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The integration of viral genomic data into public health surveillance has revolutionized our ability to track and forecast infectious disease dynamics. This review addresses two critical aspects of infectious disease forecasting and monitoring: the methodological workflow for epidemic forecasting and the transformative role of molecular surveillance. We first present a detailed approach for validating epidemic models, emphasizing an iterative workflow that utilizes ordinary differential equation (ODE)-based models to investigate and forecast disease dynamics. We recommend a more structured approach to model validation, systematically addressing key stages such as model calibration, assessment of structural and practical parameter identifiability, and effective uncertainty propagation in forecasts. Furthermore, we underscore the importance of incorporating multiple data streams by applying both simulated and real epidemiological data from the COVID-19 pandemic to produce more reliable forecasts with quantified uncertainty. Additionally, we emphasize the pivotal role of viral genomic data in tracking transmission dynamics and pathogen evolution. By leveraging advanced computational tools such as Bayesian phylogenetics and phylodynamics, researchers can more accurately estimate transmission clusters and reconstruct outbreak histories, thereby improving data-driven modeling and forecasting and informing targeted public health interventions. Finally, we discuss the transformative potential of integrating molecular epidemiology with mathematical modeling to complement and enhance epidemic forecasting and optimize public health strategies. 

The 2022–2023 mpox outbreak exhibited an uneven global distribution. While countries such as the UK, Brazil, and the USA were most heavily affected in 2022, many Asian countries, specifically China, Japan, South Korea, and Thailand, experienced the outbreak later, in 2023, with significantly fewer reported cases relative to their populations. This variation in timing and scale distinguishes the outbreaks in these Asian countries from those in the first wave. This study evaluates the predictability of mpox outbreaks with smaller case counts in Asian countries using popular epidemic forecasting methods, including the ARIMA, Prophet, GLM, GAM, n-Sub-epidemic, and Sub-epidemic Wave frameworks. Despite the fact that the ARIMA and GAM models performed well for certain countries and prediction windows, their results were generally inconsistent and highly dependent on the country, i.e., the dataset, as well as the prediction interval length. In contrast, n-Sub-epidemic Ensembles demonstrated more reliable and robust performance across different datasets and predictions, indicating the effectiveness of this model on small datasets and its utility in the early stages of future pandemics. 

Abstract Simple dynamic modeling tools can help generate real-time short-term forecasts with quantified uncertainty of the trajectory of diverse growth processes unfolding in nature and society, including disease outbreaks. An easy-to-use and flexible toolbox for this purpose is lacking. This tutorial-based primer introduces and illustratesGrowthPredict, a user-friendly MATLAB toolbox for fitting and forecasting time-series trajectories using phenomenological dynamic growth models based on ordinary differential equations. This toolbox is accessible to a broad audience, including students training in mathematical biology, applied statistics, and infectious disease modeling, as well as researchers and policymakers who need to conduct short-term forecasts in real-time. The models included in the toolbox capture exponential and sub-exponential growth patterns that typically follow a rising pattern followed by a decline phase, a common feature of contagion processes. Models include the 1-parameter exponential growth model and the 2-parameter generalized-growth model, which have proven useful in characterizing and forecasting the ascending phase of epidemic outbreaks. It also includes the 2-parameter Gompertz model, the 3-parameter generalized logistic-growth model, and the 3-parameter Richards model, which have demonstrated competitive performance in forecasting single peak outbreaks. We provide detailed guidance on forecasting time-series trajectories and available software (https://github.com/gchowell/forecasting_growthmodels), including the full uncertainty distribution derived through parametric bootstrapping, which is needed to construct prediction intervals and evaluate their accuracy. Functions are available to assess forecasting performance across different models, estimation methods, error structures in the data, and forecasting horizons. The toolbox also includes functions to quantify forecasting performance using metrics that evaluate point and distributional forecasts, including the weighted interval score. This tutorial and toolbox can be broadly applied to characterizing and forecasting time-series data using simple phenomenological growth models. As a contagion process takes off, the tools presented in this tutorial can help create forecasts to guide policy regarding implementing control strategies and assess the impact of interventions. The toolbox functionality is demonstrated through various examples, including a tutorial video, and the examples use publicly available data on the monkeypox (mpox) epidemic in the USA. 

During the 2022–2023 unprecedented mpox epidemic, near real-time short-term forecasts of the epidemic’s trajectory were essential in intervention implementation and guiding policy. However, as case levels have significantly decreased, evaluating model performance is vital to advancing the field of epidemic forecasting. Using laboratory-confirmed mpox case data from the Centers for Disease Control and Prevention and Our World in Data teams, we generated retrospective sequential weekly forecasts for Brazil, Canada, France, Germany, Spain, the United Kingdom, the United States and at the global scale using an auto-regressive integrated moving average (ARIMA) model, generalized additive model, simple linear regression, Facebook’s Prophet model, as well as the sub-epidemic wave andn-sub-epidemic modelling frameworks. We assessed forecast performance using average mean squared error, mean absolute error, weighted interval scores, 95% prediction interval coverage, skill scores and Winkler scores. Overall, then-sub-epidemic modelling framework outcompeted other models across most locations and forecasting horizons, with the unweighted ensemble model performing best most frequently. Then-sub-epidemic and spatial-wave frameworks considerably improved in average forecasting performance relative to the ARIMA model (greater than 10%) for all performance metrics. Findings further support sub-epidemic frameworks for short-term forecasting epidemics of emerging and re-emerging infectious diseases. 

Abstract BackgroundDynamical mathematical models defined by a system of differential equations are typically not easily accessible to non-experts. However, forecasts based on these types of models can help gain insights into the mechanisms driving the process and may outcompete simpler phenomenological growth models. Here we introduce a friendly toolbox,SpatialWavePredict, to characterize and forecast the spatial wave sub-epidemic model, which captures diverse wave dynamics by aggregating multiple asynchronous growth processes and has outperformed simpler phenomenological growth models in short-term forecasts of various infectious diseases outbreaks including SARS, Ebola, and the early waves of the COVID-19 pandemic in the US. ResultsThis tutorial-based primer introduces and illustrates a user-friendly MATLAB toolbox for fitting and forecasting time-series trajectories using an ensemble spatial wave sub-epidemic model based on ordinary differential equations. Scientists, policymakers, and students can use the toolbox to conduct real-time short-term forecasts. The five-parameter epidemic wave model in the toolbox aggregates linked overlapping sub-epidemics and captures a rich spectrum of epidemic wave dynamics, including oscillatory wave behavior and plateaus. An ensemble strategy aims to improve forecasting performance by combining the resulting top-ranked models. The toolbox provides a tutorial for forecasting time-series trajectories, including the full uncertainty distribution derived through parametric bootstrapping, which is needed to construct prediction intervals and evaluate their accuracy. Functions are available to assess forecasting performance, estimation methods, error structures in the data, and forecasting horizons. The toolbox also includes functions to quantify forecasting performance using metrics that evaluate point and distributional forecasts, including the weighted interval score. ConclusionsWe have developed the first comprehensive toolbox to characterize and forecast time-series data using an ensemble spatial wave sub-epidemic wave model. As an epidemic situation or contagion occurs, the tools presented in this tutorial can facilitate policymakers to guide the implementation of containment strategies and assess the impact of control interventions. We demonstrate the functionality of the toolbox with examples, including a tutorial video, and is illustrated using daily data on the COVID-19 pandemic in the USA. 

Abstract The emergence of viral variants with altered phenotypes is a public health challenge underscoring the need for advanced evolutionary forecasting methods. Given extensive epistatic interactions within viral genomes and known viral evolutionary history, efficient genomic surveillance necessitates early detection of emerging viral haplotypes rather than commonly targeted single mutations. Haplotype inference, however, is a significantly more challenging problem precluding the use of traditional approaches. Here, using SARS-CoV-2 evolutionary dynamics as a case study, we show that emerging haplotypes with altered transmissibility can be linked to dense communities in coordinated substitution networks, which become discernible significantly earlier than the haplotypes become prevalent. From these insights, we develop a computational framework for inference of viral variants and validate it by successful early detection of known SARS-CoV-2 strains. Our methodology offers greater scalability than phylogenetic lineage tracing and can be applied to any rapidly evolving pathogen with adequate genomic surveillance data. 

Abstract The emergence of viral variants with altered phenotypes is a public health challenge underscoring the need for advanced evolutionary forecasting methods. Given extensive epistatic interactions within viral genomes and known viral evolutionary history, efficient genomic surveillance necessitates early detection of emerging viral haplotypes rather than commonly targeted single mutations. Haplotype inference, however, is a significantly more challenging problem precluding the use of traditional approaches. Here, using SARS-CoV-2 evolutionary dynamics as a case study, we show that emerging haplotypes with altered transmissibility can be linked to dense communities in coordinated substitution networks, which become discernible significantly earlier than the haplotypes become prevalent. From these insights, we develop a computational framework for inference of viral variants and validate it by successful early detection of known SARS-CoV-2 strains. Our methodology offers greater scalability than phylogenetic lineage tracing and can be applied to any rapidly evolving pathogen with adequate genomic surveillance data. 

Abstract In this work, the COVID-19 pandemic burden in Ukraine is investigated retrospectively using the excess mortality measures during 2020–2021. In particular, the epidemic impact on the Ukrainian population is studied via the standardized both all-cause and cause-specific mortality scores before and during the epidemic. The excess mortality counts during the pandemic were predicted based on historic data using parametric and nonparametric modeling and then compared with the actual reported counts to quantify the excess. The corresponding standardized mortalityP-score metrics were also compared with the neighboring countries. In summary, there were three “waves” of excess all-cause mortality in Ukraine in December 2020, April 2021 and November 2021 with excess of 32%, 43% and 83% above the expected mortality. Each new “wave” of the all-cause mortality was higher than the previous one and the mortality “peaks” corresponded in time to three “waves” of lab-confirmed COVID-19 mortality. The lab-confirmed COVID-19 mortality constituted 9% to 24% of the all-cause mortality during those three peak months. Overall, the mortality trends in Ukraine over time were similar to neighboring countries where vaccination coverage was similar to that in Ukraine. For cause-specific mortality, the excess observed was due to pneumonia as well as circulatory system disease categories that peaked at the same times as the all-cause and lab-confirmed COVID-19 mortality, which was expected. The pneumonias as well as circulatory system disease categories constituted the majority of all cases during those peak times. The seasonality in mortality due to the infectious and parasitic disease category became less pronounced during the pandemic. While the reported numbers were always relatively low, alcohol-related mortality also declined during the pandemic. 

Abstract BackgroundBeginning May 7, 2022, multiple nations reported an unprecedented surge in monkeypox cases. Unlike past outbreaks, differences in affected populations, transmission mode, and clinical characteristics have been noted. With the existing uncertainties of the outbreak, real-time short-term forecasting can guide and evaluate the effectiveness of public health measures. MethodsWe obtained publicly available data on confirmed weekly cases of monkeypox at the global level and for seven countries (with the highest burden of disease at the time this study was initiated) from the Our World in Data (OWID) GitHub repository and CDC website. We generated short-term forecasts of new cases of monkeypox across the study areas using an ensemble n-sub-epidemic modeling framework based on weekly cases using 10-week calibration periods. We report and assess the weekly forecasts with quantified uncertainty from the top-ranked, second-ranked, and ensemble sub-epidemic models. Overall, we conducted 324 weekly sequential 4-week ahead forecasts across the models from the week of July 28th, 2022, to the week of October 13th, 2022. ResultsThe last 10 of 12 forecasting periods (starting the week of August 11th, 2022) show either a plateauing or declining trend of monkeypox cases for all models and areas of study. According to our latest 4-week ahead forecast from the top-ranked model, a total of 6232 (95% PI 487.8, 12,468.0) cases could be added globally from the week of 10/20/2022 to the week of 11/10/2022. At the country level, the top-ranked model predicts that the USA will report the highest cumulative number of new cases for the 4-week forecasts (median based on OWID data: 1806 (95% PI 0.0, 5544.5)). The top-ranked and weighted ensemble models outperformed all other models in short-term forecasts. ConclusionsOur top-ranked model consistently predicted a decreasing trend in monkeypox cases on the global and country-specific scale during the last ten sequential forecasting periods. Our findings reflect the potential impact of increased immunity, and behavioral modification among high-risk populations.