Protocol - GeARF

Background: Systematic reviews of genetic association studies play a central role in synthesizing evidence related to gene expression and genome-wide association studies (GWAS). However, the validity and interpretability of their findings depend on appropriate assessment of methodological quality and risk of bias. Existing appraisal tools are not specifically designed to address key sources of bias in genetic association research, limiting their applicability in this field. Objective: To develop and validate a methodological tool for assessing study quality and risk of bias in genetic association studies. Methods: This study follows a modified Delphi design for tool development and validation. Potential domains of bias were initially identified through a structured review of the literature and internal methodological evaluation. A pilot round of the first Delphi iteration was conducted to refine item wording and procedures. Subsequently, national and international experts will be invited to participate in iterative Delphi rounds to rate the relevance and importance of each proposed domain until consensus is achieved. The preliminary version of the tool will then be externally validated by applying it to genetic association studies to assess feasibility and clarity. Finally, the finalized tool will be independently applied by two reviewers within ongoing systematic reviews to evaluate consistency and practical performance. Feedback from each phase will be used to refine, modify, or exclude domains as necessary. Ethics and Registration: The study received ethical approval from an institutional research ethics committee (CAAE 88693925.8.0000.0106; opinion no. 7.665.552). The development of the tool is informed by a previously registered systematic review (PROSPERO CRD420251104461) and is prospectively registered on the Open Science Framework. Expected Outcomes: The final tool is expected to include core domains related to reproducibility, methodological replicability, data availability and storage, linkage disequilibrium, participant selection, statistical analysis, functional relevance, accessibility of study reports, and study design characteristics.