Dr. Rogers is an expert in Pulmonary and Critical Care Medicine. She has practiced in these fields for 10 years. She has a special interest in ICU medicine, with a research focus on acute respiratory failure and ARDS. She researchers in blood biomarkers of these diseases, and is very active in teaching residents and fellows about critical care.
- Critical Care
- Pulmonary Disease
Associate Director, Stanford Pulmonary and Critical Care Fellowship (2015 - Present)
Associate Program Director, Stanford Internal Medicine Residency (2015 - Present)
Boards, Advisory Committees, Professional Organizations
Planning Committee Chair, Allergy, Immunology, and Inflammation Assembly, American Thoracic Society, (2014 - Present)
Fellowship:Massachusetts General Hosp Harvard Med School (2009) MA
Board Certification: Critical Care Medicine, American Board of Internal Medicine (2007)
Board Certification: Pulmonary Disease, American Board of Internal Medicine (2006)
Residency:Brigham and Women's Hospital Harvard Medical School (2004) MA
Internship:Brigham and Women's Hospital Harvard Medical School (2002) MA
Medical Education:Harvard Medical School (2001) MA
Current Research and Scholarly Interests
We use genetics and genomics methodologies to identify novel ARDS pathobiology; we hope that this will enable identification of novel biomarkers, phenotypes, and treatments for the disease. We are building a plasma biobank of critically ill patients at Stanford, with a particular focus on metabolic changes in critical illness.
Human Mesenchymal Stromal Cells For Acute Respiratory Distress Syndrome (START)
This was a Phase 2a, randomized, double-blind, placebo-controlled, multi-center trial to assess the safety and efficacy of a single dose of Allogeneic Bone Marrow-derived Human Mesenchymal Stromal Cells (hMSCs) infusion in patients with Acute Respiratory Distress Syndrome (ARDS).
Reevaluation Of Systemic Early Neuromuscular Blockade
This study evaluates whether giving a neuromuscular blocker (skeletal muscle relaxant) to a patient with acute respiratory distress syndrome will improve survival. Half of the patients will receive a neuromuscular blocker for two days and in the other half the use of neuromuscular blockers will be discouraged .
- MUC5B Promoter Polymorphism and Development of ARDS. American journal of respiratory and critical care medicine 2018
- GWAS in ARDS: Finding the Needle in the Haystack to Advance our Understanding of ARDS. American journal of respiratory and critical care medicine 2018
Multicohort Analysis of Whole-Blood Gene Expression Data Does Not Form a Robust Diagnostic for Acute Respiratory Distress Syndrome.
Critical care medicine
2018; 46 (2): 244–51
To identify a novel, generalizable diagnostic for acute respiratory distress syndrome using whole-blood gene expression arrays from multiple acute respiratory distress syndrome cohorts of varying etiologies.We performed a systematic search for human whole-blood gene expression arrays of acute respiratory distress syndrome in National Institutes of Health Gene Expression Omnibus and ArrayExpress. We also included the Glue Grant gene expression cohorts.We included investigator-defined acute respiratory distress syndrome within 48 hours of diagnosis and compared these with relevant critically ill controls.We used multicohort analysis of gene expression to identify genes significantly associated with acute respiratory distress syndrome, both with and without adjustment for clinical severity score. We performed gene ontology enrichment using Database for Annotation, Visualization and Integrated Discovery and cell type enrichment tests for both immune cells and pneumocyte gene expression. Finally, we selected a gene set optimized for diagnostic power across the datasets and used leave-one-dataset-out cross validation to assess robustness of the model.We identified datasets from three adult cohorts with sepsis, one pediatric cohort with acute respiratory failure, and two datasets of adult patients with trauma and burns, for a total of 148 acute respiratory distress syndrome cases and 268 critically ill controls. We identified 30 genes that were significantly associated with acute respiratory distress syndrome (false discovery rate < 20% and effect size >1.3), many of which had been previously associated with sepsis. When metaregression was used to adjust for clinical severity scores, none of these genes remained significant. Cell type enrichment was notable for bands and neutrophils, suggesting that the gene expression signature is one of acute inflammation rather than lung injury per se. Finally, an attempt to develop a generalizable diagnostic gene set for acute respiratory distress syndrome showed a mean area under the receiver-operating characteristic curve of only 0.63 on leave-one-dataset-out cross validation.The whole-blood gene expression signature across a wide clinical spectrum of acute respiratory distress syndrome is likely confounded by systemic inflammation, limiting the utility of whole-blood gene expression studies for uncovering a generalizable diagnostic gene signature.
View details for PubMedID 29337789
Gene Expression Analysis to Assess the Relevance of Rodent Models to Human Lung Injury.
American journal of respiratory cell and molecular biology
Rationale The relevance of animal models to human diseases is an area of intense scientific debate. The degree to which mouse models of lung injury recapitulate human lung injury has never been assessed. Integrating data from both human and animal expression studies allows for increased statistical power and identification of conserved differential gene expression across organisms and conditions. Objectives Comprehensive integration of gene expression data in experimental ALI in rodents compared to humans. Methods We performed two separate gene expression multi-cohort analyses to determine differential gene expression in experimental animal and human lung injury. We used correlational and pathway analyses combined with external in vitro gene expression data to identify both potential drivers of underlying inflammation and therapeutic drug candidates. Main Results We identified 21 animal lung tissue datasets and 3 human lung injury BAL datasets. We show that the meta-signatures of animal and human experimental ALI are significantly correlated despite these widely varying experimental conditions. The gene expression changes among mice and rats across diverse injury models (ozone, VILI, LPS) are significantly correlated with human models of lung injury (Pearson r 0.33-0.45, P<1e-16). Neutrophil signatures are enriched in both animal and human lung injury. Predicted therapeutic targets, peptide ligand signatures, and pathway analyses are also all highly overlapping. Conclusions Gene expression changes are similar in animal and human experimental ALI, and provide several physiologic and therapeutic insights to the disease.
View details for DOI 10.1165/rcmb.2016-0395OC
View details for PubMedID 28324666
Profiling of ARDS Pulmonary Edema Fluid Identifies a Metabolically Distinct Subset.
American journal of physiology. Lung cellular and molecular physiology
2017: ajplung 00438 2016-?
There is considerable biologic and physiologic heterogeneity among patients who meet standard clinical criteria for acute respiratory distress syndrome (ARDS). In this study, we tested the hypothesis that there exists a sub-group of ARDS patients who exhibit a metabolically distinct profile. We examined undiluted pulmonary edema fluid obtained at the time of endotracheal intubation from 16 clinically phenotyped ARDS patients and 13 control patients with hydrostatic pulmonary edema. Non-targeted metabolic profiling was carried out on the undiluted edema fluid. Univariate and multivariate statistical analyses including principal components analysis (PCA) and partial least squares discriminant analysis (PLSDA) were conducted to find discriminant metabolites. 760 unique metabolites were identified in the pulmonary edema fluid of these 29 patients. We found that a subset of ARDS patients (6/16, 38%) presented a distinct metabolic profile with the overrepresentation of 235 metabolites compared to edema fluid from the other 10 ARDS patients, whose edema fluid metabolic profile was indistinguishable from those of the 13 control patients with hydrostatic edema. This "high metabolite" endotype was characterized by higher concentrations of metabolites belonging to all of the main metabolic classes including lipids, amino acids, and carbohydrates. This distinct group with high metabolite levels in the edema fluid was also associated with a higher mortality rate. Thus, metabolic profiling of the edema fluid of ARDS patients supports the hypothesis that there is considerable biologic heterogeneity among ARDS patients who meet standard clinical and physiologic criteria for ARDS.
View details for DOI 10.1152/ajplung.00438.2016
View details for PubMedID 28258106
Applying metabolomics to uncover novel biology in ARDS.
American journal of physiology. Lung cellular and molecular physiology
2014; 306 (11): L957-61
A better understanding of the pathogenesis and the resolution of the acute respiratory distress syndrome (ARDS) is needed. While some progress has been made with the use of protein biomarkers and candidate gene studies in understanding the pathobiology of ARDS, we propose that new studies that measure the chemical breakdown products of cellular metabolism (metabolomics) may provide new insights into ARDS, in part because the metabolomics targets a later point in the genomics cascade than is possible with studies of DNA, RNA and protein biomarkers. Technological advances have made large-scale metabolomic profiling increasingly feasible. Metabolomic approaches have already achieved novel insights in non-pulmonary diseases such as Diabetes Mellitus and malignancy, as well as in sepsis, a major risk factor for developing ARDS. Metabolomic profiling is a promising approach to identify novel pathways in both patients at risk for developing ARDS as well as in the early phase of established ARDS.
View details for DOI 10.1152/ajplung.00376.2013
View details for PubMedID 24727586
Plasma mitochondrial DNA and metabolomic alterations in severe critical illness.
Critical care (London, England)
2018; 22 (1): 360
BACKGROUND: Cell-free plasma mitochondrial DNA (mtDNA) levels are associated with endothelial dysfunction and differential outcomes in critical illness. A substantial alteration in metabolic homeostasis is commonly observed in severe critical illness. We hypothesized that metabolic profiles significantly differ between critically ill patients relative to their level of plasma mtDNA.METHODS: We performed a metabolomic study with biorepository plasma samples collected from 73 adults with systemic inflammatory response syndrome or sepsis at a single academic medical center. Patients were treated in a 20-bed medical ICU between 2008 and 2010. To identify key metabolites and metabolic pathways related to plasma NADH dehydrogenase 1 (ND1) mtDNA levels in critical illness, we first generated metabolomic data using gas and liquid chromatography-mass spectroscopy. We performed fold change analysis and volcano plot visualization based on false discovery rate-adjusted p values to evaluate the distribution of individual metabolite concentrations relative to ND1 mtDNA levels. We followed this by performing orthogonal partial least squares discriminant analysis to identify individual metabolites that discriminated ND1 mtDNA groups. We then interrogated the entire metabolomic profile using pathway overrepresentation analysis to identify groups of metabolite pathways that were different relative to ND1 mtDNA levels.RESULTS: Metabolomic profiles significantly differed in critically ill patients with ND1 mtDNA levels ≥3200 copies/mul plasma relative to those with an ND1 mtDNA level <3200 copies/mul plasma. Several analytical strategies showed that patients with ND1 mtDNA levels ≥3200 copies/mul plasma had significant decreases in glycerophosphocholines and increases in short-chain acylcarnitines.CONCLUSIONS: Differential metabolic profiles during critical illness are associated with cell-free plasma ND1 mtDNA levels that are indicative of cell damage. Elevated plasma ND1 mtDNA levels are associated with decreases in glycerophosphocholines and increases in short-chain acylcarnitines that reflect phospholipid metabolism dysregulation and decreased mitochondrial function, respectively.
View details for DOI 10.1186/s13054-018-2275-7
View details for PubMedID 30594224
Current Status and Future Opportunities in Lung Precision Medicine Research with a Focus on Biomarkers
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
2018; 198 (12): 1479–89
View details for Web of Science ID 000453253600011
Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial.
The Lancet. Respiratory medicine
BACKGROUND: Treatment with bone-marrow-derived mesenchymal stromal cells (MSCs) has shown benefits in preclinical models of acute respiratory distress syndrome (ARDS). Safety has not been established for administration of MSCs in critically ill patients with ARDS. We did a phase 2a trial to assess safety after administration of MSCs to patients with moderate to severe ARDS.METHODS: We did a prospective, double-blind, multicentre, randomised trial to assess treatment with one intravenous dose of MSCs compared with placebo. We recruited ventilated patients with moderate to severe ARDS (ratio of partial pressure of oxygen to fractional inspired oxygen <27 kPa and positive end-expiratory pressure [PEEP] ≥8 cm H2O) in five university medical centres in the USA. Patients were randomly assigned 2:1 to receive either 10 * 106/kg predicted bodyweight MSCs or placebo, according to a computer-generated schedule with a variable block design and stratified by site. We excluded patients younger than 18 years, those with trauma or moderate to severe liver disease, and those who had received cancer treatment in the previous 2 years. The primary endpoint was safety and all analyses were done by intention to treat. We also measured biomarkers in plasma. MSC viability was tested in a post-hoc analysis. This trial is registered with ClinicalTrials.gov, number NCT02097641.FINDINGS: From March 24, 2014, to Feb 9, 2017 we screened 1038 patients, of whom 60 were eligible for and received treatment. No patient experienced any of the predefined MSC-related haemodynamic or respiratory adverse events. One patient in the MSC group died within 24 h of MSC infusion, but death was judged to be probably unrelated. 28-day mortality did not differ between the groups (30% in the MSC group vs 15% in the placebo group, odds ratio 2·4, 95% CI 0·5-15·1). At baseline, the MSC group had numerically higher mean scores than the placebo group for Acute Physiology and Chronic Health Evaluation III (APACHE III; 104 [SD 31] vs 89 ), minute ventilation (11·1 [3·2] vs 9·6 [2·4] L/min), and PEEP (12·4 [3·7] vs 10·8 [2·6] cm H2O). After adjustment for APACHE III score, the hazard ratio for mortality at 28 days was 1·43 (95% CI 0·40-5·12, p=0·58). Viability of MSCs ranged from 36% to 85%.INTERPRETATION: One dose of intravenous MSCs was safe in patients with moderate to severe ARDS. Larger trials are needed to assess efficacy, and the viability of MSCs must be improved.FUNDING: National Heart, Lung, and Blood Institute.
View details for PubMedID 30455077
A Nasal Brush-based Classifier of Asthma Identified by Machine Learning Analysis of Nasal RNA Sequence Data
2018; 8: 8826
Asthma is a common, under-diagnosed disease affecting all ages. We sought to identify a nasal brush-based classifier of mild/moderate asthma. 190 subjects with mild/moderate asthma and controls underwent nasal brushing and RNA sequencing of nasal samples. A machine learning-based pipeline identified an asthma classifier consisting of 90 genes interpreted via an L2-regularized logistic regression classification model. This classifier performed with strong predictive value and sensitivity across eight test sets, including (1) a test set of independent asthmatic and control subjects profiled by RNA sequencing (positive and negative predictive values of 1.00 and 0.96, respectively; AUC of 0.994), (2) two independent case-control cohorts of asthma profiled by microarray, and (3) five cohorts with other respiratory conditions (allergic rhinitis, upper respiratory infection, cystic fibrosis, smoking), where the classifier had a low to zero misclassification rate. Following validation in large, prospective cohorts, this classifier could be developed into a nasal biomarker of asthma.
View details for DOI 10.1038/s41598-018-27189-4
View details for Web of Science ID 000434776600032
View details for PubMedID 29891868
View details for PubMedCentralID PMC5995932
- VITAMIN C AND METABOLOME ALTERATIONS IN SEVERE CRITICAL ILLNESS LIPPINCOTT WILLIAMS & WILKINS. 2018: 712
- Epidemiologic and Population Genetic Studies CLINICAL AND TRANSLATIONAL SCIENCE: PRINCIPLES OF HUMAN RESEARCH, 2ND EDITION 2017: 313–26
New Strategies and Challenges in Lung Proteomics and Metabolomics. An Official American Thoracic Society Workshop Report.
Annals of the American Thoracic Society
2017; 14 (12): 1721–43
This document presents the proceedings from the workshop entitled, "New Strategies and Challenges in Lung Proteomics and Metabolomics" held February 4th-5th, 2016, in Denver, Colorado. It was sponsored by the National Heart Lung Blood Institute, the American Thoracic Society, the Colorado Biological Mass Spectrometry Society, and National Jewish Health. The goal of this workshop was to convene, for the first time, relevant experts in lung proteomics and metabolomics to discuss and overcome specific challenges in these fields that are unique to the lung. The main objectives of this workshop were to identify, review, and/or understand: (1) emerging technologies in metabolomics and proteomics as applied to the study of the lung; (2) the unique composition and challenges of lung-specific biological specimens for metabolomic and proteomic analysis; (3) the diverse informatics approaches and databases unique to metabolomics and proteomics, with special emphasis on the lung; (4) integrative platforms across genetic and genomic databases that can be applied to lung-related metabolomic and proteomic studies; and (5) the clinical applications of proteomics and metabolomics. The major findings and conclusions of this workshop are summarized at the end of the report, and outline the progress and challenges that face these rapidly advancing fields.
View details for DOI 10.1513/AnnalsATS.201710-770WS
View details for PubMedID 29192815
Metabolome alterations in severe critical illness and vitamin D status.
Critical care (London, England)
2017; 21 (1): 193
Metabolic homeostasis is substantially disrupted in critical illness. Given the pleiotropic effects of vitamin D, we hypothesized that metabolic profiles differ between critically ill patients relative to their vitamin D status.We performed a metabolomics study on biorepository samples collected from a single academic medical center on 65 adults with systemic inflammatory response syndrome or sepsis treated in a 20-bed medical ICU between 2008 and 2010. To identify key metabolites and metabolic pathways related to vitamin D status in critical illness, we first generated metabolomic data using gas and liquid chromatography mass spectroscopy. We followed this by partial least squares-discriminant analysis to identify individual metabolites that were significant. We then interrogated the entire metabolomics profile using metabolite set enrichment analysis to identify groups of metabolites and pathways that were differentiates of vitamin D status. Finally we performed logistic regression to construct a network model of chemical-protein target interactions important in vitamin D status.Metabolomic profiles significantly differed in critically ill patients with 25(OH)D ≤ 15 ng/ml relative to those with levels >15 ng/ml. In particular, increased 1,5-anhydroglucitol, tryptophan betaine, and 3-hydroxyoctanoate as well as decreased 2-arachidonoyl-glycerophosphocholine and N-6-trimethyllysine were strong predictors of 25(OH)D >15 ng/ml. The combination of these five metabolites led to an area under the curve for discrimination for 25(OH)D > 15 ng/ml of 0.82 (95% CI 0.71-0.93). The metabolite pathways related to glutathione metabolism and glutamate metabolism are significantly enriched with regard to vitamin D status.Vitamin D status is associated with differential metabolic profiles during critical illness. Glutathione and glutamate pathway metabolism, which play principal roles in redox regulation and immunomodulation, respectively, were significantly altered with vitamin D status.
View details for DOI 10.1186/s13054-017-1794-y
View details for PubMedID 28750641
View details for PubMedCentralID PMC5532782
A resident-created hospitalist curriculum for internal medicine housestaff.
Journal of hospital medicine
2016; 11 (9): 646-649
The growth of hospital medicine has led to new challenges, and recent graduates may feel unprepared to meet the expanding clinical duties expected of hospitalists. At our institution, we created a resident-inspired hospitalist curriculum to address the training needs for the next generation of hospitalists. Our program provided 3 tiers of training: (1) clinical excellence through improved training in underemphasized areas of hospital medicine, (2) academic development through required research, quality improvement, and medical student teaching, and (3) career mentorship. In this article, we describe the genesis of our program, our final product, and the challenges of creating a curriculum while being internal medicine residents. Journal of Hospital Medicine 2016. © 2016 Society of Hospital Medicine.
View details for DOI 10.1002/jhm.2590
View details for PubMedID 27079160
A computational approach to mortality prediction of alcohol use disorder inpatients
COMPUTERS IN BIOLOGY AND MEDICINE
2016; 75: 74-79
Health information technologies can assist clinicians in the Intensive Care Unit (ICU) by providing additional analysis of patient stability. However, because patient diagnoses can be confounded by chronic alcohol use, the predictive value of existing systems is suboptimal. Through the use of Electronic Health Records (EHR), we have developed computer software called AutoTriage to generate accurate predictions through multi-dimensional analysis of clinical variables. We analyze the performance of AutoTriage on the Alcohol Use Disorder (AUD) subpopulation in this study, and build on results we reported for AutoTriage performance on the general population in previous work.AUD-related ICD-9 codes were used to obtain a patient population from MIMIC III ICU dataset for a retrospective study. Patient mortality risk score is generated through analysis of eight EHR-based clinical variables. The score is determined by combining weighted subscores, each of which are obtained from singlets, doublets or triplets of one or more of the eight continuous-valued clinical variable inputs. A temporally updating risk score is computed with a continuously revised 12-hour mortality prediction.Among AUD patients, in a non-overlapping test set, AutoTriage outperforms existing systems with an Area Under Receiver Operating Characteristic (AUROC) value of 0.934 for 12-h mortality prediction. At a sensitivity of 90%, AutoTriage achieves a specificity of 80%, positive predictive value of 40%, negative predictive value of 89%, and an Odds Ratio of 36.For mortality prediction, AutoTriage demonstrates improvements in both the accuracy and the Odds Ratio over current systems among the AUD patient population.
View details for DOI 10.1016/j.compbiomed.2016.05.015
View details for Web of Science ID 000380623100009
View details for PubMedID 27253619
Metabolism, Metabolomics, and Nutritional Support of Patients with Sepsis
CLINICS IN CHEST MEDICINE
2016; 37 (2): 321-?
Sepsis is characterized by profound changes in systemic and cellular metabolism that disrupt normal metabolic homeostasis. These metabolic changes can serve as biomarkers for disease severity. Lactate, a metabolite of anaerobic metabolism, is the most widely used ICU biomarker and it is incorporated into multiple management algorithms. Technological advances now make broader metabolic profiling possible, with early studies identifying metabolic changes associated with sepsis mortality. Finally, given the marked changes in metabolism in sepsis and the association of worse prognosis in patients with severe metabolic derangements, we summarize the seminal trials conducted to optimize nutrition in the ICU.
View details for DOI 10.1016/j.ccm.2016.01.011
View details for Web of Science ID 000378582800015
View details for PubMedID 27229648
Proteomic study of acute respiratory distress syndrome: current knowledge and implications for drug development
EXPERT REVIEW OF PROTEOMICS
2016; 13 (5): 457-469
The acute respiratory distress syndrome (ARDS) is a common cause of acute respiratory failure, and is associated with substantial mortality and morbidity. Dozens of clinical trials targeting ARDS have failed, with no drug specifically targeting lung injury in widespread clinical use. Thus, the need for drug development in ARDS is great. Targeted proteomic studies in ARDS have identified many key pathways in the disease, including inflammation, epithelial injury, endothelial injury or activation, and disordered coagulation and repair. Recent studies reveal the potential for proteomic changes to identify novel subphenotypes of ARDS patients who may be most likely to respond to therapy and could thus be targeted for enrollment in clinical trials. Nontargeted studies of proteomics in ARDS are just beginning and have the potential to identify novel drug targets and key pathways in the disease. Proteomics will play an important role in phenotyping of patients and developing novel therapies for ARDS in the future.
View details for DOI 10.1586/14789450.2016.1172481
View details for PubMedID 27031735
- ATS Core Curriculum 2016: Part II. Adult Critical Care Medicine. Annals of the American Thoracic Society 2016; 13 (5): 731-740
Metabolites Associated With Malnutrition in the Intensive Care Unit Are Also Associated With 28-Day Mortality: A Prospective Cohort Study.
JPEN. Journal of parenteral and enteral nutrition
We hypothesized that metabolic profiles would differ in critically ill patients with malnutrition relative to those without.We performed a prospective cohort study on 85 adult patients with systemic inflammatory response syndrome or sepsis admitted to a 20-bed medical intensive care unit (ICU) in Boston. We generated metabolomic profiles using gas and liquid chromatography and mass spectroscopy. We followed this by logistic regression and partial least squares discriminant analysis to identify individual metabolites that were significant. We then interrogated the entire metabolomics profile using metabolite set enrichment analysis and network model construction of chemical-protein target interactions to identify groups of metabolites and pathways that were differentiates in patients with and without malnutrition.Of the cohort, 38% were malnourished at admission to the ICU. Metabolomic profiles differed in critically ill patients with malnutrition relative to those without. Ten metabolites were significantly associated with malnutrition (P < .05). A parsimonious model of 5 metabolites effectively differentiated patients with malnutrition (AUC = 0.76), including pyroglutamine and hypoxanthine. Using pathway enrichment analysis, we identified a critical role of glutathione and purine metabolism in predicting nutrition. Nutrition status was associated with 28-day mortality, even after adjustment for known phenotypic variables associated with ICU mortality. Importantly, 7 metabolites associated with nutrition status were also associated with 28-day mortality.Malnutrition is associated with differential metabolic profiles early in critical illness. Common to all of our metabolome analyses, glutathione and purine metabolism, which play principal roles in cellular redox regulation and accelerated tissue adenosine triphosphate degradation, respectively, were significantly altered with malnutrition.
View details for DOI 10.1177/0148607116656164
View details for PubMedID 27406941
Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
2015; 308 (11): L1102-L1113
The early sequence of events leading to the development of the acute respiratory distress syndrome (ARDS) in patients with sepsis remains inadequately understood. The purpose of this study was to identify changes in gene expression early in the course of illness, when mechanisms of injury may provide the most relevant treatment and prognostic targets. We collected whole blood RNA in critically ill patients admitted from the Emergency Department to the intensive care unit within 24 h of admission at a tertiary care center. Whole genome expression was compared in patients with sepsis and ARDS to patients with sepsis alone. We selected genes with >1 log2 fold change and false discovery rate <0.25, determined their significance in the literature, and performed pathway analysis. Several genes were upregulated in 29 patients with sepsis with ARDS compared with 28 patients with sepsis alone. The most differentially expressed genes included key mediators of the initial neutrophil response to infection: olfactomedin 4, lipocalin 2, CD24, and bactericidal/permeability-increasing protein. These gene expression differences withstood adjustment for age, sex, study batch, white blood cell count, and presence of pneumonia or aspiration. Pathway analysis demonstrated overrepresentation of genes involved in known respiratory and infection pathways. These data indicate that several neutrophil-related pathways may be involved in the early pathogenesis of sepsis-related ARDS. In addition, identifiable gene expression differences occurring early in the course of sepsis-related ARDS may further elucidate understanding of the neutrophil-related mechanisms in progression to ARDS.
View details for DOI 10.1152/ajplung.00380.2014
View details for Web of Science ID 000357509200002
View details for PubMedID 25795726
View details for PubMedCentralID PMC4451399
- Finding an early warning signal for acute respiratory distress syndrome: are we getting closer? Critical care medicine 2015; 43 (3): 721-722
Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial.
The Lancet. Respiratory medicine
2015; 3 (1): 24-32
No effective pharmacotherapy for acute respiratory distress syndrome (ARDS) exists, and mortality remains high. Preclinical studies support the efficacy of mesenchymal stem (stromal) cells (MSCs) in the treatment of lung injury. We aimed to test the safety of a single dose of allogeneic bone marrow-derived MSCs in patients with moderate-to-severe ARDS.The STem cells for ARDS Treatment (START) trial was a multicentre, open-label, dose-escalation, phase 1 clinical trial. Patients were enrolled in the intensive care units at University of California, San Francisco, CA, USA, Stanford University, Stanford, CA, USA, and Massachusetts General Hospital, Boston, MA, USA, between July 8, 2013, and Jan 13, 2014. Patients were included if they had moderate-to-severe ARDS as defined by the acute onset of the need for positive pressure ventilation by an endotracheal or tracheal tube, a PaO2:FiO2 less than 200 mm Hg with at least 8 cm H2O positive end-expiratory airway pressure (PEEP), and bilateral infiltrates consistent with pulmonary oedema on frontal chest radiograph. The first three patients were treated with low dose MSCs (1 million cells/kg predicted bodyweight [PBW]), the next three patients received intermediate dose MSCs (5 million cells/kg PBW), and the final three patients received high dose MSCs (10 million cells/kg PBW). Primary outcomes included the incidence of prespecified infusion-associated events and serious adverse events. The trial is registered with ClinicalTrials.gov, number NCT01775774.No prespecified infusion-associated events or treatment-related adverse events were reported in any of the nine patients. Serious adverse events were subsequently noted in three patients during the weeks after the infusion: one patient died on study day 9, one patient died on study day 31, and one patient was discovered to have multiple embolic infarcts of the spleen, kidneys, and brain that were age-indeterminate, but thought to have occurred before the MSC infusion based on MRI results. None of these severe adverse events were thought to be MSC-related.A single intravenous infusion of allogeneic, bone marrow-derived human MSCs was well tolerated in nine patients with moderate to severe ARDS. Based on this phase 1 experience, we have proceeded to phase 2 testing of MSCs for moderate to severe ARDS with a primary focus on safety and secondary outcomes including respiratory, systemic, and biological endpoints.The National Heart, Lung, and Blood Institute.
View details for DOI 10.1016/S2213-2600(14)70291-7
View details for PubMedID 25529339
Expression Quantitative Trait Loci Information Improves Predictive Modeling of Disease Relevance of Non-Coding Genetic Variation.
2015; 10 (10)
Disease-associated loci identified through genome-wide association studies (GWAS) frequently localize to non-coding sequence. We and others have demonstrated strong enrichment of such single nucleotide polymorphisms (SNPs) for expression quantitative trait loci (eQTLs), supporting an important role for regulatory genetic variation in complex disease pathogenesis. Herein we describe our initial efforts to develop a predictive model of disease-associated variants leveraging eQTL information. We first catalogued cis-acting eQTLs (SNPs within 100kb of target gene transcripts) by meta-analyzing four studies of three blood-derived tissues (n = 586). At a false discovery rate < 5%, we mapped eQTLs for 6,535 genes; these were enriched for disease-associated genes (P < 10-04), particularly those related to immune diseases and metabolic traits. Based on eQTL information and other variant annotations (distance from target gene transcript, minor allele frequency, and chromatin state), we created multivariate logistic regression models to predict SNP membership in reported GWAS. The complete model revealed independent contributions of specific annotations as strong predictors, including evidence for an eQTL (odds ratio (OR) = 1.2-2.0, P < 10-11) and the chromatin states of active promoters, different classes of strong or weak enhancers, or transcriptionally active regions (OR = 1.5-2.3, P < 10-11). This complete prediction model including eQTL association information ultimately allowed for better discrimination of SNPs with higher probabilities of GWAS membership (6.3-10.0%, compared to 3.5% for a random SNP) than the other two models excluding eQTL information. This eQTL-based prediction model of disease relevance can help systematically prioritize non-coding GWAS SNPs for further functional characterization.
View details for DOI 10.1371/journal.pone.0140758
View details for PubMedID 26474488
View details for PubMedCentralID PMC4608673
METABOLOME ALTERATION IN CRITICAL ILLNESS ACCORDING TO VITAMIN D STATUS: A PROSPECTIVE COHORT STUDY
LIPPINCOTT WILLIAMS & WILKINS. 2014
View details for Web of Science ID 000346211800310
Pharmacogenomics: novel loci identification via integrating gene differential analysis and eQTL analysis.
Human molecular genetics
2014; 23 (18): 5017-5024
Nearly one-half of asthmatic patients do not respond to the most commonly prescribed controller therapy, inhaled corticosteroids (ICS). We conducted an expression quantitative trait loci (eQTL) analysis using more than 300 expression microarrays (from 117 lymphoblastoid cell lines) in corticosteroid (dexamethasone) treated and untreated cells derived from asthmatic subjects in the Childhood Asthma Management Program (CAMP) clinical trial. We then tested the associations of eQTL with longitudinal change in airway responsiveness to methacholine (LnPC20) on ICS. We identified 2,484 cis-eQTL affecting 767 genes following dexamethasone treatment. A significant over-representation of lnPC20-associated cis-eQTL (190 SNPs) among differentially expressed genes (OR=1.76, 95% CI: 1.35-2.29) was noted in CAMP Caucasians. Forty-six of these 190 clinical associations were replicated in CAMP African Americans, including 7 SNPs near 6 genes meeting criteria for genome-wide significance (p<2x10(-7)). Notably, the majority of genome-wide findings would not have been uncovered via analysis of untreated samples. These results indicate that identifying eQTL after relevant environmental perturbation enables identification of true pharmacogenetic variants.
View details for DOI 10.1093/hmg/ddu191
View details for PubMedID 24770851
Integrative "omic" analysis of experimental bacteremia identifies a metabolic signature that distinguishes human sepsis from systemic inflammatory response syndromes.
American journal of respiratory and critical care medicine
2014; 190 (4): 445-455
Sepsis is a leading cause of morbidity and mortality. Currently, early diagnosis and the progression of the disease are difficult to make. The integration of metabolomic and transcriptomic data in a primate model of sepsis may provide a novel molecular signature of clinical sepsis.To develop a biomarker panel to characterize sepsis in primates and ascertain its relevance to early diagnosis and progression of human sepsis.Intravenous inoculation of Macaca fascicularis with Escherichia coli produced mild to severe sepsis, lung injury, and death. Plasma samples were obtained before and after 1, 3, and 5 days of E. coli challenge and at the time of killing. At necropsy, blood, lung, kidney, and spleen samples were collected. An integrative analysis of the metabolomic and transcriptomic datasets was performed to identify a panel of sepsis biomarkers.The extent of E. coli invasion, respiratory distress, lethargy, and mortality was dependent on the bacterial dose. Metabolomic and transcriptomic changes characterized severe infections and death, and indicated impaired mitochondrial, peroxisomal, and liver functions. Analysis of the pulmonary transcriptome and plasma metabolome suggested impaired fatty acid catabolism regulated by peroxisome-proliferator activated receptor signaling. A representative four-metabolite model effectively diagnosed sepsis in primates (area under the curve, 0.966) and in two human sepsis cohorts (area under the curve, 0.78 and 0.82).A model of sepsis based on reciprocal metabolomic and transcriptomic data was developed in primates and validated in two human patient cohorts. It is anticipated that the identified parameters will facilitate early diagnosis and management of sepsis.
View details for DOI 10.1164/rccm.201404-0624OC
View details for PubMedID 25054455
- Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome ANNALS OF INTENSIVE CARE 2014; 4
Factors associated with bronchiolitis obliterans syndrome and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation
AMERICAN JOURNAL OF HEMATOLOGY
2014; 89 (4): 404-409
Bronchiolitis obliterans syndrome (BOS) is a form of chronic graft vs. host disease (cGVHD) and a highly morbid pulmonary complication after allogeneic hematopoietic stem cell transplantation (HSCT). We assessed the prevalence and risk factors for BOS and cGVHD in a cohort of HSCT recipients, including those who received reduced intensity conditioning (RIC) HSCT. Between January 1, 2000 and June 30, 2010, all patients who underwent allogeneic HSCT at our institution (n = 1854) were retrospectively screened for the development of BOS by PFT criteria. We matched the BOS cases with two groups of control patients: (1) patients who had concurrent cGVHD without BOS and (2) those who developed neither cGVHD nor BOS. Comparisons between BOS patients and controls were conducted using t-test or Fisher's exact tests. Multivariate regression analysis was performed to examine factors associated with BOS diagnosis. All statistical analyses were performed using SAS 9.2. We identified 89 patients (4.8%) meeting diagnostic criteria for BOS at a median time of 491 days (range: 48-2067) after HSCT. Eighty-six (97%) of our BOS cohort had extra-pulmonary cGVHD. In multivariate analysis compared to patients without cGVHD, patients who received busulfan-based conditioning, had unrelated donors, and had female donors were significantly more likely to develop BOS, while ATG administration was associated with a lower risk of BOS. Our novel results suggest that busulfan conditioning, even in RIC transplantation, could be an important risk factor for BOS and cGVHD.
View details for DOI 10.1002/ajh.23656
View details for Web of Science ID 000334645900011
View details for PubMedID 24375545
Metabolomic Derangements Are Associated with Mortality in Critically Ill Adult Patients
2014; 9 (1)
To identify metabolomic biomarkers predictive of Intensive Care Unit (ICU) mortality in adults.Comprehensive metabolomic profiling of plasma at ICU admission to identify biomarkers associated with mortality has recently become feasible.We performed metabolomic profiling of plasma from 90 ICU subjects enrolled in the BWH Registry of Critical Illness (RoCI). We tested individual metabolites and a Bayesian Network of metabolites for association with 28-day mortality, using logistic regression in R, and the CGBayesNets Package in MATLAB. Both individual metabolites and the network were tested for replication in an independent cohort of 149 adults enrolled in the Community Acquired Pneumonia and Sepsis Outcome Diagnostics (CAPSOD) study.We tested variable metabolites for association with 28-day mortality. In RoCI, nearly one third of metabolites differed among ICU survivors versus those who died by day 28 (N = 57 metabolites, p<.05). Associations with 28-day mortality replicated for 31 of these metabolites (with p<.05) in the CAPSOD population. Replicating metabolites included lipids (N = 14), amino acids or amino acid breakdown products (N = 12), carbohydrates (N = 1), nucleotides (N = 3), and 1 peptide. Among 31 replicated metabolites, 25 were higher in subjects who progressed to die; all 6 metabolites that are lower in those who die are lipids. We used Bayesian modeling to form a metabolomic network of 7 metabolites associated with death (gamma-glutamylphenylalanine, gamma-glutamyltyrosine, 1-arachidonoylGPC(20:4), taurochenodeoxycholate, 3-(4-hydroxyphenyl) lactate, sucrose, kynurenine). This network achieved a 91% AUC predicting 28-day mortality in RoCI, and 74% of the AUC in CAPSOD (p<.001 in both populations).Both individual metabolites and a metabolomic network were associated with 28-day mortality in two independent cohorts. Metabolomic profiling represents a valuable new approach for identifying novel biomarkers in critically ill patients.
View details for DOI 10.1371/journal.pone.0087538
View details for Web of Science ID 000330617100092
View details for PubMedID 24498130
View details for PubMedCentralID PMC3907548
Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome.
Annals of intensive care
2014; 4: 22-?
Despite advances in supportive care, moderate-severe acute respiratory distress syndrome (ARDS) is associated with high mortality rates, and novel therapies to treat this condition are needed. Compelling pre-clinical data from mouse, rat, sheep and ex vivo perfused human lung models support the use of human mesenchymal stem (stromal) cells (MSCs) as a novel intravenous therapy for the early treatment of ARDS.This article describes the study design and challenges encountered during the implementation and phase 1 component of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of bone marrow-derived human MSCs for moderate-severe ARDS. A trial enrolling 69 subjects is planned (9 subjects in phase 1, 60 subjects in phase 2 treated with MSCs or placebo in a 2:1 ratio).This report describes study design features that are unique to a phase 1 trial in critically ill subjects and the specific challenges of implementation of a cell-based therapy trial in the ICU.Experience gained during the design and implementation of the START study will be useful to investigators planning future phase 1 clinical trials based in the ICU, as well as trials of cell-based therapy for other acute illnesses.NCT01775774 and NCT02097641.
View details for DOI 10.1186/s13613-014-0022-z
View details for PubMedID 25593740
View details for PubMedCentralID PMC4273700
Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation
2013; 10 (12)
Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients.Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10(-4)) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers.Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
View details for DOI 10.1371/journal.pmed.1001577
View details for PubMedID 24391478
Copy number variation genotyping using family information
In recent years there has been a growing interest in the role of copy number variations (CNV) in genetic diseases. Though there has been rapid development of technologies and statistical methods devoted to detection in CNVs from array data, the inherent challenges in data quality associated with most hybridization techniques remains a challenging problem in CNV association studies.To help address these data quality issues in the context of family-based association studies, we introduce a statistical framework for the intensity-based array data that takes into account the family information for copy-number assignment. The method is an adaptation of traditional methods for modeling SNP genotype data that assume Gaussian mixture model, whereby CNV calling is performed for all family members simultaneously and leveraging within family-data to reduce CNV calls that are incompatible with Mendelian inheritance while still allowing de-novo CNVs. Applying this method to simulation studies and a genome-wide association study in asthma, we find that our approach significantly improves CNV calls accuracy, and reduces the Mendelian inconsistency rates and false positive genotype calls. The results were validated using qPCR experiments.In conclusion, we have demonstrated that the use of family information can improve the quality of CNV calling and hopefully give more powerful association test of CNVs.
View details for DOI 10.1186/1471-2105-14-157
View details for Web of Science ID 000319743600001
View details for PubMedID 23656838
Copy number variation prevalence in known asthma genes and their impact on asthma susceptibility
CLINICAL AND EXPERIMENTAL ALLERGY
2013; 43 (4): 455-462
Genetic studies have identified numerous genes reproducibly associated with asthma, yet these studies have focussed almost entirely on single nucleotide polymorphisms (SNPs), and virtually ignored another highly prevalent form of genetic variation: Copy Number Variants (CNVs).To survey the prevalence of CNVs in genes previously associated with asthma, and to assess whether CNVs represent the functional asthma-susceptibility variants at these loci.We genotyped 383 asthmatic trios participating in the Childhood Asthma Management Program (CAMP) using a competitive genomic hybridization (CGH) array designed to interrogate 20 092 CNVs. To ensure comprehensive assessment of all potential asthma candidate genes, we purposely used liberal asthma gene inclusion criteria, resulting in consideration of 270 candidate genes previously implicated in asthma. We performed statistical testing using FBAT-CNV.Copy number variation in asthma candidate genes was prevalent, with 21% of tested genes residing near or within one of 69 CNVs. In six instances, the complete candidate gene sequence resides within the CNV boundaries. On average, asthmatic probands carried six asthma-candidate CNVs (range 1-29). However, the vast majority of identified CNVs were of rare frequency (< 5%) and were not statistically associated with asthma. Modest evidence for association with asthma was observed for 2 CNVs near NOS1 and SERPINA3. Linkage disequilibrium analysis suggests that CNV effects are unlikely to explain previously detected SNP associations with asthma.Although a substantial proportion of asthma-susceptibility genes harbour polymorphic CNVs, the majority of these variants do not confer increased asthma risk. The lack of linkage disequilibrium (LD) between CNVs and asthma-associated SNPs suggests that these CNVs are unlikely to represent the functional variant responsible for most known asthma associations.
View details for DOI 10.1111/cea.12060
View details for Web of Science ID 000316623800010
View details for PubMedID 23517041
An integrated clinico-metabolomic model improves prediction of death in sepsis.
Science translational medicine
2013; 5 (195): 195ra95
Sepsis is a common cause of death, but outcomes in individual patients are difficult to predict. Elucidating the molecular processes that differ between sepsis patients who survive and those who die may permit more appropriate treatments to be deployed. We examined the clinical features and the plasma metabolome and proteome of patients with and without community-acquired sepsis, upon their arrival at hospital emergency departments and 24 hours later. The metabolomes and proteomes of patients at hospital admittance who would ultimately die differed markedly from those of patients who would survive. The different profiles of proteins and metabolites clustered into the following groups: fatty acid transport and β-oxidation, gluconeogenesis, and the citric acid cycle. They differed consistently among several sets of patients, and diverged more as death approached. In contrast, the metabolomes and proteomes of surviving patients with mild sepsis did not differ from survivors with severe sepsis or septic shock. An algorithm derived from clinical features together with measurements of five metabolites predicted patient survival. This algorithm may help to guide the treatment of individual patients with sepsis.
View details for DOI 10.1126/scitranslmed.3005893
View details for PubMedID 23884467
Inflammasome-regulated Cytokines Are Critical Mediators of Acute Lung Injury
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
2012; 185 (11): 1225-1234
Despite advances in clinical management, there are currently no reliable diagnostic and therapeutic targets for acute respiratory distress syndrome (ARDS). The inflammasome/caspase-1 pathway regulates the maturation and secretion of proinflammatory cytokines (e.g., IL-18). IL-18 is associated with injury in animal models of systemic inflammation.We sought to determine the contribution of the inflammasome pathway in experimental acute lung injury and human ARDS.We performed comprehensive gene expression profiling on peripheral blood from patients with critical illness. Gene expression changes were assessed using real-time polymerase chain reaction, and IL-18 levels were measured in the plasma of the critically ill patients. Wild-type mice or mice genetically deficient in IL-18 or caspase-1 were mechanically ventilated using moderate tidal volume (12 ml/kg). Lung injury parameters were assessed in lung tissue, serum, and bronchoalveolar lavage fluid.In mice, mechanical ventilation enhanced IL-18 levels in the lung, serum, and bronchoalveolar lavage fluid. IL-18-neutralizing antibody treatment, or genetic deletion of IL-18 or caspase-1, reduced lung injury in response to mechanical ventilation. In human patients with ARDS, inflammasome-related mRNA transcripts (CASP1, IL1B, and IL18) were increased in peripheral blood. In samples from four clinical centers, IL-18 was elevated in the plasma of patients with ARDS (sepsis or trauma-induced ARDS) and served as a novel biomarker of intensive care unit morbidity and mortality.The inflammasome pathway and its downstream cytokines play critical roles in ARDS development.
View details for DOI 10.1164/rccm.201201-0003OC
View details for Web of Science ID 000304384600016
View details for PubMedID 22461369
The CD4+ T-cell transcriptome and serum IgE in asthma: IL17RB and the role of sex.
BMC pulmonary medicine
2011; 11: 17-?
The relationships between total serum IgE levels and gene expression patterns in peripheral blood CD4+ T cells (in all subjects and within each sex specifically) are not known.Peripheral blood CD4+ T cells from 223 participants from the Childhood Asthma Management Program (CAMP) with simultaneous measurement of IgE. Total RNA was isolated, and expression profiles were generated with Illumina HumanRef8 v2 BeadChip arrays. Modeling of the relationship between genome-wide gene transcript levels and IgE levels was performed in all subjects, and stratified by sex.Among all subjects, significant evidence for association between gene transcript abundance and IgE was identified for a single gene, the interleukin 17 receptor B (IL17RB), explaining 12% of the variance (r2) in IgE measurement (p value = 7 × 10(-7), 9 × 10(-3) after adjustment for multiple testing). Sex stratified analyses revealed that the correlation between IL17RB and IgE was restricted to males only (r2 = 0.19, p value = 8 × 10(-8); test for sex-interaction p < 0.05). Significant correlation between gene transcript abundance and IgE level was not found in females. Additionally we demonstrated substantial sex-specific differences in IgE when considering multi-gene models, and in canonical pathway analyses of IgE level.Our results indicate that IL17RB may be the only gene expressed in CD4+ T cells whose transcript measurement is correlated with the variation in IgE level in asthmatics. These results provide further evidence sex may play a role in the genomic regulation of IgE.
View details for DOI 10.1186/1471-2466-11-17
View details for PubMedID 21473777
On the Genome-Wide Analysis of Copy Number Variants in Family-Based Designs: Methods for Combining Family-Based and Population-Based Information for Testing Dichotomous or Quantitative Traits, or Completely Ascertained Samples
2010; 34 (6): 582-590
We propose a new approach for the analysis of copy number variants (CNVs)for genome-wide association studies in family-based designs. Our new overall association test combines the between-family component and the within-family component of the family-based data so that the new test statistic is fully efficient and, at the same time, maintains robustness against population-admixture and stratification, like classical family-based association tests that are based only on the within-family component. Although all data are incorporated into the test statistic, an adjustment for genetic confounding is not needed, even for the between-family component. The new test statistic is valid for testing either quantitative or dichotomous phenotypes. If external CNV data are available, the approach can also be applied to completely ascertained samples. Similar to the approach by Ionita-Laza et al. (. Genet Epidemiol 32:273-284), the proposed test statistic does not require a CNV-calling algorithm and is based directly on the CNV probe intensities. We show, via simulation studies, that our methodology increases the power of the FBAT statistic to levels comparable to those of population-based designs. The advantages of the approach in practice are demonstrated by an application to a genome-wide association study for body mass index.
View details for DOI 10.1002/gepi.20515
View details for Web of Science ID 000282038200008
View details for PubMedID 20718041
A Role for Wnt Signaling Genes in the Pathogenesis of Impaired Lung Function in Asthma
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
2010; 181 (4): 328-336
Animal models demonstrate that aberrant gene expression in utero can result in abnormal pulmonary phenotypes.We sought to identify genes that are differentially expressed during in utero airway development and test the hypothesis that variants in these genes influence lung function in patients with asthma.Stage 1 (Gene Expression): Differential gene expression analysis across the pseudoglandular (n = 27) and canalicular (n = 9) stages of human lung development was performed using regularized t tests with multiple comparison adjustments. Stage 2 (Genetic Association): Genetic association analyses of lung function (FEV(1), FVC, and FEV(1)/FVC) for variants in five differentially expressed genes were conducted in 403 parent-child trios from the Childhood Asthma Management Program (CAMP). Associations were replicated in 583 parent-child trios from the Genetics of Asthma in Costa Rica study.Of the 1,776 differentially expressed genes between the pseudoglandular (gestational age: 7-16 wk) and the canalicular (gestational age: 17-26 wk) stages, we selected 5 genes in the Wnt pathway for association testing. Thirteen single nucleotide polymorphisms in three genes demonstrated association with lung function in CAMP (P < 0.05), and associations for two of these genes were replicated in the Costa Ricans: Wnt1-inducible signaling pathway protein 1 with FEV(1) (combined P = 0.0005) and FVC (combined P = 0.0004), and Wnt inhibitory factor 1 with FVC (combined P = 0.003) and FEV(1)/FVC (combined P = 0.003).Wnt signaling genes are associated with impaired lung function in two childhood asthma cohorts. Furthermore, gene expression profiling of human fetal lung development can be used to identify genes implicated in the pathogenesis of lung function impairment in individuals with asthma.
View details for DOI 10.1164/rccm.200907-1009OC
View details for Web of Science ID 000274637100008
View details for PubMedID 19926868
The interaction of glutathione S-transferase M1-null variants with tobacco smoke exposure and the development of childhood asthma
CLINICAL AND EXPERIMENTAL ALLERGY
2009; 39 (11): 1721-1729
The glutathione S-transferase M1 (GSTM1)-null variant is a common copy number variant associated with adverse pulmonary outcomes, including asthma and airflow obstruction, with evidence of important gene-by-environment interactions with exposures to oxidative stress.To explore the joint interactive effects of GSTM1 copy number and tobacco smoke exposure on the development of asthma and asthma-related phenotypes in a family-based cohort of childhood asthmatics.We performed quantitative PCR-based genotyping for GSTM1 copy number in children of self-reported white ancestry with mild to moderate asthma in the Childhood Asthma Management Program. Questionnaire data regarding intrauterine (IUS) and post-natal, longitudinal smoke exposure were available. We performed both family-based and population-based tests of association for the interaction between GSTM1 copy number and tobacco smoke exposure with asthma and asthma-related phenotypes.Associations of GSTM1-null variants with asthma (P=0.03), younger age of asthma symptom onset (P=0.03), and greater airflow obstruction (reduced forced expiratory volume in 1 s / forced vital capacity, P=0.01) were observed among the 50 children (10% of the cohort) with exposure to IUS. In contrast, no associations were observed between GSTM1-null variants and asthma-related phenotypes among children without IUS exposure. Presence of at least one copy of GSTM1 conferred protection.These findings support an important gene-by-environment interaction between two common factors: increased risk of asthma and asthma-related phenotypes conferred by GSTM1-null homozygosity in children is restricted to those with a history of IUS exposure.
View details for DOI 10.1111/j.1365-2222.2009.03372.x
View details for Web of Science ID 000271001600014
View details for PubMedID 19860819
Predictors of poor response during asthma therapy differ with definition of outcome
2009; 10 (8): 1231-1242
To evaluate phenotypic and genetic variables associated with a poor long-term response to inhaled corticosteroid therapy for asthma, based independently on lung function changes or asthma exacerbations.We tested 17 phenotypic variables and polymorphisms in FCER2 and CRHR1 in 311 children (aged 5-12 years) randomized to a 4-year course of inhaled corticosteroid during the Childhood Asthma Management Program (CAMP).Predictors of recurrent asthma exacerbations are distinct from predictors of poor lung function response. A history of prior asthma exacerbations, younger age and a higher IgE level (p < 0.05) are associated with recurrent exacerbations. By contrast, lower bronchodilator response to albuterol and the minor alleles of RS242941 in CRHR1 and T2206C in FCER2 (p < 0.05) are associated with poor lung function response. Poor lung function response does not increase the risk of exacerbations and vice versa (p = 0.72).Genetic and phenotypic predictors of a poor long-term response to inhaled corticosteroids differ markedly depending on definition of outcome (based on exacerbations vs lung function). These findings are important in comparing outcomes of clinical trials and in designing future pharmacogenetic studies.
View details for DOI 10.2217/PGS.09.86
View details for Web of Science ID 000269408100011
View details for PubMedID 19663668
Assessing the Reproducibility of Asthma Candidate Gene Associations, Using Genome-wide Data
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
2009; 179 (12): 1084-1090
Association studies have implicated many genes in asthma pathogenesis, with replicated associations between single-nucleotide polymorphisms (SNPs) and asthma reported for more than 30 genes. Genome-wide genotyping enables simultaneous evaluation of most of this variation, and facilitates more comprehensive analysis of other common genetic variation around these candidate genes for association with asthma.To use available genome-wide genotypic data to assess the reproducibility of previously reported associations with asthma and to evaluate the contribution of additional common genetic variation surrounding these loci to asthma susceptibility.Illumina Human Hap 550Kv3 BeadChip (Illumina, San Diego, CA) SNP arrays were genotyped in 422 nuclear families participating in the Childhood Asthma Management Program. Genes with at least one SNP demonstrating prior association with asthma in two or more populations were tested for evidence of association with asthma, using family-based association testing.We identified 39 candidate genes from the literature, using prespecified criteria. Of the 160 SNPs previously genotyped in these 39 genes, 10 SNPs in 6 genes were significantly associated with asthma (including the first independent replication for asthma-associated integrin beta(3) [ITGB3]). Evaluation of 619 additional common variants included in the Illumina 550K array revealed additional evidence of asthma association for 15 genes, although none were significant after adjustment for multiple comparisons.We replicated asthma associations for a minority of candidate genes. Pooling genome-wide association study results from multiple studies will increase the power to appreciate marginal effects of genes and further clarify which candidates are true "asthma genes."
View details for DOI 10.1164/rccm.200812-1860OC
View details for Web of Science ID 000266787500006
View details for PubMedID 19264973
Asthma genetics and genomics 2009
CURRENT OPINION IN GENETICS & DEVELOPMENT
2009; 19 (3): 279-282
Asthma Genetic Association studies have been plagued by methodologic problems that are common in all studies of complex traits: small sample size, lack of replication, and lack of control of population stratification. Despite this, the field has identified 43 replicated genes from association studies. The most frequently replicated are: TNF alpha, IL4, FCERB, Adam 33, and GSTP1. Several genes have been identified by linkage and fine mapping (ADAM33, DPP10, GPR154, and PHF11) and one gene has been identified by GWAS (ORMD3). The major issue is that these genes have been looked at one at a time rather than in some more holistic manner where epistasis is considered. For asthma genetics to begin to have an impact on clinical medicine we need to consider epistatic interaction.
View details for DOI 10.1016/j.gde.2009.05.001
View details for Web of Science ID 000267585000012
View details for PubMedID 19481925
Genetic association analysis of copy-number variation (CNV) in human disease pathogenesis
2009; 93 (1): 22-26
Structural genetic variation, including copy-number variation (CNV), constitutes a substantial fraction of total genetic variability and the importance of structural genetic variants in modulating human disease is increasingly being recognized. Early successes in identifying disease-associated CNVs via a candidate gene approach mandate that future disease association studies need to include structural genetic variation. Such analyses should not rely on previously developed methodologies that were designed to evaluate single nucleotide polymorphisms (SNPs). Instead, development of novel technical, statistical, and epidemiologic methods will be necessary to optimally capture this newly-appreciated form of genetic variation in a meaningful manner.
View details for DOI 10.1016/j.ygeno.2008.08.012
View details for Web of Science ID 000262492000006
View details for PubMedID 18822366
Filaggrin mutations confer susceptibility to atopic dermatitis but not to asthma
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
2007; 120 (6): 1332-1337
Loss-of-function mutations in the filaggrin gene (FLG) have been strongly associated with atopic dermatitis and allergic phenotypes in multiple populations. The role of these mutations in the development of asthma is less clear, particularly in patients who do not have coincident atopic dermatitis.To determine whether FLG mutations are associated with asthma or asthma-related intermediate phenotypes.We genotyped 2 loss-of-function FLG mutations (R501X and 2282del4) in white children (age 5-12 years) with mild to moderate asthma in the Childhood Asthma Management Program. We assessed the relationship of these mutations to asthma and allergy-related phenotypes in children with and without atopic dermatitis using both population-based and family-based tests of association.Nearly 1/3 (185/646) of the participating children had atopic dermatitis. Although strong associations were observed between FLG mutations and atopic dermatitis (odds ratio, 2.4; P = 7.6 x 10(-5)) and between the mutations and total serum IgE level (P = .009 in the atopic dermatitis cohort), no association was noted with either asthma or asthma-related phenotypes, including FEV(1), FEV(1)/forced vital capacity, and methacholine PC(20) (P > .1 for all tests).Although FLG loss-of-function mutations are consistently associated with atopic dermatitis and other allergic phenotypes, these mutations do not appear to influence either susceptibility to asthma or asthma severity phenotypes.Filaggrin mutations that predispose to atopic dermatitis do not modulate the asthma phenotype.
View details for DOI 10.1016/j.jaci.2007.09.037
View details for Web of Science ID 000251653800013
View details for PubMedID 18073125