Systems Metabolic Engineering Meets Machine Learning: A New Era for Data‐Driven Metabolic Engineering

The recent increase in high‐throughput capacity of ‘omics datasets combined with advances and interest in machine learning (ML) have created great opportunities for systems metabolic engineering. In this regard, data‐driven modeling methods have become increasingly valuable to metabolic strain design. In this review, the nature of ‘omics is discussed and a broad introduction to the ML algorithms combining these datasets into predictive models of metabolism and metabolic rewiring is provided. Next, this review highlights recent work in the literature that utilizes such data‐driven methods to inform various metabolic engineering efforts for different classes of application including product maximization, understanding and profiling phenotypes, de novo metabolic pathway design, and creation of robust system‐scale models for biotechnology. Overall, this review aims to highlight the potential and promise of using ML algorithms with metabolic engineering and systems biology related datasets.

[1]  M. Marra,et al.  Applications of next-generation sequencing technologies in functional genomics. , 2008, Genomics.

[2]  Takahiro Ochiya,et al.  Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis , 2010, Cancer science.

[3]  D. G. Gibson,et al.  Enzymatic assembly of DNA molecules up to several hundred kilobases , 2009, Nature Methods.

[4]  M. Metzker Sequencing technologies — the next generation , 2010, Nature Reviews Genetics.

[5]  Sung Kyu Park,et al.  A quantitative analysis software tool for mass spectrometry–based proteomics , 2008, Nature Methods.

[6]  Nicola Zamboni,et al.  SUMOFLUX: A Generalized Method for Targeted 13C Metabolic Flux Ratio Analysis , 2016, PLoS Comput. Biol..

[7]  Hal S Alper,et al.  Central metabolic nodes for diverse biochemical production. , 2016, Current opinion in chemical biology.

[8]  Sotiris B. Kotsiantis,et al.  Supervised Machine Learning: A Review of Classification Techniques , 2007, Informatica.

[9]  Gang Li,et al.  MiYA, an efficient machine-learning workflow in conjunction with the YeastFab assembly strategy for combinatorial optimization of heterologous metabolic pathways in Saccharomyces cerevisiae. , 2018, Metabolic engineering.

[10]  Michael B. Miller Linear Regression Analysis , 2013 .

[11]  Hanlee P. Ji,et al.  Next-generation DNA sequencing , 2008, Nature Biotechnology.

[12]  M. Gerstein,et al.  The Transcriptional Landscape of the Yeast Genome Defined by RNA Sequencing , 2008, Science.

[13]  Peter D. Karp,et al.  EcoCyc: a comprehensive database resource for Escherichia coli , 2004, Nucleic Acids Res..

[14]  Douglas L. Brutlag,et al.  Remote homology detection: a motif based approach , 2003, ISMB.

[15]  William Stafford Noble,et al.  A new pairwise kernel for biological network inference with support vector machines , 2007, BMC Bioinformatics.

[16]  Gunnar Rätsch,et al.  Improving the Caenorhabditis elegans Genome Annotation Using Machine Learning , 2006, PLoS Comput. Biol..

[17]  Pablo Carbonell,et al.  Origins of Specificity and Promiscuity in Metabolic Networks , 2011, The Journal of Biological Chemistry.

[18]  Michael Banf,et al.  Genome-Wide Prediction of Metabolic Enzymes, Pathways, and Gene Clusters in Plants1[OPEN] , 2017, Plant Physiology.

[19]  Eric W Deutsch,et al.  State of the human proteome in 2013 as viewed through PeptideAtlas: comparing the kidney, urine, and plasma proteomes for the biology- and disease-driven Human Proteome Project. , 2014, Journal of proteome research.

[20]  Mshelia Ds,et al.  Effect of increased patient-physician contact time and health education in achieving diabetes mellitus management objectives in a resource-poor environment. , 2007 .

[21]  J. Keasling,et al.  Principal component analysis of proteomics (PCAP) as a tool to direct metabolic engineering. , 2015, Metabolic engineering.

[22]  Cole Trapnell,et al.  TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions , 2013, Genome Biology.

[23]  Forrest Sheng Bao,et al.  Leveraging knowledge engineering and machine learning for microbial bio-manufacturing. , 2018, Biotechnology advances.

[24]  Peter D. Karp,et al.  The Pathway Tools Pathway Prediction Algorithm , 2011, Standards in genomic sciences.

[25]  Rachael Lammey CrossRef text and data mining services , 2015 .

[26]  Tanya Barrett,et al.  The Gene Expression Omnibus Database , 2016, Statistical Genomics.

[27]  R. Plackett,et al.  THE DESIGN OF OPTIMUM MULTIFACTORIAL EXPERIMENTS , 1946 .

[28]  Apoorv Gupta,et al.  Screening and modular design for metabolic pathway optimization. , 2015, Current opinion in biotechnology.

[29]  Robert Hoehndorf,et al.  Prediction of Metabolic Pathway Involvement in Prokaryotic UniProtKB Data by Association Rule Mining , 2016, PloS one.

[30]  Olivier Martin,et al.  MetaNetX/MNXref – reconciliation of metabolites and biochemical reactions to bring together genome-scale metabolic networks , 2015, Nucleic Acids Res..

[31]  Zak Costello,et al.  A machine learning approach to predict metabolic pathway dynamics from time-series multiomics data , 2018, npj Systems Biology and Applications.

[32]  Liang Li,et al.  Sample normalization methods in quantitative metabolomics. , 2016, Journal of chromatography. A.

[33]  Carol A Marchant,et al.  In Silico Tools for Sharing Data and Knowledge on Toxicity and Metabolism: Derek for Windows, Meteor, and Vitic , 2008, Toxicology mechanisms and methods.

[34]  M. Gerstein,et al.  RNA-Seq: a revolutionary tool for transcriptomics , 2009, Nature Reviews Genetics.

[35]  J. Gasteiger,et al.  Enabling the exploration of biochemical pathways. , 2004, Organic & biomolecular chemistry.

[36]  William Stafford Noble,et al.  Support vector machine , 2013 .

[37]  M. Snyder,et al.  Protein arrays and microarrays. , 2001, Current opinion in chemical biology.

[38]  David S. Wishart,et al.  MetaboAnalyst 3.0—making metabolomics more meaningful , 2015, Nucleic Acids Res..

[39]  Bernhard E. Boser,et al.  A training algorithm for optimal margin classifiers , 1992, COLT '92.

[40]  Yoshihiro Yamanishi,et al.  Cartesian Kernel: An Efficient Alternative to the Pairwise Kernel , 2010, IEICE Trans. Inf. Syst..

[41]  Rachel Chen,et al.  Biofuels and bio-based chemicals from lignocellulose: metabolic engineering strategies in strain development , 2015, Biotechnology Letters.

[42]  Christoph Steinbeck,et al.  Navigating freely-available software tools for metabolomics analysis , 2017, Metabolomics.

[43]  Lior Pachter,et al.  Near-optimal probabilistic RNA-seq quantification , 2016, Nature Biotechnology.

[44]  Nathan J Hillson,et al.  The Experiment Data Depot: A Web-Based Software Tool for Biological Experimental Data Storage, Sharing, and Visualization. , 2017, ACS synthetic biology.

[45]  Gaël Varoquaux,et al.  Scikit-learn: Machine Learning in Python , 2011, J. Mach. Learn. Res..

[46]  Keng C. Soh,et al.  Towards kinetic modeling of genome-scale metabolic networks without sacrificing stoichiometric, thermodynamic and physiological constraints. , 2013, Biotechnology journal.

[47]  Johannes Griss,et al.  The Proteomics Identifications (PRIDE) database and associated tools: status in 2013 , 2012, Nucleic Acids Res..

[48]  Wolfgang Wiechert,et al.  13CFLUX2—high-performance software suite for 13C-metabolic flux analysis , 2012, Bioinform..

[49]  D. Ruppert The Elements of Statistical Learning: Data Mining, Inference, and Prediction , 2004 .

[50]  Eiichiro Fukusaki,et al.  Metabolomics-driven approach to solving a CoA imbalance for improved 1-butanol production in Escherichia coli. , 2017, Metabolic engineering.

[51]  H. Alper,et al.  Systems metabolic engineering: Genome‐scale models and beyond , 2010, Biotechnology journal.

[52]  Jeffrey D Orth,et al.  What is flux balance analysis? , 2010, Nature Biotechnology.

[53]  Jean-Charles Portais,et al.  IsoCor: correcting MS data in isotope labeling experiments , 2012, Bioinform..

[54]  Edith D. Wong,et al.  Saccharomyces Genome Database: the genomics resource of budding yeast , 2011, Nucleic Acids Res..

[55]  Yasset Perez-Riverol,et al.  Making proteomics data accessible and reusable: Current state of proteomics databases and repositories , 2015, Proteomics.

[56]  G. Stephanopoulos,et al.  Improving Metabolic Pathway Efficiency by Statistical Model-Based Multivariate Regulatory Metabolic Engineering. , 2017, ACS synthetic biology.

[57]  Lin Wang,et al.  A review of computational tools for design and reconstruction of metabolic pathways , 2017, Synthetic and systems biotechnology.

[58]  David W. Hosmer,et al.  Applied Logistic Regression , 1991 .

[59]  Edward M Marcotte,et al.  Highly parallel single-molecule identification of proteins in zeptomole-scale mixtures , 2018, Nature Biotechnology.

[60]  J. McPherson,et al.  Coming of age: ten years of next-generation sequencing technologies , 2016, Nature Reviews Genetics.

[61]  Susumu Goto,et al.  LIGAND: chemical database for enzyme reactions , 1998, Bioinform..

[62]  Jean-Loup Faulon,et al.  Genome scale enzyme–metabolite and drug–target interaction predictions using the signature molecular descriptor , 2008 .

[63]  Emma L. Schymanski,et al.  Identifying small molecules via high resolution mass spectrometry: communicating confidence. , 2014, Environmental science & technology.

[64]  Sotiris B. Kotsiantis,et al.  Decision trees: a recent overview , 2011, Artificial Intelligence Review.

[65]  Guocheng Du,et al.  Comparative genomics and transcriptome analysis of Aspergillus niger and metabolic engineering for citrate production , 2017, Scientific Reports.

[66]  Cole Trapnell,et al.  Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. , 2010, Nature biotechnology.

[67]  Ljubisa Miskovic,et al.  iSCHRUNK--In Silico Approach to Characterization and Reduction of Uncertainty in the Kinetic Models of Genome-scale Metabolic Networks. , 2016, Metabolic engineering.

[68]  G. Siuzdak,et al.  XCMS Online: a web-based platform to process untargeted metabolomic data. , 2012, Analytical chemistry.

[69]  J. Keasling,et al.  Targeted proteomics for metabolic pathway optimization: application to terpene production. , 2011, Metabolic engineering.

[70]  W. Wiechert,et al.  How to measure metabolic fluxes: a taxonomic guide for (13)C fluxomics. , 2015, Current opinion in biotechnology.

[71]  Petra Perner,et al.  Data Mining - Concepts and Techniques , 2002, Künstliche Intell..

[72]  Paul Geladi,et al.  Principal Component Analysis , 1987, Comprehensive Chemometrics.

[73]  Pablo Carbonell,et al.  RetroPath2.0: A retrosynthesis workflow for metabolic engineers. , 2018, Metabolic engineering.

[74]  Rodney X. Sturdivant,et al.  Applied Logistic Regression: Hosmer/Applied Logistic Regression , 2005 .

[75]  James G. Jeffryes,et al.  A pathway for every product? Tools to discover and design plant metabolism. , 2018, Plant science : an international journal of experimental plant biology.

[76]  Antje Chang,et al.  BRENDA, enzyme data and metabolic information , 2002, Nucleic Acids Res..

[77]  Mattheos A G Koffas,et al.  Experimental and computational optimization of an Escherichia coli co-culture for the efficient production of flavonoids. , 2016, Metabolic engineering.

[78]  M. DePristo,et al.  The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. , 2010, Genome research.

[79]  Susumu Goto,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 2000, Nucleic Acids Res..

[80]  M. Mann,et al.  MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification , 2008, Nature Biotechnology.

[81]  Haren B. Gosai,et al.  Bioengineering for multiple PAHs degradation using process centric and data centric approaches , 2018, Chemometrics and Intelligent Laboratory Systems.

[82]  Juho Rousu,et al.  Machine Learning of Protein Interactions in Fungal Secretory Pathways , 2016, PloS one.

[83]  Carola Engler,et al.  Golden Gate Shuffling: A One-Pot DNA Shuffling Method Based on Type IIs Restriction Enzymes , 2009, PloS one.

[84]  Yinjie J. Tang,et al.  Facilitate Collaborations among Synthetic Biology, Metabolic Engineering and Machine Learning , 2016 .

[85]  Atina G. Coté,et al.  Evaluation of methods for modeling transcription factor sequence specificity , 2013, Nature Biotechnology.

[86]  Robertson Craig,et al.  Open source system for analyzing, validating, and storing protein identification data. , 2004, Journal of proteome research.

[87]  Yoshihiro Yamanishi,et al.  GENIES: gene network inference engine based on supervised analysis , 2012, Nucleic Acids Res..

[88]  Christoph Steinbeck,et al.  Computational tools and workflows in metabolomics: An international survey highlights the opportunity for harmonisation through Galaxy , 2016, Metabolomics.

[89]  Johann Gasteiger,et al.  Combining Chemoinformatics with Bioinformatics: In Silico Prediction of Bacterial Flavor-Forming Pathways by a Chemical Systems Biology Approach “Reverse Pathway Engineering” , 2014, PloS one.

[90]  R. Shamir,et al.  A comparative analysis of transcription factor binding models learned from PBM, HT-SELEX and ChIP data , 2014, Nucleic acids research.

[91]  Paul Sajda,et al.  Machine learning for detection and diagnosis of disease. , 2006, Annual review of biomedical engineering.

[92]  C. Huttenhower,et al.  Sequencing and beyond: integrating molecular 'omics' for microbial community profiling , 2015, Nature Reviews Microbiology.

[93]  Ruedi Aebersold,et al.  Mass-spectrometric exploration of proteome structure and function , 2016, Nature.

[94]  F. Létisse,et al.  Recent advances in high-throughput 13C-fluxomics. , 2017, Current opinion in biotechnology.

[95]  James D. Winkler,et al.  The LASER database: Formalizing design rules for metabolic engineering , 2015, Metabolic engineering communications.

[96]  V. Fromion,et al.  A comparative transcriptomic, fluxomic and metabolomic analysis of the response of Saccharomyces cerevisiae to increases in NADPH oxidation , 2012, BMC Genomics.

[97]  P. K. Ajikumar,et al.  The future of metabolic engineering and synthetic biology: towards a systematic practice. , 2012, Metabolic engineering.

[98]  M D Luque de Castro,et al.  The analytical process to search for metabolomics biomarkers. , 2018, Journal of pharmaceutical and biomedical analysis.

[99]  Tom Ellis,et al.  One-pot DNA construction for synthetic biology: the Modular Overlap-Directed Assembly with Linkers (MODAL) strategy , 2013, Nucleic acids research.

[100]  Chao Li,et al.  CeCaFDB: a curated database for the documentation, visualization and comparative analysis of central carbon metabolic flux distributions explored by 13C-fluxomics , 2014, Nucleic Acids Res..

[101]  Mitsutoshi Nakada,et al.  Hyperperfusion syndrome after trapping with high-flow bypass for a giant paraclinoid internal carotid artery aneurysm. , 2018, World neurosurgery.

[102]  Mark Johnson,et al.  NCBI BLAST: a better web interface , 2008, Nucleic Acids Res..

[103]  B. Palsson,et al.  Towards multidimensional genome annotation , 2006, Nature Reviews Genetics.

[104]  C. Claudel-Renard,et al.  Enzyme-specific profiles for genome annotation: PRIAM. , 2003, Nucleic acids research.

[105]  Peter D. Karp,et al.  The MetaCyc Database , 2002, Nucleic Acids Res..

[106]  Adam M. Feist,et al.  Generation of an atlas for commodity chemical production in Escherichia coli and a novel pathway prediction algorithm, GEM-Path. , 2014, Metabolic engineering.

[107]  Nathan Halko,et al.  Finding Structure with Randomness: Probabilistic Algorithms for Constructing Approximate Matrix Decompositions , 2009, SIAM Rev..

[108]  D. Kell,et al.  Metabolic footprinting and systems biology: the medium is the message , 2005, Nature Reviews Microbiology.

[109]  Keng C. Soh,et al.  Identification of metabolic engineering targets for the enhancement of 1,4-butanediol production in recombinant E. coli using large-scale kinetic models. , 2016, Metabolic engineering.

[110]  Jong Myoung Park,et al.  Constraints-based genome-scale metabolic simulation for systems metabolic engineering. , 2009, Biotechnology advances.

[111]  Yoshihiro Yamanishi Supervised Inference of Metabolic Networks from the Integration of Genomic Data and Chemical Information , 2010 .

[112]  J. Nielsen Systems Biology of Metabolism. , 2017, Annual review of biochemistry.

[113]  Hal S. Alper,et al.  Metabolic engineering of strains: from industrial-scale to lab-scale chemical production , 2015, Journal of Industrial Microbiology & Biotechnology.

[114]  Adam P. Arkin,et al.  The JBEI quantitative metabolic modeling library (jQMM): a python library for modeling microbial metabolism , 2017, BMC Bioinformatics.

[115]  Thomas J. Watson,et al.  An empirical study of the naive Bayes classifier , 2001 .

[116]  Ruben G. A. van Heck,et al.  More than just a gut feeling: constraint-based genome-scale metabolic models for predicting functions of human intestinal microbes , 2017, Microbiome.

[117]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[118]  V. Hatzimanikatis,et al.  ATLAS of Biochemistry: A Repository of All Possible Biochemical Reactions for Synthetic Biology and Metabolic Engineering Studies. , 2016, ACS synthetic biology.

[119]  A. Burgard,et al.  Metabolic engineering of Escherichia coli for direct production of 1,4-butanediol. , 2011, Nature chemical biology.

[120]  R. Aebersold,et al.  Mass spectrometry-based proteomics , 2003, Nature.

[121]  William Stafford Noble,et al.  Machine learning applications in genetics and genomics , 2015, Nature Reviews Genetics.

[122]  Tom Ronan,et al.  Avoiding common pitfalls when clustering biological data , 2016, Science Signaling.

[123]  P. Karp,et al.  Creation of a Genome-Wide Metabolic Pathway Database for Populus trichocarpa Using a New Approach for Reconstruction and Curation of Metabolic Pathways for Plants1[W][OA] , 2010, Plant Physiology.

[124]  S. Oliver,et al.  Metabolic control analysis as a tool in the elucidation of the function of novel genes , 1998 .

[125]  Peter E. Hart,et al.  Nearest neighbor pattern classification , 1967, IEEE Trans. Inf. Theory.

[126]  Mark W Dewhirst,et al.  Inhibition of in vivo tumor angiogenesis and growth via systemic delivery of an angiopoietin 2-specific RNA aptamer. , 2008, The Journal of surgical research.

[127]  Anne E Carpenter,et al.  Opportunities and obstacles for deep learning in biology and medicine , 2017, bioRxiv.

[128]  Peter D. Karp,et al.  Machine learning methods for metabolic pathway prediction , 2010 .

[129]  J. Selbig,et al.  Parallel analysis of transcript and metabolic profiles: a new approach in systems biology , 2003, EMBO reports.

[130]  David R. Kelley,et al.  Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks , 2012, Nature Protocols.

[131]  R. Goodacre,et al.  The role of metabolites and metabolomics in clinically applicable biomarkers of disease , 2010, Archives of Toxicology.

[132]  Hal S. Alper,et al.  Thermodynamic and first-principles biomolecular simulations applied to synthetic biology: promoter and aptamer designs , 2018 .

[133]  Tilmann Weber,et al.  Metabolic engineering with systems biology tools to optimize production of prokaryotic secondary metabolites. , 2016, Natural product reports.

[134]  María Martín,et al.  UniProt: A hub for protein information , 2015 .

[135]  Alexey I Nesvizhskii,et al.  MSFragger: ultrafast and comprehensive peptide identification in shotgun proteomics , 2017, Nature Methods.

[136]  David I. Ellis,et al.  A tutorial review: Metabolomics and partial least squares-discriminant analysis--a marriage of convenience or a shotgun wedding. , 2015, Analytica chimica acta.

[137]  Anil K. Jain Data clustering: 50 years beyond K-means , 2010, Pattern Recognit. Lett..

[138]  Kathleen A. Curran,et al.  Expanding the chemical palate of cells by combining systems biology and metabolic engineering. , 2012, Metabolic engineering.

[139]  Susumu Goto,et al.  Metabolic pathway reconstruction strategies for central metabolism and natural product biosynthesis , 2016, Biophysics and physicobiology.

[140]  J Sharon Mano Pappu,et al.  Modeling and simulation of xylitol production in bioreactor by Debaryomyces nepalensis NCYC 3413 using unstructured and artificial neural network models. , 2016, Bioresource technology.

[141]  Michael Domaratzki,et al.  Metabolic network prediction through pairwise rational kernels , 2014, BMC Bioinformatics.

[142]  Sudhir Kumar,et al.  MEGA7: Molecular Evolutionary Genetics Analysis Version 7.0 for Bigger Datasets. , 2016, Molecular biology and evolution.

[143]  Pablo Carbonell,et al.  XTMS: pathway design in an eXTended metabolic space , 2014, Nucleic Acids Res..

[144]  Zoubin Ghahramani,et al.  Unifying linear dimensionality reduction , 2014, 1406.0873.

[145]  D. Kell,et al.  High-throughput classification of yeast mutants for functional genomics using metabolic footprinting , 2003, Nature Biotechnology.

[146]  Fadhl M Alakwaa,et al.  Deep Learning Accurately Predicts Estrogen Receptor Status in Breast Cancer Metabolomics Data , 2017, bioRxiv.

[147]  Steffen Neumann,et al.  Highly sensitive feature detection for high resolution LC/MS , 2008, BMC Bioinformatics.

[148]  Abiel Roche-Lima,et al.  Implementation and comparison of kernel-based learning methods to predict metabolic networks , 2016, Network Modeling Analysis in Health Informatics and Bioinformatics.

[149]  C. Ouzounis,et al.  Expansion of the BioCyc collection of pathway/genome databases to 160 genomes , 2005, Nucleic acids research.

[150]  Robert A. Edwards,et al.  From DNA to FBA: How to Build Your Own Genome-Scale Metabolic Model , 2016, Frontiers in microbiology.

[151]  John R Yates,et al.  Proteomics by mass spectrometry: approaches, advances, and applications. , 2009, Annual review of biomedical engineering.

[152]  Yuxuan Wang,et al.  Rapid Prediction of Bacterial Heterotrophic Fluxomics Using Machine Learning and Constraint Programming , 2016, PLoS Comput. Biol..

[153]  Michael Sauer,et al.  Engineering of the citrate exporter protein enables high citric acid production in Aspergillus niger. , 2019, Metabolic engineering.

[154]  Steffen Neumann,et al.  Prediction, Detection, and Validation of Isotope Clusters in Mass Spectrometry Data , 2016, Metabolites.

[155]  Kai Blin,et al.  antiSMASH 3.0—a comprehensive resource for the genome mining of biosynthetic gene clusters , 2015, Nucleic Acids Res..

[156]  D. Kell,et al.  A functional genomics strategy that uses metabolome data to reveal the phenotype of silent mutations , 2001, Nature Biotechnology.

[157]  Oliver Fiehn,et al.  MINEs: open access databases of computationally predicted enzyme promiscuity products for untargeted metabolomics , 2015, Journal of Cheminformatics.

[158]  Heung-Il Suk,et al.  Deep Learning in Medical Image Analysis. , 2017, Annual review of biomedical engineering.

[159]  William Stafford Noble,et al.  Learning to predict protein-protein interactions from protein sequences , 2003, Bioinform..

[160]  Adam M. Feist,et al.  A genome-scale metabolic reconstruction for Escherichia coli K-12 MG1655 that accounts for 1260 ORFs and thermodynamic information , 2007, Molecular systems biology.

[161]  So Young Ryu,et al.  Bioinformatics tools to identify and quantify proteins using mass spectrometry data. , 2014, Advances in protein chemistry and structural biology.

[162]  C. Tomlin,et al.  Expression-level optimization of a multi-enzyme pathway in the absence of a high-throughput assay , 2013, Nucleic acids research.

[163]  Nikos Kyrpides,et al.  Genomes OnLine Database (GOLD) v.6: data updates and feature enhancements , 2016, Nucleic Acids Res..

[164]  Christoph Steinbeck,et al.  MetaboLights—an open-access general-purpose repository for metabolomics studies and associated meta-data , 2012, Nucleic Acids Res..

[165]  Elise A. R. Serin,et al.  Learning from Co-expression Networks: Possibilities and Challenges , 2016, Front. Plant Sci..

[166]  Rob Patro,et al.  Salmon provides fast and bias-aware quantification of transcript expression , 2017, Nature Methods.

[167]  Daniel J. Gaffney,et al.  A survey of best practices for RNA-seq data analysis , 2016, Genome Biology.

[168]  K. Veselkov,et al.  A guide to the identification of metabolites in NMR-based metabonomics/metabolomics experiments , 2016, Computational and structural biotechnology journal.

[169]  Rick L. Stevens,et al.  KBase: The United States Department of Energy Systems Biology Knowledgebase , 2018, Nature Biotechnology.

[170]  R. Durbin,et al.  Mapping Quality Scores Mapping Short Dna Sequencing Reads and Calling Variants Using P

, 2022 .

[171]  Kenneth J. Kauffman,et al.  Advances in flux balance analysis. , 2003, Current opinion in biotechnology.

[172]  Chidchanok Lursinsap,et al.  Metabolic pathway synthesis based on predicting compound transformable pairs by using neural classifiers with imbalanced data handling , 2017, Expert Syst. Appl..

[173]  David H. Wolpert,et al.  No free lunch theorems for optimization , 1997, IEEE Trans. Evol. Comput..

[174]  Pablo Carbonell,et al.  Semisupervised Gaussian Process for Automated Enzyme Search. , 2016, ACS synthetic biology.

[175]  Di Liu,et al.  Machine learning framework for assessment of microbial factory performance , 2019, PloS one.

[176]  Tong Un Chae,et al.  Recent advances in systems metabolic engineering tools and strategies. , 2017, Current opinion in biotechnology.

[177]  Susumu Goto,et al.  PathPred: an enzyme-catalyzed metabolic pathway prediction server , 2010, Nucleic Acids Res..