Disentangling age, gender, and racial/ethnic disparities in multiple myeloma burden: a modeling study.

Multiple myeloma (MM) is a hematological malignancy that is consistently preceded by an asymptomatic condition, monoclonal gammopathy of undetermined significance (MGUS). Disparities by age, gender, and race/ethnicity in both MGUS and MM are well-established. However, it remains unclear whether these disparities can be explained by increased incidence of MGUS and/or accelerated progression from MGUS to MM. Here, we fit a mathematical model to nationally representative data from the United States and showed that the difference in MM incidence can be explained by an increased incidence of MGUS among male and non-Hispanic Black populations. We did not find evidence showing differences in the rate of progression from MGUS to MM by either gender or race/ethnicity. Our results suggest that screening for MGUS among high-risk groups (e.g., non-Hispanic Black men) may hold promise as a strategy to reduce the burden and MM health disparities.

Does ignoring transmission dynamics lead to underestimation of the impact of interventions against mosquito-borne disease?

New vector-control technologies to fight mosquito-borne diseases are urgently needed, the adoption of which depends on efficacy estimates from large-scale cluster-randomised trials (CRTs). The release of Wolbachia-infected mosquitoes is one promising strategy to curb dengue virus (DENV) transmission, and a recent CRT reported impressive reductions in dengue incidence following the release of these mosquitoes. Such trials can be affected by multiple sources of bias, however. We used mathematical models of DENV transmission during a CRT of Wolbachia-infected mosquitoes to explore three such biases: human movement, mosquito movement and coupled transmission dynamics between trial arms. We show that failure to account for each of these biases would lead to underestimated efficacy, and that the majority of this underestimation is due to a heretofore unrecognised bias caused by transmission coupling. Taken together, our findings suggest that Wolbachia-infected mosquitoes could be even more promising than the recent CRT suggested. By emphasising the importance of accounting for transmission coupling between arms, which requires a mathematical model, we highlight the key role that models can play in interpreting and extrapolating the results from trials of vector control interventions.

Mortality in the US Populations With Monoclonal Gammopathy of Undetermined Significance.

This cohort study analyzes a nationally representative sample with a screening test for monoclonal gammopathy of undetermined significance (MGUS) to evaluate overall survival of populations with MGUS compared with those without MGUS among the general population in the US.

The Impact of Emerging Plasmodium knowlesi on Accurate Diagnosis by Light Microscopy: A Systematic Review and Modeling Analysis.

The five major Plasmodium spp. that cause human malaria appear similar under light microscopy, which raises the possibility that misdiagnosis could routinely occur in clinical settings. Assessing the extent of misdiagnosis is of particular importance for monitoring P. knowlesi, which cocirculates with the other Plasmodium spp. We performed a systematic review and meta-analysis of studies comparing the performance of microscopy and polymerase chain reaction (PCR) for diagnosing malaria in settings with co-circulation of the five Plasmodium spp. We assessed the extent to which co-circulation of Plasmodium parasites affects diagnostic outcomes. We fit a Bayesian hierarchical latent class model to estimate variation in microscopy sensitivity and specificity measured against PCR as the gold standard. Mean sensitivity of microscopy was low, yet highly variable across Plasmodium spp., ranging from 65.7% (95% confidence interval: 48.1-80.3%) for P. falciparum to 0.525% (95% confidence interval 0.0210-3.11%) for P. ovale. Observed PCR prevalence was positively correlated with estimated microscopic sensitivity and negatively correlated with estimated microscopic specificity, though the strength of the associations varied by species. Our analysis suggests that cocirculation of Plasmodium spp. undermines the accuracy of microscopy. Sensitivity was considerably lower for P. knowlesi, P. malariae, and P. ovale. The negative association between specificity and prevalence imply that less frequently encountered species may be misdiagnosed as more frequently encountered species. Together, these results suggest that the burden of P. knowlesi, P. malariae, and P. ovale may be underappreciated in a clinical setting.

Projecting vaccine demand and impact for emerging zoonotic pathogens.

BACKGROUND: Despite large outbreaks in humans seeming improbable for a number of zoonotic pathogens, several pose a concern due to their epidemiological characteristics and evolutionary potential. To enable effective responses to these pathogens in the event that they undergo future emergence, the Coalition for Epidemic Preparedness Innovations is advancing the development of vaccines for several pathogens prioritized by the World Health Organization. A major challenge in this pursuit is anticipating demand for a vaccine stockpile to support outbreak response. METHODS: We developed a modeling framework for outbreak response for emerging zoonoses under three reactive vaccination strategies to assess sustainable vaccine manufacturing needs, vaccine stockpile requirements, and the potential impact of the outbreak response. This framework incorporates geographically variable zoonotic spillover rates, human-to-human transmission, and the implementation of reactive vaccination campaigns in response to disease outbreaks. As proof of concept, we applied the framework to four priority pathogens: Lassa virus, Nipah virus, MERS coronavirus, and Rift Valley virus. RESULTS: Annual vaccine regimen requirements for a population-wide strategy ranged from > 670,000 (95% prediction interval 0-3,630,000) regimens for Lassa virus to 1,190,000 (95% PrI 0-8,480,000) regimens for Rift Valley fever virus, while the regimens required for ring vaccination or targeting healthcare workers (HCWs) were several orders of magnitude lower (between 1/25 and 1/700) than those required by a population-wide strategy. For each pathogen and vaccination strategy, reactive vaccination typically prevented fewer than 10% of cases, because of their presently low R0 values. Targeting HCWs had a higher per-regimen impact than population-wide vaccination. CONCLUSIONS: Our framework provides a flexible methodology for estimating vaccine stockpile needs and the geographic distribution of demand under a range of outbreak response scenarios. Uncertainties in our model estimates highlight several knowledge gaps that need to be addressed to target vulnerable populations more accurately. These include surveillance gaps that mask the true geographic distribution of each pathogen, details of key routes of spillover from animal reservoirs to humans, and the role of human-to-human transmission outside of healthcare settings. In addition, our estimates are based on the current epidemiology of each pathogen, but pathogen evolution could alter vaccine stockpile requirements.

Inferring person-to-person networks of Plasmodium falciparum transmission: are analyses of routine surveillance data up to the task?

BACKGROUND: Inference of person-to-person transmission networks using surveillance data is increasingly used to estimate spatiotemporal patterns of pathogen transmission. Several data types can be used to inform transmission network inferences, yet the sensitivity of those inferences to different data types is not routinely evaluated. METHODS: The influence of different combinations of spatial, temporal, and travel-history data on transmission network inferences for Plasmodium falciparum malaria were evaluated. RESULTS: The information content of these data types may be limited for inferring person-to-person transmission networks and may lead to an overestimate of transmission. Only when outbreaks were temporally focal or travel histories were accurate was the algorithm able to accurately estimate the reproduction number under control, Rc. Applying this approach to data from Eswatini indicated that inferences of Rc and spatiotemporal patterns therein depend upon the choice of data types and assumptions about travel-history data. CONCLUSIONS: These results suggest that transmission network inferences made with routine malaria surveillance data should be interpreted with caution.

How radical is radical cure? Site-specific biases in clinical trials underestimate the effect of radical cure on Plasmodium vivax hypnozoites.

BACKGROUND: Plasmodium vivax blood-stage relapses originating from re-activating hypnozoites are a major barrier for control and elimination of this disease. Radical cure is a form of therapy capable of addressing this problem. Recent clinical trials of radical cure have yielded efficacy estimates ranging from 65 to 94%, with substantial variation across trial sites. METHODS: An analysis of simulated trial data using a transmission model was performed to demonstrate that variation in efficacy estimates across trial sites can arise from differences in the conditions under which trials are conducted. RESULTS: The analysis revealed that differences in transmission intensity, heterogeneous exposure and relapse rate can yield efficacy estimates ranging as widely as 12-78%, despite simulating trial data under the uniform assumption that treatment had a 75% chance of clearing hypnozoites. A longer duration of prophylaxis leads to a greater measured efficacy, particularly at higher transmission intensities, making the comparison between the protection of different radical cure treatment regimens against relapse more challenging. Simulations show that vector control and parasite genotyping offer two potential means to yield more standardized efficacy estimates that better reflect prevention of relapse. CONCLUSIONS: Site-specific biases are likely to contribute to variation in efficacy estimates both within and across clinical trials. Future clinical trials can reduce site-specific biases by conducting trials in low-transmission settings where re-infections from mosquito bite are less common, by preventing re-infections using vector control measures, or by identifying and excluding likely re-infections that occur during follow-up, by using parasite genotyping methods.

Burden is in the eye of the beholder: Sensitivity of yellow fever disease burden estimates to modeling assumptions.

Estimates of disease burden are important for setting public health priorities. These estimates involve numerous modeling assumptions, whose uncertainties are not always well described. We developed a framework for estimating the burden of yellow fever in Africa and evaluated its sensitivity to modeling assumptions that are often overlooked. We found that alternative interpretations of serological data resulted in a nearly 20-fold difference in burden estimates (range of central estimates, 8.4 × 104 to 1.5 × 106 deaths in 2021­2030). Uncertainty about the vaccination status of serological study participants was the primary driver of this uncertainty. Even so, statistical uncertainty was even greater than uncertainty due to modeling assumptions, accounting for a total of 87% of variance in burden estimates. Combined with estimates that most infections go unreported (range of 95% credible intervals, 99.65 to 99.99%), our results suggest that yellow fever's burden will remain highly uncertain without major improvements in surveillance.

Trade-offs between individual and ensemble forecasts of an emerging infectious disease.

Probabilistic forecasts play an indispensable role in answering questions about the spread of newly emerged pathogens. However, uncertainties about the epidemiology of emerging pathogens can make it difficult to choose among alternative model structures and assumptions. To assess the potential for uncertainties about emerging pathogens to affect forecasts of their spread, we evaluated the performance 16 forecasting models in the context of the 2015-2016 Zika epidemic in Colombia. Each model featured a different combination of assumptions about human mobility, spatiotemporal variation in transmission potential, and the number of virus introductions. We found that which model assumptions had the most ensemble weight changed through time. We additionally identified a trade-off whereby some individual models outperformed ensemble models early in the epidemic, but on average the ensembles outperformed all individual models. Our results suggest that multiple models spanning uncertainty across alternative assumptions are necessary to obtain robust forecasts for emerging infectious diseases.

Lives saved with vaccination for 10 pathogens across 112 countries in a pre-COVID-19 world.

Background: Vaccination is one of the most effective public health interventions. We investigate the impact of vaccination activities for Haemophilus influenzae type b, hepatitis B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, rotavirus, rubella, Streptococcus pneumoniae, and yellow fever over the years 2000-2030 across 112 countries. Methods: Twenty-one mathematical models estimated disease burden using standardised demographic and immunisation data. Impact was attributed to the year of vaccination through vaccine-activity-stratified impact ratios. Results: We estimate 97 (95%CrI[80, 120]) million deaths would be averted due to vaccination activities over 2000-2030, with 50 (95%CrI[41, 62]) million deaths averted by activities between 2000 and 2019. For children under-5 born between 2000 and 2030, we estimate 52 (95%CrI[41, 69]) million more deaths would occur over their lifetimes without vaccination against these diseases. Conclusions: This study represents the largest assessment of vaccine impact before COVID-19-related disruptions and provides motivation for sustaining and improving global vaccination coverage in the future. Funding: VIMC is jointly funded by Gavi, the Vaccine Alliance, and the Bill and Melinda Gates Foundation (BMGF) (BMGF grant number: OPP1157270 / INV-009125). Funding from Gavi is channelled via VIMC to the Consortium's modelling groups (VIMC-funded institutions represented in this paper: Imperial College London, London School of Hygiene and Tropical Medicine, Oxford University Clinical Research Unit, Public Health England, Johns Hopkins University, The Pennsylvania State University, Center for Disease Analysis Foundation, Kaiser Permanente Washington, University of Cambridge, University of Notre Dame, Harvard University, Conservatoire National des Arts et Métiers, Emory University, National University of Singapore). Funding from BMGF was used for salaries of the Consortium secretariat (authors represented here: TBH, MJ, XL, SE-L, JT, KW, NMF, KAMG); and channelled via VIMC for travel and subsistence costs of all Consortium members (all authors). We also acknowledge funding from the UK Medical Research Council and Department for International Development, which supported aspects of VIMC's work (MRC grant number: MR/R015600/1).JHH acknowledges funding from National Science Foundation Graduate Research Fellowship; Richard and Peggy Notebaert Premier Fellowship from the University of Notre Dame. BAL acknowledges funding from NIH/NIGMS (grant number R01 GM124280) and NIH/NIAID (grant number R01 AI112970). The Lives Saved Tool (LiST) receives funding support from the Bill and Melinda Gates Foundation.This paper was compiled by all coauthors, including two coauthors from Gavi. Other funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Malaria Elimination in Costa Rica: Changes in Treatment and Mass Drug Administration.

Costa Rica is a candidate to eliminate malaria by 2020. The remaining malaria transmission hotspots are located within the Huétar Norte Region (HNR), where 90% of the country's 147 malaria cases have occurred since 2016, following a 33-month period without transmission. Here, we examine changes in transmission with the implementation of a supervised seven-day chloroquine and primaquine treatment (7DCPT). We also evaluate the impact of a focal mass drug administration (MDA) in January 2019 at Boca Arenal, the town in HNR reporting the greatest local transmission. We found that the change to a seven-day treatment protocol, from the prior five-day program, was associated with a 98% reduction in malaria transmission. The MDA helped to reduce transmission, keeping the basic reproduction number, RT, significantly below 1, for at least four months. However, following new imported cases from Nicaragua, autochthonous transmission resumed. Our results highlight the importance of appropriate treatment delivery to reduce malaria transmission, and the challenge that highly mobile populations, if their malaria is not treated, pose to regional elimination efforts in Mesoamerica and México.

Seasonal temperature variation influences climate suitability for dengue, chikungunya, and Zika transmission.

Dengue, chikungunya, and Zika virus epidemics transmitted by Aedes aegypti mosquitoes have recently (re)emerged and spread throughout the Americas, Southeast Asia, the Pacific Islands, and elsewhere. Understanding how environmental conditions affect epidemic dynamics is critical for predicting and responding to the geographic and seasonal spread of disease. Specifically, we lack a mechanistic understanding of how seasonal variation in temperature affects epidemic magnitude and duration. Here, we develop a dynamic disease transmission model for dengue virus and Aedes aegypti mosquitoes that integrates mechanistic, empirically parameterized, and independently validated mosquito and virus trait thermal responses under seasonally varying temperatures. We examine the influence of seasonal temperature mean, variation, and temperature at the start of the epidemic on disease dynamics. We find that at both constant and seasonally varying temperatures, warmer temperatures at the start of epidemics promote more rapid epidemics due to faster burnout of the susceptible population. By contrast, intermediate temperatures (24-25°C) at epidemic onset produced the largest epidemics in both constant and seasonally varying temperature regimes. When seasonal temperature variation was low, 25-35°C annual average temperatures produced the largest epidemics, but this range shifted to cooler temperatures as seasonal temperature variation increased (analogous to previous results for diurnal temperature variation). Tropical and sub-tropical cities such as Rio de Janeiro, Fortaleza, and Salvador, Brazil; Cali, Cartagena, and Barranquilla, Colombia; Delhi, India; Guangzhou, China; and Manila, Philippines have mean annual temperatures and seasonal temperature ranges that produced the largest epidemics. However, more temperate cities like Shanghai, China had high epidemic suitability because large seasonal variation offset moderate annual average temperatures. By accounting for seasonal variation in temperature, the model provides a baseline for mechanistically understanding environmental suitability for virus transmission by Aedes aegypti. Overlaying the impact of human activities and socioeconomic factors onto this mechanistic temperature-dependent framework is critical for understanding likelihood and magnitude of outbreaks.

Temperature modulates dengue virus epidemic growth rates through its effects on reproduction numbers and generation intervals.

Epidemic growth rate, r, provides a more complete description of the potential for epidemics than the more commonly studied basic reproduction number, R0, yet the former has never been described as a function of temperature for dengue virus or other pathogens with temperature-sensitive transmission. The need to understand the drivers of epidemics of these pathogens is acute, with arthropod-borne virus epidemics becoming increasingly problematic. We addressed this need by developing temperature-dependent descriptions of the two components of r-R0 and the generation interval-to obtain a temperature-dependent description of r. Our results show that the generation interval is highly sensitive to temperature, decreasing twofold between 25 and 35°C and suggesting that dengue virus epidemics may accelerate as temperatures increase, not only because of more infections per generation but also because of faster generations. Under the empirical temperature relationships that we considered, we found that r peaked at a temperature threshold that was robust to uncertainty in model parameters that do not depend on temperature. Although the precise value of this temperature threshold could be refined following future studies of empirical temperature relationships, the framework we present for identifying such temperature thresholds offers a new way to classify regions in which dengue virus epidemic intensity could either increase or decrease under future climate change.

Quantitative, model-based estimates of variability in the generation and serial intervals of Plasmodium falciparum malaria.

BACKGROUND: The serial interval is a fundamentally important quantity in infectious disease epidemiology that has numerous applications to inferring patterns of transmission from case data. Many of these applications are apropos of efforts to eliminate falciparum malaria from locations throughout the world, yet the serial interval for this disease is poorly understood quantitatively. METHODS: To obtain a quantitative estimate of the serial interval for falciparum malaria, the sum of the components of the falciparum malaria transmission cycle was taken based on a combination of mathematical models and empirical data. During this process, a number of factors were identified that account for substantial variability in the serial interval across different contexts. RESULTS: Treatment with anti-malarial drugs roughly halves the serial interval due to an abbreviated period of human infectiousness, seasonality results in different serial intervals at different points in the transmission season, and variability in within-host dynamics results in many individuals whose serial intervals do not follow average behaviour. Furthermore, 24.5 % of secondary cases presenting clinically did so prior to the primary cases being identified through active detection of infection. CONCLUSIONS: These results have important implications for epidemiological applications that rely on quantitative estimates of the serial interval of falciparum malaria and other diseases characterized by prolonged infections and complex ecological drivers.