No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing
Abstract
The common approach to the multiplicity problem calls for controlling the familywise error rate (FWER). This approach, though, has faults, and we point out a few. A different approach to problems of multiple significance testing is presented. It calls for controlling the expected proportion of falsely rejected hypotheses — the false discovery rate. This error rate is equivalent to the FWER when all hypotheses are true but is smaller otherwise. Therefore, in problems where the control of the false discovery rate rather than that of the FWER is desired, there is potential for a gain in power. A simple sequential Bonferronitype procedure is proved to control the false discovery rate for independent test statistics, and a simulation study shows that the gain in power is substantial. The use of the new procedure and the appropriateness of the criterion are illustrated with examples.
... As a rule, differences between lines manifested themselves in one of the first two principal components, which together accounted for more than half of the total variance. The significance of the differences between each pair of lines for each principal component was assessed using a two-sample t-test, applying the Benjamini-Hochberg P adjustment to correct for multiple testing [24]. ...
... Euclidean distance was used to assess differences in developmental rates for each pair of vials. Next, just as for fertility, the principal components were calculated by the Gower principal coordinate method and the lines were compared with each other according to the first two principal components by t-test, applying the Benjamini-Hochberg P adjustment [24] (see the previous section). ...
... Survival rates were calculated as the percentage of survivors in each vial. The groups were compared on this trait using the t-test by the Benjamini-Hochberg method [24]. ...
The best-known effect of the intracellular bacterium Wolbachia is its mostly negative influence on the reproduction of the host. However, there is evidence of a positive influence of Wolbachia on the host’s resistance to stress, pathogens, and viruses. Here, we analyzed the effects of two Wolbachia strains belonging to wMel and wMelCS genotypes on D. melanogaster traits, such as fertility, survival under acute heat stress, and developmental rate. We found that D. melanogaster lines under study differ significantly in the above-mentioned characteristics, both when the natural infection was preserved, and when it was eliminated. One of Wolbachia strains, wMel, did not affect any of the studied traits. Another strain, wMelPlus, had a significant effect on the development time. Moreover, this effect is observed not only in the line in which it was discovered but also in the one it was transferred to. When transferred to a new line, wMelPlus also caused changes in survival under heat stress. Thus, it could be concluded that Wolbachia–Drosophila interaction depends on the genotypes of both the host and the symbiont, but some Wolbachia effects could depend not on the genotypes, but on the fact of recent transfer of the symbiont.
... We adjusted for multiple testing within families of outcomes defined by food group and promotion location (i.e., 3 tests per food group for analyses overall, among SNAP participants, and among non-participants) by controlling the false discovery rate at q=0.05 using the Benjamini-Hochberg method. 44 Finally, to assess whether associations differed for healthier versus less healthy foods, we examined associations stratifying by product healthfulness; these analyses did not examine beverages, which were not rated by Guiding Stars at the time of the study. These analyses also used the Benjamini-Hochberg method to adjust for multiple comparisons within food groups (i.e., 2 tests per food group for analyses among healthier and less healthy foods). ...
... These analyses also used the Benjamini-Hochberg method to adjust for multiple comparisons within food groups (i.e., 2 tests per food group for analyses among healthier and less healthy foods). 44 We report two-sided 95% confidence intervals and adjusted p-values (i.e., q-values). ...
... P-values were adjusted for multiple comparisons within food groups (2 tests per group) by controlling the false discovery rate at q=0.05 using Benjamini and Hochberg's linear step-up method. 44 ...
Objective
Most food retailers display foods in prominent locations as a marketing strategy (i.e., “placement promotions”). We examined the extent to which households with children change their food and beverage purchases in response to these promotions.
Design
We analyzed a novel dataset of all products promoted in two supermarkets from 2016–2017, including promotion dates and locations (e.g., aisle endcaps, front registers). We linked promotions to all purchases from the supermarkets from 2016–2017 by a cohort of households with children. We calculated the number of weekly promotions in each of 13 food and beverage groups (e.g., bread, candy) and used fixed effects regressions to estimate associations between number of weekly promotions and households’ weekly food purchases, overall and by Supplemental Nutrition Assistance Program (SNAP) participation.
Setting
Two large supermarkets in Maine, USA.
Participants
821 households with children.
Results
Most promotions (74%) were for less healthy foods. The most promoted food groups were sweet and salty snacks (mean=131.0 promotions/week), baked goods (mean=68.2), and sugar-sweetened beverages (mean=41.6). Households generally did not change their food group purchases during weeks when they were exposed to more promotions for those groups, except that a 1-standard-deviation increase in endcap candy promotions (∼1 promotion/week) was associated with $0.19/week (∼14.5%) increase in candy purchases among SNAP nonparticipants (adjusted p <0.001).
Conclusions
In-store placement promotions for food groups were generally not associated with purchases of promoted food groups, perhaps because exposure to unhealthy food marketing was consistently high. Substantial changes to in-store food marketing may be needed to promote healthier purchases.
... When Cov is fixed, P Error decreases with Alt. If P Error < 0.05 after multiple testing correction [78], it means that the variation observed is unlikely due to sequencing error and should be regarded as a genuine difference between the RNA reads and the reference genome. In RNA-Seq data, if a variation site has Cov = 100 and Alt = 1, then this alternative base might come from sequencing error because although the base quality Q has already been controlled, sequencing errors still exist. ...
... When Cov is fixed, PError decreases with Alt. If PError < 0.05 after multiple testing correction [78], it means that the variation observed is unlikely due to sequencing error and should be regarded as a genuine difference between the RNA reads and the reference genome. ...
Adenosine-to-inosine (A-to-I) RNA editing is the most prevalent RNA modification in the nervous systems of metazoans. To study the biological significance of RNA editing, we first have to accurately identify these editing events from the transcriptome. The genome-wide identification of RNA editing sites remains a challenging task. In this review, we will first introduce the occurrence, regulation, and importance of A-to-I RNA editing and then describe the established bioinformatic procedures and difficulties in the accurate identification of these sit esespecially in small sized non-model insects. In brief, (1) to obtain an accurate profile of RNA editing sites, a transcriptome coupled with the DNA resequencing of a matched sample is favorable; (2) the single-cell sequencing technique is ready to be applied to RNA editing studies, but there are a few limitations to overcome; (3) during mapping and variant calling steps, various issues, like mapping and base quality, soft-clipping, and the positions of mismatches on reads, should be carefully considered; (4) Sanger sequencing of both RNA and the matched DNA is the best verification of RNA editing sites, but other auxiliary evidence, like the nonsynonymous-to-synonymous ratio or the linkage information, is also helpful for judging the reliability of editing sites. We have systematically reviewed the understanding of the biological significance of RNA editing and summarized the methodology for identifying such editing events. We also raised several promising aspects and challenges in this field. With insightful perspectives on both scientific and technical issues, our review will benefit the researchers in the broader RNA editing community.
... Prior to conducting the paired t-tests, the approximate normality of peptide binding intensity distributions were assessed with quantile-quantile plots (Supplementary Figures S1-S10) generated with the geom_qq () and geom_qq_line() functions in R with ggplot v3.4.2. False discovery rate control of paired t-test p values was performed via Benjamini-Hochberg (FDR) correction (21), adjusting for multiple comparisons with a protein (i.e., peptide-level t-tests were penalized based on the number of total peptides within their respective protein) and imposing an adjusted p value threshold <0.05. Peptides with significant adjusted p values were considered to have undergone a significant IgE/IgG4 ratio increase or decrease over the course of the study if their mean difference was >1 or <1, respectively. ...
... Between-group (i.e., Active vs. Placebo) comparisons of perpeptide IgE/IgG4 were performed with linear regression models (LM) using the lm() function in R: IgE/IgG4 Post = IgE/IgG4 Pre + Treatment. LM fit metrics are available in Supplementary Table 2. Raw p values were adjusted for multiple testing via FDR correction (21). Contrasting least-squares means were computed using the emmeans v1.8.7 package (25). ...
Background
Oral immunotherapy (OIT) with peanut ( Arachis hypogaea ) allergen powder-dnfp (PTAH; Aimmune Therapeutics) is an FDA-approved treatment to desensitize peanut allergic participants.
Objective
Here we assessed shifts in IgE and IgG4 binding to peanut allergens and their epitopes recognized by United States (US) peanut allergic participants ( n = 20) enrolled in phase 3 PTAH OIT clinical trials.
Methods
Pre- and post- trial participant sera were collected approximately 12 months apart and tested for IgE binding to intact peanut proteins via ImmunoCAP ISAC immunoassays. IgE and IgG4 linear epitopes were identified based on binding to synthetic overlapping 15-mer linear peptides of 10 peanut allergens (Ara h 1-11) synthesized on microarray slides.
Results
Statistically significant decreases in IgE binding were identified for intact Ara h 2, 3, and 6, and known and newly identified IgE epitopes were shown to exhibit shifts towards IgG4 binding post-OIT, with most linear peptides having increased IgG4 binding after treatment with PTAH. While PTAH does not seem to alter the actual peptide binding patterns significantly after one year of treatment, the IgE and IgG4 binding ratios and intensity are altered.
Conclusion
At a population level, the linear IgE and IgG4 epitopes of 10 peanut allergens overlap and that increase in IgG4 with OIT results in displacement of IgE binding to both conformational and linear epitopes. Furthermore, it appears as though the increase in IgG4 is more important to achieve desensitization at the 12-month timepoint than the decrease in IgE. This type of knowledge can be useful in the identification of IgE and IgG4-binding allergen and peptide biomarkers that may indicate desensitization or sustained unresponsiveness of allergic individuals to peanut.
... Similar tract-specific linear regression analyses were repeated for the sub-cohort excluding infants born small for gestational age. All p-values were also adjusted for multiple comparisons using the Benjamini-Hochberg procedure 33 . ...
It is known that the rate of caesarean section (C-section) has been increasing among preterm births. However, the relationship between C-section and long-term neurological outcomes is unclear. In this study, we utilized diffusion tensor imaging (DTI) to characterize the association of delivery method with brain white matter (WM) microstructural integrity in preterm infants. We retrospectively analyzed the DTI scans and health records of preterm infants without neuroimaging abnormality on pre-discharge term-equivalent MRI. We applied both voxel-wise and tract-based analyses to evaluate the association between delivery method and DTI metrics across WM tracts while controlling for numerous covariates. We included 68 preterm infants in this study (23 delivered vaginally, 45 delivered via C-section). Voxel-wise and tract-based analyses revealed significantly lower fractional anisotropy values and significantly higher diffusivity values across major WM tracts in preterm infants delivered via C-section when compared to those delivered vaginally. These results may be partially, but not entirely, mediated by lower birth weight among infants delivered by C-section. Nevertheless, these infants may be at risk for delayed neurodevelopment and could benefit from close neurological follow up for early intervention and mitigation of adverse long-term outcomes.
... One sample t-tests were used to evaluate differences between C. elegans strain proportions after competition to the theoretical value of 0.5, while two sample t-tests served to assess variation in competitive fitness on OP50 and MYb11 [67]. False discovery rate (FDR) correction was used to account for multiple testing where appropriate [68]. Observer bias was minimized by coding of samples and the compared treatments were assayed in parallel in randomized Table 1. ...
The microbiota shapes host biology in numerous ways. One example is protection against pathogens, which is likely critical for host fitness in consideration of the ubiquity of pathogens. The host itself can affect abundance of microbiota or pathogens, which has usually been characterized in separate studies. To date, however, it is unclear how the host influences the interaction with both simultaneously and how this triangular interaction determines fitness of the host–microbe assemblage, the so-called metaorganism. To address this current knowledge gap, we focused on a triangular model interaction, consisting of the nematode Caenorhabditis elegans, its protective symbiont Pseudomonas lurida MYb11 and its pathogen Bacillus thuringiensis Bt679. We combined the two microbes with C. elegans mutants with altered immunity and/or microbial colonization, and found that (i) under pathogen stress, immunocompetence has a larger influence on metaorganism fitness than colonization with the protective microbe; (ii) in almost all cases, MYb11 still improves fitness; and (iii) disruption of p38 MAPK signalling, which contributes centrally to immunity against Bt679, completely reverses the protective effect of MYb11, which further reduces nematode survival and fitness upon infection with Bt679. Our study highlights the complex interplay between host, protective microbe and pathogen in shaping metaorganism biology.
... The expected heterozygosity (H E ), the observed heterozygosity (H O ) and the Hardy-Weinberg equilibrium per sample were also calculated with GENEPOP. Correction for multiple tests was performed with the false discovery rate approach (FDR) [49]. Putative frequencies of null alleles co-segregating in the allelic systems and their confidence intervals were checked per locus and sample using the EM algorithm [50] and 1000 permutations, as implemented in FreeNA [51]. ...
The Mediterranean mussel Mytilus galloprovincialis is distributed in both hemispheres either natively or introduced. The updated population genetic distribution of this species provides a useful knowledge against which future distribution shifts could be assessed. This study, performed with seven microsatellite markers and three reference species (M. edulis, M. chilensis and M. trossulus), aimed to determine the scenario of genetic divergence between 15 samples of M. galloprovincialis from 10 localities in Europe, Africa, Asia, Australia, North America and South America. In agreement with previous data, M. trossulus was the most divergent taxon of the genus, but M. chilensis appeared as an intermediate taxon between M. edulis and M. galloprovincialis, though closer to this latter. M. galloprovincialis from the Atlantic Northeast appears as the most likely source of worldwide exotic settlements instead of the previously thought Mediterranean population. The successful worldwide establishment of M. galloprovincialis suggests it is a flexible evolutionary species (FES), i.e., a species or population whose genetic background allows it to rapidly adapt to changing environments. This natural endowed plastic adaptation makes it a candidate resilient species amidst the ongoing climatic change.
... We compared both conditions, i.e., sealevel and altitude, using the residuals from the regression with age. All p-values were corrected for multiple comparisons with the Benjamini-Hochberg method (Benjamini & Hochberg, 1995), to decrease the probability of making a type I error (false positives). ...
High-altitude hypoxia triggers brain function changes reminiscent of those in healthy aging and Alzheimer's disease, compromising cognition and executive functions. Our study sought to validate high-altitude hypoxia as a model for assessing brain activity disruptions akin to aging. We collected EEG data from sixteen healthy volunteers during acute high-altitude hypoxia (at 4000 masl) and at sea-level, focusing on relative changes in power and aperiodic slope of the EEG spectrum due to hypoxia. Additionally, we examined functional connectivity using wPLI, and functional segregation and integration in using graph theory tools. High altitude led to slower brain oscillations, i.e., increased δ and reduced α power, and flattened the 1/f aperiodic slope, indicating higher electrophysiological noise, akin to healthy aging. Notably, functional integration strengthened in the θ band, exhibiting unique topographical patterns at the subnetwork level, including increased frontocentral and reduced occipitoparietal integration. Moreover, we discovered significant correlations between subjects' age, 1/f slope, θ band integration, and observed robust effects of hypoxia after adjusting for age. Our findings shed light on how reduced oxygen levels at high-altitudes influence brain activity patterns resembling those in neurodegenerative disorders and aging, making high-altitude hypoxia a promising model for comprehending the brain in health and disease.
... ANOVAs were performed on each sample from 0 to 500 ms (256 samples). ANOVA p-values were then corrected at false-discovery rates (FDRs) from 0.001 to 0.5 for the 256 samples tested (Benjamini & Hochberg, 1995). ANOVA results were considered signi cant at p < 0.05 after FDR correction. ...
Previous event-related potentials (ERP) studies examining of orthographic processing have reported N1 results that are incompatible with one another, some reporting larger N1 responses to letters and some reporting larger and broader N1 responses to pseudoletters. Conflicting results may be due to different tasks, which required different cognitive demands and thus resulted in different ERPs. Our study compared the ERPs of 20 participants across three different tasks: mixed viewing of letters and pseudoletters, blocked viewing of letters and pseudoletters, and 1-back memory tasks. We evaluated the timing, amplitude, and hemispheric dominance/laterality of the early ERP components (e.g., N1) to letter and pseudoletter stimuli. Results showed the same significant ERP differences between letters and pseudoletters across all tasks. This indicated that letter processing may be independent of the tasks employed and that the early ERPs for orthographic processing appear not to be not altered by volitional control or task demands used in this study.
... in R); see "Gene expression association". We used the Benjamini & Hochberg (BH) false discovery rate (FDR) approach ("p.adjust" in R; Benjamini and Hochberg 1995). For a single, binary phenotype ("number of kidneys at birth"), we tested for association with MT haplotype using a Fisher's exact test ("fisher.test" ...
Genome-wide association studies typically evaluate the autosomes and sometimes the X Chromosome, but seldom consider the Y or mitochondrial Chromosomes. We genotyped the Y and mitochondrial chromosomes in heterogeneous stock rats (Rattus norvegicus), which were created in 1984 by intercrossing eight inbred strains and have subsequently been maintained as an outbred population for 100 generations. As the Y and mitochondrial Chromosomes do not recombine, we determined which founder had contributed these chromosomes for each rat, and then performed association analysis for all complex traits (n=12,055; intersection of 12,116 phenotyped and 15,042 haplotyped rats).
We found the eight founders had 8 distinct Y and 4 distinct mitochondrial Chromosomes, however only two of each were observed in our modern heterogeneous stock rat population (Generations 81-97). Despite the unusually large sample size, the p-value distribution did not deviate from expectations; there were no significant associations for behavioral, physiological, metabolome, or microbiome traits after correcting for multiple comparisons. However, both Y and mitochondrial Chromosomes were strongly associated with expression of a few genes located on those chromosomes, which provided a positive control. Our results suggest that within modern heterogeneous stock rats there are no Y and mitochondrial Chromosomes differences that strongly influence behavioral or physiological traits. These results do not address other ancestral Y and mitochondrial Chromosomes that do not appear in modern heterogeneous stock rats, nor do they address effects that may exist in other rat populations, or in other species.
... To investigate whether NEPA changes impacted the secondary outcome measures, partial correlations between NEPA changes (T1 to T3) and changes in secondary outcomes were made for the whole group, corrected for baseline values and sex. Correction for multiple testing was implemented using the Benjamini-Hochberg false discovery rate (FDR) method [29]. To explore explanatory factors for the NEPA changes, partial correlations between NEPA changes (T1 to T3) and demographics (age, EDSS, MS duration), baseline secondary outcomes (total and physical fatigue, walking mobility, VȮ 2peak , fat%) and exercise information (exercise protocol and duration) were made for the whole group, and PwMS only. ...
Background
Exercise interventions fail to increase objective physical activity (PA) in persons with Multiple Sclerosis (PwMS), while they self-report higher exercise participation. This suggests that PwMS change their non-exercise PA (NEPA). We aimed to explore NEPA changes of PwMS and healthy controls (HC), and whether these constrain exercise adaptations.
Methods
Twenty-nine mildly-disabled PwMS and 26 HC completed a 10-month home-based running program. A non-randomised controlled study design was used. The primary outcome was time in different NEPA intensities (light intensity PA [LIPA] and moderate-to-vigorous intensity PA [MVPA]) and in sedentary behaviour ([SB]; total and uninterrupted SB) at baseline (T1), after 5 (T2) and 10 (T3) months of exercise. Data were averaged over days with and without exercise sessions (EX and NONEX days). Secondary outcomes included patient-reported and physical exercise adaptations (fatigue, walking mobility, blood pressure, body composition and cardiorespiratory fitness).
Results
A significant reduction in non-exercise MVPA was observed from T1 to T2 (− 113 ± 31 min/week, p < 0.01) and from T1 to T3 (− 95 ± 26 min/week, p < 0.01) in PwMS, which approximately matched the weekly exercise duration at those time points. PwMS also increased their uninterrupted SB on NONEX days compared to EX days (+ 0.7 ± 0.3 h, p < 0.01). There were no changes in MVPA or SB of HC (group × time effect MVPA: p < 0.05; group × EX day effect uninterrupted SB: p < 0.01). Secondary outcomes improved similarly in both groups and were not associated with NEPA/SB changes.
Conclusions
In contrast to HC, PwMS significantly changed their NEPA and the pattern in which they accumulated SB in response to structured exercise. This might be a necessary behavioural compensation in order to adhere to the exercise intervention and did not constrain patient-reported and physical outcomes. Future research is warranted to unravel the underlying causes and to investigate the effects on other exercise adaptations, such as cardiometabolic health.
Trial registration The present study was registered (December 10, 2019) at clinicaltrials.gov as NCT04191772
... An extensive correlation analysis [74] was performed considering the linear correlation (Pearson's r) between yeast growth rate (i.e. Δ mass/ Δ t, with Δ t = ti-ti-1 at each i-th observation time) in the growing media and 1 H NMR data recorded for the same media at each resonance signal (n = 1000, from 0.01 ppm t 10 ppm with interval 0.01 ppm), providing a fine-resolution profile of the variation in 1 H types in the tested media with its associated effect on yeast growth. ...
Extracellular DNA (exDNA) can be actively released by living cells and different putative functions have been attributed to it. Further, homologous exDNA has been reported to exert species-specific inhibitory effects on several organisms. Here, we demonstrate by different experimental evidence, including 1H-NMR metabolomic fingerprint, that the growth rate decline in Saccharomyces cerevisiae fed-batch cultures is determined by the accumulation of exDNA in the medium. Sequencing of such secreted exDNA represents a portion of the entire genome, showing a great similarity with extrachromosomal circular DNA (eccDNA) already reported inside yeast cells. The recovered DNA molecules were mostly single strands and specifically associated to the yeast metabolism displayed during cell growth. Flow cytometric analysis showed that the observed growth inhibition by exDNA corresponded to an arrest in the S phase of the cell cycle. These unprecedented findings open a new scenario on the functional role of exDNA produced by living cells.
... The individual statistical tests are indicated for each case in which p-values are reported. In the case of multiple tests, false discovery rate control using the Benjamini and Hochberg procedure (Benjamini and Hochberg, 1995) implemented in the p.adjust function of R was used. ...
The SARS-CoV-2 pandemic has reemphasized the urgent need for broad-spectrum antiviral therapies. We developed a computational pipeline using scRNA-Seq data to assess cellular metabolism during viral infection. With this pipeline we predicted the capacity of cells to sustain SARS-CoV-2 virion production in patients and found a tissue-wide induction of metabolic pathways that support viral replication. Expanding our analysis to influenza A and dengue viruses, we identified metabolic targets and inhibitors for potential broad-spectrum antiviral treatment. These targets were highly enriched for known interaction partners of all analyzed viruses. Indeed, phenformin, an NADH:ubiquinone oxidoreductase inhibitor, suppressed SARS-CoV-2 and dengue virus replication. Atpenin A5, blocking succinate dehydrogenase, inhibited SARS-CoV-2, dengue virus, respiratory syncytial virus, and influenza A with high selectivity indices. In vivo, phenformin showed antiviral activity against SARS-CoV-2 in a Syrian hamster model. Our work establishes host metabolism as druggable for broad-spectrum antiviral strategies, providing invaluable tools for pandemic preparedness.
... These values were calculated using the scipy [79] library in Python. To adjust the statistical significance for multiple comparisons, we used a false discovery rate (FDR) [80] employing 'multipletests' from 'statsmodels.stats.multitest' in the Python library using the method 'fdr_bh' . Figure 3 shows a DVR comparison between MCI and controls within each Braak stage. ...
Mild cognitive impairment (MCI) is a transitional stage between normal aging and early Alzheimer’s disease (AD). The presence of extracellular amyloid-beta (Aβ) in Braak regions suggests a connection with cognitive dysfunction in MCI/AD. Investigating the multivariate predictive relationships between regional Aβ biomarkers and cognitive function can aid in the early detection and prevention of AD. We introduced machine learning approaches to estimate cognitive dysfunction from regional Aβ biomarkers and identify the Aβ-related dominant brain regions involved with cognitive impairment. We employed Aβ biomarkers and cognitive measurements from the same individuals to train support vector regression (SVR) and artificial neural network (ANN) models and predict cognitive performance solely based on Aβ biomarkers on the test set. To identify Aβ-related dominant brain regions involved in cognitive prediction, we built the local interpretable model-agnostic explanations (LIME) model. We found elevated Aβ in MCI compared to controls and a stronger correlation between Aβ and cognition, particularly in Braak stages III–IV and V–VII ( p < 0.05) biomarkers. Both SVR and ANN, especially ANN, showed strong predictive relationships between regional Aβ biomarkers and cognitive impairment ( p < 0.05). LIME integrated with ANN showed that the parahippocampal gyrus, inferior temporal gyrus, and hippocampus were the most decisive Braak regions for predicting cognitive decline. Consistent with previous findings, this new approach suggests relationships between Aβ biomarkers and cognitive impairment. The proposed analytical framework can estimate cognitive impairment from Braak staging Aβ biomarkers and delineate the dominant brain regions collectively involved in AD pathophysiology.
... For aim 2, we tested whether there were differences in regional z-scores between patients and control participants using a Mann-Whitney U test for each region [19] and controlling for multiple comparisons using the Benjamini-Hochberg method [20]. ...
There is currently no quantifiable method to predict long-term clinical outcomes in patients presenting with a first episode of psychosis. A major barrier to developing useful markers for this is biological heterogeneity, where many different pathological mechanisms may underly the same set of symptoms in different individuals. Normative modelling has been used to quantify this heterogeneity in established psychotic disorders by identifying regions of the cortex which are thinner than expected based on a normative healthy population range. These brain atypicalities are measured at the individual level and therefore potentially useful in a clinical setting. However, it is still unclear whether alterations in individual brain structure can be detected at the time of the first psychotic episode, and whether they are associated with subsequent clinical outcomes. We applied normative modelling of cortical thickness to a sample of first-episode psychosis patients, with the aim of quantifying heterogeneity and to use any pattern of cortical atypicality to predict symptoms and response to antipsychotic medication at timepoints from baseline up to 95 weeks (median follow-ups = 4). T1-weighted brain magnetic resonance images from the GAP and OPTiMiSE samples were processed with Freesurfer V6.0.0 yielding 148 cortical thickness features. An existing normative model of cortical thickness ( n = 37,126) was adapted to integrate data from each clinical site and account for effects of gender and site. Our test sample consisted of control participants ( n = 149, mean age = 26, SD = 6.7) and patient data ( n = 295, mean age = 26, SD = 6.7), this sample was used for estimating deviations from the normative model and subsequent statistical analysis. For each individual, the 148 cortical thickness features were mapped to centiles of the normative distribution and converted to z-scores reflecting the distance from the population mean. Individual cortical thickness metrics of +/– 2.6 standard deviations from the mean were considered extreme deviations from the norm. We found that no more than 6.4% of psychosis patients had extreme deviations in a single brain region (regional overlap) demonstrating a high degree of heterogeneity. Mann-Whitney U tests were run on z-scores for each region and significantly lower z-scores were observed in FEP patients in the frontal, temporal, parietal and occipital lobes. Finally, linear mixed-effects modelling showed that negative deviations in cortical thickness in parietal and temporal regions at baseline are related to more severe negative symptoms over the medium-term. This study shows that even at the early stage of symptom onset normative modelling provides a framework to identify individualised cortical markers which can be used for early personalised intervention and stratification.
... The UpSetR package (version 1.4.0) [44] was used to compare tool outcomes, and the three most suitable methods were applied to all taxonomic ranks to compare enrichment groups and Benjamini-Hochberg (BH) adjusted p-values [45]. ...
Background: Extreme weather events induced by climate change, particularly droughts, have detrimental consequences for crop yields and food security. Concurrently, these conditions provoke substantial changes in the soil metagenome. The application of interpretable Machine Learning with SHAP values to this metagenomic data and the comparison with conventional Differential Abundance Analysis methods holds immense potential for identifying marker taxa and enhancing the capacity to predict drought stress.
Results: This study demonstrates that the metagenomics approach of Differential Abundance Analysis methods, and Machine Learning-based Shapley Additive Explanation values provide similar information and exhibit their potential as complementary approaches for identifying marker taxa and investigating their enrichment or depletion under drought stress. Additionally, the Random Forest Classifier trained on a diverse range of relative abundance data from the soil metagenome of various plant species achieves a high accuracy of 92.3 % at the genus rank. It demonstrates its generalization capacity to a wide spectrum of drought stress levels of various grass lineages.
Conclusions: In the detection of drought stress in the soil metagenome, this study emphasizes the potential of an optimized and generalized location-based ML classifier. By identifying marker taxa, this approach holds promising implications for microbe-assisted plant breeding programs and contributes to the development of sustainable agriculture practices. These findings are crucial for preserving global food security in the face of climate change.
Keywords: Metagenomics, Machine Learning, SHAP values, Differential Abundance Analysis, Soil microbiome, Drought stress
... As such, random uniform (0.0001, 0.0003) values were added to the duplicated coordinates. To control the false discovery rate resulting from multiple tests, a Benjamini and Hochberg [43] correction was used to adjust all subsequent p-values. Hence, all p-values reported represent the corrected estimates. ...
The relationship between plant productivity, measured according to biomass and species richness, is a fundamental focal point in community ecology, as it provides the basis for understanding plant responses or adaptive strategies. Although studies have been conducted on plant biomass and environmental factors, research concerning mountainous grassland areas is scarce. Therefore, the aim of the present study was to examine the influence of environmental factors on aboveground plant biomass in the mountainous grassland of the Mountain Zebra National Park, South Africa. Biomass distribution was uneven within the park, owing to certain species having relatively higher biomass values. These differences may be attributed to the chemical and physical properties of the soil, including carbon and nitrogen content, soil pH, and soil texture (sand, silt, and coarse fragments). A disc pasture meter was used to collect biomass data. Multiple regression analysis revealed that most environmental factors did not significantly influence plant biomass. The only environmental factor influencing plant biomass was soil pH; the influences of other factors were not statistically significant. The results of this study elucidate the interactions of environmental factors with plant biomass. Future research could investigate how environmental factors influence plant biomass, both below and above the ground in mountainous grassland.
... The low-temperature tolerance indices of the 296 domestic and foreign elite maize inbred lines were used, together with SNP genotypes, population structures, and relatedness, to perform genome-wide association analysis using a mixed linear model in the TASSEL software. False positives resulting from multiple comparisons in the genome-wide association analysis results were controlled using the Benjamini and Hochberg method for controlling the false discovery rate, and the false discovery rate was set to 0.10 [25]. ...
Low-temperature stress during the germination stage is an important abiotic stress that affects the growth and development of northern spring maize and seriously restricts maize yield and quality. Although some quantitative trait locis (QTLs) related to low-temperature tolerance in maize have been detected, only a few can be commonly detected, and the QTL intervals are large, indicating that low-temperature tolerance is a complex trait that requires more in-depth research. In this study, 296 excellent inbred lines from domestic and foreign origins (America and Europe) were used as the study materials, and a low-coverage resequencing method was employed for genome sequencing. Five phenotypic traits related to low-temperature tolerance were used to assess the genetic diversity of maize through a genome-wide association study (GWAS). A total of 14 SNPs significantly associated with low-temperature tolerance were detected (−log10(P) > 4), and an SNP consistently linked to low-temperature tolerance in the field and indoors during germination was utilized as a marker. This SNP, 14,070, was located on chromosome 5 at position 2,205,723, which explained 4.84–9.68% of the phenotypic variation. The aim of this study was to enrich the genetic theory of low-temperature tolerance in maize and provide support for the innovation of low-temperature tolerance resources and the breeding of new varieties.
... A generalized linear model including the replicate effect, the cell line, the infection status as well as the cell line-infection interaction was set up to test for the differential expression between the conditions. For each pairwise comparison, raw p-values were adjusted for multiple testing according to the Benjamini and Hochberg (BH) procedure [38] and genes with an adjusted p-value lower than 0.05 were considered differentially expressed. ...
Streptococcus gallolyticus sp . gallolyticus (SGG) is a gut pathobiont involved in the development of colorectal cancer (CRC). To decipher SGG contribution in tumor initiation and/or acceleration respectively, a global transcriptome was performed in human normal colonic cells (FHC) and in human tumoral colonic cells (HT29). To identify SGG -specific alterations, we chose the phylogenetically closest relative, Streptococcus gallolyticus subsp. macedonicus ( SGM) as control bacterium. We show that SGM , a bacterium generally considered as safe, did not induce any transcriptional changes on the two human colonic cells. The transcriptional reprogramming induced by SGG in normal FHC and tumoral HT29 cells was significantly different, although most of the genes up- and down-regulated were associated with cancer disease. Top up-regulated genes related to cancer were: (i) IL-20 , CLK1 , SORBS2 , ERG1 , PIM1 , SNORD3A for normal FHC cells and (ii) TSLP , BHLHA15 , LAMP3 , ZNF27B , KRT17 , ATF3 for cancerous HT29 cells. The total number of altered genes were much higher in cancerous than in normal colonic cells (2,090 vs 128 genes being affected, respectively). Gene set enrichment analysis reveals that SGG -induced strong ER- (endoplasmic reticulum) stress and UPR- (unfolded protein response) activation in colonic epithelial cells. Our results suggest that SGG induces a pro-tumoral shift in human colonic cells particularly in transformed cells potentially accelerating tumor development in the colon.
... Differences in profilespecific means on peer-and self-reported victimization and depressive symptoms were tested using the Wald chi-square test, while controlling for youth gender and grade level. To adjust p values for multiple comparisons in mean difference tests across profiles, the Benjamini-Hochberg correction method was conducted to detect significant effects (Benjamini & Hochberg, 1995). ...
Adolescents use various strategies to help their victimized peers during bullying episodes. However, prior research has primarily adopted a variable-centered approach that examines the effect of each defending strategies separately and does not address whether there were different types of defenders who exhibit specific combinations of defending strategies and how these profiles related to youth’s adjustment outcomes. Using latent profile analysis, this study identified defending profiles among a sample of Chinese adolescents (N = 1618, Mage = 13.81, SDage = 0.94, 42% girls) and examined whether these profiles differ on victimization experiences and depressive symptoms. The results yielded four defending profiles: nonaggressive defenders (15%), aggressive defenders (7%), average defenders (54%), and infrequent defenders (24%). Aggressive defenders and infrequent defenders exhibited the highest levels of self-reported victimization and depressive symptoms, whereas nonaggressive defenders demonstrated the lowest. There were no statistical profile differences in peer-reported victimization. Findings suggest that investigating the heterogeneity of youth using defending strategies is important for understanding whether defending actually puts youth at increased risk for negative adjustment.
... TMM normalization (Robinson and Oshlack, 2010) plus negative binomial generalized log-linear model (McCarthy et al., 2012) was used to test for differential expression between treated and untreated groups, while accounting for pairing of U and T replicates from three different cultures. p-values were adjusted using the false discovery rate method (Benjamini and Hochberg, 1995). ...
Addressing the current antibiotic-resistance challenge would be aided by the identification of compounds with novel mechanisms of action. Epilancin 15X, a lantibiotic produced by Staphylococcus epidermidis 15 × 154, displays antimicrobial activity in the submicromolar range against a subset of pathogenic Gram-positive bacteria. S. epidermidis is a common member of the human skin or mucosal microbiota. We here investigated the mechanism of action of epilancin 15X. The compound is bactericidal against Staphylococcus carnosus as well as Bacillus subtilis and appears to kill these bacteria by membrane disruption. Structure–activity relationship studies using engineered analogs show that its conserved positively charged residues and dehydroamino acids are important for bioactivity, but the N-terminal lactyl group is tolerant of changes. Epilancin 15X treatment negatively affects fatty acid synthesis, RNA translation, and DNA replication and transcription without affecting cell wall biosynthesis. The compound appears localized to the surface of bacteria and is most potent in disrupting the membranes of liposomes composed of negatively charged membrane lipids in a lipid II independent manner. Epilancin 15X does not elicit a LiaRS response in B. subtilis but did upregulate VraRS in S. carnosus. Treatment of S. carnosus or B. subtilis with epilancin 15X resulted in an aggregation phenotype in microscopy experiments. Collectively these studies provide new information on epilancin 15X activity.
... Supplementary Materials: The following supporting information [77][78][79] can be downloaded at: https://www.mdpi.com/article/10.3390/md21120621/s1, Figure S1: Effects of ectoine treatment on skin cell's pathway and functions.; Figure S2: Ectoine suppressed skin cells proliferation.; Table S1: Primers used in this study. Data Availability Statement: All data included in this study are available for public use. ...
Epigenetic modifications, mainly aberrant DNA methylation, have been shown to silence the expression of genes involved in epigenetic diseases, including cancer suppression genes. Almost all conventional cancer therapeutic agents, such as the DNA hypomethylation drug 5-aza-2-deoxycytidine, have insurmountable side effects. To investigate the role of the well-known DNA protectant (ectoine) in skin cell DNA methylation and cancer cell proliferation, comprehensive methylome sequence analysis, 5-methyl cytosine (5mC) analysis, proliferation and tumorigenicity assays, and DNA epigenetic modifications-related gene analysis were performed. The results showed that extended ectoine treatment globally hypomethylated DNA in skin cells, especially in the CpG island (CGIs) element, and 5mC percentage was significantly reduced. Moreover, ectoine mildly inhibited skin cell proliferation and did not induce tumorigenicity in HaCaT cells injected into athymic nude mice. HaCaT cells treated with ectoine for 24 weeks modulated the mRNA expression levels of Dnmt1, Dnmt3a, Dnmt3b, Dnmt3l, Hdac1, Hdac2, Kdm3a, Mettl3, Mettl14, Snrpn, and Mest. Overall, ectoine mildly demethylates DNA in skin cells, modulates the expression of epigenetic modification-related genes, and reduces cell proliferation. This evidence suggests that ectoine is a potential anti-aging agent that prevents DNA hypermethylation and subsequently activates cancer-suppressing genes.
... In the analyses, we used the Type III Sum of Squares, for which the order of effects they enter the model does not play a role. All obtained p-values from all regressions/ANOVA models were adjusted (as we made multiple analyses on the same data which increases the likelihood of a false significant result) using false discovery rate correction (Benjamini and Hochberg 1995). All other analyses were performed using R software (R Core Team 2020). ...
Mobility is highly species-specific and individual species mobility can be predicted by species traits, yet this topic remains largely understudied. We analyzed data on species presences/absences in permanent subplots (1m × 1m) within 15 main plots 10m × 10m) over 24 years originating from a grassland biodiversity experiment in Czechia. Plots differed in initial species richness and composition. We estimated mean individual species persistence and searched for any relationship with individual species traits. We also tested the effect of sowing richness/composition on species persistence and community mobility. Our results show that individual species have very different mobilities which vary in time and can be predicted by species traits, most importantly by leaf traits, clonal traits, and traits characterizing species life forms. Trait syndrome corresponding to the traveler part of the mobility gradient typically includes annuals having a taproot, long-lasting seedbank, and high SLA. Trait syndrome of sitters includes perennial hemicryptophytes with effective clonal reproduction and transient seedbank. Importantly, trait association with species mobility is spatial scale dependent, whereas studies on the spatial scale of 0.01m² show that clonality increases mobility, in our case clonality increases the persistence of species in 1m² units. In contrast with an evident linkage between mobility and traits, the effect of community richness/composition on species/community mobility was weak and detectable in the very first years of the experiment only.
... Due to the insufficient information (unassigned gene symbols and/or orthology status) of 963 out of the 1 880 genes containing significantly different 5hmC levels, we used their protein names based on NCBI's eukaryotic genome annotation pipeline (NCBI Oreochromis niloticus Annotation Release 104) in combination with the human gene symbols in UniProt Protein knowledgebase and modified our gene list accordingly [Gene Symbols (NCBI-UniProtKB)]; Supplemental Tables S2A and S2B). Functional enrichment analysis for biological processes and KEGG pathways were performed based on the data sources available for Nile tilapia and Human orthologs, respectively, using the online platform g:Profiler [79], version e98_eg45_p14_-ce5b097 with Benjamini-Hochberg FDR [80] as our multiple testing correction method and a significance threshold of 0.01. ...
Because measuring expansion volume (EV) is simple and inexpensive, popcorn breeders have developed high‐quality single crosses ignoring the contents of zeins, starch, lipids, and cellular wall components in selection. However, some methods of quantification of these quality‐related traits can be applied to popcorn breeding, increasing the selection efficacy for quality. The objectives of this study were to assess methods of zeins and starch quantification that can be used in popcorn breeding, characterize a temperate and a tropical populations for zeins and starch contents and identify candidate genes for these quality‐related traits. We genotyped and phenotyped 286 plants. For quantification of total zeins and zein subunits we choose the ‘lab‐on‐a‐chip’ microfluidic electrophoresis. For quantification of starch and amylose/amylopectin, we choose the Megazyme's Amylose/Amylopectin kit assay. The temperate population has superior EV (36.0%), a higher level of the 19 kDa zein subunit (32.0%), lower levels of the 21, 22 and 27 kDa subunits (−1543.0%, −40.0% and −47.0%, respectively) and no statistical difference for the 10 kDa zein content, relative to the tropical population. Although there are statistical differences between the two populations regarding starch, amylose, and amylose/amylopectin ratio, the differences are not significant (−2.0% to 8.0%). Thirteen candidate genes were identified for the 19 and 22 kDa zeins, two for amylose and one for starch, with emphasis on the genes coding for the 19 and 22 kDa alpha‐zeins, located on chromosome 4. The evaluated quantification methods can be used in popcorn breeding but for a limited number of samples, mainly because costs.
Importance
Fetal growth in the critical rapid growth stage (CRGS) before delivery, approximately between 30 to 37 gestational weeks, carries significant implications for subsequent overweight, obesity, and arterial health. Previous evidence has demonstrated the association between maternal depressive symptoms and fetal growth trajectories from early to late pregnancy, but there remains limited understanding of the association of these symptoms with the longitudinal fetal growth change within the CRGS.
Objective
To investigate the association between maternal depressive symptoms and fetal growth during the CRGS before delivery.
Design, Setting, and Participants
This prospective birth cohort study was conducted from January 2018 to December 2020. Volunteer pregnant women were enrolled in their first trimester of prenatal visits. Women with severe disease before pregnancy and multiple births, fetuses with congenital anomalies, and preterm or postterm births were excluded. This multicenter study was based in 13 hospitals covering 81 counties across 12 cities in Sichuan Province, China. Follow-up visits were performed at the second trimester, the third trimester, and 24 hours after delivery. The analysis was conducted from January to May 2023.
Exposures
Maternal depressive symptoms, as a continuous variable, measured by the Edinburgh Postpartum Depression Scale (EPDS) at a median gestational week of 24 (range, 14 to 27) weeks of gestation. A higher score on the EPDS indicates worse depressive symptoms.
Main Outcomes and Measures
The main outcomes included ultrasonography-measured biparietal diameter (BPD), femur length (FL), and abdominal circumference (AC), along with calculated estimated fetal weight (EFW). These parameters were evaluated longitudinally at a median gestational week of 30 (range, 28 to 32) and 37 (range, 35 to 39) weeks. Linear mixed models were used to estimate the associations between maternal depressive symptoms and fetal growth parameters.
Results
A total of 2676 mother-offspring dyads were included, in which the mean (SD) age of mothers was 28.0 (4.4) years, and 1294 (48.4%) of the offspring were female. The median (IQR) maternal EPDS score was 5.0 (4.0 to 9.0). After adjustment for confounders, a significant correlation was found between a higher score of depressive symptoms in mothers and a slower rate of fetal growth across FL (β = −0.40; 95% CI, −0.58 to −0.22), AC (β = −1.97; 95% CI, −2.90 to −1.03), and EFW (β = −50.11; 95% CI, −68.46 to −31.75). These associations were stronger in female fetuses or those with better family socioeconomic conditions.
Conclusions and Relevance
In this prospective cohort study, maternal depressive symptoms were associated with slower fetal growth rate in the CRGS before delivery. Early screening for depressive disorders in pregnant women appears to be essential for fetal growth and later health.
Background
Regulatory flexibility (RF) involves three distinct components of self‐regulation: context sensitivity, repertoire, and feedback responsiveness. Subgroups based on differences in RF have been identified in a general sample and are differentially associated with symptoms of anxiety and depression. However, potential RF profiles have not been examined in individuals with substance use disorders. This study examined RF subtypes in individuals with alcohol use disorder (AUD) and their associations with psychosocial outcomes (i.e., depression, anxiety, and stress) and delay discounting (a core feature of addiction).
Methods
Individuals ( n = 200) with an Alcohol Use Disorders Identification Test score of > 16 (mean = 24.12 (±6.92)) were recruited from Amazon Mechanical Turk (mean = 37.26 years old (±11.41); 94 (47%) women). Participants completed the Context Sensitivity Index, the Flexible Regulation of Emotional Expression Scale, and the Coping Flexibility Scale to assess RF. Participants also completed an Adjusting Amount Delay Discounting Task and the Depression, Anxiety, and Stress Scale (DASS‐21). Latent profile analyses (LPA) were used to identify patterns in RF deficits. Kruskal–Wallis and Dunn's tests were performed to examine differences in discounting rates and symptoms of depression, anxiety, and stress across RF profiles.
Results
The LPA revealed a 2‐profile characterization, including (1) context sensitive regulators (CSR; n = 39) and (2) moderate flexibility regulators (MFR; n = 161). CSR demonstrated significantly lower symptoms of depression ( p = 0.004), anxiety ( p < 0.001), and stress ( p < 0.001) than MFR. CSR also displayed significantly lower AUDIT scores ( p = 0.031).
Conclusions
Findings illustrate that among individuals with moderate–severe AUD, those high in context sensitivity coupled with moderate abilities in repertoire and feedback responsiveness have fewer symptoms of depression, anxiety, and stress. Together, context sensitivity may be an important and protective component of RF among individuals with AUD.
La construcción de caminos genera impactos ambientales en los ecosistemas que atraviesan, al fragmentar y transformar los hábitats. Esto afecta el ensamble de especies en áreas degradadas y contribuye a la introducción y al aumento de especies de plantas exóticas e invasoras. La introducción de especies invasoras cambia la abundancia y la composición de especies nativas, representando una amenaza para la biodiversidad a nivel global. El objetivo de este trabajo fue analizar el ensamble de la vegetación en pie y el banco de semillas, e identificar las especies invasoras en taludes de desmonte en bordes de camino de matorrales de Nothofagus antarctica en el noroeste patagónico. Se analizó la composición, la riqueza, la diversidad y la abundancia de especies exóticas y nativas, y de grupos funcionales de la vegetación en pie y en el banco de semillas en taludes y áreas de referencia cercanas. Los taludes presentaron diferente composición florística, con menor cobertura de la vegetación y densidad de semillas de especies totales, menor riqueza y cobertura de especies nativas, y menor densidad de semillas de especies exóticas que las áreas de referencia. La similitud entre la vegetación en pie y el banco fue alta para las especies exóticas. En la vegetación de los taludes predominaron las hierbas, las gramíneas anuales/bianuales y las perennes exóticas invasoras, y las hierbas, las gramíneas perennes y los arbustos nativos; no se encontraron semillas de arbustos. La presencia de especies exóticas en los taludes puede deberse a las condiciones de los micrositios y a los rasgos de las especies que los colonizan, como a la capacidad de formar banco de semillas, la alta producción de semillas y la forma y el ciclo de vida. Este trabajo en matorrales del noroeste patagónico mostró que los bordes de camino y sus áreas cercanas albergan especies exóticas potencialmente invasoras, y que es importante identificarlas tempranamente para controlarlas.
Dinosaurs were the dominant megaherbivores during the Cretaceous when angiosperms, the flowering plants, emerged and diversified. How herbivorous dinosaurs responded to the increasing diversity of angiosperms is largely unknown due to the lack of methods that can reconstruct diet directly from body fossils. We applied dental microwear texture analysis (DMTA), an approach that quantifies microtopography of diet‐induced wear marks on tooth surfaces, to ornithopods, the dinosaur clade that includes taxa with the most sophisticated masticatory system. We found that Late Cretaceous ornithopods have significantly rougher dental microwear texture (DMT) compared to pre‐Late Cretaceous ornithopods, and DMT variation increased in hadrosaurids, a derived Late Cretaceous ornithopod clade. These changes indicate a likely temporal dietary shift towards more abrasive foodstuffs within ornithopods, probably due to the increased ingestion of phytoliths (amorphous silica bodies in plants). Phytoliths are a main source of rough DMT in modern herbivores, along with exogenous dust and grit, and were generally more concentrated in Late Cretaceous angiosperms than in other major plant groups. Our results show that DMTA of the occlusal enamel surface can be used to reconstruct the diets of herbivorous dinosaurs, with a resolution superior to conventional methods.
Despite the study of subterranean biodiversity facing harsh sampling and mapping challenges, the huge diversity of taxa, ecological adaptations and evolutionary trajectories in subterranean environments is gaining increasing attention. Yet, the spatial and environmental factors driving the composition of groundwater communities are still poorly understood. To partially fill this knowledge gap, we collected copepod crustaceans from 12 caves along the Italian peninsula between 2019 and 2022, sampling each cave twice. The resulting presence-absence data were analysed to assess: (i) between-cave taxonomic beta diversity, also partitioning between turnover and nestedness-resultant dissimilarity; (ii) the relative weight of geographic distance and climatic differences in shaping observed beta diversity. Seventy-one species of copepods were collected overall. Pairwise beta diversity was high for most pairs of caves, with turnover being the major component. Geographic distance-decay models partially explained total beta diversity and turnover patterns. However, in Generalized Dissimilarity Models (GDM), including surface climatic conditions as predictors, the contribution of seasonal temperature averages was generally higher than that of geographic distance. Further, the explanatory and predictive performance of the GDMs notably increased, along with temperature contribution, when widening the spatial extent from which climate data were gathered. Our results confirmed a high spatial turnover in groundwater copepods’ assemblages and strengthened the link between regional climate and subterranean biodiversity.
Perinatal stroke describes a group of focal, vascular brain injuries that occur early in development, often resulting in lifelong disability. Two types of perinatal stroke predominate, arterial ischemic stroke (AIS) and periventricular venous infarction (PVI). Though perinatal stroke is typically considered a motor disorder, other comorbidities commonly exist including attention-deficit hyperactivity disorder (ADHD) and deficits in executive function. Rates of ADHD symptoms are higher in children with perinatal stroke and deficits in executive function may also occur but underlying mechanisms are not known. We measured resting state functional connectivity in children with perinatal stroke using previously established dorsal attention, frontoparietal, and default mode network seeds. Associations with parental ratings of executive function and ADHD symptoms were examined. A total of 120 participants aged 6–19 years [AIS N = 31; PVI N = 30; Controls N = 59] were recruited. In comparison to typically developing peers, both the AIS and PVI groups showed lower intra- and inter-hemispheric functional connectivity values in the networks investigated. Group differences in between-network connectivity were also demonstrated, showing weaker anticorrelations between task-positive (frontoparietal and dorsal attention) and task-negative (default mode) networks in stroke groups compared to controls. Both within-network and between-network functional connectivity values were highly associated with parental reports of executive function and ADHD symptoms. These results suggest that differences in functional connectivity exist both within and between networks after perinatal stroke, the degree of which is associated with ADHD symptoms and executive function.
Aims
Both anatomical and reverse total shoulder arthroplasty (aTSA and rTSA) provide functional improvements. A reported benefit of aTSA is better range of motion (ROM). However, it is not clear which procedure provides better outcomes in patients with limited foward elevation (FE). The aim of this study was to compare the outcome of aTSA and rTSA in patients with glenohumeral osteoarthritis (OA), an intact rotator cuff, and limited FE.
Methods
This was a retrospective review of a single institution’s prospectively collected shoulder arthroplasty database for TSAs undertaken between 2007 and 2020. A total of 344 aTSAs and 163 rTSAs, which were performed in patients with OA and an intact rotator cuff with a minimum follow-up of two years, were included. Using the definition of preoperative stiffness as passive FE ≤ 105°, three cohorts were matched 1:1 by age, sex, and follow-up: stiff aTSAs (85) to non-stiff aTSAs (85); stiff rTSAs (74) to non-stiff rTSAs (74); and stiff rTSAs (64) to stiff aTSAs (64). We the compared ROMs, outcome scores, and complication and revision rates.
Results
Compared with non-stiff aTSAs, stiff aTSAs had poorer passive FE and active external rotation (ER), whereas there were no significant postoperative differences between stiff rTSAs and non-stiff rTSAs. There were no significant differences in preoperative function when comparing stiff aTSAs with stiff rTSAs. However, stiff rTSAs had significantly greater postoperative active and passive FE (p = 0.001 and 0.004, respectively), and active abduction (p = 0.001) compared with stiff aTSAs. The outcome scores were significantly more favourable in stiff rTSAs for the Shoulder Pain and Disability Index, Simple Shoulder Test, American Shoulder and Elbow Surgeons score, University of California, Los Angeles score, and the Constant score, compared with stiff aTSAs. When comparing the proportion of stiff aTSAs versus stiff rTSAs that exceeded the minimal clinically important difference and substantial clinical benefit, stiff rTSAs achieved both at greater rates for all measurements except active ER. The complication rate did not significantly differ between stiff aTSAs and stiff rTSAs, but there was a significantly higher rate of revision surgery in stiff aTSAs (p = 0.007).
Conclusion
Postoperative overhead ROM, outcome scores, and rates of revision surgery favour the use of a rTSA rather than aTSA in patients with glenohumeral OA, an intact rotator cuff and limited FE, with similar rotational ROM in these two groups.
Cite this article: Bone Joint J 2023;105-B(12):1303–1313.
Introduction
The sustainability and rising costs of the health‐care system are of concern. Although health‐care reforms impact various areas of care, there is only limited evidence on how regulations affect home‐care agencies and health‐care delivery.
Objectives
The primary aim was to explore different financial and regulatory mechanisms and how they drive differences in the organizational structures, processes, and work environment of home‐care agencies.
Design and methods
We used data from a national multicenter cross‐sectional study of Swiss home care that included a random sample of 88 home‐care agencies with a total of 3223 employees. Data was collected in 2021 through agency and personnel questionnaires including geographic characteristics, financial and regulatory mechanisms, service provision, financing, work environment, resources and time allocation, and personnel recruitment. We first conducted a cluster analysis to build agency groups with similar financial and regulatory mechanisms. We then performed Fisher's exact, ANOVA, and Kruskal–Wallis tests to determine group differences in organizational structures, processes, and work environments. Finally, we performed a lasso regression to determine which variables were predictive for the groups.
Results
Four agency groups were built, differing in view of financial and regulatory mechanisms and we found differences in the range and amount of services provided, with regard to employment conditions and cost structures.
Discussion
The most prominent differences were found between agency groups with versus agency groups without a service obligation. Financial incentives must be well aligned with the goal of achieving and maintaining financially sustainable, accessible, and high‐quality home care.
Inadequate glycogen branching enzyme 1 (GBE1) activity results in different forms of glycogen storage disease type IV, including adult polyglucosan body disorder (APBD). APBD is clinically characterized by adult-onset development of progressive spasticity, neuropathy, and neurogenic bladder and is histologically characterized by the accumulation of structurally abnormal glycogen (polyglucosan bodies) in multiple cell types. How insufficient GBE1 activity causes the disease phenotype of APBD is poorly understood. We hypothesized that proteomic analysis of tissue from GBE1-deficient individuals would provide insights into GBE1-mediated pathobiology. In this discovery study, we utilized label-free LC–MS/MS to quantify the proteomes of lymphoblasts from 3 persons with APBD and 15 age- and gender-matched controls, with validation of the findings by targeted MS. There were 531 differentially expressed proteins out of 3,427 detected between APBD subjects vs. controls, including pronounced deficiency of GBE1. Bioinformatic analyses indicated multiple canonical pathways and protein–protein interaction networks to be statistically markedly enriched in APBD subjects, including: RNA processing/transport/translation, cell cycle control/replication, mTOR signaling, protein ubiquitination, unfolded protein and endoplasmic reticulum stress responses, glycolysis and cell death/apoptosis. Dysregulation of these processes, therefore, are primary or secondary factors in APBD pathobiology in this model system. Our findings further suggest that proteomic analysis of GBE1 mutant lymphoblasts can be leveraged as part of the screening for pharmaceutical agents for the treatment of APBD.
Genomic and transcriptomic studies of expression quantitative trait loci (eQTL) revealed that SINE-VNTR-Alu (SVA) retrotransposon insertion polymorphisms (RIPs) within human genomes markedly affect the co-expression of many coding and noncoding genes by coordinated regulatory processes. This study examined the polymorphic SVA modulation of gene co-expression within the major histocompatibility complex (MHC) genomic region where more than 160 coding genes are involved in innate and adaptive immunity. We characterized the modulation of SVA RIPs utilizing the genomic and transcriptomic sequencing data obtained from whole blood of 1266 individuals in the Parkinson’s Progression Markers Initiative (PPMI) cohort that included an analysis of human leukocyte antigen ( HLA) -A regulation in a subpopulation of the cohort. The regulatory properties of eight SVAs located within the class I and class II MHC regions were associated with differential co-expression of 71 different genes within and 75 genes outside the MHC region. Some of the same genes were affected by two or more different SVA. Five SVA are annotated in the human genomic reference sequence GRCh38.p14/hg38, whereas the other three were novel insertions within individuals. We also examined and found distinct structural effects (long and short variants and the CT internal variants) for one of the SVA ( R_SVA_24) insertions on the differential expression of the HLA-A gene within a subpopulation (550 individuals) of the PPMI cohort. This is the first time that many HLA and non-HLA genes (multilocus expression units) and splicing mechanisms have been shown to be regulated by eight structurally polymorphic SVA within the MHC genomic region by applying precise statistical analysis of RNA data derived from the blood samples of a human cohort population. This study shows that SVA within the MHC region are important regulators or rheostats of gene co-expression that might have potential roles in diversity, health, and disease.
Mutations in the PQBP1 gene (polyglutamine-binding protein-1) are responsible for a syndromic X-linked form of neurodevelopmental disorder (XL-NDD) with intellectual disability (ID), named Renpenning syndrome. PQBP1 encodes a protein involved in transcriptional and post-transcriptional regulation of gene expression. To investigate the consequences of PQBP1 loss, we used RNA interference to knock-down (KD) PQBP1 in human neural stem cells (hNSC). We observed a decrease of cell proliferation, as well as the deregulation of the expression of 58 genes, comprising genes encoding proteins associated with neurodegenerative diseases, playing a role in mRNA regulation or involved in innate immunity. We also observed an enrichment of genes involved in other forms of NDD (CELF2, APC2, etc). In particular, we identified an increase of a non-canonical isoform of another XL-NDD gene, UPF3B, an actor of nonsense mRNA mediated decay (NMD). This isoform encodes a shorter protein (UPF3B_S) deprived from the domains binding NMD effectors, however no notable change in NMD was observed after PQBP1-KD in fibroblasts containing a premature termination codon. We showed that short non-canonical and long canonical UPF3B isoforms have different interactomes, suggesting they could play distinct roles. The link between PQBP1 loss and increase of UPF3B_S expression was confirmed in mRNA obtained from patients with pathogenic variants in PQBP1, particularly pronounced for truncating variants and missense variants located in the C-terminal domain. We therefore used it as a molecular marker of Renpenning syndrome, to test the pathogenicity of variants of uncertain clinical significance identified in PQPB1 in individuals with NDD, using patient blood mRNA and HeLa cells expressing wild-type or mutant PQBP1 cDNA. We showed that these different approaches were efficient to prove a functional effect of variants in the C-terminal domain of the protein. In conclusion, our study provided information on the pathological mechanisms involved in Renpenning syndrome, but also allowed the identification of a biomarker of PQBP1 deficiency useful to test variant effect.
The purpose of this study was to examine the pragmatic competence of writing request emails by Chinese learners of Japanese (CLJs). The study focused on the features of the external modification devices and framing moves of request emails by CLJs when compared to emails by native speakers of Japanese (NSJs). Data were collected from 104 CLJs and 53 NSJs, using an Electronic Writing Discourse Completion Test questionnaire. One-way ANOVA results showed that as the CLJs’ levels of proficiency in Japanese increased, their use of external modification devices and framing moves tended to increase. In addition, a Fisher’s exact test showed that as the CLJs’ proficiency increased, a distinct statistical difference only existed in the use of individual framing moves, but not in that of individual external modification devices. This study provides conceptual categories and utterances used in both external modification devices and framing moves for teaching email communication to CLJs.
Conceptual replications are part and parcel of education science. Methodologically rigorous conceptual replication studies permit researchers to test and strengthen the generalizability of a study’s initial findings. The current conceptual replication sought to replicate the efficacy of a small-group, first-grade mathematics intervention with 240 first-grade students with mathematics difficulties in a new geographical region. Participating students were randomized into one of three conditions: (a) 2:1 mathematics intervention group, (b) 5:1 mathematics intervention group, or (c) business-as-usual instruction. Relative to the original study, findings from the replication varied. When comparing the treatment groups to the control, results suggested positive effects on all outcome measures, including a follow-up assessment administered one year later. However, differences between the two treatment groups based on group size were not found in the mathematics outcome measures. Both groups also received commensurate levels of observed instructional interactions. Implications for unpacking contextual differences between original research and their replications as well as using future research to explore the quantity and quality of instructional interactions as ways to explain variation in findings of group size are discussed.
Rare‐variants (RVs) genetic association studies enable researchers to uncover the variation in phenotypic traits left unexplained by common variation. Traditional single‐variant analysis lacks power; thus, researchers have developed various methods to aggregate the effects of RVs across genomic regions to study their collective impact. Some existing methods utilize a static delineation of genomic regions, often resulting in suboptimal effect aggregation, as neutral subregions within the test region will result in an attenuation of signal. Other methods use varying windows to search for signals but often result in long regions containing many neutral RVs. To pinpoint short genomic regions enriched for disease‐associated RVs, we developed a novel method, DYNamic Aggregation TEsting (DYNATE). DYNATE dynamically and hierarchically aggregates smaller genomic regions into larger ones and performs multiple testing for disease associations with a controlled weighted false discovery rate. DYNATE's main advantage lies in its strong ability to identify short genomic regions highly enriched for disease‐associated RVs. Extensive numerical simulations demonstrate the superior performance of DYNATE under various scenarios compared with existing methods. We applied DYNATE to an amyotrophic lateral sclerosis study and identified a new gene, EPG5 , harboring possibly pathogenic mutations.
Objective
The psychological profile of the moral person might depend on whose perspective is being used. Here, we decompose moral impressions into three components: (a) Shared Moral Character (shared variance across self‐ and informant reports), (b) Moral Identity (how a person uniquely views their morality), and (c) Moral Reputation (how others uniquely view that person's morality).
Method
In two samples (total N = 458), we used an extended version of the Trait‐Reputation‐Identity model to examine the extent to which each perspective accounts for the overall variance in moral impressions and the degree to which social and personal outcomes were associated with each perspective, controlling for method variance (i.e., positivity and acquiescence bias).
Results
Results suggest that moral character impressions are strongly influenced by positivity and largely idiosyncratic. All components were related to higher levels of agreeableness. For the most part, however, the three components had unique correlates: people higher in Shared Moral Character tended to have higher standings on conscientiousness and honesty‐humility, were more respected, and donated more during an in‐lab game; people higher in Moral Identity endorsed various moral foundations to a greater extent; and people higher in Moral Reputation valued the loyalty foundation less.
Conclusion
These results demonstrate the value of considering multiple perspectives when measuring moral character.
Background
Cardiovascular disease (CVD) is an escalating global health crisis, contributing significantly to worldwide mortality and morbidity. Dyslipidemia stands as a critical risk factor for CVD. Vascular endothelial growth factor A ( VEGFA ) is pivotal in angiogenesis and represents a clinical target for CVD intervention. However, the impact of genetic modulation of VEGFA on lipid levels and the subsequent risk of cardiovascular events remains unclear.
Methods
We used LDpred2 to calculate genetic scores for lipid levels based on VEGFA variation, serving as instrumental variables to simulate the effect of VEGFA inhibitors. We then assessed the associations between genetic risk for lipid levels and CVD risk by conducting One-sample Mendelian randomization.
Results
Our results indicated that low-density lipoprotein cholesterol [LDL-C; odds ratio (OR) = 1.09, 95% CI: 1.06–1.11], remnant cholesterol (RC; OR = 1.24, 95% CI: 1.13–1.36), and triglycerides (TG; OR = 1.14, 95% CI: 1.07–1.22) were positively associated with the incidence of CVD. In contrast, high-density lipoprotein cholesterol (HDL-C) was inversely associated with the incidence of CVD (OR = 0.80, 95% CI: 0.76–0.86). When considering the genetic score for LDL-C constructed based on VEGFA , the group with a high genetic score demonstrated an elevated CVD risk (OR = 1.11, 95% CI: 1.04–1.19) compared to those with a low genetic score. Notably, One-sample Mendelian randomization results provided evidence of a causal relationship between LDL-C and CVD ( p = 8.4×10 ⁻³ ) when using genetic variation in VEGFA as an instrumental variable.
Conclusions
Genetic variation mimicking the effect of VEGFA inhibition, which lowers LDL-C levels, was causally associated with a reduced risk of cardiovascular events. These findings offer insight into the potential therapeutic relevance of modulating VEGFA -mediated lipid changes in the prevention and management of CVD.
Purpose/objectives
To evaluate the effects of implementing an evidence‐based teaching approach (EBTA) in a traditional dental curriculum course on predoctoral dental students’ knowledge and attitudes about evidence‐based dentistry, and to determine its benefit on enhancing students’ academic performance.
Methods
Fundamentals of periodontics for first‐year dental students ( D 1, n = 100) span a period of 12 weeks. In the first 6 weeks, we teach the basic principles of periodontal disease pathogenesis and introduce the concepts of EBTA (basics of research study design, statistical principles, literature search, and critically analyzing the evidence) without active implementation. In the second 6 weeks, we build on the initial knowledge of periodontal disease pathogenesis and actively implement EBTA activities to enhance the learning of the course content. Pre‐ and post‐EBTA implementation, students completed a validated survey assessing students’ knowledge, attitudes, access of evidence, and confidence related to evidence‐based dentistry. Midterm and final grades were used to assess student academic performance.
Results
Post‐EBTA implementation survey responses showed: significant increase in students’ knowledge regarding critical appraisal of the literature ( p = 0.0001), significant improvement in students’ attitudes about evidence‐based dentistry ( p = 0.0001), significant increase in students’ frequency of accessing evidence from various sources ( p = 0.01), and significant increase in students’ confidence in evaluating various aspects of a published research report ( p = 0.009). Post‐EBTA final grade scores were significantly higher than pre‐EBTA midterm grade scores ( p = 0.0001).
Conclusions
Integrating an EBTA within a traditional dental curriculum course improves students’ knowledge and attitudes about evidence‐based dentistry as well as enhances students’ academic performance.
Solar radiation is the main risk factor for cSCC development, yet it is unclear whether the progression of cSCC is promoted by solar radiation in the same way as initial tumorigenesis. Additionally, the role of miRNAs, which exert crucial functions in various tumors, needs to be further elucidated in the context of cSCC progression and connection to solar radiation. Thus, we chronically irradiated five cSCC cell lines (Met-1, Met-4, SCC-12, SCC-13, SCL-II) with a custom-built irradiation device mimicking the solar spectrum (UVB, UVA, visible light (VIS), and near-infrared (IRA)). Subsequently, miRNA expression of 51 cancer-associated miRNAs was scrutinized using a flow cytometric multiplex quantification assay (FirePlex®, Abcam). In total, nine miRNAs were differentially expressed in cell-type-specific as well as universal manners. miR-205-5p was the only miRNA downregulated after SSR-irradiation in agreement with previously gathered data in tissue samples. However, inhibition of miR-205-5p with an antagomir did not affect cell cycle, cell growth, apoptosis, or migration in vitro despite transient upregulation of oncogenic target genes after miR-205-5p knockdown. These results render miR-205-5p an unlikely intracellular effector in cSCC progression. Thus, effects on intercellular communication in cSCC or the simultaneous examination of complementary miRNA sets should be investigated.
Huntington disease (HD) is a degenerative brain disease caused by the expansion of CAG (cytosine-adenine-guanine) repeats, which is inherited as a dominant trait and progressively worsens over time possessing threat. Although HD is monogenetic, the specific pathophysiology and biomarkers are yet unknown specifically, also, complex to diagnose at an early stage, and identification is restricted in accuracy and precision. This study combined bioinformatics analysis and network-based system biology approaches to discover the biomarker, pathways, and drug targets related to molecular mechanism of HD etiology. The gene expression profile data sets GSE64810 and GSE95343 were analyzed to predict the molecular markers in HD where 162 mutual differentially expressed genes (DEGs) were detected. Ten hub genes among them ( DUSP1, NKX2-5, GLI1, KLF4, SCNN1B, NPHS1, SGK2, PITX2, S100A4, and MSX1) were identified from protein-protein interaction (PPI) network which were mostly expressed as down-regulated. Following that, transcription factors (TFs)-DEGs interactions (FOXC1, GATA2, etc), TF-microRNA (miRNA) interactions (hsa-miR-340, hsa-miR-34a, etc), protein-drug interactions, and disorders associated with DEGs were predicted. Furthermore, we used gene set enrichment analysis (GSEA) to emphasize relevant gene ontology terms (eg, TF activity, sequence-specific DNA binding) linked to DEGs in HD. Disease interactions revealed the diseases that are linked to HD, and the prospective small drug molecules like cytarabine and arsenite was predicted against HD. This study reveals molecular biomarkers at the RNA and protein levels that may be beneficial to improve the understanding of molecular mechanisms, early diagnosis, as well as prospective pharmacologic targets for designing beneficial HD treatment.
Background
Mindfulness‐based intervention ( MBI ) has been associated with positive health outcomes in adults; however, there are important gaps in our knowledge of factors that influence which individuals are more likely to engage with and benefit from these interventions. Research on other types of behavioural interventions suggests that motivation changes over the course of intervention and may moderate attendance and therapeutic outcomes. This study investigated changes in motivation for practising mindfulness across an MBI and associations between baseline motivation and outcomes, to gain a preliminary understanding of the role of motivation in MBI adherence and outcomes.
Methods
In a sample of adults ( N = 80) who received an MBI , we characterised change in motivation from pre‐ to postintervention and tested whether baseline motivation predicted change in attendance and outcomes.
Results
We found that some, but not all, dimensions of motivation for practising mindfulness increased and also were associated with attendance and pre–post change stress and emotion regulation.
Conclusions
Our findings suggest that there may be potential for optimising MBI through attention to individual differences in motivation and change in motivation over time. The findings justify research with larger sample sizes, control groups and repeated measurements to test the temporal ordering of changes in these outcomes.
A modification of the Bonferroni procedure for testing multiple hypotheses is presented. The method, based on the ordered p-values of the individual tests, is less conservative than the classical Bonferroni procedure but is still simple to apply. A simulation study shows that the probability of a type I error of the procedure does not exceed the nominal significance level, α, for a variety of multivariate normal and multivariate gamma test statistics. For independent tests the procedure has type I error probability equal to α. The method appears particularly advantageous over the classical Bonferroni procedure when several highly-correlated test statistics are involved.
Current methods of statistical inference are correct but incomplete. Small probability (α) of wrong null-hypothesis rejections can be misunderstood. Definitive rejections of null hypotheses, as well as interval assessments of effect sizes, are impossible in single cases with significance probabilities like .05. Sufficiently large sets of independent experiments and attained significance levels (p-values) should be registered. From such data it is possible to calculate least upper bounds for proportions of fallacies in sets of null-hypothesis rejections or effect-size assessments. A provisional rejection of a null hypothesis in a one-tailed test, or a one-sided confidence interval showing a nonzero effect, is here called a discovery. Consider a large number n of independent experiments with r discoveries. For r rejections of null hypotheses the proportion of fallacies Q has least upper bound Qmax = (n/r — 1)α/(1 — α) < 1. For r confidence intervals, the proportion of fallacies is E = αn/r (assuming that no alternative is in the “wrong” direction).
A sharper Bonferroni procedure for multiple tests of significance is derived. This procedure is an improvement of Hochberg's
(1988) procedure which contrasts the individual P-values with corresponding critical points. It is shown that Hochberg's original procedure is conservative, and can be made
more powerful by enlarging the rejection region so that the type-one error is exactly at the nominal level. It is also shown
that the modified procedure retains all the desired properties of the original procedure.
Simes (1986) has proposed a modified Bonferroni procedure for the test of an overall hypothesis which is the combination of n individual hypotheses. In contrast to the classical Bonferroni procedure, it is not obvious how statements about individual hypotheses are to be made for this procedure. In the present paper a multiple test procedure allowing statements on individual hypotheses is proposed. It is based on the principle of closed test procedures (Marcus, Peritz & Gabriel, 1976) and controls the multiple level α.
A practicing statistician looks at the multiple comparison controversy and related issues through the eyes of the users. The concept of consistency is introduced and discussed in relation to five of the more common multiple comparison procedures. All of the procedures are found to be inconsistent except the simplest procedure, the unrestricted least significant difference (LSD) procedure (or multiple t test). For this and other reasons the unrestricted LSD procedure is recommended for general use, with the proviso that it should be viewed as a hypothesis generator rather than as a method for simultaneous hypothesis generation and testing. The implications for Scheffé's test for general contrasts are also discussed, and a new recommendation is made.
A simple procedure for multiple tests of significance based on individual p-values is derived. This simple procedure is sharper than Holm's (1979) sequentially rejective procedure. Both procedures contrast the ordered p- values with the same set of critical values. Holm's procedure rejects an hypothesis only if its p-value and each of the smaller p-values are less than their corresponding critical-values. The new procedure rejects all hypotheses with smaller or equal p-values to that of any one found less than its critical value.
This paper presents a simple and widely ap- plicable multiple test procedure of the sequentially rejective type, i.e. hypotheses are rejected one at a tine until no further rejections can be done. It is shown that the test has a prescribed level of significance protection against error of the first kind for any combination of true hypotheses. The power properties of the test and a number of possible applications are also discussed.
Optimality criteria formulated in terms of the power functions of the individual tests are given for problems where several hypotheses are tested simultaneously. Subject to the constraint that the expected number of false rejections is less than a given constant $\gamma$ when all null hypotheses are true, tests are found which maximize the minimum average power and the minimum power of the individual tests over certain alternatives. In the common situations in the analysis of variance this leads to application of multiple $t$-tests. In that case the resulting procedure is to use Fisher's "least significant difference," but without a preliminary $F$-test and with a smaller level of significance. Recommendations for choosing the value of $\gamma$ are given by relating $\gamma$ to the probability of no false rejections if all hypotheses are true. Based upon the optimality of the tests, a similar optimality property of joint confidence sets is also derived.
Simes (1986) has proposed a modified Bonferroni procedure for the test of an overall hypothesis which is the combination of
n individual hypotheses. In contrast to the classical Bonferroni procedure, it is not obvious how statements about individual
hypotheses are to be made for this procedure. In the present paper a multiple test procedure allowing statements on individual
hypotheses is proposed. It is based on the principle of closed test procedures (Marcus, Peritz & Gabriel, 1976) and controls
the multiple level α.
Thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) and anisoylated plasminogen streptokinase activator (APSAC) in myocardial infarction has been proved to reduce mortality. A new front-loaded infusion regimen of 100 mg of rt-PA with an initial bolus dose of 15 mg followed by an infusion of 50 mg over 30 min and 35 mg over 60 min has been reported to yield higher patency rates than those achieved with standard regimens of thrombolytic treatment. The effects of this front-loaded administration of rt-PA versus those obtained with APSAC on early patency and reocclusion of infarct-related coronary arteries were investigated in a randomized multicenter trial in 421 patients with acute myocardial infarction. Coronary angiography 90 min after the start of treatment revealed a patent infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3) in 84.4% of 199 patients given rt-PA versus 70.3% of 202 patients given APSAC (p = 0.0007). Early reocclusion within 24 to 48 h was documented in 10.3% of 174 patients given rt-PA versus 2.5% of 163 patients given APSAC. Late reocclusion within 21 days was observed in 2.6% of 152 patients given rt-PA versus 6.3% of 159 patients given APSAC. There were 5 in-hospital deaths (2.4%) in the rt-PA group and 17 deaths (8.1%) in the APSAC group (p = 0.0095). The reinfarction rate was 3.8% and 4.8%, respectively. Peak serum creatine kinase and left ventricular ejection fraction at follow-up angiography were essentially identical in both treatment groups. There were more bleeding complications after APSAC (45% vs. 31%, p = 0.0019).(ABSTRACT TRUNCATED AT 250 WORDS)
The problem of multiple comparisons is discussed in the context of medical research. The need for more powerful procedures than classical multiple comparison procedures is indicated. To this end some new, general and simple procedures are discussed and demonstrated by two examples from the medical literature: the neuropsychologic effects of unidentified childhood exposure to lead, and the sleep patterns of sober chronic alcoholics.
The randomized clinical trial is the preferred research design for evaluating competing diagnostic and therapeutic alternatives, but confidence in the conclusions from a randomized clinical trial depends on the authors' attention to acknowledged methodologic and statistical standards. This survey assessed the level of attention to the problem of multiple comparisons in the analyses of contemporary randomized clinical trials. Of the 67 trials surveyed, 66 (99 percent) performed multiple comparisons with a mean of 30 therapeutic comparisons per trial. When criteria for statistical impairment were applied, 50 trials (75 percent) had the statistical significance of at least one comparison impaired by the problem of multiple comparisons, and 15 (22 percent) had the statistical significance of all comparisons impaired by the problem of multiple comparisons. Although some statistical techniques are available, there still exists a great need for future work to clarify further the problem of multiple comparisons and determine how the impact of this problem can best be minimized in subsequent research.
This article discusses statistical methods for comparing the means of several groups and focuses on examples from 50 Original Articles published in the Journal in 1978 and 1979. Although medical authors often present comparisons of the means of several groups, the most common method of analysis, multiple t-tests, is usually a poor choice. Which method of analysis is appropriate depends on what questions the investigators wish to ask. If the investigators want to identify which of the groups under study are different from the rest, they will need a different method from the one required if they wish simply to decide whether or not the groups share a common mean. More complicated questions about the group means call for more sophisticated techniques. Of the 50 Journal articles examined, 27 (54 per cent) used inappropriate statistical methods to analyze the differences between group means. Investigators need to become better acquainted with statistical techniques for making multiple comparisons between group means.
- Hochberg
Statistical problems in reporting of clinical trials
- S. J. Pocock
- M. D. Hughes
- R. J. Lee