| Summary: | 碩士 === 國立臺灣大學 === 流行病學與預防醫學研究所 === 107 === Introduction
Although intra-familial aggregation of helicobacter pylori infection has been well studied before, the effect size of family aggregation has been scarcely elucidated by using a well-designed genetic epidemiological study. While the familial aggregation of HP has been extended to include pre-cancerous lesions like atrophy gastritis (AG) and intestine metaplasia (IM), the effect size of familial aggregation accounting for the dynamic transition study has been even neglected.
Aims
The objective of this thesis is to employ a case-control proband study design and its variants in conjunction with different statistical models to estimate the effect size of familial aggregation of genetic typing associated with HP infection and the dynamic transitions between HP, AG, and IM under the context of the Correa model.
Material and Methods
Two data sources were used for studying familial aggregation of HP and HP-related pre-cancerous lesions. The first dataset was derived from a 35 index Japanese pediatric patients familial study with the available information on two genetic typing procedures, Multilocus Sequence Typing (MLST) and random amplified polymorphic DNA (RAPD) fingerprinting used for detecting transmission route of familial aggregation. The second dataset was descended from the Matsu community-based prevention of gastric neoplasm under the context of Correa model with three periods, 1996-2003 before intervention, 2004-2007 after screening, and 2008 after chemoprevention. The case-control proband study design with two-state was designed to estimate the effect size of familial aggregation associated with the same sequence of MLST and also RAPD. Bayesian directed acyclic graphic (DAG) model was built up to develop fully conditional distribution given the observed data and unknown quantity to estimate the effect size of family aggregation of HP infection making allowance for the correlation of HP infection across the same family members with the random effect model.
To model how family aggregation affects the dynamic transition of HP and gastric pre-cancerous neoplasm under the context of the Correa multistate model, three statistical approaches were used, including the multi-nominal logistic regression model, the discrete-state and discrete-time Markov chain model, and continuous-time Markov process.
Results
Part I Japanese familial aggregation study on genotyping associated with HP infection
When using first child as index case the estimated results on the DNA fingerprint sequence with Bayesian DAG model show the tendency of familial aggregation for the matched sequence of RAPD was 56-fold (95% CI: 3.99-1878.07) for RAPD and 68.10-fold (95% CI: 4.85-2171.12) for MLST compared with the unmatched sequence.
Part II Family aggregation for the dynamic transition of HP and gastric neoplasm
With the application of multi-nominal logistic regression model to the Matsu data, the effect sizes of familial aggregation of HP infection, AG, and IM were statistically significant with the range from 1.39 (95% CI: 1.09-1.77) to 2.02 (95% CI: 1.26-3.55) after adjustment for smoking and dietary factors.
The estimated results of Markov chain with the ergodicity theory show there was a strong tendency of familial aggregation for reaching equilibrium with the property of the Correa model in 1996 but not in the two periods after interventions as the ratio of the summation of transition probability in the upper triangle to that of in the lower triangle was around 2.24 whether the corresponding values in 2004 and 2008 were 0.91 and 0.87.
The estimated results of continuous-time Markov process demonstrate family aggregation was highly associated with the dynamic transition of the Correa model mainly in the transition from normal to HP infection with the order of 1.30 (95% CI: 1.18-1.44), 1.21 (95% CI: 1.07-1.36), and 1.35 (95% CI: 1.14-1.59) for the index case of HP infection , AG, and IM. The influence of family aggregation dwindled from HP infection to AG with the order of 0.74 (95% CI: 0.62-0.88), 1.33 (95% CI: 1.10-1.60), and 1.06 (95% CI: 0.82-1.37) to AG to IM with insignificant findings, 1.28 (95% CI: 0.94-1.75), 0.95 (95% CI: 0.68-1.34), and 1.14 (95% CI: 0.72-1.81)
Conclusions
Statistical models are proposed here to model familial aggregation of HP infection and the dynamic transition of HP-related gastric precancerous lesion under the context of the Correa model. The proposed models were applied to one data with genotyping HP infection and the community-based data before and after prevention of gastric neoplasm.
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