Benchmark dose profiles for bivariate exposures.

While benchmark dose (BMD) methodology is well-established for settings with a single exposure, these methods cannot easily handle multidimensional exposures with nonlinear effects. We propose a framework for BMD analysis to characterize the joint effect of a two-dimensional exposure on a continuous outcome using a generalized additive model while adjusting for potential confounders via propensity scores. This leads to a dose-response surface which can be summarized in two dimensions by a contour plot in which combinations of exposures leading to the same expected effect are identified. In our motivating study of prenatal alcohol exposure, cognitive deficits in children are found to be associated with both the frequency of drinking as well as the amount of alcohol consumed on each drinking day during pregnancy. The general methodological framework is useful for a broad range of settings, including combinations of environmental stressors, such as chemical mixtures, and in explorations of the impact of dose rate rather than simply cumulative exposure on adverse outcomes.

A dose-response analysis of the effects of prenatal alcohol exposure on cognitive development.

BACKGROUND: Most studies of the effects of prenatal alcohol exposure (PAE) on cognitive function have assumed that the dose-response curve is linear. However, data from a few animal and human studies suggest that there may be an inflection point in the dose-response curve above which PAE effects are markedly stronger and that there may be differences associated with pattern of exposure, assessed in terms of alcohol dose per drinking occasion and drinking frequency. METHODS: We performed second-order confirmatory factor analysis on data obtained at school age, adolescence, and early adulthood from 2227 participants in six US longitudinal cohorts to derive a composite measure of cognitive function. Regression models were constructed to examine effects of PAE on cognitive function, adjusted for propensity scores. Analyses based on a single predictor (absolute alcohol (AA)/day) were compared with analyses based on two predictors (dose/occasion and drinking frequency), using (1) linear models and (2) nonparametric general additive models (GAM) that allow for both linear and nonlinear effects. RESULTS: The single-predictor GAM model showed virtually no nonlinearity in the effect of AA/day on cognitive function. However, the two-predictor GAM model revealed differential effects of maternal drinking pattern. Among offspring of infrequent drinkers, PAE effects on cognitive function were markedly stronger in those whose mothers drank more than ~3 drinks/occasion, and the effect of dose/occasion was strongest among the very frequent drinkers. Frequency of drinking did not appear to alter the PAE effect on cognitive function among participants born to mothers who limited their drinking to ~1 drink/occasion or less. CONCLUSIONS: These findings suggest that linear models based on total AA/day are appropriate for assessing whether PAE affects a given cognitive outcome. However, examination of alcohol dose/occasion and drinking frequency is needed to fully characterize the impact of different levels of alcohol intake on cognitive impairment.

Meta-analysis on studies with heterogeneous and partially observed covariates.

Individual participant data meta-analysis is a commonly used alternative to the traditional aggregate data meta-analysis. It is popular because it avoids relying on published results and enables direct adjustment for relevant covariates. However, a practical challenge is that the studies being combined often vary in terms of the potential confounders that were measured. Furthermore, it will inevitably be the case that some individuals have missing values for some of those covariates. In this paper, we demonstrate how these challenges can be resolved using a propensity score approach, combined with multiple imputation, as a strategy to adjust for covariates in the context of individual participant data meta-analysis. To illustrate, we analyze data from the Bill and Melinda Gates Foundation-funded Healthy Birth, Growth, and Development Knowledge Integration project to investigate the relationship between physical growth rate in the first year of life and cognition measured later during childhood. We found that the overall effect of average growth velocity on cognitive outcome is slightly, but significantly, positive with an estimated effect size of 0.36 (95% CI 0.18, 0.55).

Sensommatic: an efficient pipeline to mine and predict sensory receptor genes in the era of reference-quality genomes.

SUMMARY: Sensory receptor gene families have undergone extensive expansion and loss across vertebrate evolution, leading to significant variation in receptor counts between species. However, due to their species-specific nature, conventional reference-based annotation tools often underestimate the true number of sensory receptors in a given species. While there has been an exponential increase in the taxonomic diversity of publicly available genome assemblies in recent years, only ∼30% of vertebrate species on the NCBI database are currently annotated. To overcome these limitations, we developed 'Sensommatic', an automated and accessible sensory receptor annotation pipeline. Sensommatic implements BLAST and AUGUSTUS to mine and predict sensory receptor genes from whole genome assemblies, adopting a one-to-many gene mapping approach. While designed for vertebrates, Sensommatic can be extended to run on non-vertebrate species by generating customized reference files, making it a scalable and generalizable tool. AVAILABILITY AND IMPLEMENTATION: Source code and associated files are available at: https://github.com/GMHughes/Sensommatic.

Bayesian outcome selection modeling.

In psychiatric and social epidemiology studies, it is common to measure multiple different outcomes using a comprehensive battery of tests thought to be related to an underlying construct of interest. In the research that motivates our work, researchers wanted to assess the impact of in utero alcohol exposure on child cognition and neuropsychological development, which are evaluated using a range of different psychometric tests. Statistical analysis of the resulting multiple outcomes data can be challenging, because the outcomes measured on the same individual are not independent. Moreover, it is unclear, a priori, which outcomes are impacted by the exposure under study. While researchers will typically have some hypotheses about which outcomes are important, a framework is needed to help identify outcomes that are sensitive to the exposure and to quantify the associated treatment or exposure effects of interest. We propose such a framework using a modification of stochastic search variable selection, a popular Bayesian variable selection model and use it to quantify an overall effect of the exposure on the affected outcomes. The performance of the method is investigated empirically and an illustration is given through application using data from our motivating study.

Evolutionary constraint and innovation across hundreds of placental mammals.

Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes for 240 species, we identify bases that, when mutated, are likely to affect fitness and alter disease risk. At least 332 million bases (~10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats, and 4552 ultraconserved elements are nearly perfectly conserved. Of 101 million significantly constrained single bases, 80% are outside protein-coding exons and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Changes in genes and regulatory elements are associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth's vast and imperiled biodiversity offers distinctive power for identifying genetic variants that affect genome function and organismal phenotypes.

Asthma medication adherence and exacerbations and lung function in children managed in Leicester primary care.

Poor adherence to asthma preventer medication is associated with life-threatening asthma attacks. The quality and outcomes framework mandated primary care annual asthma review does not include adherence monitoring and the effect of poor adherence on lung function in paediatric primary care patients is unknown. The aim was to investigate the link between inhaled corticosteroid (ICS) adherence and spirometry, fraction of exhaled nitric oxide (FeNO) and asthma control in asthmatic school-age children in this cross-sectional observational study involving three Leicestershire general practices. Children 5-16 years on the practice's asthma registers, were invited for a routine annual asthma review between August 2018 and August 2019. Prescription and clinical data were extracted from practice databases. Spirometry, bronchodilator reversibility (BDR) and FeNO testing were performed as part of the review. 130 of 205 eligible children (63.4%) attended their review. Mean adherence to ICS was 36.2% (SEM 2.1%) and only 14.6% of children had good adherence (≥75% prescriptions issued). We found no differences in asthma exacerbations in the preceding 12 months between the adherence quartiles. 28.6% of children in the lowest and 5.6% in the highest adherence quartile had BDR ≥ 12% but this was not statistically significant (p = 0.55). A single high FeNO value did not predict adherence to ICS. Adherence to ICS in children with asthma in primary care is poor. The link between adherence to ICS and asthma exacerbations, spirometry and FeNO is complex but knowledge of adherence to ICS is critical in the management of children with asthma.

"What are you doing here?": Narratives of border crossings among diverse Afghans going to the UK at different times.

Through the "hostile environment" migration policy, the UK government has expressed its commitment to do whatever possible to deter and expel unwanted migrants. Faced with the loss of power in the context of globalization, the Conservative administration, elected in 2010, presented itself as a guarantor of citizens' security. The political discourse of "taking back control" of the nation's borders has resulted in increasingly restrictive immigration and asylum policies. In this paper, we present narratives of Afghans who arrived in the UK at different times and through different routes. As well as those evacuated from Kabul airport in 2021, we also interviewed participants who traveled via insecure routes over land and sea often taking months, or even years, and involving expensive people smugglers. While the evacuation from Kabul was a very public and highly reported event, often with celebratory tones in the international media as Western governments sought to "rescue" Afghan allies, those Afghans who travel to the UK via illegal routes are often stigmatized; demonized in press and political discourses. Building on the emerging body of literature that uses "journey as a narrative device" and drawing upon our novel dataset, we analyze how diverse migrants tell their stories and present agency, within contexts of extreme hazards, to achieve their imagined future. Moreover, applying a spatio-temporal lens we advance understanding of the intersection of place and time in how Afghans traveling to the UK, including recent evacuees, are framed differently with resultant consequences for how border crossings are negotiated and narrated. In so doing, we complicate simplistic categories of deserving vs. undeserving, genuine vs. fraudulent, evacuees vs. irregularised migrants.

A novel programme of supportive two-exchange assisted continuous ambulatory peritoneal dialysis for frail patients with end-stage kidney disease.

We have developed a supportive two-exchange assisted continuous ambulatory peritoneal dialysis (asCAPD) programme for the older frail person who cannot do autonomous PD and do not want or are considered to be too high risk for haemodialysis (HD). Evaluation of the programme was determined by data collected retrospectively from patient records. Primary outcome was comparison of symptoms at start of dialysis and 3 months following dialysis start. Secondary outcomes were survival and peritonitis rate. Over a 4-year period (2016-2020), 49 patients with mean age 79.6 years (range 47-90) enrolled in the programme with eGFR 7.7 ± 2.6 ml/min (mean ± SD) at dialysis start. Forty-one patients had been on asCAPD for >3 months. There was an improvement in all symptoms at 3 months compared to baseline: anorexia (46% to 15%), fatigue (46% to 15%), shortness of breath (27% to 2%) and oedema (51% to 32%). One-year survival was 55%. Peritonitis rate was 0.52 episodes per patient year. The novel supportive two-exchange asCAPD programme shows potential improvement of symptoms after 3 months and may provide an acceptable dialysis modality for the frail co-morbid person with established kidney failure. More detailed study and evaluation are needed.

Forecasting Multiple Groundwater Time Series with Local and Global Deep Learning Networks.

Time series data from environmental monitoring stations are often analysed with machine learning methods on an individual basis, however recent advances in the machine learning field point to the advantages of incorporating multiple related time series from the same monitoring network within a 'global' model. This approach provides the opportunity for larger training data sets, allows information to be shared across the network, leading to greater generalisability, and can overcome issues encountered in the individual time series, such as small datasets or missing data. We present a case study involving the analysis of 165 time series from groundwater monitoring wells in the Namoi region of Australia. Analyses of the multiple time series using a variety of different aggregations are compared and contrasted (with single time series, subsets, and all of the time series together), using variations of the multilayer perceptron (MLP), self-organizing map (SOM), long short-term memory (LSTM), and a recently developed LSTM extension (DeepAR) that incorporates autoregressive terms and handles multiple time series. The benefits, in terms of prediction performance, of these various approaches are investigated, and challenges such as differing measurement frequencies and variations in temporal patterns between the time series are discussed. We conclude with some discussion regarding recommendations and opportunities associated with using networks of environmental data to help inform future resource-related decision making.

Contradictory Phylogenetic Signals in the Laurasiatheria Anomaly Zone.

Relationships among laurasiatherian clades represent one of the most highly disputed topics in mammalian phylogeny. In this study, we attempt to disentangle laurasiatherian interordinal relationships using two independent genome-level approaches: (1) quantifying retrotransposon presence/absence patterns, and (2) comparisons of exon datasets at the levels of nucleotides and amino acids. The two approaches revealed contradictory phylogenetic signals, possibly due to a high level of ancestral incomplete lineage sorting. The positions of Eulipotyphla and Chiroptera as the first and second earliest divergences were consistent across the approaches. However, the phylogenetic relationships of Perissodactyla, Cetartiodactyla, and Ferae, were contradictory. While retrotransposon insertion analyses suggest a clade with Cetartiodactyla and Ferae, the exon dataset favoured Cetartiodactyla and Perissodactyla. Future analyses of hitherto unsampled laurasiatherian lineages and synergistic analyses of retrotransposon insertions, exon and conserved intron/intergenic sequences might unravel the conflicting patterns of relationships in this major mammalian clade.

A hierarchical meta-analysis for settings involving multiple outcomes across multiple cohorts.

Evidence from animal models and epidemiological studies has linked prenatal alcohol exposure (PAE) to a broad range of long-term cognitive and behavioural deficits. However, there is a paucity of evidence regarding the nature and levels of PAE associated with increased risk of clinically significant cognitive deficits. To derive robust and efficient estimates of the effects of PAE on cognitive function, we have developed a hierarchical meta-analysis approach to synthesize information regarding the effects of PAE on cognition, integrating data on multiple outcomes from six U.S. Iongitudinal cohort studies. A key assumption of standard methods of meta-analysis, effect sizes are independent, is violated when multiple intercorrelated outcomes are synthesized across studies. Our approach involves estimating the dose-response coefficients for each outcome and then pooling these correlated dose-response coefficients to obtain an estimated "global" effect of exposure on cognition. In the first stage, we use individual participant data to derive estimates of the effects of PAE by fitting regression models that adjust for potential confounding variables using propensity scores. The correlation matrix characterizing the dependence between the outcome-specific dose-response coefficients estimated within each cohort is then run, while accommodating incomplete information on some outcome. We also compare inferences based on the proposed approach to inferences based on a full multivariate analysis.

"You Still Want to Go Lots of Places": Exploring Walking Interviews in Research With Older Migrants.

BACKGROUND AND OBJECTIVES: Walking interviews have become prevalent in social sciences; however, their use in research with older people is limited. This article offers a reflexive account of our ethical and methodological choices and practices while conducting walking interviews with older migrants, and considers the potential of this method in researching migrants' aging in place. RESEARCH DESIGN AND METHODS: The study had a longitudinal, multisited (London and Yorkshire), qualitatively driven multimethod research design. In 2018-2019, in-depth interviews were conducted with 45 older migrants originally from the Caribbean, Ireland, and Poland, followed by walking interviews with a subsample of 9 participants 6-12 months later. The majority of participants were older than 80 years. RESULTS: Our study demonstrated that walking interviews are a promising method to explore in depth a variety of relevant issues including older migrants' mobility, and health and well-being; navigating places through everyday activities; interactions with local neighborhoods over time; and the meanings associated with such experiences. Through direct exposure to the physicality of places, walking interviews can elicit rich and complex data that would be difficult to collect through other methods. DISCUSSION AND IMPLICATIONS: Conducting walking interviews with older migrants has unique thematic potential. However, a range of ethical and practical challenges need to be considered, including a risk to revealing participants' identities and adopting an ethics-in-practice approach. The method has some limitations, especially with less-mobile participants. Implications for researchers, policymakers, and practitioners are suggested.

Effects of prenatal alcohol exposure on cognitive and behavioral development: Findings from a hierarchical meta-analysis of data from six prospective longitudinal U.S. cohorts.

BACKGROUND: Cognitive and behavioral sequelae of prenatal alcohol exposure (PAE) continue to be prevalent in the United States and worldwide. Because these sequelae are also common in other neurodevelopmental disorders, researchers have attempted to identify a distinct neurobehavioral profile to facilitate the differential diagnosis of fetal alcohol spectrum disorders (FASD). We used an innovative, individual participant meta-analytic technique to combine data from six large U.S. longitudinal cohorts to provide a more comprehensive and reliable characterization of the neurobehavioral deficits seen in FASD than can be obtained from smaller samples. METHODS: Meta-analyses were performed on data from 2236 participants to examine effects of PAE (measured as oz absolute alcohol/day (AA/day)) on IQ, four domains of cognition function (learning and memory, executive function, reading achievement, and math achievement), sustained attention, and behavior problems, after adjusting for potential confounders using propensity scores. RESULTS: The effect sizes for IQ and the four domains of cognitive function were strikingly similar to one another and did not differ at school age, adolescence, or young adulthood. Effect sizes were smaller in the more middle-class Seattle cohort and larger in the three cohorts that obtained more detailed and comprehensive assessments of AA/day. PAE effect sizes were somewhat weaker for parent- and teacher-reported behavior problems and not significant for sustained attention. In a meta-analysis of five aspects of executive function, the strongest effect was on set-shifting. CONCLUSIONS: The similarity in the effect sizes for the four domains of cognitive function suggests that PAE affects an underlying component or components of cognition involving learning and memory and executive function that are reflected in IQ and academic achievement scores. The weaker effects in the more middle-class cohort may reflect a more cognitively stimulating environment, a different maternal drinking pattern (lower alcohol dose/occasion), and/or better maternal prenatal nutrition. These findings identify two domains of cognition-learning/memory and set-shifting-that are particularly affected by PAE, and one, sustained attention, which is apparently spared.

A cohort study to investigate sex-specific differences in ANCA-associated glomerulonephritis outcomes.

Data surrounding sex-specific differences in ANCA-associated vasculitis glomerulonephritis (ANCA-GN) outcomes is sparse. We hypothesised that the previously observed increased risk of end-stage kidney disease (ESKD) in males is driven by sex-specific variation in immunosuppression dosing. Patients were recruited to the Irish Rare Kidney Disease Registry or followed by the Royal Free Hospital vasculitis team (2012-2020). Inclusion criteria: prior diagnosis of ANCA-GN (biopsy proven pauci-immune glomerulonephritis) and positive serology for anti-MPO or -PR3 antibodies. Renal and patient survival, stratified by sex and Berden histological class, was analysed. The cumulative- and starting dose/kilogram of induction agents and prednisolone, respectively, was compared between sexes. 332 patients were included. Median follow-up was time 40.2 months (IQR 17.3-69.2). 73 (22%) reached ESKD and 47 (14.2%) died. Overall 1- and 5-year renal survival was 82.2% and 76.7% in males and 87.1% and 82.0% in females, respectively (p 0.13). The hazard ratio for ESKD in males versus females, after adjustment for age, ANCA serology, baseline creatinine and histological class was 1.07 (95% CI 0.59-1.93). There was no difference between sexes in the dose/kilogram of any induction agent. We did not observe a strong impact of sex on renal outcome in ANCA-GN. Treatment intensity does not vary by sex.

Resuming Deceased Donor Kidney Transplantation in the COVID-19 Era: What Do Patients Want?

BACKGROUND: The rapidly evolving novel coronavirus 2019 (COVID-19) pandemic bought many kidney transplant (KT) programs to a halt. Integral to resuming KT activity is understanding the perspectives of potential transplant candidates during this highly dynamic time. METHODS: From June 1 to July 7, 2020, a telephone survey of KT candidates on the deceased donor waiting list at Imperial College Renal and Transplant Centre in West London was conducted. The survey captured ongoing COVID-19 exposure risks and patients' views on waitlist (WL) reactivation and undergoing transplantation. RESULTS: Two hundred seven responses were received. Of the respondents, 180 patients (87%) were happy to be reactivated onto the WL; with 141 patients (68%) willing to give consent to transplantation currently, while 53 patients (26%) felt unsure, and 13 patients (6%) would decline a KT. The vast majority of patients had no concerns. In the responses from those who were uncertain or who would decline a KT, concerns about COVID-19 infection and the need for reassurance from transplant units dominated. Universally patients wanted more information about COVID-19 infection risk with KT and the precautions being taken to reduce this risk. CONCLUSIONS: The majority of surveyed patients are in favor of reactivation and receiving a KT despite the ongoing COVID-19 pandemic. Reactivation of candidates cannot be assumed and should take an individualized approach, incorporating clinical risk with patient perspectives. Improved communication with KT candidates is highly requested.

Propensity score analysis for a semi-continuous exposure variable: a study of gestational alcohol exposure and childhood cognition.

Propensity score methodology has become increasingly popular in recent years as a tool for estimating causal effects in observational studies. Much of the related research has been directed at settings with binary or discrete exposure variables with more recent work involving continuous exposure variables. In environmental epidemiology, a substantial proportion of individuals is often completely unexposed while others may experience heavy exposure leading to an exposure distribution with a point mass at zero and a heavy right tail. We suggest a new approach to handle this type of exposure data by constructing a propensity score based on a two-part model and show how this model can be used to more reliably adjust for covariates of a semi-continuous exposure variable. We also consider the case when a misspecified propensity score is used in a regression adjustment and derive an explicit form of the bias. We show that the potential bias gets smaller as the estimated propensity score gets closer to the true expectation of the exposure variable given a set of observed covariates. While this result pertains to a more general setting, we use it to evaluate the potential bias in settings in which the true exposure has a semi-continuous structure. We also evaluate and compare the performance of our proposed method through simulation studies relative to a simpler linear regression-based propensity score for a continuous exposure variable as well as through direct covariate adjustment. Overall, we find that using a propensity score constructed via a two-part model significantly improves the regression estimate when the exposure variable is semi-continuous in nature. Specifically when the proportion of non-exposed subjects is high and the effects of covariates on exposure and outcome are strong, the proposed two-part propensity score method outperforms the more standard competing methods. We illustrate our method using data from the Detroit Longitudinal Cohort Study in which the exposure variable reflects gestational alcohol exposure featuring zero values and a long tail.

A Longitudinal Analysis of the Executive Functions in High-Level Soccer Players.

INTRODUCTION: Assessments of executive functions (EFs) with varying levels of perceptual information or action fidelity are common talent-diagnostic tools in soccer, yet their validity still has to be established. Therefore, a longitudinal development of EFs in high-level players to understand their relationship with increased exposure to training is required. METHODS: A total of 304 high-performing male youth soccer players (10-21 years old) in Germany were assessed across three seasons on various sport-specific and non-sport-specific cognitive functioning assessments. RESULTS: The posterior means (90% highest posterior density) of random slopes indicated that both abilities predominantly developed between 10 and 15 years of age. A plateau was apparent for domain-specific abilities during adolescence, whereas domain-generic abilities improved into young adulthood. CONCLUSION: The developmental trajectories of soccer players' EFs follow the general populations' despite long-term exposure to soccer-specific training and game play. This brings into question the relationship between high-level experience and EFs and renders including EFs in talent identification questionable.