A cookbook for using model diagnostics in integrated stock assessments

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The effect of dopamine agonists on adaptive and aberrant salience in Parkinson's disease

Clinical evidence suggests that after initiation of dopaminergic medications some patients with Parkinson's disease (PD) develop psychotic symptoms, such as hallucinations and delusions. Here, we tested the hypothesis that the neurocognitive basis of this phenomenon can be defined as the formation of arbitrary and illusory associations between conditioned stimuli and reward signals, called aberrant salience. Young, never-medicated PD patients and matched controls were assessed on a speeded reaction time task in which the probe stimulus was preceded by conditioned stimuli that could signal monetary reward by color or shape. The patients and controls were re-evaluated after 12 weeks during which the patients received a dopamine agonist (pramipexole or ropinirole). Results indicated that dopamine agonists increased both adaptive and aberrant salience in PD patients, that is, formation of real and illusory associations between conditioned stimuli and reward, respectively. This effect was present when associations were assessed by means of faster responding after conditioned stimuli signaling reward (implicit salience) and overt rating of stimulus-reward links (explicit salience). However, unusual feelings and experiences, which are subclinical manifestations of psychotic-like symptoms, were specifically related to irrelevant and illusory stimulus-reward associations (aberrant salience) in PD patients receiving dopamine agonists. The learning of relevant and real stimulus-reward associations (adaptive salience) was not related to unusual experiences. These results suggest that dopamine agonists may increase psychotic-like experiences in young patients with PD, possibly by facilitating dopaminergic transmission in the ventral striatum, which results in aberrant associations between conditioned stimuli and reward

Confidence and psychosis: a neuro-computational account of contingency learning disruption by NMDA blockade.

A state of pathological uncertainty about environmental regularities might represent a key step in the pathway to psychotic illness. Early psychosis can be investigated in healthy volunteers under ketamine, an NMDA receptor antagonist. Here, we explored the effects of ketamine on contingency learning using a placebo-controlled, double-blind, crossover design. During functional magnetic resonance imaging, participants performed an instrumental learning task, in which cue-outcome contingencies were probabilistic and reversed between blocks. Bayesian model comparison indicated that in such an unstable environment, reinforcement learning parameters are downregulated depending on confidence level, an adaptive mechanism that was specifically disrupted by ketamine administration. Drug effects were underpinned by altered neural activity in a fronto-parietal network, which reflected the confidence-based shift to exploitation of learned contingencies. Our findings suggest that an early characteristic of psychosis lies in a persistent doubt that undermines the stabilization of behavioral policy resulting in a failure to exploit regularities in the environment.FV was supported by the Groupe Pasteur Mutualité. RG was supported by the Fondation pour la Recherche Médicale and the Fondation Bettencourt Schueller. SP is supported by a Marie Curie Intra-European fellowship (FP7-PEOPLE-2012-IEF). AF was supported by National Health and Medical Research Council grants (IDs : 1050504 and 1066779) and an Australian Research Council Future Fellowship (ID: FT130100589). This work was supported by the Wellcome Trust and the Bernard Wolfe Health Neuroscience Fund.This is the final version of the article. It first appeared from the Nature Publishing Group via http://dx.doi.org/10.1038/mp.2015.7

Comprehensive review:Computational modelling of Schizophrenia

Computational modelling has been used to address: (1) the variety of symptoms observed in schizophrenia using abstract models of behavior (e.g. Bayesian models - top-down descriptive models of psychopathology); (2) the causes of these symptoms using biologically realistic models involving abnormal neuromodulation and/or receptor imbalance (e.g. connectionist and neural networks - bottom-up realistic models of neural processes). These different levels of analysis have been used to answer different questions (i.e. understanding behavioral vs. neurobiological anomalies) about the nature of the disorder. As such, these computational studies have mostly supported diverging hypotheses of schizophrenia's pathophysiology, resulting in a literature that is not always expanding coherently. Some of these hypotheses are however ripe for revision using novel empirical evidence.Here we present a review that first synthesizes the literature of computational modelling for schizophrenia and psychotic symptoms into categories supporting the dopamine, glutamate, GABA, dysconnection and Bayesian inference hypotheses respectively. Secondly, we compare model predictions against the accumulated empirical evidence and finally we identify specific hypotheses that have been left relatively under-investigated

Dopamine, affordance and active inference.

The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Testing Spatial Management Strategies for Hawaii's Future Reefs: A Biophysical, Metacommunity Approach

M.S. University of Hawaii at Manoa 2016.Includes bibliographical references.Coral reefs are invaluable resources in tropical communities, and support the cultural and substantial livelihoods of millions of coastal peoples. Reefs are home to a massive proportion of earth’s biodiversity, and form the basis of commercially valuable fisheries and tourism industries. However, reefs are globally in decline, and it is in the interest of marine resource managers to understand and modulate impacts of climate- and human-induced effects on the continued resilience of their reef ecosystems. Simulation models have proven to be useful, though not perfect, tools to test and evaluate potential futures of reef ecosystems at a variety of spatial scales. These are most effective when incorporating a broad set of biological, climactic and environmental data, and can be adapted to various regions. This thesis presents the development, validation, and application of a pre-existing biophysical coral reef model, CORSET (Coral Reef Scenario Evaluation Tool) to a novel system, the Main Hawaiian Islands (MHI). The model was originally developed by Jessica Melbourne-Thomas and colleagues at the University of Tasmania as a portable framework to address biophysical processes on coral reefs across multiple spatial scales1. The model incorporates local ecology, larval connectivity, and anthropogenic and environmental forcings across an array of differential equations, run on a desktop computer and visualized using spatial or graphical software. It is a decision support tool for visualizing reef futures at regional scales in the order of 102 -103 km. This study applies and demonstrates the portability of the CORSET model, and applies a test-case to examine potential reef scenarios under alternative climate, land-use and fishing protection regimes. The results hold implications for simulation testing in reef ecology and decision-support for marine fisheries management. The study conclusion also provides simulative evidence against the common paradigm that top-down management strategies will be the most effective in preserving coral cover

A Management Strategy Evaluation for Transboundary Sablefish in the Northeast Pacific Ocean

Thesis (Ph.D.)--University of Washington, 2023Fisheries assessment science has long concerned itself about the incorporation of spatial stock structure into the development, testing and deployment of management strategies. The population dynamics of a stock may not match static political boundaries due to migration, ontogenetic changes in demography, and spatially varying exploitation. Correctly specifying spatial structure can reduce bias in management quantities to a greater degree than correcting other parameters or population processes. While the value of developing spatially-structured assessment models is well recognized, there are many barriers to implementation, including the cost of collecting and evaluating datasets at the appropriate spatial resolution to determine how such assessments should be structured. The management strategy evaluation (MSE) approach enables scientists to test how various spatial assessment configurations might impact management performance, before moving to tactical implementation. Sablefish (Anoplopoma fimbria) of the northeast Pacific support a highly mobile, valuable fishery resource worth over $112 million USD. At the federal level, sablefish in this region are currently managed as three separate populations (Alaska, British Columbia and the US West Coast) by the National Oceanic and Atmospheric Administration (NOAA-US) and the Department of Fisheries and Oceans (DFO – Canada). Recent work has shown sablefish to be genetically mixed across the range, tagging studies confirm high movement rates and there is range wide synchrony in biomass trends, including declines during the last decade. These observations have led scientists and managers to consider whether evaluating the stock as a spatially structured population might reveal transboundary dynamics, and/or preclude poor management outcomes at the regional scale. An investigation of growth rates throughout the northeast Pacific revealed roughly four regions of distinct sablefish growth. These regions correspond with large oceanographic features that characterize large marine ecosystems (LME). A spatially structured statistical catch-at-age model, conditioned to historical catch, discard, survey and age-composition data from the three management regions suggested that the data can be plausibly fit as a spatially structured population, and corroborated other investigations indicating that LMEs delineate sablefish spawning populations within each management area. An MSE including estimation methods across a gradient of spatial complexity revealed that spatial models of intermediate structural complexity, including those that match the current paradigm in terms of having three modeled areas, can satisfy stakeholder objectives and avoid negative outcomes for the sablefish fishery. The MSE tool built for this dissertation can be used to evaluate management performance in the context of climate-induced changes to reproduction, alternative structural hypotheses, or changes to fleet dynamics

Simulating future climate impacts on tropical fisheries: are contemporary spatial fishery management strategies sufficient?

We demonstrated a possible future wherein coral reefs shift to an algae-dominated state that retains low coral cover and a functional biomass of herbivorous fishes that sustains a reef fish fishery. We evaluate the effect of no-take MPAs and increased coastal nutrients under two IPCC climate scenarios for years 2000-2100, which are implemented as coral bleaching events. Coral mortality from bleaching events drove a lagged increase in herbivorous fish populations, via a shift from coral-dominated to algae-dominated habitats. Biomass and catch of piscivorous fish declined significantly with the fishery shifting to the harvest of herbivorous fish. No-take MPAs for 20% of reef areas represented a threshold that had a positive effect on herbivorous fishes but no influence on the steep declines of corals and piscivorous fishes. Contemporary no-take MPAs protect less than 1% of coral reef areas around the Hawaiian Islands; significant management action would be required to approach the 20% area threshold.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author