The economic burden of tuberous sclerosis complex in the UK: A retrospective cohort study in the Clinical Practice Research Datalink

Figures & data

Figure 1. Criteria for the continuous 3-year period of data applied to the identified TSC population (n = 334) in order to arrive at the final study population (n = 286).

Table 1. Medical inventory of TSC primary organ system codes (MedITOSC).

Organ System	Manifestations
Central Nervous System (CNS)^a	Brain (Structural): Brain neoplasms (including subependymal giant cell astrocytoma [SEGA]), hydrocephalus, cerebral cyst, stroke/transient ischemic attack (TIA)
	Nervous System: Epilepsy (including convulsions and any fit; excluding febrile convulsions), ataxia/hemiplegia
	Psychiatric: Learning/intellectual disability, autism spectrum disorders, sleep disorder, hallucinations, behavioral disorder, speech and language disorders, attention deficit hyperactivity disorder (ADHD), bipolar disorder, depression, anxiety, psychosis/schizophrenia, dysphasia/aphasia, anorexia
Kidney and Urinary Tract^a	Polycystic kidney disease, kidney cyst, chronic kidney disease (stage 3–5), kidney neoplasms (including angiomyolipomas), hematuria
Circulatory System^a	Cardiac rhabdomyoma, hypertension, arrhythmia, myocardial infarction/angina, cerebral/cardiac aneurysm
Dermatological^a^,^b	Angiofibroma, benign skin neoplasms, naevus, acne vulgaris/rosacea, café au lait spots, rhinophyma, nail manifestations, skin tag, impetigo, other skin-related lesions, lymphoedema
Respiratory^a	Lymphangioleiomyomatosis (LAM)^c

^a Primary organ system.

^b Hypomelanotic lesions were not captured by coding.

^c Suspected cases of LAM due to unavailability of specific LAM diagnosis codes in CPRD-HES.

Table 2. Most commonly prescribed drugs in primary care in TSC patients during the most recent 3-year period.

	TSC (n = 286)					Comparator (n = 1430)
	<18 years (n = 79)	95% CI	≥ 18 years (n = 207)	95% CI	Overall (n = 286)	<18 years (n = 395)	95% CI	≥18 years (n = 1035)	95% CI	Overall (n = 1430)
Top 5 most frequently issued drug prescriptions by BNF chapter Number of patients receiving at least one prescription, (%)
All prescriptions	48 (60.8)	50–72	146 (70.5)	64–77	194 (67.8), (62–73)	274 (69.4)	65–74	696 (67.2)	65–70	970 (67.8), (65–70)
Antibacterials (BNF chapter 5.1)	32 (40.5)	29–52	100 (48.3)	41–55	132 (46.2), (40–52)	193 (48.9)	44–54	423 (40.9)	38–44	616 (43.1), (41–46)
Anti-epileptics (BNF chapter 4.8)	36 (45.6)	34–57	86 (41.6)	35–48	122 (42.7), (37–48)	4 (1.0)	0–2	69 (6.7)	5–8	73 (5.1), (4–6)
Topical preparations (BNF chapter 13)	18 (22.8)	13–32	73 (35.3)	28–42	91 (31.8), (26–37)	146 (37.0)	32–42	268 (25.9)	23–29	414 (29.0), (27–31)
Non-Opioid/Opioid Analgesics (BNF chapters 4.7.1/4.7.2)	13 (16.5)	8–25	73 (35.3)	28–42	86 (30.0), (25–35)	83 (21.0)	17–25	316 (30.5)	28–33	399 (27.9), (26–30)
Hypnotics/Antipsychotics (BNF chapters 4.1/4.2)	16 (20.3)	11–29	69 (33.3)	27–40	85 (29.7), (24–35)	10 (2.5)	1–4	210 (20.3)	18–23	220 (15.4), (14–17)
Mean number of drug prescriptions per patient (includes repeat drug prescriptions)	35.7	24–48	88.8	69–109	74.1 (59–89)	9.2	7–11	24.5	20–29	20.3 (17–24)

Note: 2.1% of the TSC cohort and 6.4% of the Comparator cohort did not have any drug prescriptions recorded throughout their available history.

Table 3. Most commonly conducted medical procedures and surgical interventions conducted in TSC patients during the most recent 3-year period.

	TSC (n = 286)					Comparator (n = 1430)
	<18 years (n = 79)	95% CI	≥18 years (n = 207)	95% CI	Overall (n = 286)	<18 years (n = 395)	95% CI	≥18 years (n = 1035)	95% CI	Overall (n = 1430)
Top 5 most frequently performed procedures in TSC Number of patients receiving at least one procedure (%)
Dermatological-related procedure	3 (3.8)	0–8	35 (16.9)	12–22	38 (13.3), (9–17)	4 (1.0)	0–2	49 (4.7)	3–6	53 (3.7), (3–5)
Dental-related procedure	10 (12.7)	5–20	21 (10.1)	6–14	31 (10.8), (7–14)	23 (5.8)	4–8	40 (3.9)	3–5	63 (4.4), (3–5)
Fracture-related procedure/plaster cast application/change	5 (6.3)	1–12	15 (7.2)	4–11	25 (8.7), (5–12)	17 (4.3)	2–6	32 (3.1)	2–4	49 (3.4), (2–4)
Neurosurgical procedure	4 (5.1)	0–10	10 (4.8)	2–7	14 (4.9), (2–7)	0 (0)	0	2 (0.2)	0	2 (0.1), (0)
Blood transfusion	0	0	8 (3.9)	1–6	8 (2.8), (1–5)	1 (0)	0–1	5 (0)	0–1	6 (0), (0–1)
Number of patients receiving at least one procedure, (%)	32 (40.5)	30–51	110 (53.1)	50–57	142 (49.7), (46–53)	85 (21.5)	17–26	385 (37.2)	32–42	470 (32.9), (28–37)
Number of procedures performed in patients, (%)
0	47 (59.5)	49–70	97 (46.9)	40–54	144 (50.3), (45–56)	310 (78.5)	74–83	650 (62.8)	60–66	960 (67.1), (65–70)
1	13 (16.5)	8–25	31 (15.0)	10–20	44 (15.4), (11–20)	40 (10.1)	7–13	163 (15.8)	14–18	203 (14.2), (12–16)
2	7 (8.9)	3–15	28 (13.5)	9–18	35 (12.2), (8–16)	20 (5.1)	3–7	100 (9.7)	8–11	120 (8.4), (7–10)
3	3 (3.8)	0–8	15 (7.3)	4–11	18 (6.3), (3–9)	8 (2.0)	1–3	34 (3.3)	2–4	42 (2.9), (2–4)
≥ 4	9 (11.4)	4–18	36 (17.4)	12–23	45 (15,7), (12–20)	17 (4.3)	2–6	88 (8.5)	7–10	105 (7.3), (6–9)

Table 4. Most commonly conducted diagnostic tests and investigations conducted in TSC patients during the most recent 3-year period.

	TSC (n = 286)					Comparator (n = 1430)
	<18 years (n = 79)	95% CI	≥18 years (n = 207)	95% CI	Overall (n = 286)	<18 years (n = 395)	95% CI	≥18 years (n = 1035)	95% CI	Overall (n = 1430)
Top 5 most frequently conducted diagnostic tests in TSC Number of patients receiving at least one diagnostic test, %
Radiology	38 (48.1)	37–59	52 (25.1)	19–31	90 (31.5), (26–37)	9 (2.2)	1–4	77 (7.4)	6–9	86 (6.0), (5–7)
Magnetic resonance imaging (MRI)	30 (38.0)	27–49	25 (12.1)	8–17	55 (19.2), (15–24)	3 (0.1)	0	18 (1.7)	1–3	21 (1.5), (1–2)
Blood test	10 (12.7)	5–20	33 (15.9)	11–21	43 (15.0), (11–19)	8 (2.0)	1–3	145 (14.0)	12–16	153 (10.7), (9–12)
Computed tomography (CT) scan	12 (15.2)	7–23	31 (15.0)	10–20	43 (15.0), (11–19)	3 (0.1)	0	54 (5.2)	4–7	57 (4.0), (3–5)
Electrocardiography (ECG)/ Echocardiography	12 (15.2)	7–23	31 (15.0)	10–20	43 (15.0), (11–19)	6 (1.5)	0–3	46 (4.4)	3–6	52 (3.6), (3–5)
Ultrasound	14 (17.7)	9–26	28 (13.5)	9–18	42 (14.7), (11–19)	1 (0)	0	79 (7.6)	6–9	80 (5.6), (4–7)
Number of patients receiving at least one diagnostic test, (%)	62 (78.5)	69–88	165 (79.7)	71–89	227 (79.4), (70–88)	117 (29.6)	25–34	775 (74.9)	71–79	892 (62.3), (58–67)
Number of diagnostic tests performed in patients, (%)
0	17 (21.5)	12–31	42 (20.3)	15–26	59 (20.6), (16–25)	278 (70.4)	66–75	260 (25.1)	22–28	538 (37.6), (35–40)
1	7 (8.9)	3–15	21 (10.1)	6–14	28 (9.8), (6–13)	47 (11.9)	9–15	138 (13.3)	11–15	185 (12.9), (11–15)
2	11 (13.9)	6–22	12 (5.8)	3–9	23 (8.0), (5–11)	31 (7.9)	5–11	124 (12.0)	10–14	155 (10.8), (9–12)
3	4 (5.1)	0–10	15 (7.3)	4–11	19 (6.6), (4–10)	16 (4.1)	2–6	89 (8.6)	7–10	105 (7.3), (6–9)
≥ 4	40 (50.6)	40–62	117 (56.5)	50–63	157 (54.9), (49–61)	23 (5.8)	4–8	424 (38.7)	38–44	447 (31.3), (29–34)

Figure 2. Age and sex distribution of TSC (n = 286) and Comparator (n = 1430) cohorts. Age is defined at the last record available for each patient.

Table 5. Healthcare encounters in primary care and secondary care settings in TSC patients during the most recent 3-year period.

	TSC (n = 286)			Comparator (n = 1430)
	<18 years (n = 79)	≥18 years (n = 207)	Overall (n = 286)	<18 years (n = 395)	≥18 years (n = 1035)	Overall (n = 1430)
Mean number of General Practitioner (GP) visits per patient, by category of consultation (95% CI)
All GP visits^a	40.4 (31–50)	64.5 (54–75)	57.9 (50–66)	17.1 (15–19)	30.4 (28–33)	26.8 (25–29)
Clinic visits	21.6 (16–27)	39.7 (33–46)	34.7 (30–40)	11.1 (10–13)	19.0 (17–21)	16.8 (16–18)
Home visits	0.1 (0)	0.3 (0)	0.2 (0)	0 (0)	0 (0)	0 (0)
Telephone consultations	0.7 (0–1)	1.4 (1–2)	1.2 (1–2)	0.6 (0–1)	0.9 (1–1)	0.8 (1–1)
Out of hours	0.3 (0–1)	0.4 (0–1)	0.4 (0–1)	0.4 (0–1)	0.2 (0)	0.3 (0)
Other^b	17.7 (13–22)	22.8 (18–27)	21.4 (18–25)	5.0 (4–6)	10.4 (9–11)	8.9 (8–10)
Mean number of inpatient admissions per patient, by category of admission (95% CI)
All admissions	2.5 (2–3)	3.3 (2–5)	3.1 (2–4)	0.5 (0–1)	1.5 (1–2)	1.3 (1–1)
Elective admission	1.5 (1–2)	1.8 (1–3)	1.7 (1–3)	0.3 (0)	0.7 (0–1)	0.6 (1–1)
A&E admission	0.9 (0–2)	1.4 (1–2)	1.3 (1–2)	0.3 (0)	0.5 (0–1)	0.4 (0–1)
Other admission	0 (0)	0.1 (0)	0.1 (0)	0 (0)	0.3 (0)	0.2 (0)
Median length of stay in hospital (days) per patient (Interquartile Range)
All admissions	1 (1–3)	2 (1–4)	2 (1–4)	1 (1–2)	1 (1–3)	1 (1–3)
Elective admission	1 (1–2)	2 (1–2)	1 (1–2)	1 (1–2)	1 (1–1)	1 (1–1)
A&E admission	2 (1–5)	3 (2–8)	3 (2–8)	2 (1–3)	2 (1–6)	2 (1–5)
Other admission	0 (0)	2 (1–3)	2 (1–3)	3 (2–6)	2 (1–3)	2 (1–3)
Top 10 most frequently visited outpatient specialties in TSC (Mean visits, 95% CI)
All outpatient visits	17.0 (14–20)	12.4 (10–15)	13.7 (12–15)	3.3 (3–4)	5.6 (5–6)	5.0 (5–5)
Neurology/neurosurgery	2.6 (2–3)	1.9 (2–4)	2.1 (2–3)	0.1 (0)	0.1 (0)	0.1 (0)
Pediatric	6.0 (5–7)	0.5 (0–1)	2.0 (2–2)	0.7 (1–1)	0 (0)	0.2 (0)
Psychiatry/mental disorders	1.0 (0–2)	2.1 (1–3)	1.8 (1–3)	0.2 (0)	0.2 (0)	0.2 (0)
Ophthalmology	1.8 (0–1)	0.5 (0–1)	0.9 (1–1)	0.3 (0)	0.3 (0)	0.3 (0)
Trauma and orthopedics	0.7 (0–1)	0.9 (1–1)	0.9 (1–1)	0.5 (0–1)	0.6 (0–1)	0.6 (0–1)
Allied health professional	1.5 (0–3)	0.5 (0–1)	0.8 (0–1)	0.2 (0)	0.4 (0–1)	0.4 (0)
Nursing episode	0.4 (0–1)	0.6 (0–1)	0.5 (0–1)	0.1 (0)	0.3 (0)	0.2 (0)
Dermatology	0.4 (0–1)	0.5 (0–1)	0.5 (0–1)	0.1 (0)	0.2 (0)	0.2 (0)
General medicine	0.1 (0)	0.4 (0–1)	0.3 (0)	0 (0)	0.2 (0)	0.2 (0)
Gastroenterology	0.1 (0)	0.2 (0–1)	0.2 (0)	0 (0)	0.1 (0)	(0)

^a Analyses exclude administration encounters. When administration encounters are added to each of the overall cohorts, the total visits on average per patient are 72.2 for TSC and 33.6 for Comparator. For pediatric patients, this total is 51.1 for TSC and 21.1 for Comparator. For adult patients, this total is 26.7 for TSC and 38.3 for Comparator.

^b Other includes: non-consultation data, non-consultation medication data, radiology result, hospital inpatient report, third party consultation, mail to patient, results recording, letter from outpatients, discharge details, mail from patient.

Figure 3. Total direct costs (£) (a) per patient in the TSC cohort (n = 286) versus Comparator cohort (n = 1430), and (b) in the TSC cohort (n = 286) by primary organ system manifestation during the most recent 3-year period. Total costs (including GP administration encounters): Brain, £22,809; Circulatory, £16,581; Dermatological, £13,250; Kidney & Urinary, £15,695; Nervous System, £14,753; Psychiatric £15,976; Respiratory, £40,993. * Only includes the cost of GP visits (costs of tests conducted at the GP practice are not included); **Only includes the cost of drugs prescribed in primary care. (a) †Costs including GP administration encounters: £2,816 TSC vs £1338 Comparator; ‡Total including GP administration encounters: £12,681 TSC vs £4777 Comparator. (b) †GP visit costs including admin: Brain, £4,753; Circulatory, £4269; Dermatological, £3,060; Kidney & Urinary, £3967; Nervous System, £2,970; Psychiatric £3,431; Respiratory, £7,330. ‡Organ system involvement was determined over the entire course of the patients’ available history.

Table 6. Model 1: Key drivers of direct costs in TSC during the most recent 3-year period.

Variable	TSC patients (n)	p-value
Single manifestations
Brain [structural]	55	0.5143
Circulatory	42	0.3910
Dermatological	233	0.2545
Kidney & urinary tract	79	0.0474
Nervous system	209	0.0340
Psychiatric	194	0.3343
Respiratory	3	0.1904
Combinations of manifestation categories
Brain [structural]/Circulatory	12	0.0574
Brain [structural]/Dermatological	46	0.4773
Brain [structural]/Kidney & urinary tract	19	0.2295
Brain [structural]/Psychiatric	45	0.3966
Dermatological/Circulatory	31	0.3072
Dermatology/Kidney & urinary tract	67	0.0052
Dermatology/Psychiatric	163	0.1251
Kidney & urinary tract/Circulatory	16	0.0065
Kidney & urinary tract/Psychiatric	61	0.8181
Nervous system/Brain	46	0.4456
Nervous system/Circulatory	27	0.0923
Nervous system/Dermatological	173	0.2206
Nervous system/Kidney & urinary tract	57	0.2326
Nervous system/Psychiatric	157	0.0095

p-values are returned from a gamma distribution regression assessing the significance of manifestations in terms of driving the costs associated with TSC.

Table 7. Model 2: Key drivers of direct costs in TSC during the most recent 3-year period.

Parameter^a	p-value
Age (<18 and ≥18)	0.6089
Sex	0.2285
Number of manifestation categories	<0.0001

^a All parameters include the total TSC cohort with 3-years of continuous data (n = 286).

Table 8. Model 2: Key drivers of direct costs in TSC by specific number of primary manifestation categories during the most recent 3-year period.

Combination	p-value
1 manifestation vs 2 manifestations	0.0054
1 manifestation vs 3 manifestations	<0.0001
1 manifestation vs ≥4 manifestations	<0.0001
2 manifestations vs 3 manifestations	0.0365
2 manifestations vs ≥4 manifestations	<0.0001
3 manifestations vs ≥4 manifestations	0.0019

n = 28 for 1 manifestation; n = 76 for 2 manifestations; n = 97 for 3 manifestations; n = 79 for ≥4 manifestations.