Topological augmentation to infer hidden processes in biological systems

Motivation: A common problem in understanding a biochemical system is to infer its correct structure or topology. This topology consists of all relevant state variables—usually molecules and their interactions. Here we present a method called topological augmentation to infer this structure in a statistically rigorous and systematic way from prior knowledge and experimental data. Results: Topological augmentation starts from a simple model that is unable to explain the experimental data and augments its topology by adding new terms that capture the experimental behavior. This process is guided by representing the uncertainty in the model topology through stochastic differential equations whose trajectories contain information about missing model parts. We first apply this semiautomatic procedure to a pharmacokinetic model. This example illustrates that a global sampling of the parameter space is critical for inferring a correct model structure. We also use our method to improve our understanding of glutamine transport in yeast. This analysis shows that transport dynamics is determined by glutamine permeases with two different kinds of kinetics. Topological augmentation can not only be applied to biochemical systems, but also to any system that can be described by ordinary differential equations. Availability and implementation: Matlab code and examples are available at: http://www.csb.ethz.ch/tools/index. Contact: [email protected]; [email protected] Supplementary information: Supplementary data are available at Bioinformatics onlin

Topological sensitivity analysis for systems biology.

Mathematical models of natural systems are abstractions of much more complicated processes. Developing informative and realistic models of such systems typically involves suitable statistical inference methods, domain expertise, and a modicum of luck. Except for cases where physical principles provide sufficient guidance, it will also be generally possible to come up with a large number of potential models that are compatible with a given natural system and any finite amount of data generated from experiments on that system. Here we develop a computational framework to systematically evaluate potentially vast sets of candidate differential equation models in light of experimental and prior knowledge about biological systems. This topological sensitivity analysis enables us to evaluate quantitatively the dependence of model inferences and predictions on the assumed model structures. Failure to consider the impact of structural uncertainty introduces biases into the analysis and potentially gives rise to misleading conclusions

Fruit Detection and Tree Segmentation for Yield Mapping in Orchards

Accurate information gathering and processing is critical for precision horticulture, as growers aim to optimise their farm management practices. An accurate inventory of the crop that details its spatial distribution along with health and maturity, can help farmers efficiently target processes such as chemical and fertiliser spraying, crop thinning, harvest management, labour planning and marketing. Growers have traditionally obtained this information by using manual sampling techniques, which tend to be labour intensive, spatially sparse, expensive, inaccurate and prone to subjective biases. Recent advances in sensing and automation for field robotics allow for key measurements to be made for individual plants throughout an orchard in a timely and accurate manner. Farmer operated machines or unmanned robotic platforms can be equipped with a range of sensors to capture a detailed representation over large areas. Robust and accurate data processing techniques are therefore required to extract high level information needed by the grower to support precision farming. This thesis focuses on yield mapping in orchards using image and light detection and ranging (LiDAR) data captured using an unmanned ground vehicle (UGV). The contribution is the framework and algorithmic components for orchard mapping and yield estimation that is applicable to different fruit types and orchard configurations. The framework includes detection of fruits in individual images and tracking them over subsequent frames. The fruit counts are then associated to individual trees, which are segmented from image and LiDAR data, resulting in a structured spatial representation of yield. The first contribution of this thesis is the development of a generic and robust fruit detection algorithm. Images captured in the outdoor environment are susceptible to highly variable external factors that lead to significant appearance variations. Specifically in orchards, variability is caused by changes in illumination, target pose, tree types, etc. The proposed techniques address these issues by using state-of-the-art feature learning approaches for image classification, while investigating the utility of orchard domain knowledge for fruit detection. Detection is performed using both pixel-wise classification of images followed instance segmentation, and bounding-box regression approaches. The experimental results illustrate the versatility of complex deep learning approaches over a multitude of fruit types. The second contribution of this thesis is a tree segmentation approach to detect the individual trees that serve as a standard unit for structured orchard information systems. The work focuses on trellised trees, which present unique challenges for segmentation algorithms due to their intertwined nature. LiDAR data are used to segment the trellis face, and to generate proposals for individual trees trunks. Additional trunk proposals are provided using pixel-wise classification of the image data. The multi-modal observations are fine-tuned by modelling trunk locations using a hidden semi-Markov model (HSMM), within which prior knowledge of tree spacing is incorporated. The final component of this thesis addresses the visual occlusion of fruit within geometrically complex canopies by using a multi-view detection and tracking approach. Single image fruit detections are tracked over a sequence of images, and associated to individual trees or farm rows, with the spatial distribution of the fruit counting forming a yield map over the farm. The results show the advantage of using multi-view imagery (instead of single view analysis) for fruit counting and yield mapping. This thesis includes extensive experimentation in almond, apple and mango orchards, with data captured by a UGV spanning a total of 5 hectares of farm area, over 30 km of vehicle traversal and more than 7,000 trees. The validation of the different processes is performed using manual annotations, which includes fruit and tree locations in image and LiDAR data respectively. Additional evaluation of yield mapping is performed by comparison against fruit counts on trees at the farm and counts made by the growers post-harvest. The framework developed in this thesis is demonstrated to be accurate compared to ground truth at all scales of the pipeline, including fruit detection and tree mapping, leading to accurate yield estimation, per tree and per row, for the different crops. Through the multitude of field experiments conducted over multiple seasons and years, the thesis presents key practical insights necessary for commercial development of an information gathering system in orchards

2016 Conference Abstracts: Annual Undergraduate Research Conference at the Interface of Biology and Mathematics

Schedule and abstract book for the Eighth Annual Undergraduate Research Conference at the Interface of Biology and Mathematics Date: October 8-9, 2016Location: UT Conference Center, KnoxvillePlenary Speaker: Jorge X. Velasco Hernández, Universidad Nacional Autónoma de MéxicoFeatured Speaker: Judy Day, University of Tennessee, Knoxvill

Computationally Linking Chemical Exposure to Molecular Effects with Complex Data: Comparing Methods to Disentangle Chemical Drivers in Environmental Mixtures and Knowledge-based Deep Learning for Predictions in Environmental Toxicology

Chemical exposures affect the environment and may lead to adverse outcomes in its organisms. Omics-based approaches, like standardised microarray experiments, have expanded the toolbox to monitor the distribution of chemicals and assess the risk to organisms in the environment. The resulting complex data have extended the scope of toxicological knowledge bases and published literature. A plethora of computational approaches have been applied in environmental toxicology considering systems biology and data integration. Still, the complexity of environmental and biological systems given in data challenges investigations of exposure-related effects. This thesis aimed at computationally linking chemical exposure to biological effects on the molecular level considering sources of complex environmental data. The first study employed data of an omics-based exposure study considering mixture effects in a freshwater environment. We compared three data-driven analyses in their suitability to disentangle mixture effects of chemical exposures to biological effects and their reliability in attributing potentially adverse outcomes to chemical drivers with toxicological databases on gene and pathway levels. Differential gene expression analysis and a network inference approach resulted in toxicologically meaningful outcomes and uncovered individual chemical effects — stand-alone and in combination. We developed an integrative computational strategy to harvest exposure-related gene associations from environmental samples considering mixtures of lowly concentrated compounds. The applied approaches allowed assessing the hazard of chemicals more systematically with correlation-based compound groups. This dissertation presents another achievement toward a data-driven hypothesis generation for molecular exposure effects. The approach combined text-mining and deep learning. The study was entirely data-driven and involved state-of-the-art computational methods of artificial intelligence. We employed literature-based relational data and curated toxicological knowledge to predict chemical-biomolecule interactions. A word embedding neural network with a subsequent feed-forward network was implemented. Data augmentation and recurrent neural networks were beneficial for training with curated toxicological knowledge. The trained models reached accuracies of up to 94% for unseen test data of the employed knowledge base. However, we could not reliably confirm known chemical-gene interactions across selected data sources. Still, the predictive models might derive unknown information from toxicological knowledge sources, like literature, databases or omics-based exposure studies. Thus, the deep learning models might allow predicting hypotheses of exposure-related molecular effects. Both achievements of this dissertation might support the prioritisation of chemicals for testing and an intelligent selection of chemicals for monitoring in future exposure studies.:Table of Contents ... I Abstract ... V Acknowledgements ... VII Prelude ... IX 1 Introduction 1.1 An overview of environmental toxicology ... 2 1.1.1 Environmental toxicology ... 2 1.1.2 Chemicals in the environment ... 4 1.1.3 Systems biological perspectives in environmental toxicology ... 7 Computational toxicology ... 11 1.2.1 Omics-based approaches ... 12 1.2.2 Linking chemical exposure to transcriptional effects ... 14 1.2.3 Up-scaling from the gene level to higher biological organisation levels ... 19 1.2.4 Biomedical literature-based discovery ... 24 1.2.5 Deep learning with knowledge representation ... 27 1.3 Research question and approaches ... 29 2 Methods and Data ... 33 2.1 Linking environmental relevant mixture exposures to transcriptional effects ... 34 2.1.1 Exposure and microarray data ... 34 2.1.2 Preprocessing ... 35 2.1.3 Differential gene expression ... 37 2.1.4 Association rule mining ... 38 2.1.5 Weighted gene correlation network analysis ... 39 2.1.6 Method comparison ... 41 Predicting exposure-related effects on a molecular level ... 44 2.2.1 Input ... 44 2.2.2 Input preparation ... 47 2.2.3 Deep learning models ... 49 2.2.4 Toxicogenomic application ... 54 3 Method comparison to link complex stream water exposures to effects on the transcriptional level ... 57 3.1 Background and motivation ... 58 3.1.1 Workflow ... 61 3.2 Results ... 62 3.2.1 Data preprocessing ... 62 3.2.2 Differential gene expression analysis ... 67 3.2.3 Association rule mining ... 71 3.2.4 Network inference ... 78 3.2.5 Method comparison ... 84 3.2.6 Application case of method integration ... 87 3.3 Discussion ... 91 3.4 Conclusion ... 99 4 Deep learning prediction of chemical-biomolecule interactions ... 101 4.1 Motivation ... 102 4.1.1Workflow ...105 4.2 Results ... 107 4.2.1 Input preparation ... 107 4.2.2 Model selection ... 110 4.2.3 Model comparison ... 118 4.2.4 Toxicogenomic application ... 121 4.2.5 Horizontal augmentation without tail-padding ...123 4.2.6 Four-class problem formulation ... 124 4.2.7 Training with CTD data ... 125 4.3 Discussion ... 129 4.3.1 Transferring biomedical knowledge towards toxicology ... 129 4.3.2 Deep learning with biomedical knowledge representation ...133 4.3.3 Data integration ...136 4.4 Conclusion ... 141 5 Conclusion and Future perspectives ... 143 5.1 Conclusion ... 143 5.1.1 Investigating complex mixtures in the environment ... 144 5.1.2 Complex knowledge from literature and curated databases predict chemical- biomolecule interactions ... 145 5.1.3 Linking chemical exposure to biological effects by integrating CTD ... 146 5.2 Future perspectives ... 147 S1 Supplement Chapter 1 ... 153 S1.1 Example of an estrogen bioassay ... 154 S1.2 Types of mode of action ... 154 S1.3 The dogma of molecular biology ... 157 S1.4 Transcriptomics ... 159 S2 Supplement Chapter 3 ... 161 S3 Supplement Chapter 4 ... 175 S3.1 Hyperparameter tuning results ... 176 S3.2 Functional enrichment with predicted chemical-gene interactions and CTD reference pathway genesets ... 179 S3.3 Reduction of learning rate in a model with large word embedding vectors ... 183 S3.4 Horizontal augmentation without tail-padding ... 183 S3.5 Four-relationship classification ... 185 S3.6 Interpreting loss observations for SemMedDB trained models ... 187 List of Abbreviations ... i List of Figures ... vi List of Tables ... x Bibliography ... xii Curriculum scientiae ... xxxix Selbständigkeitserklärung ... xlii