VisANT 4.0 User Manual Contents
Contents
1. See hep p 60 Annotation z 5 7 Disease Annotation t Using Most Specific Disease Terms CASP Si apoptosis related cysteine z 3 psa fa Sid ee j i Label Protein Gene with Official Name Clear Disease Annotation Alias ALPS2B CAP4 CASPE CASP Total 7 links and 5 visible Available Links Tae ste en Se EK y LA H Label es Select Linked Nodes re oA Delete Selected Nodes 4 geimi a Rj Grouping Duplication NFS Sh40 6 85 5E 1 Postion Operation p Select Genes with NO Disease Annotation Calor f C Thickn e Disease E 0 01 User Defined Label The user defined label af node Mouse wheel to ZO 0h 3 The default FDR cut off value of the enrichment analysis is 0 01 Before starting the analysis we can adjust this value from the property sheet Y W RAI I L Edge 1 Exelud J Color f a Thickn v4 Fig Disease E Di 0 014 FOR cutoff Right click drag to FAM Mouse wheelto 200M 4 The disease enrichment analysis can be started by clicking on MetaGraph gt Predict Associated Disease of Metanodes gt Using Hypergeometric Test over All Diseases Databases from the menu When there are more than one metanode gene set available and none of them are selected by the user VisANT will perform the enrichment analysis over all possible metanodes The analysis of each metanode is independent to each other and the result will be listed separately in the final report In contrast if on2. 568 247x0R 7 Correlation 0_61 Node Degree k Link to Network Note that when dragging a rectangle over the distribution plot for node degree one only drug nodes with degree 1 are selected indicating that the degree distribution is for drug nodes only This achieved in tow steps 1 select a drug node and applying menu Nodes gt Select Deselect Nodes of The Same Properties All drug nodes will be selected 2 Applying menu Topology gt Global Statistics gt Degree Distribution the degree distribution will pop out As shown in above figure there are only four type of degree for drugs 1 2 3 and 5 The network shown in above figure can be downloaded at http visant bu edu sample visml _ files Breast_ cancer gene drug no legend xml and can be loaded into VisANT directly using the menu Files gt Open URL it can also be loaded into VisANT through Java Web Start by clicking on the following URL htto visant bu edu 8080 vserver DAI command link amp location http visant bu edu sample visml files Breast_ cancer gene drug no legend xml Network Legend It is necessary to distinguish the types of nodes in a network comprised of mixed data types and various visual customizations such as the drug target network shown above VisANT 4 0 automatically creates the network legend node such as the one shown in both Fig 2 and 3 using the menu View gt Network Legend The legend node is a metanode and can therefore be collapsed exp
3. Meta network where diseases and therapies are represented as metnaodes with embedded genes drugs The nodes for diseases therapies can easily be created through drag amp drop operations from the Hierarchy Explorer to the network panel in VisANT There are 4 total options for the drag amp drop operation and two of them allows for the embedding of sub terms in the metanodes to achieve the multi scale visualization Please reference previous ViSANT manual for detail An example is shown below with expanded metanodes of diseases represented using convex polygons E Network Legend ANTI PARKINSON DRUGS Non insulin dependent diabetes mellitus Adrenergic and dopaminergic agents ADRENERGICS INHALANTS Disease disease network where only collapsed metanodes of diseases are retained in the metanetwork example The correlations between diseases are inferred based on shared components genes between two metanodes or based on the interactions between components in two metanodes Breast Neoplasms gt Non insulin dependent diabetes mellitus obesity Therapy therapy network where only collapsed metanodes of therapies are retained in the metanetwork example The correlations between therapies are inferred based on shared components drugs between two metanodes ANTI PARKINSON DRUGS ais tag INHALANTS Adrenergic and dopaminergic agents Disease therapy network where both collapsed metanodes of therapies and diseases ar
4. C breast cancer cervical cancer col C breast cancer colorectal cancer C breast cancer colorectal cancer e C breast cancer colorectal cancer C breast cancer colorectal cancer 7 ts se C breast cancer colorectal cancer lien ned nrnmane antnenantnl nannanane v E lt eC D f breast car Search 2 N 2406 SN 871 E 5718 SE Bytes loaded 21850 Right click drag to PAN Mouse wheel to ZOOM Color the node associated with breast cancer in blue and ungroup the metanode of breast cancer the network shown above will becomes the one shown in following figure Note There are also menus to allow users to select genes proteins which have no disease GO annotations or drugs have no ATC classifications Filtering Nodes in a Network Based on Their Properties This approach is to filter the nodes based on the data type e g protein gene drug disease etc or visual customization e g color size shape etc Two menus have been added Nodes gt Select Deselect Nodes of The Same Properties to allow the user to select deselect nodes with the same data or visual properties based on the current node selection If the current selected node has a particular visual customization node shape size and color the menu will select deselect other nodes with the same data type and visual customization Following figures shows how drugs can be selected from a drug target network aes sF oe e
5. ae shape Expanded Mode Search 3 Pa round rectangle 20 Description Edge Properties Global Properties Saccharomyces cere w Please Register By default VisANT determines circle lf you dont have an account m FN Zz F PEACE eae eae E A gree Penge E M260 SA E296 SEO Processing command set_node_propermtj node_shape Network annotation Annotate Genes Using Disease Information Apply menu Nodes gt Disease Annotation gt Use Most Specific Disease Terms to annotate the genes for their associated diseases as the figure shown below MC2R melanocortin Gene Protein j A pA Alias ACTHR MC2R oa yae Disease Annotation j lA ta ICD1O co eTA g G 3 3 d oo amp f4 Malignant neoplasm of adrenal gland h Ty e B yo OMIM i ps S a wal ue to ACTH unresponsiveness a had Modes Guery Interaction of Selected Nodes af Edit Guery Internal Interactions Mew Update Nodes Interactions Filters Resolve Selected Nodes Name es Layout Update Selected Nodes Name save as the Image Help GO Annotation Gg Disease Annotation x 3 obesity z z f i l Label Protein Gene with Official Mame Clear Disease A iotation _ a Obesity morbid l l i select Modes of The Same Properties select Genes with NO Disease Annotate oe pof premature ovarian fai Annotate Drugs Using Therapy Information Similar to the gene annotation using the menu Nodes gt Disease Annot
6. cee cece eens 24 DOCKING windows 1 ee eee een e rererere 24 Node edge customization 6 cence tent n eens 2T Network ANNOLACION seriski iru triere 6 woneawn EEEE REEE E E 28 Annotate Genes Using Disease Information 0 000s 28 Annotate Drugs Using Therapy Information 0 0 0c cece eens 28 Prediction Functions Using Enrichment Analysis 0e eee ee 28 Prediction Associated Diseases for A Set of GeneS 0 0 cee 28 Prediction Associated Therapies for A Set of DrugS 0 cece nee 33 This user manual describes the new features available in VisANT 4 08 Manuals for the functions developed before VisANT 4 0 can be found at http visant bu edu vmanual Visualization of Disease Therapy and GO Hierarchies Using Hierarchy Explorer VisANT 4 0 add two new hierarchies in VisANT and therefore the GO Explorer in VisANT 3 5 is renamed as Hierarchy Explorer The basic functions of Hierarchy Explorer is similar to GO Explorer therefore we only highlights the new features here Toolbox ee Hierarchy Explorer Cd Hierarchical Knowledge EJ Gene Ontology 2 C1 Disease Classification C Onin PharmGKB Ez Drug Classification E3 F Anatomical Therapeutic Chemical Classification co v E As shown in the figure above there are four disease hierarchies available in VisANT which however is a temporary solution because among the four databases where disease gene
7. enrichment analysis e Ametanode representing a disease or a therapy or a GO term e g dragged from the Hierarchy Explorer as shown in the figure below Wi VisANT File opened start_up xml Ka File Edit View Filters Layout Modes Cogels MletaGraph Orthology Topology Options Expression Plugins Help Weight Cutott 1R to ig Edge Optimization Ee E a T ae Expression Plot Play Precictome v o Exp p Toolbox Network janine Hierarchy Explorer Ae E 1 Disease Classification E F International Classification of Diseases ICD 1 02529 I Neoplasms EERE E Fi AVI Congenital malformations deformations and chror T C Certain infectious and parasitic diseases 6 W hental and belagvioural disorders ix F Il meagan at the hong and Bood torning organs arnt Disease ICD1Ol Disease ll Fi iy Endocrine nutritional and metabolic diseases 500 Y Mental and behavioural disorders 63 Vi Diseases of the nervous system 334 kal contains 61 nodes with total 0 edges k3 Lili gt Drug ka B Cutott of informative terma TS Salado Y Mental and behavioural disorders General Options Cutoff of number of genes 145 Link to network Operation of drag amp drop Metanode of components onl s tii Metanode of components only o Z o YFLAMMATION AND INFECTION DETECTION TIWELAMMLATORY AGENTS a lf a node has the hierarchy information left mouse clicking will show the corresponding hiera
8. the complete list of child terms for the hierarchy term shown in the path will NOT be shown when display the path unless it has been queried before In order to know all its child nodes user can first IRT then SRERE the interested hierarchy term in the Hierarchy explorer Following figure shows the result of such operation for the term response to virus 107 Shown at the bottom of above figure as E response to other organisrn 2 19 Eb response to virus 107 z regulating host cell cycle in response to virus 0 E C response to virus 107 E cellular process regulating host cell cycle in response to virus 0 E phage shock 0 detection of virus 2 defense response to virus 29 Search Terms Using Gene Drug Names or IDs Search Disease or GO Terms Using Gene Names or IDs The search box at the bottom of Hierarchy Explorer does not support search of Disease or GO terms using gene protein names or IDs unless the name is part of the term description such as the case of p53 However VisANT does support indirect search of disease or GO terms using gene names IDs as illustrated below 1 Make sure Homo sapiens is the current species Enter the gene names IDs e g pten in the VisANT s search box in the ToolBox and click the Search button all interactions associated with pten will be shown Search pten Homo sapiens x Please Register Note in the case there is no interaction of pten it will still be
9. when VisANT runs as a local application Note partial key word is supported as shown in the figure below Note For GO GO id can be used for search it however must stat with fe such as ATALEN Toolbox Toolbox Hierarchy Explorer E F International Classification of Diseases ICD 10 2529 F Certain infectious and parasitic diseases E ll Neoplasms 362 F Ill Diseases of the blood and blood forming organs and certain disorders involving the immane mechar F ly Endocrine nutritional and metabolic diseases S00 F ET0 E90 Metabolic disorders E F ETS Disorders of purine and pyrimidine metabolizm E E730 Hyperuricaemia without signe of inflammatory arthritis and tophaceous disease F Y Mental and behavioural disorders E3 F Y Diseases of the nervous systern 334 E 200 609 Inflammatory diseases of the central nervous syster G09 Sequelae of inflammatory diseases of central nervous system E F F60 G64 Polyneuropathies and other disorders of the peripheral nervous system ER E cti Inflammatory polyneuropathy E S61 Other inflammatory polyneuropathies E 61 9 Inflammatory polyneuropathy unepecitied F GfO GF3 Diseases of myoneural junction and muscle G 2 other myopathies E S72 4 Inflammatory myopathy not elsewhere classified F YI Diseases of the eye and adnexali 58 F HOU HO6 Disorders of eyelid lacrimal system and orbit F HOO Hordeolum and chalazion i Ds v tem Gec n By default
10. with a checkbox to allow user selection of hierarchy branches If the hierarchy term appears in multiple places of the tree selecting one of them will automatically select the rest This also applies to node highlighting Different hierarchies are highlighted using different colors GO Terms under different categories are also highlighted using different color Searching the Hierarchy Searching Terms Using Key Words Select the corresponding hierarchy to search and enter the key words in the search box at the bottom of the Hierarchy Explorer as shown below The search results are the paths from the terms containing highlighted the key words to the root of the corresponding hierarchy Following figure shows the result of searching key word inflam in disease hierarchies Note usually the search will results in the hundreds in the figure shown below there are 237 paths returned or even thousands of the paths usually happens for GO hierarchy To address this challenge the searching is processed in another thread and the tree is disabled meaning you will not be able to click the tree nodes and the number of the paths being added to the tree is shown in the status bar bottom of the above figure At the same time you can still play with the network Because of the large number of the paths shown the Hierarchy Explorer VisANT may run out of the memory especially when VisANT is run as an Applet Please reference here for the solutions
11. 4lignant neoplasm of bron ichus and lung metal ion binding See PAR cine i magnesiurn ic Fes aie er d SE E protein binding 7273 AANA eoplasm of breast C protein complex bindi f ea anavan Pilev Ruyalca a amp EE H enzyme binding 1048 cone Rvsicaba syndrary J kinase binding 38 Edge s gt Y Hf protein kinas Nodgel s b a Dn amna Node s Query Interaction of Selected Nodes E FOZ domain bindi Edit gt Query Internal Interactions EE MB lipid binding 736 i gt Update Nodes Interactions catalytic activity 5361 View P Jhiological_process Filters gt Resolve Selected Nodes Name cellular_component Layout Update Selected Nodes Name Cf Disease Classification _ International Classification of Dise Save as the Image Expand Pathway J Neoplasms GO Annotation b C c15 C26 Malignant neople x l m phosphoprotein phosphat Disease Annotation y Using Most Specific Disease B E C30 C39 Malignant neople i protein eri TE p Label Protein Gene with OfficiaName Clear Disease Annotation e CETERE Sa protein tyrosine phosphate Select Nodes of The Same Properties Select Genes with NO Disea lt jil gt protein binding amp 0 00055 Deselect Nodes of The Same Properties Search i i i 2 een tyrosine serine thre porate Linke gt N 84 SN 1 E 83 SE 0 Weight lt 0 is trimed as 0 Right click drag to PAN Mouse w Y Label Note start from version 3 5 VisANT will automati
12. Associated Therpay of Metanodes gt Using Hypergeometric Test over selected Therapies to perform the enrichment analysis Only the enriched therapies will be listed in final report BLOOD AND BLOOD FORMING ORGAN Predict Functions of Metanodes Using GO a C CARDIOVASCULAR SYSTEM 643 Predict Associated Disease of Metanodes gt Shape F DERMATOLOGICALS 591 Using Hypergeometric Test over ALL Therapies ES A a E a amp r SYSTEMIC HORMONAL PREPARATIONS E E onfiguration i Pre raiie width amp r ANTINFECTIVES FOR SYSTEMIC USE 628 on Cal ANTINEOPLASTIC AND IMMUNOMODULA CA ne Color r MUSCULO SKELETAL SYSTEM 281 MUSCULO SKELETAL SYSTEM snow Ta z NERVOUS SYSTEM 818 Descript Mm Glahal Pran
13. BO SMT E107 SE 0 Edges parsed 10 Right click drag to FAM Mouse wheel to zoh To hide the docking window click the small button outlined in the small red circle upper right corner as shown in above figure One advantage of the docking windows is that they can provide increased working space when necessary as shown below Mi VisANT File opened start_up xml Mm Eg File Edi View Filter Layou Modei ooet MetaGrap Ortholoc Topoloc Option Expressie Plugin Helt SS C hs mnie ati i Weight Cutoff bs to b 1 Edge Optimization E ee Network MAPOOZ40 alwada I c00122 warono eS co0062 E marooae O ce cooose ie coo1ra Es aa C webo134 LJ HACS MBO SMO E107 5E 0 Edges parsed 107 Right click drag to PAN MOUSE wheel to lt OOh To make docking window either mouse over or click the button on the side bar as shown below Mi VisANT File opened start_up xml Network Properties Node Pro Mame Type Size C cooaz2 Color Expan a KEGG mapo Fix no mas Aaah Height eu ee Vidth Expar Label MAPOOeO Descri A Edge Pro e o HAAGS NBO SA E 107 5E 0 Edges parsed 10 Right click drag to PAN Mouse wheel to 00h Docking window will become invisible when you leave the window for several seconds or click on some other components such as the empty place in the network You can however the fix the do
14. ODUCTS INSECTICIDES 4ND REPE RESPIRATORY SYSTEM 563 C SENSORY ORGANS 630 a C OPHTHALMOLOGICALS a i i z G E A TT K w E TTR alein 67 AANTIAF GAARA TORY SGA TS E al Corticosteroids and mydriatios in combina Drug Classification ATC S501B Drug Classification a LA AMMATORY 4 gt AND ANTIN ANTINFLAMMATORY AGENTS o E PP ory agents non steroids 3 contains 97 nodes with total 0 edges VARIOUSI292 a O Plo EEE PADIOPHARMACEUTICAL E E E o Weis teas PEE peat ae eee INFLAMMATION AND INFECTION DETECTION i F Technetium 9omTc aS i P Indium 11110 compounds 0 _ THERAPEUTIC S x inflamma inflamma Search 2 M 101 50 1 E 0 SE Bytes loaded 7977 Right click drag to PAN Mouse vheel ta ZOOM saedog Interactive Visualization of GO Hierarchy in A Network Back to main manual Visualize the Hierarchies of the Node s Hierarchical Information The hierarchies of a given term is defined as paths from the term to the root of the corresponding ontology Because terms may have multiple ancestors they may therefore have many different paths to reach the root In VisANT there are three cases in which a node will have associated hierarchy information e A gene protein node with queried disease GO annotations e A drug node with queried therapy annotations e A gene protein node or a metanode of a subnetwork with predicted disease GO functions resulted from the annotation
15. The Metanode s gt rocks g _ AGING 824 Group Subnetwork as Metanode A 9611 al CANCER 20216 Network Transformation gt y ines C CARDIOVASCULAR 1182 Go annotation of All Nodes j en C CHEMDEPENDENCY14809 Resolve All Nodes Name VA sag 5728 we 7y 4 N _ DEVELOPMENTAL 2437 Predict Functions of Metanodes Using GO gt A A ibe yar C HEMATOLOGICAL 1216 i Predict Associated Disease of Metanodes gt Using Hypergeometric Test over ALL diseases Databases IMMUNE 11637 y i K Using Hypergeometric Test over Selected Disease Branches 2 Configuration C INFECTION 8077 a 7 The enriched diseases will be listed in the browsers Similar to the previous result breast cancer and some of other cancers are also overrepresented os e IsANT Disease Enrichment Analysis Metanode 5720 Total number of tested diseases 12794 FDR cutoff 0 07 Database Disease Name P Value FDR esophageal adenocarcinoma 1 35 11 breast neoplasms 2 1E 11 rectal neoplasms 2 7E 11 squamous cell carcinoma microsatellite instability breast cancer colorectal neoplasms retinoblastoma retinal neoplasms stomach neoplasms neoplasms second primary neoplasm metastasis ovarian neoplasms endometrial cancer pancreatic cancer thyroid neoplasms epithelial ovarian cancer esophageal neoplasms precancerous conditions lung cancer adenocarcinoma papillary carcinoma squamous cell colorectal cancer pancrea
16. Thick K i oe Disease E E a FDR c 0 01 ra sel Fa ly User Defined Label enne D aa go The user defined label of node Ds Mera SRh1 6 63 SEO Edges parsed 83 Rightclick drag to PAN Mouse wheel to 200M j KA ee 2 If the imported genes do not contain any disease information then we will have to annotate those genes using VisANT platform First select all genes and then select Node s gt Disease Annotation gt Using Most Specific Disease Terms from the right click menu to perform the disease annotation function for all genes VisANT will automatically annotate genes by using the disease gene associations available in the public databases such as KEGG GAD OMIM and PharmGKB Al VisANT Open File breast drivers_2 co fee File Edit View Filters Layout Nodejs Edge s MetaGraph Orthology Topology Options Expression Plugins Help Wel ee E Weight Cutoff 055 to _ Edge Optimization i T 4 Sait Properties Breast Cancer Drivers arn laan 2 E RE op j Sho w om oss ae a y i 19511 4 fi oz 5 z5 Size Auto Cancer Drivers DP L i 2525 Color le a Poe Pos Auto 6926 ka A A 15728 dylem oh 7 2 Sie Mode s i Query Interaction of Selected Nodes LIL epe Edit Query Internal Interactions View Update Nodes Interactions Edge Prop Filters Resolve Selected Nodes Name he Layout Update Selected Nodes Name Weight 0 0 as my Color Save as the Image Sm Show
17. VISANT 4 0 User Manual Contents Visualization of Disease Therapy and GO Hierarchies Using Hierarchy Explorer hae E E E E E E E E E E E A ewes 2 Navigation of Hierarchi S 0 00 ccc eee eee een eens 2 Searching the Hierarchy x ww Gar kotew toon 4c 07 2 8 He ba Wb Eh We eae we Oe ee ae 5 Searching Terms Using Key Words 0 ccc cece cence nenee 3 Search Terms Using Gene Drug Names or IDS cece cece ccc ceeeeeeeeees D Search Disease or GO Terms Using Gene Names or Ds 0465 5 Search Therapy Using Drug Names or IDS 0 0 06 0c tenes T Search Genes and or Their Interactions Using Key Words 0000 T Search Genes Using Key Words of Diseases 0 ce eens fi Search Drugs Using Key Words of Therapy 0 cen eens 9 Visualize the Hierarchies of the Node s Hierarchical Information 9 Netvork Transi ormat Oh 4 4 a b 0 cca ao ece da ps are g ae sb Oe i eee ae ee eee ad 11 Network Ome iC CI O eeen a a ak argu E ahs eect E a ee 13 Enhanced Network Filtering cus ack os uh Sob ad aot sneen ennenen nornerne om OO OS 18 Filtering Network Using Biomedical Knowledge 0000een eae 18 Filtering Nodes in a Network Based on Their Properties 065 21 Enhanced Topological Analysis 0 0 ee ee ec eee ee ee nee eee ee eas 21 Network Nie SOI ore ace tras o ask riire ts AEN ERE EAA E Ree D EA 29 Enhanced Graphic User Interface UI ccc cc
18. anded The appearance of the legend node as well as its embedded node can also be customized like any general node Following figure shows an example Mi VisANT File opened start_up xml Mea Go Sio e E E F h Network Legend Network m BAS F en ela le Vemegs t i GeneProtein det Statistic Report wi Gene Protein a 4 Toolbar diamond metanode is locked ig GeneProtein Look amp Feel b __ Gene Protein Ppa Preference b Gene Protein Clear Zoom Back wi Gene Protein Reset Fitto Page I Gene Protein i OY senesFrotein Search 7 OD cenerProteir round rectangle 20 42 2 i his salladqd J L a a as ee ater Wh neni O Processing command setnode_property node_shape Here is another example where drug nodes are sized based on the number of targets Enhanced Graphic User Interface UI Docking windows There are two docking windows in this new release ToolBox Hierarchy Explorer by default is visible property window a window that is used to customize the node edge as well as global properties as shown below Mi VisANT Bile ee oe ott up xml Tooo Hierarchy Weight Cutoff oolbox Toolbox Labels w Auto Fit W Quick Tip Help Select Zoom Pan zoom Out Gear ZoomBack Reset Fit to Page I Search e e 1 maroo oOo a ee L Y co0624 PEDOT NAGS SAT M
19. associations are collected only KEGG Disease database adopts ICD 10 International Classification of Disease The other disease databases will be integrated into ICD 10 whenever possible The number of annotated genes e g 2529 for ICD 10 will only be shown when the tree node is expanded Note it is recommended that the current species to be set as Homo sapiens so that the number of disease associated gene or therapy associated drugs e g there are total 2529 genes annotated in ICD 10 will be shown correctly disease and drugs are for Homo sapiens only Note the hierarchy can be saved as image through the popup menu with right mouse clicking Note hierarchy information is retrieved from Predictome database that is synchronized with GO database monthly Disease gene drug therapy and gene GO association are also synchronized with corresponding database monthly Navigation of Hierarchies Clicking on the expansion symbol or double clicking over the tree node will expand collapse it A database query will be sent to the VisANT server to retrieve the node s descendents The number shown in for each tree node indicates the total genes annotated under this hierarchy branch for the current species Other information such as the number of genes directly annotated under the term is shown in the tooltip by a mouse over of the tree node Note When the species changes these information will change accordingly Each tree node is associated
20. ation gt Use Most Specific Disease Terms The annotation will be part of drug description available in tooltiowhen mouse over the node Prediction Functions Using Enrichment Analysis Prediction Associated Diseases for A Set of Genes With the latest release of the VisANT 4 0 users can easily perform a disease enrichment analysis on any input gene sets In the following tutorial we will use the breast cancer driver genes published by Gray Joe and Brian as an example to demonstrate how to determine the overrepresentative diseases in VisANT 1 First load gene set network into VisANT Here total 40 driver genes are imported and formed a signal metanode in VisANT Multiple gene sets can be imported into VisANT at the same time In this case each gene set must be presented as an individual metanode in VisANT a VisANT Open File breast drivers_2 ef File Edt View Filters Layout Hodeis MetaGraph Orthology Topology Options Expression Plugins Help Weight cutott o to 4 j C Edge Optimization moe en x Network Properties nt a i Expan auto Breast Cancer Drivers P z o fi Sho 1 _ ie Label Ls Cancer Drivers size 25 g amac a g S r col MetaNode 5720 00 0 oon are Above contains 40 nodes with total 0 edges A UA Styli IG u A TAD l f a34 Descri Edge Prop WDE i i 1027 ane IE Baas rD 4 p 208 Global aa a Edge fe j Ji Pe ell Exclud soz KY a L A 27
21. cally resolve the name of user added nodes when query the GO annotation 3 Although it is convenience to display the annotation of hierarchy it does impact the performance and you may want to turn off this function simply uncheck the checkbox Link to network in the configuration panel of Hierarchy Explorer as shown below Metyyork HE Toolbox Toolbox Hierarchy Explorer 2 Hierarchical Knowledge A 2 1 Cene Ontology E C molecular _tunction E J binding14914 ee lt fl lt op General Options Cutott of informative terms Cutoff of number of genes Linkto network Detautt LJ Interaction PTE Operation of drag edrope oe Note The configuration panel can be activate deactivated by the small button circled in above figure Search Therapy Using Drug Names or IDs The menu Nodes is context specific When the selected node is drug node there will be a menu Therapy Annotation instead of menus of GO Annotation and Disease Annotation as shown in the following figure is Node s Query Interaction of Selected Nodes Edit b Query Internal Interactions Wiew Update Nodes Interactions Filters b ResoWe Selected Nodes Name Layout b Update Selected Nodes Name save as the Image Therapy Annotation sim Most Specific Disease Term Help t Label Protein Gene with Official Name Clear Disease Annotation oo Select Nodes of The Sa
22. chy Explorer o 1 Hierarchical Knowledge Gene Ontology Disease Classification Drug Classification General Of Cutoff of inf Cutoff of n pw Link to network l ation of drag amp drop Aal Metanode of existing components or As an example the figure below shows how to find out the genes that are associated with breast cancer in the drug target network The association of genes with breast cancer is predicted by the GAD database the filtering starts with the drag amp drop of the term breast cancer in the GAD hierarchy to the drug target network as shown below Default I Mi VisANT Open File NAR2013_figS3 xml fL fox Fie Edit View Filters Layout Node s Foce MetaGraph Orthology Topology Options Expression Plugins Help __ Weight Cutott f to 1E C Edge Optimization EE O 4 Expression Piot Play Preaictome Exp Exp 10 Toolbox Network Hierarchy Explorer J Hierarchical Knowledge C Gene Ontology CJ Disease Classification Intemational Classification of Diseases salwedold 1 GAD CANCER at benign breast disease breast orl al breast and colorectal cancers Oe hreact and time cancer 4 7 breast cancer 879 breast cancer and body mass C breast cancer breast cancer mal C breast cancer breast disease be C breast cancer by the age of 50 y C breast cancer cancer colorectal c C breast cancer cell proliferation u
23. cking window by clicking the small button red circle shown in above figure Node edge customization One key purpose to implement the docking window in VisANT is to make the properties customization easier and extensible As shown in the above figure the properties window is in the style of spread sheet with common user convention to make it easier to use When node s edge s are selected all corresponding properties are editable except those that are grayed Properties are grouped and these groups can be collapsed expanded As shown in the figure below Edge properties and global properties are collapsed while node properties are expanded in which properties of node label are however collapsed As also shown in the figure below the column width can be changed in case the name of property is too long Clicking on each property row will also display the detailed explanation as shown for node shape in the figure below Mi VisANT File opened start_up xml E mlx File Edit View Filters Layoul Node s ooe s MetaGrapl Ortholog Topolog Options Expressio Plugins Help Weight Cutoft oH tof 1 C Edge Optimization i oe 4 O ze li E g pi l I L Ao A Exp 10 Toolbox Network Properties Toolbox HierarchyE Node Properties saladdd Labels Auto Fit Fi F p diamond metanode is locked Size h Quick Tip Help Color Son FF Sehr Expansion Syr Pan Zoom Out KEGG Symbolik Fix node position Fit to Page
24. e retained in the metanetwork example The correlations between therapies are inferred based on integrated drug target associations ANTI PARKINSON DR G Adrenergic and dopaminergic agents Breast Neoplasms Ell Non insulin d ependent diabetes mellitus F a gt ADRENERGICS INHALANTS obesity Disease gene network where metanodes of diseases are transformed through the menu MetaGraph gt Network Transformation gt Create Bipartite Graph and metanodes of therapies are discarded in the metanetwork example An edge between a gene and a disease indicate that the gene is known to be associated with the disease wl F P ams e reast 3 Ell Non inSayp Be nder d S mellituy Rin 5050 3a a S i a Therapy drug network where metanodes of therapies are transformed through the menu MetaGraph gt Network Transformation gt Create Bipartite Graph and metanodes of diseases are discarded in the metanetwork example An edge between a drug and a therapy indicates that the drug is known to be part of the therapy Co disease gene network where metanodes of diseases are transformed through the menu MetaGraph gt Network Transformation gt Create Co Metanode Network and metanodes of therapies are discarded in the metanetwork example An edge between two genes indicates that both are known to be associated with the same disease Co therapy drug network where metanodes of therapies are transformed through th
25. e menu MetaGraph gt Network Transformation gt Create Co Metanode Network and metanodes of diseases are discarded in the metanetwork example An edge between two drugs indicates that both are known to be associated with the same therapy Disease gene drug network where genes in the disease gene network are queried for the potential drugs targeting them sgo ts ee a x Breast opias gt DI p ote Pit r isai mellitusa re m Non insi 5 A e w oe fg eo 4 Jal seen a on CJ o 9 o Therapy drug gene network where drugs in the therapy drug network are queried for their targets f L E z a i u j oO Disease gene drug therapy network where metanodes of both diseases and therapies are transformed through the menu MetaGraph gt Network Transformation gt Create Bipartite Graph Drugs are queried for their targets and genes are queried for the drugs z os n G I digi J er pdiabetes mellitus Enhanced Network Filtering Filtering Network Using Biomedical Knowledge This approach is to filter the nodes based on their annotation GO annotations and disease classifications for genes proteins and therapy classifications for drugs For a given network this filtering is carried out through the drag amp drop operation with the option Metanode of existing components only as shown in the following figure Toolbox Toolbox Hierar
26. e or more metanodes are selected by the user then VisANT will only perform the enrichment analysis on the selected metanode s Eca MetaGraph Orthology Topology Options Expression Plugins at Grouping Predictome x Duplication g MetaNode Properties ee uum MetaEdge Buk i Expan auto Layout Onty in The Metanode s gt Only in The Metanode s Fa 5 Sho Label Group Subnetwork as Metanode A Us erase once Network Transformation Size 24 7525 Color GO Annotation of All Hodes Bae anam Resolve All Nodes Name P a G vl Configuration WE Using Hypergeometric Test over Selected Disease Branches a0 19 5 The analysis will take a couple minutes depending on the size of the gene set After finishing the result will be shown in the browser Only the over presentative diseases will be listed in the report and the diseases will be grouped by the database In this example not only breast cancer but also other types of cancers are enriched in this gene set It is because many of genes in this genes set may also contribute to other cancers Metanode 5720 Total number of tested diseases 17457 FDR cutoff 0 07 Database Disease Name P Value FDR C56 Malignant neoplasm of ovary 5 1E 11 C16 Malignant neoplasm of stomach 085 Phakomatoses not elsewhere classified C23 Malignant neoplasm of gallbladder C25 Malignant neoplasm of pancreas C2 Malignant neoplasm of liver and intrahepatic bile ducts C34 Malignant neoplas
27. ee ae Models Lluery Interaction of SE hades Edit Query Internal Interactions flew Update Nodes Interactions Filters Resolve Selected Nodes Mame Layout Update Selected Nodes Name save as the Image Help GO Annotation pr cigs eee oe oe Therapy Annotation Teves y age E Bobs oie Label ProteinSene with Official Name co 4 Sua m jga sz select Nodes of The Same Properties Pe er a Se Deselect Nodes of The Same Properties DP ag pe Available Links he dew Label w n select Linked Modes Delete Selected Nodes o ee Enhanced Topological Analysis It is important for many topological analyses to be performed on a specific type of node ina network with multiple node types From this perspective the functions of these analyses have been enhanced to allow them to be applied on a select subset of the nodes In this way we will be able to for example easily find out which drugs have most targets and which genes are being targeted by the most drugs through the degree distribution in the drug target network The global statistics of the network including degree distribution and clustering coefficient distribution has been upgraded to work on selected nodes only if there are select nodes otherwise they will work as before Following example show how to create a degree distribution for the drug nodes only in combination with the new filtering functions VisANT Degree Distribution Sel
28. m of bronchus and lung C41 Malignant neoplasm of bone and articular cartilage of other and unspecified sites C15 Malignant neoplasm of oesophagus C32 Malignant neoplasm of larynx C54 Malignant neoplasm of corpus uteri C90 Multiple myeloma and malignant plasma cell neoplasms Co Malignant neoplasm of bladder C458 Malignant neoplasm of placenta C92 Myeloid leukaemia C91 Lymphoid leukaemia C83 Non follicular lymphoma C46 Kaposi sarcoma QST Other specified congenital malformation syndromes affecting multiple systems C44 Other malignant neoplasms of skin C43 Malignant melanoma of skin C73 Malignant neoplasm of thyroid gland C51 Malignant neoplasm of vulva f80 Family history of malignant neoplasm 6 In some cases a user may only want to test certain diseases Those diseases need to be specified by selecting the disease s from the Hierarchy Explorer Then select MetaGraph gt Predict Associated Disease of Metanodes gt Using Hypergeometric Test over selected Diseases Databases to perform the enrichment analysis In this example we will test if any GAD Cancer is enriched in our gene sets IT Open File breast drivers _2 ESE it View Filters Layout MetaGraph Orthology Topology Options Expression Plugins t Cutoff o to 1 C Edge Optimizati Grouping gt Predictome v Duplication gt Netwo MetaNode R Properties X Hierarchy Explorer MetaEdge Drivers 5 P C GAD 110862 Layout Only in
29. me Properties Select Genes with NO Disease Ann Deselect Nodes of The Same Properties Available Links b Label The rest functions are same as disease or GO annotations for nodes of genes Search Genes and or Their Interactions Using Key Words Search Genes Using Key Words of Diseases In VisANT 3 5 users are able to search of genes and or their interactions using key words of functions based on GO annotation In VisANT 4 0 genes can now be searched using key words of disease as illustrated below 1 Inthe search box of Hierarchy Explorer select Disease as the target hierarchy for the searching and enter the key word such as breast cancer and click Search button for detail following the session Searching Terms Using Key Words 73 paths appears Mi VisANT File opened start_up xml x File Edit View Filters Layout Models Edges MetaGraph Orthology Topology Options Expression Plugins Help Weit cutott og to 15 Let Optimization ume eosin Pt Pay Toolbox Toolbox Hierarchy Explorer Exp 10 Metwrork breast cancer paclitaxel pharmacokinetics C PSYCH C REPRODUCTION Oni Salado 4 WB Macrocephaly autism W Malignant melanoma somatic adl E3 h bol peast cancer He oe Ds breast Gea MG SM5 E0 SEO Bytes loaded 317 Right click drag to PAM Mouse wheel to Z00M 2 s3 The OMIM database annotated 5 genes for breast cancer Drag the term from Hierarchy Explo
30. o transform the network represented by metagraph to facilitate the study of the network from different perspective The two functions are available under the menu Metagraph Network Transformation One transforms the metagraph to bipartite graph between metanodes and the nodes embedded In the case of disease network it facilitates the study disease gene association from the point view of an interaction network as shown below carcinoma pancreatic ductal cervical neoplasm colon cancer carcinoma non small cell lung carcinoma p mi ri al Fi Fi Fi Note The edge color is determined by the color of corresponding metanode The other transforms the metagraph into a co metanode interaction network i e it creates an interaction network between components embedded in a metanode In the case of disease network it creates an interaction network of co disease genes where an edge between two genes indicates that they are associated with the same disease as shown below carcinoma pancreatic ductal cervical neoplasm carcinoma non small cell lung ps ie Note The edge color is determined by the color of corresponding metanode Network Construction With the full advantage of its metagraph implementation and the new network transformation functions VisSANT 4 0 supports the convenient construction of 11 total network types to support the network analysis between disease therapy modules gene and drugs etc
31. rchies of associated terms in the Hierarchy Explorer if the Link to network option is selected as shown in the figure above Because a node may associated with multiple terms and terms have multiple paths therefore the visualization of hierarchies takes a little time to finish and is carried out ina new thread Visualization of hierarchies of another node is prohibited unless the previous task is finished In addition users will not be able to expand collapse the tree during the visualization process The status of the visualization process can be checked at the status bar such as shown below M 163 5M 1 E 0 SEO Displayed toal 15 paths of the hierarchy tree Note when there are too many expanded terms always use the popup menu Collapse All to clean the GO tree through right mouse clicking Note Uncheck the Link to network option in the configuration panel to enhance the performance Updated Exploratory Navigation Starting from an initial gene drug of interest exploratory navigation allows you to walk through the interactions one by one The interactions between genes are either physical or genetic and the interactions between genes and drugs indicate the corresponding binding targets of the drugs Following figure shows an example starting with gene CACNA1D Please reference this macro link for the exploratory navigation of nteractions The result of this macro is shown below Network Transformation VisANT 4 0 provides two function t
32. rer and drop into the network panel A metanode of the disease with all 5 embedded genes will be created Note before drag the network make sure that the options click the expansion button near the search button shown below of the drag amp drop operation are set as shown below ti gt General Options Cutott of informative terms T5 Cutott of number of genes 145 Link to network Operation of dragedrop Metanode of components only od Note To drag a term first left click on it then drag it to the network If interested query of all Known interactions of 5 genes are illustrated in the figure below or user Can query interactions between 5 genes only Search Drugs Using Key Words of Therapy Simply change the hierarchy to be searched to Drug and following the same procedures to search genes using key words of diseases Following figure shows an example using the key word inflammatory W VisANT File opened start_up xml File Edit View Filters Layout Nodefs Edgels MetaGraph Orthology Topology Options Expression Plugins Weight Cutoff ig Fs ok to if F Edge Optimization p p pi Expression Plot Play Precictome x Wo Ep Ezp 10 Toolbox Network Toolbox Hierarchy Explorer C ANESTHETICS 82 SNALGESICS 153 C ANTIEPILEPTICS 53 C ANTLPARKINSON DRUGS 52 C PSYCHOLEPTICS 249 C PS CHOANALEPTICS 1 6E _ OTHER NERVOUS SYSTEM DRUGS 63 4 C ANTIPARASITIC PR
33. shown in the screen so long as this gene exist in Entrez Gene database Alternatively you can add this gene to the network as shown below 2 Select the node pten and query its disease annotation using the menu Nodes gt Disease Annotation gt Use Most Specific Disease Terms and then annotate pten with GO annotation by the menu Nodes gt GO Annotation gt Use Most Specific GOTerms The associated disease and GO annotations will be available when mouse over the node And the corresponding hierarchies of these annotation will be shown in the Hierarchy Explorer when clicking on the node as also shown in the figure below Note For illustration purpose some of the associated annotations have been removed Mi VisANT File opened start_up xml fc ex File Edit View Filters Layout Nodefs Edgels MetaGraph Orthology Topology Options Expression Plugins Help Expression Plot Play Predictorme v Weight Cutott 0 S to 1 C Edge Optimization p No Exp Exp 10 Toolbox Network D L O Jerr v p 3 Toolbox Hierarchy Explorer Pp EN phe tase GeneiProtein 2 a ipere hica Know iedoe a C GLM2 MGC11227 MHAM MMAC1 PTEN PTEN lB CJ Gene Ontology tation C molecular_function i S Jbindingl 11914 E Jion binding 4011 ignant neor Sa iver and intrahepatic bile ducts cation binding 4002
34. sociated Therapy of Metanodes gt Using Hypergeometric Test over All Therapies from the menu aan MetaGraph Orthology Topology Options Expression Plugins o Predictome Properties Mode Prope ti Grouping Duplication MetaHode MetaEdgye Layout Only in The Metanode s b Group Subnetwork as Metanode Network Transformation b GO Annotation of All Nodes KEGG 3 Resolve All Hodes Hame Predict Functions of Metanodes Using GO Predict Associated Disease of Metanodes 10 Y YA Using Hypergeometric Test over Selected Therapy Branches A My Configuration s A hd oy When there are more than one metanode gene set available and none of them are selected by the user VisANT will perform the enrichment analysis over all possible metanodes The analysis of each metanode is independent to each other and the result will be listed separately in the final report In contrast if one or more metanodes are selected by the user then VisANT will only perform the enrichment analysis on the selected metanode s 5 The analysis will take a couple minutes depending on the size of the drug set After finishing the result will be shown in the browser Only the overrepresentative therapies will be listed in the report 6 In some cases a user may only want to test certain therapies This can be done by re selecting those therapies from the Hierarchy Explorer After selection then select MetaGraph gt Predict
35. tic neoplasms neuroma acoustic neuromas acoustic neoplasms Prediction Associated Therapies for A Set of Drugs With VisANT 4 0 users can perform a therapy enrichment analysis on any input drugs The procedure is similar to the disease enrichment analysis describing in the previous section 1 First users can load drug sets network into VisANT or add new drugs into the network directly by drag and drop drugs from the Hierarchy Explorer All available drugs are organized by the Anatomical Therapeutic Chemical ATC classification in the system Drugs in the same drug set must be grouped into the same metanode Multiple drug sets are allowed In this case each drug set must be presented as an individual metanode in the network 2 If the imported drugs do not contain any disease information then we will have to annotate those drugs using VisANT platform First select all drugs and then use the annotation function from the right click menu Node s gt Therapy Annotation gt Using Most Specific Therapy Terms to add the therapy annotations for all drugs 3 The default FDR cut off value of the enrichment analysis is 0 01 Before starting the analysis we can adjust this value from the property sheet to any desired value FOR cutoff 0 01 Therapy Ent FOR cutotf 0 01 ALS FDR cutoff 4 The therapy enrichment analysis can be started by clicking on MetaGraph gt Predict As
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