Only specific subgroups of patients who exhibit specific genetic aberrations benefit from these personalized therapies. This increases the number of patients who receive adequate personalized treatment and improves their survival and quality of life. Optimal use of diagnostic tests contributes to correct and timely detection of genetic aberrations. Model-based analyses showed that parallel testing with next-generation sequencing–based DNA and RNA panels can improve the detection of potential druggable mutations and fusion genes, respectively, without increasing diagnostic costs. This study compares diagnostic testing strategies in the Dutch context, to optimize the detection of druggable targets and the cost-effectiveness of molecular predictive testing. There is substantial variation in the order and type of molecular tests used for the detection of genetic aberrations for personalized treatment in patients with metastasized nonsquamous non–small-cell lung cancer. contributed equally to this work as first authors. The special demands of interim analysis for continuous repeated measurements led to examining the properties of such interim analysis procedures for an interesting range of conditions.1Department of Epidemiology and Biostatistics, Amsterdam University Medical Center, VU Amsterdam, Amsterdam, the NetherlandsĢDepartment of Pathology, Radboudumc, Nijmegen, the NetherlandsģDepartment of Pathology, Antoni van Leeuwenhoek Hospital, the Netherlands Cancer Institute, Amsterdam, the NetherlandsĤDepartment of Pathology, Leiden University Medical Center, Leiden, the NetherlandsĥDepartment of Pulmonary Diseases, University of Groningen and University Medical Center Groningen, Groningen, the NetherlandsĦDepartment of Epidemiology, Biostatistics and HTA, Radboud University Medical Center, Nijmegen, the NetherlandsħDepartment of Pathology and Medical Biology, University Medical Center Utrecht, Utrecht University, Utrecht, the NetherlandsĨPALGA Foundation, Houten, the NetherlandsĩDepartment of Pathology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlandsġ0Department of Human Genetics, and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlandsġ1Princess Máxima Center for Pediatric Oncology, Bilthoven, the Netherlands The OMSD and IHLT procedures also provide an exact overall type I error rate, for a fixed spending pattern. The ISD and IMSD procedures provide an exact overall type I error rate, while the Bonferroni strategy does not. The lSD, IMSD and Bonferroni strategy allow testing general linear hypotheses with pre-assigned spending probabilities, and without specifying the covariance structure. Five techniques are described and evaluated for the interim analysis of continuous repeated measurements in General Linear Multivariate Models and Growth Curve Models settings: 1) the interim analysis step-down (ISD) procedure, 2) the interim analysis modified step-down (IMSD) procedure, 3) the original modified step-down (OMSD) procedure, 4) the interim analysis Hotelling Lawley trace (IHLT), and 5) the Bonferroni strategy. Only very limited techniques have been available for continuous data. Standard group-sequential methods do not apply due to correlation among observations. One approach involves conducting interim analysis as repeated measurements accumulate on subjects. In clinical trials, ethical and practical needs often lead to the use of interim analysis.
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