#MAPMAKER help file - do not edit! @TOPIC general info commands The following help topics are reference information only (not commands). @basic usage steps This is a quick reference list of the steps needed to start an analysis with SIBS. Steps in *CAPS* are common to all data sets, *lower case* steps are for specific types of data. To get more specific usage or analysis information for particular steps type 'help '. 1. *LOAD MARKER DATA* ('load markers ') The locus file can be in either Linkage format or our own internal format. 2. *SET MAP* ('set map marker1 dist1 marker2 dist2 marker3...') This step can be SKIPPED if the map was given in the loci file. If all distances between markers are less than .5 distances will be assumed to be recombination fractions, otherwise distances will be interpreted as cM. Typing 'set map' with no arguments will list the current map. 3. *sex-linked status* ('sex linked ') If data is from markers on the X chromosome, this setting must be turned on BEFORE loading the pedigrees. All males must be homozygous for X markers. You cannot load a mixture of X-linked and autosomal markers in the same session. Affected males and females are both analyzed in commands that run off affectation status (estimate, infomap, and exclude) but in this version only phenotyped MALES are looked at in the other commands (although females are used to set maternal phase). 4. *PREPARE PEDIGREES* ('prepare pedigrees ') This command loads a Linkage-format pedigree file with genotypes and checks for formatting and non-Mendelian inheritance errors. PHENOTYPE data is also loaded as part of the 'prepare' command (for more information on loading phenotype data and the FORMAT of the file see 'help prepare pedigrees'). After loading data, specific pedigrees can be removed/selected with the commands 'select pedigrees' and 'remove pedigrees'. If you have sibships with more than two affected sibs you can use the 'pairs used' command to select which pairs will be used (if you decide to use multiple pairs from the same sibship, be sure to read the help under the 'pairs used' command, as the correct weighting for multiple sibpairs is not known). 5. *set scanning increments* ('increment distance ' or 'increment steps ') The default is to scan every 1cM, use this command to change the scanning increments along the map. 6. *SCAN* ('scan') This command computes the probability of each pair of selected sibs sharing 0, 1, or 2 alleles IBD (0 or 1 alleles IBD in the case of X-linked data), which is needed for ALL the analysis commands. 'Scan' must be run after any settings related to the map change, or if the pedigrees/pairs selected change. At this point you are ready to run any of the qualitative and quantitative analysis commands ('estimate', 'exclude', 'infomap' and 'haseman elston', 'nonparametric', 'ml variance', and 'penetrance' respectively). All commands other than loading markers and pedigrees can be repeated at any time during the session. If you just type 'help' you will get a list of a variety of flags ('postscript on/off', 'single point on/off') that are available to tailor the session to your particular needs. Other helpful notes on running the program: *command abbreviations (i.e., 'prep ' instead of 'prepare pedigrees ') In addition to the abbreviations listed for each command, commands can be shortened to just a few unique letters. *default answers to input questions are provided in [] and are accepted just by hitting or . *commands can be safely broken out of by typing . *the path for default filenames is the path from which the data was loaded *the program provides a reverse-video message as to where it is in the analysis, if this is not being properly flushed from your screen with each update, try typing 'setenv TERM vt100' at your UNIX shell prompt. @journal reference How to cite MAPMAKER/SIBS: L. Kruglyak and E. Lander. (1995) "Complete Multipoint Sib Pair Analysis of Qualitative and Quantitative Traits". Am. J. Hum. Genet. 57:439-454. @copyright Copyright (c) 1995 Whitehead Institute for Biomedical Research. All rights reserved. Redistribution and use in source and binary forms, with or without modification, are permitted provided that the following conditions are met: 1. Redistributions must reproduce the above copyright notice, this list of conditions and the following disclaimer in the documentation and/or other materials provided with the distribution. Redistributions of source code must also reproduce this information in the source code itself. 2. If the program is modified, redistributions must include a notice (in the same places as above) indicating that the redistributed program is not identical to the version distributed by Whitehead Institute. 3. All advertising materials mentioning features or use of this software must display the following acknowledgment: This product includes software developed by the Whitehead Institute for Biomedical Research. 4. The name of the Whitehead Institute may not be used to endorse or promote products derived from this software without specific prior written permission. We request that users of this software inform us by sending email to software_registration@genome.wi.mit.edu (a form can be found by typing 'help registration' in the program). We also request that use of this software be cited in publications as: L. Kruglyak and E. Lander. (1995) "Complete Multipoint Sib Pair Analysis of Qualitative and Quantitative Traits". Am. J. Hum. Genet. 57:439-454. THIS SOFTWARE IS PROVIDED BY THE WHITEHEAD INSTITUTE ``AS IS'' AND ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE ARE DISCLAIMED. IN NO EVENT SHALL THE WHITEHEAD INSTITUTE BE LIABLE FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL, EXEMPLARY, OR CONSEQUENTIAL DAMAGES (INCLUDING, BUT NOT LIMITED TO, PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES; LOSS OF USE, DATA, OR PROFITS; OR BUSINESS INTERRUPTION) HOWEVER CAUSED AND ON ANY THEORY OF LIABILITY, WHETHER IN CONTRACT, STRICT LIABILITY, OR TORT (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT OF THE USE OF THIS SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGE. @registration ------------------------------------------------------------------------- SOFTWARE USAGE E-MAIL NOTIFICATION FORM We appreciate your interest in the software developed at the MIT Genome Center, and we would be grateful if you could drop us a note telling us that you are using it (this also ensures that you will receive news of any updates). Could you please take a moment to fill out this form and mail it to software_registration@genome.wi.mit.edu? <---------------------- CUT HERE ------------------> SOFTWARE PACKAGE: YOUR NAME: INSTITUTION: MAIL ADDRESS: PHONE NUMBER: FAX NUMBER: E-MAIL ADDRESS: WHERE DID YOU HEAR ABOUT THIS SOFTWARE?: WHERE DID YOU OBTAIN IT FROM?: ADDITIONAL COMMENTS WELCOME: This program was developed at the Whitehead Institute for Biomedical Research, 1995 @bug reports Please send bug reports (or any comments about new features that might be needed) to : mpreeve@genome.wi.mit.edu Please send a sample of the input that causes the error to appear, and put the 'photo' option on to record the commands used so that we can duplicate the error. Thanks! @TOPIC loading data and pedigrees Commands to set up your data for the analysis commands. @load markers This command reads in the marker-locus data (allele frequencies for each genetic marker and the map if given in the file). The file may be in one of two formats: 1. Linkage parameter file (output from PREPLINK) See the file sample.loc as an example 2. Our internal marker information format (which contains the same information and also includes map distance between markers). See the file internal.loc as an example. This should be the first command of any SIBS session as this information is required by every subsequent step in the mapping process. If all the distances in the map are < .5, the map will be interpreted as being in recombination fractions, otherwise, centimorgans will be assumed. For our internal file format map distances are required as part of correct input. Distances in the Linkage format are specified after the "<< SEX DIFFERENCE, INTERFERENCE" line near the bottom of the file. (The current map can be checked/updated at any time by using the 'set map' command. See 'help set map' for more information.) If the parents are untyped marker allele frequencies are more important and can cause false-positives if misspecified. (Underestimating the frequency of an allele will lead to overestimating the degree of IBD sharing at the locus.) See 'help allele frequencies' for more information on testing how sensitive your results are to changes in allele frequencies. Note -- It is usually better to enter recombinationally inseparable markers with a cM distance of .1, as if there is a recombination between them in your data set it will cause a likelihood = 0 error. @sex linked *Setting up for X-linked data sibpair:1> sex linked on data will be analyzed in sex-linked mode This command controls in what inheritance mode the data will be analyzed. If your data is sex-linked you must set this BEFORE loading pedigree data. All males should be homozygous for X markers and this is enforced as the pedigree file is loaded. (If you forget to toggle it on before loading pedigree data you may get INCONSISTENT Mendelian errors, if this occurs just set sex-linked on and load the pedigree file again). Once you have toggled on the sex-linked flag all the sharing proportions in the program will be altered to indicate that brother/brother pairs can share 0 or 1, brother/sister pairs can share 0 or 1, and sister/sister pairs can share 1 or 2. *Setting sex-linked status automatically -- The first line of a Linkage loci file has (for example): 12 0 0 5 << NO. OF LOCI, RISK LOCUS, SEX-LINKED (IF 1), PROGRAM If you set the third parameter to '1': 12 0 1 5 << NO. OF LOCI, RISK LOCUS, SEX-LINKED (IF 1), PROGRAM sex-linked mode will automatically be turned on and the program will correctly read past the extra liability/penetrance class lines for X-linked data. (Reading past the extra lines can also be accomplished by turning 'sex linked on' before loading marker-locus data.) There is no way to automatically turn on X-linked status with our internal marker file format. *Important note -- True X-linked analysis is ONLY done for affectation analysis commands ('estimate', 'infomap', and 'exclude'), for phenotypic analysis commands, only phenotyped males are considered (although female sib genotypes are used for determining maternal phase/allele information and to clarify whether two male sibs share IBD rather than just IBS). *Reference for more on X-linked analysis: "An Extension of the Maximum Lod Score method to X-linked loci", Cordell, et al. Annals of Human Genetics (in press, expected Oct. 95). @prepare pedigrees This command reads through a pedigree file and does some of the initial mapping set-up. The pedigree file is the same as the LINKAGE pedigree input format (before running MAKEPED or doing any preprocessing!): Each line of the file must have the structure: 3 12 8 9 1 2 1 1 2 8 3 0 0 4 6 1 3 ... (a) (b) (c) (d) (e) (f) (g) (h ------------------------) (a) pedigree name (can be a string) (b) individual ID # (c) father's ID # (d) mother's ID # (e) sex (1=MALE, 2=FEMALE, sex must be specified, 'unknown' is not valid) (f) affectation status (1=UNAFFECTED, 2=AFFECTED, 0=UNKNOWN) (g) liability class (optional) - classes specified in marker data file (h) marker genotypes (these must be integers, 0 indicates missing data) All ID numbers must be integers, use zeros if the parents are missing. Both parents must be listed (if one parent is known and the other not, just insert a dummy parent and fill the genotypes for each marker with "0 0"). Please consult documentation for the Linkage program if you need any further information regarding the Linkage file formats. SIBS requires that all pedigrees be simple nuclear pedigrees (no half-sibs, cousins, etc -- these pedigrees are better suited for GENEHUNTER) with two or more affected/phenotyped sibs. If you load more than two sibs, all sibs will be used to determine parental phase information if the parents alleles are missing. For the analysis methods the default is to use just the first pair of affected/phenotyped sibs. To use all independent pairs of sibs, or all pairs use the 'pairs used' command. When using 'all pairs', each pair is considered as an independent pedigree but a weight (2/num_affecteds) is factored in to counteract inflation of significance due to the statistical dependence among these pairs. As the pedigree file is loaded SIBS checks for any non-Mendelian inheritance errors and also checks that all the alleles present have a frequency > 0.0. You may enter as many pedigrees as you wish in a single file. After completing the "load markers" and "prepare pedigrees" steps, you are ready to map. If you'd like to become familiar with the program using the sample data then you can run the following sequence: sibpair:3> load sample.loc Parsing Linkage marker data file... #the program will determine from the first line of the file #which file format is being used Current map (11 markers): loc1 10.0 loc2 10.0 loc3 10.0 loc4 10.0 loc5 10.0 loc6 10.0 loc7 10.0 loc8 10.0 loc9 10.0 loc10 10.0 loc11 sibpair:4> prepare pedigrees sample.ped Load phenotype data? y/n [n]: n file loaded successfully sibpair:5> scan ...scan done, affection-based analysis commands can now be run. You can now run 'estimate', 'infomap' and 'exclude'. The sample data shows a completely penetrant recessive trait that lies midway between markers loc7 and loc8. Keep in mind when creating files that there must be a one-to-one correspondence (IN ORDER AND NUMBER) between the markers described in the marker data file and the markers that have genotypes listed for them in the pedigree file. The marker file must be loaded first, see 'load markers'. You may want to begin by loading your pedigree file through the MAPMAKER/PEDMANAGER program which will report all the inheritance/format errors at once. MAPMAKER/PEDMANAGER also provides drawing functionality and allele frequency calculator. ==================================== Loading and analyzing phenotype data ==================================== Phenotype data is loaded from a separate file in the format: .... .... An example phenotype file is: 4 ped1 3 6.0 6.0 5.0 5.67 ped1 4 6.0 6.0 5.0 5.67 ped2 3 5.0 5.0 6.0 5.33 ped2 4 6.0 6.0 - 6.00 Where the pedigree file could be: ped1 1 0 0 1 1 2 3 4 5 2 4 ped1 2 0 0 2 1 3 3 5 5 3 3 ped1 3 1 2 2 2 2 3 5 5 2 3 ped1 4 1 2 1 2 3 3 5 5 2 3 ped2 1 0 0 1 1 2 3 4 6 2 4 ped2 2 0 0 2 1 3 3 6 6 3 3 ped2 3 1 2 2 2 2 3 6 6 2 3 ped2 4 1 2 1 2 3 3 6 6 2 3 Where the pedigree names are the same and given in the same order as in the pedigree file. Phenotype information must be given for each sib in a pedigree, but NOT the parents. Missing phenotype values are indicated with a hyphen. (Negative data will be correctly interpreted, and not mistaken for missing data.) Note that after loading your data you must scan with regard to phenotypes (this choice allows you to run affectation status and phenotype data in the same session): sibpair:6> prep sample.ped Load phenotype data? y/n [n]: y Enter the name of the phenotypes file: sample.pheno file loaded successfully sibpair:7> scan scan pairs of phenotyped sibs or affected pairs? p/a [p]: p ...scan done, phenotype-based analysis commands can now be run. ====================================================================== Using affectation and phenotypic analysis commands in the same session ====================================================================== To use both phenotypes and affectation in the same session all you need to do is change which scan type you have done. Scanning for affectation status will allow you to run 'estimate', 'infomap', and 'exclude', whereas scanning pairs of phenotyped sibs will enable you to run 'haseman-elston', 'nonparametric', 'no dom var', and 'ml variance'. @scan This command must be run before any of the analysis commands. Also if the map, pair setting, scanning increment, or pedigree selection has changed, you must re-scan before running any of the analysis commands (such as estimate, exclude, etc). If you have loaded phenotype data you will be asked if you want to scan the phenotyped pairs or the affected pairs: sibpair:7> scan scan pairs of phenotyped sibs or affected pairs? p/a [p]: p ...scan done, phenotype-based analysis commands can now be run. Without phenotype data loaded, affected pairs are automatically scanned. 'Scan' computes the full multipoint probability that two sibs share 0, 1, or 2 alleles IBD (0 or 1 for sex-linked data) with the given map and allele frequencies. This information is then used by all the quantitative and qualitative analysis commands. The IBD distribution can be output as a text file using the command 'dump ibd'. Note: 'scan' may give the error: error: Number of positions to be calculated exceeds the max of 1000 If this occurs you need to select fewer scan points -- either set the number of points between markers back or scan at larger distance increments. (The ceiling can be changed by adjusting MAX_POSITIONS in sibpair.h and recompiling.) @TOPIC map control commands If any of the settings listed below are changed you must re-scan before they will take effect. For a list of the current map and pedigree settings type 'session summary'. @set map The 'set map' command is used to select the current map that the 'scan' command will operate on. It is called in the following manner: set map ... If marker names are specified (as they can be using our internal marker file format), markers may be specified using those names. If not, then they must be specified numerically. Distances may be specified as either recombination-fractions or centiMorgans, with the necessary caveat that if all distances are below 0.5 then they are assumed to be a recombination-fractions, otherwise centiMorgans are assumed. When data is entered using our internal marker file format, SIBS will automatically create a map using each marker and the distances specified in the file. When data is entered using the Linkage format, a map can be automatically created by specifying the recombination distances near the bottom of the file (see the sample.loc file). Note that it is usually better to enter recombinationally INSPEPARABLE markers with a cM distance of .1 or so, as if there is a recombination between them in your data set it will cause a likelihood = 0 error. If you are working with unordered markers and want to analyze them in single-point mode type 'single-point on' at the SIBS prompt. @off end This command controls how far before the first marker and after the last marker in a map scores will be calculated. For example, if this value is set to 10.0, then subsequent scan commands will begin calculating scores 10 cM before the first marker and continue stepping through until 10 cM after the last marker. The default value of 'off end' is 0.0 cM. Only off-end distances >= 0 are valid. Calling 'off end' with no arguments causes SIBS to report the current value. Distances may be specified as either recombination-fractions or centiMorgans, with the necessary caveat that any distance below 0.5 is assumed to be a recombination-fraction and any greater than or equal to 0.5 is assumed to be in centiMorgans. @increment This command controls the frequency with which the 'scan' command calculates the IBD distribution along the map. If 'increment distance 2.0' is entered, the 'scan' command will calculate a map every 2.0 cM throughout the genetic map selected (regardless of the position of markers in that map) as follows (in this example the off end distance is set to 6.0 cM): -6.0 (6 cM before the first marker), -4.0, -2.0, 0.0 (the position of the first marker), 2.0, 4.0, ...etc...until 6.0 cM after the last locus. If 'increment step 5' is selected, the scan command will calculate LOD scores at 5 equally spaced positions in each map interval. For example, if your map has three markers separated by distance of 10 and 15 cM and the off end distance is set to 5 cM, maps will be calculated at the following positions: -5.0, -4.0, -3.0, -2.0, -1.0 (equally spaced in the 5cM before the first marker) 0.0, 2.0, 4.0, 6.0, 8.0 (equally spaced in the 10 cM interval) 10.0, 13.0, 16.0, 19.0, 22.0 (equally spaced in the 15 cM interval) 25.0, 26.0, 27.0, 28.0, 29.0, 30.0 (equally spaced in the 5cM after the map) The default value of 'increment' is 1.0 cM. Calling 'increment' with no arguments causes SIBS to report the current value. Note that the first ('distance') method is not guaranteed to hit every marker position and should be considered inferior to the second ('step') method, which will compute a map at every marker position. @map function This command controls which mapping function is used to convert centiMorgans to recombination-fractions and back again both in the input and output of the program and in the internal calculations. Currently only Haldane and Kosambi map functions are available. The default 'map function' is Kosambi. If the map function is changed you must do a new 'set map ....' and re-scan before it will take affect. @allele frequencies The 'allele frequencies' command controls how the allele frequencies supplied in the marker data file are utilized by the 'scan' command. Argument :: Result given The 'scan' command uses the allele-frequencies given in the marker data file to compute probabilities. thresholded The 'scan' command uses the given allele-frequencies unless the are below the given value. Any frequency below this given value is considered to have this given value. The default case is that the 'allele frequencies' given are used. Typing 'allele frequency' with no argument causes SIBS to report the current value. Marker allele frequencies are important when the parents are untyped and in this case misspecification of allele frequencies can produce false positive results. (Underestimating the frequency of an allele will overestimate the degree of IBD sharing at the locus.) Ideally, one should obtain good estimates of allele frequencies from the appropriate population (MAPMAKER/PEDMANAGER will give a quick estimation of allele frequencies in your set of pedigrees). In addition this command is provided so that you test how sensitive your results are to changes in the allele frequencies. @single point If you set single point to 'on' each marker loaded from the locus file will be analyzed separately and the results for each marker will be output in one file. Any previously set map order will remain intact for use again if single point is turned back 'off'. There is no postscript output in single point mode since there is no continuous region to plot values along. Single point runs the analysis command for each marker in the order it was loaded regardless of what markers are included in the map that is entered. @postscript If you don't want to generate postscript output files type 'postscript off' and SIBS will not query you for the names of output files. You can turn it back on at any point during the session. (If the map only contains one marker or if you are running in single-point mode, postscript output is automatically turned off.) @TOPIC pedigree selection commands If any of the settings listed below are changed you must re-scan before they will take effect. For a list of the current map and pedigree settings type 'session summary'. @pairs used If you have loaded more than two sibs in any of your sibships this command allows you to include the extra sibs in the analysis commands (all sibs are automatically included for phase information if parents are missing). When using 'all pairs', each pair is considered as an independent pedigree but a weight (2/num_affecteds) is factored in to counteract inflation of significance due to the statistical dependence among these pairs. Simply type 'pairs used' and indicate which pair setting you would like to use: sibpair:1> pairs used the current pair setting is: *first affected/phenotyped sibpair only* Possible pair options: 1. First pair of affected/phenotyped sibs 2. All independent pairs of affected/phenotyped sibs* 3. All pairs of affected/phenotyped sibs* Enter the index of the analysis you want to use [1]: 2 *"independent" pairs of sibs are created by taking the first sib paired with sibs 2...n (for a three-sib sibship this will mean the sharing for pairs 1-2 & 1-3 will be computed). Therefore, the results can be different if you rearrange the order of the sibship. "all" pairs are created by taking the first sib paired with sibs 2...n, the second sib paired with 3...n, etc. For a four-sib sibship this means the sharing for pairs 1-2, 1-3, 1-4, 2-3, 2-4 and 3-4 will be computed. The sibs are considered as part of a whole family when inheritance vectors are determined and then each pair is treated as a essentially a separate pedigree for the purposes of analysis. You DO NOT need to re-scan for a change in the pair setting to take effect. The default is to use the first pair of affected/phenotyped sibs. @select pedigrees The 'select pedigrees' command allows the user to select which pedigrees will be analyzed in subsequent calls to 'scan'. If you wish to analyze only a subset of the pedigrees in your data file (for example, ped2 and ped6), you would enter the command: sibpair:3> select pedigrees ped2 ped6 The following pedigrees are in use: ped2 ped6 If you wish to analyze all pedigrees in the data file (the default condition when a new data file is prepared), you could enter: sibpair:4> select pedigrees all The following pedigrees are in use: ped1 ped2 ped3 ped4 ped5 ped6 ped7 Keep in mind that in the above example, the names 'ped1', 'ped2', etc., represent the names that are listed in the original pedigree file. Entering "select pedigrees" with no argument causes SIBS to report the current list of pedigrees under analysis. If you wish to remove pedigrees from the list of active pedigrees under analysis, see the 'remove pedigrees' command. After changing the list of active pedigrees you must run 'scan' to recompute the IBD distribution before running any of the qualitative or quantitative analysis commands. @remove pedigrees The 'remove pedigrees' command enables the user to remove specific pedigrees from analysis by the 'scan' command. If, for example, you wished to exclude ped5 from your analysis, the command: sibpair:5> remove pedigrees ped5 The following pedigrees are in use: ped1 ped2 ped3 ped4 ped6 ped7 would effect the appropriate change. You can go back to using the full set of pedigrees by saying 'select all'. After changing the list of active pedigrees you must run 'scan' to recompute the IBD distribution before running any of the qualitative or quantitative analysis commands. @TOPIC qualitative trait commands Commands to map loci using affectation status. @estimate Usage -- To run the command just type 'estimate' no arguments are needed. SIBS will first ask you if you want to analyze your data under the assumption of no dominance variance, or under the assumption of dominance variance where Holman's triangle is applied: analyze under the assumption of no dominance variance? y/n [n] The default is to perform the analysis with the assumption of dominance variance. SIBS will then query you for the filenames to store the text and postscript output respectively. You will be alerted if either of the chosen filenames already exist. Output -- The text file consists of the columns: (for X-linked data there is no column for z2, and z's are listed first for each type of pair -- brother/brother, brother/sister, and sister/sister pairs with the total listed afterward.) where the z-values are the calculated maximum likelihood proportions. At the end of the text output is a time-stamped summary of the session settings when the analysis was run. The first postscript output file is a graph of position vs. loglike and the second is a plot of how the maximum likelihood sharing proportions change across the region. The marker names are given along the x-axis and the distance examined in the analysis is given at end of the x-axis (this may be larger than the map distance if you have specified an off-end distance). Background -- 'estimate' scans the selected map region and identifies regions of significant excess allele sharing. Note that the LOD score is never negative, because the maximum likelihood solution for z0, z1, and z2 can never be worse than the Mendelian segregation expectation. @exclude Usage --> command line: sibs:6> exclude You are then given the option of inputting a set of z's or relative risk values (the input queries will be different depending on whether you want to analyze your data under the assumption of no dominance variance or not). For X-linked data you will be asked to input Zs/relative risk values for each pair type -- brother/brother, sister/sister, and brother/sister. Output --> The text file consists of tabbed columns in the format: position z2-1 z2-2 z2-3 ... etc. (You should be able to use this file as input to a plotting program if you don't have access to a postscript printer.) At the end of the text file is a time-stamped summary of the session settings. The postscript file consists of multiple y-axis LOD score plots for each relative risk value/set of z's and gives the distance examined in the analysis at end of the x-axis (this may be larger than the map distance if you have specified an off-end distance). A horizontal dashed line is drawn at the traditional exclusion criterion of Z < -2. Background --> Exclusion mapping is used to identify and exclude regions unlikely to have a major effect on the trait you are mapping. SIBS does this by comparing the likelihood of the observed sharing proportion of 0, 1 and 2 alleles between affected sibs (z0,z1,z2), to the likelihood under the Mendelian expectation of a0=1/4, a1=1/2, and a2=1/4. When using SIBS under the asssumption of no dominance the sharing proportions are given by: z0 = a0/Ls z1 = a1 z2 = a2((2Ls-1)/Ls) where Ls = lambda-sub-S, the relative risk ratio for a sib, defined as: prevalence of the trait in siblings of affected individuals --------------------------------------------------------- prevalence of the trait in the population at large Note that Ls = 1 when there is no observed difference in prevalence of sibs vs the population (z0=a0, z1=a1, z2=a2 and LOD = 0). If Ls < 1, it would imply that there was some protective advantage in having an affected sib. Since neither of these cases are interesting and/or reasonable, only Ls values > 1 are allowed. (The no dominance variance assumption allows us to simplify the sharing proportions above to the one variable Ls. With dominance variance Ls = Lo where Lo = relative risk ratio for an offspring, and Lm-1=2(Ls-1) where Lm is the relative risk ratio for a monozygotic twin.) The likelihood under Bayes theorem is: L(pos) = (z0*p0+z1*p1+z2*p2) / (a0*p0+a1*p1+a2*p2) and the LOD score is calculated by summing log10(L(pos)) across pedigrees for each position. The relations for z0, z1, and z2 above hold if multiple loci are involved in the trait, provided that the loci interact multiplicatively and the lambda values are defined as the component of the relative risk attributable to the locus. More details on the analytical method are present in the publication (enter 'journal ref' for complete source information). @infomap Usage -- To run the command just type 'infomap' no arguments are needed. SIBS will query you for the filenames to store the text and postscript output respectively. You will be alerted if either of the chosen filenames already exist. (With X-linked data all types of pairs are calculated together.) Output -- The text output file consists of two columns: where information content is given as a number between 0 and 1. (See the note below about the possibility of negative information content). At the end of the text output file is a time-stamped summary of the settings and files from which the analysis was generated. A postscript plot of the two columns is generated and gives one a quick view of where more markers are needed. The markers are shown along the x-axis and the distance examined in the analysis is given at end of the x-axis (this may be larger than the map distance if you have specified an off-end distance). Background -- Information content mapping gives you a way to calculate how close you are to extracting the full IBD status across the region with the current set of markers. The measure is based on the variance of the IBD distribution. @TOPIC quantitative trait commands Commands to map loci using numerical phenotype scorings. @haseman elston Usage -- After typing the command you will be queried as to which phenotype you want to analyze (if you have loaded more than one), and then queried for files to store the text output for the traditional haseman-elston and EM haseman-elston analyses, as well as the filename for the postscript output. Output -- The traditional and EM haseman-elston output files have the columns: At the bottom of each of these text output file is a time-stamped summary of the session variables when the command was run. This summary will also list which phenotype was selected and in the case of the EM algorithm, the convergence limit that was used. The postscript output file has a plot of both the traditional and EM results. Note1: The EM algorithm has been found to have very rare instabilities in large intervals between markers; if there is a sudden peak in the EM plot make sure a similarly shaped peak also appears in the traditional haseman-elston results. (The nonparametric method does not have these instabilities either and can also be used to verify your results.) Note2: In order to run this command you must have selected more than two pedigrees/pairs -- which shouldn't be a problem since it won't be very significant using any less! @ml variance Usage -- After typing the command you will be queried as to which phenotype you want to analyze (if you have loaded more than one), and then queried for a files to store the text and postscript output. Output -- The text output file has the format: (no sigsq2 for sex-linked data) At the bottom of each of these text output file is a time-stamped summary of the session variables when the command was run. This summary will also list which phenotype was selected and the convergence limit that was used. The postscript output file is a plot of position vs. LOD. Note: This EM-based algorithm has been found to have very rare instabilities in large intervals between markers; if there is a sudden peak in the plot you can verify it by checking it against the results of the nonparametric method, which is not subject to the same instabilities. @no dom var Usage -- After typing the command you will be queried as to which phenotype you want to analyze (if you have loaded more than one), and then queried for a files to store the text and postscript output. (Note that since X-linked markers are hemizygous in males, this command can not be run on sex-linked data where the no-dominance assumption isn't meaningful.) Output -- The text output file has the format: (no sigsq2 for sex-linked data) At the bottom of each of these text output file is a time-stamped summary of the session variables when the command was run. This summary will also list which phenotype was selected and the convergence limit that was used. The postscript output file is a plot of position vs. LOD. Note: This EM-based algorithm has been found to have very rare instabilities in large intervals between markers; if there is a sudden peak in the plot you can verify it by checking it against the results of the nonparametric method, which is not subject to the same instabilities. @nonparametric Usage -- After typing the command you will be queried as to which phenotype you want to analyze (if you have loaded more than one), and then queried for a files to store the text and postscript output. Output -- The text output file has the format: At the bottom of each of these text output file is a time-stamped summary of the session variables when the command was run. This summary will also list which phenotype was selected and the convergence limit that was used. The postscript output file is a plot of position vs. Z-score. @TOPIC basic commands Auxiliary SIBS commands. @session summary Prints a summary of the current map and pedigree related settings, for example: sibpair:12> session summary *Pedigree file: sample.ped *Phenotype file: (not loaded) The following 19 pedigrees are in use: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 19 pedigrees originally loaded *Pairs: first pair from each sibship *Analysis is: autosomal *Loci file: sample.loci *Current map (8 markers): loc1 9.0 loc2 3.0 loc3 11.0 loc4 4.0 loc5 1.0 loc6 1.0 loc7 3.0 loc8 map function: kosambi units: centimorgans off end distance: 0.0 scans done at constant increments of 1.0 cM (A similar summary is printed at the bottom of each text output file.) @dump ibd This command allows you to output the calculated likelihood of sharing 0, 1 or 2 alleles (0 or 1 for sex-linked data) for each pedigree, possibly for use in another program. (You will be queried for the filename to store it in.) The output format is: ... @TOPIC shell commands There are several basic features which SIBS provides to make the program more friendly and useful. These include on-line help ('help') and the ability to record session output ('photo') and to accept input from a batch file ('run'). @help 'Help' displays on-line help information for SIBS commands and features. Typing 'help' alone produces a list of available topics and commands. For a general description of a numbered topic, type 'help ', where is the displayed number of the topic. For help on a more specific command or feature, type 'help ', for example: sibpair:1> help prepare pedigrees The on-line help is an exact duplicate of the reference manual. @photo The "photo" command is used to save a copy of the current SIBS session (input and output) in a text file. If you type "photo ", for example, sibpair:1> photo sample.out all input and output from that point on will be copied into the specified file (here, the file named "sample.out"). Typing "photo off" or quitting SIBS terminates this process and closes the photo file. The default extension for a transcript file is ".out". The 'photo' command will append program output to the specified file, so output from several sessions may be collected in the same file if desired. @run The "run" command instructs SIBS to take a series of commands from any text file. This file should contain lines of commands and other input just as they would be typed into SIBS interactively. For example, you might want to use a 'run' file to save setup commands for loading your data: load markers test.loci increment distance .1 prep pedigree test.ped p (To indicate that phenotype data will be loaded) test.pheno and could be run with the command sibpair:1> run setup.in where 'setup.in' is the name of the file containing the 5 lines of commands above. (No blank lines can be used to accept defaults, you must provide input in each line of the run file.) @system The 'system' command is used to temporarily interrupt SIBS and start up a new command interpreter from the operating system. Commands which are normally typed to the operating system may then be issued. You can return to SIBS by typing 'exit' or control-D in most operating systems. If an argument is supplied to 'system', the argument is interpreted just as a normal command issued to the operating system. For example: sibpair:4> system lp results.out would execute the printing command on your operating system and then return control immediately to SIBS. @change directory The 'cd' command works essentially the same way it does under Unix. By default, all files are read or written from the current directory unless specified otherwise. @time Display the current time from the system clock. @quit Assures that the program exits properly; removes any auxillary files, then exits the session. @debug ***********Not meant for general use*********** Displays to the screen debugging output throughout the analysis code. @end