Ramon M. Felciano

A network-based analysis of systemic inflammation in humans

Oligonucleotide and complementary DNA microarrays are being used to subclassify histologically similar tumours, monitor disease progress, and individualize treatment regimens. However, extracting new biological insight from high-throughput genomic studies of human diseases is a challenge, limited by difficulties in recognizing and evaluating relevant biological processes from huge quantities of experimental data. Here we present a structured network knowledge-base approach to analyse genome-wide transcriptional responses in the context of known functional interrelationships among proteins, small molecules and phenotypes. This approach was used to analyse changes in blood leukocyte gene expression patterns in human subjects receiving an inflammatory stimulus (bacterial endotoxin). We explore the known genome-wide interaction network to identify significant functional modules perturbed in response to this stimulus. Our analysis reveals that the human blood leukocyte response to acute systemic inflammation includes the transient dysregulation of leukocyte bioenergetics and modulation of translational machinery. These findings provide insight into the regulation of global leukocyte activities as they relate to innate immune system tolerance and increased susceptibility to infection in humans.

Designing the PenPal: blending hardware and software in a user-interface for children

As part of the 1994 Apple Interface Design Competition, we designed and prototyped the PenPal, a portable communications device for children aged four to six. The PenPal enables children to learn by creating images and sending them across the Internet to a real audience of friends, classmates, and teachers. A built-in camera and microphone allow children to take pictures and add sounds or voice annotations. The pictures can be modified by plugging different tools into the PenPal, and sent through the Internet using the PenPal Dock. The limited symbolic reasoning and planning abilities, short attention span, and pre-literacy of children in this age range were taken into account in the PenPal design. The central design philosophy and main contribution of the project was to create a single interface based on continuity of action between hardware and software elements. The physical interface flows smoothly into the software interface, with a fuzzy boundary between the two. We discuss the design process and usability tests that went into designing the PenPal, and the insights we gained from the project.

Predictive systems biology approach to broad-spectrum, host-directed drug target discovery in infectious diseases.

Knowledge of immune system and host-pathogen pathways can inform development of targeted therapies and molecular diagnostics based on a mechanistic understanding of disease pathogenesis and the host response. We investigated the feasibility of rapid target discovery for novel broad-spectrum molecular therapeutics through comprehensive systems biology modeling and analysis of pathogen and host-response pathways and mechanisms. We developed a system to identify and prioritize candidate host targets based on strength of mechanistic evidence characterizing the role of the target in pathogenesis and tractability desiderata that include optimal delivery of new indications through potential repurposing of existing compounds or therapeutics. Empirical validation of predicted targets in cellular and mouse model systems documented an effective target prediction rate of 34%, suggesting that such computational discovery approaches should be part of target discovery efforts in operational clinical or biodefense research initiatives. We describe our target discovery methodology, technical implementation, and experimental results. Our work demonstrates the potential for in silico pathway models to enable rapid, systematic identification and prioritization of novel targets against existing or emerging biological threats, thus accelerating drug discovery and medical countermeasures research.

Graphical style sheets: towards reusable representations of biomedical graphics

We propose that the design characteristics shared by a family of data graphics can be represented as declarative, knowledge-based graphical style sheets that a generalpurpose visualization system can use to generate domainspecific data graphics automatically. Graphical style sheets (GSS) define the layout and drawing conventions shared by members of a particular family of data graphics. A GSS is a declarative mapping between Postscript-like graphical objects and biomedical data stored in object-oriented data structures. We describe the conceptual framework underlying our approach, and a prototype constraint-based visualization system (PALLADIO) and design representation language (P-SPEAK) we are building to evaluate this framework.

Functional modularity in a large-scale mammalian molecular interaction network

The Ingenuity/spl trade/ Pathways Knowledge Base (IPKB) contains over one million findings manually curated from the scientific literature. Highly-structured content from the IPKB forms the basis for a large-scale molecular network of direct interactions observed between mammalian orthologs, which is used in Ingenuitys Pathway Analysis (IPA) system. In this study we explore the relationship between this global network and known functional annotations of genes. In particular we show that (a) subnetworks formed by genes annotated with the same functional category have significantly more edges than equivalent random subnetworks, and (b) highly-interconnected subnetworks are significantly enriched in genes with specific functional annotations.