High-dimensional quantile mediation analysis with application to a birth cohort study of mother-newborn pairs.

MOTIVATION: There has been substantial recent interest in developing methodology for high-dimensional mediation analysis. Yet, the majority of mediation statistical methods lean heavily on mean regression, which limits their ability to fully capture the complex mediating effects across the outcome distribution. To bridge this gap, we propose a novel approach for selecting and testing mediators throughout the full range of the outcome distribution spectrum. RESULTS: The proposed high-dimensional quantile mediation model provides a comprehensive insight into how potential mediators impact outcomes via their mediation pathways. This method's efficacy is demonstrated through extensive simulations. The study presents a real-world data application examining the mediating effects of DNA methylation on the relationship between maternal smoking and offspring birthweight. AVAILABILITY AND IMPLEMENTATION: Our method offers a publicly available and user-friendly function qHIMA(), which can be accessed through the R package HIMA at https://CRAN.R-project.org/package=HIMA.

The effect of vitamin D status on the occurrence of Kawasaki Disease: a meta-analysis.

AIM: The relationship between vitamin D status and Kawasaki Disease (KD), as well as coronary artery lesion (CAL), has yet to be established. METHODS: A meta-analysis was conducted to assess the correlation between vitamin D status and KD, as well as the impact of vitamin D status on the progression of KD into CAL. RESULTS: The meta-analysis revealed a consistent and significant association between serum 25(OH)D level and the occurrence KD (studies N = 22; z = -3.51, P < 0.001). Patients with KD had markedly lower levels of vitamin D than healthy controls (SMD: -1.30 ng/mL, 95%CI: -2.05 to -0.55 ng/mL). CONCLUSION: The study provided evidence supporting a significant association between lower serum vitamin D levels and the occurrence of KD, particularly within the Chinese population. However, the findings did not suggest a direct impact of vitamin D on the development of CAL in KD patients.

Association of Cardiovascular Health Through Young Adulthood With Genome-Wide DNA Methylation Patterns in Midlife: The CARDIA Study.

BACKGROUND: Cardiovascular health (CVH) from young adulthood is strongly associated with an individual's future risk of cardiovascular disease (CVD) and total mortality. Defining epigenomic biomarkers of lifelong CVH exposure and understanding their roles in CVD development may help develop preventive and therapeutic strategies for CVD. METHODS: In 1085 CARDIA study (Coronary Artery Risk Development in Young Adults) participants, we defined a clinical cumulative CVH score that combines body mass index, blood pressure, total cholesterol, and fasting glucose measured longitudinally from young adulthood through middle age over 20 years (mean age, 25-45). Blood DNA methylation at >840 000 methylation markers was measured twice over 5 years (mean age, 40 and 45). Epigenome-wide association analyses on the cumulative CVH score were performed in CARDIA and compared in the FHS (Framingham Heart Study). We used penalized regression to build a methylation-based risk score to evaluate the risk of incident coronary artery calcification and clinical CVD events. RESULTS: We identified 45 methylation markers associated with cumulative CVH at false discovery rate <0.01 (P=4.7E-7-5.8E-17) in CARDIA and replicated in FHS. These associations were more pronounced with methylation measured at an older age. CPT1A, ABCG1, and SREBF1 appeared as the most prominent genes. The 45 methylation markers were mostly located in transcriptionally active chromatin and involved lipid metabolism, insulin secretion, and cytokine production pathways. Three methylation markers located in genes SARS1, SOCS3, and LINC-PINT statistically mediated 20.4% of the total effect between CVH and risk of incident coronary artery calcification. The methylation risk score added information and significantly (P=0.004) improved the discrimination capacity of coronary artery calcification status versus CVH score alone and showed association with risk of incident coronary artery calcification 5 to 10 years later independent of cumulative CVH score (odds ratio, 1.87; P=9.66E-09). The methylation risk score was also associated with incident clinical CVD in FHS (hazard ratio, 1.28; P=1.22E-05). CONCLUSIONS: Cumulative CVH from young adulthood contributes to midlife epigenetic programming over time. Our findings demonstrate the role of epigenetic markers in response to CVH changes and highlight the potential of epigenomic markers for precision CVD prevention, and earlier detection of subclinical CVD, as well.

Manipulation of Particle/Cell Based on Compressibility in a Divergent Microchannel by Surface Acoustic Wave.

The mechanical properties (compressibility or deformability) of cells are closely related to their death, migration, and differentiation. Accurate separation and manipulation of bioparticles based on these mechanical properties are still a challenging in the field of acoustofluidics. In this work, based on surface acoustic waves (SAW) and divergent microchannels, we developed a new method for separating and detecting particles or cells with different compressibility. The difference in acoustic radiation force (Fr) caused by compressibility are gradually amplified and accumulated by decreasing the flow velocity, and they are finally reflected in the particle migration distance. During the transverse migration process, the alternating dominance of the acoustic radiation force and the Stokes resistance force (Fs) drives the particles to create three typical migration patterns: intermittent migration, compound migration, and near-wall migration. In the present tilted SAW device, a 91% separation success rate of ∼10 µm polystyrene (PS) and polydimethylsiloxane (PDMS) particles can be achieved by optimizing the acoustic field input power and the fluid velocity. The application potential of the present divergent microchannel is validated by separating the myelogenous leukemia cell K562 and the natural killer cell NK92 that have similar densities and sizes (∼15 µm) but different compressibility. The results of this work are expected to provide valuable insights into the acoustofluidics separation and detection of the cells that are with different compressibility.

A murine monoclonal antibody against H5N1 avian influenza virus cross-reacts with human kidney cortex cells.

To investigate the biological characteristics of monoclonal antibodies (mAbs) against avian influenza virus (AIV) and the possible mechanism of AIV-related kidney injury. BALB/c mice were immunized with inactivated H5N1 AIV to prepare monoclonal antibody H5-32, and its subtype, titer and cross-reactivity with other influenza viruses were identified. The reactivity of monoclonal antibody with normal human tissue was analyzed by immunohistochemistry. Immunofluorescence and confocal laser scanning technique were used to detect the binding sites between mAb and human renal cortical cells, and Western blotting was used to detect the size of binding fragments. Immunohistochemical analysis confirmed that monoclonal antibody H5-32 cross-reacted with normal human kidney tissue. In human kidney, mAb H5-32 was localized in the cytoplasm of human renal tubular epithelial cells, and its binding fragment size was about 43 kDa. H5N1 AIV appears to bind to human renal tubular epithelial cells, which may be one of the mechanisms of kidney injury caused by AIV infection.

A flexible quasi-likelihood model for microbiome abundance count data.

In this article, we present a flexible model for microbiome count data. We consider a quasi-likelihood framework, in which we do not make any assumptions on the distribution of the microbiome count except that its variance is an unknown but smooth function of the mean. By comparing our model to the negative binomial generalized linear model (GLM) and Poisson GLM in simulation studies, we show that our flexible quasi-likelihood method yields valid inferential results. Using a real microbiome study, we demonstrate the utility of our method by examining the relationship between adenomas and microbiota. We also provide an R package "fql" for the application of our method.

A novel N-arachidonoyl-l-alanine-catabolizing strain of Serratia marcescens for the bioremediation of Cd and Cr co-contamination.

Cadmium (Cd) and chromium (Cr) are widespread contaminants with a high risk to the environment and humans. Herein we isolated a novel strain of Serratia marcescens, namely strain S27, from soil co-contaminated with Cd and Cr. This strain showed strong resistance to Cd as well as Cr. S27 cells demonstrated Cd adsorption rate of 45.8% and Cr reduction capacity of 84.4% under optimal growth conditions (i.e., 30 °C, 200 rpm, and pH 7.5). Microscopic characterization of S27 cells revealed the importance of the functional groups C-O-C, C-H-O, C-C, C-H, and -OH, and also indicated that Cr reduction occurred on bacterial cell membrane. Cd(II) and Cr(VI) bioaccumulation on S27 cell surface was mainly in the form of Cd(OH)2 and Cr2O3, respectively. Further, metabolomic analyses revealed that N-arachidonoyl-l-alanine was the key metabolite that promoted Cd and Cr complexation by S27; it primarily promotes γ-linolenic acid (GLA) metabolism, producing siderophores and coordinating with organic acids to enhance metal bioavailability. To summarize, our results suggest that S27 is promising for the bioremediation of environments contaminated with Cd and Cr in tropical regions.

SSA Net: Small Scale-Aware Enhancement Network for Human Pose Estimation.

In the field of human pose estimation, heatmap-based methods have emerged as the dominant approach, and numerous studies have achieved remarkable performance based on this technique. However, the inherent drawbacks of heatmaps lead to serious performance degradation in methods based on heatmaps for smaller-scale persons. While some researchers have attempted to tackle this issue by improving the performance of small-scale persons, their efforts have been hampered by the continued reliance on heatmap-based methods. To address this issue, this paper proposes the SSA Net, which aims to enhance the detection accuracy of small-scale persons as much as possible while maintaining a balanced perception of persons at other scales. SSA Net utilizes HRNetW48 as a feature extractor and leverages the TDAA module to enhance small-scale perception. Furthermore, it abandons heatmap-based methods and instead adopts coordinate vector regression to represent keypoints. Notably, SSA Net achieved an AP of 77.4% on the COCO Validation dataset, which is superior to other heatmap-based methods. Additionally, it achieved highly competitive results on the Tiny Validation and MPII datasets as well.

HIMA2: high-dimensional mediation analysis and its application in epigenome-wide DNA methylation data.

Mediation analysis plays a major role in identifying significant mediators in the pathway between environmental exposures and health outcomes. With advanced data collection technology for large-scale studies, there has been growing research interest in developing methodology for high-dimensional mediation analysis. In this paper we present HIMA2, an extension of the HIMA method (Zhang in Bioinformatics 32:3150-3154, 2016). First, the proposed HIMA2 reduces the dimension of mediators to a manageable level based on the sure independence screening (SIS) method (Fan in J R Stat Soc Ser B 70:849-911, 2008). Second, a de-biased Lasso procedure is implemented for estimating regression parameters. Third, we use a multiple-testing procedure to accurately control the false discovery rate (FDR) when testing high-dimensional mediation hypotheses. We demonstrate its practical performance using Monte Carlo simulation studies and apply our method to identify DNA methylation markers which mediate the pathway from smoking to reduced lung function in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Mediation analysis for survival data with high-dimensional mediators.

MOTIVATION: Mediation analysis has become a prevalent method to identify causal pathway(s) between an independent variable and a dependent variable through intermediate variable(s). However, little work has been done when the intermediate variables (mediators) are high-dimensional and the outcome is a survival endpoint. In this paper, we introduce a novel method to identify potential mediators in a causal framework of high-dimensional Cox regression. RESULTS: We first reduce the data dimension through a mediation-based sure independence screening method. A de-biased Lasso inference procedure is used for Cox's regression parameters. We adopt a multiple-testing procedure to accurately control the false discovery rate when testing high-dimensional mediation hypotheses. Simulation studies are conducted to demonstrate the performance of our method. We apply this approach to explore the mediation mechanisms of 379 330 DNA methylation markers between smoking and overall survival among lung cancer patients in The Cancer Genome Atlas lung cancer cohort. Two methylation sites (cg08108679 and cg26478297) are identified as potential mediating epigenetic markers. AVAILABILITY AND IMPLEMENTATION: Our proposed method is available with the R package HIMA at https://cran.r-project.org/web/packages/HIMA/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Solid-Phase Peptide Synthesis Using a Four-Dimensional (Safety-Catch) Protecting Group Scheme.

Peptides of importance to both academia and industry are mostly synthesized in the solid-phase mode using a two-dimensional scheme. The so-called Fmoc/tBu strategy, where the groups are removed by piperidine and TFA, respectively, is currently the method of choice for peptide synthesis. However, as the molecular diversity of cyclic and branched peptides becomes a challenging interest, a high level of orthogonal dimensionality is required, such as through triorthogonal protection schemes. Here we present a fourth category of orthogonal protecting groups that are stable under cleavage conditions, including the TFA treatment that removes the tBu-based groups. At the end of the synthetic process and upon some chemical manipulation, the groups in this fourth category were removed with TFA. This new concept of protecting groups could facilitate the synthesis and manipulation of difficult peptides.

Diaphragmatic ultrasonography-based rapid shallow breathing index for predicting weaning outcome during a pressure support ventilation spontaneous breathing trial.

BACKGROUND: The optimum timing to wean is crucial to avoid negative outcomes for mechanically ventilated patients. The rapid shallow breathing index (RSBI), a widely used weaning index, has limitations in predicting weaning outcomes. By replacing the tidal volume of the RSBI with diaphragmatic excursion (DE) and diaphragm thickening fraction (DTF) assessed by ultrasonography, we calculated two weaning indices, the diaphragmatic excursion rapid shallow breathing index (DE-RSBI, respiratory rate [RR]/DE) and the diaphragm thickening fraction rapid shallow breathing index (DTF-RSBI, RR/DTF). The aim of this study was to evaluate the predictive values of DTF-RSBI, DE-RSBI and traditional RSBI in weaning failure. METHODS: This prospective observational study included patients undergoing mechanical ventilation (MV) for > 48 h and who were readied for weaning. During a pressure support ventilation (PSV) spontaneous breathing trial (SBT), right hemidiaphragmatic excursion and DTF were measured by bedside ultrasonography as well as RSBI. Weaning failure was defined as: (1) failing the SBT and (2) SBT success but inability to maintain spontaneous breathing for more than 48 h without noninvasive or invasive ventilation. A receiver operator characteristic (ROC) curve was used for analyzing the diagnostic accuracy of RSBI, DE-RSBI, and DTF-RSBI. RESULTS: Of the 110 patients studied, 37 patients (33.6%) failed weaning. The area under the ROC (AUROC) curves for RSBI, DE-RSBI, and DTF-RSBI for predicting failed weaning were 0.639, 0.813, and 0.859, respectively. The AUROC curves for DE-RSBI and DTF-RSBI were significantly higher than for RSBI (P = 0.004 and P < 0.001, respectively). The best cut-off values for predicting failed weaning were RSBI > 51.2 breaths/min/L, DE-RSBI > 1.38 breaths/min/mm, and DTF-RSBI > 78.1 breaths/min/%. CONCLUSIONS: In this study, two weaning indices determined by bedside ultrasonography, the DE-RSBI (RR/DE) and DTF-RSBI (RR/DTF), were shown to be more accurate than the traditional RSBI (RR/VT) in predicting weaning outcome during a PSV SBT.

Lower Leg Muscle Stiffness on Two-Dimensional Shear Wave Elastography in Subjects With Medial Tibial Stress Syndrome.

OBJECTIVES: We aimed to explore, which muscle stiffness changes may be related to medial tibial stress syndrome (MTSS) and the correlation between the medial tibial periosteal thickness and lower leg muscle stiffness. METHODS: This study included 63 subjects distributed into 3 groups: the symptomless group, the MTSS group, and the control group. The lower leg muscle stiffness of the tibialis anterior (TA), extensor digitorum longus (EDL), peroneus longus (PL), soleus (SOL), lateral gastrocnemius (LG), medial gastrocnemius (MG), tibialis posterior (TP), and flexor digitorum longus (FDL) in the 3 groups was obtained by two-dimensional shear wave elastography. Differences in the muscle stiffness and medial tibial periosteal thickness in the 3 groups were determined by one-way analysis of variance (ANOVA) and least significant difference tests. The relationships between the periosteal thickness and the muscle stiffness were assessed using Pearson correlations. RESULTS: The shear wave velocity (SWV) of all lower leg muscles except the EDL was higher in the symptomless and MTSS groups than in the control group (TA, P = .001; PL, P = .006; SOL, P < .001; LG, P < .001; MG, P < .001; TP, P < .001; FDL, P = .013; and ANOVA). A significant difference was found in the SWV of the SOL, TP, and FDL between the control and symptomless groups (P = .041, P < .001, and P = .013, respectively). Moreover, the medial tibial periosteum was thickened after running training, and its thickness was positively correlated with muscle stiffness. CONCLUSION: The medial tibia periosteal thickness is positively correlated with the lower leg muscles stiffness. Changes in SOL, TP, and FDL stiffness may be related to the occurrence of MTSS.

Sampling-based estimation for massive survival data with additive hazards model.

For massive survival data, we propose a subsampling algorithm to efficiently approximate the estimates of regression parameters in the additive hazards model. We establish consistency and asymptotic normality of the subsample-based estimator given the full data. The optimal subsampling probabilities are obtained via minimizing asymptotic variance of the resulting estimator. The subsample-based procedure can largely reduce the computational cost compared with the full data method. In numerical simulations, our method has low bias and satisfactory coverage probabilities. We provide an illustrative example on the survival analysis of patients with lymphoma cancer from the Surveillance, Epidemiology, and End Results Program.

Mediation effect selection in high-dimensional and compositional microbiome data.

The microbiome plays an important role in human health by mediating the path from environmental exposures to health outcomes. The relative abundances of the high-dimensional microbiome data have an unit-sum restriction, rendering standard statistical methods in the Euclidean space invalid. To address this problem, we use the isometric log-ratio transformations of the relative abundances as the mediator variables. To select significant mediators, we consider a closed testing-based selection procedure with desirable confidence. Simulations are provided to verify the effectiveness of our method. As an illustrative example, we apply the proposed method to study the mediation effects of murine gut microbiome between subtherapeutic antibiotic treatment and body weight gain, and identify Coprobacillus and Adlercreutzia as two significant mediators.

Clinical and radiological predictors of epidermal growth factor receptor mutation in nonsmall cell lung cancer.

PURPOSE: To determine the prognostic factors of epidermal growth factor receptor (EGFR) mutation status in a group of patients with nonsmall cell lung cancer (NSCLC) by analyzing their clinical and radiological features. MATERIALS AND METHODS: Patients with NSCLC who underwent EGFR mutation detection between 2014 and 2017 were included. Clinical features and general imaging features were collected, and radiomic features were extracted from CT data by 3D Slicer software. Prognostic factors of EGFR mutation status were selected by least absolute shrinkage and selection operator (LASSO) logistic regression analysis, and receiver operating characteristic (ROC) curves were drawn for each prediction model of EGFR mutation. RESULTS: A total of 118 patients were enrolled in this study. The smoking index (P = 0.028), pleural retraction (P = 0.041), and three radiomic features were significantly associated with EGFR mutation status. The areas under the ROC curve (AUCs) for prediction models of clinical features, general imaging features, and radiomic features were 0.284, 0.703, and 0.815, respectively, and the AUC for the combined prediction model of the three models was 0.894. Finally, a nomogram was established for individualized EGFR mutation prediction. CONCLUSIONS: The combination of radiomic features with clinical features and general imaging features can enable discrimination of EGFR mutation status better than the use of any group of features alone. Our study may help develop a noninvasive biomarker to identify EGFR mutation status by using a combination of the three group features.

Regularized estimation in sparse high-dimensional multivariate regression, with application to a DNA methylation study.

In this article, we consider variable selection for correlated high dimensional DNA methylation markers as multivariate outcomes. A novel weighted square-root LASSO procedure is proposed to estimate the regression coefficient matrix. A key feature of this method is tuning-insensitivity, which greatly simplifies the computation by obviating cross validation for penalty parameter selection. A precision matrix obtained via the constrained ℓ1 minimization method is used to account for the within-subject correlation among multivariate outcomes. Oracle inequalities of the regularized estimators are derived. The performance of our proposed method is illustrated via extensive simulation studies. We apply our method to study the relation between smoking and high dimensional DNA methylation markers in the Normative Aging Study (NAS).

Ultra-high dimensional variable selection with application to normative aging study: DNA methylation and metabolic syndrome.

BACKGROUND: Metabolic syndrome has become a major public health challenge worldwide. The association between metabolic syndrome and DNA methylation is of great research interest. RESULTS: We constructed a binomial model to investigate the association between a metabolic syndrome index and DNA methylation in the Normative Aging Study. We applied the Iterative Sure Independence Screening (ISIS) method with elastic net penalty to DNA methylation levels at 484,548 CpG markers from 659 human subjects, and demonstrated that the screening step in ISIS can significantly improve the performance of the elastic net. CONCLUSION: The proposed method identifies four CpGs which can be mapped to two biologically relevant and functional genes. Identification of significant CpG markers may potentially have practical implications for disease prevention and treatment.

Estimating and testing high-dimensional mediation effects in epigenetic studies.

MOTIVATION: High-dimensional DNA methylation markers may mediate pathways linking environmental exposures with health outcomes. However, there is a lack of analytical methods to identify significant mediators for high-dimensional mediation analysis. RESULTS: Based on sure independent screening and minimax concave penalty techniques, we use a joint significance test for mediation effect. We demonstrate its practical performance using Monte Carlo simulation studies and apply this method to investigate the extent to which DNA methylation markers mediate the causal pathway from smoking to reduced lung function in the Normative Aging Study. We identify 2 CpGs with significant mediation effects. AVAILABILITY AND IMPLEMENTATION: R package, source code, and simulation study are available at https://github.com/YinanZheng/HIMA CONTACT: lei.liu@northwestern.edu.

Persistent hyperlactatemia-high central venous-arterial carbon dioxide to arterial-venous oxygen content ratio is associated with poor outcomes in early resuscitation of septic shock.

OBJECTIVE: Several studies reported Pv-aCO2/Ca-vO2 ratio as a surrogate of VCO2/VO2 to detect global tissue hypoxia. The present study aimed to evaluate the prognostic value of Pv-aCO2/Ca-vO2 ratio combined with lactate levels during the early phases of resuscitation in septic shock. METHODS: A retrospective study was conducted in 144 septic shock patients in a 30-bed mixed ICU. A Pv-aCO2/Ca-vO2 ratio>1.4 was considered abnormal. Patients were classified into four predefined groups according to lactate levels and Pv-aCO2/Ca-vO2 ratio after the first 6h of resuscitation. Sequential Organ Failure Assessment (SOFA) score at day 3 was assessed. A Kaplan-Meier curve showed the survival probabilities at day 28 using a log-rank test to evaluate the differences between groups. A receiver operating characteristics (ROC) curve evaluated the ability of lactate, Pv-aCO2/Ca-vO2 ratio and Pv-aCO2/Ca-vO2 ratio combined with lactate to predict mortality at day 28. RESULTS: Combination of hyperlactatemia and high Pv-aCO2/Ca-vO2 ratio was associated with poor SOFA scores and low survival rates at day 28 (P<0.001). The Cox multivariate survival analysis demonstrated that Pv-aCO2/Ca-vO2 ratio and lactate at T6 were independent predictors of mortality at day 28. The area under the ROC curve of the Pv-aCO2/Ca-vO2 ratio combined with lactate for predicting mortality at day 28 was highest and superior to that of lactate and Pv-aCO2/Ca-vO2 ratios. CONCLUSION: Combination of Pv-aCO2/Ca-vO2 ratio and lactate at early stages of resuscitation of septic shock can better predict the prognosis of patients. The Pv-aCO2/Ca-vO2 ratio may become a useful parameter supplementary to lactate in the resuscitation of septic shock.