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"Biological variation"
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Reproducibility of animal research in light of biological variation
Context-dependent biological variation presents a unique challenge to the reproducibility of results in experimental animal research, because organisms’ responses to experimental treatments can vary with both genotype and environmental conditions. In March 2019, experts in animal biology, experimental design and statistics convened in Blonay, Switzerland, to discuss strategies addressing this challenge. In contrast to the current gold standard of rigorous standardization in experimental animal research, we recommend the use of systematic heterogenization of study samples and conditions by actively incorporating biological variation into study design through diversifying study samples and conditions. Here we provide the scientific rationale for this approach in the hope that researchers, regulators, funders and editors can embrace this paradigm shift. We also present a road map towards better practices in view of improving the reproducibility of animal research.In this Perspective, Hanno Würbel and colleagues argue that a disregard for incorporating biological variation in study design is an important cause of poor reproducibility in animal research. They put the case for the use of systematic heterogenization of study samples and conditions in studies to improve reproducibility.
Journal Article
ARDS Subphenotypes: Understanding a Heterogeneous Syndrome
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2020. Other selected articles can be found online at
https://www.biomedcentral.com/collections/annualupdate2020
. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from
http://www.springer.com/series/8901
.
Journal Article
A Bayesian Approach to Biological Variation Analysis
Biological variation (BV) data have many applications for diagnosing and monitoring disease. The standard statistical approaches for estimating BV are sensitive to \"noisy data\" and assume homogeneity of within-participant CV. Prior knowledge about BV is mostly ignored. The aims of this study were to develop Bayesian models to calculate BV that (
) are robust to \"noisy data,\" (
) allow heterogeneity in the within-participant CVs, and (
) take advantage of prior knowledge.
We explored Bayesian models with different degrees of robustness using adaptive Student
distributions instead of the normal distributions and when the possibility of heterogeneity of the within-participant CV was allowed. Results were compared to more standard approaches using chloride and triglyceride data from the European Biological Variation Study.
Using the most robust Bayesian approach on a raw data set gave results comparable to a standard approach with outlier assessments and removal. The posterior distribution of the fitted model gives access to credible intervals for all parameters that can be used to assess reliability. Reliable and relevant priors proved valuable for prediction.
The recommended Bayesian approach gives a clear picture of the degree of heterogeneity, and the ability to crudely estimate personal within-participant CVs can be used to explore relevant subgroups. Because BV experiments are expensive and time-consuming, prior knowledge and estimates should be considered of high value and applied accordingly. By including reliable prior knowledge, precise estimates are possible even with small data sets.
Journal Article
YAP/TAZ deficiency reprograms macrophage phenotype and improves infarct healing and cardiac function after myocardial infarction
Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional changes in the heart leading to heart failure. The initial post-MI pro-inflammatory response followed by reparative or anti-inflammatory response is essential for minimizing the myocardial damage, healing, and scar formation. Bone marrow–derived macrophages (BMDMs) are recruited to the injured myocardium and are essential for cardiac repair as they can adopt both pro-inflammatory or reparative phenotypes to modulate inflammatory and reparative responses, respectively. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the key mediators of the Hippo signaling pathway and are essential for cardiac regeneration and repair. However, their functions in macrophage polarization and post-MI inflammation, remodeling, and healing are not well established. Here, we demonstrate that expression of YAP and TAZ is increased in macrophages undergoing pro-inflammatory or reparative phenotype changes. Genetic deletion of YAP/TAZ leads to impaired pro-inflammatory and enhanced reparative response. Consistently, YAP activation enhanced pro-inflammatory and impaired reparative response. We show that YAP/TAZ promote pro-inflammatory response by increasing interleukin 6 ( IL6 ) expression and impede reparative response by decreasing Arginase-I ( Arg1 ) expression through interaction with the histone deacetylase 3 (HDAC3)-nuclear receptor corepressor 1 (NCoR1) repressor complex. These changes in macrophages polarization due to YAP/TAZ deletion results in reduced fibrosis, hypertrophy, and increased angiogenesis, leading to improved cardiac function after MI. Also, YAP activation augmented MI-induced cardiac fibrosis and remodeling. In summary, we identify YAP/TAZ as important regulators of macrophage-mediated pro-inflammatory or reparative responses post-MI.
Journal Article
Enhancing bacterial survival through phenotypic heterogeneity
Variations in the number of nucleotides within an SSR in a coding sequence may cause a frameshift mutation that creates a premature stop codon and a truncated product (OFF) or, conversely, may restore the reading frame and production of the gene product (ON). [...]phase variation can be achieved by shuffling alleles of the same gene between an expressed locus and a distal, silent locus. Consistent with this result, phase-locked OFF mutants lacking fimbriae are attenuated in disease models of urinary tract infection [12, 13]. Some DNA methyltransferases, enzymes that methylate specific nucleotide motifs, are subject to phase variation, resulting in a population of bacteria with different methylation patterns. Because methylation can influence gene expression, methyltransferase phase variation can influence the transcription of multiple genes simultaneously.
Journal Article
Biological Variation of Cardiac Troponins in Health and Disease: A Systematic Review and Meta-analysis
Abstract
Background
Many studies have assessed the biological variation (BV) of cardiac-specific troponins (cTn), reporting widely varying within-subject BV (CVI) estimates. The aim of this study was to provide meta-analysis-derived BV estimates for troponin I (cTnI) and troponin T (cTnT) for different sampling intervals and states of health.
Methods
Relevant studies were identified by a systematic literature search. Studies were classified according to their methodological quality by the Biological Variation Data Critical Appraisal Checklist (BIVAC). Meta-analyses of BIVAC-compliant studies were performed after stratification by cTn isoform, exclusion of results below the limit of detection, states of health, and sampling interval to deliver reference change values (RCV), index of individuality (II) and analytical performance specifications (APS) for these settings.
Results
Sixteen and 15 studies were identified for cTnI and cTnT, respectively, out of which 6 received a BIVAC grade A. Five studies had applied contemporary cTnI assays, but none contemporary cTnT. High-sensitivity (hs-) cTnI and cTnT delivered similar estimates in all settings. Long-term CVI estimates (15.1; 11.3%) derived from healthy individuals were higher than short-term (4.3%; 5.3%) for hs-cTnI and hs-cTnT, respectively, although confidence intervals overlapped. Estimates derived from diseased subjects were similar to estimates in healthy individuals for all settings.
Conclusions
This study provides robust estimates for hs-cTnI and hs-cTnT applicable for different clinical settings and states of health, allowing for the use of RCV both to aid in the diagnosis of myocardial injury and for prognosis. BV-based APS appear too strict for some currently available technologies.
Journal Article
EEG microstates associated with intra- and inter-subject alpha variability
Variation of the magnitude of posterior alpha rhythm (8–12 Hz) has functional and behavioural effects in sensory processing and cognitive performances. Electrical brain activity, as revealed by electroencephalography (EEG), can be represented by a sequence of microstates of about 40–120 ms duration, in which distributed neural pools are synchronously active and generate stable spatial potential topographies on the scalp. Microstate dynamics may reflect transitions between global states characterized by selective inhibition of specific intra-cortical regions, mediated by alpha activity. We investigated the intra-subject and inter-subject relationship between microstate features and alpha band. High-density EEG signals were acquired in 29 healthy subjects during ten minutes of eyes closed rest. Individual EEG signal epochs were classified into four groups depending on the amount of occipital alpha power, and microstate metrics (duration, coverage and frequency of occurrence) were calculated and compared across groups. Correlations between alpha power and microstate metrics between individuals were also performed. To assess if microstate parameter variations are specific for the alpha band, the same analysis was also performed for theta and beta bands, as well as for global field power. We observed an increase in the metrics of microstate, previously associated to the visual system, with the level of intra-subject amplitude alpha oscillations, together with lower coverage of microstate associated with executive attention network and a higher frequency of microstate associated with task negative network. Other modulation effects of broad-band EEG power level on microstate metrics were observed. These effects are not specific for the alpha band, since they can equally be attributed to fluctuations in other frequency bands. We can interpret our results as a regulation mechanism mediated by posterior alpha level, dynamically interacting with other frequency bands, responsible for the switching between active areas.
Journal Article
scMC learns biological variation through the alignment of multiple single-cell genomics datasets
Distinguishing biological from technical variation is crucial when integrating and comparing single-cell genomics datasets across different experiments. Existing methods lack the capability in explicitly distinguishing these two variations, often leading to the removal of both variations. Here, we present an integration method scMC to remove the technical variation while preserving the intrinsic biological variation. scMC learns biological variation via variance analysis to subtract technical variation inferred in an unsupervised manner. Application of scMC to both simulated and real datasets from single-cell RNA-seq and ATAC-seq experiments demonstrates its capability of detecting context-shared and context-specific biological signals via accurate alignment.
Journal Article
Gut microbiota plasticity is correlated with sustained weight loss on a low-carb or low-fat dietary intervention
While low-carbohydrate and low-fat diets can both lead to weight-loss, a substantial variability in achieved long-term outcomes exists among obese but otherwise healthy adults. We examined the hypothesis that structural differences in the gut microbiota explain a portion of variability in weight-loss using two cohorts of obese adults enrolled in the Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) study. A total of 161 pre-diet fecal samples were sequenced from a discovery cohort (n = 66) and 106 from a validation cohort (n = 56). An additional 157 fecal samples were sequenced from the discovery cohort after 10 weeks of dietary intervention. We found no specific bacterial signatures associated with weight loss that were consistent across both cohorts. However, the gut microbiota plasticity (i.e. variability), was correlated with long-term (12-month) weight loss in a diet-dependent manner; on the low-fat diet subjects with higher pre-diet daily plasticity had higher sustained weight loss, whereas on the low-carbohydrate diet those with higher plasticity over 10 weeks of dieting had higher 12-month weight loss. Our findings suggest the potential importance of gut microbiota plasticity for sustained weight-loss. We highlight the advantages of evaluating kinetic trends and assessing reproducibility in studies of the gut microbiota.
Journal Article