Scapular motion during shoulder joint extension movement.

A few reports on scapular motion during shoulder joint extension exist. Understanding the normal motion of shoulder joint extension may be useful in evaluating and treating patients with diminished or minimal shoulder joint extension. Therefore, this study aimed to identify scapular motion during shoulder joint extension movement in a sitting position. Shoulder joint extension movement in the sitting position were measured in 22 healthy adults (age, 25.8 ± 2.7 years). Shoulder joint extension, scapular upward rotation, anterior tilt, external rotation angles, and the acromion position were investigated using a three-dimensional motion analyzer. The difference from each value of 10° to 50° shoulder joint extension to each value of 0° shoulder joint extension were checked. The results were compared using multiple comparison method. In most participants, the scapula tilted posteriorly up to 30° of the shoulder joint extension and anteriorly after 30°. Scapular upward and external rotation continued to increase with shoulder extension. Furthermore, the acromion was displaced upward and backward. Thus, scapular posterior tilt is necessary for shoulder joint extension during the initial movement, followed by anterior tilt. The acromion may have been displaced posteriorly because of clavicular retraction, causing the scapula to tilt posteriorly. After 30° of shoulder joint extension, the scapular anterior tilt may have prevailed over the scapular posterior tilt.

Modifying the false discovery rate procedure based on the information theory under arbitrary correlation structure and its performance in high-dimensional genomic data.

BACKGROUND: Controlling the False Discovery Rate (FDR) in Multiple Comparison Procedures (MCPs) has widespread applications in many scientific fields. Previous studies show that the correlation structure between test statistics increases the variance and bias of FDR. The objective of this study is to modify the effect of correlation in MCPs based on the information theory. We proposed three modified procedures (M1, M2, and M3) under strong, moderate, and mild assumptions based on the conditional Fisher Information of the consecutive sorted test statistics for controlling the false discovery rate under arbitrary correlation structure. The performance of the proposed procedures was compared with the Benjamini-Hochberg (BH) and Benjamini-Yekutieli (BY) procedures in simulation study and real high-dimensional data of colorectal cancer gene expressions. In the simulation study, we generated 1000 differential multivariate Gaussian features with different levels of the correlation structure and screened the significance features by the FDR controlling procedures, with strong control on the Family Wise Error Rates. RESULTS: When there was no correlation between 1000 simulated features, the performance of the BH procedure was similar to the three proposed procedures. In low to medium correlation structures the BY procedure is too conservative. The BH procedure is too liberal, and the mean number of screened features was constant at the different levels of the correlation between features. The mean number of screened features by proposed procedures was between BY and BH procedures and reduced when the correlations increased. Where the features are highly correlated the number of screened features by proposed procedures reached the Bonferroni (BF) procedure, as expected. In real data analysis the BY, BH, M1, M2, and M3 procedures were done to screen gene expressions of colorectal cancer. To fit a predictive model based on the screened features the Efficient Bayesian Logistic Regression (EBLR) model was used. The fitted EBLR models based on the screened features by M1 and M2 procedures have minimum entropies and are more efficient than BY and BH procedures. CONCLUSION: The modified proposed procedures based on information theory, are much more flexible than BH and BY procedures for the amount of correlation between test statistics. The modified procedures avoided screening the non-informative features and so the number of screened features reduced with the increase in the level of correlation.

Adaptive Multiple Comparison Sequential Design (AMCSD) for clinical trials.

We propose an adaptive sequential testing procedure for clinical trials that test the efficacy of multiple treatment options, such as dose/regimen, different drugs, sub-populations, endpoints, or a mixture of them in one trial. At any interim analyses, sample size re-estimation can be conducted, and any option can be dropped for lack of efficacy or unsatisfactory safety profile. Inference after the trial, including p-value, conservative point estimate and confidence intervals, are provided.

Combining Item Purification and Multiple Comparison Adjustment Methods in Detection of Differential Item Functioning.

Many of the differential item functioning (DIF) detection methods rely on a principle of testing for DIF item by item, while considering the rest of the items or at least some of them being DIF-free. Computational algorithms of these DIF detection methods involve the selection of DIF-free items in an iterative procedure called item purification. Another aspect is the need to correct for multiple comparisons, which can be done with a number of existing multiple comparison adjustment methods. In this article, we demonstrate that implementation of these two controlling procedures together may have an impact on which items are detected as DIF items. We propose an iterative algorithm combining item purification and adjustment for multiple comparisons. Pleasant properties of the newly proposed algorithm are shown with a simulation study. The method is demonstrated on a real data example.

Grading Criteria of Anthurium DUS Quantitative Characteristics by Multiple Comparison.

The determination of the grades and interval of quantitative characteristics is an important job while we draft new distinctness, uniformity and stability (DUS) test guidelines. Grading criteria should be adjusted because of the effect of year and site; it is also a key task to establish applicable criteria in the DUS test. Excellent criteria will improve the accuracy of the DUS evaluation. In this study, we analyzed the variability and distribution patterns of nine quantitative characteristics of 251 anthurium varieties. Three methods were used to establish the grade criteria: the two standard deviation methods, the two LSD0.05 methods and the multiple comparison method. The results showed that the coefficient of variation within varieties varied from 6.96% to 10.11%. The quantitative characteristics observed in this study did not follow a normal distribution, except spadix thickness at the middle and spathe size. In most characteristics, the standard deviations and LSD0.05 were similar, except for spathe size. The state interval set by multiple comparison methods for every characteristic was variable, and its mean was about 1.25 times that of the other two methods. The process of establishing grading criteria using the multiple comparison method was simpler, and the criteria were more accurate, with a lower error rate.

Evaluation of thresholding methods for activation likelihood estimation meta-analysis via large-scale simulations.

In recent neuroimaging studies, threshold-free cluster enhancement (TFCE) gained popularity as a sophisticated thresholding method for statistical inference. It was shown to feature higher sensitivity than the frequently used approach of controlling the cluster-level family-wise error (cFWE) and it does not require setting a cluster-forming threshold at voxel level. Here, we examined the applicability of TFCE to a widely used method for coordinate-based neuroimaging meta-analysis, Activation Likelihood Estimation (ALE), by means of large-scale simulations. We created over 200,000 artificial meta-analysis datasets by independently varying the total number of experiments included and the amount of spatial convergence across experiments. Next, we applied ALE to all datasets and compared the performance of TFCE to both voxel-level and cluster-level FWE correction approaches. All three multiple-comparison correction methods yielded valid results, with only about 5% of the significant clusters being based on spurious convergence, which corresponds to the nominal level the methods were controlling for. On average, TFCE's sensitivity was comparable to that of cFWE correction, but it was slightly worse for a subset of parameter combinations, even after TFCE parameter optimization. cFWE yielded the largest significant clusters, closely followed by TFCE, while voxel-level FWE correction yielded substantially smaller clusters, showcasing its high spatial specificity. Given that TFCE does not outperform the standard cFWE correction but is computationally much more expensive, we conclude that employing TFCE for ALE cannot be recommended to the general user.

Assessment of PM2.5-related health effects: A comparative study using multiple methods and multi-source data in China.

In China, PM2.5 pollution has caused extensive death and economic loss. Thus, an accurate assessment of the spatial distribution of these losses is crucial for delineating priority areas for air pollution control in China. In this study, we assessed the PM2.5 exposure-related health effects according to the integrated exposure risk function and non-linear power law (NLP) function in 338 prefecture-level cities in China by utilizing online monitoring data and the PM2.5 Hindcast Database (PHD). Our results revealed no significant difference between the monitoring data and PHD (p value = 0.66 > 0.05). The number of deaths caused by PM2.5-related Stroke (cerebrovascular disease), ischemic heart disease, chronic obstructive pulmonary disease, and lung cancer at the national level estimated through the NLP function was 0.27 million (95% CI: 0.06-0.50), 0.23 million (95% CI: 0.08-0.38), 0.31 million (95% CI: 0.04-0.57), and 0.31 million (95% CI: 0.16-0.40), respectively. The total economic cost at the national level in 2016 was approximately US$80.25 billion (95% CI: 24.46-132.25). Based on a comparison of Z statistics, we propose that the evaluation results obtained using the NLP function and monitoring data are accurate. Additionally, according to scenario simulations, Beijing, Chongqing, Tianjin, and other cities should be priority areas for PM2.5 pollution control to achieve considerable health benefits. Our statistics can help improve the accuracy of PM2.5-related health effect assessments in China.

A Review of High-Dimensional Mediation Analyses in DNA Methylation Studies.

DNA methylation alterations have been widely studied as mediators of environmentally induced disease risks. With new advances in technique, epigenome-wide DNA methylation data (EWAS) have become the new standard for epigenetic studies in human populations. However, to date most epigenetic studies of mediation effects only involve selected (gene-specific) candidate methylation markers. There is an urgent need for appropriate analytical methods for EWAS mediation analysis. In this chapter, we provide an overview of recent advances on high-dimensional mediation analysis, with application to two DNA methylation data.

CaV1.3 enhanced store operated calcium promotes resistance to androgen deprivation in prostate cancer.

Androgen deprivation therapy (ADT) is the main treatment for advanced prostate cancer (PCa) but resistance results in progression to terminal castrate resistant PCa (CRPC), where there is an unmet therapeutic need. Aberrant intracellular calcium (Cai2+) is known to promote neoplastic transformation and treatment resistance. There is growing evidence that voltage gated calcium channel (VGCC) expression is increased in cancer, particularly CACNA1D/CaV1.3 in CRPC. The aim of this study was to investigate if increased CaV1.3 drives resistance to ADT and determine its associated impact on Cai2+ and cancer biology. Bioinformatic analysis revealed that CACNA1D gene expression is increased in ADT treated PCa patients. This was corroborated in both in vivo LNCaP xenograft mouse and in vitro PCa cell line models, which demonstrated a significant increase in CaV1.3 protein expression following ADT with bicalutamide. Expression was found to be of a shortened 170kDa CaV1.3 isoform associated with plasma and intracellular membranes, which failed to induce calcium influx following membrane depolarisation. Instead, under ADT CaV1.3 mediated a rise in basal cytosolic calcium and an increase in store operated calcium entry (SOCE). This mechanism was found to promote the proliferation and survival of ADT resistant CRPC cells. Overall, this study demonstrates for the first time in PCa that under ADT specific CaV1.3 isoforms promote an upregulation of SOCE which contributes to treatment resistance and CRPC biology. Thus, this novel oncochannel represents a target for therapeutic development to improve PCa patient outcomes.

Power analysis for stepped wedge trials with multiple interventions.

Stepped wedge design (SWD) trials are cluster randomized trials that feature staggered, unidirectional cross-over between treatment conditions. Existing literature on power for SWDs focuses primarily on designs with two conditions, typically a control and an intervention condition. However, SWDs with more than one treatment condition are being proposed and conducted. We present a linear mixed model for SWDs with two or more interventions, including both multiarm and factorial designs. We derive standard errors of the intervention effect coefficients, and present power calculation methods. We consider both repeated cross-sectional and cohort designs. Design features, with a focus on treatment allocations, are examined to determine their impact on power.

Methodological approaches for analysing data from therapeutic efficacy studies.

Several anti-malarial drugs have been evaluated in randomized clinical trials to treat acute uncomplicated Plasmodium falciparum malaria. The outcome of anti-malarial drug efficacy studies is classified into one of four possible outcomes defined by the World Health Organization: adequate clinical and parasitological response, late parasitological failure, late clinical failure, early treatment failure. These four ordered categories are ordinal data, which are reduced to either a binary outcome (i.e., treatment success and treatment failure) to calculate the proportions of treatment failure or to time-to-event outcome for Kaplan-Meier survival analysis. The arbitrary transition from 4-level ordered categories to 2-level type categories results in a loss of statistical power. In the opinion of the authors, this outcome can be considered as ordinal at a fixed endpoint or at longitudinal endpoints. Alternative statistical methods can be applied to 4-level ordinal categories of therapeutic response to optimize data exploitation. Furthermore, network meta-analysis is useful not only for direct comparison of drugs which were evaluated together in a randomized design, but also for indirect comparison of different artemisinin-based combinations across different clinical studies using a common drug comparator, with the aim to determine the ranking order of drug efficacy. Previous works conducted in Cameroonian children served as data source to illustrate the feasibility of these novel statistical approaches. Data analysis based on ordinal end-point may be helpful to gain further insight into anti-malarial drug efficacy.

Trans-base and trans-vault low-velocity penetrating brain injury: A retrospective comparative study of characteristics, treatment, and outcomes.

PURPOSE: Low-velocity penetrating brain injury (LVPBI) caused by foreign bodies can pose life-threatening emergencies. Their complexity and lack of validated classification data have prevented standardization of clinical management. We aimed to compare the trans-base and trans-vault phenotypes of LVPBI to help provide guidance for clinical decision-making of such injury type. METHODS: A retrospective study on LVPBI patients managed at our institution from November 2013 to March 2020 was conducted. We included LVPBI patients admitted for the first time for surgery, and excluded those with multiple injuries, gunshot wounds, pregnancy, severe blunt head trauma, etc. Patients were categorized into trans-base and trans-vault LVPBI groups based on the penetration pathway. Discharged patients were followed up by outpatient visit or telephone. The data were entered into the Electronic Medical Record system by clinicians, and subsequently derived by researchers. The demography and injury characteristics, treatment protocols, complications, and outcomes were analyzed and compared between the two groups. A t-test was used for analysis of normally distributed data, and a Mann-Whitney U test for non-parametric data. A generalized linear model was further established to determine whether the factors length of stay and performance scale score were influenced by each factor. RESULTS: A total of 27 LVPBI patients were included in this analysis, comprised of 13 (48.1%) trans-base cases and 14 (51.9%) trans-vault cases. Statistical analyses suggested that trans-base LVPBI was correlated with deeper wounds; while the trans-vault phenotype was correlated with injury by metal foreign bodies. There was no difference in Glasgow Coma Scale score and the risk of intracranial hemorrhage between the two groups. Surgical approaches in the trans-base LVPBI group included subfrontal (n = 5, 38.5%), subtemporal (n = 5, 38.5%), lateral fissure (n = 2, 15.4%), and distal lateral (n = 1, 7.7%). All patients in the trans-vault group underwent a brain convex approach using the foreign body as reference (n = 14, 100%). Moreover, the two groups differed in application prerequisites for intracranial pressure monitoring and vessel-related treatment. Trans-base LVPBI was associated with higher rates of cranial nerve and major vessel injuries; in contrast, trans-vault LVPBI was associated with lower functional outcome scores. CONCLUSION: Our findings suggest that trans-base and trans-vault LVPBIs differ in terms of characteristics, treatment, and outcomes. Further understanding of these differences may help guide clinical decisions and contribute to a better management of LVPBIs.

High-dimensional brain-wide functional connectivity mapping in magnetoencephalography.

BACKGROUND: Brain functional connectivity (FC) analyses based on magneto/electroencephalography (M/EEG) signals have yet to exploit the intrinsic high-dimensional information. Typically, these analyses are constrained to regions of interest to avoid the curse of dimensionality, with the latter leading to conservative hypothesis testing. NEW METHOD: We removed such constraint by estimating high-dimensional source-based M/EEG-FC using cluster-permutation statistic (CPS) and demonstrated the feasibility of this approach by identifying resting-state changes in mild cognitive impairment (MCI), a prodromal stage of Alzheimer's disease. Particularly, we proposed a unified framework for CPS analysis together with a novel neighbourhood measure to estimate more compact and neurophysiological plausible neural communication. As clusters could more confidently reveal interregional communication, we proposed and tested a cluster-strength index to demonstrate other advantages of CPS analysis. RESULTS: We found clusters of increased communication or hypersynchronization in MCI compared to healthy controls in delta (1-4 Hz) and higher-theta (6-8 Hz) bands oscillations. These mainly consisted of interactions between occipitofrontal and occipitotemporal regions in the left hemisphere, which may be critically affected in the early stages of Alzheimer's disease. CONCLUSIONS: Our approach could be important to create high-resolution FC maps from neuroimaging studies in general, allowing the multimodal analysis of neural communication across multiple spatial scales. Particularly, FC clusters more robustly represent the interregional communication by identifying dense bundles of connections that are less sensitive to inter-individual anatomical and functional variability. Overall, this approach could help to better understand neural information processing in healthy and disease conditions as needed for developing biomarker research.

Trans-base and trans-vault low-velocity penetrating brain injury: A retrospective comparative study of characteristics, treatment, and outcomes / 中华创伤杂志(英文版)

PURPOSE@#Low-velocity penetrating brain injury (LVPBI) caused by foreign bodies can pose life-threatening emergencies. Their complexity and lack of validated classification data have prevented standardization of clinical management. We aimed to compare the trans-base and trans-vault phenotypes of LVPBI to help provide guidance for clinical decision-making of such injury type.@*METHODS@#A retrospective study on LVPBI patients managed at our institution from November 2013 to March 2020 was conducted. We included LVPBI patients admitted for the first time for surgery, and excluded those with multiple injuries, gunshot wounds, pregnancy, severe blunt head trauma, etc. Patients were categorized into trans-base and trans-vault LVPBI groups based on the penetration pathway. Discharged patients were followed up by outpatient visit or telephone. The data were entered into the Electronic Medical Record system by clinicians, and subsequently derived by researchers. The demography and injury characteristics, treatment protocols, complications, and outcomes were analyzed and compared between the two groups. A t-test was used for analysis of normally distributed data, and a Mann-Whitney U test for non-parametric data. A generalized linear model was further established to determine whether the factors length of stay and performance scale score were influenced by each factor.@*RESULTS@#A total of 27 LVPBI patients were included in this analysis, comprised of 13 (48.1%) trans-base cases and 14 (51.9%) trans-vault cases. Statistical analyses suggested that trans-base LVPBI was correlated with deeper wounds; while the trans-vault phenotype was correlated with injury by metal foreign bodies. There was no difference in Glasgow Coma Scale score and the risk of intracranial hemorrhage between the two groups. Surgical approaches in the trans-base LVPBI group included subfrontal (n = 5, 38.5%), subtemporal (n = 5, 38.5%), lateral fissure (n = 2, 15.4%), and distal lateral (n = 1, 7.7%). All patients in the trans-vault group underwent a brain convex approach using the foreign body as reference (n = 14, 100%). Moreover, the two groups differed in application prerequisites for intracranial pressure monitoring and vessel-related treatment. Trans-base LVPBI was associated with higher rates of cranial nerve and major vessel injuries; in contrast, trans-vault LVPBI was associated with lower functional outcome scores.@*CONCLUSION@#Our findings suggest that trans-base and trans-vault LVPBIs differ in terms of characteristics, treatment, and outcomes. Further understanding of these differences may help guide clinical decisions and contribute to a better management of LVPBIs.

Risks and Challenges in Interpreting Simultaneous Analyses of Multiple Cytokines.

Purpose: To determine the inherent risks of handling results below the lowest detectable value in the analysis of multiple cytokines in the aqueous humor of patients with retinal diseases by comparing possible statistical strategies to lower the risk of mis interpretation or over interpretation of results. Furthermore, in analyzing multiple cytokines simultaneously, the challenge of multiple comparison arises. Methods: The analyses were based on parallel testing of 43 cytokines in 58 aqueous humor samples from patients with macular hole or epiretinal membrane. Substitution of values below the detection limit with 0.1 ×, 0.5 ×, or 1.0× of the lowest level of quantitation was compared with handling as missing value. The impact of correction for multiple comparisons was assessed using the Holm correction. Results: When comparing macular hole with epiretinal membrane, not substituting the missing data revealed a difference (P < 0.05) for five compared with wight cytokines after their substitution, indicating an increased risk for under-estimating group differences (type II error). Correcting for multiple comparisons revealed a relevant risk of over estimating group differences (type I error). Conclusions: Physiologic cytokine concentrations in ocular fluids typically range at or below the lowest level of quantitation. Handling of results below this cutoff as missing leads to increased type II errors. Not correcting for multiple comparisons increases the risk of a type I error. Taken together, both harbor a systematic inherent risk of misinterpretation of the results. Translational Relevance: Ignoring the inherent risks of data misinterpretation in analyses of ocular fluid samples may result in mis leading conclusions regarding their biological relevance.

Graphical approaches for the control of generalized error rates.

When simultaneously testing multiple hypotheses, the usual approach in the context of confirmatory clinical trials is to control the familywise error rate (FWER), which bounds the probability of making at least one false rejection. In many trial settings, these hypotheses will additionally have a hierarchical structure that reflects the relative importance and links between different clinical objectives. The graphical approach of Bretz et al (2009) is a flexible and easily communicable way of controlling the FWER while respecting complex trial objectives and multiple structured hypotheses. However, the FWER can be a very stringent criterion that leads to procedures with low power, and may not be appropriate in exploratory trial settings. This motivates controlling generalized error rates, particularly when the number of hypotheses tested is no longer small. We consider the generalized familywise error rate (k-FWER), which is the probability of making k or more false rejections, as well as the tail probability of the false discovery proportion (FDP), which is the probability that the proportion of false rejections is greater than some threshold. We also consider asymptotic control of the false discovery rate, which is the expectation of the FDP. In this article, we show how to control these generalized error rates when using the graphical approach and its extensions. We demonstrate the utility of the resulting graphical procedures on three clinical trial case studies.

Dataset decay and the problem of sequential analyses on open datasets.

Open data allows researchers to explore pre-existing datasets in new ways. However, if many researchers reuse the same dataset, multiple statistical testing may increase false positives. Here we demonstrate that sequential hypothesis testing on the same dataset by multiple researchers can inflate error rates. We go on to discuss a number of correction procedures that can reduce the number of false positives, and the challenges associated with these correction procedures.

When "facts" are not facts: what does p value really mean, and how does it deceive us?

The recent paper in JAMA alleging that frozen embryo transfer causes twice the risk of childhood cancer in the offspring is an excellent example of the erroneous use of statistical tests (and the misinterpretation of p value) that is common in much of the medical literature, even in very high impact journals. These myths backed by misleading statements of "statistical significance" can cause far-reaching harm to patients and doctors who might not understand the pitfalls of specious statistical testing.

Exact Unconditional Tests for Dichotomous Data When Comparing Multiple Treatments With a Single Control.

In contemporary clinical trials, often evaluated simultaneously are multiple new treatments or the same treatment at multiple dose levels. These treatments are first compared with a control, and the best candidate with sufficient activity is then picked for the following trial for further investigation. When the primary outcome is binary, several testing procedures including Dunnett's test, have been proposed for the assessment of hypotheses. The sample size of each group is predetermined; thus, an unconditional exact approach is aligned with the study design. The exact unconditional approach based on maximization has been studied for comparing multiple treatments with a control. The newly developed exact unconditional approach based on estimation and maximization could possibly increase the effectiveness of exact approaches by smoothing the tail probability surface. We compare these 2 exact unconditional approaches based on 3 commonly used test statistics under various design settings. Based on results from numerical studies, we provide recommendations on the usage of these exact approaches. A real clinical trial to treat psoriasis is used to illustrate the application of the considered exact approaches.

Voxel-based analysis in radiation oncology: A methodological cookbook.

Recently, 2D or 3D methods for dose distribution analysis have been proposed as evolutions of the Dose Volume Histogram (DVH) approaches. Those methods, collectively referred to as pixel- or voxel-based (VB) methods, evaluate local dose response patterns and go beyond the organ-based philosophy of Normal Tissue Complication Probability (NTCP) modelling. VB methods have been introduced in the context of radiation oncology in the very last years following the virtuous example of neuroimaging experience. In radiation oncology setting, dose mapping is a suitable scheme to compare spatial patterns of local dose distributions between patients who develop toxicity and who do not. In this critical review, we present the methods that include spatial dose distribution information for evaluating different toxicity endpoints after radiation therapy. The review addresses two main topics. First, the critical aspects in dose map building, namely the spatial normalization of the dose distributions from different patients. Then, the issues related to the actual dose map comparison, i.e. the viable options for a robust VB statistical analysis and the potential pitfalls related to the adopted solutions. To elucidate the different theoretical and technical issues, the covered topics are illustrated in relation to practical applications found in the existing literature. We conclude the overview on the VB philosophy in radiation oncology by introducing new phenomenological approaches to NTCP modelling that accounts for inhomogeneous organ radiosensitivity.