Abstract
Aims: Tuberous sclerosis complex (TSC) is a multi-organ autosomal-dominant, genetic disorder with incomplete penetrance. The multiple manifestations of TSC and impacts to numerous organ systems represent significant disease, healthcare, and treatment burden. The economic and employment burden of the disease on individuals and their families is poorly understood. This study assessed the cost of illness and work and school productivity burden associated with TSC in a cross-sectional web-survey sample.
Materials and methods: Eligible TSC individuals and caregivers were invited through the Tuberous Sclerosis Alliance advocacy group to complete a web-based survey about illness characteristics, treatment, disease burden, direct and indirect healthcare costs, work and school impairment.
Results: Data from 609 TSC adults or caregiver respondents with no cognitive impairments were analyzed. TSC adults (>18 years of age) had significantly higher direct out-of-pocket costs for ER visits, expenses for medical tests and procedures, alternative treatments, medications and lifetime cost of surgeries compared to TSC pediatric individuals. Both TSC adults and TSC caregivers reported work and school absenteeism and presenteeism; however, adults reported significantly higher absenteeism and presenteeism and overall activity impairment due to TSC, as might be expected, compared to TSC caregivers. TSC adults had significantly higher absenteeism and presenteeism rates compared to adults with moderate-to-severe plaque psoriasis and muscular sclerosis.
Conclusions: TSC results in considerable direct out-of-pocket medical costs and impairment to work productivity, especially for adults. Future studies should include the comparator group and examine direct cost burden in the US using electronic medical records and insurance databases.
Introduction
Tuberous sclerosis complex (TSC) is a rare, slowly progressing autosomal dominant genetic disorder characterized by benign tumors in multiple organ systemsCitation1,Citation2. Tumors can evolve in any organ system, with some more prevalent during infancy and childhood, and others more likely to affect adults. A few of the major manifestations include epilepsy, autistic spectrum disorder, intellectual disability, angiofibromas, ungual fibromas, subependymal nodules, subependymal giant cell astrocytomas, lymphangioleiomyomatosis, and angiomyolipomasCitation3. Many manifestations can be life-threatening, and appropriate surveillance and management is necessary to limit morbidity and mortalityCitation1. The multiple manifestations of TSC and effects on numerous organ systems represent significant disease, healthcare, and treatment burden, as well as substantial economic burden on individuals and their families. Second and additional paragraphs after the heading should be indented.
In a systematic review of the TSC literature, Lennert et al.Citation4 concluded there has been limited economic and humanistic outcome research in TSC, representing an important knowledge gap in the cost of illness and treatmentCitation4, and real-world treatment patterns and resource utilizationCitation5.
We undertook a survey to assess the landscape of health, social, and economic burden amongst a convenience sample of TSC individuals and their families through patient advocacy networks at a time when there was little information in the published literature. The objective of the survey was to assess the humanistic burden of TSC, encompassing health-related quality-of-life, symptoms, and manifestations of the disease, healthcare resource use, cost, work productivity, and effect on schooling and careers. The results of the clinical characteristics, healthcare utilization, and health-related quality-of-life burden have been previously reported for the overall sample, caregivers of individuals with TSC, and TSC individuals with subependymal giant cell astrocytomas (SEGA)Citation6–8. This analysis assesses the direct cost burden to individuals living with TSC and work and school productivity impact on TSC caregivers and adults.
Methods
Study design
This cross-sectional, non-intervention web-based survey study included TSC individuals and TSC caregivers in the US. Between May 2012 and June 2012, survey respondents were recruited via direct e-mail and member-only social networking websites associated with the TS Alliance, a US-based patient advocacy organization. The survey and recruitment methodology were developed by the authors of this manuscript and approved by the Ethical & Independent Review Services institutional review board (Independence, MO). Survey responses were anonymous, and all respondents provided electronic consent prior to completing the survey. The survey was completed by either an adult with TSC, or a caregiver of individual of any age with TSC. Caregivers provided proxy report for clinical, cost, lifetime impact questions, and self-report on work productivity questions and some demographic questions. Eligibility criteria for TSC adult participants included a minimum age (>18 years); TSC diagnosis; ability to read English and complete a web-based survey; and ability and willingness to provide online assent. Eligible TSC caregivers had to be >18 years; care for someone diagnosed with TSC; able to read English and complete a web-based survey; and able and willing to provide online assent. To acknowledge their effort, survey completers received remuneration of $25.
Survey components
A study-specific survey was developed which included questions to assess TSC disease manifestations, clinical treatment, healthcare utilization, and out-of-pocket expenses. TSC adult respondents and caregiver respondents were asked to estimate the number of visits and direct out-of-pocket spending for appointments with health professionals, hospitalizations, emergency room visits, diagnostic tests, surgical procedures, or other treatments. Additionally, respondents were asked to estimate out-of-pocket indirect healthcare spending related to time and money spent for TSC-related medical care travel and childcare expenses. Recall periods ranged from the past month to the past 12 months.
The Work Productivity and Activity Impairment plus Classroom Impairment Questions: Special Health Problem (WPAI CIQ-SHP) version 2 questionnaire was also administered. The WPAI CIQ-SHP v2 questionnaire is a version of the Work Productivity and Activity Impairment (WPAI) questionnaireCitation9, and includes 10 questions about work, classroom, and activity impairment due to a specific health problem over the last 7 days. In this survey, the specific health problem referred to TSC. The questionnaire results were analyzed per accepted scoring algorithmsCitation9, resulting in the following scores:
Absenteeism: the percentage of work or school time missed due to TSC;
Presenteeism: a measure of time at work or school that is impaired due to TSC (shows reduced on-the-job effectiveness);
Productivity loss: the overall proportion of work or school productivity loss due to TSC; it is the sum of absenteeism and presenteeism; and
Activity impairment: a measure of regular activities affected by TSC. Regular activities include work around the house, shopping, child care, exercising, studying, etc.
Results were expressed as impairment percentages. Higher numbers indicate greater time missed or greater impairment.
Statistical analysis
The analysis included all caregiver survey respondents and the TSC adult respondents who reported no cognitive impairments. Descriptive statistics (percent, mean, standard deviation) were used to summarize the sociodemographic characteristics and direct cost burden. Sub-group analyses were conducted: (1) Age-based TSC groups ≤18 (pediatric group) and >18 years of age (adult group); or (2) Survey respondent (TSC adults vs TSC caregivers) using t-tests (two groups) or analysis of variance (three or more groups) for mean differences or Chi-squares for proportions where appropriate. T-tests were used to compare WPAI absenteeism and presenteeism to other WPAI results available in the literature. The TSC adult WPAI results were compared to available WPAI results of individuals with moderate-to-severe plaque psoriasis (PP)Citation10, and those with multiple sclerosis (MS)Citation11, both conditions which may have similar morbidity and disability outcomes as TSC. Two-tailed p-values are reported for t-tests; p < .05 was considered statistically significant. All analyses were conducted using SAS version 9.2.
Results
Survey completion time was between 45–60 min. describes the sample for this analysis. Of the total 676 survey respondents, 60% were TSC adults (n = 401) and 40% were TSC caregiver respondents (n = 275). Of the TSC adult respondents, 67 reported cognitive impairments and were excluded from the analysis. The final analysis group included 609 respondents: 334 (55%) TSC adult respondents and 275 (45%) TSC caregiver respondents ().
Figure 1. Selection of study respondents.
Sociodemographic information provided by caregiver and TSC adult respondent groups is presented in . TSC caregivers were 79% female, 66% had a college degree or higher, and 64% were employed full-time or part-time. In contrast, TSC adults were 44% female, 52% had a college degree or higher, and 71% were employed full-time or part-time.
Table 1. Sociodemographic characteristics—survey respondent.
Sociodemographic information by pediatric and adult groups is presented in The average age and standard deviation (SD) of the pediatric group was 7.1 ± 4.6 years and 38.0 ± 13.1 years for the adult group (). More than two-thirds (70%) of the TSC adult group rely on government health insurance, compared to less than half (42%) of the pediatric group (p < .0001). also presents information on healthcare setting by pediatric and adult groups. There were minor differences in location of care for TSC adult and pediatric groups, with 26%, 21%, and 18% of the pediatric group receiving TSC care in the East Coast, Midwest, and Southeast, respectively, and 24%, 22%, and 18% of the adult group reported receiving care on the West Coast, Midwest, and Southeast, respectively (p = .0062). Less than half of the TSC patient or adult groups received medical care at a TSC specialty clinic (43%). More TSC adults (76%) received TSC care in an urban setting compared to the pediatric group (69%) (p = .0282). More of the pediatric group reported living closer to a TSC clinic (less than 100 miles away, 51%) compared to TSC adults (27%) (p < .0001).
Table 2. Sociodemographic and clinical characteristics—TSC pediatric and adult group.
Data describing the clinical characteristics, healthcare utilization, and health-related quality-of-life burden of the TSC adult and pediatric groups is reported in Rentz et al.Citation6.
Direct cost burden due to TSC
presents the “out-of-pocket” direct spending in the past year between TSC groups. Overall, TSC adults had significantly higher annual expenses for ER visits ($500 vs $400; p < .0001), monthly medical tests and procedures ($1,200 vs $300, p < .0001), alternative treatments ($680 vs $100, p = .0008), and medications ($600 vs $150, p < .0001), and lifetime cost from surgeries ($4,000 vs $1,000, p = .0004) compared to the pediatric group. The median direct “out-of-pocket” monthly spending was also higher for adults compared to the pediatric group, but was not statistically significant: doctor’s visits ($500 vs $400), medical expenses related to hospital stays ($1,650 vs $1,200), and non-medical expenses related to hospital stays ($1,000 vs $475). presents these data by region of care in the US. None of the cost categories were significantly different by region.
Figure 2. Out-of-pocket healthcare spending related to TSC (n = 609). Abbreviations. ER, emergency room; NS, not significant.
Figure 3. Out-of-pocket healthcare spending related to TSC by region of US (n = 609). Abbreviations. ER, emergency room; NS, not significant.
Reduced Work Productivity of Adult Caregivers and TSC Adults Due to TSC
describes information on work productivity, school productivity, and activity impairment in this sample, as measured by the WPAI. Approximately 62% of caregivers (n = 171) and 71% of TSC adults (n = 237) reported currently working for pay. In general, caregivers reported less impact than TSC adults on work absenteeism and presenteeism due to TSC. On average, caregivers missed 11% (±17%) of work time (“absenteeism”) due to TSC compared to TSC adults who missed an average of 15% (±16%) (p = .029). Caregivers reported 38% (±25%) of their work time as impaired due to TSC caregiving, while TSC adults reported 58% (±26%) of their work time as impaired due to their TSC (p < .0001). TSC adults reported significantly more overall work productivity loss due to TSC in the past week compared to caregivers (42% ± 27% vs 63% ± 27%, p < .0001). The total sample reported 52% (±27%) impairment of regular activities due to TSC. TSC caregivers reported significantly less impairment of regular activities due to TSC compared to TSC adults (49% ± 28% vs 55% ± 25%, p = .0035).
Table 3. Work productivity and activity impairment in TSC adults and caregiversa (n = 609).
Comparing WPAI results between the TSC adults (n = 237), individuals with moderate-to-severe plaque psoriasis (n = 8,273), and individuals with multiple sclerosis (n = 2,966) showed TSC adults had much higher absenteeism (TSC 13 ± 17; vs plaque psoriasis 4 ± 15, p < .0001; multiple sclerosis 3 ± 12, p < .0001) and presenteeism rates (TSC 50 ± 27; vs plaque psoriasis 14 ± 20, p < .0001; multiple sclerosis 18 ± 23, p < .0001)10,Citation11.
Reduced school productivity due to TSC
A few caregivers (n = 13; 5%) and TSC adults (n = 56; 17%) reported being enrolled in school (). In general, TSC adults reported missing ∼27% of school time in the past 7 days due to TSC; caregivers reported missing ∼11% of school time in the past week (absenteeism; p = .0608). TSC adults reported 60% impairment due to TSC during the past 7 days of school, compared to 37% for TSC caregivers (presenteeism; p = 0004). TSC adults reported 67% productivity loss in school due to TSC, compared to caregivers, who reported a productivity loss of 40% (p = .0002).
Discussion
This study identified several demographic differences between TSC pediatric and adult groups that may influence the degree of direct healthcare costs experienced by both; namely type of health insurance, distance, and setting of TSC provider. TSC adults tend to travel further distance to receive TSC medical care and rely on government health insurance programs to pay for their healthcare compared to the TSC pediatric group.
This study provides new information about work and school productivity burden for TSC adults and TSC caregivers. The analysis identified that the proportion of work loss (absenteeism) and work impairment (presenteeism) was significantly higher in TSC adults compared to TSC caregivers. Likewise, significantly higher rates of presenteeism and absenteeism were identified in the TSC adults compared to cohorts of adults with moderate-to-severe PP10 and those with MS. Both PP and MS are chronic, lifelong conditions that involve frequent use of healthcare resources and a high health burden. Adults with moderate-to-severe PP experience thick, scaly, red skin, which is often itchy and painful and can crack and bleedCitation12. Similarly, close to 90% of TSC adults experience some type of dermatologic feature, that can include skin lesions, hypopigmented macules, facial angiofibromas, and fibrous cephalic plaquesCitation3,Citation13. MS is an unpredictable, often disabling disease of the central nervous system that can cause fatigue, weakness, walking difficulties, vertigo, numbness, pain, muscle spasticity, vision problems, and cognitive changesCitation14. In comparison, up to 80% of TSC individuals can experience neurological problems caused by cortical tubers, subependymal nodules, and subependymal giant cell astrocytoma, leading to clumsiness or the inability to walk, increased frequency and/or severity of seizures, behavioral changes, visual problems, and/or behavioral problemsCitation3,Citation13,Citation15. The findings of higher absenteeism and impairment rates as measured by the WPAI in TSC adults compared to plaque psoriasis and multiple sclerosis are an indicator of the increased morbidity and economic burden of this disease.
This study provides additional evidence of the direct cost experienced by TSC individuals and familiesCitation4–8,Citation16,Citation17. The high number of tests and out-of-pocket burden for expenses related to ER visits and hospitalizations indicate that TSC individuals and their families are shouldering significant economic burden. Higher emergency room visits and hospital admissions in the past year for TSC adults compared to the pediatric group may indicate greater morbidity. This study has previously identified higher burden of medical tests, procedures, and treatments in the TSC pediatric group, yet higher indirect medical costs in terms of time spent seeking out healthcare in the adult group6. The higher burden of testing in the pediatric group may be associated with the higher average number of TSC manifestations and more clinically severe manifestations compared to the adult TSC group6. This significant use of healthcare resources and time dedicated to managing healthcare places a burden on TSC individuals and their families.
Since the initiation of this study, several studies have been published reporting the substantial healthcare, humanistic, and economic burden of TSC4,Citation16,Citation17. Recently published research of a retrospective cohort study utilized routinely collected general practitioner (GP) primary care data from electronic medical records in the Clinical Practice Research Datalink database. Their results showed substantial healthcare use by individuals with a TSC diagnosis living in the UK compared to individuals randomly selected from the GP primary care databasesCitation16. This same study conducted a separate analysis of TSC individuals with epilepsy, and found that costs increased incrementally as the number of TSC manifestations increased: £5,053 (∼$7,000) for TSC individuals with epilepsy and no additional manifestations to £24,901 (∼$34,600) for individuals with up to four manifestationsCitation18. An online survey to identify individual use of resources for systemic sclerosis identified that the average annual cost was estimated at €22,459 (∼$27,700) per individualCitation19, while the yearly out-of-pocket costs reported by our TSC study sample was estimated at $26,600. Chevreul et al.Citation19 offered a detailed look at specific cost drivers: direct healthcare costs amounted to €8,452 (∼$10,400), direct non-healthcare formal costs were €1,606 (∼$2,000), and direct non-healthcare informal costs were €1,875 (∼$2,300). Vekeman et al.Citation17 presented significant healthcare use and cost burden associated with TSC using medical record data for 369 individuals with TSC treated at a specialty center in the Netherlands. The authors concluded that the association with significantly higher costs for advancing chronic kidney disease highlights the need for routine monitoring of kidney function and alternative TSC treatment approaches that preserve kidney function, and may substantially reduce healthcare utilization and costs associated with kidney problems related to TSC17.
Long-term medical issues can cause disruption to education and career pursuits, both of which may contribute to the economic burden on TSC individuals and familiesCitation20,Citation21. Interestingly, work and school absenteeism and presenteeism results were similar between TSC adults compared to caregivers. This lost work time and productivity imposes direct costs to individuals and families. In the systemic sclerosis patient study, direct costs resulting from patients’ absence from the labor market was calculated to be ∼ €10,52619. Likewise, the morbidity related to TSC, healthcare utilization burden, and the resulting economic burden on individuals and households affects education and career opportunities TSC individuals and caregivers can pursue, resulting in additional humanistic burdens. The TSC guideline recommendations for annual screening and testing to monitor TSC may represent a time cost and financial expense that may be burdensome for the aging TSC adultsCitation2,Citation3. As individuals with TSC age, challenges may exist to access the needed medical expertise to comprehensively manage their medical care. As individuals transition from a pediatric to an adult healthcare system, they may experience a lack of continuity of care and/or encounter a healthcare system unfamiliar with the TSC medical conditionCitation21. Within recent years, revised diagnostic criteriaCitation3 and surveillance and management recommendations for the standardized, optimal clinical management of individuals with TSC have been publishedCitation20, which may explain the higher testing in younger individuals.
There are several limitations to this study. Our sample represents a cross-section of respondents who were recruited via social networking websites associated with the TS Alliance and, therefore, is not representative of the overall TSC individual or caregiver population. This study was a one-time survey that relied on patient-reported and caregiver-reported information. The reliability of the data is wholly dependent on the recall of information with varying recall periods depending on the question. This study did not include a comparator cohort, although, for the WPAI analysis, TSC findings were compared to published comparison cohorts. To limit recall issues, this analysis only included TSC adult respondents with no self-reported cognitive impairment.
Conclusions
This study contributes to the growing body of literature on the economic burden of TSC. TSC individuals experience direct out-of-pocket costs and work impairments that continue throughout their lifespan. Direct cost burden should be examined more closely in the US using electronic medical records and insurance databases in conjunction with a comparator cohort. The economic effects of TSC on families over time and encompassing the varied manifestations of TSC should be studied in healthcare systems that have comprehensive healthcare practice and direct cost data.
Transparency
Declaration of funding
Funding for this study was provided by Novartis Oncology.
Declaration of financial/other relationships
AMR and AMS are employed by Evidera, which provides consulting and other research services to pharmaceutical, device, government, and non-government organizations. As Evidera employees, they work with a variety of companies and organizations and are expressly prohibited from receiving any payment or honoraria directly from these organizations for services rendered. ZL and QS are employees of Novartis. DWD receives research support from Eli Lilly. JWW is currently a consultant for Eisai, Lundbeck, NeuroPace, Sun,Supernus and Upsher-Smith; he is part of a speaker's bureau for Lundbeck, Mallinckroft, LivaNova, Eisai, Supernus, Upsher-Smith. He has received research grants from the Shainberg Foundation, Mallinckrodt, LivaNova, Upsher-Smith, GW Pharma, INSYS, Inc, Neuralis, Zogenix and NeuroPace. JAN is employed by the Tuberous Sclerosis Alliance. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Acknowledgments
This work was conducted by Evidera, Bethesda, MD. The authors thank Kelly McDaniel, Katherine Kim, and Zaneta Balantac for their assistance with data collection, Ren Yu for data analysis, and Amara Tiebout for production assistance. They were employed in the Outcomes Research (OR) division of United BioSource Corporation (UBC) at the time of the study. UBC received funding from Novartis Oncology for this study. The UBC OR division has since become a wholly owned subsidiary called Evidera. The authors gratefully acknowledge the support of the Tuberous Sclerosis Alliance and the adults with TSC and caregivers who participated in this survey.
References
- Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010;363:1801-11
- Krueger DA, Franz DN. Current management of tuberous sclerosis complex. Paediatr Drugs 2008;10:299-313
- Northrup H, Krueger DA, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 international tuberous sclerosis complex consensus conference. Pediat Neurol 2013;49:243-54
- Lennert B, Farrelly E, Sacco P, et al. Resource utilization in children with tuberous sclerosis complex and associated seizures: a retrospective chart review study. J Child Neurol 2013;28:461-9
- Hallett L, Foster T, Liu Z, et al. Burden of disease and unmet needs in tuberous sclerosis complex with neurological manifestations: systematic review. Curr Med Res Opin 2011;27:1571-83
- Rentz AM, Skalicky AM, Liu Z, et al. Tuberous sclerosis complex: a survey of health care resource use and health burden. Pediat Neurol 2015;52:435-41
- Rentz AM, Skalicky AM, Pashos CL, et al. Caring for children with tuberous sclerosis complex: what is the physical and mental health impact on caregivers? J Child Neurol 2015;30:1574-81
- Skalicky AM, Rentz AM, Liu Z, et al. The burden of subependymal giant cell astrocytomas associated with tuberous sclerosis complex: results of a patient and caregiver survey. J Child Neurol 2015;30:563-9
- Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and activity impairment instrument. PharmacoEconomics 1993;4:353-65
- Kimball AB, Yu AP, Signorovitch J, et al. The effects of adalimumab treatment and psoriasis severity on self-reported work productivity and activity impairment for patients with moderate to severe psoriasis. J Am Acad Dermatol 2012;66:e67-76
- Coyle PK, Cohen BA, Leist T, et al. Therapy optimization in multiple sclerosis: a prospective observational study of therapy compliance and outcomes. BMC Neurol 2014;14:49
- National Psoriasis Foundation (NPF). Portland, OR: NPF. Available from: https://www.psoriasis.org/ [Last accessed December 28, 2017]
- TS Alliance. Signs and symptoms of TSC. Silver Spring, MD: TS Alliance; 2017. Available from: http://www.tsalliance.org/about-tsc/signs-and-symptoms-of-tsc/; 2018 [Last accessed June 25, 2018]
- National Multiple Sclerosis Society. Available from: https://www.nationalmssociety.org/Symptoms-Diagnosis/MS-Symptoms [Last accessed June 25, 2018]
- National Institute of Neurological Disorders and Stroke (NINDS). Tuberous sclerosis fact sheet. NIH Publication No. 07-1846. Bethesda, MD: NINDS; May 10, 2017. Available from: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Tuberous-Sclerosis-Fact-Sheet [Last accessed December 28, 2017]
- Kingswood JC, Crawford P, Johnson SR, et al. The economic burden of tuberous sclerosis complex in the UK: a retrospective cohort study in the Clinical Practice Research Datalink. J Med Econ 2016;19:1087-98
- Vekeman F, Magestro M, Karner P, et al. Kidney involvement in tuberous sclerosis complex: the impact on healthcare resource use and costs. J Med Econ 2015;18:1060-70
- Shepherd C, Koepp M, Myland M, et al. Understanding the health economic burden of patients with tuberous sclerosis complex (TSC) with epilepsy: a retrospective cohort study in the UK Clinical Practice Research Datalink (CPRD). BMJ Open 2017;7:e015236
- Chevreul K, Brigham KB, Gandre C, et al. The economic burden and health-related quality of life associated with systemic sclerosis in France. Scand J Rheumatol 2015;44:238-46
- Krueger DA, Northrup H, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediat Neurol 2013;49:255-65
- Van Lierde A, Menni F, Bedeschi MF, et al. Healthcare transition in patients with rare genetic disorders with and without developmental disability: neurofibromatosis 1 and Williams-Beuren syndrome. Am J Med Genet A 2013;161A:1666-74