A mechanistic model for atherosclerosis and its application to the cohort of Mayak workers

Abstract

We propose a stochastic model for use in epidemiological analysis, describing the age-dependent development of atherosclerosis with adequate simplification. The model features the uptake of monocytes into the arterial wall, their proliferation and transition into foam cells. The number of foam cells is assumed to determine the health risk for clinically relevant events such as stroke. In a simulation study, the model was checked against the age-dependent prevalence of atherosclerotic lesions. Next, the model was applied to incidence of atherosclerotic stroke in the cohort of male workers from the Mayak nuclear facility in the Southern Urals. It describes the data as well as standard epidemiological models. Based on goodness-of-fit criteria the risk factors smoking, hypertension and radiation exposure were tested for their effect on disease development. Hypertension was identified to affect disease progression mainly in the late stage of atherosclerosis. Fitting mechanistic models to incidence data allows to integrate biological evidence on disease progression into epidemiological studies. The mechanistic approach adds to an understanding of pathogenic processes, whereas standard epidemiological methods mainly explore the statistical association between risk factors and disease outcome. Due to a more comprehensive scientific foundation, risk estimates from mechanistic models can be deemed more reliable. To the best of our knowledge, such models are applied to epidemiological data on cardiovascular diseases for the first time.

Health Impacts of Low-Dose Ionizing Radiation: Current Scientific Debates and Regulatory Issues

“…A dose–response relationship between α-radiation exposure and incidence of various cancerous and noncancerous disorders was observed in nuclear workers chronically exposed by inhalation to plutonium ( 239 Pu) in the Mayak Nuclear Enterprise (Chelyabinsk region, Russia). 98 - 120 For instance, the incidence of lung cancer corrected for smoking was 0.56, 0.59, and 0.83 at body burdens of 343, 1180, and 4200 Bq, respectively, in 500 nuclear workers relative to internal controls. Of note, the lung cancer incidence was linearly associated with cigarette smoking, with 2-fold risk of lung cancer in those workers who smoked 1 pack of cigarettes per day for at least 5 years.…”

Simulating the dynamics of atherosclerosis to the incidence of myocardial infarction, applied to the KORA population

“…Moreover, process oriented modeling may help to better evaluate the potentially individually different short‐ and long‐term benefits of the manifold options of prevention. Still, little effort has been put so far into the modeling of atherosclerosis development and its relation to incidence data, 8,9 which may partially be caused by model limitations.…”

Modeling cholesterol metabolism and atherosclerosis

“…In contrast other approaches have modeled atherosclerosis by introducing stochasticity. For instance, Simonetto and colleagues used a stochastic model to investigate atherosclerosis (Simonetto et al, 2017). Although there was limited focus on the role cholesterol plays atherosclerosis.…”