Long-Term Outcomes Associated with Traumatic Brain Injury in Childhood and Adolescence: A Nationwide Swedish Cohort Study of a Wide Range of Medical and Social Outcomes

BACKGROUND: Traumatic brain injury (TBI) is the leading cause of disability and mortality in children and young adults worldwide. It remains unclear, however, how TBI in childhood and adolescence is associated with adult mortality, psychiatric morbidity, and social outcomes. METHODS AND FINDINGS: In a Swedish birth cohort between 1973 and 1985 of 1,143,470 individuals, we identified all those who had sustained at least one TBI (n = 104,290 or 9.1%) up to age 25 y and their unaffected siblings (n = 68,268) using patient registers. We subsequently assessed these individuals for the following outcomes using multiple national registries: disability pension, specialist diagnoses of psychiatric disorders and psychiatric inpatient hospitalisation, premature mortality (before age 41 y), low educational attainment (not having achieved secondary school qualifications), and receiving means-tested welfare benefits. We used logistic and Cox regression models to quantify the association between TBI and specified adverse outcomes on the individual level. We further estimated population attributable fractions (PAF) for each outcome measure. We also compared differentially exposed siblings to account for unobserved genetic and environmental confounding. In addition to relative risk estimates, we examined absolute risks by calculating prevalence and Kaplan-Meier estimates. In complementary analyses, we tested whether the findings were moderated by injury severity, recurrence, and age at first injury (ages 0-4, 5-9, 6-10, 15-19, and 20-24 y). TBI exposure was associated with elevated risks of impaired adult functioning across all outcome measures. After a median follow-up period of 8 y from age 26 y, we found that TBI contributed to absolute risks of over 10% for specialist diagnoses of psychiatric disorders and low educational attainment, approximately 5% for disability pension, and 2% for premature mortality. The highest relative risks, adjusted for sex, birth year, and birth order, were found for psychiatric inpatient hospitalisation (adjusted relative risk [aRR] = 2.0; 95% CI: 1.9-2.0; 6,632 versus 37,095 events), disability pension (aRR = 1.8; 95% CI: 1.7-1.8; 4,691 versus 29,778 events), and premature mortality (aRR = 1.7; 95% CI: 1.6-1.9; 799 versus 4,695 events). These risks were only marginally attenuated when the comparisons were made with their unaffected siblings, which implies that the effects of TBI were consistent with a causal inference. A dose-response relationship was observed with injury severity. Injury recurrence was also associated with higher risks-in particular, for disability pension we found that recurrent TBI was associated with a 3-fold risk increase (aRR = 2.6; 95% CI: 2.4-2.8) compared to a single-episode TBI. Higher risks for all outcomes were observed for those who had sustained their first injury at an older age (ages 20-24 y) with more than 25% increase in relative risk across all outcomes compared to the youngest age group (ages 0-4 y). On the population level, TBI explained between 2%-6% of the variance in the examined outcomes. Using hospital data underestimates milder forms of TBI, but such misclassification bias suggests that the reported estimates are likely conservative. The sibling-comparison design accounts for unmeasured familial confounders shared by siblings, including half of their genes. Thus, residual genetic confounding remains a possibility but will unlikely alter our main findings, as associations were only marginally attenuated within families. CONCLUSIONS: Given our findings, which indicate potentially causal effects between TBI exposure in childhood and later impairments across a range of health and social outcomes, age-sensitive clinical guidelines should be considered and preventive strategies should be targeted at children and adolescents

Increased schizophrenia family history burden and reduced premorbid IQ in treatment-resistant schizophrenia: a Swedish National Register and Genomic Study

A high proportion of those with schizophrenia experience treatment non-response, placing them at higher risk for mortality and suicide attempts, compared to treatment responders. The clinical, social, and economic burden of treatment-resistant schizophrenia (TRS) are substantial. Previous genomic and epidemiological studies of TRS were often limited by sample size or lack of comprehensive genomic data. We aimed to systematically understand the clinical, demographic, and genomic correlates of TRS using epidemiological and genetic epidemiological modelling in a Swedish national population sample (n = 24,706) and then in a subgroup with common variant genetic risk scores, rare copy-number variant burden, and rare exonic burden (n = 4936). Population-based analyses identified increasing schizophrenia family history to be significantly associated with TRS (highest quartile of familial burden vs. lowest: adjusted odds ratio (aOR): 1.31, P = 4.8 × 10-8). In males, a decrease of premorbid IQ of one standard deviation was significantly associated with greater risk of TRS (minimal aOR: 0.94, P = 0.002). In a subset of cases with extensive genomic data, we found no significant association between the genetic risk scores of four psychiatric disorders and two cognitive traits with TRS (schizophrenia genetic risk score: aOR = 1.07, P = 0.067). The association between copy number variant and rare variant burden measures and TRS did not reach the pre-defined statistical significance threshold (all P ≥ 0.005). In conclusion, direct measures of genomic risk were not associated with TRS; however, premorbid IQ in males and schizophrenia family history were significantly correlated with TRS and points to new insights into the architecture of TRS

The impact of educational attainment, intelligence and intellectual disability on schizophrenia: a Swedish population-based register and genetic study

Schizophrenia (SCZ) is highly heterogenous and no subtypes characterizing treatment response or longitudinal course well. Cognitive impairment is a core clinical feature of SCZ and a determinant of poorer outcome. Genetic overlap between SCZ and cognitive traits is complex, with limited studies of comprehensive epidemiological and genomic evidence. To examine the relation between SCZ and three cognitive traits, educational attainment (EDU), premorbid cognitive ability, and intellectual disability (ID), we used two Swedish samples: a national cohort (14,230 SCZ cases and 3,816,264 controls) and a subsample with comprehensive genetic data (4992 cases and 6009 controls). Population-based analyses confirmed worse cognition as a risk factor for SCZ, and the pedigree and SNP-based genetic correlations were comparable. In the genotyped cases, those with high EDU and premorbid cognitive ability tended to have higher polygenetic risk scores (PRS) of EDU and intelligence and fewer rare exonic variants. Finally, by applying an empirical clustering method, we dissected SCZ cases into four replicable subgroups characterized by EDU and ID. In particular, the subgroup with higher EDU in the national cohort had fewer adverse outcomes including long hospitalization and death. In the genotyped subsample, this subgroup had higher PRS of EDU and no excess of rare genetic burdens than controls. In conclusion, we found extensive evidence of a robust relation between cognitive traits and SCZ, underscoring the importance of cognition in dissecting the heterogeneity of SCZ

The association between childhood relocations and subsequent risk of suicide attempt, psychiatric problems, and low academic achievement

Background: Given the frequency with which families change residences, the effects of childhood relocations have gained increasing research attention. Many researchers have demonstrated that childhood relocations are associated with a variety of adverse outcomes. However, drawing strong causal claims remains problematic due to uncontrolled confounding factors. Methods: We utilized longitudinal, population-based Swedish registers to generate a nationally representative sample of offspring born 1983-1997 (n=1,510,463). Using Cox regression and logistic regression, we examined the risk for numerous adverse outcomes after childhood relocation while controlling for measured covariates. To account for unmeasured genetic and environmental confounds, we also compared differentially exposed cousins and siblings. Results: In the cohort baseline model, each annual relocation was associated with risk for the adverse outcomes, including suicide attempt (HR=1.19; 95% CI, 1.19-1.20). However, when accounting for offspring and parental covariates (e.g., HR=1.08; 95% CI, 1.07-1.09), as well as genetic and environmental confounds shared by cousins (HR=1.07; 95% CI, 1.05-1.09) and siblings (e.g., HR=1.00; 95% CI, 0.97-1.04), the risk for suicide attempt attenuated. We found a commensurate pattern of results for severe mental illness, substance abuse, criminal convictions, and low academic achievement. Conclusions: Previous research may have overemphasized the independent association between relocations and later adverse outcomes. The results suggest that the association between childhood relocations and suicide attempt, psychiatric problems, and low academic achievement is partially explained by genetic and environmental confounds correlated with relocations. This study demonstrates the importance of using family-based, quasi-experimental designs to test plausible alternate hypotheses when examining causality.National Institute of Child Health and Development, HD061817Indiana Clinical Translational Institute Project Development TeamsSwedish Council for Working Life and Social ResearchSwedish Research Council through the Swedish Initiative for Research on Microdata in the Social and Medical Sciences, 340-2013-5867Manuscrip

Violent aggression predicted by multiple pre-adult environmental hits

Early exposure to negative environmental impact shapes individual behavior and potentially contributes to any mental disease. We reported previously that accumulated environmental risk markedly decreases age at schizophrenia onset. Follow-up of matched extreme group individuals (≤1 vs. ≥3 risks) unexpectedly revealed that high-risk subjects had >5 times greater probability of forensic hospitalization. In line with longstanding sociological theories, we hypothesized that risk accumulation before adulthood induces violent aggression and criminal conduct, independent of mental illness. We determined in 6 independent cohorts (4 schizophrenia and 2 general population samples) pre-adult risk exposure, comprising urbanicity, migration, physical and sexual abuse as primary, and cannabis or alcohol as secondary hits. All single hits by themselves were marginally associated with higher violent aggression. Most strikingly, however, their accumulation strongly predicted violent aggression (odds ratio 10.5). An epigenome-wide association scan to detect differential methylation of blood-derived DNA of selected extreme group individuals yielded overall negative results. Conversely, determination in peripheral blood mononuclear cells of histone-deacetylase1 mRNA as 'umbrella mediator' of epigenetic processes revealed an increase in the high-risk group, suggesting lasting epigenetic alterations. Together, we provide sound evidence of a disease-independent unfortunate relationship between well-defined pre-adult environmental hits and violent aggression, calling for more efficient prevention

Towards a more evidence-based risk assessment for people in the criminal justice system: the case of OxRec in the Netherlands

Risk assessment tools are widely used throughout the criminal justice system to assist in making decisions about sentencing, supervision, and treatment. In this article, we discuss several methodological and practical limitations associated with risk assessment tools currently in use. These include variable predictive performance due to the exclusion of important background predictors; high costs, including the need for regular staff training, in order to use many tools; development of tools using suboptimal methods and poor transparency in how they create risk scores; included risk factors being based on dated evidence; and ethical concerns highlighted by legal scholars and criminologists, such as embedding systemic biases and uncertainty about how these tools influence judicial decisions. We discuss the potential that specific predictors, such as living in a deprived neighbourhood, may indirectly select for individuals in racial or ethnic minority groups. To demonstrate how these limitations and ethical concerns can be addressed, we present the example of OxRec, a risk assessment tool used to predict recidivism for individuals in the criminal justice system. OxRec was developed in Sweden and has been externally validated in Sweden and the Netherlands. The advantages of OxRec include its predictive accuracy based on rigorous multivariable testing of predictors, transparent reporting of results and the final model (including how the probability score is derived), scoring simplicity (i.e. without the need for additional interview), and the reporting of a wide range of performance measures, including those of discrimination and calibration, the latter of which is rarely reported but a key metric. OxRec is intended to be used alongside professional judgement, as a support for decision-making, and its performance measures need to be interpreted in this light. The reported calibration of the tool in external samples clearly suggests no systematic overestimation of risk, including in large subgroups