Modeling Complexity, the Elston Pedigree and Genetic Epidemiology

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Modeling Complexity, the Elston Pedigree and
Genetic Epidemiology

• Chris Amos, U.T. M.D. Anderson Cancer Center

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Thanks to Sponsors!

• Triaj, Inc.
• Glaxo SmithKline
• John Wiley and Sons, Ltd.
• Statistical Solutions, Ltd.
• Institutional Sponsors
• Case-Western Reserve University
• Washington University, St. Louis
• Louisiana State University Medical Center

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Thanks to Local Organizers

• Bronya Keats, Ph.D. - Chair
• Stephanie Laurent
• Diptasri Mandal, Ph.D.
• Judy Laborde
• Jerlyn Rose
• Jean MacCluer, Ph.D.
• Vanessa Olmo

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Thanks to Scientific Organizing Committee

• John Witte (Chair)
• Jenny Chang-Claude
• Bronya Keats
• Kim Siegmund
• Cornelia Van Duijn
• Bruce Weir

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Genetic Epidemiology

• "the study of genetic components in complex
  biological phenomena" JVNeel
• The successful mapping of the human genome will
  greatly facilitate the study of health and
  disease in a manner that integrates both host and
  environmental factors.

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Why Identify Genetic Factors for Complex Diseases?

• Some genetic factors may permit modulation
• Identifying and conditioning on genetic factors
  may assist in identifying environmental triggers

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Alice laughed "There's no use trying," she said
"one can't believe impossible things.""I daresay
you haven't had much practice," said the Queen.
"When I was younger, I always did it for half an
hour a day. Why, sometimes I've believed as many
as six impossible things before breakfast."
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Robert Elston, Vanquisher of Chaos
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Algorithmic and computational approaches to
modeling complexity

• Elston RC. Simulation dun processus
  stochastique implique dans la gestion dune
  banque de sang. Biometrie-prazimetrie 3129-140,
  1962.
• Elston RC and Pickrel JC. A statistical approach
  to ordering and usage policies for a hospital
  blood bank, Transfusion 341-47

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Summary (Elston and Pickrel, 1963)

• An electronic computer (Univac 1105) is used in a
  simulation study to determine ordering and usage
  policies for a hospital blood bank. It is
  assumed that only type specific transfusions are
  given, and that all use of fresh blood ob-tained
  for specific cases is excluded. A ratio of 254
  is taken as the ratio of the cost when-ever the
  bank is short of a unit for actual transfusion
  to the cost of an outdated unit.

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Elston and Stewart, 1971

• Recognition that extended families contain (far)
  more information for evaluating
  segregation-related parameters than smaller
  families

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Elston RC, Stewart J. A General Model for the
Genetic Analysis of Pedigree Data. Hum Hered
21523-534.

• Provides algorithms for estimating single and
  multiple major gene effects (possibly linked) in
  extended pedigrees
• Algorithm for polygenic effects in pedigrees
• Discusses the mixed model
• Provides methods for genotype classification
  (genetic counseling)
• Provides approaches for hypothesis testing
  (randomization, Wald tests, LR tests)

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Stewarts commentsHuman Heredity 1992 42915

• When I first met Robert Elston in 1968 and he
  introduced me to maximum likelihood techniques, I
  rapidly formed the conviction that these methods
  held the key to a canonical solution to a problem
  I had been wrestling with the genetic analysis
  of characters which do not display an immediate
  one-to-one correspondance between discrete
  phenotypes and Mendelian genotypes.. . .I
  predicted that it would become a landmark paper.
  Robert was sceptical.

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Stewarts comments (cont)

• In order to interpret a diversified syndrome of
  symptoms in terms of a branching tree of causes
  and effects from a single initial cause (the
  segregating allele), considerable biological
  knowledge is necessary.
• Stewart comments on the need for development and
  study of experimental organisms to understand
  biological effects of genes, holistic not
  reductionist approach

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Genetic Analysis of Familial Periodic Fever
Syndromes

• Autosomal Dominant
• Variable phenotype consisting of
  episodic/periodic high fevers sometimes requiring
  long-term treatment with steroids
• Extended Pedigrees, Age-Dependent Penetrance,
  requires Elston-Stewart Algorithm
• Families collected from registries, cant
  correct for ascertainment

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Genetic Linkage analysis of 3 Familial Periodic
Fever Families
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Salient Developments in Mapping Familial Periodic
Fevers

• Lack of linkage to TNF receptor 1 (p55)
• Increased p55 levels from patients with FPF
  compared to family controls (bad assay?, no
  replicate on fresh sample)
• Missense mutations of p55 cause increased binding
  to cellular membrane (decreased serum levels)

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Treatment of FPFs

• P75 (TNFR2) had previously been approved for use
  and treatment in RA patients
• P75 administration leads to a reversion of most
  clinical symptoms of FPFs

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A few comments

• Biological knowledge helped in identifying
  appropriate measures, but did not provide correct
  knowledge of the effects on p55. Quantitative
  analysis was critical.
• Need for robust approach in evaluating pedigree
  information, multiple potential sources for error
  (clinical mistyping).
• Need for international collaborative study to
  attain sufficient power for disease mapping

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Models for Quantitative Traits

• Numerous alleles may affect the trait levels,
  presenting a problem in building an adequate
  model
• Distributional assumptions may play a role in
  inferences (hard to evaluate whether nonnormality
  is due to skewing or allelic effects)
• Multiple loci are likely to be involved

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Development of Quantitative Modeling Approach

• Haseman-Elston (1972) approach provides a rapid,
  efficient, robust test for linkage using
  quantitative traits
• Numerous extensions eg. Blackwelder and Elston,
  1982 Amos and Elston, 1989
• Extension to covariance modeling (Elston et al.
  2000), multivariate modeling
• Very wide application - e.g. mapping of DBH
  (Wilson et al., 1988)

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Other Contributions

• Models for multilocus segregation analysis in
  backcrosses and intercrosses
• Methods for ascertainment correction
• Cost and efficiency of genetic linkage procedures
• Huge number of students

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The Elston Pedigree

• We (naively) set out to collect data on the
  offspring of Robert Elston.
• Pedigree Spans 5 generations and includes 382
  (possibly redundant) individuals
• Limited inbreeding - indicating a preference for
  exogamous relationships with some exceptions
  (inbreeding at UCLA)
• All talks in the first session have a student of
  Elstons among the authors, great breadth

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UNC Chapel Hill (60-79)
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LSU New Orleans (79-95)
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Elston Pedigree - CWRU
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Elston Pedigree - Comments

• Some Students had very large clutches, Anne
  Spence, Nancy Mendell, Joan Bailey-Wilson, Lynn
  Goldin. Some overlaps.
• Pedigree fails to show the web of complex
  relationships to Elston
• Trainees come from very wide range of
  backgrounds, disciplines

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Robert Elston and IGES

• Strong impact on the I and S parts of the society
• Strong emphasis on the International conduct of
  science
• These international ties are critical but must be
  nurtured following 9/11. Travel restrictions
  limit travel of US alien residents but also
  impede travel from other countries

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Robert Elston and the Society

• First Secretary of Society 1993-1994, spent hours
  struggling with rules for incorporation in
  Louisiana
• With DC Rao drafted the By-Laws of the society
• Served as President 1997

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Societal Issues in Genetic Epidemiology

• Increasing pressure from IRBs and other
  regulatory bodies impede collection of patient
  information, sharing of data (even after some
  level of de-identification)
• HIPAA regulations impede the abstraction of
  medical chart data, sharing of patient
  information from hospitals, affect informed
  consent process

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Role of IGES in the International Genetics
Community

• Limited membership with a focused area of
  research - focused areas of expertise
• Associate member of the International Federation
  of Human Genetics Societies
• Widely read manuscript reviewing charges from
  Tierney against conduct by James V. Neel (Thanks
  to Duncan, Max, Partha)
• Outreach through Education committee to
  Epidemiological and Genetic Societies

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Identifying genetic factors for complex traits
and diseases

• Most effective approaches depend upon situation
  (which is probably unknown)
• Genetic Model-free methods are easily applied and
  can allow for oligogenic inheritance will little
  information loss
• Goring H, et al. Genet Epidemiol 200121 1S783
• Monte Carlo Markov Chain approaches can be
  effective for resolving multiple genetic effects,
  but operating characteristics for overdetermined
  models need further study

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Resolving Complex Genetic Effects

• Newer machine-learning tools hold promise for
  gene identification
• Moore JH, Hahn LW Pac Sym Biocomput 200253-64
• Shannon WD et al. Genetic Epidemiology 2001,
  20293-306.
• Cladograms and other approaches for sorting data
  show promise for interpreting complex associations

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Tree Diagram 8 Chr1, 269 cM
?0.54
Both sibs have 2 DR4 alleles
?0.55
?0.47
Non-Caucasians
?0.65
?0.54
Concordant for nodules
?0.51
?0.56
?1 sib with RF100
?0.53
?0.64
Both sibs have 0 DR4 alleles
Same sex sibs
?0.68
?0.56
?0.71
?0.61
T22b
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Resolving Complex Effects

• Studies in isolated populations may provide novel
  insights
• Greater extent of linkage disequilibrium
• Less complex genetic architecture
• More power for identifying recessive loci
• Animal models can be highly effective for
  evaluating potential genetic factors in humans
  (Carrasquillo MM et al., Nat Genet
  200232237-44)

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Figure a, Region analyzed from HLA-DNA to Tap b,
LD in this region in north Europeans. Classic
D' measures27 of complete LD (lower right),
where D'1 for marker pairs showing only three
haplotypes, are shown for all pairs of markers
with minor allele frequencies of at least 0.15,
together with the associated likelihood ratio
(LR) versus free association (upper left), and
color-coded as indicated at top right. c,
Corresponding LD plot for markers with minor
allele frequencies less than 0.15. d, Expansion
of plot b in the HLA-DNA region e, Expansion of
plot b in the HLA-DMB region. Nat Genet
29217-222, 2001.
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Genetic Epidemiology and Population Genetics

• Evaluation of haplotype structure in different
  populations indicates the value of population
  genetic studies
• Importance of clear knowledge of genetic
  background of populations indicates need for
  collaboration with fieldworkers/anthropologists
• Existence of LD over extended regions indicates
  value of association approaches

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Genetic Epidemiology and Epidemiology

• An ultimate goal in genetic epidemiology is
  identification of modifiable factors
• Environment is hard to measure but much easier to
  change than genetic factors
• Continued interaction with our epidemiological
  colleagues will help us to develop optimal
  designs for understanding genetic and
  environmental determinants of disease

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Studying Complex Traits

• Best studies are those with clear hypotheses -
  Often best science results from finding ones
  hypothesis is completely incorrect e.g.
  Williamson and Amos, 1995.
• Role for descriptive science - e.g. microarray
  discovery, but results are far more readily
  interpreted under hypotheses

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Complex Models, Genetic Epidemiology and Elston

• Some of Elstons great success results from an
  effective cross-fertilization of statistics,
  computational methods and genetics
• Current underrepresentation of animal
  methods/models (at this meeting, generally in our
  literature)
• Need for open-minded approach to new
  computational tools, many tools need further
  statistical development/ validation

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Acknowledgements

• Monawar Hosain - Elston Pedigree
• Sanjay Shete - Comments
• Carol Etzel - Slides
• Tracy Costello - Slides