In this study we examine the instrument selection strategies currently used throughout the type 2 diabetes and HbA1c Mendelian randomization (MR) literature. We then argue for a more integrated and thorough approach, providing a framework to do this in the context of HbA1c and diabetes. We conducted a literature search for MR studies that have instrumented diabetes and/or HbA1c. We also used data from the UK Biobank (UKB) (N = 349,326) to calculate instrument strength metrics that are key in MR studies (the F statistic for average strength and R2 for total strength) with two different methods (“individual-level data regression” and Cragg-Donald formula). We used a 157–single nucleotide polymorphism (SNP) instrument for diabetes and a 51-SNP instrument (with partition into glycemic and erythrocytic as well) for HbA1c. Our literature search yielded 48 studies for diabetes and 22 for HbA1c. Our UKB empirical examples showed that irrespective of the method used to calculate metrics of strength and whether the instrument was the main one or included partition by function, the HbA1c genetic instrument is strong in terms of both average and total strength. For diabetes, a 157-SNP instrument was shown to have good average strength and total strength, but these were both substantially lesser than those of the HbA1c instrument. We provide a careful set of five recommendations to researchers who wish to genetically instrument type 2 diabetes and/or HbA1c. In MR studies of glycemia, investigators should take a more integrated approach when selecting genetic instruments, and we give specific guidance on how to do this.

中文翻译：

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2 型糖尿病和 HbA1c 孟德尔随机研究中遗传仪器选择指南：采用综合方法


在本研究中，我们研究了目前 2 型糖尿病和 HbA1c 孟德尔随机化 (MR) 文献中使用的仪器选择策略。然后，我们主张采用更综合、更彻底的方法，提供一个在 HbA1c 和糖尿病背景下实现这一目标的框架。我们对检测糖尿病和/或 HbA1c 的 MR 研究进行了文献检索。我们还使用来自英国生物银行 (UKB) (N = 349,326) 的数据，通过两种不同的方法（“个体水平数据”）计算 MR 研究中关键的仪器强度指标（平均强度的 F 统计量和总强度的 R2）回归”和克拉格-唐纳德公式）。我们使用 157-单核苷酸多态性 (SNP) 仪器检测糖尿病，使用 51-SNP 仪器（也分为血糖和红细胞）检测 HbA1c。我们的文献检索获得了 48 项糖尿病研究和 22 项 HbA1c 研究。我们的 UKB 经验示例表明，无论计算强度指标的方法如何，也无论该工具是主要工具还是按功能划分，HbA1c 遗传工具在平均强度和总强度方面都很强。对于糖尿病，157-SNP 仪器显示出良好的平均强度和总强度，但这些均明显低于 HbA1c 仪器。我们为希望对 2 型糖尿病和/或 HbA1c 进行基因检测的研究人员提供了一套仔细的五项建议。在血糖的 MR 研究中，研究人员在选择遗传仪器时应采取更加综合的方法，我们就如何做到这一点提供了具体指导。