Including probelevel uncertainty in modelbased gene expression clustering
 Xuejun Liu^{1},
 Kevin K Lin^{2},
 Bogi Andersen^{2} and
 Magnus Rattray^{3}Email author
DOI: 10.1186/14712105898
© Liu et al; licensee BioMed Central Ltd. 2007
Received: 14 September 2006
Accepted: 21 March 2007
Published: 21 March 2007
Abstract
Background
Clustering is an important analysis performed on microarray gene expression data since it groups genes which have similar expression patterns and enables the exploration of unknown gene functions. Microarray experiments are associated with many sources of experimental and biological variation and the resulting gene expression data are therefore very noisy. Many heuristic and modelbased clustering approaches have been developed to cluster this noisy data. However, few of them include consideration of probelevel measurement error which provides rich information about technical variability.
Results
We augment a standard modelbased clustering method to incorporate probelevel measurement error. Using probelevel measurements from a recently developed Affymetrix probelevel model, multimgMOS, we include the probelevel measurement error directly into the standard Gaussian mixture model. Our augmented model is shown to provide improved clustering performance on simulated datasets and a real mouse timecourse dataset.
Conclusion
The performance of modelbased clustering of gene expression data is improved by including probelevel measurement error and more biologically meaningful clustering results are obtained.
Background
Microarrays [1, 2] are routinely used for the quantitative measurement of gene expression levels on a genomewide scale. Microarray experiments are complicated multiple step procedures and variability can be introduced in every step, so that the resulting data are often very noisy, especially for weakly expressed genes. Appropriate statistical analysis of this noisy data is very important in order to obtain meaningful biological information [3, 4]. The analysis of microarray data is usually performed in multiple stages, including probelevel analysis, normalisation and higher level analyses. The aim of the probelevel analysis is to obtain reliable gene expression measurements from the image data. Various higher level analyses, such as detecting differential gene expression or clustering, can then be carried out depending on the biological aims of the experiment.
Unsupervised clustering is the most frequently used approach for exploring gene function. By clustering, a huge number of genes can be organised into a much smaller number of categories according to their shared expression patterns. It is hoped that these shared patterns reflect similar function or common transcriptional regulation. Exploring and studying the obtained gene clusters is an important way to infer the function of uncharacterised genes from other known genes in the same cluster. There are many unsupervised algorithms which have been used to cluster gene expression data, including the most popular hierarchical clustering [5] and kmeans [6], which are based on similarity measures, and selforganising maps [7]. Most of these conventional algorithms are largely heuristically motivated. They are easily implemented and their application is usually computationally efficient. However, these methods lack the capability to deal in a principled way with the experimental variability in the gene expression data. Furthermore, there is no formal way to determine the number of clusters with these algorithms. It is hard to say which one is generally better than the others [8]. Probabilistic models provide a principled alternative to these conventional methods. In particular, modelbased approaches have been proposed as useful methods for clustering gene expression data in a probabilistic way [9–12]. By using a probabilistic model, the experimental noise can be included explicitly in the model and estimated from the data, making this approach more robust to noise. There are also useful and principled model selection methods that can be used to determine the optimal number of clusters. The advantages of modelbased probabilistic approaches over heuristic methods are already well established [10].
Affymetrix arrays contain multiple probes for each target gene and this internal replication can be used to obtain an estimate of the technical measurement error associated with each gene expression measurement [13–17]. This source of error is especially significant for weakly expressed genes. The recently developed model, multimgMOS [18], provides accurate gene expression measurements along with the associated uncertainty in this measurement. It has been shown that the probelevel measurement error obtained from multimgMOS can be propagated through a downstream probabilistic analysis, thereby improving the performance of the analysis [16, 17]. Existing modelbased clustering methods do not consider this probelevel measurement error and they therefore discard this rich source of information about variability. Although standard modelbased clustering methods are relatively robust to noise, very noisy measurements can still have a detrimental effect on these clustering methods, resulting in poor performance and many biologically irrelevant clusters. In this paper, we aim to include information about probelevel measurement error into the standard Gaussian mixture model in order to improve performance compared to standard modelbased clustering. Our augmented Gaussian mixture clustering model is called PUMACLUST (Propagating Uncertainty in Microarray Analysis – CLUSTering) and has been implemented in the Rpackage pumaclust which is available from [19].
Results and discussion
We examine the performance of the extended Gaussian mixture model on two simulated datasets and a realworld mouse timecourse dataset [12]. The simulated datasets are generated to reflect the noise commonly seen in real microarray experiments. The extended mixture model is compared with the standard Gaussian mixture models implemented in MCLUST [20], which includes all variants of standard Gaussian mixture models in terms of the representation of the covariance matrix. However, these models do not take the probelevel measurement error into consideration.
The performance of different clustering methods on datasets with known structures can be evaluated by using the adjusted Rand index [21, 22]. The adjusted Rand index measures the similarity of two clusterings on a dataset and it is widely used by the clustering research community [10, 23–25]. The adjusted Rand index lies between 0 and 1, and is calculated based on whether pairs are placed in the same or different clusters in two partitions with a higher value meaning better agreement between two clusterings. For the simulated datasets, since the true structure of the data is known, we use the adjusted Rand index to evaluate the different partitioning ability of the extended mixture model which incorporates the probelevel measurement error and the standard mixture model. For the real mouse timecourse dataset, gene ontology (GO) enrichment analysis is used to compare the performance of the two clustering methods.
Clustering on simulated data sets
Simulated periodic data
Periodic patterns are often observed in realworld timecourse microarray data [12, 26]. However, the true structure of the real datasets is unavailable. We generate simulated periodic data and include noise with magnitude estimated from real microarray data. Similar to the methods used by [23] and [25], the simulated data is generated by the following four steps.
At the first step, the logged gene expression within each known group is generated. There are six groups and 600 genes in the dataset. Each group has 100 genes. The first four groups have a periodic sine pattern. The expression of gene i in group q, q = 1, 2, 3, 4, is generated by
x_{ qij }= A_{ i }sin(2πj/10  πq/ 2) + S, (1)
where j = 1, 2,..., J and J is the number of conditions or time points. A_{ i }is a random scaling factor which is sampled from U(0, 7), where U represents the uniform distribution. S is a shifting factor which is set as 7. This assignment of A_{ i }and S is to make the gene expression level lie between 0 and 14 which is the normal range of the logged gene expression level from real Affymetrix datasets. The gene expression levels of group 5 and group 6 are generated by linear functions
x_{ qij }= jA_{ qi }/J and x_{ qij }= jA_{ qi }/J + S, (2)
respectively, where A_{ qi }is sampled from U (0,14) and S = 14 when q = 6 so as to ensure that the simulated expression level lies within the accepted logged expression range.
The simulated data from the first step follows perfectly the same sine wave within the same group except for a different magnitude. However, in practice there is biological and technical noise in the experiment distorting the true sine wave. At the second step, the real mouse dataset (described in the next section) is used to obtain an estimate of the combined noise from biological and technical sources which is related to the variance of observed gene expression level from replicated experiments. The mouse dataset has three or four replicates for each condition. Using the gene expression summaries from MAS 5.0 [27] which is the standard software provided by Affymetrix, an estimate of the combined technical and biological noise can be obtained from CyberT [28]. CyberT is a Bayesian hierarchical model which calculates the variance between replicates using point estimates of gene expression level from each replicate. Since the variance has a dependence on gene expression level, the combined noise, ${\sigma}_{qij}^{2}$, is sampled from a subset of variances calculated from CyberT whose corresponding expression levels are close to x_{ qij }. Thus, the final simulated expression level, $\widehat{x}$_{ qij }, is
Pvalues obtained from a paired ttest of adjusted Rand index from MCLUST and PUMACLUST. A paired ttest is performed for MCLUST and each of PUMACLUST results. The 10 simulated datasets in Figure 3 are used for each test. PC represents PUMACLUST results on the original simulated data. PC.01, PC.1 and PC.2 represent the PUMACLUST results on the datasets with added noise drawn from $\mathcal{N}$(0, 0.01), $\mathcal{N}$(0, 0.1) and $\mathcal{N}$(0, 0.2) respectively.
No of conditions  6 groups  7 groups  

PC  PC.01  PC.1  PC.2  PC  PC.01  PC.1  PC.2  
10  1.10e8  9.37e8  5.90e8  5.67e7  5.67e9  7.77e9  3.87e7  5.87e6 
20  2.39e8  1.80e8  2.30e7  4.22e7  4.03e9  4.10e9  1.13e7  8.56e8 
30  3.54e7  1.38e6  2.99e6  5.00e6  9.96e7  4.34e7  1.14e7  3.75e6 
Including a noise group
In a realworld microarray dataset, there are usually a certain fraction of genes whose expression levels are indistinguishable from random noise. These genes do not belong to any pattern group in the dataset [25].
To assess the performance of PUMACLUST on this kind of dataset, we add a group of random noise genes into the previously simulated datasets. The first generating step of the gene expression level for group seven is
x_{ qij }= A_{ qi }, (4)
where A_{ qi }is sampled from U(0,14). The following steps of the simulation are the same as those for the former six groups. Three sets of simulated datasets with 10 randomly generated datasets for each set are also sampled and the average adjusted Rand index for three cases with 10, 20, and 30 conditions are shown in the second column of Figure 3. The number of groups for both MCLUST and PUMACLUST is assigned to seven. From the three plots it can be seen that the performance of the clustering from both PUMACLUST and MCLUST decreases with the inclusion of the noise group, but PUMACLUST still outperforms MCLUST over all three noise levels with the three different data dimensions. The pvalues in Table 1 indicate that the improvement is statistically significant.
Testing the robustness to misspecified technical variance
The probelevel variance in the simulated datasets generated above is sampled from multimgMOS results from the real mouse dataset. When applying PUMACLUST it was assumed that the level of noise is known, but in practice it would be estimated using multimgMOS. We would like to test robustness to errors in estimating the measurement error variance. We therefore add some noise to the sampled standard deviation, $\widehat{\sigma}$_{ qij }, to simulate the error made in estimating this quantity. For the sixgroup and sevengroup datasets, three kinds of random noise are added by sampling from $\mathcal{N}$(0, 0.01), $\mathcal{N}$(0, 0.1) and $\mathcal{N}$(0, 0.2). The scatter plots of the erroradded standard deviation against the simulated gene expression are shown in Figure 2(b)–(d). Figure 3 gives the average adjusted Rand index of the clustering results from PUMACLUST on the erroradded standard deviation for various cases. In the case of PC.01, the added noise is quite small so that the clustering results of PC.01 are very close to the clustering results on the original simulated data. As the added noise variance increases, the performance of PUMACLUST decreases. The pvalues in Table 1 mostly increase when larger noise is added to the variances but all pvalues remain small and demonstrate a significant improvement for PUMACLUST over MCLUST. These results demonstrate that clustering is most accurate when the measurement error variance is known, but that the method is robust to errors in the estimate of the measurement error.
Clustering on a real mouse timecourse dataset
The improved performance of the new model, PUMACLUST, over the standard Gaussian mixture model on simulated datasets was shown in the previous section. Here, we evaluate the performance of PUMACLUST on a real mouse dataset showing periodic behavior [12] by comparing with the results of the standard mixture model implemented in MCLUST.
This timecourse dataset profiles the gene expression changes during the hair growth cycle, which is synchronised for the first two cycles following birth. After two cycles the hair growth cycle becomes progressively unsynchronised. Lin et al. use Affymetrix MGU74Av2 microarray chips to profile mRNA expression in mouse back skin from eight representative time points in order to discover regulators in hairfollicle morphogenesis and cycling [12]. The microarray dataset utilised a total of 25 chips with each time point consisting of three or four replicates. The first five time points (day 1, 6, 14, 17 and 23) cover the first synchronised cycle and the last three time points (week 9, month 5 and year 1) belong to the asynchronous cycles. They identified 2,461 potential hair cycleassociated genes using a F test comparing synchronous and asynchronous time points. This dataset is available at [29].
We apply both PUMACLUST and MCLUST clustering over the first five time points which belong to the synchronised cycle and includes 15 chips. For MCLUST the raw mouse dataset is processed using the popular probelevel method GCRMA [30]. For PUMACLUST the raw data is processed by multimgMOS. We also applied MCLUST to MAS5.0 and multimgMOS gene expression measurements and the performance was found to be similar to the results presented here using GCRMA.
To assess whether biologically relevant clusters are created using the two methods, we systematically performed GO annotation enrichment analysis for the individual clusters using DAVID 2006 (The Database for Annotation, Visualization and Integrated Discovery, [33]). The GO enrichment analysis allows the direct assessment of the biological significance for gene clusters found based on the enrichment of genes belonging to a specific GO functional category. The enrichment calculation performed in DAVID is a modified Fisher Exact test. The resulting pvalue shows the biological significance for gene clusters. Based on our experience, GO Biological Process term level 5 gives more precise category definitions which are useful in further biological interpretations. Therefore, a meaningful GO enrichment analysis is to examine enriched categories of GO Biological Process at term level 5 and to select an enrichment cutoff at a conventional pvalue of 0.05.
Conclusion
In this paper we demonstrate the usefulness of the measurement error in modelbased clustering of gene expression data. A standard Gaussian mixture model with an unequal volume spherical covariance matrix is augmented to incorporate probelevel measurement error obtained from Affymetrix microarrays. Results from simulated datasets and a real mouse timecourse dataset show that the inclusion of probelevel measurement error results in improved and more biologically meaningful clustering of gene expression data. The augmented clustering model has been implemented in an R package, pumaclust, for public use of the method.
The improved performance of the augmented model has been shown in this paper. It is possible that further improvement can also be made by considering the replicate information where repeated measurements are available for time points. Clustering on repeated measurements has been considered by [12, 23, 25], but all of these approaches do not include the probelevel measurement error. Including both probelevel noise and replicate information in the clustering would be a useful extension of our work.
Methods
multimgMOS and probelevel measurement error
Affymetrix microarrays use multiple probepairs called a probeset to measure the expression level for each gene. Each probepair consists of a perfect match (PM) probe and a mismatch (MM) probe. By design, the intensity of the PM probe measures the specific hybridisation of the target and the MM probe measures the nonspecific hybridisation associated to its corresponding PM probe. The microarray experimental data show that the intensities of both PM and MM probes vary in a probespecific way and MM probes also detect some specific hybridisation. Based on these observations, multimgMOS [18] assumes the intensities of PM and MM probes for a probeset both follow gamma distributions with parameters accounting for specific and nonspecific hybridisation, and probespecific effects. Let y_{ ijc }and m_{ ijc }represent the j th PM and MM intensities respectively for the i th probeset under the c th condition. The model is defined by
y_{ ijc }~ Ga(a_{ ic }+ α_{ ic }, b_{ ij })
m_{ ijc }~ Ga (a_{ ic }+ φα_{ ic }, b_{ ij }) (5)
b_{ ij }~ Ga(c_{ i }, d_{ i }),
where Ga represents the gamma distribution. The parameter a_{ ic }accounts for the background and nonspecific hybridisation associated with the probeset and α_{ ic }accounts for the specific hybridisation measured by the probeset. The parameter b_{ ij }is a latent variable which models probespecific effects. The Maximum a Posteriori (MAP) solution of this model can be found by efficient numerical optimisation. The posterior distribution of the logged gene expression level can then be estimated from the model and approximated by a Gaussian distribution with a mean, $\widehat{x}$_{ ic }, and a variance, ν_{ ic }. The mean of this distribution is taken as the estimated gene expression for gene i under the condition c and the variance can be considered the measurement error associated with this estimate. The Gaussian approximation to the posterior distribution is useful for propagating the probelevel measurement error in subsequent downstream analyses.
Mixture model
The mixture model is a useful tool for revealing the inherent structure of data. In a mixture model with K components, the data is generated by
where P(k) denotes the probability of selecting the k th component with parameters θ_{ k }and θ= {θ_{1}, θ_{2},..., θ_{ K }, P(k)} is the complete parameter set of the mixture model. The parameters k ar latent variables determining which cluster the data belongs to.
Mixture models are usually solved by maximum likelihood using an ExpectationMaximisation (EM) algorithm [34]. With the initialised parameters at t = 0, the values of parameters can be determined iteratively through an Estep and Mstep:

Estep: Compute
P^{ t }(kx_{ i }) = P(kx_{ i }; θ^{ t }) (7)
for each data point x_{ i }and each component k.

Mstep:
with constraint ∑_{ k }P(k) = 1.
Standard Gaussian mixture model
For mixture component distributions from the exponential family, like the Gaussian, both steps are exactly tractable. In a Gaussian mixture model where θ_{ k }= {μ_{ k }, Σ_{ k }}, each component k is modelled by a Gaussian distribution with mean μ_{ k }and covariance matrix Σ_{ k },
where · denotes determinant and p is the dimension of the data. As well as changing the number of components in the mixture, the covariance matrix Σ_{ k }can be constrained to determine the flexibility of the model. The most constrained model is parameterised by Σ_{ k }= σ^{2}I with only one free parameter in the covariance matrix for all components. The unconstrained model has full rank Σ_{ k }with p(p + l)/2 free parameters in the covariance matrix for each component where p is the data dimension. All representations of the covariance matrix are explored in [35]. Allowing the number of free parameters in the covariance matrix to vary leads to various models accommodating varying characteristics of data. All of these models have been implemented in MCLUST [20] and the BIC model selection criterion (described later) is used to select the most appropriate model.
Including measurement uncertainty in a Gaussian mixture model
From a probabilistic probelevel model, such as multimgMOS, for each data point one can obtain the measurement error, ν_{ i }, which is a vector giving the variance of the measured expression level on each chip. Suppose x_{ i }is the true expression level for data point i. The k th component of the Gaussian mixture model is modelled by p(x_{ i }k; θ_{ k }) = $\mathcal{N}$(x_{ i }μ_{ k }, Σ_{ k }). The measured expression level $\widehat{x}$_{ i }can be expressed as $\widehat{x}$_{ i }= x_{ i }+ ε_{ i }. A zeromean Gaussian measurement noise is assumed, ε_{ i }~ $\mathcal{N}$(0, diag(ν_{ i })), where diag(ν_{ i }) represents the diagonal matrix whose diagonal entries starting in the upper left corner are the elements of ν_{ i }. Since $\widehat{x}$_{ i }is a linear sum of x_{ i }and ε_{ i }, the k th Gaussian component can be augmented as
p($\widehat{x}$_{ i }k; θ_{ k }) = $\mathcal{N}$($\widehat{x}$_{ i }μ_{ k }, Σ_{ k }+ diag(ν_{ i })) (10)
We therefore augment the mixture model to account for the measurement error of each data point,
Ideally, the covariance matrix should be of full rank to obtain the largest flexibility of the model. However, this will increase the complexity of the model. Since in (11) the additive measurement error diag(ν_{ i }) accounts for inherent variability in the data, especially for extremely noisy gene expression data, the unequal volume spherical model (VI) described in [10] with the covariance Σ_{ k }= ${\sigma}_{k}^{2}$I is adopted. This model allows the spherical components to have different variances which accounts for the variability within different gene function groups. Therefore, in this model the genespecific variance ν_{ i }is known and obtained from a probabilistic probelevel analysis model and the functionspecific variance ${\sigma}_{k}^{2}$ is to be estimated from the mixture model via the EM algorithm. The parameters are denoted θ_{ k }= {μ_{ k }, ${\sigma}_{k}^{2}$} for Gaussian component k and θ= {θ_{1}, θ_{2},..., θ_{ k }} for all components, where K is the number of components. Using the Kmeans algorithm, one can obtain the initial parameters θ^{0} for all components. Equal probability of the component prior is also assumed for the initial value of P(k), P^{0}(k). At the Estep, for each data point x_{ i }the posterior probability of belonging to component k is calculated as,
At the Mstep, the component prior and the parameters of components are optimised,
Equation (14) cannot be solved analytically due to the incorporation of ν_{ i }in the variance terms. However, with fast optimisation methods available such as SNOPT [36] and donlp2 [37], it is easy to calculate the optimal parameters numerically at the Mstep. In our R implementation, pumaclust, we use donlp2.
Model selection
In the previous section the covariance matrix of the Gaussian mixture model is specified and the parameters are worked out via an EM algorithm for a given K. In practice the most appropriate number of clusters should also be determined. In mixture models, the Bayesian Information Criterion (BIC [31]) is usually used to decide the appropriate number of clusters. For model m with the number of clusters K, the calculation of BIC is
BIC_{ m }= 2log p(D$\widehat{\theta}$_{ m }) + d_{ m }log(n), (15)
where D is the dataset, d_{ m }is the number of free parameters to be estimated in model m, n is the number of genes and $\widehat{\theta}$_{ m }are the estimated maximum likelihood parameters obtained by the EM algorithm. For the unequal volume spherical model (VI), the number of free parameters is d_{ m }= K(p + 2)  1. MCLUST also uses BIC to select the most appropriate class of covariance model.
Adjusted rand index
The adjusted Rand index gives a measure of agreement between clustering results. Given a set of n data points D = {x_{1},..., x_{ n }}, suppose C^{1} = {${c}_{1}^{1}$,..., ${c}_{M}^{1}$} and C^{2} = {${c}_{1}^{2}$,..., ${c}_{N}^{2}$} represent two different partitions of the data points in D. Assume that n_{ ij }is the number of data points belonging to cluster ${c}_{i}^{1}$ and ${c}_{j}^{2}$, and n_{ i }. and n._{ j }are the number of data points in cluster ${c}_{i}^{1}$ and ${c}_{j}^{2}$ respectively. The adjusted Rand index can be calculated by
Declarations
Acknowledgements
XL was funded by the Overseas Scholarship Scheme from the University of Manchester and a studentship from the School of Computer Science. BA was supported by NIH awards AR44882 and AR52863. MR was supported by a BBSRC award 'Improved processing of microarray data with probabilistic models'.
Authors’ Affiliations
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