Methodologic Remedies for the Risk Factor Paradox in Osteoarthritis Progression

骨关节炎进展中危险因素悖论的方法学补救措施

• 批准号: 9134044
• 负责人: HYON K CHOI
• 金额: $ 10.2万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9134044
• 关键词: Activities of Daily Living; Affect; Aging; Alzheimer' s Disease; Applications Grants; Arthritis; Biological; Birth Weight; Body mass index; Bone Density; Chronic Obstructive Airway Disease; Clinical; Coronary Arteriosclerosis; Databases; Degenerative polyarthritis; Development; Discipline; Disease; Event; Evidence Based Medicine; Excess Mortality; Female; Funding; Future; Health; Individual; Infant; Infant Mortality; Joints; Knee Injuries; Knee Osteoarthritis; Knowledge; Left; Low Birth Weight Infant; Measures; Mediation; Methodology; Methods; Obesity; Occupational; Outcome; Pain; Patent Foramen Ovale; Patients; Physically Handicapped; Recommendation; Recording of previous events; Recurrence; Reporting; Research; Research Project Grants; Rheumatoid Arthritis; Rheumatology; Risk; Risk Factors; Secondary Prevention; Selection Bias; Smoking; Staging; Stress; Stroke; Time; United States National Institutes of Health; apolipoprotein E-4; base; burden of illness; causal model; cohort; design; disability; evidence base; evidence based guidelines; indexing; insight; knee replacement arthroplasty; maternal cigarette smoking; mortality; prevent; protective effect; response; risk variant; sex; simulation; study population

 DESCRIPTION (provided by applicant): This proposal is in response to NIH Research Grant Opportunity PA-13-237 using the Osteoarthritis Initiative (OAI) database. Knee osteoarthritis (OA) constitutes a tremendous disease burden in the US, as it causes pain and decreased mobility, and its progression leads to a loss of independence and functional capacity, disability, and total knee replacement. Thus, OA progression represents a compelling target for secondary prevention; however, unlike the risk factors for incident knee OA, the results of studies on risk factors for the progression of knee OA have been paradoxical. For example, a number of risk factors for incident knee OA have been consistently identified, including female sex, obesity, high bone mineral density, knee injury, and repetitive occupational stress on joints. In contrast, none of these factors have been consistently associated with the risk of OA progression. Further, studies have failed to find a consistent association even between obesity or aging (two well-established risk factors for incident knee OA) and the risk of knee OA progression. Although biological explanations for these counterintuitive results may exist, an enticing methodologic explanation is a type of selection bias called index event bias, which can affect research on disease sequelae (e.g., progression) when there are multiple risk factors for sequelae that are also risk factors for having the disease in the first place (e.g., the effect of MI on the risk of severe OA among mild to moderate OA patients [i.e., those with index events]). To date, little research has methodologically investigated the paradoxical phenomena of risk factors for OA progression, leaving a crucial gap in knowledge on this important topic. Unless an appropriate design and analytic method are used to measure the germane impact of purported risk factors in OA (i.e., the most common form of arthritis), ample research funds, time, and effort can be depleted without providing useful evidence for clinical recommendations and biological insight. To validly characterize and overcome the methodological challenges associated with assessing the risk conferred by purported risk factors for OA progression, we will investigate previously reported paradoxical findings using the OAI cohort for the following specific aims: (1) to determine and quantify the index event bias and to clarify the core mechanisms underlying the risk factor paradoxes; (2) to provide methodological remedies, including sensitivity analyses, assessment of the impact of a change in exposure status, and causal modeling approaches for the unbiased impact of purported risk factors on knee OA progression. Furthermore, we will demonstrate inherent limitations of certain exposures in this key research context. By leveraging our expertise in the relevant advanced methodology and the clinical topic, as well as the strengths and our hands-on knowledge of the OAI database, the proposed project will fill crucial gaps in our understanding of the germane impact of risk factors for knee OA progression, and provide key methodologic advances needed for evidence-based medicine in rheumatology and many other disciplines.

 描述（由适用提供）：该建议是针对NIH研究赠款机会PA-13-237使用骨关节炎计划（OAI）数据库。膝关节骨关节炎（OA）在美国构成了一种巨大的疾病，因为它会引起疼痛和扩大迁移率，并且其进展会导致独立性和功能能力丧失，残疾和总膝盖替代。这是OA的进展代表了二级预防的引人注目的目标。但是，与事件膝关节OA的危险因素不同，膝盖OA进展的危险因素的结果是自相矛盾的。例如，始终确定了许多膝盖OA的风险因素，包括女性，肥胖，高骨矿物质密度，膝盖损伤和关节重复的职业压力。相比之下，这些因素都没有始终与OA进展的风险相关。此外，研究甚至在肥胖或衰老之间也无法找到一致的关联（两个事件膝关节OA的危险因素）和膝盖OA进展的风险。尽管可能存在针对这些违反直觉结果的生物学解释，但是一种诱人的方法论解释是一种选择偏见，称为指数事件偏见，它可能会影响对疾病后遗症的研究（例如进展），当有多种后遗症的风险因素是疾病中的危险因素，这也是第一部分的危险因素（例如，MI中的MI A. aima a aima oa a aima aima oa a a a aima oa a a a aima aima a a a a aima oa a a a a a。事件]）。迄今为止，几乎没有研究在方法论上研究了OA进展的风险因素的矛盾现象，因此对这个重要主题的知识存在关键的差距。除非使用适当的设计和分析方法来衡量OA中声称的危险因素的依恋影响（即，关节炎的最常见形式），否则可以耗尽大量的研究资金，时间和精力，而无需提供有用的临床建议和生物学见解的有用证据。为了有效地表征和克服与评估OA进展的风险因素赋予的风险相关的方法论挑战，我们将研究先前报道的先前报道的矛盾的发现，使用OAI队列为以下具体目的进行以下特定目的：（1）确定和量化索引事件偏见并阐明风险因素矛盾的核心机制； （2）提供方法论补救措施，包括敏感性分析，对暴露状态变化的影响的评估以及对所谓危险因素对膝关节进展的无偏影响的催化建模方法。此外，我们将在此关键研究环境中证明某些暴露的继承局限性。通过利用我们的专家在相关的高级方法和临床主题上，以及对OAI数据库的优势和动手知识，该提议的项目将填补我们对膝盖OA进展的危险因素对危险因素的依恋影响的重要空白，并提供对循证医学在Rheumatologology和许多其他学科中所需的关键方法学进步所需的关键方法。