAPY AS WELL AS GENETIC
abnormalities in binding proteins are influencing the concentration level of the measure-
ments. The composition of the reference population is therefore decisive for the outcome
of the reference intervals.
For triiodothyronine the reference interval currently given in the Elecsys T3 package insert
IS BASICALLY CONlRMED ESPECIALLY WHEN CONSIDERING THE CONlDENCE INTERVAL OF THE
reference values for females. The reference limits are also narrower for T3. Furthermore
the ranges are slightly shifted downwards in comparison to the reference range for the
group given in the current insert.
Local differences or differences caused by the composition of the reference groups can be
OBSERVED n SEE TABLES An B
4ABLES A AND B SHOW DETAILED RESULTS FOR ADULTS INCLUDING PREGNANT WOMEN AND
CHILDREN OF VARIOUS AGE GROUPS SEPARATED ACCORDING TO SEX WOMEN TAKING CONTRACEPTIVES
are identified separately. Results of routine samples from community labs located in
various regions are also listed in the tables.
Results from investigations in Thailand show clearly decreased values for the lower
REFERENCE LIMIT QUANTILE AND THE MEDIAN
95p CI 95p 95p CI
95p CI 95 p CI 50% 95p CI
2.5% high CI low 97.5% high Year of
low (2.5% low quant. high n
quant. (2.5% (97.5% quant. (97.5% publ.
quant.) (median) median (median)
quant.) quant.) quant.)
nmol/L nmol/L nmol/L nmol/L nmol/L nmol/L nmol/L nmol/L nmol/L
Elecsys T3 package insert 1.27 1.98 3.07 514 1996
Elecsys T3 package insert 1.21 1.90 3.15 317 1998
Adults 20–69 years
Group GL1 (all blood donors) 1.17 1.23 1.28 1.75 1.77 1.81 2.70 2.80 2.90 870 2004
L1 Males all 1.17 1.28 1.31 1.68 1.72 1.75 2.24 2.29 2.47 445 2004
L1 Males 20–39 y 1.24 1.30 1.35 1.65 1.69 1.74 2.20 2.29 2.34 286 2004
L1 Males 40–69 y 0.90 1.17 1.31 1.70 1.74 1.81 2.20 2.42 3.36 150 2004
L1 Females all 1.11 1.20 1.26 1.82 1.88 1.94 2.84 2.92 3.44 425 2004
L1 Females 20–39 y 1.08 1.20 1.28 1.90 1.97 2.03 2.81 2.90 3.50 270 2004
L1 Females 40–69 y 0.98 1.17 1.28 1.58 1.65 1.76 2.37 2.70 3.26 128 2004
L1 Fem. with contracept. 1.20 1.33 1.48 2.06 2.12 2.19 2.89 3.26 4.00 236 2004
L1 Fem. with contracept. 20–39 y 1.20 1.33 1.48 2.06 2.14 2.20 2.81 2.92 3.96 181 2004
L1 Fem. with contracept. 40–69 y 1.42 1.42 1.55 1.84 1.99 2.21 2.70 3.26 3.26 33 2004
L1 Fem. w/o contracept. 0.98 1.13 1.19 1.58 1.62 1.62 2.25 2.79 2.92 188 2004
L1 Fem. w/o contracept. 20–39 y 1.06 1.11 1.24 1.59 1.66 1.73 2.12 2.84 2.92 88 2004
L1 Fem. w/o contracept. 40–69 y 0.98 1.14 1.23 1.50 1.57 1.64 2.20 2.40 2.77 95 2004
Group GL2 (TSH+SD–Sono NAD) 1.13 1.24 1.28 1.75 1.79 1.83 2.70 2.81 2.99 632 2004
L2 Males 1.13 1.28 1.31 1.66 1.72 1.75 2.23 2.29 2.51 332 2004
L2 Females 1.08 1.23 1.28 1.85 1.93 1.99 2.88 2.97 3.50 300 2004
Group GL3 (NACB crit. for TSH) 1.14 1.26 1.30 1.73 1.77 1.81 2.66 2.75 2.97 448 2004
L4 Males 0.89 1.28 1.31 1.65 1.70 1.75 2.21 2.29 2.66 274 2004
L4 Females 1.06 1.23 1.30 1.85 1.94 2.01 2.88 2.97 3.96 174 2004
Group P (Pregnancy)
1st Trimester 1.52 1.61 1.66 2.18 2.24 2.28 3.28 3.53 3.91 415 2004
2nd Trimester 1.83 1.98 2.15 2.77 2.84 2.91 3.79 4.03 4.40 368 2004
3rd Trimester 1.87 2.08 2.21 3.00 3.10 3.18 3.93 4.02 5.01 169 2004
Group GEL Children, Adolescents
0–6 Days 0.92 1.12 1.35 2.05 2.43 2.90 3.32 4.43 5.89 100 2007
6 Days 3 Months 1.00 1.23 1.52 2.09 2.54 3.08 3.07 4.22 5.81 95 2007
3 12 Months 1.05 1.32 1.66 2.11 2.60 3.20 2.88 4.07 5.74 101 2007
1 6 Years 1.09 1.42 1.84 2.07 2.61 3.28 2.59 3.80 5.58 342 2007
6 11 Years 1.07 1.43 1.91 1.94 2.49 3.20 2.34 3.55 5.37 267 2007
11 20 Years 1.02 1.40 1.92 1.81 2.35 3.05 2.15 3.34 5.18 473 2007
Results from various locations
Group A (euthyroid indiv. 2003) 1.17 1.81 2.73 126 2003
Group GHD (routine s. < 50 y) 1.20 1.87 3.00 1407 2003
Group GHD (routine s. > 50 y) 0.93 1.59 2.40 1336 2003
Thailand 1999 0.93 1.59 2.72 967 1999
Table 5a: SI units
24
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4RIIODOTHYRONINE n 4 Significant differences between males and females in group of blood donors from Leipzig,
CONTD ', WERE OBSERVED ESPECIALLY FOR THE UPPER LIMIT OF THE CENTRAL RANGE )N OUR STUDY
DIFFERENCES WERE HIGHLY SIGNIlCANT P IN ALL GROUPS ', ', AND ', .!#" FOR
43( -ALES SHOW SIGNIlCANTLY LOWER VALUES COMPARED TO WOMEN IN CASE ALL WOMEN WERE
EVALUATED TOTALLY P
! CLEAR DEPENDENCY ON THE INCREASED 4"' CONCENTRATION CAUSED BY THE INTAKE OF CONTRA-
ceptives could be observed. Significantly higher T3 values were seen in the group of
women which did take contraceptives compared to the group of women which did not
TAKE CONTRACEPTIVES P 4HE RESULTS FROM THE GROUP OF WOMEN WHICH DID NOT TAKE
contraceptives approximate those of the group of men. The dependency of the T3
concentration levels on the intake of contraceptives is statistically significant for all age
groups. Women in higher ages have slightly lower values than young women. These
OBSERVATIONS WERE MADE ALSO WITH EVALUATIONS FROM ROUTINE SAMPLES IN (EIDELBERG
As expected, pregnant women have higher T3 concentrations correlated with the gesta-
TIONAL AGE 4HE MEDIAN VALUES IN THE ST ND AND RD TRIMESTER DIFFER SIGNIlCANT P
between each other.
95p CI 95p 95p CI
95p CI 95 p CI 50% 95p CI
2.5% high CI low 97.5% high Year of
low (2.5% low quant. high n
quant. (2.5% (97.5% quant. (97.5% publ.
quant.) (median) median (median)
quant.) quant.) quant.)
ng/mL ng/mL ng/mL ng/mL ng/mL ng/mL ng/mL ng/mL ng/mL
Elecsys T3 package insert 0.83 1.29 2.00 514 1996
Elecsys T3 package insert 0.79 1.24 2.05 317 1998
Adults 20–69 years
Group GL1 (all blood donors) 0.76 0.80 0.83 1.14 1.15 1.18 1.76 1.82 1.89 870 2004
L1 Males all 0.76 0.83 0.85 1.09 1.12 1.14 1.46 1.49 1.61 445 2004
L1 Males 20–39 y 0.81 0.85 0.88 1.07 1.10 1.13 1.43 1.49 1.52 286 2004
L1 Males 40–69 y 0.59 0.76 0.85 1.11 1.13 1.18 1.43 1.58 2.19 150 2004
L1 Females all 0.72 0.78 0.82 1.18 1.22 1.26 1.85 1.90 2.24 425 2004
L1 Females 20–39 y 0.70 0.78 0.83 1.24 1.28 1.32 1.83 1.89 2.28 270 2004
L1 Females 40–69 y 0.64 0.76 0.83 1.03 1.07 1.15 1.54 1.76 2.12 128 2004
L1 Fem. with contracept. 0.78 0.87 0.96 1.34 1.38 1.43 1.88 2.12 2.60 236 2004
L1 Fem. with contracept. 20–39 y 0.78 0.87 0.96 1.34 1.39 1.43 1.83 1.90 2.58 181 2004
L1 Fem. with contracept. 40–69 y 0.92 0.92 1.01 1.20 1.30 1.44 1.76 2.12 2.12 33 2004
L1 Fem. w/o contracept. 0.64 0.74 0.77 1.03 1.05 1.05 1.46 1.82 1.90 188 2004
L1 Fem. w/o contracept. 20–39 y 0.69 0.72 0.81 1.04 1.08 1.13 1.38 1.85 1.90 88 2004
L1 Fem. w/o contracept. 40–69 y 0.64 0.74 0.80 0.98 1.02 1.07 1.43 1.56 1.80 95 2004
Group GL2 (TSH+SD–Sono NAD) 0.74 0.81 0.83 1.14 1.17 1.19 1.76 1.83 1.95 632 2004
L2 Males 0.74 0.83 0.85 1.08 1.12 1.14 1.45 1.49 1.63 332 2004
L2 Females 0.70 0.80 0.83 1.20 1.25 1.30 1.87 1.93 2.28 300 2004
Group GL3 (NACB crit. for TSH) 0.74 0.82 0.85 1.13 1.15 1.18 1.73 1.79 1.93 448 2004
L4 Males 0.58 0.83 0.85 1.07 1.11 1.14 1.44 1.49 1.73 274 2004
L4 Females 0.69 0.80 0.85 1.20 1.26 1.31 1.87 1.93 2.58 174 2004
Group P (Pregnancy)
1st Trimester 0.99 1.05 1.08 1.42 1.46 1.48 2.14 2.30 2.55 415 2004
2nd Trimester 1.19 1.29 1.40 1.80 1.85 1.89 2.47 2.62 2.86 368 2004
3rd Trimester 1.22 1.35 1.44 1.95 2.02 2.07 2.56 2.62 3.26 169 2004
Group GEL Children, Adolescents
0–6 Days 0.60 0.73 0.88 1.33 1.59 1.89 2.16 2.88 3.84 100 2007
6 Days 3 Months 0.65 0.80 0.99 1.36 1.65 2.00 2.00 2.75 3.78 95 2007
3 12 Months 0.68 0.86 1.08 1.37 1.69 2.09 1.88 2.65 3.74 101 2007
1 6 Years 0.71 0.92 1.20 1.35 1.70 2.14 1.69 2.48 3.63 342 2007
6 11 Years 0.69 0.93 1.25 1.27 1.62 2.08 1.53 2.31 3.50 267 2007
11 20 Years 0.66 0.91 1.25 1.18 1.53 1.99 1.40 2.18 3.37 473 2007
Results from various locations
Group A (euthyroid indiv. 2003) 0.76 1.18 1.78 126 2003
Group GHD (routine s. < 50 y) 0.78 1.22 1.95 1407 2003
Group GHD (routine s. > 50 y) 0.61 1.04 1.56 1336 2003
Thailand 1999 0.61 1.04 1.77 967 1999
Table 5b: conventional units
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4RIIODOTHYRONINE n 4 Figure 10 SHOWS ALL DATA FOR CHILDREN AND ADULTS FROM BIRTH TO YEARS USING SEPARATE SYM-
CONTD BOLS TO DISTINGUISH BETWEEN MALE AND FEMALE SUBJECTS
The high T3 concentrations in the first days after birth decrease continuously.
T3 (nmol/l)
age
%%%male female
Figure 10
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
,EIPZIG AND 0REGNANT )N lGURE 4 RESULTS FOR THE SUBJECTS OF THE INDIVIDUAL GROUPS ', ', AND ', OF THE
Women: POPULATION FROM ,EIPZIG AS WELL AS FOR THE PREGNANT WOMEN WERE PLOTTED AGAINST THE 43(
43( VERSUS 4 RESULTS OF THE SAME SAMPLES 4HE DASHED LINES CORRESPOND TO THE AND QUANTILES
OF THE VALID REFERENCE INTERVALS AS LISTED IN THE PACKAGE INSERTS 4HE CORRESPONDING
central range is identified by grey areas. The continuous lines and the white areas corre-
SPOND TO THE CENTRAL RANGE FOR 43( AND 4 OF THE INDIVIDUAL GROUPS ', ', AND
', AS STATED IN THE LEGENDS &OR THE RESULTS OF PREGNANT WOMEN THE LINES AND THE GREY
AREA CORRESPOND TO GROUP ', THE WHITE AREA CORRESPONDS TO THE LOWEST QUANTILE AND
TO THE HIGHEST QUANTILE DURING PREGNANCY
4RIIODOTHYRONINE n 4 The dependency of the reference values on the applied inclusion/exclusion criteria
CONTD BECOMES QUITE APPARENT
Group GL1 - all blood donors Group GL2 - TSH+Sono NAD
(n = 870: 445 males %, 425 females ) (n = 632: 332 males %, 300 females )
100
100 100
100
10
10 1010
Ref. interval 0.3-3.69
Ref. interval 0.3-3.69
TSH [mU/L] log
TSH [mU/L] log
11 11
0.1
0,1 0.1
0,1
0.01
0,01 0.01
0,01
00 0.5
0,5 11 1.5
1,5 22 2.5
2,5 33 3.5
3,5 44 4.5
4,5 55 00 0.5
0,5 11 1.5
1,5 22 2.5
2,5 33 3.5
3,5 44 4.5
4,5 55
T3 [nmol/L] T3 [nmol/L]
Ref. interval 1.23-2.80 Ref. interval 1.20-2.80
Group GL3 - (TSH-NACB) Pregnant women
(n = 447: 274 males %, 173 females ) ( 1st trim. n = 417, % 2nd trim. n = 368, 3rd trim. 169)
100
100 100
100
1010 10
10
TSH [mU/L] log - lines GL1
Ref. interval 0.40-3.8 - all
TSH [mU/L] log
11 11
c
0.1
0,1 0.1
0,1
0.01
0,01 0.01
0,01
00 0.5
0,5 11 1.5
1,5 22 2.5
2,5 33 3.5
3,5 44 4.5
4,5 55 00 11 22 33 44 55
T3 [nmol/L] T3 [nmol/L]- lines GL1
Ref. interval 1.26-2.75
Figure 11
27
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4RIIODOTHYRONINE n 4 !S EXPECTED A SIGNIlCANT DEPENDENCY OF 4 ON THE 4"' CONCENTRATIONS MEASURED WAS
CONTD OBSERVED IN THE ,EIPZIG GROUP ', 4HIS EFFECT EXPLAINS THE HIGHER VALUES OF WOMEN
compared to those of men. Among the group of women further increased values were
Leipzig Blood caused by the contraceptives taken. For the correlation presented in the scatter plots the
Donors – T3 versus 4 CONCENTRATIONS WERE MULTIPLIED BY THE FACTOR &
4"' AND !LBUMIN No relevant dependency of T3 on albumin was observed – see lower scatter plot in
Figure 12.
Group GL1 Females
50 50
50 50
Elecsys T3 [nmol/L x 10]
Elecsys T3 [nmol/L x 10]
40 40
40 40
30
30 30
30
20
20 20
20
10
10 10
10
Pearson’s r = 0.589 Pearson’s r = 0.643
0
00 0
00 10
10 20
20 30
30 40
40 50
50 00 10
10 20
20 30
30 40
40 50
50
Females With contraceptives
% Males TBG [mg/L] W/o contraceptives
5060 50
50
Pearson’s r = - 0.228 Pearson’s r = - 0.262
4048 40
Elecsys T3 [nmol/L x 10]
Elecsys T3 [nmol/L x 10]
40
3036 30
30
2024 20
20
1012 10
10
00 00
30
30 40
40 50
50 60
60 30
30 35
35 40
40 45
45 50
50
Albumin [g/L]
Figure 12
28
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4HYROXINE n 4 4HE MAJOR PART OF TOTAL THYROXINE IN SERUM IS PRESENT IN PROTEIN BOUND FORM !S
THE CONCENTRATIONS OF THE TRANSPORT PROTEINS IN SERUM ARE SUBJECT TO EXOGENOUS AND
endogenous effects, the status of the binding proteins must also be taken into account in
the assessment of the thyroid hormone concentration in serum.
As described already for T3 the total thyroid hormone levels, T3 and T4, are more
commonly influenced as a result of binding protein variances than result from true
THYROID DYSFUNCTION 0ATIENTS WITH ABNORMAL 4"' EG DURING PREGNANCY ESTROGEN
therapy, as well as genetic abnormalities in binding proteins are influencing the concen-
tration level of the measurements.
The composition of the reference population is therefore decisive for the outcome of the
reference intervals. It is furthermore recommended to determine the throxine-binding
capacity to take influences caused by varying concentrations of binding protein into
ACCOUNT BY CALCULATING THE FREE THYROXINE INDEX EG 4"' AND 4 UPTAKE 2,11
4ABLES A AND B SHOW DETAILED RESULTS FOR ADULTS INCLUDING PREGNANT WOMEN AND
CHILDREN OF VARIOUS AGE GROUPS SEPARATED ACCORDING TO SEX WOMEN TAKING CONTRACEPTIVES
are identified separately. Results of a clinical center in Austria are also listed in the tables.
For thyroxine the reference interval currently given in the Elecsys T4 package insert is
BASICALLY CONlRMED FOR THE 53! GROUP 4HE RELATIVE HIGH VALUES BASED ON SUBJECTS FROM
Europe and Japan were found in the group of women taking contraceptives also.
There is no significant difference between the median values of the different groups of
blood donors from Leipzig evaluated. The ranges are again closer compared to those of
the currently described groups.
The data in the group from Austria correspond to those of the group of blood donors.
Significant differences between males and females in group of blood donors from Leipzig
WERE OBSERVED ESPECIALLY FOR THE UPPER LIMIT OF THE CENTRAL RANGE (ERE THE DIFFERENCES
WERE HIGHLY SIGNIlCANT P IN ALL GROUPS ', ', AND ', .!#" FOR 43(
In our study males show significantly lower values as compared to women, when the total
OF ALL WOMEN WAS INCLUDED IN THE EVALUATION P 4HE RESULTS FROM THE GROUP OF
women which did not take contraceptives approximate those of the group of men. The
dependency of the T4 concentration levels on the intake of contraceptives is statistically
SIGNIlCANT FOR ALL AGE GROUPS ! DEPENDENCY ON THE INCREASED 4"' CONCENTRATION CAUSED
by the intake of contraceptives could be observed also for T4.
0REGNANT WOMEN HAVE SIGNIlCANT HIGHER 4 CONCENTRATIONS IN THE ND TRIMESTER AS
COMPARED TO THE ST TRIMESTER P 4HERE IS NO SIGNIlCANT DIFFERENCE BETWEEN THE ND
and 3rd trimester.
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4HYROXINE n 4 Figure 13 SHOWS ALL DATA FOR CHILDREN AND ADULTS FROM BIRTH TO YEARS USING SEPARATE
CONTD SYMBOLS TO DISTINGUISH BETWEEN MALE AND FEMALE SUBJECTS
4HE MEDIANS OF THE AGE GROUPS SHOWN IN GROUP ', DO NOT DIFFER SIGNIlCANTLY AMONG THE
GROUP OF MALES P &EMALES HAD HIGHLY SIGNIlCANT LOWER VALUES P IN THE
AGE GROUP n YEARS COMPARED TO THE GROUP IN THE AGE n YEARS n 4ABLES AB
T4 (nmol/l)
age
%%%male female
Figure 13
95p CI 95p 95p CI
95p CI 95 p CI 50% 95p CI
2.5% high CI low 97.5% high Year of
low (2.5% low quant. high n
quant. (2.5% (97.5% quant. (97.5% publ.
quant.) (median) median (median)
quant.) quant.) quant.)
nmol/L nmol/L nmol/L nmol/L nmol/L nmol/L nmol/L nmol/L ng/mL
Elecsys T4 insert Europe / Japan 66.0 105 181 2526 1998
Elecsys T4 insert USA 99% centr. 59.0 96.0 154 275 1998
Adults 20–69 years
Group GL1 (all blood donors) 68.3 71.5 72.7 99.4 101 103 152 158 163 870 2004
L1 Males all 65.8 71.6 72.7 93.5 95.9 97.3 125 128 130 445 2004
L1 Males 20–39 y 62.6 71.8 73.6 92.2 94.7 97 122 125 130 286 2004
L1 Males 40–69 y 52.1 68.4 75.4 95.3 97.4 100 124 129 144 150 2004
L1 Females all 63.5 71.5 75.6 108 110 114 161 166 192 425 2004
L1 Females 20–39 y 70.0 76.2 80.0 113 116 119 160 166 193 270 2004
L1 Females 40–69 y 55.2 63.5 72.5 95.9 99.7 105 143 157 168 128 2004
L1 Fem. with contracept. 70.0 81.8 89.4 121 124 126 166 173 209 236 2004
L1 Fem. with contracept. 20–39 y 70.0 85.5 91.2 120 123 126 162 172 198 181 2004
L1 Fem. with contracept. 40–69 y 75.8 75.8 83.7 105 118 135 163 168 168 33 2004
L1 Fem. w/o contracept. 55.2 68.0 71.5 92.9 95.7 99.0 126 138 170 188 2004
L1 Fem. w/o contracept. 20–39 y 69.1 71.5 76.5 91.7 96.1 103 122 138 161 88 2004
L1 Fem. w/o contracept. 40–69 y 55.2 59.8 70.5 92.1 95.7 101 121 127 139 95 2004
Group GL2 (TSH+SD–Sono NAD) 68.3 71.4 73.1 98.4 101 103 152 160 166 632 2004
L2 Males 62.6 68.9 72.7 92.1 94.6 96.4 122 124 131 332 2004
L2 Females 68.0 71.5 76.5 109 113 116 161 166 175 300 2004
Group GL3 (NACB crit. for TSH) 68.0 69.1 71.8 96.1 98.5 101 150 159 166 448 2004
L4 Males 61.8 68.4 71.8 90.6 93.0 96.3 122 125 144 274 2004
L4 Females 63.5 71.4 76.5 107 113 118 161 166 173 174 2004
Group P (Pregnancy)
1st Trimester 87.9 94.4 96.4 126 130 132 186 191 210 417 2004
2nd Trimester 96.7 102 106 144 147 151 197 208 228 368 2004
3rd Trimester 81.4 89.5 104 140 145 149 193 202 279 169 2004
Group GEL Children, Adolescents
0–6 Days 45.5 64.9 92.6 128 147 170 176 239 323 93 2007
6 Days 3 Months 46.8 69.6 104 117 138 161 156 219 309 99 2007
3 12 Months 47.6 73.0 112 110 131 155 143 206 299 105 2007
1 6 Years 47.7 76.6 123 101 122 148 125 189 287 341 2007
6 11 Years 46.2 77.1 129 94.9 116 142 113 178 280 264 2007
11 20 Years 44.3 76.1 131 90.8 112 139 104 170 277 470 2007
Results from various locations
Group A (euthyr. Prob. 2003) 71.0 162 127 2003
T4 – Table 6a, SI Units
30
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4HYROXINE n 4 95p CI
95p CI
95 p CI 50% 95p CI
95p 95p CI
2.5% high CI low 97.5% high Year of
CONTD low (2.5%
quant. (2.5%
low quant. high
(97.5% quant. (97.5%
n
publ.
quant.) (median) median (median)
quant.) quant.) quant.)
µg/dL µg/dL µg/dL µg/dL µg/dL µg/dL µg/dL µg/dL µg/dL
Elecsys T4 insert Europe / Japan 5.13 8.16 14.1 2526 1998
Elecsys T4 insert USA 99% centr. 4.58 7.46 12.0 275 1998
Adults 20–69 years
Group GL1 (all blood donors) 5.31 5.56 5.65 7.72 7.84 8.00 11.8 12.2 12.7 870 2004
L1 Males all 5.11 5.56 5.65 7.26 7.45 7.56 9.67 9.91 10.1 445 2004
L1 Males 20–39 y 4.86 5.57 5.72 7.16 7.36 7.51 9.51 9.69 10.1 286 2004
L1 Males 40–69 y 4.05 5.32 5.86 7.40 7.57 7.80 9.59 10.0 11.2 150 2004
L1 Females all 4.93 5.56 5.88 8.38 8.58 8.86 12.5 12.9 14.9 425 2004
L1 Females 20–39 y 5.44 5.92 6.22 8.79 9.01 9.22 12.4 12.9 15.0 270 2004
L1 Females 40–69 y 4.29 4.93 5.63 7.45 7.75 8.17 11.1 12.2 13.0 128 2004
L1 Fem. with contracept. 5.44 6.35 6.94 9.40 9.61 9.79 12.9 13.4 16.3 236 2004
L1 Fem. with contracept. 20–39 y 5.44 6.64 7.09 9.34 9.57 9.82 12.6 13.3 15.4 181 2004
L1 Fem. with contracept. 40–69 y 5.88 5.88 6.50 8.17 9.14 10.49 12.6 13.0 13.0 33 2004
L1 Fem. w/o contracept. 4.29 5.29 5.56 7.22 7.43 7.69 9.80 10.7 13.2 188 2004
L1 Fem. w/o contracept. 20–39 y 5.37 5.56 5.95 7.12 7.46 7.96 9.45 10.7 12.5 88 2004
L1 Fem. w/o contracept. 40–69 y 4.29 4.64 5.48 7.16 7.44 7.85 9.36 9.9 10.8 95 2004
Group GL2 (TSH+SD–Sono NAD) 5.31 5.55 5.68 7.64 7.81 8.01 11.8 12.4 12.9 632 2004
L2 Males 4.86 5.35 5.65 7.15 7.35 7.49 9.51 9.6 10.2 332 2004
L2 Females 5.29 5.56 5.95 8.48 8.79 9.02 12.5 12.9 13.6 300 2004
Group GL3 (NACB crit. for TSH) 5.29 5.37 5.58 7.47 7.65 7.84 11.7 12.3 12.9 448 2004
L4 Males 4.80 5.31 5.58 7.04 7.23 7.48 9.51 9.71 11.2 274 2004
L4 Females 4.93 5.55 5.95 8.32 8.80 9.19 12.5 12.9 13.4 174 2004
Group P (Pregnancy)
1st Trimester 6.83 7.33 7.49 9.80 10.1 10.2 14.4 14.8 16.3 417 2004
2nd Trimester 7.51 7.93 8.23 11.2 11.4 11.7 15.3 16.1 17.7 368 2004
3rd Trimester 6.33 6.95 8.06 10.9 11.3 11.6 15.0 15.7 21.7 169 2004
Group GEL Children, Adolescents
0–6 Days 3.54 5.04 7.19 9.94 11.4 13.2 13.7 18.5 25.1 93 2007
6 Days 3 Months 3.64 5.41 8.04 9.13 10.7 12.5 12.1 17.0 24.0 99 2007
3 12 Months 3.70 5.67 8.68 8.58 10.2 12.1 11.1 16.0 23.2 105 2007
1 6 Years 3.71 5.95 9.53 7.87 9.50 11.5 9.72 14.7 22.3 341 2007
6 11 Years 3.59 5.99 9.97 7.38 9.03 11.1 8.75 13.8 21.8 264 2007
11 20 Years 3.45 5.91 10.1 7.06 8.73 10.8 8.10 13.2 21.5 470 2007
Results from various locations
Group A (euthyr. Prob. 2003) 5.52 12.6 127 2003
T4 – Table 6b, Conventional Units
31
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
,EIPZIG AND 0REGNANT )N lGURE 4 RESULTS FOR THE SUBJECTS OF THE INDIVIDUAL GROUPS ', ', AND ', OF THE
Women: POPULATION FROM ,EIPZIG AS WELL AS FOR THE PREGNANT WOMEN WERE PLOTTED AGAINST THE 43(
43( VERSUS 4 RESULTS OF THE SAME SAMPLES 4HE DASHED LINES CORRESPOND TO THE AND QUANTILES
OF THE VALID REFERENCE INTERVALS AS LISTED IN THE PACKAGE INSERTS 4HE CORRESPONDING
central range is identified by grey areas. The continuous lines and the white areas corre-
SPOND TO THE CENTRAL RANGE FOR 43( AND 4 OF THE INDIVIDUAL GROUPS ', ', AND
', AS STATED IN THE LEGENDS &OR THE RESULTS OF PREGNANT WOMEN THE LINES AND THE GREY
AREA CORRESPOND TO GROUP ', THE WHITE AREA CORRESPONDS TO THE LOWEST QUANTILE AND
TO THE HIGHEST QUANTILE DURING PREGNANCY
4HYROXINE n 4 The dependency of the reference values on the applied inclusion/exclusion criteria
CONTD BECOMES QUITE APPARENT
Group GL1 - all blood donors Group GL2 - TSH+Sono NAD
(n = 870: 445 males %, 425 females ) (n = 632: 332 males %, 300 females )
100 100
100
10 10
10
Ref. interval 0.3-3.89
Ref. interval 0.6-3.69
TSH [mU/L] log
TSH [mU/L] log
1 1
0.1 0.1
0,1
0.01 0.01
0,01
0 50 100 150 200 250 00 50
50 100
100 150
150 200
200 250
250
T4 [nmol/L] T4 [nmol/L]
Ref. interval 71.5-158 Ref. interval 71.4-160
Group GL3- (TSH-NACB) Pregnant women
(n = 447: 274 males %, 173 females ) ( 1st trim. n = 417, % 2nd trim. n = 368, 3rd trim. 169)
100
100 100
100
TSH [mU/L] log - lines GL1
10
10 10
10
Ref. interval 0.62-3.59
TSH [mU/L] log
11 11
0,1
0.1 0.1
0,1
0.01
0,01 0.01
0,01
00 50
50 100
100 150
150 200
200 250
250 00 50
50 100
100 150
150 200
200 250
250
T4 [nmol/L] T4 [nmol/L]- lines GL1
Ref. interval 71.6-159
Figure 14
32
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4HYROXINE n 4 !S EXPECTED A HIGHLY SIGNIlCANT DEPENDENCY OF 4 ON THE 4"' WAS OBSERVED 4HIS EFFECT
CONTD explains the higher values of women compared to those of men. Among the group of
women further increased values were caused by the contraceptives taken.
Leipzig Blood Donors No relevant dependency of T4 on albumin was observed in the group investigated – see
4 VERSUS 4"' AND LOWER SCATTER PLOT IN &IGURE
Albumin
Group GL1 Females
210
210 210
210
168
168
168168
Elecsys T4 [nmol/L]
Elecsys T4 [nmol/L]
126
126
126126
84
84
8484
4242 4242
Pearsons r = 0.700 Pearson’s r = 0.700
00 00
00 10
10 20
20 30
30 40
40 50
50 00 10
10 20
20 30
30 40
40 50
50
Females With contraceptives
% Males TBG [mg/L] W/o contraceptives
210
210 210
210
168 168
Elecsys T4 [nmol/L]
168
168
Elecsys T4 [nmol/L]
126
126 126
126
8484 84
84
4242 42
42
00
00
30
30 40
40 50
50 60
60
30 35 40 45 50 55 60
30 35 40 45 50 55 60
Albumin [g/L]
Figure 15
4.7 Thyroxine-binding !S THE MAJOR PART OF THE TOTAL THYROXINE IS BOUND TO TRANSPORT PROTEINS 4"' PREALBUMIN
capacity - Free AND ALBUMIN THE DETERMINATION OF TOTAL THYROXINE ONLY PROVIDES CORRECT INFORMATION
T4-Index – fT4I when the thyroxine-binding capacity in serum is normal. The free thyroid hormones are
44") IN EQUILIBRIUM WITH THE HORMONES BOUND TO THE CARRIER PROTEINS ! CHANGE IN THE 4"'
concentration can lead to elevated or lowered total T4 concentrations being measured
although the free T4 concentration is in the euthyroid range.
The performance of a T-uptake or TBC assay provides a measure of the available
thyroxine-binding sites.
$ETERMINATION OF THE FREE THYROXINE INDEX F4) FROM THE RATIO OF TOTAL 4 AND 4")
THYROXINE BINDING INDEX RESULT OF THE 4 UPTAKE DETERMINATION TAKES INTO ACCOUNT
changes in the thyroid hormone carrier proteins and the thyroxine level.
4ABLE SHOWS DETAILED RESULTS FOR ADULTS INCLUDING PREGNANT WOMEN AND CHILDREN OF
VARIOUS AGE GROUPS SEPARATED ACCORDING TO SEX WOMEN TAKING CONTRACEPTIVES ARE IDENTIlED
separately.
The data basically confirm the reference interval currently given in the Elecsys T-Uptake
PACKAGE INSERT 4HE QUANTILE VALUE IS SLIGHTLY LOWER 4HE REFERENCE LIMIT CURRENTLY GIVEN
IS WITHIN THE CONlDENCE INTERVAL FOR THE GROUP OF WOMEN AND AS SUCH IN LINE WITH THE
new results.
33
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.7 Thyroxine-binding There is no significant difference between the median values of the different groups of
capacity - Free BLOOD DONORS FROM ,EIPZIG EVALUATED ALSO P AND P 4HE RANGES ARE AGAIN
T4-Index – fT4I narrower as compared to those of the described groups.
44") )N OUR STUDY MALES SHOW SIGNIlCANTLY LOWER VALUES P IN ALL GROUPS ', ', AND
CONTD ', .!#" FOR 43( AS COMPARED TO WOMEN WHEN THE TOTAL OF ALL WOMEN WAS INCLUDED
in the evaluation. The results from the group of women which did not take contraceptives
approximate those of the group of men. The dependency of the T-uptake concentration
levels on the intake of contraceptives is statistically significant for all age groups. A
DEPENDENCY ON THE INCREASED 4"' CONCENTRATION CAUSED BY THE INTAKE OF CONTRACEPTIVES
could be observed also for T-uptake.
4HE MEDIAN VALUE OF 4") WHICH WAS SET ARBITRARILY FOR A GROUP OF HEALTHY SUBJECTS
WOMEN WITHOUT TAKING CONTRACEPTIVES WAS CONlRMED IN ALL GROUPS EVALUATED
As expected T-uptake concentrations are increasing with gestational age. The median
VALUES IN THE ST ND AND RD TRIMESTER DIFFER HIGHLY SIGNIlCANT P BETWEEN EACH
other.
Figure 16 SHOWS ALL DATA FOR CHILDREN AND ADULTS FROM BIRTH TO YEARS USING SEPARATE SYM-
BOLS TO DISTINGUISH BETWEEN MALE AND FEMALE SUBJECTS
The dependency of the T-uptake concentration levels on sex is statistically significant for
all age groups.
The median T-uptake concentration levels of children are nearly constant over all age
groups.
4HE MEDIANS OF THE SEX SPECIlC AGE GROUPS SHOWN IN GROUP ', DO NOT DIFFER SIGNIlCANTLY
AMONG THE GROUP OF MALES P &EMALES HAD HIGHLY SIGNIlCANT LOWER VALUES
P IN THE AGE GROUP n YEAR AS COMPARED TO THE GROUP IN THE AGE n YEARS
– Table 7.
T-uptake (TBI)
age
%%%male female
Figure 16: T-uptake
34
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.7 Thyroxine-binding Figure 17 SHOWS ALL DATA FOR CHILDREN AND ADULTS FROM BIRTH TO YEARS USING SEPARATE
capacity - Free SYMBOLS TO DISTINGUISH BETWEEN MALE AND FEMALE SUBJECTS 4HE HIGHER F4 INDEX CONCEN-
T4-Index – fT4I trations in the first years of age decrease continuously up to approx. 40 years of age.
44") 4HE MEDIANS OF THE AGE GROUPS SHOWN IN GROUP ', DO NOT DIFFER SIGNIlCANTLY AMONG THE
CONTD GROUPS OF MALES AND FEMALES P AND n 4ABLES AB
fT4-index (nmol/l)
age
%%%male female
Figure 17: fT4-index
T-uptake 95p CI
95p CI
95 p CI 50% 95p CI
95p 95p CI
2.5% high CI low 97.5% high Year of
low (2.5% low quant. high n
quant. (2.5% (97.5% quant. (97.5% publ.
quant.) (median) median (median)
quant.) quant.) quant.)
TBI TBI TBI TBI TBI TBI TBI TBI TBI
Elecsys T-Uptake Insert Europe/Japan 0.80 1.00 1.30 974 1998
Elecsys T-Uptake Insert USA 99% centr. 0.78 1.39 275 1998
Adults 20–69 years
Group GL1 (all blood donors) 0.80 0.81 0.84 0.99 0.99 1.00 1.22 1.23 1.25 870 2004
L1 Males all 0.77 0.80 0.82 0.96 0.97 0.97 1.06 1.08 1.09 445 2004
L1 Males 20–39 y 0.77 0.80 0.83 0.96 0.97 0.97 1.05 1.07 1.09 285 2004
L1 Males 40–69 y 0.70 0.77 0.85 0.95 0.97 0.99 1.07 1.09 1.18 150 2004
L1 Females all 0.75 0.85 0.87 1.04 1.05 1.07 1.25 1.26 1.30 425 2004
L1 Females 20–39 y 0.75 0.85 0.90 1.06 1.08 1.11 1.25 1.27 1.32 270 2004
L1 Females 40–69 y 0.56 0.84 0.87 0.99 1.01 1.03 1.19 1.22 1.31 128 2004
L1 Fem. with contracept. 0.80 0.94 0.96 1.11 1.12 1.13 1.26 1.27 1.32 236 2004
L1 Fem. with contracept. 20–39 y 0.80 0.94 0.96 1.11 1.12 1.14 1.26 1.27 1.32 181 2004
L1 Fem. with contracept. 40–69 y 0.95 0.95 1.00 1.07 1.09 1.13 1.25 1.31 1.31 33 2004
L1 Fem. w/o contracept. 0.56 0.81 0.85 0.98 0.99 1.00 1.13 1.16 1.34 188 2004
L1 Fem. w/o contracept. 20–39 y 0.73 0.81 0.85 0.98 0.99 1.00 1.12 1.16 1.34 88 2004
L1 Fem. w/o contracept. 40–69 y 0.56 0.81 0.86 0.96 0.98 1.00 1.11 1.16 1.20 95 2004
Group GL2 (TSH+SD–Sono NAD) 0.77 0.81 0.84 0.99 1.00 1.01 1.23 1.25 1.27 632 2004
L2 Males 0.76 0.80 0.82 0.96 0.97 0.98 1.06 1.08 1.09 332 2004
L2 Females 0.73 0.86 0.90 1.05 1.07 1.09 1.25 1.27 1.32 300 2004
Group GL3 (NACB crit. for TSH) 0.77 0.81 0.83 0.99 0.99 1.00 1.22 1.25 1.27 448 2004
L4 Males 0.70 0.80 0.82 0.96 0.97 0.98 1.07 1.09 1.18 274 2004
L4 Females 0.73 0.84 0.90 1.05 1.08 1.10 1.25 1.27 1.34 174 2004
Group P (Pregnancy)
1st Trimester 0.91 0.96 0.98 1.10 1.11 1.12 1.29 1.31 1.35 415 2004
2nd Trimester 1.06 1.17 1.18 1.32 1.33 1.34 1.46 1.48 1.51 369 2004
3rd Trimester 0.84 1.28 1.28 1.39 1.41 1.42 1.50 1.52 1.55 169 2004
Group GEL Children, Adolescents
0–6 Days 0.64 0.81 1.03 0.97 1.02 1.07 1.04 1.20 1.39 60 2007
6 Days 3 Months 0.62 0.81 1.06 0.95 1.01 1.07 1.02 1.21 1.43 64 2007
3 12 Months 0.61 0.81 1.08 0.94 1.00 1.07 1.01 1.21 1.45 88 2007
1 6 Years 0.59 0.81 1.12 0.93 1.00 1.07 0.99 1.22 1.49 335 2007
6 11 Years 0.57 0.81 1.15 0.92 0.99 1.07 0.97 1.22 1.53 253 2007
11 20 Years 0.56 0.81 1.17 0.92 0.99 1.07 0.96 1.22 1.56 462 2007
Table 7
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.7 Thyroxine-binding )N lGURE 4 UPTAKE RESULTS FOR THE SUBJECTS OF THE INDIVIDUAL GROUPS ', ', AND ',
capacity - Free of the population from Leipzig as well as for the pregnant women were plotted against the
T4-Index – fT4I 43( RESULTS OF THE SAME SAMPLES 4HE DASHED LINES CORRESPOND TO THE AND
44") QUANTILES OF THE VALID REFERENCE INTERVALS AS LISTED IN THE PACKAGE INSERTS 4HE CORRESPOND-
CONTD ING CENTRAL RANGE IS IDENTIlED BY GREY AREAS 4HE CONTINUOUS LINES AND THE WHITE AREAS
CORRESPOND TO THE CENTRAL RANGE FOR 43( AND 4 UPTAKE OF THE INDIVIDUAL GROUPS ',
,EIPZIG AND 0REGNANT ', AND ', AS STATED IN THE LEGENDS &OR THE RESULTS OF PREGNANT WOMEN THE LINES AND
7OMEN 43( VERSUS THE GREY AREA CORRESPOND TO GROUP ', THE WHITE AREA CORRESPONDS TO THE LOWEST
T-uptake QUANTILE AND TO THE HIGHEST QUANTILE DURING PREGNANCY
The dependency of the reference values on the applied inclusion/exclusion criteria
BECOMES QUITE APPARENT
Group GL1 - all blood donors Group GL2 - TSH+Sono NAD
(n = 870: 445 males %, 425 females ) (n = 632: 332 males %, 300 females )
100
100 100
100
10
10 10
10
Ref. interval 0.3-3.69
Ref. interval 0.6-3.69
TSH [mU/L] log
TSH [mU/L] log
11 11
0.1
0,1 0,1
0.1
0.01
0,01 0,01
0.01
0.0
0,0 0.5
0,5 1.0
1,0 1.5
1,5 2.0
2,0 0.0
0,0 0.5
0,5 1.0
1,0 1.5
1,5 2.0
2,0
T-uptake [TBI] T-uptake [TBI]
Ref. interval 0.81-1.23 Ref. interval 0.81-1.25
Group GL3 - (TSH-NACB) Pregnant women
(n = 447: 274 males %, 173 females ) ( 1st trim. n = 415, % 2nd trim. n = 369, 3rd trim. 169)
100
100 100
100
TSH [mU/L] log - lines GL1
1010 10
10
Ref. interval 0.40-3.8 - all
TSH [mU/L] log
11 11
0,10.1 0.1
0,1
0.01
0,01 0.01
0,01
0.0
0,0 0.5
0,5 1.0
1,0 1.5
1,5 2.0
2,0 0.0
0,0 0.5
0,5 1.0
1,0 1.5
1,5 2.0
2,0
T-uptake [TBI] T-uptake [TBI]- lines GL1
Ref. interval 0.81-1.25
Figure 18
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.7 Thyroxine-binding 95p CI
95p CI
95 p CI 50% 95p CI
95p 95p CI
2.5% high CI low 97.5% high Year of
capacity – Free low (2.5%
quant. (2.5%
low quant. high
(97.5% quant. (97.5%
n
publ.
quant.) (median) median (median)
T4-Index – fT4I quant.) quant.) quant.)
nmol/L nmol/L nmol/L nmol/L nmol/L nmol/L nmol/L nmol/L nmol/L
44") FT4 Index (T4 /T-Upt.) Eur./Jap – insert 62.0 99.0 164 825 1998
CONTD FT4 Index (T4 /T-Upt.) USA 99% centr. ins. 57.0 147 275 1998
Adults 20–69 years
Group GL1 (all blood donors) 68.6 72.2 74.4 101 102 103 145 147 154 870 2004
L1 Males all 67.6 72.2 74.4 97.7 99.4 101.3 135 138 152 445 2004
L1 Males 20–39 y 67.1 73.0 75.8 96.8 98.7 101.2 132 136 152 286 2004
L1 Males 40–69 y 58.5 68.7 76.0 96.7 101 104.1 135 144 153 150 2004
L1 Females all 66.0 72.9 76.3 103 105 107 147 154 176 425 2004
L1 Females 20–39 y 70.7 76.4 80.1 103 106 108 146 154 191 270 2004
L1 Females 40–69 y 48.0 66.0 74.3 97.5 101 106 131 142 165 128 2004
L1 Fem. with contracept. 70.8 79.7 82.9 108 109 112 148 156 204 236 2004
L1 Fem. with contracept. 20–39 y 74.6 81.8 83.4 106 109 112 146 154 204 181 2004
L1 Fem. with contracept. 40–69 y 70.8 70.8 79.7 95 108 121 137 148 148 33 2004
L1 Fem. w/o contracept. 48.0 66.1 72.9 96.0 98.7 102 134 148 173 188 2004
L1 Fem. w/o contracept. 20–39 y 70.1 72.9 76.8 93.7 98.4 103 125 148 173 88 2004
L1 Fem. w/o contracept. 40–69 y 48.0 60.8 70.9 94.0 98.9 105 125 142 165 95 2004
Group GL2 (TSH+SD–Sono NAD) 68.7 72.2 74.6 100 102 103 143 147 154 632 2004
L2 Males 67.1 71.8 73.8 96.5 98.1 101 134 137 153 332 2004
L2 Females 66.0 74.4 76.9 103 104 107 146 150 176 300 2004
Group GL3 (NACB crit. for TSH) 67.6 71.8 73.5 97.7 100 102 137 147 154 448 2004
L4 Males 64.0 70.3 73.0 95.5 97 100 133 137 161 274 2004
L4 Females 60.8 72.9 76.9 100 103 107 146 153 176 174 2004
Group P (Pregnancy)
1st Trimester 79.6 83.2 85.9 113 116 118 158 166 176 414 2004
2nd Trimester 71.7 75.8 78.5 109 112 115 153 159 184 368 2004
3rd Trimester 55.4 65.8 69.6 101 103 107 142 160 199 168 2004
Group GEL Children, Adolescents
0–6 Days 43.1 65.3 98.9 119 131 146 178 268 403 53 2007
6 Days 3 Months 43.7 70.5 114 113 127 143 145 232 372 55 2007
3 12 Months 43.8 73.1 122 110 125 142 130 216 357 81 2007
1 6 Years 43.3 76.3 134 105 121 139 110 193 337 330 2007
6 11 Years 41.8 76.8 141 100 117 136 98.2 179 326 249 2007
11 20 Years 40.1 76.1 144 96.5 113 133 90.7 170 320 455 2007
fT4I - Table 8a, SI Units
95p CI 95p 95p CI
95p CI 95 p CI 50% 95p CI
2.5% high CI low 97.5% high Year of
low (2.5% low quant. high n
quant. (2.5% (97.5% quant. (97.5% publ.
quant.) (median) median (median)
quant.) quant.) quant.)
µg/dL µg/dL µg/dL µg/dL µg/dL µg/dL µg/dL µg/dL µg/dL
FT4 Index (T4 /T-Upt.) Eur./Jap – insert 4.82 7.69 12.7 825 1998
FT4 Index (T4 /T-Upt.) USA 99% centr. ins. 4.43 11.4 275 1998
Adults 20–69 years
Group GL1 (all blood donors) 5.33 5.61 5.78 7.85 7.92 8.00 11.3 11.4 12.0 870 2004
L1 Males all 5.25 5.61 5.78 7.59 7.72 7.87 10.5 10.7 11.8 445 2004
L1 Males 20–39 y 5.21 5.67 5.89 7.52 7.67 7.86 10.3 10.5 11.8 286 2004
L1 Males 40–69 y 4.54 5.34 5.91 7.51 7.83 8.08 10.5 11.2 11.9 150 2004
L1 Females all 5.13 5.66 5.93 8.00 8.17 8.30 11.4 12.0 13.7 425 2004
L1 Females 20–39 y 5.49 5.94 6.22 8.03 8.20 8.41 11.4 12.0 14.8 270 2004
L1 Females 40–69 y 3.73 5.13 5.77 7.58 7.85 8.25 10.2 11.0 12.8 128 2004
L1 Fem. with contracept. 5.50 6.19 6.44 8.39 8.46 8.70 11.5 12.1 15.8 236 2004
L1 Fem. with contracept. 20–39 y 5.79 6.36 6.48 8.26 8.46 8.72 11.4 12.0 15.8 181 2004
L1 Fem. with contracept. 40–69 y 5.50 5.50 6.19 7.39 8.41 9.37 10.7 11.5 11.5 33 2004
L1 Fem. w/o contracept. 3.73 5.13 5.66 7.46 7.67 7.92 10.4 11.5 13.4 188 2004
L1 Fem. w/o contracept. 20–39 y 5.45 5.66 5.96 7.28 7.64 8.00 9.73 11.5 13.5 88 2004
L1 Fem. w/o contracept. 40–69 y 3.73 4.72 5.51 7.30 7.68 8.16 9.67 11.0 12.8 95 2004
Group GL2 (TSH+SD–Sono NAD) 5.33 5.61 5.79 7.74 7.89 7.99 11.1 11.4 12.0 632 2004
L2 Males 5.21 5.58 5.73 7.50 7.62 7.85 10.4 10.6 11.9 332 2004
L2 Females 5.13 5.78 5.97 8.00 8.08 8.31 11.3 11.7 13.7 300 2004
Group GL3 (NACB crit. for TSH) 5.25 5.58 5.71 7.59 7.75 7.92 10.6 11.4 12.0 448 2004
L4 Males 4.98 5.46 5.67 7.42 7.57 7.77 10.4 10.6 12.5 274 2004
L4 Females 4.72 5.66 5.97 7.79 8.01 8.29 11.4 11.9 13.7 174 2004
Group P (Pregnancy)
1st Trimester 6.18 6.46 6.68 8.79 9.02 9.20 12.3 12.9 13.7 414 2004
2nd Trimester 5.57 5.89 6.10 8.48 8.71 8.91 11.9 12.4 14.3 368 2004
3rd Trimester 4.30 5.11 5.41 7.82 7.98 8.31 11.0 12.4 15.5 168 2004
Group GEL Children, Adolescents
0–6 Days 3.35 5.08 7.69 9.21 10.2 11.3 13.9 20.8 31.3 53 2007
6 Days 3 Months 3.39 5.48 8.85 8.76 9.87 11.1 11.2 18.0 28.9 55 2007
3 12 Months 3.41 5.68 9.48 8.53 9.70 11.0 10.1 16.8 27.8 81 2007
1 6 Years 3.36 5.93 10.4 8.13 9.37 10.8 8.55 15.0 26.2 330 2007
6 11 Years 3.25 5.97 11.0 7.78 9.06 10.5 7.63 13.9 25.4 249 2007
11 20 Years 3.12 5.91 11.2 7.49 8.79 10.3 7.05 13.2 24.9 455 2007
fT4I - Table 8b, Conventional Units
37
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.7 Thyroxine-binding 4ABLES A AND B SHOW DETAILED RESULTS FOR ADULTS INCLUDING PREGNANT WOMEN AND
capacity – Free CHILDREN OF VARIOUS AGE GROUPS SEPARATED ACCORDING TO SEX WOMEN TAKING CONTRACEPTIVES
T4-Index – fT4I are identified separately.
44") !S FOR 4 THE REFERENCE INTERVAL CALCULATED FOR THE F4 INDEX FROM 4 AND 4") 44")
CONTD currently given in the Elecsys T-Uptake package insert is basically confirmed for the USA
GROUP 4HE RELATIVLY HIGH VALUES BASED ON SUBJECTS FROM %UROPE AND *APAN WERE FOUND IN
the group of women taking contraceptives.
Significant differences between males and females in the group of blood donors from
,EIPZIG WERE OBSERVED ESPECIALLY FOR THE UPPER LIMIT OF THE CENTRAL RANGE (ERE THE
DIFFERENCES WERE HIGHLY SIGNIlCANT P AND P IN ALL GROUPS ', ', AND ',
In our study males show significantly lower values as compared to women, when the total
of all women was included in the evaluation. The results from the group of women which
did not take contraceptives approximate those of the group of men. A dependency on the
INCREASED 4"' CONCENTRATION CAUSED BY THE INTAKE OF CONTRACEPTIVES COULD BE OBSERVED
ALSO FOR THIS PARAMETER HIGHER F4) VALUES
7ITH THE EXCEPTION OF SMALL DIFFERENCES P FOR THE GROUP ', EVALUATED ACCORD-
ING THE CRITERIA OF THE .!#" FOR 43( THERE IS NO SIGNIlCANT DIFFERENCE BETWEEN THE
median values of the different groups of blood donors from Leipzig evaluated. The ranges
are again narrower as compared to those of the currently described groups.
As expected fT4-index concentrations are decreasing with gestational age. The median
VALUES IN THE ST ND AND RD TRIMESTER DIFFER HIGHLY SIGNIlCANT P BETWEEN EACH
other.
)N lGURE F4 INDEX RESULTS FOR THE SUBJECTS OF THE INDIVIDUAL GROUPS ', ', AND
', OF THE POPULATION FROM ,EIPZIG AS WELL AS FOR THE PREGNANT WOMEN WERE PLOTTED
AGAINST THE 43( RESULTS OF THE SAME SAMPLES 4HE DASHED LINES CORRESPOND TO THE AND
QUANTILES OF THE VALID REFERENCE INTERVALS AS LISTED IN THE PACKAGE INSERTS 4HE
CORRESPONDING CENTRAL RANGE IS IDENTIlED BY GREY AREAS 4HE CONTINUOUS LINES AND THE
WHITE AREAS CORRESPOND TO THE CENTRAL RANGE FOR 43( AND F4 INDEX OF THE INDIVIDUAL
GROUPS ', ', AND ', AS STATED IN THE LEGENDS &OR THE RESULTS OF PREGNANT WOMEN
THE LINES AND THE GREY AREA CORRESPOND TO GROUP ', THE WHITE AREA CORRESPONDS TO THE
LOWEST QUANTILE AND TO THE HIGHEST QUANTILE DURING PREGNANCY
38
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.7 Thyroxine-binding The dependency of the reference values on the applied inclusion/exclusion criteria
capacity – Free BECOMES QUITE APPARENT
T4-Index – fT4I
44") Group GL1 - all blood donors Group GL2 - TSH+Sono NAD
CONTD (n = 870: 445 males %, 425 females ) (n = 632: 332 males %, 300 females )
100
100 100
100
,EIPZIG AND 0REGNANT
7OMEN 43( VERSUS
1010 10
10
fT4-index
Ref. interval 0.3-3.89
Ref. interval 0.6-3.69
TSH [mU/L] log
TSH [mU/L] log
11 1
0.1
0,1 0.1
0,1
0.01
0,01 0.01
0,01
00 50
50 100
100 150
150 200
200 250
250 00 50
50 100
100 150
150 200
200 250
250
fT4-index [nmol/L] fT4-index [nmol/L]
Ref. interval 72.2-147 Ref. interval 72.2-147
Group GL3 - (TSH-NACB) Pregnant women
(n = 447: 274 males %, 173 females ) ( 1st trim. n = 417, % 2nd trim. n = 368, 3rd trim. 169)
100
100 100
100
10
10 10
10
TSH [mU/L] log - lines GL1
Ref. interval 0.62-3.59
TSH [mU/L] log
1 11
c
0.1
0,1 0.1
0,1
0.01
0,01 0.01
0,01
00 50
50 100
100 150
150 200
200 250
250 00 50
50 100
100 150
150 200
200 250
250
fT4-index [nmol/L] fT4-index [nmol/L]- lines GL1
Ref. interval 71.8-147
Figure 19
Leipzig Blood !S EXPECTED A SIGNIlCANT DEPENDENCY OF 4 UPTAKE WAS OBSERVED ON THE 4"' n SEE THE TWO
Donors – T-uptake upper graphics in figure 20. This effect explains the higher values for women compared to
AND F4) VERSUS 4"' those of men. Among the group of women further increased values were caused by the
and Albumin contraceptives taken.
4HESE INmUENCES ARE ELIMINATED WHEN DETERMINING THE FREE 4 )NDEX ;44 UPTAKE 4") =
– see the two lower graphics in figure 20.
No dependency of fT4I on albumin was seen.
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.7 Thyroxine-binding
capacity – Free Group GL1 Females
2.02 2.0
T4-Index – fT4I
44")
CONTD 1,5
1.5 1.5
T-uptake [TBI]
T-uptake [TBI]
Leipzig Blood 1.01 1.0
Donors – T-uptake
AND F4) VERSUS 4"'
0.5
0,5
0.5
Pearson’s r = 0.710 Pearsons’s r = 0.735
00 0
00 10
10 20
20 30
30 40
40 50
50
0 10 20 30 40 50
Females TBG [mg/L] W/o contraceptives
% Males With contraceptives
300
300 300
300
250
250 250
250
fT4-index [nmol/L]
fT4-Index [nmol/L]
200
200 200
200
150
150 150
150
100
100 100
100
5050 50
50
00 00
00 10
10 20
20 30
30 40
40 50
50 00 10
10 20
20 30
30 40
40 50
50
TBG [mg/L]
Figure 20
4.8 Antibodies to 4HE DETERMINATION OF ANTI 40/ USED TOGETHER WITH 43( IS RECOMMENDED ALSO FOR THE
thyroid peroxidase – detection of suspected dysfunction especially regarding the long-term risk of the develop-
ANTI 40/ MENT OF A THYROID DISEASE AND AFTER PREGNANCY 4HE DETERMINATION OF ANTI 40/ IS ALSO
recommended with subclinical hypo-thyroidism.
4ABLE SHOWS DETAILED RESULTS FOR ADULTS INCLUDING PREGNANT WOMEN AND CHILDREN OF
VARIOUS AGE GROUPS SEPARATED ACCORDING TO SEX INCLUDING THE GROUP %1!,)3 FROM 3WEDEN
The selection of inclusion and exclusion criteria clearly influences the cutoff level.
4HE GROUP ', SELECTED ACCORDING TO THE .!#" CRITERIA FOR THE REFERENCE INTERVAL DETERMI-
NATION OF ANTI 40/ AND ANTI 4G EG ONLY MALES YEARS SHOWS WITH )5M, A
LOWER CUTOFF AS COMPARED TO THAT OF %LECSYS !NTI 40/ 4HE CUTOFF OF )5M, CURRENTLY
GIVEN IN THE PACKAGE INSERT IS CLOSE TO THE UPPER LIMIT OF THE CONlDENCE INTERVAL OF
32.7 IU/mL.
4HE CUTOFF OF )5M, OBTAINED FOR THE MEN IN GROUP ', IS IN LINE WITH THAT GIVEN IN
THE %LECSYS ANTI 40/ PACKAGE INSERT
4HE NON SELECTED GROUP OF BLOOD DONORS ', AND THE ', GROUP SHOW SIGNIlCANT HIGHER
values. These results are caused by the group of women, which gave essentially higher
VALUES P AND P n SEE TABLE
4HE CUTOFF PUBLISHED BY THE %1!,)3 IS THE LOWEST WITH A QUANTILE LIMIT OF )5M,
)N PREGNANT WOMEN THE ANTI 40/ CONCENTRATIONS ARE SLIGHTLY HIGHER IN THE RD TRIMESTER
There is no significant difference between the three trimesters.
40
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.8 Antibodies to 95 p CI 50% 95p CI 95p CI
95%
95p CI
Year of
low quant. high low (95% high (95% n
thyroid peroxidase – (median) median (median) quant.)
quant.
quant.)
publ.
ANTI 40/ IU/mL IU/mL IU/mL IU/mL IU/mL IU/mL
Elecsys Anti-TPO package insert 34 208 2000
CONTD Adults 20–69 years
Group GL5 (NACB crit. for A-TPO) 90% c. 17 25 28 23 28 33 80 2004
Group GL2 (TSH+SD–Sono NAD) 13 14 15 62 167 297 632 2004
L2 Males 13 13 14 32 37 63 332 2004
L2 Females 14 15 15 194 308 426 300 2004
Group GL1 (all blood donors) 14 14 15 93 186 287 870 2004
L1 Males all 13 13 14 33 37 63 445 2004
L1 Females all 14 15 16 227 312 422 425 2004
Group P (Pregnancy)
1st Trimester 11 11 12 47 64 119 410 2004
2nd Trimester 10 10 11 30 51 91 362 2004
3rd Trimester 12 13 15 40 123 171 165 2004
Group GEL Children, Adolescents
0–6 Days 5.0 5.0 5.1 28 117 269 54 2007
6 Days 3 Months 5.0 5.9 8.0 29 47 158 57 2007
3 12 Months 5.0 5.1 5.6 29 32 52 72 2007
1 6 Years 5.0 5.0 5.0 13 13 16 327 2007
6 11 Years 7.4 8.1 8.8 17 18 26 247 2007
11 20 Years 6.9 7.4 8.1 20 26 36 457 2007
Results from various locations
Group SE (EQALIS) 19 2003
Table 9
,EIPZIG AND 0REGNANT )N lGURE ANTI 40/ RESULTS FOR THE SUBJECTS OF THE INDIVIDUAL GROUPS ', ', AND
7OMEN 43( VERSUS ', OF THE POPULATION FROM ,EIPZIG AS WELL AS FOR THE PREGNANT WOMEN WERE PLOTTED
ANTI 40/ AGAINST THE 43( RESULTS OF THE SAME SAMPLES 4HE DASHED LINES CORRESPOND TO THE AND
QUANTILES OF 43( AND THE QUANTILE OF ANTI 40/ OF THE VALID REFERENCE INTERVALS
AS LISTED IN THE PACKAGE INSERTS 4HE CORRESPONDING AND CENTRAL RANGE IS IDENTI-
lED BY GREY AREAS 4HE CONTINUOUS LINES AND THE WHITE AREAS CORRESPOND TO THE AND
CENTRAL RANGE FOR 43( AND ANTI 40/ OF THE INDIVIDUAL GROUPS ', ', AND ', AS
stated in the legends. For the results of pregnant women the lines and the grey area
CORRESPOND TO GROUP ', THE WHITE AREA CORRESPONDS TO THE HIGHEST QUANTILE DURING
pregnancy.
The dependency of the reference values on the applied inclusion/exclusion criteria
BECOMES QUITE APPARENT
41
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.8 Antibodies to
Group GL1 - all blood donors Group GL2 - TSH+Sono NAD
thyroid peroxidase – (n = 870: 445 males %, 425 females ) (n = 632: 332 males %. 300 females )
ANTI 40/ 100
100 100
100
CONTD
10
10 10
10
Ref. interval 0.6-3.69
Ref. interval 0.3-3.69
TSH [mU/L] log
TSH [mU/L] log
11 1
0,1
0.1 0,1
0.1
0.01 0.01
0,01
00 100
100 200
200 300
300 400
400 500
500 600
600 00 100
100 200
200 300
300 400
400 500
500 600
600
anti-TPO [IU/mL] cutoff all 186; females 312; males 37 anti-TPO [IU/mL] cutoff all 167; females 308; males 37
Group GL1 - blood donors, males only % Group GL2 - TSH+Sono NAD, males only %
(n = 445) (n = 332)
100 100
100
10 10
10
Ref. interval 0.3-3.69
Ref. interval 0.6-3.69
TSH [mU/L] log
TSH [mU/L] log
1 1
0.1 0,1
0.1
0.01 0.01
0,01
0 100 200 300 400 500 600 00 100
100
200
200
300
300
400
400
500
500
600
600
anti-TPO [IU/mL] cutoff males 37 anti-TPO [IU/mL] cutoff males 37
Group GL5 - (Anti-TPO-NACB) Pregnant women
(n = 80 males %) ( 1st trim. n = 417, % 2nd trim. n = 368, 3rd trim. 169)
100
100 100
100
10
10 10
10
TSH [mU/L] log - lines GL1
Ref. interval 0.40-3.8
TSH [mU/L] log
11 11
0.1
0,1 0.1
0,1
0.01
0,01 0.01
0,01
00 10
10 20
20 30
30 40
40 50
50 60
60 70
70 80
80 90
90 100
100
00 100
100 200
200 300
300 400
400 500
500 600
600
anti-TPO [IU/mL] cutoff males: 28 anti-TPO [IU/mL] - lines GL1
Figure 21
42
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
!NTIBODIES TO 4HE !NTI 4G ASSAY IS USED IN MONITORING THE COURSE OF (ASHIMOTOS THYROIDITIS AND FOR THE
thyroglobulin – DIFFERENTIAL DIAGNOSIS CASES OF SUSPECTED AUTOIMMUNE THYROIDITIS OF UNKNOWN ORIGIN WITH
anti-Tg NEGATIVE ANTI 40/ TEST RESULTS 'RAVES DISEASE WITHOUT LYMPHOCYTIC INlLTRATION AND TO
RULE OUT INTERFERENCE BY 4G AUTOANTIBODIES IN THE 4G TEST 4HE PREVALENCE OF ANTI 4G WAS
REPORTED OF ^ FOR THE GENERAL POPULATION21 The TgAb prevalence appears to be
two-fold higher than normal for patients diagnosed with differentiated thyroid cancer
$4# 22 The anti-Tg assay is also used to to verify measurements of the Tg test.
4ABLE SHOWS DETAILED RESULTS FOR ADULTS INCLUDING PREGNANT WOMEN AND CHILDREN OF
various age groups separated according to sex.
7ITH )5M, GROUP ', SELECTED ACCORDING TO THE .!#" CRITERIA FOR THE REFERENCE
INTERVAL DETERMINATION OF ANTI 40/ AND ANTI 4G EG ONLY MALES YEARS SHOWS CLEARLY
A LOWER CUTOFF AS COMPARED TO THAT OF %LECSYS !NTI 4G 4HE CUTOFF OF )5M, CURRENTLY
GIVEN IN THE PACKAGE INSERT IS STILL NOT COVERED BY THE UPPER LIMIT OF THE CONlDENCE
INTERVAL OF )5M,
4HE NON SELECTED GROUP OF BLOOD DONORS ', AND THE ', GROUP SHOW SIGNIlCANT HIGHER
values. These results are caused by the group of women, which gave essentially higher
VALUES P AND P
In pregnant women the anti-Tg concentrations are significantly higher in the 1st trimester
as compared to the 2nd and 3rd trimester. The results for the 2nd and the 3rd trimester
are nearly identical.
95 p CI 50% 95p CI 95p CI 95p CI
95% Year of
low quant. high low (95% high (95% n
quant. publ.
(median) median (median) quant.) quant.)
IU/mL IU/mL IU/mL IU/mL IU/mL IU/mL
Elecsys Anti-Tg package insert 115 392 2001
Adults 20–69 years
Group DL5 (NACB crit. for A-Tg) 90% c. 18.6 23.7 25.0 25 33 98 80 2004
Group GL2 (TSH+SD–Sono NAD) 16.4 16.9 17.6 218 350 415 632 2004
L2 Males 15.7 16.3 16.9 34 72 248 332 2004
L2 Females 17.2 18.2 19.2 402 436 531 300 2004
Group GL1 (all blood donors) 17.2 17.6 18.2 313 400 455 870 2004
L1 Males all 16.2 16.7 17.3 37 67 188 445 2004
L1 Females all 18.1 18.9 20.3 443 492 623 425 2004
Group P (Pregnancy)
1st Trimester 18.1 18.7 19.8 371 454 598 418 2004
2nd Trimester 16.0 16.5 17.4 113 166 231 369 2004
3rd Trimester 17.0 17.4 17.9 42 177 370 170 2004
Group GEL Children, Adolescents
0–6 Days 10.0 13 24.6 97.6 134 295 57 2007
6 Days 3 Months 14.6 23 33.3 125 146 182 83 2007
3 12 Months 10.0 13 17.0 103 130 180 91 2007
1 6 Years 11.8 13 12.9 27.0 38 57.1 337 2007
6 11 Years 12.3 13 13.7 29.7 37 77.1 253 2007
11 20 Years 13.4 14 14.6] 37.8 64 191 463 2007
Table 10
43
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
!NTIBODIES TO )N lGURE ANTI 4G RESULTS FOR THE SUBJECTS OF THE INDIVIDUAL GROUPS ', ', AND ',
thyroglobulin – of the population from Leipzig as well as for the pregnant women were plotted against the
anti-Tg 43( RESULTS OF THE SAME SAMPLES 4HE DASHED LINES CORRESPOND TO THE AND
CONTD QUANTILES OF 43( AND THE QUANTILE OF ANTI 40/ OF THE VALID REFERENCE INTERVALS AS
LISTED IN THE PACKAGE INSERTS 4HE CORRESPONDING AND CENTRAL RANGE IS IDENTIlED
,EIPZIG AND 0REGNANT BY GREY AREAS 4HE CONTINUOUS LINES AND THE WHITE AREAS CORRESPOND TO THE AND
7OMEN 43( VERSUS CENTRAL RANGE FOR 43( AND ANTI 4G OF THE INDIVIDUAL GROUPS ', ', AND ', AS STATED
anti-Tg in the legends. For the results of pregnant women the lines and the grey area correspond
TO GROUP ', THE WHITE AREA CORRESPONDS TO THE HIGHEST QUANTILE DURING PREGNANCY
The dependency of the reference values on the applied inclusion/exclusion criteria
BECOMES QUITE APPARENT
Group GL1 - all blood donors Group GL2 - TSH+Sono, NAD
(n = 870: 445 males %, 425 females ) (n = 632: 332 males %, 300 females )
100
100 100
100
10
10 10
10
Ref. interval 0.6-3.69
Ref. interval 0.3-3.69
TSH [mU/L] log
TSH [mU/L] log
1 11
0,1
0.1 0,1
0.1
0,01
0.01 0.01
0,01
0 200
200 400
400 600
600 800
800 1000
1000 1200
1200 00 200
200 400
400 600
600 800
800 1000
1000 1200
1200
anti-Tg [IU/mL] cutoff all 400; females 492; males 67 anti-Tg [IU/mL] cutoff all 350; females 436; males 72
Group GL1 - blood donors, males only % Group GL2 - TSH+Sono, NAD, males only %
(n = 445) (n = 332)
100
100 100
100
10
10 10
10
Ref. interval 0.3-3.89
Ref. interval 0.6-3.69
TSH [mU/L] log
TSH [mU/L] log
11 11
0.1
0,1 0.1
0,1
0.01
0,01 0.01
0,01
00 100 200
200 300 400
400 500 600
600 700 800
800 00 100 200
200 300 400
400 500 600
600 700 800
800
anti-Tg [IU/mL] cutoff males 67 anti-Tg [IU/mL] cutoff males 72
Group GL5 - (Anti-Tg-NACB) Pregnant women
(n = 80 males %) ( 1st ttim. n = 417, % 2nd trim. n = 368, 3rd trim. 169)
100
100 100
100
10
10 10
10
TSH [mU/L] log - lines GL1
Ref. interval 0.40-3.8
TSH [mU/L] log
1 11
0.1
0,1 0.1
0,1
0,01
0.01 0.01
0,01
00 20
20 40
40 60
60 80
80 100
100 120
120 140
140 00 200
200 400
400 600
600 800
800 1000
1000 1200
1200
anti-Tg [IU/mL] cutoff males 33 anti-Tg [IU/mL] - lines GL1
Figure 22
44
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.10 Thyroglobulin –Tg $URING 4G SYNTHESIS BY THYROCYTES AND THE TRANSPORT OF 4G TO THE FOLLICLES SMALL QUANTITIES
of the protein can pass into the bloodstream. Accordingly, low concentrations of Tg can
also be found in the blood of persons not suffering from thyroid diseases. Following
successful total thyroidectomy, Tg is no longer detectable.
In cases of congenital hypothyroidism the determination of Tg can be used to distinguish
between the complete absence of the thyroid gland and thyroid hypoplasia or other
pathological conditions. Tg is therefore regarded in particular as a marker for the mor-
phological integrity of the thyroid gland. The determination of Tg can also be useful in
distinguishing between subacute thyroiditis and factitious thyrotoxicosis.
4ABLE SHOWS DETAILED RESULTS FOR ADULTS INCLUDING PREGNANT WOMEN AND CHILDREN OF
VARIOUS AGE GROUPS SEPARATED ACCORDING TO SEX WOMEN TAKING CONTRACEPTIVES ARE IDENTIlED
SEPARATELY 4HE UPPER LIMIT OF THE CONlDENCE INTERVAL FOR THE QUANTILE
NGM, TO NGM, OF THE NON SELECTED GROUP OF BLOOD DONORS ', IS CLOSE TO THE
Tg value of 78 ng/mL given in the package insert for Elecsys Tg. No significant difference
WAS OBTAINED BETWEEN MALES AND FEMALES IN THE ', AND ', GROUPS P AND
P
4HE GROUP ', SELECTED ACCORDING TO THE .!#" CRITERIA FOR THE REFERENCE INTERVAL DETERMI-
NATION OF 4G EG 43( n M)5, AGE YEARS NON SMOKER ANTI 40/ AND ANTI 4G
NEGATIVE WITHOUT PERSONAL OR FAMILY HISTORY OF THYROID DYSFUNCTIONS SHOWS LOWER VALUES
FOR WOMEN THAN FOR MEN P 4HIS DOESNT CORRESPOND TO RESULTS REPORTED EARLIER
7ITH NGM, GROUP ', EVALUATED IN ACCORDANCE TO THE .!#" CRITERIA SHOWS CLEARLY A
LOWER CUTOFF FOR THE QUANTILE IF COMPARED TO THAT OF THE UNSELECTED GROUP OF BLOOD
DONORS WITH NGM, P 4HE QUANTILE OF NGM, FOR GROUP ', IS
SIGNIlCANTLY LOWER AS WELL P
The high Tg concentrations in the first months after birth start to approach those of the
adults starting with the 2nd year of age. The values are slightly lower than those of the
ADULT MEN 4HE MEDIANS OF THE SEX SPECIlC AGE GROUPS SHOWN IN GROUP ', DIFFER HIGHLY
SIGNIlCANTLY BETWEEN MALES AND FEMALES P 4HE CONCENTRATIONS OBTAINED IN THE
AGE GROUP n YEARS ARE SIGNIlCANTLY HIGHER P AS COMPARED TO THE GROUP IN THE
age 20–30 years – table 11.
In pregnant women the Tg concentrations are significantly higher in the 3rd trimester as
compared to the 2nd trimester. The results for the 1st and the 2nd trimester do not differ
significantly.
95 p CI 50% 95p CI 95p CI 95p CI
95% Year of
low quant. high low (95% high (95% n
quant. publ.
(median) median (median) quant.) quant.)
ng/mL ng/mL ng/mL ng/mL ng/mL ng/mL
Elecsys Tg package insert 78 130 2001
Adults 20–69 years
Group GL1 (all blood donors) 14 15 16 51 58 76 870 2004
L1 Males all 13 14 16 44 54 84 445 2004
L1 Males 20–39 y 11 12 14 33 38 47 286 2004
L1 Males 40–69 y 17 20 24 76 92 243 150 2004
L1 Females all 14 16 18 51 63 86 425 2004
L1 Females 20–39 y 12 14 16 37 41 56 270 2004
L1 Females 40–69 y 18 22 26 80 95 231 128 2004
L1 Fem. with contracept. 13 14 17 39 48 58 236 2004
L1 Fem. with contracept. 20–39 y 12 14 16 37 40 56 181 2004
L1 Fem. with contracept. 40–69 y 15 21 27 36 92 129 33 2004
L1 Fem. w/o contracept. 14 17 20 67 84 132 188 2004
L1 Fem. w/o contracept. 20–39 y 9.1 12 17 30 41 132 88 2004
L1 Fem. w/o contracept. 40–69 y 17 23 29 80 95 308 95 2004
Group GL2 (TSH+SD–Sono NAD) 12 13 14 39 43 50 632 2004
L2 Males 12 12 14 35 42 48 332 2004
L2 Females 12 13 16 39 46 60 300 2004
Group DL4 (NACB crit. for Tg) 90% c. 10 12 13 29 35 50 209 2004
L1 Males all 9 11 13 28 42 104 117 2004
L1 Females all 10 13 16 27 35 120 92 2004
Group P (Pregnancy)
1st Trimester 14 16 18 45 54 66 416 2004
2nd Trimester 12 13 15 38 46 59 368 2004
3rd Trimester 14 16 21 47 69 90 168 2004
Group GEL Children, Adolescents
0–6 Days 98 113 142 253 307 643 85 2007
6 Days 3 Months 81 91 105 190 228 278 96 2007
3 12 Months 49 55 58 111 125 158 118 2007
1 6 Years 26 28 29 61 67 74 339 2007
6 11 Years 15 16 17 35 43 55 249 2007
11 20 Years 12 12 13 32 36 40 454 2007
Table 11
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.10 Thyroglobulin –Tg )N lGURE 4G RESULTS FOR THE SUBJECTS OF THE INDIVIDUAL GROUPS ', ', AND ', OF THE
CONTD POPULATION FROM ,EIPZIG AS WELL AS FOR THE PREGNANT WOMEN WERE PLOTTED AGAINST THE 43(
RESULTS OF THE SAME SAMPLES 4HE DASHED LINES CORRESPOND TO THE AND QUANTILES
Leipzig and OF 43( AND THE QUANTILE OF 4G OF THE VALID REFERENCE INTERVALS AS LISTED IN THE PACKAGE
0REGNANT 7OMEN INSERTS 4HE CORRESPONDING AND CENTRAL RANGE IS IDENTIlED BY GREY AREAS 4HE
43( VERSUS 4G CONTINUOUS LINES AND THE WHITE AREAS CORRESPOND TO THE AND CENTRAL RANGE FOR
43( AND 4G OF THE INDIVIDUAL GROUPS ', ', AND ', AS STATED IN THE LEGENDS &OR THE
RESULTS OF PREGNANT WOMEN THE LINES AND THE GREY AREA CORRESPOND TO GROUP ', THE WHITE
AREA CORRESPONDS TO THE HIGHEST QUANTILE DURING PREGNANCY
The dependency of the reference values on the applied inclusion/exclusion criteria
BECOMES QUITE APPARENT
Group GL1 - all blood donors Group GL2 - TSH+Sono, NAD
(n = 870: 445 males %, 425 females ) (n = 632: 332 males %, 300 females )
100
100 100
100
10
10 10
10
Ref. interval 0.6-3.69
Ref. interval 0.3-3.89
TSH [mU/L] log
TSH [mU/L] log
1 11
0,1
0.1 0.1
0,1
0.01
0,01 0.01
0,01
00 40
40 80
80 120
120 160
160 200
200 240
240 280
280 320
320 360
360 00 40
40 80
80 120
120 160
160 200
200 240
240 280
280 320
320 360
360
Tg [ng/mL] cutoff 50 Tg [ng/mL] cutoff 43
Group GL4 - (Tg-NACB) Pregnant women
(n = 209, 117 males %, 92 females ) ( 1st trim. n = 417, % 2nd trim. n = 368, 3rd trim. 169)
100
100 100
100
10
10 10
10
TSH [mU/L] log - lines GL1
Ref. interval 0.62-3.59
TSH [mU/L] log
11 11
0.1
0,1 0.1
0,1
0.01
0,01 0.01
0,01
0 20
20 40
40 60
60 80
80 100
100 120
120 140
140 00 40
40 80
80 120
120 160
160 200
200 240
240 280
280 320
320 360
360
Tg [ng/mL] cutoff 35 Tg [ng/mL]- lines GL1
Figure 23
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
4.10 Thyroglobulin –Tg !S EXPECTED 4G SHOWED A SLIGHTLY DEPENDENCY ON THYROID VOLUME 0EARSONS R
CONTD – see figure 24.
Leipzig Blood 0EARSONS R 200
Donors – females
4' VERSUS 4HYROID %males
160
6OLUME
Elecsys Tg [ng/mL]
120
80
40
0
0 10 20 30 40 50 60
Thyroid volume [mL]
Figure 24
47
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
5 Conclusion
This brochure provides a rather complete survey of results on the reference intervals of
the Elecsys thyroid parameters. The data evaluated embrace the time-span from launch of
THE %LECSYS SYSTEMS UNTIL )N PARTICULAR STUDIES ON 43( AND 4 CONDUCTED IN
STUDIES ON F4 4 AND 4UPTAKE FROM 4G ANTI 4G ANTI 40/ FROM
and fT3 from 2003 are covered. To update and complete the children reference range
values a new study was performed in 2007.
7HEN THE NEW %LECSYS &4 TEST #AT .O WAS LAUNCHED A NEW REFERENCE VALUE
study was initiated for all Elecsys thyroid parameters to investigate whether there might
have been any significant shifts in the ranges obtained earlier. A further goal was to
characterize in great detail the most important influencing factors on thyroid parameters.
Allowing for minor changes in the estimated reference values due to the particular
compositions of the respective reference groups we observe a remarkable stability of the
reference intervals of the Elecsys thyroid parameters during the course of time. In fact,
there are only very few cases where the established reference value of the package insert
WAS NOT COVERED BY THE CONlDENCE INTERVAL OF THE NEWLY CALCULATED QUANTILE
In the very well characterized group of blood donors from Leipzig for most parameters
AGE AND SEX OF THE SUBJECTS COULD BE IDENTIlED AS THE MOST IMPORTANT INmUENCING FACTORS
Within the females, the use of oral contraceptives was another decisive influencing factor
OF THE VALUES )N THE FUTURE THE CONSIDERATION OF THESE FACTORS MAY JUSTIFY THE APPLICATION
of own reference intervals.
The number of pregnant women included in the study allows additional statements on
the values for all thyroid parameters differentiated according to trimesters. The ranges,
especially those for thyroid autoantibodies must be assessed under consideration of the
information available on the pregnant women.
The studies on the reference intervals of the thyroid parameters for children in Erlangen
and Leipzig allow statistically significant statements for the age groups. The reference
VALUES INDICATE QUITE DRAMATIC CHANGES IN THE LEVELS OF THE MOST THYROID PARAMETERS DURING
early childhood.
48
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
6 References
$EMERS ,- 4HYROID DISEASE PATHOPHYSIOLOGY AND DIAGNOSIS #LIN ,AB -ED n
$EMERS ,- 3PENCER #! .ATIONAL !CADEMY OF #LINICAL "IOCHEMISTRY .!#" ,ABORATORY 3UPPORT FOR THE
Diagnosis and Monitoring of Thyroid Disease. 2002
53 0REVENTIVE 3ERVICES 4ASK &ORCE 3CREENING FOR 4HYROID $ISEASE 2ECOMMENDATION 3TATEMENT
!NN )NTERN -ED n
!NDERSEN 3 "RUUN .( 0EDERSEN +- ,AURBERG 0 "IOLOGIC 6ARIATION IS )MPORTANT FOR )NTERPRETATION OF
4HYROID &UNCTION 4ESTS 4HYROID n
3URKS -) /RTIZ % $ANIELS '( 3AWIN #4 .ANADA & #OBIN 2( ET AL 3UBCLINICAL 4HYROID $ISEASE n
3CIENTIlC 2EVIEW AND 'UIDELINES FOR $IAGNOSIS AND -ANAGEMENT *!-! n
-ONACO & #LINICAL 0ERSPECTIVE n #LASSIlCATION OF 4HYROID $ISEASES 3UGGESTIONS FOR A 2EVISION
* #LIN %NDOCRINOL -ETAB n
$AYAN #- 2EVIEW )NTERPRETATION OF THYROID FUNCTION TESTS ,ANCET n
.ANADA & 3URKS -) $ANIELS '( 3UBCLINICAL 4HYROID $ISEASE n #LINICAL !PPLICATIONS 3CIENTIlC 2EVIEW
*!-! n
,OCK 2* -ARDEN .! +EMP (* 4HOMAS 0( 'OLDIE $* 'OMPELS -- 3UBCLINICAL HYPOTHYROIDISM A
COMPARISON OF STRATEGIES ADHERENCE TO TREATMENT GUIDELINES !NN #LIN "IOCHEM n
3COlELD (2 2APID 2EVIEW !UTOANTIBODIES AS PREDICTORS OF DISEASE ,ANCET n
:IGMAN *- #OHEN 3% 'ARBER *2 )MPACT OF 4HYROXINE "INDING 'LOBULIN IN 4HYROID (ORMONE %CONOMY
$URING 0REGNANCY 4HYROID n
"JORO 4 (OLMEN Y +RÓGER / -IDTHJELL + (UNDSTAD +$ 3CHREINER 4 ET AL 0REVALENCE OF THYROID DISEASE
THYROID DYSFUNCTION AND THYROID PEROXIDASE ANTIBODIES IN A LARGE UNSELECTED POPULATION 4HE (EALTH 3TUDY
OF .ORD 4RONDELAG (5.4 %UR * %NDOCRIN n
)&## !PPROVED RECOMMENDATION ON THE THEORY OF REFERENCE VALUES 0ART 3TATISTICAL TREATMENT OF COLLECTED
REFERENCE VALUES $ETERMINATION OF REFERENCE LIMITS * #LIN #HEM #LIN "IOCHEM Cn
(ARRIS %+ "OYD *# 3TATISTICAL BASES OF REFERENCE VALUES IN THE LABORATORY MEDICINE $EKKER - ED
)NC .EW 9ORK
3!3 )NSTITUTE /NLINE $OCUMENTATION 6
(AHN ' -EEKER 71 3TATISTICAL )NTERVALS ! 'UIDE FOR 0RACTITIONERS 7ILEY 3ERIES IN 0ROBABILITY
-ATHEMATICAL 3TATISTICS
&UENTES !RDERIU 8 &ERRER -ASFERRER - 'ONZÕLEZ !LBA *- 6ILLARINO 'ONZÕLEZ -) !RRIMADAS %STEBAN %
#ABRERO /LIV£ $ ET AL -ULTICENTRIC REFERENCE VALUES FOR SOME QUANTITIES MEASURED WITH THE %LECSYS
ANALYSER #LIN #HIM !CTA n
(UBL & 3CHMIEDER * 'LADROW % $EMANT 4 2EFERENCE )NTERVALS FOR 4HYROID (ORMAONES ON THE !RCHITECT
!NALYSER #LIN #HEM ,AB -ED n
'ONZÕLEZ 3AGRADO - -ART¤N 'IL &* 0OPULATION SPECIlC REFERENCE VALUES FOR THYROID HORMONES ON THE
!BBOTT !2#()4%#4 I ANALYZER #LIN #HEM ,AB -ED n
20 Spencer CA. Takeuchi M, Kazarosyan M. Current status and performance goals for serum thyrotropin
43( ASSAYS #LIN #HEM n
(OLLOWELL *' 3TAEHLING .7 (ANNON 7( &LANDERS 7$ 'UNTER %7 3PENCER #! ET AL 3ERUM THYROTROPIN
THYROXINE AND THYROID ANTIBODIES IN THE 5NITED 3TATES POPULATION TO .(!.%3 ))) * #LIN
%NDOCRINOL -ETAB
3PENCER #! 7ANG # &ATEMI 3 'UTTLER 2" 4AKEUCHI - AND +AZAROSYAN - 3ERUM 4HYROGLOBULIN !UTOANTI-
BODIES 0REVALENCE INmUENCE ON SERUM THYROGLOBULIN MEASUREMENT AND PROGNOSTIC SIGNIlCANCE IN PATIENTS
WITH DIFFERENTIATED THYROID CARCINOMA * #LIN %NDOCRINOL -ETAB
+OENKER 2 AND (ALLOCK + 1UANTILE REGRESSION *OURNAL OF %CONOMIC 0ERSPECTIVES
#HEN # !N )NTRODUCTION TO 1UANTILE 2EGRESSION AND THE 1UANTREG 0ROCEDURE 3!3 )NSTIUTE 35')
213-30.
+GER 2 2OCHE INTERNAL REPORT
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
Notes
ELECSYS, COBAS, COBAS E and LIFE NEEDS ANSWERS
are trademarks of Roche.
Other brand or product names are trademarks
of their respective holders.
© 2009 Roche
Roche Diagnostics GmbH
68298 Mannheim
Germany
[Link]
04640292001 1 0309 – 1.0 Kn
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