{"title":"基于血液的生物标志物预先筛选与不同的测试组合和截止：一项模拟研究检查阿尔茨海默病预防研究的疗效和成本效益","authors":"Kenichiro Sato, Yoshiki Niimi, Ryoko Ihara, Atsushi Iwata, Kazushi Suzuki, Takeshi Iwatsubo","doi":"10.1002/trc2.70065","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>Blood-based biomarkers (BBBMs), including plasma amyloid beta (Aβ) or phosphorylated tau (p-tau), combined with apolipoprotein E (<i>APOE</i>) testing, are anticipated to serve as prescreening tools before amyloid positron emission tomography (PET) for recruiting participants for Alzheimer's disease (AD) prevention studies. The predictive efficacy and cost-effectiveness of prescreening may vary with different testing combinations, sequences, and cutoff levels.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>We conducted a simulation study utilizing data from our ongoing Japanese Trial-Ready Cohort (J-TRC) onsite study (<i>n</i> = 202) recruited online. We included cognitively unimpaired individuals who had undergone amyloid PET, <i>APOE</i> genotyping, and evaluation of BBBMs (i.e., plasma Aβ42/Aβ40 ratio, plasma p-tau217, and plasma p-tau217/Aβ42 ratio). We examined 14 different prescreening models incorporating <i>APOE</i> genotype and/or BBBMs with varied combinations and cutoff levels. Models were evaluated for predictive performance (sensitivity, specificity, and positive predictive value [PPV]) and cost-effectiveness (cost per identified amyloid-positive case) across varied testing costs and the prevalence of amyloid positivity.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>Applying BBBM prescreening significantly decreased sensitivity and increased specificity and PPV compared to the no-prescreening scenario. Although no single model was superior in all performance metrics, a trade-off between sensitivity and specificity was observed. Generalized linear models (GLMs) simultaneously incorporating plasma Aβ42/Aβ40 ratio and p-tau217 showed a balanced efficacy (the best level of improvement in number needed to screen (NNS) but modest worsening in sensitivity) and the best level of cost-effectiveness compared to other models, although there were substantial overlaps in their 95% confidence intervals (CIs). The minimum-required PET/BBBM cost ratio to achieve improved cost-effectiveness by employing the prescreening process was negatively associated with the background prevalence of amyloid positivity.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>The choice of prescreening strategy in AD prevention studies/trials should be tailored to specific trial requirements, considering the relative importance of sensitivity versus cost-effectiveness, local testing cost environments, and background population characteristics.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>We investigated different models of blood-based biomarker (BBBM) prescreening.</li>\n \n <li>Data from Japanese Trial-Ready Cohort Study were used for simulation.</li>\n \n <li>BBBM reduced the number needed to screen with positron emission tomography (PET) but decreased the sensitivity.</li>\n \n <li>The cost-effectiveness improved with a higher PET/BBBM cost ratio.</li>\n \n <li>No single model was optimal for all scenarios.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9000,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70065","citationCount":"0","resultStr":"{\"title\":\"Blood-based biomarker prescreening with different testing combinations and cutoffs: A simulation study examining efficacy and cost-effectiveness in Alzheimer's disease prevention studies\",\"authors\":\"Kenichiro Sato, Yoshiki Niimi, Ryoko Ihara, Atsushi Iwata, Kazushi Suzuki, Takeshi Iwatsubo\",\"doi\":\"10.1002/trc2.70065\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> INTRODUCTION</h3>\\n \\n <p>Blood-based biomarkers (BBBMs), including plasma amyloid beta (Aβ) or phosphorylated tau (p-tau), combined with apolipoprotein E (<i>APOE</i>) testing, are anticipated to serve as prescreening tools before amyloid positron emission tomography (PET) for recruiting participants for Alzheimer's disease (AD) prevention studies. 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引用次数: 0
摘要
基于血液的生物标志物（BBBMs），包括血浆淀粉样蛋白β (Aβ)或磷酸化tau (p-tau)，结合载脂蛋白E （APOE）检测，有望作为淀粉样正电子发射断层扫描（PET）前的预筛选工具，用于招募阿尔茨海默病（AD）预防研究的参与者。预筛选的预测效果和成本效益可能因不同的检测组合、序列和截止水平而异。方法：我们利用正在进行的日本试验就绪队列（J-TRC）现场研究（n = 202）在线招募的数据进行了一项模拟研究。我们纳入了接受淀粉样蛋白PET、APOE基因分型和bbbm评估（即血浆a - β42/ a - β40比值、血浆p-tau217和血浆p-tau217/ a - β42比值）的认知未受损个体。我们研究了包含APOE基因型和/或bbbm的14种不同的预筛选模型，这些模型具有不同的组合和切断水平。评估模型的预测性能（敏感性、特异性和阳性预测值[PPV]）和成本效益（每个确定的淀粉样蛋白阳性病例的成本），包括不同的检测成本和淀粉样蛋白阳性的患病率。结果与未进行预筛选的情况相比，应用BBBM预筛选可显著降低敏感性，增加特异性和PPV。虽然没有单一的模型在所有的性能指标上都是优越的，但观察到敏感性和特异性之间的权衡。与其他模型相比，同时纳入血浆a - β42/ a - β40比率和p-tau217的广义线性模型（GLMs）显示出平衡的疗效（筛查所需数量的最佳改善水平（NNS）但敏感性适度恶化）和最佳成本-效果水平，尽管它们的95%置信区间（ci）存在大量重叠。通过采用预筛选过程来提高成本效益所需的PET/BBBM最低成本比与淀粉样蛋白阳性背景患病率呈负相关。在阿尔茨海默病预防研究/试验中，预先筛选策略的选择应根据具体的试验要求进行调整，考虑敏感性与成本效益、当地测试成本环境和背景人群特征的相对重要性。我们研究了不同的血液生物标志物（BBBM）预筛选模型。采用日本试验就绪队列研究的数据进行模拟。BBBM减少了用正电子发射断层扫描（PET）筛查所需的次数，但降低了灵敏度。成本效益随着PET/BBBM成本比的提高而提高。没有一个模型对所有情况都是最优的。
Blood-based biomarker prescreening with different testing combinations and cutoffs: A simulation study examining efficacy and cost-effectiveness in Alzheimer's disease prevention studies
INTRODUCTION
Blood-based biomarkers (BBBMs), including plasma amyloid beta (Aβ) or phosphorylated tau (p-tau), combined with apolipoprotein E (APOE) testing, are anticipated to serve as prescreening tools before amyloid positron emission tomography (PET) for recruiting participants for Alzheimer's disease (AD) prevention studies. The predictive efficacy and cost-effectiveness of prescreening may vary with different testing combinations, sequences, and cutoff levels.
METHODS
We conducted a simulation study utilizing data from our ongoing Japanese Trial-Ready Cohort (J-TRC) onsite study (n = 202) recruited online. We included cognitively unimpaired individuals who had undergone amyloid PET, APOE genotyping, and evaluation of BBBMs (i.e., plasma Aβ42/Aβ40 ratio, plasma p-tau217, and plasma p-tau217/Aβ42 ratio). We examined 14 different prescreening models incorporating APOE genotype and/or BBBMs with varied combinations and cutoff levels. Models were evaluated for predictive performance (sensitivity, specificity, and positive predictive value [PPV]) and cost-effectiveness (cost per identified amyloid-positive case) across varied testing costs and the prevalence of amyloid positivity.
RESULTS
Applying BBBM prescreening significantly decreased sensitivity and increased specificity and PPV compared to the no-prescreening scenario. Although no single model was superior in all performance metrics, a trade-off between sensitivity and specificity was observed. Generalized linear models (GLMs) simultaneously incorporating plasma Aβ42/Aβ40 ratio and p-tau217 showed a balanced efficacy (the best level of improvement in number needed to screen (NNS) but modest worsening in sensitivity) and the best level of cost-effectiveness compared to other models, although there were substantial overlaps in their 95% confidence intervals (CIs). The minimum-required PET/BBBM cost ratio to achieve improved cost-effectiveness by employing the prescreening process was negatively associated with the background prevalence of amyloid positivity.
DISCUSSION
The choice of prescreening strategy in AD prevention studies/trials should be tailored to specific trial requirements, considering the relative importance of sensitivity versus cost-effectiveness, local testing cost environments, and background population characteristics.
Highlights
We investigated different models of blood-based biomarker (BBBM) prescreening.
Data from Japanese Trial-Ready Cohort Study were used for simulation.
BBBM reduced the number needed to screen with positron emission tomography (PET) but decreased the sensitivity.
The cost-effectiveness improved with a higher PET/BBBM cost ratio.
期刊介绍：
Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.
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