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Lowe, R.

Publications and source records attributed to Lowe, R..

15 recordsLinked to original sources

Integrated Multiomics Reveals Intergenerational Brain Sensory System Remodeling Induced by Parental Intermittent Fasting

Intermittent fasting (IF) is increasingly recognized as a potent modulator of metabolic health, but its effects on brain function across generations remain poorly understood. Here, we show that parental IF, administered to both mothers and fathers before mating, is associated with coordinated molecular remodeling in the cerebral cortex of fathers and their offspring, with shared molecular signatures identified between these generations and a pronounced enrichment of sensory-associated pathways. Using whole-genome bisulfite sequencing, transcriptomic profiling, and proteomic analysis, we found that IF elicited widespread cortical epigenetic remodeling in fathers, accompanied by transcriptional and protein-level changes enriched for olfactory, taste, synaptic, and neurometabolic pathways. Strikingly, related molecular signatures were detected in F1 offspring that had never been directly exposed to fasting, consistent with intergenerational transmission of IF-associated cortical remodeling. Offspring responses were sex dependent, with female and male progeny exhibiting distinct patterns of DNA methylation, gene expression, and protein abundance. Integrated multiomic analyses identified conserved candidate networks involved in sensory perception, glutamatergic signaling, synaptic organization, intracellular trafficking, cytoskeletal regulation, and stress-response pathways. Together, these findings identify sensory-associated cortical remodeling as a prominent molecular feature associated with parental IF and reveal persistent, sex-dependent molecular alterations in the offspring brain.

genomics↗

ENSO-driven climate variability reconfigures the altitudinal frontier of dengue risk in the Andes

Despite the high burden of dengue in Latin America, high elevations have historically protected megacities such as Mexico City, Quito, and Bogota. Climate change is expected to shift elevational suitability frontiers, yet the mechanisms governing disease expansion into highland regions and the timescales over which it occurs remain poorly characterized. Using spatiotemporal decomposition techniques, we identified a mechanistic cascade linking (1) the El Nino-Southern Oscillation (ENSO) to local Colombian climate, accounting for [~]85% of interannual temperature variability and [~]53% of rainfall variability, and (2) local climate to dengue dynamics, accounting for [~]66-76% of variation in incidence and [~]44-55% of its altitudinal range. Multiple lines of evidence, including spatial ENSO signatures across Andean ridges, temporal predictive performance, and vectorial-capacity modeling, identified the local temperature expression of the ENSO teleconnection as the dominant driver of transmission. During warm ENSO phases, dengue incidence increases exponentially and transmission expands into higher elevations. This shifts the altitudinal distribution of dengue transmission upward, exposing immunologically naive populations in highland areas that were previously considered unsuitable. Mechanistically, this altitudinal shift arises because a coherent warming across elevational strata disproportionately increases transmission in highland regions, where small temperature increments produce the largest increase in vectorial capacity. These findings challenge the view that disease expansion is primarily a gradual response to long-term warming and highlight the importance of climate variability for disease projection, attribution, and public health preparedness. Significance statementWhile increasing mean temperatures are a known threat to the changing landscape of infectious diseases, this study reveals that interannual climate variability can be a more immediate driver of disease burden and expansion. We show that the El Nino phenomenon produces local temperature anomalies in Colombia that exponentially increase dengue cases and extend dengues reach into high-altitude areas, potentially exposing millions of immunologically naive people. This finding is highly relevant to the elevated dengue-free megacities in Latin America, such as Mexico City, Quito, and Bogota. By shifting the focus from multi-decadal trends to interannual climate variability, this paper provides a methodological blueprint for more accurate predictions of how infectious diseases will behave as our climate becomes increasingly unstable.

ecology↗

Uncovering Shared and Tissue-Specific Molecular Adaptations to Intermittent Fasting in Liver, Brain, and Muscle

Intermittent fasting (IF) has emerged as a powerful dietary intervention with profound metabolic benefits, yet the tissue-specific molecular mechanisms underlying these effects remain poorly understood. In this study, we employed comprehensive proteomics and transcriptomics analysis to investigate the systemic and organ-specific adaptations to IF in male C57BL/6 mice. Following a 16-hour daily fasting regimen (IF16) over four months, IF reduced blood glucose, HbA1c, and cholesterol levels while increasing ketone bodies, indicative of enhanced metabolic flexibility. Proteomic profiling of the liver, skeletal muscle, and cerebral cortex revealed tissue-specific responses, with the liver exhibiting the most pronounced changes, including upregulation of pathways involved in fatty acid oxidation, ketogenesis, and glycan degradation, and downregulation of steroid hormone and cholesterol metabolism. In muscle, IF enhanced pyruvate metabolism, fatty acid biosynthesis, and AMPK signaling, while suppressing oxidative phosphorylation and thermogenesis. The cerebral cortex displayed unique adaptations, with upregulation of autophagy, PPAR signaling, and metabolic pathways, and downregulation of TGF-beta and p53 signaling, suggesting a shift toward energy conservation and stress resilience. Notably, Serpin A1c emerged as the only protein commonly upregulated across all three tissues, highlighting its potential role in systemic adaptation to IF. Integrative transcriptomic and proteomic analyses revealed partial concordance between mRNA and protein expression, underscoring the complexity of post-transcriptional regulation. Shared biological signaling processes were identified across tissues, suggesting unifying mechanisms linking metabolic changes to cellular communication. Our findings reveal both conserved and tissue-specific responses by which IF may optimize energy utilization, enhance metabolic flexibility, and promote cellular resilience.

molecular biology↗

Axolotl epigenetic clocks offer insights into the nature of negligible senescence

Renowned for their regenerative abilities, axolotls also exhibit exceptional longevity, resistance to age-related diseases and apparent lack of physiological declines through lifespan, and have thus been considered organisms of negligible senescence. Whether axolotls display epigenetic hallmarks of ageing remains unknown. Here, we probe the axolotl DNA methylome throughout lifespan and present its first epigenetic clocks. Both at tissue-specific or pan-tissue levels, the clocks are biphasic, capable of predicting age during early life but not for the rest of its lifespan. We show that axolotls exhibit evolutionarily conserved features of epigenetic ageing during early life, yet their methylome is remarkably stable across lifespan, including at Polycomb Repressive Complex 2 (PRC2) target sites, suggesting that this species deviates from known patterns of epigenetic ageing. This study provides molecular insights into negligible senescence and furthers our understanding of ageing dynamics in animals capable of extreme regeneration.

developmental biology↗

Early growth response 2 (EGR2) is a novel regulator of the senescence program

Senescence, a state of stable growth arrest, plays an important role in ageing and age-related diseases in vivo. Although the INK4/ARF locus is known to be essential for senescence programs, the key regulators driving p16 and ARF transcription remain largely underexplored. Using siRNA screening for modulators of the p16/pRB and ARF/p53/p21 pathways in deeply senescent human mammary epithelial cells (DS HMECs) and fibroblasts (DS HMFs), we identified EGR2 as a novel regulator of senescence. EGR2 expression is up-regulated during senescence and its ablation by siRNA in DS HMECs and HMFs transiently reverses the senescent phenotype. We demonstrate that EGR2 activates the ARF and p16 promoters and directly binds to the ARF promoter. Loss of EGR2 downregulates p16 levels and increases the pool of p16- p21- reversed cells in the population. Moreover, EGR2 overexpression is sufficient to induce senescence. Our data suggest that EGR2 is a regulator of the p16/pRB and direct transcriptional activator of the ARF/p53/p21 pathways in senescence and a novel marker of senescence.

cell biology↗

Areca catechu-(Betel-nut)-induced whole transcriptome changes associated with diabetes, obesity and metabolic syndrome in a human monocyte cell line

Betel-nut consumption is the fourth most common addictive habit globally and there is good evidence to link it with obesity, type 2 diabetes and the metabolic syndrome. We adopted a genome-wide transcriptomic approach in a human monocyte cell line incubated with arecoline and its nitrosated products to identify gene expression changes relevant to obesity, type 2 diabetes and the metabolic syndrome. The THP1 monocyte cell line was incubated separately with arecoline and 3-methylnitrosaminopropionaldehyde (MNPA) in triplicate for 24 hours and pooled cDNA indexed paired-end libraries were sequenced (Illumina NextSeq 500). After incubation with arecoline and MNPA, 15 and 39 genes respectively had significant changes in their expression (q<0.05, log fold change 1.5). Eighteen of those genes have reported associations with type 2 diabetes and obesity in humans; of these genes there was strong evidence to implicate CLEC10A, MAPK8IP1, NEGR1, NQ01 and INHBE. In summary, these pilot studies have identified a large number of genes whose expression was changed significantly in human TPH1 cells following incubation with arecoline or with 3-methylnitrosaminopropionaldehyde. These findings suggest that further investigation of these genes in betel-quid chewers with obesity and/or type 2 diabetes is warranted.

genomics↗

Resistance to the antifungal activity of Aprotinin occurs through mutations in genes that function in cation homeostasis

An increase in the prevalence of fungal infections is coinciding with an increase of resistance to current clinical antifungals, placing pressure on the discovery of new antifungal candidates. One option is to investigate drugs that have been approved for use for other medical conditions that have secondary antifungal activity. Aprotinin, also known as Bovine Pancreatic Trypsin inhibitor (BPTI), is an antifibrinolytic that has been approved for systemic use in patients in some countries. Bleackley and coworkers (2014) revealed that BPTI also has antifungal activity against S. cerevisiae and C. albicans and does this by targeting the magnesium transporter ALR1. Here we have further investigated the potential for aprotinin to be used as an antifungal by assessing the development of resistance. We used an in vitro model to assess the evolution of BPTI resistance/tolerance whereby BPTI was serial passaged with the model organism S. cerevisiae. Resistance to BPTI developed more quickly than resistance to the plant defensin NaD1 and the clinical antifungal, caspofungin. Full genome sequencing of resistant lines revealed that resistance to BPTI developed as the result of a deleterious mutation in either the ptk2 or sky1 genes. This revealed that cation homeostasis and transport functions were particularly affected in S. cerevisiae after exposure to BPTI. Therefore, the mutations in these genes probably decreases release of magnesium and other cations from the cell, protecting the yeast from the limiting intracellular magnesium levels that arise when BPTI blocks the magnesium transporter Alr1p.

microbiology↗

Malaria in Southern Venezuela: The Hottest Hotspot in Latin America

Malaria cases in Latin America reached ~1 million in 2017 and 2018, with 53% and 51% reported from Venezuela, respectively. In this study, we characterized the spatiotemporal dynamics of malaria transmission between 2007-2017 in southern Venezuela, the main endemic area of the country. We found that disease transmission was focal and more prevalent in the southeast of southern Venezuela where two persistent hotspots of Plasmodium vivax (76%) and P. falciparum (18%) linked to deforestation for illegal gold mining accounted for ~60% of the country-wide number of cases. Incidence has increased nearly tenfold in the last decade, showing an explosive epidemic growth due to a significant lack of disease control. We suggest that a source-sink pattern of Plasmodium sp. dispersal account for the re-emergence and progression of malaria transmission in the last 4 years across the country due to the internal migration of infected people to and from the hotspots and other malaria-prone ecosystems. We observe a similar pattern explaining the spillover of cases across international borders affecting neighboring countries. This study provides baseline epidemiological data and guidance for malaria control to further assess the dynamics of cross-border malaria, the role of asymptomatic carriers, drug-resistant evolution, and innovative control efforts in the Latin America region.

ecology↗

A CellAge epigenetic clock for expedited discovery of anti-ageing compounds in vitro

We aim to improve anti-ageing drug discovery, currently achieved through laborious and lengthy longevity analysis. Recent studies demonstrated that the most accurate molecular method to measure human age is based on CpG methylation profiles, as exemplified by several epigenetics clocks that can accurately predict an individuals age. Here, we developed CellAgeClock, a new epigenetic clock that measures subtle ageing changes in primary human cells in vitro. As such, it provides a unique tool to measure effects of relatively short pharmacological treatments on ageing. We validated the CellAgeClock against known longevity drugs such as rapamycin and trametinib. Moreover, we uncovered novel anti-ageing drugs, torin2 and Dactolisib (BEZ-235), demonstrating the value of our approach as a screening and discovery platform for anti-ageing strategies. The CellAgeClock outperforms other epigenetic clocks in measuring subtle ageing changes in primary human cells in culture. The tested drug treatments reduced senescence and other ageing markers, further consolidating our approach as a screening platform. Finally, we show that the novel anti-ageing drugs we uncovered in vitro, indeed increased longevity in vivo. Our method expands the scope of CpG methylation profiling from measuring human chronological and biological age from human samples in years, to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, providing a novel accelerated discovery platform to test sought after geroprotectors.

molecular biology↗

Co-developing climate services for public health: stakeholder needs and perceptions for the prevention and control of Aedes-transmitted diseases in the Caribbean.

BackgroundSmall island developing states (SIDS) in the Caribbean region are challenged with managing the health outcomes of a changing climate. Health and climate sectors have partnered to co-develop climate services to improve the management of these diseases, for example, through the development of climate-driven early warning systems. The objective of this study was to identify health and climate stakeholder perceptions and needs in the Caribbean, with respect to the development of climate services for arboviruses (e.g. dengue, chikungunya, and Zika).\n\nMethodsStakeholders included public decision makers and practitioners from the climate and health sectors at the regional (Caribbean) level and from the countries of Dominica and Barbados. From April to June 2017, we conducted interviews (n=41), surveys (n=32), and national workshops with stakeholders. Survey responses were tabulated and audio recordings were transcribed and analyzed using qualitative coding to identify responses by research topic, country/region, and sector.\n\nResultsHealth practitioners indicated that their jurisdiction is currently experiencing an increased risk of diseases transmitted by Ae. aegypti due to climate variability, and most anticipated that this risk will increase in the future. National health sectors reported financial limitations and a lack of technical expertise in geographic information systems (GIS), statistics, and modeling, which constrained their ability to implement climate services for arboviruses. National climate sectors were constrained by a lack of personnel. Stakeholders highlighted the need to strengthen partnerships with the private sector, academia, and civil society. They identified a gap in local research on climate-arbovirus linkages, which constrained the ability of the health sector to make informed decisions. Strategies to strengthen the climate-health partnership included a top-down approach by engaging senior leadership, multi-lateral collaboration agreements, national committees on climate and health, and shared spaces of dialogue. Mechanisms for mainstreaming climate services for health operations to control arboviruses included climate-health bulletins and an online GIS platform that would allow for regional data sharing and the generation of spatiotemporal epidemic forecasts.\n\nConclusionsThese findings support the creation of interdisciplinary and intersectoral communities of practices and the co-design of climate services for the Caribbean public health sector. By fostering the effective use of climate information within health policy, research and practice, nations will have greater capacity to adapt to a changing climate.

scientific communication and education↗

Local climate and social inequality drive spatio-temporal variation in malaria risk across a complex urban landscape

BackgroundCities are becoming increasingly important habitats for mosquito-borne infections. The pronounced heterogeneity of urban landscapes challenges our understanding of the spatio-temporal dynamics of these diseases, and of the influence of climate and socio-economic factors at different spatial scales. Here, we quantify this joint influence on malaria risk by taking advantage of an extensive dataset in both space and time for reported Plasmodium falciparum cases in the city of Surat, Northwest India. MethodsWe analyzed 10 years of monthly falciparum cases resolved at three nested spatial resolutions (for 7 zones, 32 units and 478 workers units subdivisions, respectively). With a Bayesian hierarchical mixed model that incorporates effects of population density, poverty, humidity and temperature, we investigate the main drivers of spatio-temporal malaria risk at the intermediate scale of districts. The significance of covariates and the model fit is then examined at lower and higher resolutions. FindingsThe spatial variation of urban malaria cases is strongly stationary in time, whereby locations exhibiting high and low yearly cases remain largely consistent across years. Local socio-economic variation can be summarized with two main principal components, representing poverty and population density respectively. The model that incorporates these two factors together with local temperature and global relative humidity, best explains monthly malaria patterns at the intermediate resolution. The effects of local temperature and population density remain significant at the finest spatial scale. We further identify the specific areas where such increased resolution improves model fit. InterpretationMalaria risk patterns within the city are largely driven by fixed spatial structures, highlighting the key role of local climate conditions and social inequality. As a result, malaria elimination efforts in the Indian subcontinent can benefit from identifying, predicting and targeting disease hotspots within cities. Spatio-temporal statistical models for the mesoscale of administrative units can inform control efforts, and be complemented with bespoke plans in the identified areas where finer scale data could be of value. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSUrban areas have become the new dominant ecosystem around the globe. Developing countries comprise the most urbanized regions of the world, with 80% of their population living in cities and an expected increase to 90% by 2050. The large and heterogeneous environments of today challenge the understanding and control of infectious disease dynamics, including of those transmitted by vectors. Malaria in the Indian subcontinent has an important urban component given the existence of a truly urban mosquito vector Anopheles stephensi. A literature search in Mendeley of "urban malaria" and "India" returned 161 publications, in their majority on diagnostics or brief reports on the disease, and on cross-sectional rather than longitudinal studies addressing the spatio-temporal variation of disease risk for a whole city, the subject of our work. A relevant exception is a study for the city of Ahmedabad; this not address multiple seasons across different spatial scales, and climatic conditions are not considered jointly with socio-economic drivers in the modeling. A second Mendeley search on A. stephensi returned 11 publications into two distinct groups: early entomological studies for India and recent reports of the mosquito in the Horn of Africa. This geographical expansion makes the specter of urban malaria a future possibility for the African continent where the disease remains so far rural and peri-urban. Added value of this studyThis paper relies on an extensive surveillance data set of Plasmodium falciparum cases for Surat (India) to investigate the variation and drivers of malaria risk in an heterogenous urban environment. A statistical model for the spatio-temporal variability of cases is developed, which includes both climatic and socio-economic drivers, with the latter summarized into two major axes of variation. Model fits are compared across three spatial resolutions, ranging from a few zones to a few hundred units. Seasonal hotspots are shown to be largely stationary in time, which allows identification of dominant drivers, including population density and local temperatures, whereas humidity acts globally modulating year-to-year burden. More granular statistical models and datasets like the one analyzed here are needed to capture the effects of socioeconomic and climatic drivers, and to predict current and future malaria incidence patterns within cities. Implications of all the available evidenceThe analysis identifies relevant resolution which can vary across the city for targeted intervention, including vector control, that would focus on reducing and eliminating transmission hotspots. The modeling framework, incorporating predictors representing climate at local vs. aggregate levels, and major axes of socio-economic variation, should apply to other vector-borne diseases and other cities for which surveillance records are available. The importance of spatially-explicit and sustained surveillance data for informing these models cannot be overstated.

ecology↗

Space-time clusters of dengue, chikungunya, and Zika cases in the city of Rio de Janeiro

Brazil is a dengue-endemic country where all four dengue virus serotypes circulate and cause seasonal epidemics. Recently, chikungunya and Zika viruses were also introduced. In Rio de Janeiro city, the three diseases co-circulated for the first time in 2015-2016, resulting in what is known as the triple epidemic. In this study, we identify space-time clusters of dengue, chikungunya, and Zika, to understand the dynamics and interaction between these simultaneously circulating arboviruses in a densely populated and heterogeneous city.\n\nWe conducted a spatio-temporal analysis of weekly notified cases of the three diseases in Rio de Janeiro city (July 2015 - January 2017), georeferenced by 160 neighbourhoods, using Kulldorffs scan statistic with discrete Poisson probability models.\n\nThere were 26549, 13662, and 35905 notified cases of dengue, chikungunya, and Zika, respectively. The 17 dengue clusters and 15 Zika clusters were spread all over the city, while the 14 chikungunya clusters were more concentrated in the North and Downtown areas. Zika clusters persisted over a longer period of time. The multivariate scan statistic - used to analyse the three diseases simultaneously - detected 17 clusters, nine of which included all three diseases.\n\nThis is the first study exploring space-time clustering of dengue, chikungunya, and Zika in an intraurban area. In general, the clusters did not coincide in time and space. This is probably the result of the competition between viruses for host resources, and of vector-control attitudes promoted by previous arbovirus outbreaks. The main affected area - the North region - is characterised by a combination of high population density and low human development index, highlighting the importance of targeting interventions in this area. Spatio-temporal scan statistics have the potential to direct interventions to high-risk locations in a timely manner and should be considered as part of the municipal surveillance routine as a tool to optimize prevention strategies.\n\nAuthor summaryDengue, an arboviral disease transmitted by Aedes mosquitoes, has been endemic in Brazil for decades, but vector-control strategies have not led to a significant reduction in the disease burden and were not sufficient to prevent chikungunya and Zika entry and establishment in the country. In Rio de Janeiro city, the first Zika and chikungunya epidemics were detected between 2015-2016, coinciding with a dengue epidemic. Understanding the behaviour of these diseases in a triple epidemic scenario is a necessary step for devising better interventions for prevention and outbreak response. We applied scan statistics analysis to detect spatio-temporal clustering for each disease separately and for all three simultaneously. In general, clusters were not detected in the same locations and time periods, possibly due to competition between viruses for host resources, and change in behaviour of the human population (e.g. intensified vector-control activities in response to increasing cases of a particular arbovirus). Neighbourhoods with high population density and social vulnerability should be considered as important targets for interventions. Particularly in the North region, where clusters of the three diseases exist and the first chikungunya cluster occurred. The use of space-time cluster detection can direct intensive interventions to high-risk locations in a timely manner.

epidemiology↗

Projecting the end of the Zika virus epidemic in Latin America: a modelling analysis

Background Zika virus (ZIKV) emerged in Latin America & the Caribbean (LAC) region in 2013, and has had serious implications for population health in the region. In 2016, the World Health Organization declared the ZIKV outbreak a Public Health Emergency of International Concern following a cluster of associated neurological disorders and neonatal malformations. In 2017, Zika cases declined, but future incidence in LAC remains uncertain due to gaps in our understanding, considerable variation in surveillance and a lack of a comprehensive collation of data from affected countries.\n\nMethods Our analysis combines information on confirmed and suspected Zika cases across LAC countries and a spatio-temporal dynamic transmission model for ZIKV infection to determine key transmission parameters and projected incidence in 91 major cities within 35 countries. Seasonality was determined by spatio-temporal estimates of Aedes aegypti vector capacity. We used country and state-level data from 2015 to mid-2017 to infer key model parameters, country-specific disease reporting rates, and the 2018 projected incidence. A 10-fold cross-validation approach was used to validate parameter estimates to out-of-sample epidemic trajectories.\n\nResults There was limited transmission in 2015, but in 2016 and 2017 there was sufficient opportunity for wide-spread ZIKV transmission in most cities, resulting in the depletion of susceptible individuals. We predict that the highest number of cases in 2018 within some Brazilian States (Sao Paulo and Rio de Janeiro), Colombia and French Guiana, but the estimated number of cases were no more than a few hundred. Model estimates of the timing of the peak in incidence were correlated (p<0.05) with the reported peak in incidence. The reporting rate varied across countries, with lower reporting rates for those with only confirmed cases compared to those who reported both confirmed and suspected cases.\n\nConclusions The findings suggest that the ZIKV epidemic is by and large over, with incidence projected to be low in most cities in LAC in 2018. Local low levels of transmission are probable but the estimated rate of infection suggests that most cities have a population with high levels of herd immunity.

epidemiology↗

Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci

Human genetic studies have emphasised the dominant contribution of pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, limited annotation of the islet epigenome has constrained efforts to define the molecular mechanisms mediating the, largely regulatory, signals revealed by Genome-Wide Association Studies (GWAS). We characterised patterns of chromatin accessibility (ATAC-seq, n=17) and DNA methylation (whole-genome bisulphite sequencing, n=10) in human islets, generating high-resolution chromatin state maps through integration with established ChIP-seq marks. We found enrichment of GWAS signals for T2D and fasting glucose was concentrated in subsets of islet enhancers characterised by open chromatin and hypomethylation, with the former annotation predominant. At several loci (including CDC123, ADCY5, KLHDC5) the combination of fine-mapping genetic data and chromatin state enrichment maps, supplemented by allelic imbalance in chromatin accessibility pinpointed likely causal variants. The combination of increasingly-precise genetic and islet epigenomic information accelerates definition of causal mechanisms implicated in T2D pathogenesis.

genomics↗

Assessing the performance of real-time epidemic forecasts

Real-time forecasts based on mathematical models can inform critical decision-making during infectious disease outbreaks. Yet, epidemic forecasts are rarely evaluated during or after the event, and there is little guidance on the best metrics for assessment. Here, we propose an evaluation approach that disentangles different components of forecasting ability using metrics that separately assess the calibration, sharpness and unbiasedness of forecasts. This makes it possible to assess not just how close a forecast was to reality but also how well uncertainty has been quantified. We used this approach to analyse the performance of weekly forecasts we generated in real time in Western Area, Sierra Leone, during the 2013-16 Ebola epidemic in West Africa. We investigated a range of forecast model variants based on the model fits generated at the time with a semi-mechanistic model, and found that good probabilistic calibration was achievable at short time horizons of one or two weeks ahead but models were increasingly inaccurate at longer forecasting horizons. This suggests that forecasts may have been of good enough quality to inform decision making requiring predictions a few weeks ahead of time but not longer, reflecting the high level of uncertainty in the processes driving the trajectory of the epidemic. Comparing forecasts based on the semi-mechanistic model to simpler null models showed that the best semi-mechanistic model variant performed better than the null models with respect to probabilistic calibration, and that this would have been identified from the earliest stages of the outbreak. As forecasts become a routine part of the toolkit in public health, standards for evaluation of performance will be important for assessing quality and improving credibility of mathematical models, and for elucidating difficulties and trade-offs when aiming to make the most useful and reliable forecasts.

epidemiology↗