Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer.

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.

The Immune Landscape of Cancer.

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-ß 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.

Complete sequence verification of plasmid DNA using the Oxford Nanopore Technologies' MinION device.

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.

Using a cognitive model to understand crowdsourced data from citizen scientists.

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.

A large-scale analysis of task switching practice effects across the lifespan.

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.

Preferences for life expectancy discussions following diagnosis with a life-threatening illness: a discrete choice experiment.

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.

The Effects of Increased Visual Information on Cognitive Workload in a Helicopter Simulator.

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.

A Broader Application of the Detection Response Task to Cognitive Tasks and Online Environments.

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.

Identifying relationships between cognitive processes across tasks, contexts, and time.

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.

Defining the clonality of peripheral T cell lymphomas using RNA-seq.

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 (T H ), T follicular helper (T FH ) 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. Contacts: rholt@bcgsc.ca or ksavage@bccancer.bc.ca. Supplementary information: Supplementary data are available at Bioinformatics online.

Quality versus quantity in end-of-life choices of cancer patients and support persons: a discrete choice experiment.

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.

Bayes factors for the linear ballistic accumulator model of decision-making.

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.

Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival.

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.

Need for closure is associated with urgency in perceptual decision-making.

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).

Revisiting the evidence for collapsing boundaries and urgency signals in perceptual decision-making.

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.

Discriminating evidence accumulation from urgency signals in speeded decision making.

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.

Brain and behavior in decision-making.

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.

Variability in visual working memory ability limits the efficiency of perceptual decision making.

The ability to make rapid and accurate decisions based on limited sensory information is a critical component of visual cognition. Available evidence suggests that simple perceptual discriminations are based on the accumulation and integration of sensory evidence over time. However, the memory system(s) mediating this accumulation are unclear. One candidate system is working memory (WM), which enables the temporary maintenance of information in a readily accessible state. Here, we show that individual variability in WM capacity is strongly correlated with the speed of evidence accumulation in speeded two-alternative forced choice tasks. This relationship generalized across different decision-making tasks, and could not be easily explained by variability in general arousal or vigilance. Moreover, we show that performing a difficult discrimination task while maintaining a concurrent memory load has a deleterious effect on the latter, suggesting that WM storage and decision making are directly linked.

Using group level factor models to resolve high dimensionality in model-based sampling.

Joint modeling of decisions and neural activation poses the potential to provide significant advances in linking brain and behavior. However, methods of joint modeling have been limited by difficulties in estimation, often due to high dimensionality and simultaneous estimation challenges. In the current article, we propose a method of model estimation that draws on state-of-the-art Bayesian hierarchical modeling techniques and uses factor analysis as a means of dimensionality reduction and inference at the group level. This hierarchical factor approach can adopt any model for the individual and distill the relationships of its parameters across individuals through a factor structure. We demonstrate the significant dimensionality reduction gained by factor analysis and good parameter recovery, and illustrate a variety of factor loading constraints that can be used for different purposes and research questions, as well as three applications of the method to previously analyzed data. We conclude that this method provides a flexible and usable approach with interpretable outcomes that are primarily data-driven, in contrast to the largely hypothesis-driven methods often used in joint modeling. Although we focus on joint modeling methods, this model-based estimation approach could be used for any high dimensional modeling problem. We provide open-source code and accompanying tutorial documentation to make the method accessible to any researchers. (PsycInfo Database Record (c) 2024 APA, all rights reserved).