Evidence-based Evaluation of Preventing Progression of Hoehn-Yahr-stage-based Parkinson’s Disease with Stochastic Process

Background Parkinson’s disease (PD) is the second most common degenerative disorder which will eventually cause functional decline and reduce lifespan. The development of therapies that slow disease progression and improve survival makes early detection and treatment of PD especially important. Besides, the characteristics of heterogeneity in natural history and the uncertainty in the decision analysis of early detection of PD prevention have not been fully investigated. The aims of this thesis consist of three parts: (1) the first was to to use a community-based cohort to compare the detection methods for active detecting PD. (2) the second was to elucidate the temporal natural history of Hoehn-Yahr-stage-based PD with a Markov process with and without the incorporation of covariates into different transitions corresponding to the natural history model and the third part was to evaluate the cost-effectiveness analysis.Material and Method First part of data were derived from a community-based screening survey for PD in 2001. Cumulative detection rate and Hoehn-Yahr (H-Y) stage distribution of both the active and passive detection groups were estimated and compared. In the second part, we use a non-standard case-cohort design for modelling the natural history of H- Y stage-base PD. We built a three-state and a five-state Markov models for the H-Y stage-based natural history. Variables such as baseline characteristic, life style and dietary habit were collected and were incorporated into the model to assess the effect of each covariate on respective transitions. In the final part, the Markov decision analysis was envisaged to estimate the cost-effectiveness and cost-utility of active screening for PD in the community setting for residents aged 60 years or older over a 20-year period. We used a five-state Markov model to simulate the progression of PD and the sequel afterwards. The cumulative cost under different strategies was also collected. Parameters of disease progression followed the empirical estimates of the temporal natural history in the second Part. The main outcome measure was cost per life-year gain and per quality-adjusted life-year (QALY) gained with a 3% annual discount rate. The scattered cost-effectiveness plane (CE plane) and acceptability curve was presented given a 1000 Monte Carlo simulated samples for running 10,000 trials. Results One hundred and ninty-two IPD cases and 89 IPD were detected by the active and passive detection methods, respectively. The active method detected approximately 1.8-fold (95% confidence interval: 1.4-2.3) the IPD cases of the passive method. Early H-Y stage (stage I and II) IPD cases were statistically significantly higher in the active method than in the passive method (80.4% vs. 61.5%, p=0.04). Base on a three-state homogeneous Markov model, annual incidence rate of being susceptible to PD for subjects aged 60 years or older was 8.2 per 1000 person-years. Annual transition rate from screening detectable (SD) phase to clinical detectable (CD) phase was 0.5935 (95% CI: 0.4330-0.7541), which yielded 1.68 years of mean sojourn time staying in the SD phase. In a five-state homogeneous Markov model, the estimate incidence of SD phase PD was similar to that estimated from the three-state model, 7.8 per 1000. The transition rate from H-Y I/II to H-Y III+ in the SD phase was 0.2498 (95% CI: 0.1420-0.3576). The transition rates from SD to CD for early stage (H-Y I/II) and late stage (H-Y III+) were 0.3982 (95% CI: 0.2564-0.5399) and 2.1227 (95% CI: 0.5109-3.7346), respectively. Considering the effects of patient specific covariate on the transitions in the five-state model, the results of multivariable analysis on multiple transition shows that advancing age led to an increased 10 years risk of developing PD (aRR=1.79, 95% CI: 1.32-2.44) and faster transition from HY I/II to HY III+ before surfacing to CD phase (RR=5.08, 95% CI: 1.94-13.29). Low level of uric acid also played the role of risk factor in the incidence of PD (RR=1.54, 95% CI: 1.04-2.28). High level of education strongly affected the transition from HY I/II to HY III+ before surfacing to CD phase (RR=14.65, 95% CI: 2.94-54.53). In the simulated results for effectiveness of different screening interval, annual screening reduced 71% (95% CI: 64-77%) reduction of advanced stage (H-Y stage III+) cases compared to no screen. When the inter-screening intervals were 2-yearly, 3-yearly, 4-year, or 6-yearly, reduction of advanced H-Y stage cases was 54% (95% CI: 45-62%), 43% (95% CI: 32-52%), 35% (95% CI: 23-45%), and 25% (95% CI: 12-36%), respectively. The results from deterministic Markov decision analysis of the cost-effectiveness and cost-utility analysis shows that the incremental cost-effectiveness ratios (ICER) of PD screening with different inter-screening intervals compared to no screen ranged from $1169 to $1804 per life-year gained. The incremental cost-utility ratio ranged from $1715 to $2606 per quality-adjusted life-year gained. The annual screen had the greatest net monetary benefit (NMB) ($280,687) in terms of life-year gained, followed by biennial ($280,511), triennial ($280,416) screen, and no screen ($280,113). The same trend was observed for the NMB in terms of QALY gained. The results of the probabilistic Markov decision models shows that the probability of screening programs being cost-effective at $20,000 of willingness-to-pay (WTP) was 69-79% and 64-74% given 100% and 60% of attendance rates, respectively. The corresponding figures in the cost-utility analyses were 62.6%-70.2% and 58.2-62.6% given 100% and 60% of attendance rates, respectively.Conclusion The active method detected almost two times the PD cases as the passive method and also reduced 49 % (95% CI: 4%-73%) the IPD cases classed in H-Y stage III or greater. Our results reveal that an individual aged 60 year or older who is susceptible to PD and entered the SD phase would progress to CD, on average around 1.5 years. The progression from the SD to the CD by H-Y stage had been quantified with detectable window for the identification of early H-Y stage before the transition to late H-Y stage which form the bases of the best-case estimates for the disease progression of PD in the absence of screening. With the application of these transition parameters, this thesis demonstrates that if the intensive screening for PD is offered, the large the reduction in late H-Y PD would be achieved and the probability of being cost-effective could be high.