More Like this

1. GSMA: an approach to identify robust global and test Gene Signatures using Meta-Analysis

   https://doi.org/10.1093/bioinformatics/btz561  

   Shafi, Adib ; Nguyen, Tin ; Peyvandipour, Azam ; Draghici, Sorin ; Kelso, ed., Janet ( July 2019 , Bioinformatics)

   Recent advances in biomedical research have made massive amount of transcriptomic data available in public repositories from different sources. Due to the heterogeneity present in the individual experiments, identifying reproducible biomarkers for a given disease from multiple independent studies has become a major challenge. The widely used meta-analysis approaches, such as Fisher’s method, Stouffer’s method, minP and maxP, have at least two major limitations: (i) they are sensitive to outliers, and (ii) they perform only one statistical test for each individual study, and hence do not fully utilize the potential sample size to gain statistical power.

   Here, we propose a gene-level meta-analysis framework that overcomes these limitations and identifies a gene signature that is reliable and reproducible across multiple independent studies of a given disease. The approach provides a comprehensive global signature that can be used to understand the underlying biological phenomena, and a smaller test signature that can be used to classify future samples of a given disease. We demonstrate the utility of the framework by constructing disease signatures for influenza and Alzheimer’s disease using nine datasets including 1108 individuals. These signatures are then validated on 12 independent datasets including 912 individuals. The results indicate that the proposed approach performs better than the majority of the existing meta-analysis approaches in terms of both sensitivity as well as specificity. The proposed signatures could be further used in diagnosis, prognosis and identification of therapeutic targets.

   Supplementary data are available at Bioinformatics online.

    

   more » « less
2. Multiscale topology in interactomic network: from transcriptome to antiaddiction drug repurposing

   https://doi.org/10.1093/bib/bbae054  

   Du, Hongyan ; Wei, Guo-Wei ; Hou, Tingjun ( March 2024 , Briefings in Bioinformatics)

   The escalating drug addiction crisis in the United States underscores the urgent need for innovative therapeutic strategies. This study embarked on an innovative and rigorous strategy to unearth potential drug repurposing candidates for opioid and cocaine addiction treatment, bridging the gap between transcriptomic data analysis and drug discovery. We initiated our approach by conducting differential gene expression analysis on addiction-related transcriptomic data to identify key genes. We propose a novel topological differentiation to identify key genes from a protein–protein interaction network derived from DEGs. This method utilizes persistent Laplacians to accurately single out pivotal nodes within the network, conducting this analysis in a multiscale manner to ensure high reliability. Through rigorous literature validation, pathway analysis and data-availability scrutiny, we identified three pivotal molecular targets, mTOR, mGluR5 and NMDAR, for drug repurposing from DrugBank. We crafted machine learning models employing two natural language processing (NLP)-based embeddings and a traditional 2D fingerprint, which demonstrated robust predictive ability in gauging binding affinities of DrugBank compounds to selected targets. Furthermore, we elucidated the interactions of promising drugs with the targets and evaluated their drug-likeness. This study delineates a multi-faceted and comprehensive analytical framework, amalgamating bioinformatics, topological data analysis and machine learning, for drug repurposing in addiction treatment, setting the stage for subsequent experimental validation. The versatility of the methods we developed allows for applications across a range of diseases and transcriptomic datasets.

    

   more » « less
3. Causal network models of SARS-CoV-2 expression and aging to identify candidates for drug repurposing

   https://doi.org/10.1038/s41467-021-21056-z  

   Belyaeva, Anastasiya ; Cammarata, Louis ; Radhakrishnan, Adityanarayanan ; Squires, Chandler ; Yang, Karren Dai ; Shivashankar, G. V. ; Uhler, Caroline ( February 2021 , Nature Communications)

   Given the severity of the SARS-CoV-2 pandemic, a major challenge is to rapidly repurpose existing approved drugs for clinical interventions. While a number of data-driven and experimental approaches have been suggested in the context of drug repurposing, a platform that systematically integrates available transcriptomic, proteomic and structural data is missing. More importantly, given that SARS-CoV-2 pathogenicity is highly age-dependent, it is critical to integrate aging signatures into drug discovery platforms. We here take advantage of large-scale transcriptional drug screens combined with RNA-seq data of the lung epithelium with SARS-CoV-2 infection as well as the aging lung. To identify robust druggable protein targets, we propose a principled causal framework that makes use of multiple data modalities. Our analysis highlights the importance of serine/threonine and tyrosine kinases as potential targets that intersect the SARS-CoV-2 and aging pathways. By integrating transcriptomic, proteomic and structural data that is available for many diseases, our drug discovery platform is broadly applicable. Rigorous in vitro experiments as well as clinical trials are needed to validate the identified candidate drugs.

    

   more » « less
4. Cystic fibrosis transmembrane conductance regulator function, not TAS2R38 gene haplotypes, predict sinus surgery in children and young adults with cystic fibrosis

   https://doi.org/10.1002/alr.22548  

   Dalesio, Nicholas M. ; Aksit, Melis A. ; Ahn, Kwangmi ; Raraigh, Karen S. ; Collaco, Joseph M. ; McGrath‐Morrow, Sharon ; Zeitlin, Pamela L. ; An, Steven S. ; Cutting, Garry R. ( April 2020 , International Forum of Allergy & Rhinology)

   Chronic rhinosinusitis symptomatology begins in early childhood individuals with cystic fibrosis (CF). Cystic fibrosis transmembrane conductance regulator (CFTR) function contributes to sinus development and disease. Genetic variants of the bitter taste receptorTAS2R38have been suggested to contribute to sinus disease severity in individuals without CF. Our objective was to explore whether functionalTAS2R38haplotypes and CFTR function are associated with sinus disease or the need for sinus surgery in individuals with CF.

   We conducted a retrospective study using prospectively collected data from the CF Twin‐Sibling Study. The function of CFTR was assessed via chloride conductance. Genotyping of theTAS2R38gene identified patients who were homozygous for the functional haplotype, heterozygous, or homozygous for nonfunctional haplotypes. Clustered multivariate logistic regression was performed, controlling for sex and family relationship.

   A total of 1291 patients were evaluated. Patients with ≤1% CFTR function were 1.56 times more likely to require sinus surgery than those with >1% CFTR function (p= 0.049). CFTR function did not correlate significantly with the presence of sinus disease (p= 0.30). In addition, there were no statistically significant differences in diagnosis of sinus disease or need for sinus surgery between patients with functional and nonfunctionalTAS2R38haplotypes.

   CFTR function correlates with need for sinus surgery, whereasTAS2R38function does not appear to contribute to sinus disease or the need for sinus surgery in patients with CF.

    

   more » « less
5. Risk factors for neo‐osteogenesis in cystic fibrosis and non‒cystic fibrosis chronic rhinosinusitis

   https://doi.org/10.1002/alr.22507  

   Karempelis, Peter ; Karp, Emily ; Rubin, Nathan ; Hunter, Ryan ; Dunitz, Jordan ; Boyer, Holly ( December 2019 , International Forum of Allergy & Rhinology)

   The purpose of this retrospective review was to determine how patient‐related factors and culture data affect neo‐osteogenesis in patients with chronic rhinosinusitis (CRS) and patients with cystic fibrosis (CF) with CRS.

   Information from a database associated with a large tertiary medical center was used to assess adult patients with CF CRS and non‐CF CRS (total, n = 102; CF CRS, n = 31; non‐CF CRS, n = 71). Radiologic evidence of neo‐osteogenesis was measured using the Global Osteitis Scoring Scale (GOSS), and mucosal disease was assessed using the Lund‐Mackay score (LMS) by 2 independent reviewers who were blinded to the patient's disease state. Bacterial cultures were obtained endoscopically. Multiple logistic regression models were used to evaluate the effect of age, sex, number of previous surgeries, CF, and culture species on the odds of neo‐osteogenesis.

   Fifty‐one of the 102 patients (50%) met radiologic criteria for neo‐osteogenesis. Sixty‐nine patients (67.6%) with CF CRS and non‐CF CRS had culture data. In the multiple logistic regression model, male gender was significantly associated with neo‐osteogenesis (odds ratio [OR], 5.2; 95% confidence interval [CI], 1.68‐17.86;p= 0.006).Pseudomonas aeruginosawas not associated with neo‐osteogenesis (OR, 3.12; 95% CI, 0.84‐12.80;p= 0.097). Age, number of surgeries, CF,Staphylococcus aureus, and coagulase‐negativeStaphylococcuswere not statistically significant.

   To our knowledge, this is the first study to assess risk factors associated with neo‐osteogenesis and patients with CF CRS. Interestingly, male gender was the only significant predictor of neo‐osteogenesis.

    

   more » « less