Causal modeling using network ensemble simulations of genetic and gene expression data predicts genes involved in rheumatoid arthritis.

Tumor necrosis factor α (TNF-α) is a key regulator of inflammation and rheumatoid arthritis (RA). TNF-α blocker therapies can be very effective for a substantial number of patients, but fail to work in one third of patients who show no or minimal response. It is therefore necessary to discover new molecular intervention points involved in TNF-α blocker treatment of rheumatoid arthritis patients. We describe a data analysis strategy for predicting gene expression measures that are critical for rheumatoid arthritis using a combination of comprehensive genotyping, whole blood gene expression profiles and the component clinical measures of the arthritis Disease Activity Score 28 (DAS28) score. Two separate network ensembles, each comprised of 1024 networks, were built from molecular measures from subjects before and 14 weeks after treatment with TNF-α blocker. The network ensemble built from pre-treated data captures TNF-α dependent mechanistic information, while the ensemble built from data collected under TNF-α blocker treatment captures TNF-α independent mechanisms. In silico simulations of targeted, personalized perturbations of gene expression measures from both network ensembles identify transcripts in three broad categories. Firstly, 22 transcripts are identified to have new roles in modulating the DAS28 score; secondly, there are 6 transcripts that could be alternative targets to TNF-α blocker therapies, including CD86--a component of the signaling axis targeted by Abatacept (CTLA4-Ig), and finally, 59 transcripts that are predicted to modulate the count of tender or swollen joints but not sufficiently enough to have a significant impact on DAS28.

multiplierz: an extensible API based desktop environment for proteomics data analysis.

BACKGROUND: Efficient analysis of results from mass spectrometry-based proteomics experiments requires access to disparate data types, including native mass spectrometry files, output from algorithms that assign peptide sequence to MS/MS spectra, and annotation for proteins and pathways from various database sources. Moreover, proteomics technologies and experimental methods are not yet standardized; hence a high degree of flexibility is necessary for efficient support of high- and low-throughput data analytic tasks. Development of a desktop environment that is sufficiently robust for deployment in data analytic pipelines, and simultaneously supports customization for programmers and non-programmers alike, has proven to be a significant challenge. RESULTS: We describe multiplierz, a flexible and open-source desktop environment for comprehensive proteomics data analysis. We use this framework to expose a prototype version of our recently proposed common API (mzAPI) designed for direct access to proprietary mass spectrometry files. In addition to routine data analytic tasks, multiplierz supports generation of information rich, portable spreadsheet-based reports. Moreover, multiplierz is designed around a "zero infrastructure" philosophy, meaning that it can be deployed by end users with little or no system administration support. Finally, access to multiplierz functionality is provided via high-level Python scripts, resulting in a fully extensible data analytic environment for rapid development of custom algorithms and deployment of high-throughput data pipelines. CONCLUSION: Collectively, mzAPI and multiplierz facilitate a wide range of data analysis tasks, spanning technology development to biological annotation, for mass spectrometry-based proteomics research.

Unbiased gene expression analysis implicates the huntingtin polyglutamine tract in extra-mitochondrial energy metabolism.

The Huntington's disease (HD) CAG repeat, encoding a polymorphic glutamine tract in huntingtin, is inversely correlated with cellular energy level, with alleles over approximately 37 repeats leading to the loss of striatal neurons. This early HD neuronal specificity can be modeled by respiratory chain inhibitor 3-nitropropionic acid (3-NP) and, like 3-NP, mutant huntingtin has been proposed to directly influence the mitochondrion, via interaction or decreased PGC-1alpha expression. We have tested this hypothesis by comparing the gene expression changes due to mutant huntingtin accurately expressed in STHdh(Q111/Q111) cells with the changes produced by 3-NP treatment of wild-type striatal cells. In general, the HD mutation did not mimic 3-NP, although both produced a state of energy collapse that was mildly alleviated by the PGC-1alpha-coregulated nuclear respiratory factor 1 (Nrf-1). Moreover, unlike 3-NP, the HD CAG repeat did not significantly alter mitochondrial pathways in STHdh(Q111/Q111) cells, despite decreased Ppargc1a expression. Instead, the HD mutation enriched for processes linked to huntingtin normal function and Nf-kappaB signaling. Thus, rather than a direct impact on the mitochondrion, the polyglutamine tract may modulate some aspect of huntingtin's activity in extra-mitochondrial energy metabolism. Elucidation of this HD CAG-dependent pathway would spur efforts to achieve energy-based therapeutics in HD.