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Register a new userSequential knockoffs for continuous and categorical predictors: with application to a large Psoriatic Arthritis clinical trial pool
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Matthias Kormaksson
Publication date
2020
fields
Mathematical Statistics
and research's language is
English
Authors
Matthias Kormaksson
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Knockoffs provide a general framework for controlling the false discovery rate when performing variable selection. Much of the Knockoffs literature focuses on theoretical challenges and we recognize a need for bringing some of the current ideas into practice. In this paper we propose a sequential algorithm for generating knockoffs when underlying data consists of both continuous and categorical (factor) variables. Further, we present a heuristic multiple knockoffs approach that offers a practical assessment of how robust the knockoff selection process is for a given data set. We conduct extensive simulations to validate performance of the proposed methodology. Finally, we demonstrate the utility of the methods on a large clinical data pool of more than $2,000$ patients with psoriatic arthritis evaluated in 4 clinical trials with an IL-17A inhibitor, secukinumab (Cosentyx), where we determine prognostic factors of a well established clinical outcome. The analyses presented in this paper could provide a wide range of applications to commonly encountered data sets in medical practice and other fields where variable selection is of particular interest.
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Model-X knockoffs is a general procedure that can leverage any feature importance measure to produce a variable selection algorithm, which discovers true effects while rigorously controlling the number or fraction of false positives. Model-X knockoffs is a randomized procedure which relies on the one-time construction of synthetic (random) variables. This paper introduces a derandomization method by aggregating the selection results across multiple runs of the knockoffs algorithm. The derandomization step is designed to be flexible and can be adapted to any variable selection base procedure to yield stable decisions without compromising statistical power. When applied to the base procedure of Janson et al. (2016), we prove that derandomized knockoffs controls both the per family error rate (PFER) and the k family-wise error rate (k-FWER). Further, we carry out extensive numerical studies demonstrating tight type-I error control and markedly enhanced power when compared with alternative variable selection algorithms. Finally, we apply our approach to multi-stage genome-wide association studies of prostate cancer and report locations on the genome that are significantly associated with the disease. When cross-referenced with other studies, we find that the reported associations have been replicated.
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Clinicians and researchers alike are increasingly interested in how best to personalize interventions. A dynamic treatment regimen (DTR) is a sequence of pre-specified decision rules which can be used to guide the delivery of a sequence of treatments or interventions that are tailored to the changing needs of the individual. The sequential multiple-assignment randomized trial (SMART) is a research tool which allows for the construction of effective DTRs. We derive easy-to-use formulae for computing the total sample size for three common two-stage SMART designs in which the primary aim is to compare mean end-of-study outcomes for two embedded DTRs which recommend different first-stage treatments. The formulae are derived in the context of a regression model which leverages information from a longitudinal outcome collected over the entire study. We show that the sample size formula for a SMART can be written as the product of the sample size formula for a standard two-arm randomized trial, a deflation factor that accounts for the increased statistical efficiency resulting from a longitudinal analysis, and an inflation factor that accounts for the design of a SMART. The SMART design inflation factor is typically a function of the anticipated probability of response to first-stage treatment. We review modeling and estimation for DTR effect analyses using a longitudinal outcome from a SMART, as well as the estimation of standard errors. We also present estimators for the covariance matrix for a variety of common working correlation structures. Methods are motivated using the ENGAGE study, a SMART aimed at developing a DTR for increasing motivation to attend treatments among alcohol- and cocaine-dependent patients.
When fitting statistical models, some predictors are often found to be correlated with each other, and functioning together. Many group variable selection methods are developed to select the groups of predictors that are closely related to the continuous or categorical response. These existing methods usually assume the group structures are well known. For example, variables with similar practical meaning, or dummy variables created by categorical data. However, in practice, it is impractical to know the exact group structure, especially when the variable dimensional is large. As a result, the group variable selection results may be selected. To solve the challenge, we propose a two-stage approach that combines a variable clustering stage and a group variable stage for the group variable selection problem. The variable clustering stage uses information from the data to find a group structure, which improves the performance of the existing group variable selection methods. For ultrahigh dimensional data, where the predictors are much larger than observations, we incorporated a variable screening method in the first stage and shows the advantages of such an approach. In this article, we compared and discussed the performance of four existing group variable selection methods under different simulation models, with and without the variable clustering stage. The two-stage method shows a better performance, in terms of the prediction accuracy, as well as in the accuracy to select active predictors. An athletes data is also used to show the advantages of the proposed method.
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