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Towards the elimination of iodine deficiency and preventable thyroid-related diseases in Europe

Deliverables

Web-based training and certification tools online

Since the mean thyroid size in population samples reflects the iodine status, most of the regional surveys will include thyroid ultrasound measurements. To minimise the bias across the studies, a web-based reader certification tool will be established. Beyond the information integrated in the training tool (see Task 2.4), ultrasound observers will be offered to be certificated according to the standards of the Study of Health in Pomerania (SHIP)32. From a pool of 100 ultrasound images, each observer has to read a randomly selected set of 2 x 25 ultrasound images for dimensions of the thyroid lobes. The results of the readings will be analysed for intra- and inter-observer differences and compared to the readings of two EUthyroid expert sonographers. Statistical analyses will be performed using Bland & Altman plots; a mean bias of ± 5% and a 2SD of ± 25% must not be exceeded. In case a certification will have not been passed, the procedure can be repeated after a new training cycle. After successful certification, a EUthyroid certificate can be printed out, indicating that the exam was passed was passed by the reader. As for the training module, also the certification module will be published on the EUthyroid websites. The access to the module will also be open to researchers and study staff outside the EUthyroid consortium to strategically establish EUthyroid as a gold standard for international thyroid ultrasound studies.

Training modules finalised on EUthyroid websites

To reduce bias by study staff, a training programme will be established. All training procedures will be established web-based to minimise costs. The training tool will include standard operating procedures as well as graphical and cinematic visualisation of key points and main pitfalls in conducting interviews, blood and urine sampling, laboratory analyses and thyroid ultrasound. Access to the training modules will not only be restricted to staff from national and regional studies involved in EUthyroid, but will be an open source for all interested researchers. Promoting the training programme through the IGN will enlarge the awareness level among international thyroid researchers. Thus, EUthyroid will not only set the standards for European IDD research but will have the potential to harmonise studies globally.

Joint European database prepared for combining national/or regional registry outcome data related to iodine status

The first task related to WP1 is to request the 22 national representatives involved in EUthyroid to get access to relevant data from registries in their respective countries. Requested registry data includes numbers of patients registered with relevant disease codes according to the ICD-10 system by WHO (E00-E07 including subcodes and C73), numbers of thyroid surgery and fine needle biopsy procedures performed, numbers of radio-iodine doses applied, and sales figures of relevant medication (ATC-codes H03A+H03B). Data from at least the past three years will be requested. Approval from local ethical committees will be obtained if required. As national registry data becomes available, a joint database will be built up at CCRP. The database will include measures of thyroid related disorders and treatments in addition to demographic data describing the distributions of age and gender in the different European populations. Tight communication between WP1 and WP2 will ensure a common structure of the two WP databases. In collaboration with the principal investigator of WP1, handling and documentation of the database will be carried out by an experienced data manager. The joint database will constitute a model for future Pan-European data collections aiming to monitor the effects of IDD prevention programmes.

Website published

WP6 will create a multilingual website (consumer and publicly accessible). It will be the main information resource for EUthyroid describing the project objectives and phases, work areas, main results, publications and links to relevant websites. The content of the EUthyroid website will be divided in sections for the various stakeholder groups based on the requirements defined in the communication plan. The content will be regularly updated with input of all partners to keep interested stake holders and the public informed of the project’s objectives and progress as well as general issues about iodine deficiency. Additional visitors will be attracted by using established networks such as YouTube. The website will also report on new developments, open positions and the work done within the EUthyroid consortium on a more general basis. It will exploit synergies with the website of IGN to transfer visibility from this established portal. The site layout and graphic aspect will be specifically designed to optimise communication to scientific experts, policy makers and also to the general public and allow downloading of dissemination material. The website will ensure appropriate representation of health issues through complying with the HONcode principles and applying for a HON certificate. A very limited version of the website will be made available in a wider variety of languages to support regional monitors in their dissemination tasks.

Tg as a risk biomarker of iodine deficiency in pregnancy for neurocognitive function of the offspring evaluated

The potential of Tg as a risk biomarker in pregnancy for neurocognitive function of the offspring will be tested. Applying methods described in Task 3.1, WP3 will measure serum Tg in 3500 samples of the WP4 studies in pregnant women whose children have neurocognitive data, and the meta-analysis detailed in Task 4.5b will be done.

Iodine status assessed by repeated UIC measurements

Repeated gestational maternal UIC/creatinine ratio (UICcr) measurements have not yet been studied in such large numbers. We will therefore first investigate the classification and determinant characteristics. We will study to what extent first trimester UICcr measurements (currently used in most clinical studies) correlate to second and third trimester UICcr measurements. Furthermore, we will investigate which maternal and pregnancy characteristics are determinants of UICcr levels, or of the gestational variation in UICcr levels by using (non)linear mixed models. Future analyses can then be adjusted and/or stratified accordingly. Subsequently, iodine status will be classified according to the number of (ab)normal samples. Three groups will be created:1) iodine sufficient: women in which all samples measured a UICcr of >150 µg/L; 2) borderline insufficient status: women in which one sample measured a UICcr of <150 µg/L, 3) iodine insufficient: women with all, or 2/3 samples with a UICcr of <150 µg/L. Sensitivity analyses will be performed in order to investigate UICcr variation in women with borderline iodine status (mean UICcr >150 µg/L vs. <150 µg/L) and to investigate possible severe iodine insufficiency (at least one sample UICcr < 50 µg/L).

Infrastructure of the data transfer unit established

A joint database will be established to collect and pool standardised national and regional IDD monitoring data. The University Medicine Greifswald will also take responsibility to back-up the WP1 database on registry data. Both the WP and WP2 databases will be organised according to identical standards. The University Medicine Greifswald will be in charge for the maintenance of the centralised databases and the transfer of EUthyroid data to the scientific community. Existing data infrastructure established for large-scale population and patient studies will be extended by experienced computer scientists and data managers. The data management is described in more detail in section 2.2.1.1.

Report on the identification of a best-practice model of IDD prevention available

When results regarding the current iodine status are available from WP2 statistical analyses of associations between registry-based outcome variables and current iodine status will be performed to show a more detailed picture of the association between iodine intake and IDD-related outcomes across Europe. These analyses will take into account that the actual intake of iodine may vary considerably among countries irrespective of the presence of IDD prevention programs. Special emphasis will be laid on the incidence of hypothyroidism and autoimmune thyroid disease and related treatments. IDD prevention in the country will be defined as best-practice model that will have no socioeconomic gradient in the efficacy of the IDD prevention as well as the most balanced relation between a low prevalence/ decrease of IDD-related outcomes and low prevalence/ increase of hypothyroidism and autoimmune thyroid disease.

Statistical analyses of associations between registry based outcome variables and actual iodine status finalised

When results regarding the current iodine status are available from WP2 statistical analyses of associations between registry-based outcome variables and current iodine status will be performed to show a more detailed picture of the association between iodine intake and IDD-related outcomes across Europe. These analyses will take into account that the actual intake of iodine may vary considerably among countries irrespective of the presence of IDD prevention programs. Special emphasis will be laid on the incidence of hypothyroidism and autoimmune thyroid disease and related treatments. IDD prevention in the country will be defined as best-practice model that will have no socioeconomic gradient in the efficacy of the IDD prevention as well as the most balanced relation between a low prevalence/ decrease of IDD-related outcomes and low prevalence/ increase of hypothyroidism and autoimmune thyroid disease.

Association between repeated UICr measurements and IQ established

Primary endpoint: We will investigate whether mean child IQ levels differ according to mild-to-moderate iodine deficiency (classified using repeated urinary iodine measurements, see Tasks 4.2. and 4.4) by using multivariate linear regression models and combining the individual data from the three cohorts (see Task 4.1). Furthermore, we will investigate whether the iodine status is associated with the risk of learning disabilities (IQ<85) by using multivariate logistic regression analyses. (minimum odds ratio of 1.2 detectable as statistically significant). Secondary endpoints: Secondary studies will focus on the associations between repeated maternal UICcr measurements and child language development or autistic traits. The main analyses will investigate whether mean language development scores or autistic trait scores differ according to maternal iodine status by using multivariate linear regression models. Furthermore, we will investigate whether iodine status is associated with an increased risk of language delay and/or an increased risk of autistic traits by using multivariate logistic regression analyses. To study differential effects of specific pregnancy time-frames, UIC measurement analyses will be stratified according to gestational age. Neuropsychological outcomes will be analysed in relation to age of the child because differences in child neuropsychological development are likely to become more apparent with increasing age. We will furthermore investigate differential effects according to maternal thyroid function, socioeconomic status (SES) and child gender. Because iodine excess has also been associated with thyroid dysfunction, we will also explore neuropsychological development across the whole distribution of UICcr.

Communication plan established

The communication plan will fix all relevant issues for an optimised dissemination strategy including target audiences, distribution lists, national contact lists for regional monitors, the selection of appropriate measures and tools in specific areas of communication and the definition of key messages. The communication plan will outline risk factors and counter measures regarding the strategic aims of the dissemination and will be updated continuously during the lifetime of the project.

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Publications

Iodine Deficiency and Iodine Prophylaxis in Pregnancy

Author(s): Malgorzata Trofimiuk-Mudlner, Alicja Hubalewska-Dydejczyk
Published in: Recent Patents on Endocrine, Metabolic & Immune Drug Discovery, Issue 10/2, 2017, Page(s) 85-95, ISSN 1872-2148
DOI: 10.2174/1872214811666170309151538

Relevance of iodine nutrition to health in the 21st century

Author(s): Lazarus JH
Published in: Minerva Medica, Issue 108(2), 2017, Page(s) 114-5, ISSN 0026-4806
DOI: 10.23736/S0026-4806.17.05030-3

Thyroid Function in Early Pregnancy, Child IQ, and Autistic Traits: a Meta-analysis of Individual-participant Data

Author(s): Deborah Levie, Tim I M Korevaar, Sarah C Bath, Albert Dalmau-Bueno, Mario Murcia, Mercedes Espada, Mariana Dineva, Jesús M Ibarluzea, Jordi Sunyer, Henning Tiemeier, Marisa Rebagliato, Margaret P Rayman, Robin P Peeters, Mònica Guxens
Published in: The Journal of Clinical Endocrinology & Metabolism, 2018, ISSN 0021-972X
DOI: 10.1210/jc.2018-00224

Thyroid disease in the Czech Republic: the EUthyroid project and the evaluation of the General Health Insurance Company epidemiological data for the period of 2012-2015

Author(s): Bílek R, Horáková L, Goš R, Zamrazil V.
Published in: Vnitřní lékařství, Issue 63(9), 2017, Page(s) 548-554, ISSN 0042-773X

Iodine deficiency and nutrition in Scandinavia

Author(s): Manousou S, Dahl L, Thuesen BH, Hulthén L, Filipsson HN.
Published in: Minerva Medica, 2016, ISSN 0026-4806
DOI: 10.23736/S0026-4806.16.04849-7

First Israeli National Iodine Survey Demonstrates Iodine Deficiency Among School-Aged Children and Pregnant Women

Author(s): Yaniv S. Ovadia, Jonathan E. Arbelle, Dov Gefel, Hadassah Brik, Tamar Wolf, Varda Nadler, Sandra Hunziker, Michael B. Zimmermann, Aron M. Troen
Published in: Thyroid, Issue 27/8, 2017, Page(s) 1083-1091, ISSN 1050-7256
DOI: 10.1089/thy.2017.0251

Interlaboratory variability of urinary iodine measurements

Author(s): Till Ittermann, Simone Johner, Harald Below, Matthias Leiterer, Michael Thamm, Thomas Remer, Henry Völzke
Published in: Clinical Chemistry and Laboratory Medicine (CCLM), Issue 56/3, 2018, Page(s) 441-447, ISSN 1434-6621
DOI: 10.1515/cclm-2017-0580

Changes in the incidence of thyroid disorders in the Czech Republic according to the VZP Registry in the period 2012-2015.

Author(s): Zamrazil V, Bílek R, Horáková L, Goš R
Published in: Praktický lékař, 2017, ISSN 0032-6739

Trends in Costs of Thyroid Disease Treatment in Denmark during 1995–2015

Author(s): Line Tang Møllehave, Allan Linneberg, Tea Skaaby, Nils Knudsen, Lars Ehlers, Torben Jørgensen, Betina Heinsbæk Thuesen
Published in: European Thyroid Journal, Issue 7/2, 2018, Page(s) 75-83, ISSN 2235-0640
DOI: 10.1159/000485973

Defining Optimal Health Range for Thyroid Function Based on the Risk of Cardiovascular Disease

Author(s): Layal Chaker, Tim I M Korevaar, Dimitris Rizopoulos, Tinh-Hai Collet, Henry Völzke, Albert Hofman, Nicolas Rodondi, Anne R Cappola, Robin P Peeters, Oscar H Franco
Published in: The Journal of Clinical Endocrinology & Metabolism, Issue 102/8, 2017, Page(s) 2853-2861, ISSN 0021-972X
DOI: 10.1210/jc.2017-00410

Ensuring Effective Prevention of Iodine Deficiency Disorders

Author(s): Henry Völzke, Philippe Caron, Lisbeth Dahl, João J. de Castro, Iris Erlund, Simona Gaberšček, Ingibjörg Gunnarsdottir, Alicja Hubalewska-Dydejczyk, Till Ittermann, Ludmila Ivanova, Borislav Karanfilski, Rehman M. Khattak, Zvonko Kusić, Peter Laurberg, John H. Lazarus, Kostas B. Markou, Rodrigo Moreno-Reyes, Endre V. Nagy, Robin P. Peeters, Valdis Pīrāgs, Ján Podoba, Margaret P. Rayman, Ur
Published in: Thyroid, Issue 26/2, 2016, Page(s) 189-196, ISSN 1050-7256
DOI: 10.1089/thy.2015.0543

Dried blood spot thyroglobulin as a biomarker of iodine status in pregnant women

Author(s): Sara Stinca, Maria Andersson, Sandra Weibel, Isabelle Aeberli-Herter, Ralph Fingerhut, Sueppong Gowachirapant, Sonja Y. Hess, Nidhi Jaiswal, Tomislav Jukić, Zvonko Kusic, Ngoako Solomon Mabapa, Ashwini Kumar Nepal, Teofilo O.L. San Luis, Jia Qing Zhen, Michael Bruce Zimmermann
Published in: The Journal of Clinical Endocrinology & Metabolism, 2016, Page(s) jc.2016-2829, ISSN 0021-972X
DOI: 10.1210/jc.2016-2829

Development and Validation of a New Low-Cost Enzyme-Linked Immunoassay for Serum and Dried Blood Spot Thyroglobulin

Author(s): Sara Stinca, Maria Andersson, Jürgen Erhardt, Michael B. Zimmermann
Published in: Thyroid, Issue 25/12, 2015, Page(s) 1297-1305, ISSN 1050-7256
DOI: 10.1089/thy.2015.0428

Monitoring the prevalence of thyroid disorders in the adult population of Northeast Germany

Author(s): Rehman Mehmood Khattak, Till Ittermann, Matthias Nauck, Harald Below, Henry Völzke
Published in: Population Health Metrics, Issue 14/1, 2016, ISSN 1478-7954
DOI: 10.1186/s12963-016-0111-3

Pregnant Greek Women May Have a Higher Prevalence of Iodine Deficiency than the General Greek Population

Author(s): Eftychia G. Koukkou, Ioannis Ilias, Irene Mamalis, Kostas B. Markou
Published in: European Thyroid Journal, 2016, ISSN 2235-0640
DOI: 10.1159/000449285

The challenges of harmonising the iodine supply across Europe

Author(s): Sarah C Bath
Published in: The Lancet Diabetes & Endocrinology, 2016, ISSN 2213-8587
DOI: 10.1016/S2213-8587(16)30329-1