Bayesian workflow for time-varying transmission in stratified compartmental infectious disease transmission models.

Compartmental models that describe infectious disease transmission across subpopulations are central for assessing the impact of non-pharmaceutical interventions, behavioral changes and seasonal effects on the spread of respiratory infections. We present a Bayesian workflow for such models, including four features: (1) an adjustment for incomplete case ascertainment, (2) an adequate sampling distribution of laboratory-confirmed cases, (3) a flexible, time-varying transmission rate, and (4) a stratification by age group. Within the workflow, we benchmarked the performance of various implementations of two of these features (2 and 3). For the second feature, we used SARS-CoV-2 data from the canton of Geneva (Switzerland) and found that a quasi-Poisson distribution is the most suitable sampling distribution for describing the overdispersion in the observed laboratory-confirmed cases. For the third feature, we implemented three methods: Brownian motion, B-splines, and approximate Gaussian processes (aGP). We compared their performance in terms of the number of effective samples per second, and the error and sharpness in estimating the time-varying transmission rate over a selection of ordinary differential equation solvers and tuning parameters, using simulated seroprevalence and laboratory-confirmed case data. Even though all methods could recover the time-varying dynamics in the transmission rate accurately, we found that B-splines perform up to four and ten times faster than Brownian motion and aGPs, respectively. We validated the B-spline model with simulated age-stratified data. We applied this model to 2020 laboratory-confirmed SARS-CoV-2 cases and two seroprevalence studies from the canton of Geneva. This resulted in detailed estimates of the transmission rate over time and the case ascertainment. Our results illustrate the potential of the presented workflow including stratified transmission to estimate age-specific epidemiological parameters. The workflow is freely available in the R package HETTMO, and can be easily adapted and applied to other infectious diseases.

Health of singleton neonates in Switzerland through time and crises: a cross-sectional study at the population level, 2007-2022.

BACKGROUND: Being exposed to crises during pregnancy can affect maternal health through stress exposure, which can in return impact neonatal health. We investigated temporal trends in neonatal outcomes in Switzerland between 2007 and 2022 and their variations depending on exposure to the economic crisis of 2008, the flu pandemic of 2009, heatwaves (2015 and 2018) and the COVID-19 pandemic. METHODS: Using individual cross-sectional data encompassing all births occurring in Switzerland at the monthly level (2007-2022), we analysed changes in birth weight and in the rates of preterm birth (PTB) and stillbirth through time with generalized additive models. We assessed whether the intensity or length of crisis exposure was associated with variations in these outcomes. Furthermore, we explored effects of exposure depending on trimesters of pregnancy. RESULTS: Over 1.2 million singleton births were included in our analyses. While birth weight and the rate of stillbirth have remained stable since 2007, the rate of PTB has declined by one percentage point. Exposure to the crises led to different results, but effect sizes were overall small. Exposure to COVID-19, irrespective of the pregnancy trimester, was associated with a higher birth weight (+12 grams [95% confidence interval (CI) 5.5 to 17.9 grams]). Being exposed to COVID-19 during the last trimester was associated with an increased risk of stillbirth (odds ratio 1.24 [95%CI 1.02 to 1.50]). Exposure to the 2008 economic crisis during pregnancy was not associated with any changes in neonatal health outcomes, while heatwave effect was difficult to interpret. CONCLUSION: Overall, maternal and neonatal health demonstrated resilience to the economic crisis and to the COVID-19 pandemic in a high-income country like Switzerland. However, the effect of exposure to the COVID-19 pandemic is dual, and the negative impact of maternal infection on pregnancy is well-documented. Stress exposure and economic constraint may also have had adverse effects among the most vulnerable subgroups of Switzerland. To investigate better the impact of heatwave exposure on neonatal health, weekly or daily-level data is needed, instead of monthly-level data.

Area-level excess mortality in times of COVID-19 in Switzerland: geographical, socioeconomic and political determinants.

The coronavirus disease 2019 (COVID-19)-related excess mortality in Switzerland is well documented, but no study examined mortality at the small-area level. We analysed excess mortality in 2020 for 2141 Swiss municipalities using a Bayesian spatiotemporal model fitted to 2011-19 data. Areas most affected included the Ticino, the Romandie and the Northeast. Rural areas, municipalities within cross-border labour markets, of lower socioeconomic position and with less support for control measures in the popular vote on the COVID-19 Act had greater excess mortality. Particularly vulnerable municipalities require special efforts to mitigate the impact of pandemics.

Socio-demographic characteristics associated with COVID-19 vaccination uptake in Switzerland: longitudinal analysis of the CoMix study.

BACKGROUND: Vaccination is an effective strategy to reduce morbidity and mortality from coronavirus disease 2019 (COVID-19). However, the uptake of COVID-19 vaccination has varied across and within countries. Switzerland has had lower levels of COVID-19 vaccination uptake in the general population than many other high-income countries. Understanding the socio-demographic factors associated with vaccination uptake can help to inform future vaccination strategies to increase uptake. METHODS: We conducted a longitudinal online survey in the Swiss population, consisting of six survey waves from June to September 2021. Participants provided information on socio-demographic characteristics, history of testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), social contacts, willingness to be vaccinated, and vaccination status. We used a multivariable Poisson regression model to estimate the adjusted rate ratio (aRR) and 95% confidence intervals (CI) of COVID-19 vaccine uptake. RESULTS: We recorded 6,758 observations from 1,884 adults. For the regression analysis, we included 3,513 observations from 1,883 participants. By September 2021, 600 (75%) of 806 study participants had received at least one vaccine dose. Participants who were older, male, and students, had a higher educational level, household income, and number of social contacts, and lived in a household with a medically vulnerable person were more likely to have received at least one vaccine dose. Female participants, those who lived in rural areas and smaller households, and people who perceived COVID-19 measures as being too strict were less likely to be vaccinated. We found no significant association between previous SARS-CoV-2 infections and vaccination uptake. CONCLUSIONS: Our results suggest that socio-demographic factors as well as individual behaviours and attitudes played an important role in COVID-19 vaccination uptake in Switzerland. Therefore, appropriate communication with the public is needed to ensure that public health interventions are accepted and implemented by the population. Tailored COVID-19 vaccination strategies in Switzerland that aim to improve uptake should target specific subgroups such as women, people from rural areas or people with lower socio-demographic status.

COVID-19 among adults living with HIV: correlates of mortality among public sector healthcare users in Western Cape, South Africa.

INTRODUCTION: While a large proportion of people with HIV (PWH) have experienced SARS-CoV-2 infections, there is uncertainty about the role of HIV disease severity on COVID-19 outcomes, especially in lower-income settings. We studied the association of mortality with characteristics of HIV severity and management, and vaccination, among adult PWH. METHODS: We analysed observational cohort data on all PWH aged ≥15 years experiencing a diagnosed SARS-CoV-2 infection (until March 2022), who accessed public sector healthcare in the Western Cape province of South Africa. Logistic regression was used to study the association of mortality with evidence of antiretroviral therapy (ART) collection, time since first HIV evidence, CD4 cell count, viral load (among those with evidence of ART collection) and COVID-19 vaccination, adjusting for demographic characteristics, comorbidities, admission pressure, location and time period. RESULTS: Mortality occurred in 5.7% (95% CI: 5.3,6.0) of 17,831 first-diagnosed infections. Higher mortality was associated with lower recent CD4, no evidence of ART collection, high or unknown recent viral load and recent first HIV evidence, differentially by age. Vaccination was protective. The burden of comorbidities was high, and tuberculosis (especially more recent episodes of tuberculosis), chronic kidney disease, diabetes and hypertension were associated with higher mortality, more strongly in younger adults. CONCLUSIONS: Mortality was strongly associated with suboptimal HIV control, and the prevalence of these risk factors increased in later COVID-19 waves. It remains a public health priority to ensure PWH are on suppressive ART and vaccinated, and manage any disruptions in care that occurred during the pandemic. The diagnosis and management of comorbidities, including for tuberculosis, should be optimized.

Projecting the development of antimicrobial resistance in Neisseria gonorrhoeae from antimicrobial surveillance data: a mathematical modelling study.

BACKGROUND: The World Health Organization recommends changing the first-line antimicrobial treatment for gonorrhoea when ≥ 5% of Neisseria gonorrhoeae cases fail treatment or are resistant. Susceptibility to ceftriaxone, the last remaining treatment option has been decreasing in many countries. We used antimicrobial resistance surveillance data and developed mathematical models to project the time to reach the 5% threshold for resistance to first-line antimicrobials used for N. gonorrhoeae. METHODS: We used data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in England and Wales from 2000-2018 about minimum inhibitory concentrations (MIC) for ciprofloxacin, azithromycin, cefixime and ceftriaxone and antimicrobial treatment in two groups, heterosexual men and women (HMW) and men who have sex with men (MSM). We developed two susceptible-infected-susceptible models to fit these data and produce projections of the proportion of resistance until 2030. The single-step model represents the situation in which a single mutation results in antimicrobial resistance. In the multi-step model, the sequential accumulation of resistance mutations is reflected by changes in the MIC distribution. RESULTS: The single-step model described resistance to ciprofloxacin well. Both single-step and multi-step models could describe azithromycin and cefixime resistance, with projected resistance levels higher with the multi-step than the single step model. For ceftriaxone, with very few observed cases of full resistance, the multi-step model was needed to describe long-term dynamics of resistance. Extrapolating from the observed upward drift in MIC values, the multi-step model projected ≥ 5% resistance to ceftriaxone could be reached by 2030, based on treatment pressure alone. Ceftriaxone resistance was projected to rise to 13.2% (95% credible interval [CrI]: 0.7-44.8%) among HMW and 19.6% (95%CrI: 2.6-54.4%) among MSM by 2030. CONCLUSIONS: New first-line antimicrobials for gonorrhoea treatment are needed. In the meantime, public health authorities should strengthen surveillance for AMR in N. gonorrhoeae and implement strategies for continued antimicrobial stewardship. Our models show the utility of long-term representative surveillance of gonococcal antimicrobial susceptibility data and can be adapted for use in, and for comparison with, other countries.

Continuous population-level monitoring of SARS-CoV-2 seroprevalence in a large European metropolitan region.

Effective public health measures against SARS-CoV-2 require granular knowledge of population-level immune responses. We developed a Tripartite Automated Blood Immunoassay (TRABI) to assess the IgG response against three SARS-CoV-2 proteins. We used TRABI for continuous seromonitoring of hospital patients and blood donors (n = 72'250) in the canton of Zurich from December 2019 to December 2020 (pre-vaccine period). We found that antibodies waned with a half-life of 75 days, whereas the cumulative incidence rose from 2.3% in June 2020 to 12.2% in mid-December 2020. A follow-up health survey indicated that about 10% of patients infected with wildtype SARS-CoV-2 sustained some symptoms at least twelve months post COVID-19. Crucially, we found no evidence of a difference in long-term complications between those whose infection was symptomatic and those with asymptomatic acute infection. The cohort of asymptomatic SARS-CoV-2-infected subjects represents a resource for the study of chronic and possibly unexpected sequelae.

Direct and indirect effects of the COVID-19 pandemic on mortality in Switzerland.

The direct and indirect impact of the COVID-19 pandemic on population-level mortality is of concern to public health but challenging to quantify. Using data for 2011-2019, we applied Bayesian models to predict the expected number of deaths in Switzerland and compared them with laboratory-confirmed COVID-19 deaths from February 2020 to April 2022 (study period). We estimated that COVID-19-related mortality was underestimated by a factor of 0.72 (95% credible interval [CrI]: 0.46-0.78). After accounting for COVID-19 deaths, the observed mortality was -4% (95% CrI: -8 to 0) lower than expected. The deficit in mortality was concentrated in age groups 40-59 (-12%, 95%CrI: -19 to -5) and 60-69 (-8%, 95%CrI: -15 to -2). Although COVID-19 control measures may have negative effects, after subtracting COVID-19 deaths, there were fewer deaths in Switzerland during the pandemic than expected, suggesting that any negative effects of control measures were offset by the positive effects. These results have important implications for the ongoing debate about the appropriateness of COVID-19 control measures.

Impact of cross-border-associated cases on the SARS-CoV-2 epidemic in Switzerland during summer 2020 and 2021.

During the summers of 2020 and 2021, the number of confirmed cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in Switzerland remained at relatively low levels, but grew steadily over time. It remains unclear to what extent epidemic growth during these periods was a result of the relaxation of local control measures or increased traveling and subsequent importation of cases. A better understanding of the role of cross-border-associated cases (imports) on the local epidemic dynamics will help to inform future surveillance strategies. We analyzed routine surveillance data of confirmed cases of SARS-CoV-2 in Switzerland from 1 June to 30 September 2020 and 2021. We used a stochastic branching process model that accounts for superspreading of SARS-CoV-2 to simulate epidemic trajectories in absence and in presence of imports during summer 2020 and 2021. The Swiss Federal Office of Public Health reported 22,919 and 145,840 confirmed cases of SARS-CoV-2 from 1 June to 30 September 2020 and 2021, respectively. Among cases with known place of exposure, 27% (3,276 of 12,088) and 25% (1,110 of 4,368) reported an exposure abroad in 2020 and 2021, respectively. Without considering the impact of imported cases, the steady growth of confirmed cases during summer periods would be consistent with a value of Re that is significantly above the critical threshold of 1. In contrast, we estimated Re at 0.84 (95% credible interval, CrI: 0.78-0.90) in 2020 and 0.82 (95% CrI: 0.74-0.90) in 2021 when imported cases were taken into account, indicating that the local Re was below the critical threshold of 1 during summer. In Switzerland, cross-border-associated SARS-CoV-2 cases had a considerable impact on the local transmission dynamics and can explain the steady growth of the epidemic during the summers of 2020 and 2021.

COVID-19 among adults living with HIV: Correlates of mortality in a general population in a resource-limited setting.

Introduction: While a large proportion of people with HIV (PWH) have experienced SARS-CoV-2 infections, there is uncertainty about the role of HIV disease severity on COVID-19 outcomes, especially in lower income settings. We studied the association between mortality and characteristics of HIV severity and management, and vaccination, among adult PWH. Methods: We analysed observational cohort data on all PWH aged ≥15 years experiencing a diagnosed SARS-CoV-2 infection (until March 2022), who accessed public sector healthcare in the Western Cape province of South Africa. Logistic regression was used to study the association of mortality with CD4 cell count, viral load, evidence of ART, time since first HIV evidence, and vaccination, adjusting for demographic characteristics, comorbidities, admission pressure, location and time period. Results: Mortality occurred in 5.7% (95% CI: 5.3,6.0) of 17 831 first diagnosed infections. Higher mortality was associated with lower recent CD4, no evidence of ART collection, high or unknown recent viral load (among those with ART evidence), and recent first HIV evidence, differentially by age. Vaccination was protective. The burden of comorbidities was high, and tuberculosis, chronic kidney disease, diabetes and hypertension were associated with higher mortality, more strongly in younger adults. Conclusions: Mortality was strongly associated with suboptimal HIV control, and prevalence of these risk factors increased in later COVID-19 waves. It remains a public health priority to ensure PWH are on suppressive ART and vaccinated, and manage any disruptions in care that occurred during the pandemic. The diagnosis and management of comorbidities, including for tuberculosis, should be optimised.

Assessing real-world vaccine effectiveness against severe forms of SARS-CoV-2 infection: an observational study from routine surveillance data in Switzerland.

BACKGROUND: In Switzerland, SARS-CoV-2 vaccination campaigns started in early 2021. Vaccine coverage reached 65% of the population in December 2021, mostly with mRNA vaccines from Moderna and Pfizer-BioNtech. Simultaneously, the proportion of vaccinated among COVID-19-related hospitalisations and deaths rose, creating some confusion in the general population. We aimed to assess vaccine effectiveness against severe forms of SARS-CoV-2 infection using routine surveillance data on the vaccination status of COVID-19-related hospitalisations and deaths, and data on vaccine coverage in Switzerland. METHODS: We considered all routine surveillance data on COVID-19-related hospitalisations and deaths received at the Swiss Federal Office of Public Health from 1 July to 1 December 2021. We estimated the relative risk of COVID-19-related hospitalisation or death for not fully vaccinated compared with fully vaccinated individuals, adjusted for the dynamics of vaccine coverage over time, by age and location. We stratified the analysis by age group and by calendar month. We assessed variations in the relative risk of hospitalisation associated with the time since vaccination. RESULTS: We included a total of 5948 COVID-19-related hospitalisations of which 1245 (21%) were fully vaccinated patients, and a total of 739 deaths of which 259 (35%) were fully vaccinated. We found that the relative risk of COVID-19 related hospitalisation was 12.5 (95% confidence interval [CI] 11.7-13.4) times higher for not fully vaccinated than for fully vaccinated individuals. This translates into a vaccine effectiveness against hospitalisation of 92.0% (95% CI 91.4-92.5%). Vaccine effectiveness against death was estimated to be 90.3% (95% CI 88.6-91.8%). Effectiveness appeared to be comparatively lower in age groups over 70 and during the months of October and November 2021. We also found evidence of a decrease in vaccine effectiveness against hospitalisation for individuals vaccinated for 25 weeks or more, but this decrease appeared only in age groups below 70. CONCLUSIONS: The observed proportions of vaccinated among COVD-19-related hospitalisations and deaths in Switzerland were compatible with a high effectiveness of mRNA vaccines from Moderna and Pfizer-BioNtech against hospitalisation and death in all age groups. Effectiveness appears comparatively lower in older age groups, suggesting the importance of booster vaccinations. We found inconclusive evidence that vaccine effectiveness wanes over time. Repeated analyses will be able to better assess waning and the effect of boosters.

Survival among people hospitalized with COVID-19 in Switzerland: a nationwide population-based analysis.

BACKGROUND: Increasing age, male sex, and pre-existing comorbidities are associated with lower survival from SARS-CoV-2 infection. The interplay between different comorbidities, age, and sex is not fully understood, and it remains unclear if survival decreases linearly with higher ICU occupancy or if there is a threshold beyond which survival falls. METHOD: This national population-based study included 22,648 people who tested positive for SARS-CoV-2 infection and were hospitalized in Switzerland between February 24, 2020, and March 01, 2021. Bayesian survival models were used to estimate survival after positive SARS-CoV-2 test among people hospitalized with COVID-19 by epidemic wave, age, sex, comorbidities, and ICU occupancy. Two-way interactions between age, sex, and comorbidities were included to assess the differential risk of death across strata. ICU occupancy was modeled using restricted cubic splines to allow for a non-linear association with survival. RESULTS: Of 22,648 people hospitalized with COVID-19, 4785 (21.1%) died. The survival was lower during the first epidemic wave than in the second (predicted survival at 40 days after positive test 76.1 versus 80.5%). During the second epidemic wave, occupancy among all available ICU beds in Switzerland varied between 51.7 and 78.8%. The estimated survival was stable at approximately 81.5% when ICU occupancy was below 70%, but worse when ICU occupancy exceeded this threshold (survival at 80% ICU occupancy: 78.2%; 95% credible interval [CrI] 76.1 to 80.1%). Periods with higher ICU occupancy (>70 vs 70%) were associated with an estimated number of 137 (95% CrI 27 to 242) excess deaths. Comorbid conditions reduced survival more in younger people than in older people. Among comorbid conditions, hypertension and obesity were not associated with poorer survival. Hypertension appeared to decrease survival in combination with cardiovascular disease. CONCLUSIONS: Survival after hospitalization with COVID-19 has improved over time, consistent with improved management of severe COVID-19. The decreased survival above 70% national ICU occupancy supports the need to introduce measures for prevention and control of SARS-CoV-2 transmission in the population well before ICUs are full.

Acquired HIV drug resistance mutations on first-line antiretroviral therapy in Southern Africa: Systematic review and Bayesian evidence synthesis.

OBJECTIVE: To estimate the prevalence of NRTI and NNRTI drug resistance mutations in patients failing NNRTI-based ART in Southern Africa. STUDY DESIGN: We conducted a systematic review to identify studies reporting drug resistance mutations among adult people living with HIV (PLWH) who experienced virological failure on first-line NNRTI-based ART in Southern Africa. We used a Bayesian hierarchical meta-regression model to synthesize the evidence on the frequency of eight NRTI- and seven NNRTI-DRMs across different ART regimens, accounting for ART duration and study characteristics. RESULTS: We included 19 study populations, including 2,690 PLWH. Patients failing first-line ART including emtricitabine or lamivudine showed high levels of the M184V/I mutation after 2 years: 75.7% (95% Credibility Interval [CrI] 61.9%-88.9%) if combined with tenofovir, and 72.1% (95% CrI 56.8%-85.9%) with zidovudine. With tenofovir disoproxil fumarate, the prevalence of the K65R mutation was 52.0% (95% CrI 32.5%-76.8%) at 2 years. On efavirenz, K103 was the most prevalent NNRTI resistance mutation (57.2%, 95% CrI 40.9%-80.1%), followed by V106 (46.8%, 95% CrI 31.3%-70.4%). CONCLUSIONS: NRTI/NNRTI drug resistance mutations are common in patients failing first-line ART in Southern Africa. These patients might switch to dolutegravir-based regimen with compromised NRTIs, which could impair the long-term efficacy of ART.

Historically High Excess Mortality During the COVID-19 Pandemic in Switzerland, Sweden, and Spain.

BACKGROUND: Excess mortality quantifies the overall mortality impact of a pandemic. Mortality data have been accessible for many countries in recent decades, but few continuous data have been available for longer periods. OBJECTIVE: To assess the historical dimension of the COVID-19 pandemic in 2020 for 3 countries with reliable death count data over an uninterrupted span of more than 100 years. DESIGN: Observational study. SETTING: Switzerland, Sweden, and Spain, which were militarily neutral and not involved in combat during either world war and have not been affected by significant changes in their territory since the end of the 19th century. PARTICIPANTS: Complete populations of these 3 countries. MEASUREMENTS: Continuous series of recorded deaths (from all causes) by month from the earliest available year (1877 for Switzerland, 1851 for Sweden, and 1908 for Spain) were jointly modeled with annual age group-specific death and total population counts using negative binomial and multinomial models, which accounted for temporal trends and seasonal variability of prepandemic years. The aim was to estimate the expected number of deaths in a pandemic year for a nonpandemic scenario and the difference in observed and expected deaths aggregated over the year. RESULTS: In 2020, the number of excess deaths recorded per 100 000 persons was 100 (95% credible interval [CrI], 60 to 135) for Switzerland, 75 (CrI, 40 to 105) for Sweden, and 155 (CrI, 110 to 195) for Spain. In 1918, excess mortality was 6 to 7 times higher. In all 3 countries, the peaks of monthly excess mortality in 2020 were greater than most monthly excess mortality since 1918, including many peaks due to seasonal influenza and heat waves during that period. LIMITATION: Historical vital statistics might be affected by minor completeness issues before the beginning of the 20th century. CONCLUSION: In 2020, the COVID-19 pandemic led to the second-largest infection-related mortality disaster in Switzerland, Sweden, and Spain since the beginning of the 20th century. PRIMARY FUNDING SOURCE: Foundation for Research in Science and the Humanities at the University of Zurich, Swiss National Science Foundation, and National Institute of Allergy and Infectious Diseases.

Estimating Tuberculosis Transmission Risks in a Primary Care Clinic in South Africa: Modeling of Environmental and Clinical Data.

BACKGROUND: Congregate settings, such as healthcare clinics, may play an essential role in Mycobacterium tuberculosis (Mtb) transmission. Using patient and environmental data, we studied transmission at a primary care clinic in South Africa. METHODS: We collected patient movements, cough frequency, and clinical data, and measured indoor carbon dioxide (CO2) levels, relative humidity, and Mtb genomes in the air. We used negative binomial regression model to investigate associations. RESULTS: We analyzed 978 unique patients who contributed 14 795 data points. The median patient age was 33 (interquartile range [IQR], 26-41) years, and 757 (77.4%) were female. Overall, median CO2 levels were 564 (IQR 495-646) parts per million and were highest in the morning. Median number of coughs per day was 466 (IQR, 368-503), and overall median Mtb DNA copies/µL/day was 4.2 (IQR, 1.2-9.5). We found an increased presence of Mtb DNA in the air of 32% (95% credible interval, 7%-63%) per 100 additional young adults (aged 15-29 years) and 1% (0-2%) more Mtb DNA per 10% increase of relative humidity. Estimated cumulative transmission risks for patients attending the clinic monthly for at least 1 hour range between 9% and 29%. CONCLUSIONS: We identified young adults and relative humidity as potentially important factors for transmission risks in healthcare clinics. Our approach should be used to detect transmission and evaluate infection control interventions.

Regional excess mortality during the 2020 COVID-19 pandemic in five European countries.

The impact of the COVID-19 pandemic on excess mortality from all causes in 2020 varied across and within European countries. Using data for 2015-2019, we applied Bayesian spatio-temporal models to quantify the expected weekly deaths at the regional level had the pandemic not occurred in England, Greece, Italy, Spain, and Switzerland. With around 30%, Madrid, Castile-La Mancha, Castile-Leon (Spain) and Lombardia (Italy) were the regions with the highest excess mortality. In England, Greece and Switzerland, the regions most affected were Outer London and the West Midlands (England), Eastern, Western and Central Macedonia (Greece), and Ticino (Switzerland), with 15-20% excess mortality in 2020. Our study highlights the importance of the large transportation hubs for establishing community transmission in the first stages of the pandemic. Here, we show that acting promptly to limit transmission around these hubs is essential to prevent spread to other regions and countries.

Drivers of HIV-1 drug resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTIs) in nine southern African countries: a modelling study.

INTRODUCTION: The rise of HIV-1 drug resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTI) threatens antiretroviral therapy's long-term success (ART). NNRTIs will remain an essential drug for the management of HIV-1 due to safety concerns associated with integrase inhibitors. We fitted a dynamic transmission model to historical data from 2000 to 2018 in nine countries of southern Africa to understand the mechanisms that have shaped the HIV-1 epidemic and the rise of pretreatment NNRTI resistance. METHODS: We included data on HIV-1 prevalence, ART coverage, HIV-related mortality, and survey data on pretreatment NNRTI resistance from nine southern Africa countries from a systematic review, UNAIDS and World Bank. Using a Bayesian hierarchical framework, we developed a dynamic transmission model linking data on the HIV-1 epidemic to survey data on NNRTI drug resistance in each country. We estimated the proportion of resistance attributable to unregulated, off-programme use of ART. We examined each national ART programme's vulnerability to NNRTI resistance by defining a fragility index: the ratio of the rate of NNRTI resistance emergence during first-line ART over the rate of switching to second-line ART. We explored associations between fragility and characteristics of the health system of each country. RESULTS: The model reliably described the dynamics of the HIV-1 epidemic and NNRTI resistance in each country. Predicted levels of resistance in 2018 ranged between 3.3% (95% credible interval 1.9-7.1) in Mozambique and 25.3% (17.9-33.8) in Eswatini. The proportion of pretreatment NNRTI resistance attributable to unregulated antiretroviral use ranged from 6% (2-14) in Eswatini to 64% (26-85) in Mozambique. The fragility index was low in Botswana (0.01; 0.0-0.11) but high in Namibia (0.48; 0.16-10.17), Eswatini (0.64; 0.23-11.8) and South Africa (1.21; 0.83-9.84). The combination of high fragility of ART programmes and high ART coverage levels was associated with a sharp increase in pretreatment NNRTI resistance. CONCLUSIONS: This comparison of nine countries shows that pretreatment NNRTI resistance can be controlled despite high ART coverage levels. This was the case in Botswana, Mozambique, and Zambia, most likely because of better HIV care delivery, including rapid switching to second-line ART of patients failing first-line ART.

Bayesian workflow for disease transmission modeling in Stan.

This tutorial shows how to build, fit, and criticize disease transmission models in Stan, and should be useful to researchers interested in modeling the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and other infectious diseases in a Bayesian framework. Bayesian modeling provides a principled way to quantify uncertainty and incorporate both data and prior knowledge into the model estimates. Stan is an expressive probabilistic programming language that abstracts the inference and allows users to focus on the modeling. As a result, Stan code is readable and easily extensible, which makes the modeler's work more transparent. Furthermore, Stan's main inference engine, Hamiltonian Monte Carlo sampling, is amiable to diagnostics, which means the user can verify whether the obtained inference is reliable. In this tutorial, we demonstrate how to formulate, fit, and diagnose a compartmental transmission model in Stan, first with a simple susceptible-infected-recovered model, then with a more elaborate transmission model used during the SARS-CoV-2 pandemic. We also cover advanced topics which can further help practitioners fit sophisticated models; notably, how to use simulations to probe the model and priors, and computational techniques to scale-up models based on ordinary differential equations.

Accounting for uncertainty during a pandemic.

We discuss several issues of statistical design, data collection, analysis, communication, and decision-making that have arisen in recent and ongoing coronavirus studies, focusing on tools for assessment and propagation of uncertainty. This paper does not purport to be a comprehensive survey of the research literature; rather, we use examples to illustrate statistical points that we think are important.