Biology subjects

Dondelinger, F.

Publications and source records attributed to Dondelinger, F..

6 recordsLinked to original sources

bioRxiv2023

Weak interactions cause poor performance of common network inference models

O_LINetwork inference models have been widely applied in ecological, genetic and social studies to infer unknown interactions. However, little is known about how well the models perform and whether they produce reliable results when confronted with networks where weak interactions predominate and for different amounts of data. This is an important consideration as empirical interaction strengths are commonly skewed towards weaker interactions, which is especially relevant in ecological networks, and a number of studies suggest the importance of weak interactions for ensuring the dynamic stability of a system. C_LIO_LIHere we investigate four commonly used network methods (Bayesian Networks, Graphical Gaussian Models, L1-regularised regression with the least absolute shrinkage and selection operator, and Sparse Bayesian Regression) and employ network simulations with different interaction strengths to assess their accuracy and reliability. C_LIO_LIThe results show poor performance, in terms of the ability to discriminate between existing relationships and no relationships, in the presence of weak interactions, for all the selected network inference methods. C_LIO_LIOur findings suggest that though these models have some promise for network inference with networks that consist of medium or strong interactions and larger amounts of data, data with weak interactions does not provide enough information for the models to reliably identify interactions. Therefore, networks inferred from data of that type should be interpreted with caution. C_LI

ecology↗

bioRxiv2020

Capturing the transcription factor interactome in response to sub-lethal insecticide exposure

The increasing levels of pesticide resistance in agricultural pests and disease vectors represents a threat to both food security and global health. As insecticide resistance intensity strengthens and spreads, the likelihood of a pest encountering a sub-lethal dose of pesticide dramatically increases. Here, we apply dynamic Bayesian networks to a transcriptome time-course generated using sub-lethal pyrethroid exposure on a highly resistant Anopheles coluzzii population. The model accounts for circadian rhythm and ageing effects allowing high confidence identification of transcription factors with key roles in pesticide response. The associations generated by this model show high concordance with lab-based validation and identifies 44 transcription factors regulating insecticide-responsive transcripts. We identify six key regulators, with each displaying differing enrichment terms, demonstrating the complexity of pesticide response. The considerable overlap of resistance mechanisms in agricultural pests and disease vectors strongly suggests that these findings are relevant in a wide variety of pest species.

systems biology↗

bioRxiv2020

A regularized functional regression model enabling transcriptome-wide dosage-dependent association study of cancer drug response

Cancer treatments can be highly toxic and frequently only a subset of the patient population will benefit from a given treatment. Tumour genetic makeup plays an important role in cancer drug sensitivity. We suspect that gene expression markers could be used as a decision aid for treatment selection or dosage tuning. Using in vitro cancer cell line dose-response and gene expression data from the Genomics of Drug Sensitivity in Cancer (GDSC) project, we build a dose-varying regression model. Unlike existing approaches, this allows us to estimate dosage-dependent associations with gene expression. We include the transcriptomic profiles as dose-invariant covariates into the regression model and assume that their effect varies smoothly over the dosage levels. A two-stage variable selection algorithm (variable screening followed by penalised regression) is used to identify genetic factors that are associated with drug response over the varying dosages. We evaluate the effectiveness of our method using simulation studies focusing on the choice of tuning parameters and cross-validation for predictive accuracy assessment. We further apply the model to data from five BRAF targeted compounds applied to different cancer cell lines under different dosage levels. We highlight the dosage-dependent dynamics of the associations between the selected genes and drug response, and we perform pathway enrichment analysis to show that the selected genes play an important role in pathways related to tumourgenesis and DNA damage response. Author SummaryTumour cell lines allow scientists to test anticancer drugs in a laboratory environment. Cells are exposed to the drug in increasing concentrations, and the drug response, or amount of surviving cells, is measured. Generally, drug response is summarized via a single number such as the concentration at which 50% of the cells have died (IC50). To avoid relying on such summary measures, we adopted a functional regression approach that takes the dose-response curves as inputs, and uses them to find biomarkers of drug response. One major advantage of our approach is that it describes how the effect of a biomarker on the drug response changes with the drug dosage. This is useful for determining optimal treatment dosages and predicting drug response curves for unseen drug-cell line combinations. Our method scales to large numbers of biomarkers by using regularisation and, in contrast with existing literature, selects the most informative genes by accounting for drug response at untested dosages. We demonstrate its value using data from the Genomics of Drug Sensitivity in Cancer project to identify genes whose expression is associated with drug response. We show that the selected genes recapitulate prior biological knowledge, and belong to known cancer pathways.

bioinformatics↗

bioRxiv2020

A statistical framework for assessing pharmacological response and biomarkers with confidence

Drug high-throughput screenings across large molecular-characterised cancer cell line panels enable the discovery of biomarkers, and thereby, cancer precision medicine. The ability to experimentally generate drug response data has accelerated. However, this data is typically quantified by a summary statistic from a best-fit dose response curve, whilst neglecting the uncertainty of the curve fit and the potential variability in the raw readouts. Here, we model the experimental variance using Gaussian Processes, and subsequently, leverage this uncertainty for identifying associated biomarkers with a new statistical framework based on Bayesian testing. Applied to the Genomics of Drug Sensitivity in Cancer, in vitro screening data on 265 compounds across 1,074 cell lines, our uncertainty models identified 24 clinically established drug response biomarkers, and in addition provided evidence for 6 novel biomarkers. We validated our uncertainty estimates with an additional drug screen of 26 drugs, 10 cell lines with 8 to 9 replicates. Our method is applicable to drug high-throughput screens without replicates, and enables robust biomarker discovery for new cancer therapies.

cancer biology↗

bioRxiv2020

A Bayesian Multi-Task Approach for Detecting Global Microbiome Associations

MotivationThe human gut microbiome has been shown to be associated with a variety of human diseases, including cancer, metabolic conditions and inflammatory bowel disease. Current statistical techniques for microbiome association studies are limited by relying on measures of ecological distance, or only allowing for the detection of associations with individual bacterial species, rather than the whole microbiome. ResultsIn this work, we develop a novel Bayesian multi-task approach for detecting global microbiome associations. Our method is not dependent on a choice of distance measure, and is able to incorporate phylogenetic information about microbial species. We apply our method to simulated data and show that it allows for consistent estimation of global microbiome effects. Additionally, we investigate the performance of the model on two real-world microbiome studies: a study of microbiome-metabolome associations in inflammatory bowel disease (Beamish, 2017), and a study of associations between diet and the gut microbiome in mice (Turnbaugh et al., 2009). We show that we can use the method to reliably detect associations in real-world datasets with varying numbers of samples and covariates. AvailabilityOur method is implemented using the R interface to the Stan Hamiltonian Monte Carlo sampler. Software for running our methods is available at https://github.com/FrankD/MicrobiomeGlobalAssociations. Contactf.dondelinger@lancaster.ac.uk

microbiology↗

bioRxiv2016

High-dimensional regression over disease subgroups

We consider high-dimensional regression over subgroups of observations. Our work is motivated by biomedical problems, where disease subtypes, for example, may differ with respect to underlying regression models, but sample sizes at the subgroup-level may be limited. We focus on the case in which subgroup-specific models may be expected to be similar but not necessarily identical. Our approach is to treat subgroups as related problem instances and jointly estimate subgroup-specific regression coefficients. This is done in a penalized framework, combining an{ell} 1 term with an additional term that penalizes differences between subgroup-specific coefficients. This gives solutions that are globally sparse but that allow information-sharing between the subgroups. We present algorithms for estimation and empirical results on simulated data and using Alzheimers disease, amyotrophic lateral sclerosis and cancer datasets. These examples demonstrate the gains our approach can offer in terms of prediction and the ability to estimate subgroup-specific sparsity patterns.

bioinformatics↗