Machine learning and statistical approaches for classification of risk of coronary artery disease using plasma cytokines.

BACKGROUND: As per the 2017 WHO fact sheet, Coronary Artery Disease (CAD) is the primary cause of death in the world, and accounts for 31% of total fatalities. The unprecedented 17.6 million deaths caused by CAD in 2016 underscores the urgent need to facilitate proactive and accelerated pre-emptive diagnosis. The innovative and emerging Machine Learning (ML) techniques can be leveraged to facilitate early detection of CAD which is a crucial factor in saving lives. The standard techniques like angiography, that provide reliable evidence are invasive and typically expensive and risky. In contrast, ML model generated diagnosis is non-invasive, fast, accurate and affordable. Therefore, ML algorithms can be used as a supplement or precursor to the conventional methods. This research demonstrates the implementation and comparative analysis of K Nearest Neighbor (k-NN) and Random Forest ML algorithms to achieve a targeted "At Risk" CAD classification using an emerging set of 35 cytokine biomarkers that are strongly indicative predictive variables that can be potential targets for therapy. To ensure better generalizability, mechanisms such as data balancing, repeated k-fold cross validation for hyperparameter tuning, were integrated within the models. To determine the separability efficacy of "At Risk" CAD versus Control achieved by the models, Area under Receiver Operating Characteristic (AUROC) metric is used which discriminates the classes by exhibiting tradeoff between the false positive and true positive rates. RESULTS: A total of 2 classifiers were developed, both built using 35 cytokine predictive features. The best AUROC score of .99 with a 95% Confidence Interval (CI) (.982,.999) was achieved by the Random Forest classifier using 35 cytokine biomarkers. The second-best AUROC score of .954 with a 95% Confidence Interval (.929,.979) was achieved by the k-NN model using 35 cytokines. A p-value of less than 7.481e-10 obtained by an independent t-test validated that Random Forest classifier was significantly better than the k-NN classifier with regards to the AUROC score. Presently, as large-scale efforts are gaining momentum to enable early, fast, reliable, affordable, and accessible detection of individuals at risk for CAD, the application of powerful ML algorithms can be leveraged as a supplement to conventional methods such as angiography. Early detection can be further improved by incorporating 65 novel and sensitive cytokine biomarkers. Investigation of the emerging role of cytokines in CAD can materially enhance the detection of risk and the discovery of mechanisms of disease that can lead to new therapeutic modalities.

Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function.

IMPORTANCE: The identification of a patient with a rare form of severe dysbetalipoproteinemia allowed the study of the consequences of total absence of apolipoprotein E (apoE). OBJECTIVES: To discover the molecular basis of this rare disorder and to determine the effects of complete absence of apoE on neurocognitive and visual function and on lipoprotein metabolism. DESIGN, SETTING, AND PARTICIPANTS: Whole-exome sequencing was performed on the patient's DNA. He underwent detailed neurological and visual function testing and lipoprotein analysis. Lipoprotein analysis was also performed in the Cardiovascular Research Institute, University of California, San Francisco, on blood samples from the proband's mother, wife, 2 daughters, and normolipidemic control participants. MAIN OUTCOME MEASURES: Whole-exome sequencing, lipoprotein analysis, and neurocognitive function. RESULTS: The patient was homozygous for an ablative APOE frameshift mutation (c.291del, p.E97fs). No other mutations likely to contribute to the phenotype were discovered, with the possible exception of two, in ABCC2 (p.I670T) and LIPC (p.G137R). Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of ß-amyloid and tau proteins. He had no significant symptoms of cardiovascular disease except a suggestion of myocardial ischemia on treadmill testing and mild atherosclerosis noted on carotid ultrasonography. He had exceptionally high cholesterol content (760 mg/dL; to convert to millimoles per liter, multiply by 0.0259) and a high cholesterol to triglycerides ratio (1.52) in very low-density lipoproteins with elevated levels of small-diameter high-density lipoproteins, including high levels of prebeta-1 high-density lipoprotein. Intermediate-density lipoproteins, low-density lipoproteins, and very low-density lipoproteins contained elevated apoA-I and apoA-IV levels. The patient's apoC-III and apoC-IV levels were decreased in very low-density lipoproteins. Electron microscopy revealed large lamellar particles having electron-opaque cores attached to electron-lucent zones in intermediate-density and low-density lipoproteins. Low-density lipoprotein particle diameters were distributed bimodally. CONCLUSIONS AND RELEVANCE: Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects. This suggests that functions of apoE in the brain and eye are not essential or that redundant mechanisms exist whereby its role can be fulfilled. Targeted knockdown of apoE in the central nervous system might be a therapeutic modality in neurodegenerative disorders.

Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency.

BACKGROUND & AIMS: Lysosomal acid lipase deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase. METHODS: Sebelipase alfa (1mg/kg or 3mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals. RESULTS: 216 infusions were administered to eight adult subjects through week 52 during LAL-CL04. At week 52, mean alanine aminotransferase and aspartate aminotransferase levels were normal with mean change from baseline of -58% and -40%. Mean changes for low-density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were -60%, -39%, -36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of a hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected. CONCLUSIONS: Long-term dosing with sebelipase alfa in lysosomal acid lipase-deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in the hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184).

Short-term physical inactivity impairs vascular function.

BACKGROUND: Sedentarism, also termed physical inactivity, is an independent risk factor for cardiovascular diseases. Mechanisms thought to be involved include insulin resistance, dyslipidemia, hypertension, and increased inflammation. It is unknown whether changes in vascular and endothelial function also contribute to this excess risk. We hypothesized that short-term exposure to inactivity would lead to endothelial dysfunction, arterial stiffening, and increased vascular inflammation. METHODS: Five healthy subjects (four men and one woman) underwent 5 d of bed rest (BR) to simulate inactivity. Measurements of vascular function (flow-mediated vasodilation to evaluate endothelial function; applanation tonometry to assess arterial resistance), inflammation, and metabolism were made before BR, daily during BR, and 2 d after BR recovery period. Subjects maintained an isocaloric diet throughout. RESULTS: BR led to significant decreases in brachial artery and femoral artery flow-mediated vasodilation (brachial: 11 ± 3% pre-BR versus 9 ± 2% end-BR, P = 0.04; femoral: 4 ± 1% versus 2 ± 1%, P = 0.04). The central augmentation index increased with BR (-4 ± 9% versus 5 ± 11%, P = 0.03). Diastolic blood pressure increased (58 ± 7 mm Hg versus 62 ± 7 mm Hg, P = 0.02), whereas neither systolic blood pressure nor heart rate changed. 15-Hydroxyeicosatetraenoic acid, an arachidonic acid metabolite, increased but the other inflammatory and metabolic biomarkers were unchanged. CONCLUSIONS: Our findings show that acute exposure to sedentarism results in decreased endothelial function, arterial stiffening, increased diastolic blood pressure, and an increase in 15-hydroxyeicosatetraenoic acid. We speculate that inactivity promotes a vascular "deconditioning" state characterized by impaired endothelial function, leading to arterial stiffness and increased arterial tone. Although physiologically significant, the underlying mechanisms and clinical relevance of these findings need to be further explored.

Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease.

UNLABELLED: Cholesteryl ester storage disease (CESD), an inherited deficiency of lysosomal acid lipase (LAL), is an underappreciated cause of progressive liver disease with no approved therapy. Presenting features include dyslipidemia, elevated transaminases, and hepatomegaly. To assess the clinical effects and safety of the recombinant human LAL, sebelipase alfa, nine patients received four once-weekly infusions (0.35, 1, or 3 mg·kg(-1) ) in LAL-CL01, which is the first human study of this investigational agent. Patients completing LAL-CL01 were eligible to enroll in the extension study (LAL-CL04) in which they again received four once-weekly infusions of sebelipase alfa (0.35, 1, or 3 mg·kg(-1) ) before transitioning to long-term every-other-week infusions (1 or 3 mg·kg(-1) ). Sebelipase alfa was well tolerated, with mostly mild adverse events unrelated to sebelipase alfa. No antidrug antibodies were detected. Transaminases decreased in patients in LAL-CL01 and increased between studies. In seven patients receiving ongoing sebelipase alfa treatment in LAL-CL04, the mean ± standard deviation (SD) decreases for alanine transaminase and aspartate aminotransferase at week 12 compared to the baseline values in LAL-CL01 were 46 ± 21 U/L (-52%) and 21 ± 14 U/L (-36%), respectively (P ≤ 0.05). Through week 12 of LAL-CL04, these seven patients also showed mean decreases from baseline in total cholesterol of 44 ± 41 mg/dL (-22%; P = 0.047), low density lipoprotein-cholesterol of 29 ± 31 mg/dL (-27%; P = 0.078), and triglycerides of 50 ± 38 mg/dL (-28%, P = 0.016) and increases in high density lipoprotein-cholesterol of 5 mg/dL (15%; P = 0.016). CONCLUSION: These data establish that sebelipase alfa, an investigational enzyme replacement, in patients with CESD is well tolerated, rapidly decreases serum transaminases, and that these improvements are sustained with long-term dosing and are accompanied by improvements in serum lipid profile.