Testing for association between RNA-Seq and high-dimensional data

Background: Testing for association between RNA-Seq and other genomic data is challenging due to high variability of the former and high dimensionality of the latter. Results: Using the negative binomial distribution and a random-effects model, we develop an omnibus test that overcomes both difficulties. It may be conceptualised as a test of overall significance in regression analysis, where the response variable is overdispersed and the number of explanatory variables exceeds the sample size. Conclusions: The proposed test can detect genetic and epigenetic alterations that affect gene expression. It can examine complex regulatory mechanisms of gene expression. The R package globalSeq is available from Bioconductor

Exploring Effectiveness of Explanations for Appropriate Trust: Lessons from Cognitive Psychology

The rapid development of Artificial Intelligence (AI) requires developers and designers of AI systems to focus on the collaboration between humans and machines. AI explanations of system behavior and reasoning are vital for effective collaboration by fostering appropriate trust, ensuring understanding, and addressing issues of fairness and bias. However, various contextual and subjective factors can influence an AI system explanation's effectiveness. This work draws inspiration from findings in cognitive psychology to understand how effective explanations can be designed. We identify four components to which explanation designers can pay special attention: perception, semantics, intent, and user & context. We illustrate the use of these four explanation components with an example of estimating food calories by combining text with visuals, probabilities with exemplars, and intent communication with both user and context in mind. We propose that the significant challenge for effective AI explanations is an additional step between explanation generation using algorithms not producing interpretable explanations and explanation communication. We believe this extra step will benefit from carefully considering the four explanation components outlined in our work, which can positively affect the explanation's effectiveness.Comment: 2022 IEEE Workshop on TRust and EXpertise in Visual Analytics (TREX

A Dynamical Study of the Black Hole X-ray Binary Nova Muscae 1991

We present a dynamical study of the Galactic black hole binary system Nova Muscae 1991 (GS/GRS 1124-683). We utilize 72 high resolution Magellan Echellette (MagE) spectra and 72 strictly simultaneous V-band photometric observations; the simultaneity is a unique and crucial feature of this dynamical study. The data were taken on two consecutive nights and cover the full 10.4-hour orbital cycle. The radial velocities of the secondary star are determined by cross-correlating the object spectra with the best-match template spectrum obtained using the same instrument configuration. Based on our independent analysis of five orders of the echellette spectrum, the semi-amplitude of the radial velocity of the secondary is measured to be K_2 = 406.8+/-2.7 km/s, which is consistent with previous work, while the uncertainty is reduced by a factor of 3. The corresponding mass function is f(M) = 3.02+/-0.06 M_\odot. We have also obtained an accurate measurement of the rotational broadening of the stellar absorption lines (v sin i = 85.0+/-2.6 km/s) and hence the mass ratio of the system q = 0.079+/-0.007. Finally, we have measured the spectrum of the non-stellar component of emission that veils the spectrum of the secondary. In a future paper, we will use our veiling-corrected spectrum of the secondary and accurate values of K_2 and q to model multi-color light curves and determine the systemic inclination and the mass of the black hole.Comment: ApJ accepted version; minor revision; added a subsection about systematic uncertaintie

Sparse classification with paired covariates

Funder: Department of Epidemiology and Biostatistics, Amsterdam UMC, VU University AmsterdamAbstractThis paper introduces the paired lasso: a generalisation of the lasso for paired covariate settings. Our aim is to predict a single response from two high-dimensional covariate sets. We assume a one-to-one correspondence between the covariate sets, with each covariate in one set forming a pair with a covariate in the other set. Paired covariates arise, for example, when two transformations of the same data are available. It is often unknown which of the two covariate sets leads to better predictions, or whether the two covariate sets complement each other. The paired lasso addresses this problem by weighting the covariates to improve the selection from the covariate sets and the covariate pairs. It thereby combines information from both covariate sets and accounts for the paired structure. We tested the paired lasso on more than 2000 classification problems with experimental genomics data, and found that for estimating sparse but predictive models, the paired lasso outperforms the standard and the adaptive lasso. The R package is available from cran.</jats:p

Linking toxicant physiological mode of action with induced gene expression changes in Caenorhabditis elegans

Background Physiologically based modelling using DEBtox (dynamic energy budget in toxicology) and transcriptional profiling were used in Caenorhabditis elegans to identify how physiological modes of action, as indicated by effects on system level resource allocation were associated with changes in gene expression following exposure to three toxic chemicals: cadmium, fluoranthene (FA) and atrazine (AZ). Results For Cd, the physiological mode of action as indicated by DEBtox model fitting was an effect on energy assimilation from food, suggesting that the transcriptional response to exposure should be dominated by changes in the expression of transcripts associated with energy metabolism and the mitochondria. While evidence for effect on genes associated with energy production were seen, an ontological analysis also indicated an effect of Cd exposure on DNA integrity and transcriptional activity. DEBtox modelling showed an effect of FA on costs for growth and reproduction (i.e. for production of new and differentiated biomass). The microarray analysis supported this effect, showing an effect of FA on protein integrity and turnover that would be expected to have consequences for rates of somatic growth. For AZ, the physiological mode of action predicted by DEBtox was increased cost for maintenance. The transcriptional analysis demonstrated that this increase resulted from effects on DNA integrity as indicated by changes in the expression of genes chromosomal repair. Conclusions Our results have established that outputs from process based models and transcriptomics analyses can help to link mechanisms of action of toxic chemicals with resulting demographic effects. Such complimentary analyses can assist in the categorisation of chemicals for risk assessment purposes

The Structure of the Accretion Disk in the ADC X-Ray Binary 4U 1822-371 at Optical and Ultraviolet Wavelengths

The eclipsing low-mass X-ray binary 4U 1822-371 is the prototypical accretion disk corona (ADC) system. We have obtained new time-resolved UV spectroscopy of 4U 1822-371 with the Advanced Camera for Surveys/Solar Blind Channel (ACS/SBC) on the Hubble Space Telescope (HST) and new V- and J-band photometry with the 1.3-m SMARTS telescope at CTIO. We use the new data to construct its UV/optical spectral energy distribution and its orbital light curve in the UV, V, and J bands. We derive an improved ephemeris for the optical eclipses and confirm that the orbital period is changing rapidly, indicating extremely high rates of mass flow in the system; and we show that the accretion disk in the system has a strong wind with projected velocities up to 4000 km/s. We show that the disk has a vertically-extended, optically-thick component at optical wavelengths.This component extends almost to the edge of the disk and has a height equal to ~0.5 of the disk radius. As it has a low brightness temperature, we identify it as the optically-thick base of a disk wind, not as the optical counterpart of the ADC. Like previous models of 4U 1822-371, ours needs a tall obscuring wall near the edge of the accretion disk, but we interpret the wall as a layer of cooler material at the base of the disk wind, not as a tall, luminous disk rim.Comment: 37 pages, 12 figures, submitted to Ap

European expert recommendations on clinical investigation and evaluation of high‐risk medical devices for children

Several high-risk medical devices for children have become unavailable in the European Union (EU), since requirements and costs for device certification increased markedly due to the EU Medical Device Regulation. The EU-funded CORE-MD project held a workshop in January 2023 with experts from various child health specialties, representatives of European paediatric associations, a regulatory authority and the European Commission Directorate General Health and Food Safety. A virtual follow-up meeting took place in March 2023. We developed recommendations for investigation of high-risk medical devices for children building on participants' expertise and results of a scoping review of clinical trials on high-risk medical devices in children. Approaches for evaluating and certifying high-risk medical devices for market introduction are proposed

Pellino-1 Regulates the Responses of the Airway to Viral Infection

Exposure to respiratory pathogens is a leading cause of exacerbations of airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). Pellino-1 is an E3 ubiquitin ligase known to regulate virally-induced inflammation. We wished to determine the role of Pellino-1 in the host response to respiratory viruses in health and disease. Pellino-1 expression was examined in bronchial sections from patients with GOLD stage two COPD and healthy controls. Primary bronchial epithelial cells (PBECs) in which Pellino-1 expression had been knocked down were extracellularly challenged with the TLR3 agonist poly(I:C). C57BL/6 Peli1-/- mice and wild type littermates were subjected to intranasal infection with clinically-relevant respiratory viruses: rhinovirus (RV1B) and influenza A. We found that Pellino-1 is expressed in the airways of normal subjects and those with COPD, and that Pellino-1 regulates TLR3 signaling and responses to airways viruses. In particular we observed that knockout of Pellino-1 in the murine lung resulted in increased production of proinflammatory cytokines IL-6 and TNFα upon viral infection, accompanied by enhanced recruitment of immune cells to the airways, without any change in viral replication. Pellino-1 therefore regulates inflammatory airway responses without altering replication of respiratory viruses.</p

Exploring immune status in peripheral blood and tumor tissue in association with survival in patients with multi-organ metastatic colorectal cancer

Colorectal cancer (CRC) raises considerable clinical challenges, including a high mortality rate once the tumor spreads to distant sites. At this advanced stage, more accurate prediction of prognosis and treatment outcome is urgently needed. The role of cancer immunity in metastatic CRC (mCRC) is poorly understood. Here, we explore cellular immune cell status in patients with multi-organ mCRC. We analyzed T cell infiltration in primary tumor sections, surveyed the lymphocytic landscape of liver metastases, and assessed circulating mononuclear immune cells. Besides asking whether immune cells are associated with survival at this stage of the disease, we investigated correlations between the different tissue types; as this could indicate a dominant immune phenotype. Taken together, our analyses corroborate previous observations that higher levels of CD8+ T lymphocytes link to better survival outcomes. Our findings therefore extend evidence from earlier stages of CRC to indicate an important role for cancer immunity in disease control even after metastatic spreading to multiple organs. This finding may help to improve predicting outcome of patients with mCRC and suggests a future role for immunotherapeutic strategies.</p