瑞士，星期四，2020年4月2日4:30 PM 欧洲中部时间*
作为全球首家发现COVID-19精准病因和病理1的AI生物医药公司，我们致力于公益发布Demiurge的COVID-19科学发现并公开验证Demiurge的COVID-19临床预测。
新冠病毒（SARS-CoV-2）在进入宿主细胞后抑制ACE2表达量是我们基于精准病理模型做出的一个与大多数专家意见相反的临床预测。因为新冠病毒一方面依赖ACE2受体实现入侵宿主细胞2，
另一方面又抑制ACE2表达量以实现病毒复制1，这两者表面上看是相互矛盾的，但是：
“进入宿主细胞后，SARS-CoV-2劫持了表达ACE2的宿主细胞的PI3K信号通路，以驱动病毒复制。此外，SARS-CoV-2增强了宿主细胞中ACE2基因的远端启动子的激活，从而进一步抑制了宿主细胞中ACE2的表达并破坏了宿主细胞正常的维持体内平衡的功能。” 1
“ACE2远端启动子转录本（DPT）是抑制ACE2表达的进化上保守的结合基序，而ACE2近端启动子转录本（PPT）是激发ACE2表达的进化上保守的结合基序。 DPT / PPT比值具有组织特异性，肺中的DPT显著大于PPT（> 49倍），而肾脏、脑和心脏中的PPT显著大于DPT（> 20倍）。不寻常的是，ACE2转录水平主要是由 ACE2 DPT / PPT比值而非ACE2基因型决定的。”1
基于Demiurge关于COVID-19的精准病因和病理模型，我们还公布了关于ACE2表达量的进一步临床预测，即ACE2表达量下降是驱动COVID-19临床进展的核心因素3：
“COVID-19的临床结果是由 (1)组织特异性和患者特异性的ACE2缺陷引起的损伤和 (2)先天性-适应性免疫失衡引起的淋巴细胞减少症所共同驱动的。” 1
“因此，肺部极易受到COVID-19引发的ACE2缺陷的影响，并且肺部损伤是COVID-19的主要临床特征。” 1
在以上预测于2020年3月7日3首次公布时，绝大多数专家持相反的观点：东亚人与比欧美人相比，ACE2表达水平更低，因此更容易被SARS-CoV-2入侵和感染。于2020年2月24日发布的人类基因组数据显示，东亚人在与ACE2高表达相关的eQTL变体中具有更高的等位基因表达频率4：
数据验证
可以通过分析特定人群的ACE2基因组数据与特定人群的COVID-19死亡率数据之间的关系来验证Demiurge以上两个与大多数专家观点相反的前瞻性临床预测。
截至2020年4月1日，有14个国家报告了7000多例确诊的COVID-19病例。根据图14的定义，可将这些国家分为四个特定区域，即中国（CHN），非中国东亚（EAS），欧洲（EUR）和美洲（AMR）5：
截至2020年4月1日，在这14个国家中，每百万人口中已确认的COVID-19死亡总数为：
群体协方差（-4.13）和Pearson相关性（-0.86）均清楚表明，特定人群的ACE2表达量与特定人群的COVID-19死亡率呈强负相关的关系。
换句话说，基线ACE2 mRNA水平较高的人群（例如东亚人）不太容易受到ACE2缺乏所驱动的COVID-19临床结果，而基线ACE2 mRNA水平较低的人群（例如欧美人）会更容易受到由ACE2缺乏所驱动的COVID-19临床结果。
因此，真实世界的数据已经验证了我们基于精准病理模型做出的与主流观点相反的临床预测—即ACE2表达量下降是驱动COVID-19临床进展的关键因素3。
现实世界的数据进一步证明，对于缺少临床数据和开发时间的新型疾病，基于AI的疾病建模和临床预测与传统方法相比，可提供更好的预测能力和解释能力。
预测性生物标记物
基于上述经过验证的临床预测，我们因此进一步建议ACE2 的mRNA或蛋白表达水平可以作为COVID-19临床结果的预测生物标记物。
入院的COVID-19患者可以根据其ACE2 mRNA水平在入院时进行分诊，因此医院可以提前准备好对应分诊患者临床进展所需的相关医疗资源。
疑似的COVID-19患者，在接受SARS-CoV-2 核酸检测的同时，可以接受ACE2 mRNA的检测进行分诊。
优先开发重症治疗方案
与主流观点相反，事实上COVID-19在欧美人中的临床进展比东亚人要快得多，临床症状比东亚人要重得多，因为欧美人遗传的ACE2表达水平要比东亚人低得多。
正如Demiurge的精准病因和病理模型1表明，COVID-19依赖抑制ACE2表达以维持病毒复制，因此基准ACE2表达量低得多的欧美人比东亚人更容易产生严重的临床结果。
因此，除了增加口罩和呼吸机的供应之外，与亚洲国家相比，对于欧美国家来说，优先发现和开发针对重症患者的有效且价格低廉的治疗方法更为重要和紧迫。
COVID-19的重症患者人群的死亡率为61.5％7，其中败血症（100％）、呼吸衰竭（98％）和急性呼吸窘迫综合征（93％）是致死的三大临床结果8，人群特异性较低的基线ACE2表达水平，欧美国家的年轻人中会出现比亚洲国家更多的COVID-19的重症患者。
因此，欧美国家更需要优先发现强效廉价的重症治疗方案，以降低COVID-19的死亡率。
参考文献
1. Lovetrue, B. The AI-Discovered Aetiology of COVID-19 and Rationale of the Irinotecan+Etoposide Combination Therapy for Critically Ill COVID-19 Patients. (2020). doi:10.20944/PREPRINTS202003.0341.V1
2. Wrapp, D. et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science (80-. ). 367, 1260–1263 (2020).
3. Demiurge AI Discovers the Complete Aetiology of COVID-19 and the Optimal Treatment Strategy for COVID-19. Available at: http://www.prweb.com/releases/demiurge_ai_discovers_the_complete_aetiology_of_covid_19_and_the_optimal_treatment_strategy_for_covid_19/prweb16966447.htm. (Accessed: 1st April 2020)
4. Cao, Y. et al. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov. 6, 4–7 (2020).
5. COVID-19 Map - Johns Hopkins Coronavirus Resource Center. Available at: https://coronavirus.jhu.edu/map.html. (Accessed: 1st April 2020)
6. Coronavirus deaths: The stark differences in countries’ case fatality rates, explained - Vox. Available at: https://www.vox.com/2020/4/1/21203198/coronavirus-deaths-us-italy-china-south-korea. (Accessed: 2nd April 2020)
7. Yang, X. et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir. Med. 2600, 1–7 (2020).
8. Zhou, F. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan , China : a retrospective cohort study. Lancet 6736, 1–9 (2020).
关于Demiurge Technologies AG
Demiurge Technologies是一家以研究为基础的AI技术与生物医药公司，致力于将公开的海量生命科学数据转换为精确疾病模型。Demiurge创新地建立了利用全球医药三期临床试验结果预测的准确性来验证并改良精准疾病模型的科学进化闭环。同时Demiurge 致力于将精准疾病模型发现的创新药物进行商业化开发。 Demiurge于2016年开始运营，总部位于瑞士。
AI已成为一种新型强大的技术方法，它可以帮助人类更深入地了解疾病和更快地发现药物。但AI必须经过严格的测试，在公众的监督下证明其价值。Demiurge已经完成了90多个三期临床试验结果的预测，实现了大于80%的准确率。同时，我们在推特（Twitter）上邀请公众参与见证我们对正在进行中的全球新药三期临床试验结果的预测（@DemiurgeTech）。
因此，我们在这里基于AI提出了COVID-19的完整致病机理和最佳治疗方案的科学假设，并公开邀请世界各地验证。Demiurge敦促大众在任何相关临床数据公布之前，不应将任何COVID-19候选治疗方案等同于COVID-19的治疗药物擅自使用。
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* 本文译自于2020年4月2日发布的英文通告“Clinically Validated Pathology-based AI Prediction of ACE2 Expression as A Predictive Biomarker of COVID-19 Mortality.” 中英文通告的最终解释以英文为准。
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