European Journal of Epidemiology

, Volume 30, Issue 10, pp 1129–1135 | Cite as

Molecular pathological epidemiology gives clues to paradoxical findings

  • Reiko Nishihara
  • Tyler J. VanderWeele
  • Kenji Shibuya
  • Murray A. Mittleman
  • Molin Wang
  • Alison E. Field
  • Edward Giovannucci
  • Paul Lochhead
  • Shuji Ogino


A number of epidemiologic studies have described what appear to be paradoxical associations, where an incongruous relationship is observed between a certain well-established risk factor for disease incidence and favorable clinical outcome among patients with that disease. For example, the “obesity paradox” represents the association between obesity and better survival among patients with a certain disease such as coronary heart disease. Paradoxical observations cause vexing clinical and public health problems as they raise questions on causal relationships and hinder the development of effective interventions. Compelling evidence indicates that pathogenic processes encompass molecular alterations within cells and the microenvironment, influenced by various exogenous and endogenous exposures, and that interpersonal heterogeneity in molecular pathology and pathophysiology exists among patients with any given disease. In this article, we introduce methods of the emerging integrative interdisciplinary field of molecular pathological epidemiology (MPE), which is founded on the unique disease principle and disease continuum theory. We analyze and decipher apparent paradoxical findings, utilizing the MPE approach and available literature data on tumor somatic genetic and epigenetic characteristics. Through our analyses in colorectal cancer, renal cell carcinoma, and glioblastoma (malignant brain tumor), we can readily explain paradoxical associations between disease risk factors and better prognosis among disease patients. The MPE paradigm and approach can be applied to not only neoplasms but also various non-neoplastic diseases where there exists indisputable ubiquitous heterogeneity of pathogenesis and molecular pathology. The MPE paradigm including consideration of disease heterogeneity plays an essential role in advancements of precision medicine and public health.


Bias Cardiovascular disease Molecular diagnostics Multifactorial diseases Personalized medicine 



CpG island methylator phenotype


Molecular pathological epidemiology


Microsatellite instability


Renal cell carcinoma


Single nucleotide polymorphism



This work was supported by U.S. National Institutes of Health (NIH) Grants [R01 CA151993 to S.O.; R35 CA197735 to S.O., and K07 CA190673 to R.N.]. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflicts of interest.


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Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Reiko Nishihara
    • 1
    • 2
    • 3
  • Tyler J. VanderWeele
    • 4
    • 5
  • Kenji Shibuya
    • 3
  • Murray A. Mittleman
    • 4
    • 6
  • Molin Wang
    • 4
    • 5
    • 7
  • Alison E. Field
    • 4
    • 7
    • 8
    • 9
  • Edward Giovannucci
    • 1
    • 4
    • 7
  • Paul Lochhead
    • 10
  • Shuji Ogino
    • 2
    • 4
    • 11
  1. 1.Department of NutritionHarvard T.H. Chan School of Public HealthBostonUSA
  2. 2.Department of Medical OncologyDana-Farber Cancer Institute, Harvard Medical SchoolBostonUSA
  3. 3.Department of Global Health Policy, Graduate School of MedicineThe University of TokyoTokyoJapan
  4. 4.Department of EpidemiologyHarvard T.H. Chan School of Public HealthBostonUSA
  5. 5.Department of BiostatisticsHarvard T.H. Chan School of Public HealthBostonUSA
  6. 6.Cardiovascular Epidemiology Research Unit, Department of MedicineBeth Israel Deaconess Medical Center, Harvard Medical SchoolBostonUSA
  7. 7.Channing Division of Network Medicine, Department of MedicineBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  8. 8.Division of Adolescent MedicineBoston Children’s HospitalBostonUSA
  9. 9.Department of EpidemiologyBrown UniversityProvidenceUSA
  10. 10.Division of GastroenterologyMassachusetts General HospitalBostonUSA
  11. 11.Department of PathologyBrigham and Women’s Hospital, Boston, Harvard Medical SchoolBostonUSA

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