Mechanisms of Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . .. 4 2.2 Carcinogenesis Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.2.1 Armitage-Doll Multistage Model . . . . . . . . . . . . . . . . . . . . 5 2.2.2 Xxxxxxxxxx-Xxxxxx-Xxxxxxx Two-stage Clonal Expansion (TSCE) Carcinogenesis Model . . . . . . . . . . . . . . . . . . . . . . . . . . 7 2.3 Age-Period-Cohort (APC) Model . . . . . . . . . . . . . . . . . . . . . . . . 9 2.3.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2.3.2 Identifiability Issue 10 2.3.3 Area-APC Model 11 3 Bayesian Armitage-Doll Multistage Carcinogenesis Model 14 3.1 Background 14 3.2 Significance and Innovation 17 3.3 Build the Bayesian Armitage-Doll Multistage Carcinogenesis Model 18 3.3.1 Normal Likelihood and Conjugate Prior 18 3.3.2 Poisson Likelihood and Noninformative Prior 20 3.3.3 Binomial Likelihood and Noninformative Priors 22 3.3.4 Weibull Likelihood and Noninformative Priors 23 3.3.5 Results - NIG Priors 23 3.3.6 Results - Noninformative Priors 26 3.4 Assess the Bayesian Armitage-Doll Multistage Carcinogenesis Model 27 3.4.1 Sensitivity Analysis 27 3.4.2 Model Assessment 29 3.5 Simulation 32 4 Bayesian extended Age-Period-Cohort Model 34 4.1 Background 34 4.2 Significance and Innovation 36 4.3 Apply Armitage-Doll Multistage Carcinogenesis Model into APC Model 37 4.4 Apply TSCE Carcinogenesis Model into APC Model 41 4.5 Results 42 4.5.1 Convergence Diagnostics 42 4.5.2 Model Comparison 44 4.5.3 Rate Estimation and Projection 47 5 Bayesian extended Area-Age-Period-Cohort (AAPC) Model 51 5.1 Background 51 5.2 Significance and Innovation 52 5.3 Bayesian AAPC Model 53
Mechanisms of Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . .. Cancer is a term used for disease in which abnormal cells divide without control and are able to invade other tissues. In most cases, these cancer cells form a tumor. A benign tumor can proliferate but cannot grow into other tissues. In contrast, a malignant tumor can spread to other parts of body through the blood and lymph systems which is defined as metastasis. No matter where a cancer may spread, it is always named for the place where it started. For example, breast cancer that has spread to the liver is still called breast cancer, not liver cancer. Likewise, prostate cancer that has spread to the bone is metastatic prostate cancer, not bone cancer. The mechanism of cancer development is still unclear. However, most of cancer researchers strongly believe there are multiple events involved in carcinogenesis, the process by which normal cells are transformed into cancer cells [Armitage and Doll, 1954, Xxxxxxxxxx and Xxxxxx, 0000, Xxxxxxxxxx and Xxxxxxx, 1981, Xxxxxxxxxx and Luebeck, 1990]. Research shows that several genomic mutations occurred in the cells, such as the activation of onco- genes and inactivation of tumor suppressor genes, which demonstrated the multistage na- ture of carcinogenesis [Xxxxxx, 1991, Xxxxxx and Xxxxxxxxxx, 1990]. Inheritable genetic alterations for neoplastic transformation also accounts for the carcinogenic process [Xxxxxx, 1991, Xxxxxx and Xxxxxxxxxx, 1990]. Three consecutive phases are assumed in the carcinogenesis: initiation, promotion and progression. The first step is cell initiation, where normal stem cells are initiated to start to divide and expand slowly so that they can form the tumor. The substances that triggers the cell initiation is called initiator, for example, radiation, chemical agents or a virus. In the promotion phase, with the help of promoter, an initiated cell can expand clonally and reproduce a population of initiated cells. A promoter is a substance that stimulates the growth of initiated cells. During tumor progression, initiated cells can convert to malignant cancer cells via additional genetic alterations. The fast growth of malignant cancer cells can outpace cell apoptosis and enable cancer cells to invade other organs (metastasis) and build up their own vessel system for nutrition (angiogenesis). Aggressive metastatic tumors can kill their hosts quickly. Stochastic models for carcinogenesis have been developed in the last 50 years to predict the risk of cancer. The process of carcinogenesis is ...
