Abstract
Introduction
Severe asthma incurs a financial burden on both patients and societies. However, little is known about the long-term financial burden and impact of biologic therapy.
Methods
All Danish adults initiating biologic therapy for severe asthma between 2016 and 2020 were included and followed retrospectively between 2002 and 2022, both prior to and during biologic therapy. Excess healthcare costs, foregone income and welfare transfers were calculated on an annual basis using a level of education-adjusted, zero-inflated generalised linear model with a gamma distribution and a log-link compared with age, sex, residence and civil status matched comparators.
Results
In total, 562 patients and 2207 comparators (median age 56 years, 51% female) were included. Excess healthcare costs during the year prior to biologic therapy were €10 590 and foregone income was €5389 per patient. The excess welfare transfers for patients aged 18–64 were €3335.
Prior to biologic therapy, pooling of crude annual costs resulted in an accumulation of €59 364 and €44 155 in excess healthcare costs and foregone income per patient, respectively. Patients aged 18–64 had accumulated €32 021 in excess welfare transfers.
Biologic therapy was associated with an increase in excess outpatient care costs (€25 938,+398.6%) compared with the year prior to biologic therapy. Outpatient care costs declined to (€14 486,+78.5%) during treatment year 4. Furthermore, at year 4, reductions in hospitalisations (€–2270, –67.7%) and patient-facing medication costs (€−557, –29.7%) compared with the year prior to biologic therapy were observed. Welfare transfers and foregone income were unaffected.
Conclusions
In the present study, patients with severe asthma initiating biologic therapy accumulated a substantial financial burden for both healthcare and welfare institutions, as well as a significant loss of personal income over time. Biologic therapy was associated with increased healthcare costs overall, but did not affect welfare transfers or foregone income.
Keywords: Asthma, Asthma Epidemiology, Clinical Epidemiology
WHAT IS ALREADY KNOWN ON THIS TOPIC
Severe asthma imposes substantial economic burdens on societies and affected individuals, and although biologic therapies have rendered disease control attainable, there are concerns regarding cost-effectiveness.
WHAT THIS STUDY ADDS
Before biologic treatment, patients incurred substantial excess healthcare and welfare costs and personal income losses compared to matched comparators. The study demonstrates that initiation of biologic therapy markedly reduced excess hospitalisations and patient-facing medication costs but initially increased healthcare expenditure, which diminished over time, while welfare transfers and income loss remained unaffected.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Patients with severe asthma accrue substantial healthcare, welfare and personal financial burdens prior to biologic therapy, and this study indicates that biologics substantially reduce hospitalisation-related costs while welfare transfers were unaffected. The study opens a discussion that there, from a societal perspective, may be favourable to initiate earlier interventions to prevent patients from leaving the workforce due to severe asthma.
Introduction
Severe asthma represents approximately 5%–10% of the overall asthma population and approximately 50% of the costs incurred by the disease.1 2 Recurrent exacerbations despite high-intensity pharmacotherapy and/or prescription of maintenance oral corticosteroids to maintain disease control are hallmarks of severe asthma and have historically resulted in a high societal and individual financial burden due to frequent exacerbations and reductions in or even loss of the ability to be an active part of the workforce.13,6 An increased understanding of the pathology of type 2 inflammation-driven severe asthma has led to the introduction of highly specific monoclonal antibodies targeting the type 2 inflammatory cascade, such as anti-interleukin (IL) 5 and IL-5 receptor α (IL5/5Rα), anti-IL4/13, anti-IgE and anti-thymic stromal lymphopoietin,7 transforming severe asthma care for patients with type 2 inflammation-driven severe asthma.
The introduction of biologic therapies, however, came with the challenge of high costs, with many pharmacoeconomic studies showing a lack of cost-effectiveness despite the efficacy of therapy where up to 30% of patients achieve on-treatment remission.8 9 The high costs of biologic therapies have also resulted in skewed access to biologic therapy in both international and national settings, while further complicated by a lack of international consensus on the eligibility for biologic therapy.10,12 However, severe asthma is a chronic disease,13 but little is known about the long-term financial burden incurred by severe asthma, as most studies have cross-sectional designs or short observation periods.3,514 Furthermore, there is a paucity of evidence on whether biologic therapy impacts other financial domains such as foregone income and utilisation of welfare transfers (income-assistance subsidies eg, sick leave transfers and disability pensions), which are key aspects in a holistic approach to cost of disease studies.
In the present study, we aimed to, using a prospective cohort of severe asthma patients initiating biologics, estimate the societal excess healthcare and welfare costs of severe asthma, as well as personal foregone income, compared with healthy comparators from a longitudinal perspective. Furthermore, due to the chronicity of severe asthma, we aimed to estimate the pre-biologic accumulated excess financial burden incurred by patients with severe asthma during a 15-year prebiologic period prior to the initiation of biologic therapy, compared with healthy comparators.
Methods
The Danish severe asthma registry
The study uses the Danish Severe Asthma Register (DSAR), a nationwide registry consisting of all Danish patients treated with biologics for severe asthma.17 DSAR follows a clinical protocol with baseline information collected before the initiation of biologic therapy and follow-up data collected after 4 months of treatment and subsequently annually. All clinics administering biologic therapy in Denmark use the DSAR electronic patient record form.
Patient and public involvement
Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of the present study.
Study population
The present study included all Danish residents aged 18 years or older who were initiated on biologic therapy (anti-IgE (omalizumab), anti-IL5/5Rα (mepolizumab, reslizumab, benralizumab) or anti-IL4/13 (dupilumab)) between 2016 and 2020 and had completed at least 2 years of treatment. Patients were excluded if they permanently stopped treatment for any reason or if they lacked a valid central person registry number (figure 1).
Figure 1. Inclusion and exclusion flow of a nationwide cohort of patients with severe asthma who initiated biologic therapy. CPR, central person registry.
All patients were linked from DSAR to nationwide registries using unique central person registry numbers, allowing for individual-level data capture over time and across multiple registries.
All patients were matched 1:4 with randomly selected comparators from the general Danish population without asthma (defined as no secondary care diagnosis of International Classification of Diseases, 10th revision (ICD-10) J45 and no redemption of ≥2 prescriptions for inhalers (anatomical therapeutic chemical (ATC) code R03) within 12 months). Matching was based on age, sex, marital status and municipality of residence. Comparator index dates were assigned to correspond with the index date of their matched patient (initiation of biologic therapy). Matching with healthy controls was chosen to allow for societal financial burden estimation, rather than incremental financial burden (eg, comparing towards severe asthma patients not initiating a biologic).
Observation and cost periods
The cost analysis used annually calculated healthcare costs and income per patient for each year before and after initiation of biologic therapy (the ‘index date’), based on individual health and income data from Danish National registries,18 with year 0 defined as the 12-month period starting at the index date.
Information on healthcare costs at the individual level was obtained from: (1) the Danish National Patient Registry, which includes all hospital contacts with ICD-10 diagnoses and associated tariffs; (2) the National Health Insurance Service Register, which covers all primary-care contacts (general practitioners, specialists, etc) and (3) the Danish National Prescription Registry, which contains all dispensed prescription medicines (ATC-coded) in Denmark. Healthcare cost data were available from 2002 onward. Data on income and public transfers were obtained from the Danish Income Register.
Registry coverage from 2002 to 2022 allowed up to 16 years pre-index and up to 5 years postindex, depending on when individuals initiated biologic therapy (2016–2020). Patients were included from their first available year within 2002–2022 until 31 December 2022 or the last year alive before that date. Consequently, the number of patients contributing to each relative year varied; analyses focused on relative years −14 to +4, while years −16,–15 and +5 were excluded due to sparse observations.
All costs and income were converted from Danish kroner (DKK) to euros (€) using the fixed exchange rate of €1=DKK7.45 and were adjusted to 2022 price levels using the consumer price index from Statistics Denmark.
Cost differentiation
Cost differentiation was based on methods published by Håkansson et al,3 as specified:
Direct costs were defined as both asthma-related and other healthcare costs stemming from primary care utilisation (general practitioners, primary care specialists, etc), secondary care utilisation (subdivided into emergency room-related, hospitalisation-related and outpatient care-related, the latter including the cost of the administered biologic itself, even if administered by the patient at home), and patient-facing costs related to medication redemption (eg, inhalers) at pharmacies.
Indirect costs were defined as foregone income: the difference in annual earned income (defined as wage, profit from self-employment and labour market contributions) between cases and their comparators.
Welfare transfers were defined as temporary transfers (eg, sick leave, unemployment and social security), permanent transfers (eg, disability pensions and early retirement), and other transfers (eg, student grants, housing benefits, child benefits).
Comorbidities
General comorbidity burden was assessed using the revised version of the Charlson comorbidity index by Quan et al.19 Further adjustment for comorbid conditions typically requiring treatment with systemic corticosteroids (eg, sarcoidosis, inflammatory bowel disease) was performed based on Skov et al,20 with relevant diagnostic codes available in online supplemental table 1.
Statistical analyses
Longitudinal analyses of prebiologic and postbiologic costs
GLM regressions using a gamma distribution with log link, implemented as a two-part specification to handle the zero-mass (allowing for the large occurrence of costs equalling zero; eg, step 1: probability of having any cost, step 2: estimating said cost if it occurred), was used to estimate annual costs and income per patient-year for patients and their matched comparators during their individual-level observation periods.21 The longitudinal model design allows for cost estimation both on an annual basis, as well as testing for statistically significant changes over the entire observation period. Individual models were constructed for both overall (eg, direct healthcare costs) as well as differentiated (eg, emergency department attendance) costs, to allow for identification of overall cost drivers. The models account for patients who died during the year by incorporating weights for patient-years, ensuring an accurate representation of partial-year contributions to costs and income. The models were adjusted for education level, the Charlson comorbidity index and systemic corticosteroid-dependent comorbidities to allow for estimation of excess severe asthma costs in isolation from other significant comorbidities and known differences in education level between cases and matched comparators. Predicted excess costs were calculated using the models described above for a representative patient who has completed vocational education, has a Charlson comorbidity index of 0 and no systemic corticosteroid-dependent comorbidities. Excess costs are presented as euros (95% CI), and example covariate estimates for the models used for predictions can be found in online supplemental table 1.
Accumulated cost analyses
To estimate the financial burden incurred prior to initiation of a biologic, the crude costs captured in national databases were pooled on an annual basis and calculated as unadjusted mean excess (case minus comparator) costs. The crude accumulated estimates were used as adjusted estimates are time-varying and cannot reliably be pooled into a sum.
SAS (V9.4, The SAS Institute) was used for statistical analyses. Biorender.com and ggplot2 were used for the graphics. Statistical significance was set at p≤0.05.
Results
The present study included 562 individuals with severe asthma who initiated biologic therapy between 2016 and 2020. At biologic initiation, the median age was 56 years (IQR 19) and 51.1% were female. In terms of socioeconomic parameters, 35.4% had a bachelor’s degree or higher, with no difference compared with the comparators. In terms of employment status, significant differences between individuals with severe asthma and comparators were observed, with 51.2% and 59.5% employed in the index year, respectively (table 1).
Table 1. Demographics of 562 individuals with severe asthma who initiated biologic therapy in a nationwide Danish cohort and matched comparators at the time of treatment initiation.
| Severe asthma (n=562)* | Comparators (n=2211)* | P value | |
|---|---|---|---|
| Age (years) | 56 (19) | 55 (19) | Matched |
| Female | 287 (51.1%) | 1131 (51,2%) | Matched |
| Married/cohabiting | 401 (71.4%) | 1595 (72.1%) | Matched |
| Capital region residency | 180 (32.1%) | 710 (31.1%) | Matched |
| Education | 0.79 | ||
| Primary only | 125 (22.2%) | 455 (20.6%) | |
| Secondary only | 26 (4.6%) | 123 (5.6%) | |
| Vocational | 202 (35.9%) | 804 (36.4%) | |
| Professional BSc | 27 (4.8%) | 116 (5.2%) | |
| BSc | 115 (20.5%) | 420 (19.0%) | |
| MSc or higher | 57 (10.1%) | 259 (11.7%) | |
| Unknown | 10 (1.8%) | 34 (1.5%) | |
| Employment status | <0.0001 | ||
| Employed | 288 (51.2%) | 1316 (59.5%) | |
| Under education | 54 (9.6%) | 133 (6.0%) | |
| Unemployed | 14 (2.5%) | 58 (2.6%) | |
| Disability pension | 61 (10.9%) | 102 (4.6%) | |
| Early retirement | 6 (1.1%) | 44 (2.0%) | |
| Age pension | 132 (23.5%) | 501 (22.7%) | |
| Unknown | 7 (1.2%) | 57 (2.6%) | |
| Income (index year) | 20 689 (55 412) | 38 435 (62 694) | <0.0001 |
| Charlson Comorbidity Index ≥1 | 26 (4.6%) | 114 (5.2%) | 0.61 |
| Systemic corticosteroid-dependent comorbidity | 57 (10.1%) | 139 (6.3%) | 0.0014 |
Statistics presented: n (%); median (IQR).
Among individuals with severe asthma, 80.0% initiated anti-IL5/5Rα, whereas 14.4% and 4.8% initiated anti-IgE and anti-IL4/13, respectively. Uncontrolled symptoms were observed in 74.3% of patients, and 29.5% were on maintenance oral corticosteroids prior to biologic therapy. Type 2 inflammation markers were generally high, the median percent predicted forced expiratory volume in one second (FEV1%pred) was 70 (IQR 29) and 46.4% were current or ex-smokers with a median tobacco exposure of 12 (17) pack-years (online supplemental table 2).
Direct healthcare costs and evolution over time
The year prior to initiation of biologic therapy, the excess healthcare costs for individuals with severe asthma was €10 590 (95% CI €9531 to €11 763) compared with comparators, representing a 6.5-fold increase over the course of 14 years. Individuals with severe asthma had excess healthcare costs during the entire prebiologic observation period. An acceleration in excess costs can be seen from year eight prior to biologic therapy (figure 2). When stratified by cost type, the increase in excess healthcare costs was driven by increased hospitalisation, outpatient care and medication costs. The emergency department and primary care costs increased, but at numerically smaller rates (figure 3).
Figure 2. Evolution of excess direct healthcare costs, foregone income and welfare transfers for 562 individuals with severe asthma initiating biologic therapy compared with matched comparators.
Figure 3. Annual direct healthcare costs stratified by cost type for 562 individuals with severe asthma initiating biologic therapy and matched comparators.
The initiation of biologic therapy constitutes a 2.7-fold increase in excess healthcare costs, driven by a marked increase in outpatient care costs, representing the cost of the biologic itself. However, total excess costs saw a reduction over time driven in part by reductions in the costs of biologics (figures 2 and 3).
In contrast to outpatient care costs, biologic therapy reduced costs across most remaining healthcare parameters. Hospitalisation-related excess costs were reduced 3.1-fold. Similarly, excess primary care costs were reduced by 2.2-fold and patient-facing medication costs were reduced by 1.4-fold (figure 3).
Foregone income, welfare transfers and evolution over time
For the overall severe asthma population, statistically significant differences in earned salary (eg, foregone income) were seen across the entire follow-up period. Foregone income accelerated from prebiologic year 3 and continued to increase after biologic initiation (online supplemental figure 1).
In the subpopulation aged 18–64 expected to be an active part of the workforce, no significant differences in earned salary (eg, no foregone income) compared with comparators were observed. At year prebiologic year 3 and forward, statistically significant differences in earned income were observed. Individuals with severe asthma earned €11 889 (€10 988–€12 243) less than comparators at postbiologic year 4 (figure 4).
Figure 4. Annual welfare transfers for 515 individuals aged 18–64 with severe asthma who initiated biologic therapy compared with matched comparators.
Excess welfare transfers for individuals with severe asthma were observed throughout the entire observation period, with the excess transfers increasing over time, even after biologic initiation (figure 4). When stratified by welfare transfer type, consistent excess transfers were observed. Continued increases in disability pensions and normalisation of unemployment and other welfare transfers compared with comparators after biologic therapy were observed (figure 4).
For total personal income (pooled earned wage, welfare transfers and other sources of personal income), no differences were observed between individuals with severe asthma and comparators across the entire follow-up period (figure 4).
Accumulated prebiologic direct healthcare costs, foregone income and welfare transfers
Accumulated excess costs prior to initiating biologic therapy were calculated as the pooled year-by-year unadjusted mean excess cost per annum. When initiating biologic therapy, the mean accumulated prebiologic direct healthcare cost was €59 354 for individuals with severe asthma. The accumulated prebiologic foregone income was €44 154, and the accumulated excess prebiologic welfare transfers for individuals aged 18–64 were €32 021 (online supplemental figure 2).
Discussion
In the present study of 562 individuals with severe asthma who initiated biologic therapy, we found the excess healthcare cost per patient to be €10 590 the year prior to biologic therapy. Direct healthcare costs increased after initiation of biologic therapy and failed to return to its prebiologic level during the 4 years of postbiologic follow-up, yet a decline over time was seen, driven by decreases in the cost of biologics and reductions in hospitalisation-facing and patient-facing medication costs. Furthermore, severe asthma was associated with significant increases in welfare transfers and foregone income over time, which were seemingly unaffected by the initiation of biologic therapy. Finally, patients accumulated significant prebiologic excess direct healthcare costs (€59 364), foregone income (€44 154) and welfare transfers (€32 021) over 14 years prior to initiation of biologic therapy.
The prebiologic cost of severe asthma
The cost of severe asthma has been extensively investigated, with the present study’s prebiologic estimates exceeding a previous Danish study on the cost of possible severe asthma (€10 590 vs €6192 annually), arguably due to slightly older individuals and higher disease burden.3 In an international context, the found prebiologic costs are in line with previous Swedish data,5 but lower than the estimated per-patient cost for severe, uncontrolled asthma in the USA,22 although comparisons across healthcare systems should be made with caution.
The present study is among the first to study the long-term costs of severe asthma and found an accelerating increase in healthcare expenditure 8 years prior to the initiation of biologic therapy. This phenomenon may correspond to the deterioration of mild-to-moderate asthma, or the sudden onset of severe asthma as observed in 35% and 39% of patients in a recent cluster analysis of pre-biologic disease trajectories, respectively.13 Additionally, recent studies on the financial burden of oral corticosteroids suggest that the accumulation of corticosteroid exposure over time and its resulting morbidity (eg, diabetes mellitus, osteoporosis, fractures) may, in addition to direct asthma-related costs, add to the acceleration of healthcare expenditure over time.23 24 While it can be argued that the sharp increase in healthcare costs incurred by the initiation of a biologic may decline over time as the cost of biologic therapy is reduced, it is currently unknown whether the ‘shadow costs’ incurred by corticosteroid exposure will fall, as many corticosteroid-related comorbidities such as osteoporosis and cardiovascular disease do not seem to remit over time.25 Nonetheless, the introduction of biologic therapies for patients with severe asthma can be measured as a decrease in overall systemic corticosteroid exposure on a nationwide basis.26 However, a subsequent decline in shadow costs would arguably be measurable in studies with long-term prospective follow-up data.
The indirect costs of severe asthma
The indirect costs of disease, such as loss of productivity and premature withdrawal from the workforce, make up a large part of the financial burden of chronic diseases.27 Severe asthma has previously been associated with increased indirect costs stemming from both presenteeism and absenteeism (eg, sick leave),3 28 29 as well as permanent early workforce withdrawal.30
In the present study, we observed that working-age patients with severe asthma received excessive welfare transfers for one and a half decades prior to initiating biologic therapy. This finding indicates that, similar to healthcare expenditures, the financial burden associated with severe asthma persists throughout the working lives of these patients despite the frequently fluctuating nature of asthma symptoms over time. However, it should be noted that the Danish national databases lack information on the first 14–30 days of short-term sick leave, as they are employer reimbursed. Considering that asthma typically causes shorter bursts of sick leave due to exacerbations,31 and that Scandinavian asthma patients report approximately 24 days of sick leave annually,32 the excess welfare transfer estimates in the present study underestimate the true financial burden of severe asthma.
Impact of biologic therapy
To our knowledge, this is the first longitudinal study to investigate the impact of biologic therapy on the financial burden of severe asthma. The well-established exacerbation-reducing effects of biologic therapies9 were reflected in significant reductions in hospitalisation-related costs, in addition to both primary care and patient-facing medication costs. The reductions in unscheduled care (eg, urgent care and hospitalisations) are well established in the literature9; however, the present study demonstrates why biologic therapies have struggled in terms of cost-effectiveness8: exacerbation care has been relatively cheap compared with the costs of biologic therapies. Studies that have focused on direct healthcare costs and cost-effectiveness have mainly been able to achieve positive results when isolated to settings with significant barriers to treatment (eg, a baseline exacerbation rate of four exacerbations per year).8 However, as demonstrated in the present study, the increasing competition in the biologic therapy market has led to significant (1.8-fold) reductions in outpatient care costs in the present study, suggesting that direct healthcare cost-effectiveness may be easier to achieve over time as the overall costs of biologic therapies decrease both due to decreases in the cost of biologics themselves, but also with other treatment modalities such as at-home self-administration.
Another dimension for assessing the true costs of severe asthma is the indirect costs incurred by lost productivity and increased welfare transfers, as reductions in either should arguably be factored into a holistic cost-effectiveness analysis. Patient-reported productivity has been demonstrated to significantly increase under biologic therapy33 and has in a previous DSAR study been shown to correspond to reductions in presenteeism estimated to €16 000 in salary-equivalents annually per patient.34 In terms of the impact of biologic therapy on welfare transfers, we observed that excess welfare transfers, especially those related to permanent workforce withdrawal, increased or remained unaffected despite biologic therapy. Another recent DSAR study describes this phenomenon, suggesting that the multiyear process of granting disability pensions has been under way prior to patients getting access to biologics.30 Returning to the workforce from a disability pension in Denmark is relatively rare due to the design of its welfare and social security system.35 However, other specialities with access to biologic therapy such as rheumatology do describe high rates of patients returning to the workforce in international settings,36 37 suggesting that the missing return to work observed in Denmark may be country-specific or welfare system-specific. Nonetheless, preventing or reducing the chronification of patients due to uncontrolled inflammation, repeated systemic corticosteroid exposure and repeated sick leave due to exacerbations may be key to reducing the excess rates of (permanent) workforce withdrawal in severe asthma.
Strengths and limitations
The present study is strengthened by its use of high-quality, official, long-term and individual-level data from national databases without the risk of reporting bias due to self-report and lack of loss to follow-up. However, some limitations of the methods and data sources used should be mentioned. The present study is predominantly performed on anti-IL5/5Rα (81% of patients, primarily mepolizumab), which may limit generalisability. Furthermore, the inclusion criteria of at least 2 years of therapy (although with intraclass and interclass switching allowed) do introduce selection bias, as patients with early permanent cessation are excluded. As previously mentioned, national databases lack short-term (the first 14–30 days) sick leave data, leading to an underestimation of welfare transfers in the present study. Additionally, considering the recent identification of differential onset of severe asthma trajectories,13 the present study fails to account for individual cost trajectories and represent an ‘average’ severe asthma trajectory. Furthermore, the Danish universal healthcare and welfare systems may limit generalisability to other non-universal care settings. Furthermore, the study focuses on the cost of disease from a societal perspective (eg, comparators were healthy matches) rather than incremental costs, where suitable comparators would be individuals with mild-to-moderate or severe asthma without biologic therapy. Excess costs were not differentiated by asthma relation and should therefore be considered to be representative of severe asthma and any relevant comorbidities. The excess cost analyses do, additionally, not incorporate costs associated with premature mortality, nor do they account for costs incurred by informal spousal care. Finally, data are right-censored in 2022 due to the lack of healthcare expenditure data for more recent years, limiting prospective, on-biologic follow-up, and may not reflect the current pricing of biologic therapies due to increased competition with newer molecules such as dupilumab, tezepelumab and biosimilars.
Conclusions
In this study, patients with severe asthma initiating biologic therapy accumulated a substantial financial burden for both healthcare and welfare institutions, as well as a significant loss of personal income over time. Biologic therapy increased healthcare costs overall but did not seem to impact welfare transfers or foregone income.
Supplementary material
Footnotes
Funding: This investigator-initiated study was funded by an unrestricted research grant from AstraZeneca.
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Consent obtained directly from patient(s).
Ethics approval: This study involves human participants and DSAR was approved by the Capital Region of Copenhagen’s Knowledge Centre for Data Review (VD-2018-31). Participants gave informed consent to participate in the study before taking part.
Data availability free text: Data and raw model estimates are available on reasonable request, but the prior is subject to access restrictions by Statistics Denmark and Danish law.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Data availability statement
Data may be obtained from a third party and are not publicly available.
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