Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, United States.
The Jackson Laboratory, Farmington, CT 06032, United States.
EBioMedicine. 2020 Jul;57:102837. doi: 10.1016/j.ebiom.2020.102837. Epub 2020 Jun 18.
Adverse drug reactions (ADRs) are one of the leading causes of morbidity and mortality in health care. Understanding which drug targets are linked to ADRs can lead to the development of safer medicines.
Here, we analyse in vitro secondary pharmacology of common (off) targets for 2134 marketed drugs. To associate these drugs with human ADRs, we utilized FDA Adverse Event Reports and developed random forest models that predict ADR occurrences from in vitro pharmacological profiles.
By evaluating Gini importance scores of model features, we identify 221 target-ADR associations, which co-occur in PubMed abstracts to a greater extent than expected by chance. Amongst these are established relations, such as the association of in vitro hERG binding with cardiac arrhythmias, which further validate our machine learning approach. Evidence on bile acid metabolism supports our identification of associations between the Bile Salt Export Pump and renal, thyroid, lipid metabolism, respiratory tract and central nervous system disorders. Unexpectedly, our model suggests PDE3 is associated with 40 ADRs.
These associations provide a comprehensive resource to support drug development and human biology studies.
This study was not supported by any formal funding bodies.
药物不良反应（ADR）是医疗保健中发病率和死亡率的主要原因之一。了解哪些药物靶点与 ADR 相关，可有助于开发更安全的药物。
在这里，我们分析了 2134 种市售药物常见（非）靶标的体外二次药理学。为了将这些药物与人类 ADR 相关联，我们利用了 FDA 不良事件报告，并开发了随机森林模型，可根据体外药理学特征预测 ADR 的发生。
通过评估模型特征的基尼重要性得分，我们确定了 221 个靶标-ADR 关联，这些关联在 PubMed 摘要中比随机出现的可能性更大。其中包括已建立的关系，例如体外 hERG 结合与心律失常的关联，这进一步验证了我们的机器学习方法。关于胆汁酸代谢的证据支持我们鉴定出胆汁盐输出泵与肾脏、甲状腺、脂质代谢、呼吸道和中枢神经系统疾病之间的关联。出乎意料的是，我们的模型表明 PDE3 与 40 种 ADR 相关。
这些关联为支持药物开发和人类生物学研究提供了全面的资源。
本研究没有得到任何正式资助机构的支持。
