A key issue in supervised protein classification is the representation of input sequences of amino acids. Recent work using string kernels for protein data has achieved state-of-the-art classification performance. However, such representations are based only on labeled data — examples with known 3D structures, organized into structural classes — while in practice, unlabeled data is far more plentiful. In this work, we develop simple and scalable cluster kernel techniques for incorporating unlabeled data into the representation of protein sequences. We show that our methods greatly improve the classification performance of string kernels and outperform standard approaches for using unlabeled data, such as adding close homologs of the positive examples to the training data. We achieve equal or superior performance to previously presented cluster kernel methods while achieving far greater computational efficiency.

We describe several families of k-mer based string kernels related to the recently presented mismatch kernel and designed for use with support vector machines (SVMs) for classification of protein sequence data. These new kernels – restricted gappy kernels, substitution kernels, and wildcard kernels – are based on feature spaces indexed by k-length subsequences (“k-mers”) from the string alphabet Σ. However, for all kernels we define here, the kernel value K(x,y) can be computed in O(cK(|x|+|y|)) time, where the constant cK depends on the parameters of the kernel but is independent of the size |Σ | of the alphabet. Thus the computation of these kernels is linear in the length of the sequences, like the mismatch kernel, but we improve upon the parameter-dependent constant cK = k m+1 |Σ | m of the (k,m)-mismatch kernel. We compute the kernels efficiently using a trie data structure and relate our new kernels to the recently described transducer formalism. In protein classification experiments on two benchmark SCOP data sets, we show that our new faster kernels achieve SVM classification performance comparable to the mismatch kernel and the Fisher kernel derived from profile hidden Markov models, and we investigate the dependence of the kernels on parameter choice.

We propose novel algorithms for solving the so-called Support Vector Multiple Kernel Learning problem and show how they can be used to understand the resulting support vector decision function. While classical kernel-based algorithms (such as SVMs) are based on a single kernel, in Multiple Kernel Learning a quadraticallyconstraint quadratic program is solved in order to find a sparse convex combination of a set of support vector kernels. We show how this problem can be cast into a semi-infinite linear optimization problem which can in turn be solved efficiently using a boosting-like iterative method in combination with standard SVM optimization algorithms. The proposed method is able to deal with thousands of examples while combining hundreds of kernels within reasonable time. In the second part we show how this technique can be used to understand the obtained decision function in order to extract biologically relevant knowledge about the sequence analysis problem at hand. We consider the problem of splice site identification and combine string kernels at different sequence positions and with various substring (oligomer) lengths. The proposed algorithm computes a sparse weighting over the length and the substring, highlighting which substrings are important for discrimination. Finally, we propose a bootstrap scheme in order to reliably identify a few statistically significant positions, which can then be used for further analysis such as consensus finding.

Motivation: Remote homology detection between protein sequences is a central problem in computational biology. Supervised learning algorithms based on support vector machines are currently the most effective method for remote homology detection. The performance of these methods depends on how the protein sequences are modeled and on the method used to compute the kernel function between them. Results: We introduce new classes of kernel functions that are constructed by directly combining automatically generated sequence profiles with new and existing approaches for determining the similarity between pairs of protein sequences, which employ effective schemes for scoring the aligned profile positions. Experiments with remote homology detection and fold recognition problems show that these kernels are capable of producing results that are substantially better than those produced by all of the existing state-of-the-art SVM-based methods. In addition, the experiments show that these kernels, even when used in the absence of profiles, produce results that are better than those produced by existing nonprofile-based schemes.

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Abstract — The subcellular locations of proteins are important functional annotations. An effective and reliable subcellular localization method is necessary for proteomics research. This paper introduces a new method—PairProSVM—to automatically predict the subcellular locations of proteins. The profiles of all protein sequences in the training set are constructed by PSI-BLAST and the pairwise profile-alignment scores are used to form feature vectors for training a support vector machine (SVM) classifier. It was found that PairProSVM outperforms the methods that are based on sequence alignment and amino-acid compositions even if most of the homologous sequences have been removed. PairProSVM was evaluated on Huang and Li’s and Gardy et al.’s protein datasets. The overall accuracies on these datasets reach 75.3 % and 91.9%, respectively, which are higher than or comparable to those obtained by sequence alignment and composition-based methods. Index Terms — Protein subcellular localization; sequence alignment; profile alignment; kernel methods; support vector machines. I.

Motivation Protein remote homology prediction 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 problem. 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. Methods We developed a number of methods for building SVMbased multiclass classification schemes in the context of the SCOP protein classification. These methods includes 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. Results We performed a comprehensive study analyzing the different approaches using four different datasets. Our results 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 qualitatively improve the prediction results. Website:

Motivation: Protein sequence alignment plays a critical role in computational biology as it is an integral part in many analysis tasks designed to solve problems in comparative genomics, structure and function prediction, and homology modeling. Methods: We have developed novel sequence alignment algorithms that compute the alignment between a pair of sequences based on short fixed- or variable-length high-scoring subsequences. Our algorithms build the alignments by repeatedly selecting the highest scoring pairs of subsequences and using them to construct small portions of the final alignment. We utilize PSI-BLAST generated sequence profiles and employ a profile-to-profile scoring scheme derived from PICASSO. Results: We evaluated the performance of the computed alignments on two recently published benchmark datasets and compared them against the alignments computed by existing state-of-the-art dynamic programming-based profile-to-profile local and global sequence alignment algorithms. Our results show that the new algorithms achieve alignments that are comparable or better to those achieved by existing algorithms. Moreover, our results also showed that these algorithms can be used to provide better information as to which of the aligned positions are more reliable—a critical piece of information for comparative modeling applications. Suppl. Data

We present a new family of linear time algorithms for string comparison with mismatches under the string kernels framework. Based on sufficient statistics, our algorithms improve theoretical complexity bounds of existing approaches while scaling well in sequence alphabet size, the number of allowed mismatches and the size of the dataset. In particular, on large alphabets and under loose mismatch constraints our algorithms are several orders of magnitude faster than the existing algorithms for string comparison under the mismatch similarity measure. We evaluate our algorithms on synthetic data and real applications in music genre classification, protein remote homology detection and protein fold prediction. The scalability of the algorithms allows us to consider complex sequence transformations, modeled using longer string features and larger numbers of mismatches, leading to a state-of-the-art performance with significantly reduced running times. 1

In biological sequence classification, it is common to convert variable-length sequences into fixed-length vectors via pairwise sequence comparison. This pairwise approach, however, can lead to feature vectors with dimension equal to the training set size, causing the curse of dimensionality. This calls for feature selection methods that can weed out irrelevant features to reduce training and recognition time. In this paper, we propose to train an SVM using the full-feature column vectors of a pairwise scoring matrix and select the relevant features based on the support vectors of the SVM. The idea stems from the fact that pairwise scoring matrices are symmetric and support vectors are important for classification. We refer to this approach as vector-index-adaptive SVM (VIA-SVM). We compare VIA-SVM with other feature selection schemes—including SVM-RFE, R-SVM, and a filter method based on symmetric divergence (SD)—in protein subcellular localization. Results show that VIA-SVM is able to automatically bound the number of selected features within a small range. We also found that fusion of VIA-SVM and SD can produce more compact feature subsets without decreasing prediction accuracy, and that while VIA-SVM is superior for large feature-set size, the combination of SD and VIA-SVM performs better at small feature-set size. Index Terms — Feature selection, pairwise scoring, kernel methods, SVM, subcellular localization 1.