Educational attainment, structural brain reserve and Alzheimer's disease: a Mendelian randomization analysis.

Higher educational attainment is observationally associated with lower risk of Alzheimer's disease. However, the biological mechanisms underpinning this association remain unclear. The protective effect of education on Alzheimer's disease may be mediated via increased brain reserve. We used two-sample Mendelian randomization to explore putative causal relationships between educational attainment, structural brain reserve as proxied by MRI phenotypes and Alzheimer's disease. Summary statistics were obtained from genome-wide association studies of educational attainment (n = 1 131 881), late-onset Alzheimer's disease (35 274 cases, 59 163 controls) and 15 measures of grey or white matter macro- or micro-structure derived from structural or diffusion MRI (nmax = 33 211). We conducted univariable Mendelian randomization analyses to investigate bidirectional associations between (i) educational attainment and Alzheimer's disease; (ii) educational attainment and imaging-derived phenotypes; and (iii) imaging-derived phenotypes and Alzheimer's disease. Multivariable Mendelian randomization was used to assess whether brain structure phenotypes mediated the effect of education on Alzheimer's disease risk. Genetically proxied educational attainment was inversely associated with Alzheimer's disease (odds ratio per standard deviation increase in genetically predicted years of schooling = 0.70, 95% confidence interval 0.60, 0.80). There were positive associations between genetically predicted educational attainment and four cortical metrics (standard deviation units change in imaging phenotype per one standard deviation increase in genetically predicted years of schooling): surface area 0.30 (95% confidence interval 0.20, 0.40); volume 0.29 (95% confidence interval 0.20, 0.37); intrinsic curvature 0.18 (95% confidence interval 0.11, 0.25); local gyrification index 0.21 (95% confidence interval 0.11, 0.31)]; and inverse associations with cortical intracellular volume fraction [-0.09 (95% confidence interval -0.15, -0.03)] and white matter hyperintensities volume [-0.14 (95% confidence interval -0.23, -0.05)]. Genetically proxied levels of surface area, cortical volume and intrinsic curvature were positively associated with educational attainment [standard deviation units change in years of schooling per one standard deviation increase in respective genetically predicted imaging phenotype: 0.13 (95% confidence interval 0.10, 0.16); 0.15 (95% confidence interval 0.11, 0.19) and 0.12 (95% confidence interval 0.04, 0.19)]. We found no evidence of associations between genetically predicted imaging-derived phenotypes and Alzheimer's disease. The inverse association of genetically predicted educational attainment with Alzheimer's disease did not attenuate after adjusting for imaging-derived phenotypes in multivariable analyses. Our results provide support for a protective causal effect of educational attainment on Alzheimer's disease risk, as well as potential bidirectional causal relationships between education and brain macro- and micro-structure. However, we did not find evidence that these structural markers affect risk of Alzheimer's disease. The protective effect of education on Alzheimer's disease may be mediated via other measures of brain reserve not included in the present study, or by alternative mechanisms.

Investigation of risk of dementia diagnosis and death in patients in older people's secondary care mental health services.

OBJECTIVES: Previous studies have shown increased rates of death and dementia in older people in specific serious mental illnesses (SMI) such as bipolar disorder or depression. We examined the rates of death and dementia in older people referred into a secondary care psychiatric service across a range of SMIs. METHODS: We used an anonymised dataset across 6 consecutive years with 28,340 patients aged 65 years and older from a single secondary care psychiatric trust in the United Kingdom. We identified deaths and incident dementia in patients with bipolar disorder/mania, schizophrenia, recurrent depression and anxiety disorders. We compared mortality and dementia rates between these diagnostic groups and in different treatment settings. We also examined mortality rates and dementia rates compared with general population rates. RESULTS: Patients with schizophrenia showed the highest hazard rate for death compared to other groups with SMIs (hazard ratio, 1.58; 95% confidence interval (CI), 1.18-2.1, with anxiety group the reference). Survival was reduced in patients referred to liaison psychiatry services. There were no significant differences between the SMI groups in terms of rates of dementia. However, risks of death and dementia were significantly increased compared to the general population (standardized mortality rates with 95% CI, 2.6(2.0-3.3), 3.5(2.6-4.5), 2.5(2.0-3.0) and 1.8 (1.4-2.2) and standardized dementia incidence rates with 95% CI, 2.7(1.5-4.1), 2.9(1.5-4.7), 3.8(2.6-5.2) and 4.3 (3.0-5.7) for bipolar disorder/mania, schizophrenia, recurrent depression and anxiety disorders respectively. CONCLUSIONS: Older adults referred into an old age psychiatry service show higher rates of dementia and death than those reported for the general population.

Suicide risk assessment tools and prediction models: new evidence, methodological innovations, outdated criticisms.

The number of prediction models for suicide-related outcomes has grown substantially in recent years. These models aim to assist in stratifying risk, improve clinical decision-making, and facilitate a personalised medicine approach to the prevention of suicidal behaviour. However, there are contrasting views as to whether prediction models have potential to inform and improve assessment of suicide risk. In this perspective, we discuss common misconceptions that characterise criticisms of suicide risk prediction research. First, we discuss the limitations of a classification approach to risk assessment (eg, categorising individuals as low-risk vs high-risk), and highlight the benefits of probability estimation. Second, we argue that the preoccupation with classification measures (such as positive predictive value) when assessing a model's predictive performance is inappropriate, and discuss the importance of clinical context in determining the most appropriate risk threshold for a given model. Third, we highlight that adequate discriminative ability for a prediction model depends on the clinical area, and emphasise the importance of calibration, which is almost entirely overlooked in the suicide risk prediction literature. Finally, we point out that conclusions about the clinical utility and health-economic value of suicide prediction models should be based on appropriate measures (such as net benefit and decision-analytic modelling), and highlight the role of impact assessment studies. We conclude that the discussion around using suicide prediction models and risk assessment tools requires more nuance and statistical expertise, and that guidelines and suicide prevention strategies should be informed by the new and higher quality evidence in the field.

Using Electronic Health Records to Facilitate Precision Psychiatry.

The use of clinical prediction models to produce individualized risk estimates can facilitate the implementation of precision psychiatry. As a source of data from large, clinically representative patient samples, electronic health records (EHRs) provide a platform to develop and validate clinical prediction models, as well as potentially implement them in routine clinical care. The current review describes promising use cases for the application of precision psychiatry to EHR data and considers their performance in terms of discrimination (ability to separate individuals with and without the outcome) and calibration (extent to which predicted risk estimates correspond to observed outcomes), as well as their potential clinical utility (weighing benefits and costs associated with the model compared to different approaches across different assumptions of the number needed to test). We review 4 externally validated clinical prediction models designed to predict psychosis onset, psychotic relapse, cardiometabolic morbidity, and suicide risk. We then discuss the prospects for clinically implementing these models and the potential added value of integrating data from evidence syntheses, standardized psychometric assessments, and biological data into EHRs. Clinical prediction models can utilize routinely collected EHR data in an innovative way, representing a unique opportunity to inform real-world clinical decision making. Combining data from other sources (e.g., meta-analyses) or enhancing EHR data with information from research studies (clinical and biomarker data) may enhance our abilities to improve the performance of clinical prediction models.

Violence risk assessment instruments in forensic psychiatric populations: a systematic review and meta-analysis.

BACKGROUND: Although structured tools have been widely used to predict violence risk in specialist mental health settings, there is uncertainty about the extent and quality of evidence of their predictive performance. We aimed to systematically review the predictive performance of tools used to assess violence risk in forensic mental health, where they are routinely administered. METHODS: In our systematic review and meta-analysis, we followed PRISMA guidelines and searched four databases (PsycINFO, Embase, Medline, and Global Health) from database inception to Nov 1, 2022, to identify studies examining the predictive performance of risk assessment tools in people discharged from forensic (secure) mental health hospitals. Systematic and narrative reviews were excluded from the review. Performance measures and descriptive statistics were extracted from published reports. A quality assessment was performed for each study using the Prediction Model Risk of Bias Assessment Tool. Meta-analysis was conducted on the performance of instruments that were independently externally validated with a sample size greater than 100. The study was registered with PROSPERO, CRD42022304716. FINDINGS: We conducted a systematic review of 50 eligible publications, assessing the predictive performance of 36 tools, providing data for 10 460 participants (88% men, 12% women; median age [from 47 studies] was 35 years, IQR 33-38) from 12 different countries. Post-discharge interpersonal violence and crime was most often measured by new criminal offences or recidivism (47 [94%] of 50 studies); only three studies used informant or self-report data on physical aggression or violent behaviour. Overall, the predictive performance of risk assessment tools was mixed. Most studies reported one discrimination metric, the area under the receiver operating characteristic curve (AUC); other key performance measures such as calibration, sensitivity, and specificity were not presented. Most studies had a high risk of bias (49 [98%] of 50), partly due to poor analytical approaches. A meta-analysis was conducted for violent recidivism on 29 independent external validations from 19 studies with at least 100 patients. Pooled AUCs for predicting violent outcomes ranged from 0·72 (0·65-0·79; I2=0%) for H10, to 0·69 for the Historical Clinical Risk Management-20 version 2 (95% CI 0·65-0·72; I2=0%) and Violence Risk Appraisal Guide (0·63-0·75; I2=0%), to 0·64 for the Static-99 (0·53-0·73; I2=45%). INTERPRETATION: Current violence risk assessment tools in forensic mental health have mixed evidence of predictive performance. Forensic mental health services should review their use of current risk assessment tools and consider implementing those with higher-quality evidence in support. FUNDING: Wellcome Trust.

Using natural language processing to extract self-harm and suicidality data from a clinical sample of patients with eating disorders: a retrospective cohort study.

OBJECTIVES: The objective of this study was to determine risk factors for those diagnosed with eating disorders who report self-harm and suicidality. DESIGN AND SETTING: This study was a retrospective cohort study within a secondary mental health service, South London and Maudsley National Health Service Trust. PARTICIPANTS: All diagnosed with an F50 diagnosis of eating disorder from January 2009 to September 2019 were included. INTERVENTION AND MEASURES: Electronic health records (EHRs) for these patients were extracted and two natural language processing tools were used to determine documentation of self-harm and suicidality in their clinical notes. These tools were validated manually for attribute agreement scores within this study. RESULTS: The attribute agreements for precision of positive mentions of self-harm were 0.96 and for suicidality were 0.80; this demonstrates a 'near perfect' and 'strong' agreement and highlights the reliability of the tools in identifying the EHRs reporting self-harm or suicidality. There were 7434 patients with EHRs available and diagnosed with eating disorders included in the study from the dates January 2007 to September 2019. Of these, 4591 (61.8%) had a mention of self-harm within their records and 4764 (64.0%) had a mention of suicidality; 3899 (52.4%) had mentions of both. Patients reporting either self-harm or suicidality were more likely to have a diagnosis of anorexia nervosa (AN) (self-harm, AN OR=3.44, 95% CI 1.05 to 11.3, p=0.04; suicidality, AN OR=8.20, 95% CI 2.17 to 30.1; p=0.002). They were also more likely to have a diagnosis of borderline personality disorder (p≤0.001), bipolar disorder (p<0.001) or substance misuse disorder (p<0.001). CONCLUSION: A high percentage of patients (>60%) diagnosed with eating disorders report either self-harm or suicidal thoughts. Relative to other eating disorders, those diagnosed with AN were more likely to report either self-harm or suicidal thoughts. Psychiatric comorbidity, in particular borderline personality disorder and substance misuse, was also associated with an increase risk in self-harm and suicidality. Therefore, risk assessment among patients diagnosed with eating disorders is crucial.

The relationship between heartbeat counting and heartbeat discrimination: A meta-analysis.

Interoception concerns the perception of the body's internal state. Despite the importance of this ability for health and aspects of higher-order cognition, its measurement remains problematic. Most studies of interoception employ one of two tasks: the heartbeat counting or heartbeat discrimination task. These tasks are thought to index common abilities, an assertion often used to justify the use of a single measure of cardiac interoception. However, mixed findings regarding the relationship between performance on these tasks raises the question of whether they can be used interchangeably to assess interoceptive accuracy, confidence and awareness ('metacognition'). The present study employed a meta-analytical approach to assess the association between these tasks. Pooled findings from 22 studies revealed a small relationship between accuracy scores on the measures. Additional analyses demonstrated a moderate relationship between confidence ratings but no association between measures of interoceptive awareness. These findings question the interchangeable use of the two tasks.

Evidence in cortical folding patterns for prenatal predispositions to hallucinations in schizophrenia.

All perception is a construction of the brain from sensory input. Our first perceptions begin during gestation, making fetal brain development fundamental to how we experience a diverse world. Hallucinations are percepts without origin in physical reality that occur in health and disease. Despite longstanding research on the brain structures supporting hallucinations and on perinatal contributions to the pathophysiology of schizophrenia, what links these two distinct lines of research remains unclear. Sulcal patterns derived from structural magnetic resonance (MR) images can provide a proxy in adulthood for early brain development. We studied two independent datasets of patients with schizophrenia who underwent clinical assessment and 3T MR imaging from the United Kingdom and Shanghai, China (n = 181 combined) and 63 healthy controls from Shanghai. Participants were stratified into those with (n = 79 UK; n = 22 Shanghai) and without (n = 43 UK; n = 37 Shanghai) hallucinations from the PANSS P3 scores for hallucinatory behaviour. We quantified the length, depth, and asymmetry indices of the paracingulate and superior temporal sulci (PCS, STS), which have previously been associated with hallucinations in schizophrenia, and constructed cortical folding covariance matrices organized by large-scale functional networks. In both ethnic groups, we demonstrated a significantly shorter left PCS in patients with hallucinations compared to those without, and to healthy controls. Reduced PCS length and STS depth corresponded to focal deviations in their geometry and to significantly increased covariance within and between areas of the salience and auditory networks. The discovery of neurodevelopmental alterations contributing to hallucinations establishes testable models for these enigmatic, sometimes highly distressing, perceptions and provides mechanistic insight into the pathological consequences of prenatal origins.