Biofilter - 1.1 User Manual
Contents
1. DB_PASS and DB_NAME to override any or all of the values The environment variables will take precedence over the values given in the configuration file The default values of the parameters are given below Parameter Value hostname localhost username root password database LOKI Note that if the settings were incorrect and you received an error during the compilation of the LOKI database you must follow the steps given in Rebuilding the Database below Compiling Biofilter During the compilation of Biofilter the program is built and the LOKI database is generated after the LOKI setup steps above if desired The command is S make Installation Installation is the point at which the program and database are moved into their final locations as defined during the configure step Typically the user will need administrative rights to complete the installation step To install both Biofilter and LOKI type make install If you only want to install Biofilter you can type make install exec And if you only want to install the LOKI database you can type make install data During the installation of LOKI the database is copied to the destination directory and it is named yyyy mm dd knowledge bio where yyyy mm dd is the date of creation of the knowledge database However for ease of use the installer will also create a shortcut called simply knowledge bio t2. COVERAGE RS When selected uses the given filename in the COVERAGE RS option in addition to any value given in the configuration file cov map lt filename gt See also COVERAGE MAP When selected uses the given filename in the COVERAGE MAP option in addition to any value given in the configuration file add group d lt filename gt See also ADD GROUP When given on the command line this allows the user to define a custom group as defined in the Custom Groups section of the input file formats This argument adds custom groups in addition to the groups given in the configuration file gene file g lt filename ALL gt See also GENE_ COVERAGE When selected uses the given filename in the GENE COVERAGE option overriding any value given in the configuration file list genes See also GENE REPORT Sets the value of the GENE REPORT to ON overriding this setting from the configuration file Snp report See also SNP_REPORT Sets the value of the SNP_REPORT to ON overriding this setting from the configuration file map snps to gene See also SNP_GENE_REPORT Sets the value of the SNP_GENE_REPORT to ON overriding this setting from the configuration file build B lt label gt See also GENOMIC_BUILD When selected uses the given build in the GENOMIC_BUILD option overriding any value given in the configuration file PREFIX lt label gt See also REPORT_PREFIX When selecte
3. version 5 1 or later LOKI only e Python version 2 6 or later LOKI only e suds for Python version 0 4 or later e MySQLdb for Python e SQLite bindings for python e liftOver binaries for building populations Unpacking Biofilter is distributed as a zipped tarball and the command for unpacking the distribution is S tar xvzf biofilter 1 1 0 tar gz This will unpack the source code into a directory called biofilter 1 1 0 For all of the following commands we assume that you are in this directory Sed biofilter 1 1 20 Configuration In order to compile Biofilter the user must first configure the software This script will attempt to detect all of the prerequisites on the user s system and this is the time for the user to specify system specific options such as the location of the installed program The command is configure The configure script can also take a number of helpful options some of which are detailed below e help This option will list all of the available options that can be passed to the configure script e prefix path This option tells Biofilter to install itself into the given path which is useful if you do not have administrative access to the computer By default the program will be in path bin and the LOKI database will be in path share Note when using this option the path given must be an cc 99 absolute path and cannot use any shell expansions such as th
4. aluts Scher ie cti 22 Group PELA A AA AE T 22 GOPOUP A SETE 22 EX a S E AES E EEA R AEE S OE A T 23 MOT e reer eo 25 COW CIVIL SW AE Ee wav eau ET AEEA eA EE AE eg eee 25 Calcolation of implications iba 25 CUP Eds de dz 27 Maker O NO 27 R gion Details REPO sida 27 SNP Repofta em e e r E a ii 28 SNP Gene R lati nship Repott morien tn iii a Eaa 29 Gene Gehe Models iii a BU oe ico ii 29 Gene DA e ea AS 30 SNPISNP Mods S a a RAE 31 Gene Coverage REPO iii A e dd 31 Missing SNS O a 32 o RA EEEE AEE A E AE AA EEE E 32 Gene Tiste Asiae NA NA tl 33 Binary Pis a aE a a A E a E a A Aa AARE EE Daaa Ea 33 Introduction Purpose of this manual Contained within this manual are details for configuring and running the application Biofilter If this is your first time to use the software we highly recommend that you take a few minutes to download and work through one or more tutorials Then once familiar with the capabilities of the software users can refer to this guide when making changes to the basic configuration settings Conventions Used The following lists the conventions used throughout the document in order to distinguish commentary text from the actual commands run and the input users will provide Example Commands Commands are listed as the user will input them and are shown in Courier New The commands are prefixed with a prompt which should not be typed by the user A prompt of indicates a command to be run with norma
5. gene models that were produced by Biofilter based on the configuration options The gene IDs that are given in this file are the internal IDs used by Biofilter and they can be translated into actual gene names through the use of the Gene Definition report which will always be given when this output is produced The columns of the file are Gene 1 Gene 2 The first two columns are the internal indices of the genes for the given model The indices can be converted to actual genes through the use of the Gene Definition report e Implication Index The third column lists the implication index of the model See the Model Production section for details on how the implication index is calculated Example file Gene 1 Gene 2 Implication Index 0 il 2 al 2 1 Gene Definition Suffix model archive genes This report is a tab delimited text file containing the list of genes used in model production by Biofilter This list will contain all genes that contain at least one SNP from the input data source and the columns are as follows Gene Idx Column 1 lists the gene index used in the Gene Gene models This is the internal index used by Biofilter and this file gives the conversion from gene index to actual gene Name The canonical name of the gene True Begin True End Columns 3 and 4 list the canonical NO LD boundaries of the gene in base pair locations Eff Begin Eff End Columns 5 and 6 list the population specific bou
6. given the script assumes that the liftOver binary is in the path and can simply be called liftOver The liftOver binaries can be downloaded from poploader o lt label gt This option gives the location of the pop_loader binary file that was previously built By default the script assumes that the pop_loader program is located in the path and can be called by executing the command pop loader ldspline s lt label gt This option gives the location of the LD spline tool provided by the Ritchie Lab By default LD spline is provided with Biofilter and is installed alongside the biofilter executable the default value of this option is simply Idspline db b lt label gt This option provides the location of the LOKI database that contains the gene information This value 1s passed to the Biofilter executable and mill follow the same rules for Example The following example shows the creation of LD specific boundaries for both the CEU population at R values of 0 8 and 0 9 and D values of 0 85 and 0 95 Note the different methods of specifying multiple cutoff values buildPopulations py p CEU r 0 8 r 0 9 d 0 85 0 95 Downloading hg18ToHg19 over chain gz Downloading ld chrX CEU txt gz truncated Downloading ld chr10 CEU txt gz Extracting ld chrX CE Ext gz truncated Extracting 1d chr10 CEU txt gz to be continued
7. given below To save space the description of the groups was truncated ID Name Description 89555 POSTLA NOZZLE 1S A Eremserigrioa actor Chat soo 94454 PF13807 This domain is found between two Gene List Suffix output to screen use redirection This report produced with the genes command line option lists all of the available genes in the LOKI database that meet the search criteria The output is tab delimited text with the following columns Name The first column lists the canonical name of the gene e Alias The second column lists an alias for this gene Note that each line will have only a single gene alias pair so it is possible for a gene to appear on multiple lines e Chrom Column 3 lists the chromosome on which the gene is located e Start End Columns 4 and 5 list the start and ending base pair location of the gene respectively Note that this start and stop position are for the given population if available e Description Column 6 gives a description of the gene as found in the LOKI database e Alias Type The final column lists the type of alias for the gene which corresponds to the source of the information As of Biofilter 1 1 the following alias types are available o Ensembl o Protein Accession ID o mRNA Accession ID o Entrez ID o Entrez Gene o Uniprot o Uniprot SWISSPROT An example of the output is given below For space considerations the description of the gene
8. i 1453 This configuration option allows the user to limit the search of information according to the given group IDs which must match those found in the LOKI database If given only those groups and their children will be considered when generating models and annotations This option is especially helpful in limiting Biofilter to a specific list of databases These IDs can be found in the Gene Definition report under the Groups column Note that these IDs are internal to LOKI and are not available from public data sources To use group names please see the INCLUDE_GROUP_NAMES configuration option See also Gene Definition INCLUDE_GROUP_FILE Syntax INCLUDE_GROUP_FILE filename INCLUDE GROUP PILE group ids t e This option is provided as a convenient alternative to the INCLUDE_GROUPS command above Instead of listing all of the group IDs in the configuration file the user may use a separate file where the group IDs are listed individually one per line INCLUDE_GROUP_NAMES Syntax INCLUDE_GROUP_NAMES label label INCLUDE GROUP NAMES GO 0003674 hsa00010 Pfam This option allows the user to limit the search to groups as in the INCLUDE_GROUPS command above except that groups are identified by their name instead of their ID in the LOKI database This is helpful if the user has interest in a specific pathway from a database included with Biofilter INCLUDE_GROUP_NAME_FILE Syntax INCLUDE _GROUP_NAME FILE filename I
9. in more than one group When this happens in a disease independent source the implication score is incremented by 1 for each source a pairing if found in and then by the IMPLICATION IDX DUPLICATE WEIGHT for each duplicate pairing found in a source Thus if two genes are found in three pathways in a disease independent source with this configuration value set to 0 25 the implication index will be increased by 1 5 for this source BINARY_MODEL_ARCHIVE Syntax BINARY MODEL_ ARCHIVE Yes No BINARY MODEL ARCHIVE No Enabling this option allows for the production of binary model files in order to save disk space If enabled the gene gene and SNP SNP models will be printed in a proprietary binary format This format is highly implementation dependent and may not be portable among computers See also Binary Files DISEASE_DEPENDENT_LEVEL Syntax DISEASE DEPENDENT_LEVEL ALL_MODELS GROUP_LEVEL DD_ONLY DISEASE DEPENDENT LEVEL ALL MODELS With this configuration option users can choose to filter the gene gene model results by how closely they are related to a disease dependent source This configuration option may take one of the three following values ALL MODELS When this value is used the default Biofilter will generate all gene gene models regardless of their relation to a disease dependent source e GROUP LEVEL When this value is used Biofilter will generate all gene gene models for groups that contain at least one gene in a d
10. slightly more complex collection of interrelated groups still using the Alzheimer s data above but split into two groups one with genes starting with the letter A and one with genes starting with the letter C Additionally there is a parent super group that contains both subgroups Also this file demonstrates the inclusion of more than one gene on a single line as can be see in the alz assoc A group ALZ COMPLEX DISEASE DEPENDENT Alzheimer s Complicated GROUP alz assoc A Genes assoc w Alzheimer s beg w A AGT APHIA APOA1BP APOA2 GROUP alz assoc C Genes assoc w Alzheimer s beg w C CAMK1G SE CHRNB2 GROUP alz master Master group for Alzheimer s CHILDREN alz master alz assoc A alz assoc C Model Production Overview Biofilter uses biological information about gene gene relationships and gene disease relationships to construct multi SNP models for conducting statistical analysis Rather than annotating the independent effect of each SNP in a GWAS dataset Biofilter allows the explicit detection and modeling of interactions between a set of SNPs In this manner Biofilter process provides a tool to discover significant multi SNP models with non significant main effects that have established biological plausibility This approach has the added benefit of reducing both the computational and statistical burden of exhaustively evaluating all possible multi SNP models Model production is gene centri
11. to dictate the populations and cutoffs as well as the location of biofilter and any other necessary helper programs All options are given on the command line and the format is identical to the command line options given in the Biofilter description populations p lt label gt This option gives a comma separated list of HapMap populations to generate LD based boundaries from The populations must be the 3 letter HapMap abbreviations or their one letter shortcuts e g C is synonymous with CEU This option may be provided more than once on the command line and all populations given will be used Note that this is a mandatory option dprime d lt float gt This option gives a comma separated list of floating point values to use as cutoffs for the D value in generating the LD based boundaries This option may be provided more than once and all given values will be used Note that either this option or rsquared is required rsquared r lt float gt This option gives a comma separated list of floating point values to use as cutoffs for the R value in generating LD based boundaries This option may be provided more than once and all given values will be used Note that either this option or dprime is required liftover 1 lt label gt This option gives the location of the liftOver binary needed to convert the build 36 HapMap files to the build 37 Biofilter data If this option is not
12. NCLUDE GROUP NAME FILE group names txt Again as above this option is provided as an alternative to the INCLUDE _ GROUP NAMES command providing a way for the user to supply a file containing a list of group names to include one per line POPULATION Syntax POPULATION label POPULATION NO LD This command sets the population on which to base the gene boundaries The population NO LD will always be included in the LOKI database and this population is the default boundaries of a gene from either Entrez or Ensembl Often the NO LD boundaries of a gene will be referred to as the true boundaries of the gene GENE_BOUNDARY_EXTENSION Syntax GENE_BOUNDARY EXTENSION integer GENE BOUNDARY EXTENSION 1000 When using the NO LD population this option gives the user the ability to extend the gene boundaries by the given number of base pairs Th extension occurs both upstream and downstream of the actual boundaries in the database REPORT_PREFIX Syntax REPORT_BOUNDARY label REPORT PREFIX myReport This option allows the user to set a prefix for all of the output files that are generated by Biofilter This is useful when running Biofilter repeatedly as it will prevent older results from being overwritten IMPLICATION_IDX_DUPLICATE_WEIGHT Syntax IMPLICATION_IDX_DUPLICATE_WIEGHT float TMPLICATION IDX DUPLICATE WEIGHT 0 25 When calculating the implication index of a particular model often a pair of genes will appear
13. Table of Contents E CUO Nis src satin aa aaa a E a E e a Gdn adbe te aa a eE aE ease Males 4 PURPOSE of this Mantal A As 4 A S S A A NN 4 EX emp Fe Commands in 4 Program pu Outpt A oa 4 E AA oe A E pide ull ated cca cleans lcd ate 4 TMC O cel Nha di a teen ase a imal tits Sa ch aa tase EA 5 El T E T 5 DAEN O E E E EA S E EE 5 LSA Fe ne OP err O e EAE ARE 5 de he ore aera eee ey ee 5 DEST MOM series hacia A A aug ves aan Goa aaa tac Sa 5 Installing Bro AS A A AAA AOR 6 is A A A E E RR DRA SEAT MEP 6 Uppacki gaesss tani asi aes aera vi a es Gea a E Mas E A AN pale eats 6 CONAM di A a 6 COMPU A E a aak 7 WORDS CEU o E e ee oa lona e baa 7 dl A A O A A A 8 A recy ste baevesns syne e e pig a e a shea penton ae e Ea aieas aaa 8 Rebuilding the Diab das 8 Using the Biofilter Appl Mt tl ad 9 Con guration Parameters A red 9 SETIINOS DOB sy ohecass sca evs casts oxsareoaveniiexshacuanss guia is 9 MAX GENE COUNT dc 9 RS OUEN e e o od eer ee re 9 MAPSOURCE se 10 ADD GROUP Iasae A Ove bead cme aed il aia 10 INGEUIDE GROUPS ia AA A a 10 INCLUDE EROTE LE O e US 10 INCLUDE GROUP INA INS a de a on 11 INCLUDE GROUP NAME FILES iaa 11 POPULATION A A A 11 GENE BOUNDARY EXTENSION Ai E E 11 REPORTE PRT Bl E EE held ids erica ike Seley cea deel A Ol Atte Resets aide ta 11 IMPLICATION IDX DUPLICATE WEIGHT cccscsssssssescssessssesssscssssesesecsssecsssecsssvesseeseeseeseees 12 BINARY MODEL ARCHIVE 00d 12 DISEASE DEPENDENT LEVE Eddi
14. and the SNP List above are mutually exclusive with the variant List taking precendence The format of this file is a PLINK 4 column map file with the columns being Chromosome ID Genetic distance not used and base pair location An example is shown below A s10000169 0 775715270 A 810000185 0 75600656 A 2810000201 11829598 13 zs1000022 99239220 4 810000226 0 87957991 6 xr81000023 TSA a 4 rs10000255 0 162644668 4 rs10000266 0 40399629 Custom Groups In addition to the groups that have been defined in the LOKI database Biofilter allows a user to define groups of genes and submit this custom group in an input file This can be useful in defining disease dependent groups of genes The custom group must be formatted according to the Group File Format defined below Group Definition A user can create many custom groups within a single file and each file defines a single high level set of groups that are all related in some way A single group may contain a collection of genes as well as other children groups thereby allowing for a hierarchical structure to be defined in the custom group file When calculating a model s implication index each custom group file is considered to be a single source comparable to the database sources loaded from LOKI Group File Format Custom groups are defined using a plain text file with a specific format Each file defines a set of related groups and forms a single meta group The file mus
15. c and thus requires that any SNPs to be considered be mapped to genes The gene mapping takes place internally using local copies of current data sources such as Ensembl HapMap and dbSNP A structured mapping is made based on relationships from one of the knowledge sources and this information is used to identify candidates for SNP SNP models The biological knowledge used by the Biofilter is derived from various sources which are identified as Meta Groups as well as optional user defined groupings Currently the data sources represented include Gene Ontology KEGG Net Path pfam Reactome and PharmGKB drawn from the supporting biological database which we have called the Library of Knowledge Integrattion LOKI There are two basic types of data sources Disease dependent sources are user defined and relate a gene to the disease phenotype being studied i e previously associated SNP Using the appropriate group file format disease dependent genes can be included as a list or combined into multiple groups and relationships Characterizing disease dependent genes impacts the implication score the score is calculated so that more weight is given to models pertaining to the specified input Disease independent sources link more than one gene together The goal is to identify pairs of genes with some prior evidence of putative epistasis The databases collectively referred to as LOKI are disease independent sources because they provide key re
16. d overrides the REPORT_PREFIX option from the configuration file with the given prefix snps s lt filename gt See also RS_ SOURCE When selected uses the given filename in the RS_SOURCE option overriding any value given in the configuration file Set population p lt label gt See also POPULATION When selected uses the given label for the POPULATION configuration option overriding the setting found in the configuration file gene boundary lt integer gt See also GENE BOUNDARY EXTENSION When selected uses the given integer for the GENE BOUNDARY EXTENSION configuration option overriding the value in the configuration file variants v lt filename gt See also MAP_ SOURCE When selected overrides the MAP_ SOURCE configuration option with the given filename write models W lt float gt lt integer gt See also EXPORT_GENE_MODELS MINIMUM IMPLICATION INDEX MAX SNP MODEL COUNT When selected sets EXPORT GENE MODELS configuration option to ON The float and integer arguments are optional but must be given in order and if supplied will override the MINIMUM _ IMPLICATION INDEX and MAX SNP MODEL COUNT respectively export snp models X lt float gt lt integer gt See also EXPORT _SNP_MODELS MINIMUM IMPLICATION INDEX MAX SNP MODEL COUNT When selected sets EXPORT_SNP_MODELS configuration option to ON The float and integer arguments are optional but must be given in or
17. der and 1f supplied will override the MINIMUM IMPLICATION INDEX and MAX SNP MODEL COUNT respectively Input File Formats This section lists all possible input files that can be given to Biofilter With very few exceptions input files are space delimited ASCH files Gene Aliases The gene aliases are a means for a user to restrict searches on the LOKI database to a set of predefined genes Internally LOKI uses Ensembl gene IDs as the canonical name of the gene but the genes listed in this file can be alternative names such as those found in Entrez or Uniprot When using aliases for the gene only non ambiguous aliases are considered valid in this file Example file NMT1 FURIN RD1 s100B ATP2A2 SNP List The SNP Source file contains all SNPs to be used in the analysis Generally this will match the SNPs from the platform to be used in the analysis However it is also possible to use a highly restricted set for other types of analysis such as identifying which genes a set of interesting SNPs might be found in The format is very simple List all RS IDs in their integer format removing the RS before each number Each ID should be separated by whitespace An example is shown below 10000169 10000185 10000201 1000022 10000226 1000025 10000255 10000266 Variant List The variant list is a means for a user to specify SNPs or other variants which do not necessarily have an RSID associated with them This file
18. e notation e disable loki This option disables the compilation of the LOKI biological database Since the compilation of the database will take a few hours with a high speed internet connection this option is helpful if you are installing a new version of Biofilter but you want to leave the database unchanged e enable debug For the advanced users this option will turn off all optimization and turn on debugging symbols which can be helpful in diagnosing a problem with the Biofilter software Compilation LOKI Setup Due to the size of the LOKI database it is not distributed along with the Biofilter code We provide the means for a user to build the LOKI database by downloading the data directly from the sources The LOKI database must be compiled before installation described further below In order to build the LOKI database the user must have complete access to a MySQL database with permissions including the ability to drop and create tables The installer will not create a MySQL database during compilation it will create LOKI tables within an existing MySQL database Thus the MySQL database must exist and the user must have permissions to drop and create tables within the MySQL database The database settings are located in a file called BioUpdater dbsettings py The user must supply the database host username password and name Alternatively you can use the environment variables DB_HOST DB_USER
19. e 12 GENOMIC BUILD dd idbs 12 DETALED REPORTS id A aaa 13 MARKER INFO REPOR Pins nnise rae il 13 SNESRERLO RL Rias 13 SINE GIDE REPO o de edo 13 GENE COVERAGE id O IES 13 GENE REPORT a a A E A O E a E O E 14 COVERAGES EN A E a e AA a vetted day 14 COVERAGE MAP iS Eo 14 MINIMUM IMPLICATION TNDEX att ia 14 MAX SNP MODEL COUN Ta aa 15 EXPORT SNP MODELS enii ioei tada ir lead rn 15 EXPORT GENE MODE ES A A AA 15 ao A O 15 MAA AS SAS RADA ASA A ER 16 Sample CONS 15 invrins audacgzas e ale action a A Ea EO A EAE EEA 16 aslistepopulations GP A O A a A eA Savek 16 o OS 16 A O ad ueaaketbucenaitowasaies 16 penes label ALLS label ALE SA E T A E AE TEE 16 LU MM A NN T EN 17 Command SOPAS A deste A E AE O A tastes ideation cot Meas 17 DB Ei A nn II td aay andedead oad ama E a i 17 AI A IA OS 17 A A O 17 O A A 17 IES O ad 18 COV Tap lO A ria 18 a A a a Adi tend a Vaud a 18 en Ml enana A a O ida 18 A ON 18 MO O Ai aca 18 O O O a a O LS 18 A enn ey ea En a eee te ene a Ae 19 PRERIX LAE O uaa vce an a Tom aca oa a 19 AS NA easel eee 19 set population p label ds 19 LS e E O E O O AN 19 os AM r a a a a Ae 19 write models W lt float gt IMA A a ei tec 19 export snp models X lt float gt lt IMtegel gt oooonnccnooccnonononnconnoconccnnnoconncnnnccon non nn cnn nro ran nr conan cc conan 20 put Pile Roma O da 21 Gene ASS a iio 21 SNAPE te 21 O nial shay ves Wri a dais hes E a Renee eps 21 C stonr Groups ena ethan
20. e IDs of the SNPs that are associated with this gene separated by a colon Note that this column gives the IDs of the SNP as opposed to the internal SNP index Gene Name Chrom Eff Start Eff Stop True Start True Stop Alias List ci I 57 LS Dy is CIE RI e2 le oy Som 2 SB GAG 26 122 G3 de a SI 45 5D COR CORRO Gay I g 30 50 SO 0 CORRO SNP Report Suffix snp report csv This file is a comma separated text file that lists the relationships between markers and genes that Biofilter finds in the LOKI database The file has the following columns Chrom The chromosome of the marker RSID The unique identifier of the marker Usually this will be an RSID but when MAP SOURCE is used this is the identification string given to Biofilter Gene Name A colon separated list of all of the canonical names of the genes that contain the given marker Chrom IRS ILD Gene Name Ly RS ine Roy Gi Ly RSS Ly SO G2 G5 Ty RSF G5 Loy ISLA y G4 ay RSS G6 SNP Gene Relationship Report Suffix snp gene map csv This file is a comma delimited text file that details the location of the SNPs in relation to the associated genes While a SNP is typically considered to be inside a gene when using multiple populations it is helpful to differentiate the term to describe if a SNP was included due to inclusion in the canonical gene or rather due to the gene expansion The columns of the file are Chrom The cromo
21. e the integer portion of the RSID listed one per line To include multiple platforms this option can be given more than once in a configuration file See also SNP List Gene Coverage Report COVERAGE_MAP Syntax COVERAGE _ MAP filename COVERAGE MAP map ids txt This option allows a user to specify a list of markers on a platform in generating a gene coverage report The format of the file must conform to the Variant List specification To include multiple map based platforms the user may specify this option more than once in a configuration file See also Variant List Gene Coverage Report MINIMUM_IMPLICATION_INDEX Syntax MINIMUM_IMPLICATION_INDEX float MINIMUM IMPLICATION INDEX 2 0 When generating models this option gives the minimum implication score required to consider a model Output models are ordered by implication score and this can be a means to reduce the number of testable models that are generated so that the multiple testing burden is reduced Note that all gene gene models are generated but only those with an implication score surpassing this threshold are actually stored in memory Also only SNP SNP models with implication scores above the threshold are ever generated so this parameter can serve to reduce a computational burden in model generation MAX_SNP_MODEL_COUNT Syntax MAX_SNP_MODEL_COUNT integer MAX SNP MODEL COUNT 1500 This option provides a maximum number of SNP SNP models to create The SNP SNP m
22. es the list of the SNP IDs from the file that are associated with the given gene The list of IDs is separated by a colon Cene Morant SSI mejo CAE COSE SNOS CAE Gl Dy Si 2 G2 Ik Ep G3 L Ty 11 Gor AG Dy 2 Missing SNPs Suffix missing snps txt Unlike the other output files this is not a delimited file and it is intended to be read by the operator It lists all of the SNPs that were unable to be converted into a base pair location for use in generating models This file is only produced when using the RS_SOURCE configuration option and when at least one of the input RS numbers could not be located in the LOKI databse The following SNPs were unable to be found in the variations file RS10046131 RS10046212 RS10046325 RS10047718 RS10047744 RS1006093 Group List Suffix output to screen use redirection This report produced with the groups command line option lists all of the available groups in the LOKI database that meet the search criteria The output is tab delimited text with the following columns e ID The first column is the internal ID of the group This ID can be found in the Gene Definition report when generating gene gene models Name The second column lists the name of the group as given by the originating data source Description The final column is the description of the pathway as given by the original data source An example of the output is
23. fig file Above the OPTIONS are command line options which are described below and the config file is a configuration file which specifies the behavior of Biofilter If options given in the configuration file and command line differ the command line options will take precedence Configuration Parameters The following parameters can be given in the configuration file For each command we give the calling syntax of the parameter as well as an example In the syntax any optional parameters will be listed in square brackets When a specific input file is needed the format of the input file will be referenced in the See also section SETTINGS_DB Syntax SETTINGS_DB filename SETTINGS DB knowledge bio This option sets the location of the LOKI database to be used by Biofilter The filename can either be given as an absolute or relative path Ifthe database is not found relative to the current working directory Biofilter will search the data directory given during installation for the LOKI database MAX_GENE_COUNT Syntax MAX_GENE_COUNT integer MAX GENE COUNT 30 This configuration option sets the maximum number of genes in a pathway to consider the pathway valid for generating gene gene models Some pathways are so encompassing that the considering the relationships between the genes would lead to an overwhelming amount of generated models By increasing this value more values will be created and decrea
24. hat will point to this installed file This is designed so that a user may have multiple concurrent LOKI databases that each correspond to a different snapshot in time Rebuilding the Database The LOKI database that Biofilter uses is static and 1t will not capture updates made to the sources as the sources are updated Thus from time to time it becomes necessary for the user to rebuild the database with the most recent information Assuming that the user configured Biofilter to build the LOKI database in the first step the command to discard the current LOKI database from the build directory is make clean From this point the user can re run the compilation and installation steps to regenerate and reinstall the LOKI database Note that the old LOKI database will NOT be deleted from the installation directory but the shortcut will be updated to the most recent database Population Creation After the LOKI database has been created and installed the user may create population specific genetic boundaries This process is described in the Creating Populations section at the end of the document Note that if the database is rebuilt the populations must also be rebuilt Using the Biofilter Application The Biofilter application can be used for many purposes and as a result there are many options available to the user to customize the behavior of the program In general the execution of Biofilter is as follows S biofilter OPTIONS con
25. he ID given in the input file e Chrom The chromosome of the marker e Pos The base pair location of the marker Index This column lists the internal index of the marker This is used in the SNP SNP model report as seen in the SNP SNP Models section Role Detailed Reports only The final column will list the role of the SNP as found in the LOKI database ID Chrom Pos Index RS1 1 S 0 RS2 1 14 1 RSS 1 Bal 2 RSS 1 35 2 RS 7 1 49 4 RS 1 17 5 RSZS 2 21 6 Region Details Report Suffix gene report csv This file is a comma separated text file that lists all of the pertinent information about the genes used in Biofilter The output is very similar to the Gene Definition report except that SNPs are only printed when detailed reports are used and this report may be produced independently of generating gene gene models The columns in this report are Gene Name The first column holds the canonical name of the gene Chrom The second column lists the chromosome that the gene can be found on Eff Start Eff Stop Columns 3 and 4 list the population specific base pair boundaries of the gene being looked at True Start True Stop Columns 5 and 6 list the canonical NO LD population base pair boundaries of the gene Alias List Column 7 lists all available aliases of the gene separated by a colon Note that ambiguous aliases are listed in this list SNPs Detailed Reports only The final column lists th
26. ilter will produce a report which lists all of the SNPs used by Biofilter along with any genes that contain the given SNP See also SNP Report SNP_GENE_REPORT Syntax SNP_GENE_REPORT Yes No SNP_GENE REPORT On When this option is On Biofilter will produce a report that details the relationship between all of the SNPs considered to be in genes and how they are related See also SNP Gene Relationship Report GENE_COVERAGE Syntax GENE_COVERAGE filename ALL GENE COVERAGE ojene Waist txt This option is a filename containing a list of gene aliases to restrict a gene coverage report If ALL is given instead of a file all genes in the database containing at least one marker will be listed in the gene coverage report Note this option does not affect the generation of models 1t is only used in the Error Reference source not found command line option which precludes the generation of gene gene or SNP SNP models See also Gene Aliases Gene Coverage Report GENE_REPORT Syntax GENE_REPORT Yes No GENE REPORT On When set to On Biofilter will generate a report that lists all of the genes that were used to generate models along with a great deal of detail about the genes and their contained SNPs See also Gene Definition COVERAGE_RS Syntax COVERAGE RS filename COVERAGE RS rs stds er This option allows the user to specify a list of RSIDs in generating a gene coverage report The list of RSIDs must b
27. iofilter will generate a gene coverage report based on the list of genes given by GENE_COVERAGE and the list of markers defined by COVERAGE RS and COVERAGE_MAP Note that when this option is provided to Biofilter no models will be generated and the only output will the the Gene Coverage Report groups G lt label ALL gt See also Group List When this option is selected on the command line Biofilter will print a list of the groups or pathways matching the search criteria to the screen The given label is a comma separated list of criteria to search for matching groups If ALL is given Biofilter will list all available groups contained in the LOKI database When searching for groups Biofilter searches both the group name as well as the description and any group matching one or more criteria is returned The following example will list all groups related to either NOZZLE or GNVR biofilter config G NOZZLE GNVR genes lt label ALL gt lt label ALL gt See also Gene List When this option is selected Biofilter will print a list of genes and their associated aliases from the LOKI database The first label is a comma separated list of aliases to search for The aliases may be all or part of a gene identifier For example searching for an alias of AZ will produce all genes that can be identified by an alias containing the letters AZ The second label gives a comma separated list of alias types to
28. ion on converting the SNP index to an RSID Implication Index This is the implication index of the model which is a proxy for the strength of the model See Model Production for details on the calculation of the implication index SNE J SINE Z Implication Index 0 3 2 1 3 2 3 4 1 Gene Coverage Report Suffix gene coverage csv This file is a comma delimited report produced by the Error Reference source not found command line option The report contains the number of markers in each gene from platforms found using the COVERAGE RS and COVERAGE MAP configuration options The user may limit the genes listed by passing a file of gene aliases to the GENE REPORT configuration option The columns of the file are as follows Gene The first column of the file gives the canonical name of the gene Total The second column gives the total number of markers contained in all files that were given Each gene should have at least one marker associated with it in this file e All SNPs Detailed Report only This column gives a list of the SNP IDs that are associated with the gene separated by a colon Note that this is combined across all input files the contribution from individual files is given later in the report e lt filename gt This column lists the total number of markers from the file associated with a gene This column is repeated for each input platform given e lt filename gt SNPs Detailed Report only This column giv
29. is often truncated Name Alias Chrom Start End Description Alias Type ABCF1 ABCF1 6 SOSSOLGY SOSIISOS AWPloaimcbune Usos Entrez Gene BRCA1 BRCA1 g 41196311 AZ T ITAS CEMOSIE lose Entrez Gene ABCF2 ABCF2 7 OVAS LSOQZA SiG WNiwieloslinltiavsy ls yo Entrez Gene BREAT PIS BREAPP IMENI 41320086 41321970 BRCA1 pseudogene 1 Entrez Gene ABCF3 ABCF3 3 18909 8022ko OTO AEn Entrez Gene Binary Files Some of the files listed above have the option of being printed in a strictly binary format to save space in the directory This is especially helpful if the user is generating a large number of SNP SNP or gene gene models To enable output in binary format simply enable the BINARY MODEL ARCHIVE configuration option When this option is enabled the output is written without any delimiters or headers and an integer is printed that indicates the number of lines contained within the file The reports that are available in a binary format are Gene Gene Models and SNP SNP Models WARNING This feature has not been well tested and may cause compatibility issues among different machines If the only issue is long term storage space the user may be able to compress the text output sufficiently to avert the problem Creating Populations Biofilter has the capability to use population specific boundaries of genes through the use of the POPULATION configuration option By default only the single population NO LD is defined by the loader a
30. isease dependent group Note that a model may be generated from two genes not in any disease dependent group if they are in the same group as a third gene which is also in a disease dependent group DD ONLY When this value is used Biofilter will only generate gene gene models in which one of the genes in the model is contained in a disease dependent group GENOMIC_BUILD Syntax GENOMIC_BUILD string GENOMTE BUELD 37 This setting tells Biofilter the build of the genome that the input data is based on This is especially important for input that is based on position as in the MAP_ SOURCE configuration option Ifthe input data is not the same build as used internally by Biofilter the software will perform a lift over of the input data into the genomic build used by Biofilter DETAILED_REPORTS Syntax DETAILED_REGeneGeneModelPORTS Yes No DETATLED REPORTS On When this option is set to On Biofilter will add in more details in the output reports See the Output Files section for more information on what information is included only in the detailed reports MARKER_INFO_REPORT Syntax MARKER _INFO_REPORT Yes No MARKER INFO REPORT On When this option is set to On Biofilter will produce a marker report which lists the SNPs considered by Biofilter along with their chromosome and base pair locations See also Marker Info Report SNP_REPORT Syntax SNP_REPORT Yes No SNP REPORT On When this option is On Biof
31. l user privileges and a prompt of indicates a command to be run with elevated privileges such as installation Examples are shown below S sample command sample command admin Program Input Output Files that are used as either input or output will be listed in a gray box as shown below Example Program Output Column1 Column2 Column3 really long darca short more data truncated Additionally lines may be suppressed in some very long files as shown above by the truncated line Common Parameters There are a number of parameters which are used commonly across multiple configuration settings In order to simplify the descriptions of the various properties of each command we ll describe those properties here Integer Parameters specified in this way just simply refer to a whole number In general these values should be equal to or greater than 0 except when specified otherwise Float Values specified as float are decimal values Yes No These parameters accept a boolean Yes No type setting Users can use ON OFF or YES NO to set them and Biofilter recognizes the options regardless of case Filename When a configuration refers to a file for input or output the filename is generally used This can be either a fully qualified path such as home user file txt or it can specified as a path relative to the directory where the application was run such as data goodfilename It can also be just a plain file
32. lationships between genes in important biological processes Bush 2009 However the user can also define additional custom disease independent groups Users can provide a set of SNPs that reflect the platform on which their analysis will be run This can be a GWAS platform such as Illumina Human 1M DUo BeadChip or one designed for the user s specific study see Input File Formats SNP List and Variant List Ifa SNP in the input file does not exist according to Biofilter it is ignored in the analysis and added to the Missing SNPs file As a result only those SNPs available in the Biofilter s local copy will be considered All variants in the variant list input would be included because there is no internal representation of all possible base pair positions that contain SNPs Calculation of Implication Index To rank the strength of the potential interactions Biofilter uses an implication score which is a measure of how many times the two genes or SNPs in the model are associated with each other Since SNP SNP models are generated from the gene gene models the implication index of a SNP SNP model is defined by the generating gene gene model s implication index For a gene gene model the implication index is calculated by counting the number of unique sources that associate the two genes When a pair of genes are contained in the same group twice or more in the same source the implication index is increased by 1 for each group for disease de
33. name as long as the file itself is available from the directory in which the application was run Label A label refers to a parameter whose value can be any text string without whitespace These labels are generally used for reporting but in many cases are used to determine filenames As a result users should avoid using unusual characters such as or fP in the string that could possibly cause problems with filenames Because spaces and tabs are used to separate each parameter on a given line labels can not contain spaces Description A description is a chunk of text that can contain spaces It will always be at the very end of a line and is generally optional Installing Biofilter Biofilter is packaged with the GNU autotools so installation occurs in four steps unpacking configuration compilation and installation Each of those steps will be described below but first the user must ensure that the prerequisites for running Biofilter are met as well as the prerequisites for generating the supporting biological database which we have called the Library of Knowledge Integration LOKI Prerequisites The following are prerequisites for building and running Biofilter The packages that are needed only for building the LOKI database are indicated e A modern C compiler e Boost Libraries for C version 1 46 or later e SQLite version 3 5 4 or later e SOCI with SQLite support compiled e MySQL client libraries
34. nd it is incumbent on the user to define any auxiliary populations A population is defined by both a HapMap population and a cutoff defined by either an R value or a D value Note that it is possible to have multiple boundary populations based on a single HapMap population An example could be a CEU population with a D cutoff of either 0 9 or 0 8 To create these populations within Biofilter we provide a script buildPopulations py that downloads the data from HapMap and loads the data into the LOKI database for use by Biofilter Note that if the database is rebuilt the populations must also be rebuilt and this is not an automated step Prerequisites In order to use the buildPopulations py script the user must have available boththe liftOver binaries as well as the helper program pop loader which is distributed with Biofilter The liftOver binaries can be downloaded from http hgdownload cse ucsc edu admin exe By default when Biofilter is made the Usage In order to run buildPopulations py the user must be able to write to the LOKI database Typically this will mean that the user must have the same rights as described in the Installation section which is usually administrative rights By default buildPopulations py is installed alongside Biofilter so the command to use is buildPopulations py OPTIONS Where the options are described below Options The options to the buildPopulations py script allow the user
35. ndaries of the gene When using the NO LD population these columns should be identical to columns 3 and 4 e Groups This column lists all of the groups that this gene has been found in The groups are separated by source by a pipe Within each source the group ids are separated by either an exclamation point for disease independent sources or a tilde for disease dependent sources The first group in a source is always prefixed with the appropriate separator so the user can determine the correct category of source even if there is only one group from the source Aliases Column 8 lists all of the aliases available for the gene separated by a pipe This list even includes potentially ambiguous aliases for this gene SNPs Column 9 lists the indexes of the SNPs included in this gene separated by a pipe See Marker Info Report for details on converting a SNP index to an RSID Gene Idx Name True Begin True End Eff Begin Eff End Groups Aliases SNPs 0 Gl 5 15 5 15 a TEA Ra 0 11 il G2 25 35 25 35 HALLS G2 G23 R2 3 2 G3 45 55 45 55 2 G23 G3 R3 4 3 G5 30 50 30 50 G5 R5 314 SNP SNP Models Suffix model archive snp snp This file is a tab delimited listing of all of the SNP SNP models generated by Biofilter The models are organized by implication index and the file has the following columns SNP1 SNP2 The first two columns list the SNP indices of the SNPs in the given model See Marker Info Report for informat
36. odels are ordered by their implication index with higher implication scores receiving priority Note that this number is a hard cutoff so there may be additional models at the same implication score as the last model provided that were not output This parameter can be used to reduce the computational burden by reducing the number of SNP SNP models generated to a known fixed constant EXPORT_SNP_MODELS Syntax EXPORT_SNP_MODELS Yes No EXPORT SNP MODELS On When set to On Biofilter will output a list of SNP SNP models based on the Gene Gene models that are generated The models will be ranked in order of their implication index with higher implication scores appearing first Note that when this option is enabled MARKER INFO REPORT will also be enabled See also SNP SNP Models EXPORT_GENE_MODELS Syntax EXPORT_GENE_MODELS Yes No EXPORT GENE MODELS On When set to On Biofilter will output a list of Gene Gene models that are identified in the LOKI database as biologically relevant The models will be ranked in order of their implication index just as the SNP SNP models are Note that when this option is enabled GENE REPORT will also be enabled See also Gene Gene Models Optional Commands In default operation Biofilter generates gene gene and SNP SNP models for testing purposes However certain features of Biofilter can be activated by using certain command line flags When any of the flags below are used the Bi
37. ofilter will perform only the given task and models will not be performed For the most part these tasks are used to gather data from the LOKI database or to get help about the correct usage of Biofilter Typically command line options are called with two dashes preceding the name of the option However come options are available as a short version which are preceded by a single dash When available the optional short version is in parentheses Any arguments that the options take are given in angle brackets lt gt and are explained in the text help h Prints a summary of the available command line options and exits Sample config S This parameter takes no arguments and causes the output of the Biofilter to generate a basic configuration based on the default settings and any that have been overridden by other parameters No other execution is performed list populations P Lists the populations available in the database in use Populations are used to adjust the gene boundaries to include additional SNPs that are observed to be within an LD threshold By default there is only one population given by NO LD Note that if this option is given no analysis will be done the only output will be the list of populations available which is written to the screen report gene coverage See also GENE_COVERAGE COVERAGE_RS COVERAGE_MAP Gene Coverage Report When this option is given on the command line B
38. pendent sources and by the value given by IMPLICATION_IDX DUPLICATE WEIGHT for each group in a disease independent source As an example if IMPLICATION_IDX_DUPLICATE_WEIGHT was 0 25 and two genes were in three groups from a disease independent source and two groups from a disease dependent source the implication index would be 3 5 1 0 5 3 1 1 1 1 Output Files The output files that Biofilter produces are typically delimited ASCH text files The files are differentiated by their suffix which is given in each section The naming convention for the files is lt prefix gt lt suffix gt where the prefix is either given in the configuration file or is the name of the configuration file with any extensions removed Occasionally reports will have more information available using the DETAILED REPORTS configuration option This additional information will typically be included as extra columns in a report and they will be indicated as such but the given examples will not be shown Marker Info Report Suffix marker info map This file gives the list of all SNPs used in the generation of models in Biofilter When generating SNP SNP models this file will always be produced regardless of the MARKER INFO REPORT configuration setting The file is a tab delimited text file with the following columns e ID This column lists the unique identifier for the given marker Typically this is an RSID but if using MAP SOURCE this is t
39. restrict the search to The following example searches for a gene with the alias BRCA1 or ABCF restricted to aliases found in the Entrez database biofilter config genes BRCA1 ABCF Entrez Command Line Options Below is a list of all of the available command line options and the manner in which they are called These options will not affect the manner in which Biofilter runs and these options typically override options given in the configuration file which can help the user when making rapid small adjustments to the configuration DB lt filename gt See also SETTINGS DB This option overrides the SETTINGS_DB value in the configuration file and uses the given LOKI database This is helpful for using a LOKI database that was downloaded earlier than the most recent one marker info See also MARKER INFO REPORT Sets the value of the MARKER INFO REPORT configuration option to On overriding the value given in the configuration file binary b lt Yes No gt See also BINARY MODEL_ARCHIVE When this option is given on the command line it overrides the BINARY MODEL ARCHIVE setting from the configuration file and uses the value given detailed D See also DETAILED REPORTS When selected on the command line this overrides the configuration setting for DETAILED REPORTS from the configuration file and produces detailed reports for all appropriate outputs COV rs lt filename gt See also
40. sing this value will create fewer models Note that this setting applies only to groups found in LOKI and it will not restrict the size of groups loaded with the ADD_ GROUP configuration option RS_SOURCE Syntax RS_SOURCE filename RS SOURCE Illumina 660Quad txt This option allows the user to limit the list of SNPs to those included in the file of interest Typically this will be a list of SNPs that are on a given platform as the above example illustrates The file must be a list of only unique SNP RS identification numbers the RS prefix removed as described in the input files section See also SNP List MAP_SOURCE Syntax MAP_SOURCE filename MAP SOURCK Variants es This option is similar to the RS_ SOURCE except that it allows the user to include variants that may not have actual RS numbers The format of this file must be PLINK 4 column format which we summarize in the Variant List section For more details on PLINK see http pngu mgh harvard edu purcell plink See also Variant List ADD_GROUP Syntax ADD_GROUP filename ADD GROUP new group txt This gives the user the option of adding in custom groups of genes that are known to the user but are not captured in the LOKI database The input is a plain text file containing the type of group collection as well as the groups and their associated genes See also Custom Groups INCLUDE_GROUPS Syntax INCLUDE_GROUPS integer integer INCLUDE GROUPS
41. some of the marker RSID The unique identifier of the marker Usually this will be an RSID but when MAP SOURCE is used this is the identification string given to Biofilter Gene Name The name of the gene containing the marker Note that if a given marker is in multiple genes each SNP gene combination will be on a separate line as the location within the gene may be different for each SNP gene pair e Location w in Gene This describes the location of the marker within the associated gene This value can take one of the following values o Interior The SNP is located both within the canonical NO LD population boundaries of the gene as well as the boundaries of the gene defined by the population Note when using the NO LD population this is the only valid value for this column o Flanking The SNP is located outside the canonical boundaries of the gene but inside the population specific boundaries o Exterior The SNP is located outside the population specific boundaries of the gene This should only be seen if the SNP was explicitly linked to the gene in question which is currently not available as of Biofilter v1 1 Chrom RSID Gene Name Location w in Gene A Roz G1 InNtTErior dE RSSI G2 Interior TE RSSI G5 Interior e EST G5 Interior 1 IRS IL AL G4 Flanking ae RS2 3 y G6 Flanking Gene Gene Models Suffix model archive gene gene This report is a tab delimited text file containing the list of the gene
42. t follow the following format which will be explained below Source Name Source Type Source Description GROUP Name Description lalias alias CHILDREN group group GROUP Source Name Source Type Source Description The first line of the file must contain the name of the collection of groups along with the type of collection The Source Name must be a string with no spaces and it must be unique from any other source already defined in the LOKI database The number of sources is very limited and if the name of this group is not the same as any database of biological knowledge there should be no namespace conflicts The Source Type defines the type of information contained within this custom collection of groups This value must be a string taking one of the following values DISEASE INDEPENDENT This option is for a collection of groups that is not related to any particular disease DISEASE DEPENDENT This option is for a collection of groups that is related to a particular disease of interest GENE_COLLECTION SNP_COLLECTION The Source Description is an optional string designed to help the user keep track of the actual meaning behind the group The description may contain any character except a newline An GROUP Name Description This line defines the beginning of a new group This line must be given on the second line and it may occur on subsequent lines wi
43. thin the file The Name must be a string with no spaces and it must be unique from any other group name defined within the current custom group file This name can be used to identify the current group as a child of another group The Description is an optional string used to describe the group CHILDREN group group This line defines associations between groups within the custom group collection The first group given is considered the parent and all subsequent groups are the children Note that there must be at least two groups given in this line alias alias This line is a whitespace separated list of gene names that can be found in the LOKI database Currently only non ambiguous gene aliases are considered valid inputs Examples Because this is possibly the most complex input file available to Biofilter we have provided a couple examples below The simple group definition should be sufficient for anyone attempting to use a list of genes that are associated with a given disease The more complex example illustrates an interrelated pathology Simple Group Definition This file is a single group containing a simple collection of genes that are associated with Alzheimer s ALZHEIMERS DISEASE DEPENDENT Alzheimer s Collection ROUP alz assoc Genes associated with Alzheimer s E H1A POA1BP POA2 CAMK1G CFH CHRNB2 W Q G A A A A Complex Group Collection The following example shows a
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