DataSheet1_A Case Study on Integrating a New Key Event Into an Existing Adverse Outcome Pathway on Oxidative DNA Damage: Challenges and Approaches in a Data-Rich Area.PDF

Adverse outcome pathways (AOPs) synthesize toxicological information to convey and weigh evidence in an accessible format. AOPs are constructed in modules that include key events (KEs) and key event relationships (KERs). This modular structure facilitates AOP expansion and network development. AOP development requires finding relevant information to evaluate the weight of evidence supporting each KER. To do this, the use of transparent/reproducible search methods, such as systematic review (SR), have been proposed. Applying SR to AOP development in a data-rich area is difficult as SR requires screening each article returned from a search. Here we describe a case study to integrate a single new KE into an existing AOP. We explored the use of SR concepts and software to conduct a transparent and documented literature search to identify empirical data supporting the incorporation of a new KE, increase in cellular reactive oxygen species (ROS), upstream of an existing AOP: “Oxidative DNA Damage Leading to Chromosomal Aberrations and Mutations”. Connecting this KE to the AOP is supported by the development of five new KERs, the most important being the first adjacent KER (increase in ROS leading to oxidative DNA damage). We initially searched for evidence of all five KERs and screened 100 papers to develop a preliminary evidence map. After removing papers not containing relevant data based on our Population, Exposure, Comparator and Outcome statement, 39 articles supported one or more KERs; these primarily addressed temporal or dose concordance of the non-adjacent KERs with limited evidence supporting the first adjacent KER. We thus conducted a second focused set of searches using search terms for specific methodologies to measure these first two KEs. After screening, 12 articles were identified that contained quantitative evidence supporting the first adjacent KER. Given that integrating a new KE into an existing AOP requires the development of multiple KERs, this approach of building a preliminary evidence map, focusing evidence gathering on the first adjacent KER, and applying reproducible search strategies using specific methodologies for the first adjacent KER, enabled us to prioritize studies to support expansion of this data-rich AOP.

不良结局途径（Adverse outcome pathways, AOPs）可整合毒理学信息，以易懂的形式呈现证据并权衡其权重。AOPs采用模块化结构构建，包含关键事件（key events, KEs）与关键事件关系（key event relationships, KERs）。该模块化结构便于AOP的扩展与网络构建。
AOP的开发需检索相关信息，以评估支撑每项关键事件关系的证据权重。对此，学界已提出采用透明、可复现的检索方法，例如系统综述（systematic review, SR）。
在数据富集领域将系统综述应用于AOP开发存在难点，因系统综述需对检索返回的每一篇文献进行筛选。本研究介绍一则案例，旨在将单个新关键事件整合至已有的AOP中。我们探索了利用系统综述的理念与软件，开展透明且可溯源的文献检索，以识别可支撑将新关键事件——细胞活性氧（cellular reactive oxygen species, ROS）水平升高——整合至现有AOP“氧化性DNA损伤导致染色体畸变与突变”上游的实证数据。
将该关键事件与该AOP相连，需构建5项全新的关键事件关系，其中最为核心的是首个相邻关键事件关系（ROS水平升高导致氧化性DNA损伤）。我们最初针对全部5项关键事件关系检索证据，筛选100篇文献以构建初步证据图谱。在依据我们制定的研究对象、暴露因素、对照设置与结局指标（Population, Exposure, Comparator and Outcome）准则剔除不含相关数据的文献后，最终有39篇文献可支撑至少1项关键事件关系；此类文献主要聚焦于非相邻关键事件关系的时间或剂量一致性，针对首个相邻关键事件关系的证据较为有限。
因此，我们开展了第二轮针对性检索，使用针对检测前两项关键事件的特定方法学检索词。经筛选后，共识别出12篇包含定量证据的文献，可支撑首个相邻关键事件关系。
鉴于将新关键事件整合至现有AOP需构建多项关键事件关系，本研究采用的先构建初步证据图谱、将证据收集聚焦于首个相邻关键事件关系、并针对首个相邻关键事件关系采用基于特定方法学的可复现检索策略的方法，使我们能够优先筛选相关研究，以支撑该数据富集型AOP的扩展。