To systematically review methods developed and employed to evaluate the diagnostic accuracy of medical test when there is a missing or no gold standard.
Articles that proposed or applied any methods ...to evaluate the diagnostic accuracy of medical test(s) in the absence of gold standard were reviewed. The protocol for this review was registered in PROSPERO (CRD42018089349).
Identified methods were classified into four main groups: methods employed when there is a missing gold standard; correction methods (which make adjustment for an imperfect reference standard with known diagnostic accuracy measures); methods employed to evaluate a medical test using multiple imperfect reference standards; and other methods, like agreement studies, and a mixed group of alternative study designs. Fifty-one statistical methods were identified from the review that were developed to evaluate medical test(s) when the true disease status of some participants is unverified with the gold standard. Seven correction methods were identified and four methods were identified to evaluate medical test(s) using multiple imperfect reference standards. Flow-diagrams were developed to guide the selection of appropriate methods.
Various methods have been proposed to evaluate medical test(s) in the absence of a gold standard for some or all participants in a diagnostic accuracy study. These methods depend on the availability of the gold standard, its' application to the participants in the study and the availability of alternative reference standard(s). The clinical application of some of these methods, especially methods developed when there is missing gold standard is however limited. This may be due to the complexity of these methods and/or a disconnection between the fields of expertise of those who develop (e.g. mathematicians) and those who employ the methods (e.g. clinical researchers). This review aims to help close this gap with our classification and guidance tools.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This paper examines the forecasting skill of eight Global Climate Models from the North-American Multi-Model Ensemble project (CCSM3, CCSM4, CanCM3, CanCM4, GFDL2.1, FLORb01, GEOS5, and CFSv2) over ...seven major regions of the continental United States. The skill of the monthly forecasts is quantified using the mean square error skill score. This score is decomposed to assess the accuracy of the forecast in the absence of biases (potential skill) and in the presence of conditional (slope reliability) and unconditional (standardized mean error) biases. We summarize the forecasting skill of each model according to the initialization month of the forecast and lead time, and test the models’ ability to predict extended periods of extreme climate conducive to eight ‘billion-dollar’ historical flood and drought events. Results indicate that the most skillful predictions occur at the shortest lead times and decline rapidly thereafter. Spatially, potential skill varies little, while actual model skill scores exhibit strong spatial and seasonal patterns primarily due to the unconditional biases in the models. The conditional biases vary little by model, lead time, month, or region. Overall, we find that the skill of the ensemble mean is equal to or greater than that of any of the individual models. At the seasonal scale, the drought events are better forecast than the flood events, and are predicted equally well in terms of high temperature and low precipitation. Overall, our findings provide a systematic diagnosis of the strengths and weaknesses of the eight models over a wide range of temporal and spatial scales.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Over the past decade, synthetic biology has emerged as an engineering discipline for biological systems. Compared with other substrates, biology poses a unique set of engineering challenges resulting ...from an incomplete understanding of natural biological systems and tools for manipulating them. To address these challenges, synthetic biology is advancing from developing proof-of-concept designs to focusing on core platforms for rational and high-throughput biological engineering. These platforms span the entire biological design cycle, including DNA construction, parts libraries, computational design tools, and interfaces for manipulating and probing synthetic circuits. The development of these enabling technologies requires an engineering mindset to be applied to biology, with an emphasis on generalizable techniques in addition to application-specific designs. This review aims to discuss the progress and challenges in synthetic biology and to illustrate areas where synthetic biology may impact biomedical engineering and human health.
The transcription factor HIF1A is a key mediator of the cellular response to hypoxia. Despite the importance of HIF1A in homeostasis and various pathologies, little is known about how it regulates ...RNA polymerase II (RNAPII). We report here that HIF1A employs a specific variant of the Mediator complex to stimulate RNAPII elongation. The Mediator-associated kinase CDK8, but not the paralog CDK19, is required for induction of many HIF1A target genes. HIF1A induces binding of CDK8-Mediator and the super elongation complex (SEC), containing AFF4 and CDK9, to alleviate RNAPII pausing. CDK8 is dispensable for HIF1A chromatin binding and histone acetylation, but it is essential for binding of SEC and RNAPII elongation. Global analysis of active RNAPII reveals that hypoxia-inducible genes are paused and active prior to their induction. Our results provide a mechanistic link between HIF1A and CDK8, two potent oncogenes, in the cellular response to hypoxia.
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•CDK8 is a positive regulator of hypoxia-inducible genes•HIF1A associates with and induces binding of CDK8-Mediator to its target loci•CDK8 is required for HIF1A-dependent recruitment of transcription elongation factors•Hypoxia-inducible genes are paused and active prior to HIF1A activation
HIF1A target genes assemble with a paused polymerase under normal oxygen conditions. When oxygen becomes scarce, an interaction between HIF1A and the kinase CDK8, a component of the Mediator complex, releases paused RNAPII and stimulates elongation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Modern molecular mechanics force fields are widely used for modeling the dynamics and interactions of small organic molecules using libraries of transferable force field parameters. However, for ...molecules outside the training set, the parameters are potentially inaccurate and it may be preferable to derive molecule-specific parameters. Here we present an intuitive parameter derivation toolkit, QUBEKit (QUantum mechanical BEspoke Kit), which enables the automated generation of system-specific small molecule force field parameters directly from quantum mechanics. QUBEKit is written in python and combines bond, angle, torsion, charge, and Lennard-Jones parameter derivation methodologies alongside a method for deriving the positions and charges of off-center virtual sites from the partitioned quantum mechanical electron density. As a proof of concept, we have rederived a complete set of parameters for 109 small organic molecules and assessed the accuracy by comparing computed liquid properties with experiments. QUBEKit gives competitive results when compared to standard transferable force fields, with mean unsigned errors of 0.024 g/cm3, 0.79 kcal/mol, and 1.17 kcal/mol for the liquid density, heat of vaporization, and free energy of hydration, respectively. This indicates that the derived parameters are suitable for molecular modeling applications, including computer-aided drug design.
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IJS, KILJ, NUK, PNG, UL, UM
•Mg/Al LDH was employed for phosphate adsorption.•A maximum adsorption capacity of 71.2mg-P/L was obtained in 4h.•The phosphate uptake by Mg/Al LDH was in agreement with Freundlich model.•The ...adsorption was pH-dependent and was affected by competitive anions.•Phosphate adsorbed on LDH is effectively desorbed at acid and basic pH values.
In the present study, the adsorptive properties of phosphate on Mg/Al layered double hydroxides (LDHs) from aqueous solution were evaluated. The FTIR results confirmed the anionic exchange of the nitrate anions from the interlayer space with phosphate anions took place successfully. The kinetics experiments indicated that the kinetic models which best describe phosphate adsorption on LDHs are the pseudo-second order and intraparticle diffusion models. The effects of the pH and the amount of adsorbent on phosphate uptake were investigated and it was determined that the optimum conditions are pH 3 and 0.6g/L LDH. The equilibrium isotherms showed that the phosphate uptake by Mg/Al LDH was in agreement with Freundlich model with constants of logKF=1.84 and 1/n=0.52. The effect of interfering anions on the adsorption capacity was also evaluated in the presence of several competitive anions. The results showed that in presence of other ions phosphate ion uptake decreases in the order NO3−>HCO3−>Cl−>SO42−. The desorption studies showed that the phosphate adsorbed on LDH is effectively desorbed at acid and basic pH values.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background Obstructive sleep apnea (OSA) patients are at increased risk of cardiovascular disease (CVD). Cell adhesion molecules (CAM) are increased in OSA and CAM are also implicated in the ...development of CVD. Research question Do CAM (ICAM-1, VCAM-1 and E-selectin) have prognostic value in identifying risk of cardiovascular events in OSA? Study design and methods Patients with suspected OSA referred for a polysomnogram provided a fasting blood sample. Plasma levels of ICAM-1, VCAM-1 and E-selectin were determined by multiplex Luminex Assay (Milliporesigma ON, Canada). Cardiovascular events were determined by deterministic linkage to provincial health databases. Results 418 patients were included in the analysis. Mostly male (68.2%), mean age of 50.7 yrs, median AHI 16.5 events/hour, and mean BMI of 31.7 kg/m.sup.2 . 36 cardiovascular events occurred in 8-yrs of follow up. Higher levels of ICAM-1 were associated with developing CVD (HR = 3.65 95% CI 1.40-9.53, 2.sup.nd and 3rd tertiles vs. 1.sup.st tertile), including in patients with OSA (HR = 3.1 95% CI 1.16-8.25). E-selectin was significantly associated with cardiovascular events in patients with moderate to severe OSA (HR = 3.31 95% CI 0.94-11.72, 2.sup.nd and 3.sup.rd tertiles vs. 1.sup.st tertile) but not in patients without moderate to severe OSA (HR = 0.67 95% CI 0.19-2.38), p-value for interaction = 0.07. Interpretation In a suspected OSA cohort, patients with higher levels of ICAM-1 (>816 ng/ml) were significantly more likely to experience a cardiovascular event within 8 years after PSG. In moderate to severe OSA patients, a higher E-selectin (>36.4 ng/ml) was significantly associated with cardiovascular events.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Clostridium difficile spores must germinate in vivo to become actively growing bacteria in order to produce the toxins that are necessary for disease. C. difficile spores germinate in vitro in ...response to certain bile acids and glycine. In other sporulating bacteria, proteins embedded within the inner membrane of the spore sense the presence of germinants and trigger the release of Ca⁺⁺-dipicolinic acid (Ca⁺⁺-DPA) from the spore core and subsequent hydrolysis of the spore cortex, a specialized peptidoglycan. Based upon homology searches of known germinant receptors from other spore-forming bacteria, C. difficile likely uses unique mechanisms to recognize germinants. Here, we identify the germination-specific protease, CspC, as the C. difficile bile acid germinant receptor and show that bile acid-mediated germination is important for establishing C. difficile disease in the hamster model of infection. These results highlight the importance of bile acids in triggering in vivo germination and provide the first description of a C. difficile spore germinant receptor. Blocking the interaction of bile acids with the C. difficile spore may represent an attractive target for novel therapeutics.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Spontaneous fluctuations are a hallmark of recordings of neural signals, emergent over time scales spanning milliseconds and tens of minutes. However, investigations of intrinsic brain organization ...based on resting-state functional magnetic resonance imaging have largely not taken into account the presence and potential of temporal variability, as most current approaches to examine functional connectivity (FC) implicitly assume that relationships are constant throughout the length of the recording. In this work, we describe an approach to assess whole-brain FC dynamics based on spatial independent component analysis, sliding time window correlation, and k-means clustering of windowed correlation matrices. The method is applied to resting-state data from a large sample (n = 405) of young adults. Our analysis of FC variability highlights particularly flexible connections between regions in lateral parietal and cingulate cortex, and argues against a labeling scheme where such regions are treated as separate and antagonistic entities. Additionally, clustering analysis reveals unanticipated FC states that in part diverge strongly from stationary connectivity patterns and challenge current descriptions of interactions between large-scale networks. Temporal trends in the occurrence of different FC states motivate theories regarding their functional roles and relationships with vigilance/arousal. Overall, we suggest that the study of time-varying aspects of FC can unveil flexibility in the functional coordination between different neural systems, and that the exploitation of these dynamics in further investigations may improve our understanding of behavioral shifts and adaptive processes.
Recent outbreaks of Zika virus （ZIKV） highlight an urgent need for therapeutics. The protease complex NS2B- NS3 plays essential roles during flaviviral polyprotein processing, and thus represents an ...attractive drug target. Here, we developed a split luciferase complementation-based high-throughput screening assay to identify orthosteric inhibitors that directly target flavivirus NS2B-NS3 interactions. By screening a total of 2 816 approved and investigational drugs, we identified three potent candidates, temoporfin, niclosamide, and nitazoxanide, as flavivirus NS2B- NS3 interaction inhibitors with nanomolar potencies. Significantly, the most potent compound, temoporfin, not only inhibited ZIKV replication in human placental and neural progenitor cells, but also prevented ZIKV-induced viremia and mortality in mouse models. Structural docking suggests that temoporfin potentially binds NS3 pockets that hold critical NS2B residues, thus inhibiting flaviviral polyprotein processing in a non-competitive manner. As these drugs have already been approved for clinical use in other indications either in the USA or other countries, they represent promising and easily developed therapies for the management of infections by ZIKV and other flaviviruses.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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