Abstract：
300 million people live with at least one of 6,000 rare diseases worldwide. However, rare disease research is not always reviewed with scrutiny, making it susceptible to what the author refers to as nontransparent science. Nontransparent science can obscure animal model flaws, misguide medicine regulators and drug developers, delay or frustrate orphan drug development, or waste limited resources for rare disease research. Flawed animal models not only lack pharmacologic relevance, but also give rise to issue of clinical translatability. Sadly, these consequences and risks are grossly overlooked. Nontransparency in science can take many forms, such as premature publication of animal models without clinically significant data, not providing corrections when flaws to the model are discovered, lack of warning of critical study limitations, missing critical control data, questionable data quality, surprising results without a sound explanation, failure to rule out potential factors which may affect study conclusions, lack of sufficient detail for others to replicate the study, dubious authorship and study accountability. Science has no boarders, neither does nontransparent science. Nontransparent science can happen irrespective of the researcher\'s senority, institutional affiliation or country. As a patient-turned researcher suffering from Bietti crystalline dystrophy (BCD), I use BCD as an example to analyze various forms of nontransparent science in rare disease research. This article analyzes three papers published by different research groups on Cyp4v3-/-, high-fat diet (HFD)-Cyp4v3-/-, and Exon1-Cyp4v3-/- mouse models of BCD. As the discussion probes various forms of nontransparent science, the flaws of these knockout mouse models are uncovered. These mouse models do not mimic BCD in humans nor do they address the lack of Cyp4v3 (murine ortholog of human CYP4V2) expression in wild type (WT) mouse retina which is markedly different from CYP4V2 expression in human retina. Further, this article discusses the impact of nontransparent science on drug development which can lead to significant delays ultimately affecting the patients. Lessons from BCD research can be helpful to all those suffering from rare diseases. As a patient, I call for transparent science in rare disease research.
摘要：
3亿人生活在全球6,000种罕见疾病中的至少一种。然而,罕见疾病研究并不总是经过审查，使它容易受到作者所说的非透明科学的影响。不透明的科学可以掩盖动物模型的缺陷，误导药品监管机构和药物开发商，延迟或阻碍孤儿药物的开发，或者浪费有限的资源进行罕见疾病研究。有缺陷的动物模型不仅缺乏药理学相关性，但也引起了临床可译性的问题。可悲的是,这些后果和风险被严重忽视。科学中的不透明可以有多种形式，如过早发表没有临床重要数据的动物模型，当发现模型的缺陷时不提供修正，缺乏关键研究局限性的警告，缺少关键控制数据，数据质量有问题，令人惊讶的结果没有合理的解释，未能排除可能影响研究结论的潜在因素，缺乏足够的细节让其他人复制这项研究，可疑的作者身份和研究责任。科学没有寄宿生，非透明科学也没有。不透明的科学可以发生，无论研究人员的资历如何，机构隶属关系或国家。作为一名患有Bietti晶体营养不良（BCD）的患者研究人员，我以BCD为例，分析罕见疾病研究中各种形式的非透明科学。本文分析了不同研究小组在Cyp4v3-/-上发表的三篇论文，高脂饮食（HFD）-Cyp4v3-/-，和Exon1-Cyp4v3-/-BCD小鼠模型。当讨论探讨各种形式的非透明科学时，这些敲除小鼠模型的缺陷被发现。这些小鼠模型在人中不模拟BCD,也不解决在野生型(WT)小鼠视网膜中缺乏Cyp4v3(人CYP4V2的鼠直系同源物)表达的问题,这明显不同于在人视网膜中的CYP4V2表达。Further,本文讨论了非透明科学对药物开发的影响，这可能导致严重的延误，最终影响患者。BCD研究的经验教训对所有患有罕见疾病的人都有帮助。作为一个病人,我呼吁在罕见疾病研究中进行透明的科学。
