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Table 2 Overview of studies reporting burden of illness by health care resource use, direct costs or mortality in TSC patients

From: A systematic review on the burden of illness in individuals with tuberous sclerosis complex (TSC)

Study Type of study and data approach Data source/ country of patient origin Cohorts Organ systems Incl. / excl. Criteria N total N caregiver Evaluated period (year) Duration time (years) Actual time evaluated (years) Mean age Mean age adults Mean age children N female (%) N children (%) Percentage caregiver HRCU - inpatient HRCU - outpatient Direct costs Cost drivers (regression analysis) Social costs Mortality Individual BOI Caregiver BOI
Shepherd et al. 1991 [100] Retrospective chart review, bottom-up Mayo Clinic/ USA all TSC all Clinical diagnosis of TSC according to 1988 Gomez criteria 355 0 n. r. n. r. n. r. n. r. n. r. n. r. n. r. n. r. n. r. n. r. n. r. n. r. n. r. n. r. yes only via mortality n. r.
Liang et al. 2019 [101] Prospective, single-center Capital Epilepsy Therapy Center Beijing/ China TSC + E all Pharmacoresistant epilepsy, surgery in year 2007 25 N/A 2007 1 1 14.3 (R 6–23) n. r. n. r. 8 (32) 100 N/A n. r. n. r. n. r. n. r. n. r. n. r. Quality of life in epilepsy inventory-31 (QOLIE-31) n. r.
Lennert et al. 2012 [24] Retrospective chart review, bottom-up Minnesota Epilepsy Group/ USA only TSC + E all Inclusion: TSC–related seizure disorder within the first 6 months after tuberous sclerosis complex diagnosis
exclusion: TSC–unrelated seizure disorder
95 (only children) 0 1973–2010 37 0.5 to 5 3.1 (SD 7.8) N/A 3.1 (SD 7.8) 48 (51.0) 91 (95.8) N/A yes yes n. r. n. r. n. r. n. r. only via clinical information and HCRU n. r.
Graffigna et al. 2013 [102] Qualitative interview survey of patients from 15 TSC centers/ Italy Caregivers of children with TSC + SEGA all Caregivers of children with TSC + SEGA 0 48 2011–2012 1 N/A 47 (SD 6.3) (caregiver) N/A N/A 62.5 (caregiver) N/A 100 n. r. n. r. n. r. n. r. n. r. n. r. n. r. Qualitative statements
Krueger et al. 2013 [103] Prospective, multicenter,open-label, phase!/ II clinical trial TSC clinics at Cincinnati Children’s Hospital Medical Center (CCHMC) and Texas Children’s Hospital/ USA Pharmacoresistant epilepsy brain > = 2 years of age, confirmed diagnosis of TSC (1998 clinical diagnostic criteria or identified disease-causing mutation, pharmacoreistant epilepsy) 23 N/A   16 months 16 months 8 (R 2–21) n. r. n. r. 50 n. r. N/A n. r. n. r. n. r. n. r. n. r. n. r. Quality of Life for Children with Epilepsy (QOLCE), Nisonger Child Behavioral Rating Form (NCBRF) n. r.
Eijkemans et al. 2015 [86] Retrospective observational, bottom-up University Medical Center Utrecht (UMCU)/ Netherlands all TSC/ TSC + AML kidney Diagnosis of TSC according to the modified Gomez criteria and aged 18 years or older 351* (only adults) 0 1990–2012 22 median 15.8 39.8 (R 18–89) 39.8 (R 18–89) N/A 175 (49.8) N/A (0) N/A yes n. r. n. r. n. r. n. r. yes only via HCRU n. r.
Kristof et al. 2015 [104] Retrospective cohort study, top-down Régie de l’Assurance-Maladie du Québec (RAMQ; Quebec Health Care Insurance Board) database/ Canada all TSC/ TSC + LAM/ LAM/ controls lung LAM and/or TSC and controls 1004 (children and adults) 0 1996–2011 15 n. r. 39.5 (SD 24.4) n. r. n. r. 555 (55.3) n. r. N/A yes yes yes n. r. n. r. yes only via HCRU n. r.
Rentz et al. 2015a [56] Cross-sectional, non-interventional, bottom-up web-based survey/ USA paediatric/ adult TSC patients/ caregivers all Inclusion: age 18 years or older, TSC diagnosis (or care for individual with TSC), read English and ability to participate, and consent
exclusion: patients with cognitive impairment or other health impairment that interfere w/ survey completion
676** (children and adults) 275 (179 adult caregiver, 96 pediatric caregiver) 2012 N/A 2 months (May and June 2012) 29.8 (SD 17.7) 38 (SD 12.8) 7.1 (SD 4.6) 400 (59.2) 197 (26.5) 40.7 yes yes n. r. n. r. n. r. n. r. Short Form (12) Health Survey (SF-12), Hamilton Depression Rating Scale-Short Form (HDI-SF) SF-12,HDI-SF
Rentz et al. 2015b [105] Cross-sectional, non-interventional, bottom-up web-based survey/ USA TSC caregivers all See Rentz et al. 2015a 275** (children and adults) 275** 2012 0 2 months (May and June 2012) n. r. n. r. n. r. 217 (79) 0 100 yes yes n. r. n. r. n. r. n. r. SF-12, HDI-SF SF-12, HDI-SF
Skalicky et al. 2015 [106] Cross-sectional, non-interventional, bottom-up web-based survey/ USA paediatric/ adult TSC patients all See Rentz et al. 2015 a 116** (children and adults) 69** 2012 0 2 months (May and June 2012) 25.5 (SD 16.6) 36.8 (SD 11.5) 9 (SD 5.0) n. r. 47 (40.5) 59.5 yes yes yes n. r. n. r. n. r. SF-12, HDI-SF, Work Productivity and Activity Impairment plus Classroom Impairment Questions: Special Health Problem (WPAI CIQ-SHP), version 2 SF-12, HDI-SF, WPAI CIQ-SHP-version 2
Sun et al. 2015 [107] Retrospective cohort study, top-down National claims databases (MarketScan commercial and Medicaid, Pharmetrics commercial)/ USA all TSC + SEGA surgery brain (SEGA) TSC patients with first SEGA surgery claim in study period 47 (children and adults) 0 2000–2011 11 n. r. 11.6 n. r. n. r. 16 (34) n. r. N/A yes yes yes yes n. r. n. r. only via HCRU n. r.
Vekeman et al. 2015 [35] Retrospective, longitudinal cohort study, bottom-up University Medical Center Utrecht (UMCU)/Netherlands CKD stage/ AML size kidney, lung Diagnosis of TSC according to the revised 1998 TSC criteria 369* (children and adults) 0 1990–2012 22 mean 14.3 32.4 (SD 23.7) CKD stage I n. r. n. r. n. r. n. r. N/A yes yes yes yes n. r. n. r. only via clinical information and HCRU n. r.
Crall et al. 2016 [108] Cross-sectional, bottom-up web-based survey and survey of out-patients/USA TSC with AF and caregivers skin Inclusion: clinical or genetic diagnosis of TSC, age > 6 years at enrollment /caregiver of a patient exclusion: uncertain diagnosis of TSC/ severe neurologic deficits/ survey noncompletion 219 (children and adults) 161 2014–2015 N/A N/A n. r. n. r. n. r. 94 (42.9) n. r. 73.5 n. r. yes n. r. n. r. n. r. n. r. Children’s Dermatology Life Quality Index (CDLQI) Childhood Atopic Dermatitis Impact Scale (CADIS)
Fallah et al. 2016 [109] Cost-utility analysis, bottom-up and top-down literature search (clinical data), Tufts CEA registry, Agency for Healthcare Research and Quality (AHRQ) Medical Expenditure Panel Survey/ USA TSC + E only (model) brain (seizures) N/A N/A N/A 2000–2015 15 15 for clinical outcomes, cost data updated to 2016 USD N/A N/A N/A N/A N/A (100) N/A n. r. n. r. yes yes n. r. n. r. n. r. n. r.
Kingswood et al. 2016a [110] Retrospective cohort study, bottom-up and top-down National Health Service (NHS) databases CPRD (clinical practice research datalink) and CPRD-HES (hospital event statistics)/ UK all TSC/ general population comparator all Diagnosis of TSC between 1 January 1987 and 30 June 2013 and at least 3 years of continuous data prior to the last available record 278*** (children and adults) 0*** 1987–2013 26 at least 3 31.5 (SD 18.7) n. r. n. r. 147 (53) n. r. N/A yes yes yes yes n. r. n. r. only via HCRU n. r.
Kingswood et al. 2016b [111] Retrospective cohort study, bottom-up and top-down National Health Service (NHS) databases CPRD (clinical practice research datalink) and CPRD-HES (hospital event statistics)/ UK TSC + renal manifestations/ general population comparator kidney See Kingswood et al. 2016a 79*** (children and adults) 0*** 1987–2013 26 at least 3 38,3 (SD 17.1) n. r. n. r. 37 (46.7) 8 (11.3) N/A yes yes yes yes n. r. n. r. only via HCRU n. r.
Kingswood et al. 2016c [42] Retrospective cohort study, bottom-up and top-down National Health Service (NHS) databases CPRD (clinical practice research datalink) and CPRD-HES (hospital event statistics)/ UK all TSC/ general population comparator all Diagnosis of TSC between 1 January 1987 and 30 June 2013 334*** (children and adults) 0*** 1987–2013 26 mean 17.4 (SD 6.4) 30.3 (SD 18.6) n. r. n. r. 177 (53) n. r. (29) N/A n. r. n. r. n. r. n. r. n. r. yes only via mortality n. r.
Wilson et al. 2016 [112] Retrospective, top-down Agency for Healthcare Research and Quality (AHRQ) National Inpatient Sample (NIS) database/ USA all TSC all All TSC patients in the database 5655 (hospital admissions) (children and adults) 0 2000–2010 10 n. r. 22.3 (SD 19.5) n. r. n. r. n. r. (52.5) n. r. N/A yes n. r. yes n. r. n. r. n. r. only via HCRU n. r.
Amin et al. 2017 [113] Retrospective chart review, bottom-up Bath TSC clinic database/ UK all TSC all Definite diagnosis of TSC (International TSC Consensus Group) 284 (children and adults) 0 1981–2015 34 median 8 (IQR 3–17) w/ ID 25 (IQR 15–36), wo/ ID 28 (IQR 17–43) n. r. n. r. 142 (50) n. r. N/A n. r. n. r. n. r. n. r. n. r. yes only via mortality n. r.
Shepherd et al. 2017 [23] Retrospective cohort study, bottom-up and top-down National Health Service (NHS) databases (EMR, HES, clinical practice research datalink)/ UK all TSC/ TSC + E, TSC + E/ general population comparator all Recorded diagnosis of TSC in study period and at least 3 years of continuous data prior to the last available record 209 (children and adults) 0 1997–2012 15 at least 3 26.8 (SD 17.8) N/A N/A 102 (48.8) 81 (38.8) N/A yes yes yes yes n. r. n. r. only via clinical information and HCRU n. r.
Song X. et al. 2017 [114] Cross-sectional, top-down Truven Commercial Claims and Medicaid database/ USA TSC + AML/ controls in Commercial/ Medicaid databases all Patients diagnosed with TSC-renal AML in the databases 743 (children and adults) 0 2000–2013 13 37.0 (SD 31.1) to 87.2 (SD 42.9) n. r. 36.9 (SD 13.0) 9.7 / 6.9 (SD 5.2) n. r. 256 (34.5) N/A yes yes yes n. r. n. r. n. r. only via HCRU n. r.
Welin et al. 2017 [27] Retrospective, top-down National Board of Health and Welfare (NBHW) national registers/ Sweden all TSC all All patients with TSC diagnosis in national register 551 (children and adults) 0 2004–2014 10 mean 8.8 n. r. n. r. n. r. 339 (45.1) 238 (61.6) at first observation N/A yes yes n. r. n. r. n. r. yes only via HCRU n. r.
Both et al. 2018 [115] Qualitative study using semistructured interviews Dutch Foundation for patients with TSC, healthcare providers/ Netherlands TSC patients/ parents all Adolescent TSC patients 18–30 years old with a definitive TSC diagnosis; parents of children with TSC of 18 years, or older, or younger and having transitioned into adult care 28 (children and adults) 12 n. r. n. r. n. r. R 17–30 n. r. n. r. n. r. n. r. n. r. n. r. n. r. n. r. n. r. n. r. n. r. TSC-related themes, categorized by the ICF TSC-related themes, categorized by the ICF
Hamer et al. 2018 [116] Retrospective, multi-center cohort study (12), bottom-up survey of patients from 12 German epilepsy centers/ Germany all TSC all Patients aged ≥18 years with a confirmed TSC diagnosis according to clinical Gomez criteria and/or genetic testing 262 (only adults) 0 2010–2015 5 5 36.2 (SD 9) 36.2 (SD 9) N/A 122 (46.6) 0 N/A yes yes n. r. n. r. n. r. n. r. only via HCRU n. r.
Kopp et al. 2018 [117] Retrospective observational, bottom-up Carol and James Herscot Center for Tuberous Sclerosis Complex, Massachusetts General Hospital (MGH)/ USA all TSC all All patients under the age of 18 with TSC 99 (only children) 0 2001–2007 6 n. r. N/A 7.7 (SD 4.2) 7.7 (SD 4.2) 54 (54.5) 99 (100) N/A n. r. n. r. n. r. n. r. n. r. n. r. n. r. Symptom Checklist-90—Revised (SCL-90-R), Parenting Stress Index (Short Form)
Mowrey et al. 2018 [118] Cross-sectional, bottom-up web-based survey/ USA all TSC all Having a diagnosis of TSC, age of 18 years or older, ability to independently complete a 30-min electronic survey. 71 (only adults) 0 2017–2018 N/A 3 months 43.7 (SD 13.2) 43.7 (SD 13.2) N/A 52 (73) 0 N/A yes yes n. r. n. r. n. r. n. r. Brief-Illness Perceptions Questionnaire (Brief-IPQ), Beck Anxiety Inventory (BAI), and Beck Depression Inventory-II (BDI-II). n. r.
Rentz et al. 2018 [119] Cross-sectional, non-interventional, bottom-up web-based survey/USA paediatric/ adult TSC + AML patients/ caregivers kidney see Rentz et al. 2015a 182** (110 AML) (children and adults) 59** 2012 N/A 2 months (May and June 2012) 29.1 (SD 16.6) 36.4 (SD 13.6) 10.6 (SD 4.7) n. r. 31 (28.2) 54 yes yes n. r. n. r. n. r. n. r. SF-12, HDI-SF SF-12, HDI-SF
Skalicky et al. 2018 [119] Cross-sectional, bottom-up web-based survey/ USA paediatric/ adult TSC patients/ caregivers all see Rentz et al. 2015a 609** (children and adults) 275** 2012 N/A 2 months (May and June 2012) 28.9 (SD 18) 38 (SD 13.1) 7.1 (SD 4.6) n. r. 179 (29.4) 45.2 yes yes yes n. r. yes n. r. WPAI CIQ-SHP version 2 WPAI CIQ-SHP version 2; out-of-pocket indirect healthcare spending related to time and money spent for TSC-related medical care travel and childcare expenses
Song J. et al. 2018 [120] Retrospective, bottom-up and top-down National Tuberous Sclerosis Association (NTSA), TSC Natural History Database/ USA, Belgium TSC + E only all All TSC patients in the database 1110(children and adults) 0 2006–2014 8 4.3 n. r. n. r. n. r. 535 (48.2) n. r. N/A yes yes n. r. n. r. n. r. n. r. only via HCRU n. r.
Amin et al. 2019 [121] Cross-sectional, non-interventional Bath TS clinic/ UK All TSC all TSC, as defined by the International Tuberous Sclerosis Complex Consensus Group 91 n. r. 2014 N/A n. r. n. r. 34 12 50% 35 (38.5) n. r. n. r. n. r. n. r. n. r. n. r. n. r. Pediatric Quality of Life Inventory (PedsQL) (children)
SF-36 (adults)
n. r.
Bar et al. 2019 [53] Cross-sectional, bottom-up Written questionnaire/ network of the reference center for rare epilepsies and TSC (Necker-Enfants Malades and university hospitals of Saint-Etienne, Lille and Lyon) and the French association for TSC (ASTB), France TSC patients in transition from pediatric care all Age > 18 years and confirmed diagnosis of TSC before the age of 16 60 (only adults) 30 2014 N/A n. r. 32 (range 18–55) 32 (range 18–55) N/A 29 (49%) N/A 50 yes yes n.r. n.r. yes n.r. Quality of Life Scale (QOLS), Multidimensional Fatigue Inventory-20 (MFI-20) n.r.
Tritton et al. 2019 [122] Cross-sectional, bottom-up Web-based survey/ USA and Europe TSC + epilepsy all Clinical diagnosis of TSC and epilepsy 186 N/A 2017–2018 N/A N/A 27.3 n. r. n. r. 82 (44.1) 70 (37.6) N/A n. r. n. r. n. r. n. r. n. r. n. r. European quality of life (EQ – 5 dimensions – 3 levels) n. r.
Vergeer et al. 2019 [123] Single-center retrospective chart review, bottom-up University Medical Center Utrecht (UMCU)/Netherlands TSC with AML, SEGA and/or epilepsy all Diagnosis of TSC according to the revised 1998 TSC criteria 363* 0 1990–2015 (2012) 16 N/A n. r. n. r. n. r. n. r n. r. n. r. n. r. n. r. n. r. n. r. n. r. n. r. Health Utility Index version 3 (HUI-3) n. r.
Zak et al. 2019 [124] Retrospective chart review, bottom-up Cincinnati Children’s Hospital Medical Center TSC clinic/ USA all TSC all All patients who attended the CCHMC TSC clinic during the study period, National Death Index (NDI) 567 (children and adults) 0 1998–2016 18 n. r. n. r. n. r. n. r. 247 (> 18) (%n. r.) n. r. n. r. n. r. n. r. n. r. n. r. n. r. yes only via mortality n. r.
  1. *, ** and *** denote studies with overlapping cohorts, AF facial angiofibroma, AML angiomyolipoma, LAM lymphangioleiomyomatosis, R range, SD standard deviation, SEGA subependymal giant cell astrocytoma, TSC+E TSC+epilepsy