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Register-based information on thyroid diseases in Europe: lessons and results from the EUthyroid collaboration

Objective Registers of diagnoses and treatments exist in different forms in the European countries and are potential sources to answer important research questions. Prevalence and incidence of thyroid diseases are highly dependent on iodine intake and, thus, iodine deficiency disease prevention programs. We aimed to collect European register data on thyroid outcomes to compare the rates between countries/regions with different iodine status and prevention programs. Design Register-based cross-sectional study. Methods National register data on thyroid diagnoses and treatments were requested from 23 European countries/regions. The provided data were critically assessed for suitability for comparison between countries/regions. Sex- and age-standardized rates were calculated. Results Register data on ≥1 thyroid diagnoses or treatments were available from 22 countries/regions. After critical assessment, data on medication, surgery, and cancer were found suitable for comparison between 9, 10, and 13 countries/regions, respectively. Higher rates of antithyroid medication and thyroid surgery for benign disease and lower rates of thyroid hormone therapy were found for countries with iodine insufficiency before approx. 2001, and no relationship was observed with recent iodine intake or prevention programs. Conclusions The collation of register data on thyroid outcomes from European countries is impeded by a high degree of heterogeneity in the availability and quality of data between countries. Nevertheless, a relationship between historic iodine intake and rates of treatments for hyper- and hypothyroid disorders is indicated. This study illustrates both the challenges and the potential for the application of register data of thyroid outcomes across Europe.


INTRODUCTION
Register-based data on treatments and diagnoses of thyroid disease can be used as proxies for thyroid disease frequency in a population. This has e.g. been successfully utilized in Denmark (2). In many European countries, treatments for thyroid disease and/or patients diagnosed with thyroid disorders are documented in nationwide or regional registers. This encompasses registers of diseases, medications and other treatments, hospital admissions and ambulatory care, as well as registries related to health insurances. Ideally, for use in research projects, a register should cover the entire country/region or a large, welldefined sub-population whereby it is representative, and the data should be of acceptable validity (3).
European registers have previously been collated for research projects in e.g. melanoma (5), asthma (6), and cerebral palsy (7) and several initiatives to promote and improve the collaboration and utilization of registers in Europe are established (8,9). However, the availability and applicability of register data for assessment of thyroid outcomes from the European countries have not yet been examined. After thorough assessment of the quality and comparability of data across countries, European registers can potentially represent valuable and efficient data sources for evaluating differences in thyroid outcomes across the countries/regions. Iodine intake in a population is a main factor behind thyroid disease epidemiology. Iodine deficiency is associated with adverse outcomes ranging from severe mental retardation and stunting to goiter/thyroid nodules and hyperthyroidism (1). However, the window of adequate iodine intake is narrow, hence, iodine excess may increase the risk of hypothyroidism and autoimmune thyroid disorders in a population (10).
Most regions of Europe will be iodine deficient without programs to prevent iodine deficiency disorders (IDD). However, the implementation and type of IDD prevention programs depends on stakeholder barriers, political prioritization (13), and cultural differences. The IDD prevention programs range from general recommendations for intake of iodine-rich foods, over recommendations for iodine supplementation especially for pregnant and lactating women, to voluntary or mandatory iodine fortification (IF), most commonly addition of iodine to table salt and salt in bread (14). An overview of IF programs and iodine intake across 23 European countries/regions is presented in Table 1. The optimal level of iodine intake and the most effective IDD prevention program remains to be established.
In many countries, the assessment of median urinary iodine concentration in representative population samples are used to classify the iodine status and to steer IDD prevention programs. While this approach is relatively simple, it is not sufficient to evaluate the aim of such prevention programs, which is to reduce prevalence and incidence of thyroid diseases and related treatments and to save expenditures in healthcare systems (4). This can potentially be achieved by analyses of register data. We hypothesized that efficient IDD prevention programs ensuring sufficient iodine intake are robustly associated with a low burden of thyroid related diseases in populations.
The EUthyroid project was an ambitious collaborative project with participation and representatives from most EU countries funded by the European Union's Horizon 2020 research and innovation program under grant agreement no. 634453. The overall aim of the EUthyroid project was to "evaluate iodine deficiency prevention and monitoring programs in European countries, to initiate capacity building for harmonized European ID prevention and monitoring programs." In this paper we report lessons and results from work package 1 of the EUthyroid project. First, we evaluate the availability, applicability, and comparability of register data on thyroid outcomes in the European countries, and second, we report country-specific rates of thyroid outcomes and seek to identify patterns in the relationship with iodine supply across Europe.
Treatments: Annual number of persons with at least one dispensed dose and total number of defined daily doses (DDD) of antithyroid medication and thyroid hormone therapy. Annual number of persons with at least one procedure and the total number procedures for all thyroid surgeries, thyroid surgeries with benign indication, all radioiodine treatments, radioiodine treatments with benign indication, and fine needle biopsies.
The demographic data of the total populations (total number of individuals and stratified by sex and 5-year age intervals) were derived from Eurostat (http://ec.europa.eu/eurostat) or provided from the national EUthyroid representatives for regional or sub-national populations.
Ethical and/or data handling approvals were obtained in each country according to national regulations to obtain aggregated register data. Only aggregated data was collected and, thus, no patient level data (personal data) was handled thereby protecting the privacy the individuals.

Critical assessment and selection of data and variables
The national representatives were also requested to provide a description of the data sources and health care organization factors relevant to assess the completeness and validity of the data provided.
The applicability of the provided data from each country was critically assessed. For inclusion in the database and calculation of raw rates the provided data had to fulfill the criteria for the requested data. For comparison between countries and calculation of standardized rates, the data and variables had to be stratified by sex and age, collected from comparable data sources and registered by comparable methods. The critical assessment was conducted by the senior author, BHT.

Iodine intake
Populations' iodine intakes were derived from published reports of urinary iodine concentrations in school aged children or adults and summarized in Table 1. Iodine intake was classified as insufficient, adequate or excess according to current WHO epidemiological recommendations (15). Early and recent iodine intake were classified as iodine intake approximately 15-20 years before and after 2001, respectively.

Statistical methods
Rates of medications were calculated as one-year period prevalence per 10,000 persons. Rates of diagnoses were calculated per year per 10,000 persons. Raw rates were calculated with the treatments and diagnoses as the numerator and the demographic data of the population as the denominator in the provided sex and/or age strata where possible.
Standardized rates were calculated to remove the effect of the differences in sex and age distributions between the European countries. This was done by calculating the proportion of each sex and age-specific strata in the total European Standard Population (16) and multiplying this by the raw rate in the corresponding strata for each country before summarizing the overall standardized rate in each country. When data were provided for more than one calendar year, the rates were calculated as the average of the calendar years available.
Comparisons between countries were done using standardized rates. No formal statistical tests were applied in the comparison of rates between countries. Table 2 provides an overview of the data sources and Figure 1 provides an overview of the flow of the data acquisition, critical assessments, and calculations.

Data availability and data assessment
Register data for at least one thyroid outcome was available and provided from 22 out of 23 participating countries/regions. However, critical assessment concluded that data from 3 countries were considered unsuitable to be included in the database. See overview of data and assessments in the Supplementary  Table S1 and S2. Raw rates for data included in the database are presented in the Supplementary Table S3-S5.
The outcome variables were grouped into 6 categories: thyroid medication, thyroid surgery, radioiodine treatment, fine needle biopsies, diagnoses of thyroid diseases, and diagnoses of incident thyroid cancer. Sex-and age stratified data from all categories were available from 4 countries, whereas data from only one outcome variable was available from 4 countries. The critical assessment of the data included in the database found that data on use of thyroid medication, number of thyroid surgeries and incidence of thyroid cancer were of acceptable quality and thus appropriate for calculation of standardized rates and comparison between countries.
In contrast, data on diagnoses of thyroid diseases except for thyroid cancer were not considered suitable for comparisons across countries. In some countries, registrations included patients treated in primary care whereas only patients attending hospitals were included in other countries, and it was not possible to distinguish between incidence and prevalence data. Furthermore, in some countries registration of diagnoses were based on the ICD-9 system whereas the ICD-10 system was used in other countries and the conversion of data from ICD-9 to ICD-10 caused some misclassification. Data on radioiodine and fine needle biopsies were only available from few countries and were generally considered unreliable.

Thyroid medication
Data from 9 countries were found to be appropriate for comparison of standardized rates of thyroid medication between countries. Hereby we found that the use of antithyroid medication was lowest for Sweden, Finland, Norway and Spain (8.6-13.7 users/10,000 persons) and highest for Denmark, Latvia and Hungary (34.8-43.2 users/10,000 persons). Conversely, the use of thyroid hormone therapy was lowest for Latvia, Denmark and Hungary (192.4-253.1 users/10,000 persons) and highest for Czech Republic, Belgium, Finland, Sweden and Norway (424.8-612.8 users/10,000 persons) ( Table 3).
There was a clear indication of higher use of antithyroid medication relative to thyroid hormone therapy for countries with early iodine insufficiency. However, there was no apparent pattern in the association between recent iodine intake and use of thyroid medications.

Thyroid surgeries
For thyroid surgeries, data from 10 countries were found to be appropriate for comparison between countries. We found that the standardized rates of thyroid surgeries for benign indications were lowest for Czech Republic, Slovenia, Norway, Sweden and Spain (1.4-2.0 patients/10,000 persons), all with early iodine adequacy, and highest for Belgium, Latvia, and Hungary (4.3-5.1 patients/10,000 persons), all with early iodine insufficiency (Table 4). However, no clear pattern was indicated for thyroid surgeries for all indications or when compared with recent iodine intake.

Thyroid cancer
Data on standardized rates of thyroid cancer diagnoses were assessed to be appropriate for comparison between 13 countries/regions. The lowest rates were found in Bulgaria, Northern Ireland, and Scotland (0.4-0.5 patients/10,000 persons) and the highest rates in Denmark, Latvia and Hungary (0.9-1.4 patients/10,000 persons) (Table 5), with no clear pattern in the association between early or recent iodine intake and cancer rates.

DISCUSSION
In this first collation of register data on thyroid outcomes from European countries, we found a high degree of heterogeneity in the availability and quality of register data between countries. Data for thyroid medication, thyroid surgery and thyroid cancer were suitable for comparison between 9, 10, and 13 countries, respectively. These data indicated higher rates of antithyroid medication and thyroid surgery for benign disease and lower rates of thyroid hormone therapy in countries with early iodine insufficiency. There was no apparent pattern in the association between thyroid cancer and iodine intake.

Registers, data availability, and data quality
All but one of the 23 participating countries had data on at least one thyroid outcome. However, the data sources, number of variables and quality of register data varied widely due to differences in the organization of the healthcare systems, digitization, history/culture, and political decisions. This is also recognized in previous papers acknowledging the vast potential of the European registers but also addressing the challenges (8,9,17).
Nationwide health registries were established in the Scandinavian countries, Latvia, Hungary and in the Region of Catalonia in Spain. In contrast, Croatia, Germany, Greece, Great Britain, North Macedonia, and Switzerland provided no data from registers fulfilling the requested criteria. Register data from Czech Republic, Belgium, and Bulgaria were derived from health insurance companies covering the majority of the population or a well-defined sub-population. These encompass both public and private health insurance companies. Information on thyroid cancer was available from most countries.
For all data sources the representativity and validity were assessed. There was little concern regarding the representativity in the Nordic registers (18), but some health insurance registers may carry a risk of social stratification hampering the representativity. European cancer registries have a long history and the coverage is generally high (8). The validity of registers could be compromised by over-, under-, or misreporting. Thyroid medications require prescriptions in most European countries and are rarely prescribed in hospitals. This increases the probability of correct reporting as most registers are based on redeemed prescriptions (17). However, e.g. in the Latvian National Health Service register, only reimbursed prescriptions were registered. Some patients may have private insurance or choose to pay fully out-ofpocket and are thus not registered. The validity of thyroid surgeries was also assessed to be appropriate for the included countries. In cancer registries, the data is generally reliable but comparability is still somewhat influenced by diverse methods between countries (8). In contrast, diagnoses other than cancer were considered to be unreliable. Registration of thyroid diagnoses vary both between countries and can also vary within countries between health care providers and specialists. E.g. the rates of congenital iodinedeficiency syndrome were far higher in some countries than what national experts regards as plausible. Validation studies are rarely available for any of the registers (17).
In addition, between-country differences in other risk factors for thyroid outcomes (e.g. alcohol (19,20), smoking (21), and other micronutrient deficiencies (22)) and between-country differences in diagnostic activity and treatment practices may also influence the rates of thyroid outcomes independently of iodine intake. Especially differences in ultrasound utilization can impact the detection and thus diagnoses and treatment for thyroid nodules and cancer. Despite clinical practice guidelines developed by recognized professional associations, surveys among clinicians find some variability and divergence from guidelines in clinical management of Grave's disease, hypothyroidism, and thyroid nodules (23)(24)(25). Furthermore, during 2001-2009/2015 a fall in threshold for treatment initiation of thyroid hormone therapy was observed in both Great Britain and in Denmark leading to more prescriptions of thyroid hormone therapy, but the fall in treatment threshold was markedly steeper in Denmark (26,27). It is a limitation that we were unable to adjust for these between-country differences.
Overall, collection and comparisons of register-based data from European countries is time consuming and complicated. When it comes to the burden of thyroid diseases, potential consequences of differences in iodine intake status and IDD prevention programs may be overshadowed by within-and between-country sources of bias and confounding.

Differences in thyroid medication, surgery, and cancer rates
Despite the potential biases in comparisons, we still found fairly consistent rates of thyroid outcomes in line with previous research both when comparing the Scandinavian countries who have rather similar registers, healthcare systems, and health behaviors, but also when including data from quite different countries.
Thus, the findings of the highest rates of treatments most frequently applied for hyperthyroidism and/or structural thyroid diseases in countries with early iodine insufficiency and, conversely, the highest rates of treatment for hypothyroidism in countries with early iodine adequacy correspond with previous studies within countries comparing areas with high and low iodine intake (28)(29)(30) and over time, when iodine adequacy was achieved after introduction of IDD prevention programs (31)(32)(33)(34). However, it is a limitation that the specific indication for treatment is not known.
We also found that rates of thyroid cancer did not correlate with early or recent iodine intake, for which previous results are not fully consistent (35). Previous studies have indicated that increased iodine intake is associated with an increase in the ratio between papillary and follicular thyroid cancer (36), which was not measured in our study. Nevertheless, whether the overall incidence of thyroid cancer is influenced by the population level iodine intake is still not clear (35).
We chose to only examine overall patterns in the relationship between iodine intake and rates of thyroid outcomes because the available data on iodine intake were collected by different methods, timepoints, and populations across the European countries and thus not sufficiently comparable. If valid data on early and recent iodine intake in Europe are harmonized it will be possible to perform more advanced statistical analyses of associations between the burden of thyroid diseases and iodine intake (37,38).
Of note, our results indicate a higher correlation between early iodine intake and thyroid outcomes than recent iodine intake. Many of the included countries have introduced IDD prevention programs and achieved iodine sufficiency during the past two decades, and thus the adult population may still be affected by the exposure to decades of iodine insufficiency. Biologically it is plausible that thyroid function and thereby thyroid disease is influenced by the lifetime iodine intake level (39). Furthermore, the introduction of IF can cause a temporary rise in incident hyperthyroidism in countries with previous ID (1) or may induce thyroid dysfunction due to excessive iodine intake (40). This could affect the rates of treatment in several included countries. In Denmark, steady states were achieved for rates of thyrotoxicosis but not for hypothyroidism approximately 10 years after implementation of mandatory IF (33,34). Our study indicates that it may take even longer before the difference between former iodine adequacy and iodine insufficiency is negated between countries. Despite overall iodine adequacy, iodine deficiency can still be present in vulnerable groups, e.g. pregnant women, which is observed in several countries (37).
The results show no differences between countries characterized by different IDD prevention strategies. Thus, a best-practice model of IDD prevention cannot be identified through this study. This may be explained, firstly, by the difference in coverage and impact of especially voluntary IF. Secondly, IDD prevention programs are optimally designed to compensate for the level of iodine deficiency in the target population, thus, similar iodine intakes may be achieved from different IDD prevention strategies.

Strengths and limitations
The main strengths of this study are, firstly, the strong collaboration between representatives from thyroid research and clinical environments from the European countries. The national EUthyroid representatives had or obtained knowledge of the availability and documentation of data that would not be possible for one researcher from one country. Secondly, the acquisition of several thyroid outcomes enabled us to evaluate different aspects of thyroid disease and the relationship with iodine intake. Thirdly, the critical assessment of data secured that only data of appropriate quality was included. However, the critical assessment was based on evaluations of the available documentation, and thorough validation of most of the variables was not possible. Raw rates were calculated for all provided data included in the database, however, it is important to note that these should be interpreted with caution because the validity of some data is uncertain and comparison of the raw rates will be confounded by differences in sex-and age distributions. Only few variables met the criteria for comparison between countries and these variables were only available for few countries, which is a major limitation. This in combination with the heterogeneity of iodine intake data and lack of confounding factors limited the generalizability and our ability to draw more firm conclusions on the effect of iodine intake and IDD prevention programs.
This study elucidates the limitations of the registers and points out the need for greater participation and more uniformity in reporting in the future to optimally utilize the valuable registry information. The current increase in digitization and awareness of the possibilities within register research may lead to more valid register data sources on thyroid diagnoses and treatment with easy access and utilization in the European countries in the future. This will be of great value to thyroid research.

Conclusion and perspectives
The availability and quality of register data on thyroid diagnoses and treatments are highly heterogeneous between Europeans countries. Thus, comparison of rates of thyroid outcomes is currently only possible between a limited number of countries. The available data indicate lower rates of antithyroid medication and thyroid surgery for benign disease and higher rates of thyroid hormone therapy in countries with early iodine intake adequacy, and no difference for thyroid cancer or according to recent iodine intake.
As stated in the Krakow Declaration, evaluation of primary thyroid outcomes is essential in the control of IDD prevention programs (41). Registers may be an effective tool for this evaluation. Thus, the present project serves as initial exploration of the availability and quality of register data of thyroid outcomes across Europe, while more in-depth examination of the validity and comparability of registers is still needed to fully utilize the potential of the registers.

DECLARATION OF INTEREST
The authors have no conflicts of interest to declare. The author Alicja Hubalewska-Dydejczyk is an editor of the journal.     Reasons for not included in the database/calculation of raw rates: 1 Cohort-data not related to a specific population, data only related to a small proportion of the total population, or data related to a non-representative sub-population. 2 Variables in units that cannot be translated to the requested format.