Genetic variants in genome-wide association studies (GWAS) are tested for disease association mostly using simple regression, one variant at a time. Standard approaches to improve power in detecting ...disease-associated SNPs use multiple regression with Bayesian variable selection in which a sparsity-enforcing prior on effect sizes is used to avoid overtraining and all effect sizes are integrated out for posterior inference. For binary traits, the logistic model has not yielded clear improvements over the linear model. For multi-SNP analysis, the logistic model required costly and technically challenging MCMC sampling to perform the integration. Here, we introduce the quasi-Laplace approximation to solve the integral and avoid MCMC sampling. We expect the logistic model to perform much better than multiple linear regression except when predicted disease risks are spread closely around 0.5, because only close to its inflection point can the logistic function be well approximated by a linear function. Indeed, in extensive benchmarks with simulated phenotypes and real genotypes, our Bayesian multiple LOgistic REgression method (B-LORE) showed considerable improvements (1) when regressing on many variants in multiple loci at heritabilities ≥ 0.4 and (2) for unbalanced case-control ratios. B-LORE also enables meta-analysis by approximating the likelihood functions of individual studies by multivariate normal distributions, using their means and covariance matrices as summary statistics. Our work should make sparse multiple logistic regression attractive also for other applications with binary target variables. B-LORE is freely available from: https://github.com/soedinglab/b-lore.
C-reactive protein (CRP) and coronary heart disease (CHD) have been the subject of intensive investigations over the last decades. Epidemiological studies have shown an association between moderately ...elevated CRP levels and incident CHD whereas genetic studies have shown that polymorphisms associated with elevated CRP levels do not increase the risk of ischemic vascular disease, suggesting that CRP might be a bystander rather than a causal factor in the progress of atherosclerosis. Beside all those epidemiological and genetic studies, the experimental investigations also try to reveal the role of CRP in the progress of atherosclerosis. This review will highlight the complex results of genomic, epidemiological, and experimental studies on CRP and will show why further studies investigating the relationship between CRP and atherosclerosis might be needed.
Cardiovascular diseases (CVD) annually take almost 18 million lives worldwide. Most lethal events occur months or years after the initial presentation. Indeed, many patients experience repeated ...complications or require multiple interventions (recurrent events). Apart from affecting the individual, this leads to high medical costs for society. Personalized treatment strategies aiming at prediction and prevention of recurrent events rely on early diagnosis and precise prognosis. Complementing the traditional environmental and clinical risk factors, multi-omics data provide a holistic view of the patient and disease progression, enabling studies to probe novel angles in risk stratification. Specifically, predictive molecular markers allow insights into regulatory networks, pathways, and mechanisms underlying disease. Moreover, artificial intelligence (AI) represents a powerful, yet adaptive, framework able to recognize complex patterns in large-scale clinical and molecular data with the potential to improve risk prediction. Here, we review the most recent advances in risk prediction of recurrent cardiovascular events, and discuss the value of molecular data and biomarkers for understanding patient risk in a systems biology context. Finally, we introduce explainable AI which may improve clinical decision systems by making predictions transparent to the medical practitioner.
Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that ...associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.
Summary Background A sexual dimorphism exists in the incidence and prevalence of coronary artery disease—men are more commonly affected than are age-matched women. We explored the role of the Y ...chromosome in coronary artery disease in the context of this sexual inequity. Methods We genotyped 11 markers of the male-specific region of the Y chromosome in 3233 biologically unrelated British men from three cohorts: the British Heart Foundation Family Heart Study (BHF-FHS), West of Scotland Coronary Prevention Study (WOSCOPS), and Cardiogenics Study. On the basis of this information, each Y chromosome was tracked back into one of 13 ancient lineages defined as haplogroups. We then examined associations between common Y chromosome haplogroups and the risk of coronary artery disease in cross-sectional BHF-FHS and prospective WOSCOPS. Finally, we undertook functional analysis of Y chromosome effects on monocyte and macrophage transcriptome in British men from the Cardiogenics Study. Findings Of nine haplogroups identified, two (R1b1b2 and I) accounted for roughly 90% of the Y chromosome variants among British men. Carriers of haplogroup I had about a 50% higher age-adjusted risk of coronary artery disease than did men with other Y chromosome lineages in BHF-FHS (odds ratio 1·75, 95% CI 1·20–2·54, p=0·004), WOSCOPS (1·45, 1·08–1·95, p=0·012), and joint analysis of both populations (1·56, 1·24–1·97, p=0·0002). The association between haplogroup I and increased risk of coronary artery disease was independent of traditional cardiovascular and socioeconomic risk factors. Analysis of macrophage transcriptome in the Cardiogenics Study revealed that 19 molecular pathways showing strong differential expression between men with haplogroup I and other lineages of the Y chromosome were interconnected by common genes related to inflammation and immunity, and that some of them have a strong relevance to atherosclerosis. Interpretation The human Y chromosome is associated with risk of coronary artery disease in men of European ancestry, possibly through interactions of immunity and inflammation. Funding British Heart Foundation; UK National Institute for Health Research; LEW Carty Charitable Fund; National Health and Medical Research Council of Australia; European Union 6th Framework Programme; Wellcome Trust.
Abstract
This document describes the contribution of clinical criteria to the interpretation of genetic variants using heritable Mendelian cardiomyopathies as an example. The aim is to assist ...cardiologists in defining the clinical contribution to a genetic diagnosis and the interpretation of molecular genetic reports. The identification of a genetic variant of unknown or uncertain significance is a limitation of genetic testing, but current guidelines for the interpretation of genetic variants include essential contributions from clinical family screening that can establish a de novo assignment of the variant or its segregation with the phenotype in the family. A partnership between clinicians and patients helps to solve major uncertainties and provides reliable and clinically actionable information.
Graphical Abstract
Impact of the cardiologic phenotyping of probands and relatives on ACMG criteria. The ideal ‘drawing’ of the family pedigree is complete and correct when all available family members have been clinically evaluated and, eventually, longitudinally monitored. *Cardiologists and geneticists may add their own experience, data, and local population information. oEndomyocardial biopsy - anti-GB3 immuno-stain (positive brown; §Typical ultrastructural pattern. DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; RCM = restrictive cardiomyopathy; ACM = arrhythmogenic cardiomyopathy; ASD = atrial septal defect; VSD = ventricular septal defect; GB3 = globotriaosylceramide.
Zusammenfassung
Die molekulargenetische Untersuchung ist bei einigen kardiovaskulären Erkrankungen ein wichtiger Baustein der Diagnostik. Dabei hängt die diagnostische Wertigkeit der genetischen ...Untersuchung maßgeblich von anamnestischen und klinischen Faktoren wie dem Vorliegen einer positiven Familienanamnese und dem Krankheitsphänotyp ab. Bei kardiovaskulären Erkrankungen mit hohen Mutationsdetektionsraten wie der hypertrophen Kardiomyopathie oder primären Arrhythmiesyndromen (Long-QT-Syndrom, katecholaminerge polymorphe ventrikuläre Tachykardie) sollte die genetische Analyse zum Standard-Work-up gehören. Einen besonderen Stellenwert hat die genetische Diagnostik darüber hinaus bei der systematischen Untersuchung von Familienangehörigen der Betroffenen (Kaskadenscreening), um asymptomatische Mutationsträger rechtzeitig erkennen und präventiv therapieren zu können. Eine spezielle Indikation zur genetischen Diagnostik stellt die molekulare Autopsie, also die postmortale molekulargenetische DNA-Analyse dar. Sie dient v. a. beim plötzlichen Herztod der Todesursachenaufklärung durch den Nachweis krankheitsspezifischer Genmutationen. Bei selektivem Einsatz und sorgfältiger Interpretation der Ergebnisse können die molekulargenetischen Analysen einen sinnvollen diagnostischen und prognostischen Beitrag leisten. Perspektivisch werden sich die Anwendungsgebiete der genetischen Analysen vermutlich auch auf polygene kardiovaskuläre Krankheitsbilder ausweiten. Hier erlauben die neuen Hochdurchsatztechnologien die Bestimmung zahlreicher Varianten in unterschiedlichen Genen, die dann in polygenen Risiko-Scores zur Vorhersage der Erkrankungswahrscheinlichkeit herangezogen werden können.
Numerous patients are treated with the MitraClip, although they do not fulfill the stringent inclusion criteria of the Endovascular Valve Edge-to-Edge Repair Study (EVEREST) trials. The outcome of ...those patients is not well known. Therefore, we compared the long-term outcome after MitraClip treatment between patients who matched (group 1) and did not match (group 2) the EVEREST criteria. One hundred thirty-four consecutive patients were treated from September 2009 to July 2012: 59 patients (44%) in group 1 versus 75 patients (56%) in group 2. Investigated end points were acute procedural success (for group 1 vs 2: 97% vs 95%; p = 0.694), all-cause mortality (28% vs 27%; p = 0.656), reintervention (RI) rate (11% vs 37%; p = 0.010), and improvement in mitral regurgitation (MR) (−1.3 ± 1 vs −1.5 ± 1, p = 0.221) and in New York Heart Association functional class (−0.7 ± 1 vs −0.9 ± 0.8, p = 0.253) during the follow-up of 33 months (27.9 to 38.3). The morphologic extent of a flail leaflet was an independent predictor for RI. In conclusion, although the overall outcome was comparable between both groups, recurrent symptomatic MR with need for RI was higher in group 2, mainly because of complex valve pathologies: especially flail width >15 mm and gap ≥10 mm. Improvements in the interventional strategy are warranted for reducing the need for RI in patients with primary MR.
Purpose
Bioelectric navigation is a navigation modality for minimally invasive endovascular procedures promising non-fluoroscopic navigation. However, the method offers only limited navigation ...accuracy between anatomical features and expects the tracked catheter to move only in one direction at all times. We propose to extend bioelectric navigation with additional sensing capabilities, allowing for the estimation of the distance traveled by the catheter, thereby improving accuracy between feature locations and allowing to track also under alternating forward- and backward motion.
Methods
We perform experiments in finite element method (FEM) simulations and in a 3D printed phantom. A solution for estimating the traveled distance using a stationary electrode is proposed, together with an approach on how to evaluate the signals obtained with this additional electrode. We investigate the effects of surrounding tissue conductance on this approach. Finally, the approach is refined in order to mitigate the effects of parallel conductance on the navigation accuracy.
Results
The approach allows to estimate the catheter movement direction and the distance traveled. Simulations show absolute errors below 0.89 mm for non-conducting surrounding tissue, but errors up to 60.27 mm when the tissue is electrically conductive. This effect can be mitigated by a more sophisticated modeling (errors up to 33.96 mm). In experiments in a 3D printed phantom, the mean absolute error over 6 catheter paths is 6.3 mm, with standard deviations smaller than or equal to 1.1 mm.
Conclusions
Extending the setup of bioelectric navigation with an additional stationary electrode allows to estimate the distance traveled by the catheter, as well as the movement direction. The effects of parallel conductive tissue could be partially mitigated in simulations, but further research is needed to investigate these effects in real biological tissue, and to bring the introduced errors down to a clinically acceptable level.
Atherosclerotic diseases, including coronary artery disease (CAD) and myocardial infarction (MI), are the leading causes of death in the world. The genetic basis of CAD and MI, which are caused by ...multiple interacting endogenous and exogenous factors, has gained considerable interest in the last years as genome-wide association studies (GWASs) have identified many new susceptibility loci for CAD and MI, and the underlying genes provide new insights into the genetic architecture of these diseases. Here we summarize the recent findings from GWASs of atherosclerosis and discuss their functional and biological implications. We also discuss the different post-GWAS strategies that are currently used for refining the location of causal variants, understanding their role, and shedding light on molecular mechanisms explaining their association to CAD. We finally discuss potential clinical translations of GWAS findings for individual risk prediction, advanced clinical strategies, and personalized treatments.
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