Machine learning (ML) is poised as a transformational approach uniquely positioned to discover the hidden biological interactions for better prediction and diagnosis of complex diseases. In this work, we integrated ML-based models for feature selection and classification to quantify the risk of individual susceptibility to asthma using single nucleotide polymorphism (SNP). Random forest (RF) and recursive feature elimination (RFE) algorithm were implemented to identify the SNPs with high implication to asthma. K-nearest neighbor (kNN) and support vector machine (SVM) algorithms were trained to classify the identified SNPs whether associated with non-asthmatic or asthmatic samples. Feature selection step showed that RF outperformed RFE and the feature importance score derived from RF was consistently high for a subset of SNPs, indicating the robustness of RF in selecting relevant features associated with asthma. Model comparison showed that the integration of RF-SVM obtained the highest model performance with an accuracy, precision, and sensitivity of 62.5%, 65.3%, and 69%, respectively, when compared to the baseline, RF-kNN, and an external MeanDiff-kNN models. Furthermore, results show that the occurrence of asthma can be predicted with an Area under the Curve (AUC) of 0.62 and 0.64 for RF-SVM and RF-kNN models, respectively. This study demonstrates the integration of ML models to augment traditional methods in predicting genetic predisposition to multifactorial diseases such as asthma.

Recent studies show the potential of artificial intelligence (AI) as a screening tool to detect COVID-19 pneumonia based on chest x-ray (CXR) images. However, issues on the datasets and study designs from medical and technical perspectives, as well as questions on the vulnerability and robustness of AI algorithms have emerged. In this study, we address these issues with a more realistic development of AI-driven COVID-19 pneumonia detection models by generating our own data through a retrospective clinical study to augment the dataset aggregated from external sources. We optimized five deep learning architectures, implemented development strategies by manipulating data distribution to quantitatively compare study designs, and introduced several detection scenarios to evaluate the robustness and diagnostic performance of the models. At the current level of data availability, the performance of the detection model depends on the hyperparameter tuning and has less dependency on the quantity of data. InceptionV3 attained the highest performance in distinguishing pneumonia from normal CXR in two-class detection scenario with sensitivity (Sn), specificity (Sp), and positive predictive value (PPV) of 96%. The models attained higher general performance of 91-96% Sn, 94-98% Sp, and 90-96% PPV in three-class compared to four-class detection scenario. InceptionV3 has the highest general performance with accuracy, F1-score, and g-mean of 96% in the three-class detection scenario. For COVID-19 pneumonia detection, InceptionV3 attained the highest performance with 86% Sn, 99% Sp, and 91% PPV with an AUC of 0.99 in distinguishing pneumonia from normal CXR. Its capability of differentiating COVID-19 pneumonia from normal and non-COVID-19 pneumonia attained 0.98 AUC and a micro-average of 0.99 for other classes.

Identifying disease-associated susceptibility loci is one of the most pressing and crucial challenges in modeling complex diseases. Existing approaches to biomarker discovery are subject to several limitations including underpowered detection, neglect for variant interactions, and restrictive dependence on prior biological knowledge. Addressing these challenges necessitates more ingenious ways of approaching the “missing heritability” problem. This study aims to discover disease-associated susceptibility loci by augmenting previous genome-wide association study (GWAS) using the integration of random forest and cluster analysis. The proposed integrated framework is applied to a hepatitis B virus surface antigen (HBsAg) seroclearance GWAS data. Multiple cluster analyses were performed on (1) single nucleotide polymorphisms (SNPs) considered significant by GWAS and (2) SNPs with the highest feature importance scores obtained using random forest. The resulting SNP-sets from the cluster analyses were subsequently tested for trait-association. Three susceptibility loci possibly associated with HBsAg seroclearance were identified: (1) SNP rs2399971, (2) gene LINC00578, and (3) locus 11p15. SNP rs2399971 is a biomarker reported in the literature to be significantly associated with HBsAg seroclearance in patients who had received antiviral treatment. The latter two loci are linked with diseases influenced by the presence of hepatitis B virus infection. These findings demonstrate the potential of the proposed integrated framework in identifying disease-associated susceptibility loci. With further validation, results herein could aid in better understanding complex disease etiologies and provide inputs for a more advanced disease risk assessment for patients.

IntroductionIdentifying disease-associated susceptibility loci is one of the most pressing and crucial challenges in modeling complex diseases. Existing approaches to biomarker discovery are subject to several limitations including underpowered detection, neglect for variant interactions, and restrictive dependence on prior biological knowledge. Addressing these challenges necessitates more ingenious ways of approaching the “missing heritability” problem.ObjectivesThis study aims to discover disease-associated susceptibility loci by augmenting previous genome-wide association study (GWAS) using the integration of random forest and cluster analysis.MethodsThe proposed integrated framework is applied to a hepatitis B virus surface antigen (HBsAg) seroclearance GWAS data. Multiple cluster analyses were performed on (1) single nucleotide polymorphisms (SNPs) considered significant by GWAS and (2) SNPs with the highest feature importance scores obtained using random forest. The resulting SNP-sets from the cluster analyses were subsequently tested for trait-association.ResultsThree susceptibility loci possibly associated with HBsAg seroclearance were identified: (1) SNP rs2399971, (2) gene LINC00578, and (3) locus 11p15. SNP rs2399971 is a biomarker reported in the literature to be significantly associated with HBsAg seroclearance in patients who had received antiviral treatment. The latter two loci are linked with diseases influenced by the presence of hepatitis B virus infection.ConclusionThese findings demonstrate the potential of the proposed integrated framework in identifying disease-associated susceptibility loci. With further validation, results herein could aid in better understanding complex disease etiologies and provide inputs for a more advanced disease risk assessment for patients.