Reference Brochure Thyroid 2011

Reference Intervals for Children
and Adults
Elecsys Thyroid Tests

FT3, T3, T-Uptake, Anti-TPO, Anti-Tg
Elecsys systems 2010

MODULAR ANALYTICS E170
cobas e 411, cobas e 601 and cobas e 602 analyzers
Reference Intervals Elecsys and cobas e analyzers
for Children and Adults Elecsys Thyroid Tests
2
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 0–19 years, 2003/2004/2007 6
3.1.2 Adults (20–69 years), Leipzig, Germany, 2003/2004 6
3.1.3 Pregnant women, Essen and Hamburg, Germany, 2004 7
3.1.4 Reference population mentioned in the package inserts 8
3.1.5 Local reference intervals, groups for fT3 8
3.2 Analytical methods 9
3.3 Statistical methods, Terminology 9–11
4 Results and Discussion 12–23
4.1 Cross-parameter results and explanations on the following chapters 12

4.2 Free triiodothyronine – fT3 13–15
4.3 Total triiodothyronine – T3 16–19
4.4 Thyroxine-binding capacity 19–21
4.5 Antibodies to thyroid peroxidase – anti-TPO 22
4.6 Antibodies to thyroglobulin – anti-Tg 23

5 Conclusion 24
6 References 25
Significant additions or changes are indicated by a change bar in the margin.
3
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 2010 and
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 performed
in 2007.
2 Summary
Reference ranges for all Elecsys thyroid parameters are available for the following groups:
• Children and adolescents from Erlangen and Leipzig, Germany (from birth to 19 years)
characterized as clinically healthy with respect to thyroid disorders.
• Adults from Leipzig, Germany (20 to 69 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:
1) Inclusion of all blood donors considered healthy.
2) Exclusion of persons with noticeable sonographic results (thyroid volume and
density) and TSH concentrations outside the reference limits (ADVIA Centaur, Bayer,
Germany).
3) Inclusion and exclusion criteria according to the guidelines of the National Academy
of Clinical Biochemistry (NACB) for the determination of reference intervals (criteria
applied to all parameters except anti-TPO and anti-Tg, evaluated according to the
corresponding specific criteria of the NACB guidelines).
• Healthy pregnant women from Essen and Hamburg, Germany, (1st, 2nd, and 3rd
trimester)
Additional reference groups used by clinical centers or commercial labs in various countries
for Elecsys thyroid parameters (selection criteria were partly autoantibodies, anti-TPO, or a
clinical characterization) are available:
• Norway: from Molde and Sandefjord for fT3.
• Austria: from Vienna for fT3.
• Germany: from Hamburg, Heidelberg for fT3.
• Sweden: results from a study on EQALIS for anti-TPO.
Additional results for patients with serious nonthyroidal illnesses (NTIs) and dialysis
patients and for hypo- and hyperthyroid patients for fT3 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 4.2–4.6 show the individual results
of all groups and the corresponding 95 % confidence ranges and the dependencies on
potentially influencing factors for all thyroid tests.
4
With respect to concentrations (standardization) and assay performance, the currently

available Elecsys thyroid tests have not been changed since launch. The reference intervals
(expected values) given in the package inserts were confirmed 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 95 % confidence interval of the expected values (2.5 % and
97.5 % or 95 % 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:
• Dependency of the values from sex over all age groups
Significant (p < 0.05): fT3, T-uptake
Not significant: T3
• Dependency of the values from contraceptives over all age groups:
Significant (p < 0.05): T3, T-uptake
Not significant: fT3
Using all 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: ⇑ = significantly elevated values (p < 0.05 and lower); ⇓ = significantly depressed values
(p < 0.05 and lower); ⇔ = no significant difference between values (Median test and Median
Chi-Square test or Tukey’s Studentized Range HSD test).
fT3 T3 T-upt. A-TPO A-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 ⇔ ⇔ ⇔ ⇔ ⇔
5
3 Subjects, Materials and Methods
3.1 Description of reference The information on the subjects and patient groups tested for the reference intervals
population groups information is summarized below. In addition to the populations tested for the latest studies
in Erlangen and Leipzig, Essen, and Hamburg, 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 adolescents sample material (serum and plasma collected in Erlangen, Germany, between May and
0-20 years Erlangen and August 2003 and in Leipzig, Germany, between January and June 2006). This combined
Leipzig, Germany collective is referred to as Group GEL in the brochure. In the subgroup Erlangen a total of
2003/2004/2007 420 specimens and in the subgroup Leipzig a total of 1004 specimens of newborns, children
and adolescents of both sexes between the ages of 0 and > 20 was included. Depending on
the parameter between 53 – 473 specimens in each of the GEL subgroups are shown.
The exclusion and inclusion criteria for both groups were similarly applied:
• No previous or acute thyroid disorder
• Not in intensive care
• No post-operative care
• No family history of thyroid disorder (Erlangen)
• No endocrine disorders or severe non-endocrine diseases that may influence the Thyroid
function (Leipzig).
The general presence of autoantibodies was not an exclusion criterion.
Measurements were taken for fT3, T3, T-uptake, anti-TPO, and anti-Tg.
3.1.2 Adults L
eipzig, To determine the reference ranges of all thyroid parameters, in 2003/2004, at the
Germany 2003/2004 “Universitätsklinikum Leipzig”, Germany, from May to August serum specimens were used
from a total of 870 blood donors between the ages of 18 and 60 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.
The TSH inclusion or exclusion criteria were ensured based on the results of a commercially
available test (ADVIA Centaur, Bayer, Germany).
The following groups were formed – assessment for all thyroid test parameters
• Group GL1: Blood donors, all men and women: all tested blood donors – no exclusions
• Group GL2: Normal thyroid ultrasound (volume and structure), ADVIA Centaur TSH
within reference range.
• Group GL3: Inclusion and exclusion criteria according to Guideline 22 of the National
Academy of Clinical Biochemistry (NACB), USA 2002 – Recommendations on determin-
ing reference intervals of TSH:2 No visible or palpable goiter, anti-TPO, anti-Tg negative
(determined from Elecsys results), subjects with personal or family history of thyroid
dysfunction excluded, no medications (except contraceptives). There are no other
laboratory parameters covered except for the autoantibodies.
Additionally for antibodies to thyroid peroxidase:
• Group GL5: Inclusion and exclusion criteria according to Guideline 33 of the NACB,
USA 2002 – Recommendations on determining reference intervals of anti-TPO: Men,
TSH between 0.5–2.0 mIU/L, age < 30 years, no goiter, no non-thyroid autoimmune
diseases (e.g. lupus erythematosus or diabetes).
6
3.1.3 Pregnant women Group P: Women in their 1st, 2nd, and 3rd trimester of pregnancy.
Essen/Hamburg, The group consists of 957 samples of healthy, pregnant women from Essen (436) and 521
Germany 2004 samples from healthy, pregnant women (< 40 years) from Hamburg 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, fT3
concentrations < 3 pmol/L and fT4 concentrations > 22 pmol/L. Samples with TSH concentra-
tions outside a range of 0.1 to 10 µIU/mL were excluded in both groups.
Number of individuals The following table combines the newly investigated three population groups (children from
of the reference Erlangen, adults, children from Leipzig and pregnant women from Essen and Hamburg) and
population tested 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 T3 A-TG A-TPO TUP

n n n n n
Male
0 ≤ 6 Days 51 49 28 27 29
> 6 Days ≤ 3 Months 55 50 51 35 35
> 3 ≤ 12 Months 69 59 55 48 52
> 1 ≤ 6 Years 203 202 198 192 197
> 6 ≤ 11 Years 139 139 134 131 133
> 11 ≤ 20 Years 227 229 224 221 225
> 20 ≤ 30 Years 201 201 201 201 200
> 30 ≤ 40 Years 110 110 110 110 110
> 40 ≤ 50 Years 91 91 91 91 91
> 50 ≤ 60 Years 48 48 48 48 48
> 60 ≤ 70 Years 31 31 31 31 31
Female
0 ≤ 6 Days 58 51 29 27 31
> 6 Days ≤ 3 Months 51 45 32 22 29
> 3 ≤ 12 Months 46 42 36 24 36
> 1 ≤ 6 Years 144 140 139 135 138
> 6 ≤ 11 Years 126 128 119 116 120
> 11 ≤ 20 Years 243 244 239 236 237
> 20 ≤ 30 Years 224 224 224 224 224
> 30 ≤ 40 Years 118 118 118 118 118
> 40 ≤ 50 Years 105 105 105 105 104
> 50 ≤ 60 Years 45 45 45 45 45
> 60 ≤ 70 Years 22 22 22 22 22
Total
0 ≤ 6 Days 109 100 57 54 60
> 6 Days ≤ 3 Months 106 95 83 57 64
> 3 ≤ 12 Months 115 101 91 72 88
> 1 ≤ 6 Years 347 342 337 327 335
> 6 ≤ 11 Years 265 267 253 247 253
> 11 ≤ 20 Years 470 473 463 457 462
> 20 ≤ 30 Years 425 425 425 425 423
> 30 ≤ 40 Years 228 228 228 228 228
> 40 ≤ 50 Years 196 196 196 196 195
> 50 ≤ 60 Years 93 93 93 93 93
> 60 ≤ 70 Years 53 53 53 53 53
Table 1
7
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 the package inserts for the Elecsys thyroid parameters see below:
package inserts • The study was conducted in late 1997/early 1998 to validate the reference intervals, which
1995/96 up to 1998 were established in 1995/1996 at the time of the introduction of the Elecsys systems or in
T3, T-uptake, some cases adopted from the previous tests – the Enzymun-Test parameters.
The reference population which is the basis for the information in the current package
2000 / 2001
inserts, consisted of women and men between 25 and 60 years of age whose serum
anti-TPO, anti-Tg
samples were measured in routine tests in clinical centers in Belgium, Japan, and
Germany.
The groups consisted of blood donors in addition to hospital inpatients and outpatients.
The TSH 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.
No information on possible pregnancies was available in the female groups.
The number of samples, which varied from 370 to 2526, depending on the test parameter,
is given in the tables in the chapters on the individual tests.
Measurements were taken for T3 and T-uptake.
The reference population tested for anti-TPO and anti-Tg in 2000/2001 consisted of
subjects whose TSH and fT4 concentrations were within the euthyroid range and the
clinical appearance was without any signs for thyroid dysfunction.
3.1.5 Reference population During the product launch of the Elecsys FT3 test, 03051986, in July 2003, local
for fT3 reference intervals were determined in clinical centers in Norway, Austria, and Germany,
which have kindly been provided to us for publication.
Local reference intervals
• Group N: Combined population, n = 604, Molde and Sandefjord, Norway: inclusion
criteria: TSH concentrations between 0.3–3.6 mIU/L [results published by Bjoro et. al.
2000 “Health Study of Nord-Trondelag” (HUNT) Study]11 and fT4 concentrations
between 11–22 pmol/L. This fT4 reference interval has been used in Norway for the
Elecsys method since 1998. For some specimens, the criterion anti-TPO negative was
applied. However anti-TPO measurements are not available for all samples. The same is
true for age information. In Sandefjord there were 237 outpatients; in Molde the 367 test
subjects were approximately 30 % outpatients and 70 % inpatients.
• Group GHH: Hamburg, Germany, population for fT3 n = 5366: These samples came
from a large commercial community laboratory. The criterion for inclusion was a TSH
concentration from 1–3 mIU/L. No other information on the patients was analyzed. This
corresponds to a so-called “routine collective” as was also used for earlier reference
interval determinations.
• Group GHD: Heidelberg, Germany, population for fT3, n = 374: For the inclusion/
exclusion criteria and the type of laboratory see group GHH.
• Group A: Vienna, Austria, population for fT3: Specimens from 127 clinically
characterized euthyroid patients were used. The main criteria were: no history of thyroid
medication, thyroid palpation negative, TSH concentrations within the reference range of
the routine method.
• Group SE: Reference range determined using EQALIS, Helsingborg/Boras and
Västeras, Sweden, for anti-TPO: The reference population is composed of: 157 and 100
blood donors in Västeras und Boras, respectively, 149 women, age 19–65 years; 151 men,
age 18–67 years in Helsingborg and healthy hospital staff, n = 200. Inclusion criteria for
this group were: no family history of thyroid disorder, no goiter, no medication except
contraceptives. The analysis for anti-TPO was made according to the NACB guidelines.
Thailand: 967 specimens from euthyroid subjects. No other information on the subjects was
given.
8
3.2 Analytical methods To determine the reference intervals, the Roche Electro-ChemiLuminescence ImmunoAssays,
“ECLIA,” Elecsys FT3, T3, T-Uptake, Anti-TPO, and Anti-Tg assays 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.
The performance data of the tests are described in the package inserts.
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 Essen and
Hamburg are dealt with below.
The clinical-chemical laboratory parameters were measured with the Roche Diagnostics tests.
Thyroid ultrasonography was performed on all subjects by trained physicians using an EUB-405
plus device equipped with a 7.5 MHz linear transducer (Hitachi).
Thyroid volume was calculated as length x width x depth x 0.479 (mL) for each lobe. Goiter was
defined as a thyroid volume exceeding 18 mL in women and 25 mL 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 classified as inhomogeneous. Visual nodular changes were defined as nodules.
Body mass index (BMI) was calculated using the formula: BMI = weight [kg] /
height2 [m]2 .
3.3 Statistical methods Study Population:

Frequency tables and bar charts provide an overview of the study population.
Assay data:
The dependency of assay results on clinical parameters (age, gender, medication) and
measurement conditions (study site) is visualized in scatter and dot plots.
Pooling of data:
To 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. About 50 % of
the 54 (9 assays times 6 age groups) center comparisons have been found to have statistically
significant differences. Boxplots to investigate the relevance of the observed differences have
been generated, too.12 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.12,13,14
Age dependent quantile curves:
Age dependent 2.5 and 97.5 percent reference limits have been determined as smooth curves by
means of quantile regression using the SAS V 9.1 system. Quantile regression is a statistical
technique to estimate and conduct inference about conditional quantile functions.13,14 A linear
model utilizing non-integer powers of the explanatory variable age has been used for all assays.
The 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 adolescence. In this regime we profit most from the smoothing
of the quantile regression curves.
9
3.3 Statistical methods Quantiles:

cont’d. According to the recommendation of the International Federation of Clinical Chemistry
and Laboratory Medicine (IFCC), nonparametric quantiles are used as reference values.15,16
To evaluate the reliability of these quantiles additionally the computation of respective
confidence limits is recommended. In this brochure, two approaches have been used for
the derivation of the quantiles and their corresponding two-sided confidence limits.
(i) The nonparametric procedures introduced by Hahn and Meeker17 with SAS V 8.2.18
(ii) Quantiles were obtained as readings from age dependent quantile regression curves. In
particular for the juvenile age group classes, the age class midpoints are used to derive the
respective 2.5 and 97.5 percent reference limits and their respective confidence limits.
However, to minimize updating effort the Hahn-Meeker class-specific quantiles are kept for
the elder age classes as these have been proven useful over a couple of years. A crosscheck
has demonstrated that for these classes the quantile regression curve derived quantiles and
the Hahn-Meeker quantiles closely agree.
Comparison of clinical groups:
For the evaluation of the significance of the differences in assay results between clinically
defined groups either a Wilcoxon Rank Sum -, a Median Chi Square -, or a Kruskal Wallis
-test has been applied as appropriate. However, as sample sizes have not been designed
biostatistically, p values are descriptive. Graphically different clinical groups are represented
by dot plots. For multiple pair-wise comparisons a Tukey’s Studentized Range HSD 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 fixed block factor (age class) and a fixed treat-
ment factor (contraceptive). The error term for testing the significance of the treatment
effect is the block-treatment-interaction. The generalized linear model approach 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 param-
eters 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 fixed block factor (age class) and a treatment factor (sex). The error
term for testing the treatment effect (sex) is the block-treatment-interaction. The general-
ized 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 Median Chi square test. For the respective pair-wise comparisons a
Tukey’s Studentized Range HSD test (alpha = 0.05) has been executed. A difference is
considered statistically significant if the simultaneous 95 % confidence limits of the differ-
ence between means does not include zero.
10
Terminology Reference population / reference group: Random sample from the population of asymptom-
atic patient specimens. The reference population provides the basis for determining reference
intervals. The reference population is also called reference group.
Reference intervals / reference range / reference values / expected values: In accordance
with IFCC recommendations, the reference intervals or reference ranges are the non-parametri-
cally estimated 2.5 % and 97.5 % quantiles (= percentiles) of the reference population. The
2.5 % quantile designates the value for which 2.5 % of the data are smaller or equal than this
value; the 97.5 % quantile designates the value for which 97.5 % of the data are smaller or equal
than the quantile value. Occasionally 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 (e.g. 2.5 % of all data are below and above this range) – Figure 1.
Elecsys package inserts contain the term expected values instead of reference values or reference
intervals.
Confidence interval: In the given context, the range around the estimated quantile, which
includes the true value of the quantile with a given coverage probability. The confidence interval
decreases in size as the sample size increases. Figure 1 shows the position of the 95 % confidence
intervals of the 2.5 %, the 50 % (median) and 97.5 % quantile.
Coverage probability: Probability (typically a value of 95 % is selected if possible) that the true
quantile value is covered by the confidence interval. Samples that are too small lead to insuffi-
cient 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
4 Results and Discussion
4.1 Cross-parameter results For the Leipzig blood donor group, the scatter plots of Figure 2 show the age-dependent
distribution of albumin, TBG and thyroid volume in addition to the thyroid parameters
(see chapters 4.2–4.6). There is no correlation between thyroid parameters and protein
concentration or body mass index. Information on a correlation between the concentration
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
Thyroid 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

Thyroxine binding globulin (TBG) [mg/L]
50 50
Thyroxine binding globulin (TBG) [mg/L]
50 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 ]
î Females With contraceptives
D Males î W/o contraceptives
Figure 2
Explanation on the The following details apply to each of the parameters tested:
following chapters • Age-dependency from birth to 69 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 – age: birth
to 20 years – and the individual data of the Leipzig adult group – age: 20–69. The lines
connect the medians and the 2.5 % and 97.5 % quantiles of the selected age groups of
children, youths, and adults.
• Tables with data from all evaluated test groups:
A table shows the values for all analyzed groups of the respective 95 % central ranges and
the corresponding 95 % confidence intervals for the 2.5 %, median and 97.5 % quantiles
(exception: anti-TPO and anti-Tg: median and 95 % quantiles).
12
4.2 Free triiodo- Establishing values in reference range studies is based primarily on samples obtained from
thyronine – fT3 outpatient clinics, hospitals, and commercial laboratories. TSH and fT4 levels are found to be in
the euthyroid ranges 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. Besides 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 2a and 2b.
Tables 2a and 2b 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.
The median fT3 results of the groups from Leipzig do not differ significantly (p = 0.592).
95p CI low 95p CI high 95 p CI 50 % 95p CI 95p CI low 95p CI high

2.5 % 97.5 % Year of
(2.5 % (2.5 % low quant. high (97.5 % (97.5 % n
quant. quant. publ.
quant.) quant.) (median) median (median) 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. 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
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 2a: SI units
13
4.2 Free triiodo- Significant differences between males and females in group GL1 were observed especially for
thyronine – fT3 the lower limit of the 95 % central range. Literature references describe both significant and
cont’d. nonsignificant differences between the sex groups.19,20 In our study differences were highly
significant (p < 0.01) in all groups (GL1, GL2 and GL3). Males show higher values as
compared to women especially for the 2.5 % 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 = 0.092).
As expected, pregnant women have lower fT3 concentrations correlated with the gestational
age. The median values in the 1st, 2nd and 3rd trimester differ significantly (p < 0.05)
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 GHH group listed also in the package insert.
Local differences as well as differences caused by the composition of the groups can be
observed.

2.5 % 97.5 % Year of
(2.5 % (2.5 % low quant. high (97.5 % (97.5 % n
quant. quant. publ.
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
Group GL1 (all blood donors) _ins. 2.39 2.53 2.60 3.27 3.32 3.35 4.26 4.34 4.56 870 2004
final
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
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
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
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
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 2b: conventional units
14
4.2 Free triiodo- Figure 3 shows all data for children and adults from birth to 69 years using separate symbols to
thyronine – fT3 distinguish between male and female subjects.
cont’d.
The dependency of the fT3 concentration levels on sex is statistically significant for all age
groups.
The medians of the age groups shown in group GL1 do not differ significantly (males p = 0.946,
females p = 0.133) – Tables 2 a/b.
fT3 (pmol/l)
age
DDD male îîî female
Figure 3

Leipzig Blood Donors - No dependency of fT3 (Pearson’s r = –0.09) was observed on the TBG concentrations measured
fT3 versus TBG in the Leipzig group GL1 – see Figure 4.
Group GL1 Females

10
10 12
10
88
Elecsys FT3 [pmol/L]
Elecsys FT3 [pmol/L]
8
66
44
22
2
00 0
00 1010 2020 3030 4040 5050 0 10 20 30 40 50
î Females TBG [mg/L] î With contraceptives
D Males W/o contraceptives
Figure 4
15
4.3 Triiodothyronine – 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. As with T4, over 99 %
of T3 is bound to transport proteins. However, the affinity of T3 to them is around
10-fold lower.
Patients with abnormal TBG, e.g. during pregnancy, estrogen therapy, as well as genetic
abnormalities in binding proteins, are influencing the concentration level of the
measurements. 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 confirmed especially when considering the 95 % confidence 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 – see Tables 3a– 3b.
Tables 3a and 3b show detailed results for adults (including pregnant women) and children
of various age groups separated according to sex; women taking contraceptives are identi-
fied 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 (2.5 % quantile) and the median.

2.5 % 97.5 % Year of
(2.5 % (2.5 % low quant. high (97.5 % (97.5 % n
quant. quant. publ.
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
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
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
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
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
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 3a: SI units
16
4.3 Triiodothyronine – T3 Significant differences between males and females in the group of blood donors from Leipzig,
cont’d. GL1, were observed especially for the upper limit of the 95 % central range. In our study,
differences were highly significant (p < 0.001) in all groups: GL1, GL2 and GL3 (NACB for TSH).
Males show significantly lower values compared to women, in case all women were evaluated
totally (p < 0.001).
A clear dependency on the increased TBG concentration caused by the intake of contraceptives
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 < 0.001). The results from the group of women which did not take contraceptives approxi-
mate 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 Heidelberg.
As expected, pregnant women have higher T3 concentrations correlated with the gestational age.
The median values in the 1st, 2nd and 3rd trimester differ significantly (p < 0.05) between each
other.

2.5 % 97.5 % Year of
(2.5 % (2.5 % low quant. high (97.5 % (97.5 % n
quant. quant. publ.
ng/mL ng/mL ng/mL ng/mL ng/mL ng/mL ng/mL ng/mL ng/mL
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
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
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
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
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 3b: conventional units
17
4.3 Triiodothyronine – T3 Figure 5 shows all data for children and adults from birth to 69 years using separate symbols
cont’d. to distinguish between male and female subjects.
The high T3 concentrations in the first days after birth decrease continuously.
T3 (nmol/l)
age
Figure 5
18
4.3 Triiodothyronine – T3 As expected a significant dependency of T3 on the TBG concentrations measured was observed
cont’d. in the Leipzig group GL1. This effect explains the higher values of women compared to those
of men. Among the group of women further increased values were caused by the contraceptives
Leipzig Blood taken. For the correlation presented in the scatter plots the T3 concentrations were multiplied
Donors – T3 versus by the factor 10 (F = 10).
TBG and Albumin No relevant dependency of T3 on albumin was observed – see lower scatter plot in F igure 6.
Group GL1 Females

5050
50
50
Elecsys T3 [nmol/L x 10]

40
40 4040
30
30 3030
20
20 2020
10
10 1010
Pearson’s r = 0.589 Pearson’s r = 0.643

0
00 0
00 10
10 20
20 30
30 40
40 50
50 0 0 10 10 20 20 30 30 40 40 5050
î Females î With contraceptives

D Males TBG [mg/L] W/o contraceptives
50
60 50
50
Pearson’s r = - 0.228 Pearson’s r = - 0.262
40 40

48 40
30
36 30
30
20
24 20
20
10
12 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 6
4.4 Thyroxine-binding As the major part of the total thyroxine is bound to transport proteins (TBG, prealbumin, and
capacity albumin), the determination of total thyroxine only provides correct information when the
thyroxine-binding capacity in serum is normal. The free thyroid hormones are in equilibrium
with the hormones bound to the carrier proteins. A change in the TBG 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.
Determination of the free thyroxine index (fT4I) from the ratio of total T4 and TBI (thyroxine-
binding index = result of the T-uptake determination) takes into account changes in the thyroid
hormone carrier proteins and the thyroxine level.
Table 4 shows detailed results for adults (including pregnant women) and children of various
age groups separated according to sex; women taking contraceptives are identified separately.
The data basically confirms the reference interval currently given in the Elecsys T-Uptake package
insert. The 97.5 quantile value is slightly lower. The reference limit currently given is within the
95 % confidence interval for the group of women and as such in line with the new results.
19
4.4 Thyroxine-binding There is no significant difference between the median values of the different groups of blood
capacity donors from Leipzig evaluated also (p = 0.432 and p = 0.799). The ranges are again nar-
cont’d. rower as compared to those of the described groups.
In our study males show significantly lower values (p < 0.001) in all groups: GL1, GL2 and
GL3 (NACB for TSH) 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 depen-
dency on the increased TBG concentration caused by the intake of contraceptives could be
observed also for T-uptake.
The median value of 1.0 TBI which was set arbitrarily for a group of healthy subjects
(women without taking contraceptives) was confirmed in all groups evaluated.
As expected T-uptake concentrations are increasing with gestational age. The median values
in the 1st, 2nd and 3rd trimester differ significantly (p < 0.05) between each other.
Figure 7 shows all data for children and adults from birth to 69 years using separate symbols
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.
The medians of the sex-specific age groups shown in group GL1 do not differ significantly
among the group of males (p = 0.859). Females had significantly lower values (p < 0.001) in
the age group 40–69 years as compared to the age group 20–30 years – Table 4.
T-uptake (TBI)
age
Figure 7: T-uptake
20
4.4 Thyroxine-binding 95p CI low 95p CI high 95 p CI 50 % 95p CI 95p CI low 95p CI high
2.5 % 97.5 % Year of
capacity, cont’d. (2.5 %
quant.
(2.5 % low quant. high (97.5 %
quant.
(97.5 % n
publ.
TBI TBI TBI TBI TBI TBI TBI TBI TBI
T-uptake Elecsys T-Uptake Insert Europe/Japan 0.80 1.00 1.30 974 1998
Elecsys T-Uptake Insert USA 99 % 0.78 1.39 275 1998
centr.
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
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
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
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 4
21
4.5 Antibodies to The determination of anti-TPO used together with TSH is recommended also for the
thyroid peroxidase – detection of suspected dysfunction especially regarding the long-term risk of the
anti-TPO development of a thyroid disease and after pregnancy. The determination of anti-TPO is
also recommended with subclinical hypo-thyroidism.9
Table 5 shows detailed results for adults (including pregnant women) and children of
various age groups separated according to sex, including the group EQALIS from Sweden.
The selection of inclusion and exclusion criteria clearly influences the cutoff level.
The group GL5 selected according to the NACB criteria for the reference interval
determination of anti-TPO and anti-Tg (e.g. only males < 30 years) shows with 28.1 IU/mL
a lower cutoff as compared to that of the Elecsys Anti-TPO assay. The cutoff of 34 IU/mL
currently given in the package insert is close to the upper limit of the 95 % confidence
interval of 32.7 IU/mL.
The cutoff of 37 IU/mL obtained for the men in group GL2 is in line with that given in the
Elecsys Anti-TPO package insert.
The non-selected group of blood donors, GL1, and the GL2 group show significantly higher
values. These results are caused by the group of women, which gave essentially higher values
(p < 0.001 and p = 0.031) – see Table 5.
The cutoff published by the EQALIS is the lowest with a 95 % quantile limit of 19 IU/mL.
In pregnant women the anti-TPO concentrations are slightly higher in the 3rd trimester.
There is no significant difference between the three trimesters.
95 p CI low 50 % quant. 95p CI high 95p CI low 95p CI high
95 % quant. n Year of publ.
(median) median (median) (95 % quant.) (95 % quant.)
IU/mL IU/mL IU/mL IU/mL IU/mL IU/mL
Elecsys Anti-TPO package insert 34 208 2000
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
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
Group SE (EQALIS) 19 2003
Table 5
22
4.6 Antibodies to The anti-Tg assay is used in monitoring the course of Hashimoto’s thyroiditis and for the
thyroglobulin – differential diagnosis (cases of suspected autoimmune thyroiditis of unknown origin with
anti-Tg negative anti-TPO test results, Graves’ disease without lymphocytic infiltration, and to rule out
interference by Tg-autoantibodies in the Tg test). The prevalence of anti-Tg was reported of
~10 % for the general population.21 The TgAb prevalence appears to be two-fold higher than
normal for patients diagnosed with differentiated thyroid cancer (DTC).22
Table 6 shows detailed results for adults (including pregnant women) and children of various
age groups separated according to sex.
With 33.5 IU/mL, group GL5 selected according to the NACB criteria for the reference interval
determination of anti-TPO and anti-Tg (e.g. only males < 30 years), shows clearly a lower cutoff
as compared to that of the Elecsys Anti-Tg assay. The cutoff of 115 IU/mL currently given in the
package insert is still not covered by the upper limit of the 95 % confidence interval of 98 IU/mL.
The non-selected group of blood donors, GL1, and the GL2 group show significantly higher
values. These results are caused by the group of women, which gave essentially higher values
(p < 0.001 and p < 0.01).
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 low 50 % quant. 95p CI high 95p CI low 95p CI high Year of

95 % quant. n
(median) median (median) (95 % quant.) (95 % quant.) publ.
IU/mL IU/mL IU/mL IU/mL IU/mL IU/mL
Elecsys Anti-Tg package insert 115 392 2001
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
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 6
23
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
Elecsys systems (1996) until 2007. In particular studies on T3 conducted in 1996, studies on
T-uptake from 1998; anti-Tg and anti-TPO from 2000/2001 and fT3 from 2003 are covered.
To update and complete the children reference range values, a new study was performed in
2007.
When the new Elecsys FT3 test, 3051986, 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 confidence 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 identified as the most important influencing factors. Within
the females, the use of oral contraceptives was another decisive influencing factor of the
values. In the future, the consideration of these factors may justify the application of their
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 most thyroid parameters during early
childhood.
24
6 References
1 Demers LM. Thyroid disease: pathophysiology and diagnosis. Clin Lab Med 2004;24(1):19–28.
2 Demers LM, Spencer CA. National Academy of Clinical Biochemistry (NACB): Laboratory Support
for the Diagnosis and Monitoring of Thyroid Disease. 2002.
3 U.S. Preventive Services Task Force. Screening for Thyroid Disease: Recommendation Statement.
Ann Intern Med 2004;140(2)125–127.
4 Andersen S, Bruun NH, Pedersen KM, Laurberg P. Biologic Variation is Important for Interpretation
of Thyroid Function Tests. Thyroid 2003;13(11):1069–1078.
5 Surks MI, Ortiz E, Daniels GH, Sawin CT, Nanada F, Cobin RH, et al. Subclinical Thyroid Disease –
Scientific Review and Guidelines for Diagnosis and Management. JAMA 2004;291(2):228–238.
6 Monaco F. Clinical Perspective – Classification of Thyroid Diseases: Suggestions for a Revision.
J Clin Endocrinol Metab 2003;88(4)1428–1432.
7 Dayan CM. Review: Interpretation of thyroid function tests. Lancet 2001;357:619–724.
8 Nanada F, Surks MI, Daniels GH. Subclinical Thyroid Disease – Clinical Applications. Scientific
Review. JAMA 2004;291(2):239–243.
9 Lock RJ , Marden NA, Kemp HJ, Thomas PH, Goldie DJ, Gompels MM. Subclinical hypothyroidism:
a comparison of strategies adherence to treatment guidelines. Ann Clin Biochem 2004;41:197–200.
10 Scofield HR. Rapid Review: Autoantibodies as predictors of disease. Lancet 2004;363:1544–1546.
11 Bjoro T, Holmen y, Krüger O, Midthjell K, Hundstad KD, Schreiner T, et al. Prevalence of thyroid
disease, thyroid dysfunction and thyroid peroxidase antibodies in a large, unselected population. The
Health Study of Nord-Trondelag (HUNT). Eur J Endocrin 2000;143:639–647.
12 Köger R (2007) Roche internal report.
13 Koenker R. and Hallock K. Quantile regression. Journal of Economic Perspectives 2001,15(4)143-156.
14 Chen C. An Introduction to Quantile Regression and the Quantreg Procedure. SAS Instiute 2005,
SUGI 30,213-30.
15 IFCC. Approved recommendation on the theory of reference values. Part 5. Statistical treatment of
collected reference values. Determination of reference limits. J Clin Chem Clin Biochem 1987c;25:
645–56.
16 Harris EK, Boyd JC. Statistical bases of reference values in the laboratory medicine. Dekker M (ed),
Inc New York 1995.
17 Hahn G, Meeker WQ. Statistical Intervals: A Guide for Practitioners. Wiley Series in: Probability &
Mathematical Statistics, 1991.
18 SAS Institute, Online Documentation V 8.
19 Hubl F, Schmieder J, Gladrow E, Demant T. Reference Intervals for Thyroid Hormones on the
Architect Analyser. Clin Chem Lab Med 2002;40(2):165–166.
20 González-Sagrado M, Martín-Gil FJ. Population-specific reference values for thyroid hormones on the
Abbott ARCHITECT i2000 analyzer. Clin Chem Lab Med 2004;42(5):540–542.
21 Hollowell JG, Staehling NW, Hannon WH, Flanders WD, Gunter EW, Spencer CA et al. Serum
thyrotropin, thyroxine and thyroid antibodies in the United States population (1988 to 1994):
NHANES III. J Clin Endocrinol Metab 2002;87:489-99.
22 Spencer CA, Wang C, Fatemi S, Guttler RB, Takeuchi M and Kazarosyan M. Serum Thyroglobulin
Autoantibodies: Prevalence, influence on serum thyroglobulin measurement and prognostic signifi-
cance in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 1998;83:1121-7.
25
Notes
26
ELECSYS, COBAS, COBAS E and LIFE NEEDS ANSWERS are trademarks of

Roche. Other brand or product names are trademarks of their respective
holders.
© 2011, Roche
Roche Diagnostics GmbH
Sandhofer Strasse 116, D-68305 Mannheim
Germany
www.roche.com
US Technical Support 1-800-428-2336
04640292160 V2 0411
27

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Reference Intervals for Children

Elecsys Thyroid Tests

Elecsys systems 2010

3 Subjects, Materials and Methods 6–11

3.1 Description of the reference population 6

4 Results and Discussion 12–23

4.1 Cross-parameter results and explanations on the following chapters 12

Significant additions or changes are indicated by a change bar in the margin.

With respect to concentrations (standardization) and assay performance, the currently

fT3 T3 T-upt. A-TPO A-Tg

Males 40–49 vs. 20–39 y. ⇔ ⇔ ⇔ ⇔ ⇔

Females 40–49 vs. 20–39 y. ⇔ ⇓ ⇓ ⇔ ⇔

Contraceptives w vs. w/o ⇔ ⇑ ⇑ ⇔ ⇔

3rd trim. vs. 2nd trim. ⇓ ⇑ ⇑ ⇔ ⇔

GL2 TSH+Sono NAD vs. all ⇔ ⇔ ⇔ ⇔ ⇔

3 Subjects, Materials and Methods

FT3 T3 A-TG A-TPO TUP

3.3 Statistical methods Study Population:

3.3 Statistical methods Quantiles:

Reference interval (corresponds in this case to the 95 % central range)

Confidence interval Confidence interval Confidence interval

4 Results and Discussion

All blood donors - Leipzig All blood donors - Leipzig

Thyroid volume [mL]

All blood donors - Leipzig Females

95p CI low 95p CI high 95 p CI 50 % 95p CI 95p CI low 95p CI high

Table 2a: SI units

95p CI low 95p CI high 95 p CI 50 % 95p CI 95p CI low 95p CI high

Table 2b: conventional units

Group GL1 Females

Elecsys FT3 [pmol/L]

95p CI low 95p CI high 95 p CI 50 % 95p CI 95p CI low 95p CI high

Table 3a: SI units

95p CI low 95p CI high 95 p CI 50 % 95p CI 95p CI low 95p CI high

Table 3b: conventional units

Group GL1 Females

Elecsys T3 [nmol/L x 10]

Elecsys T3 [nmol/L x 10]

Pearson’s r = 0.589 Pearson’s r = 0.643

î Females î With contraceptives

Pearson’s r = - 0.228 Pearson’s r = - 0.262

Elecsys T3 [nmol/L x 10]

95 p CI low 50 % quant. 95p CI high 95p CI low 95p CI high Year of

ELECSYS, COBAS, COBAS E and LIFE NEEDS ANSWERS are trademarks of

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3.3 Statistical methods Quantiles: