BACKGROUND : Construction of networks from cross-sectional biological data is increasingly common. Many recent methods have been based on Gaussian graphical modeling, and prioritize estimation of conditional pairwise dependencies among nodes in the network. However, challenges remain on how specific paths through the resultant network contribute to overall 'network-level' correlations. For biological applications, understanding these relationships is particularly relevant for parsing structural information contained in complex subnetworks. RESULTS: We propose the pair-path subscore (PPS), a method for interpreting Gaussian graphical models at the level of individual network paths. The scoring is based on the relative importance of such paths in determining the Pearson correlation between their terminal nodes. PPS is validated using human metabolomics data from the Hyperglycemia and adverse pregnancy outcome (HAPO) study, with observations confirming well-documented biological relationships among the metabolites. We also highlight how the PPS can be used in an exploratory fashion to generate new biological hypotheses. Our method is implemented in the R package pps, available at https://github.com/nathan-gill/pps . CONCLUSIONS: The PPS can be used to probe network structure on a finer scale by investigating which paths in a potentially intricate topology contribute most substantially to marginal behavior. Adding PPS to the network analysis toolkit may enable researchers to ask new questions about the relationships among nodes in network data.

MOTIVATION: High-throughput reporter assays dramatically improve our ability to assign function to noncoding genetic variants, by measuring allelic effects on gene expression in the controlled setting of a reporter gene. Unlike genetic association tests, such assays are not confounded by linkage disequilibrium when loci are independently assayed. These methods can thus improve the identification of causal disease mutations. While work continues on improving experimental aspects of these assays, less effort has gone into developing methods for assessing the statistical significance of assay results, particularly in the case of rare variants captured from patient DNA. RESULTS: We describe a Bayesian hierarchical model, called Bayesian Inference of Regulatory Differences, which integrates prior information and explicitly accounts for variability between experimental replicates. The model produces substantially more accurate predictions than existing methods when allele frequencies are low, which is of clear advantage in the search for disease-causing variants in DNA captured from patient cohorts. Using the model, we demonstrate a clear tradeoff between variant sequencing coverage and numbers of biological replicates, and we show that the use of additional biological replicates decreases variance in estimates of effect size, due to the properties of the Poisson-binomial distribution. We also provide a power and sample size calculator, which facilitates decision making in experimental design parameters. AVAILABILITY AND IMPLEMENTATION: The software is freely available from www.geneprediction.org/bird. The experimental design web tool can be accessed at http://67.159.92.22:8080. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: Metabolomics offers a unique integrative perspective for health research, reflecting genetic and environmental contributions to disease-related phenotypes. Identifying robust associations in population-based or large-scale clinical studies demands large numbers of subjects and therefore sample batching for gas-chromatography/mass spectrometry (GC/MS) non-targeted assays. When run over weeks or months, technical noise due to batch and run-order threatens data interpretability. Application of existing normalization methods to metabolomics is challenged by unsatisfied modeling assumptions and, notably, failure to address batch-specific truncation of low abundance compounds. RESULTS: To curtail technical noise and make GC/MS metabolomics data amenable to analyses describing biologically relevant variability, we propose mixture model normalization (mixnorm) that accommodates truncated data and estimates per-metabolite batch and run-order effects using quality control samples. Mixnorm outperforms other approaches across many metrics, including improved correlation of non-targeted and targeted measurements and superior performance when metabolite detectability varies according to batch. For some metrics, particularly when truncation is less frequent for a metabolite, mean centering and median scaling demonstrate comparable performance to mixnorm. CONCLUSIONS: When quality control samples are systematically included in batches, mixnorm is uniquely suited to normalizing non-targeted GC/MS metabolomics data due to explicit accommodation of batch effects, run order and varying thresholds of detectability. Especially in large-scale studies, normalization is crucial for drawing accurate conclusions from non-targeted GC/MS metabolomics data.

OBJECTIVE: To visualize and describe collaborative electronic health record (EHR) usage for hospitalized patients with heart failure. MATERIALS AND METHODS: We identified records of patients with heart failure and all associated healthcare provider record usage through queries of the Northwestern Medicine Enterprise Data Warehouse. We constructed a network by equating access and updates of a patient's EHR to a provider-patient interaction. We then considered shared patient record access as the basis for a second network that we termed the provider collaboration network. We calculated network statistics, the modularity of provider interactions, and provider cliques. RESULTS: We identified 548 patient records accessed by 5113 healthcare providers in 2012. The provider collaboration network had 1504 nodes and 83 998 edges. We identified 7 major provider collaboration modules. Average clique size was 87.9 providers. We used a graph database to demonstrate an ad hoc query of our provider-patient network. DISCUSSION: Our analysis suggests a large number of healthcare providers across a wide variety of professions access records of patients with heart failure during their hospital stay. This shared record access tends to take place not only in a pairwise manner but also among large groups of providers. CONCLUSION: EHRs encode valuable interactions, implicitly or explicitly, between patients and providers. Network analysis provided strong evidence of multidisciplinary record access of patients with heart failure across teams of 100+ providers. Further investigation may lead to clearer understanding of how record access information can be used to strategically guide care coordination for patients hospitalized for heart failure.

SUMMARY: Non-targeted metabolomics technologies often yield data in which abundance for any given metabolite is observed and quantified for some samples and reported as missing for other samples. Apparent missingness can be due to true absence of the metabolite in the sample or presence at a level below detectability. Mixture-model analysis can formally account for metabolite 'missingness' due to absence or undetectability, but software for this type of analysis in the high-throughput setting is limited. The R package metabomxtr has been developed to facilitate mixture-model analysis of non-targeted metabolomics data in which only a portion of samples have quantifiable abundance for certain metabolites. AVAILABILITY AND IMPLEMENTATION: metabomxtr is available through Bioconductor. It is released under the GPL-2 license. CONTACT: [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Proteins work together to drive biological processes in cellular machines. Summarizing global and local properties of the set of protein interactions, the interactome, is necessary for describing cellular systems. We consider a relatively simple per-protein feature of the interactome: the number of interaction partners for a protein, which in graph terminology is the degree of the protein. RESULTS: Using data subject to both stochastic and systematic sources of false positive and false negative observations, we develop an explicit probability model and resultant likelihood method to estimate node degree on portions of the interactome assayed by bait-prey technologies. This approach yields substantial improvement in degree estimation over the current practice that naively sums observed edges. Accurate modeling of observed data in relation to true but unknown parameters of interest gives a formal point of reference from which to draw conclusions about the system under study. AVAILABILITY: All analyses discussed in this text can be performed using the ppiStats and ppiData packages available through the Bioconductor project (http://www.bioconductor.org).

MOTIVATION: Systems biology requires accurate models of protein complexes, including physical interactions that assemble and regulate these molecular machines. Yeast two-hybrid (Y2H) and affinity-purification/mass-spectrometry (AP-MS) technologies measure different protein-protein relationships, and issues of completeness, sensitivity and specificity fuel debate over which is best for high-throughput 'interactome' data collection. Static graphs currently used to model Y2H and AP-MS data neglect dynamic and spatial aspects of macromolecular complexes and pleiotropic protein function. RESULTS: We apply the local modeling methodology proposed by Scholtens and Gentleman (2004) to two publicly available datasets and demonstrate its uses, interpretation and limitations. Specifically, we use this technology to address four major issues pertaining to protein-protein networks. (1) We motivate the need to move from static global interactome graphs to local protein complex models. (2) We formally show that accurate local interactome models require both Y2H and AP-MS data, even in idealized situations. (3) We briefly discuss experimental design issues and how bait selection affects interpretability of results. (4) We point to the implications of local modeling for systems biology including functional annotation, new complex prediction, pathway interactivity and coordination with gene-expression data. AVAILABILITY: The local modeling algorithm and all protein complex estimates reported here can be found in the R package apComplex, available at http://www.bioconductor.org CONTACT: [email protected] SUPPLEMENTARY INFORMATION: http://daisy.prevmed.northwestern.edu/~denise/pubs/LocalModeling

MOTIVATION: The last few years have seen the advent of high-throughput technologies to analyze various properties of the transcriptome and proteome of several organisms. The congruency of these different data sources, or lack thereof, can shed light on the mechanisms that govern cellular function. A central challenge for bioinformatics research is to develop a unified framework for combining the multiple sources of functional genomics information and testing associations between them, thus obtaining a robust and integrated view of the underlying biology. RESULTS: We present a graph-theoretic approach to test the significance of the association between multiple disparate sources of functional genomics data by proposing two statistical tests, namely edge permutation and node label permutation tests. We demonstrate the use of the proposed tests by finding significant association between a Gene Ontology-derived predictome and data obtained from mRNA expression and phenotypic experiments for Saccharomyces cerevisiae. Moreover, we employ the graph-theoretic framework to recast a surprising discrepancy presented elsewhere between gene expression and knockout phenotype, using expression data from a different set of experiments. AVAILABILITY: An R software package, GraphAT, containing the data and statistical procedures is available from Bioconductor: http://www.bioconductor.org.