Background
Methods
Results
Patient demographics
Total | Mortality group | Surviving group | ||
---|---|---|---|---|
N | N | N | P value | |
471 | 14 (3.0%) | 457 (97.0%) | ||
Sex, n (%) | ||||
Male | 232 (49.3) | 8 (57.1) | 224 (49.0) | |
Female | 239 (50.7) | 6 (42.9) | 233 (51.0) | 0.5970 |
Age at endpoint (death or end of queried period), years | ||||
Mean (SD) | 20.9 (13.3) | 32.4 (17.3) | 20.4 (13.0) | < 0.0001 |
Median (IQR) | 17.8 (11.5–27.2) | 32.8 (23.4–43.8) | 17.5 (11.3–26.4) | 0.0006 |
Cohorts by age at endpoint, n (%) | ||||
< 1 year | 2 (0.4) | 1 (7.1) | 1 (0.2) | |
1–18 years old | 235 (49.9) | 2 (14.3) | 233 (51.0) | |
19–40 years old | 196 (41.6) | 6 (42.9) | 190 (41.6) | |
> 40 years old | 38 (8.1) | 5 (35.7) | 33 (7.2) | < 0.0001 |
Age at enrollment (date of CIC acquisition), years | ||||
Mean (SD) | 15.0 (13.8) | 29.7 (17.8) | 14.5 (13.4) | < 0.0001 |
Median (IQR) | 10.9 (4.1–21.9) | 31.6 (16.6–42.6) | 10.8 (4.0–21.3) | 0.0015 |
Cohorts by age at enrollment, n (%) | ||||
< 1 year | 36 (7.6) | 1 (7.1) | 35 (7.7) | |
1–18 years old | 279 (59.2) | 3 (21.4) | 276 (60.4) | |
19–40 years old | 129 (27.4) | 5 (35.7) | 124 (27.1) | |
> 40 years old | 27 (5.7) | 5 (35.7) | 22 (4.8) | < 0.0001 |
≤ 18 years old | 315 (66.9) | 4 (28.6) | 311 (68.1) | |
> 18 years old | 156 (33.1) | 10 (71.4) | 146 (31.9) | 0.0034 |
Survived time from enrollment to endpoint, years | ||||
Mean (SD) | 5.8 (3.4) | 2.6 (2.1) | 5.9 (3.4) | 0.0003 |
Median (IQR) | 5.5 (3.1–8.1) | 2.2 (0.7–3.4) | 5.6 (3.2–8.1) | 0.0002 |
Total | 2749.11 | 2712.29 | 36.82 | |
Comorbidity (ICD-9-CM diagnostic codes queried), n (%) | ||||
Neurological symptoms | ||||
Epilepsy (345.x) | 361 (76.6) | 10 (71.4) | 351 (76.8) | 0.7479 |
Cerebral degenerations (331.x) | 8 (1.7) | 0 (0.0) | 8 (1.8) | 1.0000 |
Multiple sclerosis (340.x) | 24 (5.1) | 1 (7.1) | 23 (5.0) | 0.5242 |
Infantile cerebral palsy (343.x) | 47 (10.0) | 2 (14.3) | 45 (9.8) | 0.6405 |
Other congenital nervous system anomalies (742.x) | 142 (30.1) | 3 (21.4) | 139 (30.4) | 0.5679 |
TANDs | ||||
Dementias (290.x, 291.x, 294.x) | 31 (6.6) | 1 (7.1) | 30 (6.6) | 1.0000 |
Psychotic conditions (293.x–299.x) | 73 (15.5) | 1 (7.1) | 72 (15.8) | 0.7062 |
Neurotic disorders (300.x) | 22 (4.7) | 0 (0.0) | 22 (4.8) | 1.0000 |
Depression (311.x) | 6 (1.3) | 0 (0.0) | 6 (1.3) | 1.0000 |
ADHD (314.x) | 31 (6.6) | 0 (0.0) | 31 (6.8) | 0.6136 |
Developmental delays (315.x–319.x) | 151 (32.1) | 1 (7.1) | 150 (32.8) | 0.0442 |
Any malignant neoplasms (140.x–195.x) | 167 (35.5) | 5 (35.7) | 162 (35.4) | 1.0000 |
Oral and pharyngeal cancers (140.x–149.x) | 34 (7.2) | 1 (7.1) | 33 (7.2) | 1.0000 |
Cardiac cancer (164.1) | 5 (1.1) | 0 (0.0) | 5 (1.1) | 1.0000 |
Urological cancers (189.x) | 11 (2.3) | 1 (7.1) | 10 (2.2) | 0.2851 |
Brain cancer (191.x) | 18 (3.8) | 0 (0.0) | 18 (3.9) | 1.0000 |
Benign tumours | ||||
Benign skin tumours (216.x) | 14 (3.0) | 0 (0.0) | 14 (3.1) | 1.0000 |
Benign urological tumours (223.x) | 22 (4.7) | 3 (21.4) | 19 (4.2) | 0.0231 |
Benign brain tumours (225.x) | 13 (2.8) | 1 (7.1) | 12 (2.6) | 0.3280 |
Other systemic manifestations | ||||
Any renal diseases (403.x, 404.x, 580.x-586.x) | 30 (6.4) | 3 (21.4) | 27 (5.9) | 0.0527 |
Myocardial infarction (410.x, 411.x) | 1 (0.2) | 0 (0.0) | 1 (0.2) | 1.0000 |
Cerebrovascular diseases (430.x-433.x, 435.x) | 2 (0.4) | 0 (0.0) | 2 (0.4) | 1.0000 |
Peptic ulcers (531.x-534.x) | 10 (2.1) | 1 (7.1) | 9 (2.0) | 0.2627 |
Diabetes mellitus (250.x) | 5 (1.1) | 0 (0.0) | 5 (1.1) | 1.0000 |
LAM (516.4) | 3 (0.7) | 0 (0.0) | 3 (0.0) | 1.0000 |
Enrollment age cohorts | P value | Sex cohorts | P value | |||
---|---|---|---|---|---|---|
Enrollment age ≤ 18 | Enrollment age > 18 | Males | Females | |||
Survival time after enrollment (mortality group) | ||||||
Mean (SD) | 3.7 (2.8) | 2.2 (1.9) | 0.2743 | 1.6 (1.5) | 4.0 (2.2) | 0.0356 |
Median (IQR) | 3.8 (1.8–5.5) | 2.0 (0.7–3.0) | 0.2579 | 1.3 (0.3–2.7) | 3.2 (2.0–6.7) | 0.0707 |
Mortality rates and IRR | ||||||
Death/total subjects | 4/315 (1.27) | 10/156 (6.41) | 8/232 (3.45) | 6/239 (2.51) | ||
Person-years survived for all subjects | 2038.64 | 711.53 | 1385.37 | 1364.79 | ||
MR per 1000 person-years | 1.96 | 14.05 | 5.77 | 4.40 | ||
95% CI | 1.88–2.05 | 13.06–15.13 | 5.48–6.09 | 4.17–4.64 | ||
Crude IRR | 1.00 | 7.16 | 0.0009 | 1.00 | 0.76 | 0.6136 |
95% CI | 2.25–22.84 | 0.26–2.19 | ||||
Adjusted IRR | 1.00 | 6.60 | 0.0025 | 1.00 | 0.72 | 0.5461 |
95% CI | 1.95–22.4 | 0.25–2.09 | ||||
Comorbidities, n (% of cohort) | ||||||
Neurological symptoms | ||||||
Epilepsy | 259 (82.2) | 102 (65.4) | < 0.0001 | 182(78.4) | 179(74.9) | 0.3848 |
Cerebral degenerations | 4 (1.3) | 4 (2.6) | 0.4491 | 4 (1.7) | 4 (1.7) | 1.00 |
Multiple Sclerosis | 14 (4.4) | 10 (6.4) | 0.3781 | 13 (5.6) | 11 (4.6) | 0.68 |
Infantile cerebral palsy | 44 (14.0) | 3 (1.9) | < .0001 | 23 (9.9) | 24 (10.0) | 1.00 |
Other congenital nervous system anomalies | 110 (34.9) | 32 (20.5) | 0.0013 | 67 (28.9) | 75 (31.4) | 0.62 |
TANDs | ||||||
Dementias | 10 (3.2) | 21 (13.5) | < 0.0001 | 19(8.2) | 12(5) | 0.1948 |
Psychotic conditions | 42 (13.3) | 31 (19.9) | 0.065 | 42 (18.1) | 31 (13.0) | 0.13 |
Neurotic disorders | 6 (1.9) | 16 (10.3) | 0.0001 | 12 (5.2) | 10 (4.2) | 0.67 |
Depression | 1 (0.3) | 5 (3.2) | 0.0167 | 2 (0.9) | 4 (1.7) | 0.68 |
ADHD | 31 (9.8) | 0 (0.0) | < 0.0001 | 17 (7.3) | 14 (5.9) | 0.58 |
Development delays | 135 (42.9) | 16 (10.3) | < 0.0001 | 78 (33.6) | 73 (30.5) | 0.49 |
Any malignant neoplasms | 116 (36.8) | 51 (32.7) | 0.4135 | 77(33.2) | 90(37.7) | 0.3359 |
Oral and pharyngeal cancer | 29 (9.2) | 5 (3.2) | 0.0218 | 17 (7.3) | 17 (7.1) | 1.00 |
Cardiac cancer | 4 (1.3) | 1 (0.6) | 1.0000 | 2 (0.9) | 3 (1.3) | 1.00 |
Urological cancer | 4 (1.3) | 7 (4.5) | 0.0469 | 6 (2.6) | 5 (2.1) | 0.77 |
Brain cancer | 11 (3.5) | 7 (4.5) | 0.6146 | 7 (3.0) | 11 (4.6) | 0.47 |
Benign tumours | ||||||
Benign skin tumours | 6 (1.9) | 8 (5.1) | 0.0796 | 6 (2.6) | 8 (3.3) | 0.79 |
Benign urological tumours | 5 (1.6) | 17 (10.9) | < 0.0001 | 5 (2.2) | 17 (7.1) | 0.01 |
Benign brain tumours | 8 (2.5) | 5 (3.2) | 0.7667 | 7 (3.0) | 6 (2.6) | 0.78 |
Other systemic manifestations | ||||||
Any renal diseases | 7 (2.2) | 23 (14.7) | < 0.0001 | 13(5.6) | 17(7.1) | 0.5734 |
Myocardial infarction | 1 (0.3) | 0 (0.0) | 1.0000 | 1(0.4) | 0(0) | 0.4926 |
Cerebrovascular diseases | 1 (0.3) | 1 (0.6) | 0.5532 | 1(0.4) | 1(0.4) | 1.0000 |
Peptic ulcers | 4 (1.3) | 6 (3.8) | 0.0893 | 5(2.2) | 5(2.1) | 1.0000 |
Diabetes mellitus | 1 (0.3) | 4 (2.6) | 0.0434 | 2(0.9) | 3(1.3) | 1.0000 |
LAM | 0 (0.0) | 3 (0.0) | 1.0000 | 1 (0.4) | 2 (0.9) | 1.0000 |
Comorbidity
Life table, SMR
Age at endpoint | TSC patients | Deaths | Probability of death | Expected survivals in hypothetical group | Expected deaths in hypothetical group | Person-years lived between this age group until the next | Total number of person-years lived above age of age group | ARL |
---|---|---|---|---|---|---|---|---|
(a) | ||||||||
< 1 | 2 | 1 | 0.50 | 100,000 | 50,000 | 57,500 | 1,794,804 | 17.95 |
1–18 | 235 | 2 | 0.16 | 50,000 | 7,843 | 921,569 | 1,737,304 | 34.75 |
19–40 | 196 | 6 | 0.47 | 42,157 | 19,761 | 645,527 | 815,735 | 19.35 |
> 40 | 38 | 5 | 1.00 | 22,396 | 22,396 | 170,208 | 170,208 | 7.60 |
(b) | ||||||||
< 1 | 36 | 1 | 0.03 | 100,000 | 2,778 | 97,639 | 3,169,221 | 31.69 |
1–18 | 279 | 3 | 0.19 | 97,222 | 18,878 | 1,755,663 | 3,071,582 | 31.59 |
19–40 | 129 | 5 | 0.56 | 78,344 | 43,768 | 1,129,206 | 1,315,919 | 16.80 |
> 40 | 27 | 5 | 1.00 | 34,576 | 34,576 | 186,713 | 186,713 | 5.40 |
Year | TSC patients | Number of deaths in Taiwan | Population of Taiwan | MR in the general population | Expected deaths (TSC x MR) | Observed deaths in TSC patients |
---|---|---|---|---|---|---|
1997 | 8 | 121,000 | 21,742,815 | 0.0056 | 0.04 | 0 |
1998 | 20 | 123,180 | 21,928,591 | 0.0056 | 0.11 | 0 |
1999 | 21 | 126,113 | 22,092,387 | 0.0057 | 0.12 | 0 |
2000 | 19 | 125,958 | 22,276,672 | 0.0057 | 0.11 | 0 |
2001 | 23 | 127,647 | 22,405,568 | 0.0057 | 0.13 | 0 |
2002 | 36 | 128,636 | 22,520,776 | 0.0057 | 0.21 | 0 |
2003 | 57 | 130,801 | 22,604,550 | 0.0058 | 0.33 | 2 |
2004 | 23 | 135,092 | 22,689,122 | 0.0060 | 0.14 | 0 |
2005 | 65 | 139,398 | 22,770,383 | 0.0061 | 0.40 | 2 |
2006 | 50 | 135,839 | 22,876,527 | 0.0059 | 0.30 | 2 |
2007 | 44 | 141,111 | 22,958,360 | 0.0061 | 0.27 | 2 |
2008 | 43 | 143,624 | 23,037,031 | 0.0062 | 0.27 | 2 |
2009 | 39 | 143,582 | 23,119,772 | 0.0062 | 0.24 | 3 |
2010 | 23 | 145,772 | 23,162,123 | 0.0063 | 0.14 | 1 |
Total | 471 | 2.97%/14 years 0.21%/years | 2.81/14 years | 14/14 years | ||
MR | SMR (95% CI) | 4.99 (2.34–7.60) P = 0.0028 |
Mortality: MR, IRR, and associated HR
Mortality, n (%) | Total patients | Log-rank test | Crude HR (95% CI) | P value | Adjusted HR (95% CI) | P value | |
---|---|---|---|---|---|---|---|
Enrollment age | |||||||
≤ 18 | 4 (1.26) | 315 | 1.00 | 1.00 | |||
> 18 | 10 (6.42) | 156 | 0.0003 | 6.54 (2.03–21.04) | 0.0016 | 5.97 (1.74–20.47) | 0.0045 |
Sex | |||||||
Males | 8 (3.44) | 232 | 1.00 | 1.00 | |||
Females | 6 (2.52) | 239 | 0.6011 | 0.75 (0.26–2.18) | 0.6023 | 0.69 (0.24–2.02) | 0.4971 |
Comorbidity | |||||||
Neurological symptoms | |||||||
Epilepsy | |||||||
No | 4 (3.64) | 110 | 1.00 | 1.00 | |||
Yes | 10 (2.78) | 361 | 0.3575 | 0.58 (0.18–1.87) | 0.3633 | 0.84 (0.25–2.82) | 0.7829 |
Cerebral degenerations | |||||||
No | 14 (3.0) | 463 | 1.00 | 1.00 | |||
Yes | 0 (0.0) | 8 | 0.6026 | – | – | – | – |
Multiple sclerosis | |||||||
No | 13 (2.9) | 447 | 1.00 | 1.00 | |||
Yes | 1 (4.2) | 24 | 0.9193 | 1.11 (0.14–8.52) | 0.9193 | 1.24 (0.12–12.52) | 0.8554 |
Infantile cerebral palsy | |||||||
No | 12 (2.8) | 424 | 1.00 | 1.00 | |||
Yes | 2 (4.3) | 47 | 0.7852 | 1.23 (0.27–5.52) | 0.7855 | 6.03 (0.97–37.46) | 0.0540 |
Other congenital nervous system anomalies | |||||||
No | 11 (3.3) | 329 | 1.00 | 1.00 | |||
Yes | 3 (2.1) | 142 | 0.2588 | 0.49 (0.13–1.75) | 0.2689 | 0.78 (0.17–3.69) | 0.7567 |
TANDs | |||||||
Dementias | |||||||
No | 13 (2.96) | 440 | 1.00 | 1.00 | |||
Yes | 1 (3.22) | 31 | 0.9931 | 1.01 (0.13–7.72) | 0.993 | 0.5 (0.06–3.97) | 0.5119 |
Psychotic conditions | |||||||
No | 13 (3.3) | 398 | 1.00 | 1.00 | |||
Yes | 1 (1.4) | 73 | 0.3052 | 0.36 (0.05–2.76) | 0.3261 | – | – |
Neurotic disorders | |||||||
No | 14 (3.1) | 449 | 1.00 | 1.00 | |||
Yes | 0 (0.0) | 22 | 0.3789 | – | – | – | – |
Depression | |||||||
No | 14 (3.0) | 465 | 1.00 | 1.00 | |||
Yes | 0 (0.0) | 6 | 0.6456 | – | – | – | – |
ADHD | |||||||
No | 14 (3.2) | 440 | 1.00 | 1.00 | |||
Yes | 0 (0.0) | 31 | 0.2862 | – | – | – | – |
Developmental delays | |||||||
No | 13 (4.1) | 320 | 1.00 | 1.00 | |||
Yes | 1 (0.7) | 151 | 0.0270 | 0.14(0.02–1.07) | 0.0583 | 0.24 (0.02–2.34) | 0.2195 |
Any malignant neoplasms | |||||||
No | 9 (2.96) | 304 | 1.00 | 1.00 | |||
Yes | 5 (3.00) | 167 | 0.5822 | 0.73 (0.24–2.22) | 0.5836 | 0.62 (0.19–2.07) | 0.4413 |
Oral & pharyngeal cancer | |||||||
No | 13 (3.0) | 437 | 1.00 | 1.00 | |||
Yes | 1 (2.9) | 34 | 0.7634 | 0.73(0.1–5.63) | 0.7647 | 1.14 (0.1–12.48) | 0.9161 |
Cardiac cancer | |||||||
No | 14 (3.0) | 466 | 1.00 | 1.00 | |||
Yes | 0 (0.0) | 5 | 0.7087 | – | – | – | – |
Urological cancer | |||||||
No | 13 (2.8) | 460 | 1.00 | ||||
Yes | 1 (9.1) | 11 | 0.2763 | 2.94 (0.38–22.49) | 0.2993 | 1.87 (0.17–21.26) | 0.6121 |
Brain cancer | |||||||
No | 14 (3.1) | 453 | 1.00 | 1.00 | |||
Yes | 0 (0.0) | 18 | 0.4122 | – | – | – | – |
Benign tumours | |||||||
Benign skin tumour | |||||||
No | 14 (3.1) | 457 | 1.00 | 1.00 | |||
Yes | 0 (0.0) | 14 | 0.4934 | – | – | – | – |
Benign urological tumour | |||||||
No | 11 (2.4) | 449 | 1.00 | 1.00 | |||
Yes | 3 (13.6) | 22 | 0.0016 | 6.11 (1.70–22.03) | 0.0057 | 3.34 (0.72–15.64) | 0.1250 |
Benign brain tumour | |||||||
No | 13 (2.8) | 458 | 1.00 | 1.00 | |||
Yes | 1 (7.7) | 13 | 0.3333 | 2.63 (0.34–20.1) | 0.3519 | 5.85 (0.52–66.02) | 0.1533 |
Other systemic manifestations | |||||||
Any renal diseases | |||||||
No | 11 (2.50) | 441 | 1.00 | 1.00 | |||
Yes | 3 (10.00) | 30 | 0.0149 | 4.29 (1.19–15.41) | 0.0256 | 2.25 (0.53–9.51) | 0.2688 |
Myocardial infarctions | |||||||
No | 14 (2.98) | 470 | 1.00 | 1.00 | |||
Yes | 0 (0.00) | 1 | 0.8690 | – | – | – | |
Cerebrovascular diseases | |||||||
No | 14 (2.98) | 469 | 1.00 | 1.00 | |||
Yes | 0 (0.00) | 2 | 0.8429 | – | – | – | |
Peptic ulcers | |||||||
No | 13 (2.82) | 461 | 1.00 | 1.00 | |||
Yes | 1 (10.00) | 10 | 0.3113 | 2.74 (0.36–21.08) | 0.3316 | 1.75 (0.18–17.48) | 0.6327 |
Diabetes mellitus | |||||||
No | 14 (3.00) | 466 | 1.00 | 1.00 | |||
Yes | 0 (0.00) | 5 | 0.6947 | – | – | – | |
LAM | |||||||
No | 14 (3.00) | 468 | 1.00 | 1.00 | |||
Yes | 0 (0.00) | 3 | – | – | – | – |