Publications by authors named "Niel Hens"

204 Publications

Measuring association among censored antibody titer data.

Stat Med 2021 May 3. Epub 2021 May 3.

I-BioStat, Data Science Institute, Hasselt University, Hasselt, Belgium.

Censoring due to a limit of detection or limit of quantification happens quite often in many medical studies. Conventional approaches to deal with censoring when analyzing these data include, for example, the substitution method and the complete case (CC) analysis. More recently, maximum likelihood estimation (MLE) has been increasingly used. While the CC analysis and the substitution method usually lead to biased estimates, the MLE approach appears to perform well in many situations. This article proposes an MLE approach to estimate the association between two measurements in the presence of censoring in one or both quantities. The central idea is to use a copula function to join the marginal distributions of the two measurements. In various simulation studies, we show that our approach outperforms existing conventional methods (CC and substitution analyses). In addition, rank-based measures of global association such as Kendall's tau or Spearman's rho can be studied, hence, attention is not only confined to Pearson's product-moment correlation coefficient capturing solely linear association. We have shown in our simulations that our approach is robust to misspecification of the copula function or marginal distributions given a small association. Furthermore, we propose a straightforward MLE method to fit a (multiple) linear regression model in the presence of censoring in a covariate or both the covariate and the response. Given the marginal distribution of the censored covariate, our method outperforms conventional approaches. We also compare and discuss the performance of our method with multiple imputation and missing indicator model approaches.
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http://dx.doi.org/10.1002/sim.8995DOI Listing
May 2021

Modelling the early phase of the Belgian COVID-19 epidemic using a stochastic compartmental model and studying its implied future trajectories.

Epidemics 2021 Mar 23;35:100449. Epub 2021 Mar 23.

Data Science Institute, Interuniversity Institute of Biostatistics and statistical Bioinformatics, UHasselt, Hasselt, Belgium; Centre for Health Economic Research and Modelling Infectious Diseases, Vaccine & Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.

Following the onset of the ongoing COVID-19 pandemic throughout the world, a large fraction of the global population is or has been under strict measures of physical distancing and quarantine, with many countries being in partial or full lockdown. These measures are imposed in order to reduce the spread of the disease and to lift the pressure on healthcare systems. Estimating the impact of such interventions as well as monitoring the gradual relaxing of these stringent measures is quintessential to understand how resurgence of the COVID-19 epidemic can be controlled for in the future. In this paper we use a stochastic age-structured discrete time compartmental model to describe the transmission of COVID-19 in Belgium. Our model explicitly accounts for age-structure by integrating data on social contacts to (i) assess the impact of the lockdown as implemented on March 13, 2020 on the number of new hospitalizations in Belgium; (ii) conduct a scenario analysis estimating the impact of possible exit strategies on potential future COVID-19 waves. More specifically, the aforementioned model is fitted to hospital admission data, data on the daily number of COVID-19 deaths and serial serological survey data informing the (sero)prevalence of the disease in the population while relying on a Bayesian MCMC approach. Our age-structured stochastic model describes the observed outbreak data well, both in terms of hospitalizations as well as COVID-19 related deaths in the Belgian population. Despite an extensive exploration of various projections for the future course of the epidemic, based on the impact of adherence to measures of physical distancing and a potential increase in contacts as a result of the relaxation of the stringent lockdown measures, a lot of uncertainty remains about the evolution of the epidemic in the next months.
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http://dx.doi.org/10.1016/j.epidem.2021.100449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986325PMC
March 2021

On realized serial and generation intervals given control measures: The COVID-19 pandemic case.

PLoS Comput Biol 2021 03 29;17(3):e1008892. Epub 2021 Mar 29.

Centre for Health Economic Research and Modelling Infectious Diseases, University of Antwerp, Antwerp, Belgium.

The SARS-CoV-2 pathogen is currently spreading worldwide and its propensity for presymptomatic and asymptomatic transmission makes it difficult to control. The control measures adopted in several countries aim at isolating individuals once diagnosed, limiting their social interactions and consequently their transmission probability. These interventions, which have a strong impact on the disease dynamics, can affect the inference of the epidemiological quantities. We first present a theoretical explanation of the effect caused by non-pharmaceutical intervention measures on the mean serial and generation intervals. Then, in a simulation study, we vary the assumed efficacy of control measures and quantify the effect on the mean and variance of realized generation and serial intervals. The simulation results show that the realized serial and generation intervals both depend on control measures and their values contract according to the efficacy of the intervention strategies. Interestingly, the mean serial interval differs from the mean generation interval. The deviation between these two values depends on two factors. First, the number of undiagnosed infectious individuals. Second, the relationship between infectiousness, symptom onset and timing of isolation. Similarly, the standard deviations of realized serial and generation intervals do not coincide, with the former shorter than the latter on average. The findings of this study are directly relevant to estimates performed for the current COVID-19 pandemic. In particular, the effective reproduction number is often inferred using both daily incidence data and the generation interval. Failing to account for either contraction or mis-specification by using the serial interval could lead to biased estimates of the effective reproduction number. Consequently, this might affect the choices made by decision makers when deciding which control measures to apply based on the value of the quantity thereof.
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http://dx.doi.org/10.1371/journal.pcbi.1008892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031880PMC
March 2021

The impact of contact tracing and household bubbles on deconfinement strategies for COVID-19.

Nat Commun 2021 03 9;12(1):1524. Epub 2021 Mar 9.

Centre for Health Economic Research and Modelling Infectious Diseases, University of Antwerp, Antwerp, Belgium.

The COVID-19 pandemic caused many governments to impose policies restricting social interactions. A controlled and persistent release of lockdown measures covers many potential strategies and is subject to extensive scenario analyses. Here, we use an individual-based model (STRIDE) to simulate interactions between 11 million inhabitants of Belgium at different levels including extended household settings, i.e., "household bubbles". The burden of COVID-19 is impacted by both the intensity and frequency of physical contacts, and therefore, household bubbles have the potential to reduce hospital admissions by 90%. In addition, we find that it is crucial to complete contact tracing 4 days after symptom onset. Assumptions on the susceptibility of children affect the impact of school reopening, though we find that business and leisure-related social mixing patterns have more impact on COVID-19 associated disease burden. An optimal deployment of the mitigation policies under study require timely compliance to physical distancing, testing and self-isolation.
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http://dx.doi.org/10.1038/s41467-021-21747-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943552PMC
March 2021

Close contact infection dynamics over time: insights from a second large-scale social contact survey in Flanders, Belgium, in 2010-2011.

BMC Infect Dis 2021 Mar 18;21(1):274. Epub 2021 Mar 18.

I-Biostat, Data Science Institute, Hasselt University, Martelarenlaan 42, Hasselt, 3500, Belgium.

Background: In 2010-2011, we conducted a social contact survey in Flanders, Belgium, aimed at improving and extending the design of the first social contact survey conducted in Belgium in 2006. This second social contact survey aimed to enable, for the first time, the estimation of social mixing patterns for an age range of 0 to 99 years and the investigation of whether contact rates remain stable over this 5-year time period.

Methods: Different data mining techniques are used to explore the data, and the age-specific number of social contacts and the age-specific contact rates are modelled using a generalized additive models for location, scale and shape (GAMLSS) model. We compare different matrices using assortativeness measures. The relative change in the basic reproduction number (R) and the ratio of relative incidences with 95% bootstrap confidence intervals (BCI) are employed to investigate and quantify the impact on epidemic spread due to differences in sex, day of the week, holiday vs. regular periods and changes in mixing patterns over the 5-year time gap between the 2006 and 2010-2011 surveys. Finally, we compare the fit of the contact matrices in 2006 and 2010-2011 to Varicella serological data.

Results: All estimated contact patterns featured strong homophily in age and sex, especially for small children and adolescents. A 30% (95% BCI [17%; 37%]) and 29% (95% BCI [14%; 40%]) reduction in R was observed for weekend versus weekdays and for holiday versus regular periods, respectively. Significantly more interactions between people aged 60+ years and their grandchildren were observed on holiday and weekend days than on regular weekdays. Comparing contact patterns using different methods did not show any substantial differences over the 5-year time period under study.

Conclusions: The second social contact survey in Flanders, Belgium, endorses the findings of its 2006 predecessor and adds important information on the social mixing patterns of people older than 60 years of age. Based on this analysis, the mixing patterns of people older than 60 years exhibit considerable heterogeneity, and overall, the comparison of the two surveys shows that social contact rates can be assumed stable in Flanders over a time span of 5 years.
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http://dx.doi.org/10.1186/s12879-021-05949-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971398PMC
March 2021

Assessing the feasibility and effectiveness of household-pooled universal testing to control COVID-19 epidemics.

PLoS Comput Biol 2021 03 9;17(3):e1008688. Epub 2021 Mar 9.

Interuniversity Institute of Biostatistics and statistical Bioinformatics, Data Science Institute, Hasselt University, Hasselt, Belgium.

Outbreaks of SARS-CoV-2 are threatening the health care systems of several countries around the world. The initial control of SARS-CoV-2 epidemics relied on non-pharmaceutical interventions, such as social distancing, teleworking, mouth masks and contact tracing. However, as pre-symptomatic transmission remains an important driver of the epidemic, contact tracing efforts struggle to fully control SARS-CoV-2 epidemics. Therefore, in this work, we investigate to what extent the use of universal testing, i.e., an approach in which we screen the entire population, can be utilized to mitigate this epidemic. To this end, we rely on PCR test pooling of individuals that belong to the same households, to allow for a universal testing procedure that is feasible with the limited testing capacity. We evaluate two isolation strategies: on the one hand pool isolation, where we isolate all individuals that belong to a positive PCR test pool, and on the other hand individual isolation, where we determine which of the individuals that belong to the positive PCR pool are positive, through an additional testing step. We evaluate this universal testing approach in the STRIDE individual-based epidemiological model in the context of the Belgian COVID-19 epidemic. As the organisation of universal testing will be challenging, we discuss the different aspects related to sample extraction and PCR testing, to demonstrate the feasibility of universal testing when a decentralized testing approach is used. We show through simulation, that weekly universal testing is able to control the epidemic, even when many of the contact reductions are relieved. Finally, our model shows that the use of universal testing in combination with stringent contact reductions could be considered as a strategy to eradicate the virus.
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http://dx.doi.org/10.1371/journal.pcbi.1008688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943003PMC
March 2021

Workplace influenza vaccination to reduce employee absenteeism: An economic analysis from the employers' perspective.

Vaccine 2021 Apr 23;39(14):2005-2015. Epub 2021 Feb 23.

Centre for Health Economics Research and Modelling Infectious Diseases (CHERMID), Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium.

Background: Each year, up to 10% of unvaccinated adults contracts seasonal influenza, with half of this proportion developing symptoms. As a result, employers experience significant economic losses in terms of employee absenteeism. Influenza vaccines can be instrumental in reducing this burden. Workplace vaccination is expected to reduce employee absenteeism more than linearly as a result of positive externalities. It remains unclear whether workplace influenza vaccination yields a positive return on investment.

Methods: We simulated the spread of influenza in the seasons 2011-12 up to 2017-18 in Belgium by means of a compartmental transmission model. We accounted for age-specific social contact patterns and included reduced contact behavior when symptomatically infected. We simulated the impact of employer-funded influenza vaccination at the workplace and performed a cost-benefit analysis to assess the employers' return on workplace vaccination. Furthermore, we look into the cost-benefit of rewarding vaccinated employees by offering an additional day off.

Results: Workplace vaccination reduced the burden of influenza both on the workplace and in the population at large. Compared to the current vaccine coverage - 21% in the population at large - an employee vaccine coverage of 90% could avert an additional 355 000 cases, of which about 150 000 in the employed population and 205 000 in the unemployed population. While seasonal influenza vaccination has been cost-saving on average at about €10 per vaccinated employee, the cost-benefit analysis was prone to between-season variability.

Conclusions: Vaccinated employees can serve as a barrier to limit the spread of influenza in the population, reducing the attack rate by 78% at an employee coverage of 90%. While workplace vaccination is relatively inexpensive (due to economies of scale) and convenient, the return on investment is volatile. Government subsidies can be pivotal to encourage employers to provide vaccination at the workplace with positive externalities to society as a whole.
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http://dx.doi.org/10.1016/j.vaccine.2021.02.020DOI Listing
April 2021

The hepatitis C cascade of care in the Belgian HIV population: One step closer to elimination.

Int J Infect Dis 2021 Apr 18;105:217-223. Epub 2021 Feb 18.

Faculty of Health and Life Sciences, Hasselt University, Diepenbeek, Belgium; Department of Gastroenterology and Hepatology, Ziekenhuis Oost-Limburg, Genk, Belgium; Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium.

Objectives: The Belgian population of people living with HIV (PLHIV) has unrestricted access to direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection, since 2017. International literature claims that half of the patients remain untreated in high-income countries with unrestricted access to DAA. This study was initiated to provide an overview of the present situation in Belgium and recommendations for HCV care in PLHIV in other regions.

Methods: This was a retrospective, multicenter study of PLHIV in Belgium, from January 1, 2007 to December 31, 2018. The HCV cascade of care was examined.

Results: Out of 4607 unique PLHIV, 322 (7.0%) tested positive for HCV antibody and HCV RNA positivity was seen in 289 (6.3%). Of those with a proven HCV infection, 207/289 (71.6%) initiated treatment. Of the 171 (82.6%) persons with a sustained virologic response (SVR), 16 (9.4%) subjects were reinfected.

Conclusions: We present a care cascade of 4607 PLHIV in Belgium. Treatment initiation and SVR rates were high compared to other regions. Implementation of a national HCV register to track progress and yearly screening, especially in PLHIV with high-risk behavior, remains crucial. Identifying reasons for not initiating treatment is necessary to achieve elimination of HCV in PLHIV by 2030.
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http://dx.doi.org/10.1016/j.ijid.2021.02.068DOI Listing
April 2021

Estimating Transmission Parameters for COVID-19 Clusters by Using Symptom Onset Data, Singapore, January-April 2020.

Emerg Infect Dis 2021 Feb;27(2):582-585

We estimated the generation interval distribution for coronavirus disease on the basis of serial intervals of observed infector-infectee pairs from established clusters in Singapore. The short mean generation interval and consequent high prevalence of presymptomatic transmission requires public health control measures to be responsive to these characteristics of the epidemic.
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http://dx.doi.org/10.3201/eid2702.203018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853533PMC
February 2021

Face masks in the post-COVID-19 era: a silver lining for the damaged tuberculosis public health response?

Lancet Respir Med 2021 04 22;9(4):340-342. Epub 2021 Jan 22.

DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research and SA/MRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7550, South Africa. Electronic address:

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http://dx.doi.org/10.1016/S2213-2600(21)00020-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826055PMC
April 2021

CoMix: comparing mixing patterns in the Belgian population during and after lockdown.

Sci Rep 2020 12 14;10(1):21885. Epub 2020 Dec 14.

UHasselt, Data Science Institute and I-BioStat, Hasselt, 3500, Belgium.

The COVID-19 pandemic has shown how a newly emergent communicable disease can lay considerable burden on public health. To avoid system collapse, governments have resorted to several social distancing measures. In Belgium, this included a lockdown and a following period of phased re-opening. A representative sample of Belgian adults was asked about their contact behaviour from mid-April to the beginning of August, during different stages of the intervention measures in Belgium. Use of personal protection equipment (face masks) and compliance to hygienic measures was also reported. We estimated the expected reproduction number computing the ratio of [Formula: see text] with respect to pre-pandemic data. During the first two waves (the first month) of the survey, the reduction in the average number of contacts was around 80% and was quite consistent across all age-classes. The average number of contacts increased over time, particularly for the younger age classes, still remaining significantly lower than pre-pandemic values. From the end of May to the end of July , the estimated reproduction number has a median value larger than one, although with a wide dispersion. Estimated [Formula: see text] fell below one again at the beginning of August. We have shown how a rapidly deployed survey can measure compliance to social distancing and assess its impact on COVID-19 spread. Monitoring the effectiveness of social distancing recommendations is of paramount importance to avoid further waves of COVID-19.
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http://dx.doi.org/10.1038/s41598-020-78540-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736856PMC
December 2020

Coronavirus Disease-19: An Interim Evidence Synthesis of the World Association for Infectious Diseases and Immunological Disorders (Waidid).

Front Med (Lausanne) 2020 30;7:572485. Epub 2020 Oct 30.

Pediatric Clinic, Department of Medicine and Surgery, Pietro Barilla Children's Hospital, University of Parma, Parma, Italy.

Coronavirus disease 2019 (COVID-19) is a rapidly evolving, highly transmissible, and potentially lethal pandemic caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of June 11 2020, more than 7,000,000 COVID-19 cases have been reported worldwide, and more than 400,000 patients have died, affecting at least 188 countries. While literature on the disease is rapidly accumulating, an integrated, multinational perspective on clinical manifestations, immunological effects, diagnosis, prevention, and treatment of COVID-19 can be of global benefit. We aimed to synthesize the most relevant literature and experiences in different parts of the world through our global consortium of experts to provide a consensus-based document at this early stage of the pandemic.
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http://dx.doi.org/10.3389/fmed.2020.572485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662576PMC
October 2020

Clustering of susceptible individuals within households can drive measles outbreaks: an individual-based model exploration.

Sci Rep 2020 11 12;10(1):19645. Epub 2020 Nov 12.

Centre for Health Economics Research and Modelling Infectious Diseases (CHERMID), Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.

When estimating important measures such as the herd immunity threshold, and the corresponding efforts required to eliminate measles, it is often assumed that susceptible individuals are uniformly distributed throughout populations. However, unvaccinated individuals may be clustered in a variety of ways, including by geographic location, by age, in schools, or in households. Here, we investigate to which extent different levels of within-household clustering of susceptible individuals may impact the risk and persistence of measles outbreaks. To this end, we apply an individual-based model, Stride, to a population of 600,000 individuals, using data from Flanders, Belgium. We construct a metric to estimate the level of within-household susceptibility clustering in the population. Furthermore, we compare realistic scenarios regarding the distribution of susceptible individuals within households in terms of their impact on epidemiological measures for outbreak risk and persistence. We find that higher levels of within-household clustering of susceptible individuals increase the risk, size and persistence of measles outbreaks. Ignoring within-household clustering thus leads to underestimations of required measles elimination and outbreak mitigation efforts.
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http://dx.doi.org/10.1038/s41598-020-76746-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665185PMC
November 2020

Can COVID-19 symptoms as reported in a large-scale online survey be used to optimise spatial predictions of COVID-19 incidence risk in Belgium?

Spat Spatiotemporal Epidemiol 2020 11 25;35:100379. Epub 2020 Sep 25.

Center for Health Economics Research and Modeling Infectious Diseases, Vaccine and Infectious Disease Institute, University of Antwerp, Universiteitsplein 1, Antwerp 2610, Belgium.

Although COVID-19 has been spreading throughout Belgium since February, 2020, its spatial dynamics in Belgium remain poorly understood, partly due to the limited testing of suspected cases during the epidemic's early phase. We analyse data of COVID-19 symptoms, as self-reported in a weekly online survey, which is open to all Belgian citizens. We predict symptoms' incidence using binomial models for spatially discrete data, and we introduce these as a covariate in the spatial analysis of COVID-19 incidence, as reported by the Belgian government during the days following a survey round. The symptoms' incidence is moderately predictive of the variation in the relative risks based on the confirmed cases; exceedance probability maps of the symptoms' incidence and confirmed cases' relative risks overlap partly. We conclude that this framework can be used to detect COVID-19 clusters of substantial sizes, but it necessitates spatial information on finer scales to locate small clusters.
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http://dx.doi.org/10.1016/j.sste.2020.100379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518805PMC
November 2020

Infectious diseases epidemiology, quantitative methodology, and clinical research in the midst of the COVID-19 pandemic: Perspective from a European country.

Contemp Clin Trials 2020 12 22;99:106189. Epub 2020 Oct 22.

Belgian Health Care Knowledge Center (KCE), Belgium.

Starting from historic reflections, the current SARS-CoV-2 induced COVID-19 pandemic is examined from various perspectives, in terms of what it implies for the implementation of non-pharmaceutical interventions, the modeling and monitoring of the epidemic, the development of early-warning systems, the study of mortality, prevalence estimation, diagnostic and serological testing, vaccine development, and ultimately clinical trials. Emphasis is placed on how the pandemic had led to unprecedented speed in methodological and clinical development, the pitfalls thereof, but also the opportunities that it engenders for national and international collaboration, and how it has simplified and sped up procedures. We also study the impact of the pandemic on clinical trials in other indications. We note that it has placed biostatistics, epidemiology, virology, infectiology, and vaccinology, and related fields in the spotlight in an unprecedented way, implying great opportunities, but also the need to communicate effectively, often amidst controversy.
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http://dx.doi.org/10.1016/j.cct.2020.106189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581408PMC
December 2020

Estimating the optimal interval between rounds of indoor residual spraying of insecticide using malaria incidence data from cohort studies.

PLoS One 2020 23;15(10):e0241033. Epub 2020 Oct 23.

Department of Medicine, University of California, San Francisco, California, United States of America.

Background: Indoor residual spraying (IRS) reduces vector densities and malaria transmission, however, the most effective spraying intervals for IRS have not been well established. We estimated the optimal timing interval for IRS using a statistical approach.

Methods: Six rounds of IRS were implemented in Tororo District, a historically high malaria transmission setting in Uganda, during the study period (3 rounds with bendiocarb active ingredient (Ficam®): December 2014 to December 2015, and 3 rounds with pirimiphos methyl active ingredient (Actellic 300®CS): June 2016 to July 2018). A generalized additive model was used to estimate the optimal timing interval for IRS based on the predicted malaria incidence. The model was fitted to clinical incidence data from a cohort of children aged 0.5-10 years from selected households observed throughout the study period.

Results: 494 children, 67% aged less than 5 years at enrolment were analysed. Six-months period incidence of malaria decreased from 2.96 per person-years at the baseline to 1.74 following the first round of IRS and then to 0.02 after 6 rounds of IRS. The optimal time interval for IRS differed between bendiocarb and pirimiphos methyl and by IRS round. To retain an optimum impact, bendiocarb would require respraying 17 (95% CI: 14.2-21.0) weeks after application whereas pirimiphos methyl could remain impactful for 40 (95% CI: 37.0-42.8) weeks, although in the final year this estimates 36 (95% CI: 32.7-37.7) weeks. However, we could not estimate from the data the optimal time after the second and third rounds of bendiocarb and after the second round of pirimiphos methyl. Neither the amount of rainfall nor the EIR nor the distribution of nets were found to be statistically significant for determining the time period between spray rounds.

Conclusion: In our setting, the effect of the two IRS products was distinct. Statistically, pirimiphos methyl provided a longer window of protection than bendiocarb, although impact varied between different spray rounds and years which was not explained by rainfall or EIR or distribution of nets in our statistical approach. Understanding the effectiveness of IRS and how long it lasts can help for planning campaigns, but one should consider the financial cost and insecticide resistance. Monitoring the timing of spray campaigns using clinical incidence could be repeated in future programs to help determine the average period of protectivity of these products.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241033PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584202PMC
December 2020

Time between Symptom Onset, Hospitalisation and Recovery or Death: Statistical Analysis of Belgian COVID-19 Patients.

Int J Environ Res Public Health 2020 10 17;17(20). Epub 2020 Oct 17.

Department of Epidemiology and Public Health, Sciensano, BE-1050 Brussels, Belgium.

There are different patterns in the COVID-19 outbreak in the general population and amongst nursing home patients. We investigate the time from symptom onset to diagnosis and hospitalization or the length of stay (LoS) in the hospital, and whether there are differences in the population. Sciensano collected information on 14,618 hospitalized patients with COVID-19 admissions from 114 Belgian hospitals between 14 March and 12 June 2020. The distributions of different event times for different patient groups are estimated accounting for interval censoring and right truncation of the time intervals. The time between symptom onset and hospitalization or diagnosis are similar, with median length between symptom onset and hospitalization ranging between 3 and 10.4 days, depending on the age of the patient (longest delay in age group 20-60 years) and whether or not the patient lives in a nursing home (additional 2 days for patients from nursing home). The median LoS in hospital varies between 3 and 10.4 days, with the LoS increasing with age. The hospital LoS for patients that recover is shorter for patients living in a nursing home, but the time to death is longer for these patients. Over the course of the first wave, the LoS has decreased.
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http://dx.doi.org/10.3390/ijerph17207560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589278PMC
October 2020

Donor-derived cell-free DNA as a biomarker for rejection after kidney transplantation: a systematic review and meta-analysis.

Transpl Int 2020 12 14;33(12):1626-1642. Epub 2020 Oct 14.

Laboratory of Experimental Medicine and Pediatrics and Member of the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.

A systematic review and meta-analysis were performed to investigate the value of donor-derived cell-free DNA (dd-cfDNA) as a noninvasive biomarker in diagnosing kidney allograft rejection. We searched PubMed, Web of Science and the Cochrane Library for original research papers published between January 1994 and May 2020 on dd-cfDNA fractions in blood of kidney allograft recipients. A single-group meta-analysis was performed by computing pooled estimates for dd-cfDNA fractions using the weighted median of medians or quantile estimation (QE) approach. Weighted median differences in medians (WMDMs) and median differences based on the QE method were used for pairwise comparisons. Despite heterogeneity among the selected studies, the meta-analysis revealed significantly higher median dd-cfDNA fractions in patients with antibody-mediated rejection (ABMR) than patients without rejection or patients with stable graft function. When comparing patients with T cell-mediated rejection (TCMR) and patients with ABMR, our two statistical approaches revealed conflicting results. Patients with TCMR did not have different median dd-cfDNA fractions than patients without rejection or patients with stable graft function. dd-cfDNA may be a useful marker for ABMR, but probably not for TCMR.
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http://dx.doi.org/10.1111/tri.13753DOI Listing
December 2020

Elucidating the difference in the kinetics of antibody titres of infants in Belgium and Vietnam.

Vaccine 2020 10 12;38(45):7079-7086. Epub 2020 Sep 12.

I-Biostat, Data Science Institute, Hasselt University, Martelarenlaan 42, 3500 Hasselt, Belgium; Center for the Evaluation of Vaccination, Vaccine & Infectious Diseases Institute, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.

Serological results obtained in a single laboratory from twin-studies on maternal immunisation, in Vietnam and Belgium offer the opportunity to compare antibody kinetics in infants before and after infant vaccination in the presence of vaccine-induced maternal antibodies. Nonlinear mixed-effects models (NLMMs) making use of a hypothesised dynamic evolution that captures the change in antibody titres over time, were employed to model anti-PT and anti-Prn antibody dynamics. Our proposed modelling approach provided useful insight into understanding the differences in the infants' antibody kinetics in both countries since NLMMs offer the possibility of pooling all data in one analysis and incorporate relevant covariates of interest. In both controlled cohort studies, pregnant women were vaccinated with a tetanus, diphtheria, acellular pertussis (Tdap) vaccine (Boostrix®, Belgium; Adacel®, Vietnam), and children were followed before and after primary vaccination, and before and after booster vaccination (Infanrix hexa®). From our models, both anti-PRN and anti-PT antibody titres at birth of Vietnamese infants were significantly lower than those of Belgian infants born to vaccinated women groups. Even though the antibody titres in the cord at birth of Belgian infants were also higher than those of Vietnamese infants born to the control women groups, the difference was not significant. The significant difference between infants born to vaccinated women in the two countries was likely due to the use of different vaccine brands in pregnant women and the different vaccination histories of women in these two countries. Our analyses also suggested that the blunting effect was present during the primary immunisation but went away afterward for anti-PT data. In contrast, for anti-PRN antibodies, the blunting effect persisted after the primary vaccination and possibly went away after the booster dose. Countries should be aware of the regional situation in view of recommending maternal immunization.
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http://dx.doi.org/10.1016/j.vaccine.2020.09.003DOI Listing
October 2020

Immunogenicity and persistence of trivalent measles, mumps, and rubella vaccines: a systematic review and meta-analysis.

Lancet Infect Dis 2021 02 1;21(2):286-295. Epub 2020 Sep 1.

Data Science Institute, I-BioStat, UHasselt, Diepenbeek, Belgium; Centre for Health Economic Research and Modelling Infectious Diseases, Vaccine & Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.

Background: Despite the universal use of the two-dose trivalent measles-mumps-rubella (MMR) vaccine in the past two decades, outbreaks of these diseases still occur in countries with high vaccine uptake, giving rise to concerns about primary and secondary failure of MMR vaccine components. We aimed to provide seroconversion and waning rate estimates for the measles, mumps, and rubella components of MMR vaccines.

Methods: In this systematic review and meta-analysis we searched PubMed (including MEDLINE), Web of Science, and Embase for randomised controlled trials, cohort studies, or longitudinal studies reporting the immunogenicity and persistence of MMR vaccines, published in English from database inception to Dec 31, 2019. Studies were included if they investigated vaccine-induced immunity in healthy individuals who received a trivalent MMR vaccine, including different dosages and timepoints of vaccine administration. Studies featuring coadministration of MMR with other vaccines, maternal immunity to the MMR vaccine, or non-trivalent formulations of the vaccine were excluded. Pooled seroconversion and waning rates were estimated by random-effects meta-analyses. This study is registered with PROSPERO, CRD42019116705.

Findings: We identified 3615 unique studies, 62 (1·7%) of which were eligible for analysis. Estimated overall seroconversion rates were 96·0% (95% CI 94·5-97·4; I=91·1%) for measles, 93·3% (91·1-95·2; I=94·9%) for mumps when excluding the Rubini strain, 91·1% (87·4-94·1; I=96·6%) for mumps when including the Rubini strain, and 98·3% (97·3-99·2; I=93·0%) for rubella. Estimated overall annual waning rates were 0·009 (95% CI 0·005-0·016; I=85·2%) for measles, 0·024 (0·016-0·039; I=94·7%) for mumps, and 0·012 (0·010-0·014; I=93·3%) for rubella.

Interpretation: Our meta-analysis provides estimates of primary and secondary vaccine failure, which are essential to improve the accuracy of mathematical and statistical modelling to understand and predict the occurrence of future measles, mumps, and rubella outbreaks in countries with high vaccine uptake.

Funding: European Research Council.
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http://dx.doi.org/10.1016/S1473-3099(20)30442-4DOI Listing
February 2021

Murine induced pluripotent stem cell-derived neuroimmune cell culture models emphasize opposite immune-effector functions of interleukin 13-primed microglia and macrophages in terms of neuroimmune toxicity.

Glia 2021 Feb 31;69(2):326-345. Epub 2020 Aug 31.

Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium.

Cellular models of induced pluripotent stem cell (iPSC)-derived microglia and macrophages are an emerging toolbox to investigate neuroinflammation in vitro. We previously demonstrated that murine iPSC-microglia and iPSC-macrophages display phenotypical activation properties highly comparable to microglia and macrophages in vivo. Here we extended the characterization of iPSC-microglia and iPSC-macrophages with the analysis of their transcriptome profile. Next, these cellular models were employed to evaluate neuroimmune toxicity in vitro and to investigate the immune-modulatory properties of interleukin 13 (IL13), a cytokine known for its ability to protect against neuroinflammation-induced pathology by modulating microglia and macrophage activation. iPSC-microglia and iPSC-macrophages, in co-culture with astrocyte-committed neural stem cells (NSC), were (pre)treated with IL13 and stimulated with lipopolysaccharide (LPS) and interferon γ (IFNγ), to assess how IL13 modulates their inflammatory response. Additionally, the use of luciferase-expressing NSC (Luc-NSC) allowed real-time monitoring of immune-mediated neurotoxicity. Despite the known anti-inflammatory properties of IL13, iPSC-microglia primed with IL13 before LPS + IFNγ stimulation significantly increased NO secretion. This was associated with a marked reduction of the luminescence signal produced by Luc-NSC. Interestingly, we observed that IL13 signaling has a divergent functional outcome in microglia as compared to macrophages, as for the latter no major alterations in NO release and Luc-NSC viability were observed upon IL13 (pre)treatment. Finally, the striking IL13-induced upregulation of NO secretion by microglia under pro-inflammatory conditions was confirmed in vivo, where intracerebral delivery of IL13 increased inducible nitric oxide synthase mRNA expression. Concluding, we applied iPSC-derived neuroimmune cell culture models to identify distinct neuroimmune (toxicity) responses of microglia and macrophages to IL13-based immune modulation.
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http://dx.doi.org/10.1002/glia.23899DOI Listing
February 2021

Authors' response: Estimating the generation interval for COVID-19 based on symptom onset data.

Euro Surveill 2020 07;25(29)

Centre for Health Economics Research and Modelling Infectious Diseases (CHERMID), Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.

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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.29.2001269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384288PMC
July 2020

Early detection of chronic hepatitis B and risk factor assessment in Turkish migrants, Middle Limburg, Belgium.

PLoS One 2020 27;15(7):e0234740. Epub 2020 Jul 27.

Department of Gastroenterology and Hepatology, Ziekenhuis Oost-Limburg, Genk, Belgium.

Background: Turkey is an intermediate hepatitis B virus (HBV) endemic country. However, prevalence among Turkish migrants in Belgium is unknown, especially in those born in Belgium with a foreign-born parent, i.e. second-generation migrants (SGM).

Aims: To evaluate the prevalence of HBV infection and associated risk factors in Turkish first-generation migrants (FGM), i.e. foreign-born, and SGM.

Methods: Between September 2017 and May 2019, free outreach testing for hepatitis B surface antigen (HBsAg), hepatitis B core antibodies (anti-HBc), and antibodies against HBsAg was offered to Turkish migrants in Middle-Limburg, Belgium. Face-to-face questionnaire assessed HBV risk factors. HBsAg positive patients were referred and followed up. Turkish SGM were stratified into birth cohort born before and after 1987, since those born after 1987 should be covered by the universal infant vaccination program.

Results: A total of 1,081/1,113 (97.1%) Turkish did go for HBV testing. Twenty-six (2.4%) were HBsAg positive; 11/26 were unaware of their status and 10/11 were successfully referred. HBsAg prevalence was 3.0% in FGM and 1.5% in SGM, p = .070. Only one out of seven HBsAg positive SGM was born after 1987. In the multiple generalized estimating equations model, the most important risk factors for anti-HBc positivity were male gender (p = .021), older age (p < .001), FGM (p < .001), low educational level of the mother (p = .003), HBV infected mother (p = .008), HBV infected siblings (p = .002), HBV infected other family member (p = .004), gynaecological examination in Turkey or unsafe male circumcision (p = .032) and dental treatment in Turkey (p = .049).

Conclusion: Outreach testing was well-accepted and referral to specialist care was generally successful. National HBV screening should be implemented in the Turkish FGM population and might be considered in SGM not covered by primary prevention strategies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234740PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384618PMC
September 2020

A prospect on the use of antiviral drugs to control local outbreaks of COVID-19.

BMC Med 2020 06 25;18(1):191. Epub 2020 Jun 25.

Centre for Health Economic Research and Modelling Infectious Diseases, University of Antwerp, Antwerp, Belgium.

Background: Current outbreaks of COVID-19 are threatening the health care systems of several countries around the world. Control measures, based on isolation, contact tracing, and quarantine, can decrease and delay the burden of the ongoing epidemic. With respect to the ongoing COVID-19 epidemic, recent modeling work shows that these interventions may be inadequate to control local outbreaks, even when perfect isolation is assumed. The effect of infectiousness prior to symptom onset combined with asymptomatic infectees further complicates the use of contact tracing. We aim to study whether antivirals, which decrease the viral load and reduce infectiousness, could be integrated into control measures in order to augment the feasibility of controlling the epidemic.

Methods: Using a simulation-based model of viral transmission, we tested the efficacy of different intervention measures to control local COVID-19 outbreaks. For individuals that were identified through contact tracing, we evaluate two procedures: monitoring individuals for symptoms onset and testing of individuals. Additionally, we investigate the implementation of an antiviral compound combined with the contact tracing process.

Results: For an infectious disease in which asymptomatic and presymptomatic infections are plausible, an intervention measure based on contact tracing performs better when combined with testing instead of monitoring, provided that the test is able to detect infections during the incubation period. Antiviral drugs, in combination with contact tracing, quarantine, and isolation, result in a significant decrease of the final size and the peak incidence, and increase the probability that the outbreak will fade out.

Conclusion: In all tested scenarios, the model highlights the benefits of control measures based on the testing of traced individuals. In addition, the administration of an antiviral drug, together with quarantine, isolation, and contact tracing, is shown to decrease the spread of the epidemic. This control measure could be an effective strategy to control local and re-emerging outbreaks of COVID-19.
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http://dx.doi.org/10.1186/s12916-020-01636-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315692PMC
June 2020

Stable HEV IgG seroprevalence in Belgium between 2006 and 2014.

J Viral Hepat 2020 11 12;27(11):1253-1260. Epub 2020 Jul 12.

Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium.

Recent European studies suggest an emergence of hepatitis E virus (HEV) infection. We evaluated trends in birth cohort-specific HEV seroprevalence and regional differences in Belgium. HEV IgG seroprevalence was analysed on national serum banks (1579 and 2087 samples for 2006 and 2014, respectively. Hepatitis E virus antigen was tested on positive samples. Observed data were modelled using a generalized additive model with a complementary log-log link. No significant differences between birth cohorts or sexes were found. Modelling identified the individual's age and province as relevant factors. The probability of HEV seropositivity increases significantly with age. An estimated total of 434 819 (yearly rate of 54,352) (sero-)infections were found between 2006 and 2014. Overall, HEV IgG seroprevalences were 4.1% (64/1579, 95% CI 3.1-5.1) and 5.8% (121/2087, CI 4.8-6.9) in 2006 and 2014, respectively. Observed HEV antigen seroprevalence was 0.027% (1/3666) for the entire cohort. These results show stable HEV IgG seroprevalence in Belgium.
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http://dx.doi.org/10.1111/jvh.13347DOI Listing
November 2020

SOCRATES: an online tool leveraging a social contact data sharing initiative to assess mitigation strategies for COVID-19.

BMC Res Notes 2020 Jun 16;13(1):293. Epub 2020 Jun 16.

Centre for Health Economic Research and Modelling Infectious Diseases, University of Antwerp, Antwerp, Belgium.

Objective: Establishing a social contact data sharing initiative and an interactive tool to assess mitigation strategies for COVID-19.

Results: We organized data sharing of published social contact surveys via online repositories and formatting guidelines. We analyzed this social contact data in terms of weighted social contact matrices, next generation matrices, relative incidence and R[Formula: see text]. We incorporated location-specific physical distancing measures (e.g. school closure or at work) and capture their effect on transmission dynamics. All methods have been implemented in an online application based on R Shiny and applied to COVID-19 with age-specific susceptibility and infectiousness. Using our online tool with the available social contact data, we illustrate that physical distancing could have a considerable impact on reducing transmission for COVID-19. The effect itself depends on assumptions made about disease-specific characteristics and the choice of intervention(s).
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http://dx.doi.org/10.1186/s13104-020-05136-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296890PMC
June 2020

Factors associated with HIV serodiscordance among couples in Mozambique: Comparison of the 2009 INSIDA and 2015 IMASIDA surveys.

PLoS One 2020 16;15(6):e0234723. Epub 2020 Jun 16.

I-BioStat, Data Science Institute, Hasselt University, Diepenbeek, Belgium.

Recent studies suggest that a large proportion of new HIV-1 infections in mature epidemics occurs within discordant couples, making discordancy a major contributor to the spread of HIV/AIDS in Africa. This paper aims at assessing changes over a five-year period (2009-2015) on the (risk) factors associated with HIV serodiscordance among couples in Mozambique, using cross-sectional data from the INSIDA and IMASIDA surveys. The pooled data of both surveys were analyzed using a joint model for three parameters characterizing in a particular way disagreement and sero(con/dis)corance between the HIV statuses of couples, as introduced by Aerts et al.: the probability that the female partner is HIV positive, given that both partners differ in their HIV status, the probability that only one partner is HIV positive, given that at least one of the two partners is positive ("positive" serodiscordance), and the probability that both partners are negative given that at most one of the two partners is positive ("negative" seroconcordance). The results reveal similar significant factors and estimates as in Aerts et al. (HIV prevalence, union number for woman, STI for man, condom use by woman and wealth index), but the additional significant factors "condom use by man" (no use had a negative effect on the positive serodiscordance) and "union number for man" (for couples where the man has been married or co-habiting with a woman before had a decreased negative seroconcordance) were identified. The only factor that had a different effect over time (IMASIDA as compared to INSIDA) was the effect of "HIV prevalence of province" on the negative seroconcordance. The negative effect of a higher HIV prevalence was less pronounced in 2015 for negative seroconcordance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234723PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297311PMC
August 2020

Estimating the generation interval for coronavirus disease (COVID-19) based on symptom onset data, March 2020.

Euro Surveill 2020 04;25(17)

Centre for Health Economics Research and Modelling Infectious Diseases (CHERMID), Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.

BackgroundEstimating key infectious disease parameters from the coronavirus disease (COVID-19) outbreak is essential for modelling studies and guiding intervention strategies.AimWe estimate the generation interval, serial interval, proportion of pre-symptomatic transmission and effective reproduction number of COVID-19. We illustrate that reproduction numbers calculated based on serial interval estimates can be biased.MethodsWe used outbreak data from clusters in Singapore and Tianjin, China to estimate the generation interval from symptom onset data while acknowledging uncertainty about the incubation period distribution and the underlying transmission network. From those estimates, we obtained the serial interval, proportions of pre-symptomatic transmission and reproduction numbers.ResultsThe mean generation interval was 5.20 days (95% credible interval (CrI): 3.78-6.78) for Singapore and 3.95 days (95% CrI: 3.01-4.91) for Tianjin. The proportion of pre-symptomatic transmission was 48% (95% CrI: 32-67) for Singapore and 62% (95% CrI: 50-76) for Tianjin. Reproduction number estimates based on the generation interval distribution were slightly higher than those based on the serial interval distribution. Sensitivity analyses showed that estimating these quantities from outbreak data requires detailed contact tracing information.ConclusionHigh estimates of the proportion of pre-symptomatic transmission imply that case finding and contact tracing need to be supplemented by physical distancing measures in order to control the COVID-19 outbreak. Notably, quarantine and other containment measures were already in place at the time of data collection, which may inflate the proportion of infections from pre-symptomatic individuals.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.17.2000257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201952PMC
April 2020