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To: Multiple recipients of list HUM-MOLGEN <HUM-MOLGEN@NIC.SURFNET.NL>
Subject: COMP: First announcement of new computer-program
From: Arthur Bergen <bergen@AMC.UVA.NL>
Date: Wed, 1 Nov 1995 15:52:34 +0100

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


   
 
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