Multiomics Longitudinal Modeling of Preeclamptic Pregnancies

Preeclampsia is a complex disease of pregnancy whose physiopathology remains unclear and that poses a threat to both mothers and infants. Specific complex changes in women\u27s physiology precede a diagnosis of preeclampsia. Understanding multiple aspects of such a complex changes at different levels of biology, can be enabled by simultaneous application of multiple assays. We developed prediction models for preeclampsia risk by analyzing six omics datasets from a longitudinal cohort of pregnant women. A machine learning-based multiomics model had high accuracy (area under the receiver operating characteristics curve (AUC) of 0.94, 95% confidence intervals (CI):[0.90, 0.99]). A prediction model using only ten urine metabolites provided an accuracy of the whole metabolomic dataset and was validated using an independent cohort of 16 women (AUC= 0.87, 95% CI:[0.76, 0.99]). Integration with clinical variables further improved prediction accuracy of the urine metabolome model (AUC= 0.90, 95% CI:[0.80, 0.99], urine metabolome, validated). We identified several biological pathways to be associated with preeclampsia. The findings derived from models were integrated with immune system cytometry data, confirming known physiological alterations associated with preeclampsia and suggesting novel associations between the immune and proteomic dynamics. While further validation in larger populations is necessary, these encouraging results will serve as a basis for a simple, early diagnostic test for preeclampsia

MuCIGREF: multiple computer-interpretable guideline representation and execution framework for managing multimobidity care

Clinical Practice Guidelines (CPGs) supply evidence-based recommendations to healthcare professionals (HCPs) for the care of patients. Their use in clinical practice has many benefits for patients, HCPs and treating medical centres, such as enhancing the quality of care, and reducing unwanted care variations. However, there are many challenges limiting their implementations. Initially, CPGs predominantly consider a specific disease, and only few of them refer to multimorbidity (i.e. the presence of two or more health conditions in an individual) and they are not able to adapt to dynamic changes in patient health conditions. The manual management of guideline recommendations are also challenging since recommendations may adversely interact with each other due to their competing targets and/or they can be duplicated when multiple of them are concurrently applied to a multimorbid patient. These may result in undesired outcomes such as severe disability, increased hospitalisation costs and many others. Formalisation of CPGs into a Computer Interpretable Guideline (CIG) format, allows the guidelines to be interpreted and processed by computer applications, such as Clinical Decision Support Systems (CDSS). This enables provision of automated support to manage the limitations of guidelines. This thesis introduces a new approach for the problem of combining multiple concurrently implemented CIGs and their interrelations to manage multimorbidity care. MuCIGREF (Multiple Computer-Interpretable Guideline Representation and Execution Framework), is proposed whose specific objectives are to present (1) a novel multiple CIG representation language, MuCRL, where a generic ontology is developed to represent knowledge elements of CPGs and their interrelations, and to create the multimorbidity related associations between them. A systematic literature review is conducted to discover CPG representation requirements and gaps in multimorbidity care management. The ontology is built based on the synthesis of well-known ontology building lifecycle methodologies. Afterwards, the ontology is transformed to a metamodel to support the CIG execution phase; and (2) a novel real-time multiple CIG execution engine, MuCEE, where CIG models are dynamically combined to generate consistent and personalised care plans for multimorbid patients. MuCEE involves three modules as (i) CIG acquisition module, transfers CIGs to the personal care plan based on the patient’s health conditions and to supply CIG version control; (ii) parallel CIG execution module, combines concurrently implemented multiple CIGs by performing concurrency management, time-based synchronisation (e.g., multi-activity merging), modification, and timebased optimisation of clinical activities; and (iii) CIG verification module, checks missing information, and inconsistencies to support CIG execution phases. Rulebased execution algorithms are presented for each module. Afterwards, a set of verification and validation analyses are performed involving real-world multimorbidity cases studies and comparative analyses with existing works. The results show that the proposed framework can combine multiple CIGs and dynamically merge, optimise and modify multiple clinical activities of them involving patient data. This framework can be used to support HCPs in a CDSS setting to generate unified and personalised care recommendations for multimorbid patients while merging multiple guideline actions and eliminating care duplications to maintain their safety and supplying optimised health resource management, which may improve operational and cost efficiency in real world-cases, as well

Proteome Profiling of Breast Tumors by Gel Electrophoresis and Nanoscale Electrospray Ionization Mass Spectrometry

We have conducted proteome-wide analysis of fresh surgery specimens derived from breast cancer patients, using an approach that integrates size-based intact protein fractionation, nanoscale liquid separation of peptides, electrospray ion trap mass spectrometry, and bioinformatics. Through this approach, we have acquired a large amount of peptide fragmentation spectra from size-resolved fractions of the proteomes of several breast tumors, tissue peripheral to the tumor, and samples from patients undergoing noncancer surgery. Label-free quantitation was used to generate protein abundance maps for each proteome and perform comparative analyses. The mass spectrometry data revealed distinct qualitative and quantitative patterns distinguishing the tumors from healthy tissue as well as differences between metastatic and non-metastatic human breast cancers including many established and potential novel candidate protein biomarkers. Selected proteins were evaluated by Western blotting using tumors grouped according to histological grade, size, and receptor expression but differing in nodal status. Immunohistochemical analysis of a wide panel of breast tumors was conducted to assess expression in different types of breast cancers and the cellular distribution of the candidate proteins. These experiments provided further insights and an independent validation of the data obtained by mass spectrometry and revealed the potential of this approach for establishing multimodal markers for early metastasis, therapy outcomes, prognosis, and diagnosis in the future. © 2008 American Chemical Society

Barry Smith an sich

Festschrift in Honor of Barry Smith on the occasion of his 65th Birthday. Published as issue 4:4 of the journal Cosmos + Taxis: Studies in Emergent Order and Organization. Includes contributions by Wolfgang Grassl, Nicola Guarino, John T. Kearns, Rudolf Lüthe, Luc Schneider, Peter Simons, Wojciech Żełaniec, and Jan Woleński

Local Network Topology in Human Protein Interaction Data Predicts Functional Association

The use of high-throughput techniques to generate large volumes of protein-protein interaction (PPI) data has increased the need for methods that systematically and automatically suggest functional relationships among proteins. In a yeast PPI network, previous work has shown that the local connection topology, particularly for two proteins sharing an unusually large number of neighbors, can predict functional association. In this study we improved the prediction scheme by developing a new algorithm and applied it on a human PPI network to make a genome-wide functional inference. We used the new algorithm to measure and reduce the influence of hub proteins on detecting function-associated protein pairs. We used the annotations of the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) as benchmarks to compare and evaluate the function relevance. The application of our algorithms to human PPI data yielded 4,233 significant functional associations among 1,754 proteins. Further functional comparisons between them allowed us to assign 466 KEGG pathway annotations to 274 proteins and 123 GO annotations to 114 proteins with estimated false discovery rates of <21% for KEGG and <30% for GO. We clustered 1,729 proteins by their functional associations and made functional inferences from detailed analysis on one subcluster highly enriched in the TGF-β signaling pathway (P<10−50). Analysis of another four subclusters also suggested potential new players in six signaling pathways worthy of further experimental investigations. Our study gives clear insight into the common neighbor-based prediction scheme and provides a reliable method for large-scale functional annotation in this post-genomic era

A Multi-Layered Study on Harmonic Oscillations in Mammalian Genomics and Proteomics

Cellular, organ, and whole animal physiology show temporal variation predominantly featuring 24-h (circadian) periodicity. Time-course mRNA gene expression profiling in mouse liver showed two subsets of genes oscillating at the second (12-h) and third (8-h) harmonic of the prime (24-h) frequency. The aim of our study was to identify specific genomic, proteomic, and functional properties of ultradian and circadian subsets. We found hallmarks of the three oscillating gene subsets, including different (i) functional annotation, (ii) proteomic and electrochemical features, and (iii) transcription factor binding motifs in upstream regions of 8-h and 12-h oscillating genes that seemingly allow the link of the ultradian gene sets to a known circadian network. Our multifaceted bioinformatics analysis of circadian and ultradian genes suggests that the different rhythmicity of gene expression impacts physiological outcomes and may be related to transcriptional, translational and post-translational dynamics, as well as to phylogenetic and evolutionary components