MOTIVATION: Set-based variance component tests have been identified as a way to increase power in association studies by aggregating weak individual effects. However, the choice of test statistic has been largely ignored even though it may play an important role in obtaining optimal power. We compared a standard statistical test-a score test-with a recently developed likelihood ratio (LR) test. Further, when correction for hidden structure is needed, or gene-gene interactions are sought, state-of-the art algorithms for both the score and LR tests can be computationally impractical. Thus we develop new computationally efficient methods. RESULTS: After reviewing theoretical differences in performance between the score and LR tests, we find empirically on real data that the LR test generally has more power. In particular, on 15 of 17 real datasets, the LR test yielded at least as many associations as the score test-up to 23 more associations-whereas the score test yielded at most one more association than the LR test in the two remaining datasets. On synthetic data, we find that the LR test yielded up to 12% more associations, consistent with our results on real data, but also observe a regime of extremely small signal where the score test yielded up to 25% more associations than the LR test, consistent with theory. Finally, our computational speedups now enable (i) efficient LR testing when the background kernel is full rank, and (ii) efficient score testing when the background kernel changes with each test, as for gene-gene interaction tests. The latter yielded a factor of 2000 speedup on a cohort of size 13 500. AVAILABILITY: Software available at http://research.microsoft.com/en-us/um/redmond/projects/MSCompBio/Fastlmm/. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

We present a novel regularization-based Multitask Learning (MTL) formulation for Structured Output (SO) prediction for the case of hierarchical task relations. Structured output learning often results in difficult inference problems and requires large amounts of training data to obtain accurate models. We propose to use MTL to exploit information available for related structured output learning tasks by means of hierarchical regularization. Due to the combination of example sets, the cost of training models for structured output prediction can easily become infeasible for real world applications. We thus propose an efficient algorithm based on bundle methods to solve the optimization problems resulting from MTL structured output learning. We demonstrate the performance of our approach on gene finding problems from the application domain of computational biology. We show that 1) our proposed solver achieves much faster convergence than previous methods and 2) that the Hierarchical SO-MTL approach clearly outperforms considered non-MTL methods.

BACKGROUND: String kernels are commonly used for the classification of biological sequences, nucleotide as well as amino acid sequences. Although string kernels are already very powerful, when it comes to amino acids they have a major short coming. They ignore an important piece of information when comparing amino acids: the physico-chemical properties such as size, hydrophobicity, or charge. This information is very valuable, especially when training data is less abundant. There have been only very few approaches so far that aim at combining these two ideas. RESULTS: We propose new string kernels that combine the benefits of physico-chemical descriptors for amino acids with the ones of string kernels. The benefits of the proposed kernels are assessed on two problems: MHC-peptide binding classification using position specific kernels and protein classification based on the substring spectrum of the sequences. Our experiments demonstrate that the incorporation of amino acid properties in string kernels yields improved performances compared to standard string kernels and to previously proposed non-substring kernels. CONCLUSIONS: In summary, the proposed modifications, in particular the combination with the RBF substring kernel, consistently yield improvements without affecting the computational complexity. The proposed kernels therefore appear to be the kernels of choice for any protein sequence-based inference. AVAILABILITY: Data sets, code and additional information are available from http://www.fml.tuebingen.mpg.de/raetsch/suppl/aask. Implementations of the developed kernels are available as part of the Shogun toolbox.

BACKGROUND: The lack of sufficient training data is the limiting factor for many Machine Learning applications in Computational Biology. If data is available for several different but related problem domains, Multitask Learning algorithms can be used to learn a model based on all available information. In Bioinformatics, many problems can be cast into the Multitask Learning scenario by incorporating data from several organisms. However, combining information from several tasks requires careful consideration of the degree of similarity between tasks. Our proposed method simultaneously learns or refines the similarity between tasks along with the Multitask Learning classifier. This is done by formulating the Multitask Learning problem as Multiple Kernel Learning, using the recently published q-Norm MKL algorithm. RESULTS: We demonstrate the performance of our method on two problems from Computational Biology. First, we show that our method is able to improve performance on a splice site dataset with given hierarchical task structure by refining the task relationships. Second, we consider an MHC-I dataset, for which we assume no knowledge about the degree of task relatedness. Here, we are able to learn the task similarities ab initio along with the Multitask classifiers. In both cases, we outperform baseline methods that we compare against. CONCLUSIONS: We present a novel approach to Multitask Learning that is capable of learning task similarity along with the classifiers. The framework is very general as it allows to incorporate prior knowledge about tasks relationships if available, but is also able to identify task similarities in absence of such prior information. Both variants show promising results in applications from Computational Biology.

We study the problem of domain transfer for a supervised classification task in mRNA splicing. We consider a number of recent domain transfer methods from machine learning, including some that are novel, and evaluate them on genomic sequence data from model organisms of varying evolutionary distance. We find that in cases where the organisms are not closely related, the use of domain adaptation methods can help improve classification performance.