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Biology subjects

Murray, R.

Publications and source records attributed to Murray, R..

At least 19 recordsLinked to original sources

Striatal dopamine signals internal states related to behavioral performance over prolonged timescales in monkeys

Slowly varying internal states govern our ability to sustain goal-directed behavior over minutes to hours, imposing fundamental constraints on cognitive performance, yet the neural signals that track these states remain poorly defined. Dopamine is a powerful modulator of motivated behavior, but its best-characterized signals are in the form of reward prediction errors (RPEs) that operate at seconds timescales. Whether these fast signals also carry information about slower, ongoing states of behavioral performance has not been directly tested. Here, we recorded subsecond dopamine concentration changes across multiple sites in the caudate nucleus (CN) and putamen of rhesus monkeys performing a reward-guided saccade task. Task performance oscillated over tens to hundreds of trials, demonstrating fluctuating internal states of sustained engagement. We found that single-trial dopamine signals were strongly modulated by these slowly evolving performance states, in a manner dissociable from both trial-level RPE and cumulative reward rate. This relationship was biased toward future rather than past performance windows, indicating that dopamine tracks motivational state prospectively rather than simply reflecting the reward history on which prediction errors are computed. Furthermore, performance-state modulation was concentrated in the CN rather than the putamen, consistent with the distinct roles of these regions in oculomotor and skeletomotor control and suggesting that state-dependent dopamine signals are organized according to the behavioral demands of the task. These findings demonstrate that phasic dopamine signals in the dorsal striatum simultaneously reflect fast learning signals and slowly evolving internal states, linking dopamines canonical RPE function to its broader role in sustaining motivated performance.

neuroscience↗

Cell autonomous inflammation in VEXAS is mediated by cGAS-STING

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a severe adult-onset inflammatory disease caused by somatic mutations that reduce cytoplasmic activity of UBA1, the primary initiating enzyme for ubiquitylation. How this hypomorphic state drives cell-intrinsic immune activation in mature myeloid cells is unknown. Using unbiased multi-omic, biochemical, and cell biological analyses of model systems and patient-derived cells, we show that loss of cytoplasmic UBA1 activity convergently disrupts endoplasmic reticulum- associated degradation (ERAD) and mitochondrial homeostasis. ERAD failure arises from preferential under-charging of ERAD E2 enzymes, explaining hallmark VEXAS features, including ER-derived vacuoles and unfolded protein response activation, and promotes accumulation of the ERAD substrate STING. Simultaneously, mitochondrial dysfunction drives cytosolic leakage of mitochondrial DNA, inducing cGAS-dependent STING signaling and inflammatory cytokine production. STING inhibition or reversal of mitochondrial DNA leakage resolves multi-cytokine inflammation in VEXAS models and patient myeloid cells, establishing the cGAS-STING pathway as a therapeutically actionable vulnerability.

genetics↗

Highly Efficient Coreactant-Free Electrochemiluminescence Sensing Platform Using Novel Microfabricated Multiplexed Entwined Spiral Microelectrodes for Point-of-Care Applications

Luminol-based Electrochemiluminescence (ECL) generates weak signals in neutral media and typically requires H2O2 as a coreactant. However, H2O2 instability and the need for on-site addition hinder real-time diagnostic applications. Compact integrated sensing platforms are ideal for point-of-care (POC) testing due to portability, low sample requirements, and multiplexing. However, as sensor dimensions decrease, the low light emission issue in ECL becomes severe. We introduce a novel fully integrated miniaturized silicon device consisting of three sensors comprised of unique entwined micro-spiral electrodes in a generator-collector configuration. This enables highly sensitive, coreactant-free multiplexed sensing at physiological pH by accelerating in-situ reactive oxygen species production and boosting ECL intensity. Systematic optimization of electrode geometry (gaps and widths) yields an 11-fold improvement in ECL signal compared to a single-electrode setup, as well as excellent reproducibility and stability. In addition to Trolox and H2O2 detection, the platform demonstrates multiplex immunosensing through selective functionalization of the collector electrodes with chitosan nanocomposites, followed by Protein A/G-assisted immobilization of anti-IgG antibodies with peptide-based antifouling. The immunosensors exhibit high analytical performance (linear range: 0.001-100 pg{middle dot}mL-1, detection limit: 0.8 fg{middle dot}mL-1) with excellent reproducibility and reliability in 25% fetal bovine serum, highlighting the platforms potential for sensitive, coreactant-free multi-analyte POC diagnostics.

bioengineering↗

Phosphorylation enables allosteric control of a viral condensate

In many viruses, intrinsically disordered proteins (IDPs) drive the formation of replicative organelles essential for viral production. In species A rotaviruses, the disordered protein NSP5 forms condensates in cells via liquid-liquid phase separation (LLPS). Yet the sequence diversity of NSP5 raises the question of whether condensate formation is conserved across all strains and if distinct variants employ alternative mechanisms for nucleating phase separation. Using a machine learning approach, we demonstrate that NSP5 variants differ significantly in their propensity to phase-separate. We engineered a variant incorporating amino acid signatures from strains with low LLPS tendency, which failed to phase separate in vitro yet supported the formation of replicative condensates in recombinant viruses in cells. Low-tendency LLPS strains require phosphorylation of NSP5 to nucleate phase separation, whereas high-tendency strains do not, suggesting distinct nucleation mechanisms. Furthermore, hydrogen-deuterium exchange mass spectrometry revealed a phosphorylation-driven allosteric switch between binding sites on the high-propensity variant. These findings establish that phosphorylation plays a context-dependent role in the formation of replicative organelles across diverse rotaviruses.

biophysics↗

Aseptic, semi-sealed cranial chamber implants for chronic multi-channel neurochemical and electrophysiological neural recording in nonhuman primates

We developed an implantable neural interface for monitoring both chemical and electrical forms of brain activity in monkeys that maintains aseptic properties for year-long periods while leveraging the modular functions (e.g., sensor moveability) provided by a chamber system. Invasive electrophysiological recordings, especially in subcortical structures from nonhuman primates usually involves implanting electrodes into the brain through a skull-mounted chamber. These electrodes may be attached temporarily for several hours of recording, or permanently. Permanent attachments are favorable to allow for sealing the chamber completely from externally originating pathogenic species that can infiltrate and compromise the health of the animal. A sealed chamber also reduces the need for frequent chamber cleaning required to minimize the accumulation of pathogenic organisms. However, neurochemical measurements require specialized electrodes with extremely fragile carbon fiber tips and are not compatible with recently developed sealed chamber systems. Here, we leveraged osseointegrating materials and hermetic sealing strategies to enable both neurochemical and electrical neural activity measurements from a sealed chamber with an aspirating port for culturing chamber fluid to ensure an aseptic environment. The system was shown to provide successful recordings of neural activity in two monkeys while maintaining negative bacteria culture results for over a year post-implant.

neuroscience↗

Micro-invasive probes for monitoring electrical and chemical neural activity in nonhuman primates

We leveraged carbon fiber materials for creating sensors that provide dual neurochemical and electrical neural activity recording at micro-invasive (10 {micro}m) spatial footprints proximal to recording sites, and enabling these measurements from deep brain targets of primates with conventional cranial chambers. These shaft-assisted micro-invasive probes (s-{micro}IPs) are approximately 10 {micro}m in diameter along the distal length (1 - 15 mm) immediately surrounding the targeted recording site. This micro-invasive portion ensures that the recording site is isolated from tissue damage induced by the wider shaft portion of the device. The shaft (150 - 165 {micro}m in diameter) within the device stiffens the remaining length of the probe (> 100 mm), and provides compatibility with standard intracranial insertion protocols (e.g., guide tubes and chamber setups) that require a sufficiently rigid and long shaft for deep brain insertion in monkeys. The s-{micro}IP was further expanded to provide dual-channel chemical and electrical neural activity recording with micrometer spatial resolution. Measurements of reward- and movement-related dopamine, spikes, and local field potentials were made from single and dual-channel s-{micro}IPs implanted in task-performing monkeys. Recordings from chronically implanted s-{micro}IPs display the capability of functional multi-modal (chemical and electrical) neural activity measurements over 1-year post-implantation from micro-invasive devices.

bioengineering↗

AER-270 and TGN-020 are not aquaporin-4 water channel blockers

Aquaporin-4 (AQP4) is the most abundant water channel protein in the brain. It controls water homeostasis, facilitates glymphatic function and is a drug target for brain edema following injury or stroke. Dysregulation of brain water homeostasis affects millions of people every year leading to death, disability and cognitive decline, for which no medicines are available. Two compounds, AER-270 and TGN-020, are sold as AQP4 inhibitors and a prodrug of AER-270 is currently in a phase I human trial. However, the direct effect of these compounds on AQP4 function has not been unequivocally demonstrated. Our data across multiple cellular and molecular assay systems demonstrate, unexpectedly, that AER-270 and TGN-020 do not inhibit AQP4. Although we observed an apparent inhibitory effect of AER-270 and TGN-020 in the Xenopus laevis oocyte assay, there was no effect in assays using reconstituted recombinant AQP4 or mammalian cells expressing exogenous or endogenous AQP4. We identify alternative mechanisms of action for both molecules that may explain previously reported in vivo results that were interpreted in the context of AQP4 inhibition. Overall, we conclude that AER-270 and TGN-020 should not be used to investigate the AQP4-dependence of biological processes in the brain.

biophysics↗

Synchronous Measurements of Extracellular Action Potentials and Neurochemical Activity with Carbon Fiber Electrodes in Nonhuman Primates

Measuring the dynamic relationship between neuromodulators, such as dopamine, and neuronal action potentials is imperative to understand how these fundamental modes of neural signaling interact to mediate behavior. Here, we developed methods to measure concurrently dopamine and extracellular action potentials (i.e., spikes) and applied these in a monkey performing a behavioral task. Standard fast-scan cyclic voltammetric (FSCV) electrochemical (EChem) and electrophysiological (EPhys) recording systems are combined and used to collect spike and dopamine signals, respectively, from an array of carbon fiber (CF) sensors implanted in the monkey striatum. FSCV requires the application of small voltages at the implanted sensors to measure redox currents generated from target molecules, such as dopamine. These applied voltages create artifacts at neighboring EPhys-measurement sensors, producing signals that may falsely be classified as physiological spikes. Therefore, simple automated temporal interpolation algorithms were designed to remove these artifacts and enable accurate spike extraction. We validated these methods using simulated artifacts and demonstrated an average spike recovery rate of 84.5%. This spike extraction was performed on data collected from concurrent EChem and EPhys recordings made in a task-performing monkey to discriminate cell-type specific striatal units. These identified units were shown to correlate to specific behavioral task parameters related to reward size and eye-movement direction. Synchronous measures of spike and dopamine signals displayed contrasting relations to the behavioral task parameters, as taken from our small set of representative data, suggesting a complex relationship between these two modes of neural signaling. Future application of our methods will help advance our understanding of the interactions between neuromodulator signaling and neuronal activity, to elucidate more detailed mechanisms of neural circuitry and plasticity mediating behaviors in health and in disease. Significance statementWe present a simple method for recording synchronous molecular and neuronal spike signals. Conventional electrophysiological and electrochemical instruments are combined without the need for additional hardware. A custom-designed algorithm was made and validated for extracting neuronal action potential signals with high fidelity. We were able to compute cell-type specific spike activity along with molecular dopamine signals related to reward and movement behaviors from measurements made in the monkey striatum. Such combined measurements of neurochemical and extracellular action potentials may help pave the way to elucidating mechanisms of plasticity, and how neuromodulators and neurons are orchestrated to mediate behavior.

neuroscience↗

Comprehensive genome editing confers "off-the-shelf" CAR-T cells superior efficacy against solid tumors

Biochemical and immunological negative regulators converge to inhibit tumor-reactive Chimeric Antigen Receptor T (CAR-T) cells, which may explain clinical failures of CAR-T cell therapies against solid tumors. Here, we developed a multifaceted approach to genetically engineer allogeneic ( off -the-shelf) CAR-T cells resistant to both biochemical (adenosine) and immunological (PD-L1 and TGF-{beta}) inhibitory signaling. We multiplexed an adenine base editor with a CRISPR-Cas12b nuclease to manufacture a CAR-T cell product comprising six gene edits to evade allorejection (B2M, CIITA), prevent graft-versus-host disease (CD3E) and resist major biochemical (ADORA2A) and immunological (PDCD1, TGFBR2) immunosuppressive barriers in solid tumors. Combinatorial genetic disruption in CAR-T cells enabled superior anti-tumor efficacy leading to improved tumor elimination and survival in humanized mouse models that recapitulated the suppressive features of a human tumor microenvironment (TME). This novel engineering strategy conferred CAR-T cells resistance to a diverse TME, which may unlock the therapeutic potential of CAR-T cells against solid tumors. One Sentence SummaryMultiplex genome engineered CAR-T cells resistant to allorejection and the convergence of biochemical and immunological negative regulators within the tumor microenvironment exhibit superior efficacy against solid tumors.

cell biology↗

Whole genome error-corrected sequencing for sensitive circulating tumor DNA cancer monitoring

Circulating cell-free DNA (ccfDNA) sequencing for low-burden cancer monitoring is limited by sparsity of circulating tumor DNA (ctDNA), the abundance of genomic material within a plasma sample, and pre-analytical error rates due to library preparation, and sequencing errors. Sequencing costs have historically favored the development of deep targeted sequencing approaches for overcoming sparsity in ctDNA detection, but these techniques are limited by the abundance of ccfDNA in samples, which imposes a ceiling on the maximal depth of coverage in targeted panels. Whole genome sequencing (WGS) is an orthogonal approach to ctDNA detection that can overcome the low abundance of ccfDNA by supplanting sequencing depth with breadth, integrating signal across the entire tumor mutation landscape. However, the higher cost of WGS limits the practical depth of coverage and hinders broad adoption. Lower sequencing costs may thus allow for enhanced ctDNA cancer monitoring via WGS. We therefore applied emerging lower-cost WGS (Ultima Genomics, 1USD/Gb) to plasma samples at [~]120x coverage. Copy number and single nucleotide variation profiles were comparable between matched Ultima and Illumina datasets, and the deeper WGS coverage enabled ctDNA detection at the parts per million range. We further harnessed these lower sequencing costs to implement duplex error-corrected sequencing at the scale of the entire genome, demonstrating a [~]1,500x decrease in errors in the plasma of patient-derived xenograft mouse models, and error rates of [~]10-7 in patient plasma samples. We leveraged this highly de-noised plasma WGS to undertake cancer monitoring in the more challenging context of resectable melanoma without matched tumor sequencing. In this context, duplex-corrected WGS allowed us to harness known mutational signature patterns for disease monitoring without matched tumors, paving the way for de novo cancer monitoring.

genomics↗

Species interactions and diversity: a unified framework using Hill numbers

Biodiversity describes the variety of organisms on planet earth. Ecologists have long hoped for a synthesis between analyses of biodiversity and analyses of biotic interactions among species, such as predation, competition, and mutualism. However, it is often unclear how to connect details of these interactions with complex modern analyses of biodiversity. To resolve this gap, we propose a unification of models of biotic interactions and measurements of diversity. We show that analyses of biodiversity obscure details about biotic interactions. For example, identical changes in biodiversity can arise from predation, competition or mutualism. Our approach indicates that traditional models of community assembly miss key facets of diversity change. Instead, we suggest that analyses of diversity change should focus on partitions, which measure mechanisms that directly shape changes in diversity, notably species level selection and immigration, rather than traditional analyses of biotic interactions. SpeculationsOur paper proposes that observations of biodiversity cannot be used to distinguish different types of biotic interactions. For generations ecologists have been fascinated with the links between biodiversity and biotic interactions (i.e. competition, mutualism and predation). Many of us expect that observations of biodiversity provide vital clues about how biotic interactions operate in nature, but it is hard to tell when these clues are reliable. Our work integrates models of biotic interactions and measurements of biodiversity diversity change. This highlights how an observed change in diversity can be compatible with any type of biotic interaction (i.e. competition, mutualism, predation etc.). So for example, the same increase in Shannon diversity could indicate the superior ability of a competitor the success of mutualists or a predators tendency to harvest dominant prey species. This is so because diversity measures are designed to be concerned with changes in relative abundances but not account for absolute abundance changes. Observations of biodiversity change are unlikely to yield insights about biotic interactions per se because biodiversity itself obscures species absolute abundances. Therefore, models of diversity change should focus on mechanisms that are less influenced by changes in absolute abundances such as species-level selection.

ecology↗

MmCMS: Mouse models' Consensus Molecular Subtypes of colorectal cancer

BACKGROUNDColorectal cancer (CRC) primary tumours are molecularly classified into four consensus molecular subtypes (CMS1-4). Genetically engineered mouse models aim to faithfully mimic the complexity of human cancers and, when appropriately aligned, represent ideal pre-clinical systems to test new drug treatments. Despite its importance, dual-species classification has been limited by the lack of a reliable approach. Here we utilise, develop and test a set of options for human-to-mouse CMS classifications of CRC tissue. METHODSUsing transcriptional data from established collections of CRC tumours, including human (TCGA cohort; n=577) and mouse (n=57 across n=8 genotypes) tumours with combinations of random forest and nearest template prediction algorithms, alongside gene ontology collections, we comprehensively assess the performance of a suite of new dual-species classifiers. RESULTSWe developed three approaches: MmCMS-A; a gene-level classifier, MmCMS-B; an ontology-level approach and MmCMS-C; a combined pathway system encompassing multiple biological and histological signalling cascades. Although all options could identify tumours associated with stromal-rich CMS4-like biology, MmCMS-A was unable to accurately classify the biology underpinning epithelial-like subtypes (CMS2/3) in mouse tumours. CONCLUSIONSWhen applying human-based transcriptional classifiers to mouse tumour data, a pathway-level classifier, rather than an individual gene-level system, is optimal. Our R package with three options helps researchers select suitable mouse models of human CRC subtype for their experimental testing.

cancer biology↗

Directed Evolution of Adenine Base Editors with Increased Activity and Therapeutic Application

The foundational adenine base editors (e.g. ABE7.10) enable programmable C*G to T*A point mutations but editing efficiencies can be low at challenging loci in primary human cells. Here we further evolve ABE7.10 using a library of adenosine deaminase variants to create ABE8s. At NGG PAM sites, ABE8s result in [~]1.5x higher editing at protospacer positions A5-A7 and [~]3.2x higher editing at positions A3-A4 and A8-A10 compared with ABE7.10. Non-NGG PAM variants have a [~]4.2-fold overall higher on-target editing efficiency than ABE7.10. In human CD34+ cells, ABE8 can recreate a natural allele at the promoter of the {gamma}-globin genes HBG1 and HBG2, with up to 60% efficiency, causing persistence of fetal hemoglobin. In primary human T cells, ABE8s achieve 98-99% target modification which is maintained when multiplexed across three loci. Delivered as mRNA, ABE8s induce no significant levels of sgRNA-independent off-target adenine deamination in genomic DNA and very low levels of adenine deamination in cellular mRNA.

genomics↗

Association of extent of cannabis use and psychotic like intoxication experiences in a multi-national sample of First Episode Psychosis patients and controls

AimsFirst Episode Psychosis (FEP) patients who use cannabis experience more frequent psychotic and euphoric intoxication experiences compared to controls. It is not clear whether this is consequent to patients being more vulnerable to the effects of cannabis use or to their heavier pattern of use. We aimed to determine whether extent of use predicted psychotic-like and euphoric intoxication experiences in FEP patients and controls and whether this differs between groups. MethodsWe analysed data on lifetime cannabis using patients (n=655) and controls (n=654) across 15 sites from six countries in the EU-GEI study (2010-2015). We used multiple regression to model predictors of cannabis-induced experiences and to determine if there was an interaction between caseness and extent of use. ResultsCaseness, frequency of cannabis use and money spent on cannabis predicted psychotic-like and euphoric experiences, independent of other experiences (p[&le;]0.001). For psychotic-like experiences there was a significant interaction for caseness x frequency of use (p<0.001) and caseness x money spent on cannabis (p=0.001) such that FEP patients had increased experiences at increased levels of use compared to controls. There was no similar significant interaction for euphoric experiences (p>0.5). Conclusions and RelevanceFEP patients are particularly sensitive to increased psychotic-like, but not euphoric experiences, at higher frequency and amount of cannabis use compared to controls. This suggests a specific psychotomimetic response in patients related particularly to heavy cannabis use.

neuroscience↗

Modeling predicts that CRISPR-based activators, unlike CRISPR-based repressors, scale well with increasing gRNA competition and dCas9 bottlenecking

Synthetic transcriptional networks built from CRISPR-based repressors (CRISPRi) rely on shared use of a core dCas9 protein. In E. coli, CRISPRi cannot support more than about a dozen simultaneous gRNAs before the fold repression of any individual gRNA drops below 10x. We show with a simple model based on previous characterization of competition in CRISPRi that activation by CRISPR-based activators (CRISPRa) is much less sensitive to dCas9 bottle-necking than CRISPRi. We predict that E. coli should be able to support dozens to hundreds of CRISPRa gRNAs at >10-fold activation.

synthetic biology↗

A Method for Cost-Effective and Rapid Characterization of Engineered T7-based Transcription Factors by Cell-Free Protein Synthesis Reveals Insights into the Regulation of T7 RNA Polymerase-Driven Expression

The T7 bacteriophage RNA polymerase (T7 RNAP) serves as a model for understanding RNA synthesis, as a tool for protein expression, and as an actuator for synthetic gene circuit design in bacterial cells and cell-free extract. T7 RNAP is an attractive tool for orthogonal protein expression in bacteria owing to its compact single subunit structure and orthogonal promoter specificity. Understanding the mechanisms underlying T7 RNAP regulation is important to the design of engineered T7-based transcription factors, which can be used in gene circuit design. To explore regulatory mechanisms for T7 RNAP-driven expression, we developed a rapid and cost-effective method to characterize engineered T7-based transcription factors using cell-free protein synthesis and an acoustic liquid handler. Using this method, we investigated the effects of the tetracycline operators proximity to the T7 promoter on the regulation of T7 RNAP-driven expression. Our results reveal a mechanism for regulation that functions by interfering with the transition of T7 RNAP from initiation to elongation and validates the use of the method described here to engineer future T7-based transcription factors.\n\nHighlightsO_LIDevelopment of a rapid and cost-effective method for screening synthetic promoters.\nC_LIO_LIInsights into the regulation of engineered T7-based transcription factors and T7 RNAP enzyme kinetics.\nC_LIO_LIValidation of this method by comparison with the T7 RNAP kinetic model.\nC_LI

synthetic biology↗

Investigating the role of behaviour in the genetic risk for schizophrenia

The notion that behaviour may be on a causal path from genetics to psychiatric disorders, such as schizophrenia, highlights a potential for practical interventions. Motivated by this, we test the association between schizophrenia (SCZ) polygenic risk scores (PRS) and 420 behavioural traits (personality, psychological, lifestyle, nutritional) in a psychiatrically healthy sub-cohort of the UK Biobank. Higher schizophrenia PRS was associated with a range of traits, including lower verbal-numerical reasoning (P = 6x10-61), higher nervous feelings (P = 2x10-51) and higher self-reported risk-taking (P = 2x10-41). We follow-up the risk-taking association, hypothesising that the association may be due to a genetic propensity for risk-taking leading to greater migration, urbanicity or drug-taking - reported environmental risk factors for schizophrenia, and all positively associated with risk-taking in these data. However, schizophrenia PRS was also associated with traits, such as tea drinking (P = 2x10-34), that are highly unlikely to be on a causal path to schizophrenia. We depict four causal relationships that may in theory underlie such PRS-trait associations and illustrate ways of testing for each. For example, we contrast PRS-trait trends in the healthy sub-cohort to the corresponding trait values of medicated and non-medicated individuals diagnosed with schizophrenia, allowing some differentiation of mediation-by-behaviour, disease-onset effects and treatment effects. However, dedicated follow-up studies and new methods are required to fully disentangle these relationships. Thus, while we urge caution in interpretation of simple PRS cross-trait associations, we propose that well-designed PRS analyses can contribute to identifying behaviours on the causal path from genetics to disease.

genetics↗

The Maudsley Environmental Risk Score for Psychosis

Risk prediction algorithms have long been used in health research and practice (e.g., in prediction of cardiovascular disease, diabetes, etc.) However, similar tools have not been developed for mental health problems, despite extensive research on risk factors. For example, for psychotic disorders, attempts to sum environmental risk are rare, usually unsystematic and dictated by available data. In light of this, we sought to develop a valid, easy to use measure of the total environmental risk for psychotic disorders, which can be used in research and clinical practice.\n\nWe first reviewed the literature to identify well-replicated and validated environmental risk factors for psychosis and, then, used the largest available meta-analyses to derive current best estimates of risk. We devised a method of scoring individuals based on the level of exposure to each risk factor, using odds ratios from the meta-analyses, to produce an Environmental Risk Score (ERS).\n\nSix risk factors (ethnic minority status, urbanicity, high paternal age, obstetric complications, cannabis use, and childhood adversity) were used to generate the ERS. A distribution for different levels of risk based on permuted data showed that most of population would be at low/moderate risk with a small minority at increased environmental risk for psychosis.\n\nThis is the first systematic approach to develop an aggregate measure of environmental risk for psychoses. This can be used as a continuous measure of liability to disease or transformed to a relative risk. Its predictive ability will improve with the collection of additional, population specific data.

epidemiology↗