Real World Health Care Data Analysis. Uwe Siebert
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of the outcome (https://www.ema.europa.eu/documents/scientific-guideline/draft-ich-e9-r1-addendum-estimands-sensitivity-analysis-clinical-trials-guideline-statistical_en.pdf). At the end of Stage 1 you have a clear goal allowing for development of an analysis plan.
Stage 2 is the design stage. The goal here is to approximate the conditions of the conceptualized randomized trial and ensure balance in covariates between treatment groups. This design stage will include a quantitative assessment of the feasibility of the study and confirmation that the bias adjustment methods (such as propensity matching) bring balance similar to a randomized study. Creating directed acyclic graphs (DAGs) are very useful here as this process will inform the feasibility (do we even have the right covariates?) and selection of the variables for the bias adjustment models. A key issue here is that the design stage is conducted “outcome free.” That is, one conducts the feasibility assessment, finalizes, and documents the statistical analysis methods prior to accessing the outcome data. One can use the baseline (pre-index) data – this will allow confirmation of the feasibility of the data to achieve the research objectives – but should have no outcomes data in sight. For a detailed practical discussion of the design phase planning for causal inference studies, we recommend following the concepts described by Hernan and Robins (2016) in their target trial approach.
Stage 3 is the analysis stage. Too often this is the first step in an analysis that can lead to “cherry-picking” of methods that give the desired results or analyses not tied to the estimand of interest. In this stage, the researcher conducts the pre-planned analyses for the estimand, sensitivity analyses to assess the robustness of the results, analyses of secondary objectives (different estimands), and any ad hoc analyses driven by the results (such should be denoted as ad hoc). Note that while some sensitivity analyses should cover study specific analytic issues, in general researchers should include assessment of the core assumptions needed for causal inference using real world data (unmeasured confounding, appropriate modeling, positivity; see Chapter 2).
Lastly, stage 4 studies the causal conclusions from the findings. Because this text is focused on the analytic portions of real world research, we will focus primarily on stages 2 and 3 of this process in the chapters moving forward.
1.9 Contents of This Book
The book is organized as follows. This chapter and Chapter 2 provide foundational information about real world data research with a focus on causal inference in Chapter 2. Chapter 3 introduces the data sets that are used in the example analyses throughout the remainder of the book as well as a brief discussion on how to simulate real world data. Chapters 4–10 contain specific methods demonstrating comparative (causal) analyses of outcomes between two or more interventions that adjust for baseline confounding using propensity matching, stratification, weighting methods, and model averaging. Chapters 11 and 12 demonstrate the use of more complex methods that can adjust for both baseline and time-varying confounders and are applicable for longitudinal data such as to account for changes in the interventions over time. Lastly, Chapters 13–15 present analyses regarding the emerging topics of unmeasured confounding sensitivity analyses, quantitative generalizability analyses, and personalized medicine.
Each chapter (beginning with Chapter 3) contains: (1) an introduction to the topic and methods discussion at a sufficient level to understand the implementation of and the pros and cons of each approach, (2) a brief discussion of best practices and guidance on the use of the methods, (3) SAS code to implement the methods, and (4) an example analysis using the SAS code applied to one of the data sets discussed in Chapter 3.
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