ARTEMIS: An independently validated prognostic prediction model of breast cancer incorporating epigenetic biomarkers with main effects and gene-gene interactions,Journal of Advanced Research

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ARTEMIS: An independently validated prognostic prediction model of breast cancer incorporating epigenetic biomarkers with main effects and gene-gene interactions
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2024-08-11 , DOI: 10.1016/j.jare.2024.08.015
Maojie Xue ₁ , Ziang Xu ₂ , Xiang Wang ₁ , Jiajin Chen ₃ , Xinxin Kong ₁ , Shenxuan Zhou ₁ , Jiamin Wu ₁ , Yuhao Zhang ₄ , Yi Li ₅ , David C Christiani ₆ , Feng Chen ₇ , Yang Zhao ₇ , Ruyang Zhang ₈

Affiliation

Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, Jiangsu 210029, China; Department of Oral Special Consultation, Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital of Xiamen University, Xiamen, Fujian 361006, China.
Department of General Biology, Eberly College of Science, Pennsylvania State University, Pennsylvania 16802, USA.
Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
Pulmonary and Critical Care Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Jiangsu 211166, China.
Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Jiangsu 211166, China; Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu 213164, China.

Introduction

Breast cancer, a heterogeneous disease, is influenced by multiple genetic and epigenetic factors. The majority of prognostic models for breast cancer focus merely on the main effects of predictors, disregarding the crucial impacts of gene-gene interactions on prognosis.

Objectives

Using DNA methylation data derived from nine independent breast cancer cohorts, we developed an independently validated prognostic prediction model of breast cancer incorporating epigenetic biomarkers with main effects and gene-gene interactions (ARTEMIS) with an innovative 3-D modeling strategy. ARTEMIS was evaluated for discrimination ability using area under the receiver operating characteristics curve (AUC), and calibration using expected and observed (E/O) ratio. Additionally, we conducted decision curve analysis to evaluate its clinical efficacy by net benefit (NB) and net reduction (NR). Furthermore, we conducted a systematic review to compare its performance with existing models.

Results

ARTEMIS exhibited excellent risk stratification ability in identifying patients at high risk of mortality. Compared to those below the 25th percentile of ARTEMIS scores, patients with above the 90th percentile had significantly lower overall survival time (HR = 15.43, 95% CI: 9.57–24.88, P = 3.06 × 10^-29). ARTEMIS demonstrated satisfactory discrimination ability across four independent populations, with pooled AUC_3-year = 0.844 (95% CI: 0.805–0.883), AUC_5-year = 0.816 (95% CI: 0.775–0.857), and C-index = 0.803 (95% CI: 0.776–0.830). Meanwhile, ARTEMIS had well calibration performance with pooled E/O ratio 1.060 (95% CI: 1.038–1.083) and 1.090 (95% CI: 1.057–1.122) for 3- and 5-year survival prediction, respectively. Additionally, ARTEMIS is a clinical instrument with acceptable cost-effectiveness for detecting breast cancer patients at high risk of mortality (P_t = 0.4: NB_3-year = 19‰, NB_5-year = 62‰; NR_3-year = 69.21%, NR_5-year = 56.01%). ARTEMIS has superior performance compared to existing models in terms of accuracy, extrapolation, and sample size, as indicated by the systematic review. ARTEMIS is implemented as an interactive online tool available at http://bigdata.njmu.edu.cn/ARTEMIS/.

Conclusion

ARTEMIS is an efficient and practical tool for breast cancer prognostic prediction.

中文翻译：

ARTEMIS：一种经过独立验证的乳腺癌预后预测模型，结合了表观遗传生物标志物与主要效应和基因-基因相互作用

介绍

乳腺癌是一种异质性疾病，受多种遗传和表观遗传因素的影响。大多数乳腺癌预后模型仅关注预测因子的主要影响，而忽略了基因-基因相互作用对预后的关键影响。

目标

使用来自 9 个独立乳腺癌队列的 DNA 甲基化数据，我们开发了一个独立验证的 Breast 癌症预后预测模型，该模型结合了具有 main 效应和基因-基因 i相互作用的 epigenetic 生物标志物 s（ARTEMIS）的 100 个示例。使用受试者工作特征曲线下面积（AUC）评估 ARTEMIS 的鉴别能力，并使用预期和观察（E/O）比率进行校准。此外，我们进行了决策曲线分析，通过净收益（NB）和净减少（NR）评估其临床疗效。此外，我们进行了一项系统评价，将其性能与现有模型进行比较。

结果

ARTEMIS 在识别高死亡风险患者方面表现出优异的风险分层能力。与低于 ARTEMIS 评分第 25 个百分位数的患者相比，高于第 90 个百分位数的患者总生存时间显着缩短（HR = 15.43,95% CI：9.57-24.88，P = 3.06 × ^10-29）。ARTEMIS 在四个独立人群中表现出令人满意的鉴别能力，合并_{AUC 3 年} = 0.844 （95% CI： 0.805–0.883），AUC_{5 年} = 0.816 （95% CI： 0.775–0.857），C 指数 = 0.803 （95% CI： 0.776–0.830）。同时，ARTEMIS 具有良好的校准性能，3 年和 5 年生存预测的合并 E/O 比分别为 1.060 （95% CI： 1.038–1.083）和 1.090 （95% CI： 1.057–1.122）。此外，ARTEMIS 是一种具有可接受成本效益的临床工具，用于检测高死亡风险的乳腺癌患者（P_t = 0.4： NB_{3 年} = 19‰，NB_{5 年} = 62‰;NR_{3 年} = 69.21%，NR_{5 年} = 56.01%）。正如系统评价所表明的那样，与现有模型相比，ARTEMIS 在准确性、外推和样本量方面具有更好的性能。ARTEMIS 是作为 http://bigdata.njmu.edu.cn/ARTEMIS/ 提供的交互式在线工具实现的。

结论

ARTEMIS 是一种高效且实用的乳腺癌预后预测工具。

更新日期：2024-08-11

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