Almost without exception, everything human beings undertake involves a choice. In recent years there has been a growing interest in the development and application of quantitative statistical methods ...to study choices made by individuals with the purpose of gaining a better understanding both of how choices are made and of forecasting future choice responses. In this primer the authors provide an unintimidating introduction to the main techniques of choice analysis and include detail on themes such as data collection and preparation, model estimation and interpretation and the design of choice experiments. A companion website to the book provides practice data sets and software to estimate the main discrete choice models such as multinomial logit, nested logit and mixed logit. This primer will be an invaluable resource to students as well as of immense value to consultants and professionals, researchers and anyone else interested in choice analysis and modelling.
The estimation of chemical reaction properties such as activation energies, rates, or yields is a central topic of computational chemistry. In contrast to molecular properties, where machine learning ...approaches such as graph convolutional neural networks (GCNNs) have excelled for a wide variety of tasks, no general and transferable adaptations of GCNNs for reactions have been developed yet. We therefore combined a popular cheminformatics reaction representation, the so-called condensed graph of reaction (CGR), with a recent GCNN architecture to arrive at a versatile, robust, and compact deep learning model. The CGR is a superposition of the reactant and product graphs of a chemical reaction and thus an ideal input for graph-based machine learning approaches. The model learns to create a data-driven, task-dependent reaction embedding that does not rely on expert knowledge, similar to current molecular GCNNs. Our approach outperforms current state-of-the-art models in accuracy, is applicable even to imbalanced reactions, and possesses excellent predictive capabilities for diverse target properties, such as activation energies, reaction enthalpies, rate constants, yields, or reaction classes. We furthermore curated a large set of atom-mapped reactions along with their target properties, which can serve as benchmark data sets for future work. All data sets and the developed reaction GCNN model are available online, free of charge, and open source.
Reaction Mechanism Generator (RMG) constructs kinetic models composed of elementary chemical reaction steps using a general understanding of how molecules react. Species thermochemistry is estimated ...through Benson group additivity and reaction rate coefficients are estimated using a database of known rate rules and reaction templates. At its core, RMG relies on two fundamental data structures: graphs and trees. Graphs are used to represent chemical structures, and trees are used to represent thermodynamic and kinetic data. Models are generated using a rate-based algorithm which excludes species from the model based on reaction fluxes. RMG can generate reaction mechanisms for species involving carbon, hydrogen, oxygen, sulfur, and nitrogen. It also has capabilities for estimating transport and solvation properties, and it automatically computes pressure-dependent rate coefficients and identifies chemically-activated reaction paths. RMG is an object-oriented program written in Python, which provides a stable, robust programming architecture for developing an extensible and modular code base with a large suite of unit tests. Computationally intensive functions are cythonized for speed improvements.
Program title: RMG
Catalogue identifier: AEZW_v1_0
Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEZW_v1_0.html
Program obtainable from: CPC Program Library, Queen’s University, Belfast, N. Ireland
Licensing provisions: MIT/X11 License
No. of lines in distributed program, including test data, etc.: 958681
No. of bytes in distributed program, including test data, etc.: 9495441
Distribution format: tar.gz
Programming language: Python.
Computer: Windows, Ubuntu, and Mac OS computers with relevant compilers.
Operating system: Unix/Linux/Windows.
RAM: 1 GB minimum, 16 GB or more for larger simulations
Classification: 16.12.
External routines: RDKit, Open Babel, DASSL, DASPK, DQED, NumPy, SciPy
Nature of problem: Automatic generation of chemical kinetic mechanisms for molecules containing C, H, O, S, and N.
Solution method: Rate-based algorithm adds most important species and reactions to a model, with rate constants derived from rate rules and other parameters estimated via group additivity methods.
Additional comments: The RMG software package also includes CanTherm, a tool for computing the thermodynamic properties of chemical species and both high-pressure-limit and pressure-dependent rate coefficients for chemical reactions using results from quantum chemical calculations. CanTherm is compatible with a variety of ab initio quantum chemistry software programs, including but not limited to Gaussian, MOPAC, QChem, and MOLPRO.
Running time: From 30 s for the simplest molecules, to up to several weeks, depending on the size of the molecule and the conditions of the reaction system chosen.
Conspectus Computer-aided synthesis planning (CASP) is focused on the goal of accelerating the process by which chemists decide how to synthesize small molecule compounds. The ideal CASP program ...would take a molecular structure as input and output a sorted list of detailed reaction schemes that each connect that target to purchasable starting materials via a series of chemically feasible reaction steps. Early work in this field relied on expert-crafted reaction rules and heuristics to describe possible retrosynthetic disconnections and selectivity rules but suffered from incompleteness, infeasible suggestions, and human bias. With the relatively recent availability of large reaction corpora (such as the United States Patent and Trademark Office (USPTO), Reaxys, and SciFinder databases), consisting of millions of tabulated reaction examples, it is now possible to construct and validate purely data-driven approaches to synthesis planning. As a result, synthesis planning has been opened to machine learning techniques, and the field is advancing rapidly. In this Account, we focus on two critical aspects of CASP and recent machine learning approaches to both challenges. First, we discuss the problem of retrosynthetic planning, which requires a recommender system to propose synthetic disconnections starting from a target molecule. We describe how the search strategy, necessary to overcome the exponential growth of the search space with increasing number of reaction steps, can be assisted through a learned synthetic complexity metric. We also describe how the recursive expansion can be performed by a straightforward nearest neighbor model that makes clever use of reaction data to generate high quality retrosynthetic disconnections. Second, we discuss the problem of anticipating the products of chemical reactions, which can be used to validate proposed reactions in a computer-generated synthesis plan (i.e., reduce false positives) to increase the likelihood of experimental success. While we introduce this task in the context of reaction validation, its utility extends to the prediction of side products and impurities, among other applications. We describe neural network-based approaches that we and others have developed for this forward prediction task that can be trained on previously published experimental data. Machine learning and artificial intelligence have revolutionized a number of disciplines, not limited to image recognition, dictation, translation, content recommendation, advertising, and autonomous driving. While there is a rich history of using machine learning for structure–activity models in chemistry, it is only now that it is being successfully applied more broadly to organic synthesis and synthesis design. As reported in this Account, machine learning is rapidly transforming CASP, but there are several remaining challenges and opportunities, many pertaining to the availability and standardization of both data and evaluation metrics, which must be addressed by the community at large.
The task of learning an expressive molecular representation is central to developing quantitative structure–activity and property relationships. Traditional approaches rely on group additivity rules, ...empirical measurements or parameters, or generation of thousands of descriptors. In this paper, we employ a convolutional neural network for this embedding task by treating molecules as undirected graphs with attributed nodes and edges. Simple atom and bond attributes are used to construct atom-specific feature vectors that take into account the local chemical environment using different neighborhood radii. By working directly with the full molecular graph, there is a greater opportunity for models to identify important features relevant to a prediction task. Unlike other graph-based approaches, our atom featurization preserves molecule-level spatial information that significantly enhances model performance. Our models learn to identify important features of atom clusters for the prediction of aqueous solubility, octanol solubility, melting point, and toxicity. Extensions and limitations of this strategy are discussed.
Advances in deep neural network (DNN)-based molecular property prediction have recently led to the development of models of remarkable accuracy and generalization ability, with graph convolutional ...neural networks (GCNNs) reporting state-of-the-art performance for this task. However, some challenges remain, and one of the most important that needs to be fully addressed concerns uncertainty quantification. DNN performance is affected by the volume and the quality of the training samples. Therefore, establishing when and to what extent a prediction can be considered reliable is just as important as outputting accurate predictions, especially when out-of-domain molecules are targeted. Recently, several methods to account for uncertainty in DNNs have been proposed, most of which are based on approximate Bayesian inference. Among these, only a few scale to the large data sets required in applications. Evaluating and comparing these methods has recently attracted great interest, but results are generally fragmented and absent for molecular property prediction. In this paper, we quantitatively compare scalable techniques for uncertainty estimation in GCNNs. We introduce a set of quantitative criteria to capture different uncertainty aspects and then use these criteria to compare MC-dropout, Deep Ensembles, and bootstrapping, both theoretically in a unified framework that separates aleatoric/epistemic uncertainty and experimentally on public data sets. Our experiments quantify the performance of the different uncertainty estimation methods and their impact on uncertainty-related error reduction. Our findings indicate that Deep Ensembles and bootstrapping consistently outperform MC-dropout, with different context-specific pros and cons. Our analysis leads to a better understanding of the role of aleatoric/epistemic uncertainty, also in relation to the target data set features, and highlights the challenge posed by out-of-domain uncertainty.
We present a supervised learning approach to predict the products of organic reactions given their reactants, reagents, and solvent(s). The prediction task is factored into two stages comparable to ...manual expert approaches: considering possible sites of reactivity and evaluating their relative likelihoods. By training on hundreds of thousands of reaction precedents covering a broad range of reaction types from the patent literature, the neural model makes informed predictions of chemical reactivity. The model predicts the major product correctly over 85% of the time requiring around 100 ms per example, a significantly higher accuracy than achieved by previous machine learning approaches, and performs on par with expert chemists with years of formal training. We gain additional insight into predictions
the design of the neural model, revealing an understanding of chemistry qualitatively consistent with manual approaches.
Artificial intelligence and machine learning have demonstrated their potential role in predictive chemistry and synthetic planning of small molecules; there are at least a few reports of companies ...employing in silico synthetic planning into their overall approach to accessing target molecules. A data-driven synthesis planning program is one component being developed and evaluated by the Machine Learning for Pharmaceutical Discovery and Synthesis (MLPDS) consortium, comprising MIT and 13 chemical and pharmaceutical company members. Together, we wrote this perspective to share how we think predictive models can be integrated into medicinal chemistry synthesis workflows, how they are currently used within MLPDS member companies, and the outlook for this field.
We present a simple protocol which allows fully automated discovery of elementary chemical reaction steps using in cooperation double- and single-ended transition-state optimization algorithmsthe ...freezing string and Berny optimization methods, respectively. To demonstrate the utility of the proposed approach, the reactivity of several single-molecule systems of combustion and atmospheric chemistry importance is investigated. The proposed algorithm allowed us to detect without any human intervention not only “known” reaction pathways, manually detected in the previous studies, but also new, previously “unknown”, reaction pathways which involve significant atom rearrangements. We believe that applying such a systematic approach to elementary reaction path finding will greatly accelerate the discovery of new chemistry and will lead to more accurate computer simulations of various chemical processes.
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