A novel cognitive disease progression model for clinical trials in autosomal-dominant Alzheimer's disease
Corresponding Author
Guoqiao Wang
Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA
Correspondence
Guoqiao Wang, Division of Biostatistics, Washington University School of Medicine, Campus Box 8067, 4523 Clayton Ave., St. Louis, MO 63110-1093, USA.
Email: [email protected]
Search for more papers by this authorChengjie Xiong
Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA
Search for more papers by this authorJason Hassenstab
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
Search for more papers by this authorEric M. McDade
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
Search for more papers by this authorMatteo Vestrucci
F. Hoffmann-La Roche Ltd., Basel, Switzerland
Department of Statistics and Data Sciences, University of Texas at Austin, Austin, TX, USA
Search for more papers by this authorGopalan Sethuraman
Lilly Research Laboratories, Indianapolis, IN, USA
Search for more papers by this authorRandall J. Bateman
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
Search for more papers by this authorFor the Dominantly Inherited Alzheimer Network Trials Unit
Search for more papers by this authorCorresponding Author
Guoqiao Wang
Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA
Correspondence
Guoqiao Wang, Division of Biostatistics, Washington University School of Medicine, Campus Box 8067, 4523 Clayton Ave., St. Louis, MO 63110-1093, USA.
Email: [email protected]
Search for more papers by this authorChengjie Xiong
Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA
Search for more papers by this authorJason Hassenstab
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
Search for more papers by this authorEric M. McDade
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
Search for more papers by this authorMatteo Vestrucci
F. Hoffmann-La Roche Ltd., Basel, Switzerland
Department of Statistics and Data Sciences, University of Texas at Austin, Austin, TX, USA
Search for more papers by this authorGopalan Sethuraman
Lilly Research Laboratories, Indianapolis, IN, USA
Search for more papers by this authorRandall J. Bateman
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
Search for more papers by this authorFor the Dominantly Inherited Alzheimer Network Trials Unit
Search for more papers by this authorAbstract
Clinical trial outcomes for Alzheimer's disease are typically analyzed by using the mixed model for repeated measures (MMRM) or similar models that compare an efficacy scale change from baseline between treatment arms with or without participants' disease stage as a covariate. The MMRM focuses on a single-point fixed follow-up duration regardless of the exposure for each participant. In contrast to these typical models, we have developed a novel semiparametric cognitive disease progression model (DPM) for autosomal dominant Alzheimer's disease based on the Dominantly Inherited Alzheimer Network (DIAN) observational study. This model includes 3 novel features, in which the DPM (1) aligns and compares participants by disease stage, (2) uses a proportional treatment effect similar to the concept of the Cox proportional hazard ratio, and (3) incorporates extended follow-up data from participants with different follow-up durations using all data until last participant visit. We present the DPM model developed by using the DIAN observational study data and demonstrate through simulation that the cognitive DPM used in hypothetical intervention clinical trials produces substantial gains in power compared with the MMRM.
Supporting Information
| Filename | Description |
|---|---|
| sim7811-sup-0001-Supplementary_Material.docxWord 2007 document , 26.9 KB |
Table S1: The means (SD) of the baseline cognitive scores for mutation carriers with an EYO < = − 15. Table S2: The posterior mean (SD) of the mean cognitive decline for each EYO by the cognitive DPM without the monotonicity assumption using DIAN observational study. Table S3: Simulation parameters for each scenario Table S4: The 97.5th percentile of the maximum posterior probability of superiority for the null hypothesis trials. Using these as the threshold in that scenario would create a type I error of 2.5%. Table S5: The cumulative probability of success (Type I error rate) at the 2, 3, and 4-year analyses are presented for CPR reduction of 0% (no benefit) assuming no futility stopping. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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