Cognitive Bias in Clinical Medicine

Cognitive bias is increasingly recognised as an important source of medical error, and is both ubiquitous across clinical practice yet incompletely understood. This increasing awareness of bias has resulted in a surge in clinical and psychological research in the area and development of various ‘debiasing strategies’. This paper describes the potential origins of bias based on ‘dual process thinking’, discusses and illustrates a number of the important biases that occur in clinical practice, and considers potential strategies that might be used to mitigate their effect

A shortest path-based approach to the multileaf collimator sequencing problem

AbstractThe multileaf collimator sequencing problem is an important component in effective cancer treatment delivery. The problem can be formulated as finding a decomposition of an integer matrix into a weighted sequence of binary matrices whose rows satisfy a consecutive ones property. Minimising the cardinality of the decomposition is an important objective and has been shown to be strongly NP-hard, even for a matrix restricted to a single column or row. We show that in this latter case it can be solved efficiently as a shortest path problem, giving a simple proof that the one-row problem is fixed-parameter tractable in the maximum intensity. We develop new linear and constraint programming models exploiting this result. Our approaches significantly improve the best known for the problem, bringing real-world sized problem instances within reach of exact algorithms

Peer learning and cultural evolution

In this article, we integrate cultural evolutionary theory with empirical research from developmental psychology, cultural anthropology, and primatology to explore the role of peer learning in the development of complex instrumental skills and behavioral norms. We show that instrumental imitation, contingent teaching, generative collaboration, and selective copying contribute to domain-specific transmission of knowledge between peers. Stages of development and characteristics inherent to the learner and model influence how and when children learn from each other. Peer learning is persistent across societies despite cultural beliefs that favor adult–child transmission in some settings. Comparative research hints at the possibility that children's greater motivation to interact with and learn from each other may set humans apart from other primates. We conclude by outlining avenues for future research, including how individual characteristics and developmental changes in social networks, motivation, and cognition may contribute to cultural evolution.</p

A cognitive forcing tool to mitigate cognitive bias:A randomised control trial

Abstract Background Cognitive bias is an important source of diagnostic error yet is a challenging area to understand and teach. Our aim was to determine whether a cognitive forcing tool can reduce the rates of error in clinical decision making. A secondary objective was to understand the process by which this effect might occur. Methods We hypothesised that using a cognitive forcing tool would reduce diagnostic error rates. To test this hypothesis, a novel online case-based approach was used to conduct a single blinded randomized clinical trial conducted from January 2017 to September 2018. In addition, a qualitative series of “think aloud” interviews were conducted with 20 doctors from a UK teaching hospital in 2018. The primary outcome was the diagnostic error rate when solving bias inducing clinical vignettes. A volunteer sample of medical professionals from across the UK, Republic of Ireland and North America. They ranged in seniority from medical student to Attending Physician. Results Seventy six participants were included in the study. The data showed doctors of all grades routinely made errors related to cognitive bias. There was no difference in error rates between groups (mean 2.8 cases correct in intervention vs 3.1 in control group, 95% CI -0.94 – 0.45 P = 0.49). The qualitative protocol revealed that the cognitive forcing strategy was well received and a produced a subjectively positive impact on doctors’ accuracy and thoughtfulness in clinical cases. Conclusions The quantitative data failed to show an improvement in accuracy despite a positive qualitative experience. There is insufficient evidence to recommend this tool in clinical practice, however the qualitative data suggests such an approach has some merit and face validity to users

Brief Review Renal Aging. Causes and consequences

Individuals age >65 years old are the fastest expanding population demographic throughout the developed world. Consequently, more aged patients than before are receiving diagnoses of impaired renal function and nephrosclerosis—age–associated histologic changes in the kidneys. Recent studies have shown that the aged kidney undergoes a range of structural changes and has altered transcriptomic, hemodynamic, and physiologic behavior at rest and in response to renal insults. These changes impair the ability of the kidney to withstand and recover from injury, contributing to the high susceptibility of the aged population to AKI and their increased propensity to develop subsequent progressive CKD. In this review, we examine these features of the aged kidney and explore the various validated and putative pathways contributing to the changes observed with aging in both experimental animal models and humans. We also discuss the potential for additional study to increase understanding of the aged kidney and lead to novel therapeutic strategies

Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis

Progressive fibrosis and maladaptive organ repair result in significant morbidity and millions of premature deaths annually. Senescent cells accumulate with aging and after injury and are implicated in organ fibrosis, but the mechanisms by which senescence influences repair are poorly understood. Using 2 murine models of injury and repair, we show that obstructive injury generated senescent epithelia, which persisted after resolution of the original injury, promoted ongoing fibrosis, and impeded adaptive repair. Depletion of senescent cells with ABT-263 reduced fibrosis in reversed ureteric obstruction and after renal ischemia/reperfusion injury. We validated these findings in humans, showing that senescence and fibrosis persisted after relieved renal obstruction. We next characterized senescent epithelia in murine renal injury using single-cell RNA-Seq. We extended our classification to human kidney and liver disease and identified conserved profibrotic proteins, which we validated in vitro and in human disease. We demonstrated that increased levels of protein disulfide isomerase family A member 3 (PDIA3) augmented TGF-β–mediated fibroblast activation. Inhibition of PDIA3 in vivo significantly reduced kidney fibrosis during ongoing renal injury and as such represented a new potential therapeutic pathway. Analysis of the signaling pathways of senescent epithelia connected senescence to organ fibrosis, permitting rational design of antifibrotic therapies

Indian Hedgehog release from TNF activated renal epithelia drives local and remote organ fibrosis

Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1+) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1+ cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1+ cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell–resolution transcriptomic analysis, we identified an “inflammatory” proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)–induced IHH production in vivo. TNF-induced Ubiquitin D (Ubd) expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1+ cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by Ihh deletion in Pax8-expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1+ cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Abstract: Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH