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1. New from the menu bar or the Load Data from the tool bar An input data file for OPTricluster is a tab delimited text file which consists of gene symbols time series expression values and optionally spot IDs Spot IDs uniquely identify an entry in the data file and if they are not included in the data file then they will be automatically generated While spot IDs must be unique the same gene symbol may appear multiple times in the data file corresponding to the same gene appearing on multiple spots on the array rs A galii i A ee vk Tet Genen Ki E B ce mg Sa Sood Termi lt p Cas Hie i en ly Se B Rp isis J Frenn Peri Bf Ps Ee eee seg koe A r A otev eech a reat ent AC topp Fini aiga Pumin dir E e a k wd c d E F G H j j i i ml A oO I Spot ts ARA Dh ARG Zb ARLE Eh Cold ob Coad Zh Cod Eh Dew Dh Dr A P Cry Wal P Pde n Adee 10 SZ Spot_l ATE LOR LLG PAMI Be ree Le LAGER Le IIJ PLO ORS BS PLO Dae ee A Spot SATEGGLIPG TADS Leese TST PA Bee Pe Se SOS PLS Sea ee HET 2 Spot STEI EE ap Ee Tg TEAT Tee BARITA MIHE SORE 93121 TLS MISAO LAM SASS A Spnnt 8 ATIGOGPLE UL ea Be he ee ATLITI JHE ELIS eee HHIHH RS LS MAAL bee 1 eee D spota ATER TALAL ATILLE DAJATI SRA Oe MDH Sees OSS Oe eee ee Dro 2 App D ATHA TARJA TAH pnia E E Tee ORS SSE SRS A AEMTmTE SLES TALIESIN S ee ele TA BR Spot ATIGA SAREE FSS PSR RET SS Se eS ST Le ee ee 3 Spot BR ATIGA LO Aaa Ha ILLAT DEBET IGDERLIE ILHA SSS ELETE MLATITI Sea2. 1 contains several command buttons which in some cases are short cuts to the menu items of the menu bar Table 1 Description of the OPTricluster tool bar Information relative to the current version of OPTricluster HI 2 menu bar The menu bar Table 2 contains four menus it can be used to access the functionalities of OPTricluster Table 2 Description of the OPTricluster menu bar the last one open Refresh Close Exit Exits OPTricluster close all the open OPTricluster windows Open Data with Excel Opens the table data in excel Histogram Distribution of the input data New Allows the user to load new dataset for analysis Testing Loads datasets that can be used to test OPTricluster Update Allows the user to update the Gene Ontology and the species annotation files About OPTricluster Information relative to the current version of OPTricluster Licensing Information relative to the license of OPTricluster Quick Tutorial Quick tutorial in PDF format User manual in PDF format z II 3 working space The working space is reserved for displaying the results at each step of the analysis in the form of tables OPTricluster gt Order Preserving Triclustering Algorithm User Manual v1 0 IV Data Analysis with OPTricluster IV 1 Expression data info Once the OPTricluster is launched the OPTricluster input interface appears Figure 1 above From this screen a user specifies the input data file using the Data gt
3. Dee Lee DD Spot a ATIGI SSS NENI 34S MAASTA ROSI ST RIIAS BART LST ELET R nIREA H Spot IG ATHE 3 a E Ar Madian A7 Tee BERIT OFS 0a SS BOS Pe 32900 aT OP Se TIE k nnt LS STEE pa Te JMA TIAE EJIE BES TLS BS Ee Be BSS eT Eee ES Spotl ATLSE oa Leas 8 Se SMT rH B22 TIT See ee Oe Be BSE ero eee L Spet_li ATLGERIS ED Sgr Ri ILAHA LES IDB Lee ASS PSE OSS Se eS ILLAS eee LS Spot_la STEGLe o TASS De LSE JR LL Ee ee LL WEES RES LINATE HALG Figure 2 Above is a sample input data file 3D time series gene expression data when viewed in Microsoft Excel The first column SpotID is optional When included the SpotID box located on the OPTricluster input data file must be checked DEE ee P WE rm rm rr H E s FS Figure 3 OPTricluster input interface showing the OPTricluster input data file when Data gt oie New or Load Data is selected The Spot ID box must be check if the data contains a SpotID column Figure 2 OPTricluster gt Order Preserving Triclustering Algorithm User Manual v1 0 A sample data file representing a 3D time series gene expression data as it would appear in Microsoft Excel is shown in Figure 2 The first column is optional and if included contains spot IDs If the data file includes the spot IDs column then the field Spot ID in the OPTricluster input Data File must be checked Figure 3 otherwise the field must be unchecked The next column or the first column 1f spot IDs are not included i
4. GO Analysis button 12 OPTricluster gt Order Preserving Triclustering Algorithm User Manual v1 0 IV 3 2 Divergent patterns Divergent patterns correspond to groups of genes that behave differently in at least one sample along the time point experiments Their exploration 1s similar to that of conserved patterns This is done by selecting Divergent Patterns from the Patterns Exploration drop down menu Figure 15 shows an example of such patterns Figure 15 Example of divergent patterns exploration The patterns are constant in the first three samples first three chats but different in the last one the last chart IV 3 3 Constant patterns Constant patterns are like conserved patterns but unlike them their expression level stay unchanged across experimental time points Their exploration 1s carried out similarly to that of conserved patterns This is done by selecting Constant Patterns from the Patterns Exploration drop down menu Figure 16 shows an example of such patterns 13 OPTricluster gt Order Preserving Triclustering Algorithm User Manual v1 0 Miei e _ ll O r E EEE a cl ee T ae Figure 16 Example of constant patterns exploration In this example the patterns are unchanged in the four samples four charts V Integration to Gene Ontology GO Analysis button In a post processing step OPTricluster also makes use of external Gene Ontology files OPTricluster can download th
5. OPTricluster gt Order Preserving Triclustering Algorithm User Manual v1 0 OPTricluster Order Preserving Triclustering Algorithm User Manual Version1 0 Alain B Tchagang alain tchagang nrc cnrc gc ca Ziying Liu ziying liu nrc cnrc ge ca Sieu Phan sieu phan nrc cnrc gc ca Fazel Famili fazel famili nrc cnrc gc ca Knowledge Discovery Group Institute for Information Technology National Research Council Canada 1200 Montreal Road Ottawa ON K1A OR6 Canada 2012 OPTricluster gt Order Preserving Triclustering Algorithm Content II HI IV VI VII TM GO UNC COM EE I 1 OPTricluster clustering method overview ECD OPT e E E IS EE ue E Wonca OE iene een ieee eee Runnin e OP RT E loput Vu ET ee HE2 Re AE d WW OI EE Data Analysis with OPTricluster sssseecccocssssccccccssssssececoooosssssceesoosssssscecssssssssssee Mh Expression data IOl EE IV 2 OPTricluster input parameters mterface cc ceeeeeeeccccceeeceeeseeeeeeeeeeeeaas IV Exptorme OP THclister patterns EE De e Ee Re HERR KE E E WK Constant Eu eeen T dat eos EE Integration with Gene OntolOQy cccccssscccccccccccccccscssssssssssssssssssssccccccsssssseees Ree ER WIth BRCCC MAP E Referent Scn User Manual v1 0 GO N On OU JS RWWNN FF OPTricluster gt Order Preserving Triclustering Algorithm User Manual v1 0 I Introduction OPTricluster stands for Order Preserving Triclustering Algorithm a software package des
6. a 1 6 or later is not currently installed then it can be downloaded from http www java com e To install OPTricluster simply save the file OPTricluster zip locally and then unzip it This will create a directory called OPTricluster e To execute OPTricluster in Windows with its default initialization options simply double click on the file runOPTricluster_Windows in the OPTricluster directory e To execute OPTricluster in Linux with its default initialization options simply double click on the file runOPTricluster Linux in the OPTricluster directory e To execute OPTricluster from a command line change to the OPTricluster directory then type java mx1024M jar OPT Jar e By only double clicking on the OPT jar file in the OPTricluster directory or type java OPT jar in the command line OPTricluster will run without its defaults initialization options HI Input Interface The first window that appears after OPTricluster is launched is the user input interface Figure 1 which includes three sections the menu bar the tool bar and the working space menu bar toolbar a tool bar working space Figure 1 Main user input interface of OPTricluster software It is the first screen that appears when OPTricluster is launched It is divided into three sections the menu bar the tool bar and the working space OPTricluster gt Order Preserving Triclustering Algorithm User Manual v1 0 ILL tool bar The tool bar Table
7. bi LAKE D OH Di fi Fe DI db Di RIP DI Alb DI ot Bed BE Di an BS ME EI UTENS 1 ARIES Figure 18 Gene Ontology analysis results table The user can exploit the functionalities already integrated to the GOAL software to manipulate the table This could be through the file menu or by double clicking in a cell GO term for example to see its description or on gene count cell for the gene lists associated to the GO term VI Integration to the JFreeChart Library Portions of the interface of OPTricluster are implemented using the JFreeChart 4 library This library is mostly used for graphing Pie Chart Bar Chart XY Plot etc The user can use the 15 OPTricluster gt Order Preserving Triclustering Algorithm User Manual v1 0 rich functionalities provided in JFreeChart to manipulate the charts This is done by right clicking on the chart and exploring the chart using the dropped down menu Figure 19 Bar Chart Expression Values Distributions 8 000 7 000 6 000 3 000 4 4 LOL 7 e oom H Both Axes 3 000 Zoom Out Domain Axis Auto Range Range Axis 7 000 1 000 4 Sacks g 1 1 E 10 11 Expression Values CA H e H Oo ke L La Hu el E Figure 19 Manipulation of the JFreeChart charts by right clicking on the plot and exploiting the dropped down menu to manipulate the chart This includes changing the properties of the chart copying saving printing and z
8. ckable By double clicking click twice in one of these cells a new data table appears below it Figure 10 We call this new table Ranking Table Ranking Table describes the set of ranking patterns their percentage and their statistical significance p values computed using the methodology describes in 1 OPTricluster gt Order Preserving Triclustering Algorithm User Manual v1 0 Figure 10 Example of the OPTricluster interface when a pattern to be explored is selected and a subset of sample selected double clicking twice in a row of the Sample Table showing the Ranking Table Furthermore each cell of the first column of the Ranking Table is clickable By double clicking click twice in one of these cells a new table appears below it Figure 11 This new data table is the Cluster Table The Cluster Table describes the set of genes that belong to this group their expression level sample sets and time points eee 2 f Figure 11 Example of the OPTricluster interface when a pattern to be explored is selected Conserved Patterns Selected a subset of sample selected double clicking twice in a row of the Sample Table and a ranking profile selected double clicking twice in a row of the Ranking Table showing the Cluster Table 10 OPTricluster gt Order Preserving Triclustering Algorithm User Manual v1 0 At each step along the way via the Open Table in Excel button that appears under the Samp
9. e Gene Ontology gene annotation files directly from the websites of the Gene Ontology 2 This is done using the menu Data gt Update gt Gene Ontology for the ontology files and Data gt Update gt Species Annotation Files for the species annotation files This can also be done using the Update Annotations or the Update Gene Ontology File buttons located on the OPTricluster GO analysis input parameters interface Figure 17 Thi HI Hu j Siit 02756 Hu 2575 Ou Ou S i 0 1358 Hu yi Wait oo ij WS Oo E ag n f T Jet Gop bor in Ee 110 Sc 00 Chiles Ai Fie Dep Selec Soutien Ramee borate ze cl Teraa J i 04070 00 z em e i az ven DI Whe Ou AY Tr VW r T mm al 1 Lop Logg vg Gaia Cnmotogy Haach ta jI 019 Ou per 1276 OS Du fi 307 O23 Wie ug Binal iene Onley Pen 10i 3 Lu gg ep SESCH te I T ig 1111 1 Hu rem Hambar r este i mere i 744 bear oo Oi d 0191 H Ji O06 Haz 00 Ba irra i H sp i iii Woes oo i j ps Seii n Huez H EE E EES EG L G i Late 7 o Polis Derim Deotardn FOR Jj i23 Liz Oo NIE 255 0 0 10 DU Ou Utsi pe Geste Oreokote Te Jl Li Oo GE Dap Ou D r u H Ep j i O55471 _ 00 Figure 17 OPTricluster GO Analysis input parameters interface 14 OPTricluster gt Order Preserving Triclustering Algorithm User Manual v1 0 The GO Analysis button that appears at each step of the analysis allows the user to perform the gene ontology analysis of the current res
10. igned for clustering visualizing and studying similarities and differences between samples in terms of temporal expression profiles in 3D short time series gene expression data 2 4 samples 3 8 time points from microarray experiments 1 OPTricluster implements a novel method for analyzing and visualizing 3D short time series expression data using the order preserving concept on the time dimension and a combinatorial approach on the sample dimension OPTricluster is integrated with the Gene Ontology GO 2 3 allowing efficient biological interpretations of the data It is also integrated with the JFreeChart library 4 I 1 OPTricluster clustering method overview The triclustering algorithm we developed identifies triclusters of genes with expression level having same direction across the time point experiments in subsets of samples OPTricluster takes into consideration the sequential nature of the time series and is able to cope with the effect of noise through the order preserving approach Basically for a given subset of samples we say that a tricluster is order preserving if there exists a permutation of the time points such that the expression levels of the genes are monotonic functions In all after the data pre processing and normalization OPTricluster has five main steps First OPTricluster performs the gene expression data quantization Second it ranks the expression level of the genes across the time dimension in all the samples f
11. le Table Figure 12 Ranking Table and the Cluster Table the user can open the table in Excel and do more analysis in Excel using its rich capabilities I ess Ba Poa eee aS Figure 12 Additional OPTricluster commands that the user can exploit during the analysis to get more insights on the gene expression data The Select Chart to Plot drop down menu also allows the user to do more on the fly analyses of the data in the corresponding table Sample Table and Ranking Table These on the fly analyses are described in Table 3 Table 3 Select Chart to Plot drop down menu description Plot the pie chart of the selected items Gene Ontology analysis of the selected item Open the expression level of the selected item in Excel Merge the expression level of selected items 11 OPTricluster gt Order Preserving Triclustering Algorithm User Manual v1 0 el a pa Sp eee eee Cee bee ce Comber ro amler better Ss Aen tt pe Pr i A KI E AE Be Ki a eem uae e Es e Kee Kaz EZ 8 is DE ET peel Kan le Sak Sai KZG R lp pm fies oi Ga H Her Ouni vm o Ro Ne Hoen Ce Far Rea Arm asa H Hm kap wem tra es LACH alls L DR te hen Har sep M in of Dn Fienna Pama ou bmi Kug de ed bag Win Ke pi S RO ur l ieee be bt T Fra Ri gut AE Wie Kiel eu pu ru ig Wun rye te dee 1i pei uoe Dm hn ran tim e G a Hab res a a a Kai pirs peur paa pu At but An OU Kai Hut ns nr ker ka vz iw um DH Sun Dud om oP at E u
12. m HME Aii em ur ug ae up unt um tts Ip L p vu ven ru Ra Ken mit IP Tap ite Dn oul eut mut iren ro a ke Hisai ont mt 11R mr Wagi ai el Am ke H FMI RI Dim Wm WAN ube dp Ram Il wb mie ng a per tri MI am b Lei RR IR ien Hun ep ken ro hpt Ai e e le um ai DMA HI Sra Rita TO Ku pg Rep 1 Ru np tout Ron H t Ron dual fs rs Pa tee i Bee fe ie Km KSn KS WP L RL R n Mmes DAT nei aRi me ps mea MR wm bt ei in Hm pm lee nu am nm ges nk im Im mm il Vire War ai ee ay UL Hr ies de Afs ga umu up SO ei mu 114 Es Ilan ae mb em si up rer gei ee N he ned la lte Ales Kn V kend el S zhrer t K Kack Figure 13 Example showing the plot of the Pie Chart and the Bar Chart representing the percentage of genes conserved in each selected subset of samples The XY Plot button located at the bottom of the Cluster Table allow the user to plot the expression level of genes in the 3D cluster selected while the GO Analysis button allows the user to perform the gene ontology analysis of the selected cluster Figure 14 m Z WW _ rg rm mn pg Ep rs pd ep ven n mon D pit Baier Ree Som RS Kl deg FE fim ke Pe iia ad ae aa a Wa E Gj aa Tii Ep D ppm ee W I Katz Beef TEEN m o a os e RS a mm RER t es A ULAS i i meea EEN H ez zm ss Ed ee ed li gen ed von A AA Figure 14 Plot of the expression profile XYPlot button of a cluster and its gene ontology analysis
13. n the data file contains gene symbols If a gene symbol is not available then the field should not be left empty A no match can be placed in it Both the spot ID field and the gene symbol field may contain multiple entries delimited by an underscore _ The remaining columns contain the expression values in each sample and at each time point ordered sequentially based on time If the data contains missing values they should be taken care of prior to loading the data into OPTricluster No field should be left empty The first row of the data file contains column headers and each row below the column header corresponds to a spot on the microarray The column header describes the sample the time points and the unit of the time point and should respect the following format Sample Time Unit Example Salt 16 h OPTricluster currently only accepts tab delimited data file as input A tab delimited text file can easily be generated in Microsoft Excel by choosing Text Tab delimited as the Save as type under the Save As menu Once the user selects the data file 1t is loaded into the working space of OPTricluster Figure 4 Figure 4 Example of the OPTricluster interface once the gene expression data is loaded OPTricluster gt Order Preserving Triclustering Algorithm User Manual v1 0 sa zeng Pere errr Sa Saber Deities eee A Figure 5 Example of the OPTricluster interface once the gene expression data is loaded a
14. nd the user selects Edit gt Histogram to view the distribution of the data IV 2 OPTricluster input parameters interface Once the data is loaded the user clicks on the Run OPTricluster from the tool bar This action brings up the OPTricluster input parameters interface Figure 6 From this interface the user can input the different parameters necessary to run OPTricluster These input parameters are the minimum number of genes in a cluster the minimum number of samples in a cluster and the ranking threshold ben lO ll Figure 6 OPTricluster input parameters interface It 1s used by the user to input the parameters necessary for running OPTricluster OPTricluster gt Order Preserving Triclustering Algorithm User Manual v1 0 Once these input parameters are selected and validated a new data table appears Figure 7 in the working space of OPTricluster In this new data table new columns are added to the old ones where each newly added column correspond to the ranking of the expression level of the genes across experimental time points in each sample P P oy E eme Grp Lt ts Pe ee a kass re Coke I E i P 1 T mg D ad e D a e a5 J T d 5 a e e r LU d i i i eeplere peters H i WK H H SMS a age ge wl H E oun a SR DI b 8 1a D rat J GEI R up TTT ew Figure 7 Example of the OPTricluster interface once in
15. ooming VII References 1 Tchagang A B Phan S Famili F Shearer H Fobert P Huang Y Zou J Huang D Cutler A Liu Z and Pan Y Mining biological information from 3D short time series gene expression data the OPTricluster algorithm BMC Bioinformatics under review 2 Gene Ontology http www geneontology org 3 Tchagang AB Gawronski A B rub H Phan S Famili F Pan Y GOAL A Software Tool for Assessing Biological Significance of Genes group BMC Bioinformatics 2010 11 229 4 JFreeChart http www jfree org jfreechart 16
16. or a given filtering threshold 0 Third it identifies the set of distinct coherent 3D patterns in the 3D dataset Fourth triclusters of coherent patterns are formed by assigning genes with similar ranking along the time dimension and across subsets of samples to the same group then divergent patterns are identified Finally statistical significance and biological evaluation of the triclusters identified are performed For more details about OPTricluster methodology see 1 I 2 Citing OPTricluster To cite the OPTricluster software please reference the paper Tchagang A B Phan S Famili F Shearer H Fobert P Huang Y Zou J Huang D Cutler A Liu Z and Pan Y Mining biological information from 3D short time series gene expression data the OPTricluster algorithm BMC Bioinformatics 2012 LA Manual overview The remainder of the main portion of the manual contains five sections Section 2 contains instructions on installing and starting OPTricluster Section 3 discusses the input to OPTricluster Section 4 describes data analysis scenarios using OPTricluster which allows users to explore and OPTricluster gt Order Preserving Triclustering Algorithm User Manual v1 0 visualize different type of patterns Section 5 describes the integration of OPTricluster with Gene Ontology and Section 6 its integration with the JFreeChart library IL Running OPTricluster e To use OPTricluster a version of Java 1 6 or later must be installed If Jav
17. ora Thre SI SET 11 TAE EEE Fiber Gh amiran EDHE TEATRIN R TATIETTI PEE EEEE MEGET RETESET 2 lado DECIES 2 reo EALAR Mz anges CECI BEID AT 2 Figure 8 Example of the OPTricluster interface showing the Select Patterns drop down menu for OPTricluster patterns exploration OPTricluster gt Order Preserving Triclustering Algorithm User Manual v1 0 IV 3 1 Conserved patterns Conserved patterns correspond to group of genes having same behaviour across experimental time points in subsets of samples If Conserved Patterns are selected then the working space of OPTricluster interface becomes Figure 9 The data table on the left corresponds to the input gene expression data with their ranking profile The new table on the right corresponds to the conserved patterns We will call this new table Sample Table The fist column of the Sample Table corresponds to the subset of samples the second column their description the third the number of genes that are conserved in the corresponding subset of samples the fourth column their percentage and the fifth column are check boxes that can be selected and to perform some other analysis on the selected conserved patterns Figure 9 Example of the OPTricluster interface when a type of patterns conserved patterns to be explored is selected showing the Sample Table Each cell of the column of the Sample Table that corresponds to the subset of samples is cli
18. put parameters are selected and validated New columns are added Each newly added column corresponds to the ranking of the expression level of the genes across experimental time points in each sample IV 3 Exploring OPTricluster patterns Using the drop down menu Select Patterns from the tool bar Figure 8 the user can select one of the following three types of patterns to explore conserved divergent and constant File Ede Coin Heo G tegpegel Lon eg REAMER CEEI ae d HITRI TEFIE 114 51 sae HILD MOREM IEn i Bo Hn Drea 3 ERIC Ait eh B Bee Be Oud EE Leo Fe Sea 1 KIK Elersk rap ELW Ta LEIT ER et ED EEE a TrID HK EICH 120114 FEKETE EKKESZ TO in wip laa up sae 104 atin EEEE KRISE Wear THA up Bea ee ERGEN 91 ada a Tapa KK EEES LIAXELKEKE Rect ia GEZEI iB Tania i aaa CELE D Be Bas Cars CI pak Pape Re as a 17 ORS ha MSANE ELE ane dh MiP HIE AR KK i ARORZEGS IO zeiten MEDRA 10 rot EE EES pre Glas cy EZE MPA Wand EES KREE JEE adzira age ie hae tir RER EE n pera RAR e MARIA FEEFEE S tke Combobox Ce explore patterns oe LGT Nadie 19 Tear ERRER ACEL a wae TS ELLE UELL Gera ch SE abel 18 Tadbr so a 374Ra 12 42h sad 2 417 DRS HELENE KAFEN 11 24142 TERA Bibel EESTE Batson Tima 1030101 IFT Bamir Jarre EIEEE iTi EES AD ESKETH EPEC AE EE sta AP
19. ults In fact the GO analysis plug in of the Gene Ontology Analysis GOAL 3 package that we recently developed is integrated into OPTricluster for biological evaluation of the clusters Thus the user can use of the rich functionalities already integrated to the GOAL package to manipulate the GO results table Figure 18 ie Drini CO Aragua P Es TI Tit Doutta Ok oo Geen bo ee Am eren Or Gei goni Cl foe Qo bate OAL Results ile tel Th Gi ths eho fhe te rah B frie Cetra ray Gri ad marii Bir ted H Gi ee 150 OPO S417 8 TURAI oi tritt rop TRAI ae fOr Cad Ora and TAR Liit ia PU 1 EEr Shed ftir Cad tea a DEIT Dad Fs fre tera Gorter ih Forte rd ao om Per Se Bes mo Des apne me bo sinees Pee es Go ae ims pokape gechoplraratpr Pesos Ip emea Samu TUT PE eT aCe Ost ba ray hee ice process local zane JERNE ress chranpnsrgnr eae Dal sokutde spamep b ragrebear p ee ee pa SO rpelualkop Teo ee DO ver ber Peep st zo abateur SCH sherri phottenesis Kl para Gefuer proces Gei cache PES ROE Ip erage cee pera tian fal shih ean melds pri eens ee sft elem TESIS Io od pms K ve mmm m sell es Ben TILAS mHz Ped 9 ET Ae EECH oF CTR Ca Alt I9bIE ix n kkECKV 10 1275 PATS d EATS 13 GTS 15116275 ony fad ee FALE Gy itp i Tiz EEEN 3 ETS ERT eS ATES Bites pat 7 PE Dr mri a 14 E 0 1 ei BE Ju mM 1E Iu T Pade Ted TAHETI 1AE 1 216 THE 12016 0 1bRIIE
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