MOTIVATION: An important goal of concentration-response studies in toxicology is to determine an 'alert' concentration where a critical level of the response variable is exceeded. In a classical observation-based approach, only measured concentrations are considered as potential alert concentrations. Alternatively, a parametric curve is fitted to the data that describes the relationship between concentration and response. For a prespecified effect level, both an absolute estimate of the alert concentration and an estimate of the lowest concentration where the effect level is exceeded significantly are of interest. RESULTS: In a simulation study for gene expression data, we compared the observation-based and the model-based approach for both absolute and significant exceedance of the prespecified effect level. Results show that, compared to the observation-based approach, the model-based approach overestimates the true alert concentration less often and more frequently leads to a valid estimate, especially for genes with large variance. AVAILABILITY AND IMPLEMENTATION: The code used for the simulation studies is available via the GitHub repository: https://github.com/FKappenberg/Paper-IdentificationAlertConcentrations. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: TiQuant is a modular software tool for efficient quantification of biological tissues based on volume data obtained by biomedical image modalities. It includes a number of versatile image and volume processing chains tailored to the analysis of different tissue types which have been experimentally verified. TiQuant implements a novel method for the reconstruction of three-dimensional surfaces of biological systems, data that often cannot be obtained experimentally but which is of utmost importance for tissue modelling in systems biology. AVAILABILITY AND IMPLEMENTATION: TiQuant is freely available for non-commercial use at msysbio.com/tiquant. Windows, OSX and Linux are supported. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: An important application of high dimensional gene expression measurements is the risk prediction and the interpretation of the variables in the resulting survival models. A major problem in this context is the typically large number of genes compared to the number of observations (individuals). Feature selection procedures can generate predictive models with high prediction accuracy and at the same time low model complexity. However, interpretability of the resulting models is still limited due to little knowledge on many of the remaining selected genes. Thus, we summarize genes as gene groups defined by the hierarchically structured Gene Ontology (GO) and include these gene groups as covariates in the hazard regression models. Since expression profiles within GO groups are often heterogeneous, we present a new method to obtain subgroups with coherent patterns. We apply preclustering to genes within GO groups according to the correlation of their gene expression measurements. RESULTS: We compare Cox models for modeling disease free survival times of breast cancer patients. Besides classical clinical covariates we consider genes, GO groups and preclustered GO groups as additional genomic covariates. Survival models with preclustered gene groups as covariates have similar prediction accuracy as models built only with single genes or GO groups. CONCLUSIONS: The preclustering information enables a more detailed analysis of the biological meaning of covariates selected in the final models. Compared to models built only with single genes there is additional functional information contained in the GO annotation, and compared to models using GO groups as covariates the preclustering yields coherent representative gene expression profiles.

BACKGROUND: A major goal of the analysis of high-dimensional RNA expression data from tumor tissue is to identify prognostic signatures for discriminating patient subgroups. For this purpose genome-wide identification of bimodally expressed genes from gene array data is relevant because distinguishability of high and low expression groups is easier compared to genes with unimodal expression distributions.Recently, several methods for the identification of genes with bimodal distributions have been introduced. A straightforward approach is to cluster the expression values and score the distance between the two distributions. Other scores directly measure properties of the distribution. The kurtosis, e.g., measures divergence from a normal distribution. An alternative is the outlier-sum statistic that identifies genes with extremely high or low expression values in a subset of the samples. RESULTS: We compare and discuss scores for bimodality for expression data. For the genome-wide identification of bimodal genes we apply all scores to expression data from 194 patients with node-negative breast cancer. Further, we present the first comprehensive genome-wide evaluation of the prognostic relevance of bimodal genes. We first rank genes according to bimodality scores and define two patient subgroups based on expression values. Then we assess the prognostic significance of the top ranking bimodal genes by comparing the survival functions of the two patient subgroups. We also evaluate the global association between the bimodal shape of expression distributions and survival times with an enrichment type analysis.Various cluster-based methods lead to a significant overrepresentation of prognostic genes. A striking result is obtained with the outlier-sum statistic (p < 10-12). Many genes with heavy tails generate subgroups of patients with different prognosis. CONCLUSIONS: Genes with high bimodality scores are promising candidates for defining prognostic patient subgroups from expression data. We discuss advantages and disadvantages of the different scores for prognostic purposes. The outlier-sum statistic may be particularly valuable for the identification of genes to be included in prognostic signatures. Among the genes identified as bimodal in the breast cancer data set several have not yet previously been recognized to be prognostic and bimodally expressed in breast cancer.