Multivariate count autoregression

We are studying linear and log-linear models for multivariate count time series data with Poisson marginals. For studying the properties of such processes we develop a novel conceptual framework which is based on copulas. Earlier contributions impose the copula on the joint distribution of the vector of counts by employing a continuous extension methodology. Instead we introduce a copula function on a vector of associated continuous random variables. This construction avoids conceptual difficulties related to the joint distribution of counts yet it keeps the properties of the Poisson process marginally. Furthermore, this construction can be employed for modeling multivariate count time series with other marginal count distributions. We employ Markov chain theory and the notion of weak dependence to study ergodicity and stationarity of the models we consider. Suitable estimating equations are suggested for estimating unknown model parameters. The large sample properties of the resulting estimators are studied in detail. The work concludes with some simulations and a real data example

The European Biological Variation Study (EuBIVAS): Biological Variation Data for Coagulation Markers Estimated by a Bayesian Model

Background For biological variation (BV) data to be safely used, data must be reliable and relevant to the population in which they are applied. We used samples from the European Biological Variation Study (EuBIVAS) to determine BV of coagulation markers by a Bayesian model robust to extreme observations and used the derived within-participant BV estimates [CVP(i)] to assess the applicability of the BV estimates in clinical practice. Method Plasma samples were drawn from 92 healthy individuals for 10 consecutive weeks at 6 European laboratories and analyzed in duplicate for activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen, D-dimer, antithrombin (AT), protein C, protein S free, and factor VIII (FVIII). A Bayesian model with Student t likelihoods for samples and replicates was applied to derive CVP(i) and predicted BV estimates with 95% credibility intervals. Results For all markers except D-dimer, CVP(i) were homogeneously distributed in the overall study population or in subgroups. Mean within-subject estimates (CVI) were <5% for APTT, PT, AT, and protein S free, <10% for protein C and FVIII, and <12% for fibrinogen. For APTT, protein C, and protein S free, estimates were significantly lower in men than in women ≤50 years. Conclusion For most coagulation markers, a common CVI estimate for men and women is applicable, whereas for APTT, protein C, and protein S free, sex-specific reference change values should be applied. The use of a Bayesian model to deliver individual CVP(i) allows for improved interpretation and application of the data.publishedVersio

HIV-1 Nef Binds PACS-2 to Assemble a Multikinase Cascade That Triggers Major Histocompatibility Complex Class I (MHC-I) Down-regulation: ANALYSIS USING SHORT INTERFERING RNA AND KNOCK-OUT MICE*S⃞

Human immunodeficiency virus, type 1, negative factor (Nef) initiates down-regulation of cell-surface major histocompatibility complex-I (MHC-I) by assembling an Src family kinase (SFK)-ZAP70/Syk-phosphoinositide 3-kinase (PI3K) cascade through the sequential actions of two sites, Nef EEEE65 and PXXP75. The internalized MHC-I molecules are then sequestered in endosomal compartments by a process requiring Nef Met20. How Nef assembles the multikinase cascade to trigger the MHC-I down-regulation pathway is unknown. Here we report that EEEE65-dependent binding to the sorting protein PACS-2 targets Nef to the paranuclear region, enabling PXXP75 to bind and activate a trans-Golgi network (TGN)-localized SFK. This SFK then phosphorylates ZAP-70 to recruit class I PI3K by interaction with the p85 C-terminal Src homology 2 domain. Using splenocytes and embryonic fibroblasts from PACS-2-/- mice, we confirm genetically that Nef requires PACS-2 to localize to the paranuclear region and assemble the multikinase cascade. Moreover, genetic loss of PACS-2 or inhibition of class I PI3K prevents Nef-mediated MHC-I down-regulation, demonstrating that short interfering RNA knockdown of PACS-2 phenocopies the gene knock-out. This PACS-2-dependent targeting pathway is not restricted to Nef, because PACS-2 is also required for trafficking of an endocytosed cation-independent mannose 6-phosphate receptor reporter from early endosomes to the TGN. Together, these results demonstrate PACS-2 is required for Nef action and sorting of itinerant membrane cargo in the TGN/endosomal system