RNA sequencing and machine learning applied to develop new asthma biomarker
“Mild to moderate asthma can be difficult to diagnose because symptoms change over time and can be complicated by other respiratory conditions,” said Supinda Bunyavanich, MD, physician and researcher at the Icahn School of Medicine. “Our nasal brush test takes seconds to collect. For time-strapped clinicians, particularly primary care providers at the front lines of asthma diagnosis, this could greatly improve patient outcomes through early and accurate diagnosis.”
Currently, pulmonary function testing (PFT) is the most reliable diagnostic tool for asthma. However, the equipment and expertise needed to perform these tests are not always available in primary care settings where asthma is frequently diagnosed and treated. It is also difficult to differentiate between asthma and other respiratory diseases using PFT alone, while the nasal brush and subsequent analysis for this asthma biomarker provides a binary result of asthma or not asthma.
Data scientists leading the study applied machine learning algorithms to the genetic (RNA) data acquired from nasal brushes of patients with and without asthma. This robust data collection, and machine learning analysis, identified a 90-gene biomarker indicative of asthma status. “One of the most exciting components of this study is demonstrating the power of machine learning when applied to biomedical data,” said Gaurav Pandey, PhD, who led data science efforts to develop the biomarker. “Collaborations between computational scientists and biomedical researchers and clinicians are advancing medicine at an inspiring pace. We have the power of many insights we didn’t have in the past, and that opens a window to an entirely new world of diagnostic tools and treatments”
Similar genetic biomarker tests are currently being used in other disease areas, including MammaPrint and Oncotype DX®, both used for certain types of breast cancer prognosis. In fact, the Oncotype DX tool was used in the largest clinical trial of personalized breast cancer prognosis ever conducted, demonstrating that mammography testing is unnecessary to diagnose breast cancer in a large fraction of breast cancer patients. The positive clinical impact that biomarker tests such as this have shown indicates great potential for further diagnostic tools based on biomarkers.
Dr. Bunyavanich says the next step to bringing this test into clinical practice is a study in a larger population of patients. “With prospective validation in large cohorts, our asthma biomarker could lead to the development of a minimally invasive test to aid asthma diagnosis at clinical frontlines where time and resources often preclude pulmonary function testing.”
Asthma affects 10 percent of children and adults in the United States. When undiagnosed, it can lead to restricted activity, emergency room visits, and hospitalizations. “We’re hopeful that further studies can help bring this test into primary care settings, transforming the ease and accuracy of diagnosing asthma and our ability as doctors to appropriately treat our patients,” said Dr. Bunyavanich.
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is an international leader in medical and scientific training, biomedical research, and patient care. It is the medical school for the Mount Sinai Health System, which includes seven hospital campuses, and has more than 5,000 faculty and nearly 2,000 students, residents and fellows. The School is made up of 36 multidisciplinary research, educational, and clinical institutes and 33 academic departments. It ranks 13th among U.S. medical schools for NIH funding and 2nd in research dollars per principal investigator among U.S. medical schools by the Association of American Medical Colleges (AAMC). The School was named 4th among "World's Most Innovative Companies in Data Science" by Fast Company magazine in 2016. For more information, visit http://icahn.mssm.edu
Elsevier and the editors of the official journals of the American Academy of Allergy, Asthma & Immunology (AAAAI) would like to make these recent Asthma research articles available free through July 10th, 2018.
The Journal of Allergy and Clinical Immunology
Featuring a 13.081 Impact Factor
Inflammatory Phenotypes in Patients with Severe Asthma are Associated with Distinct Airway Microbiology
Toll-like Receptor 3 Blockade in Rhinovirus-induced Experimental Asthma Exacerbations: A Randomized Controlled Study
Overweight/obesity Status in Preschool Children Associates with Worse Asthma But Robust Improvement on Inhaled Corticosteroids
Managing Asthma in Pregnancy (MAP) Trial: FeNO Levels and Childhood Asthma
The Journal of Allergy and Clinical Immunology: In Practice
Featuring a 5.317 Impact Factor
Taming Asthma in School-Aged Children: A Comprehensive Review
The Tempest: Difficult To Control Asthma in Adolescence
Asthma over the age of 65: All's Well That Ends Well
Effects of exercise and diet in non-obese asthma patients - a randomized controlled trial
The fractional exhaled nitric oxide (FeNO) and blood eosinophils are biomarkers of eosinophilic airway inflammation used in the diagnosis and management of asthma, although induced sputum is the gold standard test for phenotypic asthma. Nevertheless, the clinical application of the correlation between sputum eosinophils, FeNO and blood eosinophils is controversial.
To investigate the clinical application of the correlation between sputum eosinophils, FeNO and blood eosinophils with uncontrolled asthmatic patients. It also examined the relationships between these biomarkers in bronchial reversibility and bronchial hyper-responsiveness (BHR).
This study evaluated 75 uncontrolled asthmatic patients (symptom control and future risk of adverse outcomes). All patients underwent the following on the same day: FeNO, spirometry, BHR or bronchodilator reversibility, sputum induction and blood collection. Eosinophilic airway inflammation was defined as sputum eosinophils ≥ 2.5% or FeNO levels ≥ 32 parts per billion (ppb).
A significant positive relationship was between percentage of sputum eosinophils and FeNO (r = 0.4556; p < 0.0001) and percentage of blood eosinophils (r = 0.3647; p = 0.0013), and a significant negative correlation was between percentage of sputum neutrophils and FeNO (r = − 0.3653; p = 0.0013). No relationship between FeNO and percentage of blood eosinophils (p = 0.5801). ROC curve analysis identified FeNO was predictive of sputum eosinophilia [area under the curve (AUC) 0.707, p = 0.004] at a cutoff point of 35.5 ppb (sensitivity = 67.3%, specificity = 73.9%). Percentage of blood eosinophils was also highly predictive with an AUC of 0.73 (p = 0.002) at a cut-off point of 1.5%, sensitivity and specificity were 61.5 and 78.3%, respectively. Although the sputum neutrophil percentage was correlated with FeNO, ROC curve of these parameters did not show useful values (AUC = 0.297, p = 0.003; AUC = 0.295, p = 0.021).
Conclusions and clinical relevance
Blood eosinophils and FeNO can accurately predict eosinophilic airway inflammation in uncontrolled asthmatic patients. FeNO is poor surrogates for sputum neutrophils and blood eosinophils. The FeNO level and blood eosinophils, which determine an optimal cutoff for sputum eosinophilia, need more studies.
Outdoor air pollution is a major threat to global public health that needs responsible participation of researchers at all levels. Assessing research output is an important step in highlighting national and international contribution and collaboration in a certain field. Therefore, the aim of this study was to analyze globally-published literature in outdoor air pollution – related respiratory health.
Outdoor air pollution documents related to respiratory health were retrieved from Scopus database. The study period was up to 2017. Mapping of author keywords was carried out using VOSviewer 1.6.6.
Search query yielded 3635 documents with an h-index of 137. There was a dramatic increase in the number of publications in the last decade of the study period. The most frequently encountered author keywords were: air pollution (835 occurrences), asthma (502 occurrences), particulate matter (198 occurrences), and children (203 occurrences). The United States of America ranked first (1082; 29.8%) followed by the United Kingdom (279; 7.7%) and Italy (198; 5.4%). Annual research productivity stratified by income and population size indicated that China ranked first (22.2) followed by the USA (18.8). Analysis of regional distribution of publications indicated that the Mediterranean, African, and South-East Asia regions had the least contribution. Harvard University (92; 2.5%) was the most active institution/organization followed the US Environmental Protection Agency (89; 2.4%). International collaboration was restricted to three regions: Northern America, Europe, and Asia. The top ten preferred journals were in the field of environmental health and respiratory health. Environmental Health Perspective was the most preferred journal for publishing documents in outdoor pollution in relation to respiratory health.
Research on the impact of outdoor air pollution on respiratory health had accelerated lately and is receiving a lot of interest. Global research networks that include countries with high level of pollution and limited resources are highly needed to create public opinion in favor of minimizing outdoor air pollution and investing in green technologies.
Mario Castro, M.D., Jonathan Corren, M.D., Ian D. Pavord, M.D., Jorge Maspero, M.D., Sally Wenzel, M.D., Klaus F. Rabe, M.D., William W. Busse, M.D., Linda Ford, M.D., Lawrence Sher, M.D., J. Mark FitzGerald, M.D., Constance Katelaris, M.D., Yuji Tohda, M.D., et al.
Dupilumab is a fully human anti–interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. We assessed its efficacy and safety in patients with uncontrolled asthma.
We randomly assigned 1902 patients 12 years of age or older with uncontrolled asthma in a 2:2:1:1 ratio to receive add-on subcutaneous dupilumab at a dose of 200 or 300 mg every 2 weeks or matched-volume placebos for 52 weeks. The primary end points were the annualized rate of severe asthma exacerbations and the absolute change from baseline to week 12 in the forced expiratory volume in 1 second (FEV1) before bronchodilator use in the overall trial population. Secondary end points included the exacerbation rate and FEV1 in patients with a blood eosinophil count of 300 or more per cubic millimeter. Asthma control and dupilumab safety were also assessed.
The annualized rate of severe asthma exacerbations was 0.46 (95% confidence interval [CI], 0.39 to 0.53) among patients assigned to 200 mg of dupilumab every 2 weeks and 0.87 (95% CI, 0.72 to 1.05) among those assigned to a matched placebo, for a 47.7% lower rate with dupilumab than with placebo (P<0.001); similar results were seen with the dupilumab dose of 300 mg every 2 weeks. At week 12, the FEV1 had increased by 0.32 liters in patients assigned to the lower dose of dupilumab (difference vs. matched placebo, 0.14 liters; P<0.001); similar results were seen with the higher dose. Among patients with a blood eosinophil count of 300 or more per cubic millimeter, the annualized rate of severe asthma exacerbations was 0.37 (95% CI, 0.29 to 0.48) among those receiving lower-dose dupilumab and 1.08 (95% CI, 0.85 to 1.38) among those receiving a matched placebo (65.8% lower rate with dupilumab than with placebo; 95% CI, 52.0 to 75.6); similar results were observed with the higher dose. Blood eosinophilia occurred after the start of the intervention in 52 patients (4.1%) who received dupilumab as compared with 4 patients (0.6%) who received placebo.
In this trial, patients who received dupilumab had significantly lower rates of severe asthma exacerbation than those who received placebo, as well as better lung function and asthma control. Greater benefits were seen in patients with higher baseline levels of eosinophils. Hypereosinophilia was observed in some patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA QUEST ClinicalTrials.gov number, NCT02414854.)
- Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma
- Clinical and Economic Impact of a One-Year Treatment With Omalizumab in Patients With Severe Allergic Asthma Within a Drug Programme in Poland
- Nerve ablation after bronchial thermoplasty and sustained improvement in severe asthma
- Prevalence of asthma among the adult general population of five Middle Eastern countries: results of the SNAPSHOT program