The Danish Multiple Sclerosis Registry

Abstract Objectives The Danish Multiple Sclerosis Registry is the oldest operative and nationwide MS registry. We present The Danish Multiple Sclerosis Registry with its history, data collection, scientific contribution, and national and international research collaboration. Materials and Methods Detailed description of data collection, completeness, quality optimizing procedures, funding, and legal, ethical and data protection issues are provided. Results The total number of registered cases with clinical isolated syndrome and multiple sclerosis since 1956 was by start of May 2020 30,023 of whom 16,515 cases were alive and residing in Denmark, giving a prevalence rate of about 284 per 100,000 population. The mean annual number of new cases receiving an MS diagnosis was 649 per year in the period 2010 to 2019. In total, 7,945 patients (48.1%) are receiving disease modifying therapy at the start of May 2020. Conclusions Multiple Sclerosis registers are becoming increasingly important, not only for epidemiological research but also by quantifying the burden of the disease for the patients and society and helping health care providers and regulators in their decisions. The Danish Multiple Sclerosis Registry has served as data source for a number of scientific publications including epidemiological studies on changes in incidence and mortality, cohort studies investigating risk factors for developing MS, comorbidities and socioeconomic outcomes in the MS population, and observational studies on effectiveness of disease modifying treatments outside the narrow realms of randomized clinical trials.

articles in the 2000s and 166 articles from 2010 to date. The nationwide Danish Multiple Sclerosis Registry is among the oldest and largest registers of MS under continuous development and update. With this article, we aim at describing its history, contents, and methods, as it is the background for much of the Danish MS research.

| History
The Danish Multiple Sclerosis Registry (DMSR) (Koch-Henriksen et al., 2001) was formally established in 1956, but prospective data collection started already in 1948. It commenced as a nationwide population-based MS prevalence survey (Hyllested, 1956)  In 2015, the DMSR established a new data collection platform, COMPOS® (Hillert & Stawiarz, 2015) which is now the common online data collection software for both the DMSR and for the clini-

| Data collection
The DMSR collects data on from the whole country on patients with the demyelinating conditions: MS, radiological isolated syndrome (RIS), and clinical isolated syndrome (CIS). We have extended the target of the DMSR to include the other demyelinating disease, neuromyelitis optica spectrum disorder (NMOSD). Data on the population with NMOSD were added retrospectively after a recent nationwide incidence and prevalence survey going back to 2007 (Papp et al., 2018).
In Denmark, far most of the neurological services are performed by the public hospitals. Diagnostic and clinical management of patients with MS and related disorders are carried out by 13 Departments of Neurology/MS clinics in public hospitals, and these are the only units that are authorized to prescribe and dispense disease modifying drugs.
All treating clinics record data online into COMPOS® on all patients with any of the above-mentioned demyelinating diseases.
Notification starts when the disease is diagnosed; however, much attention is paid to anamnestic clarification of the time of clinical disease onset. During treatment, patients are monitored in connection with scheduled clinical visits at regular intervals with recording of demographic, clinical and paraclinical data, as well as Kurtzkes Expanded Disability Status Score (EDSS) and functional systems (FS) (Kurtzke, 1983), and side effects. Relapses are recorded with their dates and whether or not treatment with corticosteroid was applied.
Notification of the DMSR is mandatory for all patients receiving DMT, and data collection is a part of the routine medical follow-up of patients. Failure of reporting mandatory data to the DMSR for a The online data collection platform facilitates the implementation of additional data modules required by specific studies, for example, a rapid implementation of data collection on Covid-19 cases in the spring of 2020.
Because notification on all patients with MS treated with DMD is mandatory, data on patients receiving DMD are virtually complete.

| Legal context, ethics, and data protection
All patients are informed about their data being recorded. According to the Danish implementation of the General Data Protection Regulation (GDPR), there is no requirement for informed consent from the patient for inclusion in the DMSR, on the explicit condition that data can never be used for any other purpose than pure science and statistics. The hospital owners and relevant councils are provided with summary counts of patients to estimate future needs for DMDs and medical care.
The DMSR is physically adjoined to the Department of Neurology, University Hospital Copenhagen, Rigshospitalet.

| Data usage rights, data-sharing, data protection and data privacy
The DMSR is a scientific research register and data cannot be accessed for other purposes. The Scientific Steering Committee of the DMSR reviews and assesses the research proposals according to scientific quality, feasibility, value of the project, and alignment with priority areas of the scientific activities of the DMSR.
After evaluation of the application by the Scientific Committee, a contract will be drawn up for each project, setting out the rules of data property and budget aspects. Access to data will then be provided. Data are only available to academics after specific permission and limited to what is necessary for the purpose of then defined scientific project. Data analysis is also carried out by DMSR or an independent third party according to GDPR regulations.

| Number of cases registered
The total number of registered with CIS and MS was by start of May 2020 30,023 of whom 16,515 cases were alive and residing in Denmark, giving a prevalence rate of about 284 per 100,000 population. Details of the register content of these patients are shown in Table 1, and the variables are listed in Table 2 The treatment history for patients has been registered since 1996, and side effect from treatment has been reported from the beginning, though more detailed since 2018. Relapses, EDSS, and MRI have been regularly reported after treatments became available and more detailed in recent years. Figure 1 shows the distribution of the patients as to vital status and sex; Figure 2 shows the distribution of onset symptom; Figure 3 shows age at onset and age at diagnosis. Current treatment by type of preparation DMT is presented in Figure 4.
TA B L E

| Validity
In the old part of the DMSR, which was based on submitted clinical records or discharge letters, the neurological staff of the register evaluated all clinical data as to compliance with the current diagnostic criteria (until 1994 those of (Allison & Millar, 1954) from 1994 the Poser criteria (Poser et al., 1983); and from 2005 the McDonald criteria (Polman et al., 2005)). Only three neurologists (one of them NKH) have since 1948 been involved in this task.

| Completeness
The DMSR is regularly linked with other registers: As a source of control of the completeness, we use the Danish National Patient Registry (NPR) (Schmidt et al., 2015). This registry is automatically To further ensure completeness of the DMSR, the data coordi- to any of the MS clinics, independent of the notifications by COMPOS, and control of correct case-definition has a high priority for the DMSR. The advantage for the doctors is that the COMPOS platform for the single patients provides an instantaneous overview of the course of relapses, EDSS, MSSS, treatments, and side effects ( Figure 5). This contributes to a high completeness of registration.

| Scientific contribution
The DMSR has alone or in collaboration with other scientists We have selected most important studies from the DMSR published within the last 10 years.

| Descriptive epidemiology
• Incidence of MS has increased markedly, particularly in elderly and in women .
• Incidence of NMOSD in Denmark was estimated at 0.029 per 100,000 person years (Papp et al., 2018).
• The incidence rates of pediatric MS and other ADS in Denmark were higher than those reported for some other European countries (Boesen et al., 2018).
• Spatial analyses revealed that even within the small geographi-

| Historical prospective population cohort studies
• Low concentrations of neonatal 25(OD) vitamin D increase the risk of MS later in life ).
• Shift work at age 15-19 increases the risk of MS in adulthood (Gustavsen et al., 2016).
• Immigrants from low-MS-risk countries only partially adapted to the risk in Denmark, most pronounced with immigration before age 15 (Nielsen et al., 2019).
• Early age at menarche appears to be associated with an increased risk of MS .
• Socioeconomic status in childhood seems of no major importance for the subsequent risk of MS.  • People born by Cesarean section were at no increased risk of MS later in life . • High body mass index in childhood is a risk factor for MS (Munger et al., 2013).
• Male infertility increases the risk of MS (Glazer et al., 2017).
• Parental MS affects educational achievements, employment, disability pension, and income of children (Moberg et al., 2016). • The efficacy of DMT in pediatric onset MS patients is comparable to that seen in adult onset MS patients. (Kopp et al., 2019) • Earlier treatment start is associated with a beneficial prognosis in the pediatric cohort (Kopp et al., 2019).

| MS cohort observational studies
• Patients who started treatment with DMT later reached an EDSS score of 6 more quickly compared with patients who started early, and the delay showed a tendency to shorten time to death (Chalmer et al., 2018).
• Multiple sclerosis patients do not have increased cancer incidence or increased cancer-specific mortality compared with the background population .
• Compared with the background population MS seriously affects the economic life of the patients, even within a few years of onset , and it often leads to broken relationships .
• Treatment effectiveness of Interferon-β is not different in women and men (Magyari et al., 2014).

F I G U R E 3
Age group at onset and diagnosis for the prevalent MS and CIS population F I G U R E 4 Distribution of ongoing disease modifying therapy by May 2020 • Clinically stable disease is associated with a lower risk of both income loss and disability pension for patients with multiple sclerosis (Chalmer et al., 2020).
• Treatment escalation leads to fewer relapses compared with lateral switching to another moderately effective therapy .
• The occurrence of vascular comorbidities is higher in the population with MS (Thormann et al., 2016).
• Comorbidities in multiple sclerosis have socioeconomic consequences and are associated with diagnostic delays and increased mortality .

| Case-control studies
• Female MS patients have fewer childbirths than women from the matched background population in the last five years up to clinical onset (Magyari et al., 2013).
• Social and physical environmental factors available from Danish registries cannot explain the increasing incidence of women in Denmark .
• Some autoimmune comorbidities are more frequent in persons with MS .

| Head-to-head comparative treatment studies
• Reduced disease activity in MS patients treated with dimethyl fumarate compared with patients treated with teriflunomide (Buron et al., 2019).

| D ISCUSS I ON
The DMSR has proved valuable as a scientific registry and has gained increasing attention through the last decades. The advantages of the DMSR are that it is close to being purely population based, and that its size in many instances secures a substantial statistical power. The scientific questions typically address range from purely descriptive questions aimed at understanding the characteristics of people who develop the disease and how the disease generally progresses, to highly focused questions intended to support decision-making on disease modifying therapy. The most important questions about registers are their completeness and validity, which can have different weights depending on the type of a study. We have aimed to achieve optimal completeness by the independent case ascertainment method using multiple sources of notification, and at our best ensured validity by the diagnostic criteria method (Goldberg et al., 1980).

Several studies have been published by linking the DMSR to
numerous other Danish population-based registers, carrying person-specific information on vast variety of clinical, social, health, financial, educational, and occupational data.
The DMSR is involved in international collaborations and is a part of the BIGMS Network which is a network of five MS patient registries, with the joint aim to analyze large-scale information on MS.
Several past and ongoing scientific projects are conducted in collaboration with national or international research groups using the DMSR as data source.
The DMSR is also a resource for post-marketing authorization safety and effectiveness studies (i.e., phase IV), which can be conducted by utilizing its prospectively collecting safety data and linkage to independently collected secondary data information from several population-based registries, such as The National Patient Registry (Schmidt Cancer Registry (Gjerstorff, 2011). Five phase IV studies are in progress regarding post-marketing safety of teriflunomide, alemtuzumab, cladribine, natalizumab, and ocrelizumab. Furthermore, by linkage of the DMSR to nationwide population based reproductive registries we are able to evaluate the association between exposure to a specific drug and different pregnancy and perinatal outcomes. Currently, the DMSR is involved in several multi-country cohort post-authorization pregnancy safety studies. Such studies are also conducted at national level if the sample size allows a sufficient statistical power.

| Ongoing efforts
In 2020, the data collection platform will be expanded with a new module to enable self-reported information from people with MS, known as patient-reported outcomes (PRO). An ongoing project in collaboration with the Danish MS Society aims to ensure patient participation in the selection of specific scales, surveys and outcomes, which will be a part of the online PRO module.
Specific modules can be implemented in order to expand the collected data or if the need to collect specific information arises. For example, a module to collect data on Covid-19 infection has been implemented very fast during April 2020. The core COVID-19 dataset will contribute to a global data sharing initiative and can serve to answer questions on the impact of the Covid-19 pandemic on different aspects of MS.
The possibility to adjust the data collection platform according to emerging research questions is of increasing importance for patients, researchers as well as for health authorities and industrials and is a step forward toward personalized patient management.

| CON CLUS ION
The DMSR has served as data source for a number of scientific publications, epidemiological studies on changes in incidence and mortality, cohort studies investigating risk factors for developing MS, comorbidities and socioeconomic outcomes in the MS population and observational studies on effectiveness of disease modifying treatments outside the narrow realms of randomized clinical trials.

ACK N OWLED G M ENTS
The Danish Multiple Sclerosis Society for supporting the MS registry and for the Danish Multiple Sclerosis Group for continuous data collection.

CO N FLI C T O F I NTE R E S T S
The authors received no financial support for the authorship, and publication of this article. Melinda Magyari has served on scien- Laursen assisted in data acquisition and revising the manuscript.
Nils Koch-Henriksen conceptualized the article, has been involved in drafting and revising the manuscript.

PE E R R E V I E W
The peer review history for this article is available at https://publo ns.com/publo n/10.1002/brb3.1921.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data will be shared upon request by any qualified investigator under approval from the Danish Data Protection Agency.