1,613 research outputs found
Alignment-based conformance checking over probabilistic events
Conformance checking techniques allow us to evaluate how well some exhibited behaviour, represented by a trace of monitored events, conforms to a specified process model. Modern monitoring and activity recognition technologies, such as those relying on sensors, the IoT, statistics and AI, can produce a wealth of relevant event data. However, this data is typically characterised by noise and uncertainty, in contrast to the assumption of a deterministic event log required by conformance checking algorithms. In this paper, we extend alignment-based conformance checking to function under a probabilistic event log. We introduce a weighted trace model and weighted alignment cost function, and a custom threshold parameter that controls the level of confidence on the event data vs. the process model. The resulting algorithm considers activities of lower but sufficiently high probability that better align with the process model. We explain the algorithm and its motivation both from formal and intuitive perspectives, and demonstrate its functionality in comparison with deterministic alignment using real-life datasets
Charting genomic heterogeneity in tumours : from bulk to single cell
Tumours do not consist of a single homogeneous population but are complex heterogeneous systems that contain billions of ever-evolving cells with no two tumours being the same. Tumour heterogeneity is present at three levels, 1) inter-patient heterogeneity; 2) intra-patient heterogeneity; and 3) intra-tumour heterogeneity (ITH). Understanding all levels of heterogeneity is crucial for patient prognosis and treatment choice. To this end, we aimed to improve our understanding of all three levels of tumour heterogeneity.
In paper I we investigated the prevalence, type, length, and genomic distribution of 853.218 somatic copy number alterations (SCNAs) across 20.249 tumours belonging to 32 cancer types. Based on the 1) number of SCNAs; 2) percentage of the genome altered; and 3) average SCNA size, we found high levels of inter-patient heterogeneity, both between and within cancer types. We found that specific chromosomes were preferentially lost or gained depending on cancer type. Lastly, we detected co-alterations of key oncogenes and TSGs. Taken together, we provided a comprehensive analysis on SCNAs across many cancer types as a valuable resource for the community.
In paper II we sought to elucidate intra-patient heterogeneity in non-small cell lung cancer (NSCLC) and their matched brain metastasis (BM). We performed shallow wholegenome sequencing (WGS) on 51 primary NSCLC and matched BM, whole exome sequencing on 40 of the pairs, multi-region sequencing of 15 BMs, and shallow WGS on an additional cohort of 115 BMs. We showed that there is significant intra-patient heterogeneity at the SCNA level, with BM samples showing, on average, more SCNAs compared to their matched NSCLC. In contrast, multi-region sequencing of 15 BMs did not show significant ITH at the level of SCNAs. Finally, we identified putative metastatic driver SCNAs and singlenucleotide variants in key tumour suppressor genes (TSGs) and oncogenes.
In paper III we aimed to assess the level of ITH in early localized prostate cancer. We performed organ-wide, multi-region, single-cell DNA sequencing on two prostate midsections. We found transient chromosomal instability (CIN) both in tumour and normal prostate tissue, evidenced by a large number of cells with unique chromosomal (arm) losses and or gains. Furthermore, we found three distinct groups of cells within the prostate: 1) diploid cells; 2) pseudo-diploid cells; and 3) monster cells. We observed an enrichment of diploid cells in normal regions and pseudo-diploid cells in tumour-rich regions, while monster cells were equally distributed over the entire prostate, again suggesting that there were elevated CIN levels across the prostate. Lastly, we detected highly localized subclones that were exclusive to tumour-rich regions and harboured deletions in TSGs that are known to be frequently deleted in prostate cancer.
Taken together, with this thesis, I have contributed to advance the understanding of inter-patient, intra-patient, and intra-tumour heterogeneity
Pristup specifikaciji i generisanju proizvodnih procesa zasnovan na inΕΎenjerstvu voΔenom modelima
In this thesis, we present an approach to the production process specification and generation based on the model-driven paradigm, with the goal to increase the flexibility of factories and respond to the challenges that emerged in the era of Industry 4.0 more efficiently. To formally specify production processes and their variations in the Industry 4.0 environment, we created a novel domain-specific modeling language, whose models are machine-readable. The created language can be used to model production processes that can be independent of any production system, enabling process models to be used in different production systems, and process models used for the specific production system. To automatically transform production process models dependent on the specific production system into instructions that are to be executed by production system resources, we created an instruction generator. Also, we created generators for different manufacturing documentation, which automatically transform production process models into manufacturing documents of different types. The proposed approach, domain-specific modeling language, and software solution contribute to introducing factories into the digital transformation process. As factories must rapidly adapt to new products and their variations in the era of Industry 4.0, production must be dynamically led and instructions must be automatically sent to factory resources, depending on products that are to be created on the shop floor. The proposed approach contributes to the creation of such a dynamic environment in contemporary factories, as it allows to automatically generate instructions from process models and send them to resources for execution. Additionally, as there are numerous different products and their variations, keeping the required manufacturing documentation up to date becomes challenging, which can be done automatically by using the proposed approach and thus significantly lower process designers' time.Π£ ΠΎΠ²ΠΎΡ Π΄ΠΈΡΠ΅ΡΡΠ°ΡΠΈΡΠΈ ΠΏΡΠ΅Π΄ΡΡΠ°Π²ΡΠ΅Π½ ΡΠ΅ ΠΏΡΠΈΡΡΡΠΏ ΡΠΏΠ΅ΡΠΈΡΠΈΠΊΠ°ΡΠΈΡΠΈ ΠΈ Π³Π΅Π½Π΅ΡΠΈΡΠ°ΡΡ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΠΈΡ
ΠΏΡΠΎΡΠ΅ΡΠ° Π·Π°ΡΠ½ΠΎΠ²Π°Π½ Π½Π° ΠΈΠ½ΠΆΠ΅ΡΠ΅ΡΡΡΠ²Ρ Π²ΠΎΡΠ΅Π½ΠΎΠΌ ΠΌΠΎΠ΄Π΅Π»ΠΈΠΌΠ°, Ρ ΡΠΈΡΡ ΠΏΠΎΠ²Π΅ΡΠ°ΡΠ° ΡΠ»Π΅ΠΊΡΠΈΠ±ΠΈΠ»Π½ΠΎΡΡΠΈ ΠΏΠΎΡΡΡΠΎΡΠ΅ΡΠ° Ρ ΡΠ°Π±ΡΠΈΠΊΠ°ΠΌΠ° ΠΈ Π΅ΡΠΈΠΊΠ°ΡΠ½ΠΈΡΠ΅Π³ ΡΠ°Π·ΡΠ΅ΡΠ°Π²Π°ΡΠ° ΠΈΠ·Π°Π·ΠΎΠ²Π° ΠΊΠΎΡΠΈ ΡΠ΅ ΠΏΠΎΡΠ°Π²ΡΡΡΡ Ρ Π΅ΡΠΈ ΠΠ½Π΄ΡΡΡΡΠΈΡΠ΅ 4.0. ΠΠ° ΠΏΠΎΡΡΠ΅Π±Π΅ ΡΠΎΡΠΌΠ°Π»Π½Π΅ ΡΠΏΠ΅ΡΠΈΡΠΈΠΊΠ°ΡΠΈΡΠ΅ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΠΈΡ
ΠΏΡΠΎΡΠ΅ΡΠ° ΠΈ ΡΠΈΡ
ΠΎΠ²ΠΈΡ
Π²Π°ΡΠΈΡΠ°ΡΠΈΡΠ° Ρ Π°ΠΌΠ±ΠΈΡΠ΅Π½ΡΡ ΠΠ½Π΄ΡΡΡΡΠΈΡΠ΅ 4.0, ΠΊΡΠ΅ΠΈΡΠ°Π½ ΡΠ΅ Π½ΠΎΠ²ΠΈ Π½Π°ΠΌΠ΅Π½ΡΠΊΠΈ ΡΠ΅Π·ΠΈΠΊ, ΡΠΈΡΠ΅ ΠΌΠΎΠ΄Π΅Π»Π΅ ΡΠ°ΡΡΠ½Π°Ρ ΠΌΠΎΠΆΠ΅ Π΄Π° ΠΎΠ±ΡΠ°Π΄ΠΈ Π½Π° Π°ΡΡΠΎΠΌΠ°ΡΠΈΠ·ΠΎΠ²Π°Π½ Π½Π°ΡΠΈΠ½. ΠΡΠ΅ΠΈΡΠ°Π½ΠΈ ΡΠ΅Π·ΠΈΠΊ ΠΈΠΌΠ° ΠΌΠΎΠ³ΡΡΠ½ΠΎΡΡ ΠΌΠΎΠ΄Π΅Π»ΠΎΠ²Π°ΡΠ° ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΠΈΡ
ΠΏΡΠΎΡΠ΅ΡΠ° ΠΊΠΎΡΠΈ ΠΌΠΎΠ³Ρ Π±ΠΈΡΠΈ Π½Π΅Π·Π°Π²ΠΈΡΠ½ΠΈ ΠΎΠ΄ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΠΈΡ
ΡΠΈΡΡΠ΅ΠΌΠ° ΠΈ ΡΠΈΠΌΠ΅ ΡΠΏΠΎΡΡΠ΅Π±ΡΠ΅Π½ΠΈ Ρ ΡΠ°Π·Π»ΠΈΡΠΈΡΠΈΠΌ ΠΏΠΎΡΡΡΠΎΡΠ΅ΡΠΈΠΌΠ° ΠΈΠ»ΠΈ ΡΠ°Π±ΡΠΈΠΊΠ°ΠΌΠ°, Π°Π»ΠΈ ΠΈ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΠΈΡ
ΠΏΡΠΎΡΠ΅ΡΠ° ΠΊΠΎΡΠΈ ΡΡ ΡΠΏΠ΅ΡΠΈΡΠΈΡΠ½ΠΈ Π·Π° ΠΎΠ΄ΡΠ΅ΡΠ΅Π½ΠΈ ΡΠΈΡΡΠ΅ΠΌ. ΠΠ°ΠΊΠΎ Π±ΠΈ ΠΌΠΎΠ΄Π΅Π»Π΅ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΠΈΡ
ΠΏΡΠΎΡΠ΅ΡΠ° Π·Π°Π²ΠΈΡΠ½ΠΈΡ
ΠΎΠ΄ ΠΊΠΎΠ½ΠΊΡΠ΅ΡΠ½ΠΎΠ³ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΠΎΠ³ ΡΠΈΡΡΠ΅ΠΌΠ° Π±ΠΈΠ»ΠΎ ΠΌΠΎΠ³ΡΡΠ΅ Π½Π° Π°ΡΡΠΎΠΌΠ°ΡΠΈΠ·ΠΎΠ²Π°Π½ Π½Π°ΡΠΈΠ½ ΡΡΠ°Π½ΡΡΠΎΡΠΌΠΈΡΠ°ΡΠΈ Ρ ΠΈΠ½ΡΡΡΡΠΊΡΠΈΡΠ΅ ΠΊΠΎΡΠ΅ ΡΠ΅ΡΡΡΡΠΈ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΠΎΠ³ ΡΠΈΡΡΠ΅ΠΌΠ° ΠΈΠ·Π²ΡΡΠ°Π²Π°ΡΡ, ΠΊΡΠ΅ΠΈΡΠ°Π½ ΡΠ΅ Π³Π΅Π½Π΅ΡΠ°ΡΠΎΡ ΠΈΠ½ΡΡΡΡΠΊΡΠΈΡΠ°. Π’Π°ΠΊΠΎΡΠ΅ ΡΡ ΠΊΡΠ΅ΠΈΡΠ°Π½ΠΈ ΠΈ Π³Π΅Π½Π΅ΡΠ°ΡΠΎΡΠΈ ΡΠ΅Ρ
Π½ΠΈΡΠΊΠ΅ Π΄ΠΎΠΊΡΠΌΠ΅Π½ΡΠ°ΡΠΈΡΠ΅, ΠΊΠΎΡΠΈ Π½Π° Π°ΡΡΠΎΠΌΠ°ΡΠΈΠ·ΠΎΠ²Π°Π½ Π½Π°ΡΠΈΠ½ ΡΡΠ°Π½ΡΡΠΎΡΠΌΠΈΡΡ ΠΌΠΎΠ΄Π΅Π»Π΅ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΠΈΡ
ΠΏΡΠΎΡΠ΅ΡΠ° Ρ Π΄ΠΎΠΊΡΠΌΠ΅Π½ΡΠ΅ ΡΠ°Π·Π»ΠΈΡΠΈΡΠΈΡ
ΡΠΈΠΏΠΎΠ²Π°. Π£ΠΏΠΎΡΡΠ΅Π±ΠΎΠΌ ΠΏΡΠ΅Π΄Π»ΠΎΠΆΠ΅Π½ΠΎΠ³ ΠΏΡΠΈΡΡΡΠΏΠ°, Π½Π°ΠΌΠ΅Π½ΡΠΊΠΎΠ³ ΡΠ΅Π·ΠΈΠΊΠ° ΠΈ ΡΠΎΡΡΠ²Π΅ΡΡΠΊΠΎΠ³ ΡΠ΅ΡΠ΅ΡΠ° Π΄ΠΎΠΏΡΠΈΠ½ΠΎΡΠΈ ΡΠ΅ ΡΠ²ΠΎΡΠ΅ΡΡ ΡΠ°Π±ΡΠΈΠΊΠ° Ρ ΠΏΡΠΎΡΠ΅Ρ Π΄ΠΈΠ³ΠΈΡΠ°Π»Π½Π΅ ΡΡΠ°Π½ΡΡΠΎΡΠΌΠ°ΡΠΈΡΠ΅. ΠΠ°ΠΊΠΎ ΡΠ°Π±ΡΠΈΠΊΠ΅ Ρ Π΅ΡΠΈ ΠΠ½Π΄ΡΡΡΡΠΈΡΠ΅ 4.0 ΠΌΠΎΡΠ°ΡΡ Π±ΡΠ·ΠΎ Π΄Π° ΡΠ΅ ΠΏΡΠΈΠ»Π°Π³ΠΎΠ΄Π΅ Π½ΠΎΠ²ΠΈΠΌ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄ΠΈΠΌΠ° ΠΈ ΡΠΈΡ
ΠΎΠ²ΠΈΠΌ Π²Π°ΡΠΈΡΠ°ΡΠΈΡΠ°ΠΌΠ°, Π½Π΅ΠΎΠΏΡ
ΠΎΠ΄Π½ΠΎ ΡΠ΅ Π΄ΠΈΠ½Π°ΠΌΠΈΡΠΊΠΈ Π²ΠΎΠ΄ΠΈΡΠΈ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄ΡΡ ΠΈ Π½Π° Π°ΡΡΠΎΠΌΠ°ΡΠΈΠ·ΠΎΠ²Π°Π½ Π½Π°ΡΠΈΠ½ ΡΠ»Π°ΡΠΈ ΠΈΠ½ΡΡΡΡΠΊΡΠΈΡΠ΅ ΡΠ΅ΡΡΡΡΠΈΠΌΠ° Ρ ΡΠ°Π±ΡΠΈΡΠΈ, Ρ Π·Π°Π²ΠΈΡΠ½ΠΎΡΡΠΈ ΠΎΠ΄ ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π° ΠΊΠΎΡΠΈ ΡΠ΅ ΠΊΡΠ΅ΠΈΡΠ°ΡΡ Ρ ΠΊΠΎΠ½ΠΊΡΠ΅ΡΠ½ΠΎΠΌ ΠΏΠΎΡΡΡΠΎΡΠ΅ΡΡ. Π’ΠΈΠΌΠ΅ ΡΡΠΎ ΡΠ΅ Ρ ΠΏΡΠ΅Π΄Π»ΠΎΠΆΠ΅Π½ΠΎΠΌ ΠΏΡΠΈΡΡΡΠΏΡ ΠΌΠΎΠ³ΡΡΠ΅ ΠΈΠ· ΠΌΠΎΠ΄Π΅Π»Π° ΠΏΡΠΎΡΠ΅ΡΠ° Π°ΡΡΠΎΠΌΠ°ΡΠΈΠ·ΠΎΠ²Π°Π½ΠΎ Π³Π΅Π½Π΅ΡΠΈΡΠ°ΡΠΈ ΠΈΠ½ΡΡΡΡΠΊΡΠΈΡΠ΅ ΠΈ ΠΏΠΎΡΠ»Π°ΡΠΈ ΠΈΡ
ΡΠ΅ΡΡΡΡΠΈΠΌΠ°, Π΄ΠΎΠΏΡΠΈΠ½ΠΎΡΠΈ ΡΠ΅ ΠΊΡΠ΅ΠΈΡΠ°ΡΡ ΡΠ΅Π΄Π½ΠΎΠ³ Π΄ΠΈΠ½Π°ΠΌΠΈΡΠΊΠΎΠ³ ΠΎΠΊΡΡΠΆΠ΅ΡΠ° Ρ ΡΠ°Π²ΡΠ΅ΠΌΠ΅Π½ΠΈΠΌ ΡΠ°Π±ΡΠΈΠΊΠ°ΠΌΠ°. ΠΠΎΠ΄Π°ΡΠ½ΠΎ, ΡΡΠ»Π΅Π΄ Π²Π΅Π»ΠΈΠΊΠΎΠ³ Π±ΡΠΎΡΠ° ΡΠ°Π·Π»ΠΈΡΠΈΡΠΈΡ
ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π° ΠΈ ΡΠΈΡ
ΠΎΠ²ΠΈΡ
Π²Π°ΡΠΈΡΠ°ΡΠΈΡΠ°, ΠΏΠΎΡΡΠ°ΡΠ΅ ΠΈΠ·Π°Π·ΠΎΠ²Π½ΠΎ ΠΎΠ΄ΡΠΆΠ°Π²Π°ΡΠΈ Π½Π΅ΠΎΠΏΡ
ΠΎΠ΄Π½Ρ ΡΠ΅Ρ
Π½ΠΈΡΠΊΡ Π΄ΠΎΠΊΡΠΌΠ΅Π½ΡΠ°ΡΠΈΡΡ, ΡΡΠΎ ΡΠ΅ Ρ ΠΏΡΠ΅Π΄Π»ΠΎΠΆΠ΅Π½ΠΎΠΌ ΠΏΡΠΈΡΡΡΠΏΡ ΠΌΠΎΠ³ΡΡΠ΅ ΡΡΠ°Π΄ΠΈΡΠΈ Π½Π° Π°ΡΡΠΎΠΌΠ°ΡΠΈΠ·ΠΎΠ²Π°Π½ Π½Π°ΡΠΈΠ½ ΠΈ ΡΠΈΠΌΠ΅ Π·Π½Π°ΡΠ°ΡΠ½ΠΎ ΡΡΡΠ΅Π΄Π΅ΡΠΈ Π²ΡΠ΅ΠΌΠ΅ ΠΏΡΠΎΡΠ΅ΠΊΡΠ°Π½Π°ΡΠ° ΠΏΡΠΎΡΠ΅ΡΠ°.U ovoj disertaciji predstavljen je pristup specifikaciji i generisanju proizvodnih procesa zasnovan na inΕΎenjerstvu voΔenom modelima, u cilju poveΔanja fleksibilnosti postrojenja u fabrikama i efikasnijeg razreΕ‘avanja izazova koji se pojavljuju u eri Industrije 4.0. Za potrebe formalne specifikacije proizvodnih procesa i njihovih varijacija u ambijentu Industrije 4.0, kreiran je novi namenski jezik, Δije modele raΔunar moΕΎe da obradi na automatizovan naΔin. Kreirani jezik ima moguΔnost modelovanja proizvodnih procesa koji mogu biti nezavisni od proizvodnih sistema i time upotrebljeni u razliΔitim postrojenjima ili fabrikama, ali i proizvodnih procesa koji su specifiΔni za odreΔeni sistem. Kako bi modele proizvodnih procesa zavisnih od konkretnog proizvodnog sistema bilo moguΔe na automatizovan naΔin transformisati u instrukcije koje resursi proizvodnog sistema izvrΕ‘avaju, kreiran je generator instrukcija. TakoΔe su kreirani i generatori tehniΔke dokumentacije, koji na automatizovan naΔin transformiΕ‘u modele proizvodnih procesa u dokumente razliΔitih tipova. Upotrebom predloΕΎenog pristupa, namenskog jezika i softverskog reΕ‘enja doprinosi se uvoΔenju fabrika u proces digitalne transformacije. Kako fabrike u eri Industrije 4.0 moraju brzo da se prilagode novim proizvodima i njihovim varijacijama, neophodno je dinamiΔki voditi proizvodnju i na automatizovan naΔin slati instrukcije resursima u fabrici, u zavisnosti od proizvoda koji se kreiraju u konkretnom postrojenju. Time Ε‘to je u predloΕΎenom pristupu moguΔe iz modela procesa automatizovano generisati instrukcije i poslati ih resursima, doprinosi se kreiranju jednog dinamiΔkog okruΕΎenja u savremenim fabrikama. Dodatno, usled velikog broja razliΔitih proizvoda i njihovih varijacija, postaje izazovno odrΕΎavati neophodnu tehniΔku dokumentaciju, Ε‘to je u predloΕΎenom pristupu moguΔe uraditi na automatizovan naΔin i time znaΔajno uΕ‘tedeti vreme projektanata procesa
Effects of municipal smoke-free ordinances on secondhand smoke exposure in the Republic of Korea
ObjectiveTo reduce premature deaths due to secondhand smoke (SHS) exposure among non-smokers, the Republic of Korea (ROK) adopted changes to the National Health Promotion Act, which allowed local governments to enact municipal ordinances to strengthen their authority to designate smoke-free areas and levy penalty fines. In this study, we examined national trends in SHS exposure after the introduction of these municipal ordinances at the city level in 2010.MethodsWe used interrupted time series analysis to assess whether the trends of SHS exposure in the workplace and at home, and the primary cigarette smoking rate changed following the policy adjustment in the national legislation in ROK. Population-standardized data for selected variables were retrieved from a nationally representative survey dataset and used to study the policy actionβs effectiveness.ResultsFollowing the change in the legislation, SHS exposure in the workplace reversed course from an increasing (18% per year) trend prior to the introduction of these smoke-free ordinances to a decreasing (β10% per year) trend after adoption and enforcement of these laws (Ξ²2β=β0.18, p-valueβ=β0.07; Ξ²3β=ββ0.10, p-valueβ=β0.02). SHS exposure at home (Ξ²2β=β0.10, p-valueβ=β0.09; Ξ²3β=ββ0.03, p-valueβ=β0.14) and the primary cigarette smoking rate (Ξ²2β=β0.03, p-valueβ=β0.10; Ξ²3β=β0.008, p-valueβ=β0.15) showed no significant changes in the sampled period. Although analyses stratified by sex showed that the allowance of municipal ordinances resulted in reduced SHS exposure in the workplace for both males and females, they did not affect the primary cigarette smoking rate as much, especially among females.ConclusionStrengthening the role of local governments by giving them the authority to enact and enforce penalties on SHS exposure violation helped ROK to reduce SHS exposure in the workplace. However, smoking behaviors and related activities seemed to shift to less restrictive areas such as on the streets and in apartment hallways, negating some of the effects due to these ordinances. Future studies should investigate how smoke-free policies beyond public places can further reduce the SHS exposure in ROK
Design of new algorithms for gene network reconstruction applied to in silico modeling of biomedical data
Programa de Doctorado en BiotecnologΓa, IngenierΓa y TecnologΓa QuΓmicaLΓnea de InvestigaciΓ³n: IngenierΓa, Ciencia de Datos y BioinformΓ‘ticaClave Programa: DBICΓ³digo LΓnea: 111The root causes of disease are still poorly understood. The success of current therapies is limited because persistent diseases are frequently treated based on their symptoms rather than the underlying cause of the disease. Therefore, biomedical research is experiencing a technology-driven shift to data-driven holistic approaches to better characterize the molecular mechanisms causing disease. Using omics data as an input, emerging disciplines like network biology attempt to model the relationships between biomolecules. To this effect, gene co- expression networks arise as a promising tool for deciphering the relationships between genes in large transcriptomic datasets. However, because of their low specificity and high false positive rate, they demonstrate a limited capacity to retrieve the disrupted mechanisms that lead to disease onset, progression, and maintenance. Within the context of statistical modeling, we dove deeper into the reconstruction of gene co-expression networks with the specific goal of discovering disease-specific features directly from expression data. Using ensemble techniques, which combine the results of various metrics, we were able to more precisely capture biologically significant relationships between genes. We were able to find de novo potential disease-specific features with the help of prior biological knowledge and the development of new network inference techniques.
Through our different approaches, we analyzed large gene sets across multiple samples and used gene expression as a surrogate marker for the inherent biological processes, reconstructing robust gene co-expression networks that are simple to explore. By mining disease-specific gene co-expression networks we come up with a useful framework for identifying new omics-phenotype associations from conditional expression datasets.In this sense, understanding diseases from the perspective of biological network perturbations will improve personalized medicine, impacting rational biomarker discovery, patient stratification and drug design, and ultimately leading to more targeted therapies.Universidad Pablo de Olavide de Sevilla. Departamento de Deporte e InformΓ‘tic
Characterising natural ventilation through open windows in the presence of wind: a theoretical and experimental investigation into the interaction between window geometry and environmental forces, and its application to envelope flow models of natural ventilation
Natural ventilation systems utilise pressure differentials that arise from wind and buoyancy forces to drive air through buildings. Natural ventilation is typically described using envelope flow models. These are used to size window openings at the design stage, and to predict the annual dynamic thermal performance of buildings. However, envelope flow models rely on highly idealised descriptions of flow through ventilation openings, which do not model realistic window geometries encountered in practice, and assume that ambient air is static. When envelope flow models are applied to building design, inadequate accounting for phenomena relating to wind and opening geometry can lead to under-sized ventilation openings and under-performing buildings.
This thesis develops empirical models that characterise the effect of wind and window geometry on ventilation rates through square orifices and square, hinged openings. To ensure that these models can be applied in the design case to an arbitrary building geometry, these models are characterised using conditions local to the opening. Here the effect of wind is accounted for by a simulated cross-flow parallel to the building façade, and dimensional scaling arguments are applied to develop empirical models of wind driven phenomena based on similarity theory. Three experimental conditions are modelled: still-air tests that measure the ventilation capacity of an opening in idealised conditions; local pressure tests that measure the wind-induced static pressure differential over an opening when no flow occurs through that opening; and dynamic flow tests that measure the ventilation capacity of an opening between these limits.
To validate the use of these local-scale models in building design, this work is then extended to predict the ventilation in a simple two-zone building. This requires the measurement of the speed and direction of the cross-flow on the building façades, and to that end a novel probe is developed that enables simultaneous measurements of these parameters. Wind-tunnel experiments are then used to measure the ventilation rate achieved in the model building, and the results are compared against the predictions of the local-scale window-characterisation models developed in this thesis. The results show an improvement over current models, which tend to overestimate ventilation rates.
This thesis shows that free area models, which are widely used to predict the ventilation capacity of windows, tend to systematically overestimate ventilation rate through simple hinged openings in still air. The Empirical Effective Area Model described in this thesis can be used to predict idealised discharge coefficients with a coefficient of determination of 0.98, compared to 0.57-0.74 for free area models.
A wind-driven cross-flow is shown to interact with window geometry to alter the local pressure field over the surface of an opening. This thesis develops experimental techniques to characterise this change in pressure using a local pressure coefficient. This is used to specify a local dimensionless pressure which is shown to describe the transition between inflow and outflow through an opening. Empirical equations are developed that characterise the local pressure coefficient for square hinged windows as a function of flow approach angle and opening angle, with a coefficient of determination of 0.98.
The generation of non-zero local pressure coefficients is shown to result in orifice discharge coefficients that tend to Β±β as the dimensionless room pressure tends to zero. Dimensional analysis is used to suggest the total dimensionless volume flow rate as an alternative metric to characterise the ventilation capacity of an opening. This is shown to tend to the idealised discharge coefficient in still-air conditions, and to tend to zero as the local dimensionless pressure tends to zero. The total dimensionless volume flow rate is shown to be finite across the whole range of potential local dimensionless pressure values, and holds positive values for outflow and negative values for inflow. Empirical models are developed to predict the total dimensionless volume flow rate through a square orifice and a square, hinged window as a function of local dimensionless pressure, flow approach angle and opening angle. Coefficients of determination are between 0.975 and 0.984 for the hinged window and between 0.993 and 0.995 for the square orifice, depending on the opening direction and the direction of flow through the opening.
The speed and direction of the cross-flow on the façade of a model cube in a simulated atmospheric boundary layer were measured using the novel cross-flow probe developed in this thesis. Here, mean cross-flow speeds measured with the novel probe agree well with hot-wire measurements. The cross-flow measurements reveal a tetra-modal distribution in façade cross-flow direction, which interacts with a uni-modal variation in cross-flow speed to generate bi-modal distributions in the x and y velocity components at all measured wind angles. This data is used to generate profiles of mean cross-flow speed and mean façade cross-flow direction with wind angle, which are used as inputs to the empirical equations developed to describe the total dimensionless volume flow rate through isolated window openings.
The empirical models used to describe the total dimensionless volume flow rate through isolated windows is used to predict measured ventilation rates in a model building with an internal partition, with a coefficient of determination between 0.94 and 0.99, depending on the ventilation configuration. This compares with coefficients of determination between -0.4 and 0.08 found when applying a conventional orifice flow model. Conventional orifice flow models are predicted to provide good estimates of net volume flow rates through buildings with simple orifice-type openings when the internal resistance is lower than that of either of the external openings. As the internal resistance increases, the orifice flow equation is predicted to increasingly overestimate net volume flow rates.
This work contributes to knowledge by: quantifying the systematic errors arising from the use of free area models common to natural ventilation design; developing an empirical model that describes an idealised discharge coefficient of a family of hinged openings as a function of geometric parameters; identifying novel dimensionless parameters that characterise the change in static pressure across an opening that results from the interaction between wind and window geometry; developing experimental techniques that provide a simple and unambiguous measurement of the local pressure coefficient; experimentally and empirically describing the aerodynamic performance of a simple, square, hinged window in wind-driven conditions; developing a cross-flow probe that can measure the instantaneous speed and direction of wind-driven flow over the surface of a building; quantifying the systematic errors associated with the use of a range of calculation methodologies used to estimate the ventilation rate in a simple model building; and providing practical design guidance to minimise the effect of calculation errors that arise from the use of conventional envelope flow models in wind-driven conditions, when adequate data to describe the phenomena is unavailable
Measuring the impact of COVID-19 on hospital care pathways
Care pathways in hospitals around the world reported significant disruption during the recent COVID-19 pandemic but measuring the actual impact is more problematic. Process mining can be useful for hospital management to measure the conformance of real-life care to what might be considered normal operations. In this study, we aim to demonstrate that process mining can be used to investigate process changes associated with complex disruptive events. We studied perturbations to accident and emergency (A &E) and maternity pathways in a UK public hospital during the COVID-19 pandemic. Co-incidentally the hospital had implemented a Command Centre approach for patient-flow management affording an opportunity to study both the planned improvement and the disruption due to the pandemic. Our study proposes and demonstrates a method for measuring and investigating the impact of such planned and unplanned disruptions affecting hospital care pathways. We found that during the pandemic, both A &E and maternity pathways had measurable reductions in the mean length of stay and a measurable drop in the percentage of pathways conforming to normative models. There were no distinctive patterns of monthly mean values of length of stay nor conformance throughout the phases of the installation of the hospitalβs new Command Centre approach. Due to a deficit in the available A &E data, the findings for A &E pathways could not be interpreted
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