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Abstract 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.
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 MPEwhich 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 tumorwe 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.
Intuitively, we tend to consider that a disease risk factor is likely associated with worse clinical outcomes among patients with that disease, because the risk factor is considered to facilitate the pathogenic process that has led to the disease.
Possible explanations to the paradox have been proposed, including selection bias, index event bias, collider bias, unmeasured confounding, measurement error, and reverse causation [ 5 — 11 ].
However, possible biological mechanisms which may provide an additional plausible explanation have not been well discussed. The purpose of this article is to demonstrate that, by means of considering molecular heterogeneity of disease based on pathogenic mechanisms, we can readily decipher some of apparent paradoxical findings.
Collapsing two or more heterogeneous disease subtypes into one disease entity would produce a similar problem as unmeasured confounding in the structure of the association between a risk factor and mortality [ 12 ].
We use examples of studies on colorectal, kidney, and brain cancers, to demonstrate that the inherent nature of inter-personal molecular heterogeneity within a disease can underlie paradoxical observations. These examples attest to the importance of taking disease heterogeneity and pathogenesis into consideration in not only research but also clinical and public health practice [ 14 ].
This trend has also been highlighted by the precision medicine initiative of the U. National Institute of Health [ 15 ]. However, it is increasingly evident that, in each individual, disease processes represent unique sets of molecular changes in cells and microenvironment, and these processes differ from person to person [ 17 ].
Furthermore, a disease process is influenced by endogenous and exogenous exposures e. Endogenous and exogenous exposures certainly vary from person to person [ 17 ].
Therefore, while there are some similarities between people with a particular disease, each individual has a unique disease process which is different from any other individuals i. The fundamental tenet of MPE is that inherent pathogenic heterogeneity is taken into account when we examine the association between a risk factor and disease incidence.
Here, we introduce the emerging field of molecular pathological epidemiology MPEand discuss the importance of considering pathogenesis and inherent heterogeneity of disease. By identifying groups of patients who share similar molecular pathologic signatures, molecular classification of disease plays a key role in integrating the unique disease principle into epidemiologic research [ 17 ].
MPE has recently emerged to facilitate this integration of molecular pathology into epidemiology [ 18 ]. MPE is defined as epidemiology of molecular pathology and heterogeneity of disease.
MPE research emphasizes the importance of considering disease heterogeneity and the complexity of pathogenic mechanisms by examining hypothetic links between exposures and molecular signatures of the disease [ 19 ].
The MPE approach can not only uncover associations between exposures and specific molecular subtypes of disease but also refine risk estimates specific for disease subtypes, thereby providing insight into pathogenic mechanisms and contributing to causal inference [ 17 — 21 ]. The MPE approach and concept have been widely accepted and utilized [ 22 — 47 ].
MPE has been a major theme of international symposia [ 144849 ] and recently-established international meeting series [ 50 ]. It is relevant to briefly review molecular pathology of colorectal cancer, because paradoxical findings exist in colorectal cancer and ample data from both conventional epidemiology and MPE research actually give us clues to the paradoxes.
Colorectal cancer is a heterogeneous group of neoplasms which arise as a result of accumulation of a differing set of molecular alterations [ 51 — 53 ].
In the initiation and progression of colorectal neoplasia, aberrant cellular genetic and epigenetic changes occur along with stromal microenvironmental changes [ 5154 ]. With these well-established molecular pathology tests, colorectal cancer represents a disease area where MPE research has been quite active.
Emerging evidence indicates that specific exposures influence the initiation and progression of different molecular subtypes of colorectal tumor [ 20 ]. For example, MPE research has shown that cigarette smoking has been associated with an increased risk for colorectal cancer subtype characterized by high-level CpG island methylator phenotype CIMP-high [ 56 — 58 ].
These data suggest that optimal colonoscopy screening may vary among individuals with different lifestyle and genetic risk profiles. Hence, MPE research can contribute to the development of more personalized prevention strategies. A better understanding of disease heterogeneity is a prerequisite for accurate assessment of the associations between risk factors and pathologic processes.
In the following section, we analyze and decipher apparent paradoxical findings, utilizing the MPE approach and available literature data. Previous studies have reported that carriage of Lynch syndrome mutations is associated with markedly higher risk of colorectal cancer; but among all colorectal cancer patients, Lynch syndrome patients in average survive longer than other colorectal cancer patients [ 6061 ].Hence, we speculate that, perhaps together with the other recognized causes of paradoxes, disease heterogeneity can contribute to some of reported paradoxical findings in not only neoplastic diseases but also non-neoplastic diseases.
The over-arching presumption in modern science and philosophy is that consciousness emerges from complex synaptic computation in networks of brain neurons acting as fundamental information units.
In this article, we provide a constitutional and economic analysis of the Greek fiscal crisis on the basis of the economic and legal findings of the committee established in early by the Greek Parliament to audit Greek debt (the Greek Debt Truth Committee).
The World Conservation Union conservatively estimates that 7, animal species and 8, plant and lichen species are now at risk of extinction primarily due to human caused habitat degradation.
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The scientific method is the process by which science is carried out. As in other areas of inquiry, science (through the scientific method) can build on previous knowledge and develop a more sophisticated understanding of its topics of study over time.