A statistical approach for array CGH data analysis

BACKGROUND: Microarray-CGH experiments are used to detect and map chromosomal imbalances, by hybridizing targets of genomic DNA from a test and a reference sample to sequences immobilized on a slide. These probes are genomic DNA sequences (BACs) that are mapped on the genome. The signal has a spatial coherence that can be handled by specific statistical tools. Segmentation methods seem to be a natural framework for this purpose. A CGH profile can be viewed as a succession of segments that represent homogeneous regions in the genome whose BACs share the same relative copy number on average. We model a CGH profile by a random Gaussian process whose distribution parameters are affected by abrupt changes at unknown coordinates. Two major problems arise : to determine which parameters are affected by the abrupt changes (the mean and the variance, or the mean only), and the selection of the number of segments in the profile. RESULTS: We demonstrate that existing methods for estimating the number of segments are not well adapted in the case of array CGH data, and we propose an adaptive criterion that detects previously mapped chromosomal aberrations. The performances of this method are discussed based on simulations and publicly available data sets. Then we discuss the choice of modeling for array CGH data and show that the model with a homogeneous variance is adapted to this context. CONCLUSIONS: Array CGH data analysis is an emerging field that needs appropriate statistical tools. Process segmentation and model selection provide a theoretical framework that allows precise biological interpretations. Adaptive methods for model selection give promising results concerning the estimation of the number of altered regions on the genome

Unsupervised Classification for Tiling Arrays: ChIP-chip and Transcriptome

Tiling arrays make possible a large scale exploration of the genome thanks to probes which cover the whole genome with very high density until 2 000 000 probes. Biological questions usually addressed are either the expression difference between two conditions or the detection of transcribed regions. In this work we propose to consider simultaneously both questions as an unsupervised classification problem by modeling the joint distribution of the two conditions. In contrast to previous methods, we account for all available information on the probes as well as biological knowledge like annotation and spatial dependence between probes. Since probes are not biologically relevant units we propose a classification rule for non-connected regions covered by several probes. Applications to transcriptomic and ChIP-chip data of Arabidopsis thaliana obtained with a NimbleGen tiling array highlight the importance of a precise modeling and the region classification

Joint segmentation of many aCGH profiles using fast group LARS

Array-Based Comparative Genomic Hybridization (aCGH) is a method used to search for genomic regions with copy numbers variations. For a given aCGH profile, one challenge is to accurately segment it into regions of constant copy number. Subjects sharing the same disease status, for example a type of cancer, often have aCGH profiles with similar copy number variations, due to duplications and deletions relevant to that particular disease. We introduce a constrained optimization algorithm that jointly segments aCGH profiles of many subjects. It simultaneously penalizes the amount of freedom the set of profiles have to jump from one level of constant copy number to another, at genomic locations known as breakpoints. We show that breakpoints shared by many different profiles tend to be found first by the algorithm, even in the presence of significant amounts of noise. The algorithm can be formulated as a group LARS problem. We propose an extremely fast way to find the solution path, i.e., a sequence of shared breakpoints in order of importance. For no extra cost the algorithm smoothes all of the aCGH profiles into piecewise-constant regions of equal copy number, giving low-dimensional versions of the original data. These can be shown for all profiles on a single graph, allowing for intuitive visual interpretation. Simulations and an implementation of the algorithm on bladder cancer aCGH profiles are provided

Optimal detection of changepoints with a linear computational cost

We consider the problem of detecting multiple changepoints in large data sets. Our focus is on applications where the number of changepoints will increase as we collect more data: for example in genetics as we analyse larger regions of the genome, or in finance as we observe time-series over longer periods. We consider the common approach of detecting changepoints through minimising a cost function over possible numbers and locations of changepoints. This includes several established procedures for detecting changing points, such as penalised likelihood and minimum description length. We introduce a new method for finding the minimum of such cost functions and hence the optimal number and location of changepoints that has a computational cost which, under mild conditions, is linear in the number of observations. This compares favourably with existing methods for the same problem whose computational cost can be quadratic or even cubic. In simulation studies we show that our new method can be orders of magnitude faster than these alternative exact methods. We also compare with the Binary Segmentation algorithm for identifying changepoints, showing that the exactness of our approach can lead to substantial improvements in the accuracy of the inferred segmentation of the data.Comment: 25 pages, 4 figures, To appear in Journal of the American Statistical Associatio

On-the-fly Approximation of Multivariate Total Variation Minimization

In the context of change-point detection, addressed by Total Variation minimization strategies, an efficient on-the-fly algorithm has been designed leading to exact solutions for univariate data. In this contribution, an extension of such an on-the-fly strategy to multivariate data is investigated. The proposed algorithm relies on the local validation of the Karush-Kuhn-Tucker conditions on the dual problem. Showing that the non-local nature of the multivariate setting precludes to obtain an exact on-the-fly solution, we devise an on-the-fly algorithm delivering an approximate solution, whose quality is controlled by a practitioner-tunable parameter, acting as a trade-off between quality and computational cost. Performance assessment shows that high quality solutions are obtained on-the-fly while benefiting of computational costs several orders of magnitude lower than standard iterative procedures. The proposed algorithm thus provides practitioners with an efficient multivariate change-point detection on-the-fly procedure

RJaCGH: Bayesian analysis of aCGH arrays for detecting copy number changes and recurrent regions

Summary: Several methods have been proposed to detect copy number changes and recurrent regions of copy number variation from aCGH, but few methods return probabilities of alteration explicitly, which are the direct answer to the question ‘is this probe/region altered?’ RJaCGH fits a Non-Homogeneous Hidden Markov model to the aCGH data using Markov Chain Monte Carlo with Reversible Jump, and returns the probability that each probe is gained or lost. Using these probabilites, recurrent regions (over sets of individuals) of copy number alteration can be found