Obsessive-compulsive disorder (OCD) is a severe and chronic mental disorder characterized by recurrent intrusive obsessive thoughts and repetitive compulsive behaviors that the individual feels driven to perform. The World Health Organization placed OCD among the 10 most disabling conditions worldwide (Murray & Lopez, Reference Murray and Lopez1996), with a lifetime prevalence of 1–3% (Kessler et al., Reference Kessler, Berglund, Demler, Jin, Merikangas and Walters2005).
Family studies demonstrated that OCD is familial and highly hereditary. It is found to be five to seven times more frequent in relatives of OCD probands than in relatives of control subjects (Hanna, Himle, Curtis, & Gillespie, Reference Hanna, Himle, Curtis and Gillespie2005; Nestadt et al., Reference Nestadt, Samuels, Riddle, Bienvenu, Liang, LaBuda and Hoehn-Saric2000). In addition, the risk for OCD decreased as the genetic distance to the relatives increased (Mataix-Cols et al., Reference Mataix-Cols, Boman, Monzani, Ruck, Serlachius, Langstrom and Lichtenstein2013). Taylor et al. included 37 samples composed of 24 161 twin pairs from 14 published studies to examine the heritability of OC behaviors. This meta-analysis suggested that additive genetic variance and non-shared environment factors contribute to most of the variance in OC behaviors (40% and 51%, respectively) (Taylor, Reference Taylor2011). These lines of evidence indicated that genetic factors play a part in the manifestation of OCD (Pauls, Abramovitch, Rauch, & Geller, Reference Pauls, Abramovitch, Rauch and Geller2014). In these decades, studies increasingly reported other major psychiatric disorders that either commonly co-occur with OCD or have overlapping obsessive-compulsive symptoms. The most frequently co-occurring condition is major depressive disorder (MDD) (Murphy et al., Reference Murphy, Moya, Fox, Rubenstein, Wendland and Timpano2013). Furthermore, OCD can co-occur with other mental disorders, such as schizophrenia and bipolar disorder (Angst et al., Reference Angst, Gamma, Endrass, Hantouche, Goodwin, Ajdacic and Rossler2005; Eisen, Beer, Pato, Venditto, & Rasmussen, Reference Eisen, Beer, Pato, Venditto and Rasmussen1997; Kruger, Cooke, Hasey, Jorna, & Persad, Reference Kruger, Cooke, Hasey, Jorna and Persad1995; Tibbo & Warneke, Reference Tibbo and Warneke1999). Findings that certain psychiatric disorders are highly co-morbid with and familially related to OCD may suggest an overlapping genetic relationship.
Only a few studies explored the familial coaggregation of OCD with other major psychiatric disorders. In a longitudinal and multigenerational family study by linking the national Swedish registers, Cederlöf et al. found that the first-degree relatives (FDRs) of OCD probands had an increased risk for schizophrenia [risk ratio (RR) 1.9, 95% confidence interval (CI) 1.6–2.1] and bipolar disorder [RR 1.7, 95% CI 1.6–1.9] across different kinships (parents, offspring, and siblings) (Cederlof et al., Reference Cederlof, Lichtenstein, Larsson, Boman, Ruck, Landen and Mataix-Cols2015). Another study indicated that offspring of bipolar parents had higher estimated morbidity risks of OCD compared with the controls (Henin et al., Reference Henin, Biederman, Mick, Sachs, Hirshfeld-Becker, Siegel and Nierenberg2005). Bienvenu et al. supported a familial coaggregation between OCD and MDD (Bienvenu et al., Reference Bienvenu, Samuels, Wuyek, Liang, Wang, Grados and Nestadt2012). However, studies with small sample sizes showed inconsistent results for familial coaggregation (Carter, Pollock, Suvak, & Pauls, Reference Carter, Pollock, Suvak and Pauls2004; Fyer, Lipsitz, Mannuzza, Aronowitz, & Chapman, Reference Fyer, Lipsitz, Mannuzza, Aronowitz and Chapman2005; Nestadt et al., Reference Nestadt, Samuels, Riddle, Liang, Bienvenu, Hoehn-Saric and Cullen2001). There is also evidence of shared familiality and heritability between OCD, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD). Geller et al. reported that the risk for OCD was elevated only among FDRs of probands with ADHD and OCD (13.0%) compared with the controls (0.5%; p < 0.001) (Geller et al., Reference Geller, Petty, Vivas, Johnson, Pauls and Biederman2007). Hollander et al. found that children who scored high on the repetitive behavior domain were more likely to have one or both parents with OCD compared with children who had low total scores on this domain (Hollander, King, Delaney, Smith, & Silverman, Reference Hollander, King, Delaney, Smith and Silverman2003). In a family history study of 99 autistic probands, Bolton et al. revealed an increased incidence of OCD in FDRs of autistic probands, while the comparison group was 36 patients with Down syndrome (Bolton, Pickles, Murphy, & Rutter, Reference Bolton, Pickles, Murphy and Rutter1998). The aforementioned studies provided evidence for the familial coaggregation between OCD and other major psychiatric disorders with limited sample sizes. Besides, comparison across these studies was hampered by the use of different diagnostic criteria and varying analytical methods. There is a need to clarify the familial coaggregation between OCD and major psychiatric disorders in FDRs with a population-based large-sample study design.
In our study, using the Taiwan National Health Insurance Research Database (NHIRD) with the whole population sample size, we investigated the risks of schizophrenia, bipolar disorder, MDD, ADHD, ASD, and OCD among the FDRs, including their parents, offspring, siblings, and twins, of patients with OCD compared with the total population. We hypothesized that the FDRs of patients with OCD would be more likely to have OCD and other major psychiatric disorders, including schizophrenia, bipolar disorder, MDD, ADHD, and ASD, compared with the total population.
Methods
Data source
The Taiwan National Health Insurance (NHI) program, established in 1995, is a mandatory universal system, providing compulsory health insurance to almost all residents of Taiwan (approximately 23 million people); its coverage rate was ~99.6% at the end of 2010. The National Health Research Institute (NHRI) audits and releases the NHIRD for scientific and study purposes. Claims data of subjects included in the NHIRD are anonymous to maintain individual privacy. Comprehensive information on insured subjects is included in the database, including demographic data (date of birth, sex, residential location, income status, family relationships) and claims data (outpatient and inpatient care, medical diagnoses, prescriptions). To protect the personal privacy, every individual is assigned a unique and anonymous identifier by the NHRI before releasing the data to researchers; thus, every individual can be followed continuously using the unique identifier. A nationwide database with a large sample size can minimize selection bias. Using a unique personal identification number assigned to each resident in Taiwan, all of the information is linked together. Following Kuo et al.'s and Cheng et al.'s method, the recorded family kinships in the NHIRD were used for genealogy reconstruction (Cheng et al., Reference Cheng, Chang, Chen, Tsai, Su, Li and Bai2018; Kuo et al., Reference Kuo, Grainge, Valdes, See, Luo, Yu and Doherty2015). Based on the National Health Insurance Act and rules, unemployed spouse, parents and grandparents who are unemployed, offspring or grandchildren with either ‘under 20 years and unemployed’ (including those in school) or ‘over 20 years but incapable of making a living’ would be indicated as dependents of the insured person. To get dependent status is a rigorous procedure of the civilian registration. With unique personal identifiers, we can identify the following family relationship groups: parents, offspring, siblings, and twins. The sibling relationship was confirmed if subjects had the same father or mother. Siblings were identified as twins if they shared a birth date; however, twin zygosity could not be determined from the NHIRD (Cheng et al., Reference Cheng, Chang, Chen, Tsai, Su, Li and Bai2018; Kuo et al., Reference Kuo, Grainge, Valdes, See, Luo, Yu and Doherty2015). Each subject may have several types of relationships in a family. 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 many epidemiologic studies in Taiwan (Chen et al., Reference Chen, Su, Chen, Hsu, Huang, Chang and Bai2013, Reference Chen, Lan, Hsu, Huang, Su, Li and Bai2016, Reference Chen, Hsu, Huang, Bai, Ko, Su and Chen2018; Cheng et al., Reference Cheng, Chang, Chen, Tsai, Su, Li and Bai2018). This study protocol was reviewed and approved by the Institutional Review Board of Taipei Veterans General Hospital.
Inclusion criteria and disease classifications
All individuals with OCD (ICD-9-CM code: 300.3) given by board-certificated psychiatrists were identified between 1 January 2001 and 31 December 2010 as the OCD patients. FDRs of patients with OCD, including parents, offspring, siblings, and twins, were assessed for the presence or absence of major psychiatric disorders. Major psychiatric disorders included MDD (ICD-9-CM codes: 296.2 and 296.3), bipolar disorder (ICD-9-CM: 296 except 296.2, 296.3, 296.9, and 296.82), schizophrenia (ICD-9-CM code: 295), ASD (ICD-9-CM code: 299), ADHD (ICD-9-CM code: 314), and OCD. These psychiatric disorders were diagnosed at least twice by board-certificated psychiatrists based on their clinical judgment and comprehensive diagnostic interviews.
Assessment of covariates
Demographic data, including age, sex, place of residence, and income status in 2010, are displayed in Table 1 and were adjusted in our study. The place of residence was classified into five categories according to the level of urbanization (Liu et al., Reference Liu, Hung, Chuang, Chen, Weng, Liu and Liang2006).
Baseline characteristics of the FDRs of patients with OCD and total population
OCD, obsessive-compulsive disorder; s.d., standard deviation; USD, US dollar.
Statistical analysis
We used independent t tests for continuous variables and Pearson's χ2 tests for categorical variables to assess the differences between the FDRs of patients with OCD and the total population. The relative risks (RRs) and 95% CIs were calculated to determine the risks of the major psychiatric disorders (ASD, ADHD, schizophrenia, bipolar disorder, MDD, and OCD) between FDRs of patients with OCD and the total population. We adjusted for demographic data (age, sex, residence, and income). Since all of these mental disorders are known to be familial, two sensitivity analyses were performed: the adjustment of five psychiatric comorbidities of OCD probands in model 1 and the exclusion of five psychiatric comorbidities of OCD probands in model 2. The RRs of major psychiatric disorders for each specific type of familial relationship (parents, offspring, siblings, and twins) were calculated as the prevalence of each major psychiatric disorder among FDRs of patients with OCD divided by the prevalence among FDRs of individuals without OCD. The clustering effect from the measurements taken on multiple subjects within one family may exist in our study. To manage the clustering effect, modified Poisson regression analysis with the robust variance estimation was used to estimate the RRs in the clustered data (Yelland, Salter, & Ryan, Reference Yelland, Salter and Ryan2011; Zou, Reference Zou2004). We further assessed the dose-dependent relationship between the risks of major psychiatric disorders and the numbers (1 or ⩾2) of OCD probands because the risk for OCD among relatives of OCD probands has been found to increase proportionally to the degree of genetic relatedness. Finally, subanalyses stratified by each relationship (parents, offspring, siblings, and twins) were conducted to investigate the RRs and 95% CIs of the major psychiatric disorders between FDRs of individuals with or without OCD. All tests were two-tailed and results with p < 0.05 were considered statistically significant. All statistical analyses were performed using SPSS Version 21.0 for Windows (IBM, Armonk, NY, USA) and SAS Version 9.2 (SAS Institute, Cary, NC, USA).
Results
We identified 23 258 175 individuals in the total population (49% male) and 89 500 FDRs of patients with OCD (Table 1). FDRs of patients with OCD had a higher prevalence of schizophrenia (1.19% v. 0.64%, p < 0.001), bipolar disorder (1.14% v. 0.42%, p < 0.001), MDD (3.56% v. 1.40%, p < 0.001), ASD (0.26% v. 0.12%, p < 0.001), and ADHD (1.31% v. 0.65%, p < 0.001) compared with the total population (Table 2). FDRs of patients with OCD were more likely to have a higher risk of major psychiatric disorders, including bipolar disorder (RR 2.85, 95% CI 2.68–3.04), MDD (RR 2.67, 95% CI 2.58–2.76), ASD (RR 2.38, 95% CI 2.10–2.71), ADHD (RR 2.19, 95% CI 2.07–2.32), and schizophrenia (RR 1.97, 95% CI 1.86–2.09), than the total population after adjusting for demographic data (Table 2). In addition, FDRs of patients with OCD had a higher prevalence of OCD (1.48% v. 0.18%, p < 0.001) and a higher risk of OCD (RR: 8.11, 95% CI 7.68–8.57) than the total population (Tables 1 and 2). A dose-dependent relationship was found between the numbers of OCD probands and the risk of each major psychiatric disorder, including OCD (1: RR 7.98, 95% CI 7.54–8.44; ⩾2: 32.54, 95% CI 26.06–40.63), bipolar disorder (RR 2.79, 95% CI 2.62–2.97; RR 8.17, 95% CI 6.08–10.98), MDD (RR 2.63, 95% CI 2.54–2.73; RR 6.05, 95% CI 5.01–7.30), ASD (RR 2.35, 95% CI 2.06–2.68; RR 5.89, 95% CI 2.81–12.36), ADHD (RR 2.18, 95% CI 2.06–2.31; RR 4.00, 95% CI 2.71–5.93), and schizophrenia (RR 1.97, 95% CI 1.85–2.09; RR 2.62, 95% CI 1.71–4.03) (Table 3). The sensitivity analyses with the adjustment of or the exclusion of five mental disorders of OCD probands showed the consistent findings (Online Supplementary Table S1).
Relative risk of different psychiatric disorders between FDRs of patients with OCD and total population
OCD, obsessive-compulsive disorder; ASD, autism spectrum disorder; ADHD, attention deficit hyperactivity disorder; MDD, major depressive disorder; FDR, first-degree relative; RR, relative risk.
a Adjusted for age, sex, urbanization, and income level.
Relative risk of different psychiatric disorders and the number of FDRs with OCD
OCD, obsessive-compulsive disorder; ASD, autism spectrum disorder; ADHD, attention deficit hyperactivity disorder; MDD, major depressive disorder; FDR, first-degree relative; RR, relative risk.
a Adjusted for age, sex, urbanization, and income level.
We performed subanalyses of the risks of major psychiatric disorders according to different familial relationships. The risks of each major psychiatric disorders among FDRs (parents, offspring, siblings, and twins) of patients with OCD are shown in Fig. 1. Parents, offspring, siblings, and twins of patients with OCD had an increased risk (RR, 95% CI) of each major psychiatric disorder, including OCD (parents of patients with OCD: 7.64, 7.10–8.23; offspring: 7.18, 6.65–7.75; siblings: 8.95, 8.44–9.49; twins: 60.76, 49.12–75.16), schizophrenia (parents: 2.07, 1.88–2.27; offspring: 1.99, 1.83–2.16; siblings: 3.66, 3.45–3.89; twins: 14.86, 11.16–19.79), bipolar disorder (parents: 3.18, 2.91–3.48; offspring: 2.65, 2.47–2.85; siblings: 3.43, 3.20–3.68; twins: 7.72, 4.95–12.06), MDD (parents: 2.85, 2.69–3.02; offspring: 2.55, 2.46–2.64; siblings: 2.96, 2.83–3.10; twins: 8.12, 6.16–10.72), ASD (parents: 1.84, 1.61–2.10; offspring: 3.73, 1.38–10.10; siblings: 2.92, 2.56–3.33; twins: 8.55, 5.34–13.70), and ADHD (parents: 2.07, 1.97–2.18; offspring: 4.53, 3.61–5.68; siblings: 1.96, 1.83–2.10; twins: 3.90, 2.85–5.33) compared with FDRs of individuals without OCD (Fig. 1, Online Supplementary Tables S2–S7).
RRs of different psychiatric disorders among FDRs of patients with OCD, stratified by kinships. OCD, obsessive-compulsive disorder; ASD, autism spectrum disorder; ADHD, attention deficit hyperactivity disorder; FDR, first-degree relative; RR, relative risk.
Discussion
The results of our population-based study supported the hypotheses that the FDRs, namely parents, offspring, siblings, and twins, of patients with OCD have higher risks of OCD, schizophrenia, bipolar disorder, MDD, ADHD, and ASD. In particular, individuals with a twin with OCD showed the highest risks of OCD, schizophrenia, bipolar disorder, MDD, and ASD. A dose-dependent relationship was found between the risks of the major psychiatric disorders and the numbers of patients with OCD in the family. The co-aggregation risk of OCD was highest with OCD, followed by bipolar disorder, MDD, ASD, ADHD, and schizophrenia. Our results of the familial co-aggregation of OCD with OCD and other major psychiatric disorders indicated a heterotypic familial transmission of psychiatric disorders and suggested that OCD may be transmitted inter-diagnostically within a family.
As aforementioned, OCD is familial and highly hereditary (do Rosario-Campos et al., Reference do Rosario-Campos, Leckman, Curi, Quatrano, Katsovitch, Miguel and Pauls2005; Hanna et al., Reference Hanna, Himle, Curtis and Gillespie2005; Nestadt et al., Reference Nestadt, Samuels, Riddle, Bienvenu, Liang, LaBuda and Hoehn-Saric2000). This familiality of OCD was shown to be mainly due to genetic influences (van Grootheest, Cath, Beekman, & Boomsma, Reference van Grootheest, Cath, Beekman and Boomsma2005). In our study, we found that the FDRs of OCD probands exhibited the highest risk of being diagnosed with OCD than other psychiatric disorders. FDRs, including parents, offspring, siblings, and co-twins, of OCD probands all displayed elevated risk for OCD, indicating that this condition was highly heritable and was commonly transmitted within a family (do Rosario-Campos et al., Reference do Rosario-Campos, Leckman, Curi, Quatrano, Katsovitch, Miguel and Pauls2005; Hanna et al., Reference Hanna, Himle, Curtis and Gillespie2005; Nestadt et al., Reference Nestadt, Samuels, Riddle, Bienvenu, Liang, LaBuda and Hoehn-Saric2000).
Previous studies supported that the parents, offspring, and siblings of patients with OCD are more likely to have schizophrenia and bipolar disorder (Cederlof et al., Reference Cederlof, Lichtenstein, Larsson, Boman, Ruck, Landen and Mataix-Cols2015; Henin et al., Reference Henin, Biederman, Mick, Sachs, Hirshfeld-Becker, Siegel and Nierenberg2005). To examine the familial coaggregation in MDD and bipolar disorder pedigrees, Goes et al. found a higher risk of OCD [odds ratio (OR) 2.60, 95% CI 1.29–5.24] among FDRs (parents, offspring, and siblings) of MDD probands. FDRs of bipolar disorder probands were also shown to have an elevated risk of OCD (OR 3.10, 95% CI 1.31–7.09) (Goes et al., Reference Goes, McCusker, Bienvenu, Mackinnon, Mondimore, Schweizer and Potash2012). The findings of our study are consistent with the previous findings of the familial coaggregation of OCD with schizophrenia, bipolar disorder, and MDD. In addition to the siblings, co-twins of the OCD probands exhibit the highest likelihood of the major psychiatric disorders, including OCD, schizophrenia, ASD, MDD, and bipolar disorder. A few studies investigated the risk of ASD and ADHD among relatives of patients with OCD. Wilcox et al. demonstrated a significant concentration of OCD in just the relatives of the autistic probands (Wilcox, Tsuang, Schnurr, & Baida-Fragoso, Reference Wilcox, Tsuang, Schnurr and Baida-Fragoso2003). A 18-year follow-up study revealed increased incidence risk ratio of ASD for OCD offspring (1.83, 95% CI 1.45–2.28) (Meier et al., Reference Meier, Petersen, Schendel, Mattheisen, Mortensen and Mors2015). Mathews et al. reported the strong genetic correlation between OCD and ADHD, and suggested that maternal ADHD was associated with offspring OCD (OR 1.8, 95% CI 1.1–3.1) (Mathews & Grados, Reference Mathews and Grados2011). In addition to maternal ADHD, we found that both fathers and mothers of patients with OCD were likely to have schizophrenia, MDD, bipolar disorder, ASD, and ADHD. On the basis of our results and the aforementioned evidence, we may conclude that OCD co-aggregates with OCD and other major psychiatric disorders within families.
OCD might be genetically complex. Factors including genetic and allelic heterogeneity, pleiotropy, epigenetics, and gene–environment interaction may contribute to this complexity (Grados, Reference Grados2010; Plomin, Haworth, & Davis, Reference Plomin, Haworth and Davis2009; Taylor, Reference Taylor2013). Genetics studies determined the genetic locus that may be relevant to OCD (Hanna et al., Reference Hanna, Veenstra-Vanderweele, Cox, Van Etten, Fischer, Himle and Cook2007; Shugart et al., Reference Shugart, Samuels, Willour, Grados, Greenberg, Knowles and Nestadt2006). However, the lack of concordance between findings may provide further evidence of genetic heterogeneity in OCD. Pleiotropy occurs when one gene influences multiple phenotypic traits, such as mental disorders. For instance, OCD may share genetic origin with depressive disorders (Hettema, Reference Hettema2008). Ten genes had been identified to be associated with the etiology of OCD, schizophrenia, bipolar disorder, and ASD, and molecular overlap at both genetic levels between these disorders had been suggested (O'Connell, McGregor, Lochner, Emsley, & Warnich, Reference O'Connell, McGregor, Lochner, Emsley and Warnich2018). However, Genome Wide Association Study (GWAS) disclosed no single nucleotide polymorphisms reaching genome wide significance between ADHD and OCD, and there was little evidence of genetic overlap between the two disorders (Ritter et al., Reference Ritter, Guo, Samuels, Wang, Nestadt, Krasnow and Shugart2017). While our results suggested the familial co-aggregation between ADHD and OCD, there is need to identify environmental risk factors that interact with genetic factors and confer risk to OCD. Additional cross-disorder GWAS will be required to confirm disorder-specific genetic factors and the degree of genetic overlap.
This study has several limitations. First, there was no routine surveillance for mental health in the general population in Taiwan. Based on the community surveys in Taiwan, the Cross National Collaborative Group reported that the prevalence of OCD was 0.4/100 in Taiwan (Weissman et al., Reference Weissman, Bland, Canino, Greenwald, Hwu, Lee and Wickramaratne1994). But, the prevalence of OCD was only 0.2/100 in our registry database study. The prevalence of major psychiatric disorders, including OCD, may be underestimated because only those who sought medical help and treatment were identified in the database. The diagnoses of major psychiatric disorders in our study were made by board-certified psychiatrists at least twice based on the comprehensive diagnostic interview and the clinical judgment, yielding an improved diagnostic validity, although there was no study comparing registry diagnosis to results of structured blind interviews until now. Furthermore, the community-based family linkage studies would be necessary to replicate our findings. Second, we defined twins as those with the same birthdate and the same mother in the NHIRD. We therefore could not differentiate between monozygotes and dizygotes because monozygote or dizygote state was not recorded in the database. A large twin study demonstrated a higher concordance rate for OCD among monozygotic twins (0.52) compared to dizygotic twins (0.21), with overall heritability for OCD estimated to be 48% (Monzani, Rijsdijk, Harris, & Mataix-Cols, Reference Monzani, Rijsdijk, Harris and Mataix-Cols2014). Clinical twin-paired studies are needed to validate our findings. Third, factors such as the education level and environmental factors are not available in the Taiwan NHIRD. Without these pieces of information, we cannot assess their impact. Fourth, familiality is not necessarily equal to a genetic heritability. Factors such as shared environmental factors may be conveyed in families and interact with shared genes. Non-genetic factors in the familial coaggregation of OCD with other major psychiatric disorders warrant further studies.
In conclusion, the FDRs, namely parents, offspring, siblings, and twins, of patients with OCD have an increased likelihood of schizophrenia, bipolar disorder, MDD, ADHD, and ASD. The familial co-aggregation of OCD with OCD and other major psychiatric disorders within families was confirmed in a dose-dependent manner. Given the increased risks of psychiatric disorders, medical practitioners should closely monitor the mental health of the FDRs of patients with OCD, especially children and siblings of patients with OCD. In addition, our findings would be useful for genetic counseling and clinical practice and may contribute to future establishment of early prevention program for mental disorders. Further cross-disorder GWASs are required to investigate the etiological heterogeneity within OCD and other major psychiatric disorders.
Supplementary material
The supplementary material for this article can be found at https://doi.org/10.1017/S0033291719003696.
Acknowledgements
We thank Mr I-Fan Hu for his friendship and support.
Funding source
The study was supported by grant from Taipei Veterans General Hospital (V103E10-001, V104E10-002, V105E10-001-MY2-1, V105A-049, V106B-020, V107B-010, V107C-181) and Ministry of Science and Technology, Taiwan (107-2314-B-075-063-MY3, 108-2314-B-075-037). The funding source had no role in any process of our study.
Financial support
All authors have no financial relationships relevant to this article to disclose.
Conflict of interest
All authors declared no conflict of interest.
