Reducing bias through directed acyclic graphs

<p>Abstract</p> <p>Background</p> <p>The objective of most biomedical research is to determine an unbiased estimate of effect for an exposure on an outcome, i.e. to make causal inferences about the exposure. Recent developments in epidemiology have shown that traditional methods of identifying confounding and adjusting for confounding may be inadequate.</p> <p>Discussion</p> <p>The traditional methods of adjusting for "potential confounders" may introduce conditional associations and bias rather than minimize it. Although previous published articles have discussed the role of the causal directed acyclic graph approach (DAGs) with respect to confounding, many clinical problems require complicated DAGs and therefore investigators may continue to use traditional practices because they do not have the tools necessary to properly use the DAG approach. The purpose of this manuscript is to demonstrate a simple 6-step approach to the use of DAGs, and also to explain why the method works from a conceptual point of view.</p> <p>Summary</p> <p>Using the simple 6-step DAG approach to confounding and selection bias discussed is likely to reduce the degree of bias for the effect estimate in the chosen statistical model.</p

Big-Data-Driven Materials Science and its FAIR Data Infrastructure

This chapter addresses the forth paradigm of materials research -- big-data driven materials science. Its concepts and state-of-the-art are described, and its challenges and chances are discussed. For furthering the field, Open Data and an all-embracing sharing, an efficient data infrastructure, and the rich ecosystem of computer codes used in the community are of critical importance. For shaping this forth paradigm and contributing to the development or discovery of improved and novel materials, data must be what is now called FAIR -- Findable, Accessible, Interoperable and Re-purposable/Re-usable. This sets the stage for advances of methods from artificial intelligence that operate on large data sets to find trends and patterns that cannot be obtained from individual calculations and not even directly from high-throughput studies. Recent progress is reviewed and demonstrated, and the chapter is concluded by a forward-looking perspective, addressing important not yet solved challenges.Comment: submitted to the Handbook of Materials Modeling (eds. S. Yip and W. Andreoni), Springer 2018/201

A repurposing strategy for Hsp90 inhibitors demonstrates their potency against filarial nematodes

Novel drugs are required for the elimination of infections caused by filarial worms, as most commonly used drugs largely target the microfilariae or first stage larvae of these infections. Previous studies, conducted in vitro, have shown that inhibition of Hsp90 kills adult Brugia pahangi. As numerous small molecule inhibitors of Hsp90 have been developed for use in cancer chemotherapy, we tested the activity of several novel Hsp90 inhibitors in a fluorescence polarization assay and against microfilariae and adult worms of Brugia in vitro. The results from all three assays correlated reasonably well and one particular compound, NVP-AUY922, was shown to be particularly active, inhibiting Mf output from female worms at concentrations as low as 5.0 nanomolar after 6 days exposure to drug. NVP-AUY922 was also active on adult worms after a short 24 h exposure to drug. Based on these in vitro data, NVP-AUY922 was tested in vivo in a mouse model and was shown to significantly reduce the recovery of both adult worms and microfilariae. These studies provide proof of principle that the repurposing of currently available Hsp90 inhibitors may have potential for the development of novel agents with macrofilaricidal properties

Do emotional difficulties and peer problems hew together from childhood to adolescence? The case of children with a history of developmental language disorder (DLD)

Children and adolescents with developmental language disorder (DLD) are, overall, vulnerable to difficulties in emotional adjustment and in peer relations. However, previous research has shown that different subgroups follow different trajectories in respect of quality of peer relations. Less is known of the trajectories of emotional development. We consider here the possibility that development in these two domains is interrelated: that is, the trajectories of emotional and peer problems will proceed in parallel. We conducted longitudinal joint trajectories analyses of emotional and peer relations in a sample of young people identified as having DLD at age 7 years and seen at intervals up to 16 years. Potential influences on joint trajectory group membership were examined. Findings revealed five distinct joint trajectories. Emotional and peer difficulties do hew together from childhood to adolescence for just over half of the sample, but not all. The variables most clearly associated with group membership were pragmatic language ability, prosociality and parental mental health. This is the first study to examine joint longitudinal trajectories of emotional and peer difficulties in individuals with DLD. We demonstrate that development in individuals with DLD is heterogeneous and identify three key variables associated with personal and social adjustment from childhood to adolescence. Theoretical and clinical implications of these findings are discussed

Hsp90 governs dispersion and drug resistance of fungal biofilms

Fungal biofilms are a major cause of human mortality and are recalcitrant to most treatments due to intrinsic drug resistance. These complex communities of multiple cell types form on indwelling medical devices and their eradication often requires surgical removal of infected devices. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and drug resistance. We previously established that in the leading human fungal pathogen, Candida albicans, Hsp90 enables the emergence and maintenance of drug resistance in planktonic conditions by stabilizing the protein phosphatase calcineurin and MAPK Mkc1. Hsp90 also regulates temperature-dependent C. albicans morphogenesis through repression of cAMP-PKA signalling. Here we demonstrate that genetic depletion of Hsp90 reduced C. albicans biofilm growth and maturation in vitro and impaired dispersal of biofilm cells. Further, compromising Hsp90 function in vitro abrogated resistance of C. albicans biofilms to the most widely deployed class of antifungal drugs, the azoles. Depletion of Hsp90 led to reduction of calcineurin and Mkc1 in planktonic but not biofilm conditions, suggesting that Hsp90 regulates drug resistance through different mechanisms in these distinct cellular states. Reduction of Hsp90 levels led to a marked decrease in matrix glucan levels, providing a compelling mechanism through which Hsp90 might regulate biofilm azole resistance. Impairment of Hsp90 function genetically or pharmacologically transformed fluconazole from ineffectual to highly effective in eradicating biofilms in a rat venous catheter infection model. Finally, inhibition of Hsp90 reduced resistance of biofilms of the most lethal mould, Aspergillus fumigatus, to the newest class of antifungals to reach the clinic, the echinocandins. Thus, we establish a novel mechanism regulating biofilm drug resistance and dispersion and that targeting Hsp90 provides a much-needed strategy for improving clinical outcome in the treatment of biofilm infections

Socio-Economic Instability and the Scaling of Energy Use with Population Size

The size of the human population is relevant to the development of a sustainable world, yet the forces setting growth or declines in the human population are poorly understood. Generally, population growth rates depend on whether new individuals compete for the same energy (leading to Malthusian or density-dependent growth) or help to generate new energy (leading to exponential and super-exponential growth). It has been hypothesized that exponential and super-exponential growth in humans has resulted from carrying capacity, which is in part determined by energy availability, keeping pace with or exceeding the rate of population growth. We evaluated the relationship between energy use and population size for countries with long records of both and the world as a whole to assess whether energy yields are consistent with the idea of an increasing carrying capacity. We find that on average energy use has indeed kept pace with population size over long time periods. We also show, however, that the energy-population scaling exponent plummets during, and its temporal variability increases preceding, periods of social, political, technological, and environmental change. We suggest that efforts to increase the reliability of future energy yields may be essential for stabilizing both population growth and the global socio-economic system

Noisy-threshold control of cell death

<p>Abstract</p> <p>Background</p> <p>Cellular responses to death-promoting stimuli typically proceed through a differentiated multistage process, involving a lag phase, extensive death, and potential adaptation. Deregulation of this chain of events is at the root of many diseases. Improper adaptation is particularly important because it allows cell sub-populations to survive even in the continuous presence of death conditions, which results, among others, in the eventual failure of many targeted anticancer therapies.</p> <p>Results</p> <p>Here, I show that these typical responses arise naturally from the interplay of intracellular variability with a threshold-based control mechanism that detects cellular changes in addition to just the cellular state itself. Implementation of this mechanism in a quantitative model for T-cell apoptosis, a prototypical example of programmed cell death, captures with exceptional accuracy experimental observations for different expression levels of the oncogene Bcl-x_Land directly links adaptation with noise in an ATP threshold below which cells die.</p> <p>Conclusions</p> <p>These results indicate that oncogenes like Bcl-x_L, besides regulating absolute death values, can have a novel role as active controllers of cell-cell variability and the extent of adaptation.</p

The Association Between Pre-pregnancy BMI and Preterm Delivery in a Diverse Southern California Population of Working Women

Whereas preterm birth has consistently been associated with low maternal pre-pregnancy weight, the relationship with high pre-pregnancy weight has been inconsistent. We quantified the pre-pregnancy BMI—preterm delivery (PTD) relationship using traditional BMI categories (underweight, normal weight, overweight and obese) as well as continuous BMI. Eligible women participated in California’s statewide prenatal screening program, worked during pregnancy, and delivered a live singleton birth in Southern California in 2002–2003. The final analytic sample included 354 cases delivering at <37 weeks, as identified by clinical estimate of gestational age from screening records, and 710 term normal-birthweight controls. Multivariable logistic regression models using categorical BMI levels and continuous BMI were compared. In categorical analyses, PTD was significantly associated with pre-pregnancy underweight only. Nonparametric local regression revealed a V-shaped relationship between continuous BMI and PTD, with minimum risk at the high end of normal, around 24 kg/m2. The odds ratio (OR) for PTD associated with low BMI within the normal range (19 kg/m2) was 2.84 (95%CI = 1.61–5.01); ORs for higher BMI in the overweight (29 kg/m2) and obese (34 kg/m2) ranges were 1.42 (95%CI = 1.10–1.84) and 2.01 (95% CI = 1.20–3.39) respectively, relative to 24 kg/m2). BMI categories obscured the preterm delivery risk associated with low-normal, overweight, and obese BMI. We found that higher BMI up to around 24 kg/m2 is increasingly protective of preterm delivery, beyond which a higher body mass index becomes detrimental. Current NHLBI/WHO BMI categories may be inadequate for identifying women at higher risk for PTD

Strategies for improving patient recruitment to focus groups in primary care: a case study reflective paper using an analytical framework

<p>Abstract</p> <p>Background</p> <p>Recruiting to primary care studies is complex. With the current drive to increase numbers of patients involved in primary care studies, we need to know more about successful recruitment approaches. There is limited evidence on recruitment to focus group studies, particularly when no natural grouping exists and where participants do not regularly meet. The aim of this paper is to reflect on recruitment to a focus group study comparing the methods used with existing evidence using a resource for research recruitment, PROSPeR (Planning Recruitment Options: Strategies for Primary Care).</p> <p>Methods</p> <p>The focus group formed part of modelling a complex intervention in primary care in the Resources for Effective Sleep Treatment (REST) study. Despite a considered approach at the design stage, there were a number of difficulties with recruitment. The recruitment strategy and subsequent revisions are detailed.</p> <p>Results</p> <p>The researchers' modifications to recruitment, justifications and evidence from the literature in support of them are presented. Contrary evidence is used to analyse why some aspects were unsuccessful and evidence is used to suggest improvements. Recruitment to focus group studies should be considered in two distinct phases; getting potential participants to contact the researcher, and converting those contacts into attendance. The difficulty of recruitment in primary care is underemphasised in the literature especially where people do not regularly come together, typified by this case study of patients with sleep problems.</p> <p>Conclusion</p> <p>We recommend training GPs and nurses to recruit patients during consultations. Multiple recruitment methods should be employed from the outset and the need to build topic related non-financial incentives into the group meeting should be considered. Recruitment should be monitored regularly with barriers addressed iteratively as a study progresses.</p

Polar vortex formation in giant-planet atmospheres due to moist convection

A strong cyclonic vortex has been observed on each of Saturn’s poles, coincident with a local maximum in observed tropospheric temperature. Neptune also exhibits a relatively warm, although much more transient, region on its south pole. Whether similar features exist on Jupiter will be resolved by the 2016 Juno mission. Energetic, small-scale storm-like features that originate from the water-cloud level or lower have been observed on each of the giant planets and attributed to moist convection, suggesting that these storms play a significant role in global heat transfer from the hot interior to space. Nevertheless, the creation and maintenance of Saturn’s polar vortices, and their presence or absence on the other giant planets, are not understood. Here we use simulations with a shallow-water model to show that storm generation, driven by moist convection, can create a strong polar cyclone throughout the depth of a planet’s troposphere. We find that the type of shallow polar flow that occurs on a giant planet can be described by the size ratio of small eddies to the planetary radius and the energy density of its atmosphere due to latent heating from moist convection. We suggest that the observed difference in these parameters between Saturn and Jupiter may preclude a Jovian polar cyclone.National Science Foundation (U.S.). Graduate Research FellowshipNational Science Foundation (U.S.) (ATM-0850639)National Science Foundation (U.S.) (AGS-1032244)National Science Foundation (U.S.) (AGS-1136480)United States. Office of Naval Research (N00014-14-1-0062