The AQUA-FONTIS Study: Protocol of a multidisciplinary, cross-sectional and prospective longitudinal study for developing standardized diagnostics and classification of non-thyroidal illness syndrome.

ral
ssBioMed CentBMC Endocrine Disorders
Open AcceStudy protocol
The AQUA-FONTIS study: protocol of a multidisciplinary,
cross-sectional and prospective longitudinal study for developing
standardized diagnostics and classification of non-thyroidal illness
syndrome
Johannes W Dietrich*1, Axel Stachon2, Biljana Antic3, Harald H Klein1 and
Steffen Hering1
Address: 1Medical Hospital 1, Bergmannsheil University Hospitals, Ruhr University of Bochum, Bochum, NRW, Germany, 2Institute of Clinical
Chemistry, Transfusion and Laboratory Medicine, Bergmannsheil University Hospitals, Ruhr University of Bochum, Bochum, NRW, Germany and
3Klinik für Innere Medizin, Evangelisches Krankenhaus Hattingen, Hattingen, NRW, Germany
Email: Johannes W Dietrich* - johannes.dietrich@ruhr-uni-bochum.de; Axel Stachon - axel.stachon@ruhr-uni-bochum.de;
Biljana Antic - Biljana.Antic@web.de; Harald H Klein - harald.klein@bergmannsheil.de; Steffen Hering - steffen.hering@ruhr-uni-bochum.de
* Corresponding author
Abstract
Background: Non-thyroidal illness syndrome (NTIS) is a characteristic functional constellation of thyrotropic
feedback control that frequently occurs in critically ill patients. Although this condition is associated with
significantly increased morbidity and mortality, there is still controversy on whether NTIS is caused by artefacts,
is a form of beneficial adaptation, or is a disorder requiring treatment. Trials investigating substitution therapy of
NTIS revealed contradictory results. The comparison of heterogeneous patient cohorts may be the cause for
those inconsistencies.
Objectives: Primary objective of this study is the identification and differentiation of different functional states
of thyrotropic feedback control in order to define relevant evaluation criteria for the prognosis of affected
patients. Furthermore, we intend to assess the significance of an innovative physiological index approach (SPINA)
in differential diagnosis between NTIS and latent (so-called "sub-clinical") thyrotoxicosis.
Secondary objective is observation of variables that quantify distinct components of NTIS in the context of
independent predictors of evolution, survival or pathophysiological condition and influencing or disturbing factors
like medication.
Design: The approach to a quantitative follow-up of non-thyroidal illness syndrome (AQUA FONTIS study) is
designed as both a cross-sectional and prospective longitudinal observation trial in critically ill patients. Patients
are observed in at least two evaluation points with consecutive assessments of thyroid status, physiological and
clinical data in additional weekly observations up to discharge. A second part of the study investigates the
neuropsychological impact of NTIS and medium-term outcomes.
The study design incorporates a two-module structure that covers a reduced protocol in form of an observation
trial before patients give informed consent. Additional investigations are performed if and after patients agree in
participation.
Published: 13 October 2008
BMC Endocrine Disorders 2008, 8:13 doi:10.1186/1472-6823-8-13
Received: 5 September 2008
Accepted: 13 October 2008
This article is available from: http://www.biomedcentral.com/1472-6823/8/13
© 2008 Dietrich et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 9
(page number not for citation purposes)
Trial Registration: ClinicalTrials.gov NCT00591032

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Background
Non-thyroidal illness syndrome (NTIS or euthyroid sick
syndrome) is a complex endocrine condition that may
occur in critically ill patients. It is associated with signifi-
cant deterioration of prognosis.
NTIS is characterised by three components that may occur
single or in combination:central hypothyroidism (tran-
sient thyrotropic insufficiency), impaired protein binding
of thyroid hormones and reduced formation of T3 with
simultaneously increased conversion to rT3 (low-T3-syn-
drome) [1,2].
In 1973, characteristic alterations of thyroid metabolism
have been first described in the starving organism [3,4].
Additional observations could reveal that these alterations
are also common in critically ill patients where they form
the correlate of endocrine dysregulation with increased
morbidity and mortality [5-8].
However, explanation concepts for this complex constel-
lation are different. Up to now, in essence five hypotheses
are discussed in literature [2]:
1. All observed abnormalities are the result of test arte-
facts. In reality, the patients are euthyroid.
2. The changes in the levels of peripheral thyroid hor-
mones mirror the effect of certain binding inhibitors that
influence
A) laboratory results only or
B) also the transfer of thyroid hormones into the tissue of
diseased persons and thus diminish binding of iodothy-
ronines to T3 receptors.
3. Due to increased local deiodation, T3-levels are normal
in the pituitary gland while they are low in the rest of the
organism.
4. Levels of peripheral thyroid hormones are actually low
so that affected patients are biochemically hypothyroid.
However, this useful physiological function should not be
manipulated.
5. NTIS is secondary or tertiary hypothyroidism. The
resulting tissue hypothyroidism should be treated with
appropriate substitution therapy [2].
Despite of intensive and long lasting research to many of
its details NTIS is still poorly characterized in an integra-
tive view. Additionally, a clinically usable classification is
Given the fact that patients with NTIS are faced with poor
prognosis, several studies have been conducted in the past
evaluating the question of possible treatment [2,7]. How-
ever, they did not yield unambiguous results. Some stud-
ies could show a benefit of substitution therapy with
thyroid hormones, e.g. regarding the incidence of atrial
fibrillation [2,7,9,10] and hemodynamic parameters
[11,12] while others could not observe relevant differ-
ences in outcome between treated and untreated patients
[13-15]. Several studies even described detrimental effects
of substitution therapy ranging from increased risk of
hyperthyroidism [16,17] over undesirably high protein
catabolism [18] to severe side effects in patients with adre-
nal insufficiency that may be difficult to identify during
critical illness [19]. Recently, a small trial investigating the
effect of selenium substitution on the development of crit-
ically ill patients demonstrated improvements in progno-
sis, but, in spite of the known selenium-dependency of
peripheral deiodinases, this outcome was not caused by a
direct effect on thyroid homeostasis [20].
The problem of inconclusive and partly contradictory
study results is aggravated by the fact that there is no con-
sistent definition of NTIS that delimits this constellation
from euthyroid state and that weighs the associated com-
ponents regarding their relevance. Therefore, it may be
assumed that the mentioned studies compared inhomo-
geneous patient groups.
An additional challenge affecting clinical practice is the
fact that partial thyrotropic insufficiency in the course of
NTIS can hardly be distinguished from latent ("subclini-
cal") hyperthyroidism – although pathophysiology and
therapeutic implications are opposed.
Objectives of the AQUA FONTIS project
The AQUA FONTIS study (approach to a quantitative fol-
low-up of non-thyroidal illness syndrome) is primarily
intended to develop a clear-cut definition and classifica-
tion of NTIS (Table 1). Overall, this project is proposed to
deliver a prognostic aid by providing a differentiated clas-
sification, to contribute to a standardised, rational and
inexpensive diagnostic procedure in form of quantitative
indices, and to lay the foundation for future therapeutic
trials by identifying subgroups that may benefit from ther-
apy.
Outcome measure of this primary objective is the compar-
ison of different decision criteria as presented in Table 2.
These criteria are assessed with regard to the prognosis of
the patients. Additionally, the significance of an innova-
tive physiological index approach (SPINA) [21] is to be
evaluated regarding its applicability for differential diag-Page 2 of 9
(page number not for citation purposes)
lacking. nosis between NTIS and latent thyrotoxicosis. It will there-

BMC Endocrine Disorders 2008, 8:13 http://www.biomedcentral.com/1472-6823/8/13
fore be evaluated in terms of sensitivity, specificity and
likelihood ratios with ROC analysis.
As secondary objective, we plan to observe variables that
quantify distinct components of NTIS in the context of
independent predictors of evolution, survival or patho-
physiological condition as well as influencing or disturb-
ing factors like medication or medical procedures.
Outcome measures are correlations between quantita-
tively described components and external factors as well
as their distributions in the context of dichotomic influ-
encing factors.
Methods
The AQUA FONTIS study is designed as both a cross-sec-
tional and prospective longitudinal observation trial (Fig-
ure 1).
Recruitment and criteria for inclusion and exclusion
This study recruits critically ill patients treated in one
medical and two surgical intensive care units of the Berg-
mannsheil University hospitals for evaluation of integra-
tive thyrotropic control and follow-up. Inclusion and
exclusion criteria are presented in table 3. The diagnostic
criteria are based on the ICD-10 system [22].
Decision criteria
Latent (so called "subclinical") thyrotoxicosis is defined
as suppressed thyrotropin levels with free T4 levels being
in their reference intervals and additional clinical evi-
dence for tissue hyperthyroidism (suggestive history or
Burch-Wartofsky point scale of more than 45 points [23]).
Decision criteria to be evaluated are reproduced in Table
2.
Calculations
Thyrotroph T4 Sensitivity Index (TTSI) is calculated as
with lu being the upper limit of the reference interval for
free T4 [24]. Theoretical secretion capacity of the thyroid
gland (GT^) is computed with
where parameters are taken from Table 4[21].
TTSI
TSH FT
lu
=
100 4[ ][ ] (1)
ˆ ( [ ])( [ ] [ ])[ ]
[ ]
,G T
DT TSH K TBG K TBPA FT
T TSH
T =
+ + +β
α
1 41 42 4
(2)
Table 1: Proposed "HPD" classification
Facet Possible values
Hypothalamic-pituitary dysfunction or adaptation ("H") H0: Normal TSH secretion, adequate to T4 level
H1: Thyrotropic insufficiency
Impaired plasma protein binding ("P") P0: Normal binding to plasma proteins
P1: Normal binding with reduced levels of plasma proteins
P2: reduced binding to proteins within normal levels
P3: reduced binding and reduced protein levels
Reduced deiodation ("D") D0: Normal deiodation
D1: Reduced deiodation activity
Example: H1P0D1: Thyrotropic insufficiency with reduced deiodation and normal protein binding.
Table 2: Decision criteria
Criterion Definition
Thyrotropic insufficiency a) Reduced levels of both TSH and free T4.
b) Thyrotroph T4 Sensitivity Index (TTSI) reduced below its reference interval.
Reduced plasma protein binding a) Reduced relative ratios of bound and free hormone levels
b) Reduced apparent dissociation constant of T3 at thyroxin binding globulin (K30)
Reduced deiodation a) Reduced level for free T3
b) diminished T3/T4-ratio
c) reduced sum activity of peripheral 5'-Dejodinase (G ^)Page 3 of 9
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D

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Page 4 of 9
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Flowchart of the AQUA-FONTIS study with its two intertwined modulesigure 1
Flowchart of the AQUA-FONTIS study with its two intertwined modules. See text and table 5 for detailed informa-
tion.
Day 0
Day 1
Day 3 to n
After discharge
Reduced protocol
Reduced protocol
Eligible
patients
Screening
(EP 1.0)
Inclusion
in study
(EP 1.1)
Inclusion
criteria
satisfied?
ICU-
treatment over
24 hrs?
Consent
obtained?
Patient able
to give informed
consent?
Patient
discharged?
Patient
on peripheral
ward?
End of
observation
(Part I)
Invitation to follow-up evaluation
after 3, 6 and 12 months
No
Yes
Yes
Yes
Yes
Yes
Yes
End of
observation
(Part I)
Invitation to follow-up evaluation
after 6 and 12 months
Yes
No
No
No
No
No No
Repetitive
observations
(EPs 1.2 to 1.n)
Neuro-
psychological
observation
(EP 2.0)
AQUA-FONTIS Study, Part I
AQUA-FONTIS Study, Part II
Repetitive
observations
(EPs 1.2 to 1.n)
Patient
discharged?
No
inclusion
No
inclusion
Exclusion

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Sum activity of peripheral 5'-deiodinase (GD^) is defined
with
parameters are again from Table 4[21].
Apparent dissociation constant of T3 binding to TBG is
obtained with
from levels of iodothyronines and TBG.
Relative binding ratio is calculated with
where ll, TT3 denotes the lower limit of the reference inter-
val for TT3 and ll, FT3 is the lower limit of the reference
interval for FT3.
Follow-up and Evaluation Points
Patients are subjected to at least one evaluation point.
Critically ill persons that are newly admitted to an ICU are
screened in the first EP (1.0) for fulfilment of the inclu-
sion and exclusion criteria from Table 3 and entered in the
database (see below). The second EP (1.1) is performed
after 24 hours; only those eligible patients that are still
under intensive care will be included in the study and sub-
sequently prospectively observed. On the occasion of this
and the subsequent EPs (after 72 hours for EP 1.2 and
weekly in the further course of the study), severity scores
like SAPS II and APACHE II as well as physiological
parameters and data regarding pharmacological therapy
or medical interventions are surveyed (Table 5). Addition-
ally, laboratory investigations that are part of routine diag-
nostics (e.g. TSH, FT4, total T3, inflammation parameters,
total protein etc.) are complemented by those parameters
that are collected for the study (total T4, free T3 and anti-
bodies against iodothyronines as well as thyroid tissue).
As all required specimens are taken in the course of rou-
ˆ ( [ ])( [ ])[ ]
[ ]
,G
K M FT K TBG FT
FTD
=
+ +β
α
31 1 4 1 30 3
31 4
(3)
ˆ [ ] [ ]
[ ][ ]
K
T FT
TBG FT30
3 3
3
=
−
(4)
R
T
ll TT
FT
ll FT
B =
[ ]
,
[ ]
,
3
3
3
3
(5)
Table 3: Inclusion and exclusion criteria of the AQUA FONTIS study
Inclusion Exclusion
Severe illness requiring intensive care Substituted hypothyroidism (E03.0, E03.1, E03.3 E03.9, E89.0) or substitution in case of thyroid carcinoma
(C73)
Stay of at least 24 hours at the ICU Hyperthyroidism treated with thyrostatic agents and exhibiting a TSH level not below the reference region
(E05.0 E05.9, E06.2)
Manifest AIDS disease (B24)
Pregnancy
Table 4: Parameters for structure parameter inference [21]
Symbol Explanation Value
αT Dilution factor for T4 (reciprocal of apparent volume of distribution) 0,1 l-1βT Clearance exponent for T4 1,1 * 10-6 sec-1
DT EC50 for TSH 2,75 mU/l
K41 Dissociation constant T4-TBG 2 * 1010 l/mol
K42 Dissociation constant T4-TBPA 2 * 108 l/mol
α 31 Dilution factor for T3 0,026 l-1β 31 Clearance exponent for T3 8 * 10-6 sec-1
KM1 Dissociation constant of type-1-deiodinase 5 * 10-7 mol/lPage 5 of 9
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K30 Dissociation constant T3-TBG 2 * 109 l/mol

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tine diagnostic procedures, additional assays, but no addi-
tional blood samples are necessary.
When patients have been transferred to a peripheral ward
they are subjected to a single additional evaluation point
(EP 2.0) surveying neuropsychological data covering anx-
will be invited to repeated neuropsychological evalua-
tions after 3, 6 and 12 months. This second part of the
study is restricted to patients that gave informed consent
(see below) and that have the mental and somatic ability
to take part in this sub-study.
Table 5: Schedule of evaluation points
EP 1.0 EP 1.1 EP 1.2 EP 1.3 EP 1.999
Screening After 24 hours After 72 hours Weekly After discharge
Screening
Inclusion and Exclusion criteria • •
Informed consent ° ° °
Demography
Age, Gender •
History •
Laboratory examinations
TSH, TT4, FT4, TT3, FT3 • • •
rT3 •
Total protein, Albumin • • •
BC, CRP, ATIII, Fibrinogen • • •
Thyroid antibodies, T4/T3-Abs. •
Other investigations • • •
Temperature, Horowitz-Quotient
Vital signs • • • •
Evolution data
Medication • • • • •
APACHE-II-/SAPS-II-Score, GCS • • • •
Diagnosis • •
HD/CVVH/CVVHDF • • • • •
IABP • • • • •
Persistent organ failure •
Outcome (survival etc.) •
EP 2.0 EP 2.1 EP 2.2 EP 2.3
After transfer to peripheral ward After 3 months After 6 months After 1 year
History and clinical data
Burch-Wartofsky score ° °
Medication ° ° ° °
Vital signs ° ° ° °
Laboratory examinations
TSH, TT4, FT4, TT3, FT3 ° °
Neuropsychological data
Number connection test ° °
RWT ° °
SKT ° °
HADS °
SF36 ° ° °
Other investigations
Thyroid ultrasonography ° °
Outcome (survival etc.) ° ° ° °
•: Scheduled at indicated EP.
°: Scheduled after transfer to peripheral ward.Page 6 of 9
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iety, depression, speed of information processing and
memory (see second part of Table 5). After discharge, they

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Patients that are admitted to an ICU a second time will
only be observed up to that date, i.e. follow-up observa-
tion will stop after readmission to the ICU.
Sample size and power calculation
The AQUA-FONTIS study has a planned sample size of
650 patients. On the premise of a beta level of 0.1 (corre-
sponding to a power of 0.9), an alpha level of 0.05, and
standard deviations and event rates as observed in the lit-
erature and in this study to date, between 200 and 566
patients would be required, depending on the objective in
question.
With an appropriate safety-margin a total required
number of 650 patients results. Most questions could be
answered with 500 patients, however.
Data management
Data are stored as electronic case report forms (eCRF) on
a Macintosh server in a network-based relational database
that has been developed with FileMaker Pro 5.5 (File-
Maker, Inc., Santa Clara, CA, USA). It accommodates
important principles of data protection by the fact that
patient data are stored in pseudonymised form, i.e. they
are referred to by number only, while mapping to patient
names is only possible with an external list that is stored
separately from the database. Additionally, the server is
operating in the hospital's intranet with access from out-
side being blocked by a firewall. Data security is provided
by a combination of established methods that cover regu-
lar backups and archiving as well as galvanic isolation of
the server by an uninterruptible power supply. Operation
of the server in a locked, dedicated room that is inaccessi-
ble for unauthorized persons serves both data protection
and data security.
Other benefits of this database-founded approach are the
ability to store very large amounts of information and the
option to enter data from several wards simultaneously.
Statistics
The main null-hypothesis to be tested is that the decision-
criteria presented in Table 2 lead to results that are inde-
pendently distributed from the prognosis of included
patients. Risk stratification will be performed with log
rank test and Cox regression; end points are mortality,
length of stay in hospital (LOSIH), length of stay in inten-
sive care unit (LOSICU) and ability to work after dis-
charge.
Cross sectional analysis will be done with the chi-squared
test (for categorial data) and Student's t-test (for continu-
ous data).
Multivariate regression analysis will be used to investigate
correlation between quantitatively determined compo-
nents of thyroid homeostasis and influencing pathophys-
iological factors.
Missing data analysis will be performed with "modern"
procedures like EM algorithm and multiple imputation
[25], if required.
Ethical considerations
For various reasons, most critically ill patients are not able
to give informed consent [26,27]. We therefore restricted
investigations in the first part of the trial to observation
and laboratory tests from sera that have been obtained for
routine diagnostics independently from this study, there-
fore not requiring extra-specimens. In essence, the
reduced sub-protocol is designed in form of an observa-
tional study that resembles epidemiological investiga-
tions; this part of the study is therefore not subject of the
German law governing clinical trials of drugs and medici-
nal products (Arzneimittelgesetz) and the corresponding
European directives 2001/20/EC and 2005/28/EC [28-
30].
After being transferred to a peripheral ward, each partici-
pant receives information about the trial both verbally
and in written form. Continued participation is voluntary,
without expected negative side effects, and the patient can
withdraw his or her consent at any time for parts of the
study (e.g. future evaluation points) or the whole trial
without consequence for treatment possibilities. All
patients will receive a copy of their rights.
Patients that are never able to give consent, e.g. because
they die before regaining consciousness, or that acquire
permanent brain damage, only traverse the simplified
procedure of the reduced observational protocol as
described above. The same holds true for patients that
have been discharged or transferred to an external hospi-
tal before being asked for consent, or that are not able to
communicate in German.
The local ethics committee of the Ruhr-University of
Bochum has approved the protocol under the file number
2848. The trial is registered at ClinicalTrials.gov as
NCT00591032.
Both significant and insignificant findings from the trial
will be published, in accordance with the STROBE state-
ment [31]. Links to publications will be made available
on the study-website http://www.aqua-fontis.eu.Page 7 of 9
(page number not for citation purposes)

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Status of the study
Up to now, 561 patients have been screened, 470 persons
are included in the study, corresponding to 72% of the
planned sample size.
In this unselected sample, currently 210 females (37%)
have been observed, the ages of included patients ranging
between 9 and 96 years. 61% of patients were screened
from the two surgical ICUs, 39% from the medical ICU.
Discussion
The approach to a quantitative follow-up of non-thyroi-
dal illness syndrome (AQUA-FONTIS study) has been
designed to develop standardised diagnostic and classifi-
cation criteria for NTIS. Apart from identification and dif-
ferentiation of distinct functional states of thyrotropic
feedback control in the context of critical illness, this
study will help to assess the correlation of variables that
quantify the components of NTIS with independent pre-
dictors of evolution, survival or pathophysiological con-
dition. Additionally, it will evaluate the effect of
influencing or disturbing factors like medication or inter-
ventional procedures.
In the past, many studies dealt with the impact of severe
diseases on thyroid metabolism [1-8]. However, they had
inconsistent results, which may be the result of lacking
standardised criteria. The objective of the AQUA FONTIS
project is to provide more clear-cut decision criteria for
prognosis and possibly therapy of affected patients. These
may help to make future studies comparable.
However, also the AQUA FONTIS study is faced with sev-
eral limitations. These predominantly accrue from the fact
that most patients receiving intensive care are not able to
give informed consent [26,32]. We therefore had to con-
strain the possible investigations to methods that are
purely observational or use patient sera that were
obtained for routine diagnostics. Due to their extensive
ethical and legal implications, we were e.g. not able to
investigate genetic aspects of NTIS without informed con-
sent: Although deferred consent for genetic investigations
could be obtained from surviving patients this is by nature
not possible in persons that are admitted as emergency
cases and die early, so that a relevant bias would be to
expect [27].
Additionally, the fact that a high proportion of patients
will be admitted in cases of accidents or emergency makes
it difficult to control relevant influencing factors. Condi-
tions like existing thyroid diseases or previous medication
may therefore in some cases be missed. Furthermore,
stratification will be impossible.
These restrictions are shared by all observational studies.
Alternative forms of data acquisition may seem more
appropriate from a pure statistical point of view. How-
ever, the mentioned medical and ethical marginal condi-
tions render them impossible.
Its two-module structure, covering an observational part
before patients gave consent and a more comprehensive
sub-study that is traversed after consent was obtained,
helps to overcome some of the limitations of the AQUA
FONTS study. Additionally, the number of patients that
could already be included up to now gives reason to
believe that some of the poorly controllable influencing
factors may partly be compensated by a large final case
number. We are therefore convinced that this study will
help to identify decision-parameters for defining states of
particular importance with respect to the prognosis of
affected patients. These may lay the basis for future epide-
miological or therapeutic trials.
Abbreviations
APACHE: acute physiology and chronic health evalua-
tion; AQUA FONTIS: approach to a quantitative follow-
up of non-thyroidal illness syndrome; BWPS: Burch-War-
tofsky point scale; eCRF: electronic case report form; EP:
evaluation point; GCS: Glasgow come scale; HADS: hos-
pital anxiety and depression scale; ICU: intensive care
unit; LOSICU: length of stay in intensive care unit; LOSIH:
length of stay in hospital; NTIS: non-thyroidal illness syn-
drome; rT3: reverse triiodothyronine; RWT: Regensburger
Wortflüssigkeitstest (Regensburg word fluidity test); SF36:
short form with 36 items; SKT: Syndrom-Kurztest (syn-
drome short evaluation); SPINA: structure parameter
inference approach; T3: triiodothyronine; T4: levothyrox-
ine; TSH: thyrotropin; TTSI: thyrotroph T4 sensitivity
index.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
All authors were involved in conception and design of the
study protocol, drafting or revising the manuscript, and
have approved the final manuscript. JWD is responsible
for performing evaluation points, data analysis and over-
all coordination. AS is responsible for laboratory assays,
SH and HHK are co-responsible for data analysis. BA was
in the planning phase of the study responsible for the
development of the ethical conception. All authors will
participate in interpretation of results.
Acknowledgements
The study has received funding by the science commission of the Berg-
mannsheil University hospitals, Bochum.Page 8 of 9
(page number not for citation purposes)

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The authors would like to thank the members of the local ethics committee
of the Ruhr-University of Bochum for valuable suggestions.
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mine the secretion capacity of the thyroid gland. European
Journal of Internal Medicine 1999, 10(Suppl 1):S34.