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William R. Holmes

Publications and source records attributed to William R. Holmes.

11 recordsLinked to original sources

Managing Cognitive Bias in Human Labeling Operations for Rare-Event AI: Evidence from a Field Experiment

Many operational AI systems depend on large-scale human annotation to detect rare but consequential events (e.g., fraud, defects, and medical abnormalities). When positives are rare, the prevalence effect induces systematic cognitive biases that inflate misses and can propagate through the AI lifecycle via biased training labels. We analyze prior experimental evidence and run a field experiment on DiagnosUs, a medical crowdsourcing platform, in which we hold the true prevalence in the unlabeled stream fixed (20% blasts) while varying (i) the prevalence of positives in the gold-standard feedback stream (20% vs. 50%) and (ii) the response interface (binary labels vs. elicited probabilities). We then post-process probabilistic labels using a linear-in-log-odds recalibration approach at the worker and crowd levels, and train convolutional neural networks on the resulting labels. Balanced feedback and probabilistic elicitation reduce rare-event misses, and pipeline-level recalibration substantially improves both classification performance and probabilistic calibration; these gains carry through to downstream CNN reliability out of sample.

cs.HC

Automating the Practice of Science -- Opportunities, Challenges, and Implications

Automation transformed various aspects of our human civilization, revolutionizing industries and streamlining processes. In the domain of scientific inquiry, automated approaches emerged as powerful tools, holding promise for accelerating discovery, enhancing reproducibility, and overcoming the traditional impediments to scientific progress. This article evaluates the scope of automation within scientific practice and assesses recent approaches. Furthermore, it discusses different perspectives to the following questions: Where do the greatest opportunities lie for automation in scientific practice?; What are the current bottlenecks of automating scientific practice?; and What are significant ethical and practical consequences of automating scientific practice? By discussing the motivations behind automated science, analyzing the hurdles encountered, and examining its implications, this article invites researchers, policymakers, and stakeholders to navigate the rapidly evolving frontier of automated scientific practice.

cs.CY

Analytic solution of chemical master equations involving gene switching. I: Representation theory and diagrammatic approach to exact solution

The chemical master equation (CME), which describes the discrete and stochastic molecule number dynamics associated with biological processes like transcription, is difficult to solve analytically. It is particularly hard to solve for models involving bursting/gene switching, a biological feature that tends to produce heavy-tailed single cell RNA counts distributions. In this paper, we present a novel method for computing exact and analytic solutions to the CME in such cases, and use these results to explore approximate solutions valid in different parameter regimes, and to compute observables of interest. Our method leverages tools inspired by quantum mechanics, including ladder operators and Feynman-like diagrams, and establishes close formal parallels between the dynamics of bursty transcription, and the dynamics of bosons interacting with a single fermion. We focus on two problems: (i) the chemical birth-death process coupled to a switching gene/the telegraph model, and (ii) a model of transcription and multistep splicing involving a switching gene and an arbitrary number of downstream splicing steps. We work out many special cases, and exhaustively explore the special functionology associated with these problems. This is Part I in a two-part series of papers; in Part II, we explore an alternative solution approach that is more useful for numerically solving these problems, and apply it to parameter inference on simulated RNA counts data.

q-bio.SC

The chemical Langevin equation: a path integral view of Gillespie's derivation

In 2000, Gillespie rehabilitated the chemical Langevin equation (CLE) by describing two conditions that must be satisfied for it yield a valid approximation of the chemical master equation (CME). In this work, we construct an original path integral description of the CME, and show how applying Gillespie's two conditions to it directly leads to a path integral equivalent to the CLE. We compare this approach to the path integral equivalent of a large system size derivation, and show that they are qualitatively different. In particular, both approaches involve converting many sums into many integrals, and the difference between the two methods is essentially the difference between using the Euler-Maclaurin formula and using Riemann sums. Our results shed light on how path integrals can be used to conceptualize coarse-graining biochemical systems, and are readily generalizable.

q-bio.QM

Stochastic path integrals can be derived like quantum mechanical path integrals

Stochastic mechanics---the study of classical stochastic systems governed by things like master equations and Fokker-Planck equations---exhibits striking mathematical parallels to quantum mechanics. In this article, we make those parallels more transparent by presenting a quantum mechanics-like formalism for deriving a path integral description of systems described by stochastic differential equations. Our formalism expediently recovers the usual path integrals (the Martin-Siggia-Rose-Janssen-De Dominicis and Onsager-Machlup forms) and is flexible enough to account for different variable domains (e.g. real line versus compact interval), stochastic interpretations, arbitrary numbers of variables, explicit time-dependence, dimensionful control parameters, and more. We discuss the implications of our formalism for stochastic biology.

cond-mat.stat-mech

Optimal models of decision-making in dynamic environments

Nature is in constant flux, so animals must account for changes in their environment when making decisions. How animals learn the timescale of such changes and adapt their decision strategies accordingly is not well understood. Recent psychophysical experiments have shown humans and other animals can achieve near-optimal performance at two alternative forced choice (2AFC) tasks in dynamically changing environments. Characterization of performance requires the derivation and analysis of computational models of optimal decision-making policies on such tasks. We review recent theoretical work in this area, and discuss how models compare with subjects' behavior in tasks where the correct choice or evidence quality changes in dynamic, but predictable, ways.

q-bio.NC

The Impact of Speed and Bias on the Cognitive Processes of Experts and Novices in Medical Image Decision-making

Training individuals to make accurate decisions from medical images is a critical component of education in diagnostic pathology. We describe a joint experimental and computational modeling approach to examine the similarities and differences in the cognitive processes of novice participants and experienced participants (pathology residents and pathology faculty) in cancer cell image identification. For this study we collected a bank of hundreds of digital images that were identified by cell type and classified by difficulty by a panel of expert hematopathologists. The key manipulations in our study included examining the speed-accuracy tradeoff as well as the impact of prior expectations on decisions. In addition, our study examined individual differences in decision-making by comparing task performance to domain general visual ability (as measured using the Novel Object Memory Test (NOMT) (Richler et al., 2017). Using Signal Detection Theory (SDT) and the Diffusion Decision Model (DDM), we found many similarities between expert and novices in our task. While experts tended to have better discriminability, the two groups responded similarly to time pressure (i.e., reduced caution under speed instructions in the DDM) and to the introduction of a probabilistic cue (i.e., increased response bias in the DDM). These results have important implications for training in this area as well as using novice participants in research on medical image perception and decision-making.

q-bio.NC

A mechano-chemical feedback underlies co-existence of qualitatively distinct cell polarity patterns within diverse cell populations

Cell polarization and directional cell migration can display random, persistent and oscillatory dynamic patterns. However, it is not clear if these polarity patterns can be explained by the same underlying regulatory mechanism. Here, we show that random, persistent and oscillatory migration accompanied by polarization can simultaneously occur in populations of melanoma cells derived from tumors with different degrees of aggressiveness. We demonstrate that all these patterns and the probabilities of their occurrence are quantitatively accounted for by a simple mechanism involving a spatially distributed, mechano-chemical feedback coupling the dynamically changing extracellular matrix (ECM)-cell contacts to the activation of signaling downstream of the Rho-family small GTPases. This mechanism is supported by a predictive mathematical model and extensive experimental validation, and can explain previously reported results for diverse cell types. In melanoma, this mechanism also accounts for the effects of genetic and environmental perturbations, including mutations linked to invasive cell spread. The resulting mechanistic understanding of cell polarity quantitatively captures the relationship between population variability and phenotypic plasticity, with the potential to account for a wide variety of cell migration states in diverse pathological and physiological conditions.

q-bio.CB

A mathematical model coupling polarity signaling to cell adhesion explains diverse cell migration patterns

Cells crawling through tissues migrate inside a complex fibrous environment called the extracellular matrix (ECM), which provides signals regulating motility. Here we investigate one such well-known pathway, involving mutually antagonistic signalling molecules (small GTPases Rac and Rho) that control the protrusion and contraction of the cell edges (lamellipodia). Invasive melanoma cells were observed migrating on surfaces with topography (array of posts), coated with adhesive molecules (fibronectin, FN) by Park et al., 2016. Several distinct qualitative behaviors they observed included persistent polarity, oscillation between the cell front and back, and random dynamics. To gain insight into the link between intracellular and ECM signaling, we compared experimental observations to a sequence of mathematical models encoding distinct hypotheses. The successful model required several critical factors. (1) Competition of lamellipodia for limited pools of GTPases. (2) Protrusion / contraction of lamellipodia influence ECM signaling. (3) ECM-mediated activation of Rho. A model combining these elements explains all three cellular behaviors and correctly predicts the results of experimental perturbations. This study yields new insight into how the dynamic interactions between intracellular signaling and the cell's environment influence cell behavior.

q-bio.CB

An efficient, nonlinear stability analysis for detecting pattern formation in reaction diffusion systems

Reaction diffusion systems are often used to study pattern formation in biological systems. However, most methods for understanding their behavior are challenging and can rarely be applied to complex systems common in biological applications. I present a relatively simple and efficient, non-linear stability technique that greatly aids such analysis when rates of diffusion are substantially different. This technique reduces a system of reaction diffusion equations to a system of ordinary differential equations tracking the evolution of a large amplitude, spatially localized perturbation of a homogeneous steady state. Stability properties of this system, determined using standard bifurcation techniques and software, describe both linear and non-linear patterning regimes of the reaction diffusion system. I describe the class of systems this method can be applied to and demonstrate its application. Analysis of Schnakenberg and substrate inhibition models is performed to demonstrate the methods capabilities in simplified settings and show that even these simple models have non-linear patterning regimes not previously detected. Analysis of a protein regulatory network related to chemotaxis shows its application in a more complex setting where other non-linear methods become intractable. Predictions of this method are verified against results of numerical simulation, linear stability, and full PDE bifurcation analyses.

math.AP

Synthetic spatially graded Rac activation drives directed cell polarization and locomotion

Migrating cells possess intracellular gradients of Rho GTPases, but it is unknown whether these shallow gradients themselves can induce motility. Here we describe a new method to present cells with induced linear gradients of active, endogenous Rac without receptor activation. Gradients as low as 15% were sufficient to not only trigger cell migration up the synthetic gradient, but also to induce both cell polarization and repolarization. Response kinetics were inversely proportional to Rac gradient values, in agreement with a new mathematical model, suggesting a role for natural input gradient amplification upstream of Rac. Increases in Rac levels beyond a well-defined threshold dramatically augmented polarization and decreased sensitivity to the gradient value. The threshold was governed by initial cell polarity and PI3K activity, supporting a role for both in defining responsiveness to natural or synthetic Rac activation. Our methodology suggests a general way to investigate processes regulated by intracellular signaling gradients.

q-bio.MN