IsoGeneGUI: Multiple Approaches for Dose-Response Analysis of Microarray Data Using R

The analysis of transcriptomic experiments with ordered covariates, such as dose-response data, has become a central topic in bioinformatics, in particular in omics studies. Consequently, multiple R packages on CRAN and Bioconductor are designed to analyse microarray data from various perspectives under the assumption of order restriction. We introduce the new R package IsoGene Graphical User Interface (IsoGeneGUI), an extension of the original IsoGene package that includes methods from most of available R packages designed for the analysis of order restricted microarray data, namely orQA, ORIClust, goric and ORCME. The methods included in the new IsoGeneGUI range from inference and estimation to model selection and clustering tools. The IsoGeneGUI is not only the most complete tool for the analysis of order restricted microarray experiments available in R but also it can be used to analyse other types of dose-response data. The package provides all the methods in a user friendly fashion, so analyses can be implemented by users with limited knowledge of R programming

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Prediction of gene expression in human using rat in vivo gene expression in Japanese Toxicogenomics Project

The Japanese Toxicogenomics Project (TGP) provides large amount of data for the toxicology and safety framework. We focus on gene expression data of rat in vivo and human in vitro. We consider two different analyses for the TGP data. The first analysis is based on two-way analysis of variance model and the goal is to detect genes with significant dose-response relationship in both humans and rats. The second analysis consists of a trend analysis at each time point and the goal is to detect genes in the rat in order to predict gene expression in humans. The first analysis leads us to conclusions about the heterogeneity of the compound set and will suggest how to address this issue to improve future analyses. In the second part, we identify, for particular compounds, groups of genes that are translatable from rats to humans, so they can be used for prediction of human in vitro data based on rat in vivo data

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 vivotoxicogenomic 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

Multinomial additive hazards 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.status: publishe

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

&lt;p&gt;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.&lt;/p&gt;</p

Parents' psychological well-being and parental self-efficacy in relation to the family's triadic interaction.

The aim of the study was to assess whether a parent's psychological well-being and/or self-efficacy relate to interaction within the family. This study is part of a Finnish follow-up study called Steps to the Healthy Development and Well-Being of Children (STEPS;). The study group included 120 families. Mother's and father's social anxiety and depression were assessed during pregnancy and at 18 months of the child's age using self-report questionnaires; the mother's and father's self-efficacy were assessed at 18 months using a parental self-efficacy scale validated within the STEPS study. Mother-father-child triadic interaction was studied at 18 months within a Lausanne Triadic Play setting. Results showed that maternal symptoms of depression during pregnancy and maternal social anxiety at 18 months were related to triadic interaction within the family. There was no relation between father's psychological well-being and triadic interaction within the family. Father's self-efficacy in teaching tasks and the Mother's self-efficacy in emotional support were associated with family interaction. The findings suggest that maternal psychological well-being and self-efficacy in emotional support may be important components of family triadic interaction whereas paternal self-efficacy in teaching tasks seems to support family coordination in triadic interaction

IsoGeneGUI: Multiple Approaches for Dose-Response Analysis of Microarray Data Using R

The analysis of transcriptomic experiments with ordered covariates, such as dose-response data, has become a central topic in bioinformatics, in particular in omics studies. Consequently, multiple R packages on CRAN and Bioconductor are designed to analyse microarray data from various perspectives under the assumption of order restriction. We introduce the new R package IsoGene Graphical User Interface (IsoGeneGUI), an extension of the original IsoGene package that includes methods from most of available R packages designed for the analysis of order restricted microarray data, namely orQA, ORIClust, goric and ORCME. The methods included in the new IsoGeneGUI range from inference and estimation to model selection and clustering tools. The IsoGeneGUI is not only the most complete tool for the analysis of order restricted microarray experiments available in R but also it can be used to analyse other types of dose-response data. The package provides all the methods in a user friendly fashion, so analyses can be implemented by users with limited knowledge of R programming