A4 | Kind Lab

A binational study assessing risk and resilience factors in 22q11.2 deletion syndrome

Raquel E Gur, Lauren K White, Shachar Shani, Ran Barzilay, Tyler M Moore, Beverly S Emanuel, Elaine H Zackai, Donna M McDonald-McGinn, Noam Matalon, Ronnie Weinberger, Ruben C Gur, Doron Gothelf

The online version contains supplementary material available at https://doi.org/10.1016/j.jpsychires.2021.03.058

Keywords: 22q11.2 deletion syndrome; Neurogenetic disorders; Neuropsychiatric disorders; Risk & resilience; Stress vulnerability.

Abstract

Background

The presentation of neurogenetic disorders such as 22q11.2 Deletion Syndrome (22q11.2DS) includes broad neuropsychiatric phenotypes that impact functioning and require assessment and treatment. Like in non-syndromal neuropsychiatric disorders, there is heterogeneity in symptom severity and illness course. The study of risk and resilience in the general population has benefited from measurement tools that parse heterogeneity and guide treatment. Suitability of such tools in neurogenetic disorders has not been examined and is essential to establish as prerequisite for examining whether similar processes modulate psychopathology in these populations.

Method

We applied the Risk & Resilience Battery assessing intrapersonal, interpersonal, and environmental domains, to 80 patients with 22q11.2DS, 30 from Philadelphia, USA and 50 from Tel-Aviv, Israel. We also evaluated global functioning and obtained self-reports of anxiety and depression. We examined the Risk & Resilience Battery reliability for each factor and used partial correlations to examine relations between the Risk & Resilience Battery factors and clinical measures.

Results

Across samples, items within each risk and resilience factor showed good to excellent internal consistency. Higher scores on peer victimization, emotion dysregulation, and hostile close relationships were related to reports of anxiety and depression. Higher levels of self-reliance related to lower anxiety while greater security in close relationships related to lower depression.

Conclusion

The Risk & Resilience Battery can be applied to 22q11.2DS samples and advance Gene X Environment research and interventions.

Introduction

The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder known in humans with an estimated prevalence of 1 in 4000 live births (McDonald-McGinn et al., 2015). A broad range of abnormalities are evident in individuals with 22q11.2DS including cardiac, immune, palatal, gastrointestinal, musculoskeletal, endocrine, renal, and CNS (McDonald-McGinn et al., 2015). Neuropsychiatric disorders are prominent and disabling in the clinical presentation of 22q11.2DS and include anxiety, attention-deficit/hyperactivity disorder (ADHD), mood and schizophrenia spectrum disorders (Green et al., 2009; Tang et al., 2014). Notably, the clinical presentation and developmental pattern of these neuropsychiatric disorders in 22q11.2DS are similar to those of idiopathic neuropsychiatric disorders, such as schizophrenia, in the general population (Schneider et al., 2014; Tang et al., 2017). Such similarities have stimulated convergence of rare variants and common variants research in schizophrenia and other neuropsychiatric disorders (Bassett et al., 2017; Davies et al., 2020; Gur et al., 2021; Zinkstok et al., 2019).

Across development and psychiatric manifestations of 22q11.2DS, there is particularly impaired tolerance to common daily life occurrences, which is especially stressful for individuals with 22q11.2DS (Mayo et al., 2019). Anticipation of upcoming events or changes in settings or routines may be accompanied by emotional reactivity well beyond expectations for their age or intellectual abilities (Swillen et al., 2018). Furthermore, facial features, below average intellectual abilities, need for special education school programs, and medical disorders are additional potential contributors to bullying, social isolation and vulnerability of individuals with 22q11.2DS (Angkustsiri et al., 2012; Beaton and Simon, 2011; Estell et al., 2009; Lessne and Yanez, 2017). However, there is also marked variability, with some individuals showing substantial psychiatric comorbidity while others manifest more limited psychopathology (Mosheva et al., 2019).

Research in idiopathic, clinically ascertained psychiatric samples, has likewise revealed heterogeneity in course and outcome, and increased attention has focused on factors that confer risk or resilience to mental illness (Feldman, 2020; Rutter, 2006). Our research team recently developed the Risk & Resilience Battery (RRB) to assess such factors (Moore et al., 2020). To date, most efforts to study resilience have examined narrow aspects of resilience and specific age ranges; the RRB was created to assess a broad range of risk-resilience domains including intrapersonal, interpersonal, and broader environmental contexts applicable across the lifespan. The RRB assesses seven risk and resilience factors - self-reliance, emotion dysregulation, supportive close relationships, hostile close relationships, neighborhood danger, and recent stressful events – validated in a large sample of youths and adults, and each factor related to multiple clinical outcomes. It is unknown whether the survey is valid in individuals with neurogenetic disorders such as 22q11.2DS.

Advancing the understanding of factors that confer risk or promote resilience in 22q11.2DS is critical to mitigate consequences of underlying neuropsychiatric and medical disorders and maximize functioning. Yet, comprehensive risk and resilience measures used in the general population have not been applied in 22q11.2DS. A tool that can briefly assess such factors in 22q11.2DS can help advance the study of risk and resilience in this vulnerable population.

This study aims to examine the feasibility of administering the RRB in two sites with ongoing collaboration in the study of individuals with 22q11.2DS (Mekori-Domachevsky et al., 2017; Yi et al., 2016). First, we examined scale validity of the seven risk and resilience domains in a sample of adolescents and adults with 22q11.2DS. Second, we evaluated the clinical validity of the battery in this sample by examining the relations between the risk and resilience factors and clinical functioning reflected in self-reported anxiety and depression. The current data enabled us to underscore the similarities between the risk and resilience factor scores in the 22q11.2DS sample and the original sample of community participants with no known genetic syndrome who were included in the battery development study (Moore et al., 2020).

Methods

Participants

The current sample was collected as part of a collaborative study across two sites, University of Pennsylvania and Children's Hospital of Philadelphia (CHOP) (United States; Site 1) and Tel-Aviv University (Israel; Site 2). The total sample was N = 80 (45 males), with a mean age of 24.6 years (SD = 9.3). Thirty participants (20 males) were assessed at Site 1. Mean age of the Philadelphia sample was 20.6 years (SD = 6.4; range 10.8–32.4). Fifty participants (25 males) were seen at Site 2, mean age of the Tel-Aviv sample was 27.0 years (SD = 10.0, range 15.1–53.0). One participant from Site 1 was Black, all other participants were White. The two samples did not differ on sex (χ2(1) = 2.12, p = .15), but the Site 1 sample was younger than the Site 2 sample, t(78) = 3.48, p = .001. All participants had the chromosome 22q11.2 deletion, confirmed by multiplex ligation-dependent probe amplification (Jalali et al., 2008), were clinically stable, and had IQ ≥ 70. Psychiatric diagnoses were common and comorbid in both samples. In Site 1, 40% had externalizing disorders, primarily attention deficit hyperactivity (ADHD); 50% anxiety/mood disorders and 17% schizophrenia spectrum disorders. In Site 2, 44% had externalizing disorders, primarily ADHD; 36% anxiety/mood disorders and 22% schizophrenia spectrum disorders. The Philadelphia sample of community participants with no known genetic syndrome (CP), as previously detailed in Moore et al. (2020), included 298 participants of whom 244 underwent the same clinical assessment as detailed below. Mean age for that study was 18.7 (SD = 5.0, range 8–35), with 21% having no psychiatric disorder, 24% having externalizing disorders, primarily ADHD, 30% anxiety/mood disorders, and 14% schizophrenia spectrum disorders.

Procedures

The Risk & Resilience Battery was developed at the Lifespan Brain Institute of Penn Medicine and CHOP, as detailed below, and was translated to Hebrew by bilingual investigators using the translation and back translation method. The battery was administered to eligible participants (meeting inclusion criteria) by clinically trained research team members at the two sites. Site 1 completed data acquisition during the pre-pandemic in-person visits and Site 2 included 18 participants evaluated before the pandemic and 32 early after the pandemic onset. The study was carried out in accordance with the latest version of the Declaration of Helsinki. The Institutional Review Boards of the University of Pennsylvania and CHOP and Sheba Medical Center reviewed the design and approved the study. Informed consent/assent was obtained from each participant and accompanying parent, for those <18, after the nature of the procedures had been fully explained.

Measures

Risk and Resilience Battery (RRB)

The recently developed 47-item battery (Moore et al., 2020) was used to assess intrapersonal, interpersonal, and environmental risk and resilience domains. This tool comprises items from well-established self-report measures. The seven risk and resilience factors measured are: self-reliance (3 items; e.g., can usually find a way out of difficult situations), peer victimization (14 items; e.g., called names or harassed online), emotion dysregulation (5 items; e.g., difficulty concentrating or controlling behaviors when upset), supportive close relationships (4 items; e.g., lasting relationship and level of care with parent), hostile close relationships (5 items; e.g., level of arguing with parent), neighborhood danger (4 items e.g., lack of perceived level of trust and safety in neighborhood), and recent personal and family-related stressors (12 items: e.g., parental divorce, move, family in trouble with the law). During pilot stages, the battery was modified according to participant age (Moore et al., 2020): the youngest participants from Site 1 (<16 years) did not complete self-reliance items (n = 9); Site 2 did not implement any age modifications, but most participants were >16 years old. Seven individual factor scores were created by summing all items within a factor and dividing by the total possible points for the participant on that factor. After instructing participants on RRB self-report completion, the trained clinical research coordinators remained nearby to answer any questions. For younger participants, research coordinators offered to read items out loud if preferred. One participant completed only the Emotion Dysregulation items, so scores were not available for remaining factors. Data is also unavailable in a subset of subjects for self-reliance scores (n = 5), peer victimization (n = 1), supportive relationships (n = 7); hostile relationships (n = 9), neighborhood danger (n = 4), and stressful life events (n = 1). Lack of completion was commonly related to length of clinical assessment procedures. Missing data was handled by pairwise deletion.

Global functioning and impaired tolerance to normal stress

Participants at the two sites underwent clinical assessments from which global functioning ratings were based. Site 1 used a computer guided semi-structured clinical interview (Calkins et al., 2017) with modules based on the K-SADS (Kaufman et al., 1997) and Structured Interview for Prodromal Syndromes (SIPS) (Miller et al., 2003). The K-SADS modules provided a standardized assessment of DSM-IV axis 1 mood disorders. The SIPS assessed psychosis spectrum symptoms. Collateral interviews of parents were also conducted and medical records were reviewed. SIPS Global Assessment of Functioning (GAF) scores range from 0 to 100 (McGlashan et al., 2003). Impaired Tolerance to Normal Stress (SIPS-G4) ranged from 0 - absent, to 6 - extreme. Scores on GAF and SIPS-G4 were based on information gained in the interviews and consensus reviewed; GAF ratings reflected functioning over the past year. Similar procedures were conducted for Site 2 and K-SADS was used as the semi-structured interview; however, SIPS evaluations were not performed simultaneously with the Risk & Resilience Battery.

Self-reported anxiety and depression

At both sites, the eight item PROMIS Depression Scale (PDS) (Pilkonis et al., 2011) was used to assess self-reported depression symptoms. The eight item PROMIS Pediatric Anxiety (PPA) scale (Irwin et al., 2010) was used to assess self-reported anxiety symptoms. The ratings for both scales were obtained following the administration of the Risk & Resilience Battery. Two participants from Site 1 did not have self-report anxiety or depression ratings.

Statistical analyses

First, descriptive statistics were examined and the two samples were compared on all variables of interest (RRB factors, GAF, PDS, and PPA). Next, we examined the internal consistency of the RRB using Chronbach's alpha to examine the scale reliability across the two samples for each factor. We then used partial correlations, controlling for Site and age, to examine relations between the seven RRB factors and the four clinical measures (anxiety, depression, global functioning, and impaired stress tolerance). Lastly, we conducted several comparisons on factor scores and structure between the current sample and a CP sample (Moore et al., 2020). First, we present the mean RRB factor scores in 22q11.2DS relative to CP controls. Next, we conducted separate exploratory factor analyses of the 47 items for the 22q11.2DS sample and the CP controls. Due to sample size limitations, we could not perform proper tests of measurement invariance (e.g., comparing factor loadings and item intercepts across samples), but qualitative comparisons were made between the extracted seven factors and the item-factor configuration in the 22q11.2DS sample to those in the CP sample. Site 2 pre-pandemic and early pandemic participants were compared and did not differ in RRB and self-report measures. Therefore they were analyzed as one group.

Results

Comparability of sites

Descriptive statistics are reported in Table 1. Participants across the two sites differed on the emotion dysregulation factor, such that participants from Site 1 reported higher emotion dysregulation scores than Site 2, t(78) = -2.04, p = .04. No other differences between the two samples were detected in the risk and resilience factors. The two samples did not differ in depression or anxiety scores, but participants from Site 2 had overall higher GAF scores than the Site 1 cohort, t(78) = 4.42, p < .001. Given the similarities across the two sites, results focus primarily on data collapsed across the two sites. Across the full sample, age was significantly correlated with self-reliance scores (r(66) = 0.30, p = .02), GAF scores (r(80) = 0.24, p = .04), and anxiety scores (r(78) = 0.22, p = .05), such that older participants scored higher on the measures. There were no sex differences across the risk and resilience factors or clinical scores.

Factor Analysis

Fig. 1 presents the risk and resilience factors in 22q11.2DS and the original sample of RRB development (Moore et al., 2020). As can be seen from the figure, the profile in the 22q11.2DS sample is similar to that of the CP sample, with or without psychiatric disorders. Moreover, exploratory factor analyses revealed that the seven factors extracted in the 22q11.2DS sample had similar structure to the CP sample (see supplemental materials for Table S1 and Figure S1). Although, there were three items (all related to perceived discrimination and neighborhood danger) that did not load on the expected factors; this is likely a result of the homogeneity of the 22q11.2DS sample.

Fig. 1. Comparison of risk and resilience factor scores in 22q11.2DS and community participants with no known genetic syndrome samples with and without neuropsychiatric disorders.

Scale Reliability

To assess the consistency of the current battery in measuring risk and resilience factors in a 22q11.2DS cohort, we examined the scales' reliability. As shown in Table 2, across both samples items within each factor showed good to excellent internal consistency. The one exception to this was the neighborhood danger scale, which showed questionable consistency. Thus, this factor should be used with caution as a measure of neighborhood danger in individuals with 22q11.2DS.

Correlations

Partial correlations controlling for age and Site (when applicable) were conducted to examine how the seven risk and resilience factors were related to clinical measures (Table 3, Fig. 2). Higher scores on peer victimization, emotion dysregulation, and hostile close relationships were related to higher reports of both anxiety and depression. Higher self-reliance was related to lower anxiety, and higher supportive close relationships was related to lower reports of depression. For global functioning ratings, only one trend level correlation emerged: higher emotion dysregulation was related to lower functioning scores. For impaired tolerance to normal stress, strong correlations emerged for emotion dysregulation and peer victimization. Hostile close relationships also showed a relation to impaired stress tolerance, but did not reach statistical significant likely due to the sample size (Site 1 only).

Fig. 2. Scatterplots illustrating the highest magnitude correlations between self-report clinical scales and risk and resilience factors. Emotion dysregulation is plotted with depression (Panel A) and anxiety (Panel B). Hostile close relationships is plotted with depression (Panel C) and anxiety (Panel D).

Discussion

Across psychiatric disorders, there is increased recognition that risk and resilience factors modulate the presentation and course of illness and their elucidation is required for genome to phenome mechanistic models that incorporate interactions with the environment. Advancing the understanding of factors that promote resilience and confer risk is especially important in neurogenetic populations, such as 22q11.2DS, who are enriched for psychiatric manifestations and posse special challenges for mental health professionals and care providers. The current study examined the validity of a brief risk and resilience battery in individuals with 22q11.2DS across two collaborating sites. Such collaborations are common and needed in the study of rare copy number variants such as 22q11.2DS (Gur et al., 2017). The Philadelphia and Tel-Aviv sites capitalized on established collaborations to evaluate the feasibility and validity of the recently developed Risk and Resilience Battery (RRB) (Moore et al., 2020). The current findings support the use of the RRB in this neurogenetic syndrome; the seven risk and resilience factors that span multiple domains were validated, both in terms of scale internal consistency and by showing expected modulation of clinical severity. Further supporting the validity of the RRB as providing a coherent independent parameter is the similarity of profile between the deleted and non-deleted samples and, within the non-deleted sample, between those with and without psychiatric disorders (Fig. 1). Based on this study, we suggest that the RRB is a promising tool that can be used across a broad age range and in rare CNV samples, such as 22q11.2DS populations, to help gauge the psychiatric course associated with the syndrome.

Understanding how a constellation of diverse risk and resilience factors relate to clinical features provides useful insight for targeting those domains that confer the most risk and promote the greatest positive outcomes. Of the seven factors, emotion dysregulation had the highest magnitude of relation with self-reported anxiety and depression and the clinical measure of impaired tolerance to daily stress; emotion dysregulation was also found to be the strongest predictor of clinical outcomes in a large community sample with no known genetic syndrome (Moore et al., 2020). Indeed, the pattern of results found in 22q11.2DS was very similar to that in the CP sample, with two notable exceptions. First, in the current sample, the magnitude of relation between hostile close relationships and anxiety and depression was significantly higher than in the CP sample (see supplemental material). Second, Moore et al. (2020) found that supportive close relationships was the most significant predictor of global functioning ratings (i.e., GAF). However, despite the factor means being similar across the two samples, GAF was unrelated to supportive close relationships in the current results. This difference may suggest that while the presence of supportive close relationships has less influence in the current sample, hostility within the bounds of family relationships significantly affects the mental health of individuals with 22q11.2DS, possibly more so than in community sample with no known genetic syndromes. This is in line with previous findings that dyads of children with 22q11.2DS are characterized by higher levels of maternal intrusiveness, lower levels of child's engagement and reduced reciprocity compared to dyads of typically developing children (Weisman et al., 2015).

The cognitive difficulties and challenges that individuals with 22q11.2DS face can raise concerns regarding their ability to complete standard scales validated in normative samples. The current findings support the use of the brief Risk and Resilience Battery in individuals with 22q11.2DS. Measures of reliability showed high internal consistency within the separate factors, although the consistency of the neighborhood danger scale was questionable. Likely the level of parental supervision and guidance provided to individuals with 22q11.2DS buffers them from much exposure to neighborhood dangers. Thus, future work using this scale should be cautious when interpreting findings from this scale in non-normative samples.

Consideration of COVID-19

Notably, the control sample (Moore et al., 2020) and most of the 22q11.2DS samples were assessed prior to the COVID-19 pandemic. The availability of the tool has enabled rapid online data collection to address the impact of the pandemic during COVID-19 lockdown in the US and Israel, primarily among healthcare professionals (Barzilay et al., 2020). We also examined racial disparities between Black and White pregnant women in Penn Medicine, Philadelphia (Gur et al., 2020). An international effort is currently collecting data for 22q11.2DS during the pandemic; this will allow us to delineate risk and resilience trajectories in this population, across time, after a sustained stressor.

Limitations

This study has several limitations. While the sample size is relatively large for a rare CNV sample, it was limited because of the pandemic outbreak. In addition to a major global stressor that must be considered as an intervening variable, the procedures for data acquisition in the US required adaptation and interviews have been rendered virtual to minimize exposure risk. We therefore in Site 1 had data acquired during the pre-pandemic in-person visits and Site 2 included participants evaluated before the pandemic and early after the pandemic onset. While no RRB differences were noted between those assessed before or after the pandemic, we cannot infer on long term effects of the pandemic. In addition, the research participants had IQ scores of 70 and above, and we are therefore not in a position to conclude that the RRB can be validly administered to individuals with more impaired intellectual functioning. Finally, the comparison sample of community controls without a known genetic syndrome was collected in Philadelphia only.

Notwithstanding these limitations, our study indicates that individuals with 22q11.2DS, like their community counterparts, show individual differences in risk and resilience factors that can be measured reliably by the RRB and relate to severity of symptoms and functional outcome. This brief scale can be used in multi-site studies and in guiding therapeutic interventions such as enhancing individuals with 22q11DS emotion regulation and targeting hostile close relations.

Conclusions

The study demonstrated the structural validity of Risk and Resilience Battery in two international sites with different languages and cultures. Such cross-site collaborations are necessary in rare neurogenetic syndromes that are enriched for neuropsychiatric burden. By showing that similar risk and resilience factors modulate psychopathology and functioning in this population as in idiopathic psychiatric disorders, the study can hopefully motivate mental health professionals to apply approaches familiar from broader clinical practices. Concurrently, the study can help facilitate integration of behavioral measures that can advance mechanistic understanding of Gene X Environment interactions affecting psychiatric disorders.

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