https://www.pure.ed.ac.uk/ws/files/40281562/1_s2.0_S0006322317316177_main.pdf

Replicable and Coupled Changes in Innate and Adaptive Immune Gene Expression in Two Case-Control Studies of Blood Microarrays in Major Depressive Disorder.

The modern drug discovery process involves multiple sources of high-dimensional data. This imposes the challenge of data integration. A typical example is the integration of chemical structure (fingerprint features), phenotypic bioactivity (bioassay read-outs) data for targets of interest, and transcriptomic (gene expression) data in early drug discovery to better understand the chemical and biological mechanisms of candidate drugs, and to facilitate early detection of safety issues prior to later and expensive phases of drug development cycles. In this paper, we discuss a joint model for the transcriptomic and the phenotypic variables conditioned on the chemical structure. This modeling approach can be used to uncover, for a given set of compounds, the association between gene expression and biological activity taking into account the influence of the chemical structure of the compound on both variables. The model allows to detect genes that are associated with the bioactivity data facilitating the identification of potential genomic biomarkers for compounds efficacy. In addition, the effect of every structural feature on both genes and pIC50 and their associations can be simultaneously investigated. Two oncology projects are used to illustrate the applicability and usefulness of the joint model to integrate multi-source high-dimensional information to aid drug discovery.

A joint modeling approach for uncovering associations between gene expression, bioactivity and chemical structure in early drug discovery to guide lead selection and genomic biomarker development

In this article, we discuss methods to select three different types of genes (treatment related, response related, or both) and investigate whether they can serve as biomarkers for a binary outcome variable. We consider an extension of the joint model introduced by Lin et al. (2010) and Tilahun et al. (2010) for a continuous response. As the model has certain drawbacks in a binary setting, we also present a way to use classical selection methods to identify subgroups of genes, which are treatment and/or response related. We evaluate their potential to serve as biomarkers by applying DLDA to predict the response level.

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Genomic Biomarkers for a Binary Clinical Outcome in Early Drug Development Microarray Experiments

Selection and evaluation of gene-specific biomarkers in preclinical and clinical microarray experiments

Recently, preclinical microarray experiments have become increasingly common laboratory tools to investigate the activity of thousands of genes simultaneously and their response to a certain treatment (Amaratunga and Cabrera 2004). In some experiments, in addition to the gene expressions, other responses are also available. In such situations, the primary question of interest is to identify whether or not the gene expressions can serve as biomarkers for the responses. In addition to gene expressions, metabolites are potential biomarkers for some responses as well. In the present study, we focus on the identification of genomic biomarkers, based on gene and metabolite expression for depression. One measure of the level of depression is the Hamilton Depression Scale (HDS or HAMD) which is a test measuring the severity of depressive symptoms in individuals. The data for this study are a result of a clinical trial in which both HAMD and gene/metabolites expression were measured. We use three modeling approach...

/pdf/genomic-biomarkers-for-depression-feature-specific-and-joint-2cwymhvhv8.pdf

Evian Gorden

Papers

Genomic Biomarkers for Depression: Feature-Specific and Joint Biomarkers