Peter Ashcroft

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Ashcroft

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Peter

ORCID

0000-0003-4067-7692

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Publications 1 - 9 of 9

Myeloproliferative Neoplasms: The Long Wait for JAK2-Mutant Clone Expansion
Luque Paz, Damien; Ashcroft, Peter; Skoda, Radek C. (2021)
Cell Stem Cell
Myeloproliferative neoplasms (MPNs) are hematological malignancies caused by somatic mutations originating from a single hematopoietic stem cell (HSC). In this issue of Cell Stem Cell, Van Egeren et al. (2021) used whole-genome sequencing of hematopoietic colonies to reconstruct the clonal history and time of acquisition of the disease-initiating gene mutation. © 2021 Elsevier
Constrained optimization of divisional load in hierarchically organized tissues during homeostasis
Ashcroft, Peter; Bonhoeffer, Sebastian (2022)
Journal of the Royal Society. Interface
It has been hypothesized that the structure of tissues and the hierarchy of differentiation from stem cell to terminally differentiated cell play a significant role in reducing the incidence of cancer in that tissue. One specific mechanism by which this risk can be reduced is by minimizing the number of divisions-and hence the mutational risk-that cells accumulate as they divide to maintain tissue homeostasis. Here, we investigate a mathematical model of cell division in a hierarchical tissue, calculating and minimizing the divisional load while constraining parameters such that homeostasis is maintained. We show that the minimal divisional load is achieved by binary division trees with progenitor cells incapable of self-renewal. Contrary to the protection hypothesis, we find that an increased stem cell turnover can lead to lower divisional load. Furthermore, we find that the optimal tissue structure depends on the time horizon of the duration of homeostasis, with faster stem cell division favoured in short-lived organisms and more progenitor compartments favoured in longer-lived organisms.
Correcting for Antibody Waning in Cumulative Incidence Estimation from Sequential Serosurveys
Kadelka, Sarah; Bouman, Judith Aveline; Ashcroft, Peter; et al. (2024)
American Journal of Epidemiology
Serosurveys are a widely used tool to estimate the cumulative incidence—the fraction of a population that has been infected by a given pathogen. These surveys rely on serological assays that measure the level of pathogen-specific antibodies. Because antibody levels are waning, the fraction of previously infected individuals that have seroreverted increases with time past infection. To avoid underestimating the true cumulative incidence, it is therefore essential to correct for waning antibody levels. We present an empirically supported approach for seroreversion correction in cumulative incidence estimation when sequential serosurveys are conducted in the context of a newly emerging infectious disease. The correction is based on the observed dynamics of antibody titers in seropositive cases and validated using several in silico test scenarios. Furthermore, through this approach we revise a previous cumulative incidence estimate relying on the assumption of an exponentially declining probability of seroreversion over time, of severe acute respiratory syndrome coronavirus 2, of 76% in Manaus, Brazil, by October 2020 to 47.6% (95% confidence region: 43.5–53.5). This estimate has implications, for example, for the proximity to herd immunity in Manaus in late 2020.
Test-trace-isolate-quarantine (TTIQ) intervention strategies after symptomatic COVID-19 case identification
Ashcroft, Peter; Lehtinen, Sonja Katriina; Bonhoeffer, Sebastian (2022)
PLoS ONE
The test-trace-isolate-quarantine (TTIQ) strategy, where confirmed-positive pathogen carriers are isolated from the community and their recent close contacts are identified and preemptively quarantined, is used to break chains of transmission during a disease outbreak. The protocol is frequently followed after an individual presents with disease symptoms, at which point they will be tested for the pathogen. This TTIQ strategy, along with hygiene and social distancing measures, make up the non-pharmaceutical interventions that are utilised to suppress the ongoing COVID-19 pandemic. Here we develop a tractable mathematical model of disease transmission and the TTIQ intervention to quantify how the probability of detecting and isolating a case following symptom onset, the fraction of contacts that are identified and quarantined, and the delays inherent to these processes impact epidemic growth. In the model, the timing of disease transmission and symptom onset, as well as the frequency of asymptomatic cases, is based on empirical distributions of SARS-CoV-2 infection dynamics, while the isolation of confirmed cases and quarantine of their contacts is implemented by truncating their respective infectious periods. We find that a successful TTIQ strategy requires intensive testing: the majority of transmission is prevented by isolating symptomatic individuals and doing so in a short amount of time. Despite the lesser impact, additional contact tracing and quarantine increases the parameter space in which an epidemic is controllable and is necessary to control epidemics with a high reproductive number. TTIQ could remain an important intervention for the foreseeable future of the COVID-19 pandemic due to slow vaccine rollout and highly-transmissible variants with the potential for vaccine escape. Our results can be used to assess how TTIQ can be improved and optimised, and the methodology represents an improvement over previous quantification methods that is applicable to future epidemic scenarios.
On the relationship between serial interval, infectiousness profile and generation time
Lehtinen, Sonja Katriina; Ashcroft, Peter; Bonhoeffer, Sebastian (2021)
Journal of the Royal Society. Interface
The timing of transmission plays a key role in the dynamics and controllability of an epidemic. However, observing generation times-the time interval between the infection of an infector and an infectee in a transmission pair-requires data on infection times, which are generally unknown. The timing of symptom onset is more easily observed; generation times are therefore often estimated based on serial intervals-the time interval between symptom onset of an infector and an infectee. This estimation follows one of two approaches: (i) approximating the generation time distribution by the serial interval distribution or (ii) deriving the generation time distribution from the serial interval and incubation period-the time interval between infection and symptom onset in a single individual-distributions. These two approaches make different-and not always explicitly stated-assumptions about the relationship between infectiousness and symptoms, resulting in different generation time distributions with the same mean but unequal variances. Here, we clarify the assumptions that each approach makes and show that neither set of assumptions is plausible for most pathogens. However, the variances of the generation time distribution derived under each assumption can reasonably be considered as upper (approximation with serial interval) and lower (derivation from serial interval) bounds. Thus, we suggest a pragmatic solution is to use both approaches and treat these as edge cases in downstream analysis. We discuss the impact of the variance of the generation time distribution on the controllability of an epidemic through strategies based on contact tracing, and we show that underestimating this variance is likely to overestimate controllability.
MPN patients with low mutant JAK2 allele burden show late expansion restricted to erythroid and megakaryocytic lineages
Nienhold, Ronny; Ashcroft, Peter; Zmajkovic, Jakub; et al. (2020)
Blood
Stochastic Gene Expression Influences the Selection of Antibiotic Resistance Mutations
Sun, Lei; Ashcroft, Peter; Ackermann, Martin; et al. (2020)
Molecular Biology and Evolution
Bacteria can resist antibiotics by expressing enzymes that remove or deactivate drug molecules. Here, we study the effects of gene expression stochasticity on efflux and enzymatic resistance. We construct an agent-based model that stochastically simulates multiple biochemical processes in the cell and we observe the growth and survival dynamics of the cell population. Resistance-enhancing mutations are introduced by varying parameters that control the enzyme expression or efficacy. We find that stochastic gene expression can cause complex dynamics in terms of survival and extinction for these mutants. Regulatory mutations, which augment the frequency and duration of resistance gene transcription, can provide limited resistance by increasing mean expression. Structural mutations, which modify the enzyme or efflux efficacy, provide most resistance by improving the binding affinity of the resistance protein to the antibiotic; increasing the enzyme’s catalytic rate alone may contribute to resistance if drug binding is not rate limiting. Overall, we identify conditions where regulatory mutations are selected over structural mutations, and vice versa. Our findings show that stochastic gene expression is a key factor underlying efflux and enzymatic resistances and should be taken into consideration in future antibiotic research.
COVID-19 infectivity profile correction
Ashcroft, Peter; Huisman, Jana; Lehtinen, Sonja Katriina; et al. (2020)
Swiss Medical Weekly
Quantifying the impact of quarantine duration on covid-19 transmission
Ashcroft, Peter; Lehtinen, Sonja Katriina; Angst, Daniel C.; et al. (2021)
eLife
The large number of individuals placed into quarantine because of possible severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) exposure has high societal and economic costs. There is ongoing debate about the appropriate duration of quarantine, particularly since the fraction of individuals who eventually test positive is perceived as being low. We use empirically determined distributions of incubation period, infectivity, and generation time to quantify how the duration of quarantine affects onward transmission from traced contacts of confirmed SARS-CoV-2 cases and from returning travellers. We also consider the roles of testing followed by release if negative (test-and-release), reinforced hygiene, adherence, and symptoms in calculating quarantine efficacy. We show that there are quarantine strategies based on a test-and-release protocol that, from an epidemiological viewpoint, perform almost as well as a 10-day quarantine, but with fewer person-days spent in quarantine. The findings apply to both travellers and contacts, but the specifics depend on the context.

Publications 1 - 9 of 9

Peter Ashcroft

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