Grant Number:	1R01CA163251-01A1 Interpret this number
Primary Investigator:	Begg, Colin
Organization:	Sloan-Kettering Inst Can Research
Project Title:	Statistical Strategies for Establishing Etiologic Heterogeneity of Tumors
Fiscal Year:	2012

DESCRIPTION (provided by applicant): The fundamental premise of this proposal is that cancer types based on anatomic site may contain sub-types that are etiologically distinct. Indeed a lot of evidence for this has emerged in recent years. The goal of the proposal is to develop a strategy for optimally identifying such etiologically distinct tumor sub-types, and to develop the statistical techniques needed to accomplish this. In addition to clarifying cancer etiology, such an approach offers the promise of a more powerful strategy for detecting new risk factors, by focusing studies to discover these new risk factors on the sub-types that possess distinct etiology. Our research plan is motivated by a crucial new result regarding the occurrence of double primary malignancies. We show that the odds ratio linking tumor sub-types of pairs of independently occurring cancers is directly related to the underlying population risk heterogeneity of the sub-types. Consequently data from studies of double primaries can be used to determine optimal tumor sub-classification from an etiologic perspective. In this proposal we build upon this result to develop multivariate clustering techniques that optimize the etiologic heterogeneity of the resulting clusters (Aim 1). We will develop analogous techniques for creating sub-types that maximize the degree of etiologic heterogeneity on the basis of known risk factors for use in settings where data on multiple primary cancers are unavailable or unobtainable (Aim 2). We will determine the implications of the use of sub-typing as a strategy for detecting new risk factors from the perspective of statistical power (Aim 3). Finally, we will develop freely-available software to allow other investigators easy access to the methods that we develop (Aim 4). The research will lead ultimately to a conceptual framework for investigating etiologic heterogeneity, and a suite of statistical tools for conducting the dat analyses. PUBLIC HEALTH RELEVANCE: Our research plan has the potential to change the landscape of how cancer epidemiologic investigations are conducted, by focusing on etiologic heterogeneity as a tool for improving the efficiency and statistical power of cancer epidemiologic investigations. As such, it can lead to greater speed in the discovery of factors affecting cancer risk.




Validity of a method for identifying disease subtypes that are etiologically heterogeneous.
Authors: Zabor E.C. , Seshan V.E. , Wang S. , Begg C.B. .
Source: Statistical Methods In Medical Research, 2021 09; 30(9), p. 2045-2056.
EPub date: 2021-07-28 00:00:00.0.
PMID: 34319833
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An EM algorithm to improve the estimation of the probability of clonal relatedness of pairs of tumors in cancer patients.
Authors: Mauguen A. , Seshan V.E. , Ostrovnaya I. , Begg C.B. .
Source: Bmc Bioinformatics, 2019-11-08 00:00:00.0; 20(1), p. 555.
EPub date: 2019-11-08 00:00:00.0.
PMID: 31703552
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Evidence for Etiologic Subtypes of Breast Cancer in the Carolina Breast Cancer Study.
Authors: Benefield H.C. , Zabor E.C. , Shan Y. , Allott E.H. , Begg C.B. , Troester M.A. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2019 Nov; 28(11), p. 1784-1791.
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There is still a place for significance testing in clinical trials.
Authors: Cook J.A. , Fergusson D.A. , Ford I. , Gonen M. , Kimmelman J. , Korn E.L. , Begg C.B. .
Source: Clinical Trials (london, England), 2019 Jun; 16(3), p. 223-224.
EPub date: 2019-05-09 00:00:00.0.
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Variance prior specification for a basket trial design using Bayesian hierarchical modeling.
Authors: Cunanan K.M. , Iasonos A. , Shen R. , Gönen M. .
Source: Clinical Trials (london, England), 2019 Apr; 16(2), p. 142-153.
EPub date: 2018-12-07 00:00:00.0.
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RE: "A MULTINOMIAL REGRESSION APPROACH TO MODEL OUTCOME HETEROGENEITY".
Authors: Begg C.B. , Seshan V.E. , Zabor E.C. .
Source: American Journal Of Epidemiology, 2018-05-01 00:00:00.0; 187(5), p. 1129-1130.
PMID: 29528373
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Contralateral breast cancers: Independent cancers or metastases?
Authors: Begg C.B. , Ostrovnaya I. , Geyer F.C. , Papanastasiou A.D. , Ng C.K.Y. , Sakr R.A. , Bernstein J.L. , Burke K.A. , King T.A. , Piscuoglio S. , et al. .
Source: International Journal Of Cancer, 2018-01-15 00:00:00.0; 142(2), p. 347-356.
EPub date: 2017-09-28 00:00:00.0.
PMID: 28921573
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A comparison of statistical methods for the study of etiologic heterogeneity.
Authors: Zabor E.C. , Begg C.B. .
Source: Statistics In Medicine, 2017-11-10 00:00:00.0; 36(25), p. 4050-4060.
EPub date: 2017-07-26 00:00:00.0.
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Associations of MC1R genotype and patient phenotypes with BRAF and NRAS mutations in melanoma.
Authors: Thomas N.E. , Edmiston S.N. , Kanetsky P.A. , Busam K.J. , Kricker A. , Armstrong B.K. , Cust A.E. , Anton-Culver H. , Gruber S.B. , Luo L. , et al. .
Source: The Journal Of Investigative Dermatology, 2017-08-22 00:00:00.0; , .
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Estimating the probability of clonal relatedness of pairs of tumors in cancer patients.
Authors: Mauguen A. , Seshan V.E. , Ostrovnaya I. , Begg C.B. .
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Examining the common aetiology of serous ovarian cancers and basal-like breast cancers using double primaries.
Authors: Begg C.B. , Rice M.S. , Zabor E.C. , Tworoger S.S. .
Source: British Journal Of Cancer, 2017-04-11 00:00:00.0; 116(8), p. 1088-1091.
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Basket Trials in Oncology: A Trade-Off Between Complexity and Efficiency.
Authors: Cunanan K.M. , Gonen M. , Shen R. , Hyman D.M. , Riely G.J. , Begg C.B. , Iasonos A. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2017-01-20 00:00:00.0; 35(3), p. 271-273.
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An Efficient Basket Trial Design
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Defining Cancer Subtypes With Distinctive Etiologic Profiles: An Application to the Epidemiology of Melanoma.
Authors: Mauguen A. , Zabor E.C. , Thomas N.E. , Berwick M. , Seshan V.E. , Begg C.B. .
Source: Journal Of The American Statistical Association, 2017; 112(517), p. 54-63.
EPub date: 2017-05-03 00:00:00.0.
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FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing.
Authors: Shen R. , Seshan V.E. .
Source: Nucleic Acids Research, 2016-09-19 00:00:00.0; 44(16), p. e131.
EPub date: 2016-06-07 00:00:00.0.
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Association of Interferon Regulatory Factor-4 Polymorphism rs12203592 With Divergent Melanoma Pathways.
Authors: Gibbs D.C. , Orlow I. , Bramson J.I. , Kanetsky P.A. , Luo L. , Kricker A. , Armstrong B.K. , Anton-Culver H. , Gruber S.B. , Marrett L.D. , et al. .
Source: Journal Of The National Cancer Institute, 2016 Jul; 108(7), .
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Using The Lorenz Curve To Characterize Risk Predictiveness And Etiologic Heterogeneity
Authors: Mauguen A. , Begg C.B. .
Source: Epidemiology (cambridge, Mass.), 2016 Jul; 27(4), p. 531-7.
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Clonal relationships between lobular carcinoma in situ and other breast malignancies.
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Source: Breast Cancer Research : Bcr, 2016-06-23 00:00:00.0; 18(1), p. 66.
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Identifying Etiologically Distinct Sub-Types of Cancer: A Demonstration Project Involving Breast Cancer.
Authors: Begg C.B. , Orlow I. , Zabor E.C. , Arora A. , Sharma A. , Seshan V.E. , Bernstein J.L. .
Source: Cancer Medicine, 2015 Sep; 4(9), p. 1432-9.
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USING SOMATIC MUTATION DATA TO TEST TUMORS FOR CLONAL RELATEDNESS.
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Inherited variation at MC1R and histological characteristics of primary melanoma.
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Comparing ROC curves derived from regression models.
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Comment on "the predictive capacity of personal genome sequencing".
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Clonality: An R Package For Testing Clonal Relatedness Of Two Tumors From The Same Patient Based On Their Genomic Profiles
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