The economic burden of tuberous sclerosis complex in UK patients with renal manifestations: a retrospective cohort study in the clinical practice research datalink (CPRD)

Figures & data

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^b
Dermatological^a^,^b	• Angiofibroma, benign skin neoplasms, naevus, 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 only due to unavailability of specific LAM diagnosis codes in CPRD-HES.

Figure 1. Patient exclusion criteria to arrive at the TSC study population and the Renal TSC study population.

Figure 2. Age and sex distribution of renal TSC and comparator cohort patients. * Age is defined at the beginning of the 3-year period.

Table 2. Renal involvement in TSC.

Age	TSC population (n = 286) Kidney involvement	n	%
<18	Yes	8	7.7
	No	96	92.3
≥18	Yes	71	39.0
	No	111	61.0
Total	Yes	79	27.6
	No	207	72.4

Figure 3. Proportions of renal TSC patients with specific renal conditions.

Table 3. Distribution of manifestations in renal TSC patients.

Age (years)	Renal TSC population (n = 79)
	PKD		Simple cyst		CKD (Stage 3–5)		Neoplasm (incl. renal angiomyolipomas)		Hypertension
	n	% (95% CI)	n	% (95% CI)	n	% (95% CI)	n	% (95% CI)	n	% (95% CI)
Total	13	16.5 (8–25)	16	20.3 (11–29)	30	38.0 (27–49)	37	46.8 (36–58)	24	30.4 (20–41)
<18	0	0	4	50.0 (5–95)	1	12.5 (0–42)	4	50.0 (5–95)	1	12.5 (0–42)
≥18	13	18.3 (9–28)	12	16.9 (8–26)	29	40.1 (29–53)	33	46.5 (35–58)	23	32.4 (21–44)
18–25	3	18.8 (0–42)	2	12.5 (0–31)	2	12.5 (0–31)	9	56.3 (29–84)	4	25.0 (1–49)
26–35	5	35.7 (7–64)	6	42.9 (13–73)	2	14.3 (0–35)	7	50.0 (20–80)	4	28.6 (2–56)
36–45	3	17.7 (0–38)	2	11.8 (0–29)	6	35.3 (10–61)	10	58.8 (33–85)	3	17.7 (0–38)
46–55	1	9.1 (0–29)	1	9.1 (0–29)	8	72.7 (41–100)	5	45.5 (10–81)	5	45.5 (10–81)
56–65	0	0 (0)	0	0 (0)	7	100	1	14.3 (0–49)	4	57.1 (8–100)
>65	1	16.7 (0–60)	1	16.7 (0–60)	4	66.7 (12–100)	1	16.7 (0–60)	3	50.0 (0–100)

Table 4. Renal-related procedures conducted in TSC and comparator patients during their entire history.

Most frequently conducted kidney related-procedures	TSC (n = 79)		Comparator (n = 395)
	n (%) of patients	95% CI	n (%) of patients	95% CI
Number of patients receiving at least one procedure (%)
Excision of lesion of kidney	6 (7.6)	2–14	0	0
Kidney transplantation	3 (3.8)	0–8	2 (0.5)	0–1
Dialysis	2 (2.5)	0–6	0	0
Nephrectomy (all)	11 (13.9)	6–22	0	0
Complete	6 (7.6)	2–14	0	0
Partial	4 (5.1)	0–10	0	0
Unspecified	5 (6.3)	1–12	0	0
Kidney embolization (all)	11 (13.9)	6–22	0	0
Emergency	2 (2.5)	0–6	0	0
Elective	8 (10.1)	3–17	0	0
Patients not receiving any procedures	56 (70.9)	61–81	393 (99.5)	99–100
Average number of kidney-related procedures per patient, (95% CI)	0.9	0–2	0	0

Table 5. Renal-related tests and investigations conducted in TSC and comparator patients during their entire history.

Most frequently conducted tests and investigations	TSC(n = 79)		Comparator(n = 395)
	n (%) of patients	95% CI	n (%) of patients	95% CI
Number of patients receiving at least test or investigation (%)
Routine tests
Computed tomography (CT)	28 (35.4)	25–46	30 (7.6)	5–10
Magnetic resonance (MRI)	18 (22.8)	13–32	12 (3.0)	1–5
Ultrasound	30 (38.0)	27–49	53 (13.4)	10–17
As required tests
Electrocardiogram (ECG)	16 (20.3)	11–29	28 (7.1)	5–10
Electroencephalography (EEG)	11 (13.9)	6–22	5 (1.3)	0–2
Patients not receiving any tests	22 (27.9)	18–38	296 (74.9)	71–79
Mean number of tests and investigations per patient	2.3	2–3	0.5	0–1

Table 6. Primary and secondary healthcare encounters in TSC and comparator cohort during the most recent 3-year period.

	TSC (n = 79)		Comparator (n = 395)
	Average number of visits per patient	95% CI	Average number of visits per patient	95% CI
Mean number of GP visits per patient, by category and consultation
All GP visits^a	81.7	61–102	30.2	26–34
Clinic visits	48.4	37–60	18.7	16–21
Home visits	0.5	0–1	0	0
Other^b	31.0	22–40	10.4	9–12
Out of hours	0.6	0–1	0.2	0
Telephone	1.3	1–2	0.9	1–1
Mean number of inpatient admissions per patient, by category of admission
All admissions	3.2	2–4	1.6	1–2
A&E admission	1.5	1–2	0.5	0–1
Elective admission	1.6	1–2	0.9	1
Other admission	0.1	0	0.2	0
Mean number of outpatient visits per patient, by frequented specialty
All outpatient visits	15.4	12–19	5.7	5–7
Nephrology	1.6	1–2	0.1	0
Urology	0.9	0–1	0.1	0

^a Analyses exclude administration encounters. When administration encounters are added to the overall cohorts, the total visits on average per patient are 100.72 for TSC and 38.09 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 4. Mean costs per renal TSC patient over the 3-year period by type of healthcare resource used. *Only includes the cost of GP visits (costs of tests conducted at the GP practice are not included). †Costs including GP administration encounters: £3,967 TSC vs £1,505 comparator. ‡Total including GP administration encounters: £15,695 TSC vs £4,765 comparator.

Figure 5. Cost of additional manifestation categories to renal TSC patients.

Table 7. Model 1: Key drivers of direct costs in renal TSC patients during the most recent 3-year period.

Variable	p-value
Single manifestation categories
Brain	0.6108
Circulatory	0.3910
Dermatological	0.7870
Nervous system	0.0279
Psychiatric	0.3128
Respiratory	0.1930
Combinations of manifestation categories
Brain/Circulatory	0.1732
Brain/Dermatological	0.2036
Brain/Psychiatric	0.6486
Dermatological/Circulatory	0.6159
Dermatology/Psychiatric	0.0246
Nervous system/Brain	0.1140
Nervous system/Circulatory	0.9934
Nervous system/Dermatological	0.1653
Nervous system/Psychiatric	0.3771

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

Table 8. Model 2: Key drivers of direct costs in renal TSC during the most recent 3-year period.

Parameter^a	p-value
Age (<18 and ≥18)*	0.2863
Sex	0.2252
Number of manifestation categories	<0.0001

^a All parameters include the total renal TSC cohort with 3-years of continuous data (n = 79).

Table 9. Model 2: Drivers of direct costs in renal TSC by specific number of primary manifestation categories during the most recent 3-year period.

Combination^a	p-value
1 manifestation vs 2 manifestations	0.2566
1 manifestation vs 3 manifestations	0.3018
1 manifestation vs ≥4 manifestations	0.0051
2 manifestations vs 3 manifestations	0.8033
2 manifestations vs ≥4 manifestations	0.0019
3 manifestations vs ≥4 manifestations	<0.0001

^a n = 2 for 1 manifestation; n = 9 for 2 manifestations; n = 16 for 3 manifestations; n = 52 for ≥4 manifestations.