An assessment of gene regulatory network inference algorithms

A conceptual issue regarding gene regulatory network (GRN) inference algorithms is establishing their validity or correctness. In this study, we argue that for this purpose it is useful to conceive these algorithms as estimators of graph-valued parameters of explicit models for gene expression data. On this basis, we perform an assessment of a selection of influential GRN inference algorithms as estimators for two types of models: (i) causal graphs with associated structural equations models (SEMs), and (ii) differential equations models based on the thermodynamics of gene expression. Our findings corroborate that networks of marginal dependence fail in estimating GRNs, but they also suggest that the strength of statistical association as measured by mutual information may be indicative of GRN structure. Also, in simulations, we find that the GRN inference algorithms GENIE3 and TIGRESS outperform competing algorithms. However, more importantly, we also find that many observed patterns hinge on the GRN topology and the assumed data generating mechanism.Un problema conceptual con respecto a los algoritmos de inferencia de redes de regulación génica (RRG) es cómo establecer su validez. En este estudio sostenemos que para este objetivo conviene concebir estos algoritmos como estimadores de parámetros de modelos estadísticos explícitos para datos de expresión génica. Sobre esta base, realizamos una evaluación de una selección de algoritmos de inferencia de RRG como estimadores para dos tipos de modelos: (i) modelos de grafos causales asociados a modelos de ecuaciones estructurales (MEE), y (ii) modelos de ecuaciones diferenciales basados en la termodinámica de la expresion genica. Nuestros hallazgos corroboran que las redes de dependencias marginales fallan en la estimación de las RRG, pero también sugieren que la fuerza de la asociación estadística medida por la información mutua puede reflejar en cierto grado la estructura de las RRG. Además, en un estudio de simulaciones, encontramos que los algoritmos de inferencia GENIE3 y TIGRESS son los de mejor desempeño. Sin embargo, crucialmente, también encontramos que muchos patrones observados en las simulaciones dependen de la topología de la RRG y del modelo generador de datos.Maestrí

Endotracheal temperature and humidity measurements in laryngectomized patients: intra- and inter-patient variability

This study assesses intra- and inter-patient variability in endotracheal climate (temperature and humidity) and effects of heat and moister exchangers (HME) in 16 laryngectomized individuals, measured repeatedly (N = 47). Inhalation Breath Length (IBL) was 1.35 s without HME and 1.05 s with HME (P < 0.0001). With HME, end-inspiratory (minimum) humidity values increased 5.8 mg H2O/L (P < 0.0001) and minimum temperature values decreased 1.6°C (P < 0.0001). For the temperature and humidity minimums, the inter-patient variability was much smaller than the short- and long-term intra-patient variability. For exhalation breath length and full breath length, the opposite was the case. Conclusions: (1) Because inter-patient variability is smaller than intra-patient variability, investigating endotracheal climate in a limited number of laryngectomized subjects is justified, provided repeated measurements per patient are accomplished; (2) main contributor to intra-patient variability is the positioning of the catheter tip in the trachea; (3) an HME leads to a shortened IBL which enhances the HME effect

A 60-year time series analyses of the upwelling along the Portuguese Coast

Coastal upwelling has a significant local impact on marine coastal environment and on marine biology, namely fisheries. This study aims to evaluate climate and environmental changes in upwelling trends between 1950 and 2010. Annual, seasonal and monthly upwelling trends were studied in three different oceanographic areas of the Portuguese coast (northwestern-NW, southwestern-SW, and south-S). Two sea surface temperature datasets, remote sensing (RS: 1985-2009) and International Comprehensive Ocean-Atmosphere Data Set (ICOADS: 1950-2010), were used to estimate an upwelling index (UPWI) based on the difference between offshore and coastal sea surface temperature. Time series analyses reveal similar yearly and monthly trends between datasets A decrease of the UPWI was observed, extending longer than 20 years in the NW (1956-1979) and SW (1956-1994), and 30 years in the S (1956-1994). Analyses of sudden shifts reveal long term weakening and intensification periods of up to 30 years. This means that in the past 60 years a normal climate UPWI occurred along the Portuguese coast. An intensification of UPWI was recorded in recent decades regardless of the areas (RS: 1985-2009). Such an intensification rate (linear increase in UPWI) is only significant in S in recent decades (increase rate: ICOADS = 0.02 degrees C decade-1; RS = 0.11 degrees C decade-1) while in NW and SW the increase rate is meaningless. In NW more stable UPWI conditions were recorded, however average UPWI values increased in autumn and winter in NW in recently decades (RS: 1985-2009). An intensification rate of UPWI was recorded during summer (July, August and September) in SW and S in latter decades (RS: 1985-2009). The average UPWI values increased in recent decades in autumn in S. Marked phenological changes were observed in S in summer (before downwelling conditions prevail whilst recently when UPWI regimes prevail) with UPWI seasonal regime in S in recent decades becoming similar to those found in SW and NW. Results of this work can contribute to a better understanding of how upwelling dynamics affect/are correlated with biological data.Agência financiadora FCT-Foundation for Science and Technology UID/Multi/04326/2019 CLIMFISH project-A framework for assess vulnerability of coastal fisheries to climate change in Portuguese n2/SAICT/2017t-SAICTinfo:eu-repo/semantics/publishedVersio

Predicting Mortality in COPD with Validated and Sensitive Biomarkers; Fibrinogen and Mid-Range-Proadrenomedullin (MR-proADM)

Although fibrinogen is a FDA qualified prognostic biomarker in COPD, it still lacks sufficient resolution to be clinically useful. Next to replication of findings in different cohorts also the combination with other validated biomarkers should be investigated. Therefore, the aim of this study was to confirm in a large well-defined population of COPD patients whether fibrinogen can predict mortality and whether a combination with the biomarker MR-proADM can increase prognostic accuracy. From the COMIC cohort study we included COPD patients with a blood sample obtained in stable state (n = 640) and/or at hospitalization for an acute exacerbation of COPD (n = 262). Risk of death during 3 years of follow up for the separate and combined biomarker models was analyzed with Cox regression. Furthermore, logistic regression models for death after one year were constructed. When both fibrinogen and MR-proADM were included in the survival model, a doubling in fibrinogen and MR-proADM levels gave a 2.2 (95% CI 1.3-3.7) and 2.1 (95% CI 1.5-3.0) fold increased risk of dying, respectively. The prediction model for death after 1 year improved significantly when MR-proADM was added to the model with fibrinogen (AUC increased from 0.78 to 0.83; p = 0.02). However, the combined model was not significantly more adequate than the model with solely MR-proADM (AUC 0.83 vs 0.82; p = 0.34). The study suggests that MR-proADM is more promising than fibrinogen in prediciting mortality. Adding fibrinogen to a model containing MR-proADM does not significantly increase the predictive capacity of the model

Advancing road ecology in Africa with robust analyses and cautious inferences: a response to Jackson et al. (2017)

Jackson et al. (2017) have written an extensive commentary on our published study of ungulate behavioral responses to roads and traffic in South Africa (Mulero-Pazmany, D’Amico & Gonzalez-Suarez, 2016). We welcome the opportunity to engage in discussion regarding road ecology in Africa and how to best assess impacts and interpret findings. We all agree that understanding anthropogenic impacts, including those of roads and traffic, on wildlife and protected areas is important and that speculative inferences should be avoided. However, we find Jackson et al.’s criticism largely unsubstantiated and affected by statistical misconceptions and errors. We comment on the key points made by Jackson et al. (2017) below

Pharmacological approaches to optimize TB treatment:An individualized approach

In order to improve tuberculosis treatment, an individualized approach is necessary. We plead for individualized dosing based on drug exposure measured in blood – Therapeutic Drug Monitoring (TDM).To measure exposure reliably, multiple blood samples are needed, which is burdening and inconvenient for the patients. Dried blood spot sampling (DBS), a method that uses blood from a finger prick– the technique diabetes patients use to control their blood sugar levels – is a more patient-friendly approach than multiple venous blood drawings, provided that the number of samplings is not excessive. To minimize the number of blood samples, we established a limited sampling strategy for ertapenem. Ertapenem is a carbapenem antibiotic that has not (yet) been accepted for tuberculosis treatment; we discuss the potential use of ertapenem for tuberculosis treatment. We also studied fixed-dose combinations in combination with TDM. Individualization and fixed-dose may seem contradictive but we argue that TDM might detect and correct treatment mistakes resulting from fixed dosing. Susceptibility of Mycobacterium tuberculosis has traditionally been reported as either susceptible or resistant. In this thesis we propose adding a shade of grey; intermediate susceptibility that would represent a dose-dependent susceptibility category. We studied whether patients with M. tuberculosis isolates with intermediate susceptibility could be treated with a higher dose of anti-tuberculosis drugs and if so, if this approach would be cost-effective. We conclude that TDM is useful and feasible, but more research is needed to address as yet unanswered questions

Onder het mes of achter de hand?

Rede uitgesproken door Prof. dr. C.L. Zuur bij de aanvaarding van het ambt van bijzonder hoogleraarKeel-, Neus- en Oorheelkunde, in het bijzonder oncologisch translationeel onderzoek, vanwege het Nederlands Kanker Instituut aan de Universiteit Leiden op maandag 19 september 2022Rede uitgesproken door Prof. dr. C.L. Zuur bij de aanvaarding van het ambt van bijzonder hoogleraar Keel-, Neus- en Oorheelkunde, in het bijzonder oncologisch translationeel onderzoek, vanwege het Nederlands Kanker Instituut aan de Universiteit Leiden op maandag 19 september 2022LUMC / Geneeskund