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Abstract Details

Clinical Trial Emulation Leveraging Genetic Effects: A Proof-of-Concept Application to SPRINT
General Neurology
P8 - Poster Session 8 (8:00 AM-9:00 AM)
11-005
To present a genomic proof-of-concept emulation of the SPRINT randomized clinical trial (RCT).
RCTs are the gold standard for evaluating treatment effects, but they are costly and time-consuming. Therefore, selecting the most promising treatments for RCTs is crucial. Genetic variants, randomly distributed during meiosis, create natural experiments for traits they encode. Drugs backed by genomics are twice as likely to gain FDA approval, yet there have not been formal RCT emulations using genomics.
We conducted SPRINT-gen, a genomic emulation of SPRINT, using UK Biobank data. SPRINT-gen used the same sample size (n=9,361), mean systolic blood pressure (BP) difference between groups (15 mmHg), analytical approach (Cox regressions), and outcome (composite of stroke, myocardial infarction, coronary artery disease, or cardiovascular death) as SPRINT, which randomized hypertensive, non-diabetic participants into intensive (systolic BP<120 mmHg, n=4,678) and standard (systolic BP<140 mmHg, n=4,683) treatment groups. To emulate this and replicate treatment effects, SPRINT-gen employed a validated polygenic risk score for systolic BP, defining both intensive and standard treatment groups.
Like SPRINT, SPRINT-gen included 4,678 participants assigned to intensive treatment, 4,683 participants assigned to standard treatment (both mean age 63, 42% female), and a follow-up time of 4.8y. The number of events in the intensive treatment groups in SPRINT and SPRINT-gen was 243 (5.2%) vs. 220 (4.7%), respectively, and 319 (6.8%) vs. 270 (5.8%) in the standard treatment groups, respectively. The effect estimate of intensive vs. standard treatment on the composite outcome was consistent between SPRINT (HR:0.75, 95%CI: 0.64-0.89) and SPRINT-gen (HR:0.76, 95%CI: 0.62–0.92).
Our genomic-based RCT emulation framework accurately reproduced the primary result of SPRINT. This framework could be valuable for simulating RCTs that target continuous and highly heritable physiological parameters. Genomic trial emulation may significantly improve the success rate of future RCTs.
Authors/Disclosures
Santiago Clocchiatti-Tuozzo (Yale University, Department of Neurology)
PRESENTER 		Mr. Clocchiatti-Tuozzo has nothing to disclose.
Cyprien Rivier, MD (Yale University) Dr. Rivier has nothing to disclose.
Shufan Huo, MD, PhD (Yale University) Dr. Huo has nothing to disclose.
Ashkan Shoamanesh, MD Dr. Shoamanesh has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bayer AG. Dr. Shoamanesh has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Daiichi Sankyo . Dr. Shoamanesh has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Servier Inc.. Dr. Shoamanesh has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurodiem.ca. The institution of Dr. Shoamanesh has received research support from Servier Canada Inc.. The institution of Dr. Shoamanesh has received research support from Daiichi Sankyo Ltd.. The institution of Dr. Shoamanesh has received research support from Bayer AG. The institution of Dr. Shoamanesh has received research support from Bristol-Myers Squibb. The institution of Dr. Shoamanesh has received research support from Octapharma Canada .
Hooman Kamel, MD (Weill Cornell Medical College) Dr. Kamel has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for JAMA Neurology. Dr. Kamel has received personal compensation in the range of $50,000-$99,999 for serving as a Endpoint adjudication committee with Boehringer-Ingelheim.
Santosh B. Murthy, MD (Weill Cornell Medicine) Dr. Murthy has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for CarePoint. Dr. Murthy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alnylam. Dr. Murthy has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Stroke and Neurological disorders. The institution of Dr. Murthy has received research support from National Institutes of Health/NINDS.
Adam De Havenon, MD, FAAN (Yale University) Dr. De Havenon has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novo Nordisk. Dr. De Havenon has or had stock in Certus.Dr. De Havenon has or had stock in TitinKM. The institution of Dr. De Havenon has received research support from NIH/NINDS. Dr. De Havenon has received publishing royalties from a publication relating to health care.
Lauren H. Sansing, MD Dr. Sansing has nothing to disclose.
Thomas Gill Thomas Gill has nothing to disclose.
Kevin N. Sheth, MD, FAAN (Yale UniversityDivision of Neuro and Critical Care) Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ceribell. Dr. Sheth has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Zoll. Dr. Sheth has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NControl. Dr. Sheth has received stock or an ownership interest from Astrocyte. Dr. Sheth has received stock or an ownership interest from Alva. The institution of Dr. Sheth has received research support from Biogen. The institution of Dr. Sheth has received research support from Novartis. The institution of Dr. Sheth has received research support from Bard. The institution of Dr. Sheth has received research support from Hyperfine. Dr. Sheth has received intellectual property interests from a discovery or technology relating to health care.
Guido J. Falcone, MD (Yale School of Medicine) The institution of Dr. Falcone has received research support from NIH. The institution of Dr. Falcone has received research support from AHA.