General dimensions of human brain morphometry inferred from genome-wide association data.

Understanding the neurodegenerative mechanisms underlying cognitive decline in the general population may facilitate early detection of adverse health outcomes in late life. This study investigates genetic links between brain morphometry, ageing and cognitive ability. We develop Genomic Principal Components Analysis (Genomic PCA) to model general dimensions of brain-wide morphometry at the level of their underlying genetic architecture. Genomic PCA is applied to genome-wide association data for 83 brain-wide volumes (36,778 UK Biobank participants) and we extract genomic principal components (PCs) to capture global dimensions of genetic covariance across brain regions (unlike ancestral PCs that index genetic similarity between participants). Using linkage disequilibrium score regression, we estimate genetic overlap between those general brain dimensions and cognitive ageing. The first genetic PCs underlying the morphometric organisation of 83 brain-wide regions accounted for substantial genetic variance (R2  = 40%) with the pattern of component loadings corresponding closely to those obtained from phenotypic analyses. Genetically more central regions to overall brain structure - specifically frontal and parietal volumes thought to be part of the central executive network - tended to be somewhat more susceptible towards age (r = -0.27). We demonstrate the moderate genetic overlap between the first PC underlying each of several structural brain networks and general cognitive ability (rg  = 0.17-0.21), which was not specific to a particular subset of the canonical networks examined. We provide a multivariate framework integrating covariance across multiple brain regions and the genome, revealing moderate shared genetic etiology between brain-wide morphometry and cognitive ageing.

Using generalized additive models to decompose time series and waveforms, and dissect heart-lung interaction physiology.

Common physiological time series and waveforms are composed of repeating cardiac and respiratory cycles. Often, the cardiac effect is the primary interest, but for, e.g., fluid responsiveness prediction, the respiratory effect on arterial blood pressure also convey important information. In either case, it is relevant to disentangle the two effects. Generalized additive models (GAMs) allow estimating the effect of predictors as nonlinear, smooth functions. These smooth functions can represent the cardiac and respiratory cycles' effects on a physiological signal. We demonstrate how GAMs allow a decomposition of physiological signals from mechanically ventilated subjects into separate effects of the cardiac and respiratory cycles. Two examples are presented. The first is a model of the respiratory variation in pulse pressure. The second demonstrates how a central venous pressure waveform can be decomposed into a cardiac effect, a respiratory effect and the interaction between the two cycles. Generalized additive models provide an intuitive and flexible approach to modelling the repeating, smooth, patterns common in medical monitoring data.

Learning conversational dependency: Children's response using un in Japanese.

This study investigates how Japanese-speaking children learn interactional dependencies in conversations that determine the use of un, a token typically used as a positive response for yes-no questions, backchannel, and acknowledgement. We hypothesise that children learn to produce un appropriately by recognising different types of cues occurring in the immediately preceding turns. We built a set of generalised linear models on the longitudinal conversation data from seven children aged 1 to 5 years and their caregivers. Our models revealed that children not only increased their un production, but also learned to attend relevant cues in the preceding turns to understand when to respond by producing un. Children increasingly produced un when their interlocutors asked a yes-no question or signalled the continuation of their own speech. These results illustrate how children learn the probabilistic dependency between adjacent turns, and become able to participate in conversational interactions.

They might all be marauders.

Circle theory predicts most offenders will reside within the smallest circle that encloses a pattern of offense locations, which defines the offender's crime range. Those who reside within the crime range reflect a marauder decision pattern, with the remainder reflecting a commuter decision pattern. Random simulations of marauders were conducted to determine the failure rate of the smallest circle to correctly identify a marauder decision pattern. Failure rates were higher as the number of offenses was reduced, but were systematic and predictable. Moreover, the published rates of the marauder vs commuter patterns correspond well with the predicted failure rate. A method for estimating the true size of an offender's criminal territory is presented and it is suggested that the vast majority of offenders are likely to be adopting a marauder decision pattern, and that true commuters may be far less than indicated by the circle test.

Time-series transcriptomics reveals a BBX32-directed control of acclimation to high light in mature Arabidopsis leaves.

The photosynthetic capacity of mature leaves increases after several days' exposure to constant or intermittent episodes of high light (HL) and is manifested primarily as changes in chloroplast physiology. How this chloroplast-level acclimation to HL is initiated and controlled is unknown. From expanded Arabidopsis leaves, we determined HL-dependent changes in transcript abundance of 3844 genes in a 0-6 h time-series transcriptomics experiment. It was hypothesized that among such genes were those that contribute to the initiation of HL acclimation. By focusing on differentially expressed transcription (co-)factor genes and applying dynamic statistical modelling to the temporal transcriptomics data, a regulatory network of 47 predominantly photoreceptor-regulated transcription (co-)factor genes was inferred. The most connected gene in this network was B-BOX DOMAIN CONTAINING PROTEIN32 (BBX32). Plants overexpressing BBX32 were strongly impaired in acclimation to HL and displayed perturbed expression of photosynthesis-associated genes under LL and after exposure to HL. These observations led to demonstrating that as well as regulation of chloroplast-level acclimation by BBX32, CRYPTOCHROME1, LONG HYPOCOTYL5, CONSTITUTIVELY PHOTOMORPHOGENIC1 and SUPPRESSOR OF PHYA-105 are important. In addition, the BBX32-centric gene regulatory network provides a view of the transcriptional control of acclimation in mature leaves distinct from other photoreceptor-regulated processes, such as seedling photomorphogenesis.

Optimal spatial monitoring of populations described by reaction-diffusion models.

Using spatialised population measurements and related geographic habitat data, it is feasible nowadays to derive parsimonious spatially explicit population models and to carry on their parameter estimation. To achieve such goal, reaction-diffusion models are common in conservation biology and agricultural plant health where they are used, for example, for landscape planning or epidemiological surveillance. Unfortunately, if the mathematical methods and computational power are readily available, biological measurements are not. Despite the high throughput of some habitat related remote sensors, the experimental cost of biological measurements are one of the worst bottleneck against a widespread usage of reaction-diffusion models. Hence we will recall some classical methods for optimal experimental design that we deem useful to spatial ecologist. Using two case studies, one in landscape ecology and one in conservation biology, we will show how to construct a priori experimental design minimizing variance of parameter estimates, enabling optimal experimental setup under constraints.

|tPRiors |: a tool for prior elicitation and obtaining posterior distributions of true disease prevalence.

BACKGROUND: Tests have false positive or false negative results, which, if not properly accounted for, may provide misleading apparent prevalence estimates based on the observed rate of positive tests and not the true disease prevalence estimates. Methods to estimate the true prevalence of disease, adjusting for the sensitivity and the specificity of the diagnostic tests are available and can be applied, though, such procedures can be cumbersome to researchers with or without a solid statistical background. This manuscript introduces a web-based application that integrates statistical methods for Bayesian inference of true disease prevalence based on prior elicitation for the accuracy of the diagnostic tests. This tool allows practitioners to simultaneously analyse and visualize results while using interactive sliders and output prior/posterior plots. METHODS - IMPLEMENTATION: Three methods for prevalence prior elicitation and four core families of Bayesian methods have been combined and incorporated in this web tool. |tPRiors| user interface has been developed with R and Shiny and may be freely accessed on-line. RESULTS: |tPRiors| allows researchers to use preloaded data or upload their own datasets and perform analysis on either single or multiple population groups clusters, allowing, if needed, for excess zero prevalence. The final report is exported in raw parts either as.rdata or.png files and can be further analysed. We utilize a real multiple-population and a toy single-population dataset to demonstrate the robustness and capabilities of |tPRiors|. CONCLUSIONS: We expect |tPRiors| to be helpful for researchers interested in true disease prevalence estimation and who are keen on accounting for prior information. |tPRiors| acts both as a statistical tool and a simplified step-by-step statistical framework that facilitates the use of complex Bayesian methods. The application of |tPRiors| is expected to aid standardization of practices in the field of Bayesian modelling on subject and multiple group-based true prevalence estimation.

Modeling road traffic fatalities in Iran's six most populous provinces, 2015-2016.

BACKGROUND: Prevention of road traffic injuries (RTIs) as a critical public health issue requires coordinated efforts. We aimed to model influential factors related to traffic safety. METHODS: In this cross-sectional study, the information from 384,614 observations recorded in Integrated Road Traffic Injury Registry System (IRTIRS) in a one-year period (March 2015-March 2016) was analyzed. All registered crashes from Tehran, Isfan, Fras, Razavi Khorasan, Khuzestan, and East Azerbaijan provinces, the six most populated provinces in Iran, were included in this study. The variables significantly associated with road traffic fatality in the uni-variate analysis were included in the multiple logistic regression. RESULTS: According to the multiple logistic regression, thirty-two out of seventy-one different variables were identified to be significantly associated with road traffic fatality. The results showed that the crash scene significantly related factors were passenger presence(OR = 4.95, 95%CI = (4.54-5.40)), pedestrians presence(OR = 2.60, 95%CI = (1.75-3.86)), night-time crashes (OR = 1.64, 95%CI = (1.52-1.76)), rainy weather (OR = 1.32, 95%CI = (1.06-1.64)), no intersection control (OR = 1.40, 95%CI = (1.29-1.51)), double solid line(OR = 2.21, 95%CI = (1.31-3.74)), asphalt roads(OR = 1.95, 95%CI = (1.39-2.73)), nonresidential areas(OR = 2.15, 95%CI = (1.93-2.40)), vulnerable-user presence(OR = 1.70, 95%CI = (1.50-1.92)), human factor (OR = 1.13, 95%CI = (1.03-1.23)), multiple first causes (OR = 2.81, 95%CI = (2.04-3.87)), fatigue as prior cause(OR = 1.48, 95%CI = (1.27-1.72)), irregulation as direct cause(OR = 1.35, 95%CI = (1.20-1.51)), head-on collision(OR = 3.35, 95%CI = (2.85-3.93)), tourist destination(OR = 1.95, 95%CI = (1.69-2.24)), suburban areas(OR = 3.26, 95%CI = (2.65-4.01)), expressway(OR = 1.84, 95%CI = (1.59-2.13)), unpaved shoulders(OR = 1.84, 95%CI = (1.63-2.07)), unseparated roads (OR = 1.40, 95%CI = (1.26-1.56)), multiple road defects(OR = 2.00, 95%CI = (1.67-2.39)). In addition, the vehicle-connected factors were heavy vehicle (OR = 1.40, 95%CI = (1.26-1.56)), dark color (OR = 1.26, 95%CI = (1.17-1.35)), old vehicle(OR = 1.46, 95%CI = (1.27-1.67)), not personal-regional plaques(OR = 2.73, 95%CI = (2.42-3.08)), illegal maneuver(OR = 3.84, 95%CI = (2.72-5.43)). And, driver related factors were non-academic education (OR = 1.58, 95%CI = (1.33-1.88)), low income(OR = 2.48, 95%CI = (1.95-3.15)), old age (OR = 1.67, 95%CI = (1.44-1.94)), unlicensed driving(OR = 3.93, 95%CI = (2.51-6.15)), not-wearing seat belt (OR = 1.55, 95%CI = (1.44-1.67)), unconsciousness (OR = 1.67, 95%CI = (1.44-1.94)), driver misconduct(OR = 2.51, 95%CI = (2.29-2.76)). CONCLUSION: This study reveals that driving behavior, infrastructure design, and geometric road factors must be considered to avoid fatal crashes. Our results found that the above-mentioned factors had higher odds of a deadly outcome than their counterparts. Generally, addressing risk factors and considering the odds ratios would be beneficial for policy makers and road safety stakeholders to provide support for compulsory interventions to reduce the severity of RTIs.

Epidemiological and clinical insights from SARS-CoV-2 RT-PCR crossing threshold values, France, January to November 2020.

BackgroundThe COVID-19 pandemic has led to an unprecedented daily use of RT-PCR tests. These tests are interpreted qualitatively for diagnosis, and the relevance of the test result intensity, i.e. the number of quantification cycles (Cq), is debated because of strong potential biases.AimWe explored the possibility to use Cq values from SARS-CoV-2 screening tests to better understand the spread of an epidemic and to better understand the biology of the infection.MethodsWe used linear regression models to analyse a large database of 793,479 Cq values from tests performed on more than 2 million samples between 21 January and 30 November 2020, i.e. the first two pandemic waves. We performed time series analysis using autoregressive integrated moving average (ARIMA) models to estimate whether Cq data information improves short-term predictions of epidemiological dynamics.ResultsAlthough we found that the Cq values varied depending on the testing laboratory or the assay used, we detected strong significant trends associated with patient age, number of days after symptoms onset or the state of the epidemic (the temporal reproduction number) at the time of the test. Furthermore, knowing the quartiles of the Cq distribution greatly reduced the error in predicting the temporal reproduction number of the COVID-19 epidemic.ConclusionOur results suggest that Cq values of screening tests performed in the general population generate testable hypotheses and help improve short-term predictions for epidemic surveillance.

Generating Alerts from Breathing Pattern Outliers.

Analysing human physiological data allows access to the health state and the state of mind of the subject individual. Whenever a person is sick, having a panic attack, happy or scared, physiological signals will be different. In terms of physiological signals, we focus, in this manuscript, on monitoring breathing patterns. The scope can be extended to also address heart rate and other variables. We describe an analysis of breathing rate patterns during activities including resting, walking, running and watching a movie. We model normal breathing behaviours by statistically analysing signals, processed to represent quantities of interest. We consider moving maximum/minimum, the amplitude and the Fourier transform of the respiration signal, working with different window sizes. We then learn a statistical model for the basal behaviour, per individual, and detect outliers. When outliers are detected, a system that incorporates our approach would send a visible signal through a smart garment or through other means. We describe alert generation performance in two datasets-one literature dataset and one collected as a field study for this work. In particular, when learning personal rest distributions for the breathing signals of 14 subjects, we see alerts generated more often when the same individual is running than when they are tested in rest conditions.

Post-hydrolysis ammonia stripping as a new approach to enhance the two-stage anaerobic digestion of poultry manure: Optimization and statistical modelling.

Post-hydrolysis ammonia stripping was investigated as a new approach to enhance the methane potential of high ammonia substrates, such as poultry manure. The objective of the proposed approach is to address some of the noticeable disadvantages in the existing ammonia-stripping techniques i.e., treatment of raw samples and side-stream stripping. Poultry manure (PM) and a co-substrate (mixed wastes from a cheese factory and a coffee house, referred to as MS) characterized by a high carbon-to-nitrogen ratio were mixed at five different ratios: PM:MS of 100:0, 75:25, 50:50, 25:75, and 0:100. Samples were hydrolyzed for six days to promote ammonia conversion from organic nitrogen and then the samples with higher ammonia levels (>2000 mg NH3-N/L) were stripped with air at initial pH values of 9 and 10 and temperatures of 40 and 55 °C. Biochemical methane potential (BMP) test results showed that post-hydrolysis ammonia stripping had alleviated ammonia inhibition and improved methane potential up to 200% when compared with untreated samples. The ammonia removal efficiency was mostly affected by pH. On the other hand, methane potential was highest in the samples treated at a higher temperature as their biodegradability was enhanced when compared with the samples treated at lower temperatures. Post-BMP characterization showed that the proposed approach had also limited the increase of ammonia in the digestate which ensured proper growth of methanogenic microorganisms.

A group of ectomycorrhizal fungi restricts organic matter accumulation in boreal forest.

Boreal forest soils are important global carbon sinks, with significant storage in the organic topsoil. Decomposition of these stocks requires oxidative enzymes, uniquely produced by fungi. Across Swedish boreal forests, we found that local carbon storage in the organic topsoil was 33% lower in the presence of a group of closely related species of ectomycorrhizal fungi - Cortinarius acutus s.l.. This observation challenges the prevailing view that ectomycorrhizal fungi generally act to increase carbon storage in soils but supports the idea that certain ectomycorrhizal fungi can complement free-living decomposers, maintaining organic matter turnover, nutrient cycling and tree productivity under nutrient-poor conditions. The indication that a narrow group of fungi may exert a major influence on carbon cycling questions the prevailing dogma of functional redundancy among microbial decomposers. Cortinarius acutus s.l. responds negatively to stand-replacing disturbance, and associated population declines are likely to increase soil carbon sequestration while impeding long-term nutrient cycling.

Detecting Rapid Spread of SARS-CoV-2 Variants, France, January 26-February 16, 2021.

Variants of severe acute respiratory syndrome coronavirus 2 raise concerns regarding the control of coronavirus disease epidemics. We analyzed 40,000 specific reverse transcription PCR tests performed on positive samples during January 26-February 16, 2021, in France. We found high transmission advantage of variants and more advanced spread than anticipated.

Predicting ecosystem responses by data-driven reciprocal modelling.

Treatment effects are traditionally quantified in controlled experiments. However, experimental control is often achieved at the expense of representativeness. Here, we present a data-driven reciprocal modelling framework to quantify the individual effects of environmental treatments under field conditions. The framework requires a representative survey data set describing the treatment (A or B), its responding target variable and other environmental properties that cause variability of the target within the region or population studied. A machine learning model is trained to predict the target only based on observations in group A. This model is then applied to group B, with predictions restricted to the model's space of applicability. The resulting residuals represent case-specific effect size estimates and thus provide a quantification of treatment effects. This paper illustrates the new concept of such data-driven reciprocal modelling to estimate spatially explicit effects of land-use change on organic carbon stocks in European agricultural soils. For many environmental treatments, the proposed concept can provide accurate effect size estimates that are more representative than could feasibly ever be achieved with controlled experiments.

Shrinkage in serial intervals across transmission generations of COVID-19.

One of the key epidemiological characteristics that shape the transmission of coronavirus disease 2019 (COVID-19) is the serial interval (SI). Although SI is commonly considered following a probability distribution at a population scale, recent studies reported a slight shrinkage (or contraction) of the mean of effective SI across transmission generations or over time. Here, we develop a likelihood-based statistical inference framework with truncation to explore the change in SI across transmission generations after adjusting the impacts of case isolation. The COVID-19 contact tracing surveillance data in Hong Kong are used for exemplification. We find that for COVID-19, the mean of individual SI is likely to shrink with a factor at 0.72 per generation (95%CI: 0.54, 0.96) as the transmission generation increases, where a threshold may exist as the lower boundary of this shrinking process. We speculate that one of the probable explanations for the shrinkage in SI might be an outcome due to the competition among multiple candidate infectors within the same case cluster. Thus, the nonpharmaceutical interventive strategies are crucially important to block the transmission chains, and mitigate the COVID-19 epidemic.

Real-time quantification of the transmission advantage associated with a single mutation in pathogen genomes: a case study on the D614G substitution of SARS-CoV-2.

BACKGROUND: The COVID-19 pandemic poses serious threats to global health, and the emerging mutation in SARS-CoV-2 genomes, e.g., the D614G substitution, is one of the major challenges of disease control. Characterizing the role of the mutation activities is of importance to understand how the evolution of pathogen shapes the epidemiological outcomes at population scale. METHODS: We developed a statistical framework to reconstruct variant-specific reproduction numbers and estimate transmission advantage associated with the mutation activities marked by single substitution empirically. Using likelihood-based approach, the model is exemplified with the COVID-19 surveillance data from January 1 to June 30, 2020 in California, USA. We explore the potential of this framework to generate early warning signals for detecting transmission advantage on a real-time basis. RESULTS: The modelling framework in this study links together the mutation activity at molecular scale and COVID-19 transmissibility at population scale. We find a significant transmission advantage of COVID-19 associated with the D614G substitution, which increases the infectivity by 54% (95%CI: 36, 72). For the early alarming potentials, the analytical framework is demonstrated to detect this transmission advantage, before the mutation reaches dominance, on a real-time basis. CONCLUSIONS: We reported an evidence of transmission advantage associated with D614G substitution, and highlighted the real-time estimating potentials of modelling framework.

Points of attention when conducting etiological research.

Epidemiological studies often aim to investigate the causal contribution of a risk factor to a disease or other outcome. In etiological research, one is usually interested in the (biological) mechanism(s) underlying the studied relationship. Inappropriate conduct of an etiological study may have major implications for the correctness of the results and interpretation of the findings. Therefore, in this paper, we aim to describe step by step how etiological research should be carried out, together with its  common pitfalls. These steps involve finding and formulating a well-defined etiological research question, choosing an appropriate study design including a suitable comparison group, adequate modelling, and adequate reporting and interpretation of the results.

Multi-level longitudinal learning curve regression models integrated with item difficulty metrics for deliberate practice of visual diagnosis: groundwork for adaptive learning.

Visual diagnosis of radiographs, histology and electrocardiograms lends itself to deliberate practice, facilitated by large online banks of cases. Which cases to supply to which learners in which order is still to be worked out, with there being considerable potential for adapting the learning. Advances in statistical modeling, based on an accumulating learning curve, offer methods for more effectively pairing learners with cases of known calibrations. Using demonstration radiograph and electrocardiogram datasets, the advantages of moving from traditional regression to multilevel methods for modeling growth in ability or performance are demonstrated, with a final step of integrating case-level item-response information based on diagnostic grouping. This produces more precise individual-level estimates that can eventually support learner adaptive case selection. The progressive increase in model sophistication is not simply statistical but rather brings the models into alignment with core learning principles including the importance of taking into account individual differences in baseline skill and learning rate as well as the differential interaction with cases of varying diagnosis and difficulty. The developed approach can thus give researchers and educators a better basis on which to anticipate learners' pathways and individually adapt their future learning.

The SARS-CoV-2 B.1.351 lineage (VOC ß) is outgrowing the B.1.1.7 lineage (VOC α) in some French regions in April 2021.

To assess SARS-CoV-2 variants spread, we analysed 36,590 variant-specific reverse-transcription-PCR tests performed on samples from 12 April-7 May 2021 in France. In this period, contrarily to January-March 2021, variants of concern (VOC) ß (B.1.351 lineage) and/or γ (P.1 lineage) had a significant transmission advantage over VOC α (B.1.1.7 lineage) in Île-de-France (15.8%; 95% confidence interval (CI): 15.5-16.2) and Hauts-de-France (17.3%; 95% CI: 15.9-18.7) regions. This is consistent with VOC ß's immune evasion abilities and high proportions of prior-SARS-CoV-2-infected persons in these regions.

Rapid spread of the SARS-CoV-2 Delta variant in some French regions, June 2021.

We analysed 9,030 variant-specific RT-PCR tests performed on SARS-CoV-2-positive samples collected in France between 31 May and 21 June 2021. This analysis revealed rapid growth of the Delta variant in three of the 13 metropolitan French regions and estimated a +79% (95% confidence interval: 52-110%) transmission advantage compared with the Alpha variant. The next weeks will prove decisive and the magnitude of the estimated transmission advantages of the Delta variant could represent a major challenge for public health authorities.