Kullback-Leibler Divergence and Akaike Information Criterion in General Hidden Markov Models

To characterize the Kullback-Leibler divergence and Fisher information in general parametrized hidden Markov models, in this paper, we first show that the log likelihood and its derivatives can be represented as an additive functional of a Markovian iterated function system, and then provide explicit characterizations of these two quantities through this representation. Moreover, we show that Kullback-Leibler divergence can be locally approximated by a quadratic function determined by the Fisher information. Results relating to the Cram\'{e}r-Rao lower bound and the H\'{a}jek-Le Cam local asymptotic minimax theorem are also given. As an application of our results, we provide a theoretical justification of using Akaike information criterion (AIC) model selection in general hidden Markov models. Last, we study three concrete models: a Gaussian vector autoregressive-moving average model of order $(p,q)$, recurrent neural networks, and temporal restricted Boltzmann machine, to illustrate our theory.Comment: 26 pages, 1 figur

Biaxial mechanical characterization and microstructure-driven modeling of elastic pulmonary artery walls of large mammals under hypertensive conditions

Pulmonary Hypertension (PH) is a disease of the pulmonary vasculature which causes right heart failure. It is known that PH causes significant remodeling of the pulmonary arterial vasculature, but the effects of this remodeling are not well-understood. In addition, there is a dearth of research in large mammals for PH. Modeling of the arteries is also important in the simulation of deformation due to blood flow. Current models either do not reflect the microstructure, or are too complex for clinical use. This work presents mechanical characterization and analysis of the artery wall, in addition to a constitutive model driven by the microstructure of the artery. In this work, mechanical characterization of the artery wall is performed via multiaxial deformation using a custom-fabricated planar biaxial tester. This test device provides higher fidelity than the standard uniaxial tests. Using the data gathered from the biaxial tester, trends in aspects of the mechanical behavior due to PH can be elucidated. Specifically, in this work, the anisotropy of the elastin protein network has been quantified, with the circumferential direction being 1.4x stiffer than the longitudinal direction. In addition to this new finding, PH has been shown to slightly decrease the anisotropy of the pulmonary artery trunk. A new microstructurally-based constitutive model for the artery wall was developed to reflect this finding. This model uses decoupled anisotropy for the elastin and collagen networks, reflecting the true behavior of the artery wall. The model uses a sinusoidal elastic beam to model the collagen fibers, reflecting the microstructure. This microstructural basis is then verified through histology and correlation of material parameters to histological images. Using information from this data, prospective future analysis of mechanical behavior will be proposed

Selective Enrichment and Identification of Azide-tagged Cross-Linked Peptides Using Chemical Ligation and Mass Spectrometry

Protein-protein interaction is one of the key regulatory mechanisms for controlling protein function in various cellular processes. Chemical cross-linking coupled with mass spectrometry has proven to be a powerful method not only for mapping protein-protein interactions of all natures, including weak and transient ones, but also for determining their interaction interfaces. One critical challenge remaining in this approach is how to effectively isolate and identify cross-linked products from a complex peptide mixture. In this work, we have developed a novel strategy using conjugation chemistry for selective enrichment of cross-linked products. An azide-tagged cross-linker along with two biotinylated conjugation reagents were designed and synthesized. Cross-linking of model peptides and cytochrome c as well as enrichment of the resulting cross-linked peptides has been assessed. Selective conjugation of azide-tagged cross-linked peptides has been demonstrated using two strategies: copper catalyzed cycloaddition and Staudinger ligation. While both methods are effective, Staudinger ligation is better suited for enriching the cross-linked peptides since there are fewer issues with sample handling. LC MSn analysis coupled with database searching using the Protein Prospector software package allowed identification of 58 cytochrome c cross-linked peptides after enrichment and affinity purification. The new enrichment strategy developed in this work provides useful tools for facilitating identification of cross-linked peptides in a peptide mixture by MS, thus presenting a step forward in future studies of protein-protein interactions of protein complexes by cross-linking and mass spectrometry

Correlation of the composite equilibrium score of computerized dynamic posturography and clinical balance tests

AbstractBackgroundThe computerized dynamic posturography has been widely used to access balance control in patients with balance dysfunction. A composite-equilibrium score (CS) can be calculated from the sensory organization test using the computerized dynamic posturography. However, the correlation between the composite equilibrium score and clinical tests and its ability to predict falls has rarely been explored in the past.MethodsA total of 60 patients with chief complaint of dizziness were enrolled in our study, and clinical assessments were done including the sensory organization test (SOT), Timed Up and Go test (TUG), Tinetti Performance-Oriented Mobility Assessment (POMA), and the dynamic gait index (DGI). The age and the subjective feeling of the severity of dizziness quantified by the visual analog scale (VAS) of each patient were also recorded.ResultsStatistical analysis revealed significant correlation between the composite equilibrium score and the TUG, POMA (gait, balance and total scores), and the DGI. However, there is statistically significant correlation between neither the CS and the age nor the VAS of dizziness. When grouping the DGI, POMA (total score), and the TUG cutoff to predict fall risks, the correlations to the CS can still be established except the TUG.ConclusionFrom the results of our study, the validity of the clinical tests was established in assessment of balance function, and clinicians can utilize these tools for preliminary evaluation of patient balance when computerized dynamic posturography is not available. In addition, CS can be used to predict the risk of falls

Causal Mediation Analysis for Difference-in-Difference Design and Panel Data

Advantages of panel data, i.e., difference in difference (DID) design data, are a large sample size and easy availability. Therefore, panel data are widely used in epidemiology and in all social science fields. The literatures on causal inferences of panel data setting or DID design are growing, but no theory or mediation analysis method has been proposed for such settings. In this study, we propose a methodology for conducting causal mediation analysis in DID design and panel data setting. We provide formal counterfactual definitions for controlled direct effect and natural direct and indirect effect in panel data setting and DID design, including the identification and required assumptions. We also demonstrate that, under the assumptions of linearity and additivity, controlled direct effects can be estimated by contrasting marginal and conditional DID estimators whereas natural indirect effects can be estimated by calculating the product of the exposure-mediator DID estimator and the mediator-outcome DID estimator. A panel regression-based approach is also proposed. The proposed method is then used to investigate mechanisms of the effects of the Covid 19 pandemic on the mental health status of the population. The results revealed that mobility restrictions mediated approximately 45 % of the causal effect of Covid 19 on mental health status

STAT2 hypomorphic mutant mice display impaired dendritic cell development and antiviral response

Interferons (IFNs) are key regulators for both innate and adaptive immune responses. By screening ENU-mutagenized mice, we identified a pedigree- P117 which displayed impaired response to type I, but not type II, IFNs. Through inheritance test, genetic mapping and sequencing, we found a T to A point mutation in the 5' splice site of STAT2 intron 4–5, leading to cryptic splicing and frame shifting. As a result, the expression of STAT2 protein was greatly diminished in the mutant mice. Nonetheless, a trace amount of functional STAT2 protein was still detectable and was capable of inducing, though to a lesser extent, IFNα-downstream gene expressions, suggesting that P117 is a STAT2 hypomorphic mutant. The restoration of mouse or human STAT2 gene in P117 MEFs rescued the response to IFNα, suggesting that the mutation in STAT2 is most likely the cause of the phenotypes seen in the pedigree. Development of different subsets of lymphocytes appeared to be normal in the mutant mice except that the percentage and basal expression of CD86 in splenic pDC and cDC were reduced. In addition, in vitro Flt3L-dependent DC development and TLR ligand-mediated DC differentiation were also defective in mutant cells. These results suggest that STAT2 positively regulates DC development and differentiation. Interestingly, a severe impairment of antiviral state and increased susceptibility to EMCV infection were observed in the mutant MEFs and mice, respectively, suggesting that the remaining STAT2 is not sufficient to confer antiviral response. In sum, the new allele of STAT2 mutant reported here reveals a role of STAT2 for DC development and a threshold requirement for full functions of type I IFNs

The incidence of symptomatic venous thromboembolism following hip fractures with or without surgery in Taiwan

AbstractBackgroundInformation on the incidence of venous thromboembolism (VTE) following hip fractures in Asia is rare. This study will investigate the epidemiology of symptomatic VTE in Taiwanese patients experiencing hip fractures.Methods and resultsWe used Taiwan's National Health Insurance Research Database to retrospectively identify patients (≧45years) who experienced hip fractures from 1998 to 2007 and were followed up for 3months after the discharge. Logistic regression analysis determined the independent risk factors of symptomatic VTE after the fractures. We identified 134,034 patients (mean age: 76.2±9.7years; female: 57.8%) who experienced hip fractures, 83.2% of whom underwent hip surgery. The overall pharmacological thromboprophylaxis rate was 2.7%. The mean length of stay was 11.3±7.9days. The 3-month cumulative incidence of symptomatic VTE was 77 events per 10,000 persons. Multivariate analysis showed that previous DVT, previous PE, varicose veins, cancer, heart failure, renal insufficiency, and older age were independent risk factors of developing VTE.ConclusionsThe incidence of symptomatic VTE after hip fractures is low in Taiwan. Patients rarely received pharmacological thromboprophylaxis following hip fractures. Universal thromboprophylaxis for patients experiencing hip fractures was not necessary in Taiwan, but it should be considered in high-risk populations