Published by Jürg Ott, Columbia University, New York.
Topics to be covered include: Introduction to the LINKAGE and MENDEL computer programs; handling of inbreeding loops, age-dependent penetrance, and sex- specific recombination fractions; problems of interference in multipoint mapping; introduction to models of disease heterogeneity; models for complex diseases; genetic heterogeneity; calculation of genetic risks, also under allelic association and allelic heterogeneity (as in CF); linkage analysis with pseudoautosomal loci.
Participants must be familiar with IBM PCs or compatible microcomputers. Extensive experience with a linkage program and/or an excellent background in statistical genetics and linkage analysis are additional criteria for admission.
The course will be advertised in scientific journals. To obtain additional material and an application form, please write to the address above. The application deadline is August 15, 1991.
An introductory course will be given from Wednesday through Saturday, August 28-31, 1991, in Cardiff, Wales (in the week following the Human Gene Mapping Workshop 11 in London). The course will be taught by myself, Lodewijk Sandkuijl, and Iain Fenton. The topics to be covered include: Introduction to population genetics, introduction to linkage analysis, practical aspects of data collection, two-point linkage, multipoint linkage, risk calculations, and linkage analysis for diseases with a complex mode of inheritance.
The total course fee is œ650.- including full room and board accommodation. The number of participants is limited to 20. The computer classroom will be equipped with 20 PC-compatible computers with 80386 microprocessors. Requests for additional information and applications should be directed to:
Mrs. G. Gulliford, secretary to Prof. P.S. Harper
Institute of Medical Genetics, Heath Hospital
Cardiff, CF4 4XN, Wales
Fax +44-222-747603
or to
Dr. L.A. Sandkuijl, Voorstraat 27a
2611 JK Delft, The Netherlands
Fax +31-15-123638
Bug in SLINK
A bug in SLINK.PAS has recently been found. This bug will cause problems any time
you try to simulate with only markers (i.e., no trait locus) and the markers aren't in the
order 1, 2, 3,....
The fix to this bug is simple: Just change the line in SLINK.PAS containing
j:=order[1];
to
j:=1;
as indicated below:
Original code:
FOR i:=1 TO 35 DO write(output, '-');
writeln(output);
{Setup unlinked trait locus}
IF trait <> 0 THEN
j:=order[trait]
ELSE
j:=order[1];
FOR i:=1 TO nlocus DO
IF i <> trait THEN
IF order[i] < j THEN
order2[i]:=order[i]+1
ELSE
order2[i]:=order[i];
Corrected code:
FOR i:=1 TO 35 DO write(output, '-');
writeln(output);
{Setup unlinked trait locus}
IF trait <> 0 THEN
j:=order[trait]
ELSE
j:=1;
FOR i:=1 TO nlocus DO
IF i <> trait THEN
IF order[i] < j THEN
order2[i]:=order[i]+1
ELSE
order2[i]:=order[i];
If you have any questions about this fix, please contact:
Daniel E. Weeks
University of Pittsburgh
Department of Human Genetics
130 DeSoto Street, A300 Crabtree Hall
Pittsburgh, PA 15261
Tel. (412) 624-3066 FAX: (412) 624-3020
WEEKS@PITTVMS.BITNET or WEEKS@VMS.CIS.PITT.EDU
The FTREE program may be obtained from:
Rodney C.P. Go, Ph.D.
UAB - University Station
Birmingham, AL 35294-0008. Tel. 205/934-6107
When you try running MLINK with the dostream program constant set to false, an error occurs. The error may be fixed by adding and dostream to a line towards the end of the iterpeds procedure, 11 lines before the start of the initmlink procedure (in the file MLK3.PAS of the DOS version). The corrected line reads:
if score and (not risk) and dostream
then writeln(stream,tlike-scorevalue);
The UNKNOWN program (DOS and other versions) does not properly read the
datafile when more than one quantitative factor is specified. The error occurs
in the getquan procedure; the corrected code reads as follows:
procedure getquan(VAR locus:locuspoint);
VAR
i:INTEGER;
begin {getquan}
WITH locus^ DO
begin
READLN(datafile,ntrait);
IF ntrait>maxtrait THEN inputerror(31,system,ntrait);
IF ntrait<=0 THEN inputerror(32,system,nclass);
FOR i:=1 TO ntrait+2 DO READLN(datafile);
END;
END; {getquan}
Generally, version 5.10 of the LINKAGE programs runs approximately 10% faster than version 5.04. The benchmark results listed below were obtained with version 5.10 of the LINKAGE programs (Turbo Pascal for DOS machines). All machines were equipped with numeric coprocessors as indicated. For the DOS machines the clock speed of the microprocessor is also given. The run time is the time in seconds taken by the MLINK program of the LINKAGE package to calculate two likelihoods for the 12-member family described above (elapsed time except where noted). The UNKNOWN program was executed and a speedfile produced prior to the test run. Program constants were the same in each of the runs listed below. The benchmark data set is available on disk 5c (see appendix).
Machine Run time
-------------------------------------------------------
Toshiba 3100-e (80286-12/80287) 2099
BUS Laptop 386SX (80386SX-16/80387) 765
IBM PS/2 model 70 (80386-16/80387) 710
Toshiba 5200 (80386-20/80387-20) 449
Dell System 310 (80386-20/80387-20) 446
BUS 386 (80386-25/80387-25) 426
Vaxstation 3100 model 30 (Vax Pascal, CPU time) 237
Vaxstation 3100 model 38 (Vax Pascal, CPU time) 167
Everex Step (80486-33) 98
BUS 486 (80486-33) 98
Sun SLC (rated at 12.5 MIPS) 70
Sun 4/370 (rated at 16 MIPS) 49
Sun Sparcstation 1+ (rated at approx. 16 MIPS) 45
-------------------------------------------------------
In the comparisons given above, the purchase price of the machines should also
be taken into account. The faster Sun machines listed run approximately
twice as fast as the fastest DOS machines but their cost (with educational
discount) is less than twice that of the DOS machines.
One important aspect of the OS/2 implementation is that the Prospero compiler in principle allows for arrays larger than 64KB. Records containing such arrays, however, cannot exceed 64KB. Whereas this restriction is not too serious, it also turns out that memory for large arrays cannot be allocated by new(p), where p is a pointer pointing to an array larger than 64KB. This limits the total number of loci that can be analyzed jointly, but the OS/2 version of the LINKAGE programs can still accommodate problems larger than can be run under MS-DOS.
As mentioned in the previous issue of the newsletter, to run under OS/2, the LINKAGE programs were adapted to Prospero Pascal. Unfortunately, the U.S. address and telephone number of the Prospero Software company are no longer correct. Readers interested in purchasing Prospero Pascal should contact Prospero Software, 190 Castelnau, London SW13 9DH, England; fax +44-81-748-9344, tel. +44-81-741-8531. I have no connection with that company whatsoever and am providing this address in response to readers who tried in vain to contact the company at their U.S. office.
** For ordering instructions, please write to us at the address above **
Abbreviations:
TPS= Turbo Pascal (TP) source code (compiler needed).
TPC= Turbo Pascal, compiled for IBM PC
FSC= Fortran (Microsoft v.4.01), source and compiled.
EXE= executable code
Item Contents
--------------------------------------------------------------------------------------------------
LINKAGE programs version 5.10, disks 4a-4c (Prospero Pascal, DOS or OS/2) and disks 5a-5e (Turbo Pascal
version 5, DOS). The programs are in archived form and will have to be uncrunched using a program supplied
on disks 4a and 5a. Printed documentation (version 5.10, May 1991) will be provided. Our benchmark
pedigree is on disk 5c.
LINKAGE programs in Prospero Pascal (general and CEPH pedigrees; DOS or OS/2, compiled for OS/2 only):
Users with a coprocessor installed in their machines (eg. all 80486 machines) order disks 4a and 4b, those
without a coprocessor order disks 4a and 4c.
4a Source code, utility programs, and documentation
4b Executable code using coprocessor
4c Executable code not making use of coprocessor
LINKAGE programs in Turbo Pascal (general and CEPH pedigrees; DOS only):
For general pedigrees order 5a-d, for 3-generation pedigrees order 5a-c and 5e.
5a LCP and other management programs
5b Various utility and batch programs, documentation files
5c Source code; benchmark data (in unarchived form)
5d Executable code, general pedigrees
5e Executable code, 3-generation pedigrees
OTHER PROGRAMS (Turbo Pascal version 5 except where noted)
6 Source code to disk 8 (TPS).
7 NOCOM program for analysis of mixture of distributions. Includes the COMPMIX and HIST program. FSC
8 Linkage Utility programs (see list below). TPC
9 PC-LIPED (two-point linkage analysis, up to 5 alleles per locus), version Oct. 1988. Includes
SEXLODS program for approx. separation of male and female recombination fractions. FSC
9a LIPED, same as disk 9 except that up to 6 alleles per locus are allowed and program requires more
memory to run.
10abcPC-WRITE version 3.02 text editor for data entry (Quicksoft, Inc.). [3 disks]
15 HOMOG programs and MTEST program to carry out homogeneity tests TPS
16 HOMOG programs and MTEST program to carry out homogeneity tests TPC
17 Kermit V2.30 program for electronic communication.
18 LIPEDMAX program version Nov. 1987 for iterative estimation of age of onset parameters (lognormal
distribution of age at onset). FSC
20a SLINK simulation program, DOS and OS/2 version, Prospero Pascal source code and documentation file
[1 DD disk]
20b SLINK for DOS and OS/2, compiled for machines with coprocessor [1 DD disk]
20c SLINK for DOS and OS/2, compiled (ISIM not included), not requiring coprocessor [1 DD disk]
21 SLINK simulation program, VAX VMS version [1 DD disk]
22a 2-locus LINKAGE programs (TMLINK, TLINKM, TILINK) for DOS and OS/2 [1 DD disk]
22b 2-locus LINKAGE programs for VAX VMS [1 DD disk]
-----------------------------------------------------------------------------------------------------------
We keep a list of people who ordered programs from us and/or who have taken our
linkage courses. These individuals regularly receive the LINKAGE NEWSLETTER
which is so far being mailed free of charge a few times a year.
E.A. Thompson: "Pedigree Analysis in Human Genetics", Johns Hopkins University Press, Baltimore and London, 1986 ($35).
K.E. Davies (editor): "Human Genetic Diseases - A Practical Approach". IRL Press, Oxford England and Washington, D.C., 1986 ($25, softbound; $40, hardbound).
2BY2 (1.0) carries out Fisher's exact test in 2þ2 tables (n < 8000).
ASSOCIATE (2.3), for two loci with codominant alleles, partitions the chi-square for phenotypic association
into two components, (1) due to allelic association, (2) other phenotypic association.
BINOM (1.63) calculates binomial probabilities (n<8000).
CELLIP (2.2) calculates points on a confidence ellipsis for two jointly estimated variables.
CHIPROB (2.2) computes the upper tail probability of the chi-square distribution.
CONTING (2.4) calculates chi-square for contingency table data.
EQUIV (2.6) calculates equivalent fully informative observations.
HIST (2.3) produces a histogram.
LSURF/LSMAX (3.3/1.3) calculate the lod score surface over the x1,x2-plane in 3-point linkage analysis (all 3
orders), where x1 and x2 are the map distances from locus 1 to 2 and from locus 2 to 3, respec-
tively. Input is offspring counts from phase known data.
MAPFUN (2.31) converts recombination fractions into map distances (6 mapping functions) and vice versa.
NORINV (1.31) accurately computes the normal deviate from a given tail probability.
NORPROB (3.2) accurately computes the tail probability associated with a normal deviate, x.
PERMUTE (2.3) produces a list of all n!/2 orders of n gene loci.
PIC (1.3) computes for given alleles at one locus the PIC value and heterozygosity.
RERI (2.2) calculates and combines relative risks from a set of 2þ2 tables and carries out homogeneity tests
among the tables.
VARCO3 (2.41) approximates mean and variance of an MLE of a variable x from three values of x and their log
likelihoods or lod scores. The likelihood is approximated by a normal density, i.e., the log like-
lihood is quadratic.
VARCO6 (2.21) approximates means, variances and correlation for two jointly estimated variables, x and y,
from six points (x,y) and associated likelihood values.