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Kullback-Leibler divergence for detection of rare haplotype common disease association.

ABSTRACT: Rare haplotypes may tag rare causal variants of common diseases; hence, detection of such rare haplotypes may also contribute to our understanding of complex disease etiology. Because rare haplotypes frequently result from common single-nucleotide polymorphisms (SNPs), focusing on rare haplotypes is much more economical compared with using rare single-nucleotide variants (SNVs) from sequencing, as SNPs are available and 'free' from already amassed genome-wide studies. Further, associated haplotypes may shed light on the underlying disease causal mechanism, a feat unmatched by SNV-based collapsing methods. In recent years, data mining approaches have been adapted to detect rare haplotype association. However, as they rely on an assumed underlying disease model and require the specification of a null haplotype, results can be erroneous if such assumptions are violated. In this paper, we present a haplotype association method based on Kullback-Leibler divergence (hapKL) for case-control samples. The idea is to compare haplotype frequencies for the cases versus the controls by computing symmetrical divergence measures. An important property of such measures is that both the frequencies and logarithms of the frequencies contribute in parallel, thus balancing the contributions from rare and common, and accommodating both deleterious and protective, haplotypes. A simulation study under various scenarios shows that hapKL has well-controlled type I error rates and good power compared with existing data mining methods. Application of hapKL to age-related macular degeneration (AMD) shows a strong association of the complement factor H (CFH) gene with AMD, identifying several individual rare haplotypes with strong signals.

SUBMITTER: Lin S

PROVIDER: S-EPMC4613467 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Kullback-Leibler divergence for detection of rare haplotype common disease association.

Lin Shili S

European journal of human genetics : EJHG 20150304 11

Rare haplotypes may tag rare causal variants of common diseases; hence, detection of such rare haplotypes may also contribute to our understanding of complex disease etiology. Because rare haplotypes frequently result from common single-nucleotide polymorphisms (SNPs), focusing on rare haplotypes is much more economical compared with using rare single-nucleotide variants (SNVs) from sequencing, as SNPs are available and 'free' from already amassed genome-wide studies. Further, associated haploty ...[more]

PMID: 25735482

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Project description:PurposePositron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) reveals altered cerebral metabolism in individuals with mild cognitive impairment (MCI) and Alzheimer's dementia (AD). Previous metabolic connectome analyses derive from groups of patients but do not support the prediction of an individual's risk of conversion from present MCI to AD. We now present an individual metabolic connectome method, namely the Kullback-Leibler Divergence Similarity Estimation (KLSE), to characterize brain-wide metabolic networks that predict an individual's risk of conversion from MCI to AD.MethodsFDG-PET data consisting of 50 healthy controls, 332 patients with stable MCI, 178 MCI patients progressing to AD, and 50 AD patients were recruited from ADNI database. Each individual's metabolic brain network was ascertained using the KLSE method. We compared intra- and intergroup similarity and difference between the KLSE matrix and group-level matrix, and then evaluated the network stability and inter-individual variation of KLSE. The multivariate Cox proportional hazards model and Harrell's concordance index (C-index) were employed to assess the prediction performance of KLSE and other clinical characteristics.ResultsThe KLSE method captures more pathological connectivity in the parietal and temporal lobes relative to the typical group-level method, and yields detailed individual information, while possessing greater stability of network organization (within-group similarity coefficient, 0.789 for sMCI and 0.731 for pMCI). Metabolic connectome expression was a superior predictor of conversion than were other clinical assessments (hazard ratio (HR) = 3.55; 95% CI, 2.77-4.55; P < 0.001). The predictive performance improved further upon combining clinical variables in the Cox model, i.e., C-indices 0.728 (clinical), 0.730 (group-level pattern model), 0.750 (imaging connectome), and 0.794 (the combined model).ConclusionThe KLSE indicator identifies abnormal brain networks predicting an individual's risk of conversion from MCI to AD, thus potentially constituting a clinically applicable imaging biomarker.

Project description:BackgroundMalware, malicious software, is the major security concern of the digital realm. Conventional cyber-security solutions are challenged by sophisticated malicious behaviors. Currently, an overlap between malicious and legitimate behaviors causes more difficulties in characterizing those behaviors as malicious or legitimate activities. For instance, evasive malware often mimics legitimate behaviors, and evasion techniques are utilized by legitimate and malicious software.ProblemMost of the existing solutions use the traditional term of frequency-inverse document frequency (TF-IDF) technique or its concept to represent malware behaviors. However, the traditional TF-IDF and the developed techniques represent the features, especially the shared ones, inaccurately because those techniques calculate a weight for each feature without considering its distribution in each class; instead, the generated weight is generated based on the distribution of the feature among all the documents. Such presumption can reduce the meaning of those features, and when those features are used to classify malware, they lead to a high false alarms.MethodThis study proposes a Kullback-Liebler Divergence-based Term Frequency-Probability Class Distribution (KLD-based TF-PCD) algorithm to represent the extracted features based on the differences between the probability distributions of the terms in malware and benign classes. Unlike the existing solution, the proposed algorithm increases the weights of the important features by using the Kullback-Liebler Divergence tool to measure the differences between their probability distributions in malware and benign classes.ResultsThe experimental results show that the proposed KLD-based TF-PCD algorithm achieved an accuracy of 0.972, the false positive rate of 0.037, and the F-measure of 0.978. Such results were significant compared to the related work studies. Thus, the proposed KLD-based TF-PCD algorithm contributes to improving the security of cyberspace.ConclusionNew meaningful characteristics have been added by the proposed algorithm to promote the learned knowledge of the classifiers, and thus increase their ability to classify malicious behaviors accurately.

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Kullback-Leibler divergence for detection of rare haplotype common disease association.

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Kullback-Leibler divergence for detection of rare haplotype common disease association.

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