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中医药研究论丛
 221.6 从台湾肝癌发现高比例带有马兜铃酸特有的基因突变特徵研究的新闻事件：以流行病学观点评述
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TJ TCM.22(1) : 63-74, 2019
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从台湾肝癌发现高比例带有马兜铃酸特有的基因突变特徵研究的新闻事件：以流行病学观点评述
Misclassification and Bias Publicized in Research Results of Aristolochic Acid Mutational Signature in Taiwan HCCs
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陈金女1 陈朝荣1,2 赖荣年3,4,5*
1 中国医药大学中西医结合研究所，台中，台湾
2 中国医药大学附设医院蛋白质体核心实验室，台中，台湾
3 中国医药大学中医学系，台中，台湾
4 中国医药大学附设医院中医部，台中，台湾
5 全国中药不良反应通报系统整合及通报教育训练，台北，台湾
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【摘要】
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2017 年10 月国际期刊《科学转译医学》(Science Translational Medicine)报导从台湾肝癌组织检体中发现带有马兜铃酸特有的基因突变特徵(aristolochic acid mutational signature) 的比例并没有因为2003 年法令禁止使用含马兜铃酸植物而下降的研究，这个研究结果引起科学家们怀疑在政府法令禁止後是否民众仍然持续地使用含有马兜铃酸的植物。
依据Rozen 团队主张2003 年之前与2003 年之後马兜铃酸的暴露比例并没有因法令禁止而下降，本文将进行对研究论文「Aristolochic acids andtheir derivatives are widely implicated in liver cancers in Taiwan and throughoutAsia」以2003 年法令禁止使用含马兜铃酸植物为切点，依据其研究目的、研究方法、研究结果及结论以流行病学的观点评述。
如果用2003 年法令禁止使用含马兜铃酸植物的当年做切点来检视台湾肝癌组织检体中发现带有马兜铃酸特有的基因突变特徵，的确比例并没有因为禁止使用而下降。然而经过敏感度分析(sensitivity analysis)，发现当用2006 至2012 年个别的年份当切点来检视时，带有马兜铃酸特有的基因突变特徵比例逐年明显的下降，比较於2003 年以前跟2003 年以後带有马兜铃酸特有的基因突变特徵比例从上升4.6% 至2012 年之前跟2012 年之後下降19.7%，差距有24.3 个百分点。同时，仅用北台湾两个医学中心的肝癌检体推论代表台湾的整体肝癌现况，产生样本不具代表性(representative) 及在缺乏暴露资料的揭露及校正不同国家人口数的情况下，做跨国的比较，亦产生选择性偏差(selection bias)，导致有过度推论之嫌。
评读一篇科学性的论文，应该时时秉持猜测与否证的态度，这一篇刊登在《科学转译医学》的论文，由於错误分类(misclassification) 产生错误的推论，以及用北台湾有限的小样本推论台湾现况，带入选择性偏差的干扰因素(selection bias)。本篇以流行病学观点评述的论文之重要性在於使医疗从业人员学习如何客观的判断一个新的研究成果。
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【关键词】马兜铃酸突变特徵、马兜铃酸、科学论文评论、肝癌
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Chin-Nu Chen1 Chao-Jung Chen1,2 Jung-Nien Lai3,4,5*
1Graduate Institute of Integrated Medicine of China Medical University, Taichung, Taiwan
2Proteomics core lab of China Medical University Hospital, Taichung, Taiwan
3School of Chinese Medicine of College of Chinese Medicine of China Medical University,
Taichung, Taiwan
4Department of Chinese Medicine of China Medical University Hospital, Taichung, Taiwan
5Center for Integrating Taiwan National Adverse Chinese Medicine Reactions Reporting
System and Training on Reporting, Taipei, Taiwan
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【Summary】
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Science Translational Medicine published article “Aristolochic acids andtheir derivatives are widely implicated in liver cancers in Taiwan and throughoutAsia”, has made statements for no difference in the prevalence or in the numbersor proportion of aristolochic acid mutational signatures in Taiwan hepatocellularcarcinomas (HCC) before and after 2003, when Taiwan government legallybanned herbal remedies containing aristolochic acid. This upraises concerns ifpublic is consistency using aristolochic acid contained herbals. The aim of thisarticle is to comment and illustrate underlying bias in this published researchresults.
Authors did not take time trend analysis into consideration in the finalanalysis and reported no percentage difference for the prevalence of aristolochicacid mutational signature by using the cut-point 2003, before and after. However,when two additional alternative cut-points were selected, a decreasing trendfrom 71.4% in 2006 to 63.6% in 2012 for the attributable proportion of detectedAA mutational signature was found. And, cross country comparisons are harshly evaluated by using sample collected from just two north medical centersare bizarre and overestimate its inferences, with poor disclosure of relativeinformation and conspicuously disregard of denominator for each country otherthan Taiwan.
It is suggested to go through the process of conjecture and refutation toscientific articles back and forth, in order to efficiently prevent misclassificationand biases.
Keywords：aristolochic acid, mutational signature, herbal remedies, paper critique, hepatocellular carcinomas
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