This is a sandwich thesis / In an interrupted time series (ITS) design, data are collected at multiple time points before and after the implementation of an intervention or program to investigate the effect of the intervention on an outcome of interest. ITS design is often implemented in healthcare settings and is considered the strongest quasi-experimental design in terms of internal and external validity as well as its ability to establish causal relationships. There are several statistical methods that can be used to analyze data from ITS studies. Nevertheless, limitations exist in practical applications, where researchers inappropriately apply the methods, and frequently ignore the assumptions and factors that may influence the optimality of the statistical analysis. Moreover, there is little to no guidance available regarding the application of the various methods, and a standardized framework for analysis of ITS studies does not exist. As such, there is a need to identify and compare existing ITS methods in terms of their strengths and limitations. Their methodological challenges also need to be investigated to inform and direct future research. In light of this, this PhD thesis addresses two main objectives: 1) to conduct a scoping review of the methods that have been employed in the analysis of ITS studies, and 2) to develop improved methods that address a major limitation of the statistical methods frequently used in ITS data analysis. These objectives are addressed in three projects. For the first project, a scoping review of the methods that have been used in analyzing ITS data was conducted, with the focus on ITS applications in health research. The review was based on the Arksey and O’Malley framework and the Joanna Briggs Handbook for scoping reviews. A total of 1389 studies were included in our scoping review. The articles were grouped into methods papers and applications papers based on the focus of the article. For the methods papers, we narratively described the identified methods and discussed their strengths and limitations. The application papers were summarized using frequencies and percentages. We identified some limitations of current methods and provided some recommendations useful in health research. In the second project, we developed and presented an improved method for ITS analysis when the data at each time point are aggregated across several participants, which is the most common case in ITS studies in healthcare settings. We considered the segmented linear regression approach, which our scoping review identified as the most frequently used method in ITS studies. When data are aggregated, heterogeneity is introduced due to variability in the patient population within sites (e.g. healthcare facilities) and this is ignored in the segmented linear regression method. Moreover, statistical uncertainty (imprecision) is introduced in the data because of the sample size (number of participants from whom data are aggregated). Ignoring this variability and uncertainty will likely lead to invalid estimates and loss of statistical power, which in turn leads to erroneous conclusions. Our proposed method incorporates patient variability and sample size as weights in a weighted segmented regression model. We performed extensive simulations and assessed the performance of our method using established performance criteria, such as bias, mean squared error, level and statistical power. We also compared our method with the segmented linear regression approach. The results indicated that the weighted segmented regression was uniformly more precise, less biased and more powerful than the segmented linear regression method. In the third project, we extended the weighted method to multisite ITS studies, where data are aggregated at two levels: across several participants within sites as well as across multiple sites. The extended method incorporates the two levels of heterogeneity using weights, where the weights are defined using patient variability, sample size, number of sites as well as site-to-site variability. This extended weighted regression model, which follows the weighted least squares approach is employed to estimate parameters and perform significance testing. We conducted extensive empirical evaluations using various scenarios generated from a multi-site ITS study and compared the performance of our method with that of the segmented linear regression model as well as a pooled analysis method previously developed for multisite studies. We observed that for most scenarios considered, our method produced estimates with narrower 95% confidence intervals and smaller p-values, indicating that our method is more precise and is associated with more statistical power. In some scenarios, where we considered low levels of heterogeneity, our method and the previously proposed method showed comparable results. In conclusion, this PhD thesis facilitates future ITS research by laying the groundwork for developing standard guidelines for the design and analysis of ITS studies. The proposed improved method for ITS analysis, which is the weighted segmented regression, contributes to the advancement of ITS research and will enable researchers to optimize their analysis, leading to more precise and powerful results. / Thesis / Doctor of Philosophy (PhD)