用于从常染色体、X 连锁和 Y 连锁孟德尔疾病的家族表型推断个体基因型的 ProbLog 程序
A ProbLog program to infer individual genotypes from familial phenotypes in autosomal, X-linked, and Y-linked Mendelian disorders
中文总结 AI 辅助
研究旨在从家族表型推断个体基因型，提出 ProbLog 概率逻辑编程算法，能推导基因多代遗传概率，可利用家族表型知识区分不同连锁疾病，开源工具获相同结果，强调为相关任务提供可解释方法的重要性。
中文摘要 AI 辅助
在疾病预防的遗传咨询中，自动重建患者家族病史是一项常见挑战。家族病史通常针对特定孟德尔（单基因）疾病子集确定，并根据基因所在染色体分为常染色体、X 连锁或 Y 连锁三类。孟德尔遗传定律允许对单基因疾病的遗传进行简单概率建模。遗传咨询师利用患者家族病史和孟德尔定律评估先天性疾病的遗传风险。我们提出了一种 ProbLog 中的概率逻辑编程算法，用于推导具有两个等位基因的基因在多代中的基因型和表型遗传概率。用户可输入患者及其家族的基因型和表型，自动确定最可能的遗传家族病史。我们通过文献和遗传咨询手册中的患者谱系实例说明了 ProbLog 模型。结果表明，我们的方法能从家族基因型知识中正确推断个体基因型概率，与 pedprobr 工具结果相同。但与 pedprobr 不同，我们的方法能利用家族表型知识，还能通过直观逻辑建模直接区分常染色体、X 连锁和 Y 连锁疾病。我们在 GitHub 上免费开源了 ProbLog 工具。我们得出结论，为临床医生可能想用专有软件执行的任务提供可解释的形式化方法很重要。
英文摘要
The automated reconstruction of patient family history is a common challenge in genetic counseling for disease prevention. Such a family history is usually determined for a particular subset of diseases that are Mendelian, i.e. monogenic, and classified into three categories depending on the chromosome the gene is located: autosomal, X-linked or Y-linked. Mendel's inheritance laws allow for simple probabilistic modeling of the genetic transmission of monogenic disorders. Genetic counsellors use knowledge about the patient's family history and Mendelian laws for assessing risks of transmitting or inheriting congenital conditions. We present mendelprob.pl, a probabilistic logic programming algorithm in ProbLog for deriving probabilities of inheritance of genotypes and phenotypes for genes with two alleles through multiple generations. In particular, the user can input genotypes and phenotypes for a patient and its family, and automatically determine the most probable genetic family history. We illustrate the ProbLog model on practical examples of patient pedigrees from the literature and from a genetic counseling handbook. We show that our method correctly infers probability of individual genotypes from knowledge about familial genotypes, yielding the same results as tool pedprobr. However, unlike pedprobr, our approach can exploit knowledge about familial phenotypes. It can also directly distinguish between autosomal, X-linked, and Y-linked disorders, using its intuitive logical modelling. We provide our ProbLog tool for free and open-source on GitHub, making it easily available for genetic counsellors. We conclude on the importance of providing explainable formal methods for a task that clinicians might want to perform using proprietary software.
