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（由申请人提供）：本提案是对使用骨关节炎倡议（OAI）数据库的NIH研究资助机会PA-13-237的回应。膝关节骨关节炎（OA）在美国构成了巨大的疾病负担，因为它会导致疼痛和活动能力下降，其进展会导致独立性和功能能力丧失、残疾和全膝关节置换术。因此，OA进展是一个引人注目的二级预防目标;然而，与膝关节OA事件的风险因素不同，膝关节OA进展风险因素的研究结果是矛盾的。例如，已经一致确定了许多膝关节OA事件的风险因素，包括女性性别、肥胖、高骨矿物质密度、膝关节损伤和关节的重复职业压力。相比之下，这些因素均与OA进展风险无关。此外，研究未能发现肥胖或衰老（膝关节OA事件的两个公认风险因素）与膝关节OA进展风险之间的一致关联。尽管这些违反直觉的结果可能存在生物学解释，但一种诱人的方法学解释是一种称为指数事件偏倚的选择偏倚，它可能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也是首先患有疾病的风险因素时（例如，MI对轻度至中度OA患者中重度OA风险的影响[即，具有索引事件的那些]）。到目前为止，很少有研究从方法学上研究OA进展的危险因素的矛盾现象，在这一重要主题上留下了重要的知识空白。除非使用适当的设计和分析方法来测量OA中声称的风险因素的密切影响（即，最常见的关节炎形式），大量的研究资金、时间和努力可能被耗尽，而不能为临床建议和生物学见解提供有用的证据。为了有效地描述和克服与评估OA进展的所谓风险因素所带来的风险相关的方法学挑战，我们将使用OAI队列研究先前报告的矛盾结果，以实现以下特定目标：（1）确定和量化指数事件偏倚，并阐明风险因素矛盾背后的核心机制;（2）提供方法学补救措施，包括敏感性分析、暴露状态变化的影响评估以及因果建模方法，以评估预期风险因素对膝关节骨性关节炎进展的无偏影响。此外，我们将在这一关键研究背景下证明某些暴露的固有局限性。通过利用我们在相关先进方法学和临床主题方面的专业知识，以及我们对OAI数据库的优势和实践知识，拟议的项目将填补我们对膝关节OA进展风险因素密切影响的理解方面的关键空白，并提供风湿病学和许多其他学科循证医学所需的关键方法学进展。