HUM-MOLGEN archive: COMP: First announcement of new computer-program

From: IN%"joe@well.ox.ac.uk" "Joe Terwilliger" 23-OCT-1995 16:30:38.33 To: All people who have downloaded or inquired about likelihood methods for linkage disequilibrium analysis or the ANALYZE program set. From: Joseph D. Terwilliger (joe@well.ox.ac.uk, jdt3@columbia.edu) NEW COMPUTER PROGRAM ANNOUNCEMENT: A new version of the ANALYZE program package has been released for simplifying the performance of a large array of parametric and nonparametric tests for linkage and linkage disequilibrium on data entered in LINKAGE format pedigree and parameter files. This program uses MLINK, ILINK, LINKMAP, UNKNOWN, and LSP from the LINKAGE package (either regular version 5.* or FASTLINK version 2.*) and several programs to perform these statistical tests. All code is provided except LINKAGE, which you must have pre-installed on your workstation. What programs are available and what do they do? ANALYSIS: 1) Lod score analysis with heterogeneity (uses MLINK, UNKNOWN, LSP, and HOMOG) 2) Transmission/disequilibrium test and likelihood based extension to multiple alleles 3) Haplotype Relative Risk test for multiallelic markers 4) Sibpair analysis 5) Lod score analysis on large pedigrees broken into nuclear pedigrees with heterogeneity 6) Polylocus linkage analysis 7) Multilocus Haplotype Relative Risk Analysis NONPARAMETRIC: 1) Sibpair Analysis 2) Haplotype Relative Risk Analysis 3) Transmission/disequilibrium test analysis 4) Multilocus Haplotype Relative Risk Analysis MULTI-ILINK Multipoint linkage analysis with intermarker distances as a nuisance parameter (uses ILINK and UNKNOWN) MULTIHOMOG Multipoint linkage analysis with heterogeneity (uses LINKMAP, LSP, UNKNOWN) DOWNFREQ Estimates allele frequencies and allows the user to downcode polymorphic marker loci EXTRACT Utility to reorder marker loci and extract subsets of marker loci from LINKAGE format pedigree and parameter files Where and how can I get the programs? The programs are distributed at two different ftp sites, officially. Either you can get them from ftp.well.ox.ac.uk in directory pub/genetics/analyze or linkage.cpmc.columbia.edu in directory software/analyze There are a number of files in these directories. OSF_analyze.tar.Z contains programs, source code, samples, and documentation for DEC Alpha OSF/1 v. 3.0 OSF_SOURCE_analyze.tar.Z contains the same without executables (can be compiled under OSF, ULTRIX, VMS) SOLARIS_analyze.tar.Z contains programs, source, samples, and documentation for SUN Solaris 2.4 SUN_SOURCE_analyze.tar.Z contains the same without executables (can be compiled under Solaris, SunOS, etc.) SAMPLE_analyze.tar.Z contains sample input and output files DOC_analyze.tar.Z contains program documentation in ASCII format for each program in the set. SAMPLE FTP SESSION AT ftp.well.ox.ac.uk 1) ftp ftp.well.ox.ac.uk 2) login as anonymous, leaving your EMAIL address as a password 3) cd pub/genetics/analyze 4) binary 5) get OSF_analyze.tar.Z 6) close 7) quit Then on your own machine 8) uncompress OSF_analyze.tar.Z 9) tar xvf OSF_analyze.tar (Installation instructions are given in the README file - Note that you can use these programs with EITHER LINKAGE v. 5.? or FASTLINK v. 2.?, which you must have installed on your computer to use these programs. LINKAGE is available from ftp.well.ox.ac.uk for DEC OSF machines, and from linkage.cpmc.columbia.edu for SUN workstations - FASTLINK is available from softlib.cs.rice.edu for either implementation) Why should I use the ANALYZE package? The ANALYSIS program set makes the process of data analysis trivially simple. Once the programs are installed, you must merely have 2 input files, pedin.dat and datain.dat in LINKAGE format containing your disease locus and many allele numbers marker loci, in chromosome order. Then, you type "analysis" on your workstation, and then the program will manipulate all your files and do all the different statistical tests you would normally do when screening the genome for a new disease locus, and then as output you get a detailed summary of each statistic, and a summary table, like the following for the sample data: Summary of statistical results from ANALYZE Loc x(cM) Z(t) Theta HetChi Z(a,t) Theta Alpha Sibpair TDT HRR-LRT HRR-2xn 2 0.00000 0.909 0.38 3.849 0.10 0.35 0.005694 0.000034 0.046822 0.015534 3 0.00502 5.583 0.28 33.511 0.08 0.39 0.000000 0.000000 0.000000 0.000000 Loc x(cM) N-Z(t) N-HetChi N-Z(a,t) P-Z(t) P-HetChi P-Z(a,t) MP-Z(t) MP-HetChi MP-Z(a,t) 2 0.00000 3.376 0.012 1.243 5.639 0.601 5.622 3 0.00502 8.841 0.337 5.583 33.511 5.505 33.607 Maximum Multilocus HRR = 53.18196 ~ Chi-Square(1) - One-sided Loc = Locus Number x(cM) = Map Distance from the first marker (Locus 2) in Haldane cM Z(t) = Maximum Lod Score HetChi = Chi-Square for Heterogeneity when Z(t) >= 3 Z(a,t) = Maximum Lod Score with Heterogeneity - when Z(t) < 3 Sibpair = p-value for Affected Sib Pair Mean Test TDT = p-value for Likelihood-Based TDT HRR-LRT = p-value for Likelihood-Based Haplotype Relative Risk HRR-2xn = p-value for 2 x n Contingency Table Chi-Square HRR test N-Z(t) = Maximum Lod Scores When Extended Pedigrees are Broken into Nuclear Pedigrees N-HetChi = Chi-square for Heterogeneity (Nuclear Pedigrees) N-Z(a,t) = Maximum Lod Score with Heterogeneity (Nuclear Pedigrees) P-Z(t) = Polylocus Maximum Lod Score P-HetChi = Chi-square for Heterogeneity (Polylocus) P-Z(a,t) = Maximum Polylocus Lod Score with Heterogeneity MP-Z(t) = Maximum Multipoint Polylocus Lod Score MP-HetChi = Chisquare for Heterogeneity (Multipoint Polylocus) MP-Z(a,t) = Maximum Multipoint Polylocus Lod Score with Heterogeneity This summarizes all the statistics for each marker along the chromosome, and even includes the map distance of each marker from the first marker in Haldane cM. There is also a more wordy output file, which gives a detailed synopsis of the tests performed, which is attached at the bottom of this announcement. The NONPARAMETRIC program works in the same manner, and produces the following sample output file (with detailed version available as well. Summary of statistical results from NONPARAM P-VALUES -------------------------------------------- Loc x(cM) Sibpair TDT HRR-LRT HRR-2xn 2 0.00000 0.005694 0.000034 0.046822 0.015534 3 0.00503 0.000000 0.000000 0.000000 0.000000 Maximum Multilocus HRR = 53.18196 ~ Chi-Square(1) - One-sided Loc = Locus Number x(cM) = Map Distance from the first marker (Locus 2) in Haldane cM Sibpair = p-value for Affected Sib Pair Mean Test TDT = p-value for Likelihood-Based TDT HRR-LRT = p-value for Likelihood-Based Haplotype Relative Risk HRR-2xn = p-value for 2 x n Contingency Table Chi-Square HRR test MULTI-ILINK and MULTIHOMOG are equally simple to use, and give also very easy-to-interpret output files as well with a minimum of effort. Documentation describing the detailed function of each of these program sets is available from the ftp servers above: I hope you will find the new version of these programs to be a useful part of your genome screening operations. Joseph D. Terwilliger, Ph.D. joe@well.ox.ac.uk jdt3@columbia.edu jterwilliger@ktl.fi DETAILED OUTPUT FILE: ANALYZE.FINAL ******************************************************************************** MLINK Pedigree File : pedin.tpd Parameter File : datain.tdt Output Pedigree File : pedfile.dat Output Parameter File : datafile.dat Log File : lsp.log Stream File : lsp.stm Date Run : 17-Oct-95 16:50:21 Sex Difference : 0 Recomb. Fraction to Vary : 1 Increment Value : 0.02000000 Stop Value : 0.48000000 Locus Order : 1 2 Male Recomb. Fractions : 0.00000000 ******************************************************************************** Output of analysis with HOMOG For significance testing use the following standard critical values: HOMOGENEITY: Z(theta) > 3 HETEROGENEITY: Z(alpha,theta) > 3.3 Under homogeneity - Maximum Lod Score = 0.909022 Theta = 0.380 Under heterogeneity - Maximum lod score = 3.849152 Theta = 0.100 Proportion of Linked Families, Alpha = 0.350 Under Heterogeneity there is significant evidence of linkage. 3.3-lod-unit support interval for alpha and theta is as follows: Alpha: ( 0.01, 1.00) Theta: ( 0.00, 0.44) ******************************************************** ***** ***** ***** You are using TDTLIKE - Alpha Test Version ***** ***** for computing TDT-like likelihood ratio ***** ***** statistics based on an algorithm of ***** ***** J. Terwilliger (AJHG 56:777-787 (1995)) ***** ***** ***** ******************************************************** Locus 1 Alleles which appear at least 5 times shown. Multiple test corrected ORIG # CASE CONTROL TDT One-Sided P-Value 1 209 129 18.9349117279 0.0000397356 2 46 83 10.6124029160 1.0000000000 3 76 129 13.7024393082 1.0000000000 4 91 93 0.0217391308 0.9880542409 5 87 75 0.8888888955 0.6593401134 Multiallelic Statistic - Based on Terwilliger (AJHG - March 1995) Maximum Likelihood Estimate of TDT Lambda = 0.62000 -2ln(L) difference = 15.8929973831 P-Value = 0.0000338507 *********************************************************** *** *** *** Program HRRLAMB *** *** For Haplotype Relative Risk Based *** *** analysis of linkage disequilibrium *** *** with ONE Marker only; Any number of alleles. *** *** JD Terwilliger: Am. J. Hum. Genet. - 56:777-787 *** *** *** *********************************************************** ------------------------------- ALLELE: 1 2 3 4 5 =============================== CASE: 43 1 13 12 11 ------------------------------- CONTROL: 27 10 14 18 11 =============================== LRT Chi-Square = 2.81060 p-value = 0.046821920085689 Lambda = 0.236227 NOT SIGNIFICANT 2 x n table Chi-square = 12.25782 P-value = 0.015533597133660 NOT SIGNIFICANT ********************************************************************* * Program SIBPAIR - Sibpair analysis on Nuclear Families * ********************************************************************* P-values 0 1 2 | SHARED NOT | 0 vs 2 Mean test | | NA/NA 6.0 15.0 7.0 | 34.0 34.0 | 0.390755713 1.000000000 NA/A 20.7 38.8 17.2 | 102.3 116.0 | 0.284681141 0.177501172 A/A 17.3 53.0 28.3 | 158.7 116.7 | 0.051785618 0.005694087 Overall Chisquare For 0-2 Sharer Comparisons = 2.97342 p-value = 0.1130575 Overall Chisquare For Mean Test Comparisons = 7.26225 p-value = 0.0132432 Affected Sib-Pair Mean Test P-value = 0.005694087 Output of analysis with HOMOG For significance testing use the following standard critical values: HOMOGENEITY: Z(theta) > 3 HETEROGENEITY: Z(alpha,theta) > 3.3 Under homogeneity - Maximum Lod Score = 3.375684 Theta = 0.220 Under homogeneity there is significant evidence of linkage. Test for heterogeneity GIVEN Linkage Chi-square for heterogeneity = 0.011600 Theta = 0.220 Alpha = 0.970 No significant evidence of heterogeneity. ******************************************************************************** MLINK Pedigree File : pedin.tpd Parameter File : datain.tdt Output Pedigree File : pedfile.dat Output Parameter File : datafile.dat Log File : lsp.log Stream File : lsp.stm Date Run : 17-Oct-95 16:51:32 Sex Difference : 0 Recomb. Fraction to Vary : 1 Increment Value : 0.02000000 Stop Value : 0.48000000 Locus Order : 1 3 Male Recomb. Fractions : 0.00000000 ******************************************************************************** Output of analysis with HOMOG For significance testing use the following standard critical values: HOMOGENEITY: Z(theta) > 3 HETEROGENEITY: Z(alpha,theta) > 3.3 Under homogeneity - Maximum Lod Score = 5.582551 Theta = 0.280 Under homogeneity there is significant evidence of linkage. Test for heterogeneity GIVEN Linkage Chi-square for heterogeneity = 33.510799 Theta = 0.080 Alpha = 0.390 Significant evidence of heterogeneity at p < 0.0001 level! ******************************************************** ***** ***** ***** You are using TDTLIKE - Alpha Test Version ***** ***** for computing TDT-like likelihood ratio ***** ***** statistics based on an algorithm of ***** ***** J. Terwilliger (AJHG 56:777-787 (1995)) ***** ***** ***** ******************************************************** Locus 1 Alleles which appear at least 5 times shown. Multiple test corrected ORIG # CASE CONTROL TDT One-Sided P-Value 1 271 71 116.9590606689 0.0000000000 2 81 169 30.9759998322 1.0000000000 3 172 284 27.5087718964 1.0000000000 Multiallelic Statistic - Based on Terwilliger (AJHG - March 1995) Maximum Likelihood Estimate of TDT Lambda = 0.79000 -2ln(L) difference = 122.5419672207 P-Value = 0.0000000000 *********************************************************** *** *** *** Program HRRLAMB *** *** For Haplotype Relative Risk Based *** *** analysis of linkage disequilibrium *** *** with ONE Marker only; Any number of alleles. *** *** JD Terwilliger: Am. J. Hum. Genet. - 56:777-787 *** *** *** *********************************************************** ----------------------- ALLELE: 1 2 3 ======================= CASE: 39 9 32 ----------------------- CONTROL: 1 23 56 ======================= LRT Chi-Square = 50.37136 p-value = 0.000000000000662 Lambda = 0.474739 SIGNIFICANT EVIDENCE OF ASSOCIATION 2 x n table Chi-square = 48.77045 P-value = 0.000000000025682 SIGNIFICANT EVIDENCE OF ASSOCIATION ********************************************************************* * Program SIBPAIR - Sibpair analysis on Nuclear Families * ********************************************************************* P-values 0 1 2 | SHARED NOT | 0 vs 2 Mean test | | NA/NA 2.0 8.0 4.0 | 24.0 25.0 | 0.207109630 0.943191707 NA/A 22.2 39.0 12.8 | 103.0 128.0 | 0.057323437 0.049996715 A/A 6.7 43.3 43.0 | 201.7 89.3 | 0.000000129 0.000000000 Overall Chisquare For 0-2 Sharer Comparisons = 29.06830 p-value = 0.0000002 Overall Chisquare For Mean Test Comparisons = 46.06913 p-value = 0.0000000 Affected Sib-Pair Mean Test P-value = 0.000000000 Output of analysis with HOMOG For significance testing use the following standard critical values: HOMOGENEITY: Z(theta) > 3 HETEROGENEITY: Z(alpha,theta) > 3.3 Under homogeneity - Maximum Lod Score = 8.841280 Theta = 0.180 Under homogeneity there is significant evidence of linkage. Test for heterogeneity GIVEN Linkage Chi-square for heterogeneity = 0.337403 Theta = 0.020 Alpha = 0.450 No significant evidence of heterogeneity. Locus Map Position 2 0.000000 3 0.005025 OUTPUT FROM PROGRAM POLYLOCUS Analysis with Polylocus method of Terwilliger and Ott Genetic Epidemiology 10(6):477-82 (1993) Primary Locus is now Locus Number 2: Polylocus Maximum Lod Score = 1.243432 Theta = 0.380000 Polylocus Maximum Lod Score with Heterogeneity = 5.639449 Theta = 0.060000 Alpha = 0.300 MULTIPOINT Polylocus Maximum Lod Score = 0.601381 Map Position = -0.458145 MULTIPOINT Polylocus Maximum Lod Score with Heterogeneity = 5.621749 Map Position = 0.057705 Alpha = 0.290000 Primary Locus is now Locus Number 3: Polylocus Maximum Lod Score = 5.582548 Theta = 0.280000 Polylocus Maximum Lod Score with Heterogeneity = 12.859349 Theta = 0.080000 Alpha = 0.390 MULTIPOINT Polylocus Maximum Lod Score = 5.505385 Map Position = -0.346574 MULTIPOINT Polylocus Maximum Lod Score with Heterogeneity = 12.803160 Map Position = 0.116597 Alpha = 0.410000 *************************************************************** * PROGRAM HRRMULT, Version 1.1 - J.D. Terwilliger * * Multilocus Haplotype Relative Risk Analysis * * Based on Terwilliger(1995) - Am J Hum Genet 56:777-787 * *************************************************************** Alpha N Inter. Position Map Position Lod Score -2ln(LR) 0.050000 98. 0 0 -2.30259 0.00000 0.00000 0.999990 20. 0 1 -0.10034 4.38822 20.20850 0.999990 20. 0 2 -0.08935 5.48019 25.23720 0.999990 20. 0 3 -0.07859 6.72511 30.97027 0.999990 20. 0 4 -0.06807 8.05915 37.11377 0.999990 20. 0 5 -0.05776 9.30234 42.83887 0.999990 20. 0 6 -0.04766 10.12986 46.64975 0.999990 22. 0 7 -0.03775 10.20475 46.99459 0.754212 20. 0 8 -0.02804 10.24532 47.18145 0.719976 28. 0 9 -0.01852 10.06069 46.33121 0.521266 20. 0 10 -0.00917 10.23737 47.14484 0.434449 20. 1 0 0.00000 10.23349 47.12698 0.433624 20. 1 1 0.00100 10.39471 47.86940 0.432761 20. 1 2 0.00200 10.54322 48.55333 0.819632 337. 1 3 0.00301 11.24992 51.80779 0.600164 233. 1 4 0.00402 11.54832 53.18196 0.473134 140. 2 0 0.00503 11.54810 53.18096 0.999990 86. 2 1 0.01420 11.44746 52.71752 0.999990 45. 2 2 0.02355 11.18352 51.50199 0.999990 31. 2 3 0.03307 11.03407 50.81375 0.999990 23. 2 4 0.04278 10.94333 50.39592 0.999990 20. 2 5 0.05268 10.81645 49.81161 0.999990 20. 2 6 0.06278 10.03082 46.19362 0.999990 20. 2 7 0.07309 8.76012 40.34187 0.999990 20. 2 8 0.08362 7.33335 33.77132 0.999990 20. 2 9 0.09437 5.97572 27.51922 0.999990 20. 2 10 0.10536 4.78090 22.01687