Multiscale likelihood analysis and complexity penalized estimation

We describe here a framework for a certain class of multiscale likelihood factorizations wherein, in analogy to a wavelet decomposition of an L^2 function, a given likelihood function has an alternative representation as a product of conditional densities reflecting information in both the data and the parameter vector localized in position and scale. The framework is developed as a set of sufficient conditions for the existence of such factorizations, formulated in analogy to those underlying a standard multiresolution analysis for wavelets, and hence can be viewed as a multiresolution analysis for likelihoods. We then consider the use of these factorizations in the task of nonparametric, complexity penalized likelihood estimation. We study the risk properties of certain thresholding and partitioning estimators, and demonstrate their adaptivity and near-optimality, in a minimax sense over a broad range of function spaces, based on squared Hellinger distance as a loss function. In particular, our results provide an illustration of how properties of classical wavelet-based estimators can be obtained in a single, unified framework that includes models for continuous, count and categorical data types

Estimation of subgraph density in noisy networks

While it is common practice in applied network analysis to report various standard network summary statistics, these numbers are rarely accompanied by uncertainty quantification. Yet any error inherent in the measurements underlying the construction of the network, or in the network construction procedure itself, necessarily must propagate to any summary statistics reported. Here we study the problem of estimating the density of an arbitrary subgraph, given a noisy version of some underlying network as data. Under a simple model of network error, we show that consistent estimation of such densities is impossible when the rates of error are unknown and only a single network is observed. Accordingly, we develop method-of-moment estimators of network subgraph densities and error rates for the case where a minimal number of network replicates are available. These estimators are shown to be asymptotically normal as the number of vertices increases to infinity. We also provide confidence intervals for quantifying the uncertainty in these estimates based on the asymptotic normality. To construct the confidence intervals, a new and non-standard bootstrap method is proposed to compute asymptotic variances, which is infeasible otherwise. We illustrate the proposed methods in the context of gene coexpression networks

On the Question of Effective Sample Size in Network Modeling: An Asymptotic Inquiry

The modeling and analysis of networks and network data has seen an explosion of interest in recent years and represents an exciting direction for potential growth in statistics. Despite the already substantial amount of work done in this area to date by researchers from various disciplines, however, there remain many questions of a decidedly foundational nature - natural analogues of standard questions already posed and addressed in more classical areas of statistics - that have yet to even be posed, much less addressed. Here we raise and consider one such question in connection with network modeling. Specifically, we ask, "Given an observed network, what is the sample size?" Using simple, illustrative examples from the class of exponential random graph models, we show that the answer to this question can very much depend on basic properties of the networks expected under the model, as the number of vertices $n_V$ in the network grows. In particular, adopting the (asymptotic) scaling of the variance of the maximum likelihood parameter estimates as a notion of effective sample size ($n_{\mathrm{eff}}$), we show that when modeling the overall propensity to have ties and the propensity to reciprocate ties, whether the networks are sparse or not under the model (i.e., having a constant or an increasing number of ties per vertex, respectively) is sufficient to yield an order of magnitude difference in $n_{\mathrm{eff}}$, from $O(n_V)$ to $O(n^2_V)$. In addition, we report simulation study results that suggest similar properties for models for triadic (friend-of-a-friend) effects. We then explore some practical implications of this result, using both simulation and data on food-sharing from Lamalera, Indonesia.Comment: Published at http://dx.doi.org/10.1214/14-STS502 in the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Improvement of experimental testing and network training conditions with genome-wide microarrays for more accurate predictions of drug gene targets

BACKGROUND: Genome-wide microarrays have been useful for predicting chemical-genetic interactions at the gene level. However, interpreting genome-wide microarray results can be overwhelming due to the vast output of gene expression data combined with off-target transcriptional responses many times induced by a drug treatment. This study demonstrates how experimental and computational methods can interact with each other, to arrive at more accurate predictions of drug-induced perturbations. We present a two-stage strategy that links microarray experimental testing and network training conditions to predict gene perturbations for a drug with a known mechanism of action in a well-studied organism. RESULTS: S. cerevisiae cells were treated with the antifungal, fluconazole, and expression profiling was conducted under different biological conditions using Affymetrix genome-wide microarrays. Transcripts were filtered with a formal network-based method, sparse simultaneous equation models and Lasso regression (SSEM-Lasso), under different network training conditions. Gene expression results were evaluated using both gene set and single gene target analyses, and the drug’s transcriptional effects were narrowed first by pathway and then by individual genes. Variables included: (i) Testing conditions – exposure time and concentration and (ii) Network training conditions – training compendium modifications. Two analyses of SSEM-Lasso output – gene set and single gene – were conducted to gain a better understanding of how SSEM-Lasso predicts perturbation targets. CONCLUSIONS: This study demonstrates that genome-wide microarrays can be optimized using a two-stage strategy for a more in-depth understanding of how a cell manifests biological reactions to a drug treatment at the transcription level. Additionally, a more detailed understanding of how the statistical model, SSEM-Lasso, propagates perturbations through a network of gene regulatory interactions is achieved.Published versio

Perturbation Detection Through Modeling of Gene Expression on a Latent Biological Pathway Network: A Bayesian hierarchical approach

Cellular response to a perturbation is the result of a dynamic system of biological variables linked in a complex network. A major challenge in drug and disease studies is identifying the key factors of a biological network that are essential in determining the cell's fate. Here our goal is the identification of perturbed pathways from high-throughput gene expression data. We develop a three-level hierarchical model, where (i) the first level captures the relationship between gene expression and biological pathways using confirmatory factor analysis, (ii) the second level models the behavior within an underlying network of pathways induced by an unknown perturbation using a conditional autoregressive model, and (iii) the third level is a spike-and-slab prior on the perturbations. We then identify perturbations through posterior-based variable selection. We illustrate our approach using gene transcription drug perturbation profiles from the DREAM7 drug sensitivity predication challenge data set. Our proposed method identified regulatory pathways that are known to play a causative role and that were not readily resolved using gene set enrichment analysis or exploratory factor models. Simulation results are presented assessing the performance of this model relative to a network-free variant and its robustness to inaccuracies in biological databases