Joint modeling of time-to-event data and multiple ratings of a discrete diagnostic test without a gold standard

Histologic tumor grade is a strong predictor of risk of recurrence in breast cancer. Nevertheless, tumor grade readings by pathologists are susceptible to intra- and inter-observer variability due to its subject nature. Because of this limitation, histologic tumor grade is not included in the breast cancer stating system. Latent class models have been considered for analysis of such discrete diagnostic tests with regarding the underlying truth as a latent variable. However, the model parameters in latent class models are only locally identifiable, that is, any permutation on the categories of the underlying truth can lead to the same likelihood value. In many clinical practices, the underlying truth is known associated with the risk of a certain event in a trend. Here, we proposed a joint model with a Cox proportional hazards model for time-to-event data where the underlying truth is a latent predictor and a latent class model for multiple ratings of a discrete diagnostic test without a gold standard. With the known association between the underlying truth and the risk of an event in a trend, the proposed joint model not only fully identifies all model parameters but also provides valid assessment of the association between the diagnostic test result and the risk of an event. The modified EM algorithm was used for estimation with employing the survey-weighted Cox model in the M-step. To test whether the known trend imposed on model parameters can be assumed, we applied the Union-Intersection principle for the proposed joint model. The proposed method is illustrated in the analysis of data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 sub-study and through simulation studies. The proposed method is relevant to public health fields, such as chronic diseases and psychiatry, where some components of the initial diagnostics are subjective but have important implications in patient management. Application of our method leads to accurate assessment on the association between the diagnostic tests and the clinical outcomes and subsequently significant improvement in decision-making on treatment or patient management

Optimal designs for asymmetric sigmoidal response curves in bioassays and immunoassays

Recent studies show that asymmetric sigmoidal response curves are not uncommonin biomedical studies. For example, the 5-parameter logistic (5PL) model isfrequently used to model and analyze responses from bioassays and immunoassayswhich can be skewed. Various types of optimal experimental designs for 2, 3 and4-parameter logistic models have been reported but not for the more complicated5-parameter logistic (5PL) model. Designs currently used for the 5PL model seemad-hoc with no formal quantitative assessment of their efficiencies. We constructdifferent types of optimal designs for studying various features of the 5PL modeland use them to evaluate efficiencies of commonly used designs in bioassays andimmunoassays. We also create a user-friendly software package to search for optimaldesigns tailor-made to user-specified problems for the 5PL model and evaluaterobustness properties of the design under a variation of criteria, model formsand mis-specification in the nominal values of the model parameters. Our designstrategies can also account for several objectives with varying degrees of importance.As an application, we generate optimal designs for the 5PL model for real studiesin immunoassays and bioassays, and show currently used designs are generallyinefficient for statistical inference

Elevated intracellular cAMP exacerbates vulnerability to oxidative stress in optic nerve head astrocytes.

Glaucoma is characterized by a progressive loss of retinal ganglion cells and their axons, but the underlying biological basis for the accompanying neurodegeneration is not known. Accumulating evidence indicates that structural and functional abnormalities of astrocytes within the optic nerve head (ONH) have a role. However, whether the activation of cyclic adenosine 3',5'-monophosphate (cAMP) signaling pathway is associated with astrocyte dysfunction in the ONH remains unknown. We report here that the cAMP/protein kinase A (PKA) pathway is critical to ONH astrocyte dysfunction, leading to caspase-3 activation and cell death via the AKT/Bim/Bax signaling pathway. Furthermore, elevated intracellular cAMP exacerbates vulnerability to oxidative stress in ONH astrocytes, and this may contribute to axonal damage in glaucomatous neurodegeneration. Inhibition of intracellular cAMP/PKA signaling activation protects ONH astrocytes by increasing AKT phosphorylation against oxidative stress. These results strongly indicate that activation of cAMP/PKA pathway has an important role in astrocyte dysfunction, and suggest that modulating cAMP/PKA pathway has therapeutic potential for glaucomatous ONH degeneration

Low energy proton-proton scattering in effective field theory

Low energy proton-proton scattering is studied in pionless effective field theory. Employing the dimensional regularization and MS-bar and power divergence subtraction schemes for loop calculation, we calculate the scattering amplitude in 1S0 channel up to next-to-next-to leading order and fix low-energy constants that appear in the amplitude by effective range parameters. We study regularization scheme and scale dependence in separation of Coulomb interaction from the scattering length and effective range for the S-wave proton-proton scattering.Comment: 23 pages, 6 eps figures, revised considerably, accepted for publication in Phys. Rev.

The Rhizome Mixture of Anemarrhena asphodeloides

We investigated the effect of DWac on the gut microbiota composition in mice with 2,3,6-trinitrobenzenesulfonic acid- (TNBS-) induced colitis. Treatment with DWac restored TNBS-disturbed gut microbiota composition and attenuated TNBS-induced colitis. Moreover, we examined the effect of DWac in mice with mesalazine-resistant colitis (MRC). Intrarectal injection of TNBS in MRC mice caused severe colitis, as well as colon shortening, edema, and increased myeloperoxidase activity. Treatment with mesalazine (30 mg/kg) did not attenuate TNBS-induced colitis in MRC mice, whereas treatment with DWac (30 mg/kg) significantly attenuated TNBS-induced colitis. Moreover, treatment with the mixture of mesalazine (15 mg/kg) and DWac (15 mg/kg) additively attenuated colitis in MRC mice. Treatment with DWac and its mixture with mesalazine inhibited TNBS-induced activation of NF-κB and expression of M1 macrophage markers but increased TNBS-suppressed expression of M2 macrophage markers. Furthermore, these inhibited TNBS-induced T-bet, RORγt, TNF-α, and IL-17 expression but increased TNBS-suppressed Foxp3 and IL-10 expression. However, Th2 cell differentiation and GATA3 and IL-5 expression were not affected. These findings suggest that DWac can ameliorate MRC by increasing the polarization of M2 macrophage and correcting the disturbance of gut microbiota and Th1/Th17/Treg, as well as additively attenuating MRC along with mesalazine

VNM: An R Package for Finding Multiple-Objective Optimal Designs for the 4-Parameter Logistic Model

A multiple-objective optimal design is useful for dose-response studies because it can incorporate several objectives at the design stage. Objectives can be of varying interests and a properly constructed multiple-objective optimal design can provide user-specified efficiencies, delivering higher efficiencies for the more important objectives. In this work, we introduce the VNM package written in R for finding 3-objective locally optimal designs for the 4-parameter logistic (4PL) model widely used in education, bioscience and in the manufacturing industry. The package implements the methodology to construct multipleobjective optimal designs in Hyun and Wong (2015). As illustrative examples, we focus on a biomedical application where our objectives are to estimate: (1) the shape of the dose-response curve, (2) the median effective dose level (ED50) and (3) the minimum effective dose level (MED) in the 4PL model. Our VNM package uses a state-of-theart algorithm to generate multiple-objective optimal designs that meet the user-specified efficiency requirement for each objective, provides tools for calculating the efficiency of the generated design under each objective and also a plot for confirming optimality of the VNM-generated design. The package can also be used to determine an optimal scheme for allocating subjects to the various doses when the number and doses of the drug are fixed in advance