文献复现 | The support of human genetic evidence for approved drug indications
文献复现是非常重要的技能，能迅速模仿顶尖的研究也是不错的能力，中二的叫法就是“写轮眼”。
核心：
- 熟悉数据
- 大致知道基本的算法
- 知道分析核心的目的
复现第一篇：
The support of human genetic evidence for approved drug indications - NG
核心结论：
- drug development：the proportion of drug mechanisms with direct genetic support increases significantly across the drug development pipeline, from 2.0% at the preclinical stage to 8.2% among mechanisms for approved drugs, and varies dramatically among disease areas.【越进入FDA后期的gene，其有direct genetic evidence的比例就越高】
- drug discovery：selecting genetically supported targets could double the success rate in clinical development【核心结论，表述很清晰】
核心：一个卡方检验，所有的gene可以分为四类。
| genetic evidence | None | |
| FDA approval | a | b |
| None | c | d |
指导意义：以后你找target，就优先去找有genetic evidence的gene，这样成功的概率更高。
知识点checkpoint：
- preclinical and clinical phases to launched drugs【一个药物获得FDA批准的大致流程】
- GWASdb（已关闭）和GWAS Catalog的数据类型，就是GWAS的lead SNP，每一行数据就是一个association
- Medical Subject Heading (MeSH) terms - treeView
数据：
- In the final data set, we had 18,566 genetic associations to 434 MeSH traits that mapped to 6,120 genes outside of the extended major histocompatibility complex (xMHC), with a total of 13,855 gene-trait combinations.
- Genes involved in rare, mendelian traits were derived from Online Mendelian Inheritance in Man (OMIM), providing a data set with 1,898 genes annotated to affect 2,145 traits with MeSH terms, for a total of 2,627 gene-trait combinations.
- 22,270 drugs known to modulate 1,824 human non-xMHC drug targets for 705 indications, giving a total of 19,085 target-indication pairs
附件数据：
具体细节：
- SNP是如何link到基因的？
- 一个基因是如何算有approve的drug？【这个维度到底是在考虑什么？假设1.进入FDA环节后审批success或fail的；假设2.被选择进入临床实验或未被选入。】
- Over a quarter of drugs that enter clinical development fail because they are ineffective. 逻辑上，应该证明有genetic evidence的更容易成功，那范围应该是所有进入FDA申请的基因（三期结果已经公布），成功vs失败。
indications：适应症
drug repositioning：第一反应pleiotropy
clinically successful drug mechanisms (the protein product modulated to elicit a clinical response)
druggable genes, that having binding domains for small molecule drugs (n = 2,639)
Residual variance intolerance score (RVIS)
