Nova Andrea, Fazia Teresa, Di Caprio Giovanni, Gentilini Davide, Bernardinelli Luisa, Bergamaschi Roberto
Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
Bioinformatics and Statistical Genomic Unit, IRCCS Istituto Auxologico Italiano, Milan, Italy.
Ann Clin Transl Neurol. 2025 Oct;12(10):1952-1961. doi: 10.1002/acn3.70119. Epub 2025 Jun 26.
Multiple sclerosis (MS) patients often experience a higher incidence of clinical conditions before diagnosis, suggesting a prodromal phase. However, their predictive value and temporal trajectories remain underexplored. We investigated these aspects using the large UK Biobank's population-based cohort, which provided clinical history through ICD-10 diagnosis codes.
We assessed associations between 600 clinical conditions and MS risk in 477,421 individuals using Cox models adjusted for demographics, smoking, and MS polygenic risk score (MS-PRS). Statistically significant conditions were included in a LASSO Cox regression (five-fold cross-validation on 70% training set) to identify key predictors, with performance assessed by the C-index and age-dependent area under the curve (AUC) in the 30% test set. Lastly, temporal trajectories of MS-associated conditions were analyzed in MS cases.
We identified 192 conditions associated with MS, of which only ~20% were onset symptoms. Integrating these conditions into a predictive model already including demographics and smoking, improved the C-index from 0.65 to 0.71. Among the 30 model-selected best predictors, ~25% were prodromal conditions, including neuromuscular diseases, thromboembolism, and depression which typically occurred more than five years before MS diagnosis. Including MS-PRS further increased the C-index to 0.78, with an age-dependent AUC exceeding 0.80 in individuals over 50 years. Trajectory analysis highlighted migraine as a common early diagnosis, often followed by hypertension, depression, and dorsalgia.
Our findings highlight early conditions and diagnostic trajectories of MS, supporting the existence of a prodromal phase. These insights could improve MS prediction and facilitate earlier detection, particularly for late-onset cases.
多发性硬化症（MS）患者在诊断前常出现较高的临床疾病发生率，提示存在前驱期。然而，它们的预测价值和时间轨迹仍未得到充分研究。我们使用英国生物银行基于人群的大型队列研究了这些方面，该队列通过国际疾病分类第10版（ICD - 10）诊断编码提供临床病史。
我们使用针对人口统计学、吸烟和MS多基因风险评分（MS - PRS）进行调整的Cox模型，评估了477421名个体中600种临床疾病与MS风险之间的关联。具有统计学意义的疾病被纳入LASSO Cox回归（在70%训练集上进行五折交叉验证）以识别关键预测因素，并通过30%测试集中的C指数和年龄依赖性曲线下面积（AUC）评估性能。最后，对MS病例中与MS相关疾病的时间轨迹进行了分析。
我们确定了192种与MS相关的疾病，其中只有约20%是发病症状。将这些疾病纳入已包括人口统计学和吸烟情况的预测模型中，C指数从0.65提高到了0.71。在30个模型选择的最佳预测因素中，约25%是前驱疾病，包括神经肌肉疾病、血栓栓塞和抑郁症，这些疾病通常在MS诊断前五年以上出现。纳入MS - PRS进一步将C指数提高到0.78，50岁以上个体的年龄依赖性AUC超过0.80。轨迹分析突出了偏头痛是常见的早期诊断疾病，随后常伴有高血压、抑郁症和背痛。
我们的研究结果突出了MS的早期疾病和诊断轨迹，支持前驱期的存在。这些见解可以改善MS的预测并促进早期检测，特别是对于晚发型病例。
