Dataset Information

OptCouple: Joint simulation of gene knockouts, insertions and medium modifications for prediction of growth-coupled strain designs.

ABSTRACT: Biological production of chemicals is an attractive alternative to petrochemical-based production, due to advantages in environmental impact and the spectrum of feasible targets. However, engineering microbial strains to overproduce a compound of interest can be a long, costly and painstaking process. If production can be coupled to cell growth it is possible to use adaptive laboratory evolution to increase the production rate. Strategies for coupling production to growth, however, are often not trivial to find. Here we present OptCouple, a constraint-based modeling algorithm to simultaneously identify combinations of gene knockouts, insertions and medium supplements that lead to growth-coupled production of a target compound. We validated the algorithm by showing that it can find novel strategies that are growth-coupled in silico for a compound that has not been coupled to growth previously, as well as reproduce known growth-coupled strain designs for two different target compounds. Furthermore, we used OptCouple to construct an alternative design with potential for higher production. We provide an efficient and easy-to-use implementation of the OptCouple algorithm in the cameo Python package for computational strain design.

SUBMITTER: Jensen K

PROVIDER: S-EPMC6431744 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

OptCouple: Joint simulation of gene knockouts, insertions and medium modifications for prediction of growth-coupled strain designs.

Jensen Kristian K Broeken Valentijn V Hansen Anne Sofie Lærke ASL Sonnenschein Nikolaus N Herrgård Markus J MJ

Metabolic engineering communications 20190316

Biological production of chemicals is an attractive alternative to petrochemical-based production, due to advantages in environmental impact and the spectrum of feasible targets. However, engineering microbial strains to overproduce a compound of interest can be a long, costly and painstaking process. If production can be coupled to cell growth it is possible to use adaptive laboratory evolution to increase the production rate. Strategies for coupling production to growth, however, are often not ...[more]

PMID: 30956947

Similar Datasets

Project description:BackgroundAdaptive clinical trials are growing in popularity as they are more flexible, efficient and ethical than traditional fixed designs. However, notwithstanding their increased use in assessing treatments for COVID-19, their use in critical care trials remains limited. A better understanding of the relative benefits of various adaptive designs may increase their use and interpretation.MethodsUsing two large critical care trials (ADRENAL.Clinicaltrialsgov number, NCT01448109. Updated 12-12-2017; NICE-SUGAR.Clinicaltrialsgov number, NCT00220987. Updated 01-29-2009), we assessed the performance of three frequentist and two bayesian adaptive approaches. We retrospectively re-analysed the trials with one, two, four, and nine equally spaced interims. Using the original hypotheses, we conducted 10,000 simulations to derive error rates, probabilities of making an early correct and incorrect decision, expected sample size and treatment effect estimates under the null scenario (no treatment effect) and alternative scenario (a positive treatment effect). We used a logistic regression model with 90-day mortality as the outcome and the treatment arm as the covariate. The null hypothesis was tested using a two-sided significance level (α) at 0.05.ResultsAcross all approaches, increasing the number of interims led to a decreased expected sample size. Under the null scenario, group sequential approaches provided good control of the type-I error rate; however, the type I error rate inflation was an issue for the Bayesian approaches. The Bayesian Predictive Probability and O'Brien-Fleming approaches showed the highest probability of correctly stopping the trials (around 95%). Under the alternative scenario, the Bayesian approaches showed the highest overall probability of correctly stopping the ADRENAL trial for efficacy (around 91%), whereas the Haybittle-Peto approach achieved the greatest power for the NICE-SUGAR trial. Treatment effect estimates became increasingly underestimated as the number of interims increased.ConclusionsThis study confirms the right adaptive design can reach the same conclusion as a fixed design with a much-reduced sample size. The efficiency gain associated with an increased number of interims is highly relevant to late-phase critical care trials with large sample sizes and short follow-up times. Systematically exploring adaptive methods at the trial design stage will aid the choice of the most appropriate method.

Project description:Motivation5-methylcytosine (5mC) is a widely studied epigenetic modification of DNA. The ten-eleven translocation (TET) dioxygenases oxidize 5mC into oxidized methylcytosines (oxi-mCs): 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). DNA methylation modifications have multiple functions. For example, 5mC is shown to be associated with diseases and oxi-mC species are reported to have a role in active DNA demethylation through 5mC oxidation and DNA repair, among others, but the detailed mechanisms are poorly understood. Bisulphite sequencing and its various derivatives can be used to gain information about all methylation modifications at single nucleotide resolution. Analysis of bisulphite based sequencing data is complicated due to the convoluted read-outs and experiment-specific variation in biochemistry. Moreover, statistical analysis is often complicated by various confounding effects. How to analyse 5mC and oxi-mC data sets with arbitrary and complex experimental designs is an open and important problem.ResultsWe propose the first method to quantify oxi-mC species with arbitrary covariate structures from bisulphite based sequencing data. Our probabilistic modeling framework combines a previously proposed hierarchical generative model for oxi-mC-seq data and a general linear model component to account for confounding effects. We show that our method provides accurate methylation level estimates and accurate detection of differential methylation when compared with existing methods. Analysis of novel and published data gave insights into to the demethylation of the forkhead box P3 (Foxp3) locus during the induced T regulatory cell differentiation. We also demonstrate how our covariate model accurately predicts methylation levels of the Foxp3 locus. Collectively, LuxGLM method improves the analysis of DNA methylation modifications, particularly for oxi-mC species.Availability and implementationAn implementation of the proposed method is available under MIT license at https://github.org/tare/LuxGLM/ CONTACT: taijo@simonsfoundation.org or harri.lahdesmaki@aalto.fiSupplementary informationSupplementary data are available at Bioinformatics online.

Dataset Information

OptCouple: Joint simulation of gene knockouts, insertions and medium modifications for prediction of growth-coupled strain designs.

Publications

OptCouple: Joint simulation of gene knockouts, insertions and medium modifications for prediction of growth-coupled strain designs.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets