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Cohort profile
Cohort profile: life with neurofibromatosis 1 – the Danish NF1 cohort
  1. Karoline Doser1,
  2. Hanne Hove2,3,
  3. John R Østergaard4,
  4. Pernille E Bidstrup5,6,
  5. Susanne O Dalton7,8,
  6. Mette Møller Handrup4,
  7. Cecilie Ejerskov4,
  8. Anja Krøyer1,
  9. Mia Aagaard Doherty1,
  10. Jens Richardt Møllegaard Jepsen9,10,
  11. John J Mulvihill11,
  12. Jeanette F Winther1,12,
  13. Line Kenborg1
  1. 1Childhood Cancer Research Group, Danish Cancer Society Research Center, Copenhagen, Denmark
  2. 2Center for Rare Diseases, Department of Pediatrics and Adolescents, Rigshospitalet, Copenhagen, Denmark
  3. 3The RAREDIS Database, Section of Rare Diseases, Department of Pediatrics and Clinical Genetics, Rigshospitalet, Copenhagen, Denmark
  4. 4Centre for Rare Diseases, Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital Skejby, Aarhus, Denmark
  5. 5Psychological Aspects of Cancer, Danish Cancer Society Research Center, Copenhagen, Denmark
  6. 6Institute of Psychology, University of Copenhagen, Copenhagen, Denmark
  7. 7Survivorship and Inequality in Cancer, Danish Cancer Society Research Center, Copenhagen, Denmark
  8. 8Department of Clinical Oncology and Palliative Care, Zealand University Hospital Naestved, Naestved, UK
  9. 9Center for Neuropsychiatric Schizophrenia Research and Center for Clinical Intervention, Mental Health Services, Copenhagen University Hospital Glostrup, Glostrup, Denmark
  10. 10Child and Adolescent Mental Health Center, Mental Health Services, Copenhagen University Hospital Glostrup, Glostrup, Denmark
  11. 11Department of Pediatrics, University of Oklahoma, Oklahoma City, Oklahoma, USA
  12. 12Department of Clinical Medicine, Aarhus Universitet, Aarhus, Denmark
  1. Correspondence to Dr Line Kenborg; kenborg{at}cancer.dk

Abstract

Purpose The Danish neurofibromatosis 1 (NF1) cohort was initiated to study health-related, socioeconomic and psychological consequences of living with the monogenetic disorder NF1 using a nationwide and population-based approach.

Participants The cohort includes all 2467 individuals in Denmark who were hospitalised with or due to NF1 from 1977 to 2013 or registered in the RAREDIS Database (1995–2013), a national clinical database for rare diseases, or both. A comparison cohort matched to individuals with NF1 on sex and date of birth was identified in the Civil Registration System (n=20 132).

Findings to date All cohort members were linked to the unique Danish registries to obtain information on hospital contacts, birth outcomes, education and partnership. A questionnaire was completed by 244 of the 629 adult cohort members with NF1 registered in the RAREDIS Database to evaluate the psychosocial and emotional burden. Further, neuropsychological tests were performed on 103 adult cohort members with NF1 and 38 adult population comparisons. To date, six studies have been published. Individuals with NF1 had an increased risk for (1) hospitalisation for disorders affecting all organ systems of the body throughout all decades of life, (2) psychiatric disorders, (3) attaining a short or medium long education and (4) not forming a life partner. Women with NF1 had an increased risk for spontaneous abortions and stillbirths. Finally, adults with NF1 had an impaired quality of life and a high need for professional support for physical, psychological and work-related problems, which was partly associated with disease severity and visibility.

Future plans The cohort will regularly be updated with newly diagnosed patients in the RAREDIS Database as well as with outcome information in the Danish registries. New studies are in progress to assess other medical and socioeconomic dimensions of living with NF1.

  • EPIDEMIOLOGY
  • GENETICS
  • PUBLIC HEALTH

Data availability statement

Data are available on reasonable request. All data are stored on a secure platform at Statistics Denmark and can only be accessed remotely. The study group welcomes collaboration with other researchers. Study protocols can be planned in collaboration with us, and the data can be analysed accordingly at the server of Statistics Denmark. Access to data can only be made available for researchers who fulfil Danish legal requirements for access to personal sensitive data. Please contact JFW (jeanette@cancer.dk) or senior researcher LK (kenborg@cancer.dk) for further information.

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STRENGTHS AND LIMITATIONS OF THIS STUDY

  • The Danish neurofibromatosis 1 (NF1) cohort is a unique data source for investigating the consequences of living with NF1.

  • Despite being a rare disorder, the inclusion of all known individuals with NF1 in Denmark enables assessment of rare outcomes, new hypotheses and age-specific manifestations of NF.

  • The cohort combines registry data with information obtained in questionnaires and neurocognitive tests to give a comprehensive description of NF1.

  • Individuals with NF1 who have not been hospitalised or registered in the clinical database are not included in our cohort.

  • A comparison group is lacking in the questionnaire studies, and as Danish norm data are not available for all measures, we have to rely on international norm data.

Introduction

The Danish neurofibromatosis 1 (NF1) cohort was initiated to investigate health-related, socioeconomic and psychological consequences of living with the single gene disorder NF1 using a nationwide and population-based approach. NF1 is one of the most common mendelian disorders, with an incidence of up to 1 in 2000 livebirths.1 About 50% of the cases are inherited from a parent, whereas the other 50% are due to de novo NF1 variants.2

NF1 is an unpredictable disorder that varies widely in severity and clinical manifestations. A hallmark feature of NF1 is neurofibromas, which are benign cutaneous lesions, subcutaneous tumours that grow from nerves or plexiform neurofibromas; the latter two of which carry a risk of malignant transformation.3 Other clinical features include café-au-lait macules (pigmentary lesions of the skin), skeletal dysplasia, Lisch nodules (iris hamartomas) and optic pathway glioma.4 The lifetime cancer risk for individuals with NF1 has been estimated to 60%5 and is the main reason for the reduced life expectancy up to 16.5 years for men and 26.1 years for women with NF1.1

Although NF was formally described back in 1882 by Friedrich Daniel von Recklinghausen,6 knowledge about all features of NF1, especially in adults, is still sparse. A wide range of medical, cognitive, social and behavioural problems have been associated with NF1.2 However, most previous research was based on small populations, relied on self-reported outcomes or lacked a population-based approach. Thus, we initiated the Danish NF1 cohort to permit a comprehensive assessment of the multifaceted burden of living with NF1 by combining information from national registries, a clinical database, questionnaires and neuropsychological tests. As NF1 is a rare disorder, few countries are capable of initiating a large, national cohort of individuals with NF1. The use of a population-based cohort to assess the consequences of living with NF1 reduces the risk of a selective inclusion and dropout, and limits the risk of reporting bias, for example, from case series at academic medical centres. Finally, we were able to establish a comparison cohort randomly sampled from the Danish general population.

To depict life with NF1, the aim of establishing this comprehensive NF1 cohort was to assess the somatic and psychiatric disease burden in individuals with NF1 as well as to assess how they manage the transition from childhood into adolescence and adulthood by determining the following psychosocial and socioeconomic achievements or life goals: cohabitation, leaving home and educational attainment. Finally, the aim was to pilot investigation of the psychosocial burden and neurocognitive function among adults with NF1 using questionnaire data and neurocognitive tests.

Cohort description

Denmark offers exceptional opportunities for carrying out population-based research because of its civil registration system based on unique personal identification numbers given to all inhabitants on 2 April 1968 and since then at birth and the existence of a number of unique population-based, nationwide administrative registries with information on for example medical and surgical hospitalisation and educational attainment. Denmark has a tax-funded welfare system, which supplies education, social welfare and healthcare free of charge. This system, in combination with the tradition for administrative registration of both health and socioeconomic factors with strong legislation to protect the individual, enables the use of grouped data for research and forms a unique platform to perform studies that have never before been conducted on a nationwide basis.

Study population

The NF1 cohort was established by combining data from the national Danish Patient Registry with data from a database for rare diseases (RAREDIS). Initially, we included all 2576 individuals, alive or born after 2 April 1968, who have been hospitalised with or for NF according to the International Classification of Diseases version 8 (ICD-8) 743.49 or ICD-10 Q85.0 since the establishment of the Patient Registry in 1977 and until 31 December 2013 (see flow chart, figure 1). The Patient Registry is a population-based administrative registry and includes information on all somatic inpatient hospitalisations; psychiatric hospitalisation and outpatient and emergency visits were added to the registry in 1995.7 The ICD system, however, does not differentiate between NF1 and the even rarer NF2, which is clinically and genetically distinct from NF1.8 Thus, we excluded 59 individuals from the cohort, who had a tumour or tumour combinations or a discharge history in the Patient Registry compatible with NF2.9 We supplemented the NF1 cohort with individuals registered with NF1 in the RAREDIS Database.10 The database includes information on patients who were followed in one of two national centres for rare diseases between 1995 and 2013 located at Aarhus University Hospital and Copenhagen University Hospital, Rigshospitalet. All diagnoses are confirmed using the diagnostic criteria set up by the National Institute of Health, USA11 or by molecular genetic testing. All inhabitants in Denmark with known NF1 are encouraged to be followed regularly in one of the two centres free-of-charge irrespective of NF1 disease severity.

Figure 1

Flow chart of cohort members in register-based studies.

Each member of the NF1 cohort was matched on sex and date of birth to up to 10 population comparisons randomly selected from the Danish Civil Registration System12 to represent the Danish background population. All individuals in the comparison cohort had to be alive on 2 April 1968 or be born thereafter and without a registration of a NF1 diagnosis in the Patient Registry or in the RAREDIS Database on the date their matched patient was diagnosed with NF1 (n=25 170).

All cohort members were linked to the Danish Civil Registration System to obtain information on vital status and migration. We excluded individuals with no known date of NF1 diagnosis (n=37) (figure 1). We also excluded cohort members who did not live in Denmark at diagnosis, comparisons with an excluded matched case, those who died before or did not live in Denmark when their matched patient was diagnosed with NF1 as well as doublet comparisons, leaving 20 132 individuals in the comparison cohort.

Participants in questionnaire study

Of the 639 individuals registered in the RAREDIS Database with NF1 in the period 1977–2016, 467 were adults aged ≥18 years living in Denmark (see flow chart, figure 2). We excluded 30 adults due to death, protection of address or other reasons, leaving 437 adults with NF1 eligible for participation. The 437 adults were mailed an invitation letter and a paper-based questionnaire, and 244 adults consented to participate and completed the questionnaire (response rate=56%).

Figure 2

Flow chart of study participants in questionnaire study and neurocognitive tests.

Participants in neurocognitive tests

Finally, 159 of the 244 participants in the questionnaire study gave written consent to be invited for neurocognitive testing (see flow chart, figure 2). In total, 103 consented to participate (response rate=65%) and were tested either in their own home or at a local centre of the Danish Cancer Society by psychology students trained by a skilled psychologist and senior researcher from Copenhagen University Hospital, Mental Health Services Copenhagen. A total of 309 NF1-free individuals sampled from the Danish Civil Registration System matched on sex and birth year were invited as a comparison group. All potential comparisons were contacted by mail and 38 consented to participate (response rate=12%) and provided data on neurocognitive tests.

Patient and public involvement

Seven patients with NF1 were consulted during the initial phase of setting up the cohort. We recruited patients from the two national Centres for Rare Diseases and the Danish Association for NF. The patients participated in interviews and a focus group session to discuss relevant research questions for the questionnaire study and neurocognitive assessments. The early input from patients were included in the final questionnaire and the neurocognitive assessments. The current results of the research programme based on the NF1 cohort have been disseminated to the Danish public by providing summaries of the results in newsletters sent by the Danish Cancer Society and published online on www.cancer.dk. Finally, we have presented all published results to members of the Danish Association for NF at their annual meeting on 10 May 2021.

Main outcomes and sources

Register-based outcomes

All cohort members were linked to several national registries to obtain individual-level information on health and sociodemographic data, including hospital history (The Danish National Patient Registry7), psychiatric hospital contacts (The Danish Psychiatric Central Research Register13), pregnancy outcomes (The Danish Medical Birth Register,14 Register on Induced Abortions15 and The Danish National Patient Registry7), marriage and cohabitation (Household and Family Statistics, a national database provided by Statistics Denmark16), leaving home (The Danish Civil Registration System12 and The Central Register of Buildings and Dwellings17) and education (The Danish Education Registry18). A description of the main outcome measures and their sources is seen in table 1.

Table 1

Register-based outcome measures and sources in the NF1 cohort

Questionnaire outcomes

The outcome measures in the questionnaires included: quality of life (QoL), severity of ADHD symptoms, symptoms of depression and anxiety, fatigue, disease severity, disease visibility and need for and received support. We used both standardised measures as well as self-developed measures, which are described in table 2.

Table 2

Outcome measures and sources for questionnaire study

Neurocognitive outcomes

Finally, we assessed the neurocognitive functioning by measuring: intelligence, other cognitive functions across several domains and executive functions. We also assessed autism spectrum disorder traits. The specific tests and questionnaire and their measurements are presented in table 3.

Table 3

Outcome measures and sources for neurocognitive study

Statistical analysis

Different statistical models have been used to assess the association between the selected exposures and NF1 in the published studies. In the register-based studies, relative risk estimates were calculated using survival analysis for time-to-event data (studies of multisystem burden, psychiatric disorders, pregnancy outcomes and relationships) and multinomial logistic regression (study of education). We also estimated proportion ratios (study of pregnancy outcomes) as well as cumulative incidences and mean cumulative number of hospital contacts (studies of multisystem burden and psychiatric disorders) or pregnancies (study of pregnancy outcomes). In the questionnaire-based study, both normal linear models and logistic regression models were used to examine the associations between the different exposures and QoL.

Findings to date

Characteristics of participants

Table 4 shows the characteristics of the large NF1 cohort of 2467 individuals with NF1 and the comparison cohort of 20 132 individuals. The distribution of men and women was equal in the cohort, with the oldest cohort members born in 1890. The mean age at study entry was 29.8 years. During follow-up through 31 December 2016, 30% (n=727) of the NF1 cohort members died, almost twice as many as in the comparison cohort (17%, n=3337).

Table 4

Characteristics of the NF1 cohort and comparison cohort

Baseline characteristics of the participants in the questionnaire study and neurocognitive tests are presented in table 5, where it is shown that the adults with NF1 are different than the NF1-free comparisons on several characteristics, including education, employment and cohabitation status.

Table 5

Baseline characteristics of participants in questionnaire study and neurocognitive tests

Somatic and psychiatric disease burden

Currently, six studies based on this NF1 cohort have been published.9 19–23 We have given a comprehensive description of the overall somatic disease burden in individuals with NF1. Using information from the Danish Patient Registry, we found that that the risk for a first hospitalisation for any somatic disorder was twice as high in individuals with NF1 as for the comparison group. Furthermore, individuals with NF1 had more hospitalisations and spent more days in hospital than the population comparisons. The increased risks were observed for both children and adults with NF1. Individuals with NF1 had an increased absolute risk for a hospitalisation in all main diagnostic groups, highest for disorders of the nervous system, benign and malignant neoplasms, and disorders of the digestive and respiratory systems.9 We have also shown that the risk for psychiatric hospitals contacts, including developmental disorders like attention deficit/hyperactivity disorders, autism spectrum disorders and intellectual disabilities, were increased in children with NF1. Only females with NF1 continued to face an increased risk for psychiatric hospitals contact in early adulthood.19

Pregnancy outcomes

The probability of a pregnancy, live birth, stillbirth and abortion was assessed in 1006 women with NF1 in the fertile age (15–49 years). The cumulative incidence of a first pregnancy was only slightly lower in women with NF1 (74%; 95 % CI 70% to 77%) at age 50 years than in women in the comparison group (78%; 95 % CI 77% to 79%). The HR of a pregnancy was similar in women with and without NF1 after adjustment for somatic and psychiatric disease, which indicates that the probability of becoming pregnant is similar for women with and without NF1. However, women with NF1 had an increased risk for spontaneous abortions and stillbirths.20

Educational achievements and cohabitation

Two studies of educational achievements and cohabitation using national registries for outcome identification have been published.21 23 The OR for obtaining a short and medium-long education compared with a long education was three fold (95% CI 2.55 to 3.99) and 1.29 fold (95% CI 0.99 to 1.69) higher, respectively, for individuals with NF1 vs population comparisons after adjusting for birth year, sex, psychiatric and somatic morbidity, and maternal education. Furthermore, individuals with NF1 graduated mandatory school significantly later.21 As for cohabitation, individuals with NF1 were less likely to form a relationship (either by marriage or cohabitation) (HR 0.65; 95% CI 0.58 to 0.73) than individuals in the comparison group. However, once the relationship was established, couples with a NF1-individual were not at greater risk of ending the relationship.23

Quality of life

Using patient-reported outcomes, we observed an impaired QoL in adults with NF1 (mean=81.3, 95% CI 76.2 to 86.4). In addition, 19% of the adults with NF1 reported symptoms of depression (mean=5.7; SD=5.4) and 15% reported anxiety (mean=5.1; SD=5.2) at a clinical level. Adults with NF1 also reported a high requirement for professional support for physical, psychological and work-related problems. We found that disease severity and partial visibility were negatively associated with psychosocial well-being and a requirement for support.22

Future plans

The NFI cohort will generate state-of-the art knowledge on the pleiotropic consequences of NF1, the underlying determinant, including somatic, psychiatric, psychological, socioeconomic and neurocognitive consequences. We are currently updating our NF1 cohort and the comparison group to include patients diagnosed after 2013. We will also continue our research and the projects will focus on both clinical (including cancer risk) and socioeconomic consequences of NF1 (including school grades, employment status, occupational position and income) and predictors of health-related QoL. A future goal is to genotype individuals with NF1 to identify any genotype–phenotype correlations and familial aggregations of certain features to increase the understanding of NF1.

Discussion

We established the Danish NF1 cohort in 2014 to provide a comprehensive assessment of the multifaceted burden of living with NF1 in Denmark, which had not previously been done. Currently, six studies based on this NF1 cohort have been published. We have shown that individuals with NF1 have an increased risk for somatic disorders affecting all organ systems and that the increased risk persists throughout life. We also found an increased risk for psychiatric hospital contacts, especially in childhood and adolescence. Previous studies focused on the risk for single diseases (eg, cancer5), disease groups (eg, neurological conditions24 or cerebrovascular disease25) or reported only prevalence when assessing psychiatric comorbidity.26 27

We found that the probability of becoming pregnant was similar for women with and without NF1, but that women with NF1 had an increased risk of spontaneous abortions and stillbirths. Other studies have observed an increased risk for pregnancy complications in women with NF1,28 29 but have not investigated the pregnancy outcomes. We have also reported a lower educational level in individuals with NF1, which has later been confirmed in a population-based Finnish cohort study.30 Our finding that individuals with NF1 were less likely to form a marital or cohabiting relationship contributes with knowledge on the social challenges that individuals with NF1 may face, including loneliness31 and social dysfunction.32 Finally, we were able to include cohort members for our questionnaire study and neurocognitive tests using a population-based design. Only the results based on the questionnaire data have been published. We found that adults with NF1 had an impaired QoL and a high need for professional support for both physical, psychological and work-related problems. Disease severity and partly visibility were associated with the psychosocial well-being and the requirement for support. An impaired QoL among adults with NF1 has also been reported in other studies33 as well as the association between disease severity and QoL or skin-specific QoL.34 35 As disease severity and to some degree visibility seem to be associated with QoL, the burden of psychological symptoms and special needs of support, screening for these characteristics might be useful to identify the most vulnerable individuals with NF1.

The main strength of the Danish NF1 cohort is the nationwide and population-based design using registries for identification of individuals with NF1 supplemented with patients from the clinical national RAREDIS Database. Due to a tax-financed health system in Denmark, all inhabitants with NF1 are offered treatment in a hospital and follow-up in a national centre for rare disease free-of-charge. Furthermore, we used the registries to randomly select a comparison group of individuals free of NF1 at entry. The registries in Denmark have virtual complete registration,36 including information on immigration, which reduces losses to follow-up. The participants in the questionnaire and neurocognitive study were sampled among individuals registered in the RAREDIS Database, which also ensured a population-based design in these studies. Furthermore, the nationwide registries provided an unselected data source with unique information on different health and socioeconomic outcomes. For the register-based studies, we did not have to rely on self-reported outcomes, which is a main strength, as we were able to depict a complete hospital history for each cohort member.

The cohort also has some limitations. As we only included individuals with NF1, who had been hospitalised with or for their NF1 or registered in the RAREDIS Database, some individuals with NF1 probably less affected by their NF1 disease may not be included in our cohort as well as some individuals who only had features of NF1 but in fact proved to have other disorders. In addition, the Danish National Patient Registry was established in 1977; thus among those individuals born before this year, a potential gap of hospitalisations exists between birth and start of the register. However, this gap applies to both individuals with NF1 and the comparisons. Despite the use of a population-based approach to identify adults with NF1 for the questionnaire and neurocognitive study, only 244 and 103 adults participated, respectively, which limited the statistical power in these studies. Finally, we did not include a comparison group in the questionnaire study. Since Danish normative data are missing for some of the measures, we include international normative data, which might differ from data generated from a Danish background population.

Our overall goal of this cohort is to fill in knowledge gaps with population-based research on health-related and psychosocial aspects of NF1. Using a novel approach to study important aspects of this genetic disorder, we will add knowledge of the implications this complicated disease may have on life. The clinical information provided by these large nationwide studies is highly requested by the patients and their families as well as by the clinicians advising these patients. Experts recommend lifelong follow-up for NF1 patients with multiple healthcare providers using a multidisciplinary approach.37 The results of the completed studies of health conditions and social aspects of life in this patient group in combination with potential predictors of well-being and functioning from the questionnaire studies can be used to develop a systematic plan for longitudinal screening and evidence-based guidelines for surveillance. The ultimate goals are to contribute to the development of targeted intervention strategies to improve the basis for patient counselling and to optimise follow-up procedures, leading to high quality of care and sufficient support to NF1 patients (see also table 6).

Table 6

Main findings and implications of published studies within the Danish research programme ‘life with NF1’

Data availability statement

Data are available on reasonable request. All data are stored on a secure platform at Statistics Denmark and can only be accessed remotely. The study group welcomes collaboration with other researchers. Study protocols can be planned in collaboration with us, and the data can be analysed accordingly at the server of Statistics Denmark. Access to data can only be made available for researchers who fulfil Danish legal requirements for access to personal sensitive data. Please contact JFW (jeanette@cancer.dk) or senior researcher LK (kenborg@cancer.dk) for further information.

Ethics statements

Patient consent for publication

Ethics approval

This study involves human participants and was approved by Danish Cancer Society: ID IORG0001095The Research Board of the Department of Defense US Army: under Award No. W81XWH-14-1-0054The Danish Health Data Authority: ID FSEID 00002527Danish Cancer Society Research Centers archive: 2018-DCRC-0012. Participants gave informed consent to participate in the study before taking part.

Acknowledgments

We gratefully dedicate this paper to the respected memory of Dr Sven Asger Sørensen, MD, DMSc (1936–2021). In the mid-1980s, he began the recontact and updating of a Danish national register of neurofibromatosis patients first assembled in the 1940s by A. Borberg. Dr Sørensen’s great contribution to the NF research made our current work feasible and possible.

References

Footnotes

  • Collaborators The study group at the Danish Cancer Society Research Center, Childhood Cancer Research Group (Jeanette F Winther and Line Kenborg) welcomes collaborations based on data from the NF1 cohort. All data are stored on Statistics Denmark. Access to the established NF1 cohort is available through Statistics Denmark and requires application to the study group (including study protocols and collaborative agreements) as well as to Statistics Denmark.

  • Contributors KD and LK wrote the first draft of the manuscript. JJM and JFW designed and established the register-based NF1 cohort, while HH, JRØ and CE contributed to enrolling of patients in the two centres for rare diseases. PEB, KD and JRMJ contributed to patient enrolment in the questionnaire and neurocognitive studies. AK, MAD and LK collected data on the platform of Statistics Denmark and AK was responsible for data management. KD, HH, JRØ, PEB, SOD, MMH, CE, JJM, JFW and LK obtained funding to establish the NF1 cohort and continue the NF1 research using this cohort. All authors reviewed, critically revised and approved the manuscript. LK is the guarantor and accepts full responsibility for the work and the conduct of the study, had access to the data, and controlled the decision to publish.

  • Funding The establishment of the NF1 cohort was supported by a grant from US Army Medical Research and Materiel Command (award number W81XWH-14-1-0054). The team has also received funding from ‘Boet efter Emanuel Poulsen’ foundation, Leo Foundation (LF-OC-19-000088) and Novo Nordisk Foundation (NNF20OC0064537) to continue the research.

  • Disclaimer The funders had no role in study design, methods, data collection and analysis, decision to publish or preparation of this manuscript.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

  • Provenance and peer review Not commissioned; externally peer reviewed.