A perspective for biomedical data integration: Design of databases for flow cytometry

<p>Abstract</p> <p>Background</p> <p>The integration of biomedical information is essential for tackling medical problems. We describe a data model in the domain of flow cytometry (FC) allowing for massive management, analysis and integration with other laboratory and clinical information. The paper is concerned with the proper translation of the Flow Cytometry Standard (FCS) into a relational database schema, in a way that facilitates end users at either doing research on FC or studying specific cases of patients undergone FC analysis</p> <p>Results</p> <p>The proposed database schema provides integration of data originating from diverse acquisition settings, organized in a way that allows syntactically simple queries that provide results significantly faster than the conventional implementations of the FCS standard. The proposed schema can potentially achieve up to 8 orders of magnitude reduction in query complexity and up to 2 orders of magnitude reduction in response time for data originating from flow cytometers that record 256 colours. This is mainly achieved by managing to maintain an almost constant number of data-mining procedures regardless of the size and complexity of the stored information.</p> <p>Conclusion</p> <p>It is evident that using single-file data storage standards for the design of databases without any structural transformations significantly limits the flexibility of databases. Analysis of the requirements of a specific domain for integration and massive data processing can provide the necessary schema modifications that will unlock the additional functionality of a relational database.</p

Continuity equation is the echocardiographic method of choice to assess degenerative mitral stenosis

We present a rare case of a patient with severe, symptomatic degenerative calcific mitral stenosis (MS). Calcification of mitral valve annulus (MVA) is a frequent finding in elderly patients. It can be isolated or associated more often with mitral valve insufficiency than MS. In rare cases, it results in severe MS. An accurate measurement of MVA in degenerative calcific MS is problematic because the limiting orifice is near the annulus and not at the leaflet tips as in rheumatic MS. Continuity equation is the best echocardiographic method to assess the MVA in degenerative MS, correlating well with invasive methods. Real-time three-dimensional echocardiography is a promising tool and provides an accurate measurement of MVA in calcific MS, with a very good correlation compared to continuity equation. On the other hand, the use of pressure half-time is often inaccurate and should be avoided, while two-dimensional planimetry is difficult and not reliable in degenerative MS. The values of mean gradient and systolic pulmonary artery pressure depend on several factors and should be only supportive signs and should not be considered as surrogate markers of the severity of MS. (Cardiol J 2011; 18, 5: 577&#8211;580

Evolution of airway inflammation in preschoolers with asthma : results of a two-year longitudinal study

Fractional exhaled nitric oxide (FeNO) is a non-invasive marker for eosinophilic airway inflammation and has been used for monitoring asthma. Here, we assess the characteristics of FeNO from preschool to school age, in parallel with asthma activity. A total of 167 asthmatic children and 66 healthy, age-matched controls were included in the 2-year prospective PreDicta study evaluating wheeze/asthma persistence in preschool-aged children. Information on asthma/rhinitis activity, infections and atopy was recorded at baseline. Follow-up visits were performed at 6-month intervals, as well as upon exacerbation/cold and 4-6 weeks later in the asthmatic group. We obtained 539 FeNO measurements from asthmatics and 42 from controls. At baseline, FeNO values did not differ between the two groups (median: 3.0 ppb vs. 2.0 ppb, respectively). FeNO values at 6, 12, 18 and 24 months (4.0, CI: 0.0-8.6; 6.0, CI: 2.8-12.0; 8.0, CI: 4.0-14.0; 8.5, CI: 4.4-14.5 ppb, respectively) increased with age (correlation p <= 0.001) and atopy (p = 0.03). FeNO was non-significantly increased from baseline to the symptomatic visit, while it decreased after convalescence (p = 0.007). Markers of disease activity, such as wheezing episodes and days with asthma were associated with increased FeNO values during the study (p < 0.05 for all). Age, atopy and disease activity were found to be important FeNO determinants in preschool children. Longitudinal and individualized FeNO assessment may be valuable in monitoring asthmatic children with recurrent wheezing or mild asthma

Myocardial Motion Analysis for Determination of Tei-Index of Human Heart

The Tei index, an important indicator of heart function, lacks a direct method to compute because it is difficult to directly evaluate the isovolumic contraction time (ICT) and isovolumic relaxation time (IRT) from which the Tei index can be obtained. In this paper, based on the proposed method of accurately measuring the cardiac cycle physical phase, a direct method of calculating the Tei index is presented. The experiments based on real heart medical images show the effectiveness of this method. Moreover, a new method of calculating left ventricular wall motion amplitude is proposed and the experiments show its satisfactory performance

Respiratory virome profiles reflect antiviral immune responses

Background: From early life, respiratory viruses are implicated in the development, exacerbation and persistence of respiratory conditions such as asthma. Complex dynamics between microbial communities and host immune responses shape immune maturation and homeostasis, influencing health outcomes. We evaluated the hypothesis that the respiratory virome is linked to systemic immune responses, using peripheral blood and nasopharyngeal swab samples from preschool-age children in the PreDicta cohort. Methods: Peripheral blood mononuclear cells from 51 children (32 asthmatics and 19 healthy controls) participating in the 2-year multinational PreDicta cohort were cultured with bacterial (Bacterial-DNA, LPS) or viral (R848, Poly:IC, RV) stimuli. Supernatants were analysed by Luminex for the presence of 22 relevant cytokines. Virome composition was obtained using untargeted high throughput sequencing of nasopharyngeal samples. The metagenomic data were used for the characterization of virome profiles and the presence of key viral families (Picornaviridae, Anelloviridae, Siphoviridae). These were correlated to cytokine secretion patterns, identified through hierarchical clustering and principal component analysis. Results: High spontaneous cytokine release was associated with increased presence of Prokaryotic virome profiles and reduced presence of Eukaryotic and Anellovirus profiles. Antibacterial responses did not correlate with specific viral families or virome profile; however, low antiviral responders had more Prokaryotic and less Eukaryotic virome profiles. Anelloviruses and Anellovirus-dominated profiles were equally distributed among immune response clusters. The presence of Picornaviridae and Siphoviridae was associated with low interferon-λ responses. Asthma or allergy did not modify these correlations. Conclusion: Antiviral cytokine responses at a systemic level reflect the upper airway virome composition. Individuals with low innate interferon responses have higher abundance of Picornaviruses (mostly Rhinoviruses) and bacteriophages. Bacteriophages, particularly Siphoviridae, appear to be sensitive sensors of host antimicrobial capacity, while Anelloviruses are not correlated with TLR-induced immune responses. Keywords: asthma; bacteriophages; interferon-λ; rhinoviruses; virome

Assessment of pulmonary artery pressure by echocardiography—A comprehensive review

Pulmonary hypertension is a pathological haemodynamic condition defined as an increase in mean pulmonary arterial pressure ≥ 25mmHg at rest, assessed using gold standard investigation by right heart catheterisation. Pulmonary hypertension could be a complication of cardiac or pulmonary disease or a primary disorder of small pulmonary arteries. Elevated pulmonary pressure (PAP) is associated with increased mortality, irrespective of the aetiology. The gold standard for diagnosis is invasive right heart catheterisation, but this has its own inherent risks. In the past 30 years, immense technological improvements in echocardiography have increased its sensitivity for quantifying pulmonary artery pressure (PAP) and it is now recognised as a safe and readily available alternative to right heart catheterisation. In future, scores combining various echo techniques can approach the gold standard in terms of sensitivity and accuracy, thereby reducing the need for repeated invasive assessments in these patients

Evolution of Airway Inflammation in Preschoolers with Asthma-Results of a Two-Year Longitudinal Study

Fractional exhaled nitric oxide (FeNO) is a non-invasive marker for eosinophilic airway inflammation and has been used for monitoring asthma. Here, we assess the characteristics of FeNO from preschool to school age, in parallel with asthma activity. A total of 167 asthmatic children and 66 healthy, age-matched controls were included in the 2-year prospective PreDicta study evaluating wheeze/asthma persistence in preschool-aged children. Information on asthma/rhinitis activity, infections and atopy was recorded at baseline. Follow-up visits were performed at 6-month intervals, as well as upon exacerbation/cold and 4-6 weeks later in the asthmatic group. We obtained 539 FeNO measurements from asthmatics and 42 from controls. At baseline, FeNO values did not differ between the two groups (median: 3.0 ppb vs. 2.0 ppb, respectively). FeNO values at 6, 12, 18 and 24 months (4.0, CI: 0.0-8.6; 6.0, CI: 2.8-12.0; 8.0, CI: 4.0-14.0; 8.5, CI: 4.4-14.5 ppb, respectively) increased with age (correlation p <= 0.001) and atopy (p = 0.03). FeNO was non-significantly increased from baseline to the symptomatic visit, while it decreased after convalescence (p = 0.007). Markers of disease activity, such as wheezing episodes and days with asthma were associated with increased FeNO values during the study (p < 0.05 for all). Age, atopy and disease activity were found to be important FeNO determinants in preschool children. Longitudinal and individualized FeNO assessment may be valuable in monitoring asthmatic children with recurrent wheezing or mild asthma

Statistical learning methodology for the prognosis of B-chronic lymphocytic leukemia (B-CLL) using flow cytometry data

B-Chronic Lymphocytic Leukemia (B-CLL) is known to be the most common type of leukemia in the Western world. Its prognosis remains one of the most interesting decision problems in clinical research and practice. Various clinical and laboratory factors are known to be associated with the evolution of the disease. However, for the parameters obtained by flow cytometry analysis that are traditionally utilized as the cornerstone during the diagnosis procedure of the disease, whether they offer additional prognostic information is an open issue. In this dissertation, we propose a decision support system to the hematologists, that provides multiparametric B-CLL patients’ prognosis, combining the usage of diverse heterogeneous factors (clinical, laboratory and flow cytometry) associated with the disease. B-CLL diagnosis is primarily derived from the study of the antigenic phenotype of the patients’ blood cells, which is held with flow cytometry analysis. Despite the fact that the method of the analysis is well defined, the process traditionally followed by the laboratory experts is characterized by amounts of inexactness and subjectivity. As flow cytometry technology advances rapidly, the need for adequate automated (computer-assisted) analysis methodologies on the data it produces is accordingly increasing. In this context, we present a useful paradigm of automated analysis of flow cytometry data that does not require the direct supervision of the expert, for B-CLL patients’ diagnosis. The values of the flow cytometry characteristic parameters extracted by applying the proposed methodology are afterward incorporated to the prognostic system for B-CLL mentioned above. By reducing the B-CLL prognosis problem to an instance of the pattern classification problem, as well as by simulating each step of the B-CLL diagnosis procedure with an instance of the data classification problem, we proceeded with applying statistical learning techniques. We focused on Bayesian network methodologies and utilized the naïve-Bayes model for both cases, in its supervised and unsupervised version, respectively. The characteristics of the data (especially of the flow cytometry ones) generated by a pathological underlying mechanism, like the disease’s one, did not encourage the direct use of the above model. Therefore, we combined the naïve-Bayes model with a set of suitable heuristic algorithmic procedures to obtain better results, not only with respect to some commonly used algorithmic optimality metrics, but also by considering the experts’ opinion. Due to their ability of incorporating the expert knowledge as a priori initial information to their learning methods, Bayesian methodologies are considered as the most appropriate ones to make use of in such types of applications.Η Β-χρόνια λεμφογενής λευχαιμία (Β-ΧΛΛ) αποτελεί τον πιο κοινό τύπο λευχαιμίας στο Δυτικό κόσμο. Η πρόγνωσή της θεωρείται ως ένα από τα πιο ενδιαφέροντα προβλήματα απόφασης στην κλινική έρευνα και πρακτική. Για διάφορους κλινικούς και εργαστηριακούς δείκτες είναι γνωστό ότι σχετίζονται με την εξέλιξη της νόσου. Για τις παραμέτρους, όμως, που εξάγονται με ανάλυση κυτταρομετρίας ροής, οι οποίες αποτελούν τον ακρογωνιαίο λίθο της διαδικασίας διάγνωσης της νόσου, το αν προσφέρουν επιπρόσθετη προγνωστική πληροφορία αποτελεί ανοιχτό πρόβλημα. Στη διατριβή αυτή προτείνουμε ένα σύστημα υποβοήθησης για τις αποφάσεις των ειδικών του πεδίου, το οποίο πραγματοποιεί πολυπαραμετρική πρόγνωση ασθενών με Β-ΧΛΛ, συνδυάζοντας τη χρήση ποικίλων ετερογενών προγνωστικών δεικτών (κλινικών, εργαστηριακών και κυτταρομετρίας ροής) που σχετίζονται με τη νόσο. Η διάγνωση της Β-ΧΛΛ βασίζεται κυρίως στη μελέτη του αντιγονικού φαινότυπου των κυττάρων των ασθενών, η οποία διενεργείται με κυτταρομετρία ροής. Αν και η διαδικασία που ακολουθείται κατά την ανάλυση αυτή είναι σαφώς ορισμένη, ο τρόπος με τον οποίο οι εργαστηριακοί υπεύθυνοι την πραγματοποιούν παραδοσιακά χαρακτηρίζεται από ανακρίβεια και υποκειμενικότητα. Καθώς η τεχνολογία της κυτταρομετρίας ροής εξελίσσεται ραγδαία, γίνεται όλο και πιο επιτακτική η ανάγκη για την ανάπτυξη αυτοματοποιημένων μεθόδων ανάλυσης των δεδομένων που παράγει. Σε αυτά τα πλαίσια, παρουσιάζουμε ένα χρήσιμο παράδειγμα αυτοματοποιημένης ανάλυσης κυτταρομετρικών δεδομένων, η οποία δεν απαιτεί την άμεση επίβλεψη των ειδικών, για τη διάγνωση ασθενών με Β-ΧΛΛ. Οι τιμές των χαρακτηριστικών παραμέτρων που εξάγονται με εφαρμογή της προτεινόμενης μεθοδολογίας, ενσωματώνονται κατόπιν στο προαναφερθέν προγνωστικό σύστημα. Ανάγοντας το πρόβλημα της πρόγνωσης της Β-ΧΛΛ σε ένα στιγμιότυπο ταξινόμησης προτύπων, καθώς και προσομοιώνοντας κάθε ένα από τα βήματα της διαδικασίας της διάγνωσης της νόσου με ένα στιγμιότυπο συσταδοποίησης δεδομένων, αντιμετωπίσαμε τα δύο προβλήματα εφαρμόζοντας τεχνικές στατιστικής μάθησης. Εστιάσαμε σε μεθοδολογίες δικτύων πεποίθησης, χρησιμοποιώντας συγκεκριμένα το naïve-Bayes μοντέλο και για τις δύο περιπτώσεις, στην επιβλεπόμενη και στη μη επιβλεπόμενη εκδοχή του, αντίστοιχα. Τα χαρακτηριστικά και η φύση των δεδομένων (κυρίως των κυτταρομετρικών) που παράγονται από έναν παθολογικό υποκείμενο μηχανισμό, όπως αυτός της νόσου, δεν ευνοούν την απευθείας εφαρμογή του παραπάνω μοντέλου στο εκάστοτε στιγμιότυπο. Για το λόγο αυτό, συνδυάσαμε την εφαρμογή του naïve-Bayes μοντέλου με κατάλληλες ευρετικές αλγοριθμικές διαδικασίες, για την επίτευξη καλύτερων αποτελεσμάτων, με κριτήριο βέλτιστου όχι μόνο κάποιες συχνά χρησιμοποιούμενες μετρικές αποτίμησης αλγόριθμων, αλλά και τη γνώμη των αιματολόγων. Χάρη στην ιδιότητά τους να ενσωματώνουν την έμπειρη γνώση των ειδικών ως εκ των προτέρων πληροφορία αρχικοποίησης των μεθόδων μάθησής τους, οι Bayesian μεθοδολογίες κρίνονται ως οι πλέον κατάλληλες για την εφαρμογή τους σε τέτοιου τύπου προβλήματα