Wisdom of artificial crowds feature selection in untargeted metabolomics: An application to the development of a blood-based diagnostic test for thrombotic myocardial infarction

Introduction: Heart disease remains a leading cause of global mortality. While acute myocardial infarction (colloquially: heart attack), has multiple proximate causes, proximate etiology cannot be determined by a blood-based diagnostic test. We enrolled a suitable patient cohort and conducted a non-targeted quantification of plasma metabolites by mass spectrometry for developing a test that can differentiate between thrombotic MI, non-thrombotic MI, and stable disease. A significant challenge in developing such a diagnostic test is solving the NP-hard problem of feature selection for constructing an optimal statistical classifier. Objective: We employed a Wisdom of Artificial Crowds (WoAC) strategy for solving the feature selection problem and evaluated the accuracy and parsimony of downstream classifiers in comparison with traditional feature selection techniques including the Lasso and selection using Random Forest variable importance criteria. Materials and methods: Artificial Crowd Wisdom was generated via aggregation of the best solutions from independent and diverse genetic algorithm populations that were initialized with bootstrapping and a random subspaces constraint. Results/Conclusions: Strong evidence was observed that a statistical classifier utilizing WoAC feature selection can discriminate between human subjects presenting with thrombotic MI, non-thrombotic MI, and stable Coronary Artery Disease given abundances of selected plasma metabolites. Utilizing the abundances of twenty selected metabolites, a leave-one-out cross-validation estimated misclassification rate of 2.6% was observed. However, the WoAC feature selection strategy did not perform better than the Lasso over the current study

Association Between Residential Greenness and Cardiovascular Disease Risk

Background Exposure to green vegetation has been linked to positive health, but the pathophysiological processes affected by exposure to vegetation remain unclear. To study the relationship between greenness and cardiovascular disease, we examined the association between residential greenness and biomarkers of cardiovascular injury and disease risk in susceptible individuals. Methods and Results In this cross-sectional study of 408 individuals recruited from a preventive cardiology clinic, we measured biomarkers of cardiovascular injury and risk in participant blood and urine. We estimated greenness from satellite-derived normalized difference vegetation index ( NDVI ) in zones with radii of 250 m and 1 km surrounding the participants' residences. We used generalized estimating equations to examine associations between greenness and cardiovascular disease biomarkers. We adjusted for residential clustering, demographic, clinical, and environmental variables. In fully adjusted models, contemporaneous NDVI within 250 m of participant residence was inversely associated with urinary levels of epinephrine (-6.9%; 95% confidence interval, -11.5, -2.0/0.1 NDVI ) and F2-isoprostane (-9.0%; 95% confidence interval, -15.1, -2.5/0.1 NDVI ). We found stronger associations between NDVI and urinary epinephrine in women, those not on β-blockers, and those who had not previously experienced a myocardial infarction. Of the 15 subtypes of circulating angiogenic cells examined, 11 were inversely associated (8.0-15.6% decrease/0.1 NDVI ), whereas 2 were positively associated (37.6-45.8% increase/0.1 NDVI ) with contemporaneous NDVI . Conclusions Independent of age, sex, race, smoking status, neighborhood deprivation, statin use, and roadway exposure, residential greenness is associated with lower levels of sympathetic activation, reduced oxidative stress, and higher angiogenic capacity

Presence of multiple coronary angiographic characteristics for the diagnosis of acute coronary thrombus

Background: Coronary angiography is frequently employed to aid in the diagnosis of acute coronary thrombosis, but there is limited data to support its efficacy. The aim of the study was to evaluate sensitivity and specificity of five commonly used angiographic characteristics for diagnosis of acute coronary thrombosis: Ambrose complex lesion morphology; spherical, ovoid, or irregular filling defect; abrupt vessel cutoff; intraluminal staining; and any coronary filling defect. Methods: Coronary angiography of 80 acute myocardial infarction or stable coronary artery disease subjects were assessed in blinded fashion, for the presence or absence of five angiographic characteristics. Only lesions of ≥ 10% stenosis were included in the analysis. Presence or absence of each angiographic characteristic was compared between lesions with or without the following study defined outcomes: 1) histologically confirmed thrombus, 2) highly probable thrombus, and 3) highly unlikely thrombus. Results: A total of 323 lesions were evaluated. All studied angiographic characteristics were associated with histologically confirmed and highly probable thrombotic lesions vs. lesions not meeting criteria for these outcomes (p < 0.03), except for complex Ambrose morphology which was not associated with any of the study outcomes (p > 0.05). Specificity for identifying histologically confirmed or highly probable thrombotic lesion was high (92–100%), especially for spherical, ovoid, or irregular filling defect (99–100%) and intraluminal staining (99%). Sensitivity for identification of histologically confirmed or highly probable thrombotic lesions was low for all tested angiographic characteristics (17–60%). Conclusions: The presence of spherical, ovoid, or irregular filling defect or intraluminal staining was highly suggestive of coronary thrombus. However, none of the evaluated angiographic characteristics were useful for ruling out the presence of coronary thrombus. If confirmed in an independent cohort, these angiographic characteristic will be of significant value in confirming the diagnosis of acute coronary thrombosis.

National Trends in Cessation Counseling, Prescription Medication Use, and Associated Costs Among US Adult Cigarette Smokers

Importance: Cigarette smoking is the leading cause of preventable disease and death in the United States. When used separately or in combination, smoking cessation counseling and cessation medications have been associated with increased cessation rates. Objectives: To present trends in self-reported receipt of physician advice to quit smoking and in use of prescription smoking cessation medication along with their associated expenditures among a nationally representative sample of active adult smokers in the United States. Design, Setting, and Participants: This repeated cross-sectional study of US adults aged 18 years or older was conducted from July 5, 2018, through August 15, 2018. Data were collected between January 1, 2006, and December 31, 2015, from the Medical Expenditure Panel Survey, an annual US survey of individuals and families, health care personnel, and employers. Participants (n = 29 106) were noninstitutionalized civilians who were randomly drawn from the respondents of the previous year’s National Health Interview Survey. Multivariable logistic regression models were used to examine the associations between sociodemographic factors and receipt of physician cessation advice and use of cessation prescription medication. A 2-part econometric model was used to assess health care expenditures. Main Outcomes and Measures: Trends in self-reported receipt of physician advice to quit and uptake of prescription smoking cessation medications with associated total and out-of-pocket expenditures. Results: The study sample consisted of 29 106 participants, with a mean (SD) age of 57 (10) years and a composition of 13 670 women (47.0%). The results were weighted to provide estimates for 31.2 million active adult cigarette smokers. The proportion of smokers who reported receiving physician advice to quit increased from 60.2% (95% CI, 58.5%-62.0%) in 2006 to 2007 to 64.9% (95% CI, 62.8%-66.9%) in 2014 to 2015, with a P for trend = .001. The odds of receiving physician cessation advice was statistically significantly higher in women (odds ratio [OR], 1.50; 95% CI, 1.39-1.59) and lower among uninsured participants (OR, 0.58; 95% CI, 0.52-0.65). Overall, prescription smoking cessation medication use decreased with a corresponding reduction in total expenditures from $146 million (out-of-pocket cost,$46 million) in 2006 to 2007 to $73 million (out-of-pocket cost,$9 million) in 2014 to 2015. Male (odds ratio [OR], 0.78; 95% CI, 0.66-0.91), uninsured (OR, 0.58; 95% CI, 0.41-0.83), and racial/ethnic minority (African American: OR, 0.51 [95% CI, 0.38-0.69]; Asian: OR, 0.31 [95% CI, 0.10-0.93]; Hispanic: OR, 0.53 [95% CI, 0.36-0.78]) participants were less likely to use prescription smoking cessation medications. Conclusions and Relevance: The lower rates of delivery of physician advice to quit smoking and the lower uptake of known prescription smoking cessation medications among men, younger adults, uninsured individuals, racial/ethnic minority groups, and those without smoking-associated comorbidities may be associated with the higher smoking rates among these subgroups despite an all-time low prevalence of smoking in the United States; this finding calls for a more targeted implementation of smoking cessation guidelines

Emerging alphaviruses are sensitive to cellular states induced by a novel small-molecule agonist of the STING pathway

The type I interferon (IFN) system represents an essential innate immune response that renders cells resistant to virus growth via the molecular actions of IFNinduced effector proteins. IFN-mediated cellular states inhibit growth of numerous and diverse virus types, including those of known pathogenicity as well as potentially emerging agents. As such, targeted pharmacologic activation of the IFN response may represent a novel therapeutic strategy to prevent infection or spread of clinically impactful viruses. In light of this, we employed a high-throughput screen to identify small molecules capable of permeating the cell and of activating IFN-dependent signaling processes. Here we report the identification and characterization of N-(methylcarbamoyl)-2-([5-(4- methylphenyl)-1,3,4-oxadiazol-2-yl]sulfanyl)-2-phenylacetamide (referred to as C11), a novel compound capable of inducing IFN secretion from human cells. Using reverse geneticsbased loss-of-function assays, we show that C11 activates the type I IFN response in a manner that requires the adaptor protein STING but not the alternative adaptors MAVS and TRIF. Importantly, treatment of cells with C11 generated a cellular state that potently blocked replication of multiple emerging alphavirus types, including chikungunya, Ross River, Venezuelan equine encephalitis, Mayaro, and O'nyong-nyong viruses. The antiviral effects of C11 were subsequently abrogated in cells lacking STING or the type I IFN receptor, indicating that they are mediated, at least predominantly, by way of STING-mediated IFN secretion and subsequent autocrine/paracrine signaling. This work also allowed characterization of differential antiviral roles of innate immune signaling adaptors and IFN-mediated responses and identified MAVS as being crucial to cellular resistance to alphavirus infection

Associations of cigarette smoking with subclinical inflammation and atherosclerosis : ELSA-Brasil (The Brazilian Longitudinal Study of Adult Health)

Background-—There is a need to identify sensitive biomarkers of early tobacco-related cardiovascular disease. We examined the association of smoking status, burden, time since quitting, and intensity, with markers of inflammation and subclinical atherosclerosis. Methods and Results-—We studied 14 103 participants without clinical cardiovascular disease in ELSA-Brasil (Brazilian Longitudinal Study of Adult Health). We evaluated baseline cross-sectional associations between smoking parameters and inflammation (highsensitivity C-reactive protein [hsCRP]) and measures of subclinical atherosclerosis (carotid intima–media thickness, ankle-brachial index, and coronary artery calcium [CAC]). The cohort included 1844 current smokers, 4121 former smokers, and 8138 never smokers. Mean age was 51.7 8.9 years; 44.8% were male. After multivariable adjustment, compared with never smokers, current smokers had significantly higher levels of hsCRP (b=0.24, 0.19–0.29 mg/L; P0 (odds ratio: 1.83; 95% confidence interval, 1.46–2.30; P0 were lower with increasing time since quitting (P0 (P=0.03) after adjusting for duration of smoking. Conclusions-—Strong associations were observed between smoking status, burden, and intensity with inflammation (hsCRP) and subclinical atherosclerosis (carotid intima–media thickness, ankle-brachial index, CAC). These markers of early cardiovascular disease injury may be used for the further study and regulation of traditional and novel tobacco products

Erectile Dysfunction as an Independent Predictor of Future Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis

Vascular erectile dysfunction (ED) and cardiovascular disease (CVD) share common risk factors including obesity, hypertension, metabolic syndrome, diabetes mellitus, and smoking. ED and CVD also have common underlying pathological mechanisms, including endothelial dysfunction, inflammation, and atherosclerosis.1 Despite these close relationships, the evidence documenting ED as an independent predictor of future CVD events is limited

Friedewald-Estimated Versus Directly Measured Low-Density Lipoprotein Cholesterol and Treatment Implications

ObjectivesThe aim of this study was to compare Friedewald-estimated and directly measured low-density lipoprotein cholesterol (LDL-C) values.BackgroundLDL-C is routinely estimated by the Friedewald equation to guide treatment; however, compatibility with direct measurement has received relatively little scrutiny, especially at levels <70 mg/dl now targeted in high-risk patients.MethodsWe examined 1,340,614 U.S. adults who underwent lipid profiling by vertical spin density gradient ultracentrifugation (Atherotech, Birmingham, Alabama) from 2009 to 2011. Following standard practice, Friedewald LDL-C was not estimated if triglyceride levels were ≥400 mg/dl (n = 30,174), yielding 1,310,440 total patients and 191,333 patients with Friedewald LDL-C <70 mg/dl.ResultsPatients were 59 ± 15 years of age and 52% were women. Lipid distributions closely matched those in the National Health and Nutrition Examination Survey. A greater difference in the Friedewald-estimated versus directly measured LDL-C occurred at lower LDL-C and higher triglyceride levels. If the Friedewald-estimated LDL-C was <70 mg/dl, the median directly measured LDL-C was 9.0 mg/dl higher (5th to 95th percentiles, 1.8 to 15.4 mg/dl) when triglyceride levels were 150 to 199 mg/dl and 18.4 mg/dl higher (5th to 95th percentiles, 6.6 to 36.0 mg/dl) when triglyceride levels were 200 to 399 mg/dl. Of patients with a Friedewald-estimated LDL-C <70 mg/dl, 23% had a directly measured LDL-C ≥70 mg/dl (39% if triglyceride levels were concurrently 150 to 199 mg/dl; 59% if triglyceride levels were concurrently 200 to 399 mg/dl).ConclusionsThe Friedewald equation tends to underestimate LDL-C most when accuracy is most crucial. Especially if triglyceride levels are ≥150 mg/dl, Friedewald estimation commonly classifies LDL-C as <70 mg/dl despite directly measured levels ≥70 mg/dl, and therefore additional evaluation is warranted in high-risk patients