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The benefits of using genetic information to design prevention trials.

ABSTRACT: Clinical trials for preventative therapies are complex and costly endeavors focused on individuals likely to develop disease in a short time frame, randomizing them to treatment groups, and following them over time. In such trials, statistical power is governed by the rate of disease events in each group and cost is determined by randomization, treatment, and follow-up. Strategies that increase the rate of disease events by enrolling individuals with high risk of disease can significantly reduce study size, duration, and cost. Comprehensive study of common, complex diseases has resulted in a growing list of robustly associated genetic markers. Here, we evaluate the utility--in terms of trial size, duration, and cost--of enriching prevention trial samples by combining clinical information with genetic risk scores to identify individuals at greater risk of disease. We also describe a framework for utilizing genetic risk scores in these trials and evaluating the associated cost and time savings. With type 1 diabetes (T1D), type 2 diabetes (T2D), myocardial infarction (MI), and advanced age-related macular degeneration (AMD) as examples, we illustrate the potential and limitations of using genetic data for prevention trial design. We illustrate settings where incorporating genetic information could reduce trial cost or duration considerably, as well as settings where potential savings are negligible. Results are strongly dependent on the genetic architecture of the disease, but we also show that these benefits should increase as the list of robustly associated markers for each disease grows and as large samples of genotyped individuals become available.

SUBMITTER: Hu Y

PROVIDER: S-EPMC3617383 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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The benefits of using genetic information to design prevention trials.

Hu Youna Y Li Li L Ehm Margaret G MG Bing Nan N Song Kijoung K Nelson Matthew R MR Talmud Philippa J PJ Hingorani Aroon D AD Kumari Meena M Kivimäki Mika M Xu Chun-Fang CF Waterworth Dawn M DM Whittaker John C JC Abecasis Gonçalo R GR Spino Cathie C Kang Hyun Min HM

American journal of human genetics 20130328 4

Clinical trials for preventative therapies are complex and costly endeavors focused on individuals likely to develop disease in a short time frame, randomizing them to treatment groups, and following them over time. In such trials, statistical power is governed by the rate of disease events in each group and cost is determined by randomization, treatment, and follow-up. Strategies that increase the rate of disease events by enrolling individuals with high risk of disease can significantly reduce ...[more]

PMID: 23541341

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Project description:BACKGROUND/AIMS:Clinical trials for Alzheimer's disease have been aimed primarily at persons who have cognitive symptoms at enrollment. However, researchers are now recognizing that the pathophysiological process of Alzheimer's disease begins years, if not decades, prior to the onset of clinical symptoms. Successful intervention may require intervening early in the disease process. Critical issues arise in designing clinical trials for primary and secondary prevention of Alzheimer's disease including determination of sample sizes and follow-up duration. We address a number of these issues through application of a unifying multistate model for the preclinical course of Alzheimer's disease. A multistate model allows us to specify at which points during the long disease process the intervention exerts its effects. METHODS:We used a nonhomogeneous Markov multistate model for the progression of Alzheimer's disease through preclinical disease states defined by biomarkers, mild cognitive impairment and Alzheimer's disease dementia. We used transition probabilities based on several published cohort studies. Sample size methods were developed that account for factors including the initial preclinical disease state of trial participants, the primary endpoint, age-dependent transition and mortality rates and specifications of which transition rates are the targets of the intervention. RESULTS:We find that Alzheimer's disease prevention trials with a clinical primary endpoint of mild cognitive impairment or Alzheimer's disease dementia will require sample sizes of the order many thousands of individuals with at least 5 years of follow-up, which is larger than most Alzheimer's disease therapeutic trials conducted to date. The reasons for the large trial sizes include the long and variable preclinical period that spans decades, high rates of attrition among elderly populations due to mortality and losses to follow-up and potential selection effects, whereby healthier subjects enroll in prevention trials. A web application is available to perform sample size calculations using the methods reported here. CONCLUSION:Sample sizes based on multistate models can account for the points in the disease process when interventions exert their effects and may lead to more accurate sample size determinations. We will need innovative strategies to help design Alzheimer's disease prevention trials with feasible sample size requirements and durations of follow-up.

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The benefits of using genetic information to design prevention trials.

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The benefits of using genetic information to design prevention trials.

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