Biomedical subjects

Ben Shneiderman

Publications and source records attributed to Ben Shneiderman.

7 recordsLinked to original sources

PubMed2006

Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration.

Mutations of lamin A/C (LMNA) cause a wide range of human disorders, including progeria, lipodystrophy, neuropathies and autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD). EDMD is also caused by X-linked recessive loss-of-function mutations of emerin, another component of the inner nuclear lamina that directly interacts with LMNA. One model for disease pathogenesis of LMNA and emerin mutations is cell-specific perturbations of the mRNA transcriptome in terminally differentiated cells. To test this model, we studied 125 human muscle biopsies from 13 diagnostic groups (125 U133A, 125 U133B microarrays), including EDMD patients with LMNA and emerin mutations. A Visual and Statistical Data Analyzer (VISDA) algorithm was used to statistically model cluster hierarchy, resulting in a tree of phenotypic classifications. Validations of the diagnostic tree included permutations of U133A and U133B arrays, and use of two probe set algorithms (MAS5.0 and MBEI). This showed that the two nuclear envelope defects (EDMD LMNA, EDMD emerin) were highly related disorders and were also related to fascioscapulohumeral muscular dystrophy (FSHD). FSHD has recently been hypothesized to involve abnormal interactions of chromatin with the nuclear envelope. To identify disease-specific transcripts for EDMD, we applied a leave-one-out (LOO) cross-validation approach using LMNA patient muscle as a test data set, with reverse transcription-polymerase chain reaction (RT-PCR) validations in both LMNA and emerin patient muscle. A high proportion of top-ranked and validated transcripts were components of the same transcriptional regulatory pathway involving Rb1 and MyoD during muscle regeneration (CRI-1, CREBBP, Nap1L1, ECREBBP/p300), where each was specifically upregulated in EDMD. Using a muscle regeneration time series (27 time points) we develop a transcriptional model for downstream consequences of LMNA and emerin mutations. We propose that key interactions between the nuclear envelope and Rb and MyoD fail in EDMD at the point of myoblast exit from the cell cycle, leading to poorly coordinated phosphorylation and acetylation steps. Our data is consistent with mutations of nuclear lamina components leading to destabilization of the transcriptome in differentiated cells.

Biopsy↗

PubMed2004

Visualization and analysis of microarray and gene ontology data with treemaps.

BACKGROUND: The increasing complexity of genomic data presents several challenges for biologists. Limited computer monitor views of data complexity and the dynamic nature of data in the midst of discovery increase the challenge of integrating experimental results with information resources. The use of Gene Ontology enables researchers to summarize results of quantitative analyses in this framework, but the limitations of typical browser presentation restrict data access. RESULTS: Here we describe extensions to the treemap design to visualize and query genome data. Treemaps are a space-filling visualization technique for hierarchical structures that show attributes of leaf nodes by size and color-coding. Treemaps enable users to rapidly compare sizes of nodes and sub-trees, and we use Gene Ontology categories, levels of RNA, and other quantitative attributes of DNA microarray experiments as examples. Our implementation of treemaps, Treemap 4.0, allows user-defined filtering to focus on the data of greatest interest, and these queried files can be exported for secondary analyses. Links to model system web pages from Treemap 4.0 enable users access to details about specific genes without leaving the query platform. CONCLUSIONS: Treemaps allow users to view and query the data from an experiment on a single computer monitor screen. Treemap 4.0 can be used to visualize various genome data, and is particularly useful for revealing patterns and details within complex data sets.

Animals↗

PubMed2004

Interactively optimizing signal-to-noise ratios in expression profiling: project-specific algorithm selection and detection p-value weighting in Affymetrix microarrays.

MOTIVATION: The most commonly utilized microarrays for mRNA profiling (Affymetrix) include 'probe sets' of a series of perfect match and mismatch probes (typically 22 oligonucleotides per probe set). There are an increasing number of reported 'probe set algorithms' that differ in their interpretation of a probe set to derive a single normalized 'signal' representative of expression of each mRNA. These algorithms are known to differ in accuracy and sensitivity, and optimization has been done using a small set of standardized control microarray data. We hypothesized that different mRNA profiling projects have varying sources and degrees of confounding noise, and that these should alter the choice of a specific probe set algorithm. Also, we hypothesized that use of the Microarray Suite (MAS) 5.0 probe set detection p-value as a weighting function would improve the performance of all probe set algorithms. RESULTS: We built an interactive visual analysis software tool (HCE2W) to test and define parameters in Affymetrix analyses that optimize the ratio of signal (desired biological variable) versus noise (confounding uncontrolled variables). Five probe set algorithms were studied with and without statistical weighting of probe sets using the MAS 5.0 probe set detection p-values. The signal-to-noise ratio optimization method was tested in two large novel microarray datasets with different levels of confounding noise, a 105 sample U133A human muscle biopsy dataset (11 groups: mutation-defined, extensive noise), and a 40 sample U74A inbred mouse lung dataset (8 groups: little noise). Performance was measured by the ability of the specific probe set algorithm, with and without detection p-value weighting, to cluster samples into the appropriate biological groups (unsupervised agglomerative clustering with F-measure values). Of the total random sampling analyses, 50% showed a highly statistically significant difference between probe set algorithms by ANOVA [F(4,10) > 14, p < 0.0001], with weighting by MAS 5.0 detection p-value showing significance in the mouse data by ANOVA [F(1,10) > 9, p < 0.013] and paired t-test [t(9) = -3.675, p = 0.005]. Probe set detection p-value weighting had the greatest positive effect on performance of dChip difference model, ProbeProfiler and RMA algorithms. Importantly, probe set algorithms did indeed perform differently depending on the specific project, most probably due to the degree of confounding noise. Our data indicate that significantly improved data analysis of mRNA profile projects can be achieved by optimizing the choice of probe set algorithm with the noise levels intrinsic to a project, with dChip difference model with MAS 5.0 detection p-value continuous weighting showing the best overall performance in both projects. Furthermore, both existing and newly developed probe set algorithms should incorporate a detection p-value weighting to improve performance. AVAILABILITY: The Hierarchical Clustering Explorer 2.0 is available at http://www.cs.umd.edu/hcil/hce/ Murine arrays (40 samples) are publicly available at the PEPR resource (http://microarray.cnmcresearch.org/pgadatatable.asp http://pepr.cnmcresearch.org Chen et al., 2004).

Cluster Analysis↗

PubMedDate not supplied

In vivo filtering of in vitro expression data reveals MyoD targets.

A published set of downstream targets of MyoD defined in a well-controlled in vitro experiment was filtered for relevance to muscle regeneration using a 27-time-point in vivo murine regeneration series. Using interactive hierarchical and Bayes soft clustering, only a minority of the targets defined in vitro can be confirmed in vivo (approximately 50% of induced transcripts, and none of repressed transcripts). This approach provided strong support that 18 targets including of MyoD are biologically relevant during myoblast differentiation.

Animals↗

PubMedDate not supplied

Balancing systematic and flexible exploration of social networks.

Social network analysis (SNA) has emerged as a powerful method for understanding the importance of relationships in networks. However, interactive exploration of networks is currently challenging because: (1) it is difficult to find patterns and comprehend the structure of networks with many nodes and links, and (2) current systems are often a medley of statistical methods and overwhelming visual output which leaves many analysts uncertain about how to explore in an orderly manner. This results in exploration that is largely opportunistic. Our contributions are techniques to help structural analysts understand social networks more effectively. We present SocialAction, a system that uses attribute ranking and coordinated views to help users systematically examine numerous SNA measures. Users can (1) flexibly iterate through visualizations of measures to gain an overview, filter nodes, and find outliers, (2) aggregate networks using link structure, find cohesive subgroups, and focus on communities of interest, and (3) untangle networks by viewing different link types separately, or find patterns across different link types using a matrix overview. For each operation, a stable node layout is maintained in the network visualization so users can make comparisons. SocialAction offers analysts a strategy beyond opportunism, as it provides systematic, yet flexible, techniques for exploring social networks.

Algorithms↗

PubMedDate not supplied

Network visualization by semantic substrates.

Networks have remained a challenge for information visualization designers because of the complex issues of node and link layout coupled with the rich set of tasks that users present. This paper offers a strategy based on two principles: (1) layouts are based on user-defined semantic substrates, which are non-overlapping regions in which node placement is based on node attributes, (2) users interactively adjust sliders to control link visibility to limit clutter and thus ensure comprehensibility of source and destination. Scalability is further facilitated by user control of which nodes are visible. We illustrate our semantic substrates approach as implemented in NVSS 1.0 with legal precedent data for up to 1122 court cases in three regions with 7645 legal citations.

Journal Article↗

PubMedDate not supplied

Knowledge discovery in high-dimensional data: case studies and a user survey for the rank-by-feature framework.

Knowledge discovery in high-dimensional data is a challenging enterprise, but new visual analytic tools appear to offer users remarkable powers if they are ready to learn new concepts and interfaces. Our three-year effort to develop versions of the Hierarchical Clustering Explorer (HCE) began with building an interactive tool for exploring clustering results. It expanded, based on user needs, to include other potent analytic and visualization tools for multivariate data, especially the rank-by-feature framework. Our own successes using HCE provided some testimonial evidence of its utility, but we felt it necessary to get beyond our subjective impressions. This paper presents an evaluation of the Hierarchical Clustering Explorer (HCE) using three case studies and an e-mail user survey (n = 57) to focus on skill acquisition with the novel concepts and interface for the rank-by-feature framework. Knowledgeable and motivated users in diverse fields provided multiple perspectives that refined our understanding of strengths and weaknesses. A user survey confirmed the benefits of HCE, but gave less guidance about improvements. Both evaluations suggested improved training methods.

Algorithms↗