Timely detection of bacterial meningitis epidemics at district level: a studyin three countries of the African Meningitis Belt

Background Bacterial meningitis is a major public health problem in the African ‘Meningitis Belt', where recurrent unpredictable epidemics occur. Despite the introduction in 2010 of the conjugate A vaccine, the reactive strategy remains important for responding to epidemics caused by other bacteria and in areas not yet vaccinated. Review of weekly numbers of suspected cases in Niger, Mali and Burkina Faso identified spatial disparities in the annual patterns of meningitis, which suggested a more local way of defining epidemics and initiating a timely vaccination campaign. Method We defined an epidemic district-year as an excess of cases compared to the incidence previously experienced in the given district. Groups of similar districts in terms of seasonal patterns were identified by cluster analysis. We investigated a cluster-specific criterion of early epidemic onset to anticipate epidemic district-years. Results These were encouraging, as epidemic district-years were fairly efficiently captured, with an average time gained of 2.5 weeks over the current strategy. Conclusion This early-onset criterion could help ensure timely implementation of vaccination campaigns without the need to modify the implemented surveillance system. The next step is to extend this study to other countries of the Meningitis Belt, and to explain the differences in seasonal patterns in the different cluster

A systematic comparison of linear regression-based statistical methods to assess exposome-health associations

BACKGROUND: The exposome constitutes a promising framework to better understand the effect of environmental exposures on health by explicitly considering multiple testing and avoiding selective reporting. However, exposome studies are challenged by the simultaneous consideration of many correlated exposures. OBJECTIVES: We compared the performances of linear regression-based statistical methods in assessing exposome-health associations. METHODS: In a simulation study, we generated 237 exposure covariates with a realistic correlation structure, and a health outcome linearly related to 0 to 25 of these covariates. Statistical methods were compared primarily in terms of false discovery proportion (FDP) and sensitivity. RESULTS: On average over all simulation settings, the elastic net and sparse partial least-squares regression showed a sensitivity of 76% and a FDP of 44%; Graphical Unit Evolutionary Stochastic Search (GUESS) and the deletion/substitution/addition (DSA) algorithm a sensitivity of 80% and a FDP of 33%. The environment-wide association study (EWAS) underperformed these methods in terms of FDP (average FDP, 86%), despite a higher sensitivity. Performances decreased considerably when assuming an exposome exposure matrix with high levels of correlation between covariates. CONCLUSIONS: Correlation between exposures is a challenge for exposome research, and the statistical methods investigated in this study are limited in their ability to efficiently differentiate true predictors from correlated covariates in a realistic exposome context. While GUESS and DSA provided a marginally better balance between sensitivity and FDP, they did not outperform the other multivariate methods across all scenarios and properties examined, and computational complexity and flexibility should also be considered when choosing between these methods

A systematic comparison of statistical methods to detect interactions in exposome-health associations

Background There is growing interest in examining the simultaneous effects of multiple exposures and, more generally, the effects of mixtures of exposures, as part of the exposome concept (being defined as the totality of human environmental exposures from conception onwards). Uncovering such combined effects is challenging owing to the large number of exposures, several of them being highly correlated. We performed a simulation study in an exposome context to compare the performance of several statistical methods that have been proposed to detect statistical interactions. Methods Simulations were based on an exposome including 237 exposures with a realistic correlation structure. We considered several statistical regression-based methods, including two-step Environment-Wide Association Study (EWAS2), the Deletion/Substitution/Addition (DSA) algorithm, the Least Absolute Shrinkage and Selection Operator (LASSO), Group-Lasso INTERaction-NET (GLINTERNET), a three-step method based on regression trees and finally Boosted Regression Trees (BRT). We assessed the performance of each method in terms of model size, predictive ability, sensitivity and false discovery rate. Results GLINTERNET and DSA had better overall performance than the other methods, with GLINTERNET having better properties in terms of selecting the true predictors (sensitivity) and of predictive ability, while DSA had a lower number of false positives. In terms of ability to capture interaction terms, GLINTERNET and DSA had again the best performances, with the same trade-off between sensitivity and false discovery proportion. When GLINTERNET and DSA failed to select an exposure truly associated with the outcome, they tended to select a highly correlated one. When interactions were not present in the data, using variable selection methods that allowed for interactions had only slight costs in performance compared to methods that only searched for main effects. Conclusions GLINTERNET and DSA provided better performance in detecting two-way interactions, compared to other existing methods

The exposome concept: a challenge and a potential driver for environmental health research

The exposome concept was defined in 2005 as encompassing all environmental exposures from conception onwards, as a new strategy to evidence environmental disease risk factors. Although very appealing, the exposome concept is challenging in many respects. In terms of assessment, several hundreds of time-varying exposures need to be considered, but increasing the number of exposures assessed should not be done at the cost of increased exposure misclassification. Accurately assessing the exposome currently requires numerous measurements, which rely on different technologies; resulting in an expensive set of protocols. In the future, high-throughput ‘omics technologies may be a promising technique to integrate a wide range of exposures from a small numbers of biological matrices. Assessing the association between many exposures and health raises statistical challenges. Due to the correlation structure of the exposome, existing statistical methods cannot fully and efficiently untangle the exposures truly affecting the health outcome from correlated exposures. Other statistical challenges relate to accounting for exposure misclassification or identifying synergistic effects between exposures. On-going exposome projects are trying to overcome technical and statistical challenges. From a public health perspective, a better understanding of the environmental risk factors should open the way to improved prevention strategies

Relying on repeated biospecimens to reduce the effects of classical-type exposure measurement error in studies linking the exposome to health

International audienceThe exposome calls for assessing numerous exposures, typically using biomarkers with varying amounts of measurement error, which can be assumed to be of classical type. We evaluated the impact of classical-type measurement error on the performance of exposome-health studies, and the efficiency of two measurement error correction methods relying on the collection of repeated biospecimens: within-subject biospecimens pooling and regression calibration. In a simulation study, we generated 237 exposures from a realistic correlation matrix, with various amounts of classical-type measurement error, and a continuous health outcome linearly influenced by exposures. Measurement error decreased the sensitivity to identify exposures influencing health from a value of 75% down to 46%, increased false discovery proportion from 26% to 49% and increased attenuation bias in the slope of true predictors from 45% to 66%. Assuming that repeated biospecimens were available, within-subject pooling and regression calibration improved sensitivity (which increased to 63%), false discovery proportion (down to 37%) and bias (down to 49%) compared to an error-prone study with a single biospecimen per subject. Performances were poorer for the exposures with the largest amount of measurement error, and increased with the number of available biospecimens. Relying on repeated biospecimens only for the exposures with the largest amount of measurement error provided similar performance improvement. Exposome studies relying on spot exposure biospecimens suffer from decreased performances if some biomarkers suffer from measurement error due to their temporal variability; performances can be improved by collecting repeated biospecimens per subject, in particular for non persistent chemicals

Seasonality of meningitis in Africa and climate forcing: aerosols stand out.

11 pagesInternational audienceBacterial meningitis is an ongoing threat for the population of the African Meningitis Belt, a region characterized by the highest incidence rates worldwide. The determinants of the disease dynamics are still poorly understood; nevertheless, it is often advocated that climate and mineral dust have a large impact. Over the last decade, several studies have investigated this relationship at a large scale. In this analysis, we scaled down to the district-level weekly scale (which is used for in-year response to emerging epidemics), and used wavelet and phase analysis methods to define and compare the time-varying periodicities of meningitis, climate and dust in Niger. We mostly focused on detecting time-lags between the signals that were consistent across districts. Results highlighted the special case of dust in comparison to wind, humidity or temperature: a strong similarity between districts is noticed in the evolution of the time-lags between the seasonal component of dust and meningitis. This result, together with the assumption of dust damaging the pharyngeal mucosa and easing bacterial invasion, reinforces our confidence in dust forcing on meningitis seasonality. Dust data should now be integrated in epidemiological and forecasting models to make them more realistic and usable in a public health perspective

Applying the exposome concept in birth cohort research: a review of statistical approaches

The exposome represents the totality of life course environmental exposures (including lifestyle and other non-genetic factors), from the prenatal period onwards. This holistic concept of exposure provides a new framework to advance the understanding of complex and multifactorial diseases. Prospective pregnancy and birth cohort studies provide a unique opportunity for exposome research as they are able to capture, from prenatal life onwards, both the external (including lifestyle, chemical, social and wider community-level exposures) and the internal (including inflammation, metabolism, epigenetics, and gut microbiota) domains of the exposome. In this paper, we describe the steps required for applying an exposome approach, describe the main strengths and limitations of different statistical approaches and discuss their challenges, with the aim to provide guidance for methodological choices in the analysis of exposome data in birth cohort studies. An exposome approach implies selecting, pre-processing, describing and analyzing a large set of exposures. Several statistical methods are currently available to assess exposome-health associations, which differ in terms of research question that can be answered, of balance between sensitivity and false discovery proportion, and between computational complexity and simplicity (parsimony). Assessing the association between many exposures and health still raises many exposure assessment issues and statistical challenges. The exposome favors a holistic approach of environmental influences on health, which is likely to allow a more complete understanding of disease etiology.This work was supported by the European Union’s Horizon 2020 research and innovation programme under Grant Agreement 733206 (LifeCycle Project) and 874583 (ATHLETE Project)

The carbon footprint of scientific visibility

International audienceAbstract In face of global warming, academics have begun to consider and analyze the environmental and carbon footprints associated with their professional activity. Among the several sources of greenhouse gas (GHG) emissions from research activities, air travel - one of the most visible and unequal fraction of this footprint - has received much attention. Of particular interest is the question of how air travel may be related to scientific success or visibility as defined by current academic evaluation norms, notably bibliometric indicators. Existing studies, conducted over a small sample of individuals or within specific disciplines, have demonstrated that the number of citations may be related to air travel frequency, but have failed to identify a link between air-travel and publication rate or h -index. Here, using a comprehensive dataset aggregating the answers from over 6000 respondents to a survey sent to randomly selected scientists and staff across all research disciplines in France, we show that a strong publication rate and h -index are significantly associated with higher individual air travel. This relationship is robust to the inclusion of the effects of gender, career stage and disciplines. Our analysis suggests that flying is a mean for early career scientists to obtain scientific visibility, and for senior scientist to maintain this visibility

An Empirical Validation of the Within-subject Biospecimens Pooling Approach to Minimize Exposure Misclassification in Biomarker-based Studies

International audienceBackground: Within-subject biospecimens pooling can theoretically reduce bias in dose-response functions from biomarker-based studies when exposure assessment suffers from classical-type error. However, collecting many urine voids each day is cumbersome. We evaluated the empirical validity of a within-subject pooling approach and compared several options to avoid sampling each void.Methods: In 16 pregnant women who collected a spot of each urine void over several nonconsecutive weeks, we compared concentrations of 10 phenols in daily, weekly, and pregnancy within-subject pools. We pooled either three or all daily samples. In a simulation study using these data, we quantified bias in dose-response functions when using one to 20 urine samples per subject to assess methylparaben (a compound with moderate within-subject variability) and bisphenol A (high variability) exposures.Results: Correlations between exposure estimates from pools of all and of only three voids per day were above 0.80 for all time windows and compounds, except for benzophenone-3 and triclosan in the daily time window (correlations, 0.57-0.68). With one spot sample to assess pregnancy exposure, correlations were all below 0.74. Using only one biospecimen led to attenuation bias in the dose-response functions of 29% (methylparaben) and 69% (bisphenol A); four samples for methylparaben and 18 for bisphenol A decreased bias to 10%.Conclusions: For nonpersistent chemicals, collecting and pooling three samples per day instead of all daily samples efficiently estimates exposures over a week or more. Collecting around 20 biospecimens can strongly limit attenuation bias for nonpersistent chemicals such as bisphenol A