Dataset Information

Diagnosis of drug-induced renal tubular toxicity using global gene expression profiles.

ABSTRACT: Toxicogenomics can measure the expression of thousands of genes to identify changes associated with drug induced toxicities. It is expected that toxicogenomics can be an alternative or complementary approach in preclinical drug safety evaluation to identify or predict drug induced toxicities. One of the major concerns in applying toxicogenomics to diagnose or predict drug induced organ toxicity, is how generalizable the statistical classification model is when derived from small datasets? Here we presented that a diagnosis of kidney proximal tubule toxicity, measured by pathology, can successfully be achieved even with a study design of limited number of training studies or samples. We selected a total of ten kidney toxicants, designed the in life study with multiple dose and multiple time points to cover samples at doses and time points with or without concurrent toxicity. We employed SVM (Support Vector Machine) as the classification algorithm for the toxicogenomic diagnosis of kidney proximal tubule toxicity. Instead of applying cross validation methods, we used an independent testing set by dividing the studies or samples into independent training and testing sets to evaluate the diagnostic performance. We achieved a Sn (sensitivity) = 88% and a Sp (specificity) = 91%. The diagnosis performance underscores the potential application of toxicogenomics in a preclinical lead optimization process of drugs entering into development.

SUBMITTER: Jiang Y

PROVIDER: S-EPMC2194664 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Diagnosis of drug-induced renal tubular toxicity using global gene expression profiles.

Jiang Ying Y Gerhold David L DL Holder Daniel J DJ Figueroa David J DJ Bailey Wendy J WJ Guan Ping P Skopek Thomas R TR Sistare Frank D FD Sina Joseph F JF

Journal of translational medicine 20071001

Toxicogenomics can measure the expression of thousands of genes to identify changes associated with drug induced toxicities. It is expected that toxicogenomics can be an alternative or complementary approach in preclinical drug safety evaluation to identify or predict drug induced toxicities. One of the major concerns in applying toxicogenomics to diagnose or predict drug induced organ toxicity, is how generalizable the statistical classification model is when derived from small datasets? Here w ...[more]

PMID: 17908307

Similar Datasets

Project description:BackgroundIn practice, some drugs produce a number of negative biological effects that can mitigate their effectiveness as a remedy. To address this issue, several studies have been performed for the prediction of drug-induced toxicity from gene-expression data, and a significant amount of work has been done on predicting limited drug-induced symptoms or single-organ toxicity. Since drugs often lead to some injuries in several organs like liver or kidney, however, it would be very useful to forecast the drug-induced injuries for multiple organs. Therefore, in this work, our aim was to develop a multi-organ toxicity prediction model using an integrative model of gene-expression data.ResultsTo train our integrative model, we used 3708 in-vivo samples of gene-expression profiles exposed to one of 41 drugs related to 21 distinct physiological changes divided between liver and kidney (liver 11, kidney 10). Specifically, we used the gene-expression profiles to learn an ensemble classifier for each of 21 pathology prediction models. Subsequently, these classifiers were combined with weights to generate an integrative model for each pathological finding. The integrative model outputs the likeliness of presenting the trained pathology in a given test sample of gene-expression profile, called an integrative prediction score (IPS). For the evaluation of an integrative model, we estimated the prediction performance with the k-fold cross-validation. Our results demonstrate that the proposed integrative model is superior to individual pathology prediction models in predicting multi-organ drug-induced toxicities over all the targeted pathological findings. On average, the AUC of the integrative models was 88% while the AUC of individual pathology prediction models was 68%.ConclusionsNot only does this integrative model produce comparable prediction performance to existing approaches, but also it produces very stable performance overall. In addition, our approach is easily expandable to a variety of other multi-organ toxicology applications.

Dataset Information

Diagnosis of drug-induced renal tubular toxicity using global gene expression profiles.

Publications

Diagnosis of drug-induced renal tubular toxicity using global gene expression profiles.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets