Congenital cleft lip and palate and elevated risks of major psychiatric disorders: A nationwide longitudinal study

Abstract

Background

Congenital cleft lip and palate (CCLP) may be associated with major psychiatric disorders, including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia, bipolar disorder, and major depressive disorder.

Methods

From the Taiwan National Health Insurance Research Database, 1,158 children and adolescents with CCLP and 11,580 age/sex-matched controls without CCLP were included in this study between 2001 and 2010; they were followed up until the end of 2011 to identify the aforementioned major psychiatric disorders.

Results

After adjustment for age, sex, income, residence, and family history, the Cox regression model revealed a positive relationship of CCLP with subsequent schizophrenia (hazard ratio [HR]: 7.60, 95% confidence interval [CI]: 2.03–28.54), ASD (HR: 6.03, 95% CI: 1.76–20.61), and ADHD (HR: 7.33, 95% CI: 5.01–10.73).

Discussion

These findings suggest that clinicians should be attentive to the presence or emergence of mental health conditions in patients with CCLP. Further studies are necessary to investigate the pathogenesis between CCLP and major psychiatric disorders.

Keywords

Cleft lip and palate autism attention deficit hyperactivity disorder schizophrenia

What is already known about this topic

(1) Congenital cleft lip and palate (CCLP) exhibits a relatively high incidence of .82–4.04 per 1,000 live births in Asians.

(2) CCLP may be associated with neurodevelopment disorders.

(3) CCLP may be associated with schizophrenia and major affective disorders.

What this study adds to the topic

(1) Children with CCLP were more likely to be diagnosed with ASD or ADHD than those without CCLP.

(2) Patients with cleft palate with cleft lip subtype exhibited the highest risks of neurodevelopment disorders and schizophrenia.

(3) Clinicians should closely monitor the mental health of patients with CCLP.

Introduction

Congenital cleft lip and palate (CCLP) are common orofacial congenital anomalies with a relatively high incidence of .82–4.04 per 1,000 live births in Asians, a moderately high incidence in Hispanic whites (.9–2.69 per 1,000 live births), and a relatively low incidence in blacks (.18–1.67 per 1,000 live births) (Shkoukani et al., 2013; Vyas et al., 2020). The exact pathogenesis of CCLP is unclear and may be genetic, including a deletion in 22q11, a missense in 3q27, and a nonsense in 11q23, with variable interactions from environmental factors such as heavy maternal drinking or fetal exposure to retinoid drugs (Shkoukani et al., 2013; Stanier & Moore, 2004; Vyas et al., 2020).

Evidence suggests that CCLP has an effect on the mental health of affected children and adolescents (Al-Namankany & Alhubaishi, 2018; Ardouin et al., 2020; Nilsson et al., 2015; Pedersen et al., 2016). Ardouin et al. assessed the emotional well-being of 207 patients with CCLP and demonstrated that patients with CCLP had lower global self-worth, higher levels of fear of negative appearance evaluations, and more depressed mood (Ardouin et al., 2020). A Danish population-based cohort study of 8,568 patients with non-syndromic CCLP found that those with CCLP were more likely to be diagnosed as having schizophrenia (hazard ratio [HR]: 1.54, 95% confidence interval [CI]: 1.15–2.06) and autism spectrum disorder (ASD; HR: 3.36, 95% CI: 2.27–4.98) but not any major affective disorder (HR: 1.22, 95% CI: .98–1.51) (Pedersen et al., 2016). Berg et al. identified a positive relationship between CCLP and ASD (relative risk [RR]: 6.6, 95% CI: 2.8–15.7) and severe learning disabilities (RR: 10.6, 95% CI: 5.5–20.2) in a Norwegian sample of 2337 individuals with syndromic or non-syndromic CCLP (Berg et al., 2016). Nilsson et al. further revealed that Swedish adolescents with syndromic or non-syndromic CCLP were more likely (odds ratio [OR]: 1.63, 95% CI: 1.08–2.46) to have been exposed to psychotropic drugs, such as antipsychotics, hypnotics, sedatives, antidepressants, and psychostimulants, compared with those without CCLP (Nilsson et al., 2015). A small-sample-size pilot study of 29 white children with non-syndromic CCLP discerned no association between CCLP and attention deficit hyperactivity disorder (ADHD) symptoms (Hopkins et al., 2015). By contrast, Zagursky reported that the prevalence of ADHD was approximately 10 times higher in patients with velocardiofacial syndrome, which is known as 22q11.2 deletion syndrome, than in the general population (Zagursky et al., 2006).

In the current study, we employed the Taiwan National Health Insurance Research Database (NHIRD), a large sample size, and a longitudinal follow-up study design to investigate the temporal association between CCLP and major psychiatric disorders including schizophrenia, bipolar disorder, major depressive disorder, ASD, and ADHD. We hypothesized that children and adolescents with CCLP are more likely to develop one or more of these major psychiatric disorders later in life compared with individuals without CCLP.

Methods

Data source

In the current study, specialized databases of behavioral health and special health care conditions of Taiwan NHIRD were used. Databases were released and audited by the Department of Health and the Bureau of the National Health Insurance (NHI) Program for the purpose of scientific research. The specialized databases of behavioral health and special health care conditions included all psychiatric medical records, including visit dates and medical diagnoses, of insured patients between 2000 and 2011, and contained the diagnostic time of insured subjects with catastrophic diseases, such as severe congenital abnormalities, between 2000 and 2011. In Taiwan, diagnostic information of severe congenital abnormalities is sent to the insurance administration for review by commissioned expert panels to confirm the diagnosis. The expert panel reviews the diagnosis. After the confirmation of diagnosis, patients are entitled to waive medical co-payment. Regarding the diagnosis of CCLP, only those who required multiple plastic surgeries and subsequent language rehabilitation were characterized as a severe congenital abnormality and included in the specialized databases of catastrophic diseases. Two databases were linked using the unique and anonymous identifier, which is assigned for every subject by the National Health Research Institutes before releasing the data to researchers. In addition, the Longitudinal Health Insurance Database, which includes all medical records of 3,000,000 insured individuals that are randomly selected from the entire Taiwanese population (∼28,000,000) between 2000 and 2011, was used for the identification of control groups in the current study. The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) was used to diagnosing diseases during the study period. The NHIRD has been used extensively in epidemiologic studies in Taiwan (Chen et al., 2015; Chen et al., 2013; Cheng et al., 2018; Liang & et al., 2020). This study was approved by the Institutional Review Board of our Hospital.

Inclusion criteria for patients with CCLP and the control group

Children and adolescents aged less than 20 years who were diagnosed as having syndromic or non-syndromic CCLP (ICD-9-CM code: 749) by board-certified pediatricians, plastic surgeons, and otorhinolaryngologists between January 1, 2001 and December 31, 2010 and who had no history of any major psychiatric disorder (ICD-9-CM codes: 295, 296, 297, 299, and 314) before enrollment were included in the CCLP cohort. The time of enrollment was defined as the first timepoint of CCLP diagnosis in the database. In addition, the subtypes of CCLP were defined based on the ICD-9-CM codes of 749.0 cleft palate, 749.1 cleft lip and 749.2 cleft palate with cleft lip. The age-, sex-, residence-, and income- -matched (1:10) control cohort was randomly identified after eliminating the study subjects, those who had been given a diagnosis of any CCLP at any time, and those with any major psychiatric disorder before enrollment. Income level (levels 1–3 per month: ≤19,100 NTD (New Taiwanese Dollars), 19,101–42,000 NTD, and ≥42,001 NTD) and urbanization level of residence (levels 1–5, most to least urbanized) were regarded as the proxies for healthcare availability in Taiwan (Liu & et al., 2006). Diagnoses of schizophrenia (ICD-9-CM code: 295), bipolar disorder (ICD-9-CM codes: 296 except 296.2x, 296.3x, 296.9x, and 296.82), major depressive disorder (ICD-9-CM codes: 296.2x, 296.3x), ASD (ICD-9-CM code: 299) and ADHD (ICD-9-CM code: 314) were identified based on the comprehensive interview and clinical judgment during the follow-up period (from enrollment to December 31, 2011, or until death). Family history of any major psychiatric disorder, including schizophrenia, bipolar disorder, major depressive disorder, ASD and ADHD, was assessed.

Statistical analysis

Regarding between-group comparisons, the F test was used for continuous variables and Pearson’s X² test for nominal variables, where appropriate. The Cox regression model with adjustment of age, sex, income, residence, and family history was used to investigate the HR with a 95% CI of any major psychiatric disorder among patients with CCLP and the control group. Subanalysis stratified by sex was further performed. A 2-tailed p value of less than .05 was considered statistically significant. All data processing and statistical analyses were performed with Statistical Analysis Software (SAS) version 9.1 (SAS Institute, Cary, NC).

Data availability statement

The NHIRD was released and audited by the Department of Health and Bureau of the NHI Program for the purpose of scientific research (https://nhird.nhri.org.tw/). NHIRD can be obtained through the formal application that is regulated by Department of Health and Bureau of the NHI Program.

Results

In all, 1,158 with children and adolescents with CCLP and 11,580 age/sex-matched controls without CCLP were included in current study, with a mean age of about ten years (Table 1). Patients with CCLP were identified as 499 (43.1%) with cleft palate only, 25 (2.2%) with cleft lip only, and 634 (54.7%) with cleft palate with cleft lip (Table 1). Patients with CCLP had higher incidence rates of subsequent schizophrenia (p = .006), ASD (p = .013) and ADHD (p < .001) than the control group (Table 1).

Table 1.

Demographic characteristics and incidences of major psychiatric disorders among patients with CCLP and controls.

	Patients with CCLP (n = 1158)	Controls (n = 11,580)	p-value
Age (years, SD)	10.48 (5.15)	10.49 (5.14)	.954
Sex (n, %)			>.999
Male	598 (51.6)	5980 (51.6)
Female	560 (48.4)	5600 (48.4)
Cleft type (n, %)
Cleft palate	499 (43.1)
Cleft lip	25 (2.2)
Cleft palate with cleft lip	634 (54.7)
Incidences of major psychiatric disorders
ASD (n, ‰)	4 (3.45)	7 (.60)	.013
Age at diagnosis (years, SD)	13.21 (9.56)	12.57 (4.39)	.881
ADHD (n, ‰)	46 (39.72)	64 (5.53)	<.001
Age at diagnosis (years, SD)	8.61 (2.86)	9.90 (3.40)	.391
Schizophrenia (n, ‰)	4 (3.45)	5 (.43)	.006
Age at diagnosis (years, SD)	17.05 (2.06)	17.66 (4.58)	.814
Bipolar disorder (n, ‰)	2 (1.73)	6 (.52)	.160
Age at diagnosis (years, SD)	19.94 (1.29)	18.62 (5.68)	.766
Major depressive disorder (n, ‰)	3 (2.59)	10 (.86)	.180
Age at diagnosis (years, SD)	19.92 (3.34)	22.20 (6.21)	.563
Family history of mental disorder (n, %)
Schizophrenia	16 (1.4)	131 (1.1)	.469
Bipolar disorder	13 (1.1)	128 (1.1)	.883
Major depressive disorder	97 (8.4)	981 (8.5)	.951
ASD	2 (.2)	46 (.4)	.317
ADHD	38 (3.3)	249 (2.2)	.014
Level of urbanization (n, %)			>.999
1 (most urbanized)	197 (17.0)	1970 (17.0)
2	346 (29.9)	3460 (29.9)
3	141 (12.2)	1410 (12.2)
4	122 (10.5)	1220 (10.5)
5 (most rural)	352 (30.4)	3520 (30.4)
Income-related insured amount (n, %)			>.999
≤19100 NTD/month	978 (84.5)	9780 (84.5)
19001–42000 NTD/month	138 (11.9)	1380 (11.9)
>42000 NTD/month	42 (3.6)	420 (3.6)

CCLP: congenital cleft lip and palate; SD: standard deviation; NTD: new Taiwan dollar; ASD: autism spectrum disorder; ADHD: attention deficit hyperactivity disorder.

The Cox regression model with adjustment of age, sex, income, residence, and family history reported a positive relationship of CCLP with subsequent schizophrenia (HR: 7.60, 95% CI: 2.03–28.54), ASD (HR: 6.03, 95% CI: 1.76–20.61), and ADHD (HR: 7.33, 95% CI: 5.01–10.73) (Table 2). Furthermore, patients with cleft palate with cleft lip subtype exhibited the highest risks of be diagnosed with ASD (HR: 14.59, 95% CI: 4.19–50.78), ADHD (HR: 9.29, 95% CI: 5.87–14.71) and schizophrenia (HR: 11.52, 95 CI: 2.71–48.95) during the follow-up (Table 2). Sex-stratified subanalysis further reported that girls with CCLP were more likely to develop major depressive disorder (HR: 10.64, 95% CI: 2.15–52.74) later in life compared with individuals without CCLP (Table 2). The Kaplan–Meier survival analyses with the log-rank test showed that patients with CCLP were more likely to develop schizophrenia, ASD and ADHD during the follow-up than did the control group (all p < .001) (Figures 1 and 2).

Table 2.

Cox regression analyses of the risks of major psychiatric disorders among patients with CCLP and controls.^a

	HR (95% CI)
	ASD	ADHD	Schizophrenia	Bipolar disorder	Major depressive disorder
CCLP	6.03 (1.76–20.61)	7.33 (5.01–10.73)	7.60 (2.03–28.54)	3.83 (.73–20.08)	3.05 (.84–11.09)
Cleft palate	n.a.	5.67 (3.35–9.60)	3.93 (.46–33.83)	4.62 (.64–33.24)	2.04 (.26–16.07)
Cleft lip	n.a.	5.78 (.80–42.08)	n.a.	n.a.	n.a.
Cleft palate with cleft lip	14.59 (4.19–50.78)	9.29 (5.87–14.71)	11.52 (2.71–48.95)	3.54 (.41–30.37)	4.27 (.93–19.70)
Controls	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)
Males
CCLP	5.16 (1.29–20.68)	6.95 (4.37–11.06)	3.57 (.68–18.78)	n.a.	n.a.
Controls	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)
Females
CCLP	8.78 (.55–140.67)	8.58 (4.35–16.92)	n.a.	4.75 (.85–26.69)	10.64 (2.15–52.74)
Controls	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)	1 (ref.)

CCLP: congenital cleft lip and palate; HR: hazard ratio; CI: confidence interval; n.a.: not available.

^aadjusting for demographic data and family history of major psychiatric disorders.

Bold type indicates statistical significance.

Figure 1.

Survival curves of developing ASD and ADHD among patients with CCLP and controls. CCLP: congenital cleft lip and palate; ASD: autism spectrum disorder; ADHD: attention deficit hyperactivity disorder.

Figure 2.

Survival curves of developing schizophrenia, bipolar disorder, and major depressive disorder among patients with CCLP and controls. CCLP: congenital cleft lip and palate.

Discussion

The study results supported the hypothesis that patients with CCLP, particularly those with cleft palate and cleft palate with cleft lip subtypes, have elevated risks of developing a neurodevelopmental disorder, including ASD, ADHD, and schizophrenia as well as major depressive disorder, during the follow-up compared with individuals without CCLP.

Epidemiological studies have revealed a positive association between CCLP and neurodevelopmental disorders in child and adolescent populations (Berg et al., 2016; Demir et al., 2011; Nopoulos et al., 2010; Pedersen et al., 2016; Wehby et al., 2012). A Norwegian cohort study of 2,860 patients treated for clefts found 12 patients with ASD (4.2‰), 24 patients with ADHD (8.4‰), 8 patients with major affective disorder (2.8‰), and 16 patients with schizophrenia (5.6‰), and revealed that only the RR (6.6, 95% CI: 2.8–15.7) of ASD was significantly increased in patients with cleft palate compared with unaffected individuals (Berg et al., 2016). Pedersen et al. demonstrated that patients with cleft palate were more likely to be diagnosed with schizophrenia (HR: 1.54, 95% CI: 1.15–2.06), ASD (HR: 3.36, 95% CI: 2.27–4.98), and behavioral and emotional disorders in childhood and adolescence (HR: 1.38, 95% CI: 1.02–1.87) (Pedersen et al., 2016). Examining the behavioral health of 104 children with CCLP aged 2–12 years, Wehby et al. found that children with CCLP had more inattention and hyperactivity symptoms than did the controls (Wehby et al., 2012). Nopoulos et al. also indicated that children with CCLP had significantly higher ratings for hyperactivity, impulsivity, and inattention on the Pediatric Behavior Scale (Nopoulos et al., 2010). Finally, Demir et al. found that major depressive disorder was more prevalent in children with CCLP than in the control group (p = .010) and reported a negative relationship between the severity of dentofacial and cleft lip nose deformities and clinical global functioning (Demir et al., 2011). Finally, one study suggested that prevalence rates of major psychiatric disorders may be higher in patients with CCLP but are often underestimated due to patient reluctance to undergo mental consultation and treatment (Tang et al., 2014).

Neurodevelopmental evidence may explain the relationship between CCLP and neurodevelopmental disorders—in particular, ASD, ADHD, and schizophrenia (Ansen-Wilson et al., 2018; Chollet et al., 2014; Nopoulos et al., 2002, 2007). Recent neuroimaging studies in humans have revealed subtle morphological brain abnormalities, especially in the frontal cortex and subcortical nuclei, in patients with CCLP (Ansen-Wilson et al., 2018; Nopoulos et al., 2007). Nopoulos et al. reported that children with CCLP had smaller frontal cortexes, temporal cortexes, subcortical nuclei (putamen, globus pallidum), and cerebellum volumes compared with healthy controls and reported that these structural abnormalities were directly related to cognitive dysfunction (Nopoulos et al., 2002, 2007). A morphometric analysis of brain shape revealed that posterior displacement of the caudate nucleus and thalamus and reorientation of the cerebellum were common in children with CCLP (Chollet et al., 2014). In a mouse model of orofacial clefts, significant disruptions in the proliferation and migration of GABA-ergic cortical interneurons were observed, leading to misspecification of the somatostatin-expressing subtype of GABAergic cortical interneurons (Ansen-Wilson et al., 2018). Structural and molecular studies have suggested that the pathophysiology of a wide range of disorders symptomatically overlap with those seen in CCLP, including neuropsychiatric illnesses and impairments of complex cognitive tasks such as working memory, sensory integration, and language skills (Ansen-Wilson et al., 2018; Chollet et al., 2014; Nopoulos et al., 2002, 2007).

The 22q11.2 deletion syndrome is caused by a 3-Mb microdeletion involving the proximal portion of the long arm of chromosome 22 within band 22q11.2 and commonly manifests as congenital heart problems, cleft lip and palate, and psychiatric symptoms. This syndrome may be an example of the overlapping genetic etiology between CCLP and psychiatric disorders, including ASD, ADHD, and schizophrenia (Tang et al., 2014; Zagursky et al., 2006). Bashir et al. reported that of 134 children with CCLP who were tested for 22q11 deletion, nine patients had positive blood results (Bashir et al., 2008). At least 30 affected genes have been mapped in 22q11.2 deletion syndrome (Zinkstok et al., 2019). For example, mutations in T-box 1 and Septin 5 were related to impaired social interaction, communication, and impaired working memory, which are characteristics of ASD and ADHD (Zinkstok et al., 2019). Mutations in the cathechol-o-methyltransferase gene were associated with increased risks of schizophrenia and major affective disorders (Zinkstok et al., 2019). Olsen et al. indicated that approximately 10% of patients with deletions or duplications on chromosome 22q11.2 had developed ADHD and ASD (Olsen et al., 2018). However, 22q11.2 deletion syndrome is only one possible mechanism because more than 400 genes associated with the occurrence of CCLP may also be involved in the pathophysiology of major psychiatric disorders (Panamonta et al., 2016).

This study has several limitations. First, only patients with severe CCLP were included for the analysis in the study. Further investigation is necessary to determine whether mild CCLP is also related to an elevated risk of subsequently developing a psychiatric disorder, such as ASD, ADHD, or schizophrenia. Second, owing to the definition of enrolled criteria based on the ICD-9-CM codes of CCLP, both syndromic and non-syndromic CCLP were included in our study. Further studies would be necessary to clarify the outcome differences between patients with syndromic CCLP and those with non-syndromic CCLP. Third, the sample size of patients with cleft lip only was small, which confounded the statistical power. Whether cleft lip may be associated with the risks of subsequent major psychiatric disorders would need further investigation. Fourth, a detection bias may exist in the current study because children with CCLP may be followed more routinely by a team of providers who might pick up on these more than the controls. Fifth, the database did not have information regarding psychosocial stress, personal lifestyle, or environmental factors; thus, we could not investigate the influences of these factors.

The analysis revealed that children and adolescents with CCLP were more likely to receive a diagnosis of ASD, ADHD, or schizophrenia compared with individuals without CCLP. Our findings indicate that clinicians should closely monitor the mental health of patients with CCLP. Further studies are necessary to understand the specific pathogenesis relating to CCLP and major psychiatric disorders.

Footnotes

Acknowledgements

The authors thank Mr I-Fan Hu, MA (Courtauld Institute of Art, University of London; National Taiwan University) for his friendship and support. Mr Hu declares no conflicts of interest.

Authors contributions

Dr MHC, Dr SJT and Dr HHH designed the study, wrote the protocol and manuscripts, Dr MHC and Dr HHH drafted the manuscript and analyzed the data, Dr KLH, Dr TPS, Dr JWH and Dr SJT assisted with the preparation and proof-reading of the manuscript, and Dr TJC and Dr MHC provided the advices on statistical analysis. All authors agreed the submission and publication of this paper.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was supported by grant from Taipei Veterans General Hospital (V111C-010, V111C-040, V111C-029), Yen Tjing Ling Medical Foundation (CI-109-21, CI-109-22, CI-110-30), Ministry of Science and Technology, Taiwan (MOST110-2314-B-075-026, MOST110-2314-B-075-024 -MY3, MOST 109-2314-B-010-050-MY3, MOST111-2314-B-075 -014 -MY2, MOST 111-2314-B-075 -013), Taipei, Taichung, Kaohsiung Veterans General Hospital, Tri-Service General Hospital, Academia Sinica Joint Research Program (VTA112-V1-6-1) and Veterans General Hospitals and University System of Taiwan Joint Research Program (VGHUST112-G1-8-1). The funding source had no role in any process of our study.

ORCID iD

Mu-Hong Chen

Author biographies

Dr. Hsiang-Hsuan Huang is a child and adolescent psychiatrist, and now, is a postdosctoral fellow in the Cai Laboratory, Department of Cell and Developmental Biology, Medical School, University of Michigan.

Dr. Ju-Wei Hsu is an assistant professor, Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan, and an assistant professor, Department of Psychiatry, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.

Dr. Kai-Lin Huang is an assistant professor, Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan, and an assistant professor, Department of Psychiatry, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.

Dr. Tung-Ping Su is a professor, Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; a professor, Department of Psychiatry, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; and a professor, Department of Psychiatry, General Cheng Hsin Hospital, Taipei, Taiwan.

Dr. Tzeng-Ji Chen is a professor, Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; a professor, Institute of Hospital and Health Care Administration, National Yang Ming Chiao Tung University, Taipei, Taiwan; and a professor, Department of Family Medicine, Taipei Veterans General Hospital, Hsinchu Branch, Hsinchu, Taiwan.

Dr. Shih-Jen Tsai is a professor, Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan, and a professor, Department of Psychiatry, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.

Dr. Mu-Hong Chen is an associate professor, Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan, and an associate professor, Department of Psychiatry, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.

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