Publications by authors named "Scott D Brown"

75 Publications

Genome and Transcriptome Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Solid Tumors.

Clin Cancer Res 2021 Jan 5;27(1):202-212. Epub 2020 Oct 5.

Department of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.

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 ( = 0.007), but immune-related CD8 T-cell and M1-M2 macrophage ratio scores were more predictive for overall survival (OS; = 0.0014 and 0.0012, respectively). While [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 ( = 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.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1163DOI Listing
January 2021

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

Hum Factors 2020 Aug 12:18720820945409. Epub 2020 Aug 12.

98493 University of Newcastle, Callaghan, NSW, Australia.

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.
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http://dx.doi.org/10.1177/0018720820945409DOI Listing
August 2020

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

Hum Factors 2020 Aug 4:18720820936800. Epub 2020 Aug 4.

98493 University of Newcastle, Callaghan, NSW, Australia.

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.
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http://dx.doi.org/10.1177/0018720820936800DOI Listing
August 2020

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

Behav Res Methods 2021 Feb;53(1):78-95

School of Psychology, University of Newcastle, Callaghan, Australia.

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.
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http://dx.doi.org/10.3758/s13428-020-01405-4DOI Listing
February 2021

How is multi-tasking different from increased difficulty?

Psychon Bull Rev 2020 Oct;27(5):937-951

School of Psychology, University of Newcastle, Callaghan, NSW, 2308, Australia.

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.
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http://dx.doi.org/10.3758/s13423-020-01741-8DOI Listing
October 2020

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

Support Care Cancer 2021 Jan 7;29(1):417-425. Epub 2020 May 7.

Health Behaviour Research Collaborative, Priority Research Centre for Health Behaviour, School of Medicine and Public Health, University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia.

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.
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http://dx.doi.org/10.1007/s00520-020-05498-7DOI Listing
January 2021

Cancer patient preferences for the provision of information regarding emotional concerns in relation to medical procedures: A discrete choice experiment.

Patient Educ Couns 2020 07 12;103(7):1439-1443. Epub 2020 Feb 12.

Health Behaviour Research Collaborative, Priority Research Centre for Health Behaviour, School of Medicine and Public Health, University of Newcastle, Callaghan, Australia; Hunter Medical Research Institute, Newcastle, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.pec.2020.02.015DOI Listing
July 2020

Identification of a CD8+ T-cell response to a predicted neoantigen in malignant mesothelioma.

Oncoimmunology 2020 3;9(1):1684713. Epub 2019 Nov 3.

National Centre for Asbestos Related Disease, School of Medicine and Pharmacology, University of Western Australia, Nedlands, Australia.

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, = .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 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.
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http://dx.doi.org/10.1080/2162402X.2019.1684713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959430PMC
November 2019

Accumulating advantages: A new conceptualization of rapid multiple choice.

Psychol Rev 2020 03 3;127(2):186-215. Epub 2019 Oct 3.

School of Psychology.

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).
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http://dx.doi.org/10.1037/rev0000166DOI Listing
March 2020

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

Proc Natl Acad Sci U S A 2019 09 19;116(36):17735-17740. Epub 2019 Aug 19.

School of Social Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.

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.
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http://dx.doi.org/10.1073/pnas.1906788116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731761PMC
September 2019

A theoretical analysis of the reward rate optimality of collapsing decision criteria.

Atten Percept Psychophys 2020 Jun;82(3):1520-1534

Department of Psychology, University of Amsterdam, 1018 XA, Amsterdam, The Netherlands.

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.
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http://dx.doi.org/10.3758/s13414-019-01806-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303092PMC
June 2020

The role of passing time in decision-making.

J Exp Psychol Learn Mem Cogn 2020 Feb 10;46(2):316-326. Epub 2019 Jun 10.

School of Psychology.

Theories of perceptual decision making have been dominated by the idea that evidence accumulates in favor of different alternatives until some fixed threshold amount is reached, which triggers a decision. Recent theories have suggested that these thresholds may not be fixed during each decision but change as time passes. These collapsing thresholds can improve performance in particular decision environments, but reviews of data from typical decision-making paradigms have failed to support collapsing thresholds. We designed three experiments to test collapsing threshold assumptions in decision environments specifically tailored to make them optimal. An emphasis on decision speed encouraged the adoption of collapsing thresholds-most strongly through the use of response deadlines but also through instruction to a lesser extent-but setting an explicit goal of reward rate optimality through both instructions and task design did not. Our results suggest that collapsing thresholds models of decision-making are inconsistent with human behaviour even in some situations where there are normative motivations for these models. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/xlm0000725DOI Listing
February 2020

Neoantigen characteristics in the context of the complete predicted MHC class I self-immunopeptidome.

Oncoimmunology 2019;8(3):1556080. Epub 2018 Dec 22.

Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia, Canada.

The self-immunopeptidome is the repertoire of all self-peptides that can be presented by the combination of MHC variants carried by an individual, defined by their HLA genotype. Each MHC variant presents a distinct set of self-peptides, and the number of peptides in a set is variable. Subjects carrying MHC variants that present fewer self-peptides should also present fewer mutated peptides, resulting in decreased immune pressure on tumor cells. To explore this, we predicted peptide-MHC binding values using all unique 8-11mer human peptides in the human proteome and all available HLA class I allelic variants, for a total of 134 billion unique peptide--MHC binding predictions. From these predictions, we observe that most peptides are able to be presented by relatively few (< 250) MHC, while some can be presented by upwards of 1,500 different MHC. There is substantial overlap among the repertoires of peptides presented by different MHC and no relationship between the number of peptides presented and HLA population frequency. Nearly 30% of self-peptides are presentable by at least one MHC, leaving 70% of the human peptidome unsurveyed by T cells. We observed similar distributions of predicted self-immunopeptidome sizes in cancer subjects compared to controls, and within the pan-cancer population, predicted self-immunopeptidome size combined with mutational load to predict survival. Self-immunopeptidome analysis revealed evidence for tumor immunoediting and identified specific peptide positions that most influence immunogenicity. Because self-immunopeptidome size is defined by HLA genotypes and approximates neoantigen load, HLA genotyping could offer a rapid predictive biomarker for response to immunotherapy.
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http://dx.doi.org/10.1080/2162402X.2018.1556080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350689PMC
December 2018

Optimal or not; depends on the task.

Psychon Bull Rev 2019 Jun;26(3):1027-1034

School of Psychology, University of Newcastle, Callaghan, Australia.

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.
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http://dx.doi.org/10.3758/s13423-018-1536-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557863PMC
June 2019

When Extremists Win: Cultural Transmission Via Iterated Learning When Populations Are Heterogeneous.

Cogn Sci 2018 09 31;42(7):2108-2149. Epub 2018 Jul 31.

School of Psychology, University of New South Wales.

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.
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http://dx.doi.org/10.1111/cogs.12667DOI Listing
September 2018

Refining the law of practice.

Psychol Rev 2018 07;125(4):592-605

Division of Psychology, University of Tasmania.

The "law of practice"-a simple nonlinear function describing the relationship between mean response time (RT) and practice-has provided a practically and theoretically useful way of quantifying the speed-up that characterizes skill acquisition. Early work favored a power law, but this was shown to be an artifact of biases caused by averaging over participants who are individually better described by an exponential law. However, both power and exponential functions make the strong assumption that the speedup always proceeds at a steadily decreasing rate, even though there are sometimes clear exceptions. We propose a new law that can both accommodate an initial delay resulting in a slower-faster-slower rate of learning, with either power or exponential forms as limiting cases, and which can account for not only mean RT but also the effect of practice on the entire distribution of RT. We evaluate this proposal with data from a broad array of tasks using hierarchical Bayesian modeling, which pools data across participants while minimizing averaging artifacts, and using inference procedures that take into account differences in flexibility among laws. In a clear majority of paradigms our results supported a delayed exponential law. (PsycINFO Database Record
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http://dx.doi.org/10.1037/rev0000105DOI Listing
July 2018

Modeling the Covariance Structure of Complex Datasets Using Cognitive Models: An Application to Individual Differences and the Heritability of Cognitive Ability.

Cogn Sci 2018 Jun 5. Epub 2018 Jun 5.

School of Psychology, University of Newcastle.

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.
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http://dx.doi.org/10.1111/cogs.12627DOI Listing
June 2018

Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer.

Cell 2018 06 10;173(7):1755-1769.e22. Epub 2018 May 10.

Department of Molecular Oncology, BC Cancer, Vancouver, BC V5Z 4E6, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address:

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.
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http://dx.doi.org/10.1016/j.cell.2018.03.073DOI Listing
June 2018

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

Support Care Cancer 2018 Oct 3;26(10):3593-3599. Epub 2018 May 3.

Health Behaviour Research Collaborative, Priority Research Centre for Health Behaviour, School of Medicine and Public Health, University of Newcastle, Callaghan, Australia.

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.
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http://dx.doi.org/10.1007/s00520-018-4226-xDOI Listing
October 2018

The Immune Landscape of Cancer.

Immunity 2018 04 5;48(4):812-830.e14. Epub 2018 Apr 5.

Institute for Systems Biology, 401 Terry Ave N, Seattle, WA 98109, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.immuni.2018.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5982584PMC
April 2018

The Quality of Response Time Data Inference: A Blinded, Collaborative Assessment of the Validity of Cognitive Models.

Psychon Bull Rev 2019 Aug;26(4):1051-1069

University of New South Wales, Sydney, Australia.

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.
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http://dx.doi.org/10.3758/s13423-017-1417-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449220PMC
August 2019

The computations that support simple decision-making: A comparison between the diffusion and urgency-gating models.

Sci Rep 2017 11 27;7(1):16433. Epub 2017 Nov 27.

School of Psychology, University of Newcastle, Callaghan, Australia.

We investigate a question relevant to the psychology and neuroscience of perceptual decision-making: whether decisions are based on steadily accumulating evidence, or only on the most recent evidence. We report an empirical comparison between two of the most prominent examples of these theoretical positions, the diffusion model and the urgency-gating model, via model-based qualitative and quantitative comparisons. Our findings support the predictions of the diffusion model over the urgency-gating model, and therefore, the notion that evidence accumulates without much decay. Gross qualitative patterns and fine structural details of the data are inconsistent with the notion that decisions are based only on the most recent evidence. More generally, we discuss some strengths and weaknesses of scientific methods that investigate quantitative models by distilling the formal models to qualitative predictions.
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http://dx.doi.org/10.1038/s41598-017-16694-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703954PMC
November 2017

Intertrial RT variability affects level of target-related interference in cued task switching.

Psychophysiology 2018 03 4;55(3). Epub 2017 Aug 4.

School of Psychology, University of Newcastle, Callaghan, New South Wales, Australia.

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.
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http://dx.doi.org/10.1111/psyp.12971DOI Listing
March 2018

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

Mem Cognit 2017 Oct;45(7):1193-1205

School of Psychology, University of Newcastle, Callaghan, NSW, 2308, Australia.

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).
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http://dx.doi.org/10.3758/s13421-017-0718-zDOI Listing
October 2017

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

Behav Res Methods 2018 04;50(2):589-603

School of Psychology, University of Newcastle, Callaghan, NSW, 2308, Australia.

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.
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http://dx.doi.org/10.3758/s13428-017-0887-5DOI Listing
April 2018

Model flexibility analysis does not measure the persuasiveness of a fit.

Psychol Rev 2017 04 2;124(3):339-345. Epub 2017 Feb 2.

School of Psychology, University of Newcastle.

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
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http://dx.doi.org/10.1037/rev0000057DOI Listing
April 2017

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

Bioinformatics 2017 04;33(8):1111-1115

Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.

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.
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http://dx.doi.org/10.1093/bioinformatics/btw810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408843PMC
April 2017

Focal striatum lesions impair cautiousness in humans.

Cortex 2016 12 15;85:37-45. Epub 2016 Oct 15.

Amsterdam Brain and Cognition Center, University of Amsterdam, Amsterdam, The Netherlands.

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.
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http://dx.doi.org/10.1016/j.cortex.2016.09.023DOI Listing
December 2016