Developing a cluster-based approach for deciphering complexity in individuals with neurodevelopmental differences.
Developing a cluster-based approach for deciphering complexity in individuals with neurodevelopmental differences.
复制标题
DOI：
10.3389/fped.2023.1171920
复制
发表时间：
2023
影响因子：
2.6
通讯作者：
Bolduc, Francois V.
中科院分区：
文献类型：
--
作者：
Cuppens, Tania;Kaur, Manpreet;Kumar, Ajay A.;Shatto, Julie;Ng, Andy Cheuk-Him;Leclercq, Mickael;Reformat, Marek Z.;Droit, Arnaud;Dunham, Ian;Bolduc, Francois V.
关键词：
患有神经发育障碍如全面发育迟缓（GDD）的个体存在基因型和表型异质性。鉴于每个个体遗传病因的相对罕见，这种多样性阻碍了有针对性的干预措施的开发。临床试验的新方法，其中不同但相关的疾病可以通过一种常见的药物治疗，称为篮子试验，这在肿瘤学中显示出益处，但尚未用于GDD。尽管如此，目前仍不清楚GDD患者如何聚类。在这里，我们评估两种不同的方法：凝聚和分裂集群。使用最大的GDD个体队列，即使用系统方法表征的解密发育障碍（DDD），我们从6，588名GDD个体中提取了基因型和表型信息。然后，我们使用k均值聚类（分裂）和层次凝聚聚类（HAC）来识别个体的子组。接下来，我们提取了基因网络和分子功能信息的聚类确定的每种方法。基于GDD个体中鉴定的表型的HAC揭示了16个聚类，每个聚类呈现一个由聚类中大多数个体显示的显性表型，沿着其他次要表型。其中最常见的表型报告延迟的语言，语言缺失，癫痫发作。有趣的是，每个表型簇在分子上包括几个（3-12）基因子网络的更密切相关的基因与不同的分子功能。k-means聚类也分离了携带这些表型的个体，但鉴定的遗传途径与从HAC鉴定的遗传途径不同。我们的研究说明了如何分裂（k-均值）和凝聚聚类，可以用来在未来的篮子试验与GDD的个人组。此外，我们的分析结果表明，表型簇应细分为分子子网络，以增加成功治疗的可能性。最后，可能需要将凝聚性和分裂性聚类相结合，以制定综合治疗方案。
Individuals with neurodevelopmental disorders such as global developmental delay (GDD) present both genotypic and phenotypic heterogeneity. This diversity has hampered developing of targeted interventions given the relative rarity of each individual genetic etiology. Novel approaches to clinical trials where distinct, but related diseases can be treated by a common drug, known as basket trials, which have shown benefits in oncology but have yet to be used in GDD. Nonetheless, it remains unclear how individuals with GDD could be clustered. Here, we assess two different approaches: agglomerative and divisive clustering. Using the largest cohort of individuals with GDD, which is the Deciphering Developmental Disorders (DDD), characterized using a systematic approach, we extracted genotypic and phenotypic information from 6,588 individuals with GDD. We then used a k-means clustering (divisive) and hierarchical agglomerative clustering (HAC) to identify subgroups of individuals. Next, we extracted gene network and molecular function information with regard to the clusters identified by each approach. HAC based on phenotypes identified in individuals with GDD revealed 16 clusters, each presenting with one dominant phenotype displayed by most individuals in the cluster, along with other minor phenotypes. Among the most common phenotypes reported were delayed speech, absent speech, and seizure. Interestingly, each phenotypic cluster molecularly included several (3–12) gene sub-networks of more closely related genes with diverse molecular function. k-means clustering also segregated individuals harboring those phenotypes, but the genetic pathways identified were different from the ones identified from HAC. Our study illustrates how divisive (k-means) and agglomerative clustering can be used in order to group individuals with GDD for future basket trials. Moreover, the result of our analysis suggests that phenotypic clusters should be subdivided into molecular sub-networks for an increased likelihood of successful treatment. Finally, a combination of both agglomerative and divisive clustering may be required for developing of a comprehensive treatment.
登录
查看更多内容
影响因子：
1.8
作者：
Hansen, Berit Hjelde;Oerbeck, Beate;Kristensen, Hanne
通讯作者：
Kristensen, Hanne
影响因子：
4.7
作者：
Androschuk, Alaura;Al-Jabri, Basma;Bolduc, Francois V.
通讯作者：
Bolduc, Francois V.
影响因子：
30.8
作者：
Coe, Bradley P.;Stessman, Holly A. F.;Eichler, Evan E.
通讯作者：
Eichler, Evan E.
影响因子：
6.3
作者：
Emerson, Eric
通讯作者：
Emerson, Eric
影响因子：
14.9
作者：
Köhler S;Gargano M;Matentzoglu N;Carmody LC;Lewis-Smith D;Vasilevsky NA;Danis D;Balagura G;Baynam G;Brower AM;Callahan TJ;Chute CG;Est JL;Galer PD;Ganesan S;Griese M;Haimel M;Pazmandi J;Hanauer M;Harris NL;Hartnett MJ;Hastreiter M;Hauck F;He Y;Jeske T;Kearney H;Kindle G;Klein C;Knoflach K;Krause R;Lagorce D;McMurry JA;Miller JA;Munoz-Torres MC;Peters RL;Rapp CK;Rath AM;Rind SA;Rosenberg AZ;Segal MM;Seidel MG;Smedley D;Talmy T;Thomas Y;Wiafe SA;Xian J;Yüksel Z;Helbig I;Mungall CJ;Haendel MA;Robinson PN
通讯作者：
Robinson PN