high - throughput genotyping technologies contribute greatly to the hunt for susceptibility genes for complex diseases by constantly improving the precision of and the capacity for parallel genotyping 1 , 2 , 3 .
driven by these emerging technologies , some challenging projects , such as hapmap phase iiii 4 , 5 , encode 6 , 7 and 1000 genomes ( 8) , were proposed to explore the pattern in the human genome of common or rare variation .
broad application of the whole - genome single nucleotide polymorphism ( snp ) chips into genome - wide association studies ( gwas ) has also led to the discovery of more than 100 loci for nearly 40 common diseases and traits ( 9 ) . due to the great challenges presented by huge datasets ,
two strategies have been developed for performing data analysis for whole - genome genotyping data .
one strategy is to use open - source or commercial packages that have been designed for gwas .
plink ( 10 ) is one of the most popular and powerful of these programs .
genabel ( 11 ) , gwaf ( 12 ) , snpassoc ( 13 ) and snpmatrix ( 14 ) are programs based on r language , which is a well - executed open - source framework .
gwas analyzer ( 15 ) , gwas gui ( 16 ) and maven ( 17 ) provide platforms for intuitively viewing the results of gwas .
snptest ( 18 ) also can be used for data analysis with a software suite consisting of several programs .
the above software packages are easily compatible with chip data and possess more or fewer functions according to the purpose of genetic analysis .
the other strategy for performing these analyses is to take advantage of classic genetic programs that implement specific functions , such as transmission disequilibrium tests ( tdt ) for alleles [ unphased ( 19 ) ] , calculating linkage disequilibrium ( ld ) measures and constructing ld maps [ haploview ( 20 ) , gold ( 21 ) and jlin ( 22 ) ] , haplotype inference [ phase ( 23 ) ] , haplotype block partition [ hapblock ( 24 ) ] , tagsnps selection [ tagger ( 25 ) ] and multilocus interaction methods [ mdr ( 26 ) ] .
however , most of the classic programs that are available would be not suitable for inputting the chip data directly and require custom - made input , which results in the inconvenience of converting raw genotyping files into various data formats . snp_tools ( 27 ) is an ms - excel add - in that can convert genotyping files into several formats , such as haploview and phase . because it is an add - in program for excel ( 255 columns and 65,536 rows in ms - excel 2003 ) , supports for the chip data are scarce .
furthermore , output formats are limited to haploview , snphap , phase and pedphase . however , as classic programs implement specific algorithms for genetic analysis and provide an option for analysis of gwas data , it is important to develop a tool to bridge these programs with raw genotyping data . here , we present a powerful , user - friendly , lightweight toolkit named snptransformer for gwas .
the major aim of snptransformer is to convert genotyping input ( such as linkage and chip formats ) into various outputs ( such as packages for association , tdt , calculating ld measures , haplotype inference , haplotype block partition , tagsnps and multilocus interaction ) . with this toolkit
, researchers can avoid manual coding between formats and can easily construct workflows for data analysis . additionally , accessory tools in snptransformer perform data previewing , relational operations on ids , recoding data files and simulating map files that assist data conversion and gwas analysis .
snptransformer v1.0 was written using c++ builder with a concise and user - friendly interface .
it was built and tested under windows xp . because snptransformer is a lightweight toolkit , no installation or other package
all binary programs , source codes , tutorials , examples and updates are available freely under the gnu general public license at the snptransformer website ( http://snptransformer.sourceforge.net ) .
the current version of snptransformer provides five major modules for gwas : transformer , previewer , operator , coder and simulator ( table 1 ) . as the most important module of this software package
, transformer is positioned in the main window of the software and is responsible for converting file formats from genotyping data to the formats of specific classic genetics analytical tools ( figure 1 and table 1 ) .
input data include genotyping files , marker files and pedigree files ( figure 2 ) .
formats of genotyping files can be one of the following : linkage format , which integrates genotyping data and pedigree information in a single file ; chip format , which is compatible with whole - genome genotyping data of affymetrix , illumina and many other chip platforms ( see manual in detail ) ; or custom format , which is similar to sequencing results . a marker file stores chromosome information and the physical positions of snps , as well as genetic positions , which are usually set to zero .
pedigree files contain information on individual ids , gender and disease status , or qualitative traits , and this file type is suitable not only for pedigree data such as linkage and tdt , but also for case / control data . because a pedigree file is the same as the pedigree part ( first six columns ) of a linkage format , it is not required for a linkage format genotyping file .
the output formats of snptransformer are diverse and represent essential genetic analyses for gwas ( figure 2 ) . similar to many other tools
plink is one of the most popular software platforms for gwas and can perform various genetic analyses , and the marker file of snptransformer references that of plink , leading to consistency between the input data in linkage format for snptransformer and those of plink .
haploview is a program that presents ld - based analysis tools : tdt , calculating ld measures and constructing ld maps , inferring haplotypes , partitioning haplotype blocks and selecting tagsnps and case / control association .
unphased , gold , jlin , phase , haploblock and tagger each carry out one of these analysis steps .
mdr excels at performing multi - locus interaction analysis and is widely used in association studies . at present , no tool related to two - locus interaction is included in snptransformer due to the lack of well - recognized analysis tools for this except for logistic regression , which has quite a different format from the output of snptransformer .
additional custom formats can be output using some options that are designed to count genotype / allele numbers and frequencies . to filter input data , snp or sample lists
can be set to improve data quality or to narrow the target scope . with these filters
, transformer can act as an extractor that searches for specific genotypes for meta - analysis .
the other four modules in snptransformer have been developed to satisfy specific demands , such as previewing data files and retrieving annotation information for positive snps ( table 1 ) . since genotyping or annotation files of whole - genome snp chips are too large to open with generic text - editor tools
, previewer performs previewing of the top n lines of these files . with this function
, users can view the format of annotation files for affymetrix genechip 6.0 sets that are larger than hundreds of megabytes .
furthermore , previewer can reorder the columns of input file to attain a new file that is arranged as required for further analysis . during the processing of genetic analyses , the relational operations can help search for specific information .
for example , annotation information for positive snps can be retrieved by performing the  inner join  or  left join 
operations including one - item ( operating on single file ) and two - item operations ( operating between two files ) are implemented by operator , similar to relational databases such as mysql and access support .
coder recodes genotypes between letters and numbers that can code one heterozygote with two alleles  a  and  t  as  at  ( acgt - coding ) ,  14  ( 1234-coding ) ,  12  ( 12-coding ) ,  ab  ( ab - coding ) or even  1  ( 012-coding ) . another module , called simulator , is used to generate pseudo map and pedigree files without the use of real information . when using haploview to calculate ld measures , physical positions are not required to be real numbers , but rather the order of snps is sufficient if the pairwise distance can be ignored and if the order of snps is correct . in such a case
considerable work remains to be accomplished in the future to meet the needs of gwas analysis .
the first step in this process is to adopt parallel technology to further improve the speed of the analysis process .
another important aim in improving snptransformer is to design a personal interface for affymetrix and illumina snp chips to provide more options . in the current version ,
as the most important module of this software package , transformer is positioned in the main window of the software and is responsible for converting file formats from genotyping data to the formats of specific classic genetics analytical tools ( figure 1 and table 1 ) .
input data include genotyping files , marker files and pedigree files ( figure 2 ) .
formats of genotyping files can be one of the following : linkage format , which integrates genotyping data and pedigree information in a single file ; chip format , which is compatible with whole - genome genotyping data of affymetrix , illumina and many other chip platforms ( see manual in detail ) ; or custom format , which is similar to sequencing results . a marker file stores chromosome information and the physical positions of snps , as well as genetic positions , which are usually set to zero .
pedigree files contain information on individual ids , gender and disease status , or qualitative traits , and this file type is suitable not only for pedigree data such as linkage and tdt , but also for case / control data . because a pedigree file is the same as the pedigree part ( first six columns ) of a linkage format , it is not required for a linkage format genotyping file .
the output formats of snptransformer are diverse and represent essential genetic analyses for gwas ( figure 2 ) .
similar to many other tools , the linkage format is considered the basic format of snptransformer .
plink is one of the most popular software platforms for gwas and can perform various genetic analyses , and the marker file of snptransformer references that of plink , leading to consistency between the input data in linkage format for snptransformer and those of plink .
haploview is a program that presents ld - based analysis tools : tdt , calculating ld measures and constructing ld maps , inferring haplotypes , partitioning haplotype blocks and selecting tagsnps and case / control association .
unphased , gold , jlin , phase , haploblock and tagger each carry out one of these analysis steps .
mdr excels at performing multi - locus interaction analysis and is widely used in association studies . at present , no tool related to two - locus interaction is included in snptransformer due to the lack of well - recognized analysis tools for this except for logistic regression , which has quite a different format from the output of snptransformer .
additional custom formats can be output using some options that are designed to count genotype / allele numbers and frequencies . to filter input data , snp or sample lists can be set to improve data quality or to narrow the target scope . with these filters , transformer can act as an extractor that searches for specific genotypes for meta - analysis .
the other four modules in snptransformer have been developed to satisfy specific demands , such as previewing data files and retrieving annotation information for positive snps ( table 1 ) . since genotyping or annotation files of whole - genome snp chips are too large to open with generic text - editor tools
, previewer performs previewing of the top n lines of these files . with this function , users can view the format of annotation files for affymetrix genechip 6.0 sets that are larger than hundreds of megabytes .
furthermore , previewer can reorder the columns of input file to attain a new file that is arranged as required for further analysis . during the processing of genetic analyses , the relational operations can help search for specific information .
for example , annotation information for positive snps can be retrieved by performing the  inner join  or  left join 
operations including one - item ( operating on single file ) and two - item operations ( operating between two files ) are implemented by operator , similar to relational databases such as mysql and access support .
coder recodes genotypes between letters and numbers that can code one heterozygote with two alleles  a  and  t  as  at  ( acgt - coding ) ,  14  ( 1234-coding ) ,  12  ( 12-coding ) ,  ab  ( ab - coding ) or even  1  ( 012-coding ) . another module , called simulator , is used to generate pseudo map and pedigree files without the use of real information . when using haploview to calculate ld measures , physical positions are not required to be real numbers , but rather
the order of snps is sufficient if the pairwise distance can be ignored and if the order of snps is correct .
in such a case , a map file can be easily simulated from a snp list by simulator .
considerable work remains to be accomplished in the future to meet the needs of gwas analysis .
the first step in this process is to adopt parallel technology to further improve the speed of the analysis process .
another important aim in improving snptransformer is to design a personal interface for affymetrix and illumina snp chips to provide more options . in the current version ,
 high - throughput genotyping chips have produced huge datasets for genome - wide association studies ( gwas ) that have contributed greatly to discovering susceptibility genes for complex diseases . 
 there are two strategies for performing data analysis for gwas . 
 one strategy is to use open - source or commercial packages that are designed for gwas . 
 the other is to take advantage of classic genetic programs with specific functions , such as linkage disequilibrium mapping , haplotype inference and transmission disequilibrium tests . 
 however , most classic programs that are available are not suitable for analyzing chip data directly and require custom - made input , which results in the inconvenience of converting raw genotyping files into various data formats . 
 we developed a powerful , user - friendly , lightweight program named snptransformer for gwas that includes five major modules ( transformer , operator , previewer , coder and simulator ) . 
 the toolkit not only works for transforming the genotyping files into ten input formats for use with classic genetics packages , but also carries out useful functions such as relational operations on ids , previewing data files , recoding data formats and simulating marker files , among other functions . 
 it bridges upstream raw genotyping data with downstream genetic programs , and can act as an in - hand toolkit for human geneticists , especially for non - programmers . 
 snptransformer is freely available at http://snptransformer.sourceforge.net . 