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      Practical considerations for measuring the effective reproductive number, R t

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          Abstract

          Estimation of the effective reproductive number R t is important for detecting changes in disease transmission over time. During the Coronavirus Disease 2019 (COVID-19) pandemic, policy makers and public health officials are using R t to assess the effectiveness of interventions and to inform policy. However, estimation of R t from available data presents several challenges, with critical implications for the interpretation of the course of the pandemic. The purpose of this document is to summarize these challenges, illustrate them with examples from synthetic data, and, where possible, make recommendations. For near real-time estimation of R t , we recommend the approach of Cori and colleagues, which uses data from before time t and empirical estimates of the distribution of time between infections. Methods that require data from after time t, such as Wallinga and Teunis, are conceptually and methodologically less suited for near real-time estimation, but may be appropriate for retrospective analyses of how individuals infected at different time points contributed to the spread. We advise caution when using methods derived from the approach of Bettencourt and Ribeiro, as the resulting R t estimates may be biased if the underlying structural assumptions are not met. Two key challenges common to all approaches are accurate specification of the generation interval and reconstruction of the time series of new infections from observations occurring long after the moment of transmission. Naive approaches for dealing with observation delays, such as subtracting delays sampled from a distribution, can introduce bias. We provide suggestions for how to mitigate this and other technical challenges and highlight open problems in R t estimation.

          Author summary

          The effective reproductive number R t is a key epidemic parameter used to assess whether an epidemic is growing, shrinking, or holding steady. R t estimates can be used as a near real-time indicator of epidemic growth or to assess the effectiveness of interventions. But due to delays between infection and case observation, estimating R t in near real time, and correctly inferring the timing of changes in R t , is challenging. Here, we provide an overview of challenges and best practices for accurate and timely R t estimation.

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          Most cited references55

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          Quantifying SARS-CoV-2 transmission suggests epidemic control with digital contact tracing

          The newly emergent human virus SARS-CoV-2 is resulting in high fatality rates and incapacitated health systems. Preventing further transmission is a priority. We analyzed key parameters of epidemic spread to estimate the contribution of different transmission routes and determine requirements for case isolation and contact-tracing needed to stop the epidemic. We conclude that viral spread is too fast to be contained by manual contact tracing, but could be controlled if this process was faster, more efficient and happened at scale. A contact-tracing App which builds a memory of proximity contacts and immediately notifies contacts of positive cases can achieve epidemic control if used by enough people. By targeting recommendations to only those at risk, epidemics could be contained without need for mass quarantines (‘lock-downs’) that are harmful to society. We discuss the ethical requirements for an intervention of this kind.
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            Early dynamics of transmission and control of COVID-19: a mathematical modelling study

            Summary Background An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to 95 333 confirmed cases as of March 5, 2020. Understanding the early transmission dynamics of the infection and evaluating the effectiveness of control measures is crucial for assessing the potential for sustained transmission to occur in new areas. Combining a mathematical model of severe SARS-CoV-2 transmission with four datasets from within and outside Wuhan, we estimated how transmission in Wuhan varied between December, 2019, and February, 2020. We used these estimates to assess the potential for sustained human-to-human transmission to occur in locations outside Wuhan if cases were introduced. Methods We combined a stochastic transmission model with data on cases of coronavirus disease 2019 (COVID-19) in Wuhan and international cases that originated in Wuhan to estimate how transmission had varied over time during January, 2020, and February, 2020. Based on these estimates, we then calculated the probability that newly introduced cases might generate outbreaks in other areas. To estimate the early dynamics of transmission in Wuhan, we fitted a stochastic transmission dynamic model to multiple publicly available datasets on cases in Wuhan and internationally exported cases from Wuhan. The four datasets we fitted to were: daily number of new internationally exported cases (or lack thereof), by date of onset, as of Jan 26, 2020; daily number of new cases in Wuhan with no market exposure, by date of onset, between Dec 1, 2019, and Jan 1, 2020; daily number of new cases in China, by date of onset, between Dec 29, 2019, and Jan 23, 2020; and proportion of infected passengers on evacuation flights between Jan 29, 2020, and Feb 4, 2020. We used an additional two datasets for comparison with model outputs: daily number of new exported cases from Wuhan (or lack thereof) in countries with high connectivity to Wuhan (ie, top 20 most at-risk countries), by date of confirmation, as of Feb 10, 2020; and data on new confirmed cases reported in Wuhan between Jan 16, 2020, and Feb 11, 2020. Findings We estimated that the median daily reproduction number (R t) in Wuhan declined from 2·35 (95% CI 1·15–4·77) 1 week before travel restrictions were introduced on Jan 23, 2020, to 1·05 (0·41–2·39) 1 week after. Based on our estimates of R t, assuming SARS-like variation, we calculated that in locations with similar transmission potential to Wuhan in early January, once there are at least four independently introduced cases, there is a more than 50% chance the infection will establish within that population. Interpretation Our results show that COVID-19 transmission probably declined in Wuhan during late January, 2020, coinciding with the introduction of travel control measures. As more cases arrive in international locations with similar transmission potential to Wuhan before these control measures, it is likely many chains of transmission will fail to establish initially, but might lead to new outbreaks eventually. Funding Wellcome Trust, Health Data Research UK, Bill & Melinda Gates Foundation, and National Institute for Health Research.
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              Association of Public Health Interventions With the Epidemiology of the COVID-19 Outbreak in Wuhan, China

              Was there an association of public health interventions with improved control of the COVID-19 outbreak in Wuhan, China? In this cohort study that included 32 583 patients with laboratory-confirmed COVID-19 in Wuhan from December 8, 2019, through March 8, 2020, the institution of interventions including cordons sanitaire , traffic restriction, social distancing, home quarantine, centralized quarantine, and universal symptom survey was temporally associated with reduced effective reproduction number of SARS-CoV-2 (secondary transmission) and the number of confirmed cases per day across age groups, sex, and geographic regions. A series of multifaceted public health interventions was temporally associated with improved control of the COVID-19 outbreak in Wuhan and may inform public health policy in other countries and regions. Coronavirus disease 2019 (COVID-19) has become a pandemic, and it is unknown whether a combination of public health interventions can improve control of the outbreak. To evaluate the association of public health interventions with the epidemiological features of the COVID-19 outbreak in Wuhan by 5 periods according to key events and interventions. In this cohort study, individual-level data on 32 583 laboratory-confirmed COVID-19 cases reported between December 8, 2019, and March 8, 2020, were extracted from the municipal Notifiable Disease Report System, including patients’ age, sex, residential location, occupation, and severity classification. Nonpharmaceutical public health interventions including cordons sanitaire , traffic restriction, social distancing, home confinement, centralized quarantine, and universal symptom survey. Rates of laboratory-confirmed COVID-19 infections (defined as the number of cases per day per million people), across age, sex, and geographic locations were calculated across 5 periods: December 8 to January 9 (no intervention), January 10 to 22 (massive human movement due to the Chinese New Year holiday), January 23 to February 1 ( cordons sanitaire , traffic restriction and home quarantine), February 2 to 16 (centralized quarantine and treatment), and February 17 to March 8 (universal symptom survey). The effective reproduction number of SARS-CoV-2 (an indicator of secondary transmission) was also calculated over the periods. Among 32 583 laboratory-confirmed COVID-19 cases, the median patient age was 56.7 years (range, 0-103; interquartile range, 43.4-66.8) and 16 817 (51.6%) were women. The daily confirmed case rate peaked in the third period and declined afterward across geographic regions and sex and age groups, except for children and adolescents, whose rate of confirmed cases continued to increase. The daily confirmed case rate over the whole period in local health care workers (130.5 per million people [95% CI, 123.9-137.2]) was higher than that in the general population (41.5 per million people [95% CI, 41.0-41.9]). The proportion of severe and critical cases decreased from 53.1% to 10.3% over the 5 periods. The severity risk increased with age: compared with those aged 20 to 39 years (proportion of severe and critical cases, 12.1%), elderly people (≥80 years) had a higher risk of having severe or critical disease (proportion, 41.3%; risk ratio, 3.61 [95% CI, 3.31-3.95]) while younger people (<20 years) had a lower risk (proportion, 4.1%; risk ratio, 0.47 [95% CI, 0.31-0.70]). The effective reproduction number fluctuated above 3.0 before January 26, decreased to below 1.0 after February 6, and decreased further to less than 0.3 after March 1. A series of multifaceted public health interventions was temporally associated with improved control of the COVID-19 outbreak in Wuhan, China. These findings may inform public health policy in other countries and regions. This population epidemiology study examines associations between phases of nonpharmaceutical public health interventions (social distancing, centralized quarantine, home confinement, and others) and rates of laboratory-confirmed COVID-19 infection in Wuhan, China, between December 2019 and early March 2020.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Comput Biol
                PLoS Comput Biol
                plos
                ploscomp
                PLoS Computational Biology
                Public Library of Science (San Francisco, CA USA )
                1553-734X
                1553-7358
                10 December 2020
                December 2020
                : 16
                : 12
                : e1008409
                Affiliations
                [1 ] Department of Ecology and Evolution, University of Chicago, Chicago, IL, United States of America
                [2 ] Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom
                [3 ] Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States of America
                [4 ] Mathematical Institute, University of Oxford, Oxford, United Kingdom
                [5 ] Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States of America
                [6 ] Department of Environmental Systems Science, ETH Zürich, Zürich, Switzerland
                [7 ] Department of Biosystems Science and Engineering, ETH Zürich, Switzerland
                [8 ] Swiss Institute of Bioinformatics, Basel, Switzerland
                [9 ] Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
                [10 ] Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, the Netherlands
                Yale School of Public Health, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0002-9369-6371
                https://orcid.org/0000-0003-4124-6472
                https://orcid.org/0000-0003-0244-0459
                https://orcid.org/0000-0003-3403-5765
                https://orcid.org/0000-0001-9511-6142
                https://orcid.org/0000-0002-6751-4124
                https://orcid.org/0000-0002-1998-1844
                https://orcid.org/0000-0002-8096-2001
                https://orcid.org/0000-0003-2683-0849
                https://orcid.org/0000-0002-6206-7134
                https://orcid.org/0000-0002-7750-5280
                https://orcid.org/0000-0003-2049-3423
                https://orcid.org/0000-0001-8545-5212
                https://orcid.org/0000-0002-0588-8235
                https://orcid.org/0000-0002-1782-8109
                https://orcid.org/0000-0003-0059-645X
                https://orcid.org/0000-0001-6431-535X
                https://orcid.org/0000-0003-1725-5627
                https://orcid.org/0000-0002-2842-3406
                https://orcid.org/0000-0003-1504-9213
                https://orcid.org/0000-0001-5298-8979
                Article
                PCOMPBIOL-D-20-01122
                10.1371/journal.pcbi.1008409
                7728287
                33301457
                89bceb0b-ab20-40fa-ab6a-90d5e4f6327e
                © 2020 Gostic et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Page count
                Figures: 6, Tables: 0, Pages: 21
                Funding
                KG was supported by the James S. McDonnell Foundation. LM was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Number F32GM134721. ML acknowledges support from the Morris-Singer Fund and from Models of Infectious Disease Agent Study (MIDAS) cooperative agreement U54GM088558 from the National Institute Of General Medical Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute Of General Medical Sciences or the National Institutes of Health. LFW acknowledges support from the National Institutes of Health (R01 GM122876). SA, JH, SM, JM, NIB, KS, RNT, SF acknowledge funding from the Wellcome Trust (210758/Z/18/Z). Thanks to Christ Church (Oxford) for funding via a Junior Research Fellowship (RNT). This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under CEIRS Contract No. HHSN272201400005C (SC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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