Abstract
Background
We develop a probabilistic model for combining kernel matrices to predict the function of proteins. It extends previous approaches in that it can handle multiple labels which naturally appear in the context of protein function.
Results
Explicit modeling of multilabels significantly improves the capability of learning protein function from multiple kernels. The performance and the interpretability of the inference model are further improved by simultaneously predicting the subcellular localization of proteins and by combining pairwise classifiers to consistent class membership estimates.
Conclusion
For the purpose of functional prediction of proteins, multilabels provide valuable information that should be included adequately in the training process of classifiers. Learning of functional categories gains from coprediction of subcellular localization. Pairwise separation rules allow very detailed insights into the relevance of different measurements like sequence, structure, interaction data, or expression data. A preliminary version of the software can be downloaded from http://www.inf.ethz.ch/personal/vroth/KernelHMM/ webcite.
Background
The problem of developing machinelearning tools for protein function prediction has gained considerable attention during the last years. From a machine learning perspective, this task exceeds the "standard" settings of learning problems in that a protein can be involved in several different biological processes exhibiting more than one function. This means that the objects we want to classify (i.e. the proteins) might belong to several classes, a setting which is referred to as multilabel classification. From a biological perspective, the information carried in these multilabels might be relevant for extracting correlations of functional classes. When it comes to predicting the function of new proteins, it is therefore desirable to develop tools that can explicitly handle such multiple labeled objects.
In this work we present a multilabel version of a nonlinear classifier employing Mercer kernels. Such kernel methods have been successfully applied to a variety of biological data analysis problems. One problem of using kernels, however, is the lacking interpretability of the decision functions. In particular, it is difficult to extract further insights into the nature of a given problem from kernel mappings which represent the data in implicitly defined feature spaces. It has been proposed to address this problem by using multiple kernels together with some combination rules, where each of the kernels measures different aspects of the data. Methods for learning sparse kernel combinations have the potential to extract relevant measurements for a given task. Moreover, the use of multiple kernels addresses the problem of data fusion which is a challenging problem in bioinformatics where data can be represented as strings, graphs, or high dimensional expression profiles. Kernels provide a suitable framework for combining such inhomogeneous data under a common matrix representation.
Existing algorithms for combining kernels recast the problem as a quadratically constrained quadratic program (QCQP), [1], as a semiinfinite linear program (SILP), [2], or within a sequential minimization optimization (SMO) framework, [3]. Methods for selecting kernel parameters have also been introduced in the boosting literature, see e.g. [4] or in the context of Gaussian processes, see e.g. [5]. Our method extends these approaches in two major aspects: due to the generative nature of the underlying classification model, it can learn class correlations induced by multilabeled objects and it can be used as a "building block" in hidden Markov models which allow the inclusion of further categorical information, such as the joint prediction of subcellular localization classes and functional classes. We show that these extensions significantly improve the predictive performance on yeast proteins.
Methods
Our classifier is based on an extension of the mixture discriminant analysis (MDA) framework, which forms a link between Gaussian mixture models and discriminant analysis [6]. The algorithm for solving multilabel classification problems emerges as a special case of this clustering approach. In the following we will briefly outline the algorithm which is composed of the "building blocks" Gaussian mixture models, discriminant analysis, adaptive ridge penalties and the proper handling of multilabels.
Learning Gaussian mixtures by LDA
The dataset is assumed to be given as a collection of n samples x_{i }∈ ℝ^{d}, summarized in the (n × d) matrix X. Consider now a Gaussian mixture model with K mixture components which share an identical covariance matrix Σ. Under this model, the data loglikelihood reads
where the mixing proportions π_{k }sum to one, and ϕ denotes a Gaussian density. The classical EMalgorithm, [7], provides a convenient method for maximizing l^{mix}: in the Estep one computes the assignment probabilities P(C_{k}x_{i}) of objects x_{i }to classes C_{k}, while in the Mstep the current parameters of the Gaussian modes are replaced by the maximum likelihood estimates.
Linear discriminant analysis (LDA) is a timehonored classifier that (asymptotically) finds the correct class boundaries if the classconditional densities are Gaussians with common covariance, which is exactly the supervised version of our model (1). This optimality is due to the fact that for given class labels, the maximum likelihood parameters of the model (1) can be found by LDA, see e.g. [8]. This result has been generalized in [6], where it has been shown that in the unsupervised "clustering" case the Mstep can be carried out via a weighted and augmented LDA: class labels are mimicked by replicating the n observations K times, with the kth replication having observation weights P(C_{k}x_{i}) and the "class label" k.
Following [9], any (standard) LDA problem can be restated as an optimal scoring problem. Let the classmemberships of the n data vectors be coded as a matrix Z, the (i, k)th entry of which equals one if the ith observation belongs to class k. The point of optimal scoring is to turn categorical variables into quantitative ones: a score vector θ assigns real numbers to the K levels of the categorical response variable, i.e. to the entries in the columns of Z. The simultaneous estimation of a sequence of scores θ_{k }and regression coefficients β_{k}, k = 1,...,K, constitutes the optimal scoring problem: minimize
under the orthogonality constraint Θ^{⊤}Z^{⊤}ZΘ = I_{K}/n, where Θ = (θ_{1},...,θ_{K}) and I_{K }denotes the (K × K) identity matrix. In [9] an algorithm for this problem has been proposed, whose main ingredient is a multiple linear regression of the scored responses Zθ_{k }against the data matrix X. The algorithm starts with Θ = I_{K}, and the optimal scores are derived from the solution of the multiple regression problem via an eigendecomposition. It can be shown that solutions to (2) must satisfy a certain orthogonality constraint which allows us to start with a (K × K  1) scoring matrix Θ' that is orthogonal to a Kvector of ones. In the following we will always consider this latter variant which is beneficial since it reduces the number of regressions to K  1. For simplicity in notation we will still write Θ instead of Θ'.
Returning to the above weighted and augmented LDA problem, it has been shown in [6] that the solution for this problem can be found by the standard optimal scoring version of LDA after replacing the class indicator matrix Z by its "blurred" counterpart
Adaptive ridge penalties and kernelization
In order to find sparse solutions, we take a Bayesian viewpoint of the multiple regression problem (2) and specify a prior distribution over the regression coefficients β. Following some ideas proposed in the Gaussian process literature, we choose Automatic Relevance Determination (ARD) priors, [10], which consist of a product of zeromean Gaussians with inverse variances ω_{i}:
The hyperparameters ω_{i }encode the "relevance" of the ith variable in the linear regression. A method called adaptive ridge regression finds the hyperparameters by requiring that the mean prior variance is proportional
to 1/λ, cf. [11]:
The balancing procedure has the effect that some hyperparameters ω_{i }go to infinity. As a consequence, the coefficients β_{i }are shrinked to zero and the corresponding input variables are discarded. Following
[11] it is numerically advantageous to introduce new variables
We now consider the case of sharing weights over J blocks containing m regression coefficients each:
Note that for given weights c, eq. (4) defines a standard ridgeregression problem in the transformed data
with
subject to
Practically, if during the iterations a component c_{j }becomes small compared to a predefined accuracy constant, c_{j }is set to zero, and in all regression problems the jth kernel vanishes.
The algorithm proceeds with iterated computations of kernel weights c and the expansion coefficients α_{k}, k = 1...K  1. We initialize the model with c_{j }= 1 ∀j. In our experiments, the initialization did not critically influence the final result, as long as the initial c_{j}'s are nonzero and J <n. Theoretical uniqueness results, however, are difficult to derive. For the special case without weight sharing (i.e. J = d) the above method is equivalent to the LASSO model of ℓ_{1}penalized regression (see [11]) for which a unique solution always exists if the dimensionality does not exceed the number of samples, d ≤ n. If d exceeds n (which might be the case for the kernel models considered here), there might exist different solutions which, however, share the same globally optimal value of the functional (4). The experimentally observed insensitivity to different initializations is probably due to the weightssharing constraints that shrink the number of different c_{j}'s from d to J. A theoretical analysis of the uniqueness of solutions, however, will be subject of future work.
Multilabel classification
In multilabel classification problems, an object x_{i }can belong to more than one class, i.e. it might come with a set of labels Y_{i}. We treat these multilabels in a probabilistic way by assigning to each observation
a set of classmembership probabilities. These probabilities might be given explicitly
by the supervisor. If such information is not available, they might be estimated uniformly
as 1/Y_{i} for classes included in the label set Y_{i}, and zero otherwise. After encoding these probabilities in the "blurred" response
matrix
Kernel discriminant analysis is a generative classifier which implicitly models the classes as Gaussians in the kernel feature space. The effect of multilabels on the classifier during the training phase can be understood intuitively as follows. If there are many objects in the training set which belong to both the classes C_{i }and C_{j}, the respective class centroids μ_{i}, μ_{j }will be shrunken towards the averaged value 1/2·(μ_{i }+ μ_{j}). In this way, the classifier can learn the correlation of class labels and favor the coprediction of class i and j.
For discriminant analysis it is straightforward to compute for each object a vector of assignment probabilities to the individual classes C_{k}, see e.g. [9]. In a traditional twoclass scenario we would typically assign an object to class C_{1 }if the corresponding membership probability exceeds 1/2(for equal class priors). In multilabel scenarios, however, an object can belong to different classes so that we have to find a suitable way of thresholding the output probabilities. In analogy to the classical twoclass case, we propose to sort the assignment probabilities in decreasing order and assign an object x_{i }to the first k classes in this order such that
where τ is a predefined threshold (e.g. τ = 1/2). By varying τ one can record the usual precisionrecall curves, cf. Figure 1 for an example.
Figure 1. Performance of different classifiers. Performance of different classifier variants under crossvalidation. Left panel: boxplots of maximum F1 measure. Left to right: 8 original kernels from [1], extended kernel set, combined subcellular location and functional prediction, pairwise learning of the kernel weights (in the combined model). Right panel: precision, recall and F1 for the pairwise classifier used as "building block" in the HMM under variation of the threshold τ which controls the label multiplicity.
Algorithm 1 Multilabel kernel learning via AdR regression
Training: /* we start with one Estep */
compute "blurred" (n × K) response matrix
/* now follows one single Mstep */
compute initial (n × K  1) scoring matrix Θ_{0}, see [9] for details;
Initialize c_{i }= 1, ∀ i = 1,...,J;
repeat
compute α_{k}, k = 1,...,K  1 as the solution of the linear systems (7);
recompute the kernel weights c^{(t+1)}, see (8);
until c^{(t+1) } c^{(t)} <ε
compute fitted values and projection matrix for the discriminant analysis subspace, see [9,13];
Prediction:
compute projected test object
compute class membership probabilities P(C_{k}x_{*}) and extract multilabels according to eq.(9).
Model selection
For the purpose of model selection, we assume that we are given a set of kernel matrices over multilabeled objects. We further assume that the rule of deriving "fractional labels" from the multilabels is given. In the absence of further prior knowledge (which is probably the case in most realworld applications), we assume that the fractional labels are derived by averaging over all classes to which an object is assigned. Under these assumptions, the model contains only two free parameters, namely the regularization constant λ in eq. (7) and the threshold τ for predicting multilabels in eq. (9). In our experiments, the former is estimated via crossvalidation on the training sets. A unique multilabelthreshold can also be estimated by crossvalidation, but in this work we report the full precisionrecallF1curves obtained by varying this threshold, see Figure 1.
Functional classes and subcellular localization
In several classification tasks in bioinformatics, more than one classification scheme is available to assign the data to certain groups. Proteins, for instance, can be classified not only according to their function, but also according to their subcellular localization. For the yeast genome, such a localizationbased scheme is available from CYGD, see Table 2. If for some proteins their subcellular localization can be predicted with high reliability, and if we find high correlations between the corresponding localization classes and certain functional classes, we can potentially exploit this prior knowledge to increase the performance of the functional classification.
Table 2. Toplevel hierarchy of subcellular localization classes from CYGD
We combine both classification schemes by way of a hidden Markov model (HMM). This choice was guided by the observation that even the standard Kclass discriminant analysis model can be viewed as a simple HMM consisting of K emitting nodes and a silent begin and end node, see the left panel of Figure 2. The K emitting nodes represent the values of the hidden variable
Figure 2. Graphical representation of hidden Markov models. Graphical representation of hidden Markov models. Left: standard 4class discriminant analysis with 4 Gaussian emission probabilities.
A second classification scheme is included in the automaton by adding another layer
with L emitting nodes. These additional nodes correspond to a Gaussian mixture model with
L components that in our case correspond to subcellular localization classes, see the
right panel of Figure 2. The emitting nodes in the first layer represent the values of the hidden variable
Locality due to pairwise kernel classifiers
The method introduced above finds a "global" set of kernels for the full multiclass
problem. In some applications, however, it might be desirable to further investigate
the discriminative power of kernels in a more classspecific or "local" setting. This
can be achieved by an alternative approach to multiclass discriminant analysis based
on the pairwise coupling scheme in [14]. The main idea is to find a Kclass discriminant rule (with classes C_{1},...,C_{K}) by training all K(K  1)/2 possible twoclass classifiers and coupling the obtained conditional membership
probabilities r_{ij }:= Prob(C_{i}C_{i }or C_{j}) to a consistent Kclass assignment probability. In other words, we want to find probabilities p_{1},...,p_{K }such that the quantities
The probabilities p_{1},...,p_{K }are finally found be minimizing the KLdivergence between r_{ij }and s_{ij}. This pairwise coupling approach can also be adapted for multiple class labels by way of "fractional" class assignments in the training step. If we find many samples in the training set which belong to both the classes i and j, multilabel discriminant analysis will effectively shrink the respective class centroids μ_{i }and μ_{j }towards their common mean while keeping the covariances constant, a procedure which will favor the coprediction of classes i and j. In our experiments, we use this pairwise approach to LDA as a "building block" in the twolayered HMM for simultaneous prediction of subcellular localization and functional class. The advantage of this pairwise method over the "global" approach is that in each of the K(K  1)/2 subproblems a taskspecific subset of kernels is learned. Concerning the computational workload, the pairwise approach is very similar to the "global" method, since the increase of classifiers to be learned is compensated by the smaller sample size in the individual twoclass problems.
Results and discussion
On the toplevel hierarchy, the functional catalog provided by the MIPS comprehensive yeast genome database (CYGD) [15] assigns roughly 4000 yeast proteins to several functional classes listed in Table 1. Note that this classification scheme corresponds to an old version of the MIPS functional catalog, whereas the newest version, funcat 2.0, further splits some of these 13 classes. To allow a better comparison with previous results reported in [1], however, we still use the older labeling scheme.
Table 1. Functional classes from MIPS CYGD
Kernel representation
One of the major advantages of our method is its capability of automatically extracting relevant data sources out of a large collection of kernels presented by the user. The user can, thus, collect as much information sources as possible and let the algorithm decide which to choose. Following this idea, we represent the yeast proteins by previously used kernels that extract information on different levels, like mRNA expression, protein sequences and proteinprotein interactions. Moreover, we enrich this set of "basis" kernels by variants thereof resulting from nonlinear feature space mappings. We further investigated additional kernels from several publicly available microarray datasets [1620].
The "basis" kernels introduced in [1] consist of (i) two kernels which analyze the domain structure: K_{pfdom }and an enriched variant K_{pf_exp}; (ii) three diffusion kernels on interaction graphs: K_{mpi}(proteinprotein interactions), K_{mgi }(genetic interactions), K_{tap }(coparticipation in protein complexes); (iii) two kernels derived from cell cycle
gene expression measurements: K_{exp_d }(binary) and K_{exp_g }(Gaussian); (iv) a string alignment kernel K_{SW}. From each of these 8 kernels we derive 3 additional Gaussian RBF variants by computing
squared Euclidean distances
Multilabels
Since a protein can have several functions, each protein comes with a set Y of functional class labels. Let Y denote the cardinality of this set, i.e. the number of classes a certain protein
is assigned to. For running Algorithm 1 in the methods section below we have to translate the label sets Y_{i}, i = 1,...,n into membership probabilities which form the entries of the "blurred" n × K indicator matrix
Performance evaluation
In [1], all 13 classes were trained separately in a oneagainstall manner, where a gene
is treated as a member of a certain class whenever it has a positive label for that
class (irrespective of other labels!). The performance of these classifiers has been
evaluated in terms of area under the ROC curves (auc). Our method, on the contrary, respects the multilabel structure of the problem by
explicitly exploiting cooccurrences of class labels. It uses fractional labels
To overcome this problem, we use two different measures: for each class C_{k}, auc_{0}/1 measures the area under the ROC curve only on the subset of genes which either
do not belong to class C_{k}, or which exclusively belong to C_{k}. For this subset (≈ 2/3 of the yeast genes) we can directly compute a ROC curve,
since there are no scaling problems. The measure auc_{weighted}, on the other hand, uses all test genes and rescales both the fractional label
Figure 3 depicts the results for the enlarged kernel set consisting of the 8 "basis" kernels and 3 additional RBF kernel variants thereof. For each of the 13 classes three performance values (area under ROC curve) are shown: the result reported in [1] (depicted solely as vertical bars since no variance measurements are provided) and the two measures auc_{weighted }and auc_{0}/1 for our multilabel approach (represented as boxplots). Each of the latter two significantly outperforms the former in most classes (marked red). The measure auc_{0}/1 shows an improved median performance in all classes (some are probably not significant, marked orange), auc_{weighted }has worse performance in 2 classes (probably not significant, light blue). A control experiment in which we used only the 8 "basis" kernels yielded a slightly lower performance.
Figure 3. Performance evaluation. Performance Evaluation for the 13 functional classes of yeast proteins. From left to right: results from [1], auc_{weighted }and auc_{0}/1. Red: significant improvements; orange: improvements of unclear significance; light blue: worse performance (unclear significance).
The improvement obtained by using the enlarged kernel set becomes more obvious when computing the F1measure which is the harmonic mean of precision and recall. The latter are similar to but different from the axes of ROC curves which encode fallout and recall. Precision is the probability that a predicted category is a true category, whereas fallout is the probability that a true absence of a category was labeled a false positive presence. Since the definite absence of a certain protein function can be hardly validated experimentally, the estimated fallout rate will strongly depend on the actual status of experimental coverage. The precision measure, on the other hand, does not so severely suffer from this problem, since the number of present categories might be estimated more reliably even with a small number of carefully designed experiments.
To compute the F1 statistics for a given threshold τ in eq. (9), we select for each gene the k most probable multilabels such that the sum of the k largest membership probabilities exceeds τ. We then compute precision and recall up to the rank k and combine both to the F1measure. Variation of τ yields a complete precisionrecallF1curve. With the enlarged kernel set the maximum F1 value increases significantly, as can be seen in the two leftmost boxplots in Figure 1.
Figure 4 depicts the learned kernel weights. Each box contains 4 bins corresponding to the original kernels from [1] and three Gaussian RBF kernel variants with decreasing kernel width. It is of particular interest that a RBF variant of the genetic interaction kernel K_{mgi }attains the highest weight, whereas the original diffusion kernel K_{mgi }on the interaction graph seems to contain almost no discriminative information (consistent with [1] where K_{mgi }is the least important kernel). The reason for the improved performance of the RBF kernel variant might be the local nature of the Gaussian kernel function. A diffusion kernel encodes transition probabilities for a random walk model on a graph G. In the light of this random walk interpretation, the steep decay of the Gaussian kernel accentuates the local graph structure.
Figure 4. Learned kernel weights. Learned kernel weights. Each box contains one of the 8 "basis" kernels and three Gaussian RBF variants (from left to right).
Functional classes and subcellular localization
For the yeast genome MIPS CYGD provides a classification scheme with respect to subcellular localization of the proteins, see Table 2. We combine both the functional and the localizationbased scheme by way of the hidden Markov model (HMM) described in the methods section below. The corresponding automaton model is depicted in Figure 5. The first layer contains 20 emitting nodes corresponding to the toplevel localization classes in Table 2. The transition probabilities are estimated from a training set by counting the occurrences of paths in the model. In order to highlight the essential graph structure, only the transitions with probability above 0.1 are shown. Note that several localization nodes have dominant transitions to only one or two functional nodes, see e.g. node "750" (nucleus) which has a strong prior for class "04" (transcription), the pair "730" (cytoskeleton) and "03" (cell cycle & DNA processing), or "745" (transport vesicles) which strongly votes for functional class "07" (cellular transport & transport mechanism).
Figure 5. The hidden Markov model. The hidden Markov model. Combined graph for subcellular location classes (upper layer) and functional classes (lower layer). Joint predictions of these two entities means finding (multiple) paths through the graph from begin to end. The nodes in the two layers encode the values of the hidden random variables location class and functional class, see also Figure 2. The arrows between the nodes encode "transition" probabilities which are estimated by frequency counts on a training set. For highlighting the main structure of this graph, only transition probabilities with p > 0.1 are shown. Width and color of the arrows encode these probabilities: > 0.8 yellow, > 0.6 blue, > 0.4 green, > 0.2 red. For instance, the yellow arrow between the nodes "745" and "07" means that more than 80% of the proteins with subcellular localization transport vesicles belong to the functional class cellular transport & transport mechanism.
In order to evaluate the possible advantages of the combined localizationfunction classifier, we again conducted a crossvalidation experiment in which both sets of labels were predicted. According to the results summarized in the left panel of Figure 1, the inclusion of the prediction step for the subcellular localization of a protein indeed improves the prediction of its function.
Towards a "local" model: pairwise kernel weights
While all previous models find a common set of kernels for all classes, the pairwise coupling approach described in the methods section couples pairwise classifiers which find individual kernel weights that are optimal for the "local" problem of separating only two classes. These pairwise classifiers can again learn class correlations induced by objects with multiple labels.
The rightmost boxplot in the left panel of Figure 1 shows that this "local" model significantly improves the predictive power of the HMMbased classifier. The right panel depicts the evolution of precision, recall and F1 under variation of the threshold τ in eq. (9).
Figure 6 shows two examples of the learned kernel weights in the 78 individual twoclass models for the 13 functional classes which nicely demonstrate the adaptiveness of the pairwise approach: while for the separation of the classes metabolism and control of cellular organization the combination of SmithWaterman sequence alignment kernels ("SW") and protein interaction kernels ("mpi") have a main role, the separation of classes energy and protein synthesis is dominated by gene expression information ("exp") and protein domain structure ("pfam"). A closer analysis of all 78 classifiers shows some general trends, for instance the importance of gene expression kernels whenever one of the classes energy or protein synthesis is involved.
Figure 6. Kernel weights for the pairwise model. Kernel weights for the pairwise model. Left: separating classes metabolism and control of cellular organization. Right: classes energy and protein synthesis. The kernels are arranged in groups according to their origin: genetic interaction (mgi), prot.prot. interaction (mpi), domain structure (pfam) string alignments (SW), protein complexes (tap) and gene expression (exp). The 8 gene expression RBF kernels represent the data in [1620] and three RBF kernel variants of the data in [21] (left to right).
Conclusion
While kernelbased classifiers have been successfully applied to a variety of prediction tasks, their main drawback is the lacking interpretability of the decision functions. One attempt to overcome this shortcoming is to find a weighted combination of multiple kernels, each of which represents a different type of measurement. The idea is that sparse kernel combinations allow the user to identify the relevant influence factors for a given task. In this work, the problem of learning such sparse kernel combinations has been addressed by reformulating classification as an indicator regression problem using adaptive ridge penalties. While the standard adaptive ridge model presented in [11] selects individual input features, our extensions concerning weight sharing and kernelization lead to a nonlinear model that finds sparse combinations of kernel matrices. A probabilistic treatment of multiple labels allows us to apply the classifier to tasks in which the input objects can belong to more than one category. The effect of multilabels can be intuitively understood as shrinking the centroids of classes which share many multilabeled objects towards their average centroid, thus favoring coprediction of these classes.
The method has been applied to the problem of predicting the function of yeast proteins which defines a classical multilabel setting. From the experiments we conclude that our model compares favorably to the approach in [1]. Two aspects seem to be of particular importance: on the modeling side, our approach directly exploits the multilabel structure of the problem, rather than ignoring class correlations.
Concerning the computational aspects, the efficiency of the method allows us to easily enlarge the set of kernels: as long as one single matrix can be hold in the main memory, the algorithm is highly efficient. For yeast proteins, the use of additional kernels has e.g. lead to the insight that genetic interactions are highly discriminative for functional predictions.
Aiming at a still higher classification rate and at more detailed information about the relevance of kernels, we have introduced two further modifications: extending the multilabel classifier to a twolayer hidden Markov model (HMM) allows us to combine two different labeling schemes. Multilabel prediction in the HMM naturally translates to reconstructing multiple paths through a graph. It could be shown that the prediction of the subcellular localization of a protein in the first layer helps to identify its functional class in the second layer, the reason for this improvement being the strong correlation of nodes in both layers. Localization in the transport vesicles, for instance, gives a strong prior for having a role in the functional class cellular transport & transport mechanism.
The second modification concerns the transition from a single "global" prediction model to several "local" models which focus on the separation of pairs of classes only. The estimated pairwise membership probabilities are coupled to a consistent set of assignment probabilities over all classes. Using the pairwise classifiers as "building blocks" in the HMM offers the advantage of increased adaptiveness, since the kernel weighting can focus on the individual requirements for separating one class from another. This approach leads not only to a significantly increased classification performance, but it also gives a much more detailed picture on the importance of different data sources for predicting protein function.
Authors' contributions
Both authors developed methods, performed comparisons of methods, and wrote the manuscript.
Acknowledgements
This work was partially funded by ETH grant TH5/043.
This article has been published as part of BMC Bioinformatics Volume 8, Supplement 2, 2007: Probabilistic Modeling and Machine Learning in Structural and Systems Biology. The full contents of the supplement are available online at http://www.biomedcentral.com/14712105/8?issue=S2.
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