Leads: Dr Hayley Crawford (Youth Mental Health), Dr Jo Moss (University of Surrey), Dr Caroline Richards (University of Birmingham), Dr Jane Waite (Aston University)

The project team have long-standing relationships with syndrome support groups (Fragile X and Cornelia de Lange Foundation UK and Ireland) and parents/carers of children with neurodevelopmental disorders. This partnership working determines priorities for research and design of projects.

Dates: October 2020 – September 2024

Background:

Children with neurodevelopmental disorders experience poor developmental, health and wellbeing outcomes compared to typically developing peers. Our work has shown that these inequalities are heightened in children with the most complex clinical presentations and particularly those with intellectual disability (ID) associated with rare genetic syndromes and/or autism. These collectively common groups evidence poorer child and family wellbeing, higher rates of challenging behaviour, and compromised mental health and sleep. Since 2008, the Cerebra Centre for Neurodevelopmental Disorders has partnered with Cerebra to reverse this position, driving a world-leading research programme delineating behavioural phenotypes, clinical need and changes with age associated with complex disorders. This has resulted in the world’s largest cross sectional and longitudinal database of behavioural characteristics for over 2,000 children and young adults with rare genetic syndromes associated with ID. From our innovative lines of research in mental health, sleep disorder, identification of autism characteristics, and pain and discomfort, we identified these areas as critical determinants of wellbeing.

Having identified these areas of clinical need, we have now secured funding over four years to establish a network of research groups that build on the findings, systems, expertise and collaborations established over the last twelve years. In the Cerebra Network for Neurodevelopmental Disorders, research will be delivered by internationally recognised PIs who have trained at the Cerebra Centre for Neurodevelopmental Disorders.

Policy and Practice Partners:

NHS, Cerebra (who have provided funding for the project), syndrome support groups e.g. Fragile X Society, Cornelia de Lange Foundation UK and Ireland.

Co-Funding Partners:

TBC.

Aims and Objectives:

This project addresses the poor and iniquitous outcomes experienced by children and families with rare and complex disorders at four levels: identification, modelling of cause, intervention, and translation to practice. The shared objectives of the network are:

1. We will improve identification of mental health problems, sleep disorders, symptoms of autism and pain and discomfort through the development of novel tools and assessment paradigms.
2. We will model the unique and shared contributions of biological, cognitive and psychological mechanisms that cause and drive poor clinical outcomes in these groups.
3. We will develop and pilot timely, precise interventions to improve mental health, sleep and behavioural outcomes derived from improved identification tools and accurate models of cause and mechanism.
4. We will partner with Cerebra to translate knowledge into practice, capitalising on our expertise in multi-media dissemination, collaboration with stakeholders and intersections with policy makers.

To achieve the shared objectives of the network, three interlinking work packages focussed on sleep, autism and mental health will be hosted at leading universities by independent PIs previously trained at the Cerebra Centre (Moss, Richards, Waite, Crawford).

Crawford (ARC-WM) co-leads work package 3 (mental health) with Dr Jane Waite (Aston University). The research aims of work package 3 are:

1. To employ survey methodologies to profile anxiety across syndrome groups to improve the sensitivity and specificity of anxiety assessments; including the differentiation of anxiety from presentations associated with autism (contributes to Network Shared Objective 1).
2. To utilise experimental techniques to delineate risk factors for anxiety and other mental health problems within and across syndromes, including autism characteristics, sensory sensitivity, genetic variation, intolerance of uncertainty, emotion regulation, pain and sleep (contributes to Network Shared Objective 2).
3. Developing a syndrome sensitive intervention that can be utilised in NHS clinical services (contributes to Network Shared Objective 3).

Methods:

Two studies will address the three aims in WP 3.

Study 1: Generating syndrome specific algorithms for the detection of anxiety.

Waite is leading a programme of research, in collaboration with Crawford, which is developing an anxiety tool (ClASP- ID) for use in clinical practice with minimally verbal children. The ]programme is supported by Autistica and Birmingham Children’s Hospital Charitable Fund. Study 1 will extend the current work to include a larger cohort of children with specific genetic syndromes (Cornelia de Lange, fragile X, CHARGE, Kleefstra and Rubinstein Taybi syndromes) so that syndrome specific anxiety algorithms can be generated. Participants will be recruited nationally and internationally through syndrome support groups, charities and through links with international collaborators (e.g. Prof Hennekam, University of Amsterdam). Participants will complete an online questionnaire that includes a newly developed anxiety measure developed by Dr Waite, several validated anxiety measures (DASH-II; ADAMS) and a battery of questionnaires that examines risk factors for the development of anxiety. Factor analysis will be conducted for the wider programme of work to develop an overall anxiety algorithm for the ClASP-ID. Following this, an expert panel of clinicians with experience of the assessment of these syndrome groups, will be asked to comment on the structure of the algorithms. The items included in the algorithm for each group will be adjusted if they are deemed to lack face validity, based on feedback from the expert panel, to examine whether removal of items that may not capture anxiety within a given group improve the Cronbach’s alphas for the subscale.

To validate the syndrome specific algorithms, minimally verbal children aged 4-16 years with specific rare genetic syndromes, such as Cornelia de Lange syndrome (N = 25), fragile X syndrome (N = 25) and Kleefstra syndrome (N = 25) will be invited to complete a direct follow-up assessment. The assessment will include an autism assessment (ADOS-II; informed by Moss & Crawford), direct anxiety assessment (Anx-DOS), sensory assessment (SAND), observational measures of pain, sleep measure (informed by Richards), physiological measurement (heart-rate, cortisol), genetic testing, as well as an in-depth clinical interview with a clinical psychologist and senior research fellow who will be blind to the participants’ anxiety status on the ClASP-ID. Participants will complete the ClASP-ID again. Cohen’s Kappa and intra-class correlation coefficients (ICCs) will be conducted to examine agreement between clinician rated anxiety and scores on the ClASP-ID to ensure that the algorithms are able to accurately predict clinician rated anxiety status and anxiety severity (Aim 1). A sample size of 25 per group is adequately powered to detect agreement of .5, at a significance level of .05, with agreement >.75 indicative of good convergent validity. This sample size is typical of numerous studies of measure development that utilise ICC. Further regression analyses will be conducted to examine factors that may be implicated in anxiety in these groups utilising both questionnaire and direct assessment data (Aim 2).

Study 2: Piloting a syndrome specific intervention for anxiety.

Having identified children experiencing clinically elevated anxiety, we will conduct a proof of principle intervention study with six minimally verbal children with one genetic syndrome from our wider study (e.g. Cornelia de Lange or fragile X syndromes) (N = 6). The intervention will combine evidence-based behavioural approaches for minimally verbal children with anxiety reduction strategies from the typically developing literature, and our existing knowledge of the mechanisms underlying anxiety in these syndromes. The start date for the intervention for each family will be staggered (multiple- baseline design), allowing us to evidence whether the intervention is leading to a reduction of anxiety related symptoms. The scores obtained on assessments in the baseline and treatment phases will be compared using Tau-U for each participant. To obtain an overall estimate of the effect size of the intervention, the design-comparable effect size for multiple-baseline designs will be computed.

Main Results (Anticipated):

To achieve our shared network goal of effective translation from research into practice, throughout our research programme we will partner with Cerebra to develop a wide range of tangible outputs for children with complex needs and their families including:

• A robust evidence-base for future research. We will publish our research in leading journals, such as the Journal of Autism and Developmental Disorders and Journal of Neurodevelopmental Disorders, to further inform the field of ID research.
• A legacy database resource. We will continue to expand our large-scale cross syndrome database of over 2,000 children, young adults and their families, providing a unique resource for researchers and professionals in the field of ID for the future. Collaboration with Parsons and Noufaily (ARC-WM, MIRR) will ensure that our unique cross syndrome longitudinal database is utilised effectively. This database is a rich resource which provides extensive behavioural phenotype data underpinning the research conducted across the proposed Network. Expansion of this database (via collaboration throughout the UK) will continue to be a primary outcome of our research and will enable us to develop an essential legacy for researchers and professionals in the field of ID.
• An infrastructure for research and impact. The Cerebra Network for Neurodevelopmental Disorders will be a flagship collaborative Network within the field of ID research. Three PhD students will be trained within the network as specialists in children with complex needs, who will then perpetuate the aims of the Network through their own research.

Conclusions:

Ongoing.

Implications for Implementation:

These studies will improve the assessment of children with the most complex needs synthesising the existing evidence-base for anxiety assessment with knowledge of syndrome specific profiles. Building on our previous work that has resulted in the development of assessment measures for intellectual disability, we will develop mental health, autism characteristics, pain and sleep assessments/protocols that are tailored for use within and across populations for children with the most complex needs (e.g. those who are minimally verbal). Our assessment tools will overcome the problems with assessment tools that are currently used within clinical practice, which are confounded as they do not differentiate behavioural markers of pain, anxiety and autism in children with complex needs. Our tools will be sensitive, reliable and valid so that children can be triaged onto the most effective care pathways. Furthermore, they will become essential tools for evaluating intervention efficacy in the future. By working closely with collaborators at Birmingham Women’s and Children’s Hospital, we will ensure that these assessment measures are translated into practice in a timely manner.

We will also provide evidence-based resources that will focus on how sleep, mental health difficulties, behavioural and social difficulties develop across conditions in children with complex needs, and, importantly, how these difficulties interlink (drawing together all work packages under our Network Shared Objectives). These resources will be developed for parents and practitioners/clinicians to provide practical advice and will be guided by our contact with syndrome support groups. By providing an integrated understanding of children’s needs, as opposed to focusing on each of these difficulties in isolation, we will ensure that our resources reflect the complexity of children’s presentations. This approach is well aligned with how psychologists and behavioural specialists formulate children’s difficulties in clinical practice, which will ensure the effective uptake of our evidence based guidelines in clinical settings.

The proof of concept study will provide data to support a further application for funding to develop protocols for adapting anxiety interventions based on syndrome characteristics. Our intervention packages will draw on knowledge gained from our collaborative research to ensure that targeted intervention is delivered at a point in development when change is most likely to occur. The interventions will improve quality of life and reduce barriers to participation. We will ensure our findings are integrated into policy guidelines by contributing to the review of policy documents (e.g. NICE guidelines) and through our existing connections with senior clinicians in NHS services, and through our involvement with a broad range of professional bodies.