Journal of clinical bioinformatics最新文献

Chronic obstructive pulmonary disease (COPD) is an inflammatory disease characterized by the progressive deterioration of pulmonary function and increasing airway obstruction, with high morality all over the world. The advent of high-throughput omics techniques provided an opportunity to gain insights into disease pathogenesis and process which contribute to the heterogeneity, and find target-specific and disease-specific therapies. As an interdispline, bioinformatics supplied vital information on integrative understanding of COPD. This review focused on application of bioinformatics in COPD study, including biomarkers searching and systems biology. We also presented the requirements and challenges in implementing bioinformatics to COPD research and interpreted these results as clinical physicians.

Background: It has been shown previously that glucocorticoids exert a dual mechanism of action, entailing cytotoxic, mitogenic as well as cell proliferative and anti-apoptotic responses, in a dose-dependent manner on CCRF-CEM cells at 72 h. Early gene expression response implies a dose-dependent dual mechanism of action of prednisolone too, something reflected on cell state upon 72 h of treatment.

Methods: In this work, a generic, computational microarray data analysis framework is proposed, in order to examine the hypothesis, whether CCRF-CEM cells exhibit an intrinsic or acquired mechanism of resistance and investigate the molecular imprint of this, upon prednisolone treatment. The experimental design enables the examination of both the dose (0 nM, 10 nM, 22 uM, 700 uM) effect of glucocorticoid exposure and the dynamics (early and late, namely 4 h, 72 h) of the molecular response of the cells at the transcriptomic layer.

Results: In this work, we demonstrated that CCRF-CEM cells may attain a mixed mechanism of response to glucocorticoids, however, with a clear preference towards an intrinsic mechanism of resistance. Specifically, at 4 h, prednisolone appeared to down-regulate apoptotic genes. Also, low and high prednisolone concentrations up-regulates genes related to metabolism and signal-transduction in both time points, thus favoring cell proliferative actions. In addition, regulation of NF-κB-related genes implies an inherent mechanism of resistance through the established link of NF-κB inflammatory role and GC-induced resistance. The analysis framework applied here highlights prednisolone-activated regulatory mechanisms through identification of early responding sets of genes. On the other hand, study of the prolonged exposure to glucocorticoids (72 h exposure) highlights the effect of homeostatic feedback mechanisms of the treated cells.

Conclusions: Overall, it appears that CCRF-CEM cells in this study exhibit a diversified, combined pattern of intrinsic and acquired resistance to prednisolone, with a tendency towards inherent resistant characteristics, through activation of different molecular courses of action.

Background: In metabolomics, biomarker discovery is a highly data driven process and requires sophisticated computational methods for the search and prioritization of novel and unforeseen biomarkers in data, typically gathered in preclinical or clinical studies. In particular, the discovery of biomarker candidates from longitudinal cohort studies is crucial for kinetic analysis to better understand complex metabolic processes in the organism during physical activity.

Findings: In this work we introduce a novel computational strategy that allows to identify and study kinetic changes of putative biomarkers using targeted MS/MS profiling data from time series cohort studies or other cross-over designs. We propose a prioritization model with the objective of classifying biomarker candidates according to their discriminatory ability and couple this discovery step with a novel network-based approach to visualize, review and interpret key metabolites and their dynamic interactions within the network. The application of our method on longitudinal stress test data revealed a panel of metabolic signatures, i.e., lactate, alanine, glycine and the short-chain fatty acids C2 and C3 in trained and physically fit persons during bicycle exercise.

Conclusions: We propose a new computational method for the discovery of new signatures in dynamic metabolic profiling data which revealed known and unexpected candidate biomarkers in physical activity. Many of them could be verified and confirmed by literature. Our computational approach is freely available as R package termed BiomarkeR under LGPL via CRAN http://cran.r-project.org/web/packages/BiomarkeR/.

Background: Medical image processing is essential in many fields of medical research and clinical practice because it greatly facilitates early and accurate detection and diagnosis of diseases. In particular, contrast enhancement is important for optimal image quality and visibility. This paper proposes a new image processing method for enhancing morphological features of masses and other abnormalities in medical images.

Method: The proposed method involves two steps: (1) selective extraction of target features by mathematical morphology and (2) enhancement of the extracted features by two contrast modification techniques.

Results: The goal of the proposed method is to enable enhancement of fine morphological features of a lesion region with high suppression of surrounding tissues. The effectiveness of the method was evaluated in quantitative terms of the contrast improvement ratio. The results clearly show that the method outperforms five conventional contrast enhancement methods. The effectiveness and usefulness of the proposed method were further demonstrated by application to three types of medical images: a mammographic image, a chest radiographic image, and a retinal image.

Conclusion: The proposed method enables specific extraction and enhancement of mass lesions, which is essential for clinical diagnosis based on medical image analysis. Thus, the method can be expected to achieve automatic recognition of lesion location and quantitative analysis of legion morphology.

Background: Health information exchange and health information integration has become one of the top priorities for healthcare systems across institutions and hospitals. Most organizations and establishments implement health information exchange and integration in order to support meaningful information retrieval among their disparate healthcare systems. The challenges that prevent efficient health information integration for heterogeneous data sources are the lack of a common standard to support mapping across distributed data sources and the numerous and diverse healthcare domains. Health Level Seven (HL7) is a standards development organization which creates standards, but is itself not the standard. They create the Reference Information Model. RIM is developed by HL7's technical committees. It is a standardized abstract representation of HL7 data across all the domains of health care. In this article, we aim to present a design and a prototype implementation of HL7 v3-RIM mapping for information integration of distributed clinical data sources. The implementation enables the user to retrieve and search information that has been integrated using HL7 v3-RIM technology from disparate health care systems.

Method and results: We designed and developed a prototype implementation of HL7 v3-RIM mapping function to integrate distributed clinical data sources using R-MIM classes from HL7 v3-RIM as a global view along with a collaborative centralized web-based mapping tool to tackle the evolution of both global and local schemas. Our prototype was implemented and integrated with a Clinical Database management Systems CDMS as a plug-in module. We tested the prototype system with some use case scenarios for distributed clinical data sources across several legacy CDMS. The results have been effective in improving information delivery, completing tasks that would have been otherwise difficult to accomplish, and reducing the time required to finish tasks which are used in collaborative information retrieval and sharing with other systems.

Conclusions: We created a prototype implementation of HL7 v3-RIM mapping for information integration between distributed clinical data sources to promote collaborative healthcare and translational research. The prototype has effectively and efficiently ensured the accuracy of the information and knowledge extractions for systems that have been integrated.

Background: Pulmonary Langerhans-cell histiocytosis (PLCH) is a rare interstitial lung disease characterized by clusters of Langerhans cells, organized in granulomas, in the walls of distal bronchioles. It is a diffuse lung disease related to tobacco smoking but otherwise of unknown etiopathogenesis.

Methods: In this study we used a proteomic approach to analyze BAL protein composition of patients with PLCH and of healthy smoker and non-smoker controls to obtain insights into the pathogenetic mechanisms of the disease, to study the effect of cigarette smoking on susceptibility to PLCH and to identify potential new biomarkers.

Results: Two-dimensional electrophoresis and image analysis revealed proteins that were differently expressed (quantitatively and qualitatively) in the three groups of subjects. The proteins were identified by mass spectrometry and have various functions (antioxidant, proinflammatory, antiprotease) and origins (plasma, locally produced, etc.). Many, such as protease inhibitors (human serpin B3) and antioxidant proteins (glutathione peroxidase and thioredoxin) are already linked to PLCH pathogenesis, whereas other proteins have never been associated with the disease. Interestingly, numerous proteolytic fragments of plasma proteins (including kininogen-1 N fragments and haptoglobin) were also identified and suggest increased proteolytic activity in this inflammatory lung disease. Differences in protein expression were found between the three groups and confirmed by Principal Component Analysis (PCA).

Conclusion: Analysis of BAL proteomes of PLCH patients and of smoker and non-smoker controls also proved to be useful for researching the pathogenetic mechanisms and for identifying biomarkers of this rare diffuse lung disease.

Atherosclerosis results from dyslipidemia and systemic inflammation, associated with the strong metabolism and interaction between diet and disease. Strategies based on the global profiling of metabolism would be important to define the mechanisms involved in pathological alterations. Metabonomics is the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification. Metabonomics has been used in combination with proteomics and transcriptomics as the part of a systems biology description to understand the genome interaction with the development of atherosclerosis. The present review describes the application of metabonomics to explore the potential role of metabolic disturbances and inflammation in the initiation and development of atherosclerosis. Metabonomics-based omics study offers a new potential for biomarker discovery by disentangling the impacts of diet, environment and lifestyle.

Background: Dyslipidemia is an important risk factor for cardiovascular disease and type II diabetes. Lipoprotein diagnostics, such as LDL cholesterol and HDL cholesterol, help to diagnose these diseases. Lipoprotein profile measurements could improve lipoprotein diagnostics, but interpretational complexity has limited their clinical application to date. We have previously developed a computational model called Particle Profiler to interpret lipoprotein profiles. In the current study we further developed and calibrated Particle Profiler using subjects with specific genetic conditions. We subsequently performed technical validation and worked at an initial indication of clinical usefulness starting from available data on lipoprotein concentrations and metabolic fluxes. Since the model outcomes cannot be measured directly, the only available technical validation was corroboration. For an initial indication of clinical usefulness, pooled lipoprotein metabolic flux data was available from subjects with various types of dyslipidemia. Therefore we investigated how well lipoprotein metabolic ratios derived from Particle Profiler distinguished reported dyslipidemic from normolipidemic subjects.

Results: We found that the model could fit a range of normolipidemic and dyslipidemic subjects from fifteen out of sixteen studies equally well, with an average 8.8% ± 5.0% fit error; only one study showed a larger fit error. As initial indication of clinical usefulness, we showed that one diagnostic marker based on VLDL metabolic ratios better distinguished dyslipidemic from normolipidemic subjects than triglycerides, HDL cholesterol, or LDL cholesterol. The VLDL metabolic ratios outperformed each of the classical diagnostics separately; they also added power of distinction when included in a multivariate logistic regression model on top of the classical diagnostics.

Conclusions: In this study we further developed, calibrated, and corroborated the Particle Profiler computational model using pooled lipoprotein metabolic flux data. From pooled lipoprotein metabolic flux data on dyslipidemic patients, we derived VLDL metabolic ratios that better distinguished normolipidemic from dyslipidemic subjects than standard diagnostics, including HDL cholesterol, triglycerides and LDL cholesterol. Since dyslipidemias are closely linked to cardiovascular disease and diabetes type II development, lipoprotein metabolic ratios are candidate risk markers for these diseases. These ratios can in principle be obtained by applying Particle Profiler to a single lipoprotein profile measurement, which makes clinical application feasible.

Network biomarker as a new type of biomarkers with protein-protein interactions was initiated and investigated with the integration of knowledge on protein annotations, interaction, and signaling pathway. A number of methodologies and computational programs have been developed to integrate selected proteins into the knowledge-based networks via the combination of genomics, proteomics and bioinformatics. Alterations of network biomarkers can be monitored and evaluated at different stages and time points during the development of diseases, named dynamic network biomarkers. Dynamic network biomarkers should be furthermore correlated with clinical informatics, including patient complaints, history, therapies, clinical symptoms and signs, physician's examinations, biochemical analyses, imaging profiles, pathologies and other measurements.

Background: The immune response to viral infection is a temporal process, represented by a dynamic and complex network of gene and protein interactions. Here, we present a reverse engineering strategy aimed at capturing the temporal evolution of the underlying Gene Regulatory Networks (GRN). The proposed approach will be an enabling step towards comprehending the dynamic behavior of gene regulation circuitry and mapping the network structure transitions in response to pathogen stimuli.

Results: We applied the Time Varying Dynamic Bayesian Network (TV-DBN) method for reconstructing the gene regulatory interactions based on time series gene expression data for the mouse C57BL/6J inbred strain after infection with influenza A H1N1 (PR8) virus. Initially, 3500 differentially expressed genes were clustered with the use of k-means algorithm. Next, the successive in time GRNs were built over the expression profiles of cluster centroids. Finally, the identified GRNs were examined with several topological metrics and available protein-protein and protein-DNA interaction data, transcription factor and KEGG pathway data.

Conclusions: Our results elucidate the potential of TV-DBN approach in providing valuable insights into the temporal rewiring of the lung transcriptome in response to H1N1 virus.