Comorbidity and mortality in systemic sclerosis and matched controls: Impact of interstitial lung disease. A population based cohort study based on health registry data

Abstract

Objective

This population-based, matched cohort study evaluates the impact of comorbidities on mortality among systemic sclerosis (SSc) patients with and without interstitial lung disease (ILD).

Method

Patients with a first-time SSc diagnosis between 2002 and 2015 were identified in the Danish National Patient Registry, separated into two cohorts – with ILD (SSc-ILD) and without ILD (non-ILD SSc), and matched 1:4 with controls from the general population on age, sex, residency and marital status. Comorbidity and mortality data were obtained from national registries. The Deyo-Charlson comorbidity score (DCcs) was used for assessment of the burden of comorbidities.

Results

1732 patients with SSc and 6919 controls were included; 258 (14.9%) patients had SSc-ILD. The hazard ratio (HR) for death was 2.8 (95% CI 2.4–3.3) in SSc, and especially increased in SSc-ILD (HR 4.2 (95% CI 3.2–5.4)), males (HR 3.1 95% CI 2.4–4.1) and younger adults (aged 18–40 (HR 6.9, 95% CI 3.4–14.2) and 41–50 (HR 7.7, 95% CI 3.8–15.6)). In non-ILD SSc, mortality increased with increasing DCcs. Cancer was the most frequent cause of death in SSc (24.9% of deaths) and in controls (33.5%), in SSc followed by musculoskeletal and connective tissue diseases (22.7%); the cause of only 0.8% of deaths among controls.

Conclusion

The high prevalence of comorbidities in SSc had extensive impact on mortality. Mortality was increased in males, in young adults and in SSc-ILD, underlining the excess mortality associated with ILD. These findings emphasise the importance of timely diagnosis and optimal management of organ involvement and comorbidities in SSc.

Keywords

Comorbidity epidemiology interstitial lung diseases mortality systemic scleroderma

Introduction

Systemic sclerosis (SSc) is a rare, chronic and heterogeneous connective tissue disease that primarily affects the skin, but in many cases involves multiple organs, including the heart, lungs, kidneys, and gastrointestinal tract. A large proportion of patients with SSc have one or more comorbidities.⁴ As SSc may involve multiple organs, the treatment of internal organ manifestations is part of the therapeutic approach.⁵ SSc is associated with high mortality, especially in patients with severe organ involvement.^6,7 Since interstitial lung disease (ILD) is prevalent in up to 50% of patients with SSc and associated with high mortality, the recognition and treatment of ILD is highly prioritised.

The significant individual and societal economic burden of SSc and particularly SSc-ILD has been described in a previous study based on registry data.¹¹ Although ILD is rare, it has a high prevalence in SSc with serious impact on morbidity and mortality. A new treatment option with nintedanib, an antifibrotic drug with proven efficacy in a range of conditions causing pulmonary fibrosis, has emerged as a result of the continuous research focus on SSc-ILD. Therefore, timely recognition of lung involvement in SSc is important.

The aim of the present study was to investigate the impact of comorbidities on mortality in patients with SSc compared to a matched control group without Ssc, and to compare patients with non-ILD SSc and SSc-ILD.

Methods

Design

The study was a retrospective descriptive, longitudinal, matched cohort study based on data from national population-based registries.

Data sources

Data on inpatient and outpatient hospital contacts were extracted from the Danish National Patient Registry (DNPR), contains information about central person registry-number, dates of hospital contacts, diagnostic and surgical procedure codes and discharge diagnoses in all somatic hospitals in Denmark. The International Classification of Diseases, tenth revision (ICD-10) coding system has been used since 1994.¹⁵ Information on date of birth and vital status was extracted from the Danish Civil Registration System (CRS),¹⁶ marital status from Statistics Denmark¹⁷ and causes of death from the Danish Register of Causes of Death.¹⁸ The unique civil registration number assigned to all Danish residents enabled individual level linkage across registries. Continuously updated information from the CRS regarding vital status ensured complete follow-up with respect to mortality.¹⁹ The data in DNPR is entered to the registry from highly specialized public hospital clinics where the patients are diagnosed and treated. The data entry is mandatory for all patients and all diseases. SSc patients are only diagnosed and treated in there clinics in Denmark. Furthermore, the validity of DNPR are regularly tested on a regional level, hospital level and even individual patient level as it also is used for reimbursement of the hospitals.

Study population

All patients with a first-time diagnosis of SSc in Denmark between 2002 and 2015 were identified based on the ICD-10 code M34, SSc. Diagnoses registered both during admissions and outpatient visits were included. Patients with SSc were matched 1:4 with controls from the general population, identified in the DNPR, based on age, sex, marital status and region of residence.

The index date was defined as the date of the first ICD-10 coded diagnosis of SSc. Matched controls were assigned the same index date as the corresponding patients with SSc.

The SSc cohort was divided into a cohort without ILD (non-ILD SSc) and a cohort with an ILD diagnosis at any time before or after the SSc diagnosis (SSc-ILD), based on DNPR data (ICD-10 code: J84, ILD).

Comorbidities

Information on comorbidities 3 years before and 3 years after the diagnosis of SSc was extracted from the DNPR, corresponding to the period 1999-2018. Comorbidity data were extracted and grouped in accordance with the 21 main diagnostic chapters of the ICD-10. For a detailed comorbidity overview, the 50 most frequent, specific diagnoses were manually grouped into the top 20 ICD-10 subchapters. The SSc and ILD diagnoses were not included in the detailed comorbidity overview. Deyo-Charlson comorbidity score (DCcs) was calculated for non-ILD SSc, SSc-ILD and controls. DCcs includes 17 weighted comorbidities in a score that predicts long-term survival in a model adapted for administrative register data. Survival curves stratified by DCcs were based on comorbidity data 3 years before the SSc diagnosis or the enrolment as matched control.

Statistical analyses

Data on comorbidity were analysed using a conditional logistic regression model yielding outputs expressed as odds ratios (OR) with 95% confidence intervals (CI). Mortality data were reported using Kaplan-Meier survival distribution functions that are non-parametric and that take into account censoring of data. Relative mortality was estimated by a Cox proportional hazards model yielding hazard ratios (HR). Patients were stratified by ILD, sex and age. Pearson’s χ² test was used for comparison of data reported in percentages. A significance level of 0.05 was assumed for all tests. Statistical analyses were performed using SAS 9.1.3 (SAS, Inc., Cary, NC, USA).

Ethical considerations

The study was approved by the Danish Data Protection Agency. Statistics Denmark approved and extracted data in an anonymised form. Results with fewer than five patients were not reported, to avoid identification of individual patients. In Denmark, ethical approval is not required for register studies.

Results

A total of 1732 patients with SSc and 6919 matched controls without SSc were identified. The matching was 99.9% complete. SSc-ILD was diagnosed in 258 patients (14.9%). Mean age at the time of SSc diagnosis was 56 years, similar in non ILD-SSc and SSc-ILD. Men constituted 24.7% of patients with SSc. The proportion of males was higher among in SSc-ILD than in non-ILD SSc (30.6% of SSc-ILD vs. 23.7% non-ILD SSc, p = .02). The distribution of age, sex and marital status is shown in Supplementary Table S1.

Comorbidities

The burden of comorbidities 3 years before and after the SSc diagnosis was considerably higher among patients with SSc, compared to controls.

Three years before the SSc diagnosis, patients with non-ILD SSc and DCcs = 0 constituted 62.8% of the cohort, compared to 9.0% 3 years after the SSc diagnosis (86.0% and 82.9% in controls). Patients with SSc-ILD and DCcs = 0 constituted 60.5% before, compared to 3.9% after, the SSc diagnosis (86.9% and 83.9% in controls).

DCcs >3 was seen in 8.9% of patients with non-ILD SSc 3 years before, compared to 24.3% 3 years after, the SSc diagnosis (2.3% and 3.5% in controls). Patients with SSc-ILD and DCcs >3 constituted 7.4% 3 years before, compared to 25.6% 3 years after, the SSc diagnosis (2.0% and 4.2% in controls) (Table 1).

Table 1.

Deyo-Charlson comorbidity index in SSc with and without ILD compared with controls before and after diagnosis.

	Three years before diagnosis
	Non-ILD SSc		Controls		SSc-ILD		Controls
DCcs	n	%	n	%	n	%	n	%
0	925	62.8	5066	86.0	156	60.5	895	86.9
1	262	17.8	442	7.5	57	22.1	78	7.6
2	156	10.6	243	4.1	26	10.1	36	3.5
3+	131	8.9	138	2.3	19	7.4	21	2.0

	Three years after diagnosis
	Non-ILD SSc		Controls		SSc-ILD		Controls
DCcs	n	%	n	%	n	%	n	%
0	133	9.0	4884	82.9	10	3.9	864	83.9
1	768	52.1	484	8.2	127	49.2	77	7.5
2	215	14.6	317	5.4	55	21.3	46	4.5
3+	358	24.3	204	3.5	66	25.6	43	4.2

Abbreviations: DCcs, Deyo-Charlson comorbidity index; ILD, interstitial lung disease; SSc, systemic sclerosis.

Diseases of the musculoskeletal system and connective tissue were the most frequent comorbidities in all patients with SSc, followed by cardiovascular diseases and respiratory diseases in non-ILD SSc and SSc-ILD, respectively. Supplementary Table S2 and Supplementary Table S3 and Supplementary Figure S1 provide an overview of the distribution of comorbidities in SSc and controls.

Mortality

Mortality was increased among patients with SSc at any time after the SSc diagnosis, compared to controls, particularly in patients with SSc-ILD. For all patients with SSc, 5-, 10- and 15-years survival was 83%, 72% and 66%, vs. 93%, 88% and 83% in controls. In non-ILD SSc, 5-, 10- and 15-years survival was 84%, 74% and 69%; and in SSc-ILD, 78%, 61% and 50%. An increasing gap in survival was seen between patients and controls in non-ILD SSc and in SSc-ILD (Figure 1).

Figure 1.

Cox Hazard regression model SSc-ILD ver control and non-ILD SSc ver. Control (Abbreviations: ILD, interstitial lung disease; SSc, systemic sclerosis).

In non-ILD SSc, mortality increased gradually with increasing DCcs, and a clear separation was seen between DCcs 0, DCcs 1-2 and DCcs 3 or greater. In SSc-ILD, we observed no clear separation in mortality between different levels of DCcs (Figure 2(a) and (b)).

Figure 2.

(a) Cox Hazard regression model non-ILD SSc survival DCcs groups (reference=DCcs 0) (Abbreviations: DCcs, Deyo-Charlson comorbidity index; ILD, interstitial lung disease; SSc, systemic sclerosis). (b) Cox Hazard regression model SSc-ILD survival DCcs groups (reference=DCcs 0).

The overall HR for death for patients with SSc compared with controls as reference was 2.8 (95% CI 2.4–3.3), more pronounced in SSc-ILD (HR 4.2, 95% CI 3.2–5.4), than in non-ILD SSc (HR 2.6, 95% CI 2.2–3.0). The risk of death was highest among: younger adults (aged 18–40, HR 6.9 (95% CI 3.4–14.2) and 41–50, HR 7.7 (95% CI 3.8–15.6)); males (HR 3.1 95% CI 2.4–4.1); and in SSc-ILD as mentioned above (Table 2).

Table 2.

The overall HR for death for patients with SSc compared with controls as reference.

	SSc		Controls
	N ^a	n (%)^b	N ^a	n (%)^b	HR	95% Cl
Age group
18–40	267	20 (7.5)	1056	12 (1.1)	6.9	3.4 - 14.2
41–50	290	40 (13.8)	1160	38 (3.3)	7.7	3.8 - 15.6
51–60	434	93 (21.4)	1736	127 (7.3)	4.7	3.1 - 7.1
61–70	426	147 (34.5)	1701	221 (13)	3.2	2.6 - 3.9
>70	315	198 (62.9)	1256	526 (41.9)	1.9	1.6 - 2.3
Sex
Male	428	151 (35.3)	1711	265 (15.5)	3.1	2.4 - 4.1
Female	1304	347 (26.6)	5208	659 (12.7)	2.6	2.2 - 3.2
SSc subgroup
non-ILD SSc	1095	391 (26.5)	4366	798 (13.6)	2.6	2.2 - 3.0
SSc-ILD	637	107 (41.5)	2553	126 (12.2)	4.2	3.2 - 5.4
Total	1732	498 (28.8)	6919	924 (13.4)

Abbreviations: ILD, interstitial lung disease; SSc, systemic sclerosis.

^aN = total number of patients with SSc and controls in each subgroup.

^bn (%) = number and percentage of deaths in each subgroup. The youngest patient groups 18–30 and 31–40 were merged due to low number of deaths.

Causes of death

A total of 498 patients with SSc (28.8%) and 924 controls (13.4%) died during 13 years of follow-up. The main cause of death in SSc and controls was cancer (24.9% of deaths in SSc and 33.5% in controls). In patients with SSc, diseases of the musculoskeletal system and connective tissue were registered as the main cause of death in 22.7% vs. 0.8% in controls, whereas the proportion of cardiovascular deaths (19.1% in SSc and 25.9% in controls) and respiratory deaths (10.0% in SSc and 11.4% in controls) was higher among controls (Table 3a). The five most common causes of death reported among patients with SSc were all significantly more common among patients with SSc than among controls (p < .05) (Table 3b).

Table 3a.

Causes of death among patients with SSc and matched controls.

Cause of death	SSc patients		Control group
	N = 1732		N = 6919
	Rank	n (%)^a	Rank	n (%)^a	p-value
All deaths		498 (28.8)		924 (13.4)
Neoplasms	1	124 (7.2)	1	310 (4.5)	<0.05
Diseases of the musculoskelatel system and connective tissue	2	113 (6.5)	12	7 (0.1)	<0.05
Diseases of the circulatory system	3	95 (5.5)	2	239 (3.5)	<0.05
Diseases of the respiratory system	4	50 (2.9)	3	105 (1.5)	<0.05
Diseases of the digestive system	5	24 (1.4)	7	32 (0.5)	<0.05
Symptoms, signs and abnormal clinical and laboratory findings not elsewhere classified	6	18 (1.0)	5	46 (0.7)	0.10
Diseases of the nervous system	7	16 (0.9)	8	32 (0.5)	<0.05
Endocrine, nutritional and metabolic diseases	8	15 (0.9)	6	39 (0.6)	0.15
Mental and behavioural disorders	9	11 (0.6)	4	55 (0.8)	0.49
Certain infectious and parasitic diseases	10	8 (0.5)	10	15 (0.2)	0.08
Other causes**		24 (1.3)		44 (0.6)

Abbreviations: SSc, systemic sclerosis.

^an (%) = number and percentage of cohort.

Table 3b.

Causes of death among patients with SSc and matched controls.

Cause of death	SSc death cohort	Control group death cohort
	N = 498	N = 924
	Share of deaths in cohort (%)^b	Share of deaths in cohort (%)^b
Neoplasms	24.9	33.5
Diseases of the musculoskelatel system and connective tissue	22.7	0.8
Diseases of the circulatory system	19.1	25.9
Diseases of the respiratory system	10.0	11.4
Diseases of the digestive system	4.8	3.5
Symptoms, signs and abnormal clinical and laboratory findings not elsewhere classified	3.6	5.0
Diseases of the nervous system	3.2	3.5
Endocrine, nutritional and metabolic diseases	3.0	4.2
Mental and behavioural disorders	2.2	6.0
Certain infectious and parasitic diseases	1.6	1.6
Other causes^c	4.8	4.8

Abbreviations: SSc, systemic sclerosis.

^an (%) = number and percentage of cohort.

^bShare of deaths in cohort (%) = n/death cohort.

^cOther causes include a number of different causes of death all representing a low absolute number.

Discussion

This longitudinal cohort study presents national registry data on comorbidities and mortality in SSc patients with and without ILD and their matched controls. The main findings were a high mortality, especially in patients with concurrent ILD, increasing burden of comorbidities in non-ILD, as expressed by the DCcs. Additionally, we found a high risk of death in males and younger patients. Cancer was the most frequent cause of death in patients with SSc, followed by musculoskeletal and connective tissue diseases.

Comorbidities

The number of registered comorbidities increased significantly following the SSc diagnosis, which may partially be explained by the registration procedure. Some conditions may be pre-existing, others new or incidentally discovered due to investigations for SSc-related diseases, and by active screening for pulmonary, cardiac, or renal involvement. Some are likely SSc-related organ involvement, as a steep increase in these manifestations is seen in the first 2 years after first presentation of Raynaud’s phenomenon.²³

Although SSc (M34) and ILD (J84) were excluded from the overview, diseases of the musculoskeletal system and connective tissue were the most frequent comorbidities in all patients with SSc. This may be explained by the assignment of a less precise initial diagnosis^24,25 or an overlap of two or more connective tissue diseases.²⁶

Due to the register-based nature of the study, we cannot distinguish between ICD-10 diagnoses representing SSc organ involvement and comorbidities unrelated to SSc. However, DCcs based on ICD-10 diagnoses provides information on the burden of multiple organ affection, regardless of the underlying cause. This assessment is indeed challenging in SSc, a disease characterized by multisystem involvement. In the present study, the DCCs is generally lower in the matched control group than in the SSc group, which also emphasizes the multimorbidity of patients with SSc.

Mortality

Mortality was significantly increased in patients with SSc, compared with matched controls, particularly in SSc-ILD. Mortality trends in our study correlate well with other studies showing that pulmonary involvement considerably influences mortality.⁶ A recent study by Hoffmann-Vold et al. showed the presence of ILD on high-resolution computed tomography (HRCT) affected mortality, even for patients with preserved forced vital capacity.²⁸

A recent Danish study reported that the sex- and age-adjusted HR for 1-year mortality associated with SSc was 5.5 (95% CI 4.7–6.4), compared with the background population, and that the 1-year mortality rate in SSc decreased slightly from 1995 to 2015.³⁰

The present study observed an overall 5- and 10-years survival in SSc in 2002-2015 at 83% and 72%, respectively. This seems to be unchanged compared to 5- and 10-years survival at 81% and 71% in a previous Danish study reporting findings from 1960 to 1996.³¹

In the present study, the pre-SSc DCcs affected the pattern of mortality in non-ILD SSc, where an increase in mortality with increasing DCcs level was more pronounced than in SSc-ILD. This finding may indicate that a high comorbidity score levelled out differences in mortality between SSc-ILD and non-ILD SSc, and that mortality due to ILD was so substantial that it overshadowed or superseded other causes of death. An important caveat in this regard is that increasing DCcs may in fact reflect the severity of multi-organ involvement due to SSc.

Mortality increased with increasing age, but the relative mortality compared to controls was highest among younger patients. This is in accordance with previous findings,^30,31 although some studies report a higher age at disease onset as a more important predictor of mortality than age itself.^7,32

Male sex and presence of ILD were other factors associated with increased risk of death. The proportion of males with SSc-ILD was significantly higher than the proportion of males with non-ILD SSc. Male sex and presence of ILD also impose higher healthcare-related costs than female sex and non-ILD SSc, underlining the severity of pulmonary involvement.¹¹ A previous study using the Danish health registries showed a 5- and 10-years mortality at 45% and 60% for ILD in general,³³ which is higher than in SSc-ILD in the present study. The difference may be explained by the inclusion of all ILDs, e.g., idiopathic interstitial pneumonias, several with fibrotic phenotypes, and a higher mean age (of 72 at the time of ILD diagnosis), compared to a mean age of 56 at the time of SSc diagnosis in the present study.

Causes of death

The five conditions reported as the most common causes of death among patients with SSc in our study were all significantly more common among patients with SSc than among controls. A study from 2010, including 234 deaths among patients with SSc in the European Scleroderma Trials and Research Group (EUSTAR) database, reported that 55% of SSc deaths were attributed to SSc itself.⁷ In accordance with this finding, our study showed a higher frequency of organ-specific, potentially SSc-associated causes of death among patients with SSc than among controls.

The proportion of cancer-related deaths among patients with SSc was higher in our study than in other observational studies based on death certificates and questionnaires.^7,34 This may be due to longer follow-up and to changes in registration procedures, leading to a higher number of cancer-related deaths; registration of cancer cases has been mandatory in Denmark since 2007.³⁵ Diseases of the musculoskeletal system were registered as the main cause of death in a high proportion of cases, but in only 0.8% of controls. Cardiovascular and respiratory deaths were less frequent than in other studies.^7,34 This difference may be caused by the high proportion of deaths registered due to musculoskeletal diseases. The lower incidence of ILD compared to other studies may be another explanation for fewer respiratory deaths.²⁸ The recent SENSCIS and INBUILD trials^13,14 have shown a new treatment option with Nintedanib in SSc-ILD. The present study highlights the increased mortality risk in SSc-ILD and hence, the importance of timely diagnosis and management.

Strengths and limitations

The strengths of the present study are the population-based design, the linkage between national registers, and the complete follow-up with respect to mortality. The matched control groups enable a broader perspective on comorbidities and their impact on mortality.

Important limitations are the lack of clinical information, e.g., the presence of limited or diffuse SSc, the extent of pulmonary fibrosis on HRCT, pulmonary function and smoking status, all of which cannot be obtained from national health registers; and the inability to differentiate between SSc organ involvement and comorbidities that are not associated with SSc, on the basis of register data.

In SSc, a small validation study of registry diagnoses exists, showing a high positive predictive value (PPV) of the SSc diagnosis,³⁰ but no validation studies of ILD diagnoses in the DNPR exist. A high PPV for SSc and SSc-ILD is expected, because the diagnoses are assigned at specialist centres that are also responsible for follow-up. As reported in patients with pulmonary fibrosis, there is a risk of the diagnoses being underreported or misclassified as other more common diseases.²⁵

Underreporting would be likely to occur in mild cases of SSc-ILD, resulting in an overestimation of the true SSc-ILD mortality.

Conclusion

Our study showed that the burden of comorbidities in SSc had an extensive impact on mortality. The risk of death was significantly increased in SSc-ILD compared with SSc alone, underlining the excess mortality associated with ILD. These findings emphasise the importance of timely diagnosis and optimal management of organ involvement and comorbidities in SSc.

Supplemental Material

Supplemental Material - Comorbidity and mortality in systemic sclerosis and matched controls: Impact of interstitial lung disease. A population based cohort study based on health registry data

Supplemental Material for Comorbidity and mortality in systemic sclerosis and matched controls: Impact of interstitial lung disease. A population based cohort study based on health registry data by Malene Knarborg, Charlotte Hyldgaard, Elisabeth Bendstrup, Jesper Rømhild Davidsen, Anders Løkke, Saher Burhan Shaker and Ole Hilberg in Chronic Respiratory Disease.

Abbreviations

SSc

systemic sclerosis

ILD

interstitial lung disease

SSc-ILD

systemic sclerosis with interstitial lung disease

Non-ILD SSc

systemic sclerosis without interstitial lung disease

DCcs

Deyo-Charlson comorbidity score

hazard ratio

confidence interval

DNPR

the Danish National Patient Registry

ICD-10

the International Classification of Diseases 10th Revision

CRS

the Danish Civil Registration System

Footnotes

Acknowledgments

Boehringer Ingelheim A/S issued an unrestricted grant for the current work. Rikke Ibsen, MSc, conducted the statistical analyses for the work. Rikke Ibsen (RI), i2minds, Aaboulevarden 39, 1.th, 8000 Aarhus, Denmark. Email: rikke@i2minds.dk.

Author contributions

MK, CH, EB, JRD, AL, SBS, and OH all contributed to the planning and design of the study. AL and RI had full access to data and take responsibility for the integrity of the data and the accuracy of the data analysis. The first draft of the article was written by MK with input and critical revision from AL, EB, JRD, CH, SBS, and OH. All authors revised the manuscript and approved the final version. All authors approved the final draft and are accountable for the accuracy and integrity of the work, including the data and analyses.

Declaration of conflicting interests

OH has received an unrestricted research grant from Boehringer Ingelheim A/S for this study. JRD reports a research fee from Roche, not related to this study. EB reports a research fee from Boehringer Ingelheim, Hoffman la Roche and Galapagos, not related to this study. MK reports lecture fees from Astra Zeneca. CH reports lecture fees and travel support from Boehringer Ingelheim. JRD and SBS report lecture fees from Boehringer Ingelheim and Roche. EB reports lecture fees from Boehringer Ingelheim, Roche, Galapagos, Astra Zeneca, Novartis and Bristol Myer Squibb. JRD, EB and SBS report travel and congress fees from Boehringer Ingelheim and Roche. JRD, EB and SBS report Advisory Board membership granted by Boehringer Ingelheim and Roche.

Funding

This work was supported by Boehringer Ingelheim A/S through an unrestricted grant. Boehringer Ingelheim A/S had no role in study design, data collection, analyses and interpretation, in the writing of the manuscript or in the decision to submit the article for publication.

Ethical approval

Ethical approval and consent were not required as this study was based on publicly available data.

ORCID iDs

Malene Knarborg

Charlotte Hyldgaard

Ole Hilberg

Supplemental Material

Supplemental material for this article is available online.

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