Ottaviani Javier I, Schroeter Hagen, Bier Dennis M, Erdman John W, Sesso Howard D, Manson JoAnn E, Kuhnle Gunter G C
Mars, Inc., McLean, VA, USA.
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Food Funct. 2025 Jun 26. doi: 10.1039/d5fo01134e.
Randomised controlled trials in nutrition (RCTN) face unique challenges, including the considerable influence of the background diet and the challenge of assuring intervention adherence by participants. The impact of these factors on the outcome of RCTNs has been difficult to quantify, but nutritional biomarkers represent a valuable tool to address these challenges. Using flavanols as a model dietary intervention and a set of recently validated flavanol biomarkers, we here investigated the impact of background diet and adherence on the outcomes of a subcohort of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS, NCT02422745). We found that 20% of participants in the placebo and cocoa-extract intervention arms had a flavanol background intake as high as the intervention, and only 5% did not consume any flavanols. Approximately 33% of participants in the intervention group did not achieve expected biomarker levels from the assigned intervention - more than the 15% estimated with pill-taking questionnaires usually implemented in RCTN. Taking these factors into account resulted in a larger effect size for all observed endpoints (HR (95% CI)) estimated using intention-to-treat per-protocol biomarker-based analyses: total cardiovascular disease (CVD) events 0.83 (0.65; 1.07); 0.79 (0.59; 1.05); 0.65 (0.47; 0.89) - CVD mortality 0.53 (0.29; 0.96); 0.51 (0.23; 1.14); 0.44 (0.20; 0.97) - all-cause mortality 0.81 (0.61; 1.08); 0.69 (0.45; 1.05); 0.54 (0.37; 0.80) -- major CVD events 0.75 (0.55; 1.02); 0.62 (0.43; 0.91); 0.48 (0.31; 0.74). These results highlight the importance of taking background diet and adherence into consideration in RCTN to obtain more reliable estimates of outcomes through nutritional biomarker-based analyses.
营养领域的随机对照试验（RCTN）面临着独特的挑战，包括背景饮食的重大影响以及确保参与者坚持干预措施的难题。这些因素对RCTN结果的影响难以量化，但营养生物标志物是应对这些挑战的宝贵工具。我们以黄烷醇作为膳食干预模型，并使用一组最近验证的黄烷醇生物标志物，在此研究了背景饮食和依从性对可可补充剂与多种维生素结果研究（COSMOS，NCT02422745）一个亚组结果的影响。我们发现，安慰剂组和可可提取物干预组中20%的参与者的黄烷醇背景摄入量与干预量一样高，只有5%的参与者未摄入任何黄烷醇。干预组中约33%的参与者未从指定干预中达到预期的生物标志物水平，这一比例高于RCTN通常采用的服药问卷估计的15%。将这些因素考虑在内后，在基于意向性分析、符合方案分析和生物标志物分析中，所有观察终点（风险比（95%置信区间））的效应量都更大：总心血管疾病（CVD）事件分别为0.83（0.65；1.07）；0.79（0.59；1.05）；0.65（0.47；0.89）——CVD死亡率分别为0.53（0.29；0.96）；0.51（0.23；1.14）；0.44（0.20；0.97）——全因死亡率分别为0.81（0.61；1.08）；0.69（0.45；1.05）；0.54（0.37；0.80）——主要CVD事件分别为0.75（0.55；1.02）；0.62（0.43；0.91）；0.48（0.31；0.74）。这些结果凸显了在RCTN中考虑背景饮食和依从性的重要性，以便通过基于营养生物标志物的分析获得更可靠的结果估计。
