Semiparametric Approaches for Joint modeling of Longitudinal and Survival Data with Time Varying Coefficients

We study joint modeling of survival and longitudinal data. There are two regression models of interest. The primary model is for survival outcomes, which are assumed to follow a time varying coefficient proportional hazards model. The second model is for longitudinal data, which are assumed to follow a random effects model. Based on the trajectory of a subject\u27s longitudinal data, some covariates in the survival model are functions of the unobserved random effects. Estimated random effects are generally different from the unobserved random effects and hence this leads to covariate measurement error. To deal with covariate measurement error, we propose a local corrected score estimator and a local conditional score estimator. Both approaches are semiparametric methods in the sense that there is no distributional assumption needed for the underlying true covariates. The estimators are shown to be consistent and asymptotically normal. Finite sample properties are assessed via simulation. The approaches are demonstrated by an application to data from an HIV clinical trial

Evaluation of SPARC as a candidate gene of juvenile-onset primary open-angle glaucoma by mutation and copy number analyses

Purpose: To investigate the involvement of SPARC (secreted protein acidic and rich in cysteine) mutations and copy number variation in juvenile-onset primary open-angle glaucoma (JPOAG). Methods: This study involved the 27 family members from the GLC1M (glaucoma 1, open angle, M)-linked Philippine pedigree with JPOAG, 46 unrelated Chinese patients with JPOAG and 95 controls. Mutation screening of the SPARC sequence, covering the promoter, 5′-untranslated region (UTR), entire coding regions, exon-intron boundaries, and part of the 3′-UTR, was performed using polymerase chain reaction and direct DNA sequencing. Copy number of the gene was analyzed by three TaqMan copy number assays. Results: No putative SPARC mutation was detected in the Philippine family. In the Chinese participants, 11 sequence variants were detected. Two were novel: IVS2+8G>T and IVS2+32C>T. For the 9 known SNPs, one was synonymous (rs2304052, p.Glu22Glu) and the others were located in noncoding regions. No individual SNP was associated with JPOAG. Five of the most common SNPs, i.e., rs2116780, rs1978707, rs7719521, rs729853, and rs1053411, were contained in a LD (linkage disequilibrium) block. Haplotype-based analysis showed that no haplotype was associated with the disorder. Copy number analysis revealed that all study subjects had two copies of the gene, suggesting no correlation between the copy number of SPARC and JPOAG. Conclusions: We have excluded SPARC as the causal gene at the GLC1M locus in the Philippine pedigree and, for the first time, revealed that the coding sequences, splice sites and copy number of SPARC do not contribute to JPOAG. Further investigations are warranted to unravel the involvement of SPARC in the pathogenesis of other forms of glaucoma

SARS Coronavirus Detection Methods

Using clinical samples from patients with severe acute respiratory syndrome, we showed that the sensitivities of a quantitative reverse transcription–polymerase chain reaction (80% for fecal samples and 25% for urine samples) were higher than those of the polyclonal (50% and 5%) and monoclonal (35% and 8%) antibody-based nucleocapsid antigen capture enzyme-linked immunosorbent assays

Danggui Buxue Tang – A Chinese herbal decoction activates the phosphorylations of extracellular signal-regulated kinase and estrogen receptor α in cultured MCF-7 cells

AbstractDanggui Buxue Tang (DBT), a Chinese herbal decoction used to treat ailments in women, contains Radix Astragali (Huangqi; RA) and Radix Angelicae Sinensis (Danggui; RAS). The weight ratio of RA to RAS used in DBT must be 5:1 as stipulated as early as AD 1247; however, DBT’s mechanism of action has never been described. Here, the estrogenic effects of DBT were investigated by determining the phosphorylations of estrogen receptor α (ERα) and extracellular signal-regulated kinase 1/2 (Erk1/2) in cultured MCF-7 cells. The application of DBT triggered the phosphorylation of ERα and Erk1/2 in a time-dependent manner. In contrast to the effect of estrogen, DBT triggered ERα phosphorylation at both S118 and S167. This DBT-specific phosphorylation was not triggered by an extract of one of the individual herbs, or by mixing the extracts of RA and RAS. DBT-induced downstream signals are described here. These signals suggest the uniqueness of this Chinese herbal decoction that requires a well-defined formulation

New Lymphogranuloma Venereum Chlamydia trachomatis Variant, Amsterdam

We retrospectively conducted a study of men who have sex with men who visited the Amsterdam, the Netherlands, sexually transmitted diseases clinic from January 2002 to December 2003 and had rectal Chlamydia trachomatis infections. We found that symptomatic (73%) as well as asymptomatic (43%) patients were infected with a new C. trachomatis LGV variant

Nonlinear wave transmission and pressure on the fixed truncated breakwater using NURBS numerical wave tank

Fully nonlinear wave interaction with a fixed breakwater is investigated in a numerical wave tank (NWT). The potential theory and high-order boundary element method are used to solve the boundary value problem. Time domain simulation by a mixed Eulerian-Lagrangian (MEL) formulation and high-order boundary integral method based on non uniform rational B-spline (NURBS) formulation is employed to solve the equations. At each time step, Laplace equation is solved in Eulerian frame and fully non-linear free-surface conditions are updated in Lagrangian manner through material node approach and fourth order Runge-Kutta time integration scheme. Incident wave is fed by specifying the normal flux of appropriate wave potential on the fixed inflow boundary. To ensure the open water condition and to reduce the reflected wave energy into the computational domain, two damping zones are provided on both ends of the numerical wave tank. The convergence and stability of the presented numerical procedure are examined and compared with the analytical solutions. Wave reflection and transmission of nonlinear waves with different steepness are investigated. Also, the calculation of wave load on the breakwater is evaluated by first and second order time derivatives of the potential

ELM mitigation by supersonic molecular beam injection: KSTAR and HL-2A experiments and theory

We report recent experimental results from HL-2A and KSTAR on ELM mitigation by supersonic molecular beam injection (SMBI). Cold particle deposition within the pedestal by SMBI is verified in both machines. The signatures of ELM mitigation by SMBI are an ELM frequency increase and ELM amplitude decrease. These persist for an SMBI influence time τI. Here, τI is the time for the SMBI influenced pedestal profile to refill. An increase in fELMSMBI/fELM0 and a decrease in the energy loss per ELM ΔWELM were achieved in both machines. Physical insight was gleaned from studies of density and vΦ (toroidal rotation velocity) evolution, particle flux and turbulence spectra, divertor heat load. The characteristic gradients of the pedestal density soften and a change in vΦ was observed during a τI time. The spectra of the edge particle flux Γ ∼ 〈ṽrñe〉 and density fluctuation with and without SMBI were measured in HL-2A and in KSTAR, respectively. A clear phenomenon observed is the decrease in divertor heat load during the τI time in HL-2A. Similar results are the profiles of saturation current density Jsat with and without SMBI in KSTAR. We note that τI/τp (particle confinement time) is close to ∼1, although there is a large difference in individual τI between the two machines. This suggests that τI is strongly related to particle-transport events. Experiments and analysis of a simple phenomenological model support the important conclusion that ELM mitigation by SMBI results from an increase in higher frequency fluctuations and transport events in the pedestal. © 2014 IAEA, Vienna

Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. Video Abstract [Figure presented] Keywords: type 2 diabetes (T2D); genetics; disease mechanism; SLC16A11; MCT11; solute carrier (SLC); monocarboxylates; fatty acid metabolism; lipid metabolism; precision medicin

Search for the Chiral Magnetic Effect in Au+Au collisions at sNN=27\sqrt{s_{_{\rm{NN}}}}=27 GeV with the STAR forward Event Plane Detectors

A decisive experimental test of the Chiral Magnetic Effect (CME) is considered one of the major scientific goals at the Relativistic Heavy-Ion Collider (RHIC) towards understanding the nontrivial topological fluctuations of the Quantum Chromodynamics vacuum. In heavy-ion collisions, the CME is expected to result in a charge separation phenomenon across the reaction plane, whose strength could be strongly energy dependent. The previous CME searches have been focused on top RHIC energy collisions. In this Letter, we present a low energy search for the CME in Au+Au collisions at $\sqrt{s_{_{\rm{NN}}}}=27$ GeV. We measure elliptic flow scaled charge-dependent correlators relative to the event planes that are defined at both mid-rapidity $|\eta|<1.0$ and at forward rapidity $2.1 < |\eta|<5.1$. We compare the results based on the directed flow plane ($\Psi_1$) at forward rapidity and the elliptic flow plane ($\Psi_2$) at both central and forward rapidity. The CME scenario is expected to result in a larger correlation relative to $\Psi_1$ than to $\Psi_2$, while a flow driven background scenario would lead to a consistent result for both event planes[1,2]. In 10-50\% centrality, results using three different event planes are found to be consistent within experimental uncertainties, suggesting a flow driven background scenario dominating the measurement. We obtain an upper limit on the deviation from a flow driven background scenario at the 95\% confidence level. This work opens up a possible road map towards future CME search with the high statistics data from the RHIC Beam Energy Scan Phase-II.Comment: main: 8 pages, 5 figures; supplementary material: 2 pages, 1 figur