Molecular pathological epidemiology: new developing frontiers of big data science to study etiologies and pathogenesis

Abstract

Molecular pathological epidemiology (MPE) is an integrative field that utilizes molecular pathology to incorporate interpersonal heterogeneity of a disease process into epidemiology. In each individual, the development and progression of a disease are determined by a unique combination of exogenous and endogenous factors, resulting in different molecular and pathological subtypes of the disease. Based on "the unique disease principle," the primary aim of MPE is to uncover an interactive relationship between a specific environmental exposure and disease subtypes in determining disease incidence and mortality. This MPE approach can provide etiologic and pathogenic insights, potentially contributing to precision medicine for personalized prevention and treatment. Although breast, prostate, lung, and colorectal cancers have been among the most commonly studied diseases, the MPE approach can be used to study any disease. In addition to molecular features, host immune status and microbiome profile likely affect a disease process, and thus serve as informative biomarkers. As such, further integration of several disciplines into MPE has been achieved (e.g., pharmaco-MPE, immuno-MPE, and microbial MPE), to provide novel insights into underlying etiologic mechanisms. With the advent of high-throughput sequencing technologies, available genomic and epigenomic data have expanded dramatically. The MPE approach can also provide a specific risk estimate for each disease subgroup, thereby enhancing the impact of genome-wide association studies on public health. In this article, we present recent progress of MPE, and discuss the importance of accounting for the disease heterogeneity in the era of big-data health science and precision medicine.

Keywords: Colorectal neoplasms; Drug therapy; Immunology; Microbiology; Personalized therapy.

Figure 1

The paradigm of molecular pathological epidemiology (MPE) research. a. Scheme of a conventional epidemiology study. The overall association of an exposure with risk of disease X appears to be weak. b. Scheme of a MPE study. By categorizing disease X into subgroups (A and B) based on molecular pathological features, the significant association of the exposure with risk of subtype A can be revealed. Note that, although we present an example of two disease subgroups for simplicity, more than two disease subgroups can be evaluated in MPE research. Typically, the primary hypothesis in MPE research tests for a difference between the associations of the exposure with subtypes classified by molecular features. MPE, molecular pathological epidemiology.

Figure 2

Risk analysis and survival analysis in molecular pathological epidemiology (MPE) research. MPE risk analysis examines differential associations of a prediagnosis exposure with incidence of disease subtypes defined by molecular features. MPE survival analysis examines differential associations of a prediagnosis or postdiagnosis exposure with prognosis of disease subtypes defined by molecular features. Arrows indicate disease process with time. MPE, molecular pathological epidemiology.

Figure 3

Further integration of several disciplines into molecular pathological epidemiology (MPE). Pharmaco-MPE integrates pharmacoepidemiology into MPE, where we evaluate differential associations of a medication as an exposure with disease subgroups. Immuno-MPE and microbial MPE integrate MPE with immunology and microbiology, respectively. Diseases are categorized into subtypes by parameters of disease immunity status or microbial profile. Arrows indicate disease process with time. MPE, molecular pathological epidemiology.