Publications by authors named "Klaus Stark"

165 Publications

Estimates of Toxoplasmosis Incidence Based on Healthcare Claims Data, Germany, 2011-2016.

Emerg Infect Dis 2021 08;27(8):2097-2106

Toxoplasmosis is a zoonotic infection contracted through Toxoplasma gondii-contaminated food, soil, or water. Seroprevalence in Germany is high, but estimates of disease incidence are scarce. We investigated incidences for various toxoplasmosis manifestations using anonymized healthcare claims data from Germany for 2011-2016. Patients with a toxoplasmosis diagnosis during the annual observational period were considered incident. The estimated incidence was adjusted to the general population age/sex distribution. We estimated an annual average of 8,047 toxoplasmosis patients in Germany. The average incidence of non-pregnancy-associated toxoplasmosis patients was 9.6/100,000 population. The incidence was highest in 2011, at 10.6 (95% CI 9.4-12.6)/100,000 population, and lowest in 2016, at 8.0 (95% CI 7.0-9.4)/100,000 population. The average incidence of toxoplasmosis during pregnancy was 40.3/100,000 pregnancies. We demonstrate a substantial toxoplasmosis disease burden in Germany. Public health and food safety authorities should implement toxoplasmosis-specific prevention programs.
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http://dx.doi.org/10.3201/eid2708.203740DOI Listing
August 2021

Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals.

Nat Commun 2021 07 16;12(1):4350. Epub 2021 Jul 16.

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

Genes underneath signals from genome-wide association studies (GWAS) for kidney function are promising targets for functional studies, but prioritizing variants and genes is challenging. By GWAS meta-analysis for creatinine-based estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics Consortium and UK Biobank (n = 1,201,909), we expand the number of eGFRcrea loci (424 loci, 201 novel; 9.8% eGFRcrea variance explained by 634 independent signal variants). Our increased sample size in fine-mapping (n = 1,004,040, European) more than doubles the number of signals with resolved fine-mapping (99% credible sets down to 1 variant for 44 signals, ≤5 variants for 138 signals). Cystatin-based eGFR and/or blood urea nitrogen association support 348 loci (n = 460,826 and 852,678, respectively). Our customizable tool for Gene PrioritiSation reveals 23 compelling genes including mechanistic insights and enables navigation through genes and variants likely relevant for kidney function in human to help select targets for experimental follow-up.
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http://dx.doi.org/10.1038/s41467-021-24491-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285412PMC
July 2021

Estimates and Determinants of SARS-Cov-2 Seroprevalence and Infection Fatality Ratio Using Latent Class Analysis: The Population-Based Tirschenreuth Study in the Hardest-Hit German County in Spring 2020.

Viruses 2021 06 10;13(6). Epub 2021 Jun 10.

Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, Schlossgarten 4, 91054 Erlangen, Germany.

SARS-CoV-2 infection fatality ratios (IFR) remain controversially discussed with implications for political measures. The German county of Tirschenreuth suffered a severe SARS-CoV-2 outbreak in spring 2020, with particularly high case fatality ratio (CFR). To estimate seroprevalence, underreported infections, and IFR for the Tirschenreuth population aged ≥14 years in June/July 2020, we conducted a population-based study including home visits for the elderly, and analyzed 4203 participants for SARS-CoV-2 antibodies via three antibody tests. Latent class analysis yielded 8.6% standardized county-wide seroprevalence, a factor of underreported infections of 5.0, and 2.5% overall IFR. Seroprevalence was two-fold higher among medical workers and one third among current smokers with similar proportions of registered infections. While seroprevalence did not show an age-trend, the factor of underreported infections was 12.2 in the young versus 1.7 for ≥85-year-old. Age-specific IFRs were <0.5% below 60 years of age, 1.0% for age 60-69, and 13.2% for age 70+. Senior care homes accounted for 45% of COVID-19-related deaths, reflected by an IFR of 7.5% among individuals aged 70+ and an overall IFR of 1.4% when excluding senior care home residents from our computation. Our data underscore senior care home infections as key determinant of IFR additionally to age, insufficient targeted testing in the young, and the need for further investigations on behavioral or molecular causes of the fewer infections among current smokers.
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http://dx.doi.org/10.3390/v13061118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230374PMC
June 2021

Frequency of hand eczema in the elderly: Cross-sectional findings from the German AugUR study.

Contact Dermatitis 2021 Jun 23. Epub 2021 Jun 23.

Institute of Social Medicine and Health Systems Research, University of Magdeburg, Magdeburg, Germany.

Background: Hand eczema (HE) is a chronic inflammatory skin disease caused by a genetic predisposition and environmental exposures. There is a lack of population-based studies on skin diseases in the elderly.

Objectives: Our aim was to estimate the frequency of HE in the elderly to determine its burden of disease in this particular population.

Methods: We analyzed data from the research platform AugUR, a study on chronic diseases in the elderly (n = 1133, ages 70-95 years, mean age 77.6, 45.1% women). Raw frequencies were estimated using self-reports on physician-diagnosed HE from a standardized personal interview. Frequencies were standardized to the Bavarian population weighted by gender and 5-year age-groups.

Results: In our sample 2.7% (95% confidence interval [CI] 1.6-4.3) of the paticipants reported to ever have been diagnosed with HE. Among those 57% were male. After standardization, the frequency was estimated at 2.8% (95% CI 1.9-3.9). There were no differences between male and female participants.

Conclusions: Compared to other studies on lifetime frequency of HE, our estimates seem to be remarkably lower. More in-depth studies with validated diagnoses are warranted to precisely estimate the burden of HE in the elderly.
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http://dx.doi.org/10.1111/cod.13920DOI Listing
June 2021

Suitability of current typing procedures to identify epidemiologically linked human Giardia duodenalis isolates.

PLoS Negl Trop Dis 2021 03 25;15(3):e0009277. Epub 2021 Mar 25.

Department of Infectious Diseases, Unit for Mycotic and Parasitic Agents and Mycobacteria, Robert Koch Institute, Berlin, Germany.

Background: Giardia duodenalis is a leading cause of gastroenteritis worldwide. Humans are mainly infected by two different subtypes, i.e., assemblage A and B. Genotyping is hampered by allelic sequence heterozygosity (ASH) mainly in assemblage B, and by occurrence of mixed infections. Here we assessed the suitability of current genotyping protocols of G. duodenalis for epidemiological applications such as molecular tracing of transmission chains.

Methodology/principal Findings: Two G. duodenalis isolate collections, from an outpatient tropical medicine clinic and from several primary care laboratories, were characterized by assemblage-specific qPCR (TIF, CATH gene loci) and a common multi locus sequence typing (MLST; TPI, BG, GDH gene loci). Assemblage A isolates were further typed at additional loci (HCMP22547, CID1, RHP26, HCMP6372, DIS3, NEK15411). Of 175/202 (86.6%) patients the G. duodenalis assemblage could be identified: Assemblages A 25/175 (14.3%), B 115/175 (65.7%) and A+B mixed 35/175 (20.0%). By incorporating allelic sequence heterozygosity in the analysis, the three marker MLST correctly identified 6/9 (66,7%) and 4/5 (80.0%) consecutive samples from chronic assemblage B infections in the two collections, respectively, and identified a cluster of five independent patients carrying assemblage B parasites of identical MLST type. Extended MLST for assemblage A altogether identified 5/6 (83,3%) consecutive samples from chronic assemblage A infections and 15 novel genotypes. Based on the observed A+B mixed infections it is estimated that only 75% and 50% of assemblage A or B only cases represent single strain infections, respectively. We demonstrate that typing results are consistent with this prediction.

Conclusions/significance: Typing of assemblage A and B isolates with resolution for epidemiological applications is possible but requires separate genotyping protocols. The high frequency of multiple infections and their impact on typing results are findings with immediate consequences for result interpretation in this field.
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http://dx.doi.org/10.1371/journal.pntd.0009277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023459PMC
March 2021

Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23.

Eur Heart J 2021 05;42(20):2000-2011

Université de Paris, INSERM, UMR-S970, Integrative Epidemiology of cardiovascular disease, Paris, France.

Aims: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure.

Methods And Results: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene.

Conclusion: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
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http://dx.doi.org/10.1093/eurheartj/ehab030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139853PMC
May 2021

Dynamics of -Specific Antibodies: Seroconversion and Seroreversion between Two Population-Based, Cross-Sectional Surveys among Adults in Germany.

Microorganisms 2020 Nov 25;8(12). Epub 2020 Nov 25.

Department for Infectious Disease Epidemiology, Robert Koch-Institute, 13353 Berlin, Germany.

Lyme borreliosis (LB) caused by spp. is the most common human tick-borne disease in Europe. Although seroprevalence studies are conducted in several countries, rates of seroconversion and seroreversion are lacking, and they are essential to determine the risk of infection. Seropositivity was determined using a two-step approach-first, a serological screening assay, and in the event of a positive or equivocal result, a confirmatory immunoblot assay. Seroconversion and seroreversion rates were assessed from blood samples taken from participants included in two nation-wide population-based surveys. Moreover, the impact of antigen reactivity on seroreversion rates was assessed. The seroprevalence of antibodies reacting against spp. in the German population was 8.5% (95% CI 7.5-9.6) in 1997-99 and 9.3% (95% CI 8.3-10.4) in 2008-2011. Seroprevalence increased with age, up to 20% among 70-79 year-olds. The age-standardized seroprevalence remained the same. The yearly seroconversion rate was 0.45% (95% CI: 0.37-0.54), and the yearly seroreversion rate was 1.47% (95% CI: 1.24-2.17). Lower levels of antibodies were associated with seroreversion. Participants with a strong response against antigen p83 had the lowest odds on seroreversion. Given the yearly seroreversion rate of 1.47% and a seroprevalence up to 20% in the oldest age groups, at least 20% of the German population becomes infected with in their lifetime. The slight increase in seroprevalence between the two serosurveys was caused by an aging population.
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http://dx.doi.org/10.3390/microorganisms8121859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761102PMC
November 2020

Nationwide outbreak of invasive listeriosis associated with consumption of meat products in health care facilities, Germany, 2014-2019.

Clin Microbiol Infect 2021 Jul 23;27(7):1035.e1-1035.e5. Epub 2020 Sep 23.

FG35 Division of Gastrointestinal Infections, Zoonoses and Tropical Infections, Robert Koch Institute, Berlin, Germany.

Objectives: Invasive listeriosis is a severe foodborne infection caused by Listeria(L.)monocytogenes. The aim of this investigation was to verify and describe a molecular cluster of listeriosis patients and identify factors leading to this outbreak.

Methods: Whole genome sequencing and core genome multilocus sequence typing were used for subtyping L. monocytogenes isolates from listeriosis cases and food samples in Germany. Patient interviews and investigational tracing of foodstuffs offered in health-care facilities (HCF), where some of the cases occurred, were conducted.

Results: We identified a German-wide listeriosis outbreak with 39 genetically related cases occurring between 2014 and 2019. Three patients died as a result of listeriosis. After identification of HCF in different regions of Germany for at least 13 cases as places of exposure, investigational tracing of food supplies in six prioritized HCF revealed meat products from one company (X) as a commonality. Subsequently the outbreak strain was analysed in six isolates from ready-to-eat meat products and one isolate from the production environment of company X. No further Sigma1 cases were detected after recall of the meat products from the market and closure of company X (as of August 2020).

Conclusions: Interdisciplinary efforts including whole genome sequencing, epidemiological investigations in patients and investigational tracing of foods were essential to identify the source of infections, and thereby prevent further illnesses and deaths. This outbreak underlines the vulnerability of hospitalized patients for foodborne diseases, such as listeriosis. Food producers and HCF should minimize the risk of microbiological hazards when producing, selecting and preparing food for patients.
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http://dx.doi.org/10.1016/j.cmi.2020.09.020DOI Listing
July 2021

Resurgence of an international hepatitis A outbreak linked to imported frozen strawberries, Germany, 2018 to 2020.

Euro Surveill 2020 09;25(37)

Robert Koch Institute, Department for Infectious Disease Epidemiology, Berlin, Germany.

Following outbreaks linked to frozen strawberries in Sweden and Austria in 2018, 65 cases linked to the same hepatitis A virus strain were detected in Germany between October 2018 and January 2020, presenting in two waves. Two case-control studies and a comparison of cases' consumption frequencies with purchase data from a large consumer panel provided strong evidence for frozen strawberry cake as the main vehicle of transmission. Of 46 cases interviewed, 27 reported consuming frozen strawberry cake and 25 of these identified cake(s) from brand A spontaneously or in product picture-assisted recall. Trace back investigations revealed that the Polish producer involved in the previous outbreaks in Sweden and Austria had received frozen strawberries from Egypt via a wholesaler that also delivered frozen strawberries to manufacturer of brand A. Phylogenetic analyses linked the outbreak strain to similar strains formerly isolated from sewage, stool and strawberries in Egypt. Complete trace back and timely recall of products with strong evidence of contamination is important to control an outbreak and prevent later resurgence, particularly for food items with a long shelf life. Continued molecular surveillance of hepatitis A is needed to identify outbreaks and monitor the success of food safety interventions.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.37.1900670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502883PMC
September 2020

1,25-dihydroxyvitamin-D3 but not the clinically applied marker 25-hydroxyvitamin-D3 predicts survival after stem cell transplantation.

Bone Marrow Transplant 2021 02 27;56(2):419-433. Epub 2020 Aug 27.

Department of Internal Medicine III, Hematology and Medical Oncology, University Medical Center of Regensburg, Regensburg, Germany.

The serum level of 25-hydroxyvitamin-D3 is accepted as marker for a person's vitamin D status but its role for the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is controversially discussed. The impact of 1,25-dihydroxyvitamin-D3 on HSCT outcome, however, has never been studied. In a discovery cohort of 143 HSCT patients we repeatedly (day -16 to 100) measured 1,25-dihydroxyvitamin-D3 and in comparison the well-established marker for serum vitamin D status 25-hydroxyvitamin-D3. Only lower 1,25-dihydroxyvitamin-D3 levels around HSCT (day -2 to 7, peritransplant) were significantly associated with higher 1-year treatment-related mortality (TRM) risk (Mann-Whitney U test, P = 0.001). This was confirmed by Cox-model regression without and with adjustment for baseline risk factors and severe acute Graft-versus-Host disease (aGvHD; unadjusted P = 0.001, adjusted P = 0.005). The optimal threshold for 1,25-dihydroxyvitamin-D3 to identify patients at high risk was 139.5 pM. Also in three replication cohorts consisting of altogether 365 patients 1,25-dihydroxyvitamin-D3 levels below 139.5 pM had a 3.3-fold increased risk of TRM independent of severe aGvHD compared to patients above 139.5 pM (Cox-model unadjusted P < 0.0005, adjusted P = 0.001). Our data highlight peritransplant 1,25-dihydroxyvitamin-D3 levels but not the commonly monitored 25-hydroxyvitamin-D3 levels as potent predictor of 1-year TRM and suggest to monitor both vitamin D metabolites in HSCT patients.
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http://dx.doi.org/10.1038/s41409-020-01031-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870805PMC
February 2021

Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease.

BMC Med Genomics 2020 08 26;13(1):120. Epub 2020 Aug 26.

Institute of Human Genetics, University of Regensburg, Regensburg, Germany.

Background: Advanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the genetic architecture of early AMD.

Methods: To identify genetic factors for early AMD, we conducted a genome-wide association study (GWAS) meta-analysis (14,034 cases, 91,214 controls, 11 sources of data including the International AMD Genomics Consortium, IAMDGC, and UK Biobank, UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and via an automated machine learning approach for > 170,000 photographs from UKBB. We searched for early AMD loci via GWAS and via a candidate approach based on 14 previously suggested early AMD variants.

Results: Altogether, we identified 10 independent loci with statistical significance for early AMD: (i) 8 from our GWAS with genome-wide significance (P < 5 × 10), (ii) one previously suggested locus with experiment-wise significance (P < 0.05/14) in our non-overlapping data and with genome-wide significance when combining the reported and our non-overlapping data (together 17,539 cases, 105,395 controls), and (iii) one further previously suggested locus with experiment-wise significance in our non-overlapping data. Of these 10 identified loci, 8 were novel and 2 known for early AMD. Most of the 10 loci overlapped with known advanced AMD loci (near ARMS2/HTRA1, CFH, C2, C3, CETP, TNFRSF10A, VEGFA, APOE), except two that have not yet been identified with statistical significance for any AMD. Among the 17 genes within these two loci, in-silico functional annotation suggested CD46 and TYR as the most likely responsible genes. Presence or absence of an early AMD effect distinguished the known pathways of advanced AMD genetics (complement/lipid pathways versus extracellular matrix metabolism).

Conclusions: Our GWAS on early AMD identified novel loci, highlighted shared and distinct genetics between early and advanced AMD and provides insights into AMD etiology. Our data provide a resource comparable in size to the existing IAMDGC data on advanced AMD genetics enabling a joint view. The biological relevance of this joint view is underscored by the ability of early AMD effects to differentiate the major pathways for advanced AMD.
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http://dx.doi.org/10.1186/s12920-020-00760-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449002PMC
August 2020

Distribution of alveolar echinococcosis according to environmental and geographical factors in Germany, 1992-2018.

Acta Trop 2020 Dec 9;212:105654. Epub 2020 Aug 9.

Department of Internal Medicine I, Ulm University Hospital, 89081 Ulm, Germany. Electronic address:

Alveolar echinococcosis (AE) is a rare zoonotic disease caused by the larval stage of Echinococcus multilocularis. Despite its low world-wide prevalence, this disease shows differences in the regional distribution of cases. In the present cohort study, we analyse the distribution of AE according to environmental and geographical factors in Germany. We identified the place of residence of 591 cases of AE from the national database for AE, and georeferenced these localities in the Universal Transverse Mercator coordinate system. Data on elevation, air temperature, precipitation height and land cover were mapped out and correlated with the distribution of cases of disease during the period 1992-2018. Moran's I statistic was used for spatial autocorrelation. Differences in frequency distribution between elevation, air temperature, precipitation height and landscape feature classes were analysed with the Kruskal-Wallis test. With the multiple linear regression analysis, we determined the influences and interactions of geographical and climatic factors on the number of AE cases. The results showed a heterogeneous distribution of AE cases with a higher concentration in southern Germany than in the rest of Germany (I = 0.225517, Z = 35.8182 and p < 0.001). There was a statistically significant difference in frequency distribution between precipitation height, air temperature, elevation and landscape feature classes and AE cases in Germany (p < 0.0001). In regions with higher elevations (505-672 m), moderate average air temperatures (6.0-7.9°C) and higher precipitation rates (701-1000 mm) most AE cases were recorded. It seems, that regions with higher precipitation rates, higher elevations and moderate average air temperatures have a higher infection burden and infection conditions. It is therefore extremely important to generate greater awareness of the disease in these regions, with the aim of recognising potential cases of AE as early as possible and introducing the appropriate therapeutic measures.
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http://dx.doi.org/10.1016/j.actatropica.2020.105654DOI Listing
December 2020

Chances and challenges of machine learning-based disease classification in genetic association studies illustrated on age-related macular degeneration.

Genet Epidemiol 2020 10 2;44(7):759-777. Epub 2020 Aug 2.

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

Imaging technology and machine learning algorithms for disease classification set the stage for high-throughput phenotyping and promising new avenues for genome-wide association studies (GWAS). Despite emerging algorithms, there has been no successful application in GWAS so far. We establish machine learning-based phenotyping in genetic association analysis as misclassification problem. To evaluate chances and challenges, we performed a GWAS based on automatically classified age-related macular degeneration (AMD) in UK Biobank (images from 135,500 eyes; 68,400 persons). We quantified misclassification of automatically derived AMD in internal validation data (4,001 eyes; 2,013 persons) and developed a maximum likelihood approach (MLA) to account for it when estimating genetic association. We demonstrate that our MLA guards against bias and artifacts in simulation studies. By combining a GWAS on automatically derived AMD and our MLA in UK Biobank data, we were able to dissect true association (ARMS2/HTRA1, CFH) from artifacts (near HERC2) and identified eye color as associated with the misclassification. On this example, we provide a proof-of-concept that a GWAS using machine learning-derived disease classification yields relevant results and that misclassification needs to be considered in analysis. These findings generalize to other phenotypes and emphasize the utility of genetic data for understanding misclassification structure of machine learning algorithms.
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http://dx.doi.org/10.1002/gepi.22336DOI Listing
October 2020

Large Nationwide Outbreak of Invasive Listeriosis Associated with Blood Sausage, Germany, 2018-2019.

Emerg Infect Dis 2020 07;26(7):1456-1464

Invasive listeriosis is a severe foodborne infection in humans and is difficult to control. Listeriosis incidence is increasing worldwide, but some countries have implemented molecular surveillance programs to improve recognition and management of listeriosis outbreaks. In Germany, routine whole-genome sequencing, core genome multilocus sequence typing, and single nucleotide polymorphism calling are used for subtyping of Listeria monocytogenes isolates from listeriosis cases and suspected foods. During 2018-2019, an unusually large cluster of L. monocytogenes isolates was identified, including 134 highly clonal, benzalkonium-resistant sequence type 6 isolates collected from 112 notified listeriosis cases. The outbreak was one of the largest reported in Europe during the past 25 years. Epidemiologic investigations identified blood sausage contaminated with L. monocytogenes highly related to clinical isolates; withdrawal of the product from the market ended the outbreak. We describe how epidemiologic investigations and complementary molecular typing of food isolates helped identify the outbreak vehicle.
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http://dx.doi.org/10.3201/eid2607.200225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323541PMC
July 2020

[An Update on the Epidemiological Situation of Alveolar Echinococcosis: Recording and Reporting Structures in Austria, Switzerland and Germany].

Gesundheitswesen 2020 Jun 8. Epub 2020 Jun 8.

Klinische Abteilung für Infektionen und Tropenmedizin, Medizinische Universität Wien Universitätsklinik für Innere Medizin I, Wien, Austria.

Objective:  Alveolar echinococcosis (AE) is a rare disease in Austria, Switzerland and Germany (DACh) caused by an infection with the parasite Echinococcus multilocularis. The aim of the study was to describe differences in the detection and reporting systems of alveolar echinococcosis in Austria, Switzerland and Germany and to describe epidemiological trends.

Methodology:  As part of an epidemiological update on 6 September 2019 in Ulm, Germany, experts and representatives discussed differences in the reporting and recording systems as well as the current epidemiological situation.

Results:  Since 2004, Austria has had an obligation to report suspected cases, diseases and deaths of alveolar echinococcosis by name in accordance with §1 Para. 1 of the Epidemiegesetz 1950 (EpidemieG) and the Ordinance on Notifiable Communicable Diseases. According to §7 Para. 3 of the German Infection Protection Act (IfSG), Germany has also been subject to a reporting obligation since 2001, but not by name. In addition, national registers are available in both countries, which can be used to answer scientific questions. In Switzerland, there is no obligation to report human alveolar echinococcosis since 1997. Efforts are currently being made to implement a national register for alveolar echinococcosis in Switzerland. Despite different reporting and recording systems, a similar epidemiological trend can be observed for DACh.

Conclusions:  In Austria, Switzerland and Germany there is a slightly increasing trend of human cases with alveolar echinococcosis. The direct comparability is limited due to different reporting obligations. The structures often do not allow a joint answering of scientific questions concerning diagnostics, treatment and care.
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http://dx.doi.org/10.1055/a-1138-0692DOI Listing
June 2020

Epidemiological trends of notified human brucellosis in Germany, 2006-2018.

Int J Infect Dis 2020 Apr 17;93:353-358. Epub 2020 Feb 17.

Department of Infectious Disease Epidemiology, Division for Gastrointestinal Infections, Zoonoses and Tropical Infections, Robert Koch Institute, Seestrasse 10, 13353 Berlin, Germany. Electronic address:

Objective: We describe epidemiological trends of human brucellosis in Germany over a 13 year period based on national surveillance data.

Methods: We analyzed demographic, clinical, laboratory and exposure information of symptomatic laboratory-confirmed brucellosis cases notified 2006-18. Using official population data, we calculated incidences and risk ratios (RR).

Results: From 2006 to 2018, 408 brucellosis cases were notified in Germany (mean annual incidence: 0.38/1,000,000 population), of which 75% were travel-associated. Yearly notifications peaked in 2014 (n = 47) and remained elevated compared to 2006-2013 (mean: n = 25). Asylum seekers (AS) arriving in Germany accounted for 9/44 (2015) and 15/36 (2016) cases, respectively. RR AS/non-AS 2015-2016: 28, 95% CI: 17-45. Unpasteurized milk products were most frequently notified as source of infection. Imported food and occupational exposure played a role in autochthonous cases.

Conclusions: The incidence of human brucellosis has markedly increased in recent years. Most of the observed rise in notifications can be explained by infections in AS. Exposure still predominantly occurs abroad. Risk factors for autochthonous infections need to be investigated further, though imported dairy products seem to play a role. Physicians should consider brucellosis as differential diagnosis in AS and people with travel to endemic regions with compatible symptoms.
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http://dx.doi.org/10.1016/j.ijid.2020.02.019DOI Listing
April 2020

Low prevalence of Borna disease virus 1 (BoDV-1) IgG antibodies in humans from areas endemic for animal Borna disease of Southern Germany.

Sci Rep 2019 12 27;9(1):20154. Epub 2019 Dec 27.

Robert Koch-Institut, Berlin, Germany.

Borna disease virus-1 (BoDV-1) was recently discovered as cause of severe and often fatal encephalitis in humans. BoDV-1 is known to cause neurological disease in horses and sheep mainly in South and Central Germany. The virus is maintained in bicolored white-toothed shrews (Crocidura leucodon). The incidence of infection and risk factors in humans are completely unresolved. Veterinarians may be disproportionally BoDV-1-exposed through contact to animals not recognized to be BoDV-1 infected. We conducted three serosurveys predominantly in endemic areas of South Germany for the presence of BoDV-1-reactive antibodies. Anonymized residual samples from two serosurveys of veterinarians (n = 736) with interview data on exposures and one serosurvey among blood donors (n = 373) were screened with an indirect immunofluorescence antibody test, followed by a newly developed immunoblot as confirmatory assay. One serum from a 55-59-year-old veterinarian who worked in an animal practice and as a meat inspector but none from blood donors tested positive by the screening and confirmatory assays. We show that seropositive individuals are rare even in areas with highest zoonotic risk and in a group with potentially elevated exposure risk. In light of the low seroprevalence demonstrated here, the high case-fatality rate in clinically observed human BoDV-1 infections is even more impressive.
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http://dx.doi.org/10.1038/s41598-019-56839-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934520PMC
December 2019

KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern.

JCI Insight 2019 12 5;4(23). Epub 2019 Dec 5.

Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

BACKGROUNDThe presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown.METHODSTo identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry.RESULTSWe identified a genome-wide significant (P < 5 × 10-8) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, P = 7.7 × 10-12) but did not reveal additional loci. Colocalization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery.CONCLUSIONSIn this study, we identified for the first time to our knowledge a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene provide insights not only into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies.FUNDINGThis project was funded by the German Center for Cardiovascular Research (DZHK Shared Expertise SE081 - STATS). For detailed funding information per study, see the Supplemental Acknowledgments.
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http://dx.doi.org/10.1172/jci.insight.131156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962032PMC
December 2019

Salmonellosis outbreak with novel subspecies serotype (11:z41:e,n,z15) attributable to sesame products in five European countries, 2016 to 2017.

Euro Surveill 2019 Sep;24(36)

European Food Safety Authority, Parma, Italy.

In spring 2016, Greece reported an outbreak caused by a previously undescribed subsp. serotype (antigenic formula 11:z41:e,n,z15) via the Epidemic Intelligence Information System for Food- and Waterborne Diseases and Zoonoses (EPIS-FWD), with epidemiological evidence for sesame products as presumptive vehicle. Subsequently, Germany, Czech Republic, Luxembourg and the United Kingdom (UK) reported infections with this novel serotype via EPIS-FWD. Concerned countries in collaboration with the European Centre for Disease Prevention and Control (ECDC) and European Food Safety Authority (EFSA) adopted a common outbreak case definition. An outbreak case was defined as a laboratory-confirmed notification of the novel serotype. Between March 2016 and April 2017, 47 outbreak cases were notified (Greece: n = 22; Germany: n = 13; Czech Republic: n = 5; Luxembourg: n = 4; UK: n = 3). Whole genome sequencing revealed the very close genetic relatedness of isolates from all affected countries. Interviews focusing on sesame product consumption, suspicious food item testing and trace-back analysis following spp. detection in food products identified a company in Greece where sesame seeds from different countries were processed. Through European collaboration, it was possible to identify and recall sesame spread as one contaminated food item serving as vehicle of infection and trace it back to its origin.
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http://dx.doi.org/10.2807/1560-7917.ES.2019.24.36.1800543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737830PMC
September 2019

Molecular and epidemiological characteristics of human Puumala and Dobrava-Belgrade hantavirus infections, Germany, 2001 to 2017.

Euro Surveill 2019 Aug;24(32)

These authors contributed equally and share last authorship.

IntroductionTwo hantavirus species, Puumala (PUUV) and Dobrava-Belgrade (DOBV) virus (genotype Kurkino), are endemic in Germany. Recent PUUV outbreaks raised questions concerning increasing frequency of outbreaks and expansion of PUUV endemic areas.AimsTo describe the epidemiology of human PUUV and DOBV infections in Germany.MethodsWe conducted an observational retrospective study analysing national hantavirus surveillance data notified to the national public health institute and hantavirus nucleotide sequences from patients collected at the national consultation laboratory between 2001 and 2017. Matching molecular sequences with surveillance data, we conducted epidemiological, phylogenetic and phylogeographic analyses.ResultsIn total, 12,148 cases of symptomatic hantavirus infection were notified 2001-17 (mean annual incidence: 0.87/100,000; range: 0.09-3.51). PUUV infections showed a highly variable space-time disease incidence pattern, causing large outbreaks every 2-3 years with peaks in early summer and up to 3,000 annually reported cases. Sex-specific differences in disease presentation were observed. Of 202 PUUV nucleotide sequences obtained from cases, 189 (93.6%) fall into well-supported phylogenetic clusters corresponding to different endemic areas in Germany. DOBV infections caused few, mostly sporadic cases in autumn and winter in the north and east of Germany.ConclusionsThe frequency of PUUV outbreaks increased between 2001 and 2017 but our data does not support the suggested expansion of endemic areas. The epidemiology of PUUV and DOBV-Kurkino infections differs in several aspects. Moreover, the latter are relatively rare and combining efforts and data of several countries to identify risk factors and develop specific recommendations for prevention could be worthwhile.
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http://dx.doi.org/10.2807/1560-7917.ES.2019.24.32.1800675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693291PMC
August 2019

Retinal Layer Thicknesses in Early Age-Related Macular Degeneration: Results From the German AugUR Study.

Invest Ophthalmol Vis Sci 2019 04;60(5):1581-1594

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

Purpose: To systematically analyze thicknesses of retinal layers in an older population and their link to early age-related macular degeneration (AMD).

Methods: In the AugUR baseline survey from a population aged ≥70 years, we conducted multimodal retinal imaging, including spectral-domain optical coherence tomography. Autosegmentation of eight distinct retinal layers was followed by manual correction of segmentation errors. AMD status was graded on color fundus images according to the Three Continent AMD Consortium Severity Scale. We tested the association of early AMD on retinal layer thicknesses by using linear mixed models and replicated significant results in independent data also from the AugUR platform.

Results: When comparing layer thicknesses between early AMD and no AMD (822 eyes, 449 participants), the retinal pigment epithelium/Bruch's membrane complex demonstrated a statistically significant thickening (e.g., P = 6.41 × 10-92 for severe early versus no AMD) and photoreceptor layers showed a significant thinning. Autosegmented retinal layer thicknesses revealed similar associations as manually corrected values but underestimated some effects. Independent replication analysis in 1026 eyes (546 participants) confirmed associations (e.g., P = 9.38 × 10-36 for retinal pigment epithelium/Bruch's membrane complex, severe early versus no AMD).

Conclusions: This first population-based study on spectral-domain optical coherence tomography-derived retinal layer thicknesses in a total of ∼1000 individuals provides insights into the reliability of autosegmentation and layer-specific reference values for an older population. Our findings show a difference in thicknesses between early AMD and no AMD for some retinal layers, suggesting these as potential imaging biomarkers. The thinning of photoreceptor layers substantiates a photoreceptor cell loss/damage already occurring in early AMD.
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http://dx.doi.org/10.1167/iovs.18-25332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892378PMC
April 2019

Poor risk factor control in outpatients with diabetes mellitus type 2 in Germany: The DIAbetes COhoRtE (DIACORE) study.

PLoS One 2019 21;14(3):e0213157. Epub 2019 Mar 21.

Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.

Introduction: Patients with diabetes mellitus type 2 (DM2) are at high risk for micro- and macrovascular disease. Here, we explore the degree of traditional risk factor control in the baseline visit of a cohort of DM2 outpatients.

Methods: DIACORE (DIAbetes COhoRtE) is a prospective cohort study of 3000 adult DM2 outpatients. Here, we present results from the baseline visit. Sociodemographic and anthropometric variables, cardiovascular risk factors, comorbidities and medication were assessed by interview and medical exams. Serum-creatinine based estimated glomerular filtration rate (eGFRcrea) and urinary albumin-creatinine ratio (UACR) were determined for classification of chronic kidney disease (CKD). The proportion of patients with adequate control of traditional risk factors (blood pressure<140/90mmHg, HbA1c<7.5%, LDL<100mg/dl) was calculated in 2892 patients with non-missing data in 9 relevant variables within each KDIGO 2012 CKD class.

Results: In the analyzed baseline data (n = 2892, 60.2% men), mean (standard deviation) values for age, DM2 duration and HbA1c were 65.3 (9.3) years, 10.3 (8.4) years and 6.9% (1.1) respectively. Of these 2892 patients, 18.7% had CKD stage 3 or higher, 25.7% had UACR≥30mg/g. Adequate blood pressure, HbA1c and LDL control was achieved in 55.7%, 78.5% and 34.4%, respectively. In 16.4% of patients (473), all three risk factors were below recommended targets. The proportion of adequate risk factor control was similar across KDIGO eGFRcrea classes. Adequate blood pressure and HbA1c control were significantly associated with lower UACR category without and with controlling for other risk factors (p<0.0001, p = 0.0002, respectively).

Conclusion: In our study of patients with diabetes mellitus type 2, we observed a low level of risk factor control indicating potential for risk reduction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213157PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428304PMC
December 2019

Malaria in Eritrean migrants newly arrived in seven European countries, 2011 to 2016.

Euro Surveill 2019 Jan;24(5)

Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.

Global migration has resulted in a large number of asylum applications in Europe. In 2014, clusters of cases were reported among newly arrived Eritreans. This study aimed to assess malaria among Eritrean migrants in Europe from 2011 to 2016. We reviewed European migration numbers and malaria surveillance data for seven countries (Denmark, Germany, Netherlands, Norway, Sweden, Switzerland and the United Kingdom) which received 44,050 (94.3%) of 46,730 Eritreans seeking asylum in Europe in 2014. The overall number of malaria cases, predominantly , increased significantly in 2014 compared to previous years, with the largest increases in Germany (44 cases in 2013 vs 294 in 2014, p < 0.001) and Sweden (18 in 2013 vs 205 in 2014, p < 0.001). Overall, malaria incidence in Eritreans increased from 1-5 to 25 cases per 1,000, and was highest in male teenagers (50 cases/1,000). In conclusion, an exceptional increase of malaria cases occurred in Europe in 2014 and 2015, due to rising numbers of Eritreans with high incidence of arriving in Europe. Our results demonstrate potential for rapid changes in imported malaria patterns, highlighting the need for improved awareness, surveillance efforts and timely healthcare in migrants.
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http://dx.doi.org/10.2807/1560-7917.ES.2019.24.5.1800139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386211PMC
January 2019

Hepatitis A virus infections, immunisations and demographic determinants in children and adolescents, Germany.

Sci Rep 2018 11 12;8(1):16696. Epub 2018 Nov 12.

Department for Infectious Disease Epidemiology, Unit of Gastrointestinal Infections, Zoonoses, and Tropical Infections, Robert Koch Institute (RKI), D-13353, Berlin, Germany.

Hepatitis A is a vaccine-preventable disease with a global distribution. It predominantly occurs in regions with inadequate living conditions, but also affects populations in industrialised countries. Children are frequently involved in the transmission of hepatitis A virus (HAV) and thus play a central role in the epidemiology of hepatitis A. Here, we investigated HAV infections, immunisations, and associated demographic determinants in a nationwide, population-based, cross-sectional survey conducted in Germany from 2003-2006. Out of 17,640 children and adolescents, complete data sets (HAV serology, demographic information and vaccination card) were available for 12,249 (69%), all aged 3-17 years. We found protective antibody levels (>=20 IU/L) in 1,755 (14%) individuals, 1,395 (11%) were vaccinated against hepatitis A, 360 (3%) individuals were HAV seropositive without prior hepatitis A vaccination, thus indicating a previous HAV infection. Antibody prevalence (attributable to vaccination or infection) increased significantly with age. Multivariate logistic regression revealed that predominantly children and adolescents with migration background-even if they were born in Germany-are affected by HAV infections. Our results provide a rationale to emphasise existing vaccination recommendations and, moreover, to consider additional groups with a higher risk of infection for targeted vaccination, especially children with a migration background.
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http://dx.doi.org/10.1038/s41598-018-34927-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232152PMC
November 2018

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.

Euro Surveill 2018 10;23(40)

Robert Koch Institute (RKI), Berlin, Germany.

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.
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http://dx.doi.org/10.2807/1560-7917.ES.2018.23.40.1700430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178587PMC
October 2018

Incidence of notified Lyme borreliosis in Germany, 2013-2017.

Sci Rep 2018 10 8;8(1):14976. Epub 2018 Oct 8.

Department of Infectious Disease Epidemiology, Robert Koch Institute, Berlin, Germany.

Lyme borreliosis (LB) is the most commonly reported tick-borne disease in Germany. In 9/16 states, notification of erythema migrans (EM), acute neuroborreliosis (NB) and Lyme arthritis (LA) is mandatory. We describe incidence measures, time trends, geographical distribution and frequencies of manifestations to better understand LB epidemiology and target prevention measures. We used cases notified in the 9 states and confirmed by local health offices, 2013-2017, to calculate incidences by time, place and person. Altogether, we observed 56,446 cases. Disease onset peaked yearly in July. Incidence ranged from 26/100,000 (2015) to 41/100,000 (2013) with mean annual incidences 2013-2017 on district level between 0.5/100,000 and 138/100,000. Median age was 54 years with peaks in boys (5-9 years, mean incidence 36/100,000) and women (50-69 years, mean incidence 57/100,000). 95% experienced EM only, 2.7% NB and 2.1% LA. 54% were female, but more men had NB (56%) and LA (53%, p < 0.001). Hospitalisation was recorded for 10% of LA and 71% of NB cases. LB remains an important public health concern in Germany with marked regional variation. To facilitate early diagnosis and treatment, health authorities should raise awareness among physicians and promote prevention strategies among the general population: tick-bite-protection, prompt tick removal and medical consultation.
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http://dx.doi.org/10.1038/s41598-018-33136-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175818PMC
October 2018

Areas with High Hazard Potential for Autochthonous Transmission of -Associated Arboviruses in Germany.

Int J Environ Res Public Health 2018 06 15;15(6). Epub 2018 Jun 15.

Robert Koch Institute, 13353 Berlin, Germany.

The intensity and extent of transmission of arboviruses such as dengue, chikungunya, and Zika virus have increased markedly over the last decades. Autochthonous transmission of dengue and chikungunya by has been recorded in Southern Europe where the invasive mosquito was already established and viraemic travelers had imported the virus. populations are spreading northward into Germany. Here, we model the current and future climatically suitable regions for establishment in Germany, using climate data of spatially high resolution. To highlight areas where vectors and viraemic travellers are most likely to come into contact, reported dengue and chikungunya incidences are integrated at the county level. German cities with the highest likelihood of autochthonous transmission of -borne arboviruses are currently located in the western parts of the country: Freiburg im Breisgau, Speyer, and Karlsruhe, affecting about 0.5 million people. In addition, 8.8 million people live in regions considered to show elevated hazard potential assuming further spread of the mosquito: Baden-Württemberg (Upper Rhine, Lake Constance regions), southern parts of Hesse, and North Rhine-Westphalia (Lower Rhine). Overall, a more targeted and thus cost-efficient implementation of vector control measures and health surveillance will be supported by the detailed maps provided here.
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http://dx.doi.org/10.3390/ijerph15061270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025521PMC
June 2018

On the impact of different approaches to classify age-related macular degeneration: Results from the German AugUR study.

Sci Rep 2018 06 6;8(1):8675. Epub 2018 Jun 6.

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

While age-related macular degeneration (AMD) poses an important personal and public health burden, comparing epidemiological studies on AMD is hampered by differing approaches to classify AMD. In our AugUR study survey, recruiting residents from in/around Regensburg, Germany, aged 70+, we analyzed the AMD status derived from color fundus images applying two different classification systems. Based on 1,040 participants with gradable fundus images for at least one eye, we show that including individuals with only one gradable eye (n = 155) underestimates AMD prevalence and we provide a correction procedure. Bias-corrected and standardized to the Bavarian population, late AMD prevalence is 7.3% (95% confidence interval = [5.4; 9.4]). We find substantially different prevalence estimates for "early/intermediate AMD" depending on the classification system: 45.3% (95%-CI = [41.8; 48.7]) applying the Clinical Classification (early/intermediate AMD) or 17.1% (95%-CI = [14.6; 19.7]) applying the Three Continent AMD Consortium Severity Scale (mild/moderate/severe early AMD). We thus provide a first effort to grade AMD in a complete study with different classification systems, a first approach for bias-correction from individuals with only one gradable eye, and the first AMD prevalence estimates from a German elderly population. Our results underscore substantial differences for early/intermediate AMD prevalence estimates between classification systems and an urgent need for harmonization.
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http://dx.doi.org/10.1038/s41598-018-26629-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989235PMC
June 2018
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