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Abstract The impact of electromagnetic radiation generated by signal transmission base stations and power stations to meet the needs of communication equipment and energy consumption on the environment has caused people concerns. Monitoring and prediction of electric and magnetic fields have become critical tasks for researchers. In this paper, we propose a granularity data method based on T–S (Takagi–Sugeno) fuzzy model, named fuzzy rule-based model, which utilizing finite rules that are determined by the deviations between the predicted values and the true values after the data goes through a granulation-degranulation mechanism, to predict the intensity of power frequency electric field and electromagnetic field. A series of experiments show that fuzzy rule-based models have better robustness and higher prediction accuracy in comparison with several existing prediction models. The improvement of the performance of the fuzzy rule-based model quantified in terms of Root Mean Squared Error is 20.86%, 51.91%, 62.28%, 65.10%, and 71.92% in comparison with that of the Ridge model, Lasso model, and a family of support vector machine model with different kernel functions, including linear kernel (SVM-linear), radial basis function (SVM-BRF), polynomial kernel (SVM-polynomial) respectively, on the electromagnetic field testing data, and 37.42%, 55.16%, 58.79%, 59.28%, 64.27% lower than that of the Ridge model, Lasso model, SVM-linear model, SVM-BRF model and SVM-polynomial model on the power frequency electric field testing data.

Copy number variation (CNV) is one of the main structural variations in the human genome and accounts for a considerable proportion of variations. As CNVs can directly or indirectly cause cancer, mental illness, and genetic disease in humans, their effective detection in humans is of great interest in the fields of oncogene discovery, clinical decision-making, bioinformatics, and drug discovery. The advent of next-generation sequencing data makes CNV detection possible, and a large number of CNV detection tools are based on next-generation sequencing data. Due to the complexity (e.g., bias, noise, alignment errors) of next-generation sequencing data and CNV structures, the accuracy of existing methods in detecting CNVs remains low. In this work, we design a new CNV detection approach, called shortest path-based Copy number variation (SPCNV), to improve the detection accuracy of CNVs. SPCNV calculates the k nearest neighbors of each read depth and defines the shortest path, shortest path relation, and shortest path cost sets based on which further calculates the mean shortest path cost of each read depth and its k nearest neighbors. We utilize the ratio between the mean shortest path cost for each read depth and the mean of the mean shortest path cost of its k nearest neighbors to construct a relative shortest path score formula that is able to determine a score for each read depth. Based on the score profile, a boxplot is then applied to predict CNVs. The performance of the proposed method is verified by simulation data experiments and compared against several popular methods of the same type. Experimental results show that the proposed method achieves the best balance between recall and precision in each set of simulated samples. To further verify the performance of the proposed method in real application scenarios, we then select real sample data from the 1,000 Genomes Project to conduct experiments. The proposed method achieves the best F1-scores in almost all samples. Therefore, the proposed method can be used as a more reliable tool for the routine detection of CNVs.

Abstract Background With the rapid development of whole exome sequencing (WES), an increasing number of tools are being proposed for copy number variation (CNV) detection based on this technique. However, no comprehensive guide is available for the use of these tools in clinical settings, which renders them inapplicable in practice. To resolve this problem, in this study, we evaluated the performances of four WES-based CNV tools, and established a guideline for the recommendation of a suitable tool according to the application requirements. Results In this study, first, we selected four WES-based CNV detection tools: CoNIFER, cn.MOPS, CNVkit and exomeCopy. Then, we evaluated their performances in terms of three aspects: sensitivity and specificity, overlapping consistency and computational costs. From this evaluation, we obtained four main results: (1) The sensitivity increases and subsequently stabilizes as the coverage or CNV size increases, while the specificity decreases. (2) CoNIFER performs better for CNV insertions than for CNV deletions, while the remaining tools exhibit the opposite trend. (3) CoNIFER, cn.MOPS and CNVkit realize satisfactory overlapping consistency, which indicates their results are trustworthy. (4) CoNIFER has the best space complexity and cn.MOPS has the best time complexity among these four tools. Finally, we established a guideline for tools’ usage according to these results. Conclusion No available tool performs excellently under all conditions; however, some tools perform excellently in some scenarios. Users can obtain a CNV tool recommendation from our paper according to the targeted CNV size, the CNV type or computational costs of their projects, as presented in Table 1, which is helpful even for users with limited knowledge of computer science.

Copy number variation (CNV) is an important type of mutation in the human genome, and is significantly associated with cancer and other diseases. Accurate detection of CNVs in tumor genomes is crucial for biologists aiming to understand tumorigenesis. One of the key steps in this task is to establish a reasonable model to conduct meaningful assessment of each genome region. Although a great number of computational approaches have been developed in the past few years, none of them is versatile enough to detect CNVs in all scenarios associated with complex genomes. In this paper, we propose a new statistical approach, called CRSCNV, to detect CNVs in individual samples, based on next-generation sequencing data. The approach adopts a cross-model-based statistical strategy to test the significance of genome bins, i.e., the genome to be analyzed is divided into N parts. The bins in each part are tested by establishing a statistical model based on the remaining (N - 1) parts. The advantage of such a cross model is that it can improve the meaning of P-value assessment. We tested the performance of CRSCNV on a large number of simulation datasets and compared it to the state-of-the-art methods. The results demonstrated that CRSCNV achieved the best trade-off between recall and precision. We further validated CRSCNV, using several real sequencing samples, where it produced a number of previously reported CNVs and some additional CNVs with potential biological importance. Thus, CRSCNV is a reliable approach for CNV detection, even in scenarios of extremely low purity.

Comprehensive identification and cataloging of copy number variation (CNVs) are essential to providing a complete view of human genetic variation and to finding diseased genes. Due to the large-scale sequencing and cost control whole-genome sequencing (WGS) data, low-coverage data is favorably disposed towards CNV identification. However, such low-coverage data is sensitive to noise and sequencing biases, which results in low resolution of CNV detection in past experimental designs for WGS datasets. In this paper, we present a control-free Dirichlet process Gaussian mixture model (dpGMM) based approach, to analyze the read depth (RD) of low-coverage WGS datasets for CNV discovery. First, noise and biases of the RD signals are corrected through the preprocessing step of dpGMM. Then we assume that RD signals across genomic regions follow a Gaussian mixture model (GMM) in which each Gaussian distribution is followed by a copy number state. Without requiring the number of Gaussian distributions, dpGMM builds a Dirichlet process (DP) GMM for RD signals and further uses a DP prior to infer the number of Gaussian models. After that, we apply dpGMM to simulation datasets with different coverages and individual datasets, and compare ours to three widely used RD-based pipelines, CNVnator, GROM-RD, and BIC-seq2. Simulation results demonstrate that our approach, dpGMM, has a high F1 score in both low- and high- coverage sequences. Also, the number of overlaps between CNVs detected in real data by ours and the standard benchmark is twice as much as that detected by other tools such as CNVnator and GROM-RD.

Copy number variation (CNV) is a well-known type of genomic mutation that is associated with the development of human cancer diseases. Detection of CNVs from the human genome is a crucial step for the pipeline of starting from mutation analysis to cancer disease diagnosis and treatment. Next-generation sequencing (NGS) data provides an unprecedented opportunity for CNVs detection at the base-level resolution, and currently, many methods have been developed for CNVs detection using NGS data. However, due to the intrinsic complexity of CNVs structures and NGS data itself, accurate detection of CNVs still faces many challenges. In this paper, we present an alternative method, called KNNCNV (K-Nearest Neighbor based CNV detection), for the detection of CNVs using NGS data. Compared to current methods, KNNCNV has several distinctive features: 1) it assigns an outlier score to each genome segment based solely on its first k nearest-neighbor distances, which is not only easy to extend to other data types but also improves the power of discovering CNVs, especially the local CNVs that are likely to be masked by their surrounding regions; 2) it employs the variational Bayesian Gaussian mixture model (VBGMM) to transform these scores into a series of binary labels without a user-defined threshold. To evaluate the performance of KNNCNV, we conduct both simulation and real sequencing data experiments and make comparisons with peer methods. The experimental results show that KNNCNV could derive better performance than others in terms of F1-score.

Copy number variation (CNV) is a genomic mutation that plays an important role in tumor evolution and tumor genesis. Accurate detection of CNVs from next-generation sequencing (NGS) data is still a challenging task due to artifacts such as uneven mapped reads and unbalanced amplitudes of gains and losses. This study proposes a new approach called HBOS-CNV to detect CNVs from NGS data. The central point of HBOS-CNV is that it uses a new statistic, the histogram-based outlier score (HBOS), to evaluate the fluctuation of genome bins to determine those of changed copy numbers. In comparison with existing statistics in the evaluation of CNVs, HBOS is a non-linearly transformed value from the observed read depth (RD) value of each genome bin, having the potential ability to relieve the effects resulted from the above artifacts. In the calculation of HBOS values, a dynamic width histogram is utilized to depict the density of bins on the genome being analyzed, which can reduce the effects of noises partially contributed by mapping and sequencing errors. The evaluation of genome bins using such a new statistic can lead to less extremely significant CNVs having a high probability of detection. We evaluated this method using a large number of simulation datasets and compared it with four existing methods (CNVnator, CNV-IFTV, CNV-LOF, and iCopyDav). The results demonstrated that our proposed method outperforms the others in terms of sensitivity, precision, and F1-measure. Furthermore, we applied the proposed method to a set of real sequencing samples from the 1000 Genomes Project and determined a number of CNVs with biological meanings. Thus, the proposed method can be regarded as a routine approach in the field of genome mutation analysis for cancer samples.

Comprehensive analysis of integrated data on multi-cancers is important for understanding the biological mechanism of these cancers at the system level. Network methods give us new insight into simultaneously identifying the characteristic genes and pathways from multi-cancers. Nevertheless, when measuring the similarity quantification of genes, it is a challenge to choose suitable methods for network construction and analysis. Herein, the NIPMI method, based on Interaction Part Mutual Information (IPMI) measure for detecting characteristic genes from multi-cancers data, is proposed. First, Robust PCA was applied to select genes for network construction. Then, a network construction measure, IPMI, was proposed to effectively quantify the similarity between genes in the network, which is the highlight of NIPMI. Furthermore, we introduced a novel topological property, Topological Score, that combined the local and global properties of each node to find more candidate nodes in the network. Finally, pathway enrichment analysis was performed to validate the biological functions of multi-cancers. The experimental results demonstrated that NIPMI facilitates the identification of characteristic genes in a multicancer network; thus, it may serve as a valuable tool for detecting characteristic genes and significantly enriched pathway terms.

Copy number variation (CNV) detection based on second-generation sequencing technology is the basis of much gene research, but the read depth is affected by mapping errors, repeated reads, and GC bias. The existing methods have low sensitivity to variation regions with a short length and small variation range. Therefore, it is necessary to improve the sensitivity of algorithms to short-variation fragments. This study proposes a new CNV-detection method named WAVECNV to solve this issue. The algorithm uses wavelet clustering to process the read depth and determine the normal cluster and abnormal cluster according to the size of the cluster. Then, according to the distance between genome bins and normal clusters, the outlier of each genome bin is evaluated. Finally, a statistical model is established, and the p-value test is used for calling CNVs. Through this method, the information of the short variation region is retained. WAVECNV was tested and compared with peer methods in terms of simulated data and real cancer-sequencing data. The results show that the sensitivity of WAVECNV is better than the existing methods. It also has high precision in data with low purity and coverage. In real data experiments, WAVECNV can detect more cancer genes than existing methods. Therefore, this method can be regarded as a conventional method in the field of genomic mutation analysis of cancer samples.

Copy number variation (CNV) is a common type of structural variations in human genome and confers biological meanings to human complex diseases. Detection of CNVs is an important step for a systematic analysis of CNVs in medical research of complex diseases. The recent development of next-generation sequencing (NGS) platforms provides unprecedented opportunities for the detection of CNVs at a base-level resolution. However, due to the intrinsic characteristics behind NGS data, accurate detection of CNVs is still a challenging task. In this article, we propose a new density peak-based method, called dpCNV, for the detection of CNVs from NGS data. The algorithm of dpCNV is designed based on density peak clustering algorithm. It extracts two features, i.e., local density and minimum distance, from sequencing read depth (RD) profile and generates a two-dimensional data. Based on the generated data, a two-dimensional null distribution is constructed to test the significance of each genome bin and then the significant genome bins are declared as CNVs. We test the performance of the dpCNV method on a number of simulated datasets and make comparison with several existing methods. The experimental results demonstrate that our proposed method outperforms others in terms of sensitivity and F1-score. We further apply it to a set of real sequencing samples and the results demonstrate the validity of dpCNV. Therefore, we expect that dpCNV can be used as a supplementary to existing methods and may become a routine tool in the field of genome mutation analysis.

Breast cancer is the most common malignancy in women, and because it has a high mortality rate, it is urgent to develop computational methods to increase the accuracy of breast cancer survival predictive models. Although multi-omics data such as gene expression have been extensively used in recent studies, the accurate prognosis of breast cancer remains a challenge. Somatic mutations are another important and promising data source for studying cancer development, and its effect on the prognosis of breast cancer remains to be further explored. Meanwhile, these omics datasets are high-dimensional and redundant. Therefore, we adopted multiple kernel learning (MKL) to efficiently integrate somatic mutation to currently molecular data including gene expression, copy number variation (CNV), methylation, and protein expression data for the prediction of breast cancer survival. Before integration, the maximum relevance minimum redundancy (mRMR) feature selection method was utilized to select features that present high relevance to survival and low redundancy among themselves for each type of data. The experimental results demonstrated that the proposed method achieved the most optimal performance and there was a remarkable improvement in the prediction performance when somatic mutations were included, indicating that somatic mutations are critical for improving breast cancer survival predictions. Moreover, mRMR was superior to other feature selection methods used in previous studies. Furthermore, MKL outperformed the other traditional classifiers in multi-omics data integration. Our analysis indicated that through employing promising omics data such as somatic mutations and harnessing the power of proper feature selection methods and effective integration frameworks, the breast cancer survival predictive accuracy can be further increased, thereby providing a more optimal clinical diagnosis and more effective treatment for breast cancer patients.

Next-generation sequencing (NGS) technologies have provided great opportunities to analyze pathogenic microbes with high-resolution data. The main goal is to accurately detect microbial composition and abundances in a sample. However, high similarity among sequences from different species and the existence of sequencing errors pose various challenges. Numerous methods have been developed for quantifying microbial composition and abundance, but they are not versatile enough for the analysis of samples with mixtures of noise. In this paper, we propose a new computational method, PGMicroD, for the detection of pathogenic microbial composition in a sample using NGS data. The method first filters the potentially mistakenly mapped reads and extracts multiple species-related features from the sequencing reads of 16S rRNA. Then it trains an Support Vector Machine classifier to predict the microbial composition. Finally, it groups all multiple-mapped sequencing reads into the references of the predicted species to estimate the abundance for each kind of species. The performance of PGMicroD is evaluated based on both simulation and real sequencing data and is compared with several existing methods. The results demonstrate that our proposed method achieves superior performance. The software package of PGMicroD is available at https://github.com/BDanalysis/PGMicroD.

Copy number variations (CNVs) are significant causes of many human cancers and genetic diseases. The detection of CNVs has become a common method by which to analyze human diseases using next-generation sequencing (NGS) data. However, effective detection of insignificant CNVs is still a challenging task. In this study, we propose a new detection method, RKDOSCNV, to meet the need. RKDOSCNV uses kernel density estimation method to evaluate the local kernel density distribution of each read depth segment (RDS) based on an expanded nearest neighbor (k-nearest neighbors, reverse nearest neighbors, and shared nearest neighbors of each RDS) data set, and assigns a relative kernel density outlier score (RKDOS) for each RDS. According to the RKDOS profile, RKDOSCNV predicts the candidate CNVs by choosing a reasonable threshold, which it uses split read approach to correct the boundaries of candidate CNVs. The performance of RKDOSCNV is assessed by comparing it with several current popular methods via experiments with simulated and real data at different tumor purity levels. The experimental results verify that the performance of RKDOSCNV is superior to that of several other methods. In summary, RKDOSCNV is a simple and effective method for the detection of CNVs from whole genome sequencing (WGS) data, especially for samples with low tumor purity.

Tandem duplication (TD) is an important type of structural variation (SV) in the human genome and has biological significance for human cancer evolution and tumor genesis. Accurate and reliable detection of TDs plays an important role in advancing early detection, diagnosis, and treatment of disease. The advent of next-generation sequencing technologies has made it possible for the study of TDs. However, detection is still challenging due to the uneven distribution of reads and the uncertain amplitude of TD regions. In this paper, we present a new method, DINTD (Detection and INference of Tandem Duplications), to detect and infer TDs using short sequencing reads. The major principle of the proposed method is that it first extracts read depth and mapping quality signals, then uses the DBSCAN (Density-Based Spatial Clustering of Applications with Noise) algorithm to find the possible TD regions. The total variation penalized least squares model is fitted with read depth and mapping quality signals to denoise signals. A 2D binary search tree is used to search the neighbor points effectively. To further identify the exact breakpoints of the TD regions, split-read signals are integrated into DINTD. The experimental results of DINTD on simulated data sets showed that DINTD can outperform other methods for sensitivity, precision, F1-score, and boundary bias. DINTD is further validated on real samples, and the experiment results indicate that it is consistent with other methods. This study indicates that DINTD can be used as an effective tool for detecting TDs.

Copy number variation (CNV) is a very important phenomenon in tumor genomes and plays a significant role in tumor genesis. Accurate detection of CNVs has become a routine and necessary procedure for a deep investigation of tumor cells and diagnosis of tumor patients. Next-generation sequencing (NGS) technique has provided a wealth of data for the detection of CNVs at base-pair resolution. However, such task is usually influenced by a number of factors, including GC-content bias, sequencing errors, and correlations among adjacent positions within CNVs. Although many existing methods have dealt with some of these artifacts by designing their own strategies, there is still a lack of comprehensive consideration of all the factors. In this paper, we propose a new method, MFCNV, for an accurate detection of CNVs from NGS data. Compared with existing methods, the characteristics of the proposed method include the following: (1) it makes a full consideration of the intrinsic correlations among adjacent positions in the genome to be analyzed, (2) it calculates read depth, GC-content bias, base quality, and correlation value for each genome bin and combines them as multiple features for the evaluation of genome bins, and (3) it addresses the joint effect among the factors via training a neural network algorithm for the prediction of CNVs. We test the performance of the MFCNV method by using simulation and real sequencing data and make comparisons with several peer methods. The results demonstrate that our method is superior to other methods in terms of sensitivity, precision, and F1-score and can detect many CNVs that other methods have not discovered. MFCNV is expected to be a complementary tool in the analysis of mutations in tumor genomes and can be extended to be applied to the analysis of single-cell sequencing data.

Inference of absolute copy numbers in tumor genomes is one of the key points in the study of tumor genesis. However, the mixture of tumor and normal cells poses a big challenge to this task. Accurate estimation of tumor purity (i.e., the fraction of tumor cells) is a necessary step to solve this problem. In this paper, we propose a new approach, AITAC, to accurately infer tumor purity and absolute copy numbers in a tumor sample by using high-throughput sequencing (HTS) data. In contrast to many existing algorithms for estimating tumor purity, which usually rely on pre-detected mutation genotypes (heterogeneity and homogeneity), AITAC just requires read depths (RDs) observed at the regions with copy number losses. AITAC creates a non-linear model to correlate tumor purity, observed and expected RDs. It adopts an exhaustive search strategy to scan tumor purity in a wide range, and chooses the tumor purity that minimizes the deviation between observed RDs and expected ones as the optimal solution. We apply the proposed approach to both simulation and real sequencing data sets and demonstrate its performance by comparing with two classical approaches. AITAC is freely available at https://github.com/BDanalysis/aitac and can be expected to become a useful approach for researchers to analyze copy numbers in cancer genome.

Abstract Background Gene expression profiling has led to the definition of breast cancer molecular subtypes: Basal-like, HER2-enriched, LuminalA, LuminalB and Normal-like. Different subtypes exhibit diverse responses to treatment. In the past years, several traditional clustering algorithms have been applied to analyze gene expression profiling. However, accurate identification of breast cancer subtypes, especially within highly variable LuminalA subtype, remains a challenge. Furthermore, the relationship between DNA methylation and expression level in different breast cancer subtypes is not clear. Results In this study, a modified ISA biclustering algorithm, termed AP-ISA, was proposed to identify breast cancer subtypes. Comparing with ISA, AP-ISA provides the optimized strategy to select seeds and thresholds in the circumstance that prior knowledge is absent. Experimental results on 574 breast cancer samples were evaluated using clinical ER/PR information, PAM50 subtypes and the results of five peer to peer methods. One remarkable point in the experiment is that, AP-ISA divided the expression profiles of the luminal samples into four distinct classes. Enrichment analysis and methylation analysis showed obvious distinction among the four subgroups. Tumor variability within the Luminal subtype is observed in the experiments, which could contribute to the development of novel directed therapies. Conclusions Aiming at breast cancer subtype classification, a novel biclustering algorithm AP-ISA is proposed in this paper. AP-ISA classifies breast cancer into seven subtypes and we argue that there are four subtypes in luminal samples. Comparison with other methods validates the effectiveness of AP-ISA. New genes that would be useful for targeted treatment of breast cancer were also obtained in this study.

The stratification of cancer into subtypes that are significantly associated with clinical outcomes is beneficial for targeted prognosis and treatment. In this study, we integrated somatic mutation and gene expression data to identify clusters of patients. In contrast to previous studies, we constructed cancer-type-specific significant co-expression networks (SCNs) rather than using a fixed gene network across all cancers, such as the network-based stratification (NBS) method, which ignores cancer heterogeneity. For each type of cancer, the gene expression data were used to construct the SCN network, while the gene somatic mutation data were mapped onto the network, propagated, and used for further clustering. For the clustering, we adopted an improved network-regularized non-negative matrix factorization (netNMF) (netNMF_HC) for a more precise classification. We applied our method to various datasets, including ovarian cancer (OV), lung adenocarcinoma (LUAD) and uterine corpus endometrial carcinoma (UCEC) cohorts derived from the TCGA (The Cancer Genome Atlas) project. Based on the results, we evaluated the performance of our method to identify survival-relevant subtypes and further compared it to the NBS method, which adopts priori networks and netNMF algorithm. The proposed algorithm outperformed the NBS method in identifying informative cancer subtypes that were significantly associated with clinical outcomes in most cancer types we studied. In particular, our method identified survival-associated UCEC subtypes that were not identified by the NBS method. Our analysis indicated valid subtyping of patient could be applied by mutation data with cancer-type-specific SCNs and netNMF_HC for individual cancers because of specific cancer co-expression patterns and more precise clustering.

Breast cancer is a heterogeneous disease. Although gene expression profiling has led to the definition of several subtypes of breast cancer, the precise discovery of the subtypes remains a challenge. Clinical data is another promising source. In this study, clinical variables are utilized and integrated to gene expressions for the stratification of breast cancer. We adopt two phases: gene selection and clustering, where the integration is in the gene selection phase; only genes whose expressions are most relevant to each clinical variable and least redundant among themselves are selected for further clustering. In practice, we simply utilize maximum relevance minimum redundancy (mRMR) for gene selection and k-means for clustering. We compare the results of our method with those of two commonly used only expression-based breast cancer stratification methods: prediction analysis of microarray 50 (PAM50) and highest variability (HV). The result is that our method outperforms them in identifying subtypes significantly associated with five-year survival and recurrence time. Specifically, our method identified recurrence-associated breast cancer subtypes that were not identified by PAM50 and HV. Additionally, our analysis discovered three survival-associated luminal-A subgroups and two survival-associated luminal-B subgroups. The study indicates that screening clinically relevant gene expressions yields improved breast cancer stratification.

MOTIVATION:Two-locus model is a typical significant disease model to be identified in genome-wide association study (GWAS). Due to intensive computational burden and diversity of disease models, existing methods have drawbacks on low detection power, high computation cost, and preference for some types of disease models. METHOD:In this study, two scoring functions (Bayesian network based K2-score and Gini-score) are used for characterizing two SNP locus as a candidate model, the two criteria are adopted simultaneously for improving identification power and tackling the preference problem to disease models. Harmony search algorithm (HSA) is improved for quickly finding the most likely candidate models among all two-locus models, in which a local search algorithm with two-dimensional tabu table is presented to avoid repeatedly evaluating some disease models that have strong marginal effect. Finally G-test statistic is used to further test the candidate models. RESULTS:We investigate our method named FHSA-SED on 82 simulated datasets and a real AMD dataset, and compare it with two typical methods (MACOED and CSE) which have been developed recently based on swarm intelligent search algorithm. The results of simulation experiments indicate that our method outperforms the two compared algorithms in terms of detection power, computation time, evaluation times, sensitivity (TPR), specificity (SPC), positive predictive value (PPV) and accuracy (ACC). Our method has identified two SNPs (rs3775652 and rs10511467) that may be also associated with disease in AMD dataset.