Search

Access to commercial CD19 CAR-T cells remains limited even in wealthy countries like Canada due to clinical, logistical, and financial barriers related to centrally manufactured products. We created a non-commercial academic platform for end-to-end manufacturing of CAR-T cells within Canada’s publicly funded healthcare system. We report initial results from a single-arm, open-label study to determine the safety and efficacy of in-house manufactured CD19 CAR-T cells (entitled CLIC-1901) in participants with relapsed/refractory CD19 positive hematologic malignancies. Using a GMP compliant semi-automated, closed process on the Miltenyi Prodigy, T cells were transduced with lentiviral vector bearing a 4-1BB anti-CD19 CAR transgene and expanded. Participants underwent lymphodepletion with fludarabine and cyclophosphamide, followed by infusion of non-cryopreserved CAR-T cells. Thirty participants with non-Hodgkin’s lymphoma (n=25) or acute lymphoblastic leukemia (n=5) were infused with CLIC-1901: 21 males (70%), median age 66 (range 18-75). Time from enrollment to CLIC-1901 infusion was a median of 20 days (range 15-48). The median CLIC-1901 dose infused was 2.3 × 106 CAR-T cells/kg (range 0.13-3.6 × 106/kg). Toxicity included ≥ grade 3 cytokine release syndrome (n=2) and neurotoxicity (n=1). Median follow-up was 6.5 months. Overall response rate at day 28 was 76.7%. Median progression-free and overall survival was 6 months (95%CI 3-not estimable) and 11 months (95% 6.6-not estimable), respectively. This is the first trial of in-house manufactured CAR-T cells in Canada and demonstrates that administering fresh CLIC-1901 product is fast, safe, and efficacious. Our experience may provide helpful guidance for other jurisdictions seeking to create feasible and sustainable CAR-T cell programs in research-oriented yet resource-constrained settings.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT03765177, identifier NCT03765177.

Objective The present research applied a well-established measure of cognitive workload in driving literature to an in-lab paradigm. We then extended this by comparing the in-lab version of the task to an online version. Background The accurate and objective measurement of cognitive workload is important in many aspects of psychological research. The detection response task (DRT) is a well-validated method for measuring cognitive workload that has been used extensively in applied tasks, for example, to investigate the effects of phone usage or passenger conversation on driving, but has been used sparingly outside of this field. Method The study investigated whether the DRT could be used to measure cognitive workload in tasks more commonly used in experimental cognitive psychology and whether this application could be extended to online environments. We had participants perform a multiple object tracking (MOT) task while simultaneously performing a DRT. We manipulated the cognitive load of the MOT task by changing the number of dots to be tracked. Results Measurements from the DRT were sensitive to changes in the cognitive load, establishing the efficacy of the DRT for experimental cognitive tasks in lab-based situations. This sensitivity continued when applied to an online environment (our code for the online DRT implementation is freely available at https://osf.io/dc39s/ ), though to a reduced extent compared to the in-lab situation. Conclusion The MOT task provides an effective manipulation of cognitive workload. The DRT is sensitive to changes in workload across a range of settings and is suitable to use outside of driving scenarios, as well as via online delivery. Application Methodology shows how the DRT could be used to measure sources of cognitive workload in a range of human factors contexts.

With the advancement of technologies like in-car navigation and smartphones, concerns around how cognitive functioning is influenced by "workload" are increasingly prevalent. Research shows that spreading effort across multiple tasks can impair cognitive abilities through an overuse of resources, and that similar overload effects arise in difficult single-task paradigms. We developed a novel lab-based extension of the Detection Response Task, which measures workload, and paired it with a Multiple Object Tracking Task to manipulate cognitive load. Load was manipulated either by changing within-task difficulty or by the addition of an extra task. Using quantitative cognitive modelling we showed that these manipulations cause similar cognitive impairments through diminished processing rates, but that the introduction of a second task tends to invoke more cautious response strategies that do not occur when only difficulty changes. We conclude that more prudence should be exercised when directly comparing multi-tasking and difficulty-based workload impairments, particularly when relying on measures of central tendency.

Few fathers enrol in web-based preventive parenting programs for adolescent mental health, despite the evidence of the benefits associated with their participation. To inform the development of father-inclusive programs, this study used a discrete choice experiment (DCE) design to determine (a) the relative influence of number of sessions, program benefits, program participants, and user control over program content on fathers’ preferences for web-based preventive parenting programs; and (b) whether selected father characteristics were associated with their preferences. One hundred and seventy-one fathers completed the DCE survey, which comprised 25 choices between hypothetical programs. Programs that included the participant’s adolescent child (z = 10.06, p < 0.0001), or parenting partner (z = 7.30, p < 0.001) were preferred over those designed for fathers only. Participants also preferred program content that was recommended for them by experts (z = −4.31, p < 0.0001) and programs with fewer sessions (z = −2.94, p < 0.01). Program benefits did not predict fathers’ choice of program. Prior use of a parenting program, level of education, perceived role of parenting for adolescent mental health, and being part of a dual-working family were associated with preferences. Application of these findings may improve paternal enrolment in web-based preventive parenting programs.

Fusobacterium nucleatum is a ubiquitous opportunistic pathogen with an emerging role as an oncomicrobe in colorectal cancer and other cancer settings. F. nucleatum can adhere to and invade host cells in a manner that varies across F. nucleatum strains and host cell phenotypes. Here, we performed pairwise cocultures between three F. nucleatum strains and two immortalized primary host cell types (human colonic epithelial [HCE] cells and human carotid artery endothelial [HCAE] cells) followed by transcriptome sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) to investigate transcriptional and epigenetic host cell responses. We observed that F. nucleatum-induced host cell transcriptional modulation involves strong upregulation of genes related to immune migration and inflammatory processes, such as TNF, CXCL8, CXCL1, and CCL20. Furthermore, we identified genes strongly upregulated in a cell line-specific manner. In HCE cells, overexpressed genes included UBD and DUOX2/DUOXA2, associated with p53 degradation-mediated proliferation and intestinal reactive oxygen species (ROS) production, respectively. In HCAE cells, overexpressed genes included EFNA1 and LIF, two genes commonly upregulated in colorectal cancer and associated with poor patient outcomes, and PTGS2 (COX2), a gene associated with the protective effect of aspirin in the colorectal cancer setting. Interestingly, we also observed downregulation of numerous histone modification genes upon F. nucleatum exposure. We used the ChIP-seq data to annotate chromatin states genome wide and found significant chromatin remodeling following F. nucleatum exposure in HCAE cells, with increased frequencies of active enhancer and low-signal/quiescent states. Thus, our results highlight increased inflammation and chemokine gene expression as conserved host cell responses to F. nucleatum exposure and extensive host cell epigenomic changes specific to host cell type. IMPORTANCE Fusobacterium nucleatum is a bacterium normally found in the healthy oral cavity but also has an emerging role in colorectal cancer and other cancer settings. The host-microbe interactions of F. nucleatum and its involvement in tumor initiation, progression, and treatment resistance are not fully understood. We explored host cell changes that occur in response to F. nucleatum. We identified key genes differentially expressed in response to various conditions of F. nucleatum exposure and determined that the conserved host cell response to F. nucleatum was dominated by increased inflammation and chemokine gene expression. Additionally, we found extensive host cell epigenomic changes as a novel aspect of host modulation associated with F. nucleatum exposure. These results extend our understanding of F. nucleatum as an emerging pathogen and highlight the importance of considering strain heterogeneity and host cell phenotypic variation when exploring pathogenic mechanisms of F. nucleatum.

Significance In modern life, we engage with many sources of information concurrently. To do this, we must continuously switch between different tasks, but this comes at a cost to performance, especially in older adults. Using a large dataset from an online cognitive-training platform, we develop a computational model of task switching that defines distinct latent measures of activating the relevant task, deactivating the irrelevant task, and making a decision. This model shows that, although task practice can improve task-switching performance, persistent costs remain even after extensive practice, and more so in older adults. We show that, with extensive task practice, older people can become functionally similar to less-practiced younger people., An important feature of human cognition is the ability to flexibly and efficiently adapt behavior in response to continuously changing contextual demands. We leverage a large-scale dataset from Lumosity, an online cognitive-training platform, to investigate how cognitive processes involved in cued switching between tasks are affected by level of task practice across the adult lifespan. We develop a computational account of task switching that specifies the temporal dynamics of activating task-relevant representations and inhibiting task-irrelevant representations and how they vary with extended task practice across a number of age groups. Practice modulates the level of activation of the task-relevant representation and improves the rate at which this information becomes available, but has little effect on the task-irrelevant representation. While long-term practice improves performance across all age groups, it has a greater effect on older adults. Indeed, extensive task practice can make older individuals functionally similar to less-practiced younger individuals, especially for cognitive measures that focus on the rate at which task-relevant information becomes available.

BackTrack is a multi-component, community-based intervention designed to build capacity amongst 14–17-year-old high risk young people. The aim of the current study seeks to explore community value and preferences for reducing youth crime and improving community safety using BackTrack in a rural setting in Armidale, New South Wales, Australia. The study design used discrete choice experiments (DCEs), designed in accordance with the 10-item checklist outlined by the International Society for Pharmacoeconomics and Outcomes Research. The DCE was pilot tested on 43 participants to test feasibility and comprehension. A revised version of the survey was subsequently completed by 282 people over a 12-day period between 30 May 2016 and 10 June 2016, representing a survey response rate of 35%. Ninety per cent of respondents were residents of Armidale, the local rural town where BackTrack was implemented. The DCE generated results that consistently demonstrated a preference for social programs to address youth crime and community safety in the Armidale area. Respondents chose BackTrack over Greater Police Presence 75% of the time with an annual benefit of Australian dollars (AUD) 150 per household, equivalent to a community benefit of AUD 2.04 million. This study estimates a strong community preference for BackTrack relative to more policing (a community willing to pay equivalent to AUD 2.04 million) highlighting the clear value of including community preferences when evaluating community-based programs for high-risk young people.

In a Dutch auction, an item is offered for sale at a set maximum price. The price is then gradually lowered over a fixed interval of time until a bid is made, securing the item for the bidder at the current price. Bidders must trade-off between certainty and price: bid early to secure the item and you pay a premium; bid later at a lower price but risk losing to another bidder. These properties of Dutch auctions provide new opportunities to study competitive decision-making in a group setting. We developed a novel computerised Dutch auction platform and conducted a set of experiments manipulating volatility (fixed vs varied number of items for sale) and price reduction interval rate (step-rate). Triplets of participants ($$N=66$$ N = 66 ) competed with hypothetical funds against each other. We report null effects of step-rate and volatility on bidding behaviour. We developed a novel adaptation of prospect theory to account for group bidding behaviour by balancing certainty and subjective expected utility. We show the model is sensitive to variation in auction starting price and can predict the associated changes in group bid prices that were observed in our data.

It is commonly assumed that a specific testing occasion (task, design, procedure, etc.) provides insights that generalise beyond that occasion. This assumption is infrequently carefully tested in data. We develop a statistically principled method to directly estimate the correlation between latent components of cognitive processing across tasks, contexts, and time. This method simultaneously estimates individual-participant parameters of a cognitive model at each testing occasion, group-level parameters representing across-participant parameter averages and variances, and across-task correlations. The approach provides a natural way to "borrow" strength across testing occasions, which can increase the precision of parameter estimates across all testing occasions. Two example applications demonstrate that the method is practical in standard designs. The examples, and a simulation study, also provide evidence about the reliability and validity of parameter estimates from the linear ballistic accumulator model. We conclude by highlighting the potential of the parameter-correlation method to provide an "assumption-light" tool for estimating the relatedness of cognitive processes across tasks, contexts, and time., Comment: 30 pages, 10 figures, 5 tables

Purpose: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid tumors with dramatic and durable responses seen across multiple tumor types. However, identifying patients who will respond to these drugs remains challenging, particularly in the context of advanced and previously treated cancers. Experimental Design: We characterized fresh tumor biopsies from a heterogeneous pan-cancer cohort of 98 patients with metastatic predominantly pretreated disease through the Personalized OncoGenomics program at BC Cancer (Vancouver, Canada) using whole genome and transcriptome analysis (WGTA). Baseline characteristics and follow-up data were collected retrospectively. Results: We found that tumor mutation burden, independent of mismatch repair status, was the most predictive marker of time to progression (P = 0.007), but immune-related CD8+ T-cell and M1-M2 macrophage ratio scores were more predictive for overall survival (OS; P = 0.0014 and 0.0012, respectively). While CD274 [programmed death-ligand 1 (PD-L1)] gene expression is comparable with protein levels detected by IHC, we did not observe a clinical benefit for patients with this marker. We demonstrate that a combination of markers based on WGTA provides the best stratification of patients (P = 0.00071, OS), and also present a case study of possible acquired resistance to pembrolizumab in a patient with non–small cell lung cancer. Conclusions: Interpreting the tumor-immune interface to predict ICI efficacy remains challenging. WGTA allows for identification of multiple biomarkers simultaneously that in combination may help to identify responders, particularly in the context of a heterogeneous population of advanced and previously treated cancers, thus precluding tumor type–specific testing.

To explore in a sample of medical oncology outpatients and their nominated support persons (SPs): (1) the relative influence of pain, consciousness and life extension on end-of-life choices using a discrete choice experiment (DCE); (2) the extent to which SPs can predict the choices of index patients and (3) whether having a previous end-of-life discussion was associated with dyad agreement. Adult medical oncology patients and their SPs were approached for consent to complete a survey containing a DCE. Participants chose between three unlabelled care scenarios characterised by three attributes: pain (mild, moderate or severe), consciousness (some, half or most of time) and extension of life (1, 2 or 3 weeks). Respondents selected (1) most-preferred and (2) least-preferred scenarios within each question. SPs answered the same questions but from patient’s perspective. A total of 110 patients and 64 SPs responded overall (42 matched patient-SP dyads). For patients, pain was the most influential predictor of most- and least-preferred scenarios (z = 12.5 and z = 12.9). For SPs, pain was the only significant predictor of most and least-preferred scenarios (z = 9.7 and z = 11.5). Dyad agreement was greater for choices about least- (69%) compared to most-preferred scenarios (55%). Agreement was slightly higher for dyads reporting a previous EOL discussion (68 versus 48%; p = 0.065). Patients and SPs place significant value on avoiding severe pain when making end-of-life choices, over and above level of consciousness or life extension. People’s views about end-of-life scenarios they most as well as least prefer should be sought.

Objective: Parenthood is central to the personal and social identity of many people. For individuals with psychotic disorders, parenthood is often associated with formidable challenges. We aimed to identify predictors of adequate parenting among parents with psychotic disorders. Methods: Data pertaining to 234 parents with psychotic disorders living with dependent children were extracted from a population-based prevalence study, the 2010 second Australian national survey of psychosis, and analysed using confirmatory factor analysis. Parenting outcome was defined as quality of care of children, based on participant report and interviewer enquiry/exploration, and included level of participation, interest and competence in childcare during the last 12 months. Results: Five hypothesis-driven latent variables were constructed and labelled psychosocial support, illness severity, substance abuse/dependence, adaptive functioning and parenting role. Importantly, 75% of participants were not identified to have any dysfunction in the quality of care provided to their child(ren). Severity of illness and adaptive functioning were reliably associated with quality of childcare. Psychosocial support, substance abuse/dependence and parenting role had an indirect relationship to the outcome variable via their association with either severity of illness and/or adaptive functioning. Conclusion: The majority of parents in the current sample provided adequate parenting. However, greater symptom severity and poorer adaptive functioning ultimately leave parents with significant difficulties and in need of assistance to manage their parenting obligations. As symptoms and functioning can change episodically for people with psychotic illness, provision of targeted and flexible support that can deliver temporary assistance during times of need is necessary. This would maximise the quality of care provided to vulnerable children, with potential long-term benefits.

Recently, Veksler, Myers, and Gluck (2015) proposed model flexibility analysis as a method that "aids model evaluation by providing a metric for gauging the persuasiveness of a given fit" (p. 755) Model flexibility analysis measures the complexity of a model in terms of the proportion of all possible data patterns it can predict. We show that this measure does not provide a reliable way to gauge complexity, which prevents model flexibility analysis from fulfilling either of the 2 aims outlined by Veksler et al. (2015): absolute and relative model evaluation. We also show that model flexibility analysis can even fail to correctly quantify complexity in the most clear cut case, with nested models. We advocate for the use of well-established techniques with these characteristics, such as Bayes factors, normalized maximum likelihood, or cross-validation, and against the use of model flexibility analysis. In the discussion, we explore 2 issues relevant to the area of model evaluation: the completeness of current model selection methods and the philosophical debate of absolute versus relative model evaluation. (PsycINFO Database Record

Objective To test the effects of enhanced display information (“symbology”) on cognitive workload in a simulated helicopter environment, using the detection response task (DRT). Background Workload in highly demanding environments can be influenced by the amount of information given to the operator and consequently it is important to limit potential overload. Methods Participants (highly trained military pilots) completed simulated helicopter flights, which varied in visual conditions and the amount of information given. During these flights, participants also completed a DRT as a measure of cognitive workload. Results With more visual information available, pilots’ landing accuracy was improved across environmental conditions. The DRT is sensitive to changes in cognitive workload, with workload differences shown between environmental conditions. Increasing symbology appeared to have a minor effect on workload, with an interaction effect of symbology and environmental condition showing that symbology appeared to moderate workload. Conclusion The DRT is a useful workload measure in simulated helicopter settings. The level of symbology-moderated pilot workload. The increased level of symbology appeared to assist pilots’ flight behavior and landing ability. Results indicate that increased symbology has benefits in more difficult scenarios. Applications The DRT is an easily implemented and effective measure of cognitive workload in a variety of settings. In the current experiment, the DRT captures the increased workload induced by varying the environmental conditions, and provides evidence for the use of increased symbology to assist pilots.

Objective To explore the preferences of people with cancer regarding the timing and format of information provision about emotional concerns that may occur when undergoing medical procedures. Methods Eligible cancer survivors were mailed a survey containing discrete choice scenarios examining their timing and format preferences for information about potential emotional concerns associated with an upcoming hypothetical medical procedure. Results Of 356 eligible patients, 271 (76 %) completed the survey. Both face-to-face discussion and written materials were preferred as the mode of information delivery over access to a website. In order of descending preference, participants preferred to receive the information 1 week, 3 days and the day of the procedure. There were no differences in preferences for timing or format between subgroups based on age, gender, education and cancer type. Conclusion This study has demonstrated that cancer patients prefer receiving information about emotional concerns that might be experienced as part of a medical procedure in either written or via face-to-face format, and one week before the procedure. Practice Implications In order to provide patient-centred care, clinicians and the healthcare system more broadly should consider patient preferences for information delivery about upcoming medical procedures. Information preparation for medical procedures; discrete choice; oncology; patient preference; emotional response.

Independent racing evidence-accumulator models have proven fruitful in advancing understanding of rapid decisions, mainly in the case of binary choice, where they can be relatively easily estimated and are known to account for a range of benchmark phenomena. Typically, such models assume a one-to-one mapping between accumulators and responses. We explore an alternative independent-race framework where more than one accumulator can be associated with each response, and where a response is triggered when a sufficient number of accumulators associated with that response reach their thresholds. Each accumulator is primarily driven by the difference in evidence supporting one versus another response (i.e., that response's "advantage"), with secondary inputs corresponding to the total evidence for both responses and a constant term. We use Brown and Heathcote's (2008) linear ballistic accumulator (LBA) to instantiate the framework in a mathematically tractable measurement model (i.e., a model whose parameters can be successfully recovered from data). We show this "advantage LBA" model provides a detailed quantitative account of a variety of benchmark binary and multiple choice phenomena that traditional independent accumulator models struggle with; in binary choice the effects of additive versus multiplicative changes to input values, and in multiple choice the effects of manipulations of the strength of lure (i.e., nontarget) stimuli and Hick's law. We conclude that the advantage LBA provides a tractable new avenue for understanding the dynamics of decisions among multiple choices. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

To explore in a sample of adult cancer patients: (1) the relative influence of initiation source, information format and consultation format on preferred approach to life expectancy disclosure using a discrete choice experiment (DCE); and (2) whether patient age, cancer type and perceived prognosis were associated with preferences within the three attributes. A DCE survey of adult solid tumour and haematological cancer patients. Participants chose between three hypothetical scenarios about life expectancy disclosure consisting of three attributes: initiation source (i.e. doctor versus patient-initiated discussion), information content (i.e. estimate presented as best-worst-typical length of life case scenario versus median survival time) and consultation format (i.e. two 20-min versus one 40-min consultation). Respondents selected their most preferred scenario within each question. Three hundred and two patients completed the DCE (78% consent rate). Initiation source was the most influential predictor of patient choice. More preferred a doctor deliver life expectancy information as soon as it is available rather than waiting for the patient to ask (59% vs 41% z = − 7.396, p

Neoantigens present unique and specific targets for personalized cancer immunotherapy strategies. Given the low mutational burden yet immunotherapy responsiveness of malignant mesothelioma (MM) when compared to other carcinogen-induced malignancies, identifying candidate neoantigens and T cells that recognize them has been a challenge. We used pleural effusions to gain access to MM tumor cells as well as immune cells in order to characterize the tumor-immune interface in MM. We characterized the landscape of potential neoantigens from SNVs identified in 27 MM patients and performed whole transcriptome sequencing of cell populations from 18 patient-matched pleural effusions. IFNγ ELISpot was performed to detect a CD8+ T cell responses to predicted neoantigens in one patient. We detected a median of 68 (range 7–258) predicted neoantigens across the samples. Wild-type non-binding to mutant binding predicted neoantigens increased risk of death in a model adjusting for age, sex, smoking status, histology and treatment (HR: 33.22, CI: 2.55–433.02, p = .007). Gene expression analysis indicated a dynamic immune environment within the pleural effusions. TCR clonotypes increased with predicted neoantigen burden. A strong activated CD8+ T-cell response was identified for a predicted neoantigen produced by a spontaneous mutation in the ROBO3 gene. Despite the challenges associated with the identification of bonafide neoantigens, there is growing evidence that these molecular changes can provide an actionable target for personalized therapeutics in difficult to treat cancers. Our findings support the existence of candidate neoantigens in MM despite the low mutation burden of the tumor, and may present improved treatment opportunities for patients.

Advanced and metastatic tumors with complex treatment histories drive cancer mortality. Here we describe the POG570 cohort, a comprehensive whole-genome, transcriptome and clinical dataset, amenable for exploration of the impacts of therapies on genomic landscapes. Previous exposure to DNA-damaging chemotherapies and mutations affecting DNA repair genes, including POLQ and genes encoding Polζ, were associated with genome-wide, therapy-induced mutagenesis. Exposure to platinum therapies coincided with signatures SBS31 and DSB5 and, when combined with DNA synthesis inhibitors, signature SBS17b. Alterations in ESR1, EGFR, CTNNB1, FGFR1, VEGFA and DPYD were consistent with drug resistance and sensitivity. Recurrent noncoding events were found in regulatory region hotspots of genes including TERT, PLEKHS1, AP2A1 and ADGRG6. Mutation burden and immune signatures corresponded with overall survival and response to immunotherapy. Our data offer a rich resource for investigation of advanced cancers and interpretation of whole-genome and transcriptome sequencing in the context of a cancer clinic.

Mechanistic studies in human cancer have relied heavily on cell lines and mouse models, but are limited by in vitro adaptation and species context issues, respectively. More recent efforts have utilized patient-derived xenografts; however, these are hampered by variable genetic background, inability to study early events, and practical issues with availability/reproducibility. We report here an efficient, reproducible model of T-cell leukemia in which lentiviral transduction of normal human cord blood yields aggressive leukemia that appears indistinguishable from natural disease. We utilize this synthetic model to uncover a role for oncogene-induced HOXB activation which is operative in leukemia cells-of-origin and persists in established tumors where it defines a novel subset of patients distinct from other known genetic subtypes and with poor clinical outcome. We show further that anterior HOXB genes are specifically activated in human T-ALL by an epigenetic mechanism and confer growth advantage in both pre-leukemia cells and established clones., Studies with patient derived xenografts are hampered by factors such as genetic variability and sample availability. Here, the authors generate a leukemia mouse model by lentiviral transduction of normal human cord blood and show an oncogenic role of HOXB genes.

Motivation In T-cell lymphoma, malignant T cells arising from a founding clone share an identical T cell receptor (TCR) and can be identified by the over-representation of this TCR relative to TCRs from the patient’s repertoire of normal T cells. Here, we demonstrate that TCR information extracted from RNA-seq data can provide a higher resolution view of peripheral T cell lymphomas (PTCLs) than that provided by conventional methods. Results For 60 subjects with PTCL, flow cytometry/FACS was used to identify and sort aberrant T cell populations from diagnostic lymph node cell suspensions. For samples that did not appear to contain aberrant T cell populations, T helper (TH), T follicular helper (TFH) and cytotoxic T lymphocyte (CTL) subsets were sorted. RNA-seq was performed on sorted T cell populations, and TCR alpha and beta chain sequences were extracted and quantified directly from the RNA-seq data. 96% of the immunophenotypically aberrant samples had a dominant T cell clone readily identifiable by RNA-seq. Of the samples where no aberrant population was found by flow cytometry, 80% had a dominant clone by RNA-seq. This demonstrates the increased sensitivity and diagnostic ability of RNA-seq over flow cytometry and shows that the presence of a normal immunophenotype does not exclude clonality. Availability and Implementation R scripts used in the processing of the data are available online at https://www.github.com/scottdbrown/RNAseq-TcellClonality Supplementary information Supplementary data are available at Bioinformatics online.

Item does not contain fulltext Functional neuroimaging data indicate the dorsal striatum is engaged when people are required to vary the cautiousness of their decisions, by emphasizing the speed or accuracy of responding in laboratory-based decision tasks. However, the functional contribution of the striatum to decision making is unknown. In the current study we tested patients with focal ischemic lesions of the dorsal striatum and matched non-lesion control participants on a speed-accuracy tradeoff (SAT) task. Analysis using a computational model of response selection in a competitive and time-pressured context indicated that the decisions of patients with striatal lesions were less cautious than those of matched controls. This deficit was most prominent when the accuracy of decisions was emphasized. The results are consistent with the hypothesis that the striatum plays an important role in strategically setting response caution, an essential function for flexible behavior.

Organisms making repeated simple decisions are faced with a tradeoff between urgent and cautious strategies. While animals can adopt a statistically optimal policy for this tradeoff, findings about human decision-makers have been mixed. Some studies have shown that people can optimize this "speed-accuracy tradeoff", while others have identified a systematic bias towards excessive caution. These issues have driven theoretical development and spurred debate about the nature of human decision-making. We investigated a potential resolution to the debate, based on two factors that routinely differ between human and animal studies of decision-making: the effects of practice, and of longer-term feedback. Our study replicated the finding that most people, by default, are overly cautious. When given both practice and detailed feedback, people moved rapidly towards the optimal policy, with many participants reaching optimality with less than 1 h of practice. Our findings have theoretical implications for cognitive and neural models of simple decision-making, as well as methodological implications.

Theory development in both psychology and neuroscience can benefit by consideration of both behavioral and neural data sets. However, the development of appropriate methods for linking these data sets is a difficult statistical and conceptual problem. Over the past decades, different linking approaches have been employed in the study of perceptual decision-making, beginning with rudimentary linking of the data sets at a qualitative, structural level, culminating in sophisticated statistical approaches with quantitative links. We outline a new approach, in which a single model is developed that jointly addresses neural and behavioral data. This approach allows for specification and testing of quantitative links between neural and behavioral aspects of the model. Estimating the model in a Bayesian framework allows both data sets to equally inform the estimation of all model parameters. The use of a hierarchical model architecture allows for a model, which accounts for and measures the variability between neurons. We demonstrate the approach by re-analysis of a classic data set containing behavioral recordings of decision-making with accompanying single-cell neural recordings. The joint model is able to capture most aspects of both data sets, and also supports the analysis of interesting questions about prediction, including predicting the times at which responses are made, and the corresponding neural firing rates.

Markov Chain Monte–Carlo (MCMC) is an increasingly popular method for obtaining information about distributions, especially for estimating posterior distributions in Bayesian inference. This article provides a very basic introduction to MCMC sampling. It describes what MCMC is, and what it can be used for, with simple illustrative examples. Highlighted are some of the benefits and limitations of MCMC sampling, as well as different approaches to circumventing the limitations most likely to trouble cognitive scientists.

Only 2-3% of cancer patients enrol in a trial. We surveyed patients' willingness to change clinician or treating centre, or to travel, to participate in trials, to improve trial recruitment. Of 188 respondents, 79% were willing to participate in a trial in at least one scenario. Increasing travel time, change in oncologist, private health insurance and out of pocket expenses decreased likelihood of joining a trial. Rural and regional patients, and those from lower socio-economic areas, were more willing to travel. To optimise access to trials, clinicians should refer within and between institutions.

Objective Using a vignette-style DCE in a sample of oncology patients, this study explored: (1) the relative influence of the patient's level of concern about their depression on preferences for care, (2) the relative influence of depression severity according to a mental health checklist on preferred treatment-seeking options, and (3) whether patient age and gender were associated with depression care preference. Methods A discrete choice experiment (DCE) survey of cancer patients was conducted. Hypothetical vignettes to elicit care preferences were created using two attributes: the cancer patient's level of concern about depression (a little or a great deal) and results of a mental health checklist (not depressed or very depressed). Three response options for care preferences were presented, including a self-directed approach, shared care approach, and clinician-directed referral approach. Participants chose their most and least preferred options. Results A total of 281 cancer patients completed the survey. There was a significant association between level of concern and the most preferred option. Those with a great deal of concern about depression preferred to receive referral from their clinician more than those with a little concern about depression. Males were significantly more likely to select a self-directed approach as their most preferred option. Conclusions An oncology patient's level of concern about depression may influence the type of care they want to receive from their cancer doctor for depression. This finding has implications for depression screening in clinical practice.

Neuroscientific theories of attention-deficit/hyperactivity disorder (ADHD) alternately posit that cognitive aberrations in the disorder are due to acute attentional lapses, slowed neural processing, or reduced signal-to-noise ratios. However, they make similar predictions about behavioral summary statistics (response times [RTs] and accuracy), hindering the field's ability to produce strong and specific tests of these theories. The current study uses the linear ballistic accumulator (LBA; BrownHeathcote, 2008), a mathematical model of choice RT tasks, to distinguish between competing theory predictions. Children with ADHD (n = 80) and age-matched controls (n = 32) completed a numerosity discrimination paradigm at 2 levels of difficulty, and RT data were fit to the LBA model to test theoretical predictions. Individuals with ADHD displayed slowed processing of evidence for correct responses (signal) relative to their peers but comparable processing of evidence for error responses (noise) and between-trial variability in processing (performance lapses). The findings are inconsistent with accounts that posit an increased incidence of attentional lapses in the disorder and provide partial support for those that posit slowed neural processing and lower signal-to-noise ratios. Results also highlight the utility of well-developed cognitive models for distinguishing between the predictions of etiological theories of psychopathology. (PsycINFO Database Record

How does the process of information transmission affect the cultural or linguistic products that emerge? This question is often studied experimentally and computationally via iterated learning: a procedure in which participants learn from previous participants in a chain. Iterated learning is a powerful tool because, when all participants share the same priors, the stationary distributions of the iterated learning chains reveal those priors. In many situations, however, it is unreasonable to assume that all participants share the same prior beliefs. We present four simulation studies and one experiment demonstrating that when the population of learners is heterogeneous, the behavior of an iterated learning chain can be unpredictable, and is often systematically distorted by the learners with the most extreme biases. This results in group-level outcomes that reflect neither the behavior of any individuals within the population nor the overall population average. We discuss implications for the use of iterated learning as a methodological tool as well as for the processes that might have shaped cultural and linguistic evolution in the real world.

Evidence accumulation models of decision-making have led to advances in several different areas of psychology. These models provide a way to integrate response time and accuracy data, and to describe performance in terms of latent cognitive processes. Testing important psychological hypotheses using cognitive models requires a method to make inferences about different versions of the models which assume different parameters to cause observed effects. The task of model-based inference using noisy data is difficult, and has proven especially problematic with current model selection methods based on parameter estimation. We provide a method for computing Bayes factors through Monte-Carlo integration for the linear ballistic accumulator (LBA; Brown and Heathcote, 2008), a widely used evidence accumulation model. Bayes factors are used frequently for inference with simpler statistical models, and they do not require parameter estimation. In order to overcome the computational burden of estimating Bayes factors via brute force integration, we exploit general purpose graphical processing units; we provide free code for this. This approach allows estimation of Bayes factors via Monte-Carlo integration within a practical time frame. We demonstrate the method using both simulated and real data. We investigate the stability of the Monte-Carlo approximation, and the LBA's inferential properties, in simulation studies.

We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes—wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant—characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field. Thorsson et al. present immunogenomics analyses of more than 10,000 tumors, identifying six immune subtypes that encompass multiple cancer types and are hypothesized to define immune response patterns impacting prognosis. This work provides a resource for understanding tumor-immune interactions, with implications for identifying ways to advance research on immunotherapy., 0, info:eu-repo/semantics/published

Reasoning and inference are well-studied aspects of basic cognition that have been explained as statistically optimal Bayesian inference. Using a simplified experimental design, we conducted quantitative comparisons between Bayesian inference and human inference at the level of individuals. In 3 experiments, with more than 13,000 participants, we asked people for prior and posterior inferences about the probability that 1 of 2 coins would generate certain outcomes. Most participants' inferences were inconsistent with Bayes' rule. Only in the simplest version of the task did the majority of participants adhere to Bayes' rule, but even in that case, there was a significant proportion that failed to do so. The current results highlight the importance of close quantitative comparisons between Bayesian inference and human data at the individual-subject level when evaluating models of cognition.

Trueblood, Brown, and Heathcote (2014) developed a new model, called the multiattribute linear ballistic accumulator (MLBA), to explain contextual preference reversals in multialternative choice. MLBA was shown to provide good accounts of human behavior through both qualitative analyses and quantitative fitting of choice data. Tsetsos, Chater, and Usher (2015) investigated the ability of MLBA to simultaneously capture 3 prominent context effects (attraction, compromise, and similarity). They concluded that MLBA must set a "fine balance" of competing forces to account for all 3 effects simultaneously and that its predictions are sensitive to the position of the stimuli in the attribute space. Through a new experiment, we show that the 3 effects are very fragile and that only a small subset of people shows all 3 simultaneously. Thus, the predictions that Tsetsos et al. generated from the MLBA model turn out to match closely real data in a new experiment. Support for these predictions provides strong evidence for the MLBA. A corollary is that a model that can "robustly" capture all 3 effects simultaneously is not necessarily a good model. Rather, a good model captures patterns found in human data, but cannot accommodate patterns that are not found.

A recent ‘crisis of confidence’ has emerged in the empirical sciences. Several studies have suggested that questionable research practices (QRPs) such as optional stopping and selective publication may be relatively widespread. These QRPs can result in a high proportion of false-positive findings, decreasing the reliability and replicability of research output. A potential solution is to register experiments prior to data acquisition and analysis. In this study we attempted to replicate studies that relate brain structure to behavior and cognition. These structural brain-behavior (SBB) correlations occasionally receive much attention in science and in the media. Given the impact of these studies, it is important to investigate their replicability. Here, we attempt to replicate five SBB correlation studies comprising a total of 17 effects. To prevent the impact of QRPs we employed a preregistered, purely confirmatory replication approach. For all but one of the 17 findings under scrutiny, confirmatory Bayesian hypothesis tests indicated evidence in favor of the null hypothesis ranging from anecdotal (Bayes factor < 3) to strong (Bayes factor > 10). In several studies, effect size estimates were substantially lower than in the original studies. To our knowledge, this is the first multi-study confirmatory replication of SBB correlations. With this study, we hope to encourage other researchers to undertake similar replication attempts.

For nearly 50 years, the dominant account of decision-making holds that noisy information is accumulated until a fixed threshold is crossed. This account has been tested extensively against behavioral and neurophysiological data for decisions about consumer goods, perceptual stimuli, eyewitness testimony, memories, and dozens of other paradigms, with no systematic misfit between model and data. Recently, the standard model has been challenged by alternative accounts that assume that less evidence is required to trigger a decision as time passes. Such “collapsing boundaries” or “urgency signals” have gained popularity in some theoretical accounts of neurophysiology. Nevertheless, evidence in favor of these models is mixed, with support coming from only a narrow range of decision paradigms compared with a long history of support from dozens of paradigms for the standard theory. We conducted the first large-scale analysis of data from humans and nonhuman primates across three distinct paradigms using powerful model-selection methods to compare evidence for fixed versus collapsing bounds. Overall, we identified evidence in favor of the standard model with fixed decision boundaries. We further found that evidence for static or dynamic response boundaries may depend on specific paradigms or procedures, such as the extent of task practice. We conclude that the difficulty of selecting between collapsing and fixed bounds models has received insufficient attention in previous research, calling into question some previous results.

With the growth of client-centered and patient-as-consumer approaches to care, understanding the preferences of psychologists' patients has never been more important. Traditional methods for measuring preference, such as Likert-type rating scales, suffer from well-known limitations, including subjectivity and positive bias. Best-worst scaling (BWS) provides an opportunity to address some of these limitations. Despite the growing use of BWS to measure preference in other areas, BWS methods are not being used in the study of psychologists' patients. We demonstrate BWS data collection and analysis. With a sample of only 31 clients from 2 Australian psychology practices, we show the strength of preference for different aspects of psychologists' appointments can be measured accurately. Additionally, the inclusion of readily available timing data from responses improved measurement sensitivity and statistical power.

High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity. Epithelial CD8+ TILs negatively associated with malignant diversity, reflecting immunological pruning of tumor clones inferred by neoantigen depletion, HLA I loss of heterozygosity, and spatial tracking between T cell and tumor clones. In addition, combinatorial prognostic effects of mutational processes and immune properties were observed, illuminating how specific genomic aberration types associate with immune response and impact survival. We conclude that within-patient spatial immune microenvironment variation shapes intraperitoneal malignant spread, provoking new evolutionary perspectives on HGSC clonal dispersion.

Constant decision-making underpins much of daily life, from simple perceptual decisions about navigation through to more complex decisions about important life events. At many scales, a fundamental task of the decision-maker is to balance competing needs for caution and urgency: fast decisions can be more efficient, but also more often wrong. We show how a single mathematical framework for decision-making explains the urgency/caution balance across decision-making at two very different scales. This explanation has been applied at the level of neuronal circuits (on a time scale of hundreds of milliseconds) through to the level of stable personality traits (time scale of years).

Somatic missense mutations can initiate tumorogenesis and, conversely, anti-tumor cytotoxic T cell (CTL) responses. Tumor genome analysis has revealed extreme heterogeneity among tumor missense mutation profiles, but their relevance to tumor immunology and patient outcomes has awaited comprehensive evaluation. Here, for 515 patients from six tumor sites, we used RNA-seq data from The Cancer Genome Atlas to identify mutations that are predicted to be immunogenic in that they yielded mutational epitopes presented by the MHC proteins encoded by each patient’s autologous HLA-A alleles. Mutational epitopes were associated with increased patient survival. Moreover, the corresponding tumors had higher CTL content, inferred from CD8A gene expression, and elevated expression of the CTL exhaustion markers PDCD1 and CTLA4. Mutational epitopes were very scarce in tumors without evidence of CTL infiltration. These findings suggest that the abundance of predicted immunogenic mutations may be useful for identifying patients likely to benefit from checkpoint blockade and related immunotherapies.

Decision-makers effortlessly balance the need for urgency against the need for caution. Theoretical and neurophysiological accounts have explained this tradeoff solely in terms of the quantity of evidence required to trigger a decision (the "threshold"). This explanation has also been used as a benchmark test for evaluating new models of decision making, but the explanation itself has not been carefully tested against data. We rigorously test the assumption that emphasizing decision speed versus decision accuracy selectively influences only decision thresholds. In data from a new brightness discrimination experiment we found that emphasizing decision speed over decision accuracy not only decreases the amount of evidence required for a decision but also decreases the quality of information being accumulated during the decision process. This result was consistent for 2 leading decision-making models and in a model-free test. We also found the same model-based results in archival data from a lexical decision task (reported by Wagenmakers, Ratcliff, Gomez,McKoon, 2008) and new data from a recognition memory task. We discuss discuss implications for theoretical development and applications.

The ability to imagine objects undergoing rotation (mental rotation) improves markedly with practice, but an explanation of this plasticity remains controversial. Some researchers propose that practice speeds up the rate of a general-purpose rotation algorithm. Others maintain that performance improvements arise through the adoption of a new cognitive strategy-repeated exposure leads to rapid retrieval from memory of the required response to familiar mental rotation stimuli. In two experiments we provide support for an integrated explanation of practice effects in mental rotation by combining behavioral and EEG measures in a way that provides more rigorous inference than is available from either measure alone. Before practice, participants displayed two well-established signatures of mental rotation: Both response time and EEG negativity increased linearly with rotation angle. After extensive practice with a small set of stimuli, both signatures of mental rotation had all but disappeared. In contrast, after the same amount of practice with a much larger set both signatures remained, even though performance improved markedly. Taken together, these results constitute a reversed association, which cannot arise from variation in a single cause, and so they provide compelling evidence for the existence of two routes to expertise in mental rotation. We also found novel evidence that practice with the large but not the small stimulus set increased the magnitude of an early visual evoked potential, suggesting increased rotation speed is enabled by improved efficiency in extracting three-dimensional information from two-dimensional stimuli.

Scientists who study cognition infer underlying processes either by observing behavior (e.g., response times, percentage correct) or by observing neural activity (e.g., the BOLD response). These two types of observations have traditionally supported two separate lines of study. The first is led by cognitive modelers, who rely on behavior alone to support their computational theories. The second is led by cognitive neuroimagers, who rely on statistical models to link patterns of neural activity to experimental manipulations, often without any attempt to make a direct connection to an explicit computational theory. Here we present a flexible Bayesian framework for combining neural and cognitive models. Joining neuroimaging and computational modeling in a single hierarchical framework allows the neural data to influence the parameters of the cognitive model and allows behavioral data, even in the absence of neural data, to constrain the neural model. Critically, our Bayesian approach can reveal interactions between behavioral and neural parameters, and hence between neural activity and cognitive mechanisms. We demonstrate the utility of our approach with applications to simulated fMRI data with a recognition model and to diffusion-weighted imaging data with a response time model of perceptual choice.

Context effects—preference changes that depend on the availability of other options—have attracted a great deal of attention among consumer researchers studying high-level decision tasks. In the experiments reported here, we showed that these effects also arise in simple perceptual-decision-making tasks. This finding casts doubt on explanations limited to consumer choice and high-level decisions, and it indicates that context effects may be amenable to a general explanation at the level of the basic decision process. We demonstrated for the first time that three important context effects from the preferential-choice literature—similarity, attraction, and compromise effects—all occurred within a single perceptual-decision task. Not only do our results challenge previous explanations for context effects proposed by consumer researchers, but they also challenge the choice rules assumed in theories of perceptual decision making.

The cognitive concept of response inhibition can be measured using the stop-signalparadigm. In this paradigm, participants perform a two-choice response time (RT) task where, on some of the trials, the primary task is interrupted by a stop-signal that prompts participants to withhold their response. The dependent variable of interest is the latency of the unobservable stop response (stop signal reaction time or SSRT). Based on the horse-race model (Logan & Cowan, 1984), several methods have been developed to estimate SSRTs. None of these approaches allow for the accurate estimation of the entire distribution of SSRTs. Here we introduce a Bayesian parametric approach that addresses this limitation. Our method is based on the assumptions of the horse-race model and rests on the concept of censored distributions. We treat response inhibition as a censoring mechanism, where the distribution of RTs on the primary task (go RTs) is censored by the distribution of SSRTs. The method assumes that go RTs and SSRTs are ex-Gaussian distributed and uses Markov chain Monte Carlo sampling to obtain posterior distributions for the model parameters. The method can be applied to individual as well as hierarchical data structures. We present the results of a number of parameter recovery and robustness studies and apply our approach to published data from a stop-signal experiment.

22q11.2 deletion syndrome (22q11DS) has a complex phenotype with more than 180 characteristics, including cardiac anomalies, cleft palate, intellectual disabilities, a typical facial morphology, and mental health problems. However, the variable phenotype makes it difficult to predict clinical outcome, such as the high prevalence of psychosis among adults with 22q11DS (∼25–30% vs. ∼1% in the general population). The purpose of this study was to investigate whether subtypes exist among people with 22q11DS, with a similar phenotype and an increased risk of developing mental health problems. Physical, cognitive and behavioural data from 50 children and adolescents with 22q11DS were included in a k -means cluster analysis. Two distinct phenotypes were identified: Type-1 presented with a more severe phenotype including significantly impaired verbal memory, lower intellectual and academic ability, as well as statistically significant reduced total brain volume. In addition, we identified a trend effect for reduced temporal grey matter. Type-1 also presented with autism-spectrum traits, whereas Type-2 could be described as having more 22q11DS-typical face morphology, being predominately affected by executive function deficits, but otherwise being relatively high functioning with regard to cognition and behaviour. The confirmation of well-defined subtypes in 22q11DS can lead to better prognostic information enabling early identification of people with 22q11DS at high risk of psychiatric disorders. The identification of subtypes in a group of people with a relatively homogenous genetic deletion such as 22q11DS is also valuable to understand clinical outcomes.

Summary No differences in blood transcriptome, virome, and B-cell/T-cell receptor patterns were found between chronic fatigue syndrome or alternatively diagnosed chronic Lyme syndrome patients and controls. Neither disease was found to be associated with transcriptionally mediated immune dysfunction or active viral infection., Background. Chronic fatigue syndrome (CFS) remains poorly understood. Although infections are speculated to trigger the syndrome, a specific infectious agent and underlying pathophysiological mechanism remain elusive. In a previous study, we described similar clinical phenotypes in CFS patients and alternatively diagnosed chronic Lyme syndrome (ADCLS) patients—individuals diagnosed with Lyme disease by testing from private Lyme specialty laboratories but who test negative by reference 2-tiered serologic analysis. Methods. Here, we performed blinded RNA-seq analysis of whole blood collected from 25 adults diagnosed with CFS and 13 ADCLS patients, comparing these cases to 25 matched controls and 11 patients with well-controlled systemic lupus erythematosus (SLE). Samples were collected at patient enrollment and not during acute symptom flares. RNA-seq data were used to study host gene expression, B-cell/T-cell receptor profiles (BCR/TCR), and potential viral infections. Results. No differentially expressed genes (DEGs) were found to be significant when CFS or ADCLS cases were compared to controls. Forty-two DEGs were found when SLE cases were compared to controls, consistent with activation of interferon signaling pathways associated with SLE disease. BCR/TCR repertoire analysis did not show significant differences between CFS and controls or ADCLS and controls. Finally, viral sequences corresponding to anelloviruses, human pegivirus 1, herpesviruses, and papillomaviruses were detected in RNA-seq data, but proportions were similar (P = .73) across all genus-level taxonomic categories. Conclusions. Our observations do not support a theory of transcriptionally mediated immune cell dysregulation in CFS and ADCLS, at least outside of periods of acute symptom flares.

In cued task switching, performance relies on proactive and reactive control processes. Proactive control is evident in the reduction in switch cost under conditions that promote advance preparation. However, the residual switch cost that remains under conditions of optimal proactive control indicates that, on switch trials, the target continues to elicit interference that is resolved using reactive control. We examined whether posttarget interference varies as a function of trial-by-trial variability in preparation. We investigated target congruence effects on behavior and target-locked ERPs extracted across the response time (RT) distribution, using orthogonal polynomial trend analysis (OPTA). Early N2, late N2, and P3b amplitudes were differentially modulated across the RT distribution. There was a large congruence effect on late N2 and P3b, which increased with RT for P3b amplitude, but did not vary with trial type. This suggests that target properties impact switch and repeat trials equally and do not contribute to residual switch cost. P3b amplitude was larger, and latency later, for switch than repeat trials, and this difference became larger with increasing RT, consistent with sustained carryover effects on highly prepared switch trials. These results suggest that slower, less prepared responses are associated with greater target-related interference during target identification and processing, as well as slower, more difficult decision processes. They also suggest that neither general nor switch-specific preparation can ameliorate the effects of target-driven interference. These findings highlight the theoretical advances achieved by integrating RT distribution analyses with ERP and OPTA to examine trial-by-trial variability in performance and brain function.

For decades sequential sampling models have successfully accounted for human and monkey decision-making, relying on the standard assumption that decision makers maintain a pre-set decision standard throughout the decision process. Based on the theoretical argument of reward rate maximization, some authors have recently suggested that decision makers become increasingly impatient as time passes and therefore lower their decision standard. Indeed, a number of studies show that computational models with an impatience component provide a good fit to human and monkey decision behavior. However, many of these studies lack quantitative model comparisons and systematic manipulations of rewards. Moreover, the often-cited evidence from single-cell recordings is not unequivocal and complimentary data from human subjects is largely missing. We conclude that, despite some enthusiastic calls for the abandonment of the standard model, the idea of an impatience component has yet to be fully established; we suggest a number of recently developed tools that will help bring the debate to a conclusive settlement.