Spatial clustering of array CGH features in combination with hierarchical multiple testing

We propose a new approach for clustering DNA features using array CGH data from multiple tumor samples. We distinguish data-collapsing: joining contiguous DNA clones or probes with extremely similar data into regions, from clustering: joining contiguous, correlated regions based on a maximum likelihood principle. The model-based clustering algorithm accounts for the apparent spatial patterns in the data. We evaluate the randomness of the clustering result by a cluster stability score in combination with cross-validation. Moreover, we argue that the clustering really captures spatial genomic dependency by showing that coincidental clustering of independent regions is very unlikely. Using the region and cluster information, we combine testing of these for association with a clinical variable in an hierarchical multiple testing approach. This allows for interpreting the significance of both regions and clusters while controlling the Family-Wise Error Rate simultaneously. We prove that in the context of permutation tests and permutation-invariant clusters it is allowed to perform clustering and testing on the same data set. Our procedures are illustrated on two cancer data sets

A temporal switch model for estimating transcriptional activity in gene expression

Motivation: The analysis and mechanistic modelling of time series gene expression data provided by techniques such as microarrays, NanoString, reverse transcription–polymerase chain reaction and advanced sequencing are invaluable for developing an understanding of the variation in key biological processes. We address this by proposing the estimation of a flexible dynamic model, which decouples temporal synthesis and degradation of mRNA and, hence, allows for transcriptional activity to switch between different states. Results: The model is flexible enough to capture a variety of observed transcriptional dynamics, including oscillatory behaviour, in a way that is compatible with the demands imposed by the quality, time-resolution and quantity of the data. We show that the timing and number of switch events in transcriptional activity can be estimated alongside individual gene mRNA stability with the help of a Bayesian reversible jump Markov chain Monte Carlo algorithm. To demonstrate the methodology, we focus on modelling the wild-type behaviour of a selection of 200 circadian genes of the model plant Arabidopsis thaliana. The results support the idea that using a mechanistic model to identify transcriptional switch points is likely to strongly contribute to efforts in elucidating and understanding key biological processes, such as transcription and degradation

Learning the optimal scale for GWAS through hierarchical SNP aggregation

Motivation: Genome-Wide Association Studies (GWAS) seek to identify causal genomic variants associated with rare human diseases. The classical statistical approach for detecting these variants is based on univariate hypothesis testing, with healthy individuals being tested against affected individuals at each locus. Given that an individual's genotype is characterized by up to one million SNPs, this approach lacks precision, since it may yield a large number of false positives that can lead to erroneous conclusions about genetic associations with the disease. One way to improve the detection of true genetic associations is to reduce the number of hypotheses to be tested by grouping SNPs. Results: We propose a dimension-reduction approach which can be applied in the context of GWAS by making use of the haplotype structure of the human genome. We compare our method with standard univariate and multivariate approaches on both synthetic and real GWAS data, and we show that reducing the dimension of the predictor matrix by aggregating SNPs gives a greater precision in the detection of associations between the phenotype and genomic regions

Modelling Grocery Retail Topic Distributions: Evaluation, Interpretability and Stability

Understanding the shopping motivations behind market baskets has high commercial value in the grocery retail industry. Analyzing shopping transactions demands techniques that can cope with the volume and dimensionality of grocery transactional data while keeping interpretable outcomes. Latent Dirichlet Allocation (LDA) provides a suitable framework to process grocery transactions and to discover a broad representation of customers' shopping motivations. However, summarizing the posterior distribution of an LDA model is challenging, while individual LDA draws may not be coherent and cannot capture topic uncertainty. Moreover, the evaluation of LDA models is dominated by model-fit measures which may not adequately capture the qualitative aspects such as interpretability and stability of topics. In this paper, we introduce clustering methodology that post-processes posterior LDA draws to summarise the entire posterior distribution and identify semantic modes represented as recurrent topics. Our approach is an alternative to standard label-switching techniques and provides a single posterior summary set of topics, as well as associated measures of uncertainty. Furthermore, we establish a more holistic definition for model evaluation, which assesses topic models based not only on their likelihood but also on their coherence, distinctiveness and stability. By means of a survey, we set thresholds for the interpretation of topic coherence and topic similarity in the domain of grocery retail data. We demonstrate that the selection of recurrent topics through our clustering methodology not only improves model likelihood but also outperforms the qualitative aspects of LDA such as interpretability and stability. We illustrate our methods on an example from a large UK supermarket chain.Comment: 20 pages, 9 figure