Effects of long-term exposure to outdoor air pollution on COVID-19 incidence: A population-based cohort study accounting for SARS-CoV-2 exposure levels in the Netherlands.

Several studies have linked air pollution to COVID-19 morbidity and severity. However, these studies do not account for exposure levels to SARS-CoV-2, nor for different sources of air pollution. We analyzed individual-level data for 8.3 million adults in the Netherlands to assess associations between long-term exposure to ambient air pollution and SARS-CoV-2 infection (i.e., positive test) and COVID-19 hospitalisation risks, accounting for spatiotemporal variation in SARS-CoV-2 exposure levels during the first two major epidemic waves (February 2020-February 2021). We estimated average annual concentrations of PM10, PM2.5 and NO2 at residential addresses, overall and by PM source (road traffic, industry, livestock, other agricultural sources, foreign sources, other Dutch sources), at 1 × 1 km resolution, and weekly SARS-CoV-2 exposure at municipal level. Using generalized additive models, we performed interval-censored survival analyses to assess associations between individuals' average exposure to PM10, PM2.5 and NO2 in the three years before the pandemic (2017-2019) and COVID-19-outcomes, adjusting for SARS-CoV-2 exposure, individual and area-specific confounders. In single-pollutant models, per interquartile (IQR) increase in exposure, PM10 was associated with 7% increased infection risk and 16% increased hospitalisation risk, PM2.5 with 8% increased infection risk and 18% increased hospitalisation risk, and NO2 with 3% increased infection risk and 11% increased hospitalisation risk. Bi-pollutant models suggested that effects were mainly driven by PM. Associations for PM were confirmed when stratifying by urbanization degree, epidemic wave and testing policy. All emission sources of PM, except industry, showed adverse effects on both outcomes. Livestock showed the most detrimental effects per unit exposure, whereas road traffic affected severity (hospitalisation) more than infection risk. This study shows that long-term exposure to air pollution increases both SARS-CoV-2 infection and COVID-19 hospitalisation risks, even after controlling for SARS-CoV-2 exposure levels, and that PM may have differential effects on these COVID-19 outcomes depending on the emission source.

Projecting COVID-19 intensive care admissions for policy advice, the Netherlands, February 2020 to January 2021.

BackgroundModel projections of coronavirus disease 2019 (COVID-19) incidence help policymakers about decisions to implement or lift control measures. During the pandemic, policymakers in the Netherlands were informed on a weekly basis with short-term projections of COVID-19 intensive care unit (ICU) admissions.AimWe aimed at developing a model on ICU admissions and updating a procedure for informing policymakers.MethodThe projections were produced using an age-structured transmission model. A consistent, incremental update procedure integrating all new surveillance and hospital data was conducted weekly. First, up-to-date estimates for most parameter values were obtained through re-analysis of all data sources. Then, estimates were made for changes in the age-specific contact rates in response to policy changes. Finally, a piecewise constant transmission rate was estimated by fitting the model to reported daily ICU admissions, with a changepoint analysis guided by Akaike's Information Criterion.ResultsThe model and update procedure allowed us to make weekly projections. Most 3-week prediction intervals were accurate in covering the later observed numbers of ICU admissions. When projections were too high in March and August 2020 or too low in November 2020, the estimated effectiveness of the policy changes was adequately adapted in the changepoint analysis based on the natural accumulation of incoming data.ConclusionThe model incorporates basic epidemiological principles and most model parameters were estimated per data source. Therefore, it had potential to be adapted to a more complex epidemiological situation with the rise of new variants and the start of vaccination.

Effectiveness of a COVID-19 contact tracing app in a simulation model with indirect and informal contact tracing.

During the COVID-19 pandemic, contact tracing was used to identify individuals who had been in contact with a confirmed case so that these contacted individuals could be tested and quarantined to prevent further spread of the SARS-CoV-2 virus. Many countries developed mobile apps to find these contacted individuals faster. We evaluate the epidemiological effectiveness of the Dutch app CoronaMelder, where we measure effectiveness as the reduction of the reproduction number R. To this end, we use a simulation model of SARS-CoV-2 spread and contact tracing, informed by data collected during the study period (December 2020 - March 2021) in the Netherlands. We show that the tracing app caused a clear but small reduction of the reproduction number, and the magnitude of the effect was found to be robust in sensitivity analyses. The app could have been more effective if more people had used it, and if notification of contacts could have been done directly by the user and thus reducing the time intervals between symptom onset and reporting of contacts. The model has two innovative aspects: i) it accounts for the clustered nature of social networks and ii) cases can alert their contacts informally without involvement of health authorities or the tracing app.

A Bayesian inference method to estimate transmission trees with multiple introductions; applied to SARS-CoV-2 in Dutch mink farms.

Knowledge of who infected whom during an outbreak of an infectious disease is important to determine risk factors for transmission and to design effective control measures. Both whole-genome sequencing of pathogens and epidemiological data provide useful information about the transmission events and underlying processes. Existing models to infer transmission trees usually assume that the pathogen is introduced only once from outside into the population of interest. However, this is not always true. For instance, SARS-CoV-2 is suggested to be introduced multiple times in mink farms in the Netherlands from the SARS-CoV-2 pandemic among humans. Here, we developed a Bayesian inference method combining whole-genome sequencing data and epidemiological data, allowing for multiple introductions of the pathogen in the population. Our method does not a priori split the outbreak into multiple phylogenetic clusters, nor does it break the dependency between the processes of mutation, within-host dynamics, transmission, and observation. We implemented our method as an additional feature in the R-package phybreak. On simulated data, our method correctly identifies the number of introductions, with an accuracy depending on the proportion of all observed cases that are introductions. Moreover, when a single introduction was simulated, our method produced similar estimates of parameters and transmission trees as the existing package. When applied to data from a SARS-CoV-2 outbreak in Dutch mink farms, the method provides strong evidence for independent introductions of the pathogen at 13 farms, infecting a total of 63 farms. Using the new feature of the phybreak package, transmission routes of a more complex class of infectious disease outbreaks can be inferred which will aid infection control in future outbreaks.

A scenario modelling analysis to anticipate the impact of COVID-19 vaccination in adolescents and children on disease outcomes in the Netherlands, summer 2021.

BackgroundSince the roll-out of COVID-19 vaccines in late 2020 and throughout 2021, European governments have relied on mathematical modelling to inform policy decisions about COVID-19 vaccination.AimWe present a scenario-based modelling analysis in the Netherlands during summer 2021, to inform whether to extend vaccination to adolescents (12-17-year-olds) and children (5-11-year-olds).MethodsWe developed a deterministic, age-structured susceptible-exposed-infectious-recovered (SEIR) model and compared modelled incidences of infections, hospital and intensive care admissions, and deaths per 100,000 people across vaccination scenarios, before the emergence of the Omicron variant.ResultsOur model projections showed that, on average, upon the release of all non-pharmaceutical control measures on 1 November 2021, a large COVID-19 wave may occur in winter 2021/22, followed by a smaller, second wave in spring 2022, regardless of the vaccination scenario. The model projected reductions in infections/severe disease outcomes when vaccination was extended to adolescents and further reductions when vaccination was extended to all people over 5 years-old. When examining projected disease outcomes by age group, individuals benefitting most from extending vaccination were adolescents and children themselves. We also observed reductions in disease outcomes in older age groups, particularly of parent age (30-49 years), when children and adolescents were vaccinated, suggesting some prevention of onward transmission from younger to older age groups.ConclusionsWhile our scenarios could not anticipate the emergence/consequences of SARS-CoV-2 Omicron variant, we illustrate how our approach can assist decision making. This could be useful when considering to provide booster doses or intervening against future infection waves.

Regional importation and asymmetric within-country spread of SARS-CoV-2 variants of concern in the Netherlands.

Background: Variants of concern (VOCs) of SARS-CoV-2 have caused resurging waves of infections worldwide. In the Netherlands, the Alpha, Beta, Gamma, and Delta VOCs circulated widely between September 2020 and August 2021. We sought to elucidate how various control measures, including targeted flight restrictions, had impacted the introduction and spread of these VOCs in the Netherlands. Methods: We performed phylogenetic analyses on 39,844 SARS-CoV-2 genomes collected under the Dutch national surveillance program. Results: We found that all four VOCs were introduced before targeted flight restrictions were imposed on countries where the VOCs first emerged. Importantly, foreign introductions, predominantly from other European countries, continued during these restrictions. After their respective introductions into the Netherlands, the Alpha and Delta VOCs largely circulated within more populous regions of the country with international connections before asymmetric bidirectional transmissions occurred with the rest of the country and the VOC became the dominant circulating lineage. Conclusions: Our findings show that flight restrictions had limited effectiveness in deterring VOC introductions due to the strength of regional land travel importation risks. As countries consider scaling down SARS-CoV-2 surveillance efforts in the post-crisis phase of the pandemic, our results highlight that robust surveillance in regions of early spread is important for providing timely information for variant detection and outbreak control. Funding: None.

Social clustering of unvaccinated children in schools in the Netherlands.

For the measles-mumps-rubella (MMR) vaccine, the World Health Organization-recommended coverage for herd protection is 95% for measles and 80% for rubella and mumps. However, a national vaccine coverage does not reflect social clustering of unvaccinated children, e.g. in schools of Orthodox Protestant or Anthroposophic identity in The Netherlands. To fully characterise this clustering, we estimated one-dose MMR vaccination coverages at all schools in the Netherlands. By combining postcode catchment areas of schools and school feeder data, each child in the Netherlands was characterised by residential postcode, primary and secondary school (referred to as school career). Postcode-level vaccination data were used to estimate vaccination coverages per school career. These were translated to coverages per school, stratified by school identity. Most schools had vaccine coverages over 99%, but major exceptions were Orthodox Protestant schools (63% in primary and 58% in secondary schools) and Anthroposophic schools (67% and 78%). School-level vaccine coverage estimates reveal strong clustering of unvaccinated children. The school feeder data reveal strongly connected Orthodox Protestant and Anthroposophic communities, but separated from one another. This suggests that even at a national one-dose MMR coverage of 97.5%, thousands of children per cohort are not protected by herd immunity.

Regional importation and asymmetric within-country spread of SARS-CoV-2 variants of concern in the Netherlands.

Variants of concern (VOCs) of SARS-CoV-2 have caused resurging waves of infections worldwide. In the Netherlands, Alpha, Beta, Gamma and Delta variants circulated widely between September 2020 and August 2021. To understand how various control measures had impacted the spread of these VOCs, we analyzed 39,844 SARS-CoV-2 genomes collected under the Dutch national surveillance program. We found that all four VOCs were introduced before targeted flight restrictions were imposed on countries where the VOCs first emerged. Importantly, foreign introductions, predominantly from other European countries, continued during these restrictions. Our findings show that flight restrictions had limited effectiveness in deterring VOC introductions due to the strength of regional land travel importation risks. We also found that the Alpha and Delta variants largely circulated more populous regions with international connections after their respective introduction before asymmetric bidirectional transmissions occurred with the rest of the country and the variant dominated infections in the Netherlands. As countries consider scaling down SARS-CoV-2 surveillance efforts in the post-crisis phase of the pandemic, our results highlight that robust surveillance in regions of early spread is important for providing timely information for variant detection and outbreak control.

Optimal vaccine allocation for COVID-19 in the Netherlands: A data-driven prioritization.

For the control of COVID-19, vaccination programmes provide a long-term solution. The amount of available vaccines is often limited, and thus it is crucial to determine the allocation strategy. While mathematical modelling approaches have been used to find an optimal distribution of vaccines, there is an excessively large number of possible allocation schemes to be simulated. Here, we propose an algorithm to find a near-optimal allocation scheme given an intervention objective such as minimization of new infections, hospitalizations, or deaths, where multiple vaccines are available. The proposed principle for allocating vaccines is to target subgroups with the largest reduction in the outcome of interest. We use an approximation method to reconstruct the age-specific transmission intensity (the next generation matrix), and express the expected impact of vaccinating each subgroup in terms of the observed incidence of infection and force of infection. The proposed approach is firstly evaluated with a simulated epidemic and then applied to the epidemiological data on COVID-19 in the Netherlands. Our results reveal how the optimal allocation depends on the objective of infection control. In the case of COVID-19, if we wish to minimize deaths, the optimal allocation strategy is not efficient for minimizing other outcomes, such as infections. In simulated epidemics, an allocation strategy optimized for an outcome outperforms other strategies such as the allocation from young to old, from old to young, and at random. Our simulations clarify that the current policy in the Netherlands (i.e., allocation from old to young) was concordant with the allocation scheme that minimizes deaths. The proposed method provides an optimal allocation scheme, given routine surveillance data that reflect ongoing transmissions. This approach to allocation is useful for providing plausible simulation scenarios for complex models, which give a more robust basis to determine intervention strategies.

Associations Between Measures of Social Distancing and Severe Acute Respiratory Syndrome Coronavirus 2 Seropositivity: A Nationwide Population-based Study in the Netherlands.

This large, nationwide, population-based, seroepidemiological study provides evidence of the effectiveness of physical distancing (>1.5 m) and indoor group size reductions in reducing severe acute respiratory syndrome coronavirus 2 infection. Additionally, young adults may play an important role in viral spread, contrary to children up until age 12 years with whom close contact is permitted. CLINICAL TRIALS REGISTRATION: NTR8473.

Measles outbreak in complex emergency: estimating vaccine effectiveness and evaluation of the vaccination campaign in Borno State, Nigeria, 2019.

BACKGROUND: From January to May 2019, large measles outbreaks affected Nigeria. Borno state was the most affected, recording 15,237 suspected cases with the state capital of Maiduguri having 1125 cases investigated and line-listed by March 2019. In Borno state, 22 of the 27 Local Government Areas (LGAs or Districts), including 37 internally displaced persons (IDPs) camps were affected. In response to the situation, an outbreak response immunization (ORI) campaign was conducted in the 13 most affected LGAs. In addition to conventional vaccination teams, special teams were deployed in security compromised areas, areas with migrants, and for nomadic and IDPs. Here we describe the outbreak and the ORI campaign. We also assess the measles-containing vaccine (MCV) coverage and vaccine effectiveness (VE) in order to quantify the population-level impact. METHODS: We reviewed the ORI activities, and conducted an analysis of the surveillance and the outbreak investigation reports. We assessed VE of MCV by applying the screening-method. Sensitivity analyses were also conducted to assess the effect of final classification of cases on the VE of MCV. The MCV coverage was assessed by a post-campaign coverage survey after completion of the ORI through a quantitative survey in the 12 LGAs that were accessible. RESULTS: Of the total 15,237 reported measles cases, 2002 cases were line-listed and investigated, and 737 were confirmed for measles by week 9 of 2019. Of the investigated cases 67.3% (n = 1348) were between 9 and 59 months of age. Among the 737 confirmed cases, only 9% (n = 64) stated being vaccinated with at least 1 dose of MCV. The overall VE for MCV was 98.4% (95%CI: 97.8-98.8). No significant differences were observed in the VE estimates of lab-confirmed and epi-linked cases when compared to the original estimates. The aggregated weighted vaccination coverage was 85.7% (95% CI: 79.6-90.1). CONCLUSION: The experience in Borno demonstrates that adequate VE can be obtained in conflict-affected areas. In complex emergencies affected by measles outbreaks, health authorities may consider integration with other health strategies and the engagement of security personnel as part of the ORI activities.

Impact of physical distancing measures against COVID-19 on contacts and mixing patterns: repeated cross-sectional surveys, the Netherlands, 2016-17, April 2020 and June 2020.

BackgroundDuring the COVID-19 pandemic, many countries have implemented physical distancing measures to reduce transmission of SARS-CoV-2.AimTo measure the actual reduction of contacts when physical distancing measures are implemented.MethodsA cross-sectional survey was carried out in the Netherlands in 2016-17, in which participants reported the number and age of their contacts the previous day. The survey was repeated among a subsample of the participants in April 2020, after strict physical distancing measures were implemented, and in an extended sample in June 2020, after some measures were relaxed.ResultsThe average number of community contacts per day was reduced from 14.9 (interquartile range (IQR): 4-20) in the 2016-17 survey to 3.5 (IQR: 0-4) after strict physical distancing measures were implemented, and rebounded to 8.8 (IQR: 1-10) after some measures were relaxed. All age groups restricted their community contacts to at most 5, on average, after strict physical distancing measures were implemented. In children, the number of community contacts reverted to baseline levels after measures were eased, while individuals aged 70 years and older had less than half their baseline levels.ConclusionStrict physical distancing measures greatly reduced overall contact numbers, which likely contributed to curbing the first wave of the COVID-19 epidemic in the Netherlands. However, age groups reacted differently when measures were relaxed, with children reverting to normal contact numbers and elderly individuals maintaining restricted contact numbers. These findings offer guidance for age-targeted measures in future waves of the pandemic.

Excess Deaths during Influenza and Coronavirus Disease and Infection-Fatality Rate for Severe Acute Respiratory Syndrome Coronavirus 2, the Netherlands.

Since the 2009 influenza pandemic, the Netherlands has used a weekly death monitoring system to estimate deaths in excess of expectations. We present estimates of excess deaths during the ongoing coronavirus disease (COVID-19) epidemic and 10 previous influenza epidemics. Excess deaths per influenza epidemic averaged 4,000. The estimated 9,554 excess deaths (41% in excess) during the COVID-19 epidemic weeks 12-19 of 2020 appeared comparable to the 9,373 excess deaths (18%) during the severe influenza epidemic of 2017-18. However, these deaths occurred in a shorter time, had a higher peak, and were mitigated by nonpharmaceutical control measures. Excess deaths were 1.8-fold higher than reported laboratory-confirmed COVID-19 deaths (5,449). Based on excess deaths and preliminary results from seroepidemiologic studies, we estimated the infection-fatality rate to be 1%. Monitoring of excess deaths is crucial for timely estimates of disease burden for influenza and COVID-19. Our data complement laboratory-confirmed COVID-19 death reports and enable comparisons between epidemics.

Incubation period of 2019 novel coronavirus (2019-nCoV) infections among travellers from Wuhan, China, 20-28 January 2020.

A novel coronavirus (2019-nCoV) is causing an outbreak of viral pneumonia that started in Wuhan, China. Using the travel history and symptom onset of 88 confirmed cases that were detected outside Wuhan in the early outbreak phase, we estimate the mean incubation period to be 6.4 days (95% credible interval: 5.6-7.7), ranging from 2.1 to 11.1 days (2.5th to 97.5th percentile). These values should help inform 2019-nCoV case definitions and appropriate quarantine durations.

Competition between Escherichia coli Populations with and without Plasmids Carrying a Gene Encoding Extended-Spectrum Beta-Lactamase in the Broiler Chicken Gut.

Extended-spectrum-beta-lactamase (ESBL)/AmpC-producing Escherichia coli strains are widely found in E. coli isolates from broiler feces, largely due to the presence of the blaCTX-M-1 gene on IncI1 plasmids. Plasmid carriage is theorized to cause fitness loss and thus should decrease under conditions of reduced antibiotic use. However, in vitro studies showed plasmid carriage to increase in the absence of antimicrobials, due to plasmid conjugation. We investigated whether this translates to increased levels of plasmid in the gastrointestinal tracts of chickens, where conjugation rates may be different and subtle differences in growth rates may have a larger impact on colonization. Eight groups of five chickens were orally inoculated at 4 days of age with a 0.5-ml volume containing 106 CFU/ml E. coli cells, of which 0%, 0.1%, 10%, or 100% carried the IncI1 plasmid with the gene blaCTX-M-1 At 13 time points during 41 days, fecal samples were taken from each chicken. E. coli strains with and without plasmids were quantified. Trends in E. coli subpopulations were analyzed using generalized linear mixed models, and population dynamics were studied by fitting to a mechanistic model. Trends in E. coli subpopulations were different between groups rather than between individual chickens, suggesting substantial levels of E. coli exchange between chickens in a group. The IncI1 plasmid carrying blaCTX-M-1 was transferred with conjugation coefficients at levels higher than those observed in vitro Across groups, the plasmids disappeared or were established independently of the initial fraction of plasmid-carrying E. coli, but no major increase occurred as observed in vitro Differences in growth rates were observed, but competitive exclusion of plasmid-carrying variants was counteracted by conjugation.IMPORTANCE Bacteria that produce extended-spectrum beta-lactamases are resistant to an important class of antimicrobials in human and veterinary medicine. Reduction in antibiotic use is expected to decrease the prevalence of resistance. However, resistance genes often lie on plasmids which can be copied and transferred to other bacteria by conjugation, so in vitro resistance was observed to increase in the absence of antimicrobials. We sought to determine whether this also occurs in the chicken gut and if competitive exclusion by similar E. coli variants without the resistance occurred. We studied the excretion of E. coli carrying IncI1 plasmids with the blaCTX-M-1 resistance gene in small groups of broiler chickens, after inoculating the chickens with E. coli suspensions containing different fractions of plasmid-carrying cells. Our results showed little variation between chickens within groups but large differences between groups that were independent of the ratio of variants with and without the plasmid and with persistence or extinction of the plasmid. However, there was no major plasmid increase as observed in vitro We conclude that in vivo studies with sufficient independent replications are important for intervention studies on plasmid-mediated antimicrobial resistance.

The roles of migratory and resident birds in local avian influenza infection dynamics.

Migratory birds are an increasing focus of interest when it comes to infection dynamics and the spread of avian influenza viruses (AIV). However, we lack detailed understanding migratory birds' contribution to local AIV prevalence levels and their downstream socio-economic costs and threats.To explain the potential differential roles of migratory and resident birds in local AIV infection dynamics, we used a susceptible-infectious-recovered (SIR) model. We investigated five (mutually non- exclusive) mechanisms potentially driving observed prevalence patterns: 1) a pronounced birth pulse (e.g. the synchronised annual influx of immunologically naïve individuals), 2) short-term immunity, 3) increase of susceptible migrants, 4) differential susceptibility to infection (i.e. transmission rate) for migrants and residents, and 5) replacement of migrants during peak migration.SIR models describing all possible combinations of the five mechanisms were fitted to individual AIV infection data from a detailed longitudinal surveillance study in the partially migratory mallard duck (Anas platyrhynchos). During autumn and winter, the local resident mallard community also held migratory mallards that exhibited distinct AIV infection dynamics.Replacement of migratory birds during peak migration in autumn was found to be the most important mechanism driving the variation in local AIV infection patterns. This suggests that a constant influx of migratory birds, likely immunological naïve to locally circulating AIV strains, is required to predict the observed temporal prevalence patterns and the distinct differences in prevalence between residents and migrants.Synthesis and applications. Our analysis reveals a key mechanism that could explain the amplifying role of migratory birds in local avian influenza virus infection dynamics; the constant flow and replacement of migratory birds during peak migration. Aside from monitoring efforts, in order to achieve adequate disease management and control in wildlife - with knock-on effects for livestock and humans, - we conclude that it is crucial, in future surveillance studies, to record host demographical parameters such as population density, timing of birth and turnover of migrants.

The Reduction of Measles Transmission During School Vacations.

BACKGROUND: Historically, measles incidence has shown clear seasonal patterns driven by the school calendar, but since the start of mass vaccination in developed countries there are only occasional outbreaks, which may have changed the effect of school vacations on transmission. In 2013-2014, a large measles epidemic took place in a low vaccination coverage area in The Netherlands, allowing us to quantify current-day measles transmission and the effect of school vacations. METHODS: We fitted a dynamic transmission model to notification and hospitalization time series data of the Dutch 2013-2014 measles epidemic. Our primary aim was to estimate the reduction in contact rate during school vacations and the number of cases averted due to the vacation. In addition, because the summer vacations were time-staggered in three regions, we could distinguish within-region from across-region effects of school vacations. RESULTS: We estimated a 53% (95% credible interval: 45%, 60%) reduction in contact rate during school vacations, resulting in 4900 (3400-7100) averted cases (estimated outbreak size: 16,600 [12,600-23,200]). There was a shift from mainly local transmission during school term to mainly cross-regional transmission during vacations. With seroprevalence data, we derived a current-day estimate of 15 to 27 for R0 (number of secondary cases per primary case in a susceptible population). CONCLUSIONS: School vacations are associated with greatly reduced overall measles transmission. However, transmission is not eliminated, and increased long-distance travel may even promote spread to other areas. Therefore, we estimate that school closure is unlikely to prevent measles epidemics unless there are still few cases and the community is well vaccinated.

Real-time Estimation of Epidemiologic Parameters from Contact Tracing Data During an Emerging Infectious Disease Outbreak.

BACKGROUND: Contact tracing can provide accurate information on relevant parameters of an ongoing emerging infectious disease outbreak. This is crucial to investigators seeking to control such an outbreak. However, crude contact tracing data are difficult to interpret and methods for analyzing these data are scarce. We present a method to estimate and visualize key outbreak parameters from contact tracing information in real time by taking into account data censoring. METHODS/RESULTS: Exposure type-specific attack rates and the reproduction number R(t) are estimated from contact tracing data by using maximum likelihood estimation to account for censored data. The attack rates reflect, in the context of contact tracing, the specificity of the contact definition; a higher value indicates relatively efficient contact tracing. The evolution of R(t) over time provides information regarding the effectiveness of interventions. To allow a real-time overview of the outbreak, the attack rates and the evolution of R(t) over time are visualized together with the case-contact network and epicurve. We applied the method to a well-documented smallpox outbreak in The Netherlands to demonstrate the added value. CONCLUSION: Our method facilitates the analysis of contact tracing information by quickly turning it into accessible information, helping outbreak investigators to make real-time decisions to more effectively and efficiently control infectious disease outbreaks.

Simultaneous inference of phylogenetic and transmission trees in infectious disease outbreaks.

Whole-genome sequencing of pathogens from host samples becomes more and more routine during infectious disease outbreaks. These data provide information on possible transmission events which can be used for further epidemiologic analyses, such as identification of risk factors for infectivity and transmission. However, the relationship between transmission events and sequence data is obscured by uncertainty arising from four largely unobserved processes: transmission, case observation, within-host pathogen dynamics and mutation. To properly resolve transmission events, these processes need to be taken into account. Recent years have seen much progress in theory and method development, but existing applications make simplifying assumptions that often break up the dependency between the four processes, or are tailored to specific datasets with matching model assumptions and code. To obtain a method with wider applicability, we have developed a novel approach to reconstruct transmission trees with sequence data. Our approach combines elementary models for transmission, case observation, within-host pathogen dynamics, and mutation, under the assumption that the outbreak is over and all cases have been observed. We use Bayesian inference with MCMC for which we have designed novel proposal steps to efficiently traverse the posterior distribution, taking account of all unobserved processes at once. This allows for efficient sampling of transmission trees from the posterior distribution, and robust estimation of consensus transmission trees. We implemented the proposed method in a new R package phybreak. The method performs well in tests of both new and published simulated data. We apply the model to five datasets on densely sampled infectious disease outbreaks, covering a wide range of epidemiological settings. Using only sampling times and sequences as data, our analyses confirmed the original results or improved on them: the more realistic infection times place more confidence in the inferred transmission trees.