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Improving Reporting of Association Study Results Timothy R. Rebbeck, Ph.D. University of Pennsylvania School of Medicine Reporting Genetic Associations Appropriate Study Design? Biological Model? Statistical Analysis? Laboratory QC? Race/Ethnicity? Biological Plausibility?

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Improving Reporting of Association Study Results

Timothy R. Rebbeck, Ph.D.

University of Pennsylvania School of Medicine


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Reporting Genetic Associations

  • Appropriate

    • Study Design?

    • Biological Model?

    • Statistical Analysis?

  • Laboratory QC?

  • Race/Ethnicity?

  • Biological Plausibility?

  • Replication?


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Example: CYP3A Locus(Chromosome 7q22)

CYP3A5

CYP3A7

CYP3AP1

CYP3A4

CYP3A43

*1B

(5’ UTR)


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Reporting Genetic Associations

  • Appropriate

    • Study Design?

    • Biological Model?

    • Statistical Analysis?

  • Laboratory QC?

  • Race/Ethnicity?

  • Biological Plausibility?

  • Replication?


Cyp3a4 substrate heterogeneity l.jpg
CYP3A4 Substrate Heterogeneity

R=Estrogens, Progesterone, Testosterone, Carcinogens, Drugs

CYP3A4

R

R-OH

Phase II

X=Sulfate, Glucuronate, Glutathione,Methyl

R-OX


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G

G

G

Exposure

Disease

Outcome

G

G

Treatment

Chemoprevention

Where Are Genes Acting?


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Lupron

Finasteride

Pleiotropic Effects of CYP3A4

and Fatal Prostate Cancer

CYP3A4

CYP3A4

Prostate Cancer

Androgens

PSA Failure

CYP3A4

CYP3A4


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Linkage Disequilibrium in the CYP3A Gene Cluster

CYP3A43

CYP3A4

CYP3AP1

CYP3A7

CYP3A5

3’

5’

LD

LD

LD

LD

Chang 2000, Kuehl 2001, Wojnowski 2002, Zeigler-Johnson 2004


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Inference

  • How Many Tests Were Performed?

  • Correction for Multiple Comparisons

    • Bonferroni

    • Bonferroni-Holm, Westfall-Young

    • False Discovery Rate (Benjamini-Hochberg)

  • FPRP/FNRP (Wacholder)

  • Others?


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Novel Analytical Methods

  • Recursive Partitioning (CART; Breiman 1984, Foulkes 2005)

  • Random Forests (Pavolov 1997)

  • Combinatorial Partitioning (Nelson 2001)

  • Multifactor-Dimensionality Reduction (Ritchie 2001)

  • Permutation-Based Procedures (Trimming/Weighting; Hoh 2000)

  • Multivariate Adaptive Regression Spines (Friedman 1991)

  • Boosting (Schapire 1990)

  • Support Vector Machines (Vapnik 2000)

  • Neural Networks (Friedman & Tukey 1974, Friedman & Stuetzle 1981)

  • Bayesian Pathway Modeling (Conti 2003, Cortessis & Thomas 2004)

  • Clique-Finding (Mushlin 2006)


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Reporting Genetic Associations

  • Appropriate

    • Study Design?

    • Biological Model?

    • Statistical Analysis?

  • Laboratory QC?

  • Race/Ethnicity?

  • Biological Plausibility?

  • Replication?


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Laboratory Error

  • Non-Differential Misclassification: Bias Toward the Null Hypothesis

  • Differential Misclassification (e.g., cryptic variants): Unpredictable Bias

  • Possible Type I or Type II Error and Lack of Replication Among Studies

  • Appropriate reporting of QC


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Reporting Genetic Associations

  • Appropriate

    • Study Design?

    • Biological Model?

    • Statistical Analysis?

  • Laboratory QC?

  • Race/Ethnicity?

  • Biological Plausibility?

  • Replication?


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Racial Differences: CYP3A4*1B Example

Zeigler-Johnson 2002, 2004


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CYP3A4*1B Frequency and Prostate Cancer Incidence by Race

AfricanAmerican

European American

ChineseAmerican


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CYP3A Haplotypes

Zeigler-Johnson 2004


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(When) Is Population Stratification a Problem?

  • Can be found if you look hard enough (Freedman 2004)

  • May be more pronounced in recently admixed populations (Ardlie 2003)

  • Adjustment or matching can be undertaken when race can be appropriately measured

  • Other approaches available when race cannot be measured:

    • Genomic Control (Pritchard 1999; Devlin 1999)

    • Structured Association (Pritchard 2000; Satten 2001)

  • Small biases likely in most situations (Wacholder 2000, Millikan 2000, Wang 2004, 2005, 2006)

  • Other forms of bias exist that may be more important (Palmer and Cardon 2003)


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Reporting Genetic Associations

  • Appropriate

    • Study Design?

    • Biological Model?

    • Statistical Analysis?

  • Laboratory QC?

  • Race/Ethnicity?

  • Biological Plausibility?

  • Replication?


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Effect of CYP3A4*1B on “Function”

Effect of CYP3A4*1BCompared with CYP3A4*1A

190%↑ in Testosterone oxidation

90%↑ in Luciferase Expression

40%↑ in Luciferase Expression

40%↑ in Nifedipine Oxidase Activity

110%↑in CYP3A4 Protein Expression

No Change in Luciferase Expression

20%↑in Luciferase Expression

20%↑in Luciferase Expression

40%↑in Luciferase Expression

20-90%↑ in Luciferase Expression

20-117%↑in transcriptional activation*

75-147%↑ in transcriptional activation*

*Upon Xenobiotic Exposure

CYP3A4*1B

ATG

5’

3’

Westlind(Hepatocytes)

Amirimani (MCF7)

Amirimani (HepG2)

Ando (Hepatocytes)

Ando (Hepatocytes)

Spurdle (HepG2)

Spurdle (HepG2+E)

Amirimani (MCF7)

Amirimani (HepG2)

Amirimani (Hepatocytes)

Hamzeiy (HepG2)

Hamzeiy (HuH7)


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Sources of “Functional” Information

Evidence Example

Experimental In vivo, In vitro assays

Nucleotide Sequence Mutation Consequences

Evolutionary Conservation Sequence Conservation (e.g., SIFT, CODDLE)

Population Genetics Hardy-Weinberg, Linkage Disequilibrium

Exposures Metabolism of relevant carcinogens

Epidemiology Association consistency

Structural Protein conformation (e.g., PolyPhen)


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Assessing SNP Functional Significance(Rebbeck, Wu, Spitz 2004)


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Assessing SNP Functional Significance(Rebbeck, Wu, Spitz 2004)


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Assessing SNP Functional Significance(Rebbeck, Wu, Spitz 2004)




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Reporting Genetic Associations

  • Appropriate

    • Study Design?

    • Biological Model?

    • Statistical Analysis?

  • Laboratory QC?

  • Race/Ethnicity?

  • Biological Plausibility?

  • Replication?


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Informative Irreproducibility:Is Replication Always Necessary or Expected?

  • When might “Irreproducibility” reflect meaningful biological phenomena?

  • Differences may reflect

    • Incorrect model (interaction vs. main effects)

    • Frequency (power?) differences

    • Context of association

  • Distinguish error from true differences


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Reporting Genetic Associations

  • Appropriate

    • Study Design?

    • Biological Model?

    • Statistical Analysis?

  • Laboratory QC?

  • Race/Ethnicity?

  • Biological Plausibility?

  • Replication?


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