Confidence intervals for point-of-stabilization of content uniformity.

Within the framework of continuous pharmaceutical manufacturing, we are interested in statistical modeling of the initial behavior of the production line. Assuming a gradually changing sequence of a suitable product quality characteristic (e.g., the content uniformity), we estimate the so-called point-of-stabilization (PoSt) and construct corresponding confidence regions based on appropriate asymptotic distributions and bootstrap. We investigate linear, quadratic, and nonlinear gradual change models both in homoscedastic and heteroscedastic setup. We propose a new nonlinear Emax gradual change model and show that it is applicable even if the true model is linear. Asymptotic distribution of the PoSt estimator is known only in a homoscedastic linear and quadratic model and, therefore, bootstrap approximations are used to construct one-sided PoSt confidence intervals.

Identification of the minimum effective dose for normally distributed data using a Bayesian variable selection approach.

The identification of the minimum effective dose is of high importance in the drug development process. In early stage screening experiments, establishing the minimum effective dose can be translated into a model selection based on information criteria. The presented alternative, Bayesian variable selection approach, allows for selection of the minimum effective dose, while taking into account model uncertainty. The performance of Bayesian variable selection is compared with the generalized order restricted information criterion on two dose-response experiments and through the simulations study. Which method has performed better depends on the complexity of the underlying model and the effect size relative to noise.

Multinomial additive hazard model to assess the disability burden using cross-sectional data.

Population aging is accompanied by the burden of chronic diseases and disability. Chronic diseases are among the main causes of disability, which is associated with poor quality of life and high health care costs in the elderly. The identification of which chronic diseases contribute most to the disability prevalence is important to reduce the burden. Although longitudinal studies can be considered the gold standard to assess the causes of disability, they are costly and often with restricted sample size. Thus, the use of cross-sectional data under certain assumptions has become a popular alternative. Among the existing methods based on cross-sectional data, the attribution method, which was originally developed for binary disability outcomes, is an attractive option, as it enables the partition of disability into the additive contribution of chronic diseases, taking into account multimorbidity and that disability can be present even in the absence of disease. In this paper, we propose an extension of the attribution method to multinomial responses, since disability is often measured as a multicategory variable in most surveys, representing different severity levels. The R function constrOptim is used to maximize the multinomial log-likelihood function subject to a linear inequality constraint. Our simulation study indicates overall good performance of the model, without convergence problems. However, the model must be used with care for populations with low marginal disability probabilities and with high sum of conditional probabilities, especially with small sample size. For illustration, we apply the model to the data of the Belgian Health Interview Surveys.

Identification of in vitro and in vivo disconnects using transcriptomic data.

BACKGROUND: Integrating transcriptomic experiments within drug development is increasingly advocated for the early detection of toxicity. This is partly to reduce costs related to drug failures in the late, and expensive phases of clinical trials. Such an approach has proven useful both in the study of toxicology and carcinogenicity. However, general lack of translation of in vitro findings to in vivo systems remains one of the bottle necks in drug development. This paper proposes a method for identifying disconnected genes between in vitro and in vivo toxicogenomic rat experiments. The analytical framework is based on the joint modeling of dose-dependent in vitro and in vivo data using a fractional polynomial framework and biclustering algorithm. RESULTS: Most disconnected genes identified belonged to known pathways, such as drug metabolism and oxidative stress due to reactive metabolites, bilirubin increase, glutathion depletion and phospholipidosis. We also identified compounds that were likely to induce disconnect in gene expression between in vitro and in vivo toxicogenomic rat experiments. These compounds include: sulindac and diclofenac (both linked to liver damage), naphtyl isothiocyanate (linked to hepatoxocity), indomethacin and naproxen (linked to gastrointestinal problem and damage of intestines). CONCLUSION: The results confirmed that there are important discrepancies between in vitro and in vivo toxicogenomic experiments. However, the contribution of this paper is to provide a tool to identify genes that are disconnected between the two systems. Pathway analysis of disconnected genes may improve our understanding of uncertainties in the mechanism of actions of drug candidates in humans, especially concerning the early detection of toxicity.

Longitudinal trends with improvement in quality of life after TVT, TVT O and Burch colposuspension procedures.

BACKGROUND: Comparison of the quality of life (QoL) trends after TVT, TVT O and Burch colposuspension (BCS) procedures and comparison of long-term subjective and objective outcomes. MATERIAL/METHODS: The study included 215 women who underwent a TVT, TVT O or BCS procedure. We monitored QoL after each procedure and the effect of complications on the QoL as assessed by the IQOL questionnaire over a 3-year period. RESULTS: The study was completed by 74.5% of women after TVT, 74.5% after TVT O, and 65.2% after BCS procedure. In the long-term, the QoL improved from 46.9 to 88.7 and remained stable after BCS; after TVT and TVT O, it declined, but only after TVT O was the decline statistically significant compared to BCS. The IQOL for women with post-operative complications has a clear descending tendency. The effect of the complications is highly significant (p<0.001). Only the OAB complication had a statistically significant effect on QoL p<0.001. Preexistent OAB does not negatively affect postoperative results of anti-incontinence surgery. CONCLUSIONS: There was a statistically significant decline with the longitudinal values of IQOL with TVT O, but not with TVT or BCS. Anti-incontinence operations significantly improve quality of life for women with MI, but compared to the SI group, the quality of life is worse when measured at a longer time interval after the operation. Anti-incontinence operations significantly improve quality of life, and the difference in preoperative status in the long-term follow-up is demonstrable.

Development of a Human iPSC Cardiomyocyte-Based Scoring System for Cardiac Hazard Identification in Early Drug Safety De-risking.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising cardiac safety platform, demonstrated by numerous validation studies using drugs with known cardiac adverse effects in humans. However, the challenge remains to implement hiPSC-CMs into cardiac de-risking of new chemical entities (NCEs) during preclinical drug development. Here, we used the calcium transient screening assay in hiPSC-CMs to develop a hazard score system for cardiac electrical liabilities. Tolerance interval calculations and evaluation of different classes of cardio-active drugs enabled us to develop a weighted scoring matrix. This approach allowed the translation of various pharmacological effects in hiPSC-CMs into a single hazard label (no, low, high, or very high hazard). Evaluation of 587 internal NCEs and good translation to ex vivo and in vivo models for a subset of these NCEs highlight the value of the cardiac hazard scoring in facilitating the selection of compounds during early drug safety screening.