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Grant Details

Grant Number: 5R01CA222833-03 Interpret this number
Primary Investigator: Dai, James
Organization: Fred Hutchinson Cancer Research Center
Project Title: Statistical Genetics and Genomics for Epidemiologic Research
Fiscal Year: 2020


Project Summary/Abstract Genome-wide association studies have identified an unprecedented number of genetic variants associated with disease risk, yet molecular mechanisms and clinical implications of genetic risk alleles are largely unknown. Epidemiologic research is extending its reach to more translational and mechanistic studies, integrating genetic risk variants with environmental exposures, interventions, gene expression and epigenetics. Motivated by population-based studies for prostate cancer research, we will develop statistical methods for emerging translational topics: how to search for genotypes that predict individual and subgroup intervention effects? how to identify epigenetic alterations that may be an interface of the environment and the genome? how to assess causal mediation effect of a modifiable risk factor or a molecular alteration in relation to disease outcomes? These topics present unmet statistical challenges because of high dimensionality and complex modeling. Specific statistical methods to be developed include high-dimensional gene- treatment interaction, multi-locus regional association, mediation analyses, instrumental variable analyses, Mendelian randomization, and shrinkage and regularization. The methodological research in this project is driven primarily by prostate cancer, the most common noncutaneous cancer and the second leading cause of cancer death in American men, a ecting one in six in his lifetime. This project nests in highly-accomplished consortium studies (PCPT/SELECT/PRACTICAL/PCPS), all of which have generated far-reaching impact on prostate cancer research. The unique feature of this project is that methodological development will be seamlessly integrated with ongoing analyses, ensuring immediate translation. Our transdisciplinary research team has been actively engaged in statistical genetics and genomics, and conducting molecular epidemiological studies. The PI brings a wealth of expertise in high-dimensional methods, molecular biomarkers, and genetic epidemiology. This project will have a far-reaching impact on methodologies in cancer etiology, prevention, and treatment outcomes.


Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.
Authors: Karlsson Q. , Brook M.N. , Dadaev T. , Wakerell S. , Saunders E.J. , Muir K. , Neal D.E. , Giles G.G. , MacInnis R.J. , Thibodeau S.N. , et al. .
Source: European urology oncology, 2021 Aug; 4(4), p. 570-579.
EPub date: 2021-01-09.
PMID: 33436325
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Genetically Predicted Circulating C-Reactive Protein Concentration and Colorectal Cancer Survival: A Mendelian Randomization Consortium Study.
Authors: Hua X. , Dai J.Y. , Lindström S. , Harrison T.A. , Lin Y. , Alberts S.R. , Alwers E. , Berndt S.I. , Brenner H. , Buchanan D.D. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2021 07; 30(7), p. 1349-1358.
EPub date: 2021-05-10.
PMID: 33972368
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EMeth: An EM algorithm for cell type decomposition based on DNA methylation data.
Authors: Zhang H. , Cai R. , Dai J. , Sun W. .
Source: Scientific reports, 2021-03-11; 11(1), p. 5717.
EPub date: 2021-03-11.
PMID: 33707472
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Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk.
Authors: Kapoor P.M. , Mavaddat N. , Choudhury P.P. , Wilcox A.N. , Lindström S. , Behrens S. , Michailidou K. , Dennis J. , Bolla M.K. , Wang Q. , et al. .
Source: Journal of the National Cancer Institute, 2021-03-01; 113(3), p. 329-337.
PMID: 32359158
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Copy number alterations are associated with metastatic-lethal progression in prostate cancer.
Authors: Wang X. , Grasso C.S. , Jordahl K.M. , Kolb S. , Nyame Y.A. , Wright J.L. , Ostrander E.A. , Troyer D.A. , Lance R. , Feng Z. , et al. .
Source: Prostate cancer and prostatic diseases, 2020 09; 23(3), p. 494-506.
EPub date: 2020-02-18.
PMID: 32071439
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DNA methylation and cis-regulation of gene expression by prostate cancer risk SNPs.
Authors: Dai J.Y. , Wang X. , Wang B. , Sun W. , Jordahl K.M. , Kolb S. , Nyame Y.A. , Wright J.L. , Ostrander E.A. , Feng Z. , et al. .
Source: PLoS genetics, 2020 03; 16(3), p. e1008667.
EPub date: 2020-03-30.
PMID: 32226005
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Assessment of interactions between 205 breast cancer susceptibility loci and 13 established risk factors in relation to breast cancer risk, in the Breast Cancer Association Consortium.
Authors: Kapoor P.M. , Lindström S. , Behrens S. , Wang X. , Michailidou K. , Bolla M.K. , Wang Q. , Dennis J. , Dunning A.M. , Pharoah P.D.P. , et al. .
Source: International journal of epidemiology, 2020-02-01; 49(1), p. 216-232.
PMID: 31605532
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Case-only trees and random forests for exploring genotype-specific treatment effects in randomized clinical trials with dichotomous endpoints.
Authors: Dai J.Y. , LeBlanc M. .
Source: Journal of the Royal Statistical Society. Series C, Applied statistics, 2019 Nov; 68(5), p. 1371-1391.
EPub date: 2019-07-08.
PMID: 32489221
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A four-gene transcript score to predict metastatic-lethal progression in men treated for localized prostate cancer: Development and validation studies.
Authors: Cheng A. , Zhao S. , FitzGerald L.M. , Wright J.L. , Kolb S. , Karnes R.J. , Jenkins R.B. , Davicioni E. , Ostrander E.A. , Feng Z. , et al. .
Source: The Prostate, 2019 10; 79(14), p. 1589-1596.
EPub date: 2019-08-02.
PMID: 31376183
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Case-only Methods Identified Genetic Loci Predicting a Subgroup of Men with Reduced Risk of High-grade Prostate Cancer by Finasteride.
Authors: Dai J.Y. , LeBlanc M. , Goodman P.J. , Lucia M.S. , Thompson I.M. , Tangen C.M. .
Source: Cancer prevention research (Philadelphia, Pa.), 2019 02; 12(2), p. 113-120.
EPub date: 2018-12-11.
PMID: 30538099
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Vigorous Physical Activity Is Associated with Lower Risk of Metastatic-Lethal Progression in Prostate Cancer and Hypomethylation in the CRACR2A Gene.
Authors: Dai J.Y. , Wang B. , Wang X. , Cheng A. , Kolb S. , Stanford J.L. , Wright J.L. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2019 02; 28(2), p. 258-264.
EPub date: 2018-11-21.
PMID: 30464020
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Diagnostics for Pleiotropy in Mendelian Randomization Studies: Global and Individual Tests for Direct Effects.
Authors: Dai J.Y. , Peters U. , Wang X. , Kocarnik J. , Chang-Claude J. , Slattery M.L. , Chan A. , Lemire M. , Berndt S.I. , Casey G. , et al. .
Source: American journal of epidemiology, 2018-12-01; 187(12), p. 2672-2680.
PMID: 30188971
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