若要制訂有效的結核病防治政策，首先要了解結核病的傳播方式以及相關介入措施的評估方法。然而，目前對於結核病新發個案中新感染與舊感染分別的比重仍不清楚，亦缺乏介入措施對於整體疫情的影響評估。本研究以傳染病數理模式探討臺灣的結核病流行動態，同時加入年齡結構以呈現人口變化與疾病傳播間的關係，並以1957年至1993年的八次全國結核病盛行率以及2010年的年齡別發生率為校正基準。在假設最年長與最年輕族群的結核病發病率相差五倍下，模擬結果呈現與實際通報資料相近的年齡別發生率趨勢，因此以此校正後的模型分析新舊感染與介入措施的貢獻。隨著結核病個案治療延遲時間的縮短，新感染在結核病傳播的角色逐漸式微，而舊感染再活化成為主要的發病途徑，成為臺灣在2010年58.2%新發個案之來源。另外，接觸者追蹤在過去結核病發生率的下降趨勢中具有一定的貢獻；而綜合出生率提升、接觸者潛伏感染治療與糖尿病患血糖控制等介入下，在最佳情況下可以使以2025年的發生率較2015年下降18.6%。從老年人具有高發病率的模型假設下可以看出共病現象與結核病發生危險性的關聯，此模型的分析結果也顯示舊感染目前雖為結核病新發個案之主要來源，但連帶造成之新感染亦不可忽視。最後，介入措施之評估指出潛伏感染治療與血糖控制在未來控制結核病疫情上具有潛力，但將來擴大潛伏感染治療至年齡較高的接觸者時，需要將可能引發的肝毒性一併考量。

Background:
The relative contribution of recent infection and remote reactivation to the current tuberculosis (TB) epidemiology remains unclear and has important implications for the design of TB control policy. As one of the main active case finding strategies for TB control, contact tracing can improve case detection of active TB and prevent disease progression of latent TB. However, the impact of contact tracing on TB epidemic has not been well evaluated.
Methods:
We built an age-structured compartmental model of TB transmission to capture the transmission dynamic of TB in Taiwan over the past decades. We calibrated the model to reflect the declining trend of TB prevalence observed in the eight national prevalence surveys (1957-1993) and the age-specific notification rate (2010). Based on the calibrated model, we further estimated the relative contributions of recent and remote transmission and evaluated the impact of contact tracing on the annual declining rate in notified rate.
Results:
In order to fit the age pattern of TB incidence in Taiwan, we assigned an age-dependent gradient for the parameters of primary progression rate and reactivation rate in the model. Using the calibrated model, we found that the proportion of remote reactivation among incident cases increased gradually with the declining TB prevalence, and reached 58.2% in 2010. The implementation of contact tracing for finding active TB cases had contributed to the decline in TB incidence in the past decade. With the combined scenarios for ageing trend, DM control and LTBI prophylaxis under the best-case scenario, the proportion of TB incidence reduction by 2025 was 18.6%.
Discussion:
The model-based analysis revealed a strong age-dependent pattern in the risk of disease infection and progression, indicating the potential high TB risk caused by comorbidities among elders. Although reactivation has contributed to the majority of TB incident cases, recent transmission still accounts for a substantial proportion of TB epidemic. To intensify the interventions for TB control, DM control among the elders and expanding the latent TB treatment to older adults were the potential approaches. However, the hepatotoxicity of preventive treatment in older adults should be carefully evaluated and monitored before scaling up the program.

Acknowledgement ... i
摘要 ... ii
Abstract ... iii
Content ... v
Chapter 1 Introduction ... 1
1.1 Tuberculosis epidemiology ... 1
1.2 Transmission dynamics of TB ... 2
1.3 TB Interventions in Taiwan ... 3
1.4 Study designs for evaluating TB interventions ... 5
1.5 Study aims ... 6
Chapter 2 Methods ... 8
2.1 Basic model structure ... 8
2.1.1 Natural history of TB transmission ... 8
2.1.2 Population and age structure ... 9
2.2 Modeling the impacts of TB interventions ... 10
2.2.1 Contact tracing for active TB cases ... 10
2.2.2 LTBI preventive therapy for young contacts ... 11
2.2.3 Ageing effect ... 11
2.2.4 Scaling-up the LTBI preventive therapy among contacts ... 12
2.2.5 DM control ... 12
2.3 Model Parameters ... 13
2.4 Model fitting ... 14
2.4.1 Age pattern of total population from 1950 to 2000 ... 14
2.4.2 Population-based prevalence from 1957 to 1993 ... 14
2.4.3 Age-specific notification rate in 2010 ... 15
2.4.4 Latent TB prevalence in 2000 ... 15
2.5 Outcome measurements ... 16
2.5.1 Relative contributions of recent transmission and reactivation ... 16
2.5.2 Impact of potential interventions ... 17
2.6 Uncertainty analysis ... 17
Chapter 3 Results ... 18
3.1 Relative contributions of recent transmission and reactivation ... 18
3.2 Impacts of existing interventions ... 18
3.3 Scenarios for TB control in the future ... 19
3.3.1 Ageing effect ... 19
3.3.2 Scaling-up LTBI prophylaxis among contacts ... 19
3.3.3 DM control among total population ... 20
3.3.4 Combined effect of potential interventions ... 20
3.4 Uncertainty analysis ... 21
Chapter 4 Discussions ... 22
4.1 Main findings ... 22
4.2 Relative contribution of recent transmission and reactivation ... 22
4.3 Age-specific pattern in TB transmission ... 23
4.4 Comparison of interventions ... 23
4.5 Strengths and limitations ... 24
4.6 Study implications and further research ... 25
References... 27
Figures ... 34
Tables ... 49
Appendix ... 56

1.World Health Organization, Global Tuberculosis Report 2013, 2013: Geneva, Switzerland.
2.Dye, C., Glaziou, P., Floyd, K. and Raviglione, M., Prospects for tuberculosis elimination. Annu Rev Public Health, 2013. 34: p. 271-86.
3.United Nations, The Millennium Development Goals Report, 2013: New York, USA.
4.World Health Organization, Global strategy and targets for tuberculosis prevention, care and control after 2015, 2013.
5.Centers for Disease Control Taiwan, Notifiable Infectious Diseases Statistics System.
6.Yu, M.C., Bai, K.J., Chang, J.H. and Lee, C.N., Age transition of tuberculosis patients in Taiwan, 1957-2001. J Formos Med Assoc, 2006. 105(1): p. 25-30.
7.Dou, H.Y., Tseng, F.C., Lin, C.W., Chang, J.R., Sun, J.R., Tsai, W.S., et al., Molecular epidemiology and evolutionary genetics of Mycobacterium tuberculosis in Taipei. BMC Infect Dis, 2008. 8: p. 170.
8.Hsu, A.H., Lin, C.B., Lee, Y.S., Chiang, C.Y., Chen, L.K., Tsai, Y.S., et al., Molecular epidemiology of multidrug-resistant Mycobacterium tuberculosis in Eastern Taiwan. Int J Tuberc Lung Dis, 2010. 14(7): p. 924-6.
9.Huang, W.L., Jou, R., Yeh, P.F. and Huang, A., Laboratory investigation of a nosocomial transmission of tuberculosis at a district general hospital. J Formos Med Assoc, 2007. 106(7): p. 520-7.
10.Ng, I.C., Wen, T.H., Wang, J.Y. and Fang, C.T., Spatial dependency of tuberculosis incidence in Taiwan. PLoS One, 2012. 7(11): p. e50740.
11.Trunz, B.B., Fine, P. and Dye, C., Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet, 2006. 367(9517): p. 1173-80.
12.Centers for Disease Control Taiwan, External review of "Halving TB in 10 years program in Taiwan, 2006-2015" 2014.
13.Chiang, C.Y., Integration of tuberculosis services in Taiwan, 2001: challenges and opportunities, 2012, University of Bergen: Norway.
14.Taiwan Department of Health, National Mobilization Plan to Halve TB in 10 Years - Phase 2, 2012.
15.Fox, G.J., Barry, S.E., Britton, W.J. and Marks, G.B., Contact investigation for tuberculosis: a systematic review and meta-analysis. Eur Respir J, 2013. 41(1): p. 140-56.
16.Control and prevention of tuberculosis in the United Kingdom: code of practice 2000. Joint Tuberculosis Committee of the British Thoracic Society. Thorax, 2000. 55(11): p. 887-901.
17.Hsu, K.H., Thirty years after isoniazid. Its impact on tuberculosis in children and adolescents. JAMA, 1984. 251(10): p. 1283-5.
18.Lin, H.H., Ezzati, M. and Murray, M., Tobacco smoke, indoor air pollution and tuberculosis: a systematic review and meta-analysis. PLoS Med, 2007. 4(1): p. e20.
19.Jeon, C.Y. and Murray, M.B., Diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies. PLoS Med, 2008. 5(7): p. e152.
20.Cavalcante, S.C., Durovni, B., Barnes, G.L., Souza, F.B., Silva, R.F., Barroso, P.F., et al., Community-randomized trial of enhanced DOTS for tuberculosis control in Rio de Janeiro, Brazil. Int J Tuberc Lung Dis, 2010. 14(2): p. 203-9.
21.Mupere, E., Schiltz, N.K., Mulogo, E., Katamba, A., Nabbuye-Sekandi, J. and Singer, M.E., Effectiveness of active case-finding strategies in tuberculosis control in Kampala, Uganda. Int J Tuberc Lung Dis, 2013. 17(2): p. 207-13.
22.Begun, M., Newall, A.T., Marks, G.B. and Wood, J.G., Contact tracing of tuberculosis: a systematic review of transmission modelling studies. PLoS One, 2013. 8(9): p. e72470.
23.Dowdy, D.W., Lotia, I., Azman, A.S., Creswell, J., Sahu, S. and Khan, A.J., Population-level impact of active tuberculosis case finding in an Asian megacity. PLoS One, 2013. 8(10): p. e77517.
24.Taiwan Department of Household Registration, Population Statistics.
25.Cronin, W.A., Golub, J.E., Lathan, M.J., Mukasa, L.N., Hooper, N., Razeq, J.H., et al., Molecular epidemiology of tuberculosis in a low- to moderate-incidence state: are contact investigations enough? Emerg Infect Dis, 2002. 8(11): p. 1271-9.
26.Yeh, Y.P., Luh, D.L., Chang, S.H., Suo, J., Chang, H.J. and Chen, T.H., Tuberculin reactivity in adults after 50 years of universal bacille Calmette-Guerin vaccination in Taiwan. Trans R Soc Trop Med Hyg, 2005. 99(7): p. 509-16.
27.Chan, P.C., Shinn-Forng Peng, S., Chiou, M.Y., Ling, D.L., Chang, L.Y., Wang, K.F., et al., Risk for tuberculosis in child contacts. Development and validation of a predictive score. Am J Respir Crit Care Med, 2014. 189(2): p. 203-13.
28.Jiang, Y.D., Chang, C.H., Tai, T.Y., Chen, J.F. and Chuang, L.M., Incidence and prevalence rates of diabetes mellitus in Taiwan: analysis of the 2000-2009 Nationwide Health Insurance database. J Formos Med Assoc, 2012. 111(11): p. 599-604.
29.Leung, C.C., Lam, T.H., Chan, W.M., Yew, W.W., Ho, K.S., Leung, G.M., et al., Diabetic control and risk of tuberculosis: a cohort study. Am J Epidemiol, 2008. 167(12): p. 1486-94.
30.Mendoza, A., The value of the tuberculin skin test in predicting the development of tyberculosis in contacts of active cases, 2004, University of British Columbia: Canada.
31.Lee, P.H., Lin, H.C., Huang, A.S., Wei, S.H., Lai, M.S. and Lin, H.H., Diabetes and risk of tuberculosis relapse: nationwide nested case-control study. PLoS One, 2014. 9(3): p. e92623.
32.Yu, N.C., Su, H.Y., Chiou, S.T., Yeh, M.C., Yeh, S.W., Tzeng, M.S., et al., Trends of ABC control 2006-2011: a National Survey of Diabetes Health Promotion Institutes in Taiwan. Diabetes Res Clin Pract, 2013. 99(2): p. 112-9.
33.Shea, K.M., Kammerer, J.S., Winston, C.A., Navin, T.R. and Horsburgh, C.R., Jr., Estimated rate of reactivation of latent tuberculosis infection in the United States, overall and by population subgroup. Am J Epidemiol, 2014. 179(2): p. 216-25.
34.Wu, P., Lau, E.H., Cowling, B.J., Leung, C.C., Tam, C.M. and Leung, G.M., The transmission dynamics of tuberculosis in a recently developed Chinese city. PLoS One, 2010. 5(5): p. e10468.
35.Vynnycky, E. and Fine, P.E., The natural history of tuberculosis: the implications of age-dependent risks of disease and the role of reinfection. Epidemiol Infect, 1997. 119(2): p. 183-201.
36.Kranzer, K., Afnan-Holmes, H., Tomlin, K., Golub, J.E., Shapiro, A.E., Schaap, A., et al., The benefits to communities and individuals of screening for active tuberculosis disease: a systematic review. Int J Tuberc Lung Dis, 2013. 17(4): p. 432-46.
37.Dye, C., After 2015: infectious diseases in a new era of health and development. Philos Trans R Soc Lond B Biol Sci, 2014. 369(1645): p. 20130426.
38.Tian, Y., Alawami, F., Al-Azem, A., Osgood, N., Hoeppner, V. and Dutchyn, C. A system dynamics model of tuberculosis diffusion with respect to contact tracing investigation. in Winter Simulation Conference. 2011. Arizona, USA.
39.Li, C.Y., Chen, H.C., Cheng, H.Y., Chian, C.F., Chang, F.Y., Chen, H.I., et al., Role of QuantiFERON-TB-Gold In Tube assay for active and latent tuberculosis infection in investigation of tuberculosis outbreak in a university. J Microbiol Immunol Infect, 2013.
40.Wang, J.Y., Shu, C.C., Lee, C.H., Yu, C.J., Lee, L.N. and Yang, P.C., Interferon-gamma release assay and Rifampicin therapy for household contacts of tuberculosis. J Infect, 2012. 64(3): p. 291-8.
41.Ling, D.L., Liaw, Y.P., Lee, C.Y., Lo, H.Y., Yang, H.L. and Chan, P.C., Contact investigation for tuberculosis in Taiwan contacts aged under 20 years in 2005. Int J Tuberc Lung Dis, 2011. 15(1): p. 50-5.
42.Huang, Y.W., Shen, G.H., Lee, J.J. and Yang, W.T., Latent tuberculosis infection among close contacts of multidrug-resistant tuberculosis patients in central Taiwan. Int J Tuberc Lung Dis, 2010. 14(11): p. 1430-5.
43.Lin, J.C., Lin, T.Y., Perng, W.C., Mai, C.S., Chen, Y.H., Ku, C.H., et al., An outbreak of tuberculosis in a bacillus Calmette-guerin-vaccinated military population. Mil Med, 2008. 173(4): p. 388-92.
44.Lee, S.S., Liu, Y.C., Huang, T.S., Chen, Y.S., Tsai, H.C., Wann, S.R., et al., Comparison of the interferon- gamma release assay and the tuberculin skin test for contact investigation of tuberculosis in BCG-vaccinated health care workers. Scand J Infect Dis, 2008. 40(5): p. 373-80.
45.Wang, P.D. and Lin, R.S., Tuberculosis transmission in the family. J Infect, 2000. 41(3): p. 249-51.
46.Leung, C.C., Lam, T.H., Chan, W.M., Yew, W.W., Ho, K.S., Leung, G., et al., Lower risk of tuberculosis in obesity. Arch Intern Med, 2007. 167(12): p. 1297-304.
47.Kunst, H. and Khan, K.S., Age-related risk of hepatotoxicity in the treatment of latent tuberculosis infection: a systematic review. Int J Tuberc Lung Dis, 2010. 14(11): p. 1374-81.
48.Tostmann, A., Kik, S.V., Kalisvaart, N.A., Sebek, M.M., Verver, S., Boeree, M.J., et al., Tuberculosis transmission by patients with smear-negative pulmonary tuberculosis in a large cohort in the Netherlands. Clin Infect Dis, 2008. 47(9): p. 1135-42.
49.Andrews, J.R., Noubary, F., Walensky, R.P., Cerda, R., Losina, E. and Horsburgh, C.R., Risk of progression to active tuberculosis following reinfection with Mycobacterium tuberculosis. Clin Infect Dis, 2012. 54(6): p. 784-91.
50.Tiemersma, E.W., van der Werf, M.J., Borgdorff, M.W., Williams, B.G. and Nagelkerke, N.J., Natural history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV negative patients: a systematic review. PLoS One, 2011. 6(4): p. e17601.
51.Centers for Disease Control Taiwan, Taiwan Tuberculosis Control Report, 2001.
52.Lee, P.H., Diabetes mellitus increases the risk of recurrent tuberculosis: a population-based nested case-control study, in Institute of Epidemiology and Preventive Medicine2012, National Taiwan University.
53.Lee, C.H., Research on relapse among pulmonary tuberculosis patients after DOTs implemented in Taiwan: empirical analysis, 2010, Centers for Disease Control Taiwan,.
54.Centers for Disease Control Taiwan, Outcome of contact tracing and LTBI prophylaxis in Taiwan: from 2008 to 2012, 2014: Taiwan