Best practices for estimating and reporting epidemiological delay distributions of infectious diseases.

Epidemiological delays are key quantities that inform public health policy and clinical practice. They are used as inputs for mathematical and statistical models, which in turn can guide control strategies. In recent work, we found that censoring, right truncation, and dynamical bias were rarely addressed correctly when estimating delays and that these biases were large enough to have knock-on impacts across a large number of use cases. Here, we formulate a checklist of best practices for estimating and reporting epidemiological delays. We also provide a flowchart to guide practitioners based on their data. Our examples are focused on the incubation period and serial interval due to their importance in outbreak response and modeling, but our recommendations are applicable to other delays. The recommendations, which are based on the literature and our experience estimating epidemiological delay distributions during outbreak responses, can help improve the robustness and utility of reported estimates and provide guidance for the evaluation of estimates for downstream use in transmission models or other analyses.

Incubation Period and Serial Interval of Mpox in 2022 Global Outbreak Compared with Historical Estimates.

Understanding changes in the transmission dynamics of mpox requires comparing recent estimates of key epidemiologic parameters with historical data. We derived historical estimates for the incubation period and serial interval for mpox and contrasted them with pooled estimates from the 2022 outbreak. Our findings show the pooled mean infection-to-onset incubation period was 8.1 days for the 2022 outbreak and 8.2 days historically, indicating the incubation periods remained relatively consistent over time, despite a shift in the major mode of transmission. However, we estimated the onset-to-onset serial interval at 8.7 days using 2022 data, compared with 14.2 days using historical data. Although the reason for this shortening of the serial interval is unclear, it may be because of increased public health interventions or a shift in the mode of transmission. Recognizing such temporal shifts is essential for informed response strategies, and public health measures remain crucial for controlling mpox and similar future outbreaks.

Reconstruction and analysis of the transmission network of African swine fever in People's Republic of China, August 2018-September 2019.

Introduction of African swine fever (ASF) to China in mid-2018 and the subsequent transboundary spread across Asia devastated regional swine production, affecting live pig and pork product-related markets worldwide. To explore the spatiotemporal spread of ASF in China, we reconstructed possible ASF transmission networks using nearest neighbour, exponential function, equal probability, and spatiotemporal case-distribution algorithms. From these networks, we estimated the reproduction numbers, serial intervals, and transmission distances of the outbreak. The mean serial interval between paired units was around 29 days for all algorithms, while the mean transmission distance ranged 332 -456 km. The reproduction numbers for each algorithm peaked during the first two weeks and steadily declined through the end of 2018 before hovering around the epidemic threshold value of 1 with sporadic increases during 2019. These results suggest that 1) swine husbandry practices and production systems that lend themselves to long-range transmission drove ASF spread; 2) outbreaks went undetected by the surveillance system. Efforts by China and other affected countries to control ASF within their jurisdictions may be aided by the reconstructed spatiotemporal model. Continued support for strict implementation of biosecurity standards and improvements to ASF surveillance is essential for halting transmission in China and spread across Asia.

Transmission Dynamics and Effectiveness of Control Measures during COVID-19 Surge, Taiwan, April-August 2021.

An unprecedented surge of COVID-19 cases in Taiwan in May 2021 led the government to implement strict nationwide control measures beginning May 15. During the surge, the government was able to bring the epidemic under control without a complete lockdown despite the cumulative case count reaching >14,400 and >780 deaths. We investigated the effectiveness of the public health and social measures instituted by the Taiwan government by quantifying the change in the effective reproduction number, which is a summary measure of the ability of the pathogen to spread through the population. The control measures that were instituted reduced the effective reproduction number from 2.0-3.3 to 0.6-0.7. This decrease was correlated with changes in mobility patterns in Taiwan, demonstrating that public compliance, active case finding, and contact tracing were effective measures in preventing further spread of the disease.

Estimation of delay-adjusted all-cause excess mortality in the USA: March-December 2020.

We estimate the delay-adjusted all-cause excess deaths across 53 US jurisdictions. Using provisional data collected from September through December 2020, we first identify a common mean reporting delay of 2.8 weeks, whereas four jurisdictions have prolonged reporting delays compared to the others: Connecticut (mean 5.8 weeks), North Carolina (mean 10.4 weeks), Puerto Rico (mean 4.7 weeks) and West Virginia (mean 5.5 weeks). After adjusting for reporting delays, we estimate the percent change in all-cause excess mortality from March to December 2020 with range from 0.2 to 3.6 in Hawaii to 58.4 to 62.4 in New York City. Comparing the March-December with September-December 2020 periods, the highest increases in excess mortality are observed in South Dakota (36.9-54.0), North Dakota (33.9-50.7) and Missouri (27.8-33.9). Our findings indicate that analysis of provisional data requires caution in interpreting the death counts in recent weeks, while one needs also to account for heterogeneity in reporting delays of excess deaths among US jurisdictions.

Antibiotic stress selects against cooperation in the pathogenic bacterium Pseudomonas aeruginosa.

Cheats are a pervasive threat to public goods production in natural and human communities, as they benefit from the commons without contributing to it. Although ecological antagonisms such as predation, parasitism, competition, and abiotic environmental stress play key roles in shaping population biology, it is unknown how such stresses generally affect the ability of cheats to undermine cooperation. We used theory and experiments to address this question in the pathogenic bacterium, Pseudomonas aeruginosa Although public goods producers were selected against in all populations, our competition experiments showed that antibiotics significantly increased the advantage of nonproducers. Moreover, the dominance of nonproducers in mixed cultures was associated with higher resistance to antibiotics than in either monoculture. Mathematical modeling indicates that accentuated costs to producer phenotypes underlie the observed patterns. Mathematical analysis further shows how these patterns should generalize to other taxa with public goods behaviors. Our findings suggest that explaining the maintenance of cooperative public goods behaviors in certain natural systems will be more challenging than previously thought. Our results also have specific implications for the control of pathogenic bacteria using antibiotics and for understanding natural bacterial ecosystems, where subinhibitory concentrations of antimicrobials frequently occur.

Modelling bistable tumour population dynamics to design effective treatment strategies.

Despite recent advances in targeted drugs and immunotherapy, cancer remains "the emperor of all maladies" due to almost inevitable emergence of resistance. Drug resistance is thought to be driven by genetic alterations and/or dynamic plasticity that deregulate pathway activities and regulatory programs of a highly heterogeneous tumour. In this study, we propose a modelling framework to simulate population dynamics of heterogeneous tumour cells with reversible drug resistance. Drug sensitivity of a tumour cell is determined by its internal states, which are demarcated by coordinated activities of multiple interconnected oncogenic pathways. Transitions between cellular states depend on the effects of targeted drugs and regulatory relations between the pathways. Under this framework, we build a simple model to capture drug resistance characteristics of BRAF-mutant melanoma, where two cell states are determined by two mutually inhibitory - main and alternative - pathways. We assume that cells with an activated main pathway are proliferative yet sensitive to the BRAF inhibitor, and cells with an activated alternative pathway are quiescent but resistant to the drug. We describe a dynamical process of tumour growth under various drug regimens using the explicit solutions of mean-field equations. Based on these solutions, we compare efficacy of three treatment strategies from simulated data: static treatments with continuous and constant dosages, periodic treatments with regular intermittent active phases and drug holidays, and treatments derived from optimal control theory (OCT). Periodic treatments outperform static treatments with a considerable margin, while treatments based on OCT outperform the best periodic treatment. Our results provide insights regarding optimal cancer treatment modalities for heterogeneous tumours, and may guide the development of optimal therapeutic strategies to circumvent plastic drug resistance. They can also be used to evaluate the efficacy of suboptimal treatments that may account for side effects of the treatment and the cost of its application.

Dynamics of the pneumonic plague epidemic in Madagascar, August to October 2017.

Transmission potential and severity of pneumonic plague in Madagascar were assessed. Accounting for reporting delay, the reproduction number was estimated at 1.73. The case fatality risk was estimated as 5.5%. Expected numbers of exported cases from Madagascar were estimated across the world and all estimates were below 1 person from August to October, 2017.

Transmission potential of mpox in mainland China, June-July 2023: estimating reproduction number during the initial phase of the epidemic.

Despite reporting very few mpox cases in early 2023, mainland China observed a surge of over 500 cases during the summer. Amid ambiguous prevention strategies and stigma surrounding mpox transmission, the epidemic silently escalated. This study aims to quantify the scale of the mpox epidemic and assess the transmission dynamics of the virus by estimating the effective reproduction number (Re) during its early phase. Publicly available data were aggregated to obtain daily mpox case counts in mainland China, and the Re value was estimated using an exponential growth model. The mean Re value was found to be 1.57 (95% credible interval [1.38-1.78]), suggesting a case doubling time of approximately 2 weeks. This estimate was compared with Re values from 16 other countries' national outbreaks in 2022 that had cumulative case count exceeding 700 symptomatic cases by the end of that year. The Re estimates for these outbreaks ranged from 1.13 for Portugal to 2.31 for Colombia. The pooled mean Re was 1.49 (95% credible interval [1.32-1.67]), which aligns closely with the Re for mainland China. These findings underscore the need for immediate and effective control measures including targeted vaccination campaigns to mitigate the further spread and impact of the epidemic.

Urban-rural health disparity among patients with chronic kidney disease: a cross-sectional community-based study from 2012 to 2019.

OBJECTIVES: The incidence of chronic kidney disease (CKD) is increasing owing to the ageing population, resulting in an increased demand for dialysis and kidney transplantation, which can be costly. Current research lacks clarity regarding the relationship between residence setting and CKD prevalence or its related risk factors. This study explored the urban-rural disparities in CKD prevalence and risk factors in Taiwan. Our findings will aid the understanding of the distribution of CKD and the design of more effective prevention programmes. DESIGN: This cross-sectional community-based study used the Renal Value Evaluation Awareness and Lift programme, which involves early screening and health education for CKD diagnosis and treatment. CKD prevalence and risk factors including alcohol consumption, smoking and betel nut chewing were compared between urban and rural areas. SETTING: Urbanisation levels were determined based on population density, education, age, agricultural population and medical resources. PARTICIPANTS: A total of 7786 participants from 26 urban and 15 rural townships were included. RESULTS: The prevalence of CKD was significantly higher in rural (29.2%) than urban (10.8%) areas, representing a 2.7-fold difference (p<0.0001). Risk factors including diabetes (rural vs urban: 21.7% and 11.0%), hypertension (59.0% vs 39.9%), hyperuricaemia (36.7% vs 18.6%), alcohol consumption (29.0% vs 19.5%), smoking (15.9% vs 12.0%), betel nut chewing (12.6% vs 2.8%) and obesity (33.6% vs 19.4%) were significantly higher (p<0.0001) in rural areas. CONCLUSIONS: The prevalence of CKD is three times higher in rural versus urban areas. Despite >99% National Health Insurance coverage, disparities in CKD prevalence persist between residential areas. Targeted interventions and further studies are crucial for addressing these disparities and enhancing CKD management across different settings.

A National Case-Crossover Study on the Risk of Kidney Injury Requiring Dialysis after Sepsis.

BACKGROUND: Patients with sepsis-associated acute kidney injury (AKI) are at risk of kidney damage, potentially necessitating acute temporary or chronic dialysis. Our study aims to estimate the odds ratio (OR) of preceding sepsis among patients requiring their first dialysis. METHODS: A nationwide population-based case-only study was conducted using claims records from the National Health insurance database of Taiwan. All patients over 20 years of age who underwent their first dialysis between 2004 and 2016 were included in the study. The six months prior to their first dialysis served as a self-control period. RESULTS: The study included 147,201 patients who required acute temporary and 75,031 patients who required chronic dialysis. The odds ratios for patients needing acute temporary dialysis after 1, 2, 3, and 4 weeks of exposure periods were 15.8, 10.7, 9.2, and 8.4, respectively. The ORs for patients requiring chronic dialysis were 7.0, 4.1, 4.2, and 3.7, respectively. CONCLUSIONS: Our findings indicate that sepsis was substantially associated with an increased risk of renal failure. The risk was highest during the first week following sepsis for both acute temporary and chronic dialysis cases.

Emergence potential of monkeypox in the Western Pacific Region, July 2022.

Although new cases of monkeypox have been expected in the Western Pacific Region (WPR) since the virus emerged in Europe earlier this year, there have been only a few reported cases across the WPR (New Zealand 2, Singapore 6, South Korea 1, Taiwan 2), other than a limited number of cases (compared to numbers of cases seen elsewhere in the world) in Australia (33), as of July 15, 2022. In our short communication, we highlight two key reasons for this: i) international travel has still not fully resumed in the WPR following the COVID-19 pandemic, and ii) local public health measures to counter the spread of COVID-19 have not been completely relaxed. We provide supporting evidence for both of these reasons.

Correlation between times to SARS-CoV-2 symptom onset and secondary transmission undermines epidemic control efforts.

Severe acute respiratory coronavirus 2 (SARS-CoV-2) infections have been associated with substantial presymptomatic transmission, which occurs when the generation interval-the time between infection of an individual with a pathogen and transmission of the pathogen to another individual-is shorter than the incubation period-the time between infection and symptom onset. We collected a dataset of 257 SARS-CoV-2 transmission pairs in Japan during 2020 and jointly estimated the mean incubation period of infectors (4.8 days, 95 % CrI: 4.4-5.1 days), mean generation interval to when they infect others (4.3 days, 95 % credible interval [CrI]: 4.0-4.7 days), and the correlation (Kendall's tau: 0.5, 95 % CrI: 0.4-0.6) between these two epidemiological parameters. Our finding of a positive correlation and mean generation interval shorter than the mean infector incubation period indicates ample infectiousness before symptom onset and suggests that reliance on isolation of symptomatic COVID-19 cases as a focal point of control efforts is insufficient to address the challenges posed by SARS-CoV-2 transmission dynamics.

Epidemiology of coronavirus disease 2019 (COVID-19) in Japan during the first and second waves.

Following the emergence and worldwide spread of coronavirus disease 2019 (COVID-19), each country has attempted to control the disease in different ways. The first patient with COVID-19 in Japan was diagnosed on 15 January 2020, and until 31 October 2020, the epidemic was characterized by two large waves. To prevent the first wave, the Japanese government imposed several control measures such as advising the public to avoid the 3Cs (closed spaces with poor ventilation, crowded places with many people nearby, and close-contact settings such as close-range conversations) and implementation of "cluster buster" strategies. After a major epidemic occurred in April 2020 (the first wave), Japan asked its citizens to limit their numbers of physical contacts and announced a non-legally binding state of emergency. Following a drop in the number of diagnosed cases, the state of emergency was gradually relaxed and then lifted in all prefectures of Japan by 25 May 2020. However, the development of another major epidemic (the second wave) could not be prevented because of continued chains of transmission, especially in urban locations. The present study aimed to descriptively examine propagation of the COVID-19 epidemic in Japan with respect to time, age, space, and interventions implemented during the first and second waves. Using publicly available data, we calculated the effective reproduction number and its associations with the timing of measures imposed to suppress transmission. Finally, we crudely calculated the proportions of severe and fatal COVID-19 cases during the first and second waves. Our analysis identified key characteristics of COVID-19, including density dependence and also the age dependence in the risk of severe outcomes. We also identified that the effective reproduction number during the state of emergency was maintained below the value of 1 during the first wave.

Phenomenological and mechanistic models for predicting early transmission data of COVID-19.

Forecasting future epidemics helps inform policy decisions regarding interventions. During the early coronavirus disease 2019 epidemic period in January-February 2020, limited information was available, and it was too challenging to build detailed mechanistic models reflecting population behavior. This study compared the performance of phenomenological and mechanistic models for forecasting epidemics. For the former, we employed the Richards model and the approximate solution of the susceptible-infected-recovered (SIR) model. For the latter, we examined the exponential growth (with lockdown) model and SIR model with lockdown. The phenomenological models yielded higher root mean square error (RMSE) values than the mechanistic models. When using the numbers from reported data for February 1 and 5, the Richards model had the highest RMSE, whereas when using the February 9 data, the SIR approximation model was the highest. The exponential model with a lockdown effect had the lowest RMSE, except when using the February 9 data. Once interventions or other factors that influence transmission patterns are identified, they should be additionally taken into account to improve forecasting.

Localized end-of-outbreak determination for coronavirus disease 2019 (COVID-19): examples from clusters in Japan.

OBJECTIVES: End-of-outbreak declarations are an important component of outbreak response because they indicate that public health and social interventions may be relaxed or lapsed. Our study aimed to assess end-of-outbreak probabilities for clusters of coronavirus disease 2019 (COVID-19) cases detected during the first wave of the COVID-19 pandemic in Japan. METHODS: A statistical model for end-of-outbreak determination, which accounted for reporting delays for new cases, was computed. Four clusters, representing different social contexts and time points during the first wave of the epidemic, were selected and their end-of-outbreak probabilities were evaluated. RESULTS: The speed of end-of-outbreak determination was most closely tied to outbreak size. Notably, accounting underascertainment of cases led to later end-of-outbreak determinations. In addition, end-of-outbreak determination was closely related to estimates of case dispersionk and the effective reproduction number Re. Increasing local transmission (Re>1) leads to greater uncertainty in the probability estimates. CONCLUSIONS: When public health measures are effective, lowerRe (less transmission on average) and larger k (lower risk of superspreading) will be in effect, and end-of-outbreak determinations can be declared with greater confidence. The application of end-of-outbreak probabilities can help distinguish between local extinction and low levels of transmission, and communicating these end-of-outbreak probabilities can help inform public health decision making with regard to the appropriate use of resources.

Predicting the effective reproduction number of COVID-19: inference using human mobility, temperature, and risk awareness.

OBJECTIVES: The effective reproduction number (Rt) has been critical for assessing the effectiveness of countermeasures during the coronavirus disease 2019 (COVID-19) pandemic. Conventional methods using reported incidences are unable to provide timely Rt data due to the delay from infection to reporting. Our study aimed to develop a framework for predicting Rt in real time, using timely accessible data - i.e. human mobility, temperature, and risk awareness. METHODS: A linear regression model to predict Rt was designed and embedded in the renewal process. Four prefectures of Japan with high incidences in the first wave were selected for model fitting and validation. Predictive performance was assessed by comparing the observed and predicted incidences using cross-validation, and by testing on a separate dataset in two other prefectures with distinct geographical settings from the four studied prefectures. RESULTS: The predicted mean values of Rt and 95% uncertainty intervals followed the overall trends for incidence, while predictive performance was diminished when Rt changed abruptly, potentially due to superspreading events or when stringent countermeasures were implemented. CONCLUSIONS: The described model can potentially be used for monitoring the transmission dynamics of COVID-19 ahead of the formal estimates, subject to delay, providing essential information for timely planning and assessment of countermeasures.

A hospital-related outbreak of SARS-CoV-2 associated with variant Epsilon (B.1.429) in Taiwan: transmission potential and outbreak containment under intensified contact tracing, January-February 2021.

OBJECTIVES: A hospital-related cluster of 22 cases of coronavirus disease 2019 (COVID-19) occurred in Taiwan in January-February 2021. Rigorous control measures were introduced and could only be relaxed once the outbreak was declared over. Each day after the apparent outbreak end, we estimated the risk of future cases occurring in order to inform decision-making. METHODS: Probabilistic transmission networks were reconstructed, and transmission parameters (the reproduction number R and overdispersion parameter k) were estimated. The reporting delay during the outbreak was estimated (Scenario 1). In addition, a counterfactual scenario with less effective interventions characterized by a longer reporting delay was considered (Scenario 2). Each day, the risk of future cases was estimated under both scenarios. RESULTS: The values of R and k were estimated to be 1.30 ((95% credible interval (CI) 0.57-3.80) and 0.38 (95% CI 0.12-1.20), respectively. The mean reporting delays considered were 2.5 days (Scenario 1) and 7.8 days (Scenario 2). Following the final case, ttthe inferred probability of future cases occurring declined more quickly in Scenario 1 than Scenario 2. CONCLUSIONS: Rigorous control measures allowed the outbreak to be declared over quickly following outbreak containment. This highlights the need for effective interventions, not only to reduce cases during outbreaks but also to allow outbreaks to be declared over with confidence.