Epidemic management and control through risk-dependent individual contact interventions.

Testing, contact tracing, and isolation (TTI) is an epidemic management and control approach that is difficult to implement at scale because it relies on manual tracing of contacts. Exposure notification apps have been developed to digitally scale up TTI by harnessing contact data obtained from mobile devices; however, exposure notification apps provide users only with limited binary information when they have been directly exposed to a known infection source. Here we demonstrate a scalable improvement to TTI and exposure notification apps that uses data assimilation (DA) on a contact network. Network DA exploits diverse sources of health data together with the proximity data from mobile devices that exposure notification apps rely upon. It provides users with continuously assessed individual risks of exposure and infection, which can form the basis for targeting individual contact interventions. Simulations of the early COVID-19 epidemic in New York City are used to establish proof-of-concept. In the simulations, network DA identifies up to a factor 2 more infections than contact tracing when both harness the same contact data and diagnostic test data. This remains true even when only a relatively small fraction of the population uses network DA. When a sufficiently large fraction of the population (≳ 75%) uses network DA and complies with individual contact interventions, targeting contact interventions with network DA reduces deaths by up to a factor 4 relative to TTI. Network DA can be implemented by expanding the computational backend of existing exposure notification apps, thus greatly enhancing their capabilities. Implemented at scale, it has the potential to precisely and effectively control future epidemics while minimizing economic disruption.

Mathematical Characterization of Private and Public Immune Receptor Sequences.

Diverse T and B cell repertoires play an important role in mounting effective immune responses against a wide range of pathogens and malignant cells. The number of unique T and B cell clones is characterized by T and B cell receptors (TCRs and BCRs), respectively. Although receptor sequences are generated probabilistically by recombination processes, clinical studies found a high degree of sharing of TCRs and BCRs among different individuals. In this work, we use a general probabilistic model for T/B cell receptor clone abundances to define "publicness" or "privateness" and information-theoretic measures for comparing the frequency of sampled sequences observed across different individuals. We derive mathematical formulae to quantify the mean and the variances of clone richness and overlap. Our results can be used to evaluate the effect of different sampling protocols on abundances of clones within an individual as well as the commonality of clones across individuals. Using synthetic and empirical TCR amino acid sequence data, we perform simulations to study expected clonal commonalities across multiple individuals. Based on our formulae, we compare these simulated results with the analytically predicted mean and variances of the repertoire overlap. Complementing the results on simulated repertoires, we derive explicit expressions for the richness and its uncertainty for specific, single-parameter truncated power-law probability distributions. Finally, the information loss associated with grouping together certain receptor sequences, as is done in spectratyping, is also evaluated. Our approach can be, in principle, applied under more general and mechanistically realistic clone generation models.

Identifying relapse predictors in individual participant data with decision trees.

BACKGROUND: Depression is a highly common and recurrent condition. Predicting who is at most risk of relapse or recurrence can inform clinical practice. Applying machine-learning methods to Individual Participant Data (IPD) can be promising to improve the accuracy of risk predictions. METHODS: Individual data of four Randomized Controlled Trials (RCTs) evaluating antidepressant treatment compared to psychological interventions with tapering ([Formula: see text]) were used to identify predictors of relapse and/or recurrence. Ten baseline predictors were assessed. Decision trees with and without gradient boosting were applied. To study the robustness of decision-tree classifications, we also performed a complementary logistic regression analysis. RESULTS: The combination of age, age of onset of depression, and depression severity significantly enhances the prediction of relapse risk when compared to classifiers solely based on depression severity. The studied decision trees can (i) identify relapse patients at intake with an accuracy, specificity, and sensitivity of about 55% (without gradient boosting) and 58% (with gradient boosting), and (ii) slightly outperform classifiers that are based on logistic regression. CONCLUSIONS: Decision tree classifiers based on multiple-rather than single-risk indicators may be useful for developing treatment stratification strategies. These classification models have the potential to contribute to the development of methods aimed at effectively prioritizing treatment for those individuals who require it the most. Our results also underline the existing gaps in understanding how to accurately predict depressive relapse.

Impact of random and targeted disruptions on information diffusion during outbreaks.

Outbreaks are complex multi-scale processes that are impacted not only by cellular dynamics and the ability of pathogens to effectively reproduce and spread, but also by population-level dynamics and the effectiveness of mitigation measures. A timely exchange of information related to the spread of novel pathogens, stay-at-home orders, and other measures can be effective at containing an infectious disease, particularly during the early stages when testing infrastructure, vaccines, and other medical interventions may not be available at scale. Using a multiplex epidemic model that consists of an information layer (modeling information exchange between individuals) and a spatially embedded epidemic layer (representing a human contact network), we study how random and targeted disruptions in the information layer (e.g., errors and intentional attacks on communication infrastructure) impact the total proportion of infections, peak prevalence (i.e., the maximum proportion of infections), and the time to reach peak prevalence. We calibrate our model to the early outbreak stages of the SARS-CoV-2 pandemic in 2020. Mitigation campaigns can still be effective under random disruptions, such as failure of information channels between a few individuals. However, targeted disruptions or sabotage of hub nodes that exchange information with a large number of individuals can abruptly change outbreak characteristics, such as the time to reach the peak of infection. Our results emphasize the importance of the availability of a robust communication infrastructure during an outbreak that can withstand both random and targeted disruptions.

On the accuracy of short-term COVID-19 fatality forecasts.

BACKGROUND: Forecasting new cases, hospitalizations, and disease-induced deaths is an important part of infectious disease surveillance and helps guide health officials in implementing effective countermeasures. For disease surveillance in the US, the Centers for Disease Control and Prevention (CDC) combine more than 65 individual forecasts of these numbers in an ensemble forecast at national and state levels. A similar initiative has been launched by the European CDC (ECDC) in the second half of 2021. METHODS: We collected data on CDC and ECDC ensemble forecasts of COVID-19 fatalities, and we compare them with easily interpretable "Euler" forecasts serving as a model-free benchmark that is only based on the local rate of change of the incidence curve. The term "Euler method" is motivated by the eponymous numerical integration scheme that calculates the value of a function at a future time step based on the current rate of change. RESULTS: Our results show that simple and easily interpretable "Euler" forecasts can compete favorably with both CDC and ECDC ensemble forecasts on short-term forecasting horizons of 1 week. However, ensemble forecasts better perform on longer forecasting horizons. CONCLUSIONS: Using the current rate of change in incidences as estimates of future incidence changes is useful for epidemic forecasting on short time horizons. An advantage of the proposed method over other forecasting approaches is that it can be implemented with a very limited amount of work and without relying on additional data (e.g., data on human mobility and contact patterns) and high-performance computing systems.

A statistical model of COVID-19 testing in populations: effects of sampling bias andtesting errors.

We develop a statistical model for the testing of disease prevalence in a population. The model assumes a binary test result, positive or negative, but allows for biases in sample selection and both type I (false positive) and type II (false negative) testing errors. Our model also incorporates multiple test types and is able to distinguish between retesting and exclusion after testing. Our quantitative framework allows us to directly interpret testing results as a function of errors and biases. By applying our testing model to COVID-19 testing data and actual case data from specific jurisdictions, we are able to estimate and provide uncertainty quantification of indices that are crucial in a pandemic, such as disease prevalence and fatality ratios. This article is part of the theme issue 'Data science approach to infectious disease surveillance'.

A Refunding Scheme to Incentivize Narrow-Spectrum Antibiotic Development.

The rapid rise of antibiotic resistance is a serious threat to global public health. The situation is exacerbated by the "antibiotics dilemma": Developing narrow-spectrum antibiotics against resistant bacteria is most beneficial for society, but least attractive for companies, since their usage and sales volumes are more limited than for broad-spectrum drugs. After developing a general mathematical framework for the study of antibiotic resistance dynamics with an arbitrary number of antibiotics, we identify efficient treatment protocols. Then, we introduce a market-based refunding scheme that incentivizes pharmaceutical companies to develop new antibiotics against resistant bacteria and, in particular, narrow-spectrum antibiotics that target specific bacterial strains. We illustrate how such a refunding scheme can solve the antibiotics dilemma and cope with various sources of uncertainty that impede antibiotic R &D. Finally, connecting our refunding approach to the recently established Antimicrobial Resistance (AMR) Action Fund, we discuss how our proposed incentivization scheme could be financed.

Using excess deaths and testing statistics to determine COVID-19 mortalities.

Factors such as varied definitions of mortality, uncertainty in disease prevalence, and biased sampling complicate the quantification of fatality during an epidemic. Regardless of the employed fatality measure, the infected population and the number of infection-caused deaths need to be consistently estimated for comparing mortality across regions. We combine historical and current mortality data, a statistical testing model, and an SIR epidemic model, to improve estimation of mortality. We find that the average excess death across the entire US from January 2020 until February 2021 is 9[Formula: see text] higher than the number of reported COVID-19 deaths. In some areas, such as New York City, the number of weekly deaths is about eight times higher than in previous years. Other countries such as Peru, Ecuador, Mexico, and Spain exhibit excess deaths significantly higher than their reported COVID-19 deaths. Conversely, we find statistically insignificant or even negative excess deaths for at least most of 2020 in places such as Germany, Denmark, and Norway.

Decisive conditions for strategic vaccination against SARS-CoV-2.

While vaccines against severe acute respiratory syndrome coronavirus (SARS-CoV-2) are being administered, in many countries it may still take months until their supply can meet demand. The majority of available vaccines elicit strong immune responses when administered as prime-boost regimens. Since the immunological response to the first ("prime") dose may provide already a substantial reduction in infectiousness and protection against severe disease, it may be more effective-under certain immunological and epidemiological conditions-to vaccinate as many people as possible with only one dose instead of administering a person a second ("booster") dose. Such a vaccination campaign may help to more effectively slow down the spread of SARS-CoV-2 and reduce hospitalizations and fatalities. The conditions that make prime-first vaccination favorable over prime-boost campaigns, however, are not well understood. By combining epidemiological modeling, random-sampling techniques, and decision tree learning, we find that prime-first vaccination is robustly favored over prime-boost vaccination campaigns even for low single-dose efficacies. For epidemiological parameters that describe the spread of coronavirus disease 2019 (COVID-19), recent data on new variants included, we show that the difference between prime-boost and single-shot waning rates is the only discriminative threshold, falling in the narrow range of 0.01-0.02 day-1 below which prime-first vaccination should be considered.

Diversity in biology: definitions, quantification and models.

Diversity indices are useful single-number metrics for characterizing a complex distribution of a set of attributes across a population of interest. The utility of these different metrics or sets of metrics depends on the context and application, and whether a predictive mechanistic model exists. In this topical review, we first summarize the relevant mathematical principles underlying heterogeneity in a large population, before outlining the various definitions of 'diversity' and providing examples of scientific topics in which its quantification plays an important role. We then review how diversity has been a ubiquitous concept across multiple fields, including ecology, immunology, cellular barcoding experiments, and socioeconomic studies. Since many of these applications involve sampling of populations, we also review how diversity in small samples is related to the diversity in the entire population. Features that arise in each of these applications are highlighted.

Why case fatality ratios can be misleading: individual- and population-based mortality estimates and factors influencing them.

Different ways of calculating mortality during epidemics have yielded very different results, particularly during the current COVID-19 pandemic. For example, the 'CFR' has been interchangeably called the case fatality ratio, case fatality rate, and case fatality risk, often without standard mathematical definitions. The most commonly used CFR is the case fatality ratio, typically constructed using the estimated number of deaths to date divided by the estimated total number of confirmed infected cases to date. How does this CFR relate to an infected individual's probability of death? To explore such issues, we formulate both a survival probability model and an associated infection duration-dependent SIR model to define individual- and population-based estimates of dynamic mortality measures to show that neither of these are directly represented by the case fatality ratio. The key parameters that affect the dynamics of different mortality estimates are the incubation period and the time individuals were infected before confirmation of infection. Using data on the recent SARS-CoV-2 outbreaks, we estimate and compare the different dynamic mortality estimates and highlight their differences. Informed by our modeling, we propose more systematic methods to determine mortality during epidemic outbreaks and discuss sensitivity to confounding effects and uncertainties in the data arising from, e.g., undertesting and heterogeneous populations.

Complex networks with complex weights.

In many studies, it is common to use binary (i.e., unweighted) edges to examine networks of entities that are either adjacent or not adjacent. Researchers have generalized such binary networks to incorporate edge weights, which allow one to encode node-node interactions with heterogeneous intensities or frequencies (e.g., in transportation networks, supply chains, and social networks). Most such studies have considered real-valued weights, despite the fact that networks with complex weights arise in fields as diverse as quantum information, quantum chemistry, electrodynamics, rheology, and machine learning. Many of the standard network-science approaches in the study of classical systems rely on the real-valued nature of edge weights, so it is necessary to generalize them if one seeks to use them to analyze networks with complex edge weights. In this paper, we examine how standard network-analysis methods fail to capture structural features of networks with complex edge weights. We then generalize several network measures to the complex domain and show that random-walk centralities provide a useful approach to examine node importances in networks with complex weights.

Forecasting drug-overdose mortality by age in the United States at the national and county levels.

The drug-overdose crisis in the United States continues to intensify. Fatalities have increased 5-fold since 1999 reaching a record high of 108,000 deaths in 2021. The epidemic has unfolded through distinct waves of different drug types, uniquely impacting various age, gender, race, and ethnic groups in specific geographical areas. One major challenge in designing interventions and efficiently delivering treatment is forecasting age-specific overdose patterns at the local level. To address this need, we develop a forecasting method that assimilates observational data obtained from the CDC WONDER database with an age-structured model of addiction and overdose mortality. We apply our method nationwide and to three select areas: Los Angeles County, Cook County, and the five boroughs of New York City, providing forecasts of drug-overdose mortality and estimates of relevant epidemiological quantities, such as mortality and age-specific addiction rates.

Control of Medical Digital Twins with Artificial Neural Networks.

The objective of personalized medicine is to tailor interventions to an individual patient's unique characteristics. A key technology for this purpose involves medical digital twins, computational models of human biology that can be personalized and dynamically updated to incorporate patient-specific data collected over time. Certain aspects of human biology, such as the immune system, are not easily captured with physics-based models, such as differential equations. Instead, they are often multi-scale, stochastic, and hybrid. This poses a challenge to existing model-based control and optimization approaches that cannot be readily applied to such models. Recent advances in automatic differentiation and neural-network control methods hold promise in addressing complex control problems. However, the application of these approaches to biomedical systems is still in its early stages. This work introduces dynamics-informed neural-network controllers as an alternative approach to control of medical digital twins. As a first use case for this method, the focus is on agent-based models, a versatile and increasingly common modeling platform in biomedicine. The effectiveness of the proposed neural-network control method is illustrated and benchmarked against other methods with two widely-used agent-based model types. The relevance of the method introduced here extends beyond medical digital twins to other complex dynamical systems.

Control of Medical Digital Twins with Artificial Neural Networks.

The objective of personalized medicine is to tailor interventions to an individual patient's unique characteristics. A key technology for this purpose involves medical digital twins, computational models of human biology that can be personalized and dynamically updated to incorporate patient-specific data collected over time. Certain aspects of human biology, such as the immune system, are not easily captured with physics-based models, such as differential equations. Instead, they are often multi-scale, stochastic, and hybrid. This poses a challenge to existing model-based control and optimization approaches that cannot be readily applied to such models. Recent advances in automatic differentiation and neural-network control methods hold promise in addressing complex control problems. However, the application of these approaches to biomedical systems is still in its early stages. This work introduces dynamics-informed neural-network controllers as an alternative approach to control of medical digital twins. As a first use case for this method, the focus is on agent-based models, a versatile and increasingly common modeling platform in biomedicine. The effectiveness of the proposed neural-network control method is illustrated and benchmarked against other methods with two widely-used agent-based model types. The relevance of the method introduced here extends beyond medical digital twins to other complex dynamical systems.

Surrogate modeling and control of medical digital twins.

The vision of personalized medicine is to identify interventions that maintain or restore a person's health based on their individual biology. Medical digital twins, computational models that integrate a wide range of health-related data about a person and can be dynamically updated, are a key technology that can help guide medical decisions. Such medical digital twin models can be high-dimensional, multi-scale, and stochastic. To be practical for healthcare applications, they often need to be simplified into low-dimensional surrogate models that can be used for optimal design of interventions. This paper introduces surrogate modeling algorithms for the purpose of optimal control applications. As a use case, we focus on agent-based models (ABMs), a common model type in biomedicine for which there are no readily available optimal control algorithms. By deriving surrogate models that are based on systems of ordinary differential equations, we show how optimal control methods can be employed to compute effective interventions, which can then be lifted back to a given ABM. The relevance of the methods introduced here extends beyond medical digital twins to other complex dynamical systems.

Impact of cross-reactivity and herd immunity on SARS-CoV-2 pandemic severity.

Public health systems reported low mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in East Asia, in low-income countries, and for children during the first year of the SARS-CoV-2 pandemic. These reports led commentators to suggest that cross-reactive immunity from prior exposure to other pathogens reduced fatality risk. Resolution of initial infection waves also contributed to speculation that herd immunity prevented further waves prior to vaccination. Serology instead implied that immunity was too limited to achieve herd immunity and that there was little impact from cross-reactive protection. Paediatric deaths exceeded those from influenza, with higher age-specific fatality risk in lower-income nations and similar fatality risk in East Asia compared with demographically similar regions. Neither pre-outbreak exposure to related pathogens nor immunity induced by initial infection waves are necessarily a reliable response to future pathogen outbreaks. Preparedness for future pathogen outbreaks should instead focus on strategies such as voluntary behavioural changes, nonpharmaceutical interventions, and vaccination.

Modeling and forecasting age-specific drug overdose mortality in the United States.

Drug overdose deaths continue to increase in the United States for all major drug categories. Over the past two decades the total number of overdose fatalities has increased more than fivefold; since 2013 the surge in overdose rates is primarily driven by fentanyl and methamphetamines. Different drug categories and factors such as age, gender, and ethnicity are associated with different overdose mortality characteristics that may also change in time. For example, the average age at death from a drug overdose has decreased from 1940 to 1990 while the overall mortality rate has steadily increased. To provide insight into the population-level dynamics of drug overdose mortality, we develop an age-structured model for drug addiction. Using an augmented ensemble Kalman filter (EnKF), we show through a simple example how our model can be combined with synthetic observation data to estimate mortality rate and an age-distribution parameter. Finally, we use an EnKF to combine our model with observation data on overdose fatalities in the United States from 1999 to 2020 to forecast the evolution of overdose trends and estimate model parameters.

Fentanyl-driven acceleration of racial, gender and geographical disparities in drug overdose deaths in the United States.

We examine trends in drug overdose deaths by race, gender, and geography in the United States during the period 2013-2020. Race and gender specific crude rates were extracted from the final National Vital Statistics System multiple cause-of-death mortality files for several jurisdictions and used to calculate the male-to-female ratios of crude rates between 2013 and 2020. We established 2013-2019 temporal trends for four major drug types: psychostimulants with addiction potential (T43.6, such as methamphetamines); heroin (T40.1); natural and semi-synthetic opioids (T40.2, such as those contained in prescription pain-killers); synthetic opioids (T40.4, such as fentanyl and its derivatives) through a quadratic regression and determined whether changes in the pandemic year 2020 were statistically significant. We also identified which race, gender and states were most impacted by drug overdose deaths. Nationwide, the year 2020 saw statistically significant increases in overdose deaths from all drug categories except heroin, surpassing predictions based on 2013-2019 trends. Crude rates for Black individuals of both genders surpassed those for White individuals for fentanyl and psychostimulants in 2018, creating a gap that widened through 2020. In some regions, mortality among White persons decreased while overdose deaths for Black persons kept rising. The largest 2020 mortality statistic is for Black males in the District of Columbia, with a record 134 overdose deaths per 100,000 due to fentanyl, 9.4 times more than the fatality rate among White males. Male overdose crude rates in 2020 remain larger than those of females for all drug categories except in Idaho, Utah and Arkansas where crude rates of overdose deaths by natural and semisynthetic opioids for females exceeded those of males. Drug prevention, mitigation and no-harm strategies should include racial, geographical and gender-specific efforts, to better identify and serve at-risk groups.

Modeling and forecasting age-specific drug overdose mortality in the United States.

Drug overdose deaths continue to increase in the United States for all major drug categories. Over the past two decades the total number of overdose fatalities has increased more than five-fold; since 2013 the surge in overdose rates is primarily driven by fentanyl and methamphetamines. Different drug categories and factors such as age, gender, and ethnicity are associated with different overdose mortality characteristics that may also change in time. For example, the average age at death from a drug overdose has decreased from 1940 to 1990 while the overall mortality rate has steadily increased. To provide insight into the population-level dynamics of drug-overdose mortality, we develop an age-structured model for drug addiction. Using an augmented ensemble Kalman filter (EnKF), we show through a simple example how our model can be combined with synthetic observation data to estimate mortality rate and an age-distribution parameter. Finally, we use an EnKF to combine our model with observation data on overdose fatalities in the United States from 1999 to 2020 to forecast the evolution of overdose trends and estimate model parameters.