Developmental Trajectories in Autism Spectrum Disorder from 6 months to 7 years

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects one-in-a-hundred people. The term 'spectrum' reflects the wide distribution of affectedness both between individuals with the diagnosis and within the same individual as they grow up. That is, there is significant variability in the presentation of both the core defining symptoms of ASD and of the presence and emergence of co-occurring psychiatric symptoms in individuals with ASD across development. However, the influences that underlie this variability are not well understood. We propose to follow-up to mid-childhood a cohort of infants at high familial risk of ASD due to being a younger sibling of a child with an ASD diagnosis. The cohorts have previously been assessed using a range of experimental techniques to measure neurocognitive function (e.g. social attention, executive attention) at ages 6-10 months, 12-15 months, 2 years and 3 years. At each timepoint we have also acquired direct observational and parent-report measures of developmental and language ability, adaptive behaviour and age-appropriate measures of the ASD symptoms, temperament and emergent psychiatric symptoms including Attention Deficit/Hyperactivity Disorder (ADHD) and anxiety. We propose to conduct an age-progressed parallel battery of neurocognitive experiments and behavioural assessments at the 7-year follow-up. We will adopt statistical modelling approaches exploiting the multiple time-points at which both neurocognitive and behavioural measures have been taken in this intensive repetitive sampling design. By these means we will be able to test hypotheses about the underlying developmental mechanisms that could help us understand more about variability over development seen in individuals with ASD. This, in turn, will identify both the potential timing and the targets of possible new early interventions both for the core defining features of ASD and for the common co-occurring psychiatric conditions that emerge in early childhood.

There is significant variability in the presentation of both the core defining symptoms and the presence and emergence of co-occurring psychiatric symptoms in individuals with ASD across development. However, the influences that underlie this variability are not well understood. We propose to follow-up to mid-childhood a cohort of infants at high familial risk of ASD by virtue of older sibling diagnosed. The cohorts have previously been assessed using a range of experimental techniques (EEG/ERP, eye-tracking, observations, behavioural experiments) to measure neurocognitive function (e.g. social attention, executive attention) at ages 6-10 months, 12-15 months, 2 years and 3 years. At each time point we have also acquired direct observational and parent-report measures of developmental and language ability, adaptive behaviour and age-appropriate measures of the ASD phenotype and emergent temperamental/psychiatric phenotypes (e.g. activity/ADHD, behavioural inhibition/anxiety). We propose to conduct an age-progressed parallel battery of neurocognitive experiments and behavioural assessments at 7 years. We will adopt structural equation and growth curve modelling approaches exploiting the multiple time-points at which both neurocognitive and behavioural measures have been taken in this intensive repetitive sampling design (5 time-points across 7 years). Our large and deeply phenotyped cohort provides a unique opportunity to identify infant neurocognitive stratification markers of childhood trajectories of core and associated symptoms of ASD. By these means we will be able to test hypotheses about the underlying developmental mechanisms that could stratify phenotypic heterogeneity in ASD. This, in turn, will identify both the potential timing and the targets of mechanistic-based pre-emptive interventions for the core defining features of ASD and for the common co-occurring psychiatric conditions that emerge in early childhood.

Autism Spectrum Disorder (ASD) affects ~1% of the population. ASD commonly co-occurs with other neurodevelopmental and neuropsychiatric conditions, including intellectual disability, Attention Deficit/Hyperactivity Disorder (ADHD) and anxiety disorders. ASD has a lifelong impact with poor adult outcomes for many individuals, including lack of employment and independent living and UK lifetime costs per individual are £0.9 to £1.5 million depending on intellectual ability. In the National Autistic Society You Need to Know campaign report on mental health (on which the PI was an advisor) parents said that the emotional, behavioural and learning disabilities that their child has are more burdensome that their autism itself. The study of at-risk infant siblings is an important and powerful approach that has already identified neurocognitive signs in infants that presage the later emergence of ASD, including from our own study of the participants in the cohorts we plan to follow-up into mid-childhood. The potential benefits and impact of our proposed new study would allow us for the first time to identify infant markers that predict later trajectories of behavioural and emotional development, including those children who will develop difficulties in the domains of attention and anxiety. Identification of stratification markers of longer-term outcome can inform a personalised medicine approach and improve targeting of intervention strategies on an individual level. This will enable us in future to develop and test mechanistic-based interventions to ameliorate these difficulties pre-emptively, as we have recently shown for core symptoms of ASD through to the age of 3 years (Green et al, in press, JCPP). This stratified or personalised medicine approach holds great promise but cannot be realised until the fundamental questions about underlying mechanisms of risk (and resilience) are answered, as we propose to do in the current study.

Individuals with ASD and their family members will benefit from the research as it will uncover the early infant neurocognitive mechanisms that underlie the wide and little understood variability in outcome seen in individuals with ASD. The potential for psychological (or in future pharmacological) interventions to be targeted towards those at risk of the most chronic trajectory of symptom course of core ASD symptoms, and the emerging mental health difficulties that are only clearly clinically detectable as children enter the school age years, has significant future potential impact for individuals with ASD and their carers. Parents often face delays in obtaining a diagnosis of ASD for their child, despite concerns first being recognised in the early years. However, the age of diagnosis of children with has not changed in the UK over the past decade (Brett et al., 2016, JADD). A better understanding of infant predictors of later-emerging ASD may, in future, lead to earlier and more reliable early identification. At the time of diagnosis parents often ask what the future holds for their child. Understanding more about what predicts variability in outcome for children with ASD, including those most at risk for developing mental health difficulties, will allow clinicians to refine prognostic advice and better guide parents to appropriate services.

Practitioners in the child mental health and child development fields will also benefit as the emerging knowledge from the study will inform future clinic guidelines, practice and training initiatives, in areas ranging from improved earlier detection and prognostic advice to a more individualised approach to early pre-emptive intervention.

Working in partnership with the leading sector charities, including the National Autistic Society and Autistica, we will continue to influence government policy on child mental health and disability. The PI (Charman) was Chair of the Advisory Group to the All Party Parliamentary Group on Autism for over 6 years.