skip to main content


Title: Fundamental and practical aspects of machine learning for the peak picking of biomolecular NMR spectra
Abstract

Rapid progress in machine learning offers new opportunities for the automated analysis of multidimensional NMR spectra ranging from protein NMR to metabolomics applications. Most recently, it has been demonstrated how deep neural networks (DNN) designed for spectral peak picking are capable of deconvoluting highly crowded NMR spectra rivaling the facilities of human experts. Superior DNN-based peak picking is one of a series of critical steps during NMR spectral processing, analysis, and interpretation where machine learning is expected to have a major impact. In this perspective, we lay out some of the unique strengths as well as challenges of machine learning approaches in this new era of automated NMR spectral analysis. Such a discussion seems timely and should help define common goals for the NMR community, the sharing of software tools, standardization of protocols, and calibrate expectations. It will also help prepare for an NMR future where machine learning and artificial intelligence tools will be common place.

 
more » « less
Award ID(s):
2103637
NSF-PAR ID:
10368479
Author(s) / Creator(s):
; ; ; ;
Publisher / Repository:
Springer Science + Business Media
Date Published:
Journal Name:
Journal of Biomolecular NMR
Volume:
76
Issue:
3
ISSN:
0925-2738
Page Range / eLocation ID:
p. 49-57
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. The analysis of nuclear magnetic resonance (NMR) spectra for the comprehensive and unambiguous identification and characterization of peaks is a difficult, but critically important step in all NMR analyses of complex biological molecular systems. Here, we introduce DEEP Picker, a deep neural network (DNN)-based approach for peak picking and spectral deconvolution which semi-automates the analysis of two-dimensional NMR spectra. DEEP Picker includes 8 hidden convolutional layers and was trained on a large number of synthetic spectra of known composition with variable degrees of crowdedness. We show that our method is able to correctly identify overlapping peaks, including ones that are challenging for expert spectroscopists and existing computational methods alike. We demonstrate the utility of DEEP Picker on NMR spectra of folded and intrinsically disordered proteins as well as a complex metabolomics mixture, and show how it provides access to valuable NMR information. DEEP Picker should facilitate the semi-automation and standardization of protocols for better consistency and sharing of results within the scientific community. 
    more » « less
  2. Abstract Why the new findings matter

    The process of teaching and learning is complex, multifaceted and dynamic. This paper contributes a seminal resource to highlight the digitisation of the educational sciences by demonstrating how new machine learning methods can be effectively and reliably used in research, education and practical application.

    Implications for educational researchers and policy makers

    The progressing digitisation of societies around the globe and the impact of the SARS‐COV‐2 pandemic have highlighted the vulnerabilities and shortcomings of educational systems. These developments have shown the necessity to provide effective educational processes that can support sometimes overwhelmed teachers to digitally impart knowledge on the plan of many governments and policy makers. Educational scientists, corporate partners and stakeholders can make use of machine learning techniques to develop advanced, scalable educational processes that account for individual needs of learners and that can complement and support existing learning infrastructure. The proper use of machine learning methods can contribute essential applications to the educational sciences, such as (semi‐)automated assessments, algorithmic‐grading, personalised feedback and adaptive learning approaches. However, these promises are strongly tied to an at least basic understanding of the concepts of machine learning and a degree of data literacy, which has to become the standard in education and the educational sciences.

    Demonstrating both the promises and the challenges that are inherent to the collection and the analysis of large educational data with machine learning, this paper covers the essential topics that their application requires and provides easy‐to‐follow resources and code to facilitate the process of adoption.

     
    more » « less
  3. Significant interest in applying Deep Neural Network (DNN) has fueled the need to support engineering of software that uses DNNs. Repairing software that uses DNNs is one such unmistakable SE need where automated tools could be very helpful; however, we do not fully understand challenges to repairing and patterns that are utilized when manually repairing them. What challenges should automated repair tools address? What are the repair patterns whose automation could help developers? Which repair patterns should be assigned a higher priority for automation? This work presents a comprehensive study of bug fix patterns to address these questions. We have studied 415 repairs from Stack Overflow and 555 repairs from GitHub for five popular deep learning libraries Caffe, Keras, Tensorflow, Theano, and Torch to understand challenges in repairs and bug repair patterns. Our key findings reveal that DNN bug fix patterns are distinctive compared to traditional bug fix patterns; the most common bug fix patterns are fixing data dimension and neural network connectivity; DNN bug fixes have the potential to introduce adversarial vulnerabilities; DNN bug fixes frequently introduce new bugs; and DNN bug localization, reuse of trained model, and coping with frequent releases are major challenges faced by developers when fixing bugs. We also contribute a benchmark of 667 DNN (bug, repair) instances. 
    more » « less
  4. The heightened dipolar interactions in solids render solid-state NMR (ssNMR) spectra more difficult to interpret than solution NMR spectra. On the other hand, ssNMR does not suffer from severe molecular weight limitations like solution NMR. In recent years, ssNMR has undergone rapid technological developments that have enabled structure–function studies of increasingly larger biomolecules, including membrane proteins. Current methodology includes stable isotope labeling schemes, non-uniform sampling with spectral reconstruction, faster magic angle spinning, and innovative pulse sequences that capture different types of interactions among spins. However, computational tools for the analysis of complex ssNMR data from membrane proteins and other challenging protein systems have lagged behind those for solution NMR. Before a structure can be determined, thousands of signals from individual types of multidimensional ssNMR spectra of samples, which may have differing isotopic composition, must be recognized, correlated, categorized, and eventually assigned to atoms in the chemical structure. To address these tedious steps, we have developed an automated algorithm for ssNMR spectra called “ssPINE”. The ssPINE software accepts the sequence of the protein plus peak lists from a variety of ssNMR experiments as inputs and offers automated backbone and side-chain assignments. The alpha version of ssPINE, which we describe here, is freely available through a web submission form. 
    more » « less
  5. INTRODUCTION A brainwide, synaptic-resolution connectivity map—a connectome—is essential for understanding how the brain generates behavior. However because of technological constraints imaging entire brains with electron microscopy (EM) and reconstructing circuits from such datasets has been challenging. To date, complete connectomes have been mapped for only three organisms, each with several hundred brain neurons: the nematode C. elegans , the larva of the sea squirt Ciona intestinalis , and of the marine annelid Platynereis dumerilii . Synapse-resolution circuit diagrams of larger brains, such as insects, fish, and mammals, have been approached by considering select subregions in isolation. However, neural computations span spatially dispersed but interconnected brain regions, and understanding any one computation requires the complete brain connectome with all its inputs and outputs. RATIONALE We therefore generated a connectome of an entire brain of a small insect, the larva of the fruit fly, Drosophila melanogaster. This animal displays a rich behavioral repertoire, including learning, value computation, and action selection, and shares homologous brain structures with adult Drosophila and larger insects. Powerful genetic tools are available for selective manipulation or recording of individual neuron types. In this tractable model system, hypotheses about the functional roles of specific neurons and circuit motifs revealed by the connectome can therefore be readily tested. RESULTS The complete synaptic-resolution connectome of the Drosophila larval brain comprises 3016 neurons and 548,000 synapses. We performed a detailed analysis of the brain circuit architecture, including connection and neuron types, network hubs, and circuit motifs. Most of the brain’s in-out hubs (73%) were postsynaptic to the learning center or presynaptic to the dopaminergic neurons that drive learning. We used graph spectral embedding to hierarchically cluster neurons based on synaptic connectivity into 93 neuron types, which were internally consistent based on other features, such as morphology and function. We developed an algorithm to track brainwide signal propagation across polysynaptic pathways and analyzed feedforward (from sensory to output) and feedback pathways, multisensory integration, and cross-hemisphere interactions. We found extensive multisensory integration throughout the brain and multiple interconnected pathways of varying depths from sensory neurons to output neurons forming a distributed processing network. The brain had a highly recurrent architecture, with 41% of neurons receiving long-range recurrent input. However, recurrence was not evenly distributed and was especially high in areas implicated in learning and action selection. Dopaminergic neurons that drive learning are amongst the most recurrent neurons in the brain. Many contralateral neurons, which projected across brain hemispheres, were in-out hubs and synapsed onto each other, facilitating extensive interhemispheric communication. We also analyzed interactions between the brain and nerve cord. We found that descending neurons targeted a small fraction of premotor elements that could play important roles in switching between locomotor states. A subset of descending neurons targeted low-order post-sensory interneurons likely modulating sensory processing. CONCLUSION The complete brain connectome of the Drosophila larva will be a lasting reference study, providing a basis for a multitude of theoretical and experimental studies of brain function. The approach and computational tools generated in this study will facilitate the analysis of future connectomes. Although the details of brain organization differ across the animal kingdom, many circuit architectures are conserved. As more brain connectomes of other organisms are mapped in the future, comparisons between them will reveal both common and therefore potentially optimal circuit architectures, as well as the idiosyncratic ones that underlie behavioral differences between organisms. Some of the architectural features observed in the Drosophila larval brain, including multilayer shortcuts and prominent nested recurrent loops, are found in state-of-the-art artificial neural networks, where they can compensate for a lack of network depth and support arbitrary, task-dependent computations. Such features could therefore increase the brain’s computational capacity, overcoming physiological constraints on the number of neurons. Future analysis of similarities and differences between brains and artificial neural networks may help in understanding brain computational principles and perhaps inspire new machine learning architectures. The connectome of the Drosophila larval brain. The morphologies of all brain neurons, reconstructed from a synapse-resolution EM volume, and the synaptic connectivity matrix of an entire brain. This connectivity information was used to hierarchically cluster all brains into 93 cell types, which were internally consistent based on morphology and known function. 
    more » « less