Epidemiology of Lyme borreliosis based on outpatient claims data of all people with statutory health insurance, Germany, 2019.

IntroductionEvidence of nationwide and regional morbidity of Lyme borreliosis (LB) in Germany is lacking.AimsWe calculated the total number of incident LB cases in Germany in 2019, compared regional variations, investigated the extent of possible under-reporting in notification data and examined the association between high incidence areas and land cover composition.MethodsWe used outpatient claims data comprising information for people with statutory health insurance who visited a physician at least once between 2010 and 2019 in Germany (n = 71,411,504). The ICD-10 code A69.2 was used to identify incident LB patients. Spatial variations of LB were assessed by means of Global and Local Moran's Index at district level. Notification data were obtained for nine federal states with mandatory notification from the Robert Koch Institute (RKI).ResultsOf all insured, 128,177 were diagnosed with LB in 2019, corresponding to an incidence of 179 per 100,000 insured. The incidence varied across districts by a factor of 16 (range: 40-646 per 100,000). We identified four spatial clusters with high incidences. These clusters were associated with a significantly larger proportion of forests and agricultural areas than low incidence clusters. In 2019, 12,264 LB cases were reported to the RKI from nine federal states, while 69,623 patients with LB were found in claims data for those states. This difference varied considerably across districts.ConclusionsThese findings serve as a solid basis for regionally tailored population-based intervention programmes and can support modelling studies assessing the development of LB epidemiology under various climate change scenarios.

EventEpi-A natural language processing framework for event-based surveillance.

According to the World Health Organization (WHO), around 60% of all outbreaks are detected using informal sources. In many public health institutes, including the WHO and the Robert Koch Institute (RKI), dedicated groups of public health agents sift through numerous articles and newsletters to detect relevant events. This media screening is one important part of event-based surveillance (EBS). Reading the articles, discussing their relevance, and putting key information into a database is a time-consuming process. To support EBS, but also to gain insights into what makes an article and the event it describes relevant, we developed a natural language processing framework for automated information extraction and relevance scoring. First, we scraped relevant sources for EBS as done at the RKI (WHO Disease Outbreak News and ProMED) and automatically extracted the articles' key data: disease, country, date, and confirmed-case count. For this, we performed named entity recognition in two steps: EpiTator, an open-source epidemiological annotation tool, suggested many different possibilities for each. We extracted the key country and disease using a heuristic with good results. We trained a naive Bayes classifier to find the key date and confirmed-case count, using the RKI's EBS database as labels which performed modestly. Then, for relevance scoring, we defined two classes to which any article might belong: The article is relevant if it is in the EBS database and irrelevant otherwise. We compared the performance of different classifiers, using bag-of-words, document and word embeddings. The best classifier, a logistic regression, achieved a sensitivity of 0.82 and an index balanced accuracy of 0.61. Finally, we integrated these functionalities into a web application called EventEpi where relevant sources are automatically analyzed and put into a database. The user can also provide any URL or text, that will be analyzed in the same way and added to the database. Each of these steps could be improved, in particular with larger labeled datasets and fine-tuning of the learning algorithms. The overall framework, however, works already well and can be used in production, promising improvements in EBS. The source code and data are publicly available under open licenses.

Surveillance on speed: Being aware of infectious diseases in migrants mass accommodations - an easy and flexible toolkit for field application of syndromic surveillance, Germany, 2016 to 2017.

Europe received an increased number of migrants in 2015. Housing in inadequate mass accommodations (MA) made migrants prone to infectious disease outbreaks. In order to enhance awareness for infectious diseases (ID) and to detect clusters early, we developed and evaluated a syndromic surveillance system in three MA with medical centres in Berlin, Germany. Healthcare workers transferred daily data on 14 syndromes to the German public health institute (Robert Koch-Institute). Clusters of ID syndromes and single cases of outbreak-prone diseases produced a signal according to a simple aberration-detection algorithm that computes a statistical threshold above which a case count is considered unusually high. Between May 2016-April 2017, 9,364 syndromes were reported; 2,717 (29%) were ID, of those 2,017 (74%) were respiratory infections, 262 (10%) skin parasites, 181 (7%) gastrointestinal infections. The system produced 204 signals, no major outbreak was detected. The surveillance reinforced awareness for public health aspects of ID. It provided real-time data on migrants' health and stressed the burden of non-communicable diseases. The tool is available online and was evaluated as being feasible and flexible. It complements traditional notification systems. We recommend its usage especially when laboratory testing is not available and real-time data are needed.

Nonlinear fitness landscape of a molecular pathway.

Genes are regulated because their expression involves a fitness cost to the organism. The production of proteins by transcription and translation is a well-known cost factor, but the enzymatic activity of the proteins produced can also reduce fitness, depending on the internal state and the environment of the cell. Here, we map the fitness costs of a key metabolic network, the lactose utilization pathway in Escherichia coli. We measure the growth of several regulatory lac operon mutants in different environments inducing expression of the lac genes. We find a strikingly nonlinear fitness landscape, which depends on the production rate and on the activity rate of the lac proteins. A simple fitness model of the lac pathway, based on elementary biophysical processes, predicts the growth rate of all observed strains. The nonlinearity of fitness is explained by a feedback loop: production and activity of the lac proteins reduce growth, but growth also affects the density of these molecules. This nonlinearity has important consequences for molecular function and evolution. It generates a cliff in the fitness landscape, beyond which populations cannot maintain growth. In viable populations, there is an expression barrier of the lac genes, which cannot be exceeded in any stationary growth process. Furthermore, the nonlinearity determines how the fitness of operon mutants depends on the inducer environment. We argue that fitness nonlinearities, expression barriers, and gene-environment interactions are generic features of fitness landscapes for metabolic pathways, and we discuss their implications for the evolution of regulation.

Towards a leptospirosis early warning system in northeastern Argentina.

Leptospirosis is a zoonotic disease with a high burden in Latin America, including northeastern Argentina, where flooding events linked to El Niño are associated with leptospirosis outbreaks. The aim of this study was to evaluate the value of using hydrometeorological indicators to predict leptospirosis outbreaks in this region. We quantified the effects of El Niño, precipitation, and river height on leptospirosis risk in Santa Fe and Entre Ríos provinces between 2009 and 2020, using a Bayesian modelling framework. Based on several goodness of fit statistics, we selected candidate models using a long-lead El Niño 3.4 index and shorter lead local climate variables. We then tested predictive performance to detect leptospirosis outbreaks using a two-stage early warning approach. Three-month lagged Niño 3.4 index and one-month lagged precipitation and river height were positively associated with an increase in leptospirosis cases in both provinces. El Niño models correctly detected 89% of outbreaks, while short-lead local models gave similar detection rates with a lower number of false positives. Our results show that climatic events are strong drivers of leptospirosis incidence in northeastern Argentina. Therefore, a leptospirosis outbreak prediction tool driven by hydrometeorological indicators could form part of an early warning and response system in the region.

Lessons from COVID-19 for rescalable data collection.

Novel data and analyses have had an important role in informing the public health response to the COVID-19 pandemic. Existing surveillance systems were scaled up, and in some instances new systems were developed to meet the challenges posed by the magnitude of the pandemic. We describe the routine and novel data that were used to address urgent public health questions during the pandemic, underscore the challenges in sustainability and equity in data generation, and highlight key lessons learnt for designing scalable data collection systems to support decision making during a public health crisis. As countries emerge from the acute phase of the pandemic, COVID-19 surveillance systems are being scaled down. However, SARS-CoV-2 resurgence remains a threat to global health security; therefore, a minimal cost-effective system needs to remain active that can be rapidly scaled up if necessary. We propose that a retrospective evaluation to identify the cost-benefit profile of the various data streams collected during the pandemic should be on the scientific research agenda.

A Novel Tool for Real-time Estimation of Epidemiological Parameters of Communicable Diseases Using Contact-Tracing Data: Development and Deployment.

BACKGROUND: The Surveillance Outbreak Response Management and Analysis System (SORMAS) contains a management module to support countries in their epidemic response. It consists of the documentation, linkage, and follow-up of cases, contacts, and events. To allow SORMAS users to visualize data, compute essential surveillance indicators, and estimate epidemiological parameters from such network data in real-time, we developed the SORMAS Statistics (SORMAS-Stats) application. OBJECTIVE: This study aims to describe the essential visualizations, surveillance indicators, and epidemiological parameters implemented in the SORMAS-Stats application and illustrate the application of SORMAS-Stats in response to the COVID-19 outbreak. METHODS: Based on findings from a rapid review and SORMAS user requests, we included the following visualization and estimation of parameters in SORMAS-Stats: transmission network diagram, serial interval (SI), time-varying reproduction number R(t), dispersion parameter k, and additional surveillance indicators presented in graphs and tables. We estimated SI by fitting lognormal, gamma, and Weibull distributions to the observed distribution of the number of days between symptom onset dates of infector-infectee pairs. We estimated k by fitting a negative binomial distribution to the observed number of infectees per infector. Furthermore, we applied the Markov Chain Monte Carlo approach and estimated R(t) using the incidence data and the observed SI computed from the transmission network data. RESULTS: Using COVID-19 contact-tracing data of confirmed cases reported between July 31 and October 29, 2021, in the Bourgogne-Franche-Comté region of France, we constructed a network diagram containing 63,570 nodes. The network comprises 1.75% (1115/63,570) events, 19.59% (12,452/63,570) case persons, and 78.66% (50,003/63,570) exposed persons, including 1238 infector-infectee pairs and 3860 transmission chains with 24.69% (953/3860) having events as the index infector. The distribution with the best fit to the observed SI data was a lognormal distribution with a mean of 4.30 (95% CI 4.09-4.51) days. We estimated a dispersion parameter k of 21.11 (95% CI 7.57-34.66) and an effective reproduction number R of 0.9 (95% CI 0.58-0.60). The weekly estimated R(t) values ranged from 0.80 to 1.61. CONCLUSIONS: We provide an application for real-time estimation of epidemiological parameters, which is essential for informing outbreak response strategies. The estimates are commensurate with findings from previous studies. The SORMAS-Stats application could greatly assist public health authorities in the regions using SORMAS or similar tools by providing extensive visualizations and computation of surveillance indicators.

Real-time monitoring of COVID-19 dynamics using automated trend fitting and anomaly detection.

As several countries gradually release social distancing measures, rapid detection of new localized COVID-19 hotspots and subsequent intervention will be key to avoiding large-scale resurgence of transmission. We introduce ASMODEE (automatic selection of models and outlier detection for epidemics), a new tool for detecting sudden changes in COVID-19 incidence. Our approach relies on automatically selecting the best (fitting or predicting) model from a range of user-defined time series models, excluding the most recent data points, to characterize the main trend in an incidence. We then derive prediction intervals and classify data points outside this interval as outliers, which provides an objective criterion for identifying departures from previous trends. We also provide a method for selecting the optimal breakpoints, used to define how many recent data points are to be excluded from the trend fitting procedure. The analysis of simulated COVID-19 outbreaks suggests ASMODEE compares favourably with a state-of-art outbreak-detection algorithm while being simpler and more flexible. As such, our method could be of wider use for infectious disease surveillance. We illustrate ASMODEE using publicly available data of National Health Service (NHS) Pathways reporting potential COVID-19 cases in England at a fine spatial scale, showing that the method would have enabled the early detection of the flare-ups in Leicester and Blackburn with Darwen, two to three weeks before their respective lockdown. ASMODEE is implemented in the free R package trendbreaker. This article is part of the theme issue 'Modelling that shaped the early COVID-19 pandemic response in the UK'.

Exploring beyond clinical routine SARS-CoV-2 serology using MultiCoV-Ab to evaluate endemic coronavirus cross-reactivity.

The humoral immune response to SARS-CoV-2 is a benchmark for immunity and detailed analysis is required to understand the manifestation and progression of COVID-19, monitor seroconversion within the general population, and support vaccine development. The majority of currently available commercial serological assays only quantify the SARS-CoV-2 antibody response against individual antigens, limiting our understanding of the immune response. To overcome this, we have developed a multiplex immunoassay (MultiCoV-Ab) including spike and nucleocapsid proteins of SARS-CoV-2 and the endemic human coronaviruses. Compared to three broadly used commercial in vitro diagnostic tests, our MultiCoV-Ab achieves a higher sensitivity and specificity when analyzing a well-characterized sample set of SARS-CoV-2 infected and uninfected individuals. We find a high response against endemic coronaviruses in our sample set, but no consistent cross-reactive IgG response patterns against SARS-CoV-2. Here we show a robust, high-content-enabled, antigen-saving multiplex assay suited to both monitoring vaccination studies and facilitating epidemiologic screenings for humoral immunity towards pandemic and endemic coronaviruses.

A Bayesian Monte Carlo approach for predicting the spread of infectious diseases.

In this paper, a simple yet interpretable, probabilistic model is proposed for the prediction of reported case counts of infectious diseases. A spatio-temporal kernel is derived from training data to capture the typical interaction effects of reported infections across time and space, which provides insight into the dynamics of the spread of infectious diseases. Testing the model on a one-week-ahead prediction task for campylobacteriosis and rotavirus infections across Germany, as well as Lyme borreliosis across the federal state of Bavaria, shows that the proposed model performs on-par with the state-of-the-art hhh4 model. However, it provides a full posterior distribution over parameters in addition to model predictions, which aides in the assessment of the model. The employed Bayesian Monte Carlo regression framework is easily extensible and allows for incorporating prior domain knowledge, which makes it suitable for use on limited, yet complex datasets as often encountered in epidemiology.

Inference of plasmid-copy-number mean and noise from single-cell gene expression data.

Plasmids are extrachromosomal DNA molecules which code for their own replication. We previously reported a setup using genes coding for fluorescent proteins of two colors that allowed us, using a simple model, to extract the plasmid-copy-number noise in a monoclonal population of bacteria [J. Wong Ng, Phys. Rev. E 81, 011909 (2010)]. Here we present a detailed calculation relating this noise to the measured levels of fluorescence, taking into account all sources of fluorescence fluctuations: not only the fluctuation of gene expression as in the simple model but also the growth and division of bacteria, the nonuniform distribution of their ages, the random partition of proteins at divisions, and the replication and partition of plasmids and chromosome. We show how to use the chromosome as a reference, which helps extracting the plasmid-copy-number noise in a self-consistent manner.