Mega2: validated data-reformatting for linkage and association analyses
© Baron et al.; licensee BioMed Central Ltd. 2014
Received: 18 July 2014
Accepted: 14 November 2014
Published: 5 December 2014
In a typical study of the genetics of a complex human disease, many different analysis programs are used, to test for linkage and association. This requires extensive and careful data reformatting, as many of these analysis programs use differing input formats. Writing scripts to facilitate this can be tedious, time-consuming, and error-prone. To address these issues, the open source Mega2 data reformatting program provides validated and tested data conversions from several commonly-used input formats to many output formats.
Mega2, the Manipulation Environment for Genetic Analysis, facilitates the creation of analysis-ready datasets from data gathered as part of a genetic study. It transparently allows users to process genetic data for family-based or case/control studies accurately and efficiently. In addition to data validation checks, Mega2 provides analysis setup capabilities for a broad choice of commonly-used genetic analysis programs. First released in 2000, Mega2 has recently been significantly improved in a number of ways. We have rewritten it in C++ and have reduced its memory requirements. Mega2 now can read input files in LINKAGE, PLINK, and VCF/BCF formats, as well as its own specialized annotated format. It supports conversion to many commonly-used formats including SOLAR, PLINK, Merlin, Mendel, SimWalk2, Cranefoot, IQLS, FBAT, MORGAN, BEAGLE, Eigenstrat, Structure, and PLINK/SEQ. When controlled by a batch file, Mega2 can be used non-interactively in data reformatting pipelines. Support for genetic data from several other species besides humans has been added.
By providing tested and validated data reformatting, Mega2 facilitates more accurate and extensive analyses of genetic data, avoiding the need to write, debug, and maintain one’s own custom data reformatting scripts.
Mega2 is freely available at https://watson.hgen.pitt.edu/register/.
The gene-discovery process is very well advanced at the data-generation end with sophisticated database management systems, laboratory information management systems, and bioinformatics tools. There has also been enormous progress in terms of analytical software. However, very little has been done to facilitate the efficient transfer of data from the generation stage to the analysis stage; analysis programs have diverse and stringent requirements (not always clearly documented) on how the input data should be formatted, which is often very different from how the generated data are formatted. Researchers face the need to collect and collate genetic data from diverse sources, and this need has increased significantly as rapidly improving technology generates orders of magnitude more data. As new analysis programs come into being, data setup and organization continues to be an error-prone and very time-consuming task if performed manually, but ideal for well-tested computer automation.
In the course of a single study of the genetics of a complex disease, the optimal analysis might require use of several different programs. For example, one might want to use pedstats  to check for data validity, PREST , to check for relationship errors, SOLAR , to test for linkage, and Mendel - to test for association in the presence of linkage. Each provides the best possible analysis but also has its own strict input format requirements, so there is great value in being able to quickly and easily convert one’s data format as required.
To meet these needs, we developed Mega2, the Manipulation Environment for Genetic Analysis ,, which automates common data reformatting tasks, thereby accelerating analyses, saving time, and reducing errors. We describe here recent major updates to Mega2, which include improvements in memory efficiency, improved support for commonly used input formats such as PLINK and VCF, and addition of several more target output formats.
Mega2 was originally released in January 2000, and has undergone continuous revisions since. Mega2 was originally written in C, but now has been written in C++, allowing us to now use modern object-oriented programming techniques. Mega2 was designed to be used in a Unix environment, and so for extended functionality, such as plotting results with R or running generated scripts, uses a few other programs commonly available in the Unix environment, such as Perl, Awk, Python, tcsh and bash-shells, and R. Perl is used for producing formatted output such as tables and HTML reports, and R is used to create graphical output using our R “nplplot” package. The currently released version (4.7.1) of Mega2 is available in Additional file 1; for updated versions, please visit the project home page as listed in the “Availability and requirements” section.
Mega2 was originally written without much attention to memory efficiency, as at that time a genome-wide scan consisted of only several hundred markers. Thus, Mega2’s memory usage was initially on the order of people x allele x 8 bytes, as each person/allele combination was assigned a pointer to the allele label. For two-allele marker data, we have markedly reduced memory requirements by replacing each pair of 8 byte pointers with a 2 bit index specifying which alleles the individual has. We also allow the user to switch out of the 2 bit mode if they want to work with more highly polymorphic markers. Further memory efficiencies have been gained by not storing (unknown) genotypes for completely untyped individuals, but who are still needed to specify the pedigree structure. As a result of these improvements, Mega2 now can handle genome-wide scale data – for example, 895K two-allele markers on 3.1K people requires only 1.12 Gb of memory for Mega2 processing.
Mega2 can now read data in from a wider variety of input formats. Many researchers now have their data in PLINK-format , so we have extended Mega2 to support reading PLINK input files. Mega2 now directly processes PLINK ‘ped’ and binary input formats. Mega2 also supports PLINK phenotype files, as well as Mega2-format map files that specify a sex-specific genetic map. Furthermore, we recently added support for reading Variant Call Format (VCF) files and their binary compressed equivalent, BCF; most sequencing-based data are now in VCF/BCF format .
Mega2 currently supports 37 output targets seven new ones have been added since 2011
SimWalk2 format 
Mendel format 
Vintage MENDEL format 
Vitesse format 
Cranefoot format 
GeneHunter-Plus format 
Testing loci for HWE
Mega2 annotated format
Allegro format 
Conversion to nuclear families
MLBQTL format 
PLINK format  (binary added 1/13)
SAGE format 
FBAT format  (added 1/13)
SPLINK format 
Morgan format  (added 6/13)
SIMULATE format 
Merlin format 
Old SAGE format
Loki format 
PLINK/SEQ format  (added 10/13)
The Mega2 distribution package has been updated to provide greater ease of installation and compatibility with many Unix environments. It contains added support for migration of legacy input data to our updated formats.
In applied data analysis, a thorough analysis often requires the use of multiple different programs, many of which have their own precise input format requirements. Reformatting programs such as Mega2 can markedly accelerate analyses by providing accurate, quick, and error-free conversion routines. This need has been recognized in the area of population genetics, where several reformatting programs have been written -, including one that converts to 52 different formats . In the area of human genetics, limited reformatting options have been made available as part of larger database systems. For example, the GeneLink database system  initially exported into LINKAGE -,, GAS , or RelCheck , formats, while the Integrated Genotyping System  exported into several formats, including Merlin , GeneHunter ,, QTDT , and Transmit  formats. However, these database systems can be difficult to install and maintain. Other more stand-alone approaches to reformatting in this area include SIB-PAIR , by David Duffy, which is a command-line oriented program that can create locus and pedigree files in a variety of formats, such as FISHER , GAS , Genehunter ,, LINKAGE -,, LOKI , MENDEL , MERLIN , PAP , and SAGE . SIB-PAIR appears to require very detailed line-by-line commands that would make it harder to use than Mega2 for most users. Another program is fcGENE  (available from SourceForge), which is focused on converting PLINK-format data for imputation (MaCH , IMPUTE , BEAGLE ,-, BIMBAM ), and then converting the resulting imputed data into the following formats: PLINK , SNPTEST , HAPLOVIEW , EIGENSOFT ,, GenABEL , and VCF . While fcGENE is fast and easy to use, it is currently limited (e.g., it does not accept VCF or LINKAGE format as input, it only supports a single dichotomous phenotype, it does not support selection by chromosome, etc.).
ALOHOMORA  provides an elegant interface for carrying out linkage analyses of Affymetrix 10K single nucleotide polymorphism (SNP) genotype data. This program actually uses Mega2 as its internal reformatting engine for some of its options.
PLINK  is an association analysis toolset that has a variety of data management and filtering options for handling large-scale SNP data. The main focus of PLINK is population-based unrelated samples, with some support for family-based association testing. PLINK only exports data in a few limited formats. We have used PLINK on our family data to carry out data cleaning, but then still needed Mega2 to reformat the data in order to carry out analyses using other external programs. In our experience, it is difficult to use PLINK on family data while maintaining the original pedigree structures upon output, as PLINK favors automatically filtering out individuals with low genotyping success rates (such as untyped founders).
From this brief survey of currently available data reformatting software, two things are immediately apparent: many researchers have recognized the need for providing one’s data in many different formats; and Mega2, which is free, open source, and available on Unix, Windows, and Macintosh platforms, is well-positioned to continue to fill this need.
When carrying out quality control and statistical analyses for a genetic study of a human disease, one quickly discovers that data organization and analysis set-up is a critical, time-consuming, and extremely tedious task. Furthermore, one often needs to use several different analysis programs, each with its own idiosyncratic input format requirements. To meet these needs, we developed Mega2, taking the time to carefully understand the precise (sometimes poorly documented) requirements of each target format, implementing our data reformatting pipeline in tested and well-documented code. Mega2’s tested and validated data conversion options expands the universe of possible analyses for the average researcher by removing the hurdle of having to tediously write, check, debug, and maintain their own conversion scripts.
Availability and requirements
Project name: Mega2
Project home page: https://watson.hgen.pitt.edu/register/
Operating systems: Linux, Macintosh OS X, Windows, Solaris
Programming language: C++
Other requirements: R, Perl, Python, awk, bash, and csh
License: GNU GPL v3
Any restrictions to use by non-academics: None.
This work was supported by the National Institutes of Health grant R01 GM076667 (P.I. Daniel E. Weeks) and the University of Pittsburgh. We thank Lee Almasy, Mark Schroeder, and William P. Mulvihill for early contributions as programmers to our Mega2 project.
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