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.

Clinical Focus

  • Critical Care
  • Pulmonary Disease

Academic Appointments

Administrative Appointments

  • 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)

Professional Education

  • Fellowship: Massachusetts General Hosp Harvard Med School (2009) MA
  • Board Certification: American Board of Internal Medicine, Critical Care Medicine (2007)
  • Board Certification: American Board of Internal Medicine, Pulmonary Disease (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.

Clinical Trials

  • ACTIV-3: Therapeutics for Inpatients With COVID-19 Recruiting

    This study looks at the safety and effectiveness of different drugs in treating COVID-19 in people who have been hospitalized with the infection. Participants in the study will be treated with either a study drug plus current standard of care (SOC), or with placebo plus current SOC.

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  • ARrest RESpiraTory Failure From PNEUMONIA Recruiting

    This research study seeks to establish the effectiveness of a combination of an inhaled corticosteroid and a beta agonist compared to placebo for the prevention of acute respiratory failure (ARF) in hospitalized patients with pneumonia and hypoxemia.

    View full details

  • COVID-19 Outpatient Pragmatic Platform Study (COPPS) - Acebilustat Sub-Protocol Recruiting

    The overall objective of this study is to efficiently evaluate the clinical efficacy and safety of different investigational therapeutics among adults who have COVID-19 but are not yet sick enough to require hospitalization. The overall hypothesis is that through an adaptive trial design, potential effective therapies (single and combination) may be identified for this group of patients. COVID-19 Outpatient Pragmatic Platform Study (COPPS) is a pragmatic platform protocol designed to evaluate COVID-19 treatments by assessing their ability to reduce viral shedding (Viral Domain) or improve clinical outcomes (Clinical Domain). To be included into the platform, every investigational product will collect data for both Domain primary endpoints. Individual treatments to be evaluated in the platform will be described in separate sub-protocols.

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  • COVID-19 Outpatient Pragmatic Platform Study (COPPS) - Master Protocol Recruiting

    The overall objective of this study is to efficiently evaluate the clinical efficacy and safety of different investigational therapeutics among adults who have COVID-19 but are not yet sick enough to require hospitalization. The overall hypothesis is that through an adaptive trial design, potential effective therapies (single and combination) may be identified for this group of patients. COVID-19 Outpatient Pragmatic Platform Study (COPPS) is a pragmatic platform protocol designed to evaluate COVID-19 treatments by assessing their ability to reduce viral shedding (Viral Domain) or improve clinical outcomes (Clinical Domain). To be included into the platform, every investigational product will collect data for both Domain primary endpoints. Individual treatments to be evaluated in the platform will be described in separate sub-protocols.

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  • Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis Recruiting

    Multicenter, prospective, phase 3 randomized non-blinded interventional trial of fluid treatment strategies in the first 24 hours for patients with sepsis-induced hypotension. The aim of the study is to determine the impact of a restrictive fluids strategy (vasopressors first followed by rescue fluids) as compared to a liberal fluid strategy (fluids first followed by rescue vasopressors) on 90-day in-hospital mortality in patients with sepsis-induced hypotension.

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  • Vaccination for Recovered Inpatients With COVID-19 (VATICO) Not Recruiting

    In this Phase 4, open-label trial, participants of the ACTIV-3/TICO clinical trial (NCT04501978) at selected study sites who receive certain pre-specified, blinded investigational agents or placebo as part of that trial and who have since achieved sustained recovery from COVID-19 and meet certain criteria, including not having received a COVID-19 vaccination since enrollment, will be randomized to one of four groups to receive the Moderna mRNA-1273 or the Pfizer BNT162b2 vaccine (mRNA vaccines). No "dummy/placebo" vaccine will be used. Choice of Moderna or Pfizer vaccine is determined based on availability at the site. The choice is individual, although participants vaccinated twice should receive the same type of vaccine when receiving two injections. The study's objective is to evaluate if the vaccine is best administered early or deferred after recovery, and whether one injection provides comparable immune response to a two injection course of vaccination. Participants will remain blinded to the interventions received in the ACTIV-3/TICO study, however allocation to the timing of vaccination and to one or two vaccinations in this (VATICO) study is not blinded.

    Stanford is currently not accepting patients for this trial.

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Stanford Advisees

All Publications

  • Cytokine profile in plasma of severe COVID-19 does not differ from ARDS and sepsis. JCI insight Wilson, J. G., Simpson, L. J., Ferreira, A., Rustagi, A., Roque, J. A., Asuni, A., Ranganath, T., Grant, P. M., Subramanian, A. K., Rosenberg-Hasson, Y., Maecker, H., Holmes, S., Levitt, J. E., Blish, C., Rogers, A. J. 2020


    BACKGROUND: Elevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare to those observed in critically ill patients with ARDS or sepsis due to other causes.METHODS: We used a luminex assay to determine expression of 76 cytokines from plasma of hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients. Our analysis focused on detecting statistical differences in levels of 6 cytokines associated with cytokine storm (IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNFalpha) between patients with moderate COVID-19, severe COVID-19, and ARDS or sepsis.RESULTS: 15 hospitalized COVID-19 patients, 9 of whom were critically ill, were compared to critically ill patients with ARDS (n = 12) or sepsis (n = 16). There were no statistically significant differences in baseline levels of IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNFalpha between patients with COVID-19 and critically ill controls with ARDS or sepsis.CONCLUSIONS: Levels of inflammatory cytokines were not higher in severe COVID-19 patients than in moderate COVID-19 or critically ill patients with ARDS or sepsis in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 may be unwarranted.FUNDING: A.J.R.: Stanford ICU Biobank NHLBI K23 HL125663. C.A.B.: Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases #1016687; NIH/NIAID U19AI057229-16 (PI MM Davis); Stanford Maternal Child Health Research Institute; Chan Zuckerberg Biohub.

    View details for DOI 10.1172/jci.insight.140289

    View details for PubMedID 32706339

  • A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nature medicine Wilk, A. J., Rustagi, A., Zhao, N. Q., Roque, J., Martinez-Colon, G. J., McKechnie, J. L., Ivison, G. T., Ranganath, T., Vergara, R., Hollis, T., Simpson, L. J., Grant, P., Subramanian, A., Rogers, A. J., Blish, C. A. 2020


    There is an urgent need to better understand the pathophysiology of Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, which has infected more than three million people worldwide1. Approximately 20% of patients with COVID-19 develop severe disease and 5% of patients require intensive care2. Severe disease has been associated with changes in peripheral immune activity, including increased levels of pro-inflammatory cytokines3,4 that may be produced by a subset of inflammatory monocytes5,6, lymphopenia7,8 and T cell exhaustion9,10. To elucidate pathways in peripheral immune cells that might lead to immunopathology or protective immunity in severe COVID-19, we applied single-cell RNA sequencing (scRNA-seq) to profile peripheral blood mononuclear cells (PBMCs) from seven patients hospitalized for COVID-19, four of whom had acute respiratory distress syndrome, and six healthy controls. We identify reconfiguration of peripheral immune cell phenotype in COVID-19, including a heterogeneous interferon-stimulated gene signature, HLA class II downregulation and a developing neutrophil population that appears closely related to plasmablasts appearing in patients with acute respiratory failure requiring mechanical ventilation. Importantly, we found that peripheral monocytes and lymphocytes do not express substantial amounts of pro-inflammatory cytokines. Collectively, we provide a cell atlas of the peripheral immune response to severe COVID-19.

    View details for DOI 10.1038/s41591-020-0944-y

    View details for PubMedID 32514174

  • Gender Differences in Authorship of Critical Care Literature. American journal of respiratory and critical care medicine Vranas, K. C., Ouyang, D., Lin, A. L., Slatore, C. G., Sullivan, D. R., Prasad Kerlin, M., Liu, K. D., Baron, R. M., Calfee, C. S., Ware, L. B., Halpern, S., Matthay, M. A., Herridge, M., Mehta, S., Rogers, A. J. 2020


    RATIONALE: Gender gaps exist in academic leadership positions in critical care. Peer-reviewed publications are crucial to career advancement, yet little is known regarding gender differences in authorship of critical care research.OBJECTIVES: To evaluate gender differences in authorship of critical care literature.METHODS: We used a validated database of author gender to analyze authorship of critical care articles indexed in PubMed between 2008-2018 in 40 frequently-cited journals. High-impact journals were defined as those in the top 5% of all journals. We used mixed-effects logistic regression to evaluate the association of senior author gender with first and middle author gender, and first author gender with journal impact factor.RESULTS: Among 18,483 studies, 30.8% had female first authors and 19.5% had female senior authors. Female authorship rose slightly over the last decade (average annual increase of 0.44% (p<0.01) and 0.51% (p<0.01) for female first and senior authors, respectively). When the senior author was female, the odds of female co-authorship rose substantially (first author aOR1.93, 95%CI:1.71-2.17; middle author aOR1.48, 95%CI:1.29-1.69). Female first authors had higher odds of publishing in lower-impact journals than men (aOR1.30, 95%CI:1.16-1.45).CONCLUSIONS: Women comprise less than one-third of first authors and one-quarter of senior authors of critical care research, with minimal increase over the past decade. When the senior author was female, the odds of female co-authorship rose substantially. However, female first authors tend to publish in lower-impact journals. These findings may help explain the underrepresentation of women in critical care academic leadership positions and identify targets for improvement.

    View details for DOI 10.1164/rccm.201910-1957OC

    View details for PubMedID 31968182

  • Prolonged Hospitalization Following Acute Respiratory Failure. Chest Marmor, M. n., Liu, S. n., Long, J. n., Chertow, G. M., Rogers, A. J. 2020


    A better understanding of the clinical features associated with prolonged hospitalization in acute respiratory failure may allow for better informed care planning.To assess the incidence, mortality, cost and clinical determinants of prolonged hospitalization among patients with acute respiratory failure (ARF).Using the National Inpatient Sample (NIS) data from 2004 to 2014, we identified adults 18 years and older with International Classification of Disease, 9th Edition (ICD-9), codes for ARF requiring mechanical ventilation for at least two days (ICD-9 518.81 or 518.82, 96.7 or 96.04, and 96.05). Outcomes studied included incidence, in-hospital mortality, cost of hospitalization, and associated patient-level and hospital-level characteristics. Trends were assessed by logistic regression, linear regression and general linear modeling with Poisson distribution.Of the 5,539,567 patients with ARF, 77,665 (1.4%) had a prolonged length of stay, defined as ≥60 days (pLOS). Among pLOS, 52,776 (68%) survived to discharge. Over the study period, incidence of pLOS decreased by 48%, in-patient mortality decreased by 18%, per patient cost-of-care rose, but percent of the total cost of ARF care consumed by patients with pLOS did not significantly decrease (p=0.06). PLOS was more likely to occur in urban teaching hospitals (OR 6.8, CI 4.6-10.2, p<0.001), hospitals located in the Northeastern US (OR 3.6, CI 3.0-4.3, p<0.001), and among patients with Medicaid insurance coverage (OR 2.1, CI 1.9-2.4, p<0.001).From 2004-2014, incidence and mortality decreased among patients with ARF and pLOS, and while per patient costs rose, percent of total cost of care remained stable. There is substantial variation in length-of-stay for patients with ARF by US region, hospital teaching status and patient insurance coverage.

    View details for DOI 10.1016/j.chest.2020.11.023

    View details for PubMedID 33333057

  • Association of Elevated Plasma Interleukin 18 Level With Increased Mortality in a Clinical Trial of Statin Treatment for Acute Respiratory Distress Syndrome. Critical care medicine Rogers, A. J., Guan, J., Trtchounian, A., Hunninghake, G. M., Kaimal, R., Desai, M., Kozikowski, L., DeSouza, L., Mogan, S., Liu, K. D., Matthay, M. A., Steingrub, J., Wheeler, A., Yoon, J. H., Nakahira, K., Choi, A. M., Baron, R. M. 2019


    OBJECTIVE: A high plasma level of inflammasome mediator interleukin-18 was associated with mortality in observational acute respiratory distress syndrome cohorts. Statin exposure increases both inflammasome activation and lung injury in mouse models. We tested whether randomization to statin therapy correlated with increased interleukin-18 in the ARDS Network Statins for Acutely Injured Lungs from Sepsis trial.DESIGN: Retrospective analysis of randomized controlled clinical trial.SETTING: Multicenter North American clinical trial, the ARDS Network Statins for Acutely Injured Lungs from Sepsis.PATIENTS: Six hundred eighty-three subjects with infection-related acute respiratory distress syndrome, representing 92% of the original trial population.INTERVENTIONS: Random assignment of rosuvastatin or placebo for up to 28 days or 3 days after ICU discharge.MEASUREMENTS AND MAIN RESULTS: We measured plasma interleukin-18 levels in all Statins for Acutely Injured Lungs from Sepsis patients with sample available at day 0 (baseline, n = 683) and day 3 (after randomization, n = 588). We tested the association among interleukin-18 level at baseline, rising interleukin-18, and the impact of statin therapy on 60-day mortality, adjusting for severity of illness. Baseline plasma interleukin-18 level greater than or equal to 800 pg/mL was highly associated with 60-day mortality, with a hazard of death of 2.3 (95% CI, 1.7-3.1). Rising plasma interleukin-18 was also associated with increased mortality. For each unit increase in log2 (interleukin-18) at day 3 compared with baseline, the hazard of death increased by 2.3 (95% CI, 1.5-3.5). Subjects randomized to statin were significantly more likely to experience a rise in plasma interleukin-18 levels. Subjects with acute kidney injury, shock, low baseline interleukin-18, and those not receiving systemic corticosteroids were more likely to experience rising interleukin-18. Randomization to statin therapy was associated with rising in interleukin-18 in all of those subsets, however.CONCLUSIONS: Elevated baseline plasma interleukin-18 was associated with higher mortality in sepsis-induced acute respiratory distress syndrome. A rise in plasma interleukin-18 was also associated with increased mortality and was more common in subjects randomized to statin therapy in this clinical trial.

    View details for DOI 10.1097/CCM.0000000000003816

    View details for PubMedID 31206358

  • Multicohort Analysis of Whole-Blood Gene Expression Data Does Not Form a Robust Diagnostic for Acute Respiratory Distress Syndrome. Critical care medicine Sweeney, T. E., Thomas, N. J., Howrylak, J. A., Wong, H. R., Rogers, A. J., Khatri, P. n. 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

  • Profiling of ARDS Pulmonary Edema Fluid Identifies a Metabolically Distinct Subset. American journal of physiology. Lung cellular and molecular physiology Rogers, A. J., Contrepois, K., Wu, M., Zheng, M., Peltz, G., Ware, L. B., Matthay, M. A. 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

  • Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19. The Journal of experimental medicine Wilk, A. J., Lee, M. J., Wei, B., Parks, B., Pi, R., Martinez-Colon, G. J., Ranganath, T., Zhao, N. Q., Taylor, S., Becker, W., Stanford COVID-19 Biobank, Jimenez-Morales, D., Blomkalns, A. L., O'Hara, R., Ashley, E. A., Nadeau, K. C., Yang, S., Holmes, S., Rabinovitch, M., Rogers, A. J., Greenleaf, W. J., Blish, C. A. 2021; 218 (8)


    Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells. We also identified chromatin accessibility changes at NF-kappaB binding sites within cytokine gene loci as a potential mechanism for the striking lack of pro-inflammatory cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.

    View details for DOI 10.1084/jem.20210582

    View details for PubMedID 34128959

  • The COVID-19 Outpatient Pragmatic Platform Study (COPPS): Study design of a multi-center pragmatic platform trial. Contemporary clinical trials Bunning, B., Hedlin, H., Purington, N., Sundaram, V., Kapphahn, K., Weng, Y., Cunanan, K., Maldonado, Y., Singh, U., Khosla, C., O'Hara, R., Nicolls, M., Springman, E., Parsonnet, J., Rogers, A., Levitt, J., Desai, M. 2021: 106509


    More than 3000 clinical trials related to COVID-19 have been registered through With so many trials, there is a risk that many will be inconclusive due to being underpowered or due to an inability to recruit patients. At academic medical centers, multiple trials are competing for the same resources; the success of one may come at the expense of another. The COVID-19 Outpatient Pragmatic Protocol Study (COPPS) is a flexible phase 2, multi-site, randomized, blinded trial based at Stanford University designed to overcome these issues by simultaneously evaluating multiple COVID-19 treatments in the outpatient setting in one common platform with shared controls. This approach reduces the overall number of patients required for statistical power, while improving the likelihood that any enrolled patient receives active treatment. The platform study has two main domains designed to evaluate COVID-19 treatments by assessing their ability to reduce viral shedding (Viral Domain), measured with self-collected nasal swabs, or improve clinical outcomes (Clinical Domain), measured through self-reported symptomology data. Data are collected on both domains for all participants enrolled. Participants are followed over a 28-day period. COPPS has the advantage of pragmatism created around its workflow that is also appealing to potential participants because of a lower probability of inactive treatment. At the conclusion of this clinical trial we expect to have identified potentially effective therapeutic strategy/ies for treating COVID-19 in the outpatient setting, which will have a transformative impact on medicine and public health.

    View details for DOI 10.1016/j.cct.2021.106509

    View details for PubMedID 34274494

  • Prospective validation of an 11-gene mRNA host response score for mortality risk stratification in the intensive care unit. Scientific reports Moore, A. R., Roque, J., Shaller, B. T., Asuni, T., Remmel, M., Rawling, D., Liesenfeld, O., Khatri, P., Wilson, J. G., Levitt, J. E., Sweeney, T. E., Rogers, A. J. 2021; 11 (1): 13062


    Several clinical calculators predict intensive care unit (ICU) mortality, however these are cumbersome and often require 24h of data to calculate. Retrospective studies have demonstrated the utility of whole blood transcriptomic analysis in predicting mortality. In this study, we tested prospective validation of an 11-gene messenger RNA (mRNA) score in an ICU population. Whole blood mRNA from 70 subjects in the Stanford ICU Biobank with samples collected within 24h of Emergency Department presentation were used to calculate an 11-gene mRNA score. We found that the 11-gene score was highly associated with 60-day mortality, with an area under the receiver operating characteristic curve of 0.68 in all patients, 0.77 in shock patients, and 0.98 in patients whose primary determinant of prognosis was acute illness. Subjects with the highest quartile of mRNA scores were more likely to die in hospital (40% vs 7%, p<0.01) and within 60days (40% vs 15%, p=0.06). The 11-gene score improved prognostication with a categorical Net Reclassification Improvement index of 0.37 (p=0.03) and an Integrated Discrimination Improvement index of 0.07 (p=0.02) when combined with Simplified Acute Physiology Score 3 or Acute Physiology and Chronic Health Evaluation II score. The test performed poorly in the 95 independent samples collected>24h after emergency department presentation. Tests will target a 30-min turnaround time, allowing for rapid results early in admission. Moving forward, this test may provide valuable real-time prognostic information to improve triage decisions and allow for enrichment of clinical trials.

    View details for DOI 10.1038/s41598-021-91201-7

    View details for PubMedID 34158514

  • Integrated analysis of multimodal single-cell data. Cell Hao, Y., Hao, S., Andersen-Nissen, E., Mauck, W. M., Zheng, S., Butler, A., Lee, M. J., Wilk, A. J., Darby, C., Zager, M., Hoffman, P., Stoeckius, M., Papalexi, E., Mimitou, E. P., Jain, J., Srivastava, A., Stuart, T., Fleming, L. M., Yeung, B., Rogers, A. J., McElrath, J. M., Blish, C. A., Gottardo, R., Smibert, P., Satija, R. 2021


    The simultaneous measurement of multiple modalities represents an exciting frontier for single-cell genomics and necessitates computational methods that can define cellular states based on multimodal data. Here, we introduce "weighted-nearest neighbor" analysis, an unsupervised framework to learn the relative utility of each data type in each cell, enabling an integrative analysis of multiple modalities. We apply our procedure to a CITE-seq dataset of 211,000 human peripheral blood mononuclear cells (PBMCs) with panels extending to 228 antibodies to construct a multimodal reference atlas of the circulating immune system. Multimodal analysis substantially improves our ability to resolve cell states, allowing us to identify and validate previously unreported lymphoid subpopulations. Moreover, we demonstrate how to leverage this reference to rapidly map new datasets and to interpret immune responses to vaccination and coronavirus disease 2019 (COVID-19). Our approach represents a broadly applicable strategy to analyze single-cell multimodal datasets and to look beyond the transcriptome toward a unified and multimodal definition of cellular identity.

    View details for DOI 10.1016/j.cell.2021.04.048

    View details for PubMedID 34062119

  • Synthetic Siglec-9 Agonists Inhibit Neutrophil Activation Associated with COVID-19 ACS CENTRAL SCIENCE Delaveris, C. S., Wilk, A. J., Riley, N. M., Stark, J. C., Yang, S. S., Rogers, A. J., Ranganath, T., Nadeau, K. C., Blish, C. A., Bertozzi, C. R., Stanford COVID-19 Biobank 2021; 7 (4): 650-657
  • The ARREST Pneumonia (Arrest Respiratory Failure due to Pneumonia) Trial: Rationale and Design. Annals of the American Thoracic Society Levitt, J. E., Festic, E., Desai, M., Hedlin, H., Mahaffey, K. W., Rogers, A. J., Gajic, O., Matthay, M. A., ARREST Pneumonia Clinical Trial Investigators 2021


    Patients hospitalized for pneumonia are at high risk for mortality. Effective therapies are therefore needed. Recent randomized clinical trials suggest that systemic steroids can reduce the length of hospital stay among patients hospitalized for pneumonia. Further, preliminary findings from a feasibility study demonstrated that early treatment with a combination of an inhaled corticosteroid and a bronchodilator can improve oxygenation and reduce risk of respiratory failure in patients at risk of acute respiratory distress syndrome. Whether such a combination administered early is effective in reducing acute respiratory failure among patients hospitalized with pneumonia is unknown. Here we describe the Arrest Respiratory Failure due to Pneumonia (ARREST Pneumonia) trial designed to address this question. ARREST Pneumonia is a two-arm randomized double-blinded placebo-controlled trial designed to test the efficacy of a combination of an inhaled corticosteroid and a beta agonist compared to placebo for the prevention of acute respiratory failure in hospitalized participants with severe pneumonia. The primary outcome is acute respiratory failure within 7 days of randomization, defined as a composite endpoint of intubation and mechanical ventilation, or need for high flow nasal cannula oxygen therapy or non-invasive ventilation for > 36 hours (each alone or combined), or death within 36 hours of being placed on respiratory support. The planned enrollment is 600 adult participants at ten academic medical centers. In addition, we will measure selected plasma biomarkers to better understand mechanisms of action. The trial is funded by the National Heart Lung and Blood Institute and is registered in (NCT04193878).

    View details for DOI 10.1513/AnnalsATS.202009-1115SD

    View details for PubMedID 33493423

  • SARS-CoV-2 RNAemia predicts clinical deterioration and extrapulmonary complications from COVID-19. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Ram-Mohan, N. n., Kim, D. n., Zudock, E. J., Hashemi, M. M., Tjandra, K. C., Rogers, A. J., Blish, C. A., Nadeau, K. C., Newberry, J. A., Quinn, J. V., O'Hara, R. n., Ashley, E. n., Nguyen, H. n., Jiang, L. n., Hung, P. n., Blomkalns, A. L., Yang, S. n. 2021


    The determinants of COVID-19 disease severity and extrapulmonary complications (EPCs) are poorly understood. We characterized relationships between SARS-CoV-2 RNAemia and disease severity, clinical deterioration, and specific EPCs.We used quantitative (qPCR) and digital (dPCR) PCR to quantify SARS-CoV-2 RNA from plasma in 191 patients presenting to the Emergency Department (ED) with COVID-19. We recorded patient symptoms, laboratory markers, and clinical outcomes, with a focus on oxygen requirements over time. We collected longitudinal plasma samples from a subset of patients. We characterized the role of RNAemia in predicting clinical severity and EPCs using elastic net regression.23.0% (44/191) of SARS-CoV-2 positive patients had viral RNA detected in plasma by dPCR, compared to 1.4% (2/147) by qPCR. Most patients with serial measurements had undetectable RNAemia within 10 days of symptom onset, reached maximum clinical severity within 16 days, and symptom resolution within 33 days. Initially RNAaemic patients were more likely to manifest severe disease (OR 6.72 [95% CI, 2.45 - 19.79]), worsening of disease severity (OR 2.43 [95% CI, 1.07 - 5.38]), and EPCs (OR 2.81 [95% CI, 1.26 - 6.36]). RNA load correlated with maximum severity (r = 0.47 [95% CI, 0.20 - 0.67]).dPCR is more sensitive than qPCR for the detection of SARS-CoV-2 RNAemia, which is a robust predictor of eventual COVID-19 severity and oxygen requirements, as well as EPCs. Since many COVID-19 therapies are initiated on the basis of oxygen requirements, RNAemia on presentation might serve to direct early initiation of appropriate therapies for the patients most likely to deteriorate.

    View details for DOI 10.1093/cid/ciab394

    View details for PubMedID 33949665

  • What Does "ARDS" Mean during the COVID-19 Pandemic? Annals of the American Thoracic Society Brown, S. M., Peltan, I. D., Barkauskas, C., Rogers, A. J., Kan, V., Gelijns, A., Thompson, B. T. 2021

    View details for DOI 10.1513/AnnalsATS.202105-534PS

    View details for PubMedID 34288834

  • A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19. The New England journal of medicine Lundgren, J. D., Grund, B., Barkauskas, C. E., Holland, T. L., Gottlieb, R. L., Sandkovsky, U., Brown, S. M., Knowlton, K. U., Self, W. H., Files, D. C., Jain, M. K., Benfield, T., Bowdish, M. E., Leshnower, B. G., Baker, J. V., Jensen, J. U., Gardner, E. M., Ginde, A. A., Harris, E. S., Johansen, I. S., Markowitz, N., Matthay, M. A., Østergaard, L., Chang, C. C., Davey, V. J., Goodman, A., Higgs, E. S., Murray, D. D., Murray, T. A., Paredes, R., Parmar, M. K., Phillips, A. N., Reilly, C., Sharma, S., Dewar, R. L., Teitelbaum, M., Wentworth, D., Cao, H., Klekotka, P., Babiker, A. G., Gelijns, A. C., Kan, V. L., Polizzotto, M. N., Thompson, B. T., Lane, H. C., Neaton, J. D. 2021; 384 (10): 905-914


    LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19.In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5.On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P = 0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P = 0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47).Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO number, NCT04501978.).

    View details for DOI 10.1056/NEJMoa2033130

    View details for PubMedID 33356051

    View details for PubMedCentralID PMC7781100

  • A generalizable 29-mRNA neural-network classifier for acute bacterial and viral infections. Nature communications Mayhew, M. B., Buturovic, L., Luethy, R., Midic, U., Moore, A. R., Roque, J. A., Shaller, B. D., Asuni, T., Rawling, D., Remmel, M., Choi, K., Wacker, J., Khatri, P., Rogers, A. J., Sweeney, T. E. 2020; 11 (1): 1177


    Improved identification of bacterial and viral infections would reduce morbidity from sepsis, reduce antibiotic overuse, and lower healthcare costs. Here, we develop a generalizable host-gene-expression-based classifier for acute bacterial and viral infections. We use training data (N=1069) from 18 retrospective transcriptomic studies. Using only 29 preselected host mRNAs, we train a neural-network classifier with a bacterial-vs-other area under the receiver-operating characteristic curve (AUROC) 0.92 (95% CI 0.90-0.93) and a viral-vs-other AUROC 0.92 (95% CI 0.90-0.93). We then apply this classifier, inflammatix-bacterial-viral-noninfected-version 1(IMX-BVN-1), without retraining, to an independent cohort (N=163). In this cohort, IMX-BVN-1 AUROCs are: bacterial-vs.-other 0.86 (95% CI 0.77-0.93), and viral-vs.-other 0.85 (95% CI 0.76-0.93). In patients enrolled within 36h of hospital admission (N=70), IMX-BVN-1 AUROCs are: bacterial-vs.-other 0.92 (95% CI 0.83-0.99), and viral-vs.-other 0.91 (95% CI 0.82-0.98). With further study, IMX-BVN-1 could provide a tool for assessing patients with suspected infection and sepsis at hospital admission.

    View details for DOI 10.1038/s41467-020-14975-w

    View details for PubMedID 32132525

  • Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome. Science immunology Röltgen, K. n., Powell, A. E., Wirz, O. F., Stevens, B. A., Hogan, C. A., Najeeb, J. n., Hunter, M. n., Wang, H. n., Sahoo, M. K., Huang, C. n., Yamamoto, F. n., Manohar, M. n., Manalac, J. n., Otrelo-Cardoso, A. R., Pham, T. D., Rustagi, A. n., Rogers, A. J., Shah, N. H., Blish, C. A., Cochran, J. R., Jardetzky, T. S., Zehnder, J. L., Wang, T. T., Narasimhan, B. n., Gombar, S. n., Tibshirani, R. n., Nadeau, K. C., Kim, P. S., Pinsky, B. A., Boyd, S. D. 2020; 5 (54)


    SARS-CoV-2-specific antibodies, particularly those preventing viral spike receptor binding domain (RBD) interaction with host angiotensin-converting enzyme 2 (ACE2) receptor, can neutralize the virus. It is, however, unknown which features of the serological response may affect clinical outcomes of COVID-19 patients. We analyzed 983 longitudinal plasma samples from 79 hospitalized COVID-19 patients and 175 SARS-CoV-2-infected outpatients and asymptomatic individuals. Within this cohort, 25 patients died of their illness. Higher ratios of IgG antibodies targeting S1 or RBD domains of spike compared to nucleocapsid antigen were seen in outpatients who had mild illness versus severely ill patients. Plasma antibody increases correlated with decreases in viral RNAemia, but antibody responses in acute illness were insufficient to predict inpatient outcomes. Pseudovirus neutralization assays and a scalable ELISA measuring antibodies blocking RBD-ACE2 interaction were well correlated with patient IgG titers to RBD. Outpatient and asymptomatic individuals' SARS-CoV-2 antibodies, including IgG, progressively decreased during observation up to five months post-infection.

    View details for DOI 10.1126/sciimmunol.abe0240

    View details for PubMedID 33288645

  • Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA Self, W. H., Semler, M. W., Leither, L. M., Casey, J. D., Angus, D. C., Brower, R. G., Chang, S. Y., Collins, S. P., Eppensteiner, J. C., Filbin, M. R., Files, D. C., Gibbs, K. W., Ginde, A. A., Gong, M. N., Harrell, F. E., Hayden, D. L., Hough, C. L., Johnson, N. J., Khan, A., Lindsell, C. J., Matthay, M. A., Moss, M., Park, P. K., Rice, T. W., Robinson, B. R., Schoenfeld, D. A., Shapiro, N. I., Steingrub, J. S., Ulysse, C. A., Weissman, A., Yealy, D. M., Thompson, B. T., Brown, S. M., Steingrub, J., Smithline, H., Tiru, B., Tidswell, M., Kozikowski, L., Thornton-Thompson, S., De Souza, L., Hou, P., Baron, R., Massaro, A., Aisiku, I., Fredenburgh, L., Seethala, R., Johnsky, L., Riker, R., Seder, D., May, T., Baumann, M., Eldridge, A., Lord, C., Shapiro, N., Talmor, D., O’Mara, T., Kirk, C., Harrison, K., Kurt, L., Schermerhorn, M., Banner-Goodspeed, V., Boyle, K., Dubosh, N., Filbin, M., Hibbert, K., Parry, B., Lavin-Parsons, K., Pulido, N., Lilley, B., Lodenstein, C., Margolin, J., Brait, K., Jones, A., Galbraith, J., Peacock, R., Nandi, U., Wachs, T., Matthay, M., Liu, K., Kangelaris, K., Wang, R., Calfee, C., Yee, K., Hendey, G., Chang, S., Lim, G., Qadir, N., Tam, A., Beutler, R., Levitt, J., Wilson, J., Rogers, A., Vojnik, R., Roque, J., Albertson, T., Chenoweth, J., Adams, J., Pearson, S., Juarez, M., Almasri, E., Fayed, M., Hughes, A., Hillard, S., Huebinger, R., Wang, H., Vidales, E., Patel, B., Ginde, A., Moss, M., Baduashvili, A., McKeehan, J., Finck, L., Higgins, C., Howell, M., Douglas, I., Haukoos, J., Hiller, T., Lyle, C., Cupelo, A., Caruso, E., Camacho, C., Gravitz, S., Finigan, J., Griesmer, C., Park, P., Hyzy, R., Nelson, K., McDonough, K., Olbrich, N., Williams, M., Kapoor, R., Nash, J., Willig, M., Ford, H., Gardner-Gray, J., Ramesh, M., Moses, M., Ng Gong, M., Aboodi, M., Asghar, A., Amosu, O., Torres, M., Kaur, S., Chen, J. T., Hope, A., Lopez, B., Rosales, K., Young You, J., Mosier, J., Hypes, C., Natt, B., Borg, B., Salvagio Campbell, E., Hite, R. D., Hudock, K., Cresie, A., Alhasan, F., Gomez-Arroyo, J., Duggal, A., Mehkri, O., Hastings, A., Sahoo, D., Abi Fadel, F., Gole, S., Shaner, V., Wimer, A., Meli, Y., King, A., Terndrup, T., Exline, M., Pannu, S., Robart, E., Karow, S., Hough, C., Robinson, B., Johnson, N., Henning, D., Campo, M., Gundel, S., Seghal, S., Katsandres, S., Dean, S., Khan, A., Krol, O., Jouzestani, M., Huynh, P., Weissman, A., Yealy, D., Scholl, D., Adams, P., McVerry, B., Huang, D., Angus, D., Schooler, J., Moore, S., Files, C., Miller, C., Gibbs, K., LaRose, M., Flores, L., Koehler, L., Morse, C., Sanders, J., Langford, C., Nanney, K., MdalaGausi, M., Yeboah, P., Morris, P., Sturgill, J., Seif, S., Cassity, E., Dhar, S., de Wit, M., Mason, J., Goodwin, A., Hall, G., Grady, A., Chamberlain, A., Brown, S., Bledsoe, J., Leither, L., Peltan, I., Starr, N., Fergus, M., Aston, V., Montgomery, Q., Smith, R., Merrill, M., Brown, K., Armbruster, B., Harris, E., Middleton, E., Paine, R., Johnson, S., Barrios, M., Eppensteiner, J., Limkakeng, A., McGowan, L., Porter, T., Bouffler, A., Leahy, J. C., deBoisblanc, B., Lammi, M., Happel, K., Lauto, P., Self, W., Casey, J., Semler, M., Collins, S., Harrell, F., Lindsell, C., Rice, T., Stubblefield, W., Gray, C., Johnson, J., Roth, M., Hays, M., Torr, D., Zakaria, A., Schoenfeld, D., Thompson, T., Hayden, D., Ringwood, N., Oldmixon, C., Ulysse, C., Morse, R., Muzikansky, A., Fitzgerald, L., Whitaker, S., Lagakos, A., Brower, R., Reineck, L., Aggarwal, N., Bienstock, K., Freemer, M., Maclawiw, M., Weinmann, G., Morrison, L., Gillespie, M., Kryscio, R., Brodie, D., Zareba, W., Rompalo, A., Boeckh, M., Parsons, P., Christie, J., Hall, J., Horton, N., Zoloth, L., Dickert, N., Diercks, D. 2020; 324 (21): 2165-2176


    Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed.To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19.This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients.Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237).The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality.Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, -0.2% [95% CI, -5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]).Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized NCT04332991.

    View details for DOI 10.1001/jama.2020.22240

    View details for PubMedID 33165621

    View details for PubMedCentralID PMC7653542

  • Association Between Peripheral Blood Oxygen Saturation (SpO2)/Fraction of Inspired Oxygen (FiO2) Ratio Time at Risk and Hospital Mortality in Mechanically Ventilated Patients. The Permanente journal Adams, J. Y., Rogers, A. J., Schuler, A., Marelich, G. P., Fresco, J. M., Taylor, S. L., Riedl, A. W., Baker, J. M., Escobar, G. J., Liu, V. X. 2020; 24


    INTRODUCTION: Acute respiratory failure requiring mechanical ventilation is a leading cause of mortality in the intensive care unit. Although single peripheral blood oxygen saturation/fraction of inspired oxygen (SpO2/FiO2) ratios of hypoxemia have been evaluated to risk-stratify patients with acute respiratory distress syndrome, the utility of longitudinal SpO2/FiO2 ratios is unknown.OBJECTIVE: To assess time-based SpO2/FiO2 ratios ≤ 150-SpO2/FiO2 time at risk (SF-TAR)-for predicting mortality in mechanically ventilated patients.METHODS: Retrospective, observational cohort study of mechanically ventilated patients at 21 community and 2 academic hospitals. Association between the SF-TAR in the first 24 hours of ventilation and mortality was examined using multivariable logistic regression and compared with the worst recorded isolated partial pressure of arterial oxygen/fraction of inspired oxygen (P/F) ratio.RESULTS: In 28,758 derivation cohort admissions, every 10% increase in SF-TAR was associated with a 24% increase in adjusted odds of hospital mortality (adjusted odds ratio = 1.24; 95% confidence interval [CI] = 1.23-1.26); a similar association was observed in validation cohorts. Discrimination for mortality modestly improved with SF-TAR (area under the receiver operating characteristic curve [AUROC] = 0.81; 95% CI = 0.81-0.82) vs the worst P/F ratio (AUROC = 0.78; 95% CI = 0.78-0.79) and worst SpO2/FiO2 ratio (AUROC = 0.79; 95% CI = 0.79-0.80). The SF-TAR in the first 6 hours offered comparable discrimination for hospital mortality (AUROC = 0.80; 95% CI = 0.79-0.80) to the 24-hour SF-TAR.CONCLUSION: The SF-TAR can identify ventilated patients at increased risk of death, offering modest improvements compared with single SpO2/FiO2 and P/F ratios. This longitudinal, noninvasive, and broadly generalizable tool may have particular utility for early phenotyping and risk stratification using electronic health record data in ventilated patients.

    View details for DOI 10.7812/TPP/19.113

    View details for PubMedID 32069205

  • Delving beneath the surface of hyperinflammation in COVID-19. The Lancet Rheumatology Reddy, K. n., Rogers, A. J., McAuley, D. F. 2020

    View details for DOI 10.1016/S2665-9913(20)30304-0

    View details for PubMedID 32864626

    View details for PubMedCentralID PMC7442423

  • Characteristics and outcomes of coronavirus disease patients under nonsurge conditions, northern California, USA, March–April 2020 Emerging Infectious Diseases Ferguson, J., Rosser, J., Quintero, O., Scott, J., Subramanian, A., Gumma, M., Rogers, A., Kappagoda, S. 2020


    Limited data are available on the clinical presentation and outcomes of coronavirus disease (COVID-19) patients in the United States hospitalized under normal-caseload or nonsurge conditions. We retrospectively studied 72 consecutive adult patients hospitalized with COVID-19 in 2 hospitals in the San Francisco Bay area, California, USA, during March 13-April 11, 2020. The death rate for all hospitalized COVID-19 patients was 8.3%, and median length of hospitalization was 7.5 days. Of the 21 (29% of total) intensive care unit patients, 3 (14.3% died); median length of intensive care unit stay was 12 days. Of the 72 patients, 43 (59.7%) had underlying cardiovascular disease and 19 (26.4%) had underlying pulmonary disease. In this study, death rates were lower than those reported from regions of the United States experiencing a high volume of COVID-19 patients.

    View details for DOI 10.3201/eid2608.201776

  • Characteristics and Outcomes of Coronavirus Disease Patients under Nonsurge Conditions, Northern California, USA, March-April 2020. Emerging infectious diseases Ferguson, J. n., Rosser, J. I., Quintero, O. n., Scott, J. n., Subramanian, A. n., Gumma, M. n., Rogers, A. n., Kappagoda, S. n. 2020; 26 (8)


    Limited data are available on the clinical presentation and outcomes of coronavirus disease (COVID-19) patients in the United States hospitalized under normal-caseload or nonsurge conditions. We retrospectively studied 72 consecutive adult patients hospitalized with COVID-19 in 2 hospitals in the San Francisco Bay area, California, USA, during March 13-April 11, 2020. The death rate for all hospitalized COVID-19 patients was 8.3%, and median length of hospitalization was 7.5 days. Of the 21 (29% of total) intensive care unit patients, 3 (14.3% died); median length of intensive care unit stay was 12 days. Of the 72 patients, 43 (59.7%) had underlying cardiovascular disease and 19 (26.4%) had underlying pulmonary disease. In this study, death rates were lower than those reported from regions of the United States experiencing a high volume of COVID-19 patients.

    View details for DOI 10.3201/eid2608.201776

    View details for PubMedID 32407284

  • Human B Cell Clonal Expansion and Convergent Antibody Responses to SARS-CoV-2. Cell host & microbe Nielsen, S. C., Yang, F. n., Jackson, K. J., Hoh, R. A., Röltgen, K. n., Jean, G. H., Stevens, B. A., Lee, J. Y., Rustagi, A. n., Rogers, A. J., Powell, A. E., Hunter, M. n., Najeeb, J. n., Otrelo-Cardoso, A. R., Yost, K. E., Daniel, B. n., Nadeau, K. C., Chang, H. Y., Satpathy, A. T., Jardetzky, T. S., Kim, P. S., Wang, T. T., Pinsky, B. A., Blish, C. A., Boyd, S. D. 2020


    B cells are critical for the production of antibodies and protective immunity to viruses. Here we show that patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) display early recruitment of B cells expressing a limited subset of IGHV genes, progressing to a highly polyclonal response of B cells with broader IGHV gene usage and extensive class switching to IgG and IgA subclasses with limited somatic hypermutation in the initial weeks of infection. We identify convergence of antibody sequences across SARS-CoV-2-infected patients, highlighting stereotyped naive responses to this virus. Notably, sequence-based detection in COVID-19 patients of convergent B cell clonotypes previously reported in SARS-CoV infection predicts the presence of SARS-CoV/SARS-CoV-2 cross-reactive antibody titers specific for the receptor-binding domain. These findings offer molecular insights into shared features of human B cell responses to SARS-CoV-2 and SARS-CoV.

    View details for DOI 10.1016/j.chom.2020.09.002

    View details for PubMedID 32941787

  • Electrical Storm in COVID-19. JACC. Case reports O'Brien, C. n., Ning, N. n., McAvoy, J. n., Mitchell, J. E., Kalwani, N. n., Wang, P. n., Nguyen, D. n., Reejhsinghani, R. n., Rogers, A. n., Lorenzo, J. n. 2020; 2 (9): 1256–60


    COVID-19 is a global pandemic caused by SARS-CoV-2. Infection is associated with significant morbidity and mortality. Individuals with pre-existing cardiovascular disease or evidence of myocardial injury are at risk for severe disease and death. Little is understood about the mechanisms of myocardial injury or life-threatening cardiovascular sequelae. (Level of Difficulty: Intermediate.).

    View details for DOI 10.1016/j.jaccas.2020.05.032

    View details for PubMedID 32835266

    View details for PubMedCentralID PMC7259914

  • The authors reply. Critical care medicine Rogers, A. J., Desai, M., Matthay, M. A., Choi, A. M., Baron, R. M. 2020; 48 (1): e78

    View details for DOI 10.1097/CCM.0000000000004081

    View details for PubMedID 31833991

  • Network study of nasal transcriptome profiles reveals master regulator genes of asthma. The Journal of allergy and clinical immunology Do, A. N., Chun, Y. n., Grishina, G. n., Grishin, A. n., Rogers, A. J., Raby, B. A., Weiss, S. T., Vicencio, A. n., Schadt, E. E., Bunyavanich, S. n. 2020


    Nasal transcriptomics can provide an accessible window into asthma pathobiology.Our goal was to move beyond gene signatures of asthma to identify master regulator genes that causally regulate genes associated with asthma phenotypes.We recruited 156 children with severe persistent asthma and controls for nasal transcriptome profiling and applied network-based and probabilistic causal methods to identify severe asthma genes and their master regulators. We then took the same approach in an independent cohort of 190 adults with mild/moderate asthma and controls to identify mild/moderate asthma genes and their master regulators. Comparative analysis of the master regulator genes followed by validation testing in independent children with severe asthma (n = 21) and mild/moderate asthma (n = 154) was then performed.Nasal gene signatures for severe persistent asthma and for mild/moderate persistent asthma were identified; both were found to be enriched in coexpression network modules for ciliary function and inflammatory response. By applying probabilistic causal methods to these gene signatures and validation testing in independent cohorts, we identified (1) a master regulator gene common to asthma across severity and ages (FOXJ1); (2) master regulator genes of severe persistent asthma in children (LRRC23, TMEM231, CAPS, PTPRC, and FYB); and (3) master regulator genes of mild/moderate persistent asthma in children and adults (C1orf38 and FMNL1). The identified master regulators were statistically inferred to causally regulate the expression of downstream genes that modulate ciliary function and inflammatory response to influence asthma.The identified master regulator genes of asthma provide a novel path forward to further uncovering asthma mechanisms and therapy.

    View details for DOI 10.1016/j.jaci.2020.07.006

    View details for PubMedID 32828590

  • Early High-Dose Vitamin D3 for Critically Ill, Vitamin D-Deficient Patients. The New England journal of medicine National Heart, L., Ginde, A. A., Brower, R. G., Caterino, J. M., Finck, L., Banner-Goodspeed, V. M., Grissom, C. K., Hayden, D., Hough, C. L., Hyzy, R. C., Khan, A., Levitt, J. E., Park, P. K., Ringwood, N., Rivers, E. P., Self, W. H., Shapiro, N. I., Thompson, B. T., Yealy, D. M., Talmor, D. 2019


    BACKGROUND: Vitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. The potential benefits of vitamin D supplementation in acute critical illness require further study.METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D3 supplementation in critically ill, vitamin D-deficient patients who were at high risk for death. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or matched placebo. The primary end point was 90-day all-cause, all-location mortality.RESULTS: A total of 1360 patients were found to be vitamin D-deficient during point-of-care screening and underwent randomization. Of these patients, 1078 had baseline vitamin D deficiency (25-hydroxyvitamin D level, <20 ng per milliliter [50 nmol per liter]) confirmed by subsequent testing and were included in the primary analysis population. The mean day 3 level of 25-hydroxyvitamin D was 46.9±23.2 ng per milliliter (117±58 nmol per liter) in the vitamin D group and 11.4±5.6 ng per milliliter (28±14 nmol per liter) in the placebo group (difference, 35.5 ng per milliliter; 95% confidence interval [CI], 31.5 to 39.6). The 90-day mortality was 23.5% in the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of 528 patients) (difference, 2.9 percentage points; 95% CI, -2.1 to 7.9; P=0.26). There were no clinically important differences between the groups with respect to secondary clinical, physiological, or safety end points. The severity of vitamin D deficiency at baseline did not affect the association between the treatment assignment and mortality.CONCLUSIONS: Early administration of high-dose enteral vitamin D3 did not provide an advantage over placebo with respect to 90-day mortality or other, nonfatal outcomes among critically ill, vitamin D-deficient patients. (Funded by the National Heart, Lung, and Blood Institute; VIOLET number, NCT03096314.).

    View details for DOI 10.1056/NEJMoa1911124

    View details for PubMedID 31826336

  • Semi-quantitative visual assessment of chest radiography is associated with clinical outcomes in critically ill patients. Respiratory research Mason, S. E., Dieffenbach, P. B., Englert, J. A., Rogers, A. A., Massaro, A. F., Fredenburgh, L. E., Higuera, A., Pinilla-Vera, M., Vilas, M., San Jose Estepar, R., Washko, G. R., Baron, R. M., Ash, S. Y. 2019; 20 (1): 218


    BACKGROUND: Respiratory pathology is a major driver of mortality in the intensive care unit (ICU), even in the absence of a primary respiratory diagnosis. Prior work has demonstrated that a visual scoring system applied to chest radiographs (CXR) is associated with adverse outcomes in ICU patients with Acute Respiratory Distress Syndrome (ARDS). We hypothesized that a simple, semi-quantitative CXR score would be associated with clinical outcomes for the general ICU population, regardless of underlying diagnosis.METHODS: All individuals enrolled in the Registry of Critical Illness at Brigham and Women's Hospital between June 2008 and August 2018 who had a CXR within 24h of admission were included. Each patient's CXR was assigned an opacification score of 0-4 in each of four quadrants with the total score being the sum of all four quadrants. Multivariable negative binomial, logistic, and Cox regression, adjusted for age, sex, race, immunosuppression, a history of chronic obstructive pulmonary disease, a history of congestive heart failure, and APACHE II scores, were used to assess the total score's association with ICU length of stay (LOS), duration of mechanical ventilation, in-hospital mortality, 60-day mortality, and overall mortality, respectively.RESULTS: A total of 560 patients were included. Higher CXR scores were associated with increased mortality; for every one-point increase in score, in-hospital mortality increased 10% (OR 1.10, CI 1.05-1.16, p<0.001) and 60-day mortality increased by 12% (OR 1.12, CI 1.07-1.17, p<0.001). CXR scores were also independently associated with both ICU length of stay (rate ratio 1.06, CI 1.04-1.07, p<0.001) and duration of mechanical ventilation (rate ratio 1.05, CI 1.02-1.07, p<0.001).CONCLUSIONS: Higher values on a simple visual score of a patient's CXR on admission to the medical ICU are associated with increased in-hospital mortality, 60-day mortality, overall mortality, length of ICU stay, and duration of mechanical ventilation.

    View details for DOI 10.1186/s12931-019-1201-0

    View details for PubMedID 31606045

  • Plasma mitochondrial DNA and metabolomic alterations in severe critical illness. Critical care (London, England) Johansson, P. I., Nakahira, K., Rogers, A. J., McGeachie, M. J., Baron, R. M., Fredenburgh, L. E., Harrington, J., Choi, A. M., Christopher, K. B. 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 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 Wu, A., Kiley, J. P., Noel, P. J., Amur, S., Burchard, E. G., Clancy, J. P., Galanter, J., Inada, M., Jones, T. K., Kropski, J. A., Loyd, J. E., Nogee, L. M., Raby, B. A., Rogers, A. J., Schwartz, D. A., Sin, D. D., Spira, A., Weiss, S. T., Young, L. R., Himes, B. E., Amer Thoracic Soc Assembly Behav, Sect Genetics Genomics 2018; 198 (12): 1479–89
  • 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 Matthay, M. A., Calfee, C. S., Zhuo, H., Thompson, B. T., Wilson, J. G., Levitt, J. E., Rogers, A. J., Gotts, J. E., Wiener-Kronish, J. P., Bajwa, E. K., Donahoe, M. P., McVerry, B. J., Ortiz, L. A., Exline, M., Christman, J. W., Abbott, J., Delucchi, K. L., Caballero, L., McMillan, M., McKenna, D. H., Liu, K. D. 2018


    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, 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 [33]), 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

  • MUC5B Promoter Polymorphism and Development of ARDS. American journal of respiratory and critical care medicine Rogers, A. J., Solus, J. F., Hunninghake, G. M., Baron, R. M., Meyer, N. J., Janz, D. R., Schwartz, D. A., May, A. K., Lawson, W. E., Blackwell, T. S., Ware, L. B. 2018

    View details for PubMedID 30025215

  • A Nasal Brush-based Classifier of Asthma Identified by Machine Learning Analysis of Nasal RNA Sequence Data SCIENTIFIC REPORTS Pandey, G., Pandey, O. P., Rogers, A. J., Ahsen, M. E., Hoffman, G. E., Raby, B. A., Weiss, S. T., Schadt, E. E., Bunyavanich, S. 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 PubMedID 29891868

  • GWAS in ARDS: Finding the Needle in the Haystack to Advance our Understanding of ARDS. American journal of respiratory and critical care medicine Rogers, A. J. 2018

    View details for PubMedID 29438627

  • VITAMIN C AND METABOLOME ALTERATIONS IN SEVERE CRITICAL ILLNESS Golmai, P., Rogers, A., Baron, R., Gazourian, L., Chary, S., Fredenburgh, L., Massaro, A., Choi, A., Christopher, K. LIPPINCOTT WILLIAMS & WILKINS. 2018: 712
  • Gene Expression Analysis to Assess the Relevance of Rodent Models to Human Lung Injury. American journal of respiratory cell and molecular biology Sweeney, T. E., Lofgren, S., Khatri, P., Rogers, A. J. 2017


    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

  • New Strategies and Challenges in Lung Proteomics and Metabolomics. An Official American Thoracic Society Workshop Report. Annals of the American Thoracic Society Bowler, R. P., Wendt, C. H., Fessler, M. B., Foster, M. W., Kelly, R. S., Lasky-Su, J. n., Rogers, A. J., Stringer, K. A., Winston, B. W. 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

  • Epidemiologic and Population Genetic Studies CLINICAL AND TRANSLATIONAL SCIENCE: PRINCIPLES OF HUMAN RESEARCH, 2ND EDITION Rogers, A. J., Weiss, S. T., Robertson, D., Williams, G. H. 2017: 313–26
  • Metabolome alterations in severe critical illness and vitamin D status. Critical care (London, England) Lasky-Su, J. n., Dahlin, A. n., Litonjua, A. A., Rogers, A. J., McGeachie, M. J., Baron, R. M., Gazourian, L. n., Barragan-Bradford, D. n., Fredenburgh, L. E., Choi, A. M., Mogensen, K. M., Quraishi, S. A., Amrein, K. n., Christopher, K. B. 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 PubMedID 28750641

    View details for PubMedCentralID PMC5532782

  • A resident-created hospitalist curriculum for internal medicine housestaff. Journal of hospital medicine Kumar, A., Smeraglio, A., Witteles, R., Harman, S., Nallamshetty, S., Rogers, A., Harrington, R., Ahuja, N. 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 Calvert, J., Mao, Q., Rogers, A. J., Barton, C., Jay, M., Desautels, T., Mohamadlou, H., Jan, J., Das, R. 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

  • 16 Years and Counting? Time to Implement Noninvasive Screening for ARDS CHEST Rogers, A. J., Liu, V. X. 2016; 150 (2): 266–67

    View details for PubMedID 27502976

  • Metabolism, Metabolomics, and Nutritional Support of Patients with Sepsis CLINICS IN CHEST MEDICINE Englert, J. A., Rogers, A. J. 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 Levitt, J. E., Rogers, A. J. 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 McSparron, J. I., Hayes, M. M., Poston, J. T., Thomson, C. C., Fessler, H. E., Stapleton, R. D., Carlos, W. G., Hinkle, L., Liu, K., Shieh, S., Ali, A., Rogers, A., Shah, N. G., Slack, D., Patel, B., Wolfe, K., Schweickert, W. D., Bakhru, R. N., Shin, S., Sell, R. E., Luks, A. M. 2016; 13 (5): 731-740

    View details for DOI 10.1513/AnnalsATS.201601-050CME

    View details for PubMedID 27144797

  • 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 Mogensen, K. M., Lasky-Su, J. n., Rogers, A. J., Baron, R. M., Fredenburgh, L. E., Rawn, J. n., Robinson, M. K., Massarro, A. n., Choi, A. M., Christopher, K. B. 2016


    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 PubMedID 27406941

  • Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Kangelaris, K. N., Prakash, A., Liu, K. D., Aouizerat, B., Woodruff, P. G., Erle, D. J., Rogers, A., Seeley, E. J., Chu, J., Liu, T., Osterberg-Deiss, T., Zhuo, H., Matthay, M. A., Calfee, C. S. 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 Rogers, A. J., Dhillon, G. S. 2015; 43 (3): 721-722

    View details for DOI 10.1097/CCM.0000000000000800

    View details for PubMedID 25700066

  • Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. The Lancet. Respiratory medicine Wilson, J. G., Liu, K. D., Zhuo, H., Caballero, L., McMillan, M., Fang, X., Cosgrove, K., Vojnik, R., Calfee, C. S., Lee, J., Rogers, A. J., Levitt, J., Wiener-Kronish, J., Bajwa, E. K., Leavitt, A., McKenna, D., Thompson, B. T., Matthay, M. A. 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, 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. PloS one Croteau-Chonka, D. C., Rogers, A. J., Raj, T., McGeachie, M. J., Qiu, W., Ziniti, J. P., Stubbs, B. J., Liang, L., Martinez, F. D., Strunk, R. C., Lemanske, R. F., Liu, A. H., Stranger, B. E., Carey, V. J., Raby, B. A. 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

  • Pharmacogenomics: novel loci identification via integrating gene differential analysis and eQTL analysis. Human molecular genetics Qiu, W., Rogers, A. J., Damask, A., Raby, B. A., Klanderman, B. J., Duan, Q. L., Tyagi, S., Niu, S., Anderson, C., Cahir-McFarland, E., Mariani, T. J., Carey, V., Tantisira, K. G. 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 Langley, R. J., Tipper, J. L., Bruse, S., Baron, R. M., Tsalik, E. L., Huntley, J., Rogers, A. J., Jaramillo, R. J., O'Donnell, D., Mega, W. M., Keaton, M., Kensicki, E., Gazourian, L., Fredenburgh, L. E., Massaro, A. F., Otero, R. M., Fowler, V. G., Rivers, E. P., Woods, C. W., Kingsmore, S. F., Sopori, M. L., Perrella, M. A., Choi, A. M., Harrod, K. S. 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 Liu, K. D., Wilson, J. G., Zhuo, H., Caballero, L., McMillan, M. L., Fang, X., Cosgrove, K., Calfee, C. S., Lee, J., Kangelaris, K. N., Gotts, J. E., Rogers, A. J., Levitt, J. E., Wiener-Kronish, J. P., Delucchi, K. L., Leavitt, A. D., McKenna, D. H., Thompson, B. T., Matthay, M. A. 2014; 4
  • Applying metabolomics to uncover novel biology in ARDS. American journal of physiology. Lung cellular and molecular physiology Rogers, A. J., Matthay, M. A. 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

  • Factors associated with bronchiolitis obliterans syndrome and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation AMERICAN JOURNAL OF HEMATOLOGY Gazourian, L., Rogers, A. J., Ibanga, R., Weinhouse, G. L., Pinto-Plata, V., Ritz, J., Soiffer, R. J., Antin, J. H., Washko, G. R., Baron, R. M., Ho, V. T. 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 PLOS ONE Rogers, A. J., McGeachie, M., Baron, R. M., Gazourian, L., Haspel, J. A., Nakahira, K., Fredenburgh, L. E., Hunninghake, G. M., Raby, B. A., Matthay, M. A., Otero, R. M., Fowler, V. G., Rivers, E. P., Woods, C. W., Kingsmore, S., Langley, R. J., Choi, A. M. 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 Liu, K. D., Wilson, J. G., Zhuo, H., Caballero, L., McMillan, M. L., Fang, X., Cosgrove, K., Calfee, C. S., Lee, J., Kangelaris, K. N., Gotts, J. E., Rogers, A. J., Levitt, J. E., Wiener-Kronish, J. P., Delucchi, K. L., Leavitt, A. D., McKenna, D. H., Thompson, B. T., Matthay, M. A. 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

  • Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation PLOS MEDICINE Nakahira, K., Kyung, S., Rogers, A. J., Gazourian, L., Youn, S., Massaro, A. F., Quintana, C., Osorio, J. C., Wang, Z., Zhao, Y., Lawler, L. A., Christie, J. D., Meyer, N. J., Mc Causland, F. R., Waikar, S. S., Waxman, A. B., Chung, R. T., Bueno, R., Rosas, I. O., Fredenburgh, L. E., Baron, R. M., Christiani, D. C., Hunninghake, G. M., Choi, A. M. 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 Web of Science ID 000330534300016

    View details for PubMedID 24391478

    View details for PubMedCentralID PMC3876981

  • Copy number variation genotyping using family information BMC BIOINFORMATICS Chu, J., Rogers, A., Ionita-Laza, I., Darvishi, K., Mills, R. E., Lee, C., Raby, B. A. 2013; 14


    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 Rogers, A. J., Chu, J., Darvishi, K., Ionita-Laza, I., Lehmann, H., Mills, R., Lee, C., Raby, B. A. 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 Langley, R. J., Tsalik, E. L., Velkinburgh, J. C., Glickman, S. W., Rice, B. J., Wang, C. n., Chen, B. n., Carin, L. n., Suarez, A. n., Mohney, R. P., Freeman, D. H., Wang, M. n., You, J. n., Wulff, J. n., Thompson, J. W., Moseley, M. A., Reisinger, S. n., Edmonds, B. T., Grinnell, B. n., Nelson, D. R., Dinwiddie, D. L., Miller, N. A., Saunders, C. J., Soden, S. S., Rogers, A. J., Gazourian, L. n., Fredenburgh, L. E., Massaro, A. F., Baron, R. M., Choi, A. M., Corey, G. R., Ginsburg, G. S., Cairns, C. B., Otero, R. M., Fowler, V. G., Rivers, E. P., Woods, C. W., Kingsmore, S. F. 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 Dolinay, T., Kim, Y. S., Howrylak, J., Hunninghake, G. M., An, C. H., Fredenburgh, L., Massaro, A. F., Rogers, A., Gazourian, L., Nakahira, K., Haspel, J. A., Landazury, R., Eppanapally, S., Christie, J. D., Meyer, N. J., Ware, L. B., Christiani, D. C., Ryter, S. W., Baron, R. M., Choi, A. M. 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 Hunninghake, G. M., Chu, J., Sharma, S. S., Cho, M. H., Himes, B. E., Rogers, A. J., Murphy, A., Carey, V. J., Raby, B. A. 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 GENETIC EPIDEMIOLOGY Murphy, A., Won, S., Rogers, A., Chu, J., Raby, B. A., Lange, C. 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. ([2008]. 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 Sharma, S., Tantisira, K., Carey, V., Murphy, A. J., Lasky-Su, J., Celedon, J. C., Lazarus, R., Klanderman, B., Rogers, A., Soto-Quiros, M., Avila, L., Mariani, T., Gaedigk, R., Leeders, S., Torday, J., Warburton, D., Raby, B., Weiss, S. T. 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 Rogers, A. J., Brasch-Andersen, C., Ionita-Laza, I., Murphy, A., Sharma, S., Klanderman, B. J., Raby, B. A. 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 PHARMACOGENOMICS Rogers, A. J., Tantisira, K. G., Fuhlbrigge, A. L., Litonjua, A. A., Lasky-Su, J. A., Szefler, S. J., Strunk, R. C., Zeiger, R. S., Weiss, S. T. 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 Rogers, A. J., Raby, B. A., Lasky-Su, J. A., Murphy, A., Lazarus, R., Klanderman, B. J., Sylvia, J. S., Ziniti, J. P., Lange, C., Celedon, J. C., Silverman, E. K., Weiss, S. T. 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 Weiss, S. T., Raby, B. A., Rogers, A. 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 GENOMICS Ionita-Laza, I., Rogers, A. J., Lange, C., Raby, B. A., Lee, C. 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 Rogers, A. J., Celedon, J. C., Lasky-Su, J. A., Weiss, S. T., Raby, B. A. 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