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School of Psychology, University of Queensland, Brisbane, AustraliaSurgical Treatment and Rehabilitation Service, Brisbane, AustraliaRadiological Sciences, Mental Health and Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, United Kingdom
Radiological Sciences, Mental Health and Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, United KingdomSir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, United Kingdom
Radiological Sciences, Mental Health and Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, United KingdomSir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, United KingdomNIHR Nottingham Biomedical Research Centre, Nottingham, United Kingdom
Nottingham Children's Hospital, Nottingham University Hospitals NHS Trust, Nottingham, United KingdomDivision of Child Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom
Radiological Sciences, Mental Health and Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, United KingdomSir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, United KingdomNIHR Nottingham Biomedical Research Centre, Nottingham, United Kingdom
Child ratings of QoL in A-T are significantly higher than parental ratings.
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Age negatively correlated with parent QoL ratings, but there was no relationship between age and child QoL self-ratings.
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Neurological function significantly predicts parental, but not the child's own ratings of their QoL.
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Over time, QoL ratings did not decline with increasing disability reflecting high levels of resilience in this sample.
Abstract
Aim
To explore neurological factors affecting quality of life (QoL) in children and young people with ataxia-telangiectasia (A-T), from both child and parent perspective.
Method
24 children/young people with A-T (mean age 11.2 ± 3.5 years; 13 males) and 20 parents were recruited, and 58% were reassessed after an average interval of 3.4 years. Participants completed the PedsQL QoL assessment. Participants with A-T underwent structured neurological examination. QoL data from 20 healthy controls and their parents was used for comparison.
Results
Children/young people with A-T rated their QoL higher than parental ratings across time points, with no longitudinal change. Higher age of the child participant correlated with lower parental (r = −0.43, p = .008) but not child ratings of QoL (r = −0.16, p = .380). Child and parent QoL ratings from the A-T group were lower than respective ratings from controls (ηp2 = 0.44 and ηp2 = 0.75 respectively, both p < .0005, controlled for socioeconomic status). Parental, but not child, ratings of QoL was predicted by a regression model based on neurological scores (R2 = 0.44, p=<.001).
Interpretation
Neurological disability does not determine child/young person QoL ratings in A-T. While certain aspects of neurological disability predict parent-proxy ratings, there is no decline in QoL over time. These results may reflect resilience in the face of a complex life-limiting disorder.
]. A-T is characterized by progressive cerebellar ataxia and extrapyramidal movement disorders, oculo-cutaneous telangiectasias, immune deficiencies, chronic lung disease, and an increased risk of malignancies [
]. The clinical course is variable, however the most common debilitating factor is the neurological decline that affects physical ability, and respiratory function [
There has been little research conducted on the quality of life (QoL) or emotional wellbeing of children and young adults with A-T. QoL is not purely a measure of health, but of an individual's global sense of wellbeing that includes physical, psychological, emotional, social, and spiritual dimensions [
]. Research into QoL of individuals living with rare genetic conditions has grown in recent years with results illuminating the complex and profound effect of these conditions on subjective ratings of QoL [
A qualitative project exploring living with A-T, the “My Life Project”, reported on many aspects of A-T including emotional wellbeing from the perspective of children and young people living with the condition [
]. The report found the main factors that affected children's emotional wellbeing and identity were the loss of the ability to walk, increasing physical tiredness, and difficulties with speech and communication. These findings are consistent with research demonstrating higher risk of adjustment difficulties in neurological disorders that impact motor functioning [
]. Parents involved in the project noted the emotional strain of their child losing the ability to walk as demoralising and causing a loss of confidence and identity in their children. Furthermore, children interviewed in the report described how the loss of mobility resulted in the loss of contact with peers, segregation from society and limited opportunities to form friendships. Children with A-T experience a gradual neurological decline, and therefore can often remember the experience of being able-bodied. This contributes to the child's emotional struggle and results in a conflict of identity and self-concept of now being a disabled person.
Measuring QoL in paediatric populations is challenging as the domains that constitute QoL change across the lifespan. Paediatric measures of QoL have age-specific versions validated per age group. It is believed that a child's self-report measure is the most accurate representation of their own QoL [
How young can children reliably and validly self-report their health-related quality of life?: an analysis of 8,591 children across age subgroups with the PedsQL 4.0 Generic Core Scales.
]. Proxy-report measures for child QoL (typically completed by the child's parent) have been developed but the objectivity of parent proxy reports can be influenced by internal and external factors. These include their personal experience of their child's condition and the modality of administration, with reporting bias an important consideration when interpreting such discrepancies [
Evaluating health-related quality-of-life studies in paediatric populations: some conceptual, methodological and developmental considerations and recent applications.
This study aimed to 1) compare child and parent ratings of QoL in A-T and examine any discrepancies between the two ratings, 2) monitor changes in QoL of children with A-T over time, 3) compare the QoL in A-T with healthy controls, and 4) explore which neurological factors influence QoL in children with A-T from both the child and parent perspective.
2. Method
2.1 Participants
Participants were children and young people with A-T and disorders closely related to A-T recruited to the Childhood Ataxia Telangiectasia Neuroimaging Assessment Project (CATNAP) [
] through the United Kingdom National Paediatric A-T clinic at the Nottingham University Hospitals NHS Trust. All parents and children over the age of sixteen gave written, informed consent. Children under the age of sixteen gave assent to participate in the study with written consent provided by their parent/legal guardian. The study was approved by NHS Health Research Authority Research Ethics Committees (14/EM/1175 and 18/SW/0078).
2.2 Measures
2.2.1 Paediatric quality of life inventory (PedsQL)
The PedsQL 4.0 is a brief standardised questionnaire designed to assess health-related QoL in children and adolescents, with and without chronic health conditions [
]. The questionnaire includes child self-report and parent proxy-report forms. The child and parent independently rate, “In the past one month, how much of a problem has this been for you/your child …” for certain situations, on a scale from 0 (never) to 4 (almost always). 23 items encompass four dimensions, including 8-items on physical functioning (e.g., “It is hard for me to run”), 5-items on emotional functioning (e.g., “I feel angry”), 5-items on social functioning (e.g., “I have trouble getting along with other kids”), and 5-items on school functioning (e.g., “It is hard for me to pay attention in class”). A total QoL score is calculated by summing all 23 items, and subscores for physical health (first 8 items) and a psychosocial health (calculated from the emotional, social, and school functioning dimension scores). The PedsQL demonstrates adequate internal consistency and construct validity [
], with eight domains as follows: Communication (including speech and handwriting); Eye movements; Ataxia; Movement disorders (including bradykinesia, hyperkinesia, and dystonia); Motor power; and Neuropathy. The neurological score of the A-TNEST (the ‘Total pure-neuro’ score) is the sum of the first six domains. The A-TNEST was administered and scored for all participants with A-T by an experienced paediatric neurologist.
2.2.3 Socio-economic status
To provide a proxy measure of socio-economic status (SES), the Income Deprivation Affecting Children Index (IDACI) was obtained from the English Indices of Multiple Deprivation 2019 dataset [
] for each participant based on their postcode at the time of participation. IDACI measures the proportion of all children aged 0 to 15 living in income deprived households (i.e., those out of employment and/or receiving financial support) with scores ranging between 0.0 and 1.0 with higher scores indicating greater deprivation.
2.3 Design and procedure
Children and young people with A-T in the CATNAP study underwent assessment with the A-TNEST and completed the PedsQL (timepoint 1, T1) and were subsequently invited to re-attend at a second timepoint (T2) after an interval of 2–4 years at which time the assessments were repeated. At T2 healthy control (HC) children and young people recruited to the CATNAP study were asked to complete the PedsQL (this was not a requirement of the protocol for healthy controls at T1). One of three age-standardised versions of the PedsQL was used depending on the age of the child (ages 5–7, 8–12, and 13–18 years). Two children over the age of 18 at T2 (aged 19, and 20), completed the 13–18 version of the PedsQL. The children and young people with A-T were supported in completing the questionnaire, due to the motor impairments experienced as part of the condition. Specifically, the PedsQL statements were read aloud, and a researcher circled the response that the child gave for each statement. Parent proxy questionnaires were administered to the parents of participants in both groups. After completion of the questionnaires, both A-T and HC children underwent an MRI scan as part of the CATNAP protocol, reported elsewhere [
], with a statistical significance criterion set at p < .05 (two-tailed). Descriptive statistics are reported as the median and interquartile range (IQR) unless stated otherwise. Shapiro-Wilk test was used to test normality of distribution of variables included in the analysis. Variables violating assumptions of normality were analysed using the appropriate non-parametric tests. Mann-Whitney U test was used to compare child and parent ratings of QoL. Between-groups analysis of covariance (ANCOVA) was used to assess differences in QoL ratings between the A-T T2 and HC groups controlling for SES according to both child and parent ratings. We used Wilcoxon Rank Sum to examine differences between QoL and neurological functioning in children and young people with A-T between T1 and T2. Data from both time points were combined to explore the relationship between neurological functioning and QoL for both child and parent ratings using Pearson and Spearman correlations as appropriate. Neurological variables that correlated significantly with QoL ratings were entered as predictors into a stepwise multiple regression analysis to identify significant neurological predictors of QoL in A-T. As the study protocol allowed recruitment of participants with disorder with close phenotypic overlap to A-T, all analyses were repeated after exclusion of participants with non-A-T diagnoses. An adult patient representative reviewed the results, supported the research team in their interpretation of results and commented on the appropriateness of the language used in the report prior to submission.
3. Results
3.1 Participants
At T1 the A-T group consisted of 13 males and 11 females ranging in age from 6.1 to 17.8 years (M = 11.2, SD = 3.5). Twenty-two children had classical A-T, and one child had A-T variant. At T1 we also included one child with A-T-like disorder (ATLD, aged 10 years with MRE11 mutation), and one had ataxia with oculomotor apraxia type 1 (AOA1, aged 6 years with Aprataxin gene APTX mutation). All children and young people in the A-T group had a parental rating of QoL completed (n = 20 parents as there were four sibling pairs). At T2, 58% of the original sample of children and young people with A-T returned, consisting of 5 females and 9 males ranging in age at time of assessment from 9.9 to 20.2 years (M = 14.4, SD = 3.6). Reason for declining participation at T2 included decline in health status preventing participation (n = 3), impact from the COVID-19 pandemic on willingness to travel (n = 5), and participants being unreachable (n = 2). There were no significant differences between any baseline characteristics (T1) of A-T dropouts versus those who returned at T2 (see Supplementary Table 3). For those who attended at T1 and T2 there was missing data on the PedsQL for 2 children and 1 parent. In the HC group at T2 16 parents completed the questionnaire, there were 10 female and 10 male children/young people ranging in age from 9.4 to 18.9 (M = 14.4, SD = 2.7).
3.2 Comparison between child and parent ratings of quality of life in A-T
Children and young people with A-T rated total QoL statistically significantly higher than their parents at both timepoints (Table 1). Children and young people with A-T rated their psychosocial QoL significantly higher than their parents at T2 and their Physical QoL higher at T1. Psychosocial QoL at T1 and Physical QoL at T2 were rated non-significantly higher by children and young people with A-T than their parents.
Table 1Mann-Whitney U test comparing child and parent QoL ratings at both T1 and T2.
For children and young people with A-T and parents who rated QoL at both time points, there was no significant change in QoL ratings between T1 and T2 (Supplementary Table 1). For the pooled (T1 and T2) dataset, there was no significant relationship between child QoL rating and age (r = −0.16, p = .380) (Fig. 1a), but a significant negative correlation was identified between parent QoL rating and the child's age (r = −0.43, p = .008) (Fig. 1b).
Fig. 1Scatterplot showing (a) child/young person and (b) parent total QoL rating plotted against the age of the child/young person for participants with A-T (red dots) and healthy controls (blue triangles). Dashed lines link ratings at T1 and T2 by the same individual. Shaded area represents 95% confidence intervals; ∗child with AOA1. †child with ATLD. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
3.3 Quality of life in healthy controls compared to children with A-T
IDACI scores for the A-T sample had a larger mean rank (28.0) than the HC sample (13.7), demonstrating a statistically significant difference between these groups (U = 63.0, p < .0005). IDACI scores (as a proxy for SES) were therefore included as a covariate when comparing child and parent total QoL ratings between children/young people with A-T and HC. Child and parent QoL ratings from the A-T groups were lower than respective rating from controls (ηp2 = 0.44 and ηp2 = 0.75 respectively, both p < .0005, controlled for SES) (Table 2, Fig. 1).
Table 2Comparison between A-T (T2) and HC groups for child and parent ratings of QoL, controlling for SES.
3.4 Neurological functioning in A-T and quality of life across time
There was a significant decline in the Total Pure Neuro score, Ataxia, and Neuropathy scores between T1 and T2 with Total Movement approaching significance (Supplementary Table 2). Child and young person ratings for total QoL showed no correlation with overall neurological status (Fig. 2a) or individual domains in the A-TNEST scores (Table 3). However, significant positive correlations were seen between parent total QoL ratings and five A-TNEST measures (Table 3): Total Pure Neuro (Fig. 2b), Speech, Eye Movements, Ataxia, and Neuropathy.
Fig. 2Scatterplot showing (a) child/young person and (b) parent total QoL rating plotted against neurological status of the child/young person (Total Pure Neuro score derived from the A-TNEST). Dashed lines link ratings at T1 and T2 by the same individual. Shaded area represents 95% confidence intervals; ∗child with AOA1. †child with ATLD.
3.5 Predictors of parent ratings for quality of life in A-T
Multiple linear regression was conducted using the A-TNEST variables correlating with parent QoL ratings on univariate analysis (Total Pure Neuro, Speech, Eye Movements, Ataxia, and Neuropathy) to develop a model predicting parent QoL ratings. Speech and Neuropathy contributed significantly to the model predicting QoL, with higher neurological scores (i.e., less impairment) predicting greater QoL (Table 4, F (2, 34) = 13.38, p=<.001, R2 = 0.44).
Table 4Results from regression analysis for A-TNEST predictors of parent QoL ratings.
3.6 Repeat analysis excluding participants with ATLD and AOA1
There were no changes to the significant group differences or associations reported above following exclusion of the two participants with ATLD and AOA1.
4. Discussion
This report is the first to quantitively explore QoL in the context of neurological disability in children and young people with A-T and compare this with parent-proxy reports and healthy controls. We show that in the A-T group across both time points child/young person's ratings of QoL were consistently higher than the parent-proxy ratings across all three QoL domains. This finding is consistent with previous literature that found children and young people often rate their QoL higher than their parent-proxy rating [
Evaluating health-related quality-of-life studies in paediatric populations: some conceptual, methodological and developmental considerations and recent applications.
]. Additionally, we found greater discrepancies between ratings of psychosocial QoL than the physical QoL ratings, which aligns with a meta-analysis that found good agreement between child and parent proxy-reports of physical QoL domains, but poor agreement for less observable aspects such as emotional and social domains [
In this sample, age had a moderate negative correlation with parent QoL ratings suggesting that the older the child, the lower the QoL is rated by their parent. This is not surprising as A-T is a progressive neurodegenerative disorder, so symptoms and psychosocial burden increase with age. However, there was no significant relationship between age and child/young person's QoL ratings, which suggests that the determinants of subjective wellbeing in progressive childhood conditions are more complex than worsening symptomology and burden. This is further supported by our findings that showed decline in neurological functioning of the children/young people with A-T over the two time points did not correspond to significantly lower QoL scores, with nominally higher psychosocial QoL at T2. This may have been related to the reason for drop-out from T1 (n = 24) to T2 (n = 14), with those who agreed to participate at T2 likely in better health than those who declined, although we found no significant difference in baseline characteristics between dropouts and completers.
Similarly, no linear relationship was found between child/young person self-reported QoL and neurological assessment from the A-TNEST scores. However, there were five domains of the A-TNEST that correlated with parent-reported QoL implying that there are neurological features of A-T that determine how parents assess their children's QoL. From these five neurological measures we found a model based on two measures (speech impairment and neuropathy) that significantly predicted parent ratings of QoL and explaining 44% of variance in scores in the sample. These results are in line with the qualitative work from the “My Life Project” that found physical decline and speech impairments were key factors impacting the well-being of children with A-T secondary to disruption in friendships and self-identity [
]. As A-T is a multisystem disorder there are other physical and health-related factors that could also impact on QoL, such as co-existent lung problems and/or cancer, recurrent infections and problems with nutrition and feeding. Repeated hospital visits or admissions and the resultant disruption to schooling and the child's social life could also be important factors that contribute to the unexplained variance in parental QoL scores. Unsurprisingly, HC parent and child/young person reports of QoL were significantly higher than those in A-T, even when controlling for differences in socio-economic status of the groups.
Together, these results can be understood in terms of resilience, which is the ability to positively adapt in the face of adversity and has been demonstrated in other chronic progressive neurological conditions. For example, children with Duchenne muscular dystrophy were found to be satisfied with life, they were not preoccupied by their disability, and did not define or limit themselves by their condition [
A limitation of these findings is that we did not directly measure resilience to support our interpretation, nor did we use qualitative methods to enrich our understanding of the quantitative data. Future research should use a mixed method design (i.e., quantitative, and qualitative) and additional measures to further delineate quality of life predictors (e.g., psychological wellbeing, self-esteem, illness perception, sense of coping etc.), which would help to further understand why children/young people's ratings of QoL are not related to their physical disability. Additionally, in the current study qualitative methods may have helped to explore why speech and neuropathy predicted parent (but not child) QoL variables.
Another potential explanation for the large difference between child/young person and parent QoL ratings, which is also a limitation of the current study, is that the child questionnaire was completed with the parent present. While parents could complete the questionnaire in private on paper, the children and young people completed the questionnaire verbally due to their motor difficulties. It may have been difficult for the child or young person to give an honest verbal response in front of their parent resulting in reporting bias. Likewise, parent-proxy ratings may have been inflated by other variables that were not measured in this study such as carer burden and their subjective distress related to the child's condition and prognosis. In addition to measuring other important metrics of psychosocial wellbeing, future research should complete the QoL questionnaire with children/young people without other family members present. A final limitation of this report is the study sample size, while A-T is a rare disease and therefore already a difficult population to recruit, the COVID-19 pandemic overlapping with recruitment for T2 further restricted our sample. In some of the analyses we pooled the data from T1 and T2 to increase data points, but this creates an issue of dependency. Therefore, while the data provides novel insights, the findings are exploratory and limited in their generalisability. Future studies using a large multinational data framework are needed.
The study protocol allowed inclusion of participants with rare conditions with a close phenotypic overlap to A-T, for whom prospective research data regarding QoL is very limited. Our recruitment included two children (one with ATLD, one with AOA1) and we note that they were not outliers in the relationships identified by our analysis. However, to check for a confounding effect of inclusion of these individuals, we repeated all analyses after their removal and found no alteration to the relationships identified.
5. Conclusion
To improve the QoL for individuals with rare genetic conditions, it is of primary importance for healthcare providers to understand the factors that affect their QoL, such as those found in this report using the A-TNEST measures. While our data showed there are certain neurological factors related to parent-proxy ratings of QoL in their children, this was not the case for children's self-ratings, and there was no change in these ratings over time suggesting protective mechanisms are at play. One such mechanism is resilience, which warrants further exploration in this cohort. We hope that this exploratory study of the psychosocial aspects of A-T will stimulate further research in this area.
Funding
The study was funded by research grants awarded jointly by A-T Children's Project and Action for A-T (grant reference: “The CATNAP Study”), and jointly by Action for A-T and BrAshA-T (grant reference: 17NOT03).
Declaration of competing interest
The authors have stated that they had no interests which might be perceived as posing a conflict or bias.
Acknowledgements
The authors would like to thank the children, young people and families who participated in the CATNAP study. We gratefully acknowledge the support of the AT Society for assistance arranging schedules and transport for participant visits; and Dr Min Ong, Dr Felix Raschke, Dr Ouliana Panagioti and Dr Jeyanthi Rangaraj for support with neurological and quality-of-life assessments respectively.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
How young can children reliably and validly self-report their health-related quality of life?: an analysis of 8,591 children across age subgroups with the PedsQL 4.0 Generic Core Scales.
Evaluating health-related quality-of-life studies in paediatric populations: some conceptual, methodological and developmental considerations and recent applications.
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