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Study Description

This sub-study phs000334 LungGO ALI contains genotype and selected phenotype of subjects available from the phs000631 study. Summary level phenotypes for the "ARDSnet and the iSPAAR Consortium: Genetic Studies" study participants can be viewed at the top-level study page phs000631 ARDSNet iSPAAR cohort. Individual level phenotype data and molecular data for all ARDSnet and the "iSPAAR Consortium: Genetic Studies" top-level study and sub-studies are available by requesting Authorized Access to the "ARDSnet and the iSPAAR Consortium: Genetic Studies" phs000631 study.

The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO.

The major goal of the NHLBI Lung Cohort Sequencing Project as part of the NHLBI Exome Sequencing Project (ESP) is to apply massive parallel re-sequencing of the exome to identify disease-causing variants affecting a key set of pediatric and adult lung diseases. The goal of the Acute Lung Injury (ALI) cohort project is to identify exonic variants that affect severity of ALI. In the "discovery" phase we performed genome-wide exon (exome) re-sequencing in 89 samples collected from two groups of Caucasian patients with ALI related to septic shock with divergent severity of lung injury. Lung injury severity was measured by the composite variable days alive and free of mechanical ventilation at 28 days (DAFMV28). Group one, the "mild" lung injury phenotype, required minimal mechanical ventilation support (DAFMV28 > 22), and the second group, the "severe" lung injury phenotype, required extended mechanical ventilation support (DAFMV28<1) or died on or soon after discontinuation of mechanical ventilator support All patients were evaluated for basic demographics, underlying co-morbidities, and severity of illness. Exome variants were compared between the Mild and Severe group using gene-centric algorithms to identify genes that harbored excess variation in either the Mild or Severe group.

In the "validation" phase we tested whether the findings from exome sequencing could be validated in 1469 ALI cases using microarray-based genotyping of exonic variants. The cases were compiled from 3 ALI cohorts collected under NIH/NHLBI funded projects. The largest set of subject data and DNA was shared by the ARDS Network, which organized multicenter phase 3 trials for ALI patients. Clinical data and DNA were available for subjects in 4 recent ARDSNet trials (FACTT, ALTA, EDEN, Omega). A second set of ALI cases came from the Molecular Epidemiology of ARDS (MEA) study at the Harvard School of Public Healthy led by David Christiani, MD, MPH. The third set of ALI cases was obtained from the Validating Acute Lung Injury biomarkers for Diagnosis (VALID) study led by Dr. Lorraine Ware of Vanderbilt University. All subjects were genotyped on the Illumina HumanExome Chip developed by the Exome Sequencing Project (ESP) and which contained >240,000 low frequency exonic variants that were identified in the ESP studies, including the Lung Cohorts studies. Our primary validation analysis tested whether genes harboring excess exonic variation in the Mild or Severe ALI in the discovery phase are associated with DAFMV28 in the validation phase. In contrast with the discovery phase, in the validation phase we used all ALI cases across the full distribution of DAFMV28 rather than selecting "extremes" as was done in the discovery phase. As in the discovery set, we used gene-centric analysis algorithms to identify genes with variation that associated with quartiles of DAFMV28.

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Publicly Available Data (Public ftp)
Study Inclusion/Exclusion Criteria

Discovery Phase

Inclusion:

  1. Caucasian
  2. ALI by AECC Criteria
  3. Presence of Septic Shock
  4. Acute physiology score > 45
  5. "Controls" (Mild ALI) - low need for mechanical ventilation DAFMV28 >22
  6. "Cases" (Severe ALI) - high need for mechanical ventilation DAFMV28 < 1

Exclusions:

  1. Metastatic cancer
  2. Hemodialysis dependence
  3. Hepatic failure
  4. Immunosuppression

Matching:

  1. Age
  2. Gender
  3. Smoking status

Validation Phase

Inclusion:

  1. Caucasian
  2. ALI by AECC Criteria

Exclusion:

  1. Metastatic cancer
  2. Hepatic failure
  3. Immunosuppression

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Exon Variant Genotyping Illumina Infinium HumanExome BeadChip N/A N/A
Exome Sequencing Roche NimbleGen SeqCap EZ Human Exome Library v2.0 N/A N/A
Whole Exome Sequencing Illumina Genome Analyzer IIX N/A N/A
Whole Exome Sequencing Illumina HiSeq1000 N/A N/A
Study History

The goal of the NHLBI Lung Cohort Sequencing Project is to apply next-generation re-sequencing to identify disease-causing variants influencing a key set of pediatric and adult lung diseases such as asthma, COPD, cystic fibrosis, pulmonary arterial hypertension, and acute lung injury (ALI). Re-sequencing genes in individuals with well-characterized lung phenotypes assesses the contribution that both rare and common variants make to lung disease by integrating the re-sequencing data with genome-wide association (GWAS) findings.

DNA samples and clinical data from a cohort of patients with ALI were originally collected by Dr. David Christiani as part of the Molecular Epidemiology of ARDS project at Harvard School of Public Health. A description of the cohort appears in recent publications from Dr. Christiani's group. Samples selected as described above were used for exome re-sequencing through the NHLBI Exome Sequencing Project.

Exome Chip genotyping for validation was performed on samples contributed by Dr. Christiani, as well as from the ARDSNet consortium (http://www.ardsnet.org), an NHLBI-funded clinical research network that performs randomized clinical trials in ALI, and from Dr. Lorraine Ware at Vanderbilt University. Dr. Ware's samples were originally collected as part of the VALID study, "Validating Acute Lung Injury Markers for Diagnosis". Cohort description is referenced in publications listed below.

Selected publications
Diseases/Traits Related to Study (MeSH terms)
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