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Abstract Gestational diabetes and the maternal mental disorders of anxiety and depression have been implicated in adverse offspring neuro-behavioural outcomes but these exposures have only been studied in isolation. 1051 children whose mothers were diagnosed with gestational diabetes in UK’s Born in Bradford cohort had linkage to maternal primary care records, providing diagnostic and treatment codes for depression and anxiety. Education record linkage provided results of the Early Years Foundation Stage Profile from the first year of school, aged five. Risk of not attaining a ‘Good level of development’ was analysed using multivariable Poisson regression within a generalised estimating equation framework. Multiple imputation was implemented for missing data. There was limited evidence of increased risk of failure to attain a ‘good level of development’ in those additionally exposed to maternal mental disorders (adjusted RR 1.21; 95% CI 0.94, 1.55). However, there was more evidence in children of Pakistani maternal ethnicity (adjusted RR 1.36; 95% CI 1.04, 1.77) than White British; this may have been driven by English not being the primary language spoken in the home. Therefore there may be groups with GDM in whom it is particularly important to optimise both maternal physical and mental health to improve child outcomes.

Abstract Autism spectrum disorder (ASD) often co-occurs with attention-deficit/hyperactivity disorder (ADHD) and people with these conditions have frontostriatal functional atypicality during motor inhibition. We compared the neural and neurocognitive correlates of motor inhibition and performance monitoring in young adult males with “pure” and combined presentations with age-and sex-matched typically developing controls, to explore shared or disorder-specific atypicality. Males aged 20–27 years with typical development (TD; n = 22), ASD (n = 21), combined diagnoses ASD + ADHD (n = 23), and ADHD (n = 25) were compared using a modified tracking fMRI stop-signal task that measures motor inhibition and performance monitoring while controlling for selective attention. In addition, they performed a behavioural go/no-go task outside the scanner. While groups did not differ behaviourally during successful stop trials, the ASD + ADHD group relative to other groups had underactivation in typical performance monitoring regions of bilateral anterior insula/inferior frontal gyrus, right posterior thalamus, and right middle temporal gyrus/hippocampus during failed inhibition, which was associated with increased stop-signal reaction time. In the behavioural go/no-go task, both ADHD groups, with and without ASD, had significantly lower motor inhibition performance compared to TD controls. In conclusion, only young adult males with ASD + ADHD had neurofunctional atypicality in brain regions associated with performance monitoring, while inhibition difficulties on go/no-go task performance was shared with ADHD. The suggests that young people with ASD + ADHD are most severely impaired during motor inhibition tasks compared to ASD and ADHD but do not reflect a combination of the difficulties associated with the pure disorders.

Objective This paper aims to report our experience of developing, implementing, and evaluating myHealthE (MHE), a digital innovation for Child and Adolescents Mental Health Services (CAMHS), which automates the remote collection and reporting of Patient-Reported Outcome Measures (PROMs) into National Health Services (NHS) electronic healthcare records. Methods We describe the logistical and governance issues encountered in developing the MHE interface with patient-identifiable information, and the steps taken to overcome these development barriers. We describe the application's architecture and hosting environment to enable its operability within the NHS, as well as the capabilities needed within the technical team to bridge the gap between academic development and NHS operational teams. Results We present evidence on the feasibility and acceptability of this system within clinical services and the process of iterative development, highlighting additional functions that were incorporated to increase system utility. Conclusion This article provides a framework with which to plan, develop, and implement automated PROM collection from remote devices back to NHS infrastructure. The challenges and solutions described in this paper will be pertinent to other digital health innovation researchers aspiring to deploy interoperable systems within NHS clinical systems.

BackgroundThe Structured E-Parenting Support (STEPS) app provides support for parents of children with elevated hyperactivity, impulsivity, inattention, and conduct problems who are awaiting clinical assessment. STEPS will be evaluated in a randomized controlled trial (RCT) within the Online Parent Training for the Initial Management of ADHD Referrals (OPTIMA) research program in the United Kingdom. Phase 1 of the OPTIMA tested the feasibility of participants’ recruitment and the app’s usability. ObjectiveThis study aimed to adapt a digital routine clinical monitoring system, myHealthE, for research purposes to facilitate waitlist recruitment; test using remote methods to screen and identify participants quickly and systematically; pilot the acceptability of the recruitment and assessment protocol; and explore the usability of STEPS. MethodsmyHealthE was adapted to screen patients’ data. Parents’ and clinicians’ feedback on myHealthE was collected, and information governance reviews were conducted in clinical services planning to host the RCT. Potential participants for the observational feasibility study were identified from new referrals using myHealthE and non-myHealthE methods. Descriptive statistics were used to summarize the demographic and outcome variables. We estimated whether the recruitment rate would meet the planned RCT sample size requirement (n=352). In addition to the feasibility study participants, another group of parents was recruited to assess the STEPS usability. They completed the adapted System Usability Scale and responded to open-ended questions about the app, which were coded using the Enlight quality construct template. ResultsOverall, 124 potential participants were identified as eligible: 121 (97.6%) via myHealthE and 3 (2.4%) via non-myHealthE methods. In total, 107 parents were contacted, and 48 (44.9%) consented and were asked if, hypothetically, they would be willing to participate in the OPTIMA RCT. Of the 28 feasibility study participants who provided demographic data, 21 (75%) identified as White. Their children had an average age of 8.4 (SD 1.7) years and 65% (31/48) were male. During the primary recruitment period (June to July 2021) when 45 participants had consented, 38 (84%) participants agreed hypothetically to take part in the RCT (rate of 19/mo, 95% CI 13.5-26.1), meeting the stop-go criterion of 18 participants per month to proceed with the RCT. All parents were satisfied or very satisfied with the study procedures. Parents (n=12) recruited to assess STEPS’ usability described it as easy to navigate and use and as having an attractive combination of colors and visual design. They described the content as useful, pitched at the right level, and sensitively presented. Suggested improvements included adding captions to videos or making the recorded reflections editable. ConclusionsRemote recruitment and study procedures for testing a parenting intervention app are feasible and acceptable for parents. The parents felt that STEPS was a useful and easy-to-use digital parenting support tool. International Registered Report Identifier (IRRID)RR2-10.1186/s40814-021-00959-0

Abstract Background Children referred for attention-deficit/hyperactivity disorder (ADHD) often present with a broader pattern of conduct problems including oppositionality and defiance. This combination can be extremely stressful to parents, lower parents’ self-esteem and negatively impact family life. The National Institute for Health and Care Excellence (NICE) recommends that families receive support as soon as possible after their referral. However, as clinical services are overstretched, and traditional in-person parenting intervention programmes are expensive, families often must wait times a long time prior to receiving this vital input. To address this, we have created a digital parenting programme called STEPS. It is delivered as a mobile phone app providing a set of tools and resources that can be easily accessed at parents’ convenience. This study aims to evaluate the clinical and cost-effectiveness of STEPS in supporting parents of children with high levels of hyperactivity/impulsivity, inattention and conduct problems, who are waiting to be assessed by specialist children’s clinical services. Methods Online Parent Training for The Initial Management of ADHD referrals (OPTIMA) is a two-arm superiority parallel randomised controlled trial with an internal pilot study. We aim to recruit 352 parents and their children, who have been accepted onto a waitlist in Child and Adolescent Mental Health Services or similar child health services. Parents who consent will be randomised 1:1 to either the STEPS or wait-as-usual (WAU) group. The trial will be conducted remotely (online and telephone) with measures taken at baseline and 3, 6, 9 and 12 months post-randomisation. The primary objective is to evaluate whether STEPS reduces the severity of children’s oppositional and defiant behaviour, as rated by parents, measured at 3 months post-randomisation compared to WAU. Discussion Digital solutions, such as mobile phone apps, have potential for delivering psychological support for parents of children with clinical-level needs in a timely and inexpensive manner. This trial will provide data on the clinical and cost-effectiveness of the STEPS app, which could support the implementation of this scalable parenting intervention programme into standard clinical care and, ultimately, improve the outcomes for families of children referred to specialist child and adolescent health services. Trial registration ISRCTN 16523503. Prospectively registered on 18 November 2021. https://www.isrctn.com/ISRCTN16523503

IntroductionCompared to full-term (FT) born peers, children who were born very preterm (VPT;

Abstract Background Individuals with autism spectrum disorder (ASD) are at particularly high risk of suicide and suicide attempts. Presentation to a hospital with self-harm is one of the strongest risk factors for later suicide. We describe the use of a novel data linkage between routinely collected education data and child and adolescent mental health data to examine whether adolescents with ASD are at higher risk than the general population of presenting to emergency care with self-harm. Methods A retrospective cohort study was conducted on the population aged 11–17 resident in four South London boroughs between January 2009 and March 2013, attending state secondary schools, identified in the National Pupil Database (NPD). Exposure data on ASD status were derived from the NPD. We used Cox regression to model time to first self-harm presentation to the Emergency Department (ED). Results One thousand twenty adolescents presented to the ED with self-harm, and 763 matched to the NPD. The sample for analysis included 113,286 adolescents (2.2% with ASD). For boys only, there was an increased risk of self-harm associated with ASD (adjusted hazard ratio 2·79, 95% CI 1·40–5·57, P

Abstract Background In the UK, children with high levels of hyperactivity, impulsivity and inattention referred to clinical services with possible attention-deficit/hyperactivity disorder (ADHD) often wait a long time for specialist diagnostic assessment. Parent training (PT) has the potential to support parents during this difficult period, especially regarding the management of challenging and disruptive behaviours that often accompany ADHD. However, traditional face-to-face PT is costly and difficult to organise in a timely way. We have created a low-cost, easily accessible PT programme delivered via a phone app, Structured E-Parenting Support (STEPS), to address this problem. The overall OPTIMA programme will evaluate the efficacy and cost-effectiveness of STEPS as a way of helping parents manage their children behaviour while on the waitlist. To ensure the timely and efficient evaluation of STEPS in OPTIMA, we have worked with children’s health services to implement a remote strategy for recruitment, screening and assessment of recently referred families. Part of this strategy is incorporated into routine clinical practice and part is OPTIMA specific. Here, we present the protocol for Phase 1 of OPTIMA—a study of the feasibility of this remote strategy, as a basis for a large-scale STEPS randomised controlled trial (RCT). Methods This is a single arm observational feasibility study. Participants will be parents of up to 100 children aged 5-11 years with high levels of hyperactivity/impulsivity, inattention and challenging behaviour who are waiting for assessment in one of five UK child and adolescent mental health or behavioural services. Recruitment, consenting and data collection will occur remotely. The primary outcome will be the rate at which the families, who meet inclusion criteria, agree in principle to take part in a full STEPS RCT. Secondary outcomes include acceptability of remote consenting and online data collection procedures; the feasibility of collecting teacher data remotely within the required timeframe, and technical difficulties with completing online questionnaires. All parents in the study will receive access to STEPS. Discussion Establishing the feasibility of our remote recruitment, consenting and assessment strategy is a pre-requisite for the full trial of OPTIMA. It can also provide a model for future trials conducted remotely.

Up to 50% of autistic people experience co-occurring anxiety, which significantly impacts their quality of life. Consequently, developing new interventions (and/ or adapting existing ones) that improve anxiety has been indicated as a priority for clinical research and practice by the autistic community. Despite this, there are very few effective, evidence-based therapies available to autistic people that target anxiety; and those that are available (e.g., autism adapted Cognitive Behavioural Therapy; CBT) can be challenging to access. Thus, the current study will provide an early-stage proof of concept for the feasibility and acceptability of a novel app-based therapeutic approach that has been developed with, and adapted for, autistic people to support them in managing anxiety using UK National Institute for Health and Care Excellence (NICE) recommended adapted CBT approaches. This paper describes the design and methodology of an ethically approved (22/LO/0291) ongoing non-randomised pilot trial that aims to enrol approximately 100 participants aged ≥16-years with an existing autism diagnosis and mild-to-severe self-reported anxiety symptoms (trial registration NCT05302167). Participants will be invited to engage with a self-guided app-based intervention-'Molehill Mountain'. Primary (Generalised Anxiety Disorder Assessment, Hospital Anxiety and Depression Scale) and secondary outcomes (medication/ service use and Goal Attainment Scaling) will be assessed at baseline (Week 2 +/- 2), endpoint (Week 15 +/- 2) and three follow-ups (Weeks 24, 32 and 41 +/- 4). Participants will also be invited to complete an app acceptability survey/ interview at the study endpoint. Analyses will address: 1) app acceptability/ useability and feasibility (via survey/ interview and app usage data); and 2) target population, performance of outcome measures and ideal timing/ duration of intervention (via primary/ secondary outcome measures and survey/ interview)-with both objectives further informed by a dedicated stakeholder advisory group. The evidence from this study will inform the future optimisation and implementation of Molehill Mountain in a randomised-controlled trial, to provide a novel tool that can be accessed easily by autistic adults and may improve mental health outcomes.

Abstract Background Irritability is a common and impairing occurrence in autistic youth, yet the underlying mechanisms are not well-known. In typically developing populations, differences in frustration response have been suggested as important driver of the behavioural symptoms of irritability. Research exploring the role of frustration response as a risk factor for irritability in autistic populations is limited and often uses parent report or observer ratings; objective measures of frustration response appropriate for use in autistic populations are required to advance the field. Methods In the current study, fifty-two autistic adolescents aged 13–17 years from a population-based longitudinal study completed an experimental task designed to induce frustration through exposure to periods of unexpected delay. Behavioural (number of button presses) and physiological (heart rate; HR) metrics were collected during delay periods. Irritability was measured using the parent-rated Affective Reactivity Index (ARI). Analyses used mixed-level models to test whether irritability was associated with different slopes of behavioural and physiological response to experimentally induced frustration during the task. Age and baseline HR (for the physiological data only) were included as covariates. Results Analyses showed a marginal association between irritability and the slope of behavioural response (incident rate ratio (IRR) =.98, p=.06), and a significant association with the slope of physiological response (b=−.10, p=.04); higher levels of irritability were associated with a dampened behavioural and physiological response, as indicated by flatter slopes of change over the course of the task. The pattern of results largely remained in sensitivity analyses, although the association with physiological response became non-significant when adjusting for IQ, autism symptom severity, and medication use (b=−.10, p=.10). Conclusions Results suggest that the current experimental task may be a useful objective measure of frustration response for use with autistic populations, and that a non-adaptive response to frustration may be one biological mechanism underpinning irritability in autistic youth. This may represent an important target for future intervention studies.

Attention-Deficit Hyperactivity Disorder (ADHD) is a complex and heterogeneous neurodevelopmental condition for which curative treatments are lacking. Whilst pharmacological treatments are generally effective and safe, there is considerable inter-individual variability among patients regarding treatment response, required dose, and tolerability. Many of the non-pharmacological treatments, which are preferred to drug-treatment by some patients, either lack efficacy for core symptoms or are associated with small effect sizes. No evidence-based decision tools are currently available to allocate pharmacological or psychosocial treatments based on the patient's clinical, environmental, cognitive, genetic, or biological characteristics. We systematically reviewed potential biomarkers that may help in diagnosing ADHD and/or stratifying ADHD into more homogeneous subgroups and/or predict clinical course, treatment response, and long-term outcome across the lifespan. Most work involved exploratory studies with cognitive, actigraphic and EEG diagnostic markers to predict ADHD, along with relatively few studies exploring markers to subtype ADHD and predict response to treatment. There is a critical need for multisite prospective carefully designed experimentally controlled or observational studies to identify biomarkers that index inter-individual variability and/or predict treatment response.

Objectives To compare, in a population of women with gestational diabetes mellitus (GDM), the time to diagnosis of Type 2 diabetes in those with and without common mental disorder (CMD) (depression and/or anxiety) during pregnancy.Design and setting prospective study of the Born in Bradford cohort in Bradford, UK.Participants 909 women diagnosed with GDM between 2007 and 2010, with linkage to their primary care records until 2017. The exposed population were women with an indicator of CMD during pregnancy in primary care records. The unexposed were those without an indicator.Outcome measures Time to diagnosis of type 2 diabetes as indicated by a diagnosis in primary care records.Analysis time to event analysis using Cox regression was employed. Multiple imputation by chained equations was implemented to handle missing data. Models were adjusted for maternal age, ethnicity, education, preconception CMD and tobacco smoking during pregnancy.Results 165 women (18%) were diagnosed with type 2 diabetes over a follow-up period of around 10 years. There was no evidence of an effect of antenatal CMD on the development of type 2 diabetes following GDM (adjusted HR 0.95; 95% CI 0.57 to 1.57).Conclusions Women with CMD were not at an increased risk of type 2 diabetes following GDM. This is reassuring for women with these co-morbidities but requires replication in other study populations.

Plain English summary Mental health difficulties are common, impacting on the wellbeing, quality of life and overall health of many individuals. Most adult mental health challenges appear before the age of 18, yet there is still a lack of understanding around the factors influencing their development. Research typically relies on young people to reflect back over long periods, making it difficult to observe small changes in a real time setting. A better understanding of short term changes in symptoms could lead to new insights and inform new treatments. Given that young people are early adopters of new technology, an obvious way forward is to use mobile devices to capture young people’s self-reported mood, wellbeing daily events and experiences as they happen in real-time. Such methods would allow researchers and clinicians to gain a more detailed understanding of daily mood changes as well as how daily experiences can impact on mood and the overall mental health of young people. In order to develop an engaging mobile product that is useful, it is important to involve the end-users (young people) in development, design and testing processes. This involvement is also useful for exploring the ethical and practical concerns of developing mobile health technologies, particularly in the context of young people. This process forms part of a larger research project which explores the possibility of young people using a mobile mood monitoring application within a school setting. This article describes our Patient and Public Involvement (PPI) work with young people, with the aim of i) informing the development of our mood monitoring application, and ii) providing feedback and advice to researchers developing web-based technologies for young people in the mental health field. We found that young people were engaged in discussions around mobile health technologies and valued the opportunity to collaborate throughout the early stages of a development process. Participants actively collaborated through co-design practises and offered insight into design and function expectations and preferences. The advisory groups provided important context to our project, informing us of attitudes towards commercially available wellbeing applications, as well as mental health school-based research more broadly. In addition, young people highlighted key considerations for future web-development work, including, the promotion of trust and transparency, consideration of accessibility, provision of support, production of engaging and functional design, and an understanding of young people’s specific context.

Background The global COVID-19 pandemic has had an unprecedented impact on European health and social care systems, with demands on testing, hospital and intensive care capacity exceeding available resources in many regions. This has led to concerns that some vulnerable groups, including autistic people, may be excluded from services.Methods We reviewed policies from 15 European member states, published in March–July 2020, pertaining to (1) access to COVID-19 tests; (2) provisions for treatment, hospitalisation and intensive care units (ICUs); and (3) changes to standard health and social care. In parallel, we analysed survey data on the lived experiences of 1301 autistic people and caregivers.Results Autistic people experienced significant barriers when accessing COVID-19 services. First, despite being at elevated risk of severe illness due to co-occurring health conditions, there was a lack of accessibility of COVID-19 testing. Second, many COVID-19 outpatient and inpatient treatment services were reported to be inaccessible, predominantly resulting from individual differences in communication needs. Third, ICU triage protocols in many European countries (directly or indirectly) resulted in discriminatory exclusion from lifesaving treatments. Finally, interruptions to standard health and social care left over 70% of autistic people without everyday support.Conclusions The COVID-19 pandemic has further exacerbated existing healthcare inequalities for autistic people, probably contributing to disproportionate increases in morbidity and mortality, mental health and behavioural difficulties, and reduced quality of life. An urgent need exists for policies and guidelines on accessibility of COVID-19 services to be updated to prevent the widespread exclusion of autistic people from services, which represents a violation of international human rights law.

The alexithymia hypothesis posits that specific aspects of the autistic socio-cognitive profile, namely emotion recognition difficulties, can be explained by the increased prevalence of alexithymia in autistic populations. However, this hypothesis has largely been tested in adults. We tested whether co-occurring alexithymia could account for associations between autistic traits and two key domains of socio-emotional cognitive functioning in adolescence. Participants were 184 (44% male) children aged 10-16 years with and without a diagnosis of autism (n = 75 autistic), who completed experimental measures of emotion recognition and theory of mind. Parents completed assessment of autistic traits and alexithymia. Pre-registered analyses tested associations between autistic traits and socio-cognitive task performance, and whether including alexithymia as an additional predictor changed the nature of the association between autistic traits and task performance. Results showed participants with higher levels of autistic traits performed lower on emotion recognition and theory of mind tasks, and that these associations were not significantly altered by including alexithymia in the models. Results suggest that more work is needed to understand the applicability of the alexithymia hypothesis in younger populations, but that at least in young adolescents and when using parent-report measures, alexithymia may not be associated with emotion recognition or theory of mind ability.

Theory of mind (ToM) or mentalizing difficulties is reported in attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), but the mechanism underpinning these apparently shared deficits is relatively unknown. Eighty-three young adult males, 19 with ASD alone, 21 with ADHD alone, 18 with dual diagnosis of ASD and ADHD, and 25 typically developing (TD) controls completed the functional magnetic resonance imaging version of the Frith-Happé animated-triangle ToM task. We compared neural function during ToM with two non-ToM conditions, random and goal directed motions, using whole-brain and region-of-interest analysis of brain activation and functional connectivity analyses. The groups showed comparable ToM task performance. All three clinical groups lacked local connectivity increase shown by TD controls during ToM in the right temporoparietal cortex, a key mentalizing region, with a differentially increased activation pattern in both ASD and comorbid groups relative to ADHD. Both ASD groups also showed reduced connectivity between right inferior lateral prefrontal and posterior cingulate cortices that could reflect an atypical information transmission to the mentalizing network. In contrast, with mentalizing both ADHD groups showed decreasing connectivity between the medial prefrontal and left temporoparietal cortices when compared to TD controls. Therefore, despite the complex pattern of atypical brain function underpinning ToM across the three disorders, some neurofunctional abnormalities during ToM are associated with ASD and appeared differentiable from those associated with ADHD, with the comorbid group displaying combined abnormalities found in each condition.

Abstract Background Many young people with autism spectrum disorder (ASD) experience emotional and behavioural problems. However, the causes of these co-occurring difficulties are not well understood. Perceptual processing atypicalities are also often reported in individuals with ASD, but how these relate to co-occurring emotional and behavioural problems remains unclear, and few studies have used objective measurement of perceptual processing. Methods Event-related potentials (ERPs) were recorded in response to both standard and deviant stimuli (which varied in pitch) in an auditory oddball paradigm in adolescents (mean age of 13.56 years, SD = 1.12, range = 11.40–15.70) with ASD (n = 43) with a wide range of IQ (mean IQ of 84.14, SD = 24.24, range 27–129). Response to deviant as compared to standard stimuli (as indexed by the mismatch negativity (MMN)) and response to repeated presentations of standard stimuli (habituation) were measured. Multivariate regression tested the association between neural indices of perceptual processing and co-occurring emotional and behavioural problems. Results Greater sensitivity to changes in pitch in incoming auditory information (discrimination), as indexed by increased MMN amplitude, was associated with higher levels of parent-rated behaviour problems. MMN amplitude also showed a trend positive correlation with parent-rated sensory hyper-sensitivity. Conversely, greater habituation at the later N2 component was associated with higher levels of emotional problems. Upon more detailed analyses, this appeared to be driven by a selectively greater ERP response to the first (but not the second or third) standard stimuli that followed deviant stimuli. A similar pattern of association was found with other measures of anxiety. All results remained in covariation analyses controlling for age, sex and IQ, although the association between MMN amplitude and behaviour problems became non-significant when controlling for ASD severity. Conclusions Findings suggest that alterations in mechanisms of perceptual processing and discrimination may be important for understanding co-occurring emotional and behavioural problems in young people with ASD.

Abstract Background Individuals with autism spectrum disorder (ASD) frequently demonstrate symptoms of attention-deficit/hyperactivity disorder (ADHD). Previous findings in children with ASD have suggested that these symptoms are associated with an impairment in executive function (EF) abilities. However, studies rarely considered this association within a single framework that controls for other related factors such as Theory of Mind (ToM) abilities and ASD symptoms. Methods We used structural equation modeling to explore the relations among EF, ToM, and symptoms of ASD and ADHD, using data from a population-based sample of 100 adolescents with ASD and full-scale IQ ≥ 50 (the Special Needs and Autism Project (SNAP) cohort). The study used a multi-measure and multi-informant approach, where performance of inhibition, planning, switching, and working memory tasks indexed EF and performance on tasks involving mentalizing indexed ToM. Measures of ASD and ADHD symptoms included parent and teacher reports and direct observation of the children. Shared source of symptom reporting was accounted for with a parental rating latent factor indexed by symptom measures reported by parents. Results Impairments in EF abilities were specifically associated with ADHD symptoms while impaired ToM was specifically associated with ASD symptoms, when accounting for the associations of each cognitive domain with the other factors. ASD and ADHD symptom latent factors were also correlated, but this association became nonsignificant once the shared source of reporting from parents was accounted for and within a model that also controlled for the correlated pathway between EF and ToM factors. The specific relations between the cognitive domains and behavioral symptoms remained even after controlling for IQ. Conclusions In this ASD sample, symptoms of ADHD and ASD are underpinned by separate cognitive domains. The association between EF and ToM impairments is a likely partial explanation for the co-occurrence of ADHD symptoms in ASD, but the role of shared reporting effects is also important and supports the inclusion of independent informants and objective measures in future research.

Abstract Background The tremendous clinical and aetiological diversity among individuals with autism spectrum disorder (ASD) has been a major obstacle to the development of new treatments, as many may only be effective in particular subgroups. Precision medicine approaches aim to overcome this challenge by combining pathophysiologically based treatments with stratification biomarkers that predict which treatment may be most beneficial for particular individuals. However, so far, we have no single validated stratification biomarker for ASD. This may be due to the fact that most research studies primarily have focused on the identification of mean case-control differences, rather than within-group variability, and included small samples that were underpowered for stratification approaches. The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study worldwide that aims to identify and validate stratification biomarkers for ASD. Methods LEAP includes 437 children and adults with ASD and 300 individuals with typical development or mild intellectual disability. Using an accelerated longitudinal design, each participant is comprehensively characterised in terms of clinical symptoms, comorbidities, functional outcomes, neurocognitive profile, brain structure and function, biochemical markers and genomics. In addition, 51 twin-pairs (of which 36 had one sibling with ASD) are included to identify genetic and environmental factors in phenotypic variability. Results Here, we describe the demographic characteristics of the cohort, planned analytic stratification approaches, criteria and steps to validate candidate stratification markers, pre-registration procedures to increase transparency, standardisation and data robustness across all analyses, and share some ‘lessons learnt’. A clinical characterisation of the cohort is given in the companion paper (Charman et al., accepted). Conclusion We expect that LEAP will enable us to confirm, reject and refine current hypotheses of neurocognitive/neurobiological abnormalities, identify biologically and clinically meaningful ASD subgroups, and help us map phenotypic heterogeneity to different aetiologies.

Abstract Background The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study on biomarkers for autism spectrum disorder (ASD). The current paper describes the clinical characteristics of the LEAP cohort and examines age, sex and IQ differences in ASD core symptoms and common co-occurring psychiatric symptoms. A companion paper describes the overall design and experimental protocol and outlines the strategy to identify stratification biomarkers. Methods From six research centres in four European countries, we recruited 437 children and adults with ASD and 300 controls between the ages of 6 and 30 years with IQs varying between 50 and 148. We conducted in-depth clinical characterisation including a wide range of observational, interview and questionnaire measures of the ASD phenotype, as well as co-occurring psychiatric symptoms. Results The cohort showed heterogeneity in ASD symptom presentation, with only minimal to moderate site differences on core clinical and cognitive measures. On both parent-report interview and questionnaire measures, ASD symptom severity was lower in adults compared to children and adolescents. The precise pattern of differences varied across measures, but there was some evidence of both lower social symptoms and lower repetitive behaviour severity in adults. Males had higher ASD symptom scores than females on clinician-rated and parent interview diagnostic measures but not on parent-reported dimensional measures of ASD symptoms. In contrast, self-reported ASD symptom severity was higher in adults compared to adolescents, and in adult females compared to males. Higher scores on ASD symptom measures were moderately associated with lower IQ. Both inattentive and hyperactive/impulsive ADHD symptoms were lower in adults than in children and adolescents, and males with ASD had higher levels of inattentive and hyperactive/impulsive ADHD symptoms than females. Conclusions The established phenotypic heterogeneity in ASD is well captured in the LEAP cohort. Variation both in core ASD symptom severity and in commonly co-occurring psychiatric symptoms were systematically associated with sex, age and IQ. The pattern of ASD symptom differences with age and sex also varied by whether these were clinician ratings or parent- or self-reported which has important implications for establishing stratification biomarkers and for their potential use as outcome measures in clinical trials.

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often co-occur and share neurocognitive deficits. One such shared impairment is in duration discrimination. However, no studies using functional magnetic resonance imaging (fMRI) have investigated whether these duration discrimination deficits are underpinned by the same or different underlying neurofunctional processes. In this study, we used fMRI to compare the neurofunctional correlates of duration discrimination between young adult males with ASD (n = 23), ADHD (n = 25), the comorbid condition of ASD+ADHD (n = 24), and typical development (TD, n = 26) using both region of interest (ROI) and whole brain analyses. Both the ROI and the whole-brain analyses showed that the comorbid ASD+ADHD group compared to controls, and for the ROI analysis relative to the other patient groups, had significant under-activation in right inferior frontal cortex (IFG) a key region for duration discrimination that is typically under-activated in boys with ADHD. The findings show that in young adult males with pure ASD, pure ADHD and comorbid ASD+ADHD with no intellectual disability, only the comorbid group demonstrates neurofunctional deficits in a typical duration discrimination region.

Background: Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) frequently persist into adolescence and young adulthood. However, there are few clinical services that support those with these disorders through adulthood. Objective: Our aim was to determine if clinical services meet the needs of people with ASD and ADHD, who are ‘at transition’ from childhood to adulthood. Design: A longitudinal study of individuals with ASD and ADHD, the impact of services and treatments. Methods: Our research methods included (1) interviewing > 180 affected individuals (and their families) with a confirmed diagnosis of ASD and/or ADHD, (2) screening for ASD and ADHD in approximately 1600 patients and (3) surveying general practitioner prescribing to 5651 ASD individuals across the UK. In addition, we tested the effectiveness of (1) new ASD diagnostic interview measures in 169 twins, 145 familes and 150 non-twins, (2) a magnetic resonance imaging-based diagnostic aid in 40 ASD individuals, (3) psychological treatments in 46 ASD individuals and (4) the feasability of e-learning in 28 clinicians. Setting: NHS clinical services and prisons. Participants: Focus – young people with ASD and ADHD as they ‘transition’ from childhood and adolescence into early adulthood. Interventions: Testing the utility of diagnostic measures and services, web-based learning interventions, pharmacological prescribing and cognitive–behavioural treatments. Main outcome measures: Symptom severity, service provision and met/unmet need. Results: People with ASD and ADHD have very significant unmet needs as they transition through adolescence and young adulthood. A major contributor to this is the presence of associated mental health symptoms. However, these are mostly undiagnosed (and untreated) by clinical services. Furthermore, the largest determinant of service provision was age and not severity of symptoms. We provide new tools to help diagnose both the core disorders and their associated symptoms. We also provide proof of concept for the effectiveness of simple psychological interventions to treat obsessional symptoms, the potential to run treatment trials in prisons and training interventions. Limitations: Our findings only apply to clinical service settings. Conclusions: As individuals ‘transition’ their contact with treatment and support services reduces significantly. Needs-led services are required, which can both identify individuals with the ‘core symptoms’ of ASD and ADHD and treat their residual symptoms and associated conditions. Future work: To test our new diagnostic measures and treatment approaches in larger controlled trials. Trial registration: Current Controlled Trials ISRCTN87114880. Funding: The National Institute for Health Research Programme Grants for Applied Research programme.

Background: The needs of children with autism spectrum disorder (ASD) are complex and this is reflected in the number and diversity of outcomes assessed and measurement tools used to collect evidence about children’s progress. Relevant outcomes include improvement in core ASD impairments, such as communication, social awareness, sensory sensitivities and repetitiveness; skills such as social functioning and play; participation outcomes such as social inclusion; and parent and family impact. Objectives: To examine the measurement properties of tools used to measure progress and outcomes in children with ASD up to the age of 6 years. To identify outcome areas regarded as important by people with ASD and parents. Methods: The MeASURe (Measurement in Autism Spectrum disorder Under Review) research collaboration included ASD experts and review methodologists. We undertook systematic review of tools used in ASD early intervention and observational studies from 1992 to 2013; systematic review, using the COSMIN checklist (Consensus-based Standards for the selection of health Measurement Instruments) of papers addressing the measurement properties of identified tools in children with ASD; and synthesis of evidence and gaps. The review design and process was informed throughout by consultation with stakeholders including parents, young people with ASD, clinicians and researchers. Results: The conceptual framework developed for the review was drawn from the International Classification of Functioning, Disability and Health, including the domains ‘Impairments’, ‘Activity Level Indicators’, ‘Participation’, and ‘Family Measures’. In review 1, 10,154 papers were sifted – 3091 by full text – and data extracted from 184; in total, 131 tools were identified, excluding observational coding, study-specific measures and those not in English. In review 2, 2665 papers were sifted and data concerning measurement properties of 57 (43%) tools were extracted from 128 papers. Evidence for the measurement properties of the reviewed tools was combined with information about their accessibility and presentation. Twelve tools were identified as having the strongest supporting evidence, the majority measuring autism characteristics and problem behaviour. The patchy evidence and limited scope of outcomes measured mean these tools do not constitute a ‘recommended battery’ for use. In particular, there is little evidence that the identified tools would be good at detecting change in intervention studies. The obvious gaps in available outcome measurement include well-being and participation outcomes for children, and family quality-of-life outcomes, domains particularly valued by our informants (young people with ASD and parents). Conclusions: This is the first systematic review of the quality and appropriateness of tools designed to monitor progress and outcomes of young children with ASD. Although it was not possible to recommend fully robust tools at this stage, the review consolidates what is known about the field and will act as a benchmark for future developments. With input from parents and other stakeholders, recommendations are made about priority targets for research. Future work: Priorities include development of a tool to measure child quality of life in ASD, and validation of a potential primary outcome tool for trials of early social communication intervention. Study registration: This study is registered as PROSPERO CRD42012002223. Funding: The National Institute for Health Research Health Technology Assessment programme.

This systematic review (Prospero Registration Number: CRD42019142910) aimed to narratively synthesise technology-aided assessments and treatments of anxiety in individuals with autism spectrum disorder (ASD) for the first time. Sixteen studies were identified: 5 assessment studies and 11 treatment studies. Assessment studies targeted state anxiety using ecological momentary assessment, wearables, or computerised tasks. Treatment studies targeted specific fears/phobias using electronic screen media or transdiagnostic anxiety using telemedicine. Broadly, results indicated technology-aided assessments and treatments may be feasible and effective at targeting anxiety in ASD, except treatments involving social scripts or peer modelling. Assessment results further indicated that state anxiety in ASD has a distinct psychophysiological signature and is evoked by idiosyncratic triggers. However, larger scale studies with representative samples are needed.

In order to reduce societal levels of violence, it is essential to advance understanding of the neurobiological mechanisms involved in initiating and maintaining individual patterns of physical aggression. New technologies such as Magnetic Resonance Imagining and analyses of DNA provide tools for identifying these mechanisms. The reliability and validity of the results of studies using these tools depend not only on aspects of the technology, but also on the methodological rigour with which the studies are conducted, particularly with respect to characterizing the phenotype. The present article discusses five challenges confronting scientists who aim to advance understanding of the neurobiological mechanisms associated with persistent violence. These challenges are: (1) to develop evidence-based hypotheses and to design studies that test alternate hypotheses; (2) to recruit samples that are homogeneous with respect to variables that may be linked to neurobiological mechanisms underpinning violent behaviour; (3) to use reliable and valid measures in order to fully characterize participants so that the external validity of the results is evident; (4) to restrict the range of age of participants so as not to confuse developmental change with group differences; and (5) to take account of sex. Our goal is to contribute to elevating methodological standards in this new field of research and to thereby improve the validity of results and move closer to finding effective ways to reduce violence