Rare-disease registries can be useful for studying the associations between environmental exposures and disease severity, but often require the addition of a healthy comparison control group. Defining a surrogate control group, matched and balanced on potentially confounding variables, would allow for the comparison of exposure distributions with cases from a registry. In the present study, we assess whether controls selected externally, using stratification score (SS) matching, can serve as effective proxies for internal controls. In addition, we use methyl paraben (MEPB) to compare the estimated associations between an externally matched sample and case-control frequencies in a cohort with internally matched controls. We started with 225 eligible cases of autism spectrum disorder (ASD) from Childhood Autism Risks from Genetics and the Environment (CHARGE), 241 internal controls from CHARGE, and 265 external controls from the National Health and Nutrition Examination Survey (NHANES) cycles 2005-2016. We calculated the SSs using demographic covariates and matched 1:1 using a caliper method without a replacement. The distribution of the covariates and the mean squared error of the paired differences (MSE_paired) in the SSs between the internal and external group were similar (MSE_paired = 0.007 and 0.011, respectively). The association between MEPB and ASD compared to the controls was similar between the externally matched SS pairs and the original frequency matched cohort. Controls selected externally, via SS matching, can provide a comparable bias reduction to that provided by the internal controls, and therefore may be a useful strategy in situations when the internal controls are not available.

BACKGROUND: Little is known about the effect of drought on all-cause mortality, especially in higher income countries such as the United States. As the frequency and severity of droughts are likely to increase, understanding the connections between drought and mortality becomes increasingly important. METHODS: Our exposure variable was an annual cumulative drought severity score based on the 1-month, county-level Standardized Precipitation Evapotranspiration Index. The outcome variables of demographic subgroup-specific all-cause mortality count data per year were obtained from the National Vital Statistics System. Any counts below 10 deaths were censored in that demographic group per county. We modeled county-stratum-year mortality using interval-censored negative binomial regression with county-level random intercepts, for each combined age-race-sex stratum either with or without further stratification by climate regions. Fixed effects meta-regression was used to test the associations between age, race, sex, and region with the drought-mortality regression coefficients. Predictive margins were then calculated from the meta-regression model to estimate larger subgroup (e.g., race or sex) associations of drought with mortality. RESULTS: Most of the results were null for associations between drought severity and mortality, across joint strata of race, age, sex and region, but incidence rate ratios (IRRs) for 17 subgroups were significant after accounting for the multiple testing; ten were < 1 indicating a possible protective effect of drought on mortality for that particular subpopulation. The meta-regression indicated heterogeneity in the association of drought with mortality according to race, climate region, and age, but not by sex. Marginal means of the estimated log-incidence rate ratios differed significantly from zero for age groups 25-34, 35-44, 45-54 and 55-64; for the white race group; and for the South, West and Southwest regions, in the analysis that included wet county-years. The margin of the meta-regression model suggested a slightly negative, but not statistically significant, association of drought with same-year mortality in the overall population. CONCLUSIONS: There were significant, heterogeneous-direction associations in subpopulation-stratified models, after controlling for multiple comparisons, suggesting that the impacts of drought on mortality may not be monolithic across the United States. Meta-regression identified systematic differences in the associations of drought severity with all-cause mortality according to climate region, race, and age. These findings suggest there may be important contextual differences in the effects of drought severity on mortality, motivating further work focused on local mechanisms. We speculate that some of the estimated negative associations of drought severity with same-year mortality could be consistent with either a protective effect of drought on total mortality in the same year, or with a delayed health effect of drought beyond the same year. Further research is needed to clarify associations of drought with more specific causes of death and with sublethal health outcomes, for specific subpopulations, and considering lagged effects occurring beyond the same year as the drought.

Although climate change occurs alongside other anthropogenic ecosystem impacts, little is known about how sea-surface temperature variability influences the ecotoxicology of persistent organic pollutants (POPs). We analyzed POP contaminant levels, and stable isotopes δ15N and δ13C as measures of trophic position, in eggs collected from the Gulf of Alaska and Bering Sea between 1999 and 2010 from two similar avian species with different trophic positions: common murres (Uria aalge) and thick-billed murres (Uria lomvia). The ebb and flow of the Pacific Decadal Oscillation (PDO), a long-lived El Niño-like pattern of climate variability in the Pacific Ocean, predicted both trophic position and polychlorinated biphenyl (PCB) levels in thick-billed murres, but not in common murres. There was a similar pattern of association of the PDO with organochlorine pesticide levels in thick-billed murres, but not in common murres. The magnitude of association in thick-billed murres of PDO with the level of a specific PCB congener was a function of the number of chlorine groups on the PCB congener. Although this statistical analysis does not account for all factors contributing to climate variation, this contrast between the species suggests that facultative changes in foraging behavior, reflected in trophic position, can determine how POPs flow through and thereby alter ecosystems under climate change.

Most host-parasite systems exhibit remarkable heterogeneity in the contribution to transmission of certain individuals, locations, host infectious states, or parasite strains. While significant advancements have been made in the understanding of the impact of transmission heterogeneity in epidemic dynamics and parasite persistence and evolution, the knowledge base of the factors contributing to transmission heterogeneity is limited. We argue that research efforts should move beyond considering the impact of single sources of heterogeneity and account for complex couplings between conditions with potential synergistic impacts on parasite transmission. Using theoretical approaches and empirical evidence from various host-parasite systems, we investigate the ecological and epidemiological significance of couplings between heterogeneities and discuss their potential role in transmission dynamics and the impact of control.

Exposure to heat is associated with a substantial burden of disease and is an emerging issue in the context of climate change. Heat is of particular concern in India, which is one of the worlds hottest countries and also most populous, where relatively little is known about personal heat exposure, particularly in rural areas. Here, we leverage data collected as part of a randomized controlled trial to describe personal temperature exposures of adult women (40-79 years of age) in rural Tamil Nadu. We also characterize measurement error in heat exposure assessment by comparing personal exposure measurements to the nearest ambient monitoring stations and to commonly used modeled temperature data products. We find that temperatures differ across individuals in the same area on the same day, sometimes by more than 5 °C within the same hour, and that some individuals experience sharp increases in heat exposure in the early morning or evening, potentially a result of cooking with solid fuels. We find somewhat stronger correlations between the personal exposure measurements and the modeled products than with ambient monitors. We did not find evidence of systematic biases, which indicates that adjusting for discrepancies between different exposure measurement methods is not straightforward.

Disease surveillance data are important for monitoring disease burden and occurrence, and for informing a wide range of efforts to improve population health. Surveillance for infectious diseases may be conducted passively, relying on reports from healthcare facilities, or actively, involving surveys of the population at risk. Passive surveillance typically provides wide spatial coverage, but is subject to biases arising from differences in care-seeking behavior, diagnostic practices, and under-reporting. Active surveillance minimizes these biases, but is typically constrained to small areas and subpopulations due to resource limitations. Methods based on linkage of individual records between passive and active surveillance datasets provide a means to estimate and correct for the biases of each system, leveraging the size and coverage of passive surveillance and the quality of data in active surveillance. We develop a spatial Bayesian hierarchical model for bias-correcting data from both systems to yield an improved estimate of disease measures after adjusting for under-ascertainment. We apply the framework to data from a passive and an active surveillance system for pulmonary tuberculosis (PTB) in Sichuan, China, and estimate the average sensitivity of the active surveillance system at 70% (95% credible interval: 62%, 78%), and the passive system at 30% (95% CI: 24%, 35%). Passive surveillance sensitivity exhibited considerable spatial variability, and was positively associated with a site's gross domestic product per capita. Bias-corrected estimates of county-level PTB prevalence in the province in 2010 identified regions in the southeast with the highest PTB burden, yielding different geographic priorities than previous reports.

Recent years have seen rising incidence of dengue and large outbreaks of Zika and chikungunya, which are all caused by viruses transmitted by Aedes aegypti mosquitoes. In most settings, the primary intervention against Aedes-transmitted viruses is vector control, such as indoor, ultra-low volume (ULV) spraying. Targeted indoor residual spraying (TIRS) has the potential to more effectively impact Aedes-borne diseases, but its implementation requires careful planning and evaluation. The optimal time to deploy these interventions and their relative epidemiological effects are, however, not well understood. We used an agent-based model of dengue virus transmission calibrated to data from Iquitos, Peru to assess the epidemiological effects of these interventions under differing strategies for deploying them. Specifically, we compared strategies where spray application was initiated when incidence rose above a threshold based on incidence in recent years to strategies where spraying occurred at the same time(s) each year. In the absence of spraying, the model predicted 361,000 infections [inter-quartile range (IQR): 347,000-383,000] in the period 2000-2010. The ULV strategy with the fewest median infections was spraying twice yearly, in March and October, which led to a median of 172,000 infections [IQR: 158,000-183,000], a 52% reduction from baseline. Compared to spraying once yearly in September, the best threshold-based strategy utilizing ULV had fewer median infections (254,000 vs. 261,000), but required more spraying (351 vs. 274 days). For TIRS, the best strategy was threshold-based, which led to the fewest infections of all strategies tested (9,900; [IQR: 8,720-11,400], a 94% reduction), and required fewer days spraying than the equivalent ULV strategy (280). Although spraying twice each year is likely to avert the most infections, our results indicate that a threshold-based strategy can become an alternative to better balance the translation of spraying effort into impact, particularly if used with a residual insecticide.

The mosquito Aedes aegypti is the vector of a number of medically-important viruses, including dengue virus, yellow fever virus, chikungunya virus, and Zika virus, and as such vector control is a key approach to managing the diseases they cause. Understanding the impact of vector control on these diseases is aided by first understanding its impact on Ae. aegypti population dynamics. A number of detail-rich models have been developed to couple the dynamics of the immature and adult stages of Ae. aegypti. The numerous assumptions of these models enable them to realistically characterize impacts of mosquito control, but they also constrain the ability of such models to reproduce empirical patterns that do not conform to the models' behavior. In contrast, statistical models afford sufficient flexibility to extract nuanced signals from noisy data, yet they have limited ability to make predictions about impacts of mosquito control on disease caused by pathogens that the mosquitoes transmit without extensive data on mosquitoes and disease. Here, we demonstrate how the differing strengths of mechanistic realism and statistical flexibility can be fused into a single model. Our analysis utilizes data from 176,352 household-level Ae. aegypti aspirator collections conducted during 1999-2011 in Iquitos, Peru. The key step in our approach is to calibrate a single parameter of the model to spatio-temporal abundance patterns predicted by a generalized additive model (GAM). In effect, this calibrated parameter absorbs residual variation in the abundance time-series not captured by other features of the mechanistic model. We then used this calibrated parameter and the literature-derived parameters in the agent-based model to explore Ae. aegypti population dynamics and the impact of insecticide spraying to kill adult mosquitoes. The baseline abundance predicted by the agent-based model closely matched that predicted by the GAM. Following spraying, the agent-based model predicted that mosquito abundance rebounds within about two months, commensurate with recent experimental data from Iquitos. Our approach was able to accurately reproduce abundance patterns in Iquitos and produce a realistic response to adulticide spraying, while retaining sufficient flexibility to be applied across a range of settings.

With the aid of laboratory typing techniques, infectious disease surveillance networks have the opportunity to obtain powerful information on the emergence, circulation, and evolution of multiple genotypes, serotypes or other subtypes of pathogens, informing understanding of transmission dynamics and strategies for prevention and control. The volume of typing performed on clinical isolates is typically limited by its ability to inform clinical care, cost and logistical constraints, especially in comparison with the capacity to monitor clinical reports of disease occurrence, which remains the most widespread form of public health surveillance. Viewing clinical disease reports as arising from a latent mixture of pathogen subtypes, laboratory typing of a subset of clinical cases can provide inference on the proportion of clinical cases attributable to each subtype (i.e., the mixture components). Optimizing protocols for the selection of isolates for typing by weighting specific subpopulations, locations, time periods, or case characteristics (e.g., disease severity), may improve inference of the frequency and distribution of pathogen subtypes within and between populations. Here, we apply the Disease Surveillance Informatics Optimization and Simulation (DIOS) framework to simulate and optimize hand foot and mouth disease (HFMD) surveillance in a high-burden region of western China. We identify laboratory surveillance designs that significantly outperform the existing network: the optimal network reduced mean absolute error in estimated serotype-specific incidence rates by 14.1%; similarly, the optimal network for monitoring severe cases reduced mean absolute error in serotype-specific incidence rates by 13.3%. In both cases, the optimal network designs achieved improved inference without increasing subtyping effort. We demonstrate how the DIOS framework can be used to optimize surveillance networks by augmenting clinical diagnostic data with limited laboratory typing resources, while adapting to specific, local surveillance objectives and constraints.

Despite estimates that, each year, as many as 300 million dengue virus (DENV) infections result in either no perceptible symptoms (asymptomatic) or symptoms that are sufficiently mild to go undetected by surveillance systems (inapparent), it has been assumed that these infections contribute little to onward transmission. However, recent blood-feeding experiments with Aedes aegypti mosquitoes showed that people with asymptomatic and pre-symptomatic DENV infections are capable of infecting mosquitoes. To place those findings into context, we used models of within-host viral dynamics and human demographic projections to (1) quantify the net infectiousness of individuals across the spectrum of DENV infection severity and (2) estimate the fraction of transmission attributable to people with different severities of disease. Our results indicate that net infectiousness of people with asymptomatic infections is 80% (median) that of people with apparent or inapparent symptomatic infections (95% credible interval (CI): 0-146%). Due to their numerical prominence in the infectious reservoir, clinically inapparent infections in total could account for 84% (CI: 82-86%) of DENV transmission. Of infections that ultimately result in any level of symptoms, we estimate that 24% (95% CI: 0-79%) of onward transmission results from mosquitoes biting individuals during the pre-symptomatic phase of their infection. Only 1% (95% CI: 0.8-1.1%) of DENV transmission is attributable to people with clinically detected infections after they have developed symptoms. These findings emphasize the need to (1) reorient current practices for outbreak response to adoption of pre-emptive strategies that account for contributions of undetected infections and (2) apply methodologies that account for undetected infections in surveillance programs, when assessing intervention impact, and when modeling mosquito-borne virus transmission.