Martin Otava

Dose–Response Modeling Under Simple Order Restrictions Using Bayesian Variable Selection Methods

Bayesian modeling of dose–response data offers the possibility to establish the relationship between a clinical or a genomic response and increasing doses of a therapeutic compound and to determine the nature of the relationship wherever it exists. In this article, we focus on an order-restricted one-way ANOVA model which can be used to test the null hypothesis of no dose effect against an ordered alternative. Within the framework of the dose–response modeling, a model uncertainty can be addressed using model averaging techniques. In this setting, the uncertainty is related to the number of all possible models that can be fitted to the data and should be taken into account for both inference and estimation. In this article, we propose an order-restricted Bayesian variable selection model that addresses the model uncertainty and can be used for both inference and estimation. The proposed method is applied to two case studies and is compared to the likelihood ratio test and the multiple contrast tests in both the analyses of the case studies and a simulation study. This article has online supplementary material.

Identification of in vitro and in vivo disconnects using transcriptomic data

BackgroundIntegrating 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.ResultsMost 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).ConclusionThe 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.

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

ABSTRACT 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.

δ-Clustering of Monotone Profiles

In Chaps. and 8, we discussed several testing procedures to detect differentially expressed genes with monotone relationship with respect to dose. The second question of primary interest in dose-response studies is the nature (or the shape of curve) of the dose-response relationship. In the context of dose-response microarray experiments, we wish to group (or classify) genes with similar dose-response relationship. Similar to the previous chapters, the subset of genes with monotone relationship is of interest.