Supplementary Material for: Bias in Peripheral Depression Biomarkers

<b><i>Background:</i></b> To aid in the differentiation of individuals with major depressive disorder (MDD) from healthy controls, numerous peripheral biomarkers have been proposed. To date, no comprehensive evaluation of the existence of bias favoring the publication of significant results or inflating effect sizes has been conducted. <b><i>Methods:</i></b> Here, we performed a comprehensive review of meta-analyses of peripheral nongenetic biomarkers that could discriminate individuals with MDD from nondepressed controls. PubMed/MEDLINE, EMBASE, and PsycINFO databases were searched through April 10, 2015. <b><i>Results:</i></b> From 15 references, we obtained 31 eligible meta-analyses evaluating biomarkers in MDD (21,201 cases and 78,363 controls). Twenty meta-analyses reported statistically significant effect size estimates. Heterogeneity was high (<i>I</i>^<i>2</i> ≥50%) in 29 meta-analyses. We plausibly assumed that the true effect size for a meta-analysis would equal the one of its largest study. A significant summary effect size estimate was observed for 20 biomarkers. We observed an excess of statistically significant studies in 21 meta-analyses. The summary effect size of the meta-analysis was higher than the effect of its largest study in 25 meta-analyses, while 11 meta-analyses had evidence of small-study effects. <b><i>Conclusions:</i></b> Our findings suggest that there is an excess of studies with statistically significant results in the literature of peripheral biomarkers for MDD. The selective publication of ‘positive studies' and the selective reporting of outcomes are possible mechanisms. Effect size estimates of meta-analyses may be inflated in this literature.

**<i>研究背景：</i>** 为辅助区分重度抑郁症（Major Depressive Disorder, MDD）患者与健康对照者，学界已提出众多外周生物标志物（peripheral biomarkers）。截至目前，尚无研究对"倾向于发表阳性结果或夸大效应量的偏倚"开展全面评估。

**<i>研究方法：</i>** 本研究针对可区分MDD患者与非抑郁对照者的外周非遗传生物标志物（peripheral nongenetic biomarkers）的荟萃分析（meta-analysis）开展全面综述。检索了PubMed/MEDLINE、EMBASE及PsycINFO数据库，检索时限截至2015年4月10日。

**<i>研究结果：</i>** 从15篇参考文献中，共纳入31项符合标准的MDD生物标志物相关荟萃分析，涉及21201例病例与78363例对照。其中20项荟萃分析报告了具有统计学意义的效应量（effect size）估计值。29项荟萃分析存在较高异质性（heterogeneity）（I²≥50%）。本研究合理假设：某荟萃分析的真实效应量等同于其纳入的最大规模研究的效应量。20项生物标志物的汇总效应量估计值具有统计学意义。21项荟萃分析中存在阳性研究数量过剩的情况。25项荟萃分析的汇总效应量高于其纳入的最大规模研究的效应量，另有11项荟萃分析存在小样本研究效应（small-study effects）的证据。

**<i>研究结论：</i>** 本研究结果显示，在MDD外周生物标志物相关文献中，存在过多具有统计学显著性结果的研究。"阳性研究的选择性发表"与"结局的选择性报告"是可能的潜在机制。此类文献中的荟萃分析效应量估计值或存在夸大情况。