An iPad interface for KEGG metabolic pathways
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1. Navigation method Yes Yes Pan with one finger zoom with two Four mouse based navigation tools Greying out reactions that are not present in the selected organism set Yes Yes Moving nodes to rearrange the layout Yes Yes Dynamic layout when no frozen layout is present Yes Yes Saving layouts for future recall Yes No Lists of processes connected pathways pathway annotations and pathway related queries in tabular form Yes No Identifying the location of the gene producing the catalyzing enzyme Yes No Hiding common molecules Yes No Display of data from ENZYME database No Yes Display of data from KEGG web site No Yes acceptable in an online visualization environment More effort should be spent for both a lazy processing and downloads of new pathways perhaps as part of soft ware updates to the app which are really data updates and b moving processing to a separate thread to allow the main user interface to remain responsive Yet another technical challenge was rendering large graphs efficiently on a device with limited memory and processing power Fortunately the iOS application frameworks made pathway rendering possible though various low level optimizations were required at different stages of development Finally similar to graph rendering dynamic graph layouts accounted for a considerable amount of develop ment time despite the convenience of the Graphviz library to provide layouts on an as needed basis2. This feature is also not provided in iPathCase since due to its small screen size we have opted not to allow users of iPathCase S to visualize multiple pathways together as one sub network of the whole metabolic network Technical challenges and possible improvements The biggest challenge of the project was controlling the passage of information from the PathCase servers to the iPad application both in how the HTTP requests were made and how the data was translated into a form usable by the rest of the application The data is requested from the PathCase SS server in a much more piecemeal way The data for each pathway is encapsulated entirely in a single request so there is no need for complex dependency management or even data storage above and beyond simple HTTP request caching The data models HTTP requests and parsing are cleanly separated When the project started we underestimated the soft ware system complexity involved in iPathCase as well as other iPathCase systems In terms of software architecture in the future the system components that download the data parse it build model objects as well as various controls should be re factored to separate each of these tasks explicitly Additionally there should be a more formal data dependency tracking system to Johnson et al Health Information Science and Systems 2012 1 4 http www hissjournal com content 1 1 4 Navigation Stack UlNavigationC
3. information Information Go to KEGG i web page oxalosuc cinate Molecule Page 5 of 15 portrait horizontal orientation it is accessed via a button in the upper left corner of the screen This inter face is described visually in Figure 1 The home screen of iPathCase S displays a list of metabolisms i e pathway categories and their documentation links in the sidebar as seen in Figure 2 Selecting a pathway cat egory takes the user to a list of pathways Figure 3 shows the list of pathways in Carbohydrate Metabolism category Selecting a pathway from the list opens the graph view of that pathway in the detail view A labeled diagram of an example visualization is shown in Figure 4 along with a legend for the different node types The view for the TCA cycle is shown in Figure 5 So far all of the displays have come from PathCase database and pathway layouts have come from GraphViz 14 TCA cycle graph view can be panned and zoomed by touch If no node is selected the system displays a but ton which when touched accesses the KEGG web API and shows the KEGG database web page for the selected pathway One example page is shown in Figure 6 When a node is selected any other node that is not connected to it by one hop is made transparent to make the node s connections easier to see Figure 7 shows an example of this behavior Organisms button in the upper right corner triggers a popover which a
4. Institute of Health grant GM088823 Received 23 April 2012 Accepted 4 September 2012 Published 10 January 2013 References 1 Kanehisa M Goto S Sato Y Furumichi M Tanabe M KEGG for integration and interpretation of large scale molecular datasets Nucleic Acids Res 2012 40 D109 D1 14 2 Kanehisa M Goto S KEGG Kyoto Encyclopedia of Genes and Genomes Nucleic Acids Res 2000 28 27 30 3 Elliott B Kirac M Cakmak A Yavas G Mayes S Cheng E Wang Y Gupta C Ozsoyoglu G Ozsoyoglu ZM PathCase pathways database system Bioinformatics 2008 24 21 2526 2533 4 Cakmak A Qi X Coskun SA Das M Cheng E Cicek AE Lai N Ozsoyoglu ZM Ozsoyoglu G PathCase SB Architecture and Database Design BMC Syst Biol 2011 5 188 5 Coskun SA Qi X Cakmak A Cheng E Cicek AE Yang L Jadeja R Dash RK Lai N Ozsoyoglu G Ozsoyoglu ZM PathCase SB Integrating data sources and providing tools for systems biology research BMC Syst Biol 2012 6 67 to appear 6 Le Nov re N Bornstein B Broicher A Courtot M Donizelli M Dharuri H Li L Sauro H Schilstra M Shapiro B Snoep JL Hucka M BioModels Database a free centralized database of curated published quantitative kinetic models of biochemical and cellular systems Nucleic Acids Res 2006 34 Database Issue 689 691 7 BioModels database A Database of Annotated Published Models http www ebi ac uk biomodels main 8 SimGene An application in Apple app store 9 Apple Pr
5. only exist in Animals Rest of the reactions are greyed out on left Tapping the button on top right opens up the list of possible organisms that can be selected converting data from GetPathwayDatas response format to the graph model in GML Graph Markup Language format The GML is generated by the yFiles library 16 iPathCase graph representation has a PCGraphNode class to represent a graphical node and a PCGraphEdge class to represent a graphical edge A PCGraphModel contains sets of these node and edge objects to represent single pathway visualization In iPathCase the node and edge objects contain no parsing code but instead expose all graphical attributes as writeable properties The responsibility for parsing a graph definition and building a graph model with the correct graphical attributes is moved to an external object that is not part of the graph rendering system After data has been parsed the graph is ready for rendering by a PCGraphView which uses a Core Anima tion layer hierarchy to draw the graph efficiently There are three layers in a PCGraphView From top to bottom 1 Text layer for drawing node labels This layer contains one sub layer for each node that renders the text for its label 2 Node layer for drawing node shapes and 3 Edge layer for drawing edges Once these layers are rendered they are drawn to the screen by a scroll view which takes care of translating and scaling th
6. with a list of links at the bottom Once clicked web pages are displayed on the detail view Johnson et al Health Information Science and Systems 2012 1 4 http www hissjournal com content 1 1 4 wireless network access and other services This section describes only those iPad specific user interface concepts that iPathCase uses Unlike traditional computer displays the iPad is designed to be held in any orientation with the display s contents rotating and resizing to fit the users perspec tive There are four possible orientations but the short cuts landscape and portrait suffice for describing and implementing most interfaces 13 The most basic component of an iPad interface is the view A view is a rectangular region that is capable of displaying content receiving events such as gestures and device orientation changes and dele gating these tasks to subviews Views can contain buttons toolbars lists other views and arbitrary graphical content Nested views consist of a view hierarchy A button is a view that renders itself in enabled disabled and pressed states and invokes some action when a touch is released inside its bounds Coc Carbohydrate Metab Amino sugar and nucleotide sugar metabolism Ascorbate and aldarate metabolism Butanoate metabolism C5 Branched dibasic acid metabolism Citrate cycle TCA cycle Fructose and mannose metabolism Galactose
7. Conclusions iPathCase has been a successful exercise in extend ing the PathCase architecture and philosophy to new devices and new users It is one thing to design a web interface and server backend in tandem and another to apply the server s web service interface to an entirely new set of applications iPathCase F shows that Path Case s architecture serves the purpose for which it was built to provide a platform for analysis and reference tools on top of multiple data sources for pathways iPathCase SS e Allows browsing of all KEGG pathways e Links reactions with the external ENZYME database and e Allows access to the KEGG web page corresponding to any pathway The application adapts the basic PathCase pathway visualization interface concepts for a touch screen specifically making heavy use of iOS idioms This adap tation and iPathCase 18 another PathCase iPad application already at the Apple App Store provide insight about how pathway visualizations can be improved across all forms of input and display iPathCase opens up many exciting possibilities for the use of tablets in educational and research environ ments The best thing that can be done to make these possibilities become realities is to perform studies and have discussions with practicing life scientists and stu dents Formal and informal feedback should be gathered from possible users to determine the most effective fu ture im
8. Johnson et al Health Information Science and Systems 2012 1 4 http www hissjournal com content 1 1 4 SOFTWARE HEALTH INFORMATION SCIENCE AND SYSTEMS Open Access iPathCase An iPad interface for KEGG metabolic pathways Stephen R Johnson Xinjian Qi A Ercument Cicek and Gultekin Ozsoyoglu Abstract Background Kyoto Encyclopedia of Genes and Genomes KEGG is an online and integrated molecular database for several organisms KEGG has been a highly useful site helping domain scientists understand research study and teach metabolisms by linking sequenced genomes to higher level systematic functions KEGG databases are accessible through the web pages of the system but the capabilities of the web interface are limited Third party systems have been built over the KEGG data to provide extensive functionalities However there have been no attempts towards providing a tablet interface for KEGG data Recognizing the rise of mobile technologies and the importance of tablets in education this paper presents the design and implementation of iPathCase an iPad interface for KEGG data which is empowered with multiple browsing and visualization capabilities Results iPathCase has been implemented and is available free of charge in the Apple App Store locatable by searching for Pathcase in the app store The application provides browsing and interactive visualization functionalities on the KEGG data
9. Systems 2012 1 4 http www hissjournal com content 1 1 4 Page 7 of 15 Figure 6 KEGG web page for TCA Cycle Once the KEGG button is tapped the web page for the displayed pathway is opened as a popever The KEGG web page for TCA Cycle is shown in this figure which trigger the display of new information in the side bar This information comes from both the pathway data structure and a stored copy of the ENZYME database There are pieces missing from the diagram in Figure 9 such as graph layout and the showing hiding of organ isms but the essential pieces are present Navigation user interface Figure 10 shows a high level representation of the user interface components of iPathCase There are two kinds of edges in the diagram Present edges are drawn when one view controller causes another to be displayed in its content area For example U SplitViewController shows the PCMasterViewController via UINavigation Controller in its sidebar area or popover and the PCDetailViewController in the rest of its content area Notify edges represent notifications that are sent between objects A notification is an abstraction of message pas sing An object may register for a notification of a certain name When any object posts a notification with that name the object that registered for the notification is passed a message that was specified at registration time This message includes a notification object which may contain addi
10. Users can pick pathways visualize them and see detail pages of reactions and molecules using the multi touch interface of iPad KEGG Conclusions iPathCase provides a mobile interface to access KEGG data Interactive visualization and browsing functionalities let users to interact with the data in multiple ways As the importance of tablets and their usage in research education continue to rise we think iPathCase researcher s KEGG will be a useful tool for life science instructors and Keywords KEGG iPad App PathCase Metabolic networks Pathways Background Kyoto Encyclopedia of Genes and Genomes KEGG is one of the well known biological knowledge bases that links genomic information to high level functions of the cell for several organisms 1 2 KEGG among others provides the association between sequenced genomes and their correspondences in metabolic networks and biochemical pathways 1 2 Although the KEGG system has added over time new tools and additional databases such as KEGG Brite the core of the system is centered on KEGG Pathways which specify the sets of reactions that participate in biochemical pathways for different organisms KEGG Genes and KEGG Ligand databases specify information about the associated genes and the chemicals molecules for KEGG Pathways respectively Through a web interface KEGG provides maps of Correspondence tekin case edu Electrical Engineering and Computer Science D
11. We believe that iPath Case S is useful for i students who use KEGG to learn metabolic networks ii instructors that teach ma terial using a visual tool and iii researchers who would like to employ metabolic pathways in their research Johnson et al Health Information Science and Systems 2012 1 4 http www hissjournal com content 1 1 4 GetGraphData Response PCGraphModel parser method Edge expression begun PCGraphNode PCGraphEdge Parse node expression Parse edge expression Path text objects for later rendering Path objects for later rendering Complete PCGraphEdge Complete PCGraphNode PCGraphModel node table PCGraphModel edge table Complete PCGraphMode l PCGraphView for rendering Figure 11 Data flow from PathCase representation to final display format Figure shows the data flow for rendering a selected pathway After the data is obtained from the server through the web service and parsed the nodes and edges are defined to form the graph model to be rendered The representation is identical to Figure 2 Comparison with Web based PathCase Table 1 compares functionalities available in the inter faces of the web based PathCase S system and the iPathCase SS app Most of the functionalities listed are self explanatory and next we discuss only a few of the functionalities listed in Table 1 Page 12 of 15 The functionality Greying out reac
12. abilities key word search function for pathways processes organisms basic molecules proteins and genes an advanced querying interface for computer savvy users and built in queries for ease of use that can be issued directly from pathway visualizations iv path way functionality analysis tools such as the gene ontology viewer and v pathway and process export and import capabilities Overview of iPad interface iPad 2 hereafter simply iPad is a device about 7 3X9 5x0 3 inches with a 1024x768 pixel touch screen 13 The touch screen can detect more than one human finger at a time allowing for actions such as zooming to be accomplished with natural gestures using two or more fingers iPad runs iOS a UNIX based operating system which presents one full screen application at a time and provides multithreading persistent storage Johnson et al Health Information Science and Systems 2012 1 4 Page 3 of 15 http www hissjournal com content 1 1 4 Master view Detail sidebar view Master Title Detail Title Master Title Detail Title j F Master view Master view Master view contents contents Figure 1 Master detail interface in landscape and portrait orientations Figure shows the organization of a typical view of the application on iPad The thin layer on the left is called the master view which contains the data to be navigated The right view is the detail view into which the selected data is loaded Naviga
13. anisms A and B are disabled then reaction R will be dimmed in the visualization Next we briefly describe the process of displaying the organism hierarchy shown in Figure 13 Selecting the toolbar button in the upper right corner of the visualization view causes PCGraphViewController to display a popover with a navigation stack The first item on this stack is a PCOrganismHierarchyTableView Controller which presents a table view containing hierarchical categories of organisms Tapping a row in the table view either pushes the subcategories of that category onto the navigation stack if the row repre sents a subcategory or it toggles the enabled disabled state of an organism if the row represents an organ ism The set of enabled organisms is then posted as a notification that is received by the PCGraphView Controller which updates the PCGraphModel with the enabled disabled state of each individual node based on the enabled disabled state of the organisms Dynamic layouts with graphviz PathCase contains human curated frozen layouts for some pathways but not all In order to display the pathways without frozen layouts iPathCase FSS uses Johnson et al Health Information Science and Systems 2012 1 4 http www hissjournal com content 1 1 4 Page 11 of 15 Legend PCAppDelegate Root application singleton prese nt r UISplitViewController Display master detail Navigation Stack UINavigationController Navigation sta
14. ck controller PCMasterViewController List of pathway categories and documentation links PCPathwayTableView Controller List of pathways PCNodelnfoViewController Information about current selection in graph view interface PCDetailViewController Multiplex detail view controllers PCGraphViewController and graph rendering subsystem PCWaitingViewController Display Loading PCWebViewController Display HTML pages Detail view Controllers Figure 10 Components of the user interface Figure details the individual components and their interactions for the user interface Rectangles represent components solid lines represent present edges that cause another controller to be displayed within that view controller and dashed edges represent message passing between components the Graphviz library Graphviz is a system which among other things provides graph layout and visualization functions 14 It provides both command line and pro grammatic interfaces for entering laying out and rendering graphs iPathCase encapsulates the layout functionality of the Graphviz library in a class called GVGraph An instance of this class represents a graph with nodes a label for each node and one directional edge that connect nodes Reading the ENZYME database The ENZYME database is provided in a flat text file format 12 15 This format is not acceptable for random seeking behavior so it has been conver
15. clusion in PubMed CAS Scopus and Google Scholar e Research which is freely available for redistribution Submit your manuscript at www biomedcentral com submit C BioMed Central
16. e device s internal storage It has a separate class for each web service named PC lt WebService gt Fetcher iPathCase s web service classes fire events to a central notification system when they have completed and controller objects check to see if any new web services should be invoked due to dependencies being made available After the XML response has been parsed into one or more KEGG internal objects these objects are not serialized In other words all objects generated by web ser vices are built from the XML each time they are needed Visualization The pathway visualization data graph data is provided by the PathCase S web service GetPathwayData Ra ther than calling the web service when the user requests to view a pathway the web service responses for all pathways are included with the application itself in the form of text files Each text file contains the HTTP re sponse to a web request for the graph data for one path way Figure 11 shows the complete pipeline for Johnson et al Health Information Science and Systems 2012 1 4 http www hissjournal com content 1 1 4 2 39 PM Citrate cycle TCA cycle Page 9 of 15 Citrate cycle TCA cycle Genes Organism Hierarchy Eukary otes af Animals Fungi Plants Protists Figure 8 Organism selection greys out the reactions not participating for selected organism Figure shows the reactions that participate in TCA Cycle pathway that
17. em in response to user interaction Life cycle of a pathway visualization The loading and display of a pathway visualization requires interactions between several components of iPathCase These interactions are illustrated in Figure 12 Loading is invoked by selecting a pathway from PCPathwayTableViewController In response to the notification posted by this action PCDetail ViewController sets its content area to the Loading screen and invokes the PCGraphDataFetcher web service class to load the pathway s information from the PathCase web service GetGraphData This class produces a set of PCNodelInfo objects that represent all aspects of the graph except node and edge positions This set is given to a PCLayoutFetcher web service class which attempts to Johnson et al Health Information Science and Systems 2012 1 4 http www hissjournal com content 1 1 4 Page 10 of 15 Web services pathway Pathway list selected view Data model storage node tapped information ENZYME Database Fetching and parsing data available Graph rendering Figure 9 High level diagram of the most important data flows and events in iPathCase KEGG download a layout for the graph from the PathCase SS web service RetrieveLayout If successful it builds a PCGraphModel including a pre drawn and manually beautified so called frozen layout information using the information in the respon
18. epartment Case Western Reserve University Cleveland OH USA C BioMed Central metabolic pathways for visualization purposes KEGG pathways data is made available at an FTP site and web services for third party applications are provided as an API PathCase SS system is one of the PathCase family of systems with a PathCase database populated from KEGG data PathCase system provides over the web additional browsing querying visualization and analysis functionalities for KEGG data such as interactive visualization 3 And PathCase SB another PathCase sys tem integrates KEGG data with data from other data sources 4 5 such as BioModels 6 7 Both PathCase sys tems provide hierarchical browsing a query interface and a JAVA applet based interactive visualization of pathways In this paper we describe iPathCase which is an iPad based system with a mobile interface that accesses PathCase 9 KEGG Pathways and ENZYME databases and provides browsing and interactive visualization functionalities on the accessed data To the best of our knowledge as of August 2012 there have been no 2012 Johnson et al licensee BioMed Central Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License http creativecommons org licenses by 2 0 which permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited Joh
19. ess Info http www apple com pr library 2011 07 19Apple Reports Third Quarter Results html 10 Apple Education http www apple com education ipad 1 Sabah Newspaper Turkish Ministry of National Education distributes tablets in schools http english sabah com tr National 2012 02 01 distribution of free tablets to students has begun 12 Bairoch A The ENZYME database in 2000 Nucleic Acid Research 2000 28 1 304 305 13 Apple Inc iOS human interface guidelines http developer apple com library ios documentation UserExperience Conceptual MobileHIG MobileHIG pdf 14 Gansner ER North SC An open graph visualization system and its applications to software engineering Software Practice and Experience 1999 1 1 5 15 The ENZYME nomenclature database user manual http enzyme expasy org enzuser txt 16 yFiles developer s guide http docs yworks com yfiles doc developers guide index html 17 About SQLite http www sglite org about html 18 iPathCasee An application in Apple app store doi 10 1186 2047 2501 1 4 Cite this article as Johnson et al iPathCase An iPad interface for KEGG metabolic pathways Health Information Science and Systems 2012 1 4 Page 15 of 15 Submit your next manuscript to BioMed Central and take full advantage of e Convenient online submission e Thorough peer review e No space constraints or color figure charges e Immediate publication on acceptance e In
20. hink that KEGG is an invaluable resource for life sciences education and there is a need for a mobile interface for instruc tors and researchers to access KEGG data In this paper we present iPathCase an iPad application to interface with KEGG data The system comes with the following functionalities e Interactive visualization of metabolic pathways e Access to the KEGG web page regarding a pathway within the app e Highlighting a node and close proximity e Highlighting organism specific subsets of reactions e Enzyme details pane from ENZYME Database for a selected reaction through EC Enzyme Commission Numbers 12 iPathCase S has been implemented extensively tested for iPad 2 and is freely available in Apple App Store Overview of KEGG As of July 23 2012 KEGG consists of seventeen databases KEGG ORTHOLOGY GENOME GENES DGENES and SSDB in genomic information KEGG COMPOUND GLYCAN REACTION RPAIR RCLASS and ENZYME in chemical information KEGG PATHWAY BRITE MODULE DISEASE DRUG and ENVIRON in systems information The most unique data object in KEGG is the molecular networks molecular Page 2 of 15 interaction reaction and relation networks representing systemic functions of the cell and the organism Systemic functions capture experimental knowledge from literature which are organized in three forms Pathway maps in KEGG PATHWAY Hierarchical list ontology in KEGG BRITE Membership
21. list in KEGG MODULE and KEGG DISEASE These databases constitute the reference knowledge base for biological interpret ation of genomes and high throughput molecular data sets through the process of KEGG mapping which is a process to map elementary datasets genes proteins small molecules etc to network datasets KEGG path way maps BRITE functional hierarchies and KEGG modules Currently there are four types of mapping operations available in KEGG pathway mapping brite mapping module mapping and taxonomy mapping which may involve molecular or non molecular datasets orthologs modules and organisms and the network dataset taxonomic tree While the main focus of KEGG has been the molecular network different types of data and knowledge such as disease genes and drug targets are also integrated as part of the KEGG molecular networks to support translational bioinformatics Overview of PathCase PathCase is a web based system to store browse query visualize and analyze KEGG metabolic pathways at different levels of genetic molecular biochemical and organismal detail It integrates i browsing interface to access different pathway information and pathway related information processes molecular entities genes ii an interactive client side visualization tool for metabolic pathways with powerful visualization capabilities and with integrated gene and organism viewers iii three distinct querying cap
22. llows the user to activate and deactivate organisms If a reaction is not Citrate cycle TCA Cycle Molecule Role Molecule Reaction R006211 Name Substrate Product Inhibitor Cofactor Figure 4 Legend for pathway visualizations Figure shows possible interactions among molecules and reactions and labels each item shown in pathway visualizations Rectangles represent reactions circles represent molecules and edges show the direction of the reaction while associating molecules with reactions Bidirectional edges represent reversible reactions Johnson et al Health Information Science and Systems 2012 1 4 http www hissjournal com content 1 1 4 dada PM Carbohydrate Metabol TEO Node Info Show KEGG Page Tap a node to see more information Page 6 of 15 Citrate cycle TCA cycle Figure 5 Visualization of TCA Cycle TCA Cycle has been visualized in the detail view Please see Figure 4 for the legend present in any activated organism it is made partially transparent The organism hierarchy menu is shown in Figure 8 on the right hand side The graph view corre sponding to the selection is shown on the left hand side In addition to displaying a node s long description from PathCase SS iPathCase uses data from the ENZYME enzyme nomenclature database 12 to show more information for reactions for which EC numbers are available ENZYME s data comes from the recom mendations of the Nomenclature Co
23. metabolism Glycolysis Gluconeogenesis Glyoxylate and dicarboxylate metabolism inositol phosphate metabolism Pentose and glucuronate interconversions Pentose phosphate pathway Propanoate metabolism Pyruvate metabolism Starch and sucrose metabolism Page 4 of 15 Toolbars are views that can be inserted at the top or bottom of another view They typically contain buttons text labels progress indicators and more A scroll view contains another larger view that the user can move around with one or two fingers For example one might be used to display a photo that is larger than the screen Scroll views can be dragged around with one finger or zoomed out by pinching two fingers together Tapping twice in the same location typically zooms in on the tapped location One common use for the scroll view is in a table view used to display lists of content The user can scroll up and down the list and tap a row to invoke some action Some types of views exist only to contain other views One view of this type is the popover A popover appears temporarily on the screen allowing the user to perform some quick interaction before dismissing it by tapping outside its bounds The popover is a key component in the PathCase Featuring KEGG Pathways Figure 3 List of carbohydrate metabolism pathways Master view shows the list of pathways in the carbohydrate metabolism category after it s selected f
24. mmittee of the International Union of Biochemistry and Molecular Biology IUBMB 15 An example of ENZYME information in the sidebar is shown in Figure 7 on the left hand side Architecture iPathCase C s architecture consists of a few well defined components e User interface objects present things like the master detail interface lists of pathways organism selection etc e Web service request classes make HTTP requests to the PathCase server process the response and notify other objects of the results e Encapsulated components provide specific functionalities such as reading the ENZYME database 12 and generating dynamic layouts with Graphviz 14 Figure 9 presents a high level diagram of the most im portant data flows and events in iPathCase Given the event driven and nonlinear nature of GUI program ming it is more appropriate to describe events and noti fications rather than straight line execution The user begins at the pathway list view which allows the selec tion of a pathway to view Selecting a pathway initiates a call to the PathCase web service or a read from the local cache the result of which is stored as an in memory data structure An event is then triggered to render the graph view from the stored data structure and then display the rendered view itself The graph view sends event notifications when nodes are tapped Johnson et al Health Information Science and
25. nson et al Health Information Science and Systems 2012 1 4 http www hissjournal com content 1 1 4 attempts with the exception of SimGene 8 towards pro viding a mobile interface for browsing and visualizing KEGG pathways SimGene designed for iPhone not for iPad is a gene related information searching tool and does not focus on pathway browsing or visualization More specifically given a gene symbol SimGene searches many databases Simbiot Ensembl NCBI Gene Ontology KEGG Pathways PubMed Genomic Variations and other databases for more than 30 species and provides annotated information about the specified gene iPad has been a revolutionizing mobile device with the multi touch based interface Apple has sold 9 25 million iPads only in the fiscal 2011 third quarter 9 With the releases of similar devices by other brands tablets are becoming widespread Ease of use with familiar gestures and mobility of tablets have contributed to their success However websites designed for computers are not opti mized for mobile devices Therefore companies release their own apps or redirect users to mobile versions of their web pages To the best of our knowledge there is no such app or mobile version for the KEGG web site Tablets also have started to attract attention in education For instance Apple has made an effort to revolutionize text books 10 and countries distribute tablets to school children such as Turkey 11 We t
26. ntiated by their abilities to oxidatively decarboxylate different 2 oxoacids and form their CoA derivatives see also EC 1 2 7 1 EC 1 2 7 7 and EC 1 2 7 8 Highly specific for 2 oxoglutarate Formerly EC 1 2 7 9 Page 8 of 15 Citrate cycle TCA cycle Figure 7 Neighborhood of a tapped node is highlighted Once a node reaction or molecule is tapped in the visualization all nodes within 1 hop distance are shown as is and the rest of the pathway is greyed out This figure also illustrates the ENZYME database information related to the catalyzing enzyme of the tapped reaction Here ENZYME database information for 2 oxoglutarate ferredoxin oxidoreductase is displayed in the sidebar displayed in the master content area The master view makes use of a navigation stack The top item on this stack is the PCMasterViewController which pushes a PCPathwayTableController onto the stack when a pathway category is selected When one of the pathways in that list is selected a show path way notification is posted and a PCNodelnfoView Controller is pushed onto the stack This is the view controller that displays information for the current selection so it responds to notifications sent by PCGraphViewController about changes in the user s selection Web services iPathCase S does not download the entire pathways data in PathCase database at once HTTP requests are made as new data is needed and the result is cached in th
27. ontroller Navigation stack controller PCMasterViewController List of pathway categories and documentation links PCPathwayTableView Controller show pathway List of pathways in master view Invoke PCGraphDataFetcher In response to show pathway pathway PCDetailViewController loaded Multiplex detail view controllers In response ta Page 13 of 15 PCGraphDataFetcher Loads node information from PathCase KEGG Invoke PCLayoutFetcher i PCLayoutFetcher Loads graph layout from PathCase KEGG or generates dynamic layout if none exists pathway loaded PCNodelnfoViewController Information about current selection in graph view PCGraphViewController and graph rendering subsystem Figure 12 Life cycle of a pathway visualization Figure shows the possible interactions among several components that contribute to pathway visualization The representation is identical to Figure 2 control the bulk download of the web service data It is common to have HTTP requests for web services A B and C rely on data from request X so there should be a formalized dependency graph that tracks this information iPathCase s biggest technical issue is a noticeable hang when selecting a large pathway to view due to the HTTP requests and responses that involve creation and transfer of large 2 5 megabytes XML documents sometime with large frozen layout information as well PCGraphViewCon
28. provements Even their simple presence in the iOS online store should provide helpful feedback posi tive or negative that will affect the development of both applications Interactive visualizations of complex biological data are no longer limited to immobile desktop workstations or cumbersome laptops the iPad is even less intrusive than a physical textbook and can display information in new and interesting ways iPathCase brings inter active pathway visualizations reference materials and even research tools to desks meetings and couches Availability and requirements Project name iPathCase SS Project download source Apple App Store Operating system iOS 5 Programming language Objective C Other requirements iPad2 or newer Competing interests The authors declare that they have no competing interests Authors contributions SRJ has written the iPad end of the code and has drafted the manuscript XQ has provided the web services on the server side and performed software testing AEC has helped with biological interpretations performed Johnson et al Health Information Science and Systems 2012 1 4 http www hissjournal com content 1 1 4 software testing and drafted the manuscript The project was led by GO All authors read and approved the final manuscript Acknowledgements This research has been supported by the National Science Foundation grants DBI 0743705 DBI 0849956 CRI 0551603 and by the National
29. rom the list shown in Figure 6 Johnson et al Health Information Science and Systems 2012 1 4 http www hissjournal com content 1 1 4 master detail interface a common arrangement of views in iPad applications A diagram of the master detail interface is shown in Figure 1 When the device is in a landscape orientation a thin view is shown to the left of a wide view The thin view called the master view or sidebar contains content for navigating the application s data such as a table view of email messages The wide view called the detail view or content view shows the selection made in the master view When the device is in a landscape orientation the detail view is resized to fill the screen A button on the left side of the top toolbar displays a popover containing the master view Implementation Overview of iPathCase capabilities Here we give a brief overview of iPathCase inter face to provide context to the implementation details that follow iPathCase S divides the iPad screen into i a master interface as a sidebar master view that provides navigation functionality and metadata for the currently selected object and ii a details interface detail view that displays content chosen from the side bar such as documentation or a graph view When the device is in the landscape vertical orientation the master view is shown to the left of the detail view In KEGG KEGG Node or pathway
30. se If not it builds a PCGraphModel from the PCNodelnfo objects and generates a dynamic layout There are two advantages to using frozen layouts provided by RetrieveLayout The first is that they are curated manually and tend to look nicer as a result The second is that when a molecule is used in multiple reactions each duplicate occurrence is drawn for each reaction thereby eliminating many incoming and outgoing edges for a single common molecule such as water or energy molecules ATP or ADP and hence sim plifying the visualization drastically When a frozen layout is not available iPathCase generates dynamic layouts where a metabolite that is used in multiple reactions will appear only once often resulting in scrambled layouts with one metabolite node having many incoming edges from many reactions When the layout step is complete PCLayoutFetcher posts a notification containing the generated PCGraphModel object This notification is received by PCDetailViewController which creates a PCGraphViewController and puts it in the detail view content area It also pushes a PCNodelnfoController onto the master view navigation stack which receives events from the PCGraphViewController about what it should display Organism hierarchy The iPathCase pathway visualization includes the ability to select only a subset of organisms to display in formation from If reaction R is present in organisms A and B but not C and org
31. ted to a SQLite database 17 for more efficient access SQLite is a minimal imple mentation of SQL intended to be used as a storage medium for single instance applications 17 iPathCase KEGG uses the description alternate name catalytic activity cofactor and comments ignoring the remaining fields Results and discussion Tablets have revolutionized the mouse and keyboard based interface with a mobile and a multi touch based interface Many gestures such zoom by pinch or swipe to turn the page are very user friendly Not to mention the new retina display iPad interface has been a break through so far As stated before tablets have already been adopted as an educational tool We foresee that tablets will keep attracting more attention and will be more widely used as prices drop universities that dis tribute laptops to students will start to give tablets classes will be held using tablets such as iPads heavy hardcopy textbooks will be replaced by e books and stu dents will be able to carry thousands of them in a single tablet device For our application KEGG is an important source for life sciences researchers and for biology bio chemistry education as it maintains extensive biochem ical pathways data With the interactive visualization interface of iPathCase SS users can interact with KEGG pathways using a multi touch interface and ges tures which is a major improvement over the static visualizations provided by KEGG
32. tion PathCase KEGG Pathway Categories Amino Acid Metabolism Biosynthesis of Other Secondary ost itvetn PathCase Featuring KEGG Pathways Energy Metabolism Glycan Biosynthesis and Metabolism Lipid Metabolism Welcome to PathCase KEGG for iPad Using this application you can view metabolic pathways from KEGG stored in the PathCase database Metabolism of Cofactors and Vitamins Additional information about reactions is proved by the ENZYME enzyme nomenclature database Metabolism of Other Amino Acids Browsing Pathways Metabolism of Terpenoids and Polyketides lf you are holding your iPad in landscape mode the list of pathways is in Nucleotide Metabolism the sidebar on the left side of the screen If you are holding it in portrait mode you can press the button in the upper left corner to see the Xenobiotics Biodegradation and Metabolism Ble mentaar a ALL E i H Ss oo eee ee Soe ees uwa a oe RS Tap a category to see the pathways within it In this list of pathways bold iterns have frozen layouts with nodes and edges arranged by hand Non bold items have automatically generated layouts which may be Help KEGG Web Sit z if more difficult to work with PathCase KEGG Web Site Interacting with Pathway Visualizations ENZYME Web Site Once vou select a pathwayv from the list vou will see a aranh much like Figure 2 Home screen for iPathCase List of pathway categories are displayed on the master view along
33. tional data depending on the specific notifi cation that was sent This system allows objects to send and receive events without storing unnecessary refer ences to other objects A good example of notifications can be found in iPathCase PCMasterViewController a view controller included in Figure 10 shows a list of pathway categories and documentation links Selecting a documentation link such as KEGG Web Site posts a notification called PCPageViewRequested that contains the URL of the corresponding web page in this case http www kegg com PCDetailViewController responds to five different notifi cations but only two are shown in Figure 10 The rest have to do with web services and pathway visualization interactions which will be discussed later in this section The remaining nodes in Figure 10 PCPathwayTable ViewController and PCNodelnfoViewController are Johnson et al Health Information Science and Systems 2012 1 4 http www hissjournal com content 1 1 4 1 2 7 3 Name 2 oxoglutarate synthase Alternate names 2 ketoglutarate ferredoxin oxidoreductase 2 oxoglutarate ferredoxin oxidoreductase Alpha ketoglutarate synthase Alpha ketoglutarate ferredoxin oxidoreductase KGOR Catalytic activity 2 oxoglutarate CoA 2 oxidized ferredoxin succinyl CoA CO 2 2 reduced ferredoxin 2 Hi Cofactors iron sulfur Thiamine diphosphate Comments One of four 2 oxoacid oxidoreductases thal are differe
34. tions that are not present in the selected organism set is available in both PathCase and iPathCase which allows the user to focus on only those reactions of the pathway available in the chosen organism set The functionality Moving nodes to rearrange the layout of the pathway at hand is also available in both interfaces As it turns out bioche mists always would like to have the same layouts for pathways and automated layouts may need to be manu ally edited by some users hence this functionality is con sidered essential for life sciences researchers Also this functionality gives the user the flexibility of changing the layouts based on their specific needs i e emphasizing a certain part of a given pathway The functionality Identifying the location of the gene producing the catalyzing enzyme allows pathway analysis in terms of the locations of genes producing catalyzing enzymes of different reactions This function ality can be viewed as a higher level pathway analysis functionality and is not provided in iPathCase SS Common molecules are those molecules that participate in many reactions i e CO ATP ADP NAD NADP NH4 NADPH NH3 NADH Oxygen CoA H H20 H 0O2 Common molecules can also be regarded as social network hubs of pathways PathCase allows users to hide common molecules when multiple pathways are drawn together as it reduces the visualization complexity of pathways
35. troller Popover from toolbar Display pathway visualization Organism states updated Node states updated Y i Organism state updated PCGraphModel Representation of visual graph as dynamic layout creation delays due to the use of Graphviz Caching pathways a priori has mostly but not fully eliminated this problem However when a new or revised pathway in the PathCase system is encoun tered and it needs a dynamic layout generation the sys tem takes significant amounts of time ranging from 30 tol00 seconds to request and receive the new revised pathway parse and produce a new layout and display it A delay of this magnitude sometimes leads users into thinking that the app has crashed which is not Navigation Stack in Popover UINavigationController PCOrganismHierairchy TableViewController Display list of categories PCOrganismSubHierairchy TableViewController Display list of subcategories or organisms Figure 13 Components of the organism hierarchy update process Figure shows the interactions among components to grey out parts of the network based the organism selection of the user The representation is identical to Figure 2 Johnson et al Health Information Science and Systems 2012 1 4 http www hissjournal com content 1 1 4 Page 14 of 15 Table 1 Comparison of web based PathCase and iPathCase interfaces Web based iPad Molecule and reaction visualization
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