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With the growing role of artificial intelligence (AI) in our lives, attention is increasingly turning to the way that humans and AI work together. A key aspect of human–AI collaboration is how people integrate judgements or recommendations from machine agents, when they differ from their own judgements. We investigated trust in human–machine teaming using a perceptual judgement task based on the judge–advisor system. Participants ( n = 89 ) estimated a perceptual quantity, then received a recommendation from a machine agent. The participants then made a second response which combined their first estimate and the machine's recommendation. The degree to which participants shifted their second response in the direction of the recommendations provided a measure of their trust in the machine agent. We analysed the role of advice distance in people's willingness to change their judgements. When a recommendation falls a long way from their initial judgement, do people come to doubt their own judgement, trusting the recommendation more, or do they doubt the machine agent, trusting the recommendation less? We found that although some participants exhibited these behaviours, the most common response was neither of these tendencies, and a simple model based on averaging accounted best for participants' trust behaviour. We discuss implications for theories of trust, and human–machine teaming. [ABSTRACT FROM AUTHOR]

Threatened species monitoring can produce enormous quantities of acoustic and visual recordings which must be searched for animal detections. Data coding is extremely time-consuming for humans and even though machine algorithms are emerging as useful tools to tackle this task, they too require large amounts of known detections for training. Citizen scientists are often recruited via crowd-sourcing to assist. However, the results of their coding can be difficult to interpret because citizen scientists lack comprehensive training and typically each codes only a small fraction of the full dataset. Competence may vary between citizen scientists, but without knowing the ground truth of the dataset, it is difficult to identify which citizen scientists are most competent. We used a quantitative cognitive model, cultural consensus theory, to analyze both empirical and simulated data from a crowdsourced analysis of audio recordings of Australian frogs. Several hundred citizen scientists were asked whether the calls of nine frog species were present on 1260 brief audio recordings, though most only coded a fraction of these recordings. Through modeling, characteristics of both the citizen scientist cohort and the recordings were estimated. We then compared the model's output to expert coding of the recordings and found agreement between the cohort's consensus and the expert evaluation. This finding adds to the evidence that crowdsourced analyses can be utilized to understand large-scale datasets, even when the ground truth of the dataset is unknown. The model-based analysis provides a promising tool to screen large datasets prior to investing expert time and resources. [ABSTRACT FROM AUTHOR]

Background: Sequence verification is essential for plasmids used as critical reagents or therapeutic products. Typically, high-quality plasmid sequence is achieved through capillary-based Sanger sequencing, requiring customized sets of primers for each plasmid. This process can become expensive, particularly for applications where the validated sequence needs to be produced within a regulated and quality-controlled environment for downstream clinical research applications. Results: Here, we describe a cost-effective and accurate plasmid sequencing and consensus generation procedure using the Oxford Nanopore Technologies' MinION device as an alternative to capillary-based plasmid sequencing options. This procedure can verify the identity of a pure population of plasmid, either confirming it matches the known and expected sequence, or identifying mutations present in the plasmid if any exist. We use a full MinION flow cell per plasmid, maximizing available data and allowing for stringent quality filters. Pseudopairing reads for consensus base calling reduces read error rates from 5.3 to 0.53%, and our pileup consensus approach provides per-base counts and confidence scores, allowing for interpretation of the certainty of the resulting consensus sequences. For pure plasmid samples, we demonstrate 100% accuracy in the resulting consensus sequence, and the sensitivity to detect small mutations such as insertions, deletions, and single nucleotide variants. In test cases where the sequenced pool of plasmids contains subclonal templates, detection sensitivity is similar to that of traditional capillary sequencing. Conclusions: Our pipeline can provide significant cost savings compared to outsourcing clinical-grade sequencing of plasmids, making generation of high-quality plasmid sequence for clinical sequence verification more accessible. While other long-read-based methods offer higher-throughput and less cost, our pipeline produces complete and accurate sequence verification for cases where absolute sequence accuracy is required. [ABSTRACT FROM AUTHOR]

Poorly differentiated chordoma (PDC) is a recently recognized subtype of chordoma characterized by expression of the embryonic transcription factor, brachyury, and loss of INI1. PDC primarily affects children and is associated with a poor prognosis and limited treatment options. Here we describe the molecular and immune tumour microenvironment profiles of two paediatric PDCs produced using whole-genome, transcriptome and whole-genome bisulfite sequencing (WGBS) and multiplex immunohistochemistry. Our analyses revealed the presence of tumour-associated immune cells, including CD8+ T cells, and expression of the immune checkpoint protein, PD-L1, in both patient samples. Molecular profiling provided the rationale for immune checkpoint inhibitor (ICI) therapy, which resulted in a clinical and radiographic response. A dominant T cell receptor (TCR) clone specific for a brachyury peptide–MHC complex was identified from bulk RNA sequencing, suggesting that targeting of the brachyury tumour antigen by tumour-associated T cells may underlie this clinical response to ICI. Correlative analysis with rhabdoid tumours, another INI1-deficient paediatric malignancy, suggests that a subset of tumours may share common immune phenotypes, indicating the potential for a therapeutically targetable subgroup of challenging paediatric cancers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

It is commonly assumed that a specific testing occasion (task, design, procedure, etc.) provides insights that generalize 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. [ABSTRACT FROM AUTHOR]

Purpose: 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. Methods: 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. Results: 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 < 0.01). More patients preferred the two 20-min rather than the one 40-min consultation format (55% vs 45%, z = 4.284, p < 0.01). Information content did not influence choice. Age, cancer type, and patient-perceived prognosis were not associated with preferences. Conclusion: Healthcare professionals should assess cancer patients' preferences for engaging in life expectancy discussions as soon as they have this information, and ensure patients have adequate time to consider the information they receive, seek additional information and involve others if they wish. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A standard assumption of most sequential sampling models is that decision-makers rely on a decision criterion that remains constant throughout the decision process. However, several authors have recently suggested that, in order to maximize reward rates in dynamic environments, decision-makers need to rely on a decision criterion that changes over the course of the decision process. We used dynamic programming and simulation methods to quantify the reward rates obtained by constant and dynamic decision criteria in different environments. We further investigated what influence a decision-maker's uncertainty about the stochastic structure of the environment has on reward rates. Our results show that in most dynamic environments, both types of decision criteria yield similar reward rates, across different levels of uncertainty. This suggests that a static decision criterion might provide a robust default setting. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 longterm 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 lesspracticed younger individuals, especially for cognitive measures that focus on the rate at which task-relevant information becomes available. [ABSTRACT FROM AUTHOR]

Most data analyses rely on models. To complement statistical models, psychologists have developed cognitive models, which translate observed variables into psychologically interesting constructs. Response time models, in particular, assume that response time and accuracy are the observed expression of latent variables including 1) ease of processing, 2) response caution, 3) response bias, and 4) non-decision time. Inferences about these psychological factors, hinge upon the validity of the models' parameters. Here, we use a blinded, collaborative approach to assess the validity of such model-based inferences. Seventeen teams of researchers analyzed the same 14 data sets. In each of these two-condition data sets, we manipulated properties of participants' behavior in a two-alternative forced choice task. The contributing teams were blind to the manipulations, and had to infer what aspect of behavior was changed using their method of choice. The contributors chose to employ a variety of models, estimation methods, and inference procedures. Our results show that, although conclusions were similar across different methods, these "modeler's degrees of freedom" did affect their inferences. Interestingly, many of the simpler approaches yielded as robust and accurate inferences as the more complex methods. We recommend that, in general, cognitive models become a typical analysis tool for response time data. In particular, we argue that the simpler models and procedures are sufficient for standard experimental designs. We finish by outlining situations in which more complicated models and methods may be necessary, and discuss potential pitfalls when interpreting the output from response time models. [ABSTRACT FROM AUTHOR]

Decision-making involves a tradeoff between pressures for caution and urgency. Previous research has investigated how well humans optimize this tradeoff, and mostly concluded that people adopt a sub-optimal strategy that over-emphasizes caution. This emphasis reduces how many decisions can be made in a fixed time, which reduces the "reward rate". However, the strategy that is optimal depends critically on the timing properties of the experiment design: the slower the rate of decision opportunities, the more cautious the optimal strategy. Previous studies have almost uniformly adopted very fast designs, which favor very urgent decision-making. This raises the possibility that previous findings—that humans adopt strategies that are too cautious—could either be ascribed to human caution, or to the experiments' design. To test this, we used a slowed-down decision-making task in which the optimal strategy was quite cautious. With this task, and in contrast to previous findings, the average strategy adopted across participants was very close to optimal, with about equally many participants adopting too-cautious as too-urgent strategies. Our findings suggest that task design can play a role in inferences about optimality, and that previous conclusions regarding human sub-optimality are conditional on the task settings. This limits claims about human optimality that can be supported by the available evidence. [ABSTRACT FROM AUTHOR]

Objectives: 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.Methods: 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.Results: 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).Conclusion: 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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Abstract: Understanding individual differences in cognitive performance is an important part of understanding how variations in underlying cognitive processes can result in variations in task performance. However, the exploration of individual differences in the components of the decision process—such as cognitive processing speed, response caution, and motor execution speed—in previous research has been limited. Here, we assess the heritability of the components of the decision process, with heritability having been a common aspect of individual differences research within other areas of cognition. Importantly, a limitation of previous work on cognitive heritability is the underlying assumption that variability in response times solely reflects variability in the speed of cognitive processing. This assumption has been problematic in other domains, due to the confounding effects of caution and motor execution speed on observed response times. We extend a cognitive model of decision‐making to account for relatedness structure in a twin study paradigm. This approach can separately quantify different contributions to the heritability of response time. Using data from the Human Connectome Project, we find strong evidence for the heritability of response caution, and more ambiguous evidence for the heritability of cognitive processing speed and motor execution speed. Our study suggests that the assumption made in previous studies—that the heritability of cognitive ability is based on cognitive processing speed—may be incorrect. More generally, our methodology provides a useful avenue for future research in complex data that aims to analyze cognitive traits across different sources of related data, whether the relation is between people, tasks, experimental phases, or methods of measurement. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 targetlocked 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The digital imaging and remote sensing image generation model is a physics-based image and data simulation model that is primarily used to generate synthetic imagery across the visible to thermal infrared regions using engineering-driven descriptions of remote sensing systems. The model recently went through a major redesign and reimplementation effort to address changes in user requirements and numerical computation trends that have emerged in the 15 years since the last major development effort. The new model architecture adopts some of the latest light transport algorithms matured by the computer graphics community and features a framework that is easily parallelized at the microscale (multithreading) and macroscale (cluster-based computing). A detailed description of the framework is provided, including a novel method for efficiently storing, evaluating, integrating, and sampling spherical and hemispherical datasets appropriate for the representation of modeled or measured bidirectional scattering, reflectance, and transmission distribution functions. The capabilities of the model are then briefly demonstrated and cross-verified with scenarios of interest to the remote sensing community. [ABSTRACT FROM PUBLISHER]

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 fromdiagnostic 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. [ABSTRACT FROM AUTHOR]

Due to advances in sequencing technology, somatically mutated cancer antigens, or neoantigens, are now readily identifiable and have become compelling targets for immunotherapy. In particular, neoantigen-targeted vaccines have shown promise in several pre-clinical and clinical studies. However, to date, neoantigen-targeted vaccine studies have involved tumors with exceptionally high mutation burdens. It remains unclear whether neoantigen-targeted vaccines will be broadly applicable to cancers with intermediate to low mutation burdens, such as ovarian cancer. To address this, we assessed whether a derivative of the murine ovarian tumor model ID8 could be targeted with neoantigen vaccines. We performed whole exome and transcriptome sequencing on ID8-G7 cells. We identified 92 somatic mutations, 39 of which were transcribed, missense mutations. For the 17 top predicted MHC class I binding mutations, we immunized mice subcutaneously with synthetic long peptide vaccines encoding the relevant mutation. Seven of 17 vaccines induced robust mutation-specific CD4 and/or CD8 T cell responses. However, none of the vaccines prolonged survival of tumor-bearing mice in either the prophylactic or therapeutic setting. Moreover, none of the neoantigen-specific T cell lines recognized ID8-G7 tumor cells in vitro, indicating that the corresponding mutations did not give rise to bonafide MHC-presented epitopes. Additionally, bioinformatic analysis of The Cancer Genome Atlas data revealed that only 12% (26/220) of HGSC cases had a ≥90% likelihood of harboring at least one authentic, naturally processed and presented neoantigen versus 51% (80/158) of lung cancers. Our findings highlight the limitations of applying neoantigen-targeted vaccines to tumor types with intermediate/low mutation burdens. [ABSTRACT FROM AUTHOR]

Deep sequencing of recombined T cell receptor (TCR) genes and transcripts has provided a view of T cell repertoire diversity at an unprecedented resolution. Beyond profiling peripheral blood, analysis of tissueresident T cells provides further insight into immunerelated diseases. We describe the extraction of TCR sequence information directly from RNA-sequencing data from 6738 tumor and 604 control tissues, with a typical yield of 1 TCR per 10 million reads. This method circumvents the need for PCR amplification of the TCR template and provides TCR information in the context of global gene expression, allowing integrated analysis of extensive RNA-sequencing data resources. [ABSTRACT FROM AUTHOR]

The dominant theoretical paradigm in explaining decision making throughout both neuroscience and cognitive science is known as “evidence accumulation”--The core idea being that decisions are reached by a gradual accumulation of noisy information. Although this notion has been supported by hundreds of experiments over decades of study, a recent theory proposes that the fundamental assumption of evidence accumulation requires revision. The "urgency gating" model assumes decisions are made without accumulating evidence, using only moment-by-moment information. Under this assumption, the successful history of evidence accumulation models is explained by asserting that the two models are mathematically identical in standard experimental procedures. We demonstrate that this proof of equivalence is incorrect, and that the models are not identical, even when both models are augmented with realistic extra assumptions. We also demonstrate that the two models can be perfectly distinguished in realistic simulated experimental designs, and in two real data sets; the evidence accumulation model provided the best account for one data set, and the urgency gating model for the other. A positive outcome is that the opposing modeling approaches can be fruitfully investigated without wholesale change to the standard experimental paradigms. We conclude that future research must establish whether the urgency gating model enjoys the same empirical support in the standard experimental paradigms that evidence accumulation models have gathered over decades of study. [ABSTRACT FROM AUTHOR]

Background: Long non-coding RNAs (lncRNAs) are emerging as molecules that significantly impact many cellular processes and have been associated with almost every human cancer. Compared to protein-coding genes, lncRNA genes are often associated with transposable elements, particularly with endogenous retroviral elements (ERVs). ERVs can have potentially deleterious effects on genome structure and function, so these elements are typically silenced in normal somatic tissues, albeit with varying efficiency. The aberrant regulation of ERVs associated with lncRNAs (ERV-lncRNAs), coupled with the diverse range of lncRNA functions, creates significant potential for ERV-lncRNAs to impact cancer biology. Methods: We used RNA-seq analysis to identify and profile the expression of a novel lncRNA in six large cohorts, including over 7,500 samples from The Cancer Genome Atlas (TCGA). Results: We identified the tumor-specific expression of a novel lncRNA that we have named Endogenous retroViral-associated ADenocarcinoma RNA or 'EVADR' , by analyzing RNA-seq data derived from colorectal tumors and matched normal control tissues. Subsequent analysis of TCGA RNA-seq data revealed the striking association of EVADR with adenocarcinomas, which are tumors of glandular origin. Moderate to high levels of EVADR were detected in 25 to 53% of colon, rectal, lung, pancreas and stomach adenocarcinomas (mean = 30 to 144 FPKM), and EVADR expression correlated with decreased patient survival (Cox regression; hazard ratio = 1.47, 95% confidence interval = 1.06 to 2.04, P = 0.02). In tumor sites of non-glandular origin, EVADR expression was detectable at only very low levels and in less than 10% of patients. For EVADR, a MER48 ERV element provides an active promoter to drive its transcription. Genome-wide, MER48 insertions are associated with nine lncRNAs, but none of the MER48-associated lncRNAs other than EVADR were consistently expressed in adenocarcinomas, demonstrating the specific activation of EVADR. The sequence and structure of the EVADR locus is highly conserved among Old World monkeys and apes but not New World monkeys or prosimians, where the MER48 insertion is absent. Conservation of the EVADR locus suggests a functional role for this novel lncRNA in humans and our closest primate relatives. Conclusions: Our results describe the specific activation of a highly conserved ERV-lncRNA in numerous cancers of glandular origin, a finding with diagnostic, prognostic and therapeutic implications. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Speed-accuracy tradeoff (SAT) is an adaptive process balancing urgency and caution when making decisions. Computational cognitive theories, known as “evidence accumulation models”, have explained SATs via a manipulation of the amount of evidence necessary to trigger response selection. New light has been shed on these processes by single-cell recordings from monkeys who were adjusting their SAT settings. Those data have been interpreted as inconsistent with existing evidence accumulation theories, prompting the addition of new mechanisms to the models. We show that this interpretation was wrong, by demonstrating that the neural spiking data, and the behavioural data are consistent with existing evidence accumulation theories, without positing additional mechanisms. Our approach succeeds by using the neural data to provide constraints on the cognitive model. Open questions remain about the locus of the link between certain elements of the cognitive models and the neurophysiology, and about the relationship between activity in cortical neurons identified with decision-making vs. activity in downstream areas more closely linked with motor effectors. [ABSTRACT FROM AUTHOR]

Discrete choice experiments-selecting the best and/or worst from a set of options-are increasingly used to provide more efficient and valid measurement of attitudes or preferences than conventional methods such as Likert scales. Discrete choice data have traditionally been analyzed with random utility models that have good measurement properties but provide limited insight into cognitive processes. We extend a well-established cognitive model, which has successfully explained both choices and response times for simple decision tasks, to complex, multi-attribute discrete choice data. The fits, and parameters, of the extended model for two sets of choice data (involving patient preferences for dermatology appointments, and consumer attitudes toward mobile phones) agree with those of standard choice models. The extended model also accounts for choice and response time data in a perceptual judgment task designed in a manner analogous to best-worst discrete choice experiments. We conclude that several research fields might benefit from discrete choice experiments, and that the particular accumulator-based models of decision making used in response time research can also provide process-level instantiations for random utility models. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]