Sample Size Determination for Effectiveness of Mass Screening for Breast Cancer
Date Issued
2012
Date
2012
Author(s)
Tsai, Wei-Ju
Abstract
Background Evaluation of mass screening for cancer based on primary endpoint often encounters long-term follow-up and enormous costs, especially when rare diseases are investigated. These problems are also particularly serious for young women screening with mammography and also the determination of optimal inter-screening interval by using randomized controlled trials. The expedient strategy is to use surrogate endpoint which can reduce variance which in turn reduce sample size. The application of surrogate endpoint to evaluation of cancer screening for the comparison of required sample sizes between surrogate endpoint and primary endpoint have been barely addressed.
Objective The objectives of this thesis were
(1) to expand the statistical operational definition for surrogate endpoints defined by Prentice. We also aim to assess whether tumor size, lymph node involvement, histological grade, and combined use of these tumor attributes can be used as surrogate endpoints for replacing breast cancer mortality reduction as a result of mammography screening.
(2) to demonstrate how the variance can be reduced by comparing a simple binary outcome and informative surrogate endpoints, and to compare the required sample sizes with primary endpoint and surrogate endpoint.
(3) to apply computer simulation in the light of multi-state Markov model for breast cancer natural history using tumor size or lymph node involvement to compare the required sample sizes with primary endpoint and surrogate endpoint with different inter-screening intervals.
Data source We used the Swedish Two-county breast screening trial data to illustrate the application of our statistical method to calculate sample size based on primary and surrogate endpoint, respectively.
Results
1. Based on the statistical operational definition for surrogate endpoints from Prentice, we found that tumour size can explain partial effect of screening group by 49.4% by using Cox proportional hazards regression model. The magnitude of partial effect were 45.2% and 62% for use of lymph node involvement and for combined use of lymph node involvement and tumour size for surrogate endpoints.
2. By using tumour size (DCIS、<20 mm and ≧20 mm) as surrogate endpoint, the required sample size was 38,914, which was smaller than the corresponding figure using lymph node involvement (n=75,764).
3. The required sample size was further reduced to 33,657 with combined use of tumor size and lymph node involvement as surrogate endpoint, which was 40.9% of 82,261 women required for primary endpoint.
4. We estimated that 261,292 women were required to demonstrate the screening effect between annual and biennial program for women aged 40-49 years with surrogate endpoint, tumour size. The required sizes were 120,916 and 1,192,296 for the comparison between annual and three-yearly screening programs and between biennial and three-yearly programs, respectively. If primary endpoint was used, the required sample sizes were four times of their corresponding figures mentioned above.
Conclusions The proposed statistical method for calculating sample size by surrogate endpoint and primary endpoint is very useful for planning mass screening for cancer particularly for randomized controlled trials.
Subjects
sample size
surrogate endpoint
SDGs
Type
thesis
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