SimWalk2 version 2.82 includes greatly improved mistyping analysis compared to version 2.80. Also, under the parametric linkage analysis option, locus heterogeneity is handled in more generality.
If you are still using a version of SimWalk2 older than 2.60, then please consider this a mandatory upgrade since the fixes introduced in version 2.60 can effect the p-values of the statistics from the Non-Parametric Linkage analysis!
Changes from version 2.80 to 2.82
MISTYPING ANALYSIS
The mistyping analysis option that was introduced in version 2.80 is now greatly improved. The format of the output remains the same: at each observed genotype an overall posterior probability of mistyping at that genotype is produced. However, the MCMC sampling procedure is now much improved and the results now agree very well with exact analysis on all those pedigrees that can be examined using both methods.
PARAMETRIC LINKAGE ANALYSIS
It is now much easier to study possible locus heterogeneity. The degree of locus heterogeneity is commonly measured by alpha, defined as the a priori portion of pedigrees linked at a location, i.e., if there is a trait locus in the region, alpha is the proportion of these pedigrees that contains an affected genotype at this trait locus.
Overall parametric linkage analysis results are now always reported in two ways: (1) for alpha = 1.0 (i.e., assumming no locus heterogeneity) and (2) maximized over a grid of alpha values: 0.00, 0.05, 0.10, ..., 0.90, 0.95, 1.00. In addition, if an alpha value less than 1.0 is specified in batch item #13.2, then several more results are listed. These additional results include for each pedigree and each position the posterior probability that that pedigree is one of the linked pedigrees, given the selected value for alpha. This enables one to separate the linked and unlinked pedigrees in an unbiased fashion.
Changes from version 2.60 to 2.80GENERAL IMPROVEMENTS
New option for SimWalk2 to run silently, i.e., with absolutely no screen output. See batch item #5 in the control file. This option is particularly useful for running SimWalk2 in the background.New output file in all analysis options, VIDEO-nn.TXT. This file contains up to date progress messages describing the current state of the SimWalk2 run. This file is produced regardless of whether SimWalk2 is reporting messages to the screen.
New input data file for the locus map information. The order of the loci and the recombination frequencies should now be listed in the map data file, whose name is specified in batch item #9 in the control file. The map data file format makes it easy to produce. Please note that all analysis is performed using only those loci in both the map and locus data files.
(If there is a trait locus to be analyzed, then it must be the first locus listed in both the map and locus data files. Also, the previous method of specifying the locus map within the control file will continue to work, for now, but is no longer the preferred method.)PARAMETRIC LINKAGE ANALYSIS
New parameter used to model complex traits. In batch item #13.2 in the control file one may now set the a priori proportion of pedigrees segregating an affected gene linked to the marker loci. That is, when one suspects the trait can be caused by more than one locus (locus heterogeneity), one can specify the likely proportion of the pedigrees in the data set that have an affected gene linked to the marker loci under study. The default value for this parameter is 1.0, i.e., all pedigrees have the linked gene. This parameter is used to weight the location scores, to appropriately take locus heterogeneity into account without "cherry picking" the pedigrees, which would bias the results.MISTYPING ANALYSIS
New analysis option detects genotype errors. This analysis option is specified by setting batch item #1 to the value 5. Under this analysis option SimWalk2 reports the overall probability of mistyping at each observed genotype (in fact, at each observed allele). Unfortunately, genotype mistypings are common and can easily mask linkage. Some of these mistypings result in non-Mendelian inheritance and are reasonably easy to find; others are consistent with Mendelian inheritance and are revealed only by the decrease in pedigree likelihood due to the spurious excess recombinations the mistypings imply. By using a multipoint analysis that includes all the available data, SimWalk2 provides mistyping probabilities that take both types of errors into account. When genotypes are flagged with a significant probability of mistyping, the raw data should be re-evaluated and perhaps replicated. As a modicum of missing data is preferable to false data, removing data that is questionable should be considered as well.
Please let me know if you have any questions about SimWalk2 and in particular if there are any changes or additions that would make this program more useful to you.
Thank you,
Eric Sobel <esobel@watson.pitt.hgen.edu>