Agnieszka Butwicka

Autism is a common lifelong condition. Autistic individuals are at a high risk of somatic disorders, such as epilepsy, and are at an increased risk for premature mortality. A better understanding of co-occurring somatic disorders in autistic individuals is thus critical from the perspective of improving public health in marginalized groups, yet existing research is limited by a descriptive focus. Our overall aim is to identify risk factors for somatic disorders in autistic individuals. We will optimize Swedish registry data, including linkage with a large genotyped sample, using powerful longitudinal study designs. First, we will test whether genetic factors account for the association between autism and somatic disorders. We will triangulate three family-based designs, and utilize contemporary molecular genetic approaches to assess genetic links between autism and somatic disorders. Second, we will assess whether the psychosocial adversity faced by autistic individuals impact on their health using longitudinal cohort designs. Finally, real-world data will allow us to circumvent the challenges of conducting randomized controlled trials to examine the impact of psychotropic medication use on somatic health in autistic individuals. This project will guide the field of somatic health in autistic individuals from descriptive epidemiology towards a mechanistic understanding, which will ultimately lead to improved prevention, detection, and treatment of these disorders.

Purpose and aims: There is so much comorbidity among psychiatric conditions that one can combine them into a single general psychopathology index. Although general psychopathology predicts adverse outcomes, it remains unknown if it responds to intervention. Therefore, we will estimate the causal effect of psychosocial interventions and psychotropic medications on general psychopathology. Method: We will apply casual inference designs (children-of-siblings design

co-twin control/within-individual design

instrumental variable

and front-door criterion) to data from the Swedish Twin Register and Swedish population registers to estimate the effect of childrearing conditions (year 1), psychotherapy (years 2-3), and psychotropic medication (years 1-5) on general psychopathology (derived from self/parent-reported symptoms and psychiatric diagnoses). The principal investigator will devote 50% of his time to this project, and he is supported by experts in epidemiology, psychotherapy, and psychiatry. Importance: Even though comorbidity is the rule rather than exception in psychiatry, most randomized clinical trials exclude individuals with several disorders. Therefore, there is a lack of knowledge of the effect of treatment on comorbidity. By applying innovative causal inference designs to large observational data, we aim to study the effect of treatment on general psychopathology in the best conceivable way. This could open a new area of research into transdiagnostic treatments.

Research problem and specific questions: About one quarter of all children have parents with mental health problems. These children are at increased risk for a wide range of adverse outcomes. Nevertheless, despite the importance of reducing this form of inequality, research on the intergenerational transmission of mental health problems is plagued by three important limitations. These include an overreliance on small samples and retrospective (biased) reports

a failure to address psychiatric comorbidity

and inadequate control of unmeasured confounding. The aim of this project is to answer three research questions: 1) What are the associations between psychiatric diagnoses in parents and adverse outcomes in their children? 2) Can these be attributed to broad comorbidity? 3) Does treatment of the parents’ psychiatric disorders reduce the risk of adverse outcomes in children?Data and method: We will include all individuals born in Sweden between 1970 and 2000 (N = 2 797 086). The exposures are 6 psychiatric diagnoses in their parents, and the outcomes are 34 adverse events in the offspring recorded until the end of 2019 (e.g., psychiatric disorders, psychotropic medications, criminality, school and employment problems, etc.). We will estimate associations between the exposures and outcomes

adjust for comorbidity using multiple regression and a general factor model

and apply causal inference techniques to control for unmeasured confounding.Plan for project realisation: We will hire a PhD student and a postdoc to complete the project. The PI, along with experts in epidemiology and psychiatry, will provide support.Relevance: Our project will contribute to the study of intergenerational transmission of mental health problems in three important ways. First, because psychiatric treatment resources are becoming increasingly scarce as more individuals seek help, parental psychiatric history can help guide treatment allocation by identifying those at higher risk and by screening out low risk persons. Second, we will highlight the importance of focusing on parental comorbidity, which will guide clinicians to additionally focus on the number of parental diagnoses (rather than only type) when predicting patient prognosis. Third, if a parental psychiatric diagnosis appears causally related to an outcome, then it would be beneficial to develop a policy for child and adolescent mental health providers to recommend that the parent also seek treatment.

RESEARCH PROBLEMAbout 1-2% of the Swedish population suffer from celiac disease. My earlier research has mainly focused on severe complications of celiac disease (e.g. death and cancer). In this project I will use laboratory data and primary care data to study early comorbidity in celiac disease, especially kidney-liver disease and neuro-cognitive/psychiatric disorders, such as stress-related illness, depression and dementia. DATA AND METHODProject 1: Through Swedish pathology departments, we have identified some 50,000 individuals with celiac disease. We expect that approx. 12-13,000 of these live in the Stockholm area and can therefore be linked to the laboratory database “SCREAM”. For these patients, we will identify all kidney and liver blood samples to follow kidney and liver function longitudinally.Project 2: Via a primary care dataset (covering 20 of 21 Swedish regions), we will examine celiac disease and the risk of neuro-cognitive disorders. WORK PLANProject 1: Using the personal identity number, data on celiac disease are linked to laboratory data in the SCREAM study. Using linear regression, we will study the development of early kidney and liver disease using laboratory data.Project 2: Data have already been linked. We will use Cox regression to calculate hazard ratios for our outcomes. RELEVANCEAn increased understanding of early comorbidity in celiac disease can improve the care of patients. In the long term, our goal is to prevent comorbidity in celiac disease.

Project aiming to improve the well-being of young people by increasing our understanding of vulnerabilities and resilience in determining post-pandemic outcomes. SISU unites a strong, multidisciplinary team of 4 Nordic partners, including renewed researchers with expertise in child and adolescent well-being, developmental psychology, child psychiatry, educational outcomes, and pandemic consequence. SISU builds on exceptional opportunities for Nordic countries with the availability of large longitudinal data sets, including school and municipality surveys, prospective cohort studies with genetic data, and population-based registries. We are aware that pandemics happen to societies as a whole

thus, our bioecological approach addresses this by integrating societal, contextual, developmental, and biological layers of inference. Through our intersection of individual dispositions, and school and societal environments, we can provide explanations relevant to municipal and national stakeholders forming schools and health services. Furthermore, by evaluating both negative and positive aspects of the pandemic environment's interaction with individual susceptibility, we aim to lay a foundation for resilient recovery from the pandemic.

Research problem and specific questions: Intellectual disability (ID) affects 2% of children worldwide. The disability is present throughout the lifespan, leading to significant morbidity and premature deaths. Early-life risk factors and low socioeconomic status (SES) are associated with ID. But the absence of genetically-informative studies prevented researchers from distinguishing between potential causal environmental influences and genetic confounding. In the proposed project, we will study the effect of early-life environmental factors for ID and identify risk groups in need of clinical follow-up.The aim of this project is to answer the following research questions:What is the causal mechanism by which early-life risk factors are associated with risk of ID?What is the mechanism underlying the association between SES and ID? Which early-life risk factors mediate this associations?Which risk groups are mostly likely to benefit from targeted pediatric surveillance and early health interventions?Data and method: We will use large-scale longitudinal linkages of administrative and health registers along with the Swedish Twin and Multi-Generation Registers. We will examine association between exposures to 1) early-life risk factors and 2) low SES with the outcome of ID. The association will be investigated in the overall population (between-family analyses) and, to address potential causality by adjusting for familial confounding in siblings (i) full-siblings, half-siblings, cousins and (ii) twins (within-family analyses). We will apply causal inference methods for mediation and interactions. 3) We will develop a Clinical Risk Score for prediction of ID based on early-life risk factors, SES and familial risk score.Plan for project realization: The project will be carried out over three years in close collaboration with reference group involving representatives from self-advocacy group “Grunden and Inre Ringen” and relevant stakeholders such as Young People and Adults with Intellectual Disability (FUB), the National Board of Health and Welfare, the Swedish Agency for Participation and the Swedish Municipalities and Regions (SKR).Relevance: The project will increase our knowledge on modifiable risk factors for ID, crucial for informing prevention in the population. If we can identify children atrisk of disabilities, we will be able to plan follow-ups and provide the best opportunities for timely diagnosis and early interventions in children and their families.

What is important?  Evidence points to substantial comorbidity between adult ADHD and cardiometabolic disease, i.e., obesity, type-2 Diabetes (T2DM), and cardiovascular disease (CVD). Guidelines for care of cardiometabolic disease stress the importance of co-occurring psychiatric disorders, yet ADHD is rarely mentioned. This is problematic as ADHD is a common psychiatric disorder (2–5%) and behaviours and cognitive challenges associated with ADHD may lead to poor outcomes due to poor adherence and risky behaviours. Also, stimulant medications used to treat ADHD may increase risk for adverse outcomes for those with underlying CVD or in interaction with other pharmacological treatments.What is to be done? First, determine how ADHD associates with outcomes (i.e., cardiometabolic risk profiles, adherence to treatments for cardiometabolic disease, and severe post-surgery/diagnosis outcomes) after bariatric surgery, T2DM and CVD diagnosis. Second, explore real-world effectiveness and safety of ADHD medication in relation to cardiometabolic outcomes/treatments. Third, develop prediction tool that allow identification of patients with ADHD at high-risk for poor cardiometabolic outcomes and treatment adherence.How the research will be carried out? An interdisciplinary team of experts will apply state-of-the art statistical approaches and beyond on data from a comprehensive linkage of national registers, including three unique quality registers of bariatric surgery, T2DM and CVD.