344 research outputs found
CEP906835 Supplemental table 1 - Supplemental material for Mitochondrial genome-wide association study of migraine – the HUNT Study
No full textSupplemental material, CEP906835 Supplemental table 1 for Mitochondrial genome-wide association study of migraine – the HUNT Study by Sigrid Børte, John-Anker Zwart, Anne Heidi Skogholt, Maiken Elvestad Gabrielsen, Laurent F Thomas, Lars G Fritsche, Ida Surakka, Jonas B Nielsen, Wei Zhou, Brooke N Wolford, Magnus D Vigeland, Knut Hagen, Espen Saxhaug Kristoffersen, Dale R Nyholt, Daniel I Chasman, Ben M Brumpton, Cristen J Willer and Bendik S Winsvold in Cephalalgia</p
Imbalance of complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age related macular degeneration (AMD)
No full textAn imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD)
No full textA frequent deletion of complement factor H (CFH)-related genes CFHR3 and CFHR1 (Delta CFHR3/CFHR1) is considered to have a protective effect against age-related macular degeneration (AMD), although the underlying mechanism remains elusive. The deletion seems to be linked to one of the two protective CFH haplotypes which are both tagged by the protective allele of single nucleotide polymorphism rs2274700 (CFH:A473A). In a German cohort of 530 AMD patients, we now show that protection against AMD conferred by Delta CFHR3/CFHR1 is independent of the effects of rs2274700 and rs1061170 (CFH:Y402H). This suggests a functional role of CFHR1 and/or CFHR3 in disease pathogenesis. We therefore characterized the CFHR3 function and identified CFHR3 as a novel human complement regulator that inhibits C3 convertase activity. CFHR3 displays anti-inflammatory effects by blocking C5a generation and C5a-mediated chemoattraction of neutrophils. In addition, CFHR3 and CFHR1 compete with factor H for binding to the central complement component C3. Thus, deficiency of CFHR3 and CFHR1 results in a loss of complement control but enhances local regulation by factor H. Our findings allude to a critical balance between the complement regulators CFHR3, CFHR1 and factor H and further emphasize the central role of complement regulation in AMD pathology
Modelling the Genetic Risk in Age-Related Macular Degeneration
No full textLate-stage age-related macular degeneration (AMD) is a common sight-threatening disease of the central retina affecting approximately 1 in 30 Caucasians. Besides age and smoking, genetic variants from several gene loci have reproducibly been associated with this condition and likely explain a large proportion of disease. Here, we developed a genetic risk score (GRS) for AMD based on 13 risk variants from eight gene loci. The model exhibited good discriminative accuracy, area-under-curve (AUC) of the receiver-operating characteristic of 0.820, which was confirmed in a cross-validation approach. Noteworthy, younger AMD patients aged below 75 had a significantly higher mean GRS (1.87, 95% CI: 1.69-2.05) than patients aged 75 and above (1.45, 95% CI: 1.36-1.54). Based on five equally sized GRS intervals, we present a risk classification with a relative AMD risk of 64.0 (95% CI: 14.11-1131.96) for individuals in the highest category (GRS 3.44-5.18, 0.5% of the general population) compared to subjects with the most common genetic background (GRS -0.05-1.70, 40.2% of general population). The highest GRS category identifies AMD patients with a sensitivity of 7.9% and a specificity of 99.9% when compared to the four lower categories. Modeling a general population around 85 years of age, 87.4% of individuals in the highest GRS category would be expected to develop AMD by that age. In contrast, only 2.2% of individuals in the two lowest GRS categories which represent almost 50% of the general population are expected to manifest AMD. Our findings underscore the large proportion of AMD cases explained by genetics particularly for younger AMD patients. The five-category risk classification could be useful for therapeutic stratification or for diagnostic testing purposes once preventive treatment is available
Exploring healthy retinal aging with deep learning
No full textPurpose
To study the individual course of retinal changes caused by healthy aging using deep learning.
Design
Retrospective analysis of a large data set of retinal OCT images.
Participants
A total of 85 709 adults between the age of 40 and 75 years of whom OCT images were acquired in the scope of the UK Biobank population study.
Methods
We created a counterfactual generative adversarial network (GAN), a type of neural network that learns from cross-sectional, retrospective data. It then synthesizes high-resolution counterfactual OCT images and longitudinal time series. These counterfactuals allow visualization and analysis of hypothetical scenarios in which certain characteristics of the imaged subject, such as age or sex, are altered, whereas other attributes, crucially the subject’s identity and image acquisition settings, remain fixed.
Main Outcome Measures
Using our counterfactual GAN, we investigated subject-specific changes in the retinal layer structure as a function of age and sex. In particular, we measured changes in the retinal nerve fiber layer (RNFL), combined ganglion cell layer plus inner plexiform layer (GCIPL), inner nuclear layer to the inner boundary of the retinal pigment epithelium (INL-RPE), and retinal pigment epithelium (RPE).
Results
Our counterfactual GAN is able to smoothly visualize the individual course of retinal aging. Across all counterfactual images, the RNFL, GCIPL, INL-RPE, and RPE changed by −0.1 μm ± 0.1 μm, −0.5 μm ± 0.2 μm, −0.2 μm ± 0.1 μm, and 0.1 μm ± 0.1 μm, respectively, per decade of age. These results agree well with previous studies based on the same cohort from the UK Biobank population study. Beyond population-wide average measures, our counterfactual GAN allows us to explore whether the retinal layers of a given eye will increase in thickness, decrease in thickness, or stagnate as a subject ages.
Conclusion
This study demonstrates how counterfactual GANs can aid research into retinal aging by generating high-resolution, high-fidelity OCT images, and longitudinal time series. Ultimately, we envision that they will enable clinical experts to derive and explore hypotheses for potential imaging biomarkers for healthy and pathologic aging that can be refined and tested in prospective clinical trials.
Financial Disclosure(s)
Proprietary or commercial disclosure may be found after the references
Features of intermediate and late dry age-related macular degeneration on adaptive optics ophthalmoscopy: Pinnacle Study Report 8
No full textBackground/Objectives: adaptive optics ophthalmoscopy (AOO) has the potential to provide insights into AMD pathology and to assess the risk of progression. We aim to utilise AOO to describe detailed features of intermediate AMD and to characterise microscopic changes during atrophy development.Subjects/Methods: patients with intermediate AMD were recruited into PINNACLE, a prospective observational cohort study. Participants underwent flood-illumination AOO using the commercially available rtx1 camera. AOO images were qualitatively assessed and correlated with clinical imaging including optical coherence tomography (OCT) and infrared scanning laser ophthalmoscopy.Results: the visibility of cone mosaic was generally compromised in eyes with intermediate AMD. We observed an association between the visibility of cone mosaic on AOO and the detection of a well-defined normal interdigitation zone on OCT. Drusen subtypes were identified on AOO as variations in reflectance at the edge and/or the centre of the druse. The absence of a hyperreflective margin was associated with the loss of the overlying ellipsoid zone on OCT prior to the collapse of the druse. With progressive attenuation of the retinal pigment epithelium and loss of photoreceptor layers, the drusenoid lesion appeared more hyperreflective with very distinctive edges.Conclusions: this cross-sectional study supports the potential value of AOO for providing information on intermediate AMD and the development of atrophic lesions that cannot be seen in conventional imaging modalities. The ongoing longitudinal PINNACLE study is assessing the significance of the described findings
Functional outcomes across high-risk OCT-based phenotypes in intermediate age-related macular degeneration in the prospective PINNACLE study
No full textPurpose : to examine how individual OCT biomarkers predict functional outcomes in eyes with intermediate (i)AMD and to investigate whether stratifying eyes by biomarkers identifies phenotypes of iAMD with impaired visual function.Methods : from the baseline cohort of the PINNACLE trial, 190 patients (247 eyes) underwent OCT imaging, standardized 24-point microperimetry, BCVA and LLVA testing. OCT volumes were assessed by retinal experts for the presence of morphologic features, including hyperreflective foci (HRF), subretinal drusenoid deposits (SDD), hyporeflective drusen cores, refractile drusen, double-layer sign, vitelliform material and the atrophic markers, outer plexiform layer subsidence, hyporeflective wedge, incomplete retinal pigment epithelium and outer retinal atrophy (iRORA). Deep learning algorithms quantified drusen volume, outer nuclear layer (ONL) and ellipsoid zone (EZ) thickness. Linear mixed-effect models (LMMs) evaluated associations between each biomarker and functional outcomes. Eyes were then stratified into groups based on significant OCT features (see Figure 1), with each eye assigned to a single group. Functional outcomes were compared across the four defined groups using LMMs.Results : in the multivariable LMM, SDD and atrophic markers were associated with significantly lower mean retinal sensitivity (-0.718 dB [p=0.022] and -0.893 dB [p=0.009], respectively). Higher drusen volume and lower ONL and EZ thickness also corresponded to lower sensitivity (-0.003 dB/nL [p=0.003], -0.053 dB/µm [p=0.027], and -0.183 dB/µm [p=0.017], respectively). BCVA and LLVA decreased with increasing drusen volume (-0.006 ltrs/nL [p=0.017] and -0.014 ltrs/nL [p<0.001]). LLVA also decreased with HRF (-3.717 ltrs [p=0.003]). Significant retinal sensitivity differences were found between the structurally defined groups (A:C [1.145 dB, p=0.003], A:D [1.911 dB, p<0.001], B:D [1.009 dB, p=0.024], C:D [0.766 dB, p=0.038]). Predicted outcomes for BCVA and LLVA were significantly lower for groups with signs of early atrophy.Conclusions : combining detailed analysis of structural OCT biomarkers with functional measures characterizes different disease stages in iAMD and highlights the existence of distinct phenotypes with significant functional impairment. Stratifying patients by high-risk drusen and atrophy markers may enhance patient selection and risk assessment
Systemic complement activation in age-related macular degeneration.
No full textDysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p<0.001), were significantly elevated in AMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H. Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes.This study is the first to show systemic complement activation in AMD patients. This suggests that AMD is a systemic disease with local disease manifestation at the ageing macula. Furthermore, the data provide evidence for an association of systemic activation of the alternative complement pathway with genetic variants of CFH that were previously linked to AMD susceptibility
An analytic framework for exploring sampling and observation process biases in genome and phenome‐wide association studies using electronic health records
No full textPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155932/1/sim8524.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155932/2/SIM8524-sup-0001-supinfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155932/3/sim8524_am.pd
European inflation expectations dynamics
No full textThis paper investigates the relevance of the sticky information model of Mankiw and Reis (2002) and Carroll (2003) for four major European economies (France, Germany, Italy and the United Kingdom). As opposed to the benchmark rational expectation models, households in the sticky information environment update their expectations sporadically rather than instantaneously owing to the costs of acquiring and processing information. We estimate two alternative parametrizations of the sticky information model which differ in the stationarity assumptions about the underlying series. Using survey data on households? and experts? inflation expectations, we find that the model adequately captures the dynamics of household inflation expectations. Both parametrizations imply comparable speeds of information updating for the European households as was previously found in the US, on average roughly once a year. --Inflation,expectations,sticky information,inflation persistence
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