jPAP: Pedigree Analysis Package for Java http://hasstedt.genetics.utah.edu/

1
jPAP Pedigree Analysis Package for
Javahttp//hasstedt.genetics.utah.edu/

• Sandy Hasstedt
• sandy_at_genetics.utah.edu
• John Elliott
• jelliott_at_genetics.utah.edu

2
Original PAP

• Written in Fortran
• Subroutines for different assumptions or
  parameterizations
• Executable created with desired subroutines

3
Current jPAP

• Interface in Java
• Analysis performed by the Fortran program
• Executable contains all the subroutines

4
PAP Modules

• Frequencies
• Transmission
• Discrete Penetrance
• Quantitative Penetrance
• Within Genotype

5
jPAP Editors

• Pedigree
• Observations
• Metadata
• Model

6
Input of Pedigree

• Direct input
• PAP trip.dat
• Free format triplet file
• Linkage format file
• ID globalization specified on main menu

7
Pedigree Editor

• Pedigrees
• Members
• Families
• Probands
• Associated disease

8
Observations Input

• Direct Input using the editor
• Free format
• Linkage format file
• ID globalization specified on main menu

9
Observations Editor

• Columns of data
• ? for missing value
• Transformed variables shown after analysis

10
Metadata Editor

• Name of variable
• Type of variable
• Column in observations
• Same column may associate with different
  variables
• Transformations
• Data supplements
• Cross references

11
Types of Variables

• Autosomal marker
• X-linked marker
• N-valued
• Dichotomous
• Gender ID
• Continuous
• Shared environmental ID

12
Transformations

• Genotypes from alleles
• Subtract a constant
• Divide by a constant
• McLean-Morton power transformation
• Convert to intervals
• Designate variables/individuals for simulation

13
Cross Reference

• Age Intervals
• Onset Intervals
• Categorial
• Gender
• BMI

14
Extended Settings

• Ascertainment correction
• Lod score or chi-square instead of likelihood
• Standard errors
• Simulated phenotypes
• Genotype probabilities

15
Commands

• Evaluate on F
• On model values
• Along parameter axis
• Over 2D grid
• Maximize F
• Global search
• Sequential search
• Standard errors
• Compute genotype probabilities
• Export simulation set

16
Analysis Examples

• Only examples
• Not exhaustive of PAP capability
• Aspects of examples can often be combined

17
Example Organization

• 5 files for most examples
• Input model (.in.xmod)
• Corresponding settings (.in.xpas)
• Output model (.out.xmod)
• Corresponding settings (.out.xpas)
• Results (.xpar)

18
Tutorial Options

• Create input models, execute commands
• No need to save since all files are available
• Open stored files for examination
• Some combination

19
A.1. Frequency Estimation
Extended Settings None
ModEd New
Number of Loci 1
Inheritance Mode Autosomal
Assignments PTPN2_1?L1
PAM Selections hw/ms
Free 1
Constraints None
Values 0.7?1
Command Global Maximization
20
Data Supplement

• Open Metadata editor
• Select alleles frequencies
• Input frequencies
• (or switch to tutorial.1.xmet)

21
A.2. Hardy-Weinberg Testing
Extended Settings None
ModEd New
Number of Loci 1
Inheritance Mode Autosomal
Assignments PTPN2_1?L1
PAM Selections g/ms
Free 1,2
Constraints None
Values 0.5?1,0.4?2
Command Global Maximization
22
H0 Hardy-Weinberg
Model Parameters -2lnLikelihood
A.1 1 533.6901
A.2 2 533.5587
Difference 1 0.0315
23
A.3.a. Linkage Equilibrium
Extended Settings None
ModEd New
Number of Loci 2
Inheritance Mode Autosomal
Assignments PTPN2_1?L1,PTPN2_2?L2
PAM Selections hw/al
Free 5,6
Constraints None
Values 0.05?5,0.05?6
Command Global Maximization
24
A.3.b. Linkage Disequilibrium D
Extended Settings None
ModEd A.3.a
Number of Loci 2
Inheritance Mode Autosomal
Assignments PTPN2_1?L1,PTPN2_2?L2
PAM Selections d/al
Free 5,6,7
Constraints None
Values 0.00.0,0.15?5,0.05?6,7
Command Global Maximization
25
H0 Linkage Equilibrium
Model Parameters -2lnLikelihood
A.3.a 3 1059.6965
A.3.b 2 1035.3204
Difference 1 24.3761
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Linkage Disequilibrium D
PTPN2_2 PTPN1_2 PTPN1_2 Total
PTPN2_2 1 2 Total
1 0.501 0.067 0.568 0.156 - 0.067 0.089 0.657
2 0.262 - 0.067 0.195 0.081 0.067 0.148 0.343
Total 0.763 0.237 1.000
27
A.3.c. Linkage Disequilibrium Conditional
Frequencies
Extended Settings None
ModEd A.3.a
Number of Loci 2 L1 conditional on L2
Inheritance Mode Autosomal
Assignments PTPN2_1?L1, PTPN2_2?L2
PAM Selections c/al
Free 1, 2, 5, 6
Constraints None
Values 0.63 ?1, 2, 0.05?5, 6
Command Global Maximization
28
Linkage Disequilibrium Conditional Frequencies
PTPN2_2 PTPN1_2 PTPN1_2 Total
PTPN2_2 1 2 Total
1 0.862 X 0.657 0.566 (1-0.862) X 0.657 0.091 0.657
2 0.562 X 0.343 0.193 (1-0.562) X 0.343 0.150 0.343
Total 0.763 0.237 1.000
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A.3.d. Linkage Disequilibrium Haplotype
Frequencies
Extended Settings None
ModEd A.3.a
Number of Loci 2
Inheritance Mode Autosomal
Assignments PTPN2_1?L1, PTPN2_2?L2
PAM Selections h/al
Free 1, 2, 3, 5, 6
Constraints None
Values 0.5?1, 0.1?2, 3, 0.05?5, 6
Command Global Maximization
30
Linkage Disequilibrium Haplotypes
PTPN2_2 PTPN1_2 PTPN1_2 Total
PTPN2_2 1 2 Total
1 0.571 0.092 0.657
2 0.1897 0.148 0.343
Total 0.763 0.237 1.000
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Linkage Disequilibrium Summary

• Slight differences in genotype frequency
  estimates
• Slight differences in likelihoods
• Identical estimates and likelihoods expected if
  allele frequencies were estimated in each
  parameterization

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A.4 Haplotype Inference
Extended Settings ProbabilitiesAll Pedigree Members
ModEd A.3.d.out
Number of Loci 2
Inheritance Mode Autosomal
Assignments PTPN2_1?L1, PTPN2_2?L2
PAM Selections h/al
Free
Constraints None
Values 0.5710?1,0.1897?2,0.0917?3,0.0431?5, 0.1281?6
Command Genotype Probabilities
33
B.1. Standardizing a Variable
Extended Settings None
ModEd New
Number of Loci 1
Inheritance Mode Autosomal
Assignments Exam1F8?L1
PAM Selections hw/ms/dd/ml
Free 3,4
Constraints None
Values
Command Global Maximization
34
Transformation in Metadata

• Open Metadata editor
• Transformation X-a with a 0.1047
• Transformation X/a with a 0.3059
• (or switch to tutorial.2.xmet)

35
B.2.a. Non-Normality TestingNo Transformation
Extended Settings None
ModEd B.1.in
Number of Loci 1
Inheritance Mode Autosomal
Assignments Exam1F8?L1
PAM Selections hw/ms/dd/ml
Free 3,4
Constraints None
Values 0.1?3, 1.5?4
Command Global Maximization
36
B.2.b. Non-Normality TestingTransformation
Extended Settings None
ModEd B.1.in
Number of Loci 1
Inheritance Mode Autosomal
Assignments Exam1F8?L1
PAM Selections hw/ms/dd/ml
Free 3,4,7
Constraints None
Values
Command Global Maximization
37
H0 Normality
Model Parameters -2lnLikelihood
B.2.a 2 735.0099
B.2.b 3 734.9801
Difference 1 0.0198
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B.3. Familial Correlations
Extended Settings None
ModEd B.1.in
Number of Loci 1
Inheritance Mode Autosomal
Assignments Exam1F8?L1
PAM Selections hw/ms/dd/fc
Free 8-15
Constraints 9101112,13141516
Values
Command Global Maximization
39
H0 Familial Correlations
Model Parameters -2lnLikelihood
B.2.a 0 735.0099
B.3 3 688.0728
Difference 3 46.9271
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B.4. Variance Components
Extended Settings None
ModEd B.1.in
Number of Loci 1
Inheritance Mode Autosomal
Assignments Exam1F8?L1,Househol d?Exam1F8
PAM Selections hw/ms/dd/vc
Free 8, 9
Constraints
Values
Command Global Maximization
41
H0 No Heritability/Household Effect
Model Parameters -2lnLikelihood
B.2.a 0 735.0099
B.4 2 685.0339
Difference 2 49.9660
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B.5.a. Epistasis One Locus
Extended Settings None
ModEd New
Number of Loci 1
Inheritance Mode Autosomal
Assignments Exam2F8?L1
PAM Selections hw/ms/mv/ml
Free 1, 3, 4, 5, 6, 7, 8
Constraints 678
Values 0.7 ?1, -1 ?3,1 ?5
Command Global Maximization
43
B.5.a. Inferred Model
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B.5.b. Epistasis One Locus
Extended Settings None
ModEd New
Number of Loci 1
Inheritance Mode Autosomal
Assignments Exam2F8?L1
PAM Selections hw/ms/dd/ml
Free 1, 3, 4, 5, 6
Constraints
Values 0.7 ?1, 0.5 ?5, 3?6
Command Global Maximization
45
Reparameterization

• ?t p2 ?1 2pq ?2 q2 ?3
• ?t2 p2 ?12 2pq ?22 q2 ?32 - ?t2 ?2wg
• d (?2 - ?1)/(?3 - ?1)
• t (?3 - ?1)/?wg
• p 0.6932, q 0.3068, ?1 -1.0498, ?2
  0.6894, ?3 1.1008, ?wg 0.4171
• ?t -0.1076, ?t 1.0041, d 0.8087, t 5.1556

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Polygenic Heritability

• Proportion of the within genotype variance
  attributed to polygenes
• Total heritability includes major locus
  heritability as well
• Likelihood approximated when a major locus in
  included.

47
B.5.c. Epistasis Two Loci -- Additive
Extended Settings None
ModEd New
Number of Loci 2
Inheritance Mode Autosomal
Assignments Exam2F8?L1,L2
PAM Selections hw/ms/dd/ml
Free 1, 3, 7-12
Constraints
Values 0.75?1,0.65 ?2,.75?9,8?11,5 ?12
Command Global Maximization
48
H0 One Locus
Model Parameters -2lnLikelihood
B.5.b 5 855.6094
B.5.c 8 826.3279
Difference 3 29.2815
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B.5.c. Two-Locus Additive Means
L1 L2 1 2 3
1 -1.2063 1.736 0.5297 0.1098 0.6395
0.4088 0.4088 0.4088
2 -0.7975 1.736 0.9386 0.1098 1.0484
0.8835 0.8835 0.8835
3 0.0860 1.736 1.8220 0.1098 1.9318
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B.5.d. Epistasis Two Loci
Extended Settings None
ModEd B.5.c.in
Number of Loci 2
Inheritance Mode Autosomal
Assignments Exam2F8?L1,L2
PAM Selections hw/ms/mv/ml
Free 1,3,7-26
Constraints 1113,17181920212226
Values 0.75?1,0.4?2,-1?7,8,10,12,15,0.5?11,13,1,5?14, 2?16,0.2?17
Command Global Maximization
51
B.5.d. Two-Locus Means
L1 L2 1 2 3
1 -0.9070 -0.3496 -1.2566 -0.1198 -1.3764
0.1135 1.7525 2.8826
2 -0.7935 1.2894 0.4959 1.0103 1.5062
1.7933 0.1698 -0.6881
3 0.9998 -0.3341 0.6657 0.1483 0.8181
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Two Locus Genotypes
L1 L2 1 2 3
1 1 4 6
2 2 5,7 9
3 3 8 10
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B.6.a.GenotypeXEnvironment No Interaction
Extended Settings None
ModEd New
Number of Loci 1
Inheritance Mode Autosomal
Assignments Exam2F8?L1,Exam2Age?Exam2F8
PAM Selections hw/ms/mv/ml
Free 1,3-8,10-12
Constraints 45,678,101112
Values 0.68?1, -1.2?3, 0.6?4, 0.5?6
Command Global Maximization
54
B.6.b.GenotypeXEnvironment Interaction
Extended Settings None
ModEd B.6.b.in
Number of Loci 1
Inheritance Mode Autosomal
Assignments Exam2F8?L1,Exam2Age?Exam2F8
PAM Selections hw/ms/mv/ml
Free 1, 3-8, 10-12
Constraints 45, 678, 1112
Values Estimates
Command Global Maximization
55
H0 No Genotype X Environment Interaction
Model Parameters -2lnLikelihood
B.6.a 5 833.0245
B.6.b 6 811.6202
Difference 1 21.4043
56
C.1.a Segregation Analysis Polygenic
Extended Settings Evaluation Ascertainment Correction
ModEd New
Number of Loci 1
Inheritance Mode Autosomal
Assignments DVT?L1
PAM Selections hw/ms/in/vc
Free 5
Constraints None
Values
Command Global Maximization
57
C.1.b. Segregation Analysis Mixed Model
Extended Settings Evaluation Ascertainment Correction
ModEd C.1.a.in
Number of Loci 1
Inheritance Mode Autosomal
Assignments DVT?L1
PAM Selections hw/ms/in/vc
Free 1, 3, 4, 5
Constraints None
Values 0.7 ?1, 0.75 ?3, 9.5 ?4
Command Global Maximization
58
H0 Polygenic Inheritance
Model Parameters -2lnLikelihood
C.1.a 1 203.2138
C.1.b 4 197.6454
Difference 3 5.5684
59
C.1.b Inferred Model
60
Liability Model

• Incidence fixed to population figures
• Earlier onset associated with higher liability
• Other options
• Prevalence figures pr
• Severity code sv
• Incidence by category inc

61
C.1.c. Segregation Analysis General Model
Extended Settings Evaluation Ascertainment Correction
ModEd C.1.b.in
Number of Loci 1
Inheritance Mode Autosomal
Assignments DVT?L1
PAM Selections hw/tp/in/vc
Free 1, 3-8
Constraints None
Values 0.7 ?1, 1 ?3, 0 ?5,0.75 ?6, 9.5 ?7
Command Global Maximization
62
H0 Major Locus
Model Parameters -2lnLikelihood
C.1.b 4 197.6454
C.1.c 7 195.6498
Difference 3 1.9956
63
C.1.d. Segregation Analysis Environmental Model
Extended Settings Evaluation Ascertainment Correction
ModEd C.1.b.in
Number of Loci 1
Inheritance Mode Autosomal
Assignments DVT?L1
PAM Selections hw/e/in/vc
Free 1, 4, 5
Constraints None
Values 0.7 ?1, 0.75 ?3, 9.5 ?4
Command Global Maximization
64
C.2.a. Gender Effects No Effect
Extended Settings Evaluation Ascertainment Correction
ModEd New
Number of Loci 1
Inheritance Mode Category-Specific Autosomal
Assignments DVT?L1,Gender?Categorical Status
PAM Selections hw/ms/in/ml
Free 1, 3-6
Constraints 34, 56
Values 0.76 ?1, 1 ?3, 6 ?5
Command Global Maximization
65
C.2.b. Gender Effects Effect
Extended Settings Evaluation Ascertainment Correction
ModEd C.2.a.in
Number of Loci 1
Inheritance Mode Category-Specific Autosomal
Assignments DVT?L1,Gender?Categorical Status
PAM Selections hw/ms/in/ml
Free 1, 3-6
Constraints
Values 0.76 ?1, 1 ?3, 6 ?5
Command Global Maximization
66
H0 Gender Effect
Model Parameters -2lnLikelihood
C.2.a 3 202.3758
C.2.b 5 201.9473
Difference 2 0.3285
67
D.1.a. Measured Genotype Polygenic Effect
Extended Settings None
ModEd New
Number of Loci 1
Inheritance Mode Autosomal
Assignments DVT,PTPN2_2?L1
PAM Selections hw/ms/in/vc
Free 5
Constraints None
Values
Command Global Maximization
68
D.1.b. Measured Genotype Variant and Polygenic
Effects
Extended Settings None
ModEd D.1.a.in
Number of Loci 1
Inheritance Mode Autosomal
Assignments DVT,PTPN2_2?L1
PAM Selections hw/ms/in/vc
Free 3, 4, 5
Constraints None
Values
Command Global Maximization
69
H0 Variant Effect
Model Parameters -2lnLikelihood
D.1.a 1 846.1648
D.1.b 3 840.0552
Difference 2 6.1096
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D.1.c. Measured Genotype Variant Effect
Extended Settings None
ModEd D.1.b.in
Number of Loci 1
Inheritance Mode Autosomal
Assignments DVT,PTPN2_2?L1
PAM Selections hw/ms/in/ml
Free 3,4
Constraints None
Values
Command Global Maximization
71
H0 Polygenic Effect
Model Parameters -2lnLikelihood
D.1.c 2 846.5940
D.1.b 3 840.0552
Difference 1 6.5388
72
D.2.a. Linkage/Association Complete
Extended Settings None
ModEd New
Number of Loci 2, L1 conditional on L2
Inheritance Mode Autosomal
Assignments DVT?L1,PTPN2_2?L2
PAM Selections c/al/in/ml
Free 7, 8
Constraints None
Values 1?1, 0?2, 0?7, 0?8
Command Global Maximization
73
Measured Genotype vs. Complete Linkage/Association

• D.1.c and D.2.a correspond to the exact same
  model
• Likelihoods are the same

74
D.2.b. Linkage/Association Complete
Extended Settings None
ModEd D.2.a.out
Number of Loci 2, L1 conditional on L2
Inheritance Mode Autosomal
Assignments DVT?L1,PTPN2_2?L2
PAM Selections c/al/in/ml
Free 1, 2, 5, 6, 7, 8
Constraints 56
Values
Command Global Maximization
75
H0 Complete Linkage and Association
Model Parameters -2lnLikelihood
D.2.a 2 846.5940
D.2.b 5 839.8954
Difference 3 6.6986
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D.2.c. Linkage/AssociationNo Association
Extended Settings None
ModEd D.2.b.out
Number of Loci 2, L1 conditional on L2
Inheritance Mode Autosomal
Assignments DVT?L1,PTPN2_2?L2
PAM Selections c/al/in/ml
Free 1, 2, 5, 6, 7, 8
Constraints 12
Values
Command Global Maximization
77
H0 No Association
Model Parameters -2lnLikelihood
D.2.c 4 848.0956
D.2.b 5 839.8954
Difference 1 9.2002
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D.3.a. Linkage
Extended Settings Evaluation Alternative Objective F
ModEd New
Number of Loci 2
Inheritance Mode Autosomal
Assignments DVT?L1, PTPN2_1?L2
PAM Selections hw/al/in/ml
Free 5, 6
Constraints 56
Values 0.9?1, 0?5, 1?7, 6?8
Command Evaluate along parameter axis
79
D.3.b. Linkage and Association
Extended Settings Evaluation Alternative Objective F
ModEd New
Number of Loci 2, L1 conditional on L2
Inheritance Mode Autosomal
Assignments DVT?L1, PTPN2_1?L2
PAM Selections hw/al/in/ml
Free 1, 2, 5, 6
Constraints 56
Values 0.9?1, 0?L5, 1?7, 6?8
Command Global Maximization
80
D.4. Transmission Disequilibrium Test
Extended Settings Evaluation Alternative Objective F
ModEd New
Number of Loci 1
Inheritance Mode Category-Specific Autosomal
Assignments PTPN2_1?L1, DVT?Categorical Status
PAM Selections hw/tdt
Free 4
Constraints None
Values
Command Global Maximization
81
TDT Parameterization

• Probability allele transmitted to affected
  offspring by heterozygous parent
• Different parameterization from gamete
  competition model
• May be estimated for N-1 alleles (constraint
  requires that at least one user-selected allele
  not estimated)
• Haplotypes also (zero recombination)

82
TDT Warning

• Sensitive to marker allele frequencies
• Genotypes inferred probabilistically when
  parental genotypes missing

83
E.1.a. Replicate DataOne Measurement
Extended Settings Gsearch Standard Errors
ModEd New
Number of Loci 1
Inheritance Mode Autosomal
Assignments Exam1F8?L1
PAM Selections hw/ms/dd/vc
Free 8
Constraints None
Values
Command Global Maximization
84
E.1.b. Replicate DataTwo Measurements
Extended Settings Gsearch Standard Errors
ModEd New
Number of Loci 1
Inheritance Mode Autosomal
Assignments Exam1F8, Exam2F8?L1
PAM Selections hw/ms/dd/vc
Free 13, 14, 16
Constraints 1314
Values 0.6?13, 0.8?16
Command Global Maximization
85
Replicate Data
Model Heritability SE
E.1.a 0.6583 0.0892
E.1.b 0.7024 0.0611
86
E.2.a. PleiotropyNo Genetic Correlation
Extended Settings None
ModEd New
Number of Loci 1
Inheritance Mode Autosomal
Assignments DVT,Exam1F8?L1
PAM Selections hw/ms/in/dd/vc
Free 10, 11, 13
Constraints None
Values
Command Global Maximization
87
E.2.b. PleiotropyGenetic Correlation
Extended Settings None
ModEd New
Number of Loci 1
Inheritance Mode Autosomal
Assignments DVT,Exam1F8?L1
PAM Selections hw/ms/in/dd/vc
Free 10, 11, 12, 13
Constraints None
Values
Command Global Maximization
88
H0 Pleiotropy
Model Parameters -2lnLikelihood
E.2.a 3 932.8798
E.2.b 4 926.7869
Difference 1 .40929
89
E.3.a. Medication Effects Constant Increment
Extended Settings None
ModEd New
Number of Loci 1
Inheritance Mode Category-Specific Autosomal
Assignments Exam1F8?L1Coumadin?Categorical Status
PAM Selections hw/ms/dd/ml
Free 1, 3-10
Constraints 56, 78, 910
Values 0.7?1, 0.5?7, 3?9
Command Global Maximization
90
E.3.b. Medication Effects Threshold
Extended Settings None
ModEd New
Number of Loci 1
Inheritance Mode Autosomal
Assignments UnmedF8?L1,Coumadin?UnmedF8
PAM Selections hw/ms/ddp/ml
Free 1, 3-6
Constraints None
Values 0.7?1, 0.3?4, 1?5, 3?6
Command Global Maximization
91
Threshold Effect

• Other options mvt
• Specify medication threshold rather than
  prevalence
• Use transformation, divide by -1, for lower tail
  effect

92
E.3.c. Medication EffectsBivariate
Extended Settings None
ModEd New
Number of Loci 1
Inheritance Mode Autosomal
Assignments UnmedF8,DVT?L1
PAM Selections hw/ms/in/dd/ml
Free 1, 3-8
Constraints None
Values 0.7?1,1?3,0.3?6,1?7,3?8, 1?10
Command Global Maximization
93
Medication Effects
Model Frequency Dominance Displacement
E.3.a 0.700 0.973 4.381
E.3.b 0.836 0.775 5.361
E.3.c 0.714 0.708 5.364
94
F.1. Mitochondrial
Extended Settings None
ModEd New
Number of Loci 1
Inheritance Mode Autosomal
Assignments Exam1F8?L1, Mitochondrial?Exam1F8
PAM Selections hw/ms/dd/vc
Free 8, 9
Constraints None
Values
Command Global Maximization
95
F.2. Imprinting
Extended Settings None
ModEd New
Number of Loci 1
Inheritance Mode Parent-Specific Autosomal
Assignments DVT?L1
PAM Selections hw/ms/in/ml
Free 1, 3, 4, 5
Constraints None
Values 0.98?1, 1?3, 1?4, 5?5
Command Global Maximization
96
Imprinting Options

• X-linked imprinting as well

97
F.3.a. Testing X-LinkageAutosomal
Extended Settings None
ModEd New
Number of Loci 1
Inheritance Mode Autosomal
Assignments DVT?L1,Gender?Categorical Status
PAM Selections hw/ms/in/ml
Free 1, 3, 4, 5, 6
Constraints None
Values 0.98?1, 1?3, 1?4, 5?5, 5?6
Command Global Maximization
98
F.3.b. Testing X-LinkageX-Linked
Extended Settings None
ModEd New
Number of Loci 1
Inheritance Mode X-Linked
Assignments DVT?L1
PAM Selections hw/ms/in/ml
Free 1, 3, 4, 5
Constraints None
Values 0.98?1, 1?3, 5?4, 5?5
Command Global Maximization
99
F.3.a. Testing X-LinkageX-Linked/Autosomal
Admixture
Extended Settings None
ModEd New
Number of Loci 2
Inheritance Mode X-linked/Autosomal
Assignments DVT?L1, L2
PAM Selections hw/axl/in/ml
Free 1, 3, 5-11
Constraints None
Values 0.9?1, .7?3, 1?5, 5?8-11
Command Global Maximization
100
H0 Autosomal
Model Parameters -2lnLikelihood
F.3.a 5 285.1065
F.3.c 9 279.6330
Difference 4 5.4735
101
H0 X-Linked
Model Parameters -2lnLikelihood
F.3.b 4 282.1065
F.3.c 9 279.6330
Difference 5 2.4735
102
Autosomal/X-Linked Mixed

• Alternative to the Autosomal/X-linked admixture
  just demonstrated
• Only one locus -- frequencies and transmission
  mimic the 2 modes of inheritance
• May be more appropriate for single pedigree than
  assuming both modes
• General model doesnt reflect reality

103
G.1. Simulation
Extended Settings GsearchUse Simulated Phenotypes Simulation 10 Replicates
ModEd New
Number of Loci 1
Inheritance Mode Autosomal
Assignments SimMark?L1
PAM Selections hw/ms
Free 1, 2, 3
Constraints None
Values 0.25 ?1, 2, 3
Command Global Maximization
104
Future Plans

• Multipoint Linkage Analysis
• Parametric and variance components
• MCMC methods developed by Alun Thomas
• Graphical visualization of data and results
• Improved maximization
• Batch runs
• Simulated data
• Estimating marker allele frequencies
• Linkage analysis

105
Towards Linkage Analysis with Linkage
Disequilibrium

• Alun Thomas
• Sunday 930

106
Acknowledgments

• John Elliott
• Peter Cartwright