Asymptotic theorems of sequential estimation-adjusted urn models

The Generalized P\'{o}lya Urn (GPU) is a popular urn model which is widely used in many disciplines. In particular, it is extensively used in treatment allocation schemes in clinical trials. In this paper, we propose a sequential estimation-adjusted urn model (a nonhomogeneous GPU) which has a wide spectrum of applications. Because the proposed urn model depends on sequential estimations of unknown parameters, the derivation of asymptotic properties is mathematically intricate and the corresponding results are unavailable in the literature. We overcome these hurdles and establish the strong consistency and asymptotic normality for both the patient allocation and the estimators of unknown parameters, under some widely satisfied conditions. These properties are important for statistical inferences and they are also useful for the understanding of the urn limiting process. A superior feature of our proposed model is its capability to yield limiting treatment proportions according to any desired allocation target. The applicability of our model is illustrated with a number of examples.Comment: Published at http://dx.doi.org/10.1214/105051605000000746 in the Annals of Applied Probability (http://www.imstat.org/aap/) by the Institute of Mathematical Statistics (http://www.imstat.org

Immigrated urn models - asymptotic properties and applications

Urn models have been widely studied and applied in both scientific and social science disciplines. In clinical studies, the adoption of urn models in treatment allocation schemes has been proved to be beneficial to both researchers, by providing more efficient clinical trials, and patients, by increasing the likelihood of receiving the better treatment. In this paper, we propose a new and general class of immigrated urn (IMU) models that incorporates the immigration mechanism into the urn process. Theoretical properties are developed and the advantages of the IMU models are discussed. In general, the IMU models have smaller variabilities than the classical urn models, yielding more powerful statistical inferences in applications. Illustrative examples are presented to demonstrate the wide applicability of the IMU models. The proposed IMU framework, including many popular classical urn models, not only offers a unify perspective for us to comprehend the urn process, but also enables us to generate several novel urn models with desirable properties

Drug Repurposing for the Treatment of COVID-19: A Knowledge Graph Approach

Identifying effective drug treatments for COVID-19 is essential to reduce morbidity and mortality. Although a number of existing drugs have been proposed as potential COVID-19 treatments, effective data platforms and algorithms to prioritize drug candidates for evaluation and application of knowledge graph for drug repurposing have not been adequately explored. A COVID-19 knowledge graph by integrating 14 public bioinformatic databases containing information on drugs, genes, proteins, viruses, diseases, symptoms and their linkages is developed. An algorithm is developed to extract hidden linkages connecting drugs and COVID-19 from the knowledge graph, to generate and rank proposed drug candidates for repurposing as treatments for COVID-19 by integrating three scores for each drug: motif scores, knowledge graph PageRank scores, and knowledge graph embedding scores. The knowledge graph contains over 48 000 nodes and 13 37 000 edges, including 13 563 molecules in the DrugBank database. From the 5624 molecules identified by the motif-discovery algorithms, ranking results show that 112 drug molecules had the top 2% scores, of which 50 existing drugs with other indications approved by health administrations reported. The proposed drug candidates serve to generate hypotheses for future evaluation in clinical trials and observational studies

Prognostic implications of surrogate markers of atherosclerosis in low to intermediate risk patients with type 2 diabetes.

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Roles of the CHADS2 and CHA2DS2-VASc scores in post-myocardial infarction patients: Risk of new occurrence of atrial fibrillation and ischemic stroke

Background: Patients with myocardial infarction (MI) are at risk of the development of atrial fibrillation (AF) and ischemic stroke. We sought to evaluate the prognostic performance of the CHADS2 and CHA2DS2-VASc scores in predicting new AF and/or ischemic stroke in post-ST segment elevation MI (STEMI) patients. Six hundred and seven consecutive post-STEMI patients with no previously documented AF were studied.Methods and Results: After a follow-up of 63 months (3,184 patient-years), 83 (13.7%) patients developed new AF (2.8% per year). Patients with a high CHADS2 and/or CHA2DS2-VASc score were more likely to develop new AF. The annual incidence of new AF was 1.18%, 2.10%, 4.52%, and 7.03% in patients with CHADS2 of 0, 1, 2, and ≥ 3; and 0.39%, 1.72%, 1.83%, and 5.83% in patients with a CHA2DS2-VASc score of 1, 2, 3 and ≥ 4. The CHA2DS2-VASc score (C-statistic = 0.676) was superior to the CHADS2 (C-statistic = 0.632) for discriminating new AF. Ischemic stroke occurred in 29 patients (0.9% per year), the incidence increasing in line with the CHADS2 (0.41%, 1.02%, 1.11%, and 1.95% with score of 0, 1, 2, and ≥ 3) and CHA2DS2-VASc scores (0.39%, 0.49%, 1.02%, and 1.48% with score of 1, 2, 3 and ≥ 4). The C-statistic of the CHA2DS2-VASc score as a predictor of ischemic stroke was 0.601, superior to that of CHADS2 score (0.573). CHADS2 and CHA2DS2-VASc scores can identify post-STEMI patients at high risk of AF and stroke.Conclusions: The CHADS2 and CHA2DS2-VASc scores can identify post-STEMI patients at high risk of AF and ischemic stroke. This enables close surveillance and prompt anticoagulation for stroke prevention

Generation of induced pluripotent stem cell lines from 3 distinct laminopathies bearing heterogeneous mutations in lamin A/C

The term laminopathies defines a group of genetic disorders caused by defects in the nuclear envelope, mostly the lamins. Lamins are the main constituents of the nuclear lamina, a filamentous meshwork associated with the inner nuclear membrane that provides mechanical stability and plays important roles in processes such as transcription, DNA replication and chromatin organization. More than 300 mutations in lamin A/C have been associated with diverse clinical phenotypes, understanding the molecular basis of these diseases may provide a rationale for treating them. Here we describe the generation of induced pluripotent stem cells (iPSCs) from a patient with inherited dilated cardiomiopathy and 2 patients with distinct accelerated forms of aging, atypical Werner syndrome and Hutchinson Gilford progeria, all of which are caused by mutations in lamin A/C. These cell lines were pluripotent and displayed normal nuclear membrane morphology compared to donor fibroblasts. Their differentiated progeny reproduced the disease phenotype, reinforcing the idea that they represent excellent tools for understanding the role of lamin A/C in normal physiology and the clinical diversity associated with these diseases

Lack of Cardiac Nerve Sprouting after Intramyocardial Transplantation of Bone Marrow-Derived Stem Cells in a Swine Model of Chronic Ischemic Myocardium

Previous experimental studies suggested that mesenchymal stem cell transplantation causes cardiac nerve sprouting; however, whether bone marrow (BM)-derived mononuclear cells (MNC) and endothelial progenitor cells (EPC) can also lead to cardiac nerve sprouting and alter gap junction expression remains unclear. We investigated the effect of electroanatomical mapping-guided direct intramyocardial transplantation of BM-MNC (n = 8) and CD31+EPC (n = 8) compared with saline control (n = 8) on cardiac nerve sprouting and gap junction expression in a swine model of chronic ischemic myocardium. At 12 weeks after transplantation, the distribution and density of cardiac nerve sprouting were determined by staining of tyrosine hydroxylase (TH) and growth associated protein 43(GAP-43) and expression of connexin 43 in the targeted ischemic and remote normal myocardium. After 12 weeks, no animal developed sudden death after the transplantation. There were no significant differences in the number of cells with positive staining of TH and GAP-43 in the ischemic and normal myocardium between three groups. Furthermore, expression of connexin 43 was also similar in the ischemic and normal myocardia in each group of animals (P > 0.05). The results of this study demonstrated that intramyocardial BM-derived MNC or EPC transplantation in a large animal model of chronic myocardial ischemia was not associated with increased cardiac nerve sprouting over the ischemic myocardium

Fumarylacetoacetate Hydrolase Knock-out Rabbit Model for Hereditary Tyrosinemia Type 1.

Hereditary tyrosinemia type 1 (HT1) is a severe human autosomal recessive disorder caused by the deficiency of fumarylacetoacetate hydroxylase (FAH), an enzyme catalyzing the last step in the tyrosine degradation pathway. Lack of FAH causes accumulation of toxic metabolites (fumarylacetoacetate and succinylacetone) in blood and tissues, ultimately resulting in severe liver and kidney damage with onset that ranges from infancy to adolescence. This tissue damage is lethal but can be controlled by administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), which inhibits tyrosine catabolism upstream of the generation of fumarylacetoacetate and succinylacetone. Notably, in animals lacking FAH, transient withdrawal of NTBC can be used to induce liver damage and a concomitant regenerative response that stimulates the growth of healthy hepatocytes. Among other things, this model has raised tremendous interest for the in vivo expansion of human primary hepatocytes inside these animals and for exploring experimental gene therapy and cell-based therapies. Here, we report the generation of FAH knock-out rabbits via pronuclear stage embryo microinjection of transcription activator-like effector nucleases. FAH-/- rabbits exhibit phenotypic features of HT1 including liver and kidney abnormalities but additionally develop frequent ocular manifestations likely caused by local accumulation of tyrosine upon NTBC administration. We also show that allogeneic transplantation of wild-type rabbit primary hepatocytes into FAH-/- rabbits enables highly efficient liver repopulation and prevents liver insufficiency and death. Because of significant advantages over rodents and their ease of breeding, maintenance, and manipulation compared with larger animals including pigs, FAH-/- rabbits are an attractive alternative for modeling the consequences of HT1.Wellcome Trus