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Abstract The aim is to investigate the evidence for shared genetic architecture between each of asthma, allergic rhinitis and eczema with gastro-esophageal reflux disease (GERD). Structural equation models (SEM) and polygenic risk score (PRS) analyses are applied to three Swedish twin cohorts (n = 46,582) and reveal a modest genetic correlation between GERD and asthma of 0.18 and bidirectional PRS and phenotypic associations ranging between OR 1.09-1.14 and no correlations for eczema and allergic rhinitis. Linkage disequilibrium score regression is applied to summary statistics of recently published GERD and asthma/allergic disease genome wide association studies and reveals a genetic correlation of 0.48 for asthma and GERD, and Genomic SEM supports a single latent factor. A gene-/gene-set analysis using MAGMA reveals six pleiotropic genes (two at 12q13.2) associated with asthma and GERD. This study provides evidence that there is a common genetic architecture unique to asthma and GERD that may explain comorbidity and requires further investigation.

Abstract Peyronie’s disease (PD) has detrimental effects on the quality of life, mental health, sexual functioning and several other aspects that increase the risk of relationship problems. However, no study to date has assessed the risk of relationship separation in med with PD. Herein, we utilized data from Swedish national registers to examine the risk of relationship separation in men with PD. We conducted a matched cohort study on men born 1933–1992, followed from 1997 to 2013. PD was defined as a physician-assigned diagnosis according to the International Classification of Diseases, Tenth version. Each man with PD (n = 8020) was matched with 10 comparison men. We defined relationship separation as (1) ever separated, and (2) separation rate. We used log-linear regression to estimate the risk ratio, and rate ratio of relationship separation. We adjusted for matching variables (birth year and country of birth), and an indicator of each follow-up year. We found that men with PD had a 13% increased risk of relationship separation (risk ratio 1.13, 95% confidence interval [CI] 1.08–1.17). The rate of relationship separation events, measured on a yearly basis, was increased by 18% (rate ratio 1.18, CI 1.12–1.24), and remained similar when adjusting for follow-up year and socio-economic status.

Background Obsessive-compulsive disorder (OCD) is associated with an increased risk of morbidity and mortality due to cardiometabolic disorders. Whether this association is driven by familial factors is unknown. This population-based family study explored the familial co-aggregation of OCD and cardiometabolic disorders.Methods We identified 6 049 717 individuals born in Sweden between 1950 and 2008, including 50 212 individuals with OCD, and followed them up to 2020. These individuals were linked to their mothers, fathers, full siblings, maternal and paternal half siblings, aunts, uncles and cousins. We estimated the risk of cardiovascular diseases (CVD) and metabolic disorders (including obesity, type 2 diabetes and hyperlipidaemia), comparing the relatives of probands with and without OCD. Cox proportional hazards regression models, incorporating time-varying exposures, estimated HRs.Results OCD was associated with an increased risk of CVD (HR 1.47; 95% CI 1.43 to 1.51), obesity (HR 1.69; 95% CI 1.63 to 1.74), type 2 diabetes (HR 2.01; 95% CI 1.90 to 2.12) and hyperlipidaemia (HR 1.42; 95% CI 1.33 to 1.52). The relatives of probands with OCD exhibited small increased risks of CVD (HRs from 1.01 to 1.11) and obesity (HRs from 1.03 to 1.20). Slightly increased risks for type 2 diabetes were observed in mothers (HR 1.11; 95% CI 1.07 to 1.15) and full siblings (HR 1.12; 95% CI 1.05 to 1.20), while for hyperlipidaemia it was only observed in mothers (HR 1.06; 95% CI 1.02 to 1.10).Conclusions Our results do not support a major contribution of familial factors to the association between OCD and cardiometabolic disorders, suggesting a more prominent role of unique environmental factors.

Background Little is known about the impact of cumulative attention-deficit/hyperactivity disorder (ADHD) medication use on the risk of type 2 diabetes (T2D).Objective The objective is to examine the association between cumulative use of ADHD medication and risk of incident T2D.Methods A nested case–control study was conducted in a national cohort of individuals aged 18–70 years with incident ADHD (n=138 778) between 2007 and 2020 through Swedish registers. Individuals with incident T2D after ADHD were selected as cases (n=2355) and matched with up to five controls (n=11 681) on age at baseline, sex and birth year. Conditional logistic regression models examined the association between cumulative duration of ADHD medication use and T2D.Findings Compared with no use, a decreased risk of T2D was observed for those on cumulative use of ADHD medications up to 3 years (ORs: 03 years, 0.97 (95% CI, 0.84 to 1.12)). When investigating medication types separately, methylphenidate showed results similar to main analyses, lisdexamfetamine showed no association with T2D, whereas long-term (>3 years) use of atomoxetine was associated with an increased risk of T2D (OR: 1.44 (95% CI, 1.01 to 2.04)).Conclusion Cumulative use of ADHD medication does not increase the risk for T2D, with the exception of long-term use of atomoxetine.Clinical implications Findings suggest that clinicians should be aware of the potential risk of T2D associated with the cumulative use of atomoxetine among patients with ADHD; however, further replication is strongly needed.

Abstract Background Over the last decades, the prevalence of Attention‐deficit/hyperactivity disorder (ADHD) has increased. However, the underlying explanation for this increase remains unclear. We aimed to assess whether there has been a secular change in how parents perceive the impairment conferred by ADHD symptomatology. Methods Data for this study were obtained from the Child and Adolescent Twin Study in Sweden, involving 27,240 individuals whose parents answered a questionnaire when the children were 9 years old. We assessed the relationship between parentally perceived impairment caused by ADHD symptoms scores over time. The analysis was performed separately for five different birth cohorts, spanning three‐year periods from 1995 to 2009 and for ADHD inattention and hyperactivity/impulsivity dimensions. Results We found a consistent upward trend of parents reporting impairment in relation to ADHD symptomatology across birth cohorts. Over a 12‐year period, comparing those born 2007–2009 (assessed 2016–2018) with those born 1995–1997 (assessed 2004–2006), impairment scores increased by 27% at clinically relevant levels of ADHD symptomatology. Notably, when specifically evaluating the hyperactivity/impulsivity dimension, the disparity was even more striking, with an increase of up to 77%. Conclusions This study revealed a significant secular change in parental perception of impairment attributed to ADHD symptomatology over recent decades, providing new insights into the increased prevalence of ADHD. It underscores the need to better understand the factors that have contributed to the increased perception of impairment related to ADHD symptoms.

Abstract Background Evidence for substance use‐related problems in individuals with mild intellectual disability is sparse and mainly limited to selected psychiatric populations. We evaluated the risk of substance use‐related problems in individuals with mild intellectual disability compared to the general population. Additionally, we have performed secondary sibling comparison analyses to account for familial confounding. Methods We conducted a population‐based cohort study of individuals born in Sweden between 1973 and 2003. A total of 18,307 individuals with mild intellectual disability were compared to 915,350 reference individuals from the general population and 18,996 full siblings of individuals with mild intellectual disability. Information on mild intellectual disability and substance use‐related problems was obtained from several Swedish national and regional school and healthcare registers. Substance use‐related problems were measured via corresponding diagnostic and legal codes and included alcohol use disorder, drug use disorder, alcohol‐related somatic disease, conviction for a substance‐related crime, and substance‐related death. Results Individuals with mild intellectual disability had a higher risk of any substance use‐related problem compared to the general population (HR, 1.81; 95% CI, 1.72–1.91), both in males (HR, 1.76; 95% CI, 1.65–1.89) and females (HR, 1.89; 95% CI, 1.74–2.05). The risks of substance use‐related problems were particularly elevated among individuals with mild intellectual disability and psychiatric comorbidities (HR, 2.21–8.24). The associations were attenuated in the sibling comparison models. Conclusions Individuals with mild intellectual disability, especially those with psychiatric comorbidity, are at an elevated risk of substance use‐related problems. Familial factors shared by full siblings contribute considerably to the association between mild intellectual disability and substance use‐related problems.

Abstract Background Emerging research suggests that attention-deficit/hyperactivity disorder (ADHD) increases the risk for cardiovascular (CVDs) and metabolic disorders (i.e., cardiometabolic disorders) in adulthood. Yet, available studies are scarce and have mainly been focused on individuals receiving clinical ADHD diagnoses. We aimed to investigate the prospective associations of ADHD symptoms in young and mid-adulthood with subsequent cardiometabolic disorders and the underlying mechanisms. Methods We studied 10,394 twins from the Swedish Twin Registry (STR), born between 1958 and 1985 without previous medical history of cardiometabolic disorders. They provided self-assessment of ADHD symptoms (score range 0–36) via a validated, DSM-IV-based scale in a web-based questionnaire/telephone interview within the Study of Twin Adults: Genes and Environment (STAGE), in 2005–2006 (aged 19–47 years), and were followed until the end of 2018 (33–59 years) to identify incident clinical diagnoses/medication prescriptions for cardiometabolic disorders acquired from Swedish national registers. We used Cox regression models to investigate the associations between ADHD symptoms score and cardiometabolic outcomes, with and without adjustment for relevant covariates, and a co-twin control design to study familial confounding. Results A one-unit increase in the level of ADHD symptoms was associated with a 2% increase in the rate of CVDs (hazard ratio [HR] = 1.02, 95% confidence interval 1.01–1.04) and a 3% increase in the rate of metabolic disorders (HR = 1.03, 1.02–1.05), after adjusting for birth year and sex. The associations were no longer significant after adjusting for educational attainment, lifestyle factors, and comorbid psychiatric disorders. The associations remained significant after adjusting for familial factors shared by dizygotic twin pairs but became nonsignificant after adjusting for factors shared by monozygotic twin pairs. However, the strength of the associations attenuated significantly in monozygotic twins compared to dizygotic twins for CVDs only, suggesting genetic confounding. Conclusions ADHD symptom score is associated with a higher risk for cardiometabolic disorders, which may be explained by lower educational attainment, adverse lifestyle factors, and psychiatric comorbidities. Moreover, the associations appear to be partly confounded by shared genetic factors, especially for CVDs. Further research is needed to investigate the identified associations at the level of individual cardiometabolic disorders and to follow-up participants until a more advanced older age.

Abstract A growing body of literature recognizes associations between eating disorders (EDs) and schizophrenia and suggests that familial liability to schizophrenia in individuals with anorexia nervosa (AN) reveals distinct patterns of clinical outcomes. To further investigate the influence of schizophrenia genetic liability among individuals with EDs, we evaluated the associations between schizophrenia polygenic risk scores (PRS) and clinical presentations of individuals with EDs including their overall health condition and ED-related symptoms. Using data from two previous studies of the genetics of EDs comprising 3,573 Anorexia Nervosa Genetics Initiative (ANGI) cases and 696 Binge Eating Genetics Initiative (BEGIN) cases born after 1973 and linked to the Swedish National Patient Register, we examined the association of schizophrenia PRS on ED clinical features, psychiatric comorbidities, and somatic and mental health burden. Among ANGI cases, higher schizophrenia PRS was statistically significantly associated with higher risk of major depressive disorder (MDD) measured by hazard ratio (HR) with 95% confidence interval (CI) (HR [95% CI]: 1.07 [1.02, 1.13]) and substance abuse disorder (SUD) (HR [95% CI]: 1.14 [1.03, 1.25]) after applying multiple testing correction. Additionally, higher schizophrenia PRS was associated with decreased clinical impairment assessment scores (−0.56, 95% CI: [−1.04, −0.08]) at the conventional significance level (p

Abstract Previous studies on brain connectivity correlates of autism have often focused on selective connections and yielded inconsistent results. By applying global fiber tracking and utilizing a within-twin pair design, we aimed to contribute to a more unbiased picture of white matter connectivity in association with clinical autism and autistic traits. Eighty-seven twin pairs (n = 174; 55% monozygotic; 24 with clinical autism) underwent diffusion tensor imaging. Linear regressions assessed within-twin pair associations between structural brain connectivity of anatomically defined brain regions and both clinical autism and autistic traits. These were explicitly adjusted for IQ, other neurodevelopmental/psychiatric conditions and multiple testing, and implicitly for biological sex, age, and all genetic and environmental factors shared by twins. Both clinical autism and autistic traits were associated with reductions in structural connectivity. Twins fulfilling diagnostic criteria for clinical autism had decreased brainstem-cuneus connectivity compared to their co-twins without clinical autism. Further, twins with higher autistic traits had decreased connectivity of the left hippocampus with the left fusiform and parahippocampal areas. These associations were also significant in dizygotic twins alone. Reduced brainstem-cuneus connectivity might point towards alterations in low-level visual processing in clinical autism while higher autistic traits seemed to be more associated with reduced connectivity in networks involving the hippocampus and the fusiform gyrus, crucial especially for processing of faces and other (higher order) visual processing. The observed associations were likely influenced by both genes and environment.

Abstract Background The causes of obsessive-compulsive disorder (OCD) remain unknown. Gene-searching efforts are well underway, but the identification of environmental risk factors is at least as important and should be a priority because some of them may be amenable to prevention or early intervention strategies. Genetically informative studies, particularly those employing the discordant monozygotic (MZ) twin design, are ideally suited to study environmental risk factors. This protocol paper describes the study rationale, aims, and methods of OCDTWIN, an open cohort of MZ twin pairs who are discordant for the diagnosis of OCD. Methods OCDTWIN has two broad aims. In Aim 1, we are recruiting MZ twin pairs from across Sweden, conducting thorough clinical assessments, and building a biobank of biological specimens, including blood, saliva, urine, stool, hair, nails, and multimodal brain imaging. A wealth of early life exposures (e.g., perinatal variables, health-related information, psychosocial stressors) are available through linkage with the nationwide registers and the Swedish Twin Registry. Blood spots stored in the Swedish phenylketonuria (PKU) biobank will be available to extract DNA, proteins, and metabolites, providing an invaluable source of biomaterial taken at birth. In Aim 2, we will perform within-pair comparisons of discordant MZ twins, which will allow us to isolate unique environmental risk factors that are in the causal pathway to OCD, while strictly controlling for genetic and early shared environmental influences. To date (May 2023), 43 pairs of twins (21 discordant for OCD) have been recruited. Discussion OCDTWIN hopes to generate unique insights into environmental risk factors that are in the causal pathway to OCD, some of which have the potential of being actionable targets.

BackgroundThe contribution of genetic and environmental factors to susceptibility to nervous system tumors remains unclear. We performed a quantitative genetic study using a sibling design to estimate the heritability of nervous system tumors, as well as the proportion of the risk of these tumors, which is attributable to environmental factors.MethodsWe conducted a population-based cohort study using Swedish National Register data. All individuals born in Sweden during 1950–2010 with available information on both biological parents were included. A Multi-Generation Register was used to identify family clusters, including both full- and half-siblings. Initially, one index person was randomly selected from each cluster containing only full siblings and one sibling was randomly assigned to this index person. Subsequently, within each of the remaining clusters of full- and half-siblings, an index person was randomly selected, and a half-sibling was randomly assigned to this index person. Among the randomly selected siblings, cases of nervous system tumors were identified using the cancer registry. Quantitative genetic models were used to estimate the proportion of the variance in nervous system tumors attributable to additive genetic factors, shared environment, and individual-specific environment.ResultsThe heritability of nervous system tumors was estimated to be 29% (95% confidence interval (CI) = 19%–39%), while the contribution of the non-shared environment to the variance of nervous system tumors was estimated to be 71% (95% CI = 61%–81%). The shared environmental parameter was estimated as zero in the full model.ConclusionThe variation in susceptibility to nervous system tumors is predominantly attributable to non-shared environmental factors, followed by genetic factors.

Prostate cancer screening using prostate-specific antigen (PSA) testing is controversial but remains prevalent in many countries. There is little information in Sweden or elsewhere on the spatial variation in PSA testing. This study aims to describe the spatio-temporal variation in PSA testing prior to a prostate cancer diagnosis in the Stockholm region at the municipality and small area levels. A population-based register study comprised men aged 40 years and over living in the Stockholm region during 2007-2016. For Stockholm in 2016, we reported the proportion of men who had a PSA test for the preceding one, two, five and ten years by ten-year age groups. The age-standardised proportion of men having a PSA test was reported for municipalities by calendar years. We used spatial smoothing for calculating the age-standardised proportion of men having a PSA test in a small area for each calendar year. In 2016, 74.0% and 77.8% of men aged 60-69 and 70-79 years respectively had taken a PSA test in the previous ten years. The municipalities of Danderyd and Ekerö showed high proportions of PSA testing. A marked heterogeneity in such proportions within each municipality was observed. The odds ratio for having a PSA test for those born in Sweden was 2.22 (95% CI 2.00-2.52). Opportunistic PSA testing is widespread with three quarters of men in their sixties and seventies having had a test in the preceding decade. We found evidence for marked geographical heterogeneity, where more affluent and metropolitan areas had higher levels of testing. Variations in PSA testing was associated with socio-economic position and demographic factors including education, income and country of birth.

Abstract Background Gaming is a popular past‐time activity among children and adolescents, but it there is also a possible link to negative consequences such as psychological distress and lowered academic achievement. However, there are fundamental knowledge gaps remaining regarding central characteristics of gaming such as heritability, stability over time, and sex differences. We examined the genetic and environmental contribution to gaming behavior, including sex differences, continuity and change, in a longitudinal cohort of twins. Methods This is the first longitudinal twin study on gaming, involving 32,006 twins in Sweden. Parents were asked about the twins' gaming at ages 9, 15 and 18. We used univariate and multivariate twin analyses to estimate the relative contribution of genetic and environmental influences at each time‐point as well as across time. Sex‐differences were also explored. Results The results showed large sex differences, where genetics explained more of the variance for boys (31.3%–62.5% depending on age) than for girls (19.4%–23.4%). Genetic factors explained an increasing amount of the variance for boys (31.3% at age 9, 62.5% at age 15 and 53.9% at age 18). Shared environmental factors explained a larger proportion of the variance among girls, which remained relatively stable over time (70.5% at age 9, 61.8% at age 15 and 60.5% at age 18). The results also indicated that most of the variance came from genetic and environmental sources specific to each age. Conclusions Compared to many other behavioral phenotypes, such as gambling, gaming was relatively unstable with a large degree of genetic innovation. There were large sex differences in the contribution of genetic and environmental factors. This suggests that excessive gaming could be the result of age‐ and sex‐specific genetic and environmental factors, and should be taken into account when mapping gaming behaviors, since these behaviors might be under continual etiological transformation.

Abstract Suicidal and aggressive behaviours cause significant personal and societal burden. As risk factors associated with these behaviours frequently overlap, combined approaches in predicting the behaviours may be useful in identifying those at risk for either. The current study aimed to create a model that predicted if individuals will exhibit suicidal behaviour, aggressive behaviour, both, or neither in late adolescence. A sample of 5,974 twins from the Child and Adolescent Twin Study in Sweden (CATSS) was broken down into a training (80%), tune (10%) and test (10%) set. The Netherlands Twin Register (NTR; N = 2702) was used for external validation. Our longitudinal data featured genetic, environmental, and psychosocial predictors derived from parental and self-report data. A stacked ensemble model was created which contained a gradient boosted machine, random forest, elastic net, and neural network. Model performance was transferable between CATSS and NTR (macro area under the receiver operating characteristic curve (AUC) [95% CI] AUCCATSS(test set) = 0.709 (0.671–0.747); AUCNTR = 0.685 (0.656–0.715), suggesting model generalisability across Northern Europe. The notable exception is suicidal behaviours in the NTR, which was no better than chance. The 25 highest scoring variable importance scores for the gradient boosted machines and random forest models included self-reported psychiatric symptoms in mid-adolescence, sex, and polygenic scores for psychiatric traits. The model’s performance is comparable to current prediction models that use clinical interviews and is not yet suitable for clinical use. Moreover, genetic variables may have a role to play in predictive models of adolescent psychopathology.

Abstract Background The knowledge of how the separate Attention-Deficit/Hyperactivity Disorder (ADHD) subdimensions (impulsivity, hyperactivity, and inattention) are associated with nonsuicidal self-injury (NSSI) and suicidal behavior (SB) is limited. The objective of this study was to investigate the associations of childhood ADHD subdimensions with NSSI and SB in children at risk of neurodevelopmental disorders (NDDs; including ADHD). Methods The sample (N = 391) included twin pairs where at least one twin screened positive for at least one NDD or common comorbidity at age 9 or 12. Data on ADHD subdimensions was collected through a telephone interview with a caregiver/legal guardian at age 9 or 12, and data on NSSI and SB was collected through an in-person clinical assessment at age 15. The associations between the ADHD subdimensions and NSSI or SB were tested in three different models: (1) univariable, (2) together with the other ADHD subdimensions, and (3) in a confounder-adjusted model including other NDD symptoms in addition to ADHD subdimensions, for NSSI and SB separately. Results A total of 32 (8.2%) adolescents reported life-time engagement of NSSI, and 18 (4.6%) SB. Childhood impulsivity was associated with SB and childhood inattention with NSSI, in all models. Hyperactivity was not meaningfully associated with any of the outcomes. Conclusion Impulsivity and inattention, but not hyperactivity, may be of particular importance in understanding SB and NSSI. Brief screening for impulsivity and inattention in childhood could facilitate detection of children vulnerable to NSSI and SB and indicate valuable information for preventive and intervention strategies.

Summary: Background: Intellectual disability (ID) is a disorder with unknown aetiology in many cases. Maternal alcohol use is a known risk factor for ID, but less is known about the importance of maternal and paternal substance use disorder (SUD) and risk of ID in offspring. Methods: Data from multiple nationwide registers were used to create a cohort of children born from January 01, 1978 to December 31, 2002. All participants were born in Sweden, had available parental identification information and did not emigrate or die before age 12 (n = 1,940,820). Logistic regression modelling was performed with exposure defined as having a parent who received any SUD diagnosis, including alcohol use disorder (AUD) and drug use disorder (DUD). The outcome was registration of diagnosis of any form of ID. First, we analysed the risk of ID if parental SUD was registered prior to childbirth with stepwise adjustment of multiple covariates. Second, the effect of timing of SUD diagnosis in relation to childbirth was analysed. Findings: Of 37,410 offspring with parental SUD registered prior to birth, 3.0% (n = 1110) had any form of ID compared to 1.2% (n = 23,168) of those 1,903,410 individuals without parental SUD prior birth. Parental SUD prior birth was associated with an increased risk of any form of ID (Odds Ratio [OR]: 2.3 [2.2–2.5]), with ORs similar for maternal (OR: 2.3 [2.1–2.5]) and paternal SUD (OR: 2.3 [2.1–2.5]). These ORs were reduced but remained statistically significant after adjusting for parental education, migration, psychiatric comorbidity, and co-parent SUD (OR parental SUD: 1.6 [1.5–1.8]; OR maternal SUD: 1.4 [1.2–1.5]; OR paternal SUD: 1.6 [1.5–1.7]). Parental SUD was associated with increased risk of ID in offspring irrespective of timing of diagnosis, but if mothers or fathers were diagnosed with AUD during pregnancy (OR maternal AUD: 5.0 [3.1–8.2]; OR paternal AUD: 2.8 [2.2–3.6]), the risk was significantly greater than if the AUD diagnosis was first registered after childbirth (OR maternal AUD: 1.9 [1.8–2.0]; OR paternal AUD: 1.6 [1.6–1.7]). Interpretation: Both paternal and maternal SUD were associated with an increased risk of ID in offspring, with greatest risk observed when AUD was diagnosed during pregnancy. Possible mechanisms may involve shared genetic and environmental factors, including toxic effects from alcohol intake. These findings have clinical implications in suggesting that parental SUD in either parent represents a possibly modifiable risk factor to consider when developing prevention, diagnostics and treatment programs for children with ID. Funding: Stockholm County Council, the Research Council of the Swedish Alcohol Retailing Monopoly, Fredrik and Ingrid Thurings stiftelse, Academy of Finland, the Swedish Research Council and the Swedish Research Council for Health, Working Life and Welfare, Nordforsk by the Nordic Council of Ministers and the Polish Medical Research Agency.

Introduction There is concern regarding suicidal behaviour risk during selective serotonin reuptake inhibitor (SSRI) treatment among the young. A clinically useful model for predicting suicidal behaviour risk should have high predictive performance in terms of discrimination and calibration; transparency and ease of implementation are desirable.Methods and analysis Using Swedish national registers, we will identify individuals initiating an SSRI aged 8–24 years 2007–2020. We will develop: (A) a model based on a broad set of predictors, and (B) a model based on a restricted set of predictors. For the broad predictor model, we will consider an ensemble of four base models: XGBoost (XG), neural net (NN), elastic net logistic regression (EN) and support vector machine (SVM). The predictors with the greatest contribution to predictive performance in the base models will be determined. For the restricted predictor model, clinical input will be used to select predictors based on the top predictors in the broad model, and inputted in each of the XG, NN, EN and SVM models. If any show superiority in predictive performance as defined by the area under the receiver-operator curve, this model will be selected as the final model; otherwise, the EN model will be selected. The training and testing samples will consist of data from 2007 to 2017 and from 2018 to 2020, respectively. We will additionally assess the final model performance in individuals receiving a depression diagnosis within 90 days before SSRI initiation.The aims are to (A) develop a model predicting suicidal behaviour risk after SSRI initiation among children and youths, using machine learning methods, and (B) develop a model with a restricted set of predictors, favouring transparency and scalability.Ethics and dissemination The research is approved by the Swedish Ethical Review Authority (2020–06540). We will disseminate findings by publishing in peer-reviewed open-access journals, and presenting at international conferences.

Abstract Background Internalizing disorders, such as anxiety and depressive disorders, are common mental disorders in young people, but a detailed understanding of the symptom continuity from childhood to adolescence that additionally includes a variety of neurodevelopmental disorder (NDD) symptoms is lacking. We therefore aimed to assess the extent to which parent-reported anxiety, depression, and NDD symptoms in childhood predict parent-reported internalizing symptoms in adolescence. Methods We used the nation-wide population-based Child and Adolescent Twin Study in Sweden, comprising 4492 twins born in Sweden between 1998 and 2003 that were assessed at age 9, and then again at age 15. Linear regression in a structural equation modelling framework was used to analyze the data. Results Overall, our results indicate that 15.9% of the variance in internalizing symptoms at age 15 can be predicted by anxiety, depression, and NDD symptoms at age 9. Anxiety and NDD symptoms in childhood predicted the largest amount of internalizing symptoms in adolescence. Conclusions Adolescent internalizing symptoms are modestly affected by childhood symptoms of anxiety, depression, and NDDs, suggesting that they may represent different constructs across age. Future studies should further empirically investigate differences in etiology and trajectories of childhood versus adolescent internalizing symptoms.

Background β-blockers are widely used for treating cardiac conditions and are suggested for the treatment of anxiety and aggression, although research is conflicting and limited by methodological problems. In addition, β-blockers have been associated with precipitating other psychiatric disorders and suicidal behaviour, but findings are mixed. We aimed to examine associations between β-blockers and psychiatric and behavioural outcomes in a large population-based cohort in Sweden. Methods and findings We conducted a population-based longitudinal cohort study using Swedish nationwide high-quality healthcare, mortality, and crime registers. We included 1,400,766 individuals aged 15 years or older who had collected β-blocker prescriptions and followed them for 8 years between 2006 and 2013. We linked register data on dispensed β-blocker prescriptions with main outcomes, hospitalisations for psychiatric disorders (not including self-injurious behaviour or suicide attempts), suicidal behaviour (including deaths from suicide), and charges of violent crime. We applied within-individual Cox proportional hazards regression to compare periods on treatment with periods off treatment within each individual in order to reduce possible confounding by indication, as this model inherently adjusts for all stable confounders (e.g., genetics and health history). We also adjusted for age as a time-varying covariate. In further analyses, we adjusted by stated indications, prevalent users, cardiac severity, psychiatric and crime history, individual β-blockers, β-blocker selectivity and solubility, and use of other medications. In the cohort, 86.8% (n = 1,215,247) were 50 years and over, and 52.2% (n = 731,322) were women. During the study period, 6.9% (n = 96,801) of the β-blocker users were hospitalised for a psychiatric disorder, 0.7% (n = 9,960) presented with suicidal behaviour, and 0.7% (n = 9,405) were charged with a violent crime. There was heterogeneity in the direction of results; within-individual analyses showed that periods of β-blocker treatment were associated with reduced hazards of psychiatric hospitalisations (hazard ratio [HR]: 0.92, 95% confidence interval [CI]: 0.91 to 0.93, p < 0.001), charges of violent crime (HR: 0.87, 95% CI: 0.81 to 0.93, p < 0.001), and increased hazards of suicidal behaviour (HR: 1.08, 95% CI: 1.02 to 1.15, p = 0.012). After stratifying by diagnosis, reduced associations with psychiatric hospitalisations during β-blocker treatment were mainly driven by lower hospitalisation rates due to depressive (HR: 0.92, 95% CI: 0.89 to 0.96, p < 0.001) and psychotic disorders (HR: 0.89, 95% CI: 0.85 to 0.93, p < 0.001). Reduced associations with violent charges remained in most sensitivity analyses, while associations with psychiatric hospitalisations and suicidal behaviour were inconsistent. Limitations include that the within-individual model does not account for confounders that could change during treatment, unless measured and adjusted for in the model. Conclusions In this population-wide study, we found no consistent links between β-blockers and psychiatric outcomes. However, β-blockers were associated with reductions in violence, which remained in sensitivity analyses. The use of β-blockers to manage aggression and violence could be investigated further. In a population-based cohort study of 1.4 million individuals in Sweden, Dr. Yasmina Molero and colleagues investigate the associations between β-blockers and psychiatric and behavioural outcomes. Author summary Why was this study done? β-blockers are primarily cardiac medications that are widely used for treating anxiety and are also suggested for the management of clinical depression and aggression, although research on efficacy is conflicting and limited by small samples and methodological problems. β-blockers have been linked to an increased risk of suicidal behaviour, but findings are inconclusive. More evidence using large samples and appropriate designs is needed on real-world effects on mental health and behavioural outcomes in people taking β-blockers. What did the researchers do and find? We examined a population-based cohort of 1,400,766 persons in Sweden who had been treated with β-blockers using a within-individual design; i.e., we compared individuals to themselves during medication and non-medication periods to account for background factors that may confound associations. Periods on β-blocker treatment were associated with an 8% lower risk of being hospitalised due to a psychiatric disorder, a 13% lower risk of being charged with a violent crime by the police, and an 8% increased risk of being treated for suicidal behaviour or suicide mortality. Reduced associations with violent charges were consistent across sensitivity analyses, while associations with suicidal behaviour and psychiatric hospitalisations varied by specific psychiatric diagnoses, past psychiatric problems, and cardiac severity. What do these findings mean? The widespread use of β-blockers to manage anxiety is not supported in this real-world study that examined presentations of anxiety in secondary care. Studies using other designs (e.g., randomised controlled trials) are needed to better understand the role of β-blockers in the management of aggression and violence. If findings on violence are confirmed by studies that use other designs, β-blockers could be considered to manage aggression and hostility in individuals with psychiatric conditions.

Abstract Background Frailty has been identified as a risk factor for cognitive impairment and dementia. However, it is not known whether familial factors, such as genetics and shared environmental factors, underlie this association. We analyzed the association between frailty and the risk of dementia in a large twin cohort and examined the role of familial factors in the association. Methods The Rockwood frailty index (FI) based on 44 health deficits was used to assess frailty. The population-level association between FI and the risk of all-cause dementia was analyzed in 41,550 participants of the Screening Across the Lifespan Twin (SALT) study (full sample, aged 41–97 years at baseline), using Cox and competing risk models. A subsample of 10,487 SALT participants aged 65 and older who received a cognitive assessment (cognitive sample) was used in a sensitivity analysis to assess the effect of baseline cognitive level on the FI-dementia association. To analyze the influence of familial effects on the FI-dementia association, a within-pair analysis was performed. The within-pair model was also used to assess whether the risk conferred by frailty varies by age at FI assessment. Results A total of 3183 individuals were diagnosed with dementia during the 19-year follow-up. A 10% increase in FI was associated with an increased risk of dementia (hazard ratio [HR] 1.17 (95% confidence interval [CI] 1.07, 1.18)) in the full sample adjusted for age, sex, education, and tobacco use. A significant association was likewise found in the cognitive sample, with an HR of 1.13 (95% CI 1.09, 1.20), adjusted for age, sex, and cognitive level at baseline. The associations were not attenuated when adjusted for APOE ɛ4 carrier status or considering the competing risk of death. After adjusting for familial effects, we found no evidence for statistically significant attenuation of the effect. The risk conferred by higher FI on dementia was constant after age 50 until very old age. Conclusions A higher level of frailty predicts the risk of dementia and the association appears independent of familial factors. Targeting frailty might thus contribute to preventing or delaying dementia.

Abstract While previous research has investigated neuroradiological findings in autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD), the entire range of neurodevelopmental disorders (NDDs) has not yet been well-studied using magnetic resonance imaging (MRI). Considering the overlap among NDDs and simultaneous development of the brain and face, guided by molecular signaling, we examined the relationship of actionable and incidental (non-actionable) MRI findings and NDD diagnoses together with facial morphological variants and genetic copy number variants (CNVs). A cross-sectional study was conducted with a twin cohort 8–36 years of age (57% monozygotic, 40% dizygotic), including 372 subjects (46% with NDDs; 47% female) imaged by MRI, 280 with data for facial morphological variants, and 183 for CNVs. Fifty-one percent of participants had MRI findings. Males had a statistically significantly higher percentage of MRI findings (57.7%) compared with females (43.8%, p = 0.03). Twin zygosity was not statistically significantly correlated with incidence or severity of specific MRI findings. No statistically significant association was found between MRI findings and any NDD diagnosis or facial morphological variants; however, MRI findings were statistically significantly associated with the number of CNVs (OR 1.20, 95% CI 1.00–1.44, p = 0.05, adjusted OR for sex 1.24, 95% CI 1.03–1.50, p = 0.02). When combining the presence of MRI findings, facial morphological variants, and CNVs, statistically significant relationships were found with ASD and ADHD diagnoses (p = 0.0006 and p = 0.002, respectively). The results of this study demonstrate that the ability to identify NDDs from combined radiology, morphology, and CNV assessments may be possible. Additionally, twins do not appear to be at increased risk for neuroradiological variants.

Abstract Background Studies have reported significant associations between asthma and attention‐deficit/hyperactivity disorder (ADHD), but whether the association is due to shared etiology such as shared genetic risk factors remains unclear. We aimed to investigate patterns of familial co‐aggregation of asthma and ADHD and also to quantify the relative contribution of genetic and environmental influences. Methods Through Swedish register linkages, we obtained a cohort of 927,956 individuals born 1992–2001 and identified monozygotic twins (MZ), dizygotic twins (DZ), full‐ and half‐siblings, and full‐ and half‐cousins. Clinical diagnosis of asthma and ADHD were identified from the Swedish national registers. We used logistic regressions to investigate the within‐individual association and familial co‐aggregation between asthma and ADHD. We then used bivariate twin modeling to quantify the genetic and environmental correlations and their contributions to the familial liability. Results Individuals with asthma had significantly higher risk of ADHD (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.47–1.54). Relatives of individuals with asthma had an increased risk of ADHD compared to relatives of individuals without asthma; in familial co‐aggregation analysis, the association was strongest in MZ twins (OR, 1.67; 95% CI, 0.99–2.84) and attenuated with degree of genetic relatedness. In the twin modeling, the phenotypic and genetic correlations between asthma and ADHD estimated from the ACE model were 0.09 (95% CI, 0.05–0.14) and 0.12 (95% CI, 0.02–0.21), respectively. The bivariate heritability was 0.88 (95% CI, 0.30–1.46). Estimates for contributions from shared and non‐shared environment factors were not statistically significant. Conclusions Asthma and ADHD co‐aggregate in families primarily due to shared genetic risk factors. Within‐individual and family history of either disorder should prompt clinical assessment of the other condition. Future studies should further investigate genetic variants underlying the co‐occurrence of ADHD and asthma.

Background Family history of atherosclerotic cardiovascular disease (ASCVD) is easily accessible and captures genetic cardiovascular risk, but its prognostic value in secondary prevention is unknown. Methods and Results We followed 25 615 patients registered in SWEDEHEART (Swedish Web‐System for Enhancement and Development of Evidence‐Based Care in Heart Disease Evaluated According to Recommended Therapies) from their 1‐year revisit after a first‐time myocardial infarction during 2005 to 2013, until December 31, 2018. Data on relatives, diagnoses and socioeconomics were extracted from national registers. The association between family history and recurrent ASCVD was studied with Cox proportional‐hazard regression, adjusting for risk factors and socioeconomics. A family history of ASCVD was defined as hospitalization due to myocardial infarction, angina with coronary revascularization, stroke, or cardiovascular death in ≥1 parent or full sibling, with early‐onset defined as disease‐onset before 55 years in men and 65 in women. The additional discriminatory value of family history to Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention was assessed with Harrell’s C‐index difference and reclassification was studied with continuous net reclassification improvement. Family history of early‐onset ASCVD in ≥1 first‐degree relative was present in 2.3% and was associated with recurrent ASCVD (hazard ratio [HR] 1.31; 95% CI, 1.17–1.47), fully adjusted for risk factors (HR, 1.22; 95% CI, 1.05–1.42). Early‐onset family history improved the discriminatory ability of the Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention, with Harrell’s C improving 0.003 points (95% CI, 0.001–0.005) from initial 0.587 (95% CI, 0.576–0.595) and improved reclassification (continuous net reclassification improvement 2.1%, P

Abstract Background Polygenic scores (PGS) for attention‐deficit/hyperactivity disorder (ADHD) negatively predicts educational attainment (EA), but it remains unclear how ADHD symptoms, PGS for EA, and shared familiar factors influence the associations between PGS for ADHD and school performance. Method We combined survey data on ADHD symptoms, PGS, and register‐based, objective measures of compulsory school performance at age 16 for 6049 twins in the Child and Adolescent Twin Study in Sweden. Linear and instrumental variable (IV) regression models were used to estimate the association between PGS for ADHD and grade point average (GPA), overall and by natural science, humanities, and practically oriented (e.g., sports, arts, music) subject categories. The models were adjusted for parent‐rated ADHD symptoms, PGS for EA, and shared familial factors (dizygotic twin comparisons) to examine how these factors influenced the associations between PGS for ADHD and school performance. Results PGS for ADHD were negatively associated with school performance; β = −0.12, 95% confidence interval = (−0.15, −0.09) for overall GPA with minor differences by subject category. Adjustment for ADHD symptoms attenuated these associations to a small degree compared to PGS for EA, and shared familial factors respectively. Stronger associations were observed using IV regressions compared to linear regression. However, in the IV regression analyses, most associations between PGS for ADHD and GPA in the practically oriented subject category were not significant. Conclusion Associations between PGS for ADHD and school performance are to a small degree influenced by ADHD symptoms, compared to PGS for EA and shared familial factors. These results highlight important considerations for research using PGS for ADHD to control for genetic factors, and for future clinical applications aiming to determine genetic liability towards ADHD.

Abstract Background It has been suggested that parents of children with autism spectrum disorder (ASD) curtail their reproduction, a phenomenon known as reproductive stoppage. To investigate the presence of reproductive stoppage, we followed the reproduction in mothers of children with or without an ASD diagnosis using Swedish population-based registries. Methods We followed all families with first child born in 1987 or later. In total 2,521,103 children, nested within 1,270,017 mothers, were included. Exposure was presence of ASD diagnosis in earlier born siblings, and outcome was considered as (1) inter-pregnancy interval and (2) number of subsequent children. Results Analyses of inter-pregnancy intervals showed that the association differed across birth orders, with a lower rate of second children when first child had ASD diagnosis, but an increased rate of third and higher birth orders in families where a previous child had an ASD diagnosis. When all birth orders were simultaneously considered, families with a child with an ASD diagnosis were less likely to have another child (hazard ratio (HR), 0.79; 95% confidence interval [95% CI], 0.78–0.80). However, when adjusted for birth order, the association was close to null (HR, 0.97; 95% CI, 0.96–0.99), and after additional adjustments (maternal age, birth period, sex, paternal age, and maternal education), the association disappeared (HR, 1.00; 95% CI, 0.99–1.02). In analyses of subsequent children, after adjustment for covariates, families with an ASD diagnosis had 4% more subsequent children (rate ratio, 1.04; 95% CI, 1.03–1.05). Limitations The study was undertaken in a country with largely tax-funded healthcare; results may not generalize to other societies. Following the current dominating umbrella concept of ASD, we did not differentiate between the ASD sub-diagnoses; it is possible that reproductive patterns can be dependent on ASD subtypes and the severity and composition of ASD phenotypes and comorbidities. Conclusions This study does not support a universal reproductive stoppage effect in ASD families, when birth order and other factors are considered. Therefore, proper attention to birth order and other factors may alleviate potential bias in familial aggregation studies of ASD.

Abstract Background Females with autism spectrum disorder have been reported to exhibit fewer and less severe restricted and repetitive behaviors and interests compared to males. This difference might indicate sex-specific alterations of brain networks involved in autism symptom domains, especially within cortico-striatal and sensory integration networks. This study used a well-controlled twin design to examine sex differences in brain anatomy in relation to repetitive behaviors. Methods In 75 twin pairs (n = 150, 62 females, 88 males) enriched for autism spectrum disorder (n = 32), and other neurodevelopmental disorders (n = 32), we explored the association of restricted and repetitive behaviors and interests—operationalized by the Autism Diagnostic Interview-Revised (C domain) and the Social Responsiveness Scale-2 (Restricted Interests and Repetitive Behavior subscale)—with cortical volume, surface area and thickness of neocortical, sub-cortical, and cerebellar networks. Results Co-twin control analyses revealed within-pair associations between RRBI symptoms and increased thickness of the right intraparietal sulcus and reduced volume of the right orbital gyrus in females only, even though the mean number of RRBIs did not differ between the sexes. In a sub-sample of ASD-discordant pairs, increased thickness in association with RRBIs was found exclusively in females in the orbitofrontal regions, superior frontal gyrus, and intraparietal sulcus, while in males RRBIs tended to be associated with increased volume of the bilateral pallidum. Limitations However, due to a small sample size and the small difference in RRBI symptoms within pairs, the results of this exploratory study need to be interpreted with caution. Conclusions Our findings suggest that structural alterations of fronto-parietal networks in association with RRBIs are found mostly in females, while striatal networks are more affected in males. These results endorse the importance of investigating sex differences in the neurobiology of autism symptoms, and indicate different etiological pathways underlying restricted and repetitive behaviors and interests in females and males.

Abstract Background Anxiety disorders in adolescence have been associated with several psychiatric outcomes. We sought to describe the prospective relationship between various levels of adolescent anxiety and psychiatric diagnoses (anxiety-, bipolar/psychotic-, depressive-, and alcohol and drug misuse disorders) and suicidal ideation in early adulthood while adjusting for childhood attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and developmental coordination disorder (DCD). Furthermore, we aimed to estimate the proportion attributable to the various anxiety levels for the outcomes. Methods We used a nation-wide population-based Swedish twin study comprising 14,106 fifteen-year-old twins born in Sweden between 1994 and 2002 and a replication sample consisting of 9211 Dutch twins, born between 1985 and 1999. Adolescent anxiety was measured with parental and self-report. Psychiatric diagnoses and suicidal ideation were retrieved from the Swedish National Patient Register and via self-report. Results Adolescent anxiety, of various levels, predicted, in the Swedish National Patient Register, anxiety disorders: hazard ratio (HR) = 4.92 (CI 3.33–7.28); depressive disorders: HR = 4.79 (3.23–7.08), and any psychiatric outcome: HR = 3.40 (2.58–4.48), when adjusting for ADHD, ASD, and DCD. The results were replicated in the Dutch data. The proportion of psychiatric outcome attributable to adolescent anxiety over time (age 15–21) was 29% for any psychiatric outcome, 43–40% for anxiety disorders, and 39–38% for depressive disorders. Conclusion Anxiety in adolescence constitutes an important risk factor in the development of psychiatric outcomes, revealing unique predictions for the different levels of anxiety, and beyond the risk conferred by childhood ADHD, ASD, and DCD. Developmental trajectories leading into psychiatric outcomes should further empirically investigated.

Background: Measures based on DNA methylation, epigenetic clocks, have recently gained attraction as predictors of mortality and age-related pathologies. However, the origins of variation in these measures are not well understood. Methods: In a pooled sample of 104 Swedish and Danish twin pairs, we estimated, at the mean age of 70 (baseline) and 79 years (follow-up), the genetic and environmental influences on the Horvath and Levine clocks. Findings: A model incorporating additive genetic (A) and person-specific environmental (E) influences best explained the variation in both clocks. Heritability was estimated at 55% at baseline and at 51% at follow-up for the Horvath clock and 34% at baseline and 41% at follow-up for the Levine clock. For the Horvath clock, new sources of A influences emerged at follow-up, whereas for the Levine clock, the same A influences accounted for the genetic variance at both measurement occasions. The cross-time phenotypic correlations, 0·52 for the Horvath clock and 0·36 for the Levine clock, were mediated primarily by genetic factors, whereas the person-specific environmental factors were completely different at the two measurement occasions. Interpretation: For both clocks, new sources of person-specific environmental influences emerge with age. The epigenetic clocks might thus be responsive to new environmental stimuli even at old age. Fund: NIH (R01;AG04563;AG10175;AG028555) the MacArthur Foundation Research Network on Successful Aging, FAS/FORTE (97:0147:1B;2009-0795), Swedish Research Council (825-2007-7460;825-2009-6141;521-2013-8689;2015-03255;2015-06796;2018-02077), FORTE (2013-2292), the Strategic Research Program in Epidemiology at KI, VELUX FOUNDATION, NIA (P01-AG08761), the EU (FP7/2007-2011;259679) and The Danish National Program for Research Infrastructure 2007 (9-063256). Keywords: Epigenetic clock, DNA methylation, Aging, Heritability, Sources of variation

BackgroundLow resting heart rate (RHR) and low systolic blood pressure (SBP) are associated with criminal behavior. However, knowledge is lacking about their predictive value for reoffending.AimWe aimed to examine associations of RHR and SBP with reoffending in a large population-based sample.MethodsWe conducted a cohort study of all convicted male conscripts born in Sweden 1958-1990 (N = 407,533). We obtained data by linking Swedish population-based registers. Predictor variables were RHR and SBP, measured at conscription which was mandatory until 2010 for men at age 18. The outcome variable was reoffending, defined as criminal convictions (any crime, violent crime and non-violent crime), obtained from the National Crime Register. We used survival analyses to test for associations of RHR and SBP with reoffending, adjusting for pertinent covariates such as socioeconomic status, height, weight and physical energy capacity.ResultsIn fully adjusted Cox regression models, men with lower RHR (≤60 bpm) had higher risk of reoffending (any crime: HR = 1.17, 95% CI: 1.14, 1.19, violent crime: HR = 1.23, 95% CI: 1.17, 1.29, non-violent crime: HR = 1.16, 95% CI: 1.14, 1.19), compared to men with higher RHR (≥ 82 bpm). Men with lower SBP (≤80 mmHg) had higher risk of reoffending (any crime: HR = 1.19, 95% CI: 1.17, 1.21, violent crime: HR = 1.16, 95% CI: 1.12, 1.20, non-violent crime: HR = 1.20, 95% CI: 1.18, 1.22), compared to men with higher SBP (≥138 mmHg).ConclusionsLow autonomic arousal is associated with increased risk of reoffending. RHR and SBP should be investigated further as potential predictors for reoffending as they each may have predictive value in risk assessment protocols.

BackgroundIndividuals with ADHD are at increased risk for poor occupational outcomes. Educational attainment and psychiatric comorbidity may be important contributing factors for these outcomes, but the role of these factors is not well characterized. This study aimed to investigate the associations between ADHD and occupational outcomes, and to examine the influence of educational attainment, comorbid developmental disorders and intellectual disability on these associations.MethodsWe linked the Swedish population graduating from compulsory school 1998-2008 (N = 1.2 millions) to population-wide register-based data on clinical psychiatric diagnoses and medications, objective annual measures of educational, and occupational outcomes. Individuals were followed for between 6 to 16 years after graduation.ResultsIndividuals with ADHD had annually on average 17 percent lower income, ratio = 0.83 (95% CI 0.83-0.84), 12.19 (11.89-12.49) more days of unemployment, and a higher likelihood of receiving disability pension, odds-ratio = 19.0 (18.4-19.6), compared to controls. Comorbid diagnoses of intellectual disability and developmental disorder explained most of the association between ADHD and disability pension, while lifetime educational attainment partially explained associations between ADHD and all occupational outcomes. Analyses of occupational trajectories found that income was lower and unemployment elevated relative to controls with the same educational attainment. Higher educational attainment correlated with higher income similarly among individuals with ADHD and controls after accounting for individual background factors.ConclusionsThe occupational burden associated with ADHD is substantial. Comorbid developmental disorders, intellectual disability and educational difficulties (e.g., failing grades) from childhood to adulthood are important factors to consider when designing interventions to improve occupational outcomes in individuals with ADHD.

Abstract Background Minor physical anomalies (MPAs) are subtle anatomical deviations in one’s appearance and may suggest altered embryogenesis. MPAs have been shown to be more common in neurodevelopmental disorders (NDDs) compared with typical development. Still, further studies are needed on MPAs in NDDs, especially using twins to adjust for confounding familial factors. Methods Clinical assessments were conducted on 116 twins (61 NDD, 55 controls) from 51 monozygotic and 7 dizygotic pairs to examine MPAs and their association with DSM-5 defined NDDs. Additionally, the relationship between the number of MPAs within twins by zygosity was investigated. Results Within the cohort sample, a specific association was found between MPAs and autism spectrum disorder (ASD) diagnosis (crude odds ratio = 1.29, p = .047; adjusted odds ratios = 1.26–1.33, adjusted p values = .032–.073) and autistic traits (crude β = 3.02, p = .002; adjusted β = 2.28, p = .019), but not NDDs in general or ADHD, nor within-pairs. Identified MPAs in ASD included overweight, hypermobility, pes planus, straight eyebrows, vision impairment, arachnodactyly/long toes, long eyelashes, and microtia. The number of MPAs within all monozygotic pairs was highly correlated (r = .88, p

BACKGROUND:Predicting which children will go on to develop mental health symptoms as adolescents is critical for early intervention and preventing future, severe negative outcomes. Although many aspects of a child's life, personality, and symptoms have been flagged as indicators, there is currently no model created to screen the general population for the risk of developing mental health problems. Additionally, the advent of machine learning techniques represents an exciting way to potentially improve upon the standard prediction modelling technique, logistic regression. Therefore, we aimed to I.) develop a model that can predict mental health problems in mid-adolescence II.) investigate if machine learning techniques (random forest, support vector machines, neural network, and XGBoost) will outperform logistic regression. METHODS:In 7,638 twins from the Child and Adolescent Twin Study in Sweden we used 474 predictors derived from parental report and register data. The outcome, mental health problems, was determined by the Strengths and Difficulties Questionnaire. Model performance was determined by the area under the receiver operating characteristic curve (AUC). RESULTS:Although model performance varied somewhat, the confidence interval overlapped for each model indicating non-significant superiority for the random forest model (AUC = 0.739, 95% CI 0.708-0.769), followed closely by support vector machines (AUC = 0.735, 95% CI 0.707-0.764). CONCLUSION:Ultimately, our top performing model would not be suitable for clinical use, however it lays important groundwork for future models seeking to predict general mental health outcomes. Future studies should make use of parent-rated assessments when possible. Additionally, it may not be necessary for similar studies to forgo logistic regression in favor of other more complex methods.