Utility of Continuous Disease Subtyping Systems for Improved Evaluation of Etiologic Heterogeneity

Ruitong Li, Tomotaka Ugai, Lantian Xu, David Zucker, Shuji Ogino, Molin Wang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Molecular pathologic diagnosis is important in clinical (oncology) practice. Integration of molecular pathology into epidemiological methods (i.e., molecular pathological epidemiology) al-lows for investigating the distinct etiology of disease subtypes based on biomarker analyses, thereby contributing to precision medicine and prevention. However, existing approaches for investigating etiological heterogeneity deal with categorical subtypes. We aimed to fully leverage continuous measures available in most biomarker readouts (gene/protein expression levels, signaling pathway activation, immune cell counts, microbiome/microbial abundance in tumor microenvironment, etc.). We present a cause-specific Cox proportional hazards regression model for evaluating how the exposure–disease subtype association changes across continuous subtyping biomarker levels. Utilizing two longitudinal observational prospective cohort studies, we investigated how the association of alcohol intake (a risk factor) with colorectal cancer incidence differed across the continuous values of tumor epigenetic DNA methylation at long interspersed nucleotide element-1 (LINE-1). The heterogeneous alcohol effect was modeled using different functions of the LINE-1 marker to demonstrate the method’s flexibility. This real-world proof-of-principle computational application demonstrates how the new method enables visualizing the trend of the exposure effect over continuous marker levels. The utilization of continuous biomarker data without categorization for investigating etiological heterogeneity can advance our understanding of biological and pathogenic mechanisms.

Original languageAmerican English
Article number1811
Issue number7
StatePublished - 1 Apr 2022

Bibliographical note

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.


  • bioinformatics
  • environment
  • epigenomics
  • immune response
  • immunology
  • interdisciplinary research
  • microbiology
  • molecular epidemiology
  • targeted intervention
  • time-to-event data


Dive into the research topics of 'Utility of Continuous Disease Subtyping Systems for Improved Evaluation of Etiologic Heterogeneity'. Together they form a unique fingerprint.

Cite this