Enhancing Longitudinal Clinical Trial Efficiency with Digital Twins and Prognostic Covariate-Adjusted Mixed Models for Repeated Measures (PROCOVA-MMRM)
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2024
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| author | Ross, Jessica L. Sabbaghi, Arman Zhuang, Run Bertolini, Daniele Study, the Alzheimer's Disease Cooperative Initiative, Alzheimer's Disease Neuroimaging Database, the Critical Path for Alzheimer's Disease Disease, the European Prevention of Alzheimer's Consortium Consortium, the Pooled Resource Open-Access ALS Clinical Trials |
| author_facet | Ross, Jessica L. Sabbaghi, Arman Zhuang, Run Bertolini, Daniele Study, the Alzheimer's Disease Cooperative Initiative, Alzheimer's Disease Neuroimaging Database, the Critical Path for Alzheimer's Disease Disease, the European Prevention of Alzheimer's Consortium Consortium, the Pooled Resource Open-Access ALS Clinical Trials |
| contents | Clinical trials are critical in advancing medical treatments but often suffer from immense time and financial burden. Advances in statistical methodologies and artificial intelligence (AI) present opportunities to address these inefficiencies. Here we introduce Prognostic Covariate-Adjusted Mixed Models for Repeated Measures (PROCOVA-MMRM) as an advantageous combination of prognostic covariate adjustment (PROCOVA) and Mixed Models for Repeated Measures (MMRM). PROCOVA-MMRM utilizes time-matched prognostic scores generated from AI models to enhance the precision of treatment effect estimators for longitudinal continuous outcomes, enabling reductions in sample size and enrollment times. We first provide a description of the background and implementation of PROCOVA-MMRM, followed by two case study reanalyses where we compare the performance of PROCOVA-MMRM versus the unadjusted MMRM. These reanalyses demonstrate significant improvements in statistical power and precision in clinical indications with unmet medical need, specifically Alzheimer's Disease (AD) and Amyotrophic Lateral Sclerosis (ALS). We also explore the potential for sample size reduction with the prospective implementation of PROCOVA-MMRM, finding that the same or better results could have been achieved with fewer participants in these historical trials if the enhanced precision provided by PROCOVA-MMRM had been prospectively leveraged. We also confirm the robustness of the statistical properties of PROCOVA-MMRM in a variety of realistic simulation scenarios. Altogether, PROCOVA-MMRM represents a rigorous method of incorporating advances in the prediction of time-matched prognostic scores generated by AI into longitudinal analysis, potentially reducing both the cost and time required to bring new treatments to patients while adhering to regulatory standards. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2404_17576 |
| institution | arXiv |
| publishDate | 2024 |
| record_format | arxiv |
| spellingShingle | Enhancing Longitudinal Clinical Trial Efficiency with Digital Twins and Prognostic Covariate-Adjusted Mixed Models for Repeated Measures (PROCOVA-MMRM) Ross, Jessica L. Sabbaghi, Arman Zhuang, Run Bertolini, Daniele Study, the Alzheimer's Disease Cooperative Initiative, Alzheimer's Disease Neuroimaging Database, the Critical Path for Alzheimer's Disease Disease, the European Prevention of Alzheimer's Consortium Consortium, the Pooled Resource Open-Access ALS Clinical Trials Applications 62J05 Clinical trials are critical in advancing medical treatments but often suffer from immense time and financial burden. Advances in statistical methodologies and artificial intelligence (AI) present opportunities to address these inefficiencies. Here we introduce Prognostic Covariate-Adjusted Mixed Models for Repeated Measures (PROCOVA-MMRM) as an advantageous combination of prognostic covariate adjustment (PROCOVA) and Mixed Models for Repeated Measures (MMRM). PROCOVA-MMRM utilizes time-matched prognostic scores generated from AI models to enhance the precision of treatment effect estimators for longitudinal continuous outcomes, enabling reductions in sample size and enrollment times. We first provide a description of the background and implementation of PROCOVA-MMRM, followed by two case study reanalyses where we compare the performance of PROCOVA-MMRM versus the unadjusted MMRM. These reanalyses demonstrate significant improvements in statistical power and precision in clinical indications with unmet medical need, specifically Alzheimer's Disease (AD) and Amyotrophic Lateral Sclerosis (ALS). We also explore the potential for sample size reduction with the prospective implementation of PROCOVA-MMRM, finding that the same or better results could have been achieved with fewer participants in these historical trials if the enhanced precision provided by PROCOVA-MMRM had been prospectively leveraged. We also confirm the robustness of the statistical properties of PROCOVA-MMRM in a variety of realistic simulation scenarios. Altogether, PROCOVA-MMRM represents a rigorous method of incorporating advances in the prediction of time-matched prognostic scores generated by AI into longitudinal analysis, potentially reducing both the cost and time required to bring new treatments to patients while adhering to regulatory standards. |
| title | Enhancing Longitudinal Clinical Trial Efficiency with Digital Twins and Prognostic Covariate-Adjusted Mixed Models for Repeated Measures (PROCOVA-MMRM) |
| topic | Applications 62J05 |
| url | https://arxiv.org/abs/2404.17576 |