Quantitative Biology

In many biological systems, chemical reactions or changes in a physical state are assumed to occur instantaneously. For describing the dynamics of those systems, Markov models that require exponentially distributed inter-event times have been used widely. However, some biophysical processes such as gene transcription and translation are known to have a significant gap between the initiation and the completion of the processes, which renders the usual assumption of exponential distribution untenable. In this paper, we consider relaxing this assumption by incorporating age-dependent random time delays into the system dynamics. We do so by constructing a measure-valued Markov process on a more abstract state space, which allows us to keep track of the "ages" of molecules participating in a chemical reaction. We study the large-volume limit of such age-structured systems. We show that, when appropriately scaled, the stochastic system can be approximated by a system of Partial Differential Equations (PDEs) in the large-volume limit, as opposed to Ordinary Differential Equations (ODEs) in the classical theory. We show how the limiting PDE system can be used for the purpose of further model reductions and for devising efficient simulation algorithms. In order to describe the ideas, we use a simple transcription process as a running example. We, however, note that the methods developed in this paper apply to a wide class of biophysical systems.

Phylogenetics uses alignments of molecular sequence data to learn about evolutionary trees. Substitutions in sequences are modelled through a continuous-time Markov process, characterised by an instantaneous rate matrix, which standard models assume is time-reversible and stationary. These assumptions are biologically questionable and induce a likelihood function which is invariant to a tree's root position. This hampers inference because a tree's biological interpretation depends critically on where it is rooted. Relaxing both assumptions, we introduce a model whose likelihood can distinguish between rooted trees. The model is non-stationary, with step changes in the instantaneous rate matrix at each speciation event. Exploiting recent theoretical work, each rate matrix belongs to a non-reversible family of Lie Markov models. These models are closed under matrix multiplication, so our extension offers the conceptually appealing property that a tree and all its sub-trees could have arisen from the same family of non-stationary models. We adopt a Bayesian approach, describe an MCMC algorithm for posterior inference and provide software. The biological insight that our model can provide is illustrated through an analysis in which non-reversible but stationary, and non-stationary but reversible models cannot identify a plausible root.

We analyzed 5,484 close contacts of COVID-19 cases from Italy, all of them tested for SARS-CoV-2 infection. We found an infection fatality ratio of 2.2% (95%CI 1.69-2.81%) and identified male sex, age >70 years, cardiovascular comorbidities, and infection early in the epidemics as risk factors for death.

There are many hard-to-reconcile numbers circulating concerning Covid-19. Using reports from random testing, the fatality ratio per infection is evaluated and used to extract further information on the actual fraction of infections and the success of their identification for different countries.

Knowing COVID-19 epidemiological distributions, such as the time from patient admission to death, is directly relevant to effective primary and secondary care planning, and moreover, the mathematical modelling of the pandemic generally. We determine epidemiological distributions for patients hospitalised with COVID-19 using a large dataset ( N=21,000−157,000 ) from the Brazilian Sistema de Informação de Vigilância Epidemiológica da Gripe database. A joint Bayesian subnational model with partial pooling is used to simultaneously describe the 26 states and one federal district of Brazil, and shows significant variation in the mean of the symptom-onset-to-death time, with ranges between 11.2-17.8 days across the different states, and a mean of 15.2 days for Brazil. We find strong evidence in favour of specific probability density function choices: for example, the gamma distribution gives the best fit for onset-to-death and the generalised log-normal for onset-to-hospital-admission. Our results show that epidemiological distributions have considerable geographical variation, and provide the first estimates of these distributions in a low and middle-income setting. At the subnational level, variation in COVID-19 outcome timings are found to be correlated with poverty, deprivation and segregation levels, and weaker correlation is observed for mean age, wealth and urbanicity.

PyRoss is an open-source Python library that offers an integrated platform for inference, prediction and optimisation of NPIs in age- and contact-structured epidemiological compartment models. This report outlines the rationale and functionality of the PyRoss library, with various illustrations and examples focusing on well-mixed, age-structured populations. The PyRoss library supports arbitrary structured models formulated stochastically (as master equations) or deterministically (as ODEs) and allows mid-run transitioning from one to the other. By supporting additional compartmental subdivision ad libitum, PyRoss can emulate time-since-infection models and allows medical stages such as hospitalization or quarantine to be modelled and forecast. The PyRoss library enables fitting to epidemiological data, as available, using Bayesian parameter inference, so that competing models can be weighed by their evidence. PyRoss allows fully Bayesian forecasts of the impact of idealized NPIs by convolving uncertainties arising from epidemiological data, model choice, parameters, and intrinsic stochasticity. Algorithms to optimize time-dependent NPI scenarios against user-defined cost functions are included. PyRoss's current age-structured compartment framework for well-mixed populations will in future reports be extended to include compartments structured by location, occupation, use of travel networks and other attributes relevant to assessing disease spread and the impact of NPIs. We argue that such compartment models, by allowing social data of arbitrary granularity to be combined with Bayesian parameter estimation for poorly-known disease variables, could enable more powerful and robust prediction than other approaches to detailed epidemic modelling. We invite others to use the PyRoss library for research to address today's COVID-19 crisis, and to plan for future pandemics.

We consider a population evolving due to mutation, selection and recombination, where selection includes single-locus terms (additive fitness) and two-loci terms (pairwise epistatic fitness). We further consider the problem of inferring fitness in the evolutionary dynamics from one or several snap-shots of the distribution of genotypes in the population. In the recent literature this has been done by applying the Quasi-Linkage Equilibrium (QLE) regime first obtained by Kimura in the limit of high recombination. Here we show that the approach also works in the interesting regime where the effects of mutations are comparable to or larger than recombination. This leads to a modified main epistatic fitness inference formula where the rates of mutation and recombination occur together. We also derive this formula using by a previously developed Gaussian closure that formally remains valid when recombination is absent. The findings are validated through numerical simulations.

To reduce the biases of traditional survey-based methods, this paper proposes an epidemic model-based approach to inference the incubation period distribution of COVID-19 utilizing the publicly reported confirmed case number. We construct an epidemic model, namely SEAIR, and take advantage of the dynamic transmission process depicted by SEAIR to estimate the onset probability in each day of exposed individuals in eight impacted countries. Based on these estimations, the general incubation probability distribution of COVID-19 has been revealed. The proposed method can avoid several biases of traditional survey-based methods. However, due to the mathematical-model-based nature of this method, the inference results are somewhat sensitive to the setting of parameters. Therefore, this method should be practiced reasonably on the basis of a certain understanding of the studied epidemic.

This study analyzed the spread and decay durations of the COVID-19 pandemic in different prefectures of Japan. During the pandemic, affordable healthcare was widely available in Japan and the medical system did not suffer a collapse, making accurate comparisons between prefectures possible. For the 16 prefectures included in this study that had daily maximum confirmed cases exceeding ten, the number of daily confirmed cases follow bell-shape or log-normal distribution in most prefectures. A good correlation was observed between the spread and decay durations. However, some exceptions were observed in areas where travelers returned from foreign countries, which were defined as the origins of infection clusters. Excluding these prefectures, the population density was shown to be a major factor affecting the spread and decay patterns, with R2=0.39 (p<0.05) and 0.42 (p<0.05), respectively, approximately corresponding to social distancing. The maximum absolute humidity was found to affect the decay duration normalized by the population density (R2>0.36, p <0.05). Our findings indicate that the estimated pandemic spread duration, based on the multivariate analysis of maximum absolute humidity, ambient temperature, and population density (adjusted R2=0.53, p-value<0.05), could prove useful for intervention planning during potential future pandemics, including a second COVID-19 outbreak.

In this work, we develop an inmate population model with a sentencing length structure. The sentence length structure of new inmates represents the problem data and can usually be estimated from the histograms corresponding to the conviction times that are sentenced in a given population. We obtain a transport equation, typically known as the McKendrick equation, the homogenous version of which is included in population models with age structures. Using this equation, we compute the inmate population and entry/exit rates in equilibrium, which are the values to consider in the design of a penitentiary system. With data from the Chilean penitentiary system, we illustrate how to perform these computations. In classifying the inmate population into two groups of sentence lengths (short and long), we incorporate the SIS (susceptible-infected-susceptible) epidemiological model, which considers the entry of infective individuals. We show that a failure to consider the structure of the sentence lengths -- as is common in epidemiological models developed for inmate populations -- for prevalences of new inmates below a certain threshold induces an underestimation of the prevalence in the prison population at steady state. The threshold depends on the basic reproduction number associated with the nonstructured SIS model with no entry of new inmates. We illustrate our findings with analytical and numerical examples for different distributions of sentencing lengths.