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.

A probabilistic model of relapse in drug addiction.

More than 60% of individuals recovering from substance use disorder relapse within one year. Some will resume drug consumption even after decades of abstinence. The cognitive and psychological mechanisms that lead to relapse are not completely understood, but stressful life experiences and external stimuli that are associated with past drug-taking are known to play a primary role. Stressors and cues elicit memories of drug-induced euphoria and the expectation of relief from current anxiety, igniting an intense craving to use again; positive experiences and supportive environments may mitigate relapse. We present a mathematical model of relapse in drug addiction that draws on known psychiatric concepts such as the "positive activation; negative activation" paradigm and the "peak-end" rule to construct a relapse rate that depends on external factors (intensity and timing of life events) and individual traits (mental responses to these events). We analyze which combinations and ordering of stressors, cues, and positive events lead to the largest relapse probability and propose interventions to minimize the likelihood of relapse. We find that the best protective factor is exposure to a mild, yet continuous, source of contentment, rather than large, episodic jolts of happiness.

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.

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.

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.

A mathematical model of reward-mediated learning in drug addiction.

Substances of abuse are known to activate and disrupt neuronal circuits in the brain reward system. We propose a simple and easily interpretable dynamical systems model to describe the neurobiology of drug addiction that incorporates the psychiatric concepts of reward prediction error, drug-induced incentive salience, and opponent process theory. Drug-induced dopamine releases activate a biphasic reward response with pleasurable, positive "a-processes" (euphoria, rush) followed by unpleasant, negative "b-processes" (cravings, withdrawal). Neuroadaptive processes triggered by successive intakes enhance the negative component of the reward response, which the user compensates for by increasing drug dose and/or intake frequency. This positive feedback between physiological changes and drug self-administration leads to habituation, tolerance, and, eventually, to full addiction. Our model gives rise to qualitatively different pathways to addiction that can represent a diverse set of user profiles (genetics, age) and drug potencies. We find that users who have, or neuroadaptively develop, a strong b-process response to drug consumption are most at risk for addiction. Finally, we include possible mechanisms to mitigate withdrawal symptoms, such as through the use of methadone or other auxiliary drugs used in detoxification.

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 statistical model of COVID-19 testing in populations: effects of sampling bias and testing 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.

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.

Impacts of California Proposition 47 on crime in Santa Monica, California.

We examine patterns of reported crime in Santa Monica, California before and after the passage of Proposition 47, a 2014 initiative that reclassified some non-violent felonies as misdemeanors. We also investigate impacts of the opening of four new light rail stations in 2016 and of increased community-based policing starting in late 2018. Our statistical analyses of reclassified crimes-larceny, fraud, possession of narcotics, forgery, receiving/possessing stolen property-and non-reclassified ones are based on publicly available reported crime data from 2006 to 2019. These analyses examine reported crime at various levels: city-wide, within eight neighborhoods, and within a 450-meter radius of the new transit stations. Monthly reported reclassified crimes increased city-wide by approximately 15% after enactment of Proposition 47, with a significant drop observed in late 2018. Downtown exhibited the largest overall surge. Reported non-reclassified crimes fell overall by approximately 9%. Areas surrounding two new train stations, including Downtown, saw significant increases in reported crime after train service began. While reported reclassified crimes increased after passage of Proposition 47, non-reclassified crimes, for the most part, decreased or stayed constant, suggesting that Proposition 47 may have impacted reported crime in Santa Monica. Reported crimes decreased in late 2018 concurrent with the adoption of new community-based policing measures. Follow-up studies needed to confirm long-term trends may be challenging due to the COVID-19 pandemic that drastically changed societal conditions. While our research detects changes in reported crime, it does not provide causative explanations. Our work, along with other considerations relevant to public utility, respect for human rights, and existence of socioeconomic disparities, may be useful to law enforcement and policymakers to assess the overall effect of Proposition 47.

Temporal clustering of disorder events during the COVID-19 pandemic.

The COVID-19 pandemic has unleashed multiple public health, socio-economic, and institutional crises. Measures taken to slow the spread of the virus have fostered significant strain between authorities and citizens, leading to waves of social unrest and anti-government demonstrations. We study the temporal nature of pandemic-related disorder events as tallied by the "COVID-19 Disorder Tracker" initiative by focusing on the three countries with the largest number of incidents, India, Israel, and Mexico. By fitting Poisson and Hawkes processes to the stream of data, we find that disorder events are inter-dependent and self-excite in all three countries. Geographic clustering confirms these features at the subnational level, indicating that nationwide disorders emerge as the convergence of meso-scale patterns of self-excitation. Considerable diversity is observed among countries when computing correlations of events between subnational clusters; these are discussed in the context of specific political, societal and geographic characteristics. Israel, the most territorially compact and where large scale protests were coordinated in response to government lockdowns, displays the largest reactivity and the shortest period of influence following an event, as well as the strongest nationwide synchrony. In Mexico, where complete lockdown orders were never mandated, reactivity and nationwide synchrony are lowest. Our work highlights the need for authorities to promote local information campaigns to ensure that livelihoods and virus containment policies are not perceived as mutually exclusive.

Using excess deaths and testing statistics to improve estimates of COVID-19 mortalities.

Factors such as non-uniform 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 is 13% 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 negligible or negative excess deaths for part and all of 2020 for Denmark, Germany, and Norway.

Using excess deaths and testing statistics to improve estimates of COVID-19 mortalities.

Factors such as non-uniform 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 is 13$\%$ 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 negligible or negative excess deaths for part and all of 2020 for Denmark, Germany, and Norway.

Mathematical modeling of depressive disorders: Circadian driving, bistability and dynamical transitions.

The hypothalamus-pituitary-adrenal (HPA) axis is a key neuroendocrine system implicated in stress response, major depression disorder, and post-traumatic stress disorder. We present a new, compact dynamical systems model for the response of the HPA axis to external stimuli, representing stressors or therapeutic intervention, in the presence of a circadian input. Our work builds upon previous HPA axis models where hormonal dynamics are separated into slow and fast components. Several simplifications allow us to derive an effective model of two equations, similar to a multiplicative-input FitzHugh-Nagumo system, where two stable states, a healthy and a diseased one, arise. We analyze the effective model in the context of state transitions driven by external shocks to the hypothalamus, but also modulated by circadian rhythms. Our analyses provide mechanistic insight into the effects of the circadian cycle on input driven transitions of the HPA axis and suggest a circadian influence on exposure or cognitive behavioral therapy in depression, or post-traumatic stress disorder treatment.

How Naive T-Cell Clone Counts Are Shaped By Heterogeneous Thymic Output and Homeostatic Proliferation.

The specificity of T cells is that each T cell has only one T cell receptor (TCR). A T cell clone represents a collection of T cells with the same TCR sequence. Thus, the number of different T cell clones in an organism reflects the number of different T cell receptors (TCRs) that arise from recombination of the V(D)J gene segments during T cell development in the thymus. TCR diversity and more specifically, the clone abundance distribution, are important factors in immune functions. Specific recombination patterns occur more frequently than others while subsequent interactions between TCRs and self-antigens are known to trigger proliferation and sustain naive T cell survival. These processes are TCR-dependent, leading to clone-dependent thymic export and naive T cell proliferation rates. We describe the heterogeneous steady-state population of naive T cells (those that have not yet been antigenically triggered) by using a mean-field model of a regulated birth-death-immigration process. After accounting for random sampling, we investigate how TCR-dependent heterogeneities in immigration and proliferation rates affect the shape of clone abundance distributions (the number of different clones that are represented by a specific number of cells, or "clone counts"). By using reasonable physiological parameter values and fitting predicted clone counts to experimentally sampled clone abundances, we show that realistic levels of heterogeneity in immigration rates cause very little change to predicted clone-counts, but that modest heterogeneity in proliferation rates can generate the observed clone abundances. Our analysis provides constraints among physiological parameters that are necessary to yield predictions that qualitatively match the data. Assumptions of the model and potentially other important mechanistic factors are discussed.

Local alliances and rivalries shape near-repeat terror activity of al-Qaeda, ISIS, and insurgents.

We study the spatiotemporal correlation of terrorist attacks by al-Qaeda, the Islamic State of Iraq and Syria (ISIS), and local insurgents, in six geographical areas identified via k-means clustering applied to the Global Terrorism Database. All surveyed organizations exhibit near-repeat activity whereby a prior attack increases the likelihood of a subsequent one by the same group within 20 km and on average 4 (al-Qaeda) to 10 (ISIS) weeks. Near-response activity, whereby an attack by a given organization elicits further attacks from a different one, is found to depend on the adversarial, neutral, or collaborative relationship between the two. When in conflict, local insurgents respond quickly to attacks by global terror groups while global terror groups delay their responses to local insurgents, leading to an asymmetric dynamic. When neutral or allied, attacks by one group enhance the response likelihood of the other, regardless of hierarchy. These trends arise consistently in all clusters for which data are available. Government intervention and spillover effects are also discussed; we find no evidence of outbidding. Understanding the regional dynamics of terrorism may be greatly beneficial in policy making and intervention design.

Perturbing the Hypothalamic-Pituitary-Adrenal Axis: A Mathematical Model for Interpreting PTSD Assessment Tests.

We use a dynamical systems model of the hypothalamic-pituitary-adrenal (HPA) axis to understand the mechanisms underlying clinical protocols used to probe patient stress response. Specifically, we address dexamethasone (DEX) and ACTH challenge tests, which probe pituitary and adrenal gland responses, respectively. We show that some previously observed features and experimental responses can arise from a bistable mathematical model containing two steady-states, rather than relying on specific and permanent parameter changes due to physiological disruption. Moreover, we show that the timing of a perturbation relative to the intrinsic oscillation of the HPA axis can affect challenge test responses. Conventional mechanistic hypotheses supported and refuted by the challenge tests are reexamined by varying parameters in our mathematical model associated with these hypotheses. We show that (a) adrenal hyposensitivity can give rise to the responses seen in ACTH challenge tests and (b) enhanced cortisol-mediated suppression of the pituitary in subjects with PTSD is not necessary to explain the responses observed in DEX stress tests. We propose a new two-stage DEX/external stressor protocol to more clearly distinguish between the conventional hypothesis of enhanced suppression of the pituitary and bistable dynamics hypothesized in our model.

The Effects of Statistical Multiplicity of Infection on Virus Quantification and Infectivity Assays.

Many biological assays are employed in virology to quantify parameters of interest. Two such classes of assays, virus quantification assays (VQAs) and infectivity assays (IAs), aim to estimate the number of viruses present in a solution and the ability of a viral strain to successfully infect a host cell, respectively. VQAs operate at extremely dilute concentrations, and results can be subject to stochastic variability in virus-cell interactions. At the other extreme, high viral-particle concentrations are used in IAs, resulting in large numbers of viruses infecting each cell, enough for measurable change in total transcription activity. Furthermore, host cells can be infected at any concentration regime by multiple particles, resulting in a statistical multiplicity of infection and yielding potentially significant variability in the assay signal and parameter estimates. We develop probabilistic models for statistical multiplicity of infection at low and high viral-particle-concentration limits and apply them to the plaque (VQA), endpoint dilution (VQA), and luciferase reporter (IA) assays. A web-based tool implementing our models and analysis is also developed and presented. We test our proposed new methods for inferring experimental parameters from data using numerical simulations and show improvement on existing procedures in all limits.

Modelling radicalization: how small violent fringe sects develop into large indoctrinated societies.

We model radicalization in a society consisting of two competing religious, ethnic or political groups. Each of the 'sects' is divided into moderate and radical factions, with intra-group transitions occurring either spontaneously or through indoctrination. We also include the possibility of one group violently attacking the other. The intra-group transition rates of one group are modelled to explicitly depend on the actions and characteristics of the other, including violent episodes, effectively coupling the dynamics of the two sects. We use a game theoretic framework and assume that radical factions may tune 'strategic' parameters to optimize given utility functions aimed at maximizing their ranks while minimizing the damage inflicted by their rivals. Constraints include limited overall resources that must be optimally allocated between indoctrination and external attacks on the other group. Various scenarios are considered, from symmetric sects whose behaviours mirror each other, to totally asymmetric ones where one sect may have a larger population or a superior resource availability. We discuss under what conditions sects preferentially employ indoctrination or violence, and how allowing sects to readjust their strategies allows for small, violent sects to grow into large, indoctrinated communities.

Phthalates, heavy metals and PAHs in an overpopulated coastal region: Inferences from Abruzzo, central Italy.

Phthalates are an emerging class of environmental pollutants whose distribution and effects in aquatic environments are not well characterized. We analyzed intertidal and emerged beach sediments from the Abruzzo coastline, along the Adriatic Sea, finding significant phthalate concentrations in marine sediments. Phthalate baseline levels in the intertidal environment, marked by substantial interplay of sediment, water and air, were determined. We used statistical rank methods to select representative phthalate compositions, for which we derived risk levels for ingestion, dermal absorption and inhalation. Our study shows that phthalates are a major cause of pollution along the Abruzzo coast, with river transport of sediments a continuous source of replenishment. Phthalate concentrations in two specific sites were determined to be of the same order of magnitude as the safety, remediation-warranting, threshold set by Italian law. Phthalates, heavy metals, PAHs appear to be correlated. We discuss possible intervention and mitigation strategies.