Integrative genetic analysis: cornerstone of precision psychiatry.

The role of genetic testing in the domain of neurodevelopmental and psychiatric disorders (NPDs) is gradually changing from providing etiological explanation for the presence of NPD phenotypes to also identifying young individuals at high risk of developing NPDs before their clinical manifestation. In clinical practice, the latter implies a shift towards the availability of individual genetic information predicting a certain liability to develop an NPD (e.g., autism, intellectual disability, psychosis etc.). The shift from mostly a posteriori explanation to increasingly a priori risk prediction is the by-product of the systematic implementation of whole exome or genome sequencing as part of routine diagnostic work-ups during the neonatal and prenatal periods. This rapid uptake of genetic testing early in development has far-reaching consequences for psychiatry: Whereas until recently individuals would come to medical attention because of signs of abnormal developmental and/or behavioral symptoms, increasingly, individuals are presented based on genetic liability for NPD outcomes before NPD symptoms emerge. This novel clinical scenario, while challenging, also creates opportunities for research on prevention interventions and precision medicine approaches. Here, we review why optimization of individual risk prediction is a key prerequisite for precision medicine in the sphere of NPDs, as well as the technological and statistical methods required to achieve this ambition.

Investigating the Use of Telemedicine by Health Care Providers to Diagnose and Manage Patients With Musculoskeletal Disorders: Systematic Review and Meta-Analysis.

BACKGROUND: Access to care is a major challenge for patients with musculoskeletal disorders (MSKDs). Telemedicine is one of the solutions to improve access to care. However, initial remote diagnosis of MSKDs involves some challenges, such as the impossibility of touching the patient during the physical examination, which makes it more complex to obtain a valid diagnosis. No meta-analysis has been performed to date to synthesize evidence regarding the initial assessment including a physical evaluation using telemedicine to diagnose patients with MSKDs. OBJECTIVE: This study aims to appraise the evidence on diagnostic and treatment plan concordance between remote assessment using synchronous or asynchronous forms of telemedicine and usual in-person assessment for the initial evaluation of various MSKDs. METHODS: An electronic search was conducted up to August 2023 using terms related to telemedicine and assessment of MSKDs. Methodological quality of studies was assessed with the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Random-effect model meta-analyses were performed. The Grading of Recommendations, Assessment, Development, and Evaluations framework was used to synthesize the quality and certainty of the evidence. RESULTS: A total of 23 concordance studies were eligible and included adult participants (N=1493) with various MSKDs. On the basis of high certainty, pooled κ and prevalence-adjusted and bias-adjusted κ for the diagnostic concordance between remote and in-person assessments of MSKDs were 0.80 (95% CI 0.72-0.89; 7 studies, 353 patients) and 0.83 (95% CI 0.76-0.89; 6 studies, 306 patients). On the basis of moderate certainty, pooled Gwet AC1 for treatment plan concordance between remote and in-person assessments of MSKDs was 0.90 (95% CI 0.80-0.99; 2 studies, 142 patients). CONCLUSIONS: The diagnostic concordance for MSKDs is good to very good. Treatment plan concordance is probably good to excellent. Studies evaluating the accuracy to detect red and yellow flags as well as the potential increase in associated health care resources use, such as imaging tests, are needed.

Genetic and phenotypic similarity across major psychiatric disorders: a systematic review and quantitative assessment.

There is widespread overlap across major psychiatric disorders, and this is the case at different levels of observations, from genetic variants to brain structures and function and to symptoms. However, it remains unknown to what extent these commonalities at different levels of observation map onto each other. Here, we systematically review and compare the degree of similarity between psychiatric disorders at all available levels of observation. We searched PubMed and EMBASE between January 1, 2009 and September 8, 2022. We included original studies comparing at least four of the following five diagnostic groups: Schizophrenia, Bipolar Disorder, Major Depressive Disorder, Autism Spectrum Disorder, and Attention Deficit Hyperactivity Disorder, with measures of similarities between all disorder pairs. Data extraction and synthesis were performed by two independent researchers, following the PRISMA guidelines. As main outcome measure, we assessed the Pearson correlation measuring the degree of similarity across disorders pairs between studies and biological levels of observation. We identified 2975 studies, of which 28 were eligible for analysis, featuring similarity measures based on single-nucleotide polymorphisms, gene-based analyses, gene expression, structural and functional connectivity neuroimaging measures. The majority of correlations (88.6%) across disorders between studies, within and between levels of observation, were positive. To identify a consensus ranking of similarities between disorders, we performed a principal component analysis. Its first dimension explained 51.4% (95% CI: 43.2, 65.4) of the variance in disorder similarities across studies and levels of observation. Based on levels of genetic correlation, we estimated the probability of another psychiatric diagnosis in first-degree relatives and showed that they were systematically lower than those observed in population studies. Our findings highlight that genetic and brain factors may underlie a large proportion, but not all of the diagnostic overlaps observed in the clinic.

Vulture poisoning in Sub-Saharan Africa and its implications for conservation planning: A systematic review.

The Old World Vultures (OWV), constituting 16 species primarily in Africa, Europe and Asia, are currently being driven to extinction mostly by anthropogenic activities, especially poisoning. The vulture losses from poisoning caused by human-related activities are en masse at a single mortality event-level and occur in complex social-ecological systems. There has been a growing body of knowledge on wildlife poisoning over the years. However, no review has been done to consolidate vulture poisoning studies in sub-Saharan Africa (SSA), with a social lens of conservation planning. Here we present a review of the vulture poisoning research by re-contextualizing the problem of vulture poisoning across SSA. We employed stepwise Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method to search for literature on vulture poisoning. The search yielded 211 studies which were trimmed to 55 after applying sets of eligibility criteria. Literature shows that efforts aimed at successful vulture conservation planning will require an understanding of the relational aspects of stakeholder social capital (assets) that are critical to the implementation of species recovery strategies. Strengthening relational social capital through multi-scale stakeholder evidence-based awareness creation and participation is necessary for addressing the African Vulture Crisis (AVC). Applying stakeholder social capital approaches to different vulture conservation scenarios at local, regional and international scales can enhance successful implementation of conservation strategies for the persistence of vultures in complex socio-ecological systems in African landscapes. Existing literature also showed the importance of stakeholder social capital as a countermeasure against vulture losses.

Integrating genomic variants and developmental milestones to predict cognitive and adaptive outcomes in autistic children.

Although the first signs of autism are often observed as early as 18-36 months of age, there is a broad uncertainty regarding future development, and clinicians lack predictive tools to identify those who will later be diagnosed with co-occurring intellectual disability (ID). Here, we developed predictive models of ID in autistic children (n=5,633 from three cohorts), integrating different classes of genetic variants alongside developmental milestones. The integrated model yielded an AUC ROC=0.65, with this predictive performance cross-validated and generalised across cohorts. Positive predictive values reached up to 55%, accurately identifying 10% of ID cases. The ability to stratify the probabilities of ID using genetic variants was up to twofold greater in individuals with delayed milestones compared to those with typical development. These findings underscore the potential of models in neurodevelopmental medicine that integrate genomics and clinical observations to predict outcomes and target interventions.

Copy-number variants and polygenic risk for intelligence confer risk for autism spectrum disorder irrespective of their effects on cognitive ability.

Introduction: Rare copy number variants (CNVs) and polygenic risk for intelligence (PRS-IQ) both confer susceptibility for autism spectrum disorder (ASD) but have opposing effects on cognitive ability. The field has struggled to disentangle the effects of these two classes of genomic variants on cognitive ability from their effects on ASD susceptibility, in part because previous studies did not include controls with cognitive measures. We aim to investigate the impact of these genomic variants on ASD risk while adjusting for their known effects on cognitive ability. Methods: In a cohort of 8,426 subjects with ASD and 169,804 controls with cognitive assessments, we found that rare coding CNVs and PRS-IQ increased ASD risk, even after adjusting for their effects on cognitive ability. Results: Bottom decile PRS-IQ and CNVs both decreased cognitive ability but had opposing effects on ASD risk. Models combining both classes of variants showed that the effects of rare CNVs and PRS-IQ on ASD risk and cognitive ability were largely additive, further suggesting that susceptibility for ASD is conferred independently from its effects on cognitive ability. Despite imparting mostly additive effects on ASD risk, rare CNVs and PRS-IQ showed opposing effects on core and associated features and developmental history among subjects with ASD. Discussion: Our findings suggest that cognitive ability itself may not be the factor driving the underlying liability for ASD conferred by these two classes of genomic variants. In other words, ASD risk and cognitive ability may be two distinct manifestations of CNVs and PRS-IQ. This study also highlights the challenge of understanding how genetic risk for ASD maps onto its dimensional traits.

Advanced practice physiotherapists can diagnose and triage patients with musculoskeletal disorders while providing effective care: a systematic review.

QUESTIONS: What is the diagnostic and surgical triage concordance between advanced practice physiotherapists (APPTs) and physicians? What is the clinical efficacy of advanced practice physiotherapy care compared with usual medical care? DESIGN: Systematic review with meta-analyses. LITERATURE SEARCH: Medline, Embase, Cochrane CENTRAL and CINAHL were searched up to March 2022. STUDY SELECTION CRITERIA: Concordance studies on diagnostic or surgical triage between APPTs and physicians and randomised controlled trials comparing the clinical efficacy of an advanced practice physiotherapy (APP) model of care compared with usual medical care for participants with musculoskeletal disorders. DATA SYNTHESIS: Meta-analyses were performed for concordance and clinical outcomes. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to evaluate the certainty of evidence. RESULTS: Nineteen concordance studies (n = 1,745) and six randomised trials (n = 1,960) were included. Based on moderate-certainty evidence, the pooled Kappa for diagnostic concordance between APPTs and physicians was 0.76 (95% CI 0.68 to 0.85, n = 1,108). Based on high-certainty evidence, the pooled Kappa for surgical triage concordance was 0.71 (95% CI 0.63 to 0.78, n = 1,128). Based on moderate-certainty evidence, APP care resulted in a comparable or greater reduction in pain (MD -0.92 out of 10, 95% CI -1.75 to -0.10, n = 494) when compared with usual medical care at medium-term follow-up. Based on low-certainty evidence, APP care resulted in a comparable or greater reduction in disability (SMD -0.31, 95% CI -0.67 to 0.04, n = 535) when compared with usual medical care at medium-term follow-up. CONCLUSION: Concordance between APPTs and physicians is probably good to very good for diagnosis and good to very good for surgical triage of musculoskeletal disorders. Patients with musculoskeletal disorders managed in an APP model of care probably report comparable or greater pain and disability reductions when compared with usual medical care. REGISTRATION: CRD42022320950.

Copy-number variants and polygenic risk for intelligence confer risk for autism spectrum disorder irrespective of their effects on cognitive ability.

Rare copy number variants (CNVs) and polygenic risk for intelligence (PRS-IQ) both confer risk for autism spectrum disorder (ASD) but have opposing effects on cognitive ability. The field has struggled to disentangle the effects of these two classes of genomic variants on cognitive ability from their effects on ASD risk, in part because previous studies did not include controls with cognitive measures. We aim to investigate the impact of these genomic variants on ASD risk while adjusting for their known effects on cognitive ability. In a cohort of 8,426 subjects with ASD and 169,804 controls with cognitive assessments, we found that rare coding CNVs and PRS-IQ increased ASD risk, even after adjusting for their effects on cognitive ability. Bottom decile PRS-IQ and CNVs both decreased cognitive ability but had opposing effects on ASD risk. Models combining both classes of variants showed that the effects of rare CNVs and PRS-IQ on ASD risk and cognitive ability were largely additive, further suggesting that risk for ASD is conferred independently from its effects on cognitive ability. Despite imparting mostly additive effects on ASD risk, rare CNVs and PRS-IQ showed opposing effects on core and associated features and developmental history among subjects with ASD. Our findings suggest that cognitive ability itself may not be the factor driving the underlying risk for ASD conferred by these two classes of genomic variants. In other words, ASD risk and cognitive ability may be two distinct manifestations of CNVs and PRS-IQ. This study also highlights the challenge of understanding how genetic risk for ASD maps onto its dimensional traits.