Bayesian inference of sample-specific coexpression networks.

Gene regulatory networks (GRNs) are effective tools for inferring complex interactions between molecules that regulate biological processes and hence can provide insights into drivers of biological systems. Inferring coexpression networks is a critical element of GRN inference, as the correlation between expression patterns may indicate that genes are coregulated by common factors. However, methods that estimate coexpression networks generally derive an aggregate network representing the mean regulatory properties of the population and so fail to fully capture population heterogeneity. Bayesian optimized networks obtained by assimilating omic data (BONOBO) is a scalable Bayesian model for deriving individual sample-specific coexpression matrices that recognizes variations in molecular interactions across individuals. For each sample, BONOBO assumes a Gaussian distribution on the log-transformed centered gene expression and a conjugate prior distribution on the sample-specific coexpression matrix constructed from all other samples in the data. Combining the sample-specific gene coexpression with the prior distribution, BONOBO yields a closed-form solution for the posterior distribution of the sample-specific coexpression matrices, thus allowing the analysis of large data sets. We demonstrate BONOBO's utility in several contexts, including analyzing gene regulation in yeast transcription factor knockout studies, the prognostic significance of miRNA-mRNA interaction in human breast cancer subtypes, and sex differences in gene regulation within human thyroid tissue. We find that BONOBO outperforms other methods that have been used for sample-specific coexpression network inference and provides insight into individual differences in the drivers of biological processes.

Sex-biased Regulation of Extracellular Matrix Genes in COPD.

Compared to men, women often develop COPD at an earlier age with worse respiratory symptoms despite lower smoking exposure. However, most preventive, and therapeutic strategies ignore biological sex differences in COPD. Our goal was to better understand sex-specific gene regulatory processes in lung tissue and the molecular basis for sex differences in COPD onset and severity. We analyzed lung tissue gene expression and DNA methylation data from 747 individuals in the Lung Tissue Research Consortium (LTRC), and 85 individuals in an independent dataset. We identified sex differences in COPD-associated gene regulation using gene regulatory networks. We used linear regression to test for sex-biased associations of methylation with lung function, emphysema, smoking, and age. Analyzing gene regulatory networks in the control group, we identified that genes involved in the extracellular matrix (ECM) have higher transcriptional factor targeting in females than in males. However, this pattern is reversed in COPD, with males showing stronger regulatory targeting of ECM-related genes than females. Smoking exposure, age, lung function, and emphysema were all associated with sex-specific differential methylation of ECM-related genes. We identified sex-based gene regulatory patterns of ECM-related genes associated with lung function and emphysema. Multiple factors including epigenetics, smoking, aging, and cell heterogeneity influence sex-specific gene regulation in COPD. Our findings underscore the importance of considering sex as a key factor in disease susceptibility and severity.

Impact of the COVID-19 induced lockdown measures on P M 2.5 concentration in USA.

In 2020, most countries around the world have observed varying degrees of public lockdown measures to mitigate the transmission of SARS-CoV-2. As an unintended consequence of reduced transportation and industrial activities, air quality has dramatically improved in many major cities around the world. In this paper, we analyze the environmental impact of the lockdown measures on P M 2.5 concentration levels in 48 core-based statistical areas (CBSA) of the United States, during the pre and post-lockdown period of January to June 2020. We model the effect of lockdown on the P M 2.5 concentration in different CBSAs while adjusting for various meteorological factors like temperature, wind-speed, precipitation and snow. Linear mixed effects models and functional regression methods with random intercepts are employed to capture the heterogeneity of the effect across different regions. Our analysis shows there is a statistically significant reduction in levels of P M 2.5 across most of the regions during the lock-down period, although interestingly, this effect is not uniform across all the CBSAs under consideration.

Management of Chylothorax After Coronary Artery Bypass Grafting: Two Case Reports and Review of Literature.

Chylothorax following coronary artery bypass graft (CABG) surgery is a very rare complication and its management is debatable. Opinions vary from early aggressive management to prolonged conservative treatment. We describe two cases of post-operative chylothorax following CABG and its management with intravenous octreotide.

Exploring the Association between Daily Distributional Patterns of Physical Activity and Cardiovascular Mortality Risk among Older Adults in NHANES 2003-2006.

PURPOSE: Cardiovascular disease (CVD) is one of the leading causes of death worldwide. Physical activity (PA) has previously been shown to be a prominent risk factor for CVD mortality. Traditionally, measurements of PA have been self-reported and based on various summary metrics. However, recent advances in wearable technology provide continuously monitored and objectively measured physical activity data. This facilitates a more comprehensive interpretation of the implications of PA in the context of CVD mortality by considering its daily patterns and compositions. METHODS: This study utilized accelerometer data from the 2003-2006 National Health and Nutrition Examination Survey (NHANES) on 2,816 older adults aged 50-85 and mortality data from the National Death Index (NDI) in December 2019. A novel partially functional distributional analysis method was used to quantify and understand the association between daily distributional patterns of physical activity and cardiovascular mortality risk through a multivariable functional Cox model. RESULTS: A higher mean intensity of daily PA during the day was associated with a reduced hazard of CVD mortality after adjusting for other higher order distributional summaries of PA and age, gender, race, body mass index (BMI), smoking and coronary heart disease (CHD). A higher daily variability of PA during afternoon was associated with a reduced hazard of CVD mortality, after adjusting for the other predictors, particularly on weekdays. The subjects with a lower variability of PA, despite having same mean PA throughout the day, could have a lower reserve of PA and hence could be at increased risk for CVD mortality. CONCLUSIONS: Our results demonstrate that not only the mean intensity of daily PA during daytime, but also the variability of PA during afternoon could be an important protective factor against the risk of CVD-mortality. Considering circadian rhythm of PA as well as its daily compositions can be useful for designing time-of-day and intensity-specific PA interventions to protect against the risk of CVD mortality.

node2vec2rank: Large Scale and Stable Graph Differential Analysis via Multi-Layer Node Embeddings and Ranking.

Computational methods in biology can infer large molecular interaction networks from multiple data sources and at different resolutions, creating unprecedented opportunities to explore the mechanisms driving complex biological phenomena. Networks can be built to represent distinct conditions and compared to uncover graph-level differences-such as when comparing patterns of gene-gene interactions that change between biological states. Given the importance of the graph comparison problem, there is a clear and growing need for robust and scalable methods that can identify meaningful differences. We introduce node2vec2rank (n2v2r), a method for graph differential analysis that ranks nodes according to the disparities of their representations in joint latent embedding spaces. Improving upon previous bag-of-features approaches, we take advantage of recent advances in machine learning and statistics to compare graphs in higher-order structures and in a data-driven manner. Formulated as a multi-layer spectral embedding algorithm, n2v2r is computationally efficient, incorporates stability as a key feature, and can provably identify the correct ranking of differences between graphs in an overall procedure that adheres to veridical data science principles. By better adapting to the data, node2vec2rank clearly outperformed the commonly used node degree in finding complex differences in simulated data. In the real-world applications of breast cancer subtype characterization, analysis of cell cycle in single-cell data, and searching for sex differences in lung adenocarcinoma, node2vec2rank found meaningful biological differences enabling the hypothesis generation for therapeutic candidates. Software and analysis pipelines implementing n2v2r and used for the analyses presented here are publicly available.

Aging-associated Alterations in the Gene Regulatory Network Landscape Associate with Risk, Prognosis and Response to Therapy in Lung Adenocarcinoma.

Aging is the primary risk factor for many individual cancer types, including lung adenocarcinoma (LUAD). To understand how aging-related alterations in the regulation of key cellular processes might affect LUAD risk and survival outcomes, we built individual (person)-specific gene regulatory networks integrating gene expression, transcription factor protein-protein interaction, and sequence motif data, using PANDA/LIONESS algorithms, for both non-cancerous lung tissue samples from the Genotype Tissue Expression (GTEx) project and LUAD samples from The Cancer Genome Atlas (TCGA). In GTEx, we found that pathways involved in cell proliferation and immune response are increasingly targeted by regulatory transcription factors with age; these aging-associated alterations are accelerated by tobacco smoking and resemble oncogenic shifts in the regulatory landscape observed in LUAD and suggests that dysregulation of aging pathways might be associated with an increased risk of LUAD. Comparing normal adjacent samples from individuals with LUAD with healthy lung tissue samples from those without LUAD, we found that aging-associated genes show greater aging-biased targeting patterns in younger individuals with LUAD compared to their healthy counterparts of similar age, a pattern suggestive of age acceleration. This implies that an accelerated aging process may be responsible for tumor incidence in younger individuals. Using drug repurposing tool CLUEreg, we found small molecule drugs with potential geroprotective effects that may alter the accelerating aging profiles we found. We also observed that, in contrast to chronological age, a network-informed aging signature was associated with survival and response to chemotherapy in LUAD.

Gene regulatory networks reveal sex difference in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) has been observed to have significant sex differences in incidence, prognosis, and response to therapy. However, the molecular mechanisms responsible for these disparities have not been investigated extensively. METHODS: Sample-specific gene regulatory network methods were used to analyze RNA sequencing data from non-cancerous human lung samples from The Genotype Tissue Expression Project (GTEx) and lung adenocarcinoma primary tumor samples from The Cancer Genome Atlas (TCGA); results were validated on independent data. RESULTS: We found that genes associated with key biological pathways including cell proliferation, immune response and drug metabolism are differentially regulated between males and females in both healthy lung tissue and tumor, and that these regulatory differences are further perturbed by tobacco smoking. We also discovered significant sex bias in transcription factor targeting patterns of clinically actionable oncogenes and tumor suppressor genes, including AKT2 and KRAS. Using differentially regulated genes between healthy and tumor samples in conjunction with a drug repurposing tool, we identified several small-molecule drugs that might have sex-biased efficacy as cancer therapeutics and further validated this observation using an independent cell line database. CONCLUSIONS: These findings underscore the importance of including sex as a biological variable and considering gene regulatory processes in developing strategies for disease prevention and management.

Lung adenocarcinoma (LUAD) is a disease that affects males and females differently. Biological sex not only influences chances of developing the disease, but also how the disease progresses and how effective various therapies may be. We analyzed sex-specific gene regulatory networks consisting of transcription factors and the genes they regulate in both healthy lung tissue and in LUAD and identified sex-biased differences. We found that genes associated with cell proliferation, immune response, and drug metabolism are differentially targeted by transcription factors between males and females. We also found that several genes that are drug targets in LUAD, are also regulated differently between males and females. Importantly, these differences are also influenced by an individual's smoking history. Extending our analysis using a drug repurposing tool, we found candidate drugs with evidence that they might work better for one sex or the other. These results demonstrate that considering the differences in gene regulation between males and females will be essential if we are to develop precision medicine strategies for preventing and treating LUAD.

Selective loss of Y chromosomes in lung adenocarcinoma modulates the tumor immune environment through cancer/testis antigens.

There is increasing recognition that the sex chromosomes, X and Y, play an important role in health and disease that goes beyond the determination of biological sex. Loss of the Y chromosome (LOY) in blood, which occurs naturally in aging men, has been found to be a driver of cardiac fibrosis and heart failure mortality. LOY also occurs in most solid tumors in males and is often associated with worse survival, suggesting that LOY may give tumor cells a growth or survival advantage. We analyzed LOY in lung adenocarcinoma (LUAD) using both bulk and single-cell expression data and found evidence suggesting that LOY affects the tumor immune environment by altering cancer/testis antigen expression and consequently facilitating tumor immune evasion. Analyzing immunotherapy data, we show that LOY and changes in expression of particular cancer/testis antigens are associated with response to pembrolizumab treatment and outcome, providing a new and powerful biomarker for predicting immunotherapy response in LUAD tumors in males.

Giant chondrosarcoma of chest wall.

Primary chest wall tumours are very rare. Chondrosarcoma is the most common tumour arising from the chest wall. We describe the occurrence of a slow-growing chondrosarcoma arising from the anterior chest wall in a 35-year-old male patient. The tumour was resected successfully and chest wall was reconstucted with prolene mesh and muscle flap. The patient was discharged uneventfully without any respiratory compromise. There was no recurrence after a three-year follow-up. Wide surgical resection with chest wall reconstruction appears to be the preferred treatment option for this rare tumour of the chest wall.

Gender difference in the effects of chronic diseases on daily physical activity patterns in older adults: analysis of objectively measured physical activity in NHATS 2021.

PURPOSE: Many chronic diseases have detrimental impact on the physical activity (PA) patterns of older adults. Often such diseases have different degrees of severity in males and females. Quantifying this gender difference would not only enhance our understanding of diseases but would also help design individual-specific PA interventions, thereby improving health outcomes for both genders. METHODS: PA data for 747 participants from round 11 (2021) of the National Health and Aging Trends Study were analyzed. Multilevel functional regression models were used to study gender difference in the effects of chronic diseases on daily PA patterns while adjusting for confounders. RESULTS: Females with dementia (or Alzheimer's disease), hypertension, heart and lung disease had lower PA at different times of day compared to females without these diseases, whereas males with and without these diseases had comparable daily PA. Males with diabetes had higher midnight PA and lower noon PA compared to males without diabetes, while females' PA with and without diabetes were similar. CONCLUSIONS: Our analysis demonstrates that although for most diseases, the daily PA patterns of individuals with the disease are negatively altered compared to healthy individuals, the extent of decline varies by gender and time of day. Designing personalized physical activity interventions considering gender and diurnal PA pattern can potentially improve quality of life across both genders.

Bayesian Optimized sample-specific Networks Obtained By Omics data (BONOBO).

Gene regulatory networks (GRNs) are effective tools for inferring complex interactions between molecules that regulate biological processes and hence can provide insights into drivers of biological systems. Inferring co-expression networks is a critical element of GRN inference as the correlation between expression patterns may indicate that genes are coregulated by common factors. However, methods that estimate co-expression networks generally derive an aggregate network representing the mean regulatory properties of the population and so fail to fully capture population heterogeneity. To address these concerns, we introduce BONOBO (Bayesian Optimized Networks Obtained By assimilating Omics data), a scalable Bayesian model for deriving individual sample-specific co-expression networks by recognizing variations in molecular interactions across individuals. For every sample, BONOBO assumes a Gaussian distribution on the log-transformed centered gene expression and a conjugate prior distribution on the sample-specific co-expression matrix constructed from all other samples in the data. Combining the sample-specific gene expression with the prior distribution, BONOBO yields a closed-form solution for the posterior distribution of the sample-specific co-expression matrices, thus making the method extremely scalable. We demonstrate the utility of BONOBO in several contexts, including analyzing gene regulation in yeast transcription factor knockout studies, prognostic significance of miRNA-mRNA interaction in human breast cancer subtypes, and sex differences in gene regulation within human thyroid tissue. We find that BONOBO outperforms other sample-specific co-expression network inference methods and provides insight into individual differences in the drivers of biological processes.

Gene regulatory Networks Reveal Sex Difference in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) has been observed to have significant sex differences in incidence, prognosis, and response to therapy. However, the molecular mechanisms responsible for these disparities have not been investigated extensively. Sample-specific gene regulatory network methods were used to analyze RNA sequencing data from non-cancerous human lung samples from The Genotype Tissue Expression Project (GTEx) and lung adenocarcinoma primary tumor samples from The Cancer Genome Atlas (TCGA); results were validated on independent data. We observe that genes associated with key biological pathways including cell proliferation, immune response and drug metabolism are differentially regulated between males and females in both healthy lung tissue, as well as in tumor, and that these regulatory differences are further perturbed by tobacco smoking. We also uncovered significant sex bias in transcription factor targeting patterns of clinically actionable oncogenes and tumor suppressor genes, including AKT2 and KRAS. Using differentially regulated genes between healthy and tumor samples in conjunction with a drug repurposing tool, we identified several small-molecule drugs that might have sex-biased efficacy as cancer therapeutics and further validated this observation using an independent cell line database. These findings underscore the importance of including sex as a biological variable and considering gene regulatory processes in developing strategies for disease prevention and management.

The Network Zoo: a multilingual package for the inference and analysis of gene regulatory networks.

Inference and analysis of gene regulatory networks (GRNs) require software that integrates multi-omic data from various sources. The Network Zoo (netZoo; netzoo.github.io) is a collection of open-source methods to infer GRNs, conduct differential network analyses, estimate community structure, and explore the transitions between biological states. The netZoo builds on our ongoing development of network methods, harmonizing the implementations in various computing languages and between methods to allow better integration of these tools into analytical pipelines. We demonstrate the utility using multi-omic data from the Cancer Cell Line Encyclopedia. We will continue to expand the netZoo to incorporate additional methods.