Mapping associations of polygenic scores with autistic and ADHD traits in a single city region.

BACKGROUND: The genetic and environmental aetiology of autistic and Attention Deficit Hyperactivity Disorder (ADHD) traits is known to vary spatially, but does this translate into variation in the association of specific common genetic variants? METHODS: We mapped associations between polygenic scores for autism and ADHD and their respective traits in the Avon Longitudinal Study of Parents and Children (N = 4,255-6,165) across the area surrounding Bristol, UK, and compared them to maps of environments associated with the prevalence of autism and ADHD. RESULTS: Our results suggest genetic associations vary spatially, with consistent patterns for autistic traits across polygenic scores constructed at different p-value thresholds. Patterns for ADHD traits were more variable across thresholds. We found that the spatial distributions often correlated with known environmental influences. CONCLUSIONS: These findings shed light on the factors that contribute to the complex interplay between the environment and genetic influences in autistic and ADHD traits.

Sex differences in self-harm and suicide in young autistic adults.

INTRODUCTION: Both suicide and self-harm are disproportionately common in autistic people. Sex differences in risk of self-harm and suicide are observed in the general population, but findings are mixed for autistic people. Self-cutting may be a particularly risky self-harm behaviour for suicide in autistic people. We aimed to explore sex differences and differences in method of self-harm in the association between self-harm and suicide in autistic and non-autistic adolescents and young adults. METHODS: We used a total population register of 2.8 million Swedish residents. Participants were followed from age 12 until December 2021 for medical treatment because of self-harm, and death from suicide. We used Cox proportional hazard regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of death from suicide following self-harm, and Relative Excessive Risk due to Interaction (RERI) to explore the interaction between self-harm and autism in females and males. RESULTS: We identified 85,143 autistic individuals (31,288 female; 53,855 male) and 2,628,382 non-autistic individuals (1,286,481 female; 1,341,901 male) aged 12-37 years. Incidence of suicide following self-harm was higher in autistic males (incidence per 100,000 risk-years = 169.0 [95% CI 135.1, 211.3]) than females (125.4 [99.4, 158.3]). The relative risk was higher for autistic females (HR 26.1 [95% CI 20.2, 33.7]) than autistic males (12.5 [9.9, 15.8]). An additive effect of both autism and self-harm was observed in both females (RERI = 9.8) and males (2.0). Autistic individuals who self-harmed through cutting were at greatest risk of death from suicide (HR 25.1 [17.9, 35.2]), compared to other methods. CONCLUSION: Autistic males and females are at increased risk of death from suicide following severe self-harm, particularly self-cutting.

Maternal smoking during pregnancy and offspring risk of intellectual disability: a UK-based cohort study.

Background: Observational studies have described associations of maternal smoking during pregnancy with intellectual disability (ID) in the exposed offspring. Whether these results reflect a causal effect or unmeasured confounding is still unclear. Methods: Using a UK-based prospectively collected birth cohort (the Avon Longitudinal Study of Parents and Children) of 13,479 children born between 1991 and 1992, we assessed the relationship between maternal smoking at 18 weeks' gestation and offspring risk of ID, ascertained through multiple sources of linked information including primary care diagnoses and education records. Using confounder-adjusted logistic regression, we performed observational analyses and a negative control analysis that compared maternal with partner smoking in pregnancy under the assumption that if a causal effect were to exist, maternal effect estimates would be of greater magnitude than estimates for partner smoking if the two exposures suffer from comparable biases. Results: In observational analysis, we found an adjusted odds ratio for ID of 0.75 (95% CI = 0.49-1.13) for any maternal smoking and 0.97 (95% CI = 0.71-1.33) per 10-cigarette increase in number of cigarettes smoked per day. In negative control analysis, comparable effect estimates were found for any partner smoking (OR = 0.94; 95% CI = 0.63-1.40) and number of cigarettes smoked per day (OR = 0.94; 95% CI = 0.74-1.20). Conclusions: The results are not consistent with a causal effect of maternal smoking during pregnancy on offspring ID.

Completion of Upper Secondary Mainstream School in Autistic Students in Sweden.

Higher education is an increasingly necessary achievement to attain employment. However, even in cases where a student has the academic skills to succeed, educational environments may not support students across all other domains necessary for education success, including social and communication needs. This is especially true for students with disabilities and autistic students, where the rate of completion of non-compulsory education is unknown. We used the Stockholm Youth Cohort (children aged 0-17 years from 2001 to 2011), a total population cohort (N = 736,180) including 3,918 autistic individuals, to investigate the association between autism without intellectual disability and completion of upper secondary education. We assessed the impact of sex and co-occurring Attention-Deficit/Hyperactivity Disorder (ADHD) on this association. By age 20 years (the expected age of completion), 68% of autistic students and 91% of non-autistic students admitted to upper secondary education had completed. In logistic regression models adjusted for student demographics, autistic students had almost five-fold higher odds of not completing secondary school (OR 4.90, 95% CI 4.56 5.26) compared to their non-autistic peers. Autistic students with ADHD had particularly high odds of non-completion of upper secondary school. Autistic students without intellectual disability attending mainstream education are substantially less likely to complete upper secondary education as compared to their peers. These findings have implications for the appraisal of how inclusive school policies serve autistic students' academic and social needs, ultimately addressing population health and independent living.

Behavioural interventions to treat anxiety in adults with autism and moderate to severe intellectual disabilities: The BEAMS-ID feasibility study.

BACKGROUND: The aim of this feasibility study was to adapt and model a behavioural intervention for anxiety with autistic adults with moderate to severe intellectual disabilities. METHOD: Twenty-eight autistic adults with moderate or severe intellectual disabilities, 37 carers, and 40 therapists took part in this single-group non-randomised feasibility study designed to test intervention feasibility and acceptability, outcome measures, and research processes. RESULTS: The intervention was judged as feasible and acceptable by autistic adults with intellectual disabilities, carers, and therapists. Minor intervention revisions were suggested. Carers completed 100% of outcome measures and the missing data rate was low. Complying with legislation governing the inclusion of participants who lack capacity to decide whether they wanted to take part in this study led to an average 5-week enrolment delay. CONCLUSION: The intervention and associated study processes were judged to be feasible and acceptable and should now be tested within a larger randomised trial.

Childhood trauma as a mediator between autistic traits and depression: evidence from the ALSPAC birth cohort.

Background: Autism and autistic traits have been associated with greater risk of childhood trauma and adulthood psychopathology. However, the role that childhood trauma plays in the association between autism, autistic traits and depression in adulthood is poorly understood. Methods: We used a UK-based birth cohort with phenotype and genotype data on autism, autistic traits, childhood trauma and depression in up to 9,659 individuals prospectively followed up from birth until age 28 years. Using mixed-effects growth-curve models, we assessed trajectories of depression symptoms over time according to the presence or absence of autism/ autistic traits and explored whether these differed by trauma exposure. We further investigated the association between autism/ autistic traits and depression in adulthood using confounder-adjusted logistic regression models and undertook mediation analyses to investigate the relationship with childhood trauma. Results: All autism variables demonstrated increased depressive symptom trajectories between ages 10-28 years. Social communication difficulties (SCDs) were the most strongly associated with a depression diagnosis in adulthood (age 24 OR= 2.15; 95%CIs: 1.22-3.76). Trauma and autistic traits combined to further increase depression symptom scores. Mediation analyses provided evidence for direct pathways between autistic traits and increased risk of depression alongside indirect pathways through increased risk of trauma. Conclusions: Autism/ autistic traits increase the odds of experiencing childhood trauma and of being diagnosed with depression at age 18 and 24. Depressive symptom trajectories emergent in childhood persist into adulthood. The combined effect of SCDs and childhood trauma is greater than the individual exposures, suggesting worse depression symptomatology following trauma in individuals with SCDs.

A Systematic Review of Gender Dysphoria Measures in Autistic Samples.

This systematic review investigated how studies have measured gender dysphoria (GD) in autistic samples and the impact of using different measures on study results. The literature search identified 339 relevant papers, with 12 of them meeting the inclusion criteria. Results showed that seven different measures of GD characteristics have been used with autistic samples and that the studies consistently reported a greater number of GD characteristics and a greater severity of GD in autistic compared to non-autistic samples. Methodological common practices were found in recruiting participants from clinical settings rather than the general population, having more autistic males than females in the samples, for studies being conducted in Europe, North America, and Oceania, and using single-item measures of GD for samples of autistic children. Issues were identified with study designs and measures of GD, suggesting a need for a more standardized multi-item self-report measure of GD for use in clinical and non-clinical samples across different ages and cultures.

First-trimester use of antiseizure medications and the risk of miscarriage: a population-based cohort study.

BACKGROUND: Antiseizure medications (ASMs) during the first trimester of pregnancy have been associated with an increased risk of miscarriage. METHODS: We carried out a population-based cohort study using routinely collected healthcare data from the UK, 1995-2018. Pregnancies were identified in the Clinical Practice Research Datalink and we estimated the HR of miscarriage associated with prescriptions of ASMs during the first trimester of pregnancy, using Cox regression, adjusting for potential confounders, including ASM indications. RESULTS: ASMs were prescribed during the first trimester in 7832 (0.8%) of 1 023 787 included pregnancies. 14.5% of pregnancies with first-trimester exposure to ASMs ended in miscarriage, while 12.2% without ASM exposure in the first trimester ended in miscarriage; after adjustment, there was a 1.06-fold relative hazard of miscarriage (95% CI 1.00 to 1.13) in women with first-trimester ASM use. After restricting to women with specific ASM indications, this association was not evident in women with epilepsy (adjusted HR 0.98, 95% CI 0.89 to 1.08), but was observed in women with bipolar or other psychiatric conditions (1.08, 95% CI 1.00 to 1.16) although CIs overlapped. Compared with discontinuation of ASMs prior to pregnancy, there was no evidence of increased risk of miscarriage for first-trimester ASM use in women with bipolar or other psychiatric conditions (1.02, 95% CI 0.87 to 1.20). CONCLUSION: We found no clear evidence to suggest that first-trimester ASM use increased the risk of miscarriage. Taken together, our analyses suggest that apparent associations between first-trimester ASM use and miscarriage may be the result of confounding by the presence of a bipolar disorder or associated unmeasured variables.

Environmental and genetic predictors of whole blood mercury and selenium concentrations in pregnant women in a UK birth cohort.

There is evidence that tissue concentrations of mercury (Hg) and selenium (Se) are predicted by numerous dietary, sociodemographic, environmental, and genetic factors. This study aimed to estimate the relative importance of predictors of Hg and Se concentrations in blood samples taken from pregnant women. The Avon Longitudinal Study of Parents and Children (ALSPAC) in the UK measured whole blood Hg and Se concentrations in 3,972 pregnant women. We identified 30 potential predictors of Hg and 24 of Se, which were evaluated using cross-validated random forests to identify the optimal models for predictive power. The relative importance of individual variables was estimated by averaging the added-R2 per predictor. Linkage disequilibrium score regression was used to estimate the variance explained by genotype. A multivariable model of 14 predictors explained 22.4% of Hg variance (95% CI: 13.0 to 37.1), including 6.9% from blood Se and 3.2% from white fish consumption. There were 11 predictors which explained 15.3% of Se variance (CI: 8.9 to 25.9), including 6.4% from blood Hg, 1.3% from blood lead, and 1.3% from oily fish. Measured genetic variation explained 30% of Hg variance (CI: 8.4 to 51.5) and 37.5% of Se (CI: 10.4 to 64.5). A high proportion of Hg and Se variance could be explained from dietary, sociodemographic, metabolic, and genetic factors. Seafood consumption was less predictive of Hg than may be expected and other factors should be considered when determining risk of exposure. There was tentative evidence that genotype is a major contributor to Hg and Se variation, possibly by modifying the efficacy of internal metabolism.

Structural models of genome-wide covariance identify multiple common dimensions in autism.

Common genetic variation has been associated with multiple phenotypic features in Autism Spectrum Disorder (ASD). However, our knowledge of shared genetic factor structures contributing to this highly heterogeneous phenotypic spectrum is limited. Here, we developed and implemented a structural equation modelling framework to directly model genomic covariance across core and non-core ASD phenotypes, studying autistic individuals of European descent with a case-only design. We identified three independent genetic factors most strongly linked to language performance, behaviour and developmental motor delay, respectively, studying an autism community sample (N = 5331). The three-factorial structure was largely confirmed in independent ASD-simplex families (N = 1946), although we uncovered, in addition, simplex-specific genetic overlap between behaviour and language phenotypes. Multivariate models across cohorts revealed novel associations, including links between language and early mastering of self-feeding. Thus, the common genetic architecture in ASD is multi-dimensional with overarching genetic factors contributing, in combination with ascertainment-specific patterns, to phenotypic heterogeneity.

Association between antidepressant use during pregnancy and miscarriage: a systematic review and meta-analysis.

BACKGROUND: Literature surrounding the association between antidepressant use during pregnancy and miscarriage is conflicting. We aimed to conduct a systematic review and meta-analysis of studies among pregnant women regarding the association between exposure to antidepressants during pregnancy and the risk of miscarriage, compared with pregnant women not exposed to antidepressants. DESIGN: We conducted a systematic review and meta-analysis of non-randomised studies. DATA SOURCES: We searched Medline, Embase and PsychINFO up to 6 August 2023. ELIGIBILITY CRITERIA AND OUTCOMES: Case-control, cohort and cross-sectional study designs were selected if they compared individuals exposed to any antidepressant class during pregnancy to comparator groups of either no antidepressant use or an alternate antidepressant. DATA EXTRACTION AND SYNTHESIS: Effect estimates were extracted from selected studies and pooled using a random-effects meta-analysis. Risk of bias (RoB) was assessed using the Risk of Bias in Non-Randomised Studies of Interventions (ROBINS-I) tool, and heterogeneity assessed using the I2 statistic. Subgroup analyses were used to explore antidepressant classes and the impact of confounding by indication. RESULTS: 1800 records were identified from the search, of which 29 were included in the systematic review and meta-analysis. The total sample included 5 671 135 individuals. Antidepressant users initially appeared to have a higher risk of miscarriage compared with unexposed individuals from the general population (summary effect estimate: 1.24, 95% CI 1.18 to 1.31, I2=69.2%; number of studies (n)=29). However, the summary estimate decreased when comparing against unexposed individuals with maternal depression (1.16, 1.04 to 1.31; I2=58.6%; n=6), suggesting confounding by indication may be driving the association. 22 studies suffered from serious RoB, and only two of the 29 studies were deemed at moderate RoB. CONCLUSIONS: After accounting for maternal depression, there is little evidence of any association between antidepressant use during pregnancy and miscarriage. Instead, the results indicate the biasing impact of confounding by indication.

Sertraline for anxiety in adults with a diagnosis of autism (STRATA): study protocol for a pragmatic, multicentre, double-blind, placebo-controlled randomised controlled trial.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to manage anxiety in adults with an autism diagnosis. However, their effectiveness and adverse effect profile in the autistic population are not well known. This trial aims to determine the effectiveness and cost-effectiveness of the SSRI sertraline in reducing symptoms of anxiety and improving quality of life in adults with a diagnosis of autism compared with placebo and to quantify any adverse effects. METHODS: STRATA is a two-parallel group, multi-centre, pragmatic, double-blind, randomised placebo-controlled trial with allocation at the level of the individual. It will be delivered through recruiting sites with autism services in 4 regional centres in the United Kingdom (UK) and 1 in Australia. Adults with an autism diagnosis and a Generalised Anxiety Disorder Assessment (GAD-7) score ≥ 10 at screening will be randomised 1:1 to either 25 mg sertraline or placebo, with subsequent flexible dose titration up to 200 mg. The primary outcome is GAD-7 scores at 16 weeks post-randomisation. Secondary outcomes include adverse effects, proportionate change in GAD-7 scores including 50% reduction, social anxiety, obsessive-compulsive symptoms, panic attacks, repetitive behaviours, meltdowns, depressive symptoms, composite depression and anxiety, functioning and disability and quality of life. Carer burden will be assessed in a linked carer sub-study. Outcome data will be collected using online/paper methods via video call, face-to-face or telephone according to participant preference at 16, 24 and 52 weeks post-randomisation, with brief safety checks and data collection at 1-2, 4, 8, 12 and 36 weeks. An economic evaluation to study the cost-effectiveness of sertraline vs placebo and a QuinteT Recruitment Intervention (QRI) to optimise recruitment and informed consent are embedded within the trial. Qualitative interviews at various times during the study will explore experiences of participating and taking the trial medication. DISCUSSION: Results from this study should help autistic adults and their clinicians make evidence-based decisions on the use of sertraline for managing anxiety in this population. TRIAL REGISTRATION: ISRCTN, ISRCTN15984604 . Registered on 08 February 2021. EudraCT 2019-004312-66. ANZCTR ACTRN12621000801819. Registered on 07 April 2021.

Trends and patterns of antiseizure medication prescribing during pregnancy between 1995 and 2018 in the United Kingdom: A cohort study.

OBJECTIVE: To examine antiseizure medication (ASM) prescription during pregnancy. DESIGN: Population-based drug utilisation study. SETTING: UK primary and secondary care data, 1995-2018, from the Clinical Practice Research Datalink GOLD version. POPULATION OR SAMPLE: 752 112 completed pregnancies among women registered for a minimum of 12 months with an 'up to standard' general practice prior to the estimated start of pregnancy and for the duration of their pregnancy. METHODS: We described ASM prescription across the study period, overall and by ASM indication, examined patterns of prescription during pregnancy including continuous prescription and discontinuation, and used logistic regression to investigate factors associated with those ASM prescription patterns. MAIN OUTCOME MEASURES: Prescription of ASMs during pregnancy and discontinuation of ASMs before and during pregnancy. RESULTS: ASM prescription during pregnancy increased from 0.6% of pregnancies in 1995 to 1.6% in 2018, driven largely by an increase in women with indications other than epilepsy. Epilepsy was an indication for 62.5% of pregnancies with an ASM prescription and non-epilepsy indications were present for 66.6%. Continuous prescription of ASMs during pregnancy was more common in women with epilepsy (64.3%) than in women with other indications (25.3%). Switching ASMs was infrequent (0.8% of ASM users). Factors associated with discontinuation included age ≥35, higher social deprivation, more frequent contact with the GP and being prescribed antidepressants or antipsychotics. CONCLUSIONS: ASM prescription during pregnancy increased between 1995 and 2018 in the UK. Patterns of prescription around the pregnancy period vary by indication and are associated with several maternal characteristics.

Antidepressants in pregnancy: applying causal epidemiological methods to understand service-use outcomes in women and long-term neurodevelopmental outcomes in exposed children.

Background: Antidepressants are commonly prescribed during pregnancy, despite a lack of evidence from randomised trials on the benefits or risks. Some studies have reported associations of antidepressants during pregnancy with adverse offspring neurodevelopment, but whether or not such associations are causal is unclear. Objectives: To study the associations of antidepressants for depression in pregnancy with outcomes using multiple methods to strengthen causal inference. Design: This was an observational cohort design using multiple methods to strengthen causal inference, including multivariable regression, propensity score matching, instrumental variable analysis, negative control exposures, comparison across indications and exposure discordant pregnancies analysis. Setting: This took place in UK general practice. Participants: Participants were pregnant women with depression. Interventions: The interventions were initiation of antidepressants in pregnancy compared with no initiation, and continuation of antidepressants in pregnancy compared with discontinuation. Main outcome measures: The maternal outcome measures were the use of primary care and secondary mental health services during pregnancy, and during four 6-month follow-up periods up to 24 months after pregnancy, and antidepressant prescription status 24 months following pregnancy. The child outcome measures were diagnosis of autism, diagnosis of attention deficit hyperactivity disorder and intellectual disability. Data sources: UK Clinical Practice Research Datalink. Results: Data on 80,103 pregnancies were used to study maternal primary care outcomes and were linked to 34,274 children with at least 4-year follow-up for neurodevelopmental outcomes. Women who initiated or continued antidepressants during pregnancy were more likely to have contact with primary and secondary health-care services during and after pregnancy and more likely to be prescribed an antidepressant 2 years following the end of pregnancy than women who did not initiate or continue antidepressants during pregnancy (odds ratioinitiation 2.16, 95% confidence interval 1.95 to 2.39; odds ratiocontinuation 2.40, 95% confidence interval 2.27 to 2.53). There was little evidence for any substantial association with autism (odds ratiomultivariableregression 1.10, 95% confidence interval 0.90 to 1.35; odds ratiopropensityscore 1.06, 95% confidence interval 0.84 to 1.32), attention deficit hyperactivity disorder (odds ratiomultivariableregression 1.02, 95% confidence interval 0.80 to 1.29; odds ratiopropensityscore 0.97, 95% confidence interval 0.75 to 1.25) or intellectual disability (odds ratiomultivariableregression 0.81, 95% confidence interval 0.55 to 1.19; odds ratiopropensityscore 0.89, 95% confidence interval 0.61 to 1.31) in children of women who continued antidepressants compared with those who discontinued antidepressants. There was inconsistent evidence of an association between initiation of antidepressants in pregnancy and diagnosis of autism in offspring (odds ratiomultivariableregression 1.23, 95% confidence interval 0.85 to 1.78; odds ratiopropensityscore 1.64, 95% confidence interval 1.01 to 2.66) but not attention deficit hyperactivity disorder or intellectual disability; however, but results were imprecise owing to smaller numbers. Limitations: Several causal-inference analyses lacked precision owing to limited numbers. In addition, adherence to the prescribed treatment was not measured. Conclusions: Women prescribed antidepressants during pregnancy had greater service use during and after pregnancy than those not prescribed antidepressants. The evidence against any substantial association with autism, attention deficit hyperactivity disorder or intellectual disability in the children of women who continued compared with those who discontinued antidepressants in pregnancy is reassuring. Potential association of initiation of antidepressants during pregnancy with offspring autism needs further investigation. Future work: Further research on larger samples could increase the robustness and precision of these findings. These methods applied could be a template for future pharmaco-epidemiological investigation of other pregnancy-related prescribing safety concerns. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/80/19) and will be published in full in Health Technology Assessment; Vol. 27, No. 15. See the NIHR Journals Library website for further project information.

About one in seven women experience depression during pregnancy. Left untreated, this may harm them and their unborn babies. However, the decision to take antidepressants during pregnancy is difficult because women often worry about the risks to their unborn baby. Research findings have been inconsistent, so women often do not have clear information to enable them to make informed decisions. We studied women's and children's outcomes after starting (compared with not starting) or continuing (compared with stopping) antidepressants in pregnancy. We used a large UK primary care database and several novel methods of analysis. We tracked 80,103 pregnancies of women with depression for up to 2 years after pregnancy. We also tracked 34,274 children from these pregnancies for at least 4 years to check for developmental outcomes. Women prescribed antidepressants were more likely than women not prescribed antidepressants to use general practice and mental health services during and after pregnancy, and to be prescribed antidepressants 2 years after pregnancy. This suggests that antidepressants were being prescribed to women with greater clinical need. Women who continued antidepressants in pregnancy had no higher likelihood than those who discontinued antidepressants of autism, attention deficit hyperactivity disorder or intellectual disability in their children. This should reassure women making the decision to continue taking their medications in pregnancy. Women who started antidepressants in pregnancy may possibly have had a slightly higher likelihood of autism in their children than those who did not start them. These findings were not seen in all analyses and were based on smaller numbers; therefore, they should be viewed with caution. Importantly, over 98 in every 100 children of women who initiated or continued antidepressants in pregnancy did not receive an autism diagnosis. The findings may help women and clinicians make informed decisions on treatment with antidepressants in pregnancy.

Autistic adults' views on the design and processes within randomised controlled trials: The APRiCoT study.

LAY ABSTRACT: Large randomised controlled trials are used to test healthcare treatments. Yet there are no large randomised controlled trials on effective treatments for common mental health issues affecting autistic adults. The purpose of this study was to learn what autistic adults think about randomised controlled trials in preparation for a randomised controlled trial testing a medication for anxiety. This means we wanted to know their opinions about the way randomised controlled trials are done, such as how people are chosen to be in the study and how the study is carried out. We did this by talking to 49 autistic adults individually and asking them questions. We found that most of the people we talked to were okay with the way randomised controlled trials are done. They thought it was fair and they liked that it was based on evidence. However, some autistic people might find it hard to take part in randomised controlled trials. Some people did not like the uncertainty of not knowing what treatment they would receive in a randomised controlled trial. Others felt too vulnerable and may have had bad experiences with healthcare in the past. We found that it is important to involve autistic people early on and at every stage when designing a clinical trial. Care about how clear and precise the study communication is will build trust and improve access to research. Our study indicates that it is possible to conduct large randomised controlled trials with and for autistic people. This can ultimately contribute to the improvement of healthcare outcomes for this population.

Lockdown Experiences and Views on Future Research Participation of Autistic Adults in the UK During the First 6 Months of the COVID-19 Pandemic.

Background: The COVID-19 pandemic resulted in large-scale public health restrictions and lockdowns across many countries. There is an increasing literature on the varied impact of such lockdowns in autistic adults. However, there is very little research on how the pandemic and related public health measures may impact the willingness of autistic people in engaging and taking part in research. The aim of this qualitative study was to explore autistic adults' experiences of the COVID-19 lockdown and how the pandemic may affect future research participation. Methods: We conducted in-depth interviews with 31 autistic adults between March and July 2020. Transcripts were analyzed thematically within a critical realism framework. Results: Participants identified positive aspects of lockdown such as enjoying the lack of social pressures and using their well-developed skills for dealing with uncertainty. Autistic people also shared challenges of adjusting to lockdown, for example, rapid change in daily routines. While hopeful about the freedom gained from easing restrictions, participants were concerned about the inconsistent communication and application of rules during the transition out of lockdown. This may have exacerbated already rising mental health issues among autistic people. The participants viewed research participation and engagement with increased relevance during the pandemic and welcomed efforts to conduct research using online methods of communication. Conclusion: The COVID-19 lockdown had a varied effect in the lives and routines of autistic people. However, health care providers and researchers need to be mindful of rising mental health issues in the aftermath of the pandemic, especially for people who were already vulnerable. The response to the pandemic may have offered opportunities for innovation in research processes enabling more autistic people to engage with research and making studies more inclusive.

Why is this an important issue?: We did not know how the pandemic and the strict restrictions that followed would affect autistic people's well-being and mental health.Also, there was a worry that the pandemic would affect the number of volunteers taking part in research that matters the most to autistic people. Thus, it was important to understand any implications for the way we conduct research with the autistic community after the pandemic. What was the purpose of this study?: We explored the experiences of autistic people living through the first 6 months of the COVID-19 lockdown in the United Kingdom. We were particularly interested in autistic people's views on how the pandemic may affect them taking part in research. What did the researchers do?: We co-produced this interview study to answer our research questions. We carried out in-depth interviews with 31 autistic people. We looked for patterns or themes in what the participants said. What were the results of the study?: Autistic people we interviewed reported being able to enjoy a quieter pace of life. They felt less anxious early in the lockdown. But they also faced great challenges adjusting to changes in their daily routines. Inconsistent public health communication caused worry during the transition out of lockdown. Unnecessary stress might have led to worsening of mental health issues in some people. Our participants held positive views on taking part in and engage with research, despite the pandemic. We identified opportunities that could make research more inclusive for autistic people, for example, online methods for taking consent and taking part in research remotely. What do these findings add to what was already known?: Our study adds to the evidence of the varied responses of autistic people to the pandemic and the public health measures that it led to. One important strength of our work is our focus on the impact of the pandemic on research and implications of future research. We learnt that autistic people welcome and value the use of online technology to reach study participants. Wider use of remote technology can make research more inclusive and participatory. What are potential weaknesses in the study?: Many of our participants were already had experience participating in research. Also most had relatively high education levels. We did not include autistic people with intellectual disabilities. We did not collect information on ethnicity. Our sample is likely to have little ethnic diversity. How will these findings help autistic adults now or in the future?: We describe the experiences of autistic people in the face of unprecedented circumstances. We found the need for clear public health communication to avoid unnecessary stress. The pandemic has provided the opportunity for a wider use of remote methods of research, even in areas where this was not done in the past (e.g., clinical trials). Our study found that such approaches would make research more inclusive.

Associations between autistic traits and early ear and upper respiratory signs: a prospective observational study of the Avon Longitudinal Study of Parents and Children (ALSPAC) geographically defined childhood population.

OBJECTIVE: To determine whether early ear and upper respiratory signs are associated with the development of high levels of autistic traits or diagnosed autism. DESIGN: Longitudinal birth cohort: Avon Longitudinal Study of Parents and Children (ALSPAC). SETTING: Area centred on the city of Bristol in Southwest England. Eligible pregnant women resident in the area with expected date of delivery between April 1991 and December 1992 inclusive. PARTICIPANTS: 10 000+ young children followed throughout their first 4 years. Their mothers completed three questionnaires between 18-42 months recording the frequency of nine different signs and symptoms relating to the upper respiratory system, as well as ear and hearing problems. OUTCOME MEASURES: Primary-high levels of autism traits (social communication, coherent speech, sociability, and repetitive behaviour); secondary-diagnosed autism. RESULTS: Early evidence of mouth breathing, snoring, pulling/poking ears, ears going red, hearing worse during a cold, and rarely listening were associated with high scores on each autism trait and with a diagnosis of autism. There was also evidence of associations of pus or sticky mucus discharge from ears, especially with autism and with poor coherent speech. Adjustment for 10 environmental characteristics made little difference to the results, and substantially more adjusted associations were at p<0.001 than expected by chance (41 observed; 0.01 expected). For example, for discharge of pus or sticky mucus from ears the adjusted odds ratio (aOR) for autism at 30 months was 3.29 (95% CI 1.85 to 5.86, p<0.001), and for impaired hearing during a cold the aOR was 2.18 (95% CI 1.43 to 3.31, p<0.001). CONCLUSIONS: Very young children exhibiting common ear and upper respiratory signs appear to have an increased risk of a subsequent diagnosis of autism or demonstrated high levels of autism traits. Results suggest the need for identification and management of ear, nose and throat conditions in autistic children and may provide possible indicators of causal mechanisms.

Bias amplification of unobserved confounding in pharmacoepidemiological studies using indication-based sampling.

PURPOSE: Estimating causal effects in observational pharmacoepidemiology is a challenging task, as it is often plagued by confounding by indication. Restricting the sample to those with an indication for drug use is a commonly performed procedure; indication-based sampling ensures that the exposed and unexposed are exchangeable on the indication-limiting the potential for confounding by indication. However, indication-based sampling has received little scrutiny, despite the hazards of exposure-related covariate control. METHODS: Using simulations of varying levels of confounding and applied examples we describe bias amplification under indication-based sampling. RESULTS: We demonstrate that indication-based sampling in the presence of unobserved confounding can give rise to bias amplification, a self-inflicted phenomenon where one inflates pre-existing bias through inappropriate covariate control. Additionally, we show that indication-based sampling generally leads to a greater net bias than alternative approaches, such as regression adjustment. Finally, we expand on how bias amplification should be reasoned about when distinct clinically relevant effects on the outcome among those with an indication exist (effect-heterogeneity). CONCLUSION: We conclude that studies using indication-based sampling should have robust justification - and that it should by no means be considered unbiased to adopt such approaches. As such, we suggest that future observational studies stay wary of bias amplification when considering drug indications.

Childhood Trauma As a Mediator of the Association Between Autistic Traits and Psychotic Experiences: Evidence From the Avon Longitudinal Study of Parents and Children Cohort.

BACKGROUND: Little is known on whether associations between childhood autistic traits and psychotic experiences persist into adulthood and whether genetic confounding and childhood trauma influence them. Here we investigate the associations between childhood autistic traits and psychotic experiences until young adulthood and assess the influence of schizophrenia polygenic risk and childhood traumatic experiences, using the Avon Longitudinal Study of Parents and Children (ALSPAC) population-based birth cohort. STUDY DESIGN: We used a measure of broad autistic traits (autism factor mean score), and four dichotomised measures of autistic traits capturing social communication difficulties (age 7), repetitive behaviours (age 5), sociability (age 3), and pragmatic language (age 9). Psychotic experiences were assessed at ages 18 and 24 using the semi-structured Psychosis-Like Symptoms interview (PLIKSi). Traumatic experiences between ages 5 and 11 were assessed with questionnaires and interviews administered to children and parents at multiple ages. STUDY RESULTS: Broad autistic traits, as well as social communication difficulties, were associated with psychotic experiences that were distressing and/or frequent until age 24 (autism factor mean score, n = 3707: OR 1.19, 95%CI 1.01-1.39; social communication difficulties, n = 3384: OR 1.54, 95%CI 0.97-2.45). Childhood trauma mediated a substantial proportion of the identified associations (~28% and 36% respectively, maximum n = 3577). Schizophrenia polygenic risk did not appear to confound the associations. Multiple imputation analyses (maximum n = 13 105) yielded comparable results. CONCLUSIONS: Childhood trauma may be an important, potentially modifiable pathway between autistic features and later onset of psychotic psychopathology.

Autism, autistic traits and multiple risk behaviours in adolescence: a longitudinal birth cohort study.

BACKGROUND: Multiple risk behaviours (MRBs), typically beginning in adolescence, are associated with increased risk of adverse health and social outcomes. The association between autism and MRBs is little understood. METHODS: Data were from the Avon Longitudinal Study of Parents and Children, an UK-based longitudinal, birth cohort study. Exposures were diagnosed autism and four autistic traits: social communication difficulties, pragmatic language, repetitive behaviours and reduced sociability. Outcomes were participation in up to 14 risk behaviours, including alcohol consumption, smoking, risky sexual behaviours and physical inactivity. Outcome data were collected at ages approximately 12, 14, 16 and 18. RESULTS: Up to 4300 participants were included in latent basis growth curve analyses with adjustment for confounders. Social communication difficulties were associated with an above average level of MRBs engagement at ~12 years (mean difference ß 0.26; 95% CI 0.13-0.40), and above average rate of engagement from ages ~12-18 (ß 0.08; 95% CI 0.02-0.13). Repetitive behaviours were associated with above average levels of engagement in MRBs at ~12 years (ß 0.24; 95% CI 0.09-0.38). Contrastingly, reduced sociability was associated with a reduced rate of engagement in MRBs from ages ~12-18 (ß -0.06; 95% CI -0.11 to -0.02). In sex-specific analyses, persisting differences in MRB engagement patterns from ages ~12-18 were observed in males with social communication difficulties and females with reduced sociability temperament. CONCLUSIONS: Having elevated levels of some autistic traits appear to have differentiated effects on MRB engagement patterns. These findings could reflect difficulties fitting in and/or coping mechanisms relating to difficulties with fitting in.