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Öğe Biological variation of peripheral blood T-lymphocytes(Elsevier, 2019) Falay, Mesude; Senes, Mehmet; Korkmaz, Selcuk; Zararsiz, Gokmen; Turhan, Turan; Okay, Murat; Yucel, CigdemBackground: Flow cytometric analysis of the lymphocyte subsets has become one of the most commonly used techniques in the routine clinical laboratory. It is frequently used in monitoring lymphocyte recovery after hematopoietic stem cell transplantation (HSCT), as well as diagnosis and treatment of acquired immunodeficiency syndrome (AIDS). Reliable biological variation (BV) data is needed for safe clinical application of these tests. In this study, similar preanalytical and analytical protocols to the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) checklist were followed and a stringent statistical approach was applied to define BV of T-lymphocytes. Methods: During the 10 weeks study period, weekly blood samples were obtained from 30 healthy individuals (20 females, 10 males) and analyzed with Facs Canto (BD Biosciences, San Jose, CA, USA) analyzer using 4colour BD Multitest CD3/CD8/CD45/CD4 reagents. Data were assessed in terms of normality, tendencies, outliers and variance homogeneity prior to applying coefficient of variance (CV)- analysis of variance (ANOVA) test. Sex-stratified within-individual (CVI) and between-individual (CVG) BV estimates of CD3+, CD3 + CD4 +, CD3 + CD8 +, and CD3 + CD4 + CD8 + T lymphocytes were calculated. Results: No difference was found between males and females. Except for the CD3 + CD4 + CD8 + subset, stable BV was found for CD3+, CD3 + CD4 +, and CD3 + CD8 + subsets. Conclussion: Instead of using the conventional reference ranges of CD3+, CD3 + CD4 + and CD3 + CD8 + counts for monitoring HIV positive or post-HSCT patients, RCV should be used. Because individualityis characteristic of lymphocytes subsets RCVS should be used instead of RIs for patient monitoring.Öğe geneSurv: An interactive web-based tool for survival analysis in genomics research(Pergamon-Elsevier Science Ltd, 2017) Korkmaz, Selcuk; Goksuluk, Dincer; Zararsiz, Gokmen; Karahan, SevilaySurvival analysis methods are often used in cancer studies. It has been shown that the combination of clinical data with genomics increases the predictive performance of survival analysis methods. But, this leads to a high-dimensional data problem. Fortunately, new methods have been developed in the last decade to overcome this problem. However, there is a strong need for easily accessible, user-friendly and interactive tool to perform survival analysis in the presence of genomics data. We developed an open-source and freely available web-based tool for survival analysis methods that can deal with high-dimensional data. This tool includes classical methods, such as Kaplan-Meier, Cox proportional hazards regression, and advanced methods, such as penalized Cox regression and Random Survival Forests. It also offers an optimal cutoff determination method based on maximizing several test statistics. The tool has a simple and interactive interface, and it can handle high dimensional data through feature selection and ensemble methods. To dichotomize gene expressions, geneSurv can identify optimal cutoff points. Users can upload their microarray, RNA-Seq, chip-Seq, proteomics, metabolomics or clinical data as a nxp dimensional data matrix, where n refers to samples and p refers to genes. This tool is available free at www.biosoft.hacettepe.edu.tr/geneSurv. All source code is available at https://github.com/selcukorkmaz/geneSurv under the GPL-3 license.Öğe Investigation of protein quaternary structure via stoichiometry and symmetry information(Public Library Science, 2018) Korkmaz, Selcuk; Duarte, Jose M.; Prlic, Andreas; Goksuluk, Dincer; Zararsiz, Gokmen; Saracbasi, Osman; Burley, Stephen K.The Protein Data Bank (PDB) is the single worldwide archive of experimentally-determined three-dimensional (3D) structures of proteins and nucleic acids. As of January 2017, the PDB housed more than 125,000 structures and was growing by more than 11,000 structures annually. Since the 3D structure of a protein is vital to understand the mechanisms of biological processes, diseases, and drug design, correct oligomeric assembly information is of critical importance. Unfortunately, the biologically relevant oligomeric form of a 3D structure is not directly obtainable by X-ray crystallography, whilst in solution methods (NMR or single particle EM) it is known from the experiment. Instead, this information may be provided by the PDB Depositor as metadata coming from additional experiments, be inferred by sequence-sequence comparisons with similar proteins of known oligomeric state, or predicted using software, such as PISA (Proteins, Interfaces, Structures and Assemblies) or EPPIC (Evolutionary Protein Protein Interface Classifier). Despite significant efforts by professional PDB Biocurators during data deposition, there remain a number of structures in the archive with incorrect quaternary structure descriptions (or annotations). Further investigation is, therefore, needed to evaluate the correctness of quaternary structure annotations. In this study, we aim to identify the most probable oligomeric states for proteins represented in the PDB. Our approach evaluated the performance of four independent prediction methods, including text mining of primary publications, inference from homologous protein structures, and two computational methods (PISA and EPPIC). Aggregating predictions to give consensus results outperformed all four of the independent prediction methods, yielding 83% correct, 9% wrong, and 8% inconclusive predictions, when tested with a well-curated benchmark dataset. We have developed a freely-available web-based tool to make this approach accessible to researchers and PDB Biocurators (http://quatstruct.rcsb.org/).Öğe Machine learning based classification of cells into chronological stages using single-cell transcriptomics(Nature Publishing Group, 2018) Singh, Sumeet Pal; Janjuha, Sharan; Chaudhuri, Samata; Reinhardt, Susanne; Kraenkel, Annekathrin; Dietz, Sevina; Eugster, Anne; Bilgin, Halil; Korkmaz, Selcuk; Zararsiz, Gokmen; Ninov, Nikolay; Reid, John E.Age-associated deterioration of cellular physiology leads to pathological conditions. The ability to detect premature aging could provide a window for preventive therapies against age-related diseases. However, the techniques for determining cellular age are limited, as they rely on a limited set of histological markers and lack predictive power. Here, we implement GERAS (GEnetic Reference for Age of Single-cell), a machine learning based framework capable of assigning individual cells to chronological stages based on their transcriptomes. GERAS displays greater than 90% accuracy in classifying the chronological stage of zebrafish and human pancreatic cells. The framework demonstrates robustness against biological and technical noise, as evaluated by its performance on independent samplings of single-cells. Additionally, GERAS determines the impact of differences in calorie intake and BMI on the aging of zebrafish and human pancreatic cells, respectively. We further harness the classification ability of GERAS to identify molecular factors that are potentially associated with the aging of beta-cells. We show that one of these factors, junba, is necessary to maintain the proliferative state of juvenile beta-cells. Our results showcase the applicability of a machine learning framework to classify the chronological stage of heterogeneous cell populations, while enabling detection of candidate genes associated with aging.Öğe MLSeq: Machine learning interface for RNA-sequencing data(Elsevier Ireland Ltd, 2019) Goksuluk, Dincer; Zararsiz, Gokmen; Korkmaz, Selcuk; Eldem, Vahap; Zararsiz, Gozde Erturk; Ozcetin, Erdener; Ozturk, AhmetBackground and Objective: In the last decade, RNA-sequencing technology has become method-of-choice and prefered to microarray technology for gene expression based classification and differential expression analysis since it produces less noisy data. Although there are many algorithms proposed for microarray data, the number of available algorithms and programs are limited for classification of RNA-sequencing data. For this reason, we developed MLSeq, to bring not only frequently used classification algorithms but also novel approaches together and make them available to be used for classification of RNA sequencing data. This package is developed using R language environment and distributed through BIOCONDUCTOR network. Methods: Classification of RNA-sequencing data is not straightforward since raw data should be preprocessed before downstream analysis. With MLSeq package, researchers can easily preprocess (normalization, filtering, transformation etc.) and classify raw RNA-sequencing data using two strategies: (i) to perform algorithms which are directly proposed for RNA-sequencing data structure or (ii) to transform RNA-sequencing data in order to bring it distributionally closer to microarray data structure, and perform algorithms which are developed for microarray data. Moreover, we proposed novel algorithms such as voom (an acronym for variance modelling at observational level) based nearest shrunken centroids (voomNSC), diagonal linear discriminant analysis (voomDLDA), etc. through MLSeq. Materials: Three real RNA-sequencing datasets (i.e cervical cancer, lung cancer and aging datasets) were used to evalute model performances. Poisson linear discriminant analysis (PLDA) and negative binomial linear discriminant analysis (NBLDA) were selected as algorithms based on dicrete distributions, and voomNSC, nearest shrunken centroids (NSC) and support vector machines (SVM) were selected as algorithms based on continuous distributions for model comparisons. Each algorithm is compared using classification accuracies and sparsities on an independent test set. Results: The algorithms which are based on discrete distributions performed better in cervical cancer and aging data with accuracies above 0.92. In lung cancer data, the most of algorithms performed similar with accuracies of 0.88 except that SVM achieved 0.94 of accuracy. Our voomNSC algorithm was the most sparse algorithm, and able to select 2.2% and 6.6% of all features for cervical cancer and lung cancer datasets respectively. However, in aging data, sparse classifiers were not able to select an optimal subset of all features. Conclusion: MLSeq is comprehensive and easy-to-use interface for classification of gene expression data. It allows researchers perform both preprocessing and classification tasks through single platform. With this property, MLSeq can be considered as a pipeline for the classification of RNA-sequencing data. (C) 2019 Elsevier B.V. All rights reserved.Öğe The Relationship Between Blood Pressure and Sleep Duration in Turkish Children: A Cross-Sectional Study(Galenos Yayincilik, 2018) Bal, Cengiz; Ozturk, Ahmet; Cicek, Betul; Ozdemir, Ahmet; Zararsiz, Gokmen; Unalan, Demet; Zararsiz, Gozde ErturkObjective: As in adults, hypertension is also an important risk factor for cardiovascular disease in children. We aimed to evaluate the effect of sleep duration on blood pressure in normal weight Turkish children aged between 11-17 years. Methods: This cross-sectional study was conducted in the primary and secondary schools of the two central and ten outlying districts of Kayseri, Turkey. Subjects were 2860 children and adolescents (1385 boys, 1475 girls). Systolic and diastolic blood pressures were measured according to the recommendations of the Fourth Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. Sleep duration was classified as follows: <= 8 hours, 8.1-8.9 hours, 9.0-9.9 hours or >= 10 hours. Results: For short sleeper boys and girls (participants with a sleep duration <= 8 h) the prevalence of prehypertension and hypertension was 35.0% and 30.8%, respectively. In univariate binary logistic regression analyses (age-adjusted), each unit increment in sleep duration (hours) in boys and girls, decreased the prehypertension and hypertension risk by 0.89 [odds ratio (OR)] [confidance interval (CI); 0.82-0.98] and 0.88 (OR) (CI; 0.81-0.97), respectively (p<0.05). In multiple binary logistic regression analyses [age-and body mass index (BMI)-adjusted] the location of the school and sleep duration categories were shown to be the most important factors for prehypertension and hypertension in both genders, while household income was the most important factor, only in boys. Conclusions: A sleep duration <= 8 h is an independent risk factor for prehypertension and hypertension in Turkish children aged 11-17 years.Öğe voomDDA: discovery of diagnostic biomarkers and classification of RNA-seq data(Peerj Inc, 2017) Zararsiz, Gokmen; Goksuluk, Dincer; Klaus, Bernd; Korkmaz, Selcuk; Eldem, Vahap; Karabulut, Erdem; Ozturk, AhmetRNA-Seq is a recent and efficient technique that uses the capabilities of next-generation sequencing technology for characterizing and quantifying transcriptomes. One important task using gene-expression data is to identify a small subset of genes that can be used to build diagnostic classifiers particularly for cancer diseases. Microarray based classifiers are not directly applicable to RNA-Seq data due to its discrete nature. Overdispersion is another problem that requires careful modeling of rnean and variance relationship of the RNA-Seq data. In this study, we present voomDDA classifiers: variance modeling at the observational level (voom) extensions of the nearest shrunken centroids (NSC) and the diagonal discriminant classifiers. VoomNSC is one of these classifiers and brings voom and NSC approaches together for the purpose of gene-expression based classification. For this purpose, we propose weighted statistics and put these weighted statistics into the NSC algorithm. The VoomNSC is a sparse classifier that models the mean-variance relationship using the voom method and incorporates voom's precision weights into the NSC classifier via weighted statistics. A comprehensive simulation study was designed and four real datasets are used for performance assessment. The overall results indicate that voomNSC performs as the sparsest classifier. It also provides the most accurate results together with power-transformed Poissan linear discriminant analysis, rlog transformed support vector machines and random forests algorithms. In addition to prediction purposes, the voomNSC classifier can be used to identify the potential diagnostic biomarkers for a condition of interest. Through this work, statistical learning methods proposed for can be reused for RNA-Seq data.