SVM-Fold: a tool for discriminative multi-class protein fold and superfamily recognition

Background: Predicting a protein's structural class from its amino acid sequence is a fundamental problem in computational biology. Much recent work has focused on developing new representations for protein sequences, called string kernels, for use with support vector machine (SVM) classifiers. However, while some of these approaches exhibit state-of-the-art performance at the binary protein classification problem, i.e. discriminating between a particular protein class and all other classes, few of these studies have addressed the real problem of multi-class superfamily or fold recognition. Moreover, there are only limited software tools and systems for SVM-based protein classification available to the bioinformatics community. Results: We present a new multi-class SVM-based protein fold and superfamily recognition system and web server called SVM-Fold, which can be found at http://svm-fold.c2b2.columbia.edu. Our system uses an efficient implementation of a state-of-the-art string kernel for sequence profiles, called the profile kernel, where the underlying feature representation is a histogram of inexact matching k-mer frequencies. We also employ a novel machine learning approach to solve the difficult multi-class problem of classifying a sequence of amino acids into one of many known protein structural classes. Binary one-vs-the-rest SVM classifiers that are trained to recognize individual structural classes yield prediction scores that are not comparable, so that standard "one-vs-all" classification fails to perform well. Moreover, SVMs for classes at different levels of the protein structural hierarchy may make useful predictions, but one-vs-all does not try to combine these multiple predictions. To deal with these problems, our method learns relative weights between one-vs-the-rest classifiers and encodes information about the protein structural hierarchy for multi-class prediction. In large-scale benchmark results based on the SCOP database, our code weighting approach significantly improves on the standard one-vs-all method for both the superfamily and fold prediction in the remote homology setting and on the fold recognition problem. Moreover, our code weight learning algorithm strongly outperforms nearest-neighbor methods based on PSI-BLAST in terms of prediction accuracy on every structure classification problem we consider. Conclusion: By combining state-of-the-art SVM kernel methods with a novel multi-class algorithm, the SVM-Fold system delivers efficient and accurate protein fold and superfamily recognition

Building multiclass classifiers for remote homology detection and fold recognition

BACKGROUND: Protein remote homology detection and fold recognition are central problems in computational biology. Supervised learning algorithms based on support vector machines are currently one of the most effective methods for solving these problems. These methods are primarily used to solve binary classification problems and they have not been extensively used to solve the more general multiclass remote homology prediction and fold recognition problems. RESULTS: We present a comprehensive evaluation of a number of methods for building SVM-based multiclass classification schemes in the context of the SCOP protein classification. These methods include schemes that directly build an SVM-based multiclass model, schemes that employ a second-level learning approach to combine the predictions generated by a set of binary SVM-based classifiers, and schemes that build and combine binary classifiers for various levels of the SCOP hierarchy beyond those defining the target classes. CONCLUSION: Analyzing the performance achieved by the different approaches on four different datasets we show that most of the proposed multiclass SVM-based classification approaches are quite effective in solving the remote homology prediction and fold recognition problems and that the schemes that use predictions from binary models constructed for ancestral categories within the SCOP hierarchy tend to not only lead to lower error rates but also reduce the number of errors in which a superfamily is assigned to an entirely different fold and a fold is predicted as being from a different SCOP class. Our results also show that the limited size of the training data makes it hard to learn complex second-level models, and that models of moderate complexity lead to consistently better results

In-Process Global Interpretation for Graph Learning via Distribution Matching

Graphs neural networks (GNNs) have emerged as a powerful graph learning model due to their superior capacity in capturing critical graph patterns. To gain insights about the model mechanism for interpretable graph learning, previous efforts focus on post-hoc local interpretation by extracting the data pattern that a pre-trained GNN model uses to make an individual prediction. However, recent works show that post-hoc methods are highly sensitive to model initialization and local interpretation can only explain the model prediction specific to a particular instance. In this work, we address these limitations by answering an important question that is not yet studied: how to provide global interpretation of the model training procedure? We formulate this problem as in-process global interpretation, which targets on distilling high-level and human-intelligible patterns that dominate the training procedure of GNNs. We further propose Graph Distribution Matching (GDM) to synthesize interpretive graphs by matching the distribution of the original and interpretive graphs in the feature space of the GNN as its training proceeds. These few interpretive graphs demonstrate the most informative patterns the model captures during training. Extensive experiments on graph classification datasets demonstrate multiple advantages of the proposed method, including high explanation accuracy, time efficiency and the ability to reveal class-relevant structure.Comment: Under Revie

Apples and oranges: avoiding different priors in Bayesian DNA sequence analysis

<p>Abstract</p> <p>Background</p> <p>One of the challenges of bioinformatics remains the recognition of short signal sequences in genomic DNA such as donor or acceptor splice sites, splicing enhancers or silencers, translation initiation sites, transcription start sites, transcription factor binding sites, nucleosome binding sites, miRNA binding sites, or insulator binding sites. During the last decade, a wealth of algorithms for the recognition of such DNA sequences has been developed and compared with the goal of improving their performance and to deepen our understanding of the underlying cellular processes. Most of these algorithms are based on statistical models belonging to the family of Markov random fields such as position weight matrix models, weight array matrix models, Markov models of higher order, or moral Bayesian networks. While in many comparative studies different learning principles or different statistical models have been compared, the influence of choosing different prior distributions for the model parameters when using different learning principles has been overlooked, and possibly lead to questionable conclusions.</p> <p>Results</p> <p>With the goal of allowing direct comparisons of different learning principles for models from the family of Markov random fields based on the <it>same a-priori information</it>, we derive a generalization of the commonly-used product-Dirichlet prior. We find that the derived prior behaves like a Gaussian prior close to the maximum and like a Laplace prior in the far tails. In two case studies, we illustrate the utility of the derived prior for a direct comparison of different learning principles with different models for the recognition of binding sites of the transcription factor Sp1 and human donor splice sites.</p> <p>Conclusions</p> <p>We find that comparisons of different learning principles using the same a-priori information can lead to conclusions different from those of previous studies in which the effect resulting from different priors has been neglected. We implement the derived prior is implemented in the open-source library Jstacs to enable an easy application to comparative studies of different learning principles in the field of sequence analysis.</p

DeePSLiM: A Deep Learning Approach to Identify Predictive Short-linear Motifs for Protein Sequence Classification

With the increasing quantity of biological data, it is important to develop algorithms that can quickly find patterns in large databases of DNA, RNA and protein sequences. Previous research has been very successful at applying deep learning methods to the problems of motif detection as well as classification of biological sequences. There are, however, limitations to these approaches. Most are limited to finding motifs of a single length. In addition, most research has focused on DNA and RNA, both of which use a four letter alphabet. A few of these have attempted to apply deep learning methods on the larger, twenty letter, alphabet of proteins. We present an enhanced deep learning model, called DeePSLiM, capable of detecting predictive, short linear motifs (SLiM) in protein sequences. The model is a shallow network that can be trained quickly on large amounts of data. The SLiMs are predictive because they can be used to classify the sequences into their respective families. The model was able to reach scores of 94.5% on accuracy, precision, recall, F1-Score and Matthews-correlation coefficient, as well as 99.9% area under the receiver operator characteristic curve (AUROC)

Learning about Sequence-Dependent DNA/Single-Wall Carbon Nanotube Hybrids

Since the single-wall carbon nanotubes (SWCNTs) were discovered in 1993, they have attracted significant interest with their extraordinary electrical and optical properties in addition to their remarkable mechanical strength and thermal conductivity. Single-stranded DNA conjugated SWCNT have shown outstanding functionality in terms of dispersibility and biocompatibility. In addition, some special DNA sequences have presented an ability to recognize specific SWCNT species, called recognition sequences. Ion-exchange chromatography and aqueous two-phase (ATP) separation technique have been widely used for SWCNT separation. However, little is known about the use of ATP as an analytical technique. Furthermore, for bio-applications, DNA/SWCNT hybrids have attracted significant interest due to their high solvatochromic sensitivity to changes in the local environment, which enables their use as sensors. Recognition properties can provide good candidates for molecular detection on the assumption that the recognition DNA/SWCNT hybrids have structurally well-defined DNA wrappings. Thus, there is a growing need for discovery of new recognition sequences. In this thesis, we explore new methods to quantify difference in solvation/binding characteristics using ATP, and a new approach to predicting recognition sequences using Machine Learning techniques. Finally, a new concept for a DNA/SWCNT-based sensing system is demonstrated

Unifying generative and discriminative learning principles

<p>Abstract</p> <p>Background</p> <p>The recognition of functional binding sites in genomic DNA remains one of the fundamental challenges of genome research. During the last decades, a plethora of different and well-adapted models has been developed, but only little attention has been payed to the development of different and similarly well-adapted learning principles. Only recently it was noticed that discriminative learning principles can be superior over generative ones in diverse bioinformatics applications, too.</p> <p>Results</p> <p>Here, we propose a generalization of generative and discriminative learning principles containing the maximum likelihood, maximum a posteriori, maximum conditional likelihood, maximum supervised posterior, generative-discriminative trade-off, and penalized generative-discriminative trade-off learning principles as special cases, and we illustrate its efficacy for the recognition of vertebrate transcription factor binding sites.</p> <p>Conclusions</p> <p>We find that the proposed learning principle helps to improve the recognition of transcription factor binding sites, enabling better computational approaches for extracting as much information as possible from valuable wet-lab data. We make all implementations available in the open-source library Jstacs so that this learning principle can be easily applied to other classification problems in the field of genome and epigenome analysis.</p