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信息论特征选择和机器学习方法在遗传风险预测模型开发中的应用。

Application of information theoretic feature selection and machine learning methods for the development of genetic risk prediction models.

机构信息

Centre for Genetics and Genomics Versus Arthritis,Centre for Musculoskeletal Research,Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, M13 9PT, UK.

Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London , UK.

出版信息

Sci Rep. 2021 Dec 2;11(1):23335. doi: 10.1038/s41598-021-00854-x.


DOI:10.1038/s41598-021-00854-x
PMID:34857774
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8640070/
Abstract

In view of the growth of clinical risk prediction models using genetic data, there is an increasing need for studies that use appropriate methods to select the optimum number of features from a large number of genetic variants with a high degree of redundancy between features due to linkage disequilibrium (LD). Filter feature selection methods based on information theoretic criteria, are well suited to this challenge and will identify a subset of the original variables that should result in more accurate prediction. However, data collected from cohort studies are often high-dimensional genetic data with potential confounders presenting challenges to feature selection and risk prediction machine learning models. Patients with psoriasis are at high risk of developing a chronic arthritis known as psoriatic arthritis (PsA). The prevalence of PsA in this patient group can be up to 30% and the identification of high risk patients represents an important clinical research which would allow early intervention and a reduction of disability. This also provides us with an ideal scenario for the development of clinical risk prediction models and an opportunity to explore the application of information theoretic criteria methods. In this study, we developed the feature selection and psoriatic arthritis (PsA) risk prediction models that were applied to a cross-sectional genetic dataset of 1462 PsA cases and 1132 cutaneous-only psoriasis (PsC) cases using 2-digit HLA alleles imputed using the SNP2HLA algorithm. We also developed stratification method to mitigate the impact of potential confounder features and illustrate that confounding features impact the feature selection. The mitigated dataset was used in training of seven supervised algorithms. 80% of data was randomly used for training of seven supervised machine learning methods using stratified nested cross validation and 20% was selected randomly as a holdout set for internal validation. The risk prediction models were then further validated in UK Biobank dataset containing data on 1187 participants and a set of features overlapping with the training dataset.Performance of these methods has been evaluated using the area under the curve (AUC), accuracy, precision, recall, F1 score and decision curve analysis(net benefit). The best model is selected based on three criteria: the 'lowest number of feature subset' with the 'maximal average AUC over the nested cross validation' and good generalisability to the UK Biobank dataset. In the original dataset, with over 100 different bootstraps and seven feature selection (FS) methods, HLA_C_*06 was selected as the most informative genetic variant. When the dataset is mitigated the single most important genetic features based on rank was identified as HLA_B_*27 by the seven different feature selection methods, consistent with previous analyses of this data using regression based methods. However, the predictive accuracy of these single features in post mitigation was found to be moderate (AUC= 0.54 (internal cross validation), AUC=0.53 (internal hold out set), AUC=0.55(external data set)). Sequentially adding additional HLA features based on rank improved the performance of the Random Forest classification model where 20 2-digit features selected by Interaction Capping (ICAP) demonstrated (AUC= 0.61 (internal cross validation), AUC=0.57 (internal hold out set), AUC=0.58 (external dataset)). The stratification method for mitigation of confounding features and filter information theoretic feature selection can be applied to a high dimensional dataset with the potential confounders.

摘要

鉴于使用遗传数据的临床风险预测模型的增长,越来越需要使用适当的方法从具有高度冗余性的大量遗传变体中选择最佳数量的特征,这种高度冗余性是由于连锁不平衡(LD)引起的。基于信息论准则的过滤特征选择方法非常适合这种挑战,它可以识别原始变量的一个子集,从而得到更准确的预测。然而,从队列研究中收集的数据通常是具有潜在混杂因素的高维遗传数据,这给特征选择和风险预测机器学习模型带来了挑战。患有银屑病的患者患慢性关节炎(称为银屑病关节炎(PsA))的风险很高。在这群患者中,PsA 的患病率可达 30%,识别高危患者是一项重要的临床研究,这将允许早期干预和减少残疾。这也为我们开发临床风险预测模型提供了一个理想的场景,并为探索信息论准则方法的应用提供了机会。在这项研究中,我们开发了特征选择和银屑病关节炎(PsA)风险预测模型,该模型应用于使用 SNP2HLA 算法推断的 1462 例 PsA 病例和 1132 例皮肤银屑病(PsC)病例的横断面遗传数据集。我们还开发了分层方法来减轻潜在混杂因素特征的影响,并说明了混杂因素会影响特征选择。减轻后的数据集用于训练七个有监督的算法。使用分层嵌套交叉验证随机选择 80%的数据用于训练七个有监督的机器学习方法,随机选择 20%的数据作为内部验证的保留集。然后在包含 1187 名参与者数据的 UK Biobank 数据集和一组与训练数据集重叠的特征中进一步验证风险预测模型。使用曲线下面积(AUC)、准确性、精度、召回率、F1 分数和决策曲线分析(净收益)评估这些方法的性能。基于三个标准选择最佳模型:具有“嵌套交叉验证中最大平均 AUC”的“最小特征子集数量”和对 UK Biobank 数据集的良好通用性。在原始数据集中,有超过 100 个不同的引导程序和七种特征选择(FS)方法,HLA_C_*06 被选为最具信息量的遗传变体。当数据集被减轻时,七种不同的特征选择方法根据等级确定了最重要的单一遗传特征是 HLA_B_*27,这与使用基于回归的方法对该数据进行的先前分析一致。然而,在减轻后,这些单一特征的预测准确性被发现是中等的(AUC=0.54(内部交叉验证),AUC=0.53(内部保留集),AUC=0.55(外部数据集))。基于等级顺序添加其他 HLA 特征可提高随机森林分类模型的性能,其中 Interaction Capping(ICAP)选择的 20 个 2 位特征表现出(AUC=0.61(内部交叉验证),AUC=0.57(内部保留集),AUC=0.58(外部数据集))。用于减轻混杂因素的分层方法和过滤信息论特征选择可以应用于具有潜在混杂因素的高维数据集。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07be/8640070/15e6a07e1792/41598_2021_854_Fig9_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07be/8640070/fb3b3d7bbcd7/41598_2021_854_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07be/8640070/15e6a07e1792/41598_2021_854_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07be/8640070/cd2bceeb3d0c/41598_2021_854_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07be/8640070/f4bab7956888/41598_2021_854_Fig2_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07be/8640070/fa22008c9e4d/41598_2021_854_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07be/8640070/f66d7d046376/41598_2021_854_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07be/8640070/80bb4288d68e/41598_2021_854_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07be/8640070/2d5f6af38e79/41598_2021_854_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07be/8640070/fb3b3d7bbcd7/41598_2021_854_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/07be/8640070/15e6a07e1792/41598_2021_854_Fig9_HTML.jpg

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