Rothman diagrams: the geometry of causal inference in epidemiology.

Here, we explain and illustrate a geometric perspective on causal inference in cohort studies that can help epidemiologists understand the role of standardization in causal inference as well as the distinctions between confounding, effect modification, and noncollapsibility. For simplicity, we focus on a binary exposure X, a binary outcome D, and a binary confounder C that is not causally affected by X. Rothman diagrams plot risk in the unexposed on the x-axis and risk in the exposed on the y-axis. The crude risks define one point in the unit square, and the stratum-specific risks define two other points in the unit square. These three points can be used to identify confounding and effect modification, and we show briefly how these concepts generalize to confounders with more than two levels. We propose a simplified but equivalent definition of collapsibility in terms of standardization, and we show that a measure of association is collapsible if and only if all of its contour lines are straight. We illustrate these ideas using data from a study conducted in Newcastle upon Tyne, United Kingdom, where the causal effect of smoking on 20-year mortality was confounded by age. We conclude that causal inference should be taught using geometry before using regression models.

Identifying beliefs driving COVID-19 vaccination: Lessons for effective messaging.

Increasing vaccination acceptance has been essential during the COVID-19 pandemic and in preparation for future public health emergencies. This study aimed to identify messaging strategies to encourage vaccine uptake by measuring the drivers of COVID-19 vaccination among the general public. A survey to assess COVID-19 vaccination acceptance and hesitancy was advertised on Facebook in February-April 2022. The survey included items asking about COVID-19 vaccination status and participant demographics, and three scales assessing medical mistrust, perceived COVID-19 risk, and COVID-19 vaccine confidence (adapted from the Oxford COVID-19 vaccine confidence and complacency scale). The main outcome was vaccination, predicted by patient demographics and survey scale scores. Of 1,915 survey responses, 1,450 (75.7%) were included, with 1,048 (72.3%) respondents reporting they had been vaccinated. In a multivariable regression model, the COVID-19 vaccine confidence scale was the strongest predictor of vaccination, along with education level and perceived COVID-19 risk. Among the items on this scale, not all were equally important in predicting COVID-19 vaccination. The items that best predicted vaccination, at a given score on the COVID-19 vaccine confidence scale, included confidence that vaccine side effects are minimal, that the vaccine will work, that the vaccine will help the community, and that the vaccine provides freedom to move on with life. This study improved our understanding of perceptions most strongly associated with vaccine acceptance, allowing us to consider how to develop messages that may be particularly effective in encouraging vaccination among the general public for both the COVID-19 pandemic and future public health emergencies.

A Potential Outcomes Approach to Selection Bias.

We propose a novel definition of selection bias in analytic epidemiology using potential outcomes. This definition captures selection bias under both the structural approach (where conditioning on selection into the study opens a noncausal path from exposure to disease in a directed acyclic graph) and the traditional definition (where a given measure of association differs between the study sample and the population eligible for inclusion). This approach is nonparametric, and selection bias under the approach can be analyzed using single-world intervention graphs both under and away from the null hypothesis. It allows the simultaneous analysis of confounding and selection bias, it explicitly links the selection of study participants to the estimation of causal effects using study data, and it can be adapted to handle selection bias in descriptive epidemiology. Through examples, we show that this approach provides a novel perspective on the variety of mechanisms that can generate selection bias and simplifies the analysis of selection bias in matched studies and case-cohort studies.

Necessary and sufficient conditions for exact closures of epidemic equations on configuration model networks.

We prove that it is possible to obtain the exact closure of SIR pairwise epidemic equations on a configuration model network if and only if the degree distribution follows a Poisson, binomial, or negative binomial distribution. The proof relies on establishing the equivalence, for these specific degree distributions, between the closed pairwise model and a dynamical survival analysis (DSA) model that was previously shown to be exact. Specifically, we demonstrate that the DSA model is equivalent to the well-known edge-based Volz model. Using this result, we also provide reductions of the closed pairwise and Volz models to a single equation that involves only susceptibles. This equation has a useful statistical interpretation in terms of times to infection. We provide some numerical examples to illustrate our results.

COVID-19 dynamics in an Ohio prison.

Incarcerated individuals are a highly vulnerable population for infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Understanding the transmission of respiratory infections within prisons and between prisons and surrounding communities is a crucial component of pandemic preparedness and response. Here, we use mathematical and statistical models to analyze publicly available data on the spread of SARS-CoV-2 reported by the Ohio Department of Rehabilitation and Corrections (ODRC). Results from mass testing conducted on April 16, 2020 were analyzed together with time of first reported SARS-CoV-2 infection among Marion Correctional Institution (MCI) inmates. Extremely rapid, widespread infection of MCI inmates was reported, with nearly 80% of inmates infected within 3 weeks of the first reported inmate case. The dynamical survival analysis (DSA) framework that we use allows the derivation of explicit likelihoods based on mathematical models of transmission. We find that these data are consistent with three non-exclusive possibilities: (i) a basic reproduction number >14 with a single initially infected inmate, (ii) an initial superspreading event resulting in several hundred initially infected inmates with a reproduction number of approximately three, or (iii) earlier undetected circulation of virus among inmates prior to April. All three scenarios attest to the vulnerabilities of prisoners to COVID-19, and the inability to distinguish among these possibilities highlights the need for improved infection surveillance and reporting in prisons.

Infection-Induced Immunity Is Associated With Protection Against Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Decreased Infectivity.

BACKGROUND: The impact of infection-induced immunity on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission has not been well established. Here we estimate the effects of prior infection induced immunity in adults and children on SARS-CoV-2 transmission in households. METHODS: We conducted a household cohort study from March 2020-November 2022 in Managua, Nicaragua; following a housheold SARS-CoV-2 infection, household members are closely monitored for infection. We estimate the association of time period, age, symptoms, and prior infection with secondary attack risk. RESULTS: Overall, transmission occurred in 70.2% of households, 40.9% of household contacts were infected, and the secondary attack risk ranged from 8.1% to 13.9% depending on the time period. Symptomatic infected individuals were more infectious (rate ratio [RR] 21.2, 95% confidence interval [CI]: 7.4-60.7) and participants with a prior infection were half as likely to be infected compared to naïve individuals (RR 0.52, 95% CI:.38-.70). In models stratified by age, prior infection was associated with decreased infectivity in adults and adolescents (secondary attack risk [SAR] 12.3, 95% CI: 10.3, 14.8 vs 17.5, 95% CI: 14.8, 20.7). However, although young children were less likely to transmit, neither prior infection nor symptom presentation was associated with infectivity. During the Omicron era, infection-induced immunity remained protective against infection. CONCLUSIONS: Infection-induced immunity is associated with decreased infectivity for adults and adolescents. Although young children are less infectious, prior infection and asymptomatic presentation did not reduce their infectivity as was seen in adults. As SARS-CoV-2 transitions to endemicity, children may become more important in transmission dynamics.

Projecting COVID-19 cases and hospital burden in Ohio.

As the Coronavirus 2019 disease (COVID-19) started to spread rapidly in the state of Ohio, the Ecology, Epidemiology and Population Health (EEPH) program within the Infectious Diseases Institute (IDI) at The Ohio State University (OSU) took the initiative to offer epidemic modeling and decision analytics support to the Ohio Department of Health (ODH). This paper describes the methodology used by the OSU/IDI response modeling team to predict statewide cases of new infections as well as potential hospital burden in the state. The methodology has two components: (1) A Dynamical Survival Analysis (DSA)-based statistical method to perform parameter inference, statewide prediction and uncertainty quantification. (2) A geographic component that down-projects statewide predicted counts to potential hospital burden across the state. We demonstrate the overall methodology with publicly available data. A Python implementation of the methodology is also made publicly available. This manuscript was submitted as part of a theme issue on "Modelling COVID-19 and Preparedness for Future Pandemics".

Catch the tweet to fight the flu: Using Twitter to promote flu shots on a college campus.

Objective: Over the 2018-2019 flu season we conducted a randomized controlled trial examining the efficacy of a Twitter campaign on vaccination rates. Concurrently we investigated potential interactions between digital social network structure and vaccination status. Participants: Undergratuates at a large midwestern public university were randomly assigned to an intervention (n = 353) or control (n = 349) group. Methods: Vaccination data were collected via monthly surveys. Participant Twitter data were collected through the public-facing Twitter API. Intervention impact was assessed with logistic regression. Standard network science tools examined vaccination coverage over online social networks. Results: The campaign had no effect on vaccination outcome. Receiving a flu shot the prior year had a positive impact on participant vaccination. Evidence of an interaction between digital social network structure and vaccination status was detected. Conclusions: Social media campaigns may not be sufficient for increasing vaccination rates. There may be potential for social media campaigns that leverage network structure.

Infection-induced immunity is associated with protection against SARS-CoV-2 infection, but not decreased infectivity during household transmission.

Background: Understanding the impact of infection-induced immunity on SARS-CoV-2 transmission will provide insight into the transition of SARS-CoV-2 to endemicity. Here we estimate the effects of prior infection induced immunity and children on SARS-CoV-2 transmission in households. Methods: We conducted a household cohort study between March 2020-June 2022 in Managua, Nicaragua where when one household member tests positive for SARS-CoV-2, household members are closely monitored for SARS-CoV-2 infection. Using a pairwise survival model, we estimate the association of infection period, age, symptoms, and infection-induced immunity with secondary attack risk. Results: Overall transmission occurred in 72.4% of households, 42% of household contacts were infected and the secondary attack risk was 13.0% (95% CI: 11.7, 14.6). Prior immunity did not impact the probability of transmitting SARS-CoV-2. However, participants with pre-existing infection-induced immunity were half as likely to be infected compared to naïve individuals (RR 0.53, 95% CI: 0.39, 0.72), but this reduction was not observed in children. Likewise, symptomatic infected individuals were more likely to transmit (RR 24.4, 95% CI: 7.8, 76.1); however, symptom presentation was not associated with infectivity of young children. Young children were less likely to transmit SARS-CoV-2 than adults. During the omicron era, infection-induced immunity remained protective against infection. Conclusions: Infection-induced immunity is associated with protection against infection for adults and adolescents. While young children are less infectious, prior infection and asymptomatic presentation did not reduce their infectivity as was seen in adults. As SARS-CoV-2 transitions to endemicity, children may become more important in transmission dynamics. Article summary: Infection-induced immunity protects against SARS-CoV-2 infection for adolescents and adults; however, there was no protection in children. Prior immunity in an infected individual did not impact the probability they will spread SARS-CoV-2 in a household setting.

Shortening Duration of Swine Exhibitions to Reduce Risk for Zoonotic Transmission of Influenza A Virus.

Reducing zoonotic influenza A virus (IAV) risk in the United States necessitates mitigation of IAV in exhibition swine. We evaluated the effectiveness of shortening swine exhibitions to <72 hours to reduce IAV risk. We longitudinally sampled every pig daily for the full duration of 16 county fairs during 2014-2015 (39,768 nasal wipes from 6,768 pigs). In addition, we estimated IAV prevalence at 195 fairs during 2018-2019 to test the hypothesis that <72-hour swine exhibitions would have lower IAV prevalence. In both studies, we found that shortening duration drastically reduces IAV prevalence in exhibition swine at county fairs. Reduction of viral load in the barn within a county fair is critical to reduce the risk for interspecies IAV transmission and pandemic potential. Therefore, we encourage fair organizers to shorten swine shows to protect the health of both animals and humans.

Projecting COVID-19 Cases and Subsequent Hospital Burden in Ohio.

As the Coronavirus 2019 (COVID-19) disease started to spread rapidly in the state of Ohio, the Ecology, Epidemiology and Population Health (EEPH) program within the Infectious Diseases Institute (IDI) at the Ohio State University (OSU) took the initiative to offer epidemic modeling and decision analytics support to the Ohio Department of Health (ODH). This paper describes the methodology used by the OSU/IDI response modeling team to predict statewide cases of new infections as well as potential hospital burden in the state. The methodology has two components: 1) A Dynamic Survival Analysis (DSA)-based statistical method to perform parameter inference, statewide prediction and uncertainty quantification. 2) A geographic component that down-projects statewide predicted counts to potential hospital burden across the state. We demonstrate the overall methodology with publicly available data. A Python implementation of the methodology has been made available publicly. Highlights: We present a novel statistical approach called Dynamic Survival Analysis (DSA) to model an epidemic curve with incomplete data. The DSA approach is advantageous over standard statistical methods primarily because it does not require prior knowledge of the size of the susceptible population, the overall prevalence of the disease, and also the shape of the epidemic curve.The principal motivation behind the study was to obtain predictions of case counts of COVID-19 and the resulting hospital burden in the state of Ohio during the early phase of the pandemic.The proposed methodology was applied to the COVID-19 incidence data in the state of Ohio to support the Ohio Department of Health (ODH) and the Ohio Hospital Association (OHA) with predictions of hospital burden in each of the Hospital Catchment Areas (HCAs) of the state.

Dynamic survival analysis for non-Markovian epidemic models.

We present a new method for analysing stochastic epidemic models under minimal assumptions. The method, dubbed dynamic survival analysis (DSA), is based on a simple yet powerful observation, namely that population-level mean-field trajectories described by a system of partial differential equations may also approximate individual-level times of infection and recovery. This idea gives rise to a certain non-Markovian agent-based model and provides an agent-level likelihood function for a random sample of infection and/or recovery times. Extensive numerical analyses on both synthetic and real epidemic data from foot-and-mouth disease in the UK (2001) and COVID-19 in India (2020) show good accuracy and confirm the method's versatility in likelihood-based parameter estimation. The accompanying software package gives prospective users a practical tool for modelling, analysing and interpreting epidemic data with the help of the DSA approach.

Analysis of individual-level data from 2018-2020 Ebola outbreak in Democratic Republic of the Congo.

The 2018-2020 Ebola virus disease epidemic in Democratic Republic of the Congo (DRC) resulted in 3481 cases (probable and confirmed) and 2299 deaths. In this paper, we use a novel statistical method to analyze the individual-level incidence and hospitalization data on DRC Ebola victims. Our analysis suggests that an increase in the rate of quarantine and isolation that has shortened the infectiousness period by approximately one day during the epidemic's third and final wave was likely responsible for the eventual containment of the outbreak. The analysis further reveals that the total effective population size or the average number of individuals at risk for the disease exposure in three epidemic waves over the period of 24 months was around 16,000-a much smaller number than previously estimated and likely an evidence of at least partial protection of the population at risk through ring vaccination and contact tracing as well as adherence to strict quarantine and isolation policies.

The COVID-19 vaccine concerns scale: Development and validation of a new measure.

Reasons for COVID-19 hesitancy are multi-faceted and tend to differ from those for general vaccine hesitancy. We developed the COVID-19 Vaccine Concerns Scale (CVCS), a self-report measure intended to better understand individuals' concerns about COVID-19 vaccines. We validated the scale using data from a convenience sample of 2,281 emergency medical services providers, a group of professionals with high occupational COVID-19 risk. Measures included the CVCS items, an adapted Oxford COVID-19 vaccine hesitancy scale, a general vaccine hesitancy scale, demographics, and self-reported COVID-19 vaccination status. The CVCS had high internal consistency reliability (α = .89). A one-factor structure was determined by exploratory and confirmatory factor analyses (EFA and CFA), resulting in a seven-item scale. The model had good fit (X2[14] = 189.26, p < .001; CFI = .95, RMSEA = .11 [.09, .12], NNFI = .93, SRMR = .03). Moderate Pearson correlations with validated scales of general vaccine hesitancy (r = .71 , p < .001; n = 2144) and COVID-19 vaccine hesitancy (r = .82; p < .001; n = 2279) indicated construct validity. The CVCS predicted COVID-19 vaccination status (B = -2.21, Exp(B) = .11 [95% CI = .09, .13], Nagelkerke R2 = .55), indicating criterion-related validity. In sum, the 7-item CVCS is a reliable and valid self-report measure to examine fears and concerns about COVID-19 vaccines. The scale predicts COVID-19 vaccination status and can be used to inform efforts to reduce COVID-19 vaccine hesitancy.

Closing the Gap on COVID-19 Vaccinations in First Responders and Beyond: Increasing Trust.

Although COVID-19 vaccines are widely available in the U.S. and much of the world, many have chosen to forgo this vaccination. Emergency medical services (EMS) professionals, despite their role on the frontlines and interactions with COVID-positive patients, are not immune to vaccine hesitancy. Via a survey conducted in April 2021, we investigated the extent to which first responders in the U.S. trusted various information sources to provide reliable information about COVID-19 vaccines. Those vaccinated generally trusted healthcare providers as a source of information, but unvaccinated first responders had fairly low trust in this information source-a group to which they, themselves, belong. Additionally, regardless of vaccination status, trust in all levels of government, employers, and their community as sources of information was low. Free-response explanations provided some context to these findings, such as preference for other COVID-19 management options, including drugs proven ineffective. A trusted source of COVID-19 vaccination information is not readily apparent. Individuals expressed a strong desire for the autonomy to make vaccination decisions for themselves, as opposed to mandates. Potential reasons for low trust, possible solutions to address them, generalizability to the broader public, and implications of low trust in official institutions are discussed.

Commentary on the use of the reproduction number R during the COVID-19 pandemic.

Since the beginning of the COVID-19 pandemic, the reproduction number [Formula: see text] has become a popular epidemiological metric used to communicate the state of the epidemic. At its most basic, [Formula: see text] is defined as the average number of secondary infections caused by one primary infected individual. [Formula: see text] seems convenient, because the epidemic is expanding if [Formula: see text] and contracting if [Formula: see text]. The magnitude of [Formula: see text] indicates by how much transmission needs to be reduced to control the epidemic. Using [Formula: see text] in a naïve way can cause new problems. The reasons for this are threefold: (1) There is not just one definition of [Formula: see text] but many, and the precise definition of [Formula: see text] affects both its estimated value and how it should be interpreted. (2) Even with a particular clearly defined [Formula: see text], there may be different statistical methods used to estimate its value, and the choice of method will affect the estimate. (3) The availability and type of data used to estimate [Formula: see text] vary, and it is not always clear what data should be included in the estimation. In this review, we discuss when [Formula: see text] is useful, when it may be of use but needs to be interpreted with care, and when it may be an inappropriate indicator of the progress of the epidemic. We also argue that careful definition of [Formula: see text], and the data and methods used to estimate it, can make [Formula: see text] a more useful metric for future management of the epidemic.

COVID-19 Vaccinations in EMS Professionals: Prevalence and Predictors.

Background: Immunizations for emergency medical services (EMS) professionals during pandemics are an important tool to increase the safety of the workforce as well as their patients. The purpose of this study was to better understand EMS professionals' decisions to receive or decline a COVID-19 vaccine.Methods: We conducted a cross-sectional analysis of nationally certified EMS professionals (18-85 years) in April 2021. Participants received an electronic survey asking whether they received a vaccine, why or why not, and their associated beliefs using three validated scales: perceived risk of COVID-19, medical mistrust, and confidence in the COVID-19 vaccine. Data were merged with National Registry dataset demographics. Analyses included descriptive analysis and multivariable logistic regression (OR, 95% CI). Multivariate imputation by chained equations was used for missingness.Results: A total of 2,584 respondents satisfied inclusion criteria (response rate = 14%). Overall, 70% of EMS professionals were vaccinated. Common reasons for vaccination among vaccinated respondents were to protect oneself (76%) and others (73%). Common reasons for non-vaccination among non-vaccinated respondents included concerns about vaccine safety (53%) and beliefs that vaccination was not necessary (39%). Most who had not received the vaccine did not plan to get it in the future (84%). Hesitation was most frequently related to wanting to see how the vaccine was working for others (55%). Odds of COVID-19 vaccination were associated with demographics including age (referent <28 years; 39-50 years: 1.56, 1.17-2.08; >51 years: 2.22, 1.64-3.01), male sex (1.26, 1.01-1.58), residing in an urban/suburban area (referent rural; 1.36, 1.08-1.70), advanced education (referent GED/high school and below; bachelor's and above: 1.72, 1.19-2.47), and working at a hospital (referent fire-based agency; 1.53, 1.04-2.24). Additionally, vaccination odds were significantly higher with greater perceived risk of COVID-19 (2.05, 1.68-2.50), and higher vaccine confidence (2.84, 2.40-3.36). Odds of vaccination were significantly lower with higher medical mistrust (0.54, 0.46-0.63).Conclusion: Despite vaccine availability, not all EMS professionals had been vaccinated. The decision to receive a COVID-19 vaccine was associated with demographics, beliefs regarding COVID-19 and the vaccine, and medical mistrust. Efforts to increase COVID-19 vaccination rates should emphasize the safety and efficacy of vaccines.

Influenza Vaccination of Swine Reduces Public Health Risk at the Swine-Human Interface.

Influenza A viruses (IAV) in swine (IAV-S) pose serious risk to public health through spillover at the human-animal interface. Continued zoonotic transmission increases the likelihood novel IAV-S capable of causing the next influenza pandemic will emerge from this animal reservoir. Because current mitigation strategies are insufficient to prevent IAV zoonosis, we investigated the ability of swine vaccination to decrease IAV-S zoonotic transmission risk. We assessed postchallenge viral shedding in market-age swine vaccinated with either live-attenuated influenza virus (LAIV), killed influenza virus (KV), or sham vaccine (NV). We also assessed postchallenge transmission by exposing naive ferrets to pigs with contact types reflective of those experienced by humans in a field setting. LAIV and KV swine groups exhibited a nearly 100-fold reduction in peak nasal titer (LAIV mean, 4.55 log 50% tissue culture infectious dose [TCID50]/ml; KV mean, 4.53 log TCID50/ml) compared to NV swine (mean, 6.40 log TCID50/ml). Air sampling during the postchallenge period revealed decreased cumulative IAV in LAIV and KV study room air (LAIV, area under the concentration-time curve [AUC] of 57.55; KV, AUC = 24.29) compared to the NV study room (AUC = 86.92). Pairwise survival analysis revealed a significant delay in onset of infection among ferrets exposed to LAIV pigs versus NV pigs (rate ratio, 0.66; P = 0.028). Ferrets exposed to vaccinated pigs had lower cumulative virus titers in nasal wash samples (LAIV versus NV, P < 0.0001; KV versus NV, P= 0.3490) and experienced reduced clinical signs during infection. Our findings support the implementation of preexhibition influenza vaccination of swine to reduce the public health risk posed by IAV-S at agricultural exhibitions. IMPORTANCE Swine exhibited at agricultural fairs in North America have been the source of repeated zoonotic influenza A virus transmission, which creates a pathway for influenza pandemic emergence. We investigated the effect of using either live-attenuated influenza virus or killed influenza virus vaccines as prefair influenza vaccination of swine on zoonotic influenza transmission risk. Ferrets were exposed to the pigs in order to simulate human exposure in a field setting. We observed reductions in influenza A virus shedding in both groups of vaccinated pigs as well as the corresponding ferret exposure groups, indicating vaccination improved outcomes on both sides of the interface. There was also significant delay in onset of infection among ferrets that were exposed to live-attenuated virus-vaccinated pigs, which might be beneficial during longer fairs. Our findings indicate that policies mandating influenza vaccination of swine before fairs, while not currently common, would reduce the public health risk posed by influenza zoonosis.