Browsing by Author "Chibnik, Lori"

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    Design and Statistical Innovations in a Platform Trial for Amyotrophic Lateral Sclerosis
    (Wiley, 2023-09) Quintana, Melanie; Saville, Benjamin R.; Vestrucci, Matteo; Detry, Michelle A.; Chibnik, Lori; Shefner, Jeremy; Berry, James D.; Chase, Marianne; Andrews, Jinsy; Sherman, Alexander V.; Yu, Hong; Drake, Kristin; Cudkowicz, Merit; Paganoni, Sabrina; Macklin, Eric A.; HEALEY ALS Platform Trial Study Group; Physical Medicine and Rehabilitation, School of Medicine
    Platform trials allow efficient evaluation of multiple interventions for a specific disease. The HEALEY ALS Platform Trial is testing multiple investigational products in parallel and sequentially in persons with amyotrophic lateral sclerosis (ALS) with the goal of rapidly identifying novel treatments to slow disease progression. Platform trials have considerable operational and statistical efficiencies compared with typical randomized controlled trials due to their use of shared infrastructure and shared control data. We describe the statistical approaches required to achieve the objectives of a platform trial in the context of ALS. This includes following regulatory guidance for the disease area of interest and accounting for potential differences in outcomes of participants within the shared control (potentially due to differences in time of randomization, mode of administration, and eligibility criteria). Within the HEALEY ALS Platform Trial, the complex statistical objectives are met using a Bayesian shared parameter analysis of function and survival. This analysis serves to provide a common integrated estimate of treatment benefit, overall slowing in disease progression, as measured by function and survival while accounting for potential differences in the shared control group using Bayesian hierarchical modeling. Clinical trial simulation is used to provide a better understanding of this novel analysis method and complex design.
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    Genome-wide association study of rate of cognitive decline in Alzheimer’s Disease patients identifies novel genes and pathways
    (Wiley, 2020-08) Sherva, Richard; Gross, Alden; Mukherjee, Shubhabrata; Koesterer, Ryan; Amouyel, Philippe; Philippe, Celine; Dufouil, Carole; Bennett, David A.; Chibnik, Lori; Cruchaga, Carlos; del-Aguila, Jorge; Farrer, Lindsay A.; Mayeux, Richard; Munsie, Leanne; Winslow, Ashley; Ashley, Stephen; Saykin, Andrew J.; Kauwe, John S.K.; Crane, Paul K.; Green, Robert C.; Radiology and Imaging Sciences, School of Medicine
    Introduction: Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome-wide association study to examine rate of cognitive decline (ROD) in patients with AD. Methods: We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes. Results: Suggestive associations (P < 1.0 × 10-6 ) were observed on chromosome 15 in DNA polymerase-γ (rs3176205, P = 1.11 × 10-7 ), chromosome 7 (rs60465337,P = 4.06 × 10-7 ) in contactin-associated protein-2, in RP11-384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10-7 ), family with sequence similarity 214 member-A on chromosome 15 (rs2899492, P = 5.94 × 10-7 ), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10-7 ) and 4 (rs1304013, P = 7.73 × 10-7 ). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified. Discussion: Pathways related to AD, intelligence, and neurological function determine AD progression, while previously identified AD risk variants, including the apolipoprotein (APOE) ε4 and ε2 variants, do not have a major impact.