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1.
Preprint in English | medRxiv | ID: ppmedrxiv-22276321

ABSTRACT

IntroductionSince the start of the pandemic SARS-CoV-2 infection has most commonly been confirmed using reverse transcriptase polymerase chain reaction (RT-PCR), with results translated into a binary positive/negative outcomes. Previous studies have found that there is additional useful information in the level of the Cycle threshold (Ct value) of positive cases. Here we characterise variation in Ct values as a proxy for viral loads in more than 3 million test-positive COVID-19 cases in England with the aim of better quantifying the utility of such data. MethodsWe used individual N gene Ct values from symptomatic PCR positive (with Ct value less than 30) Pillar 2 cases in England who self-reported the date of symptom onset, and for whom age, reinfection status, variant status, and the number of vaccines received was available. Those with a positive test result more than 6 days after their reported symptom onset were excluded to mitigate the potential impact of recall bias. We used a generalised additive model, to estimate Ct values empirical mean Ct values for each strata of interest independently as well as to predict Ct values using a model that adjusted for a range of demographic and epidemiological covariates jointly. We present empirical Ct values and compare them to predicted mean Ct values. ResultsWe found that mean Ct values varied by vaccine status, and reinfection status with the number of vaccine doses having little apparent effect. Modelling Ct values as a smooth function of time since onset and other variables struggled to reproduce the individual variation in the data but did match the population-level variation over time relatively well with this being apparently dominated by large differences between variants. Other variation over time was also captured to some degree though their remained several periods where the model could not capture the empirical means with a potential explanation being epidemic phase bias. ConclusionsAnalysing a large dataset of routine Ct values from symptomatic COVID-19 cases in England we found variation based on time since symptom onset, vaccine status, age, and variant. Ct values were highest 1-3 days after symptom onset and differed most due to variant status. We found no clear correlation between previously estimated differences in intrinsic transmissibility and Ct values indicating that this is potentially mediated at least partly by factors other than viral load as estimated using Ct values. We found evidence that a model adjusting for a range of covariates could explain some of the population-level variation over time but systematically underestimated Ct values when incidence was increasing, and overestimated them when incidence was decreasing. This indicates the utility of Ct values from this data source as a tool for surveillance, potentially avoiding some of the biases of aggregated positive counts.

2.
Katharine Sherratt; Hugo Gruson; Rok Grah; Helen Johnson; Rene Niehus; Bastian Prasse; Frank Sandman; Jannik Deuschel; Daniel Wolffram; Sam Abbott; Alexander Ullrich; Graham Gibson; Evan L Ray; Nicholas G Reich; Daniel Sheldon; Yijin Wang; Nutcha Wattanachit; Lijing Wang; Jan Trnka; Guillaume Obozinski; Tao Sun; Dorina Thanou; Loic Pottier; Ekaterina Krymova; Maria Vittoria Barbarossa; Neele Leithauser; Jan Mohring; Johanna Schneider; Jaroslaw Wlazlo; Jan Fuhrmann; Berit Lange; Isti Rodiah; Prasith Baccam; Heidi Gurung; Steven Stage; Bradley Suchoski; Jozef Budzinski; Robert Walraven; Inmaculada Villanueva; Vit Tucek; Martin Smid; Milan Zajicek; Cesar Perez Alvarez; Borja Reina; Nikos I Bosse; Sophie Meakin; Pierfrancesco Alaimo Di Loro; Antonello Maruotti; Veronika Eclerova; Andrea Kraus; David Kraus; Lenka Pribylova; Bertsimas Dimitris; Michael Lingzhi Li; Soni Saksham; Jonas Dehning; Sebastian Mohr; Viola Priesemann; Grzegorz Redlarski; Benjamin Bejar; Giovanni Ardenghi; Nicola Parolini; Giovanni Ziarelli; Wolfgang Bock; Stefan Heyder; Thomas Hotz; David E. Singh; Miguel Guzman-Merino; Jose L Aznarte; David Morina; Sergio Alonso; Enric Alvarez; Daniel Lopez; Clara Prats; Jan Pablo Burgard; Arne Rodloff; Tom Zimmermann; Alexander Kuhlmann; Janez Zibert; Fulvia Pennoni; Fabio Divino; Marti Catala; Gianfranco Lovison; Paolo Giudici; Barbara Tarantino; Francesco Bartolucci; Giovanna Jona Lasinio; Marco Mingione; Alessio Farcomeni; Ajitesh Srivastava; Pablo Montero-Manso; Aniruddha Adiga; Benjamin Hurt; Bryan Lewis; Madhav Marathe; Przemyslaw Porebski; Srinivasan Venkatramanan; Rafal Bartczuk; Filip Dreger; Anna Gambin; Krzysztof Gogolewski; Magdalena Gruziel-Slomka; Bartosz Krupa; Antoni Moszynski; Karol Niedzielewski; Jedrzej Nowosielski; Maciej Radwan; Franciszek Rakowski; Marcin Semeniuk; Ewa Szczurek; Jakub Zielinski; Jan Kisielewski; Barbara Pabjan; Kirsten Holger; Yuri Kheifetz; Markus Scholz; Marcin Bodych; Maciej Filinski; Radoslaw Idzikowski; Tyll Krueger; Tomasz Ozanski; Johannes Bracher; Sebastian Funk.
Preprint in English | medRxiv | ID: ppmedrxiv-22276024

ABSTRACT

BackgroundShort-term forecasts of infectious disease burden can contribute to situational awareness and aid capacity planning. Based on best practice in other fields and recent insights in infectious disease epidemiology, one can maximise the predictive performance of such forecasts if multiple models are combined into an ensemble. Here we report on the performance of ensembles in predicting COVID-19 cases and deaths across Europe between 08 March 2021 and 07 March 2022. MethodsWe used open-source tools to develop a public European COVID-19 Forecast Hub. We invited groups globally to contribute weekly forecasts for COVID-19 cases and deaths reported from a standardised source over the next one to four weeks. Teams submitted forecasts from March 2021 using standardised quantiles of the predictive distribution. Each week we created an ensemble forecast, where each predictive quantile was calculated as the equally-weighted average (initially the mean and then from 26th July the median) of all individual models predictive quantiles. We measured the performance of each model using the relative Weighted Interval Score (WIS), comparing models forecast accuracy relative to all other models. We retrospectively explored alternative methods for ensemble forecasts, including weighted averages based on models past predictive performance. ResultsOver 52 weeks we collected and combined up to 28 forecast models for 32 countries. We found a weekly ensemble had a consistently strong performance across countries over time. Across all horizons and locations, the ensemble performed better on relative WIS than 84% of participating models forecasts of incident cases (with a total N=862), and 92% of participating models forecasts of deaths (N=746). Across a one to four week time horizon, ensemble performance declined with longer forecast periods when forecasting cases, but remained stable over four weeks for incident death forecasts. In every forecast across 32 countries, the ensemble outperformed most contributing models when forecasting either cases or deaths, frequently outperforming all of its individual component models. Among several choices of ensemble methods we found that the most influential and best choice was to use a median average of models instead of using the mean, regardless of methods of weighting component forecast models. ConclusionsOur results support the use of combining forecasts from individual models into an ensemble in order to improve predictive performance across epidemiological targets and populations during infectious disease epidemics. Our findings further suggest that median ensemble methods yield better predictive performance more than ones based on means. Our findings also highlight that forecast consumers should place more weight on incident death forecasts than incident case forecasts at forecast horizons greater than two weeks. Code and data availabilityAll data and code are publicly available on Github: covid19-forecast-hub-europe/euro-hub-ensemble.

3.
Preprint in English | medRxiv | ID: ppmedrxiv-22273101

ABSTRACT

BackgroundRepeated measurements of cross-sectional prevalence of Polymerase Chain Reaction (PCR) positivity or seropositivity provide rich insight into the dynamics of an infection. The UK Office for National Statistics (ONS) Community Infection Survey publishes such measurements for SARS-CoV-2 on a weekly basis based on testing enrolled households, contributing to situational awareness in the country. Here we present estimates of time-varying and static epidemiological quantities that were derived from the estimates published by ONS. MethodsWe used a gaussian process to model incidence of infections and then estimated observed PCR prevalence by convolving our modelled incidence estimates with a previously published PCR detection curve describing the probability of a positive test as a function of the time since infection. We refined our incidence estimates using time-varying estimates of antibody prevalence combined with a model of antibody positivity and waning that moved individuals between compartments with or without antibodies based on estimates of new infections, vaccination, probability of seroconversion and waning. ResultsWe produced incidence curves of infection describing the UK epidemic from late April 2020 until early 2022. We used these estimates of incidence to estimate the time-varying growth rate of infections, and combined them with estimates of the generation interval to estimate time-varying reproduction numbers. Biological parameters describing seroconversion and waning, while based on a simple model, were broadly in line with plausible ranges from individual-level studies. ConclusionsBeyond informing situational awareness and allowing for estimates using individual-level data, repeated cross-sectional studies make it possible to estimate epidemiological parameters from population-level models. Studies or public health surveillance methods based on similar designs offer opportunities for further improving our understanding of the dynamics of SARS-CoV-2 or other pathogens and their interaction with population-level immunity.

4.
Preprint in English | medRxiv | ID: ppmedrxiv-22268920

ABSTRACT

BackgroundEarly estimates from South Africa indicated that the Omicron COVID-19 variant may be both more transmissible and have greater immune escape than the previously dominant Delta variant. The rapid turnover of the latest epidemic wave in South Africa as well as initial evidence from contact tracing and household infection studies has prompted speculation that the generation time of the Omicron variant may be shorter in comparable settings than the generation time of the Delta variant. MethodsWe estimated daily growth rates for the Omicron and Delta variants in each UKHSA region from the 23rd of November to the 23rd of December 2021 using surveillance case counts by date of specimen and S-gene target failure status with an autoregressive model that allowed for time-varying differences in the transmission advantage of the Delta variant where the evidence supported this. By assuming a gamma distributed generation distribution we then estimated the generation time distribution and transmission advantage of the Omicron variant that would be required to explain this time varying advantage. We repeated this estimation process using two different prior estimates for the generation time of the Delta variant first based on household transmission and then based on its intrinsic generation time. ResultsVisualising our growth rate estimates provided initial evidence for a difference in generation time distributions. Assuming a generation time distribution for Delta with a mean of 2.5-4 days (90% credible interval) and a standard deviation of 1.9-3 days we estimated a shorter generation time distribution for Omicron with a mean of 1.5-3.2 days and a standard deviation of 1.3-4.6 days. This implied a transmission advantage for Omicron in this setting of 160%-210% compared to Delta. We found similar relative results using an estimate of the intrinsic generation time for Delta though all estimates increased in magnitude due to the longer assumed generation time. ConclusionsWe found that a reduction in the generation time of Omicron compared to Delta was able to explain the observed variation over time in the transmission advantage of the Omicron variant. However, this analysis cannot rule out the role of other factors such as differences in the populations the variants were mixing in, differences in immune escape between variants or bias due to using the test to test distribution as a proxy for the generation time distribution.

5.
Preprint in English | medRxiv | ID: ppmedrxiv-21266598

ABSTRACT

1Forecasts based on epidemiological modelling have played an important role in shaping public policy throughout the COVID-19 pandemic. This modelling combines knowledge about infectious disease dynamics with the subjective opinion of the researcher who develops and refines the model and often also adjusts model outputs. Developing a forecast model is difficult, resource- and time-consuming. It is therefore worth asking what modelling is able to add beyond the subjective opinion of the researcher alone. To investigate this, we analysed different real-time forecasts of cases of and deaths from COVID-19 in Germany and Poland over a 1-4 week horizon submitted to the German and Polish Forecast Hub. We compared crowd forecasts elicited from researchers and volunteers, against a) forecasts from two semi-mechanistic models based on common epidemiological assumptions and b) the ensemble of all other models submitted to the Forecast Hub. We found crowd forecasts, despite being overconfident, to outperform all other methods across all forecast horizons when forecasting cases (weighted interval score relative to the Hub ensemble 2 weeks ahead: 0.89). Forecasts based on computational models performed comparably better when predicting deaths (rel. WIS 1.26), suggesting that epidemiological modelling and human judgement can complement each other in important ways.

6.
Preprint in English | medRxiv | ID: ppmedrxiv-21267056

ABSTRACT

BackgroundLocal estimates of the time-varying effective reproduction number (Rt) of COVID-19 in England became increasingly heterogeneous during April and May 2021. This may have been attributable to the spread of the Delta SARS-CoV-2 variant. This paper documents real-time analysis that aimed to investigate the association between changes in the proportion of positive cases that were S-gene positive, an indicator of the Delta variant against a background of the previously predominant Alpha variant, and the estimated time-varying Rt at the level of upper-tier local authorities (UTLA). MethodWe explored the relationship between the proportion of samples that were S-gene positive and the Rt of test-positive cases over time from the 23 February 2021 to the 25 May 2021. Effective reproduction numbers were estimated using the EpiNow2 R package independently for each local authority using two different estimates of the generation time. We then fit a range of regression models to estimate a multiplicative relationship between S-gene positivity and weekly mean Rt estimate. ResultsWe found evidence of an association between increased mean Rt estimates and the proportion of S-gene positives across all models evaluated with the magnitude of the effect increasing as model flexibility was decreased. Models that adjusted for either national level or NHS region level time-varying residuals were found to fit the data better, suggesting potential unexplained confounding. ConclusionsOur results indicated that even after adjusting for time-varying residuals between NHS regions, S-gene positivity was associated with an increase in the effective reproduction number of COVID-19. These findings were robust across a range of models and generation time assumptions, though the specific effect size was variable depending on the assumptions used. The lower bound of the estimated effect indicated that the reproduction number of Delta was above 1 in almost all local authorities throughout the period of investigation.

7.
Preprint in English | medRxiv | ID: ppmedrxiv-21266166

ABSTRACT

We estimate the potential remaining COVID-19 burden in 19 European countries by estimating the proportion of each countrys population that has acquired immunity to severe disease through infection or vaccination. Our results suggest that many European countries could still face a substantial burden of hospitalisations and deaths, particularly those with lower vaccination coverage, less historical transmission, and/or older populations. Continued non-pharmaceutical interventions and efforts to achieve high vaccination coverage are required in these countries to limit severe COVID-19 outcomes.

8.
Preprint in English | medRxiv | ID: ppmedrxiv-21265810

ABSTRACT

We report on the second and final part of a pre-registered forecasting study on COVID-19 cases and deaths in Germany and Poland. Fifteen independent research teams provided forecasts at lead times of one through four weeks from January through mid-April 2021. Compared to the first part (October-December 2020), the number of participating teams increased, and a number of teams started providing subnational-level forecasts. The addressed time period is characterized by rather stable non-pharmaceutical interventions in both countries, making short-term predictions more straightforward than in the first part of our study. In both countries, case counts declined initially, before rebounding due to the rise of the B.1.1.7 variant. Deaths declined through most of the study period in Germany while in Poland they increased after a prolonged plateau. Many, though not all, models outperformed a simple baseline model up to four weeks ahead, with ensemble methods showing very good relative performance. Major trend changes in reported cases, however, remained challenging to predict.

9.
Preprint in English | medRxiv | ID: ppmedrxiv-21265660

ABSTRACT

BackgroundGovernments around the world have implemented non-pharmaceutical interventions to limit the transmission of COVID-19. While lockdowns and physical distancing have proven effective for reducing COVID-19 transmission, there is still limited understanding of how NPI measures are reflected in indicators of human mobility. Further, there is a lack of understanding about how findings from high-income settings correspond to low and middle-income contexts. MethodsIn this study, we assess the relationship between indicators of human mobility, NPIs, and estimates of Rt, a real-time measure of the intensity of COVID-19 transmission. We construct a multilevel generalised linear mixed model, combining local disease surveillance data from subnational districts of Ghana with the timing of NPIs and indicators of human mobility from Google and Vodafone Ghana. FindingsWe observe a relationship between reductions in human mobility and decreases in Rt during the early stages of the COVID-19 epidemic in Ghana. We find that the strength of this relationship varies through time, decreasing after the most stringent period of interventions in the early epidemic. InterpretationOur findings demonstrate how the association of NPI and mobility indicators with COVID-19 transmission may vary through time. Further, we demonstrate the utility of combining local disease surveillance data with large scale human mobility data to augment existing surveillance capacity and monitor the impact of NPI policies. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and preprint archives for articles published in English that contained information about the COVID-19 pandemic published up to Nov 1, 2021, using the search terms "coronavirus", "CoV", "COVID-19", "mobility", "movement", and "flow". The data thus far suggests that NPI measures including physical distancing, reduction of travel, and use of personal protective equipment have been demonstrated to reduce COVID-19 transmission. Much of the existing research focuses on comparisons of NPI stringency with COVID-19 transmission among different high-income countries, or on high-income countries, leaving critical questions about the applicability of these findings to low- and middle-income settings. Added value of this studyWe used a detailed COVID-19 surveillance dataset from Ghana, and unique high resolution spatial data on human mobility from Vodafone Ghana as well as Google smartphone GPS location data. We show how human mobility and NPI stringency were associated with changes in the effective reproduction number (Rt). We further demonstrate how this association was strongest in the early COVID-19 outbreak in Ghana, decreasing after the relaxation of national restrictions. Implications of all the available evidenceThe change in association between human mobility, NPI stringency, and Rt may reflect a "decoupling" of NPI stringency and human mobility from disease transmission in Ghana as the COVID-19 epidemic progressed. This finding provides public health decision makers with important insights for the understanding of the utility of mobility data for predicting the spread of COVID-19.

10.
Preprint in English | medRxiv | ID: ppmedrxiv-21265046

ABSTRACT

BackgroundForecasting healthcare demand is essential in epidemic settings, both to inform situational awareness and facilitate resource planning. Ideally, forecasts should be robust across time and locations. During the COVID-19 pandemic in England, it is an ongoing concern that demand for hospital care for COVID-19 patients in England will exceed available resources. MethodsWe made weekly forecasts of daily COVID-19 hospital admissions for National Health Service (NHS) Trusts in England between August 2020 and April 2021 using three disease-agnostic forecasting models: a mean ensemble of autoregressive time series models, a linear regression model with 7-day-lagged local cases as a predictor, and a scaled convolution of local cases and a delay distribution. We compared their point and probabilistic accuracy to a mean-ensemble of them all, and to a simple baseline model of no change from the last day of admissions. We measured predictive performance using the Weighted Interval Score (WIS) and considered how this changed in different scenarios (the length of the predictive horizon, the date on which the forecast was made, and by location), as well as how much admissions forecasts improved when future cases were known. ResultsAll models outperformed the baseline in the majority of scenarios. Forecasting accuracy varied by forecast date and location, depending on the trajectory of the outbreak, and all individual models had instances where they were the top- or bottom-ranked model. Forecasts produced by the mean-ensemble were both the most accurate and most consistently accurate forecasts amongst all the models considered. Forecasting accuracy was improved when using future observed, rather than forecast, cases, especially at longer forecast horizons. ConclusionsAssuming no change in current admissions is rarely better than including at least a trend. Using confirmed COVID-19 cases as a predictor can improve admissions forecasts in some scenarios, but this is variable and depends on the ability to make consistently good case forecasts. However, ensemble forecasts can make forecasts that make consistently more accurate forecasts across time and locations. Given minimal requirements on data and computation, our admissions forecasting ensemble could be used to anticipate healthcare needs in future epidemic or pandemic settings.

11.
Preprint in English | medRxiv | ID: ppmedrxiv-21256386

ABSTRACT

BackgroundBrazil is one of the countries worst affected by the COVID-19 pandemic with over 20 million cases and 557,000 deaths reported. Comparison of real-time local COVID-19 data between areas is essential for understanding transmission, measuring the effects of interventions and predicting the course of the epidemic, but are often challenging due to different population sizes and structures. MethodsWe describe the development of a new app for the real-time visualisation of COVID-19 data in Brazil at the municipality level. In the CLIC-Brazil app, daily updates of case and death data are downloaded, age standardised and used to estimate reproduction number (Rt). We show how such platforms can perform real-time regression analyses to identify factors associated with the rate of initial spread and early reproduction number. We also use survival methods to predict the likelihood of occurrence of a new peak of COVID-19 incidence. FindingsAfter an initial introduction in Sao Paulo and Rio de Janeiro states in early March 2020, the epidemic spread to Northern states and then to highly populated coastal regions and the Central-West. Municipalities with higher metrics of social development experienced earlier arrival of COVID-19 (decrease of 11{middle dot}1 days [95% CI:13{middle dot}2,8{middle dot}9] in the time to arrival for each 10% increase in the social development index). Differences in the initial epidemic intensity (mean Rt) were largely driven by geographic location and the date of local onset. InterpretationThis study demonstrates that platforms that monitor, standardise and analyse the epidemiological data at a local level can give useful real-time insights into outbreak dynamics that can be used to better adapt responses to the current and future pandemics. FundingThis project was supported by a Medical Research Council UK (MRC-UK) -Sao Paulo Research Foundation (FAPESP) CADDE partnership award (MR/S0195/1 and FAPESP 18/14389-0)

12.
Estee Y Cramer; Evan L Ray; Velma K Lopez; Johannes Bracher; Andrea Brennen; Alvaro J Castro Rivadeneira; Aaron Gerding; Tilmann Gneiting; Katie H House; Yuxin Huang; Dasuni Jayawardena; Abdul H Kanji; Ayush Khandelwal; Khoa Le; Anja Muehlemann; Jarad Niemi; Apurv Shah; Ariane Stark; Yijin Wang; Nutcha Wattanachit; Martha W Zorn; Youyang Gu; Sansiddh Jain; Nayana Bannur; Ayush Deva; Mihir Kulkarni; Srujana Merugu; Alpan Raval; Siddhant Shingi; Avtansh Tiwari; Jerome White; Neil F Abernethy; Spencer Woody; Maytal Dahan; Spencer Fox; Kelly Gaither; Michael Lachmann; Lauren Ancel Meyers; James G Scott; Mauricio Tec; Ajitesh Srivastava; Glover E George; Jeffrey C Cegan; Ian D Dettwiller; William P England; Matthew W Farthing; Robert H Hunter; Brandon Lafferty; Igor Linkov; Michael L Mayo; Matthew D Parno; Michael A Rowland; Benjamin D Trump; Yanli Zhang-James; Samuel Chen; Stephen V Faraone; Jonathan Hess; Christopher P Morley; Asif Salekin; Dongliang Wang; Sabrina M Corsetti; Thomas M Baer; Marisa C Eisenberg; Karl Falb; Yitao Huang; Emily T Martin; Ella McCauley; Robert L Myers; Tom Schwarz; Daniel Sheldon; Graham Casey Gibson; Rose Yu; Liyao Gao; Yian Ma; Dongxia Wu; Xifeng Yan; Xiaoyong Jin; Yu-Xiang Wang; YangQuan Chen; Lihong Guo; Yanting Zhao; Quanquan Gu; Jinghui Chen; Lingxiao Wang; Pan Xu; Weitong Zhang; Difan Zou; Hannah Biegel; Joceline Lega; Steve McConnell; VP Nagraj; Stephanie L Guertin; Christopher Hulme-Lowe; Stephen D Turner; Yunfeng Shi; Xuegang Ban; Robert Walraven; Qi-Jun Hong; Stanley Kong; Axel van de Walle; James A Turtle; Michal Ben-Nun; Steven Riley; Pete Riley; Ugur Koyluoglu; David DesRoches; Pedro Forli; Bruce Hamory; Christina Kyriakides; Helen Leis; John Milliken; Michael Moloney; James Morgan; Ninad Nirgudkar; Gokce Ozcan; Noah Piwonka; Matt Ravi; Chris Schrader; Elizabeth Shakhnovich; Daniel Siegel; Ryan Spatz; Chris Stiefeling; Barrie Wilkinson; Alexander Wong; Sean Cavany; Guido Espana; Sean Moore; Rachel Oidtman; Alex Perkins; David Kraus; Andrea Kraus; Zhifeng Gao; Jiang Bian; Wei Cao; Juan Lavista Ferres; Chaozhuo Li; Tie-Yan Liu; Xing Xie; Shun Zhang; Shun Zheng; Alessandro Vespignani; Matteo Chinazzi; Jessica T Davis; Kunpeng Mu; Ana Pastore y Piontti; Xinyue Xiong; Andrew Zheng; Jackie Baek; Vivek Farias; Andreea Georgescu; Retsef Levi; Deeksha Sinha; Joshua Wilde; Georgia Perakis; Mohammed Amine Bennouna; David Nze-Ndong; Divya Singhvi; Ioannis Spantidakis; Leann Thayaparan; Asterios Tsiourvas; Arnab Sarker; Ali Jadbabaie; Devavrat Shah; Nicolas Della Penna; Leo A Celi; Saketh Sundar; Russ Wolfinger; Dave Osthus; Lauren Castro; Geoffrey Fairchild; Isaac Michaud; Dean Karlen; Matt Kinsey; Luke C. Mullany; Kaitlin Rainwater-Lovett; Lauren Shin; Katharine Tallaksen; Shelby Wilson; Elizabeth C Lee; Juan Dent; Kyra H Grantz; Alison L Hill; Joshua Kaminsky; Kathryn Kaminsky; Lindsay T Keegan; Stephen A Lauer; Joseph C Lemaitre; Justin Lessler; Hannah R Meredith; Javier Perez-Saez; Sam Shah; Claire P Smith; Shaun A Truelove; Josh Wills; Maximilian Marshall; Lauren Gardner; Kristen Nixon; John C. Burant; Lily Wang; Lei Gao; Zhiling Gu; Myungjin Kim; Xinyi Li; Guannan Wang; Yueying Wang; Shan Yu; Robert C Reiner; Ryan Barber; Emmanuela Gaikedu; Simon Hay; Steve Lim; Chris Murray; David Pigott; Heidi L Gurung; Prasith Baccam; Steven A Stage; Bradley T Suchoski; B. Aditya Prakash; Bijaya Adhikari; Jiaming Cui; Alexander Rodriguez; Anika Tabassum; Jiajia Xie; Pinar Keskinocak; John Asplund; Arden Baxter; Buse Eylul Oruc; Nicoleta Serban; Sercan O Arik; Mike Dusenberry; Arkady Epshteyn; Elli Kanal; Long T Le; Chun-Liang Li; Tomas Pfister; Dario Sava; Rajarishi Sinha; Thomas Tsai; Nate Yoder; Jinsung Yoon; Leyou Zhang; Sam Abbott; Nikos I Bosse; Sebastian Funk; Joel Hellewell; Sophie R Meakin; Katharine Sherratt; Mingyuan Zhou; Rahi Kalantari; Teresa K Yamana; Sen Pei; Jeffrey Shaman; Michael L Li; Dimitris Bertsimas; Omar Skali Lami; Saksham Soni; Hamza Tazi Bouardi; Turgay Ayer; Madeline Adee; Jagpreet Chhatwal; Ozden O Dalgic; Mary A Ladd; Benjamin P Linas; Peter Mueller; Jade Xiao; Yuanjia Wang; Qinxia Wang; Shanghong Xie; Donglin Zeng; Alden Green; Jacob Bien; Logan Brooks; Addison J Hu; Maria Jahja; Daniel McDonald; Balasubramanian Narasimhan; Collin Politsch; Samyak Rajanala; Aaron Rumack; Noah Simon; Ryan J Tibshirani; Rob Tibshirani; Valerie Ventura; Larry Wasserman; Eamon B O'Dea; John M Drake; Robert Pagano; Quoc T Tran; Lam Si Tung Ho; Huong Huynh; Jo W Walker; Rachel B Slayton; Michael A Johansson; Matthew Biggerstaff; Nicholas G Reich.
Preprint in English | medRxiv | ID: ppmedrxiv-21250974

ABSTRACT

Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multi-model ensemble forecast that combined predictions from dozens of different research groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naive baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-week horizon 3-5 times larger than when predicting at a 1-week horizon. This project underscores the role that collaboration and active coordination between governmental public health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks. Significance StatementThis paper compares the probabilistic accuracy of short-term forecasts of reported deaths due to COVID-19 during the first year and a half of the pandemic in the US. Results show high variation in accuracy between and within stand-alone models, and more consistent accuracy from an ensemble model that combined forecasts from all eligible models. This demonstrates that an ensemble model provided a reliable and comparatively accurate means of forecasting deaths during the COVID-19 pandemic that exceeded the performance of all of the models that contributed to it. This work strengthens the evidence base for synthesizing multiple models to support public health action.

13.
Preprint in English | medRxiv | ID: ppmedrxiv-20248826

ABSTRACT

We report insights from ten weeks of collaborative COVID-19 forecasting for Germany and Poland (12 October - 19 December 2020). The study period covers the onset of the second wave in both countries, with tightening non-pharmaceutical interventions (NPIs) and subsequently a decay (Poland) or plateau and renewed increase (Germany) in reported cases. Thirteen independent teams provided probabilistic real-time forecasts of COVID-19 cases and deaths. These were reported for lead times of one to four weeks, with evaluation focused on one- and two-week horizons, which are less affected by changing NPIs. Heterogeneity between forecasts was considerable both in terms of point predictions and forecast spread. Ensemble forecasts showed good relative performance, in particular in terms of coverage, but did not clearly dominate single-model predictions. The study was preregistered and will be followed up in future phases of the pandemic.

14.
Preprint in English | medRxiv | ID: ppmedrxiv-20248822

ABSTRACT

A novel SARS-CoV-2 variant, VOC 202012/01 (lineage B.1.1.7), emerged in southeast England in November 2020 and is rapidly spreading towards fixation. Using a variety of statistical and dynamic modelling approaches, we estimate that this variant has a 43-90% (range of 95% credible intervals 38-130%) higher reproduction number than preexisting variants. A fitted two-strain dynamic transmission model shows that VOC 202012/01 will lead to large resurgences of COVID-19 cases. Without stringent control measures, including limited closure of educational institutions and a greatly accelerated vaccine roll-out, COVID-19 hospitalisations and deaths across England in 2021 will exceed those in 2020. Concerningly, VOC 202012/01 has spread globally and exhibits a similar transmission increase (59-74%) in Denmark, Switzerland, and the United States.

15.
Preprint in English | medRxiv | ID: ppmedrxiv-20240648

ABSTRACT

Slovakia conducted multiple rounds of population-wide rapid antigen testing for SARS-CoV-2 in late 2020, combined with a period of additional contact restrictions. Observed prevalence decreased by 58% (95% CI: 57-58%) within one week in the 45 counties that were subject to two rounds of mass testing, an estimate that remained robust when adjusting for multiple potential confounders. Adjusting for epidemic growth of 4.4% (1.1-6.9%) per day preceding the mass testing campaign, the estimated decrease in prevalence compared to a scenario of unmitigated growth was 70% (67-73%). Modelling suggests that this decrease cannot be explained solely by infection control measures, but requires the additional impact of isolation as well as quarantine of household members of those testing positive.

16.
Preprint in English | medRxiv | ID: ppmedrxiv-20220962

ABSTRACT

BackgroundShort-term forecasts of infectious disease can aid situational awareness and planning for outbreak response. Here, we report on multi-model forecasts of Covid-19 in the UK that were generated at regular intervals starting at the end of March 2020, in order to monitor expected healthcare utilisation and population impacts in real time. MethodsWe evaluated the performance of individual model forecasts generated between 24 March and 14 July 2020, using a variety of metrics including the weighted interval score as well as metrics that assess the calibration, sharpness, bias and absolute error of forecasts separately. We further combined the predictions from individual models into ensemble forecasts using a simple mean as well as a quantile regression average that aimed to maximise performance. We compared model performance to a null model of no change. ResultsIn most cases, individual models performed better than the null model, and ensembles models were well calibrated and performed comparatively to the best individual models. The quantile regression average did not noticeably outperform the mean ensemble. ConclusionsEnsembles of multi-model forecasts can inform the policy response to the Covid-19 pandemic by assessing future resource needs and expected population impact of morbidity and mortality.

17.
Preprint in English | medRxiv | ID: ppmedrxiv-20214585

ABSTRACT

The time-varying reproduction number (Rt: the average number secondary infections caused by each infected person) may be used to assess changes in transmission potential during an epidemic. While new infections are not usually observed directly, they can be estimated from data. However, data may be delayed and potentially biased. We investigated the sensitivity of Rt estimates to different data sources representing Covid-19 in England, and we explored how this sensitivity could track epidemic dynamics in population sub-groups. We sourced public data on test-positive cases, hospital admissions, and deaths with confirmed Covid-19 in seven regions of England over March through August 2020. We estimated Rt using a model that mapped unobserved infections to each data source. We then compared differences in Rt with the demographic and social context of surveillance data over time. Our estimates of transmission potential varied for each data source, with the relative inconsistency of estimates varying across regions and over time. Rt estimates based on hospital admissions and deaths were more spatio-temporally synchronous than when compared to estimates from all test-positives. We found these differences may be linked to biased representations of subpopulations in each data source. These included spatially clustered testing, and where outbreaks in hospitals, care homes, and young age groups reflected the link between age and severity of disease. We highlight that policy makers could better target interventions by considering the source populations of Rt estimates. Further work should clarify the best way to combine and interpret Rt estimates from different data sources based on the desired use.

18.
Preprint in English | medRxiv | ID: ppmedrxiv-20167965

ABSTRACT

BackgroundSchool closures are a well-established non-pharmaceutical intervention in the event of infectious disease outbreaks, and have been implemented in many countries across the world, including the UK, to slow down the spread of SARS-CoV-2. As governments begin to relax restrictions on public life there is a need to understand the potential impact that reopening schools may have on transmission. MethodsWe used data provided by the UK Department for Education to construct a network of English schools, connected through pairs of pupils resident at the same address. We used the network to evaluate the potential for transmission between schools, and for long range propagation across the network, under different reopening scenarios. ResultsAmongst the options evaluated we found that reopening only Reception, Year 1 and Year 6 (4-6 and 10-11 year olds) resulted in the lowest risk of transmission between schools, with outbreaks within a single school unlikely to result in outbreaks in adjacent schools in the network. The additional reopening of Years 10 and 12 (14-15 and 16-17 year olds) resulted in an increase in the risk of transmission between schools comparable to reopening all primary school years (4-11 year olds). However, the majority of schools presented low risk of initiating widespread transmission through the school system. Reopening all secondary school years (11-18 year olds) resulted in large potential outbreak clusters putting up to 50% of households connected to schools at risk of infection if sustained transmission within schools was possible. ConclusionsReopening secondary school years is likely to have a greater impact on community transmission than reopening primary schools in England. Keeping transmission within schools limited is essential for reducing the risk of large outbreaks amongst school-aged children and their household members.

19.
Preprint in English | medRxiv | ID: ppmedrxiv-20148460

ABSTRACT

BackgroundAsymptomatic or subclinical SARS-CoV-2 infections are often unreported, which means that confirmed case counts may not accurately reflect underlying epidemic dynamics. Understanding the level of ascertainment (the ratio of confirmed symptomatic cases to the true number of symptomatic individuals) and undetected epidemic progression is crucial to informing COVID-19 response planning, including the introduction and relaxation of control measures. Estimating case ascertainment over time allows for accurate estimates of specific outcomes such as seroprevalence, which is essential for planning control measures. MethodsUsing reported data on COVID-19 cases and fatalities globally, we estimated the proportion of symptomatic cases (i.e. any person with any of fever >= 37.5{degrees}C, cough, shortness of breath, sudden onset of anosmia, ageusia or dysgeusia illness) that were reported in 210 countries and territories, given those countries had experienced more than ten deaths. We used published estimates of the case fatality ratio (CFR) as an assumed baseline. We then calculated the ratio of this baseline CFR to an estimated local delay-adjusted CFR to estimate the level of under-ascertainment in a particular location. We then fit a Bayesian Gaussian process model to estimate the temporal pattern of under-ascertainment. ResultsWe estimate that, during March 2020, the median percentage of symptomatic cases detected across the 84 countries which experienced more than ten deaths ranged from 2.38% (Bangladesh) to 99.6% (Chile). Across the ten countries with the highest number of total confirmed cases as of 6th July 2020, we estimated that the peak number of symptomatic cases ranged from 1.4 times (Chile) to 17.8 times (France) larger than reported. Comparing our model with national and regional seroprevalence data where available, we find that our estimates are consistent with observed values. Finally, we estimated seroprevalence for each country. Despite low case detection in some countries, our results that adjust for this still suggest that all countries have had only a small fraction of their populations infected as of July 2020. ConclusionsWe found substantial under-ascertainment of symptomatic cases, particularly at the peak of the first wave of the SARS-CoV-2 pandemic, in many countries. Reported case counts will therefore likely underestimate the rate of outbreak growth initially and underestimate the decline in the later stages of an epidemic. Although there was considerable under-reporting in many locations, our estimates were consistent with emerging serological data, suggesting that the proportion of each countrys population infected with SARS-CoV-2 worldwide is generally low. FundingWellcome Trust, Bill & Melinda Gates Foundation, DFID, NIHR, GCRF, ARC.

20.
Preprint in English | medRxiv | ID: ppmedrxiv-20134858

ABSTRACT

Estimation of the effective reproductive number, Rt, is important for detecting changes in disease transmission over time. During the COVID-19 pandemic, policymakers and public health officials are using Rt to assess the effectiveness of interventions and to inform policy. However, estimation of Rt 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 Rt, we recommend the approach of Cori et al. (2013), 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 (2004), 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 spread. We advise against using methods derived from Bettencourt and Ribeiro (2008), as the resulting Rt 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 Rt estimation. Author summaryThe effective reproductive number, Rt, is a key epidemic parameter used to assess whether an epidemic is growing, shrinking or holding steady. Rt 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 Rt in near real-time, and correctly inferring the timing of changes in Rt is challenging. Here, we provide an overview of challenges and best practices for accurate, timely Rt estimation.

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