A method for detecting and correcting feature misidentification on expression microarrays

BACKGROUND: Much of the microarray data published at Stanford is based on mouse and human arrays produced under controlled and monitored conditions at the Brown and Botstein laboratories and at the Stanford Functional Genomics Facility (SFGF). Nevertheless, as large datasets based on the Stanford Human array began to accumulate, a small but significant number of discrepancies were detected that required a serious attempt to track down the original source of error. Due to a controlled process environment, sufficient data was available to accurately track the entire process leading to up to the final expression data. In this paper, we describe our statistical methods to detect the inconsistencies in microarray data that arise from process errors, and discuss our technique to locate and fix these errors. RESULTS: To date, the Brown and Botstein laboratories and the Stanford Functional Genomics Facility have together produced 40,000 large-scale (10–50,000 feature) cDNA microarrays. By applying the heuristic described here, we have been able to check most of these arrays for misidentified features, and have been able to confidently apply fixes to the data where needed. Out of the 265 million features checked in our database, problems were detected and corrected on 1.3 million of them. CONCLUSION: Process errors in any genome scale high throughput production regime can lead to subsequent errors in data analysis. We show the value of tracking multi-step high throughput operations by using this knowledge to detect and correct misidentified data on gene expression microarrays

γ\gamma-SUP: A clustering algorithm for cryo-electron microscopy images of asymmetric particles

Cryo-electron microscopy (cryo-EM) has recently emerged as a powerful tool for obtaining three-dimensional (3D) structures of biological macromolecules in native states. A minimum cryo-EM image data set for deriving a meaningful reconstruction is comprised of thousands of randomly orientated projections of identical particles photographed with a small number of electrons. The computation of 3D structure from 2D projections requires clustering, which aims to enhance the signal to noise ratio in each view by grouping similarly oriented images. Nevertheless, the prevailing clustering techniques are often compromised by three characteristics of cryo-EM data: high noise content, high dimensionality and large number of clusters. Moreover, since clustering requires registering images of similar orientation into the same pixel coordinates by 2D alignment, it is desired that the clustering algorithm can label misaligned images as outliers. Herein, we introduce a clustering algorithm $\gamma$-SUP to model the data with a $q$-Gaussian mixture and adopt the minimum $\gamma$-divergence for estimation, and then use a self-updating procedure to obtain the numerical solution. We apply $\gamma$-SUP to the cryo-EM images of two benchmark macromolecules, RNA polymerase II and ribosome. In the former case, simulated images were chosen to decouple clustering from alignment to demonstrate $\gamma$-SUP is more robust to misalignment outliers than the existing clustering methods used in the cryo-EM community. In the latter case, the clustering of real cryo-EM data by our $\gamma$-SUP method eliminates noise in many views to reveal true structure features of ribosome at the projection level.Comment: Published in at http://dx.doi.org/10.1214/13-AOAS680 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Perceptions of Cardiovascular Health in Underserved Communities

Introduction: Cardiovascular disease is the leading cause of deaths and illnesses in US adults, and the prevalence is disproportionately high in underserved populations. In this study, we assessed respondents' understanding of context-specific differences in knowledge and perceptions of disease, risk, and prevention in 6 underserved communities, with the longer-term goal of developing appropriate interventions. Methods: Thirty-nine small-group sessions and 14 interviews yielded data from 318 adults. Each site's researchers coded, analyzed, and extracted key themes from local data. Investigators from all sites synthesized results and identified common themes and differences. Results: Themes clustered in 3 areas (barriers to cardiovascular health, constraints related to multiple roles, and suggestions for effective communications and programs). Barriers spanned individual, social and cultural, and environmental levels; women in particular cited multiple roles (eg, competing demands, lack of self-care). Programmatic suggestions included the following: personal, interactive, social context; information in language that people use; activities built around cultural values and interests; and community orientation. In addition, respondents preferred health-related information from trusted groups (eg, AARP), health care providers (but with noticeable differences of opinion), family and friends, and printed materials. Conclusion: Interventions to decrease barriers to cardiovascular health are needed; these strategies should include family and community context, small groups, interactive methods, culturally sensitive materials, and trusted information sources. New-immigrant communities need culturally and linguistically tailored education before receiving more substantive interventions

FAS-dependent cell death in α-synuclein transgenic oligodendrocyte models of multiple system atrophy

Multiple system atrophy is a parkinsonian neurodegenerative disorder. It is cytopathologically characterized by accumulation of the protein p25α in cell bodies of oligodendrocytes followed by accumulation of aggregated α-synuclein in so-called glial cytoplasmic inclusions. p25α is a stimulator of α-synuclein aggregation, and coexpression of α-synuclein and p25α in the oligodendroglial OLN-t40-AS cell line causes α-synuclein aggregate-dependent toxicity. In this study, we investigated whether the FAS system is involved in α-synuclein aggregate dependent degeneration in oligodendrocytes and may play a role in multiple system atrophy. Using rat oligodendroglial OLN-t40-AS cells we demonstrate that the cytotoxicity caused by coexpressing α-synuclein and p25α relies on stimulation of the death domain receptor FAS and caspase-8 activation. Using primary oligodendrocytes derived from PLP-α-synuclein transgenic mice we demonstrate that they exist in a sensitized state expressing pro-apoptotic FAS receptor, which makes them sensitive to FAS ligand-mediated apoptosis. Immunoblot analysis shows an increase in FAS in brain extracts from multiple system atrophy cases. Immunohistochemical analysis demonstrated enhanced FAS expression in multiple system atrophy brains notably in oligodendrocytes harboring the earliest stages of glial cytoplasmic inclusion formation. Oligodendroglial FAS expression is an early hallmark of oligodendroglial pathology in multiple system atrophy that mechanistically may be coupled to α-synuclein dependent degeneration and thus represent a potential target for protective intervention