RESUMO
Genome-wide association studies (GWAS) of human complex traits or diseases often implicate genetic loci that span hundreds or thousands of genetic variants, many of which have similar statistical significance. While statistical fine-mapping in individuals of European ancestry has made important discoveries, cross-population fine-mapping has the potential to improve power and resolution by capitalizing on the genomic diversity across ancestries. Here we present SuSiEx, an accurate and computationally efficient method for cross-population fine-mapping. SuSiEx integrates data from an arbitrary number of ancestries, explicitly models population-specific allele frequencies and linkage disequilibrium patterns, accounts for multiple causal variants in a genomic region and can be applied to GWAS summary statistics. We comprehensively assessed the performance of SuSiEx using simulations. We further showed that SuSiEx improves the fine-mapping of a range of quantitative traits available in both the UK Biobank and Taiwan Biobank, and improves the fine-mapping of schizophrenia-associated loci by integrating GWAS across East Asian and European ancestries.
RESUMO
The objective of this study was to examine the impact of stage of lactation (early, mid and late) and proportion of pasture in the cows diet (high: GRS, medium: PMR and no: TMR) on the composition and quality of Cheddar cheese. Triplicate trials were carried out in each stage of lactation, and milk protein and fat contents were standardized for Cheddar cheese manufacture at pilot scale. As cheese milks were standardized for milk fat and protein contents, gross composition did not differ as a result of diet. Fatty acid profiles of GRS cheese were significantly different from TMR, while PMR profiles were less distinct and more similar to both GRS and TMR profiles, as illustrated by partial least squares discriminatory analysis. Fatty acids including CLA C18:2 cis-9, trans-11, C22:1 n-9 and C18:3 n-3 were most influential in this separation of profiles. Fatty acid profiling revealed that GRS derived cheese contained higher proportions of nutrients considered beneficial for human health including higher proportions of unsaturated fatty acids and omega-3 fatty acids. A biomarker model utilizing the proportions of 5 fatty acids was constructed and was effective at distinguishing between cheese of GRS, TMR and PMR feeding systems. Proportions of ρ-κ-casein, αs2-casein and αs1-casein in cheese also differed between diets while proportions of ρ-κ-casein, αs1-casein and ß-casein were lowest in late lactation cheese. The impact of diet was less influential compared with that of stage of lactation on the ripening characteristics of cheese. An index of primary proteolysis was highest in late lactation cheese. The peptides derived from the proteolysis of κ-casein and ß-casein and levels of secondary proteolysis, in particular, the proportions of 12 free amino acids were most influenced by stage of lactation. Overall this study demonstrated the effects of increasing pasture allowance and stage of lactation on the nutritional quality and ripening properties of Cheddar cheese.
RESUMO
Background: The prefrontal cortex (PFC) has been strongly implicated in the pathophysiology of schizophrenia. Here, we combined high-resolution single-nuclei RNA sequencing data from the human PFC with large-scale genomic data for schizophrenia to identify constituent cell populations likely to mediate genetic liability to the disorder. Methods: Gene expression specificity values were calculated from a single-nuclei RNA sequencing dataset comprising 84 cell populations from the human PFC, spanning gestation to adulthood. Enrichment of schizophrenia common variant liability and burden of rare protein-truncating coding variants were tested in genes with high expression specificity for each cell type. We also explored schizophrenia common variant associations in relation to gene expression across the developmental trajectory of implicated neurons. Results: Common risk variation for schizophrenia was prominently enriched in genes with high expression specificity for a population of mature layer 4 glutamatergic neurons emerging in infancy. Common variant liability to schizophrenia increased along the developmental trajectory of this neuronal population. Fine-mapped genes at schizophrenia genome-wide association study risk loci had significantly higher expression specificity than other genes in these neurons and in a population of layer 5/6 glutamatergic neurons. People with schizophrenia had a higher rate of rare protein-truncating coding variants in genes expressed by cells of the PFC than control individuals, but no cell population was significantly enriched above this background rate. Conclusions: We identified a population of layer 4 glutamatergic PFC neurons likely to be particularly affected by common variant genetic risk for schizophrenia, which may contribute to disturbances in thalamocortical connectivity in the condition.
The prefrontal cortex (PFC) has been strongly implicated in the underlying biology of schizophrenia. We tested whether specific cell populations within the PFC preferentially express genes that increase risk for the disorder. We found that a particular type of PFC neuron prominently expresses genes associated with schizophrenia, suggesting its involvement in the condition.
RESUMO
AIMS: Use of gene expression signatures to predict adjuvant chemotherapy benefit in women with early-stage breast cancer is increasing. However, high cost, limited access, and eligibility for these tests results in the adoption of less precise assessment approaches. This study evaluates the cost impact of PreciseDx Breast (PDxBr), an AI-augmented histopathology platform that assesses the 6-year risk of recurrence in early-stage invasive breast cancer patients to help improve informed use of adjuvant chemotherapy. MATERIALS AND METHODS: A decision-tree Markov model was developed to compare the costs of treatment guided by standard of care (SOC) risk assessment (i.e. clinical diagnostic workup with or without Oncotype DX) versus PDxBr with SOC in a hypothetical cohort of U.S. women with early-stage invasive breast cancer. A commercial payer perspective compares costs of testing, adjuvant therapy, recurrence, adverse events, surveillance, and end-of-life care. RESULTS: PDxBr use in prognostic evaluation resulted in savings of $4 million (M) in year one compared to current SOC in 1 M females members. Over 6-years, savings increased to $12.5 M. The per-treated patient costs in year one amounted to $19.5 thousand (K) for SOC and $16.9K for PDxBr. LIMITATIONS: For simplicity, recurrence was not specified. We performed scenario analyses to account for variations in rates for local, regional, and distant recurrence. Second, a recurrent patient incurs the total cost of treated recurrence in the first year and goes back to remission or death. Third, CDK4/6i treatment is only incorporated in the recurrence costs but not in the first line of treatment for early-stage breast cancer due to limited data. CONCLUSIONS: Sensitivity analyses demonstrated robust overall savings to changes in all variables in the model. The use of PDxBr to assess breast cancer recurrence risk has the potential to fill gaps in care and reduce costs when gene expression signatures are not available.
Assuntos
Neoplasias da Mama , Cadeias de Markov , Recidiva Local de Neoplasia , Humanos , Neoplasias da Mama/patologia , Feminino , Medição de Risco , Árvores de Decisões , Quimioterapia Adjuvante/economia , Análise Custo-Benefício , Estados Unidos , Inteligência Artificial , Estadiamento de Neoplasias , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Individuals with psychiatric disorders have an increased risk of developing dementia. Most cross-sectional studies suffer from selection bias, underdiagnosis and poor population representation, while there is only limited evidence from longitudinal studies on the role of anxiety, bipolar and psychotic disorders. Electronic health records (EHRs) permit large cohorts to be followed across the lifespan and include a wide range of diagnostic information. OBJECTIVE: To assess the association between four groups of psychiatric disorders (schizophrenia, bipolar disorder/mania, depression and anxiety) with dementia in two large population-based samples with EHR. METHODS: Using EHR on nearly 1 million adult individuals in Wales, and from 228 937 UK Biobank participants, we studied the relationships between schizophrenia, mania/bipolar disorder, depression, anxiety and subsequent risk of dementia. FINDINGS: In Secure Anonymised Information Linkage, there was a steep increase in the incidence of a first diagnosis of psychiatric disorder in the years prior to the diagnosis of dementia, reaching a peak in the year prior to dementia diagnosis for all psychiatric diagnoses. Psychiatric disorders, except anxiety, were highly significantly associated with a subsequent diagnosis of dementia: HRs=2.87, 2.80, 1.63 for schizophrenia, mania/bipolar disorder and depression, respectively. A similar pattern was found in the UK Biobank (HRs=4.46, 3.65, 2.39, respectively) and anxiety was also associated with dementia (HR=1.34). Increased risk of dementia was observed for all ages at onset of psychiatric diagnoses when these were divided into 10-year bins. CONCLUSIONS: Psychiatric disorders are associated with an increased risk of subsequent dementia, with a greater risk of more severe disorders. CLINICAL IMPLICATIONS: A late onset of psychiatric disorders should alert clinicians of possible incipient dementia.
Assuntos
Demência , Transtornos Mentais , Humanos , Demência/epidemiologia , Demência/etiologia , Demência/diagnóstico , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Adulto , Transtornos Mentais/epidemiologia , Transtornos Mentais/diagnóstico , País de Gales/epidemiologia , Registros Eletrônicos de Saúde/estatística & dados numéricos , Transtorno Bipolar/epidemiologia , Transtorno Bipolar/diagnóstico , Reino Unido/epidemiologia , Esquizofrenia/epidemiologia , Esquizofrenia/diagnóstico , Fatores de Risco , Idoso de 80 Anos ou mais , IncidênciaRESUMO
BACKGROUND: The ganglionic eminences (GE) are fetal-specific structures that give rise to gamma-aminobutyric acid (GABA)- and acetylcholine-releasing neurons of the forebrain. Given the evidence for GABAergic, cholinergic, and neurodevelopmental disturbances in schizophrenia, we tested the potential involvement of GE neuron development in mediating genetic risk for the condition. STUDY DESIGN: We combined data from a recent large-scale genome-wide association study of schizophrenia with single-cell RNA sequencing data from the human GE to test the enrichment of schizophrenia risk variation in genes with high expression specificity for developing GE cell populations. We additionally performed the single nuclei Assay for Transposase-Accessible Chromatin with Sequencing (snATAC-Seq) to map potential regulatory genomic regions operating in individual cell populations of the human GE, using these to test for enrichment of schizophrenia common genetic variant liability and to functionally annotate non-coding variants-associated with the disorder. STUDY RESULTS: Schizophrenia common variant liability was enriched in genes with high expression specificity for developing neuron populations that are predicted to form dopamine D1 and D2 receptor-expressing GABAergic medium spiny neurons of the striatum, cortical somatostatin-positive GABAergic interneurons, calretinin-positive GABAergic neurons, and cholinergic neurons. Consistent with these findings, schizophrenia genetic risk was concentrated in predicted regulatory genomic sequence mapped in developing neuronal populations of the GE. CONCLUSIONS: Our study implicates prenatal development of specific populations of GABAergic and cholinergic neurons in later susceptibility to schizophrenia, and provides a map of predicted regulatory genomic elements operating in cells of the GE.
RESUMO
There is an increasing consumer desire for pasture-derived dairy products, as outdoor pasture-based feeding systems are perceived as a natural environment for animals. Despite this, the number of grazing animals globally has declined as a result of the higher milk yields achieved by indoor TMR feeding systems, in addition to the changing climatic conditions and lower grazing knowledge and infrastructure. This has led to the development of pasture-fed standards, stipulating the necessity of pasture and its minimum requirements as the primary feed source for products advertising such claims, with various requirements depending on the region for which it was produced. This work investigates the differences in the composition and techno-functional properties of butters produced from high, medium and no pasture allowance diets during early, mid, and late lactation. Butters were produced using milks collected from 3 feeding systems: outdoor pasture grazing (high pasture allowance); indoor TMR (no pasture allowance); and a partial mixed ration (medium pasture allowance) system, which involved outdoor pasture grazing during the day and indoor TMR feeding at night. Butters were manufactured during early, mid, and late lactation. Creams derived from TMR feeding systems exhibited the highest milk fat globule size. The fatty acid profiles of butters also differed significantly as a function of diet and could be readily discriminated by partial least squares analysis. The most important fatty acids in such an analysis, as indicated by their highest variable importance projection scores, were CLA C18:2 cis-9,trans-11 (rumenic acid), C16:1n-7 trans (trans-palmitoleic acid), C18:1 trans (elaidic acid), C18:3n-3 (α-linolenic acid), and C18:2n-6 (linoleic acid). Increasing pasture allowances resulted in reduced crystallization temperatures and hardness of butters and concurrently increasing the "yellow" color. Yellow color was strongly correlated with Raman peaks commonly associated with carotenoids. The milk fat globule size of cream decreased with advancing stage of lactation and churning time of cream was lowest in early lactation. Differences in the fatty acid and triglyceride contents of butter as a result of lactation and dietary effects demonstrated significant correlations with the hardness, rheological, melting, and crystallization profiles of the butters. This work highlighted the improved nutritional profile and functional properties of butter with increasing dietary pasture allowance, primarily as a result of increasing proportions of unsaturated fatty acids. Biomarkers of pasture feeding (response in milk proportionate to the pasture allowance) associated with the pasture-fed status of butters were also identified as a result of the significant changes in the fatty acid profile with increasing pasture allowance. This was achieved through the use of 3 authentic feeding systems with varying pasture allowances, commonly operated by farmers around the world and conducted across 3 stages of lactation.
Assuntos
Ração Animal , Manteiga , Dieta , Lactação , Leite , Animais , Leite/química , Feminino , Dieta/veterinária , Bovinos , Ácidos Graxos , Valor NutritivoRESUMO
Recent research has highlighted the role of complement genes in shaping the microstructure of the brain during early development, and in contributing to common allele risk for Schizophrenia. We hypothesised that common risk variants for schizophrenia within complement genes will associate with structural changes in white matter microstructure within tracts innervating the frontal lobe. Results showed that risk alleles within the complement gene set, but also intergenic alleles, significantly predict axonal density in white matter tracts connecting frontal cortex with parietal, temporal and occipital cortices. Specifically, risk alleles within the Major Histocompatibility Complex region in chromosome 6 appeared to drive these associations. No significant associations were found for the orientation dispersion index. These results suggest that changes in axonal packing - but not in axonal coherence - determined by common risk alleles within the MHC genomic region - including variants related to the Complement system - appear as a potential neurobiological mechanism for schizophrenia.
Assuntos
Alelos , Predisposição Genética para Doença , Complexo Principal de Histocompatibilidade , Esquizofrenia , Substância Branca , Humanos , Esquizofrenia/genética , Esquizofrenia/patologia , Substância Branca/patologia , Substância Branca/diagnóstico por imagem , Feminino , Masculino , Adulto , Complexo Principal de Histocompatibilidade/genética , Adulto Jovem , Lobo Frontal/patologia , Lobo Frontal/diagnóstico por imagem , Pessoa de Meia-Idade , Imagem de Tensor de Difusão , Cromossomos Humanos Par 6/genética , Axônios/patologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Schizophrenia is a highly heritable disorder characterized by increased cortical thinning throughout the life span. Studies have reported a shared genetic basis between schizophrenia and cortical thickness. However, no genes whose expression is related to abnormal cortical thinning in schizophrenia have been identified. METHODS: We conducted linear mixed models to estimate the rates of accelerated cortical thinning across 68 regions from the Desikan-Killiany atlas in individuals with schizophrenia compared with healthy control participants from a large longitudinal sample (ncases = 169 and ncontrols = 298, ages 16-70 years). We studied the correlation between gene expression data from the Allen Human Brain Atlas and accelerated thinning estimates across cortical regions. Finally, we explored the functional and genetic underpinnings of the genes that contribute most to accelerated thinning. RESULTS: We found a global pattern of accelerated cortical thinning in individuals with schizophrenia compared with healthy control participants. Genes underexpressed in cortical regions that exhibit this accelerated thinning were downregulated in several psychiatric disorders and were enriched for both common and rare disrupting variation for schizophrenia and neurodevelopmental disorders. In contrast, none of these enrichments were observed for baseline cross-sectional cortical thickness differences. CONCLUSIONS: Our findings suggest that accelerated cortical thinning, rather than cortical thickness alone, serves as an informative phenotype for neurodevelopmental disruptions in schizophrenia. We highlight the genetic and transcriptomic correlates of this accelerated cortical thinning, emphasizing the need for future longitudinal studies to elucidate the role of genetic variation and the temporal-spatial dynamics of gene expression in brain development and aging in schizophrenia.
Assuntos
Transtornos do Neurodesenvolvimento , Esquizofrenia , Humanos , Esquizofrenia/genética , Esquizofrenia/patologia , Esquizofrenia/diagnóstico por imagem , Adulto , Pessoa de Meia-Idade , Masculino , Feminino , Adolescente , Adulto Jovem , Idoso , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Afinamento Cortical Cerebral/genética , Afinamento Cortical Cerebral/diagnóstico por imagem , Afinamento Cortical Cerebral/patologia , Imageamento por Ressonância Magnética , Estudos Longitudinais , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Predisposição Genética para Doença/genéticaRESUMO
Importance: Large-scale biobanks provide important opportunities for mental health research, but selection biases raise questions regarding the comparability of individuals with those in clinical research settings. Objective: To compare the genetic liability to psychiatric disorders in individuals with schizophrenia in the UK Biobank with individuals in the Psychiatric Genomics Consortium (PGC) and to compare genetic liability and phenotypic features with participants recruited from clinical settings. Design, Setting, and Participants: This cross-sectional study included participants from the population-based UK Biobank and schizophrenia samples recruited from clinical settings (CLOZUK, CardiffCOGS, Cardiff F-Series, and Cardiff Affected Sib-Pairs). Data were collected between January 1993 and July 2021. Data analysis was conducted between July 2021 and June 2023. Main Outcomes and Measures: A genome-wide association study of UK Biobank schizophrenia case-control status was conducted, and the results were compared with those from the PGC via genetic correlations. To test for differences with the clinical samples, polygenic risk scores (PRS) were calculated for schizophrenia, bipolar disorder, depression, and intelligence using PRS-CS. PRS and phenotypic comparisons were conducted using pairwise logistic regressions. The proportions of individuals with copy number variants associated with schizophrenia were compared using Firth logistic regression. Results: The sample of 517â¯375 participants included 1438 UK Biobank participants with schizophrenia (550 [38.2%] female; mean [SD] age, 54.7 [8.3] years), 499â¯475 UK Biobank controls (271â¯884 [54.4%] female; mean [SD] age, 56.5 [8.1] years), and 4 schizophrenia research samples (4758 [28.9%] female; mean [SD] age, 38.2 [21.0] years). Liability to schizophrenia in UK Biobank was highly correlated with the latest genome-wide association study from the PGC (genetic correlation, 0.98; SE, 0.18) and showed the expected patterns of correlations with other psychiatric disorders. The schizophrenia PRS explained 6.8% of the variance in liability for schizophrenia case status in UK Biobank. UK Biobank participants with schizophrenia had significantly lower schizophrenia PRS than 3 of the clinically ascertained samples and significantly lower rates of schizophrenia-associated copy number variants than the CLOZUK sample. UK Biobank participants with schizophrenia had higher educational attainment and employment rates than the clinically ascertained schizophrenia samples, lower rates of smoking, and a later age of onset of psychosis. Conclusions and Relevance: Individuals with schizophrenia in the UK Biobank, and likely other volunteer-based biobanks, represent those less severely affected. Their inclusion in wider studies should enhance the representation of the full spectrum of illness severity.
Assuntos
Bancos de Espécimes Biológicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Herança Multifatorial , Fenótipo , Esquizofrenia , Humanos , Esquizofrenia/genética , Esquizofrenia/epidemiologia , Reino Unido/epidemiologia , Feminino , Masculino , Estudos Transversais , Pessoa de Meia-Idade , Herança Multifatorial/genética , Adulto , Estudos de Casos e Controles , Idoso , Variações do Número de Cópias de DNA/genética , Transtorno Bipolar/genética , Transtorno Bipolar/epidemiologia , Biobanco do Reino UnidoRESUMO
Background: Accurate diagnosis of bipolar disorder (BD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A key reason is that the first manic episode is often preceded by a depressive one, making it difficult to distinguish BD from unipolar major depressive disorder (MDD). Aims: Here, we use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores that may aid early differential diagnosis. Methods: Based on individual genotypes from case-control cohorts of BD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful merging and quality control procedure. In a resulting cohort of 51,149 individuals (15,532 BD cases, 12,920 MDD cases and 22,697 controls), we perform a variety of GWAS and polygenic risk scores (PRS) analyses. Results: While our GWAS is not well-powered to identify genome-wide significant loci, we find significant SNP-heritability and demonstrate the ability of the resulting PRS to distinguish BD from MDD, including BD cases with depressive onset. We replicate our PRS findings, but not signals of individual loci in an independent Danish cohort (iPSYCH 2015 case-cohort study, N=25,966). We observe strong genetic correlation between our case-case GWAS and that of case-control BD. Conclusions: We find that MDD and BD, including BD with a depressive onset, are genetically distinct. Further, our findings support the hypothesis that Controls - MDD - BD primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BD and, importantly, BD with depressive onset from MDD.
RESUMO
Clozapine is the only licensed medication for treatment-resistant schizophrenia (TRS). Few predictors for variation in response to clozapine have been identified, but clozapine metabolism is known to influence therapeutic response and adverse side effects. Here, we expand on genome-wide studies of clozapine metabolism, previously focused on common genetic variation, by analysing whole-exome sequencing data from 2062 individuals with schizophrenia taking clozapine in the UK. We investigated whether rare genomic variation in genes and gene sets involved in the clozapine metabolism pathway influences plasma concentrations of clozapine metabolites, assessed through the longitudinal analysis of 6585 pharmacokinetic assays. We observed a statistically significant association between the burden of rare damaging coding variants (MAF ≤ 1 %) in gene sets broadly related to drug pharmacokinetics and lower clozapine (ß = -0.054, SE = 0.019, P-value = 0.005) concentrations in plasma. We estimate that the effects in clozapine plasma concentrations of a single damaging allele in this gene set are akin to reducing the clozapine dose by about 35 mg/day. The gene-based analysis identified rare variants in CYP1A2, which encodes the enzyme responsible for converting clozapine to norclozapine, as having the strongest effects of any gene on clozapine metabolism (ß = 0.324, SE = 0.124, P = 0.009). Our findings support the hypothesis that rare genetic variants in known drug-metabolising enzymes and transporters can markedly influence clozapine plasma concentrations; these results suggest that pharmacogenomic efforts trying to predict clozapine metabolism and personalise drug therapy could benefit from the inclusion of rare damaging variants in pharmacogenes beyond those already identified and catalogued as PGx star alleles.
Assuntos
Antipsicóticos , Clozapina , Esquizofrenia , Humanos , Clozapina/efeitos adversos , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Esquizofrenia/metabolismo , Antipsicóticos/efeitos adversos , Farmacogenética , AlelosRESUMO
This study investigated the effects of diet and stage of lactation (SOL) on sensory profiles, texture, volatile profiles, and colour of Cheddar cheese. Cheddar cheese was manufactured from early-, mid-, and late-lactation milk obtained from seasonally calved cows (n = 54). Cows were assigned a diet; group 1: perennial ryegrass (GRS), group 2: total mixed ration (TMR), and group 3: partial mixed ration (PMR). Instrumental analysis was performed at 270 days (mature Cheddar). Sensory evaluation took place after 548 days (extra mature Cheddar). Toluene was the only volatile compound that was significantly influenced by diet. The trained panel rated early-lactation cheese as stronger than mid- and late- for cowy/barny flavour and late-lactation cheese as sweeter than early- and mid-lactation cheese. Mid-lactation cheese was liked least overall. Early-lactation cheeses were rated higher for 'crumbly' texture than mid- and late. Diet affected consumer ratings, with GRS and PMR cheese rated as more intense than TMR for flavour, aftertaste, and saltiness. Consumers reported that TMR cheese was lighter in colour compared to GRS cheese, which was supported by instrumental analysis. Consumers perceived GRS as more springy and less crumbly than TMR and PMR, while Texture Profile Analysis indicated that TMR was harder than GRS. Consumer segmentation was observed with two clear preference groups, one preferring GRS and one preferring TMR. For both groups, 'taste' seemed to be the main driver of liking, highlighting that consumer preference is most impacted by individual taste preferences.
Assuntos
Queijo , Feminino , Animais , Bovinos , Lactação , Paladar , Percepção Gustatória , LeiteRESUMO
BACKGROUND: Incidence of first-episode psychosis (FEP) varies substantially across geographic regions. Phenotypes of subclinical psychosis (SP), such as psychotic-like experiences (PLEs) and schizotypy, present several similarities with psychosis. We aimed to examine whether SP measures varied across different sites and whether this variation was comparable with FEP incidence within the same areas. We further examined contribution of environmental and genetic factors to SP. METHODS: We used data from 1497 controls recruited in 16 different sites across 6 countries. Factor scores for several psychopathological dimensions of schizotypy and PLEs were obtained using multidimensional item response theory models. Variation of these scores was assessed using multi-level regression analysis to estimate individual and between-sites variance adjusting for age, sex, education, migrant, employment and relational status, childhood adversity, and cannabis use. In the final model we added local FEP incidence as a second-level variable. Association with genetic liability was examined separately. RESULTS: Schizotypy showed a large between-sites variation with up to 15% of variance attributable to site-level characteristics. Adding local FEP incidence to the model considerably reduced the between-sites unexplained schizotypy variance. PLEs did not show as much variation. Overall, SP was associated with younger age, migrant, unmarried, unemployed and less educated individuals, cannabis use, and childhood adversity. Both phenotypes were associated with genetic liability to schizophrenia. CONCLUSIONS: Schizotypy showed substantial between-sites variation, being more represented in areas where FEP incidence is higher. This supports the hypothesis that shared contextual factors shape the between-sites variation of psychosis across the spectrum.
Assuntos
Transtornos Psicóticos , Transtorno da Personalidade Esquizotípica , Humanos , Transtornos Psicóticos/epidemiologia , Masculino , Feminino , Europa (Continente)/epidemiologia , Adulto , Brasil/epidemiologia , Adulto Jovem , Adolescente , Transtorno da Personalidade Esquizotípica/epidemiologia , Incidência , Pessoa de Meia-Idade , FenótipoRESUMO
INTRODUCTION/OBJECTIVE: The KidneyIntelX is a multiplex, bioprognostic, immunoassay consisting of 3 plasma biomarkers and clinical variables that uses machine learning to predict a patient's risk for a progressive decline in kidney function over 5 years. We report the 1-year pre- and post-test clinical impact on care management, eGFR slope, and A1C along with engagement of population health clinical pharmacists and patient coordinators to promote a program of sustainable kidney, metabolic, and cardiac health. METHODS: The KidneyIntelX in vitro prognostic test was previously validated for patients with type 2 diabetes and diabetic kidney disease (DKD) to predict kidney function decline within 5 years was introduced into the RWE study (NCT04802395) across the Health System as part of a population health chronic disease management program from [November 2020 to April 2023]. Pre- and post-test patients with a minimum of 12 months of follow-up post KidneyIntelX were assessed across all aspects of the program. RESULTS: A total of 5348 patients with DKD had a KidneyIntelX assay. The median age was 68 years old, 52% were female, 27% self-identified as Black, and 89% had hypertension. The median baseline eGFR was 62 ml/min/1.73 m2, urine albumin-creatinine ratio was 54 mg/g, and A1C was 7.3%. The KidneyIntelX risk level was low in 49%, intermediate in 40%, and high in 11% of cases. New prescriptions for SGLT2i, GLP-1 RA, or referral to a specialist were noted in 19%, 33%, and 43% among low-, intermediate-, and high-risk patients, respectively. The median A1C decreased from 8.2% pre-test to 7.5% post-test in the high-risk group (P < .001). UACR levels in the intermediate-risk patients with albuminuria were reduced by 20%, and in a subgroup treated with new scripts for SGLT2i, UACR levels were lowered by approximately 50%. The median eGFR slope improved from -7.08 ml/min/1.73 m2/year to -4.27 ml/min/1.73 m2/year in high-risk patients (P = .0003), -2.65 to -1.04 in intermediate risk, and -3.26 ml/min/1.73 m2/year to +0.45 ml/min/1.73 m2/year in patients with low-risk (P < .001). CONCLUSIONS: Deployment and risk stratification by KidneyIntelX was associated with an escalation in action taken to optimize cardio-kidney-metabolic health including medications and specialist referrals. Glycemic control and kidney function trajectories improved post-KidneyIntelX testing, with the greatest improvements observed in those scored as high-risk.
Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Humanos , Feminino , Idoso , Masculino , Nefropatias Diabéticas/terapia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/terapia , Hemoglobinas Glicadas , Medicina de Precisão , AlbuminúriaRESUMO
Precision medicine has the ambition to improve treatment response and clinical outcomes through patient stratification and holds great potential for the treatment of mental disorders. However, several important factors are needed to transform current practice into a precision psychiatry framework. Most important are 1) the generation of accessible large real-world training and test data including genomic data integrated from multiple sources, 2) the development and validation of advanced analytical tools for stratification and prediction, and 3) the development of clinically useful management platforms for patient monitoring that can be integrated into health care systems in real-life settings. This narrative review summarizes strategies for obtaining the key elements-well-powered samples from large biobanks integrated with electronic health records and health registry data using novel artificial intelligence algorithms-to predict outcomes in severe mental disorders and translate these models into clinical management and treatment approaches. Key elements are massive mental health data and novel artificial intelligence algorithms. For the clinical translation of these strategies, we discuss a precision medicine platform for improved management of mental disorders. We use cases to illustrate how precision medicine interventions could be brought into psychiatry to improve the clinical outcomes of mental disorders.
RESUMO
BACKGROUND: Depression and anxiety are the most common mental health problems in young people. Currently, clinicians are advised to wait before initiating treatment for young people with these disorders as many spontaneously remit. However, others develop recurrent disorder but this subgroup cannot be identified at the outset. We examined whether psychiatric polygenic scores (PGS) could help inform stratification efforts to predict those at higher risk of recurrence. METHODS: Probable emotional disorder was examined in two UK population cohorts using the emotional symptoms subscale of the Strengths and Difficulties Questionnaire (SDQ). Those with emotional disorder at two or more time points between ages 5 and 25 years were classed as 'recurrent emotional disorder' (n = 1,643) and those with emotional disorder at one time point as having 'single episode emotional disorder' (n = 1,435, controls n = 8,715). We first examined the relationship between psychiatric PGS and emotional disorders in childhood and adolescence. Second, we tested whether psychiatric PGS added to predictor variables of known association with emotional disorder (neurodevelopmental comorbidity, special educational needs, family history of depression and socioeconomic status) when discriminating between single-episode and recurrent emotional disorder. Analyses were conducted separately in individuals of European and South Asian ancestry. RESULTS: Probable emotional disorder was associated with higher PGS for major depressive disorder (MDD), anxiety, broad depression, ADHD and autism spectrum disorder (ASD) in those of European ancestry. Higher MDD and broad depression PGS were associated with emotional disorder in people of South Asian ancestry. Recurrent, compared to single-episode, emotional disorder was associated with ASD and parental psychiatric history. PGS were not associated with episode recurrence, and PGS did not improve discrimination of recurrence when combined with clinical predictors. CONCLUSIONS: Our findings do not support the use of PGS as a tool to assess the likelihood of recurrence in young people experiencing their first episode of emotional disorder.
Assuntos
Transtorno do Espectro Autista , Transtorno Depressivo Maior , Adolescente , Humanos , Transtorno Depressivo Maior/epidemiologia , Transtorno do Espectro Autista/epidemiologia , Comorbidade , Ansiedade/genética , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/genéticaRESUMO
BACKGROUND: Schizophrenia is a highly heritable brain disorder with a typical symptom onset in early adulthood. The 2-hit hypothesis posits that schizophrenia results from differential early neurodevelopment, predisposing an individual, followed by a disruption of later brain maturational processes that trigger the onset of symptoms. STUDY DESIGN: We applied hierarchical clustering to transcription levels of 345 genes previously linked to schizophrenia, derived from cortical tissue samples from 56 donors across the lifespan. We subsequently calculated clustered-specific polygenic risk scores for 743 individuals with schizophrenia and 743 sex- and age-matched healthy controls. STUDY RESULTS: Clustering revealed a set of 183 genes that was significantly upregulated prenatally and downregulated postnatally and 162 genes that showed the opposite pattern. The prenatally upregulated set of genes was functionally annotated to fundamental cell cycle processes, while the postnatally upregulated set was associated with the immune system and neuronal communication. We found an interaction between the 2 scores; higher prenatal polygenic risk showed a stronger association with schizophrenia diagnosis at higher levels of postnatal polygenic risk. Importantly, this finding was replicated in an independent clinical cohort of 3233 individuals. CONCLUSIONS: We provide genetics-based evidence that schizophrenia is shaped by disruptions of separable biological processes acting at distinct phases of neurodevelopment. The modeling of genetic risk factors that moderate each other's effect, informed by the timing of their expression, will aid in a better understanding of the development of schizophrenia.
Assuntos
Esquizofrenia , Humanos , Adulto , Esquizofrenia/genética , Encéfalo , Estratificação de Risco Genético , Herança Multifatorial , Análise por Conglomerados , Predisposição Genética para DoençaRESUMO
BACKGROUND: PreciseDx Breast (PDxBr) is a digital test that predicts early-stage breast cancer recurrence within 6-years of diagnosis. MATERIALS AND METHODS: Using hematoxylin and eosin-stained whole slide images of invasive breast cancer (IBC) and artificial intelligence-enabled morphology feature array, microanatomic features are generated. Morphometric attributes in combination with patient's age, tumor size, stage, and lymph node status predict disease free survival using a proprietary algorithm. Here, analytical validation of the automated annotation process and extracted histologic digital features of the PDxBr test, including impact of methodologic variability on the composite risk score is presented. Studies of precision, repeatability, reproducibility and interference were performed on morphology feature array-derived features. The final risk score was assessed over 20-days with 2-operators, 2-runs/day, and 2-replicates across 8-patients, allowing for calculation of within-run repeatability, between-run and within-laboratory reproducibility. RESULTS: Analytical validation of features derived from whole slide images demonstrated a high degree of precision for tumor segmentation (0.98, 0.98), lymphocyte detection (0.91, 0.93), and mitotic figures (0.85, 0.84). Correlation of variation of the assay risk score for both reproducibility and repeatability were less than 2%, and interference from variation in hematoxylin and eosin staining or tumor thickness was not observed demonstrating assay robustness across standard histopathology preparations. CONCLUSION: In summary, the analytical validation of the digital IBC risk assessment test demonstrated a strong performance across all features in the model and complimented the clinical validation of the assay previously shown to accurately predict recurrence within 6-years in early-stage invasive breast cancer patients.