Publications by authors named "Iris M Heid"

144 Publications

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cod.13920DOI Listing
June 2021

Sleep apnoea and incident malignancy in type 2 diabetes.

ERJ Open Res 2021 Apr 4;7(2). Epub 2021 May 4.

Dept of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.

Background: Sleep apnoea and type 2 diabetes (T2D) have been linked to malignancy. The aim of the present study was to evaluate the association between sleep apnoea and incidence of malignancy in patients with T2D.

Methods: The DIACORE (DIAbetes COhoRtE) study is a prospective, population-based cohort study in T2D patients. In the sleep disordered breathing substudy, the apnoea-hypopnoea index (AHI), oxygen desaturation index (ODI) and percentage of night-time spent with a peripheral oxygen saturation of <90% ( ) were assessed using a two-channel ambulatory monitoring device. Malignancy diagnoses were gathered using self-reported medical history data validated by medical records. Hazard ratios (HRs) for incident malignancy were derived by Cox regression adjusting for sex, age, body mass index, smoking status, alcohol intake, socioeconomic status and HbA1c.

Results: Of 1239 patients with T2D (mean age 67 years, 41% female, mean body mass index 30.9 kg·m), 79 (6.4%) were first-time diagnosed with a malignancy within a median follow-up period of 2.7 years (interquartile range 2.2-4.5 years). AHI, ODI and were not associated with incident malignancy. In subgroup analysis, females showed increased cancer risk per AHI unit (adjusted HR 1.03 per AHI unit, 95% CI 1.00-1.06; p=0.028) and severe sleep apnoea (defined as AHI ≥30 events·h; adjusted HR 4.19, 95% CI 1.39-12.77; p=0.012). This was not seen in males, and a significant interaction was observed (interaction terms p=0.048 and p=0.033, respectively).

Conclusion: Sleep apnoea was not associated with incident malignancy in T2D patients. However, stratified analysis revealed a significant association between sleep apnoea and incident malignancy in females, but not in males.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/23120541.00036-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093486PMC
April 2021

Periodic breathing is associated with blood pressure above the recommended target in patients with type 2 diabetes.

Sleep Med X 2020 Dec 7;2:100013. Epub 2020 May 7.

Department of Internal Medicine II, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.

Background: Due to its prognostic importance for patients with type 2 diabetes (DM2), current guidelines recommend a systolic <130 mm Hg and diastolic <80 mm Hg blood pressure target. Periodic breathing, a form of sleep-disordered breathing, acutely causes repetitive hypoxia, sympathetic nervous system activation as well as oscillations of heart rate and blood pressure. However, limited data on the association of periodic breathing and control of blood pressure (BP) in patients with DM2 are available. Thus, the aim of the present study was to assess whether there is an association between periodic breathing and increased BP above the recommended target in DM2.

Methods: Cross-sectional data of 679 patients with DM2 from the DIACORE-SDB sub-study were analysed for association of periodic breathing with BP. Sleep-disordered breathing was assessed with a 2-channel ambulatory monitoring device including validated automatic pattern recognition for periodic breathing. BP values were determined in a standardized manner with three repeated measurements at rest.

Results: Of the 679 analysed individuals (61% male, age 66 ± 9 years, Body Mass Index [BMI] 31.0 ± 5.4 kg/m), 11% had periodic breathing. Patients with periodic breathing had significantly higher systolic BP values (144 ± 19 mm Hg vs. 137 ± 18 mm Hg, p = 0.003). Multivariable regression analysis revealed that periodic breathing was associated with higher systolic BP (B [95% confidence interval, CI] = 4.4 [0.1; 8.7], p = 0.043) and not meeting the recommended BP target for patients with diabetes (<130/80 mmHg) (odds ratio, OR [95%CI] = 2.1 [1.1; 4.0], p = 0.026) independent of sex, age, high density lipoproteins, renal function, coronary heart disease and antihypertensive treatment.

Conclusion: Periodic breathing is associated with higher systolic BP in patients with DM2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.sleepx.2020.100013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041113PMC
December 2020

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.

Kidney Int 2021 04 31;99(4):926-939. Epub 2020 Oct 31.

Division of Nephrology, University of Washington, Seattle, Washington, USA; Kidney Research Institute, University of Washington, Seattle, Washington, USA.

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m at follow-up among those with eGFRcrea 60 mL/min/1.73m or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2020.09.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010357PMC
April 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12920-020-00760-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449002PMC
August 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gepi.22336DOI Listing
October 2020

Quantification of the overall contribution of gene-environment interaction for obesity-related traits.

Nat Commun 2020 03 13;11(1):1385. Epub 2020 Mar 13.

University Center for Primary Care and Public Health, University of Lausanne, Lausanne, 1010, Switzerland.

The growing sample size of genome-wide association studies has facilitated the discovery of gene-environment interactions (GxE). Here we propose a maximum likelihood method to estimate the contribution of GxE to continuous traits taking into account all interacting environmental variables, without the need to measure any. Extensive simulations demonstrate that our method provides unbiased interaction estimates and excellent coverage. We also offer strategies to distinguish specific GxE from general scale effects. Applying our method to 32 traits in the UK Biobank reveals that while the genetic risk score (GRS) of 376 variants explains 5.2% of body mass index (BMI) variance, GRSxE explains an additional 1.9%. Nevertheless, this interaction holds for any variable with identical correlation to BMI as the GRS, hence may not be GRS-specific. Still, we observe that the global contribution of specific GRSxE to complex traits is substantial for nine obesity-related measures (including leg impedance and trunk fat-free mass).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-15107-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070002PMC
March 2020

Heterogeneity in Obesity: Genetic Basis and Metabolic Consequences.

Curr Diab Rep 2020 01 22;20(1). Epub 2020 Jan 22.

Institute for Primary Care and Public Health, University of Lausanne, Lausanne, Switzerland.

Purpose Of Review: Our review provides a brief summary of the most recent advances towards the identification of the genetic basis of specific aspects of obesity and the quantification of their consequences on health. We also highlight the most promising avenues to be explored in the future.

Recent Findings: While obesity has been demonstrated to lead to adverse cardio-metabolic consequences, the determinants of inter-individual variability remain largely unknown. The elucidation of the molecular underpinnings of this relationship is hampered by the extremely heterogeneous nature of obesity as a human trait. Recent technological advances have facilitated a more in-depth characterization of body composition at large-scale. At the pace of current data acquisition and resolution, it is realistic to improve characterization of obesity and to advise individuals based on detailed body composition combined with tissue-specific molecular signatures. Individualized predictions of health implications would enable more personalized and effective public health interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11892-020-1285-4DOI Listing
January 2020

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Nat Genet 2019 10 2;51(10):1459-1474. Epub 2019 Oct 2.

Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0504-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858555PMC
October 2019

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.

Nat Commun 2019 09 11;10(1):4130. Epub 2019 Sep 11.

Department of Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT, USA.

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-11576-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739370PMC
September 2019

A catalog of genetic loci associated with kidney function from analyses of a million individuals.

Nat Genet 2019 06 31;51(6):957-972. Epub 2019 May 31.

Diabetes and Cardiovascular Disease-Genetic Epidemiology, Department of Clincial Sciences in Malmö, Lund University, Malmö, Sweden.

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0407-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698888PMC
June 2019

Response misclassification in studies on bilateral diseases.

Biom J 2019 07 14;61(4):1033-1048. Epub 2019 May 14.

Statistical Consulting Unit StaBLab, Department of Statistics, LMU Munich, München, Germany.

Misclassification in binary outcomes can severely bias effect estimates of regression models when the models are naively applied to error-prone data. Here, we discuss response misclassification in studies on the special class of bilateral diseases. Such diseases can affect neither, one, or both entities of a paired organ, for example, the eyes or ears. If measurements are available on both organ entities, disease occurrence in a person is often defined as disease occurrence in at least one entity. In this setting, there are two reasons for response misclassification: (a) ignorance of missing disease assessment in one of the two entities and (b) error-prone disease assessment in the single entities. We investigate the consequences of ignoring both types of response misclassification and present an approach to adjust the bias from misclassification by optimizing an adequate likelihood function. The inherent modelling assumptions and problems in case of entity-specific misclassification are discussed. This work was motivated by studies on age-related macular degeneration (AMD), a disease that can occur separately in each eye of a person. We illustrate and discuss the proposed analysis approach based on real-world data of a study on AMD and simulated data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bimj.201900039DOI Listing
July 2019

On the differences between mega- and meta-imputation and analysis exemplified on the genetics of age-related macular degeneration.

Genet Epidemiol 2019 07 23;43(5):559-576. Epub 2019 Apr 23.

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

While current genome-wide association analyses often rely on meta-analysis of study-specific summary statistics, individual participant data (IPD) from multiple studies increase options for modeling. When multistudy IPD is available, however, it is unclear whether this data is to be imputed and modeled across all participants (mega-imputation and mega-analysis) or study-specifically (meta-imputation and meta-analysis). Here, we investigated different approaches toward imputation and analysis using 52,189 subjects from 25 studies of the International Age-related Macular Degeneration (AMD) Genomics Consortium including, 16,144 AMD cases and 17,832 controls for association analysis. From 27,448,454 genetic variants after 1,000-Genomes-based imputation, mega-imputation yielded ~400,000 more variants with high imputation quality (mostly rare variants) compared to meta-imputation. For AMD signal detection (P < 5 × 10 ) in mega-imputed data, most loci were detected with mega-analysis without adjusting for study membership (40 loci, including 34 known); we considered these loci genuine, since genetic effects and P-values were comparable across analyses. In meta-imputed data, we found 31 additional signals, mostly near chromosome tails or reference panel gaps, which disappeared after accounting for interaction of whole-genome amplification (WGA) with study membership or after excluding studies with WGA-participants. For signal detection with multistudy IPD, we recommend mega-imputation and mega-analysis, with meta-imputation followed by meta-analysis being a computationally appealing alternative.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gepi.22204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619271PMC
July 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213157PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428304PMC
December 2019

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Nat Genet 2019 03 18;51(3):452-469. Epub 2019 Feb 18.

Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0334-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560635PMC
March 2019

Daytime napping and diabetes-associated kidney disease.

Sleep Med 2019 02 25;54:205-212. Epub 2018 Nov 25.

Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany. Electronic address:

Background: Diabetes-associated Kidney Disease (DKD) is a common comorbidity in patients with type 2 diabetes. The present study investigates whether daytime sleeping duration in patients, ill with type 2 diabetes, is associated with DKD.

Methods: A total of 733 outpatients of the cross-sectional baseline survey of the DIACORE study were analyzed with respect to their self-reported daytime sleeping duration, assessed by a standardized questionnaire. DKD was defined as eGFR <60 ml/min/1.73 m and/or urinary albumin-to-creatinine-ratio (UACR) > 30 mg/g.

Results: Mean daytime sleeping duration was 17 ± 27 min. With increasing daytime sleeping duration a statistically significant decrease in eGFR (p = 0.002) and increase in UACR (p < 0.001) were found, respectively. Prevalence of DKD was significantly higher in patients with longer daytime sleeping duration (31% in patients not napping, 40% in patients napping less than 30 min, 47% in patients napping 30-60 min, 56% in patients napping 60 min or more; p = 0.001). After accounting for known modulators (Age, sex, BMI, waist-hip-ratio, systolic and diastolic blood pressure, physical activity, diabetes duration, HbA1c, homeostasis model assessment (HOMA-Index), nighttime sleeping duration, apnea-hypopnea-index (AHI), Epworth Sleepiness Scale (ESS)), longer daytime sleeping duration was significantly associated with impaired eGFR [B (95% CI) = -0.05 (-0.09; 0.00), p = 0.044] and increased UACR [B (95% CI) = 0.01 (0.01; 0.02), p < 0.001], respectively.

Conclusion: Increased daytime sleeping duration is significantly associated with reduced eGFR and higher UACR, independent of known modulators of DKD. The direction of this relationship remains unclear.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.sleep.2018.10.034DOI Listing
February 2019

Views of ophthalmologists on the genetics of age-related macular degeneration: Results of a qualitative study.

PLoS One 2018 20;13(12):e0209328. Epub 2018 Dec 20.

Medical Sociology, Institute for Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.

Background: Age-related macular degeneration (AMD) is the leading cause of blindness in industrialized countries. It is a multifactorial disease of the retina modified by environmental/individual (e.g. smoking) and genetic factors. 34 independent genomic loci are associated with the risk to develop AMD; an interaction between smoking and genetics is currently investigated. It is unclear how the knowledge on the strong genetic component has entered the knowledge base of practicing ophthalmologists, and how they inform and counsel their (AMD) patients about it. In this study, we explore the ophthalmologists' view on AMD genetics, and their inclination towards communicating genetic risks to patients.

Methods: We recruited a purposive sample of thirty German ophthalmologists (office based: n = 15, hospital employees: n = 15, f:8/30), who took part in a recorded semi-standardized interview. Transcripts were analyzed using content analysis.

Results: The majority of office-based ophthalmologists claimed to be unfamiliar with genetics of AMD, in contrast to hospital-affiliated ophthalmologists. Both office and hospital ophthalmologists were convinced that genetics lacks practical relevance in everyday patient care. Many withhold information on heritability or genetic background of AMD from patients and their relatives, for fear of unsettling those individuals. The relevance of the genetic component of AMD or an individuals' high genetic risk for prevention, e.g. screening or lifestyle modifications in persons with adverse genetic profile, was rated low.

Conclusion: Developing genetic educational programs tailored to the routine care of ophthalmologists may be indicated, as well as a better two-way communication between research and practice. Exploring patient views about their expectations to being informed about genetic disease etiology, or about their individual risk, would help inform communication strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209328PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301605PMC
May 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-26629-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989235PMC
June 2018

Association of sleep-disordered breathing with severe chronic vascular disease in patients with type 2 diabetes.

Sleep Med 2018 08 14;48:53-60. Epub 2018 May 14.

Department of Internal Medicine II, University Medical Center Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. Electronic address:

Background: Severe chronic vascular disease (CVD) is a major cause of co-morbidity and mortality in patients with type 2 diabetes (DM2). Sleep-disordered breathing (SDB) has been linked to CVD in the general population due to enhanced sympathetic activation, oxidative stress, endothelial dysfunction, and hypertension; however data for DM2 patients is scarce. Therefore, the aim of the present analysis to assess whether SDB is associated with CVD in patients with DM2, independent of other known associated factors.

Methods: We analyzed cross-sectional data of 679 patients with DM2 from the DIACORE-SDB sub-study for association of SDB with CVD. SDB was assessed with a validated 2-channel ambulatory monitoring device. CVD was ascertained as a previous diagnosis of peripheral artery disease (PAD), coronary artery disease (CAD), or stroke via medical records and general practitioners.

Results: Of the analyzed 679 patients, 228 (34%) had SDB (respiratory event index [REI] ≥15/hour); and were significantly more often affected by CVD than patients without SDB (38% vs. 23%, p < 0.01; PAD 7% vs. 2%, p = 0.01; CAD 27% vs. 18%, p = 0.01; stroke 11% vs. 6%, p = 0.07). Regression analysis accounting for known modulators of CVD, such as age, body-mass index, systolic blood pressure, duration of DM2, HbA1c, smoking status, and low-density lipoprotein showed that the REI was independently associated with CVD (OR 1.099 per 5 REI points; 95%CI = [1.024, 1.179]).

Conclusions: In patients with DM2, SDB is significantly associated with CVD, independent of other known modulators of atherosclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.sleep.2018.05.001DOI Listing
August 2018

Association of Genetic Variants With Response to Anti-Vascular Endothelial Growth Factor Therapy in Age-Related Macular Degeneration.

JAMA Ophthalmol 2018 08;136(8):875-884

Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, England.

Importance: Visual acuity (VA) outcomes differ considerably among patients with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs. Identification of pharmacogenetic associations may help clinicians understand the mechanisms underlying this variability as well as pave the way for personalized treatment in nAMD.

Objective: To identify genetic factors associated with variability in the response to anti-VEGF therapy for patients with nAMD.

Design, Setting, And Participants: In this multicenter genome-wide association study, 678 patients with nAMD with genome-wide genotyping data were included in the discovery phase; 1380 additional patients with nAMD were genotyped for selected common variants in the replication phase. All participants received 3 monthly injections of bevacizumab or ranibizumab. Clinical data were evaluated for inclusion/exclusion criteria from October 2014 to October 2015, followed by data analysis from October 2015 to February 2016. For replication cohort genotyping, clinical data collection and analysis (including meta-analysis) was performed from March 2016 to April 2017.

Main Outcomes And Measures: Change in VA after the loading dose of 3 monthly anti-VEGF injections compared with baseline.

Results: Of the 2058 included patients, 1210 (58.8%) were women, and the mean (SD) age across all cohorts was 78 (7.4) years. Patients included in the discovery cohort and most of the patients in the replication cohorts were of European descent. The mean (SD) baseline VA was 51.3 (20.3) Early Treatment Diabetic Retinopathy Study (ETDRS) score letters, and the mean (SD) change in VA after the loading dose of 3 monthly injections was a gain of 5.1 (13.9) ETDRS score letters (ie, 1-line gain). Genome-wide single-variant analyses of common variants revealed 5 independent loci that reached a P value less than 10 × 10-5. After replication and meta-analysis of the lead variants, rs12138564 located in the CCT3 gene remained nominally associated with a better treatment outcome (ETDRS letter gain, 1.7; β, 0.034; SE, 0.008; P = 1.38 × 10-5). Genome-wide gene-based optimal unified sequence kernel association test of rare variants showed genome-wide significant associations for the C10orf88 (P = 4.22 × 10-7) and UNC93B1 (P = 6.09 × 10-7) genes, in both cases leading to a worse treatment outcome. Patients carrying rare variants in the C10orf88 and UNC93B1 genes lost a mean (SD) VA of 30.6 (17.4) ETDRS score letters (ie, loss of 6.09 lines) and 26.5 (13.8) ETDRS score letters (ie, loss of 5.29 lines), respectively, after 3 months of anti-VEGF treatment.

Conclusions And Relevance: We propose that there is a limited contribution of common genetic variants to variability in nAMD treatment response. Our results suggest that rare protein-altering variants in the C10orf88 and UNC93B1 genes are associated with a worse response to anti-VEGF therapy in patients with nAMD, but these results require further validation in other cohorts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2018.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142943PMC
August 2018

A joint view on genetic variants for adiposity differentiates subtypes with distinct metabolic implications.

Nat Commun 2018 05 16;9(1):1946. Epub 2018 May 16.

Department of Genetic Epidemiology, University of Regensburg, D-93051, Regensburg, Germany.

The problem of the genetics of related phenotypes is often addressed by analyzing adjusted-model traits, but such traits warrant cautious interpretation. Here, we adopt a joint view of adiposity traits in ~322,154 subjects (GIANT consortium). We classify 159 signals associated with body mass index (BMI), waist-to-hip ratio (WHR), or WHR adjusted for BMI (WHRadjBMI) at P < 5 × 10, into four classes based on the direction of their effects on BMI and WHR. Our classes help differentiate adiposity genetics with respect to anthropometry, fat depots, and metabolic health. Class-specific Mendelian randomization reveals that variants associated with both WHR-decrease and BMI increase are linked to metabolically rather favorable adiposity through beneficial hip fat. Class-specific enrichment analyses implicate digestive systems as a pathway in adiposity genetics. Our results demonstrate that WHRadjBMI variants capture relevant effects of "unexpected fat distribution given the BMI" and that a joint view of the genetics underlying related phenotypes can inform on important biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-04124-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956079PMC
May 2018

The role of genetic variation of human metabolism for BMI, mental traits and mental disorders.

Mol Metab 2018 06 3;12:1-11. Epub 2018 Apr 3.

Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. Electronic address:

Objective: The aim was to assess whether loci associated with metabolic traits also have a significant role in BMI and mental traits/disorders METHODS: We first assessed the number of single nucleotide polymorphisms (SNPs) with genome-wide significance for human metabolism (NHGRI-EBI Catalog). These 516 SNPs (216 independent loci) were looked-up in genome-wide association studies for association with body mass index (BMI) and the mental traits/disorders educational attainment, neuroticism, schizophrenia, well-being, anxiety, depressive symptoms, major depressive disorder, autism-spectrum disorder, attention-deficit/hyperactivity disorder, Alzheimer's disease, bipolar disorder, aggressive behavior, and internalizing problems. A strict significance threshold of p < 6.92 × 10 was based on the correction for 516 SNPs and all 14 phenotypes, a second less conservative threshold (p < 9.69 × 10) on the correction for the 516 SNPs only.

Results: 19 SNPs located in nine independent loci revealed p-values < 6.92 × 10; the less strict criterion was met by 41 SNPs in 24 independent loci. BMI and schizophrenia showed the most pronounced genetic overlap with human metabolism with three loci each meeting the strict significance threshold. Overall, genetic variation associated with estimated glomerular filtration rate showed up frequently; single metabolite SNPs were associated with more than one phenotype. Replications in independent samples were obtained for BMI and educational attainment.

Conclusions: Approximately 5-10% of the regions involved in the regulation of blood/urine metabolite levels seem to also play a role in BMI and mental traits/disorders and related phenotypes. If validated in metabolomic studies of the respective phenotypes, the associated blood/urine metabolites may enable novel preventive and therapeutic strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmet.2018.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001916PMC
June 2018

A Deep Learning Algorithm for Prediction of Age-Related Eye Disease Study Severity Scale for Age-Related Macular Degeneration from Color Fundus Photography.

Ophthalmology 2018 09 10;125(9):1410-1420. Epub 2018 Apr 10.

Institute of Human Genetics, University of Regensburg, Regensburg, Germany. Electronic address:

Purpose: Age-related macular degeneration (AMD) is a common threat to vision. While classification of disease stages is critical to understanding disease risk and progression, several systems based on color fundus photographs are known. Most of these require in-depth and time-consuming analysis of fundus images. Herein, we present an automated computer-based classification algorithm.

Design: Algorithm development for AMD classification based on a large collection of color fundus images. Validation is performed on a cross-sectional, population-based study.

Participants: We included 120 656 manually graded color fundus images from 3654 Age-Related Eye Disease Study (AREDS) participants. AREDS participants were >55 years of age, and non-AMD sight-threatening diseases were excluded at recruitment. In addition, performance of our algorithm was evaluated in 5555 fundus images from the population-based Kooperative Gesundheitsforschung in der Region Augsburg (KORA; Cooperative Health Research in the Region of Augsburg) study.

Methods: We defined 13 classes (9 AREDS steps, 3 late AMD stages, and 1 for ungradable images) and trained several convolution deep learning architectures. An ensemble of network architectures improved prediction accuracy. An independent dataset was used to evaluate the performance of our algorithm in a population-based study.

Main Outcome Measures: κ Statistics and accuracy to evaluate the concordance between predicted and expert human grader classification.

Results: A network ensemble of 6 different neural net architectures predicted the 13 classes in the AREDS test set with a quadratic weighted κ of 92% (95% confidence interval, 89%-92%) and an overall accuracy of 63.3%. In the independent KORA dataset, images wrongly classified as AMD were mainly the result of a macular reflex observed in young individuals. By restricting the KORA analysis to individuals >55 years of age and prior exclusion of other retinopathies, the weighted and unweighted κ increased to 50% and 63%, respectively. Importantly, the algorithm detected 84.2% of all fundus images with definite signs of early or late AMD. Overall, 94.3% of healthy fundus images were classified correctly.

Conclusions: Our deep learning algoritm revealed a weighted κ outperforming human graders in the AREDS study and is suitable to classify AMD fundus images in other datasets using individuals >55 years of age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ophtha.2018.02.037DOI Listing
September 2018

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet 2018 05;50(5):766-767

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

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0082-3DOI Listing
May 2018
-->