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High Throughput Sequencing in Respiratory, Critical Care and Sleep Medicine Research: An Official American Thoracic Society Workshop ReportCraig P. Hersh 1, Ian M. Adcock 2, Juan C. Celedón 3, Michael H. Cho 1, David C. Christiani 4, Blanca E. Himes 5, Naftali Kaminski 6, Rasika A. Mathias 7, Deborah A. Meyers 8, John Quackenbush 9, Susan Redline 10, Katrina A. Steiling 11, Holly K. Tabor 12, Martin D. Tobin 13, 14, Mark M. Wurfel 15, Ivana V. Yang16, and Gerard H. Koppelman 17, 18 on behalf of the American Thoracic Society Section on Genetics and Genomics 1. Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA, USA2. Airways Disease Section, National Heart and Lung Institute, Imperial College London, UK3. Division of Pediatric Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA4. Harvard T.H. Chan School of Public Health, Departments of Environmental Health and Epidemiology, and the Pulmonary and Critical Care Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.5. Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, USA6. Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA7. Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA8. University of Arizona College of Medicine, Tucson, AZ, USA.9. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA10. Departments of Medicine, Brigham and Women's Hospital and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.11. Division of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA.12. Stanford Center for Biomedical Ethics, Department of Medicine, Stanford University, School of Medicine, Stanford, CA, USA13. Department of Health Sciences, University of Leicester, Leicester, UK14. National Institute for Health Research Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK15. Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA, USA.16. Department of Medicine, University of Colorado, Denver, CO, USA17. University of Groningen, University Medical Center Groningen, Beatrix Children’s Hospital, Department of Pediatric Pulmonology and Pediatric Allergology, 18. University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPDCorresponding author:Craig P. Hersh, MD, MPHChanning Division of Network MedicineBrigham and Women's Hospital,181 Longwood Ave.Boston MA 02115Phone +1-617-525-0729Fax +1-617-525-0958craig.hersh@channing.harvard.eduKey words: bioinformatics, functional genomics, genetic epidemiology, RNA sequencing, whole genome sequencingWord count: 4478/4500Abstract High throughput, “next generation” sequencing methods are now being broadly applied across all fields of biomedical research, including respiratory disease, critical care, and sleep medicine. While there are numerous review articles and best practice guidelines related to sequencing methods and data analysis, there are fewer resources summarizing issues related to study design and interpretation, especially as applied to common, complex, non-malignant diseases. To address these gaps, a single day workshop was held at the American Thoracic Society meeting in May 2017, led by the ATS Section on Genetics and Genomics. The aim of this workshop was to review the design, analysis, interpretation, and functional follow-up of high throughput sequencing studies in respiratory, critical care, and sleep medicine research. This workshop brought together experts in multiple fields, including genetic epidemiology, biobanking, bioinformatics, and research ethics, along with physician-scientists with expertise in a range of relevant diseases. The workshop focused on application of DNA and RNA sequencing research in common, chronic diseases, and did not cover sequencing studies in lung cancer, monogenic diseases (e.g. cystic fibrosis), or microbiome sequencing. Participants reviewed and discussed study design, data analysis and presentation, interpretation, functional follow-up and reporting of results. This report summarizes the main conclusions of the workshop, specifically addressing the application of these methods in respiratory, critical care, and sleep medicine research. This workshop report may serve as a resource for our research community, as well as for journal editors and reviewers of sequencing-based manuscript submissions in our research field.Word count: 246/250ContentsOverviewWorkshop AgendaPrinciples of study designStudy designs and phenotyping for genetic epidemiologyBiobanksHealth equityResearch ethicsNext generation DNA sequencingStudy designIdentifying causal variantsNext generation RNA sequencingStudy designSequencing methodsSmall RNA sequencingReporting for RNA sequencing experimentsData analysisBioinformaticsQuality controlStatistical analysisData sharingCell type heterogeneitySingle cell sequencingMulti-omics integrationFunctional validationConclusionsOverview High throughput, next generation, sequencing technologies (NGS) (see Box 1 for a glossary of terms) are becoming increasingly used in studies of common, complex diseases, including respiratory diseases such as asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis; critical illnesses; and sleep disorders (Table 1) (Figure 1) PGtleSBhcHA9IkVOIiBkYi1pZD0iYXdlc3JkcGZxcHZmZjNlc3JkcXhkNXZucDBkOXdldnN4eGZ6

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ADDIN EN.CITE.DATA (1-15). RNA sequencing is now more cost-effective than microarrays, and exome and whole genome DNA sequencing are rapidly replacing genotyping arrays. Given the widespread application of these techniques in respiratory, critical care and sleep medicine research, a workshop was organized at the ATS International Conference in Washington, DC in May 2017. The aim of this workshop was to review the design, analysis, interpretation, and functional follow-up of high throughput sequencing studies in respiratory, critical care, and sleep medicine research. Whereas reviews and best practices guidelines for DNA and RNA sequencing have been published PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db25lc2E8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (16, 17), this workshop focused on the application of DNA and RNA sequencing to common, complex diseases in human populations, but not on epigenome or microbiome studies, or cancer genetics. Workshop AgendaThe workshop participants focused on five topics, each of which concluded with a panel discussion. Areas of emphasis included study design, ethical considerations and health inequalities, applications of DNA and RNA sequencing, cell type heterogeneity, and functional studies. Biomedical literature searches were conducted by the speakers and co-chairs. The co-chairs collected summaries from speakers, and a writing group prepared the document for review by the workshop participants. Recommendations were formulated by discussion and consensus (Box 2).Principles of Study DesignStudy Designs and Phenotyping for Genetic EpidemiologyThe general principles of epidemiology study design remain true for genetic epidemiology studies, including subject ascertainment, phenotype definition, and sample size considerations, as summarized in the STrengthening the REporting of Genetic Association Studies (STREGA) Guidelines PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXR0bGU8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (18). There are several possible designs for genetics studies of respiratory disease. In the past, most studies enrolled subjects ascertained for a specific condition. These studies usually employ careful phenotyping to define the disease of interest using endotypes, such as methacholine challenge testing or polysomnography PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IaW1lczwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (19-21). General population (cohort) studies may offer the advantage of large sample sizes and the ability to study multiple outcomes, though the phenotyping may not be as precise. Questionnaires may be the primary source of respiratory disease diagnosis, though several large cohorts have included spirometry PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxrPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (25). General population cohorts have limited utility in studies of critical illness, where subjects are enrolled in the hospital ADDIN EN.CITE <EndNote><Cite><Author>Rogers</Author><Year>2018</Year><RecNum>5286</RecNum><DisplayText>(26)</DisplayText><record><rec-number>5286</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1519420818">5286</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rogers, A. J.</author></authors></contributors><auth-address>1 Department of Medicine Stanford University Stanford, California.</auth-address><titles><title>Genome-Wide Association Study in Acute Respiratory Distress Syndrome. Finding the Needle in the Haystack to Advance Our Understanding of Acute Respiratory Distress Syndrome</title><secondary-title>Am J Respir Crit Care Med</secondary-title></titles><periodical><full-title>Am J Respir Crit Care Med</full-title></periodical><pages>1373-1374</pages><volume>197</volume><number>11</number><keywords><keyword>Ards</keyword><keyword>Gwas</keyword><keyword>Genomics</keyword><keyword>Selplg</keyword></keywords><dates><year>2018</year><pub-dates><date>Jun 1</date></pub-dates></dates><isbn>1535-4970 (Electronic)&#xD;1073-449X (Linking)</isbn><accession-num>29438627</accession-num><urls><related-urls><url>;(26). Although most recent studies have been case-control or cohort studies, family-based studies still play a role, especially in the analysis of rare variants, where transmission can be followed through a pedigree ADDIN EN.CITE <EndNote><Cite><Author>Bamshad</Author><Year>2011</Year><RecNum>5287</RecNum><DisplayText>(27)</DisplayText><record><rec-number>5287</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1519421372">5287</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bamshad, M. J.</author><author>Ng, S. B.</author><author>Bigham, A. W.</author><author>Tabor, H. K.</author><author>Emond, M. J.</author><author>Nickerson, D. A.</author><author>Shendure, J.</author></authors></contributors><auth-address>Department of Pediatrics, University of Washington, Health Sciences Building RR349, 1959 NE Pacific Street, Seattle, Washington 98195-6320, USA. mbamshad@u.washington.edu</auth-address><titles><title>Exome sequencing as a tool for Mendelian disease gene discovery</title><secondary-title>Nat Rev Genet</secondary-title></titles><periodical><full-title>Nat Rev Genet</full-title></periodical><pages>745-55</pages><volume>12</volume><number>11</number><keywords><keyword>Alleles</keyword><keyword>Base Sequence</keyword><keyword>Exome/*genetics</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>*Genome, Human</keyword><keyword>Genome-Wide Association Study</keyword><keyword>Humans</keyword><keyword>Molecular Sequence Data</keyword><keyword>Pedigree</keyword><keyword>Phenotype</keyword><keyword>Sequence Analysis, DNA/*methods</keyword></keywords><dates><year>2011</year><pub-dates><date>Sep 27</date></pub-dates></dates><isbn>1471-0064 (Electronic)&#xD;1471-0056 (Linking)</isbn><accession-num>21946919</accession-num><urls><related-urls><url>;(27).As genomic data sharing has become the norm, secondary analysis for respiratory diseases is now routinely performed in general population studies, such as the Framingham Heart Study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxrPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (22). When secondary data will be used or when multiple studies will be combined in a meta-analysis, investigators must carefully review the phenotyping methods, including the specific questionnaire items, to be sure that similar traits are being compared. In case-control studies, control subjects should have comparable exposures, such as smokers with normal lung function in COPD studies or patients with multi-trauma, pneumonia, or sepsis who did not develop ARDS PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaG88L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (28-30). BiobanksSequencing studies undertaken at the scale required for well-powered association testing require organized efforts, with coordinated biobanking.? Rare diseases and phenotypes may be due to genetic variants with high penetrance, which may be detectable in relatively modest numbers of samples. Even in this situation, and in the absence of many different mutations causing similar phenotypes, it is helpful to draw upon very large numbers of sequenced individuals. Genomics England (the “100,000 Genomes Project”) ADDIN EN.CITE <EndNote><Cite><Author>Turnbull</Author><Year>2018</Year><RecNum>5340</RecNum><DisplayText>(31)</DisplayText><record><rec-number>5340</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1525956529">5340</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Turnbull, C.</author></authors></contributors><auth-address>Professor of Genomic Medicine, Queen Mary University of London; Consultant in Clinical Genetics, Guy&apos;s and St Thomas&apos; NHS Trust, UK.</auth-address><titles><title>Introducing whole-genome sequencing into routine cancer care: the Genomics England 100 000 Genomes Project</title><secondary-title>Ann Oncol</secondary-title></titles><periodical><full-title>Annals of Oncology</full-title><abbr-1>Ann. Oncol.</abbr-1><abbr-2>Ann Oncol</abbr-2></periodical><pages>784-787</pages><volume>29</volume><number>4</number><dates><year>2018</year><pub-dates><date>Apr 1</date></pub-dates></dates><isbn>1569-8041 (Electronic)&#xD;0923-7534 (Linking)</isbn><accession-num>29462260</accession-num><urls><related-urls><url>;(31), the NHLBI Trans-Omics in Precision Medicine (TOPMed)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccm9keTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (33) are initiatives that will enhance such comparisons, which are critical to confirm whether variants are causal for the disease in question (Table 2). The Genomics England project is recruiting patients with cancers, infectious diseases such as tuberculosis, and rare diseases, including primary ciliary dyskinesia, spontaneous pneumothorax, familial pulmonary fibrosis and familial multiple pulmonary arteriovenous malformations. Complementing efforts that specifically recruit individuals with particular diseases are population biobanks that are agnostic to health status, many of which have extensive longitudinal follow-up. The UK Biobank recruited 500,000 participants aged 40-69 years ADDIN EN.CITE <EndNote><Cite><Author>Collins</Author><Year>2012</Year><RecNum>5342</RecNum><DisplayText>(34)</DisplayText><record><rec-number>5342</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1525956532">5342</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Collins, R.</author></authors></contributors><auth-address>UK Biobank, Adswood, Stockport SK3 0SA, UK. ukbiobank@ukbiobank.ac.uk</auth-address><titles><title>What makes UK Biobank special?</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>1173-4</pages><volume>379</volume><number>9822</number><keywords><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Biological Specimen Banks/*organization &amp; administration</keyword><keyword>Chronic Disease/*epidemiology/prevention &amp; control</keyword><keyword>Cohort Studies</keyword><keyword>Cross-Sectional Studies</keyword><keyword>*Databases as Topic</keyword><keyword>Female</keyword><keyword>Health Surveys</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Longitudinal Studies</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>*National Health Programs</keyword><keyword>Prospective Studies</keyword><keyword>Risk Factors</keyword><keyword>Translational Medical Research/*organization &amp; administration</keyword><keyword>United Kingdom</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar 31</date></pub-dates></dates><isbn>1474-547X (Electronic)&#xD;0140-6736 (Linking)</isbn><accession-num>22463865</accession-num><urls><related-urls><url>(12)60404-8</electronic-resource-num></record></Cite></EndNote>(34). In addition to a baseline assessment, subsequent health status is evaluated via linked electronic health care records. Beginning with respiratory studies in 50,000 participants PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWluPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (35), genome-wide genotyping has now been extended to all participants. Whole exome sequencing (WES) is underway, and whole genome sequencing (WGS) has recently been announced in collaboration with industry partners. The sequence data will be made available to the research community. While 95% of the UK Biobank is of European ancestry, similar efforts are in progress in China in the Kadoorie Biobank PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGVuPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (36).Health Equity Many respiratory, critical care, and sleep disorders have substantial differences in disease susceptibility, prevalence, and burden according to race and ethnicity ADDIN EN.CITE <EndNote><Cite><Author>Celedon</Author><Year>2017</Year><RecNum>5343</RecNum><DisplayText>(37)</DisplayText><record><rec-number>5343</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1525956534">5343</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Celedon, J. C.</author><author>Burchard, E. G.</author><author>Schraufnagel, D.</author><author>Castillo-Salgado, C.</author><author>Schenker, M.</author><author>Balmes, J.</author><author>Neptune, E.</author><author>Cummings, K. J.</author><author>Holguin, F.</author><author>Riekert, K. A.</author><author>Wisnivesky, J. P.</author><author>Garcia, J. G. N.</author><author>Roman, J.</author><author>Kittles, R.</author><author>Ortega, V. E.</author><author>Redline, S.</author><author>Mathias, R.</author><author>Thomas, A.</author><author>Samet, J.</author><author>Ford, J. G.</author><author>American Thoracic Society,</author><author>the National Heart Lung and Blood Institute,</author></authors></contributors><titles><title>An American Thoracic Society/National Heart, Lung, and Blood Institute Workshop Report: Addressing Respiratory Health Equality in the United States</title><secondary-title>Ann Am Thorac Soc</secondary-title></titles><periodical><full-title>Ann Am Thorac Soc</full-title></periodical><pages>814-826</pages><volume>14</volume><number>5</number><dates><year>2017</year><pub-dates><date>May</date></pub-dates></dates><isbn>2325-6621 (Electronic)&#xD;2325-6621 (Linking)</isbn><accession-num>28459618</accession-num><urls><related-urls><url>;(37). Genetic and genomic factors, along with their interplay with the environment, contribute to these differences. For example, African ancestry is a strong predictor of lung function PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LdW1hcjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (42, 43). While most of these studies have been performed using common variants, there is even more ethnic diversity for rare variants PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXRoaWFzPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

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ADDIN EN.CITE.DATA (45). To date, there has been a large gap in research studies involving non-whites, for reasons including convenience, access, and genetic heterogeneity ADDIN EN.CITE <EndNote><Cite><Author>Bustamante</Author><Year>2011</Year><RecNum>5349</RecNum><DisplayText>(46)</DisplayText><record><rec-number>5349</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1525956543">5349</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bustamante, C. D.</author><author>Burchard, E. G.</author><author>De la Vega, F. M.</author></authors></contributors><auth-address>Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA. cdbustam@stanford.edu</auth-address><titles><title>Genomics for the world</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>163-5</pages><volume>475</volume><number>7355</number><keywords><keyword>Emigrants and Immigrants/statistics &amp; numerical data</keyword><keyword>Europe/ethnology</keyword><keyword>European Continental Ancestry Group/genetics</keyword><keyword>Genetic Variation/genetics</keyword><keyword>Genetics, Medical/*statistics &amp; numerical data/*trends</keyword><keyword>Genome, Human/*genetics</keyword><keyword>Genome-Wide Association Study</keyword><keyword>Genomics/*statistics &amp; numerical data/*trends</keyword><keyword>Humans</keyword><keyword>Minority Groups/*statistics &amp; numerical data</keyword></keywords><dates><year>2011</year><pub-dates><date>Jul 13</date></pub-dates></dates><isbn>1476-4687 (Electronic)&#xD;0028-0836 (Linking)</isbn><accession-num>21753830</accession-num><urls><related-urls><url>;(46). In addition, there have also been disparities in funding minority investigators or diseases that predominately affect minorities, such as sickle cell disease ADDIN EN.CITE <EndNote><Cite><Author>Strouse</Author><Year>2013</Year><RecNum>5350</RecNum><DisplayText>(47)</DisplayText><record><rec-number>5350</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1525956544">5350</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Strouse, John J.</author><author>Lobner, Katie</author><author>Lanzkron, Sophie</author><author>Haywood, Carlton</author></authors></contributors><titles><title>NIH and National Foundation Expenditures For Sickle Cell Disease and Cystic Fibrosis Are Associated With Pubmed Publications and FDA Approvals [abstract]</title><secondary-title>Blood</secondary-title></titles><periodical><full-title>Blood</full-title><abbr-1>Blood</abbr-1></periodical><pages>1739</pages><volume>122</volume><dates><year>2013</year></dates><urls></urls></record></Cite></EndNote>(47). By 2060, only 44% of the USA will be non-Hispanic white ADDIN EN.CITE <EndNote><Cite><Author>Colby</Author><Year>2015</Year><RecNum>5351</RecNum><DisplayText>(48)</DisplayText><record><rec-number>5351</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1525956546">5351</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors><authors><author>Colby, Sandra L.</author><author>Ortman, Jennifer M.</author></authors></contributors><titles><title>Projections of the Size and Composition of the U.S. Population: 2014 to 2060</title><tertiary-title>Current Population Reports</tertiary-title></titles><pages>P25-1143</pages><dates><year>2015</year></dates><pub-location>Washington, D.C.</pub-location><publisher>U.S. Census Bureau</publisher><urls></urls></record></Cite></EndNote>(48). There is a strong scientific and moral justification for expanding sequencing studies into other ancestries. Efforts such as TOPMed are performing WGS in a large number of non-European samples. These and other efforts can help ensure that sequencing efforts improve health equity for the benefit of all.Research Ethics Several ethical challenges have emerged related to next-generation sequencing studies. Due to the ability to assay numerous sites and the requirements for data sharing by NIH and other funders ADDIN EN.CITE <EndNote><Cite><Author>Paltoo</Author><Year>2014</Year><RecNum>5352</RecNum><DisplayText>(49)</DisplayText><record><rec-number>5352</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1525956547">5352</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Paltoo, D. N.</author><author>Rodriguez, L. L.</author><author>Feolo, M.</author><author>Gillanders, E.</author><author>Ramos, E. M.</author><author>Rutter, J. L.</author><author>Sherry, S.</author><author>Wang, V. O.</author><author>Bailey, A.</author><author>Baker, R.</author><author>Caulder, M.</author><author>Harris, E. L.</author><author>Langlais, K.</author><author>Leeds, H.</author><author>Luetkemeier, E.</author><author>Paine, T.</author><author>Roomian, T.</author><author>Tryka, K.</author><author>Patterson, A.</author><author>Green, E. D.</author><author>National Institutes of Health Genomic Data Sharing Governance Committees,</author></authors></contributors><titles><title>Data use under the NIH GWAS data sharing policy and future directions</title><secondary-title>Nat Genet</secondary-title></titles><periodical><full-title>Nat Genet</full-title></periodical><pages>934-8</pages><volume>46</volume><number>9</number><keywords><keyword>Databases, Genetic/*legislation &amp; jurisprudence</keyword><keyword>Genome-Wide Association Study/*standards</keyword><keyword>Humans</keyword><keyword>Information Dissemination/*legislation &amp; jurisprudence</keyword><keyword>National Institutes of Health (U.S.)/*legislation &amp; jurisprudence</keyword><keyword>United States</keyword></keywords><dates><year>2014</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1546-1718 (Electronic)&#xD;1061-4036 (Linking)</isbn><accession-num>25162809</accession-num><urls><related-urls><url>;(49), genome-wide association studies (GWAS) and sequencing data are often used for secondary studies, which may be unrelated to the initial trait or disease proposed. 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ADDIN EN.CITE.DATA (51), providing a list of 59 actionable genes, which interestingly does not include the genes for cystic fibrosis or alpha-1 antitrypsin deficiency. However, it is not clear how these recommendations would apply to research studies, where the sequencing is not performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. There is usually no mechanism or resources for confirmatory clinical sequencing or genetic counseling. Sequencing studies of DNA of patients with a critical illness require consent from patient proxies, as well as the designation of an individual to receive study results if the patient remains incapacitated or dies ADDIN EN.CITE <EndNote><Cite><Author>Goodman</Author><Year>2017</Year><RecNum>5354</RecNum><DisplayText>(52)</DisplayText><record><rec-number>5354</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1525956550">5354</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Goodman, J. L.</author><author>Amendola, L. M.</author><author>Horike-Pyne, M.</author><author>Trinidad, S. B.</author><author>Fullerton, S. M.</author><author>Burke, W.</author><author>Jarvik, G. P.</author></authors></contributors><auth-address>Division of Medical Genetics University of Washington Seattle Washington.&#xD;Department of Bioethics and Humanities University of Washington Seattle Washington.&#xD;Division of Medical GeneticsUniversity of WashingtonSeattleWashington; Department of Bioethics and HumanitiesUniversity of WashingtonSeattleWashington.&#xD;Division of Medical GeneticsUniversity of WashingtonSeattleWashington; Department of Genome SciencesUniversity of WashingtonSeattleWashington.</auth-address><titles><title>Discordance in selected designee for return of genomic findings in the event of participant death and estate executor</title><secondary-title>Mol Genet Genomic Med</secondary-title></titles><periodical><full-title>Mol Genet Genomic Med</full-title></periodical><pages>172-176</pages><volume>5</volume><number>2</number><keywords><keyword>Executor</keyword><keyword>family communication</keyword><keyword>genomic sequencing</keyword><keyword>return of results</keyword></keywords><dates><year>2017</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>2324-9269 (Print)&#xD;2324-9269 (Linking)</isbn><accession-num>28361104</accession-num><urls><related-urls><url>;(52).Next generation DNA sequencing Study DesignHumans carry an extraordinary amount of genetic diversity. While most variants in a given individual are common, most genetic variants in a population are rare (i.e. present in less than 1 % of the population). Genotyping microarrays, together with methods of genotype imputation, efficiently allow testing of more prevalent genetic variants. However, comprehensive assessment of DNA variation, including discovery of rare or novel variants, requires a test that assays each base pair. The exponential decrease in sequencing costs has led to the ability to perform WGS studies to identify the contributions of rare variants to disease. The design of a DNA sequencing study should consider several factors. Sequencing depth determines the accuracy of variant calling in an individual. For example, 30x coverage leads to high accuracy over most of the genome. However, one can sequence more samples for the same cost using lower coverage (e.g. 3-6x). While less accurate, lower coverage still provides suitable variant information for genetic association testing and may be superior to genotyping PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXNhbml1YzwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+

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ADDIN EN.CITE.DATA (54). Identifying Causal VariantsNGS has led to breakthroughs in the discovery of genes for Mendelian diseases and other rare variants of strong effect PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaG9uZzwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (55, 56). Several groups have provided guidelines for identifying causal variants for Mendelian disease PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWNBcnRodXI8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy

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ADDIN EN.CITE.DATA (5, 58, 62). The growing availability of population-specific high-quality reference genomes will aid comparison of diseased study populations to these reference datasets. Coordinated efforts are providing population-based reference data important for filtering causal variants PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWs8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (33), and performing WGS in large numbers of subjects such as the NIH Center for Common Disease Genetics and TOPMed. These efforts will lead to new rare variant discoveries, as well as improved reference panels for genotyping studies and fine mapping. Table 3 details recommendations for reporting the results of a WES or WGS study.Next generation RNA sequencingStudy DesignIn contrast to genome sequence, gene expression is dependent on cell, tissue and disease state. Although this context dependence makes sample collection and assays more challenging, gene expression may be more closely reflective of disease pathophysiology. Gene expression microarrays have been largely replaced by RNA-seq, which can assay a broader range of RNA types with increased sensitivity and lower costs. RNA-seq studies can be grouped into two broad categories, based on their study designs ADDIN EN.CITE <EndNote><Cite><Author>Garber</Author><Year>2011</Year><RecNum>5362</RecNum><DisplayText>(63)</DisplayText><record><rec-number>5362</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1525956562">5362</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Garber, M.</author><author>Grabherr, M. G.</author><author>Guttman, M.</author><author>Trapnell, C.</author></authors></contributors><auth-address>Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA. mgarber@</auth-address><titles><title>Computational methods for transcriptome annotation and quantification using RNA-seq</title><secondary-title>Nat Methods</secondary-title></titles><periodical><full-title>Nat Methods</full-title></periodical><pages>469-77</pages><volume>8</volume><number>6</number><keywords><keyword>Animals</keyword><keyword>Computational Biology/methods</keyword><keyword>Gene Expression Profiling/*statistics &amp; numerical data</keyword><keyword>Genomics/statistics &amp; numerical data</keyword><keyword>High-Throughput Nucleotide Sequencing/*statistics &amp; numerical data</keyword><keyword>Humans</keyword><keyword>Sequence Alignment/statistics &amp; numerical data</keyword><keyword>Sequence Analysis, RNA/*statistics &amp; numerical data</keyword></keywords><dates><year>2011</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1548-7105 (Electronic)&#xD;1548-7091 (Linking)</isbn><accession-num>21623353</accession-num><urls><related-urls><url>;(63). Annotation studies aim to define the transcriptome of a specific cell type or organism, including novel transcripts. In comparison, quantification or differential expression studies compare transcript levels across experimental conditions or diseases. An introduction to RNA-seq for bench science has been recently published PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2NoPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (67, 68). For most human disease studies, the number of samples may be more important than the number of reads ADDIN EN.CITE <EndNote><Cite><Author>Liu</Author><Year>2014</Year><RecNum>4918</RecNum><DisplayText>(69)</DisplayText><record><rec-number>4918</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1431698763">4918</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Liu, Y.</author><author>Zhou, J.</author><author>White, K. P.</author></authors></contributors><auth-address>Institute of Genomics and Systems Biology, Committee on Development, Regeneration, and Stem Cell Biology and Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.</auth-address><titles><title>RNA-seq differential expression studies: more sequence or more replication?</title><secondary-title>Bioinformatics</secondary-title><alt-title>Bioinformatics</alt-title></titles><periodical><full-title>Bioinformatics</full-title></periodical><alt-periodical><full-title>Bioinformatics</full-title></alt-periodical><pages>301-4</pages><volume>30</volume><number>3</number><keywords><keyword>Gene Expression Profiling/*methods</keyword><keyword>High-Throughput Nucleotide Sequencing/*methods</keyword><keyword>Humans</keyword><keyword>MCF-7 Cells</keyword><keyword>Reproducibility of Results</keyword><keyword>Sample Size</keyword><keyword>Sequence Analysis, RNA/*methods</keyword></keywords><dates><year>2014</year><pub-dates><date>Feb 1</date></pub-dates></dates><isbn>1367-4811 (Electronic)&#xD;1367-4803 (Linking)</isbn><accession-num>24319002</accession-num><urls><related-urls><url>;(69).Sequencing methodsSequencing technology has been reviewed elsewhere PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZXR6a2VyPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48

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ADDIN EN.CITE.DATA (70, 71). Library construction follows one of three general protocols ADDIN EN.CITE <EndNote><Cite><Author>Raz</Author><Year>2011</Year><RecNum>5368</RecNum><DisplayText>(72)</DisplayText><record><rec-number>5368</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1525956569">5368</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Raz, T.</author><author>Kapranov, P.</author><author>Lipson, D.</author><author>Letovsky, S.</author><author>Milos, P. M.</author><author>Thompson, J. F.</author></authors></contributors><auth-address>Applications, Methods, and Collaborations Group, Helicos BioSciences, Cambridge, Massachusetts, United States of America.</auth-address><titles><title>Protocol dependence of sequencing-based gene expression measurements</title><secondary-title>PLoS One</secondary-title></titles><periodical><full-title>PLoS ONE</full-title></periodical><pages>e19287</pages><volume>6</volume><number>5</number><keywords><keyword>Brain/metabolism</keyword><keyword>Cell Line, Tumor</keyword><keyword>DNA, Complementary</keyword><keyword>Humans</keyword><keyword>Liver/metabolism</keyword><keyword>Sequence Analysis, RNA/*methods</keyword></keywords><dates><year>2011</year><pub-dates><date>May 6</date></pub-dates></dates><isbn>1932-6203 (Electronic)&#xD;1932-6203 (Linking)</isbn><accession-num>21573114</accession-num><urls><related-urls><url>;(72). Poly-A capture is best for selecting coding transcripts, but requires the highest quality input RNA. Total RNA libraries include more RNA species; ribosomal RNA depletion is used to improve yield. Methods to capture specific target sequences can be used for lower quality or fragmented RNA, including formalin-fixed paraffin embedded tissue. Globin depletion is a common step for whole blood samples. Small RNA sequencing (i.e. microRNA) requires a specific library construction protocol. Investigators must determine the minimum quality for input RNA, based on RNA integrity number (RIN). Other variables in sequencing include stranded vs. unstranded protocols, single vs. paired end reads and insert length. Single end short reads (≤75bp) are acceptable for standard differential expression PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZWFkPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (74). The latter can be addressed by deconvolution methods, which require additional information, either cell counts or cell specific reference transcriptomes. A review of the specific steps and analytic tools for RNA-seq data analysis has been recently published PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db25lc2E8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (75-79). Furthermore, selection of an analytic approach is also dependent on the experimental design; for example, not all available tools support inclusion of covariates. Caution is advised regarding the interpretation of results where the number of biologic replicates an experiment is small or where transcripts are expressed at very low levels.Reporting for RNA-seq experimentsWe propose minimum elements to be reported for RNA-seq experiments (Table 3), which extend the Minimal Information About Microarray Experiments (MIAME) guidelines ADDIN EN.CITE <EndNote><Cite><Author>Brazma</Author><Year>2001</Year><RecNum>1182</RecNum><DisplayText>(80)</DisplayText><record><rec-number>1182</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="0">1182</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brazma, A.</author><author>Hingamp, P.</author><author>Quackenbush, J.</author><author>Sherlock, G.</author><author>Spellman, P.</author><author>Stoeckert, C.</author><author>Aach, J.</author><author>Ansorge, W.</author><author>Ball, C. A.</author><author>Causton, H. C.</author><author>Gaasterland, T.</author><author>Glenisson, P.</author><author>Holstege, F. C.</author><author>Kim, I. F.</author><author>Markowitz, V.</author><author>Matese, J. C.</author><author>Parkinson, H.</author><author>Robinson, A.</author><author>Sarkans, U.</author><author>Schulze-Kremer, S.</author><author>Stewart, J.</author><author>Taylor, R.</author><author>Vilo, J.</author><author>Vingron, M.</author></authors></contributors><auth-address>European Bioinformatics Institute, EMBL outstation, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. brazma@ebi.ac.uk</auth-address><titles><title>Minimum information about a microarray experiment (MIAME)-toward standards for microarray data</title><secondary-title>Nat Genet</secondary-title></titles><periodical><full-title>Nat Genet</full-title></periodical><pages>365-71</pages><volume>29</volume><number>4</number><keywords><keyword>*Computational Biology</keyword><keyword>Gene Expression Profiling/methods</keyword><keyword>Oligonucleotide Array Sequence Analysis/*standards</keyword></keywords><dates><year>2001</year><pub-dates><date>Dec</date></pub-dates></dates><accession-num>11726920</accession-num><urls><related-urls><url>;(80). These minimal reporting requirements are important due to the rapidly evolving landscape of methods and tools for the analysis of RNA-seq data, the need to ensure RNA-seq data are both interpretable and reproducible, and the need to facilitate access to and integration of RNA-seq experiments across a spectrum of biologic and experimental conditions. Given the lack of consensus on the optimal methods for mapping versus assembling RNA-seq reads, normalizing RNA-seq data, and assessing for differential expression, we encourage investigators to repeat key analyses using more than one approach. Data AnalysisBioinformaticsSequencing technologies have improved to the point where the greatest barrier to obtaining scientific insights is more related to data storage, analysis and interpretation than its generation ADDIN EN.CITE <EndNote><Cite><Author>Mardis</Author><Year>2010</Year><RecNum>5373</RecNum><DisplayText>(81)</DisplayText><record><rec-number>5373</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1525956576">5373</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mardis, E. R.</author></authors></contributors><auth-address>The Genome Center at Washington University School of Medicine, 4444 Forest Park Blvd, St Louis, MO 63108, USA. emardis@wustl.edu.</auth-address><titles><title>The $1,000 genome, the $100,000 analysis?</title><secondary-title>Genome Med</secondary-title></titles><periodical><full-title>Genome Med</full-title></periodical><pages>84</pages><volume>2</volume><number>11</number><dates><year>2010</year><pub-dates><date>Nov 26</date></pub-dates></dates><isbn>1756-994X (Electronic)&#xD;1756-994X (Linking)</isbn><accession-num>21114804</accession-num><urls><related-urls><url>;(81). The first critical component is an interdisciplinary team with expertise encompassing both the design and use of specialized methods on sophisticated computational resources PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccm9va2VzPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

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ADDIN EN.CITE.DATA (82, 83). Institutional infrastructure or external service providers that offer high-performance computing environments, including cloud computing and core facilities, are important to facilitate the generation and analysis of high-throughput sequence data. One significant advantage to these solutions is that they distribute costs over many users. Additionally, these resources can help ensure high quality data and results, as they are generated by devoted personnel who are more familiar with NGS approaches than occasional users. On the other hand, some analytic steps are best performed with feedback from those familiar with experimental design, rather than by pipelines that may overlook important issues. Ideally, researchers with backgrounds in (1) chemistry and molecular biology involved in generating the data, (2) in-depth familiarity with analysis of sequencing data, and (3) design of a particular experiment, will communicate intermediate results and tailor analytical steps as needed. Quality ControlQuality control (QC) in a rigorous and standardized matter is critical. After raw reads are de-multiplexed following their generation by the sequencing instrument, QC steps to ensure sequencing worked appropriately provide output including number of reads per sample, quality score of reads at each base, and over-represented sequences (e.g., primers). Subject level QC includes checking for gender consistencies, duplicates, and related subjects. After reads are aligned to a reference genome, additional parameters assess mapping quality. For example, software tools (Tables 4 and 5) can be used to summarize the number of mapped reads, including junction spanning reads for RNA-seq, and can compute the number of bases assigned to various classes of DNA/RNA according to a reference file. For RNA-seq, use of Ambion External RNA Controls Consortium (ERCC) spike-ins offers an additional QC measure. Scripts that provide standardized and reproducible reports based on output from these various programs, such as those that are part of the GATK best-practices pipeline for DNA-Seq PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZVByaXN0bzwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

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ADDIN EN.CITE.DATA (85) facilitate the assessment of QC and decisions about which samples should be excluded or what kinds of bias might be present. Mapped read files that are in bam format can be converted to bigwig or other compressed format for display in a browser such as the UCSC genome browser to verify that mapping of particular genes looks as expected (e.g., that full lengths of genes are covered vs. highly irregular portions). Statistical AnalysisFollowing alignment of reads, DNA-Seq data is analyzed to search for variation relative to a reference genome and Variant Call Format (vcf/bcf) files are obtained. There are a variety of statistical tests for association within the WGS framework. The simplest consideration is based on frequency of the variant and/or a prior probability of being associated with disease (e.g., known pathogenic, deleterious, functionally relevant). Common variants, defined as those with minor allele frequency (MAF) >0.01-0.05 or minor allele count >10-20, depending on the sample size and factors such as case-control imbalance, are usually analyzed with a GWAS approach of single SNP association tests ADDIN EN.CITE <EndNote><Cite><Author>Spencer</Author><Year>2009</Year><RecNum>1373</RecNum><DisplayText>(86)</DisplayText><record><rec-number>1373</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="0">1373</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Spencer, C. C.</author><author>Su, Z.</author><author>Donnelly, P.</author><author>Marchini, J.</author></authors></contributors><auth-address>Department of Statistics, University of Oxford, Oxford, United Kingdom.</auth-address><titles><title>Designing genome-wide association studies: sample size, power, imputation, and the choice of genotyping chip</title><secondary-title>PLoS Genet</secondary-title></titles><periodical><full-title>PLoS Genet</full-title></periodical><pages>e1000477</pages><volume>5</volume><number>5</number><edition>2009/06/06</edition><keywords><keyword>Genome, Human</keyword><keyword>Genome-Wide Association Study/*methods</keyword><keyword>*Genotype</keyword><keyword>Humans</keyword><keyword>Linkage Disequilibrium</keyword><keyword>Polymorphism, Single Nucleotide</keyword><keyword>Sample Size</keyword><keyword>Software</keyword></keywords><dates><year>2009</year><pub-dates><date>May</date></pub-dates></dates><isbn>1553-7404 (Electronic)</isbn><accession-num>19492015</accession-num><urls><related-urls><url>;(86). Rare and/or deleterious variants are generally analyzed using a window-based approach, where windows consist of SNPs in or near a gene or are based on sliding genome regions of 5-50kb. Statistics for each window are obtained using different approaches: burden tests collapse many variants into a single risk score but assume all variants are similar in effect (i.e. risk alleles); adaptive burden tests collapse many variants but allow for risk, protective and neutral; and variance component tests apply random effects modeling ADDIN EN.CITE <EndNote><Cite><Author>Lee</Author><Year>2014</Year><RecNum>5378</RecNum><DisplayText>(87)</DisplayText><record><rec-number>5378</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1525956582">5378</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lee, S.</author><author>Abecasis, G. R.</author><author>Boehnke, M.</author><author>Lin, X.</author></authors></contributors><auth-address>Department of Biostatistics, University of Michigan, Ann Arbor, MI 48105, USA.&#xD;Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA. Electronic address: xlin@hsph.harvard.edu.</auth-address><titles><title>Rare-variant association analysis: study designs and statistical tests</title><secondary-title>Am J Hum Genet</secondary-title></titles><periodical><full-title>Am J Hum Genet</full-title></periodical><pages>5-23</pages><volume>95</volume><number>1</number><keywords><keyword>*Genome-Wide Association Study</keyword><keyword>Genotype</keyword><keyword>Humans</keyword></keywords><dates><year>2014</year><pub-dates><date>Jul 3</date></pub-dates></dates><isbn>1537-6605 (Electronic)&#xD;0002-9297 (Linking)</isbn><accession-num>24995866</accession-num><urls><related-urls><url>;(87). There is also a class of window-based rare variant tests that combine the variance component and burden test framework to take advantage of strengths of both; SKAT-O is the most commonly used ADDIN EN.CITE <EndNote><Cite><Author>Lee</Author><Year>2012</Year><RecNum>4984</RecNum><DisplayText>(88)</DisplayText><record><rec-number>4984</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1452877381">4984</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lee, S.</author><author>Emond, M. J.</author><author>Bamshad, M. J.</author><author>Barnes, K. C.</author><author>Rieder, M. J.</author><author>Nickerson, D. A.</author><author>NHLBI GO Exome Sequencing Project-ESP Lung Project Team,</author><author>Christiani, D. C.</author><author>Wurfel, M. M.</author><author>Lin, X.</author></authors></contributors><auth-address>Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.</auth-address><titles><title>Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies</title><secondary-title>Am J Hum Genet</secondary-title></titles><periodical><full-title>Am J Hum Genet</full-title></periodical><pages>224-37</pages><volume>91</volume><number>2</number><keywords><keyword>*Case-Control Studies</keyword><keyword>Computer Simulation</keyword><keyword>*Data Interpretation, Statistical</keyword><keyword>Exome/*genetics</keyword><keyword>Genetic Association Studies/*methods</keyword><keyword>*Genetic Variation</keyword><keyword>Humans</keyword><keyword>Models, Genetic</keyword><keyword>Rare Diseases/*genetics</keyword><keyword>Sequence Analysis, DNA/*methods</keyword></keywords><dates><year>2012</year><pub-dates><date>Aug 10</date></pub-dates></dates><isbn>1537-6605 (Electronic)&#xD;0002-9297 (Linking)</isbn><accession-num>22863193</accession-num><urls><related-urls><url>;(88). It is routine to apply multiple rare variant tests and use alternative options of windows, resulting in increased multiple testing complexity. In addition to Bonferroni correction, permutation and Bayesian approaches are employed to adjust for multiple comparisons. Controversy about the best way to analyze RNA-seq data still exists, and methods development is ongoing PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UZW5nPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj

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RW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aZXJiaW5vPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48

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ADDIN EN.CITE.DATA (90) or RefSeq PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PJmFwb3M7TGVhcnk8L0F1dGhvcj48WWVhcj4yMDE2PC9Z

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ADDIN EN.CITE.DATA (91). The output of the quantification process is then used with an appropriate software package to measure differential expression and assess related QC. Regardless of program used, it is important to report false-discovery rate adjusted p-values and fold changes.Data SharingTo ensure that high-throughput sequence results are reproducible and that costly data can benefit all stakeholders, data sharing resources have grown significantly. Both raw data and results generated from projects sponsored by major funders are required to be deposited into publicly available databases. DNA-Seq data, including that of TOPMed, are deposited in dbGaP, along with individual-level phenotype and association results PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWlsbWFuPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48

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ADDIN EN.CITE.DATA (50). RNA-seq and other sequencing data is available in the Sequence Read Archive and can be discovered via the Gene Expression Omnibus ADDIN EN.CITE <EndNote><Cite><Author>Leinonen</Author><Year>2011</Year><RecNum>5402</RecNum><DisplayText>(92)</DisplayText><record><rec-number>5402</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1527875638">5402</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Leinonen, R.</author><author>Sugawara, H.</author><author>Shumway, M.</author><author>International Nucleotide Sequence Database Collaboration,</author></authors></contributors><auth-address>European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. rasko@ebi.ac.uk</auth-address><titles><title>The sequence read archive</title><secondary-title>Nucleic Acids Res</secondary-title></titles><periodical><full-title>Nucleic Acids Res</full-title></periodical><pages>D19-21</pages><volume>39</volume><number>Database issue</number><keywords><keyword>*Databases, Nucleic Acid</keyword><keyword>*High-Throughput Nucleotide Sequencing</keyword></keywords><dates><year>2011</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1362-4962 (Electronic)&#xD;0305-1048 (Linking)</isbn><accession-num>21062823</accession-num><urls><related-urls><url>;(92).Cell type heterogeneity An important issue for consideration in many omics studies of the lung is cell heterogeneity. The lung is a complex organ comprising approximately forty resident cell types PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmFua3M8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (93), a growing number of cell subpopulations that are present either transiently during development or in adult lung ADDIN EN.CITE <EndNote><Cite><Author>Wansleeben</Author><Year>2013</Year><RecNum>5381</RecNum><DisplayText>(94)</DisplayText><record><rec-number>5381</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1525956586">5381</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wansleeben, C.</author><author>Barkauskas, C. E.</author><author>Rock, J. R.</author><author>Hogan, B. L.</author></authors></contributors><auth-address>Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.</auth-address><titles><title>Stem cells of the adult lung: their development and role in homeostasis, regeneration, and disease</title><secondary-title>Wiley Interdiscip Rev Dev Biol</secondary-title></titles><periodical><full-title>Wiley Interdiscip Rev Dev Biol</full-title></periodical><pages>131-48</pages><volume>2</volume><number>1</number><keywords><keyword>Animals</keyword><keyword>Cell Differentiation</keyword><keyword>Homeostasis/*physiology</keyword><keyword>Humans</keyword><keyword>Lung/*cytology/*physiology</keyword><keyword>Mice</keyword><keyword>Regeneration/*physiology</keyword><keyword>Stem Cells/*cytology/physiology</keyword><keyword>*Wound Healing</keyword></keywords><dates><year>2013</year><pub-dates><date>Jan-Feb</date></pub-dates></dates><isbn>1759-7692 (Electronic)&#xD;1759-7684 (Linking)</isbn><accession-num>23799633</accession-num><urls><related-urls><url>;(94), as well as many types of inflammatory cells that infiltrate the airways and alveoli during periods of injury or disease. Thus, a signal measured by omics technologies in the whole lung can reflect a change in the pattern of expression of the molecules measured within a certain cell type, a change in the cellular composition of the lung, or both. There are three main approaches to deal with cellular heterogeneity. One approach is to perform statistical deconvolution of omic profiles by relying on cell specific features from reference datasets. This approach has been used widely in peripheral blood profiling studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3VzZW1hbjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+

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Pn==

ADDIN EN.CITE.DATA (97), it is limited by the need for known cell markers and antibodies for cell populations of interest, as well as concerns that stress from cell sorting may affect gene expression patterns. LCM can be technically challenging on human lung tissue, but has had some success in conjunction with sequencing technologies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb25nPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (98). However, in most benign tissues, the resolution of LCM allows for enriching for a regional microenvironment, but not for dissecting between different cell types. Single Cell SequencingThe recently developed single cell technologies provide the best solution to identification of all relevant cell populations, though technical limitations remain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QcmFrYWRhbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+

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ADDIN EN.CITE.DATA (99-101). The reproducibility and success of such studies depend greatly on availability of high quality human tissue, on cellular susceptibility to stress, and on the platforms used ADDIN EN.CITE <EndNote><Cite><Author>Haque</Author><Year>2017</Year><RecNum>5415</RecNum><DisplayText>(102)</DisplayText><record><rec-number>5415</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1533566715">5415</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Haque, A.</author><author>Engel, J.</author><author>Teichmann, S. A.</author><author>Lonnberg, T.</author></authors></contributors><auth-address>QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, 4006, Australia. ashraful.haque@qimrberghofer.edu.au.&#xD;QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, 4006, Australia.&#xD;Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.&#xD;Turku Centre for Biotechnology, University of Turku and Abo Akademi University, FI-20520, Turku, Finland. taplon@utu.fi.</auth-address><titles><title>A practical guide to single-cell RNA-sequencing for biomedical research and clinical applications</title><secondary-title>Genome Med</secondary-title></titles><periodical><full-title>Genome Med</full-title></periodical><pages>75</pages><volume>9</volume><number>1</number><keywords><keyword>Animals</keyword><keyword>*Biomedical Research</keyword><keyword>Computational Biology/*methods</keyword><keyword>Humans</keyword><keyword>Sequence Analysis, RNA/*methods</keyword><keyword>Single-Cell Analysis/*methods</keyword></keywords><dates><year>2017</year><pub-dates><date>Aug 18</date></pub-dates></dates><isbn>1756-994X (Electronic)&#xD;1756-994X (Linking)</isbn><accession-num>28821273</accession-num><urls><related-urls><url>;(102). Despite these limitations, single cell RNA-seq studies have shed light on lung cell population heterogeneity during lung development PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UcmV1dGxlaW48L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy

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ADDIN EN.CITE.DATA (103) and in lung diseases such as IPF ADDIN EN.CITE <EndNote><Cite><Author>Xu</Author><Year>2016</Year><RecNum>5198</RecNum><DisplayText>(15)</DisplayText><record><rec-number>5198</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1511204814">5198</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Xu, Y.</author><author>Mizuno, T.</author><author>Sridharan, A.</author><author>Du, Y.</author><author>Guo, M.</author><author>Tang, J.</author><author>Wikenheiser-Brokamp, K. A.</author><author>Perl, A. T.</author><author>Funari, V. A.</author><author>Gokey, J. J.</author><author>Stripp, B. R.</author><author>Whitsett, J. A.</author></authors></contributors><auth-address>Division of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children&apos;s Hospital Medical Center (CCHMC), Cincinnati, Ohio, USA.&#xD;Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California, USA.&#xD;Division of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children&apos;s Hospital Medical Center (CCHMC), Cincinnati, Ohio, USA.; Division of Pathology, CCHMC, Cincinnati, Ohio, USA.</auth-address><titles><title>Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis</title><secondary-title>JCI Insight</secondary-title></titles><periodical><full-title>JCI Insight</full-title></periodical><pages>e90558</pages><volume>1</volume><number>20</number><dates><year>2016</year><pub-dates><date>Dec 08</date></pub-dates></dates><isbn>2379-3708 (Print)&#xD;2379-3708 (Linking)</isbn><accession-num>27942595</accession-num><urls><related-urls><url>;(15). The recent development of single-nucleus RNA-seq may address some of the issues with tissue quality PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWJpYjwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (107). Since eQTLs may be cell specific, lung cell eQTL maps are needed to increase our understanding of lung specific disease SNPs. Secondly, RNA-seq enables assessment of the relation of genetic variation with splicing events leading to alternative isoform expression (splice QTL). Finally, the association of genetic variation with transcripts induced by disease or specific stimuli (context dependent eQTLs) can be investigated either in paired observational human studies or ex vivo in laboratory settings (Table 6). Since most respiratory diseases develop as a result from environmental exposures and genetic background, the study of inducible eQTLs may offer a good model to understand disease development by integrating genetic variation with induced gene expression. Using study-specific subsets of RNA-seq data or external reference datasets such as the GTEx consortium ADDIN EN.CITE <EndNote><Cite><Author>GTEx Consortium</Author><Year>2013</Year><RecNum>1814</RecNum><DisplayText>(108)</DisplayText><record><rec-number>1814</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="0">1814</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>GTEx Consortium,</author></authors></contributors><auth-address>National Disease Research Interchange, Philadelphia, Pennsylvania, USA.</auth-address><titles><title>The Genotype-Tissue Expression (GTEx) project</title><secondary-title>Nat Genet</secondary-title></titles><periodical><full-title>Nat Genet</full-title></periodical><pages>580-5</pages><volume>45</volume><number>6</number><edition>2013/05/30</edition><keywords><keyword>Consensus Development Conferences, NIH as Topic</keyword><keyword>Gene Expression</keyword><keyword>*Gene Expression Profiling</keyword><keyword>*Genome-Wide Association Study</keyword><keyword>Government Programs/ethics/*legislation &amp; jurisprudence</keyword><keyword>Humans</keyword><keyword>Molecular Sequence Annotation</keyword><keyword>Organ Specificity</keyword><keyword>Quantitative Trait Loci</keyword><keyword>Tissue Banks</keyword><keyword>United States</keyword></keywords><dates><year>2013</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1546-1718 (Electronic)&#xD;1061-4036 (Linking)</isbn><accession-num>23715323</accession-num><urls><related-urls><url> [pii]&#xD;10.1038/ng.2653</electronic-resource-num><language>eng</language></record></Cite></EndNote>(108) allows for the ability to impute gene expression in large numbers of individuals on whom only genetic variant data are available PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYW1hem9uPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

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ADDIN EN.CITE.DATA (109). These integrative approaches can expand the value of smaller sample sizes with transcript data to the larger datasets to identify gene expression correlated with phenotype (Table 6).We anticipate that further integration of other omics data in bulk tissue or at the single cell level, though efforts such as the Lung Map PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BcmRpbmktUG9sZXNrZTwvQXV0aG9yPjxZZWFyPjIwMTc8

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ADDIN EN.CITE.DATA (111) in future research programs in respiratory medicine, particularly as the approach can be used for all types of omics analysis including transcriptomics, proteomics, metabolomics and epigenetics. Omics integration analysis has advanced considerably, and many machine learning methods are now being used, including Bayesian and Network-based approaches ADDIN EN.CITE <EndNote><Cite><Author>Li</Author><Year>2018</Year><RecNum>5405</RecNum><DisplayText>(112)</DisplayText><record><rec-number>5405</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1527875643">5405</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Li, C. X.</author><author>Wheelock, C. E.</author><author>Skold, C. M.</author><author>Wheelock, A. M.</author></authors></contributors><auth-address>Respiratory Medicine Unit, Dept of Medicine and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.&#xD;Integrative Molecular Phenotyping Laboratory, Division of Physiological Chemistry II, Dept of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.&#xD;Lung-Allergy Clinic, Karolinska University Hospital, Stockholm, Sweden.</auth-address><titles><title>Integration of multi-omics datasets enables molecular classification of COPD</title><secondary-title>Eur Respir J</secondary-title></titles><periodical><full-title>Eur Respir J</full-title></periodical><volume>51</volume><number>5</number><dates><year>2018</year><pub-dates><date>May</date></pub-dates></dates><isbn>1399-3003 (Electronic)&#xD;0903-1936 (Linking)</isbn><accession-num>29545283</accession-num><urls><related-urls><url>;(112) and more recently, deep learning and neural networks ADDIN EN.CITE <EndNote><Cite><Author>Chaudhary</Author><Year>2018</Year><RecNum>5332</RecNum><DisplayText>(113)</DisplayText><record><rec-number>5332</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1524860639">5332</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chaudhary, K.</author><author>Poirion, O. B.</author><author>Lu, L.</author><author>Garmire, L. X.</author></authors></contributors><auth-address>Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.&#xD;Molecular Biosciences and Bioengineering Graduate Program, University of Hawaii at Manoa, Honolulu, Hawaii.&#xD;Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii. lgarmire@cc.hawaii.edu.</auth-address><titles><title>Deep Learning-Based Multi-Omics Integration Robustly Predicts Survival in Liver Cancer</title><secondary-title>Clin Cancer Res</secondary-title></titles><periodical><full-title>Clin Cancer Res</full-title></periodical><pages>1248-1259</pages><volume>24</volume><number>6</number><dates><year>2018</year><pub-dates><date>Mar 15</date></pub-dates></dates><isbn>1078-0432 (Print)&#xD;1078-0432 (Linking)</isbn><accession-num>28982688</accession-num><urls><related-urls><url>;(113). Functional ValidationIn functional studies, gene expression may also be used as outcome, either in vivo when human subjects or patients are exposed to an environmental stimulus or drugs, or in human samples or animal models. Comparative analysis of humans and mouse models through RNA-seq may enable swift validation of downstream targets and provide insight in the validity of the animal model ADDIN EN.CITE <EndNote><Cite><Author>Breschi</Author><Year>2017</Year><RecNum>5388</RecNum><DisplayText>(114)</DisplayText><record><rec-number>5388</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1525956597">5388</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Breschi, A.</author><author>Gingeras, T. R.</author><author>Guigo, R.</author></authors></contributors><auth-address>Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain.&#xD;Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain.&#xD;Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11742, USA.</auth-address><titles><title>Comparative transcriptomics in human and mouse</title><secondary-title>Nat Rev Genet</secondary-title></titles><periodical><full-title>Nat Rev Genet</full-title></periodical><pages>425-440</pages><volume>18</volume><number>7</number><keywords><keyword>Animals</keyword><keyword>Conserved Sequence</keyword><keyword>*Disease Models, Animal</keyword><keyword>*Evolution, Molecular</keyword><keyword>*Gene Expression Regulation</keyword><keyword>Genome, Human</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>RNA, Long Noncoding/genetics</keyword><keyword>*Transcriptome</keyword></keywords><dates><year>2017</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1471-0064 (Electronic)&#xD;1471-0056 (Linking)</isbn><accession-num>28479595</accession-num><urls><related-urls><url>;(114). Additional sequencing methods such as DNA-Seq, ATAC-Seq, and ChIP-Seq can identify functional regions affected by genetic variants. Gene editing techniques including Crispr-Cas9 that enable knockdown of genes or SNP-specific editing may be followed up by a readout on the effects of gene regulatory networks ADDIN EN.CITE <EndNote><Cite><Author>Sander</Author><Year>2014</Year><RecNum>5389</RecNum><DisplayText>(115)</DisplayText><record><rec-number>5389</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1525956598">5389</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sander, J. D.</author><author>Joung, J. K.</author></authors></contributors><auth-address>1] Molecular Pathology Unit, Center for Computational and Integrative Biology, Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts, USA. [2] Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.</auth-address><titles><title>CRISPR-Cas systems for editing, regulating and targeting genomes</title><secondary-title>Nat Biotechnol</secondary-title></titles><periodical><full-title>Nat Biotechnol</full-title></periodical><pages>347-55</pages><volume>32</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>*CRISPR-Cas Systems</keyword><keyword>*Clustered Regularly Interspaced Short Palindromic Repeats</keyword><keyword>Genetic Engineering/*methods</keyword><keyword>Genomics/*methods</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Rabbits</keyword><keyword>Rats</keyword></keywords><dates><year>2014</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1546-1696 (Electronic)&#xD;1087-0156 (Linking)</isbn><accession-num>24584096</accession-num><urls><related-urls><url>;(115) (Table 6). Conclusions With large efforts such as TOPMed and the UK Biobank, in addition to specific disease studies, there is an ever-increasing amount of sequencing data available for studies of respiratory disease, critical care and sleep medicine. Due to the complex nature of these studies, it is critical to include researchers with multiple backgrounds at the outset of study design, including clinician-scientists and epidemiologists who can enroll and phenotype subjects; laboratory personnel with skills in biobanking, sample management, and high-throughput sequencing; bioinformaticians, statisticians, and computational biologists who can manage and analyze data; and molecular biologists who can conduct functional validation studies. All of these experts must collaborate to design studies, interpret data, and present results. This should not discourage new investigators from participating in omics studies, as each person can provide complementary expertise. Specific recommendations regarding study design, analysis, and follow-up (Box 1) should serve as guides for starting a new sequencing study or for the critical appraisal of a completed study. Genomics is a rapidly-evolving field, and researchers must keep abreast of best practices. However, general principles of study design and data reporting are likely to remain valid in the future.Acknowledgements:This workshop report was prepared by a subcommittee of the American Thoracic Society Section on Genetics and Genomics in the Assembly on Allergy, Immunology and Inflammation. Workshop Participants:Craig P. Hersh, M.D., M.P.H. (Co-Chair)Gerard H. Koppelman, M.D., Ph.D. (Co-Chair)Ian M. Adcock, Ph.D.Juan C. Celedón, M.D., Dr.P.H.Michael H. Cho, M.D., M.P.H.David C. Christiani, M.D., M.P.H.Blanca E. Himes, Ph.D.Naftali Kaminski, M.D.Rasika A. Mathias, Sc.D.Deborah A. Meyers, Ph.D.John Quackenbush, Ph.D.Susan Redline, M.D., M.P.H.Katrina A. Steiling, M.D., M.Sc.Holly K. Tabor, Ph.D.Martin Tobin, Ph.D., M.B.Ch.B.Mark M. Wurfel, M.D., Ph.D.Ivana V. Yang, Ph.D.DisclosuresDr. Hersh reports personal fees from Mylan, personal fees from AstraZeneca, personal fees from Concert Pharmaceuticals, personal fees from 23andMe, grants from Novartis, grants from Boehringer-Ingelheim, grants from National Institutes of Health, outside the submitted work. Dr. Adcock reports grants from Boehringer Ingelhein, grants from Novartis, outside the submitted work. Dr. Celedón has received research materials from Pharmavite (vitamin D and placebo capsules), and Merck and GSK (inhaled steroids) to provide medications free of cost to participants in NIH-funded studies, unrelated to this work. Dr. Cho has received grant support from GSK. Dr. Kaminski reports personal fees from Biogen Idec, Boehringer Ingelheim, Third Rock, MMI, personal fees from Pliant, Samumed, NuMedii, Indaloo, non-financial support from miRagen , outside the submitted work; In addition, Dr. Kaminski has a patent on New Threapies in Pulmonary Fibrosis with royalties paid by Biotech, and a patent on Peripheral Blood Gene Expression issue. He is a Member of the Scientific Advisory Committee, the Research Advisory Forum and serves as Deputy Editor of Thorax, BMJ. Dr. Redline reports grants from NIH, during the conduct of the study. Dr. Steiling reports other from UpToDate, other from Academic Research Coalition LLC, grants from Lungevity Foundation, from null, outside the submitted work; In addition, Dr. Steiling has a patent US Patent 9,677,138 issued to Boston University. Dr. Tobin reports grants from GSK, grants from Pfizer, outside the submitted work. Dr. Yang reports grants from NIH, outside the submitted work. Dr. Koppelman reports grants from Lung Foundation of the Netherlands, TEVA the Netherlands, GSK, TETRI Foundation, UBBO Emmius Foundation, VERTEX, outside the submitted work.Drs. Christiani, Himes, Mathias, Meyers, Quackenbush, Tabor, and Wurfel have nothing to disclose.FundingDr. Hersh reports funding from NIH grants R01HL125583 and R01HL130512. Dr. Cho is supported by NHLBI grants R01HL113264, R01HL137927, and R01HL135142. Dr. Tobin has received support from a Wellcome Trust Investigator Award (WT202849/Z/16/Z) and from the UK Medical Research Council (MR/N011317/1). The research was partially supported by the NIHR Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Dr. Himes if funded by NIH R01 HL133433 and R01 HL141992. S Redline has received support from NIH R35HL135818 and HL113338.Figure LegendsFigure 1: Next Generation Sequencing methodology (Illumina)Genomic DNA is fragmented and sequencing adaptors are attached. The genomic library is then hybridized to complementary oligo-nucleotide probes in the flow cell chamber. Since there are adaptors on both ends, hybridization results in a bridge. Amplification leads to clusters of fragments with the same sequence. Clusters are denatured, then sequencing-by-synthesis involves the addition of fluorescently-labeled nucleotides, with serial imaging after the incorporation of each nucleotide. Reprinted from Tucker T, Marra M, Friedman JM. Massively parallel sequencing: the next big thing in genetic medicine. Am J Hum Genet 2009;85:142-152 with permission from Elsevier. ADDIN EN.CITE <EndNote><Cite><Author>Tucker</Author><Year>2009</Year><RecNum>5410</RecNum><DisplayText>(116)</DisplayText><record><rec-number>5410</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1528984748">5410</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tucker, T.</author><author>Marra, M.</author><author>Friedman, J. M.</author></authors></contributors><auth-address>Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. tbtucker@interchange.ubc.ca</auth-address><titles><title>Massively parallel sequencing: the next big thing in genetic medicine</title><secondary-title>Am J Hum Genet</secondary-title></titles><periodical><full-title>Am J Hum Genet</full-title></periodical><pages>142-54</pages><volume>85</volume><number>2</number><keywords><keyword>Base Sequence</keyword><keyword>*Genetics, Medical</keyword><keyword>*Genome, Human</keyword><keyword>Genomics</keyword><keyword>Humans</keyword><keyword>Molecular Sequence Data</keyword><keyword>Sequence Alignment</keyword><keyword>*Sequence Analysis, DNA/instrumentation/methods</keyword></keywords><dates><year>2009</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1537-6605 (Electronic)&#xD;0002-9297 (Linking)</isbn><accession-num>19679224</accession-num><urls><related-urls><url>;(116).Figure 2: Workflow for a next generation sequencing study in human diseaseBox 1. Definitions of commonly used terms in sequencing studiesBatch effect: In a large study, library construction and sequencing is done in batches (e.g. 96 well plate), which is a source of technical variation that should be addressed in the data plex trait: A disease or phenotype that does not follow Mendelian inheritance. Complex traits are likely influenced by multiple genes and environmental factors. Most common human diseases would be considered complex diseases.Deconvolution: RNA sequencing is frequently performed in tissues such as blood or lung, which are composed of multiple cell types. Deconvolution methods aim to estimate the cell type proportions and/or identify the cell type(s) responsible for the expression of specific genes. Exome: The portion of the human genome (approximately 1%) that encodes for proteins. Whole exome sequencing (WES) specifically targets these sequences.Expression Quantitative Trait Locus (eQTL): A genetic variant, usually a SNP (see below), that affects the expression of a gene. eQTLs can be located near the gene of interest (cis-eQTL) or distant (> 1 MB away) (trans-eQTL).Genome-wide association study (GWAS): A study which assays hundreds of thousands to millions of SNPs across the genome and tests each variant for association with a disease or trait of interest.Mendelian disorder: A disease determined by variation in a single gene, e.g. cystic fibrosis or sickle cell disease.Next generation sequencing: Highly automated parallel sequencing technique of small fragments of DNA or RNA. Millions or even billions of nucleotides, up to a whole genome, can be determined in one day.RNA Integrity Number (RIN): A proprietary algorithm that quantifies RNA degradation based on an electropherogram.Single nucleotide polymorphism: A single base pair change in DNA sequence (e.g. C to T) which is prevalent (>1 %) in the general populations. SNPs are the most common type of genetic variation.Sequencing coverage/depth: For DNA sequencing, the number of reads that include a specific nucleotide in the sequencing experiment. This can be averaged across the genome, e.g. 30x. For RNA sequencing, sequencing depth is usually presented as the total number of sequencing reads.Variant calling: The process of identifying genetic variants (usually SNPs) in an individual exome or genome sequence.Box 2: Recommendations for design and analysis of next generation sequencing studiesGeneral principles of genetic epidemiology study design are especially important in next generation sequencing studies. Disease specific studies may have more detailed phenotyping, whereas population studies may allow for larger sample sizes. Investigators must clearly define the phenotypes of both cases and control subjects, including consideration of relevant exposures, such as smoking. Relying only on datasets largely composed on individuals of European ancestry will limit discoveries, especially in diseases which may be more prevalent in other racial or ethnic groups. Therefore, we suggest expanding sequencing efforts in subjects of different ancestries.Studies should consider broad consent for secondary data use.Researchers should employ standardized methods of experimental design and data analysis for exome and whole genome sequencing studies.Methods for design and analysis in RNA sequencing studies are more variable. Researchers should clearly document their methods, including software versions and input parameters, and consider validating key results with a different analysis method.Multidisciplinary teams should include bioinformaticians, statisticians and computational biologists to assist in the management and analysis of large datasets.Quality control is the responsibility of the investigators. It should not be assumed that the core sequencing facility has performed all the necessary QC steps.Data sharing is required by many funders and should be the default. Due to the extreme cellular heterogeneity of the lung, future studies should address cellular heterogeneity in the design and analysis, by any of the proposed methods.We anticipate an important role of single cell sequencing in the future. For wider acceptance, single cell sequencing has to address specific hypotheses and should be held to the same rigorous standards as other study designs, even while the laboratory and statistical methods are under development. Given the pervasive influence of circadian biology on multiple cellular processes including gene expression, studies should time stamp sample collection.Integrating different omics datasets, both at the single cell or at the tissue level, will likely increase our understanding of the complex diseases in respiratory, critical care and sleep medicine. Laboratory validation is an important next step towards the eventual translation of results.Table 1: Examples of human next generation sequencing studies in respiratory, critical care and sleep medicineTechnologyDisease/traitStudy Design/subjectsMain FindingsValidationReferenceWhole Exome SequencingNarcolepsy18 families8 missense variants in P2Y11?Resequencing in 250 cases, 150 controls; in vitro P2Y11 signaling assaysPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZWduPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (6)Whole Exome SequencingIdiopathic Pulmonary Fibrosis79 probands with familial pulmonary fibrosis, 2816 controlsMutations in PARN found in cases, not controls. Mutations in RTEL1 more common in cases vs. controlsMutations segregated in families. Shorter leukocyte telomeres in mutation carriers.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdHVhcnQ8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (3)RNA-sequencingSmokingBlood samples from 229 current, 286 former smokers171 DE genes, including 7 lncRNAs, 8 genes with differential exon usePublished microarray studyPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXJrZXI8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (13)RNA-sequencingCOPDLung tissue from 98 cases, 91 controls2312 DE genesqPCR for 7 genesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (2)Single cell RNA-sequencingIdiopathic Pulmonary FibrosisFACS sorted lung epithelial cells from 6 IPF, 3 controls4 cell clusters: AT2, basal, goblet, and indeterminateImmunofluorescence confocal microscopy for epithelial cell markers ADDIN EN.CITE <EndNote><Cite><Author>Xu</Author><Year>2016</Year><RecNum>5198</RecNum><DisplayText>(15)</DisplayText><record><rec-number>5198</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1511204814">5198</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Xu, Y.</author><author>Mizuno, T.</author><author>Sridharan, A.</author><author>Du, Y.</author><author>Guo, M.</author><author>Tang, J.</author><author>Wikenheiser-Brokamp, K. A.</author><author>Perl, A. T.</author><author>Funari, V. A.</author><author>Gokey, J. J.</author><author>Stripp, B. R.</author><author>Whitsett, J. A.</author></authors></contributors><auth-address>Division of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children&apos;s Hospital Medical Center (CCHMC), Cincinnati, Ohio, USA.&#xD;Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California, USA.&#xD;Division of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children&apos;s Hospital Medical Center (CCHMC), Cincinnati, Ohio, USA.; Division of Pathology, CCHMC, Cincinnati, Ohio, USA.</auth-address><titles><title>Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis</title><secondary-title>JCI Insight</secondary-title></titles><periodical><full-title>JCI Insight</full-title></periodical><pages>e90558</pages><volume>1</volume><number>20</number><dates><year>2016</year><pub-dates><date>Dec 08</date></pub-dates></dates><isbn>2379-3708 (Print)&#xD;2379-3708 (Linking)</isbn><accession-num>27942595</accession-num><urls><related-urls><url>;(15)miRNA-sequencingSepsisPlasma from 29 sepsis, 44 non-infective SIRS, 16 controls6 miRNAs distinguish sepsis from SIRSqPCR, correlation with inflammatory cytokinesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXNlcnRhPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48

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ADDIN EN.CITE.DATA (14)PMVEC = pulmonary microvascular endothelial cells, PVOD = pulmonary veno-occlusive disease, PCH = pulmonary capillary hemangiomatosisTable 2: Biobanks and commonly used databases for next generation sequencing researchBiobanks and other large sequencing studiesURLCenter for Common Disease Genetics27563570China Kadoorie BiobankGenomics England (“100,000 Genomes Project”)genomicsengland.co.ukTrans-Omics in Precision Medicine (TOPMed)United Kingdom Biobankbiobank.ac.ukDatabasesDatabase of Genotypes and Phenotypes (dbGaP)ncbi.nlm.gapEnsembl genome browserGene Expression Omnibus (GEO)ncbi.nlm.geoGenome Aggregation Database (gnomAD)gnomad.Genotype-Tissue Expression project (GTEx)Human Cell AtlasLung MapReference Sequence Database (RefSeq)ncbi.nlm.refseqSequence Read Archive (SRA)ncbi.nlm.sraUniversity of California Santa Cruz (UCSC) Genome Browsergenome.ucsc.eduTable 3: Minimal elements required in the reporting of high throughput sequencing studies. Required elements should also include the package or software name, version number, and settings used for the analysis. Analytic StepRequired elementsPre-processing and pre-analysis quality control Randomization of samplesTarget design, when applicable (e.g. WES)Methods for quality assessment of:Raw readsAligned reads and coverageGlobal data qualityAncestry of samples (comparison with study and to reference genomes)Core analyticsMethod of read alignmentMethod of variant callingMethod of association analysesAdvanced analyticsMethods for integration with other data typesWhole exome and genome sequencingRNA SequencingAnalytic StepRequired elementsPre-processing and pre-analysis quality control Spike-in useRandomization of samplesNumber of raw readsMethods for quality assessment of:Raw readsAligned readsQuantification of readsReproducibility of replicatesGlobal data qualityCore analyticsMethod of transcript/gene identificationMethod of transcript/gene quantificationMethod of normalizationMethod of batch correctionMethod of detection of differential expressionAdvanced analyticsMethod of transcript/isoform discoveryMethod of indel detectionMethod of gene fusion detectionMethod of variant detectionMethod for single cell analysesMethods for integration with other data types Table 4: Software for DNA sequencing studies. This table provides an overview of commonly used software tools for performing analysis of next generation sequencing data. Because the field continues to evolve rapidly, additional tools not listed in this table may also be useful to researchers. 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L.</author></authors></contributors><auth-address>Center for Bioinformatics and Computational Biology, Institute for Advanced Computer Studies, University of Maryland, College Park, Maryland, USA. blangmea@jhsph.edu</auth-address><titles><title>Fast gapped-read alignment with Bowtie 2</title><secondary-title>Nat Methods</secondary-title></titles><periodical><full-title>Nat Methods</full-title></periodical><pages>357-9</pages><volume>9</volume><number>4</number><keywords><keyword>*Algorithms</keyword><keyword>Computational Biology/*methods</keyword><keyword>Databases, Genetic</keyword><keyword>Genome, Human/genetics</keyword><keyword>Humans</keyword><keyword>Sequence Alignment/*methods</keyword><keyword>Sequence Analysis, DNA/methods</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar 4</date></pub-dates></dates><isbn>1548-7105 (Electronic)&#xD;1548-7091 (Linking)</isbn><accession-num>22388286</accession-num><urls><related-urls><url>;(118) ControlRaw reads: FastQC FASTX-ToolkitMapping: BAMtools ADDIN EN.CITE <EndNote><Cite><Author>Barnett</Author><Year>2011</Year><RecNum>5297</RecNum><DisplayText>(119)</DisplayText><record><rec-number>5297</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1524153653">5297</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barnett, D. W.</author><author>Garrison, E. K.</author><author>Quinlan, A. R.</author><author>Stromberg, M. P.</author><author>Marth, G. T.</author></authors></contributors><auth-address>Department of Biology, Boston College, Chestnut Hill, MA 02467, USA. barnetde@bc.edu</auth-address><titles><title>BamTools: a C++ API and toolkit for analyzing and managing BAM files</title><secondary-title>Bioinformatics</secondary-title></titles><periodical><full-title>Bioinformatics</full-title></periodical><pages>1691-2</pages><volume>27</volume><number>12</number><keywords><keyword>Genomics/*methods</keyword><keyword>Sequence Alignment</keyword><keyword>*Sequence Analysis, DNA</keyword><keyword>*Software</keyword></keywords><dates><year>2011</year><pub-dates><date>Jun 15</date></pub-dates></dates><isbn>1367-4811 (Electronic)&#xD;1367-4803 (Linking)</isbn><accession-num>21493652</accession-num><urls><related-urls><url>;(119) Picard ToolsVariants: GATK ADDIN EN.CITE <EndNote><Cite><Author>McKenna</Author><Year>2010</Year><RecNum>5154</RecNum><DisplayText>(120)</DisplayText><record><rec-number>5154</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1487605914">5154</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McKenna, A.</author><author>Hanna, M.</author><author>Banks, E.</author><author>Sivachenko, A.</author><author>Cibulskis, K.</author><author>Kernytsky, A.</author><author>Garimella, K.</author><author>Altshuler, D.</author><author>Gabriel, S.</author><author>Daly, M.</author><author>DePristo, M. 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ADDIN EN.CITE.DATA (125)SKAT-O (rare variants) ADDIN EN.CITE <EndNote><Cite><Author>Lee</Author><Year>2012</Year><RecNum>4984</RecNum><DisplayText>(88)</DisplayText><record><rec-number>4984</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1452877381">4984</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lee, S.</author><author>Emond, M. J.</author><author>Bamshad, M. J.</author><author>Barnes, K. C.</author><author>Rieder, M. J.</author><author>Nickerson, D. A.</author><author>NHLBI GO Exome Sequencing Project-ESP Lung Project Team,</author><author>Christiani, D. C.</author><author>Wurfel, M. M.</author><author>Lin, X.</author></authors></contributors><auth-address>Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.</auth-address><titles><title>Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies</title><secondary-title>Am J Hum Genet</secondary-title></titles><periodical><full-title>Am J Hum Genet</full-title></periodical><pages>224-37</pages><volume>91</volume><number>2</number><keywords><keyword>*Case-Control Studies</keyword><keyword>Computer Simulation</keyword><keyword>*Data Interpretation, Statistical</keyword><keyword>Exome/*genetics</keyword><keyword>Genetic Association Studies/*methods</keyword><keyword>*Genetic Variation</keyword><keyword>Humans</keyword><keyword>Models, Genetic</keyword><keyword>Rare Diseases/*genetics</keyword><keyword>Sequence Analysis, DNA/*methods</keyword></keywords><dates><year>2012</year><pub-dates><date>Aug 10</date></pub-dates></dates><isbn>1537-6605 (Electronic)&#xD;0002-9297 (Linking)</isbn><accession-num>22863193</accession-num><urls><related-urls><url>;(88)GENESIS (rare variants) ADDIN EN.CITE <EndNote><Cite><Author>Conomos</Author><Year>2018</Year><RecNum>5407</RecNum><DisplayText>(126)</DisplayText><record><rec-number>5407</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1527875647">5407</key></foreign-keys><ref-type name="Computer Program">9</ref-type><contributors><authors><author>Conomos, M.P.</author><author>Gogarten, S.M.</author><author>Brown, L.</author><author>Chen, H.</author><author>Rice, K.</author><author>Sofer, T.</author><author>Thornton, T.</author><author>Yu, C.</author></authors></contributors><titles><title>GENESIS: GENetic EStimation and Inference in Structured samples (GENESIS): Statistical methods for analyzing genetic data from samples with population structure and/or relatedness</title></titles><edition> R package version 2.10.0</edition><dates><year>2018</year></dates><urls></urls></record></Cite></EndNote>(126)BOLT-LMM PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb2g8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (127) 5: Software for RNA sequencing studies. This table provides an overview of commonly used software tools for performing analysis of RNA sequencing data. Because the field continues to evolve rapidly, additional tools not listed in this table may also be useful to researchers. TaskToolsURLAlignmentBowtie ADDIN EN.CITE <EndNote><Cite><Author>Langmead</Author><Year>2009</Year><RecNum>1858</RecNum><DisplayText>(128)</DisplayText><record><rec-number>1858</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="0">1858</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Langmead, B.</author><author>Trapnell, C.</author><author>Pop, M.</author><author>Salzberg, S. L.</author></authors></contributors><auth-address>Center for Bioinformatics and Computational Biology, Institute for Advanced Computer Studies, University of Maryland, College Park, MD 20742, USA. langmead@cs.umd.edu</auth-address><titles><title>Ultrafast and memory-efficient alignment of short DNA sequences to the human genome</title><secondary-title>Genome Biol</secondary-title></titles><periodical><full-title>Genome Biol</full-title></periodical><pages>R25</pages><volume>10</volume><number>3</number><edition>2009/03/06</edition><keywords><keyword>Algorithms</keyword><keyword>*Base Sequence</keyword><keyword>Genome, Human/*genetics</keyword><keyword>Humans</keyword><keyword>Sequence Alignment/*methods</keyword></keywords><dates><year>2009</year></dates><isbn>1465-6914 (Electronic)&#xD;1465-6906 (Linking)</isbn><accession-num>19261174</accession-num><urls><related-urls><url> [pii]&#xD;10.1186/gb-2009-10-3-r25</electronic-resource-num><language>eng</language></record></Cite></EndNote>(128)STAR ADDIN EN.CITE <EndNote><Cite><Author>Dobin</Author><Year>2013</Year><RecNum>4979</RecNum><DisplayText>(129)</DisplayText><record><rec-number>4979</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1452522515">4979</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dobin, A.</author><author>Davis, C. A.</author><author>Schlesinger, F.</author><author>Drenkow, J.</author><author>Zaleski, C.</author><author>Jha, S.</author><author>Batut, P.</author><author>Chaisson, M.</author><author>Gingeras, T. R.</author></authors></contributors><auth-address>Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. dobin@cshl.edu</auth-address><titles><title>STAR: ultrafast universal RNA-seq aligner</title><secondary-title>Bioinformatics</secondary-title></titles><periodical><full-title>Bioinformatics</full-title></periodical><pages>15-21</pages><volume>29</volume><number>1</number><keywords><keyword>Algorithms</keyword><keyword>Cluster Analysis</keyword><keyword>Gene Expression Profiling</keyword><keyword>Genome, Human</keyword><keyword>Humans</keyword><keyword>RNA Splicing</keyword><keyword>Sequence Alignment/*methods</keyword><keyword>Sequence Analysis, RNA/methods</keyword><keyword>*Software</keyword></keywords><dates><year>2013</year><pub-dates><date>Jan 1</date></pub-dates></dates><isbn>1367-4811 (Electronic)&#xD;1367-4803 (Linking)</isbn><accession-num>23104886</accession-num><urls><related-urls><url>;(129)TopHat ADDIN EN.CITE <EndNote><Cite><Author>Trapnell</Author><Year>2012</Year><RecNum>1861</RecNum><DisplayText>(130)</DisplayText><record><rec-number>1861</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="0">1861</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Trapnell, C.</author><author>Roberts, A.</author><author>Goff, L.</author><author>Pertea, G.</author><author>Kim, D.</author><author>Kelley, D. R.</author><author>Pimentel, H.</author><author>Salzberg, S. L.</author><author>Rinn, J. L.</author><author>Pachter, L.</author></authors></contributors><auth-address>Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. cole@</auth-address><titles><title>Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks</title><secondary-title>Nat Protoc</secondary-title></titles><periodical><full-title>Nat Protoc</full-title></periodical><pages>562-78</pages><volume>7</volume><number>3</number><edition>2012/03/03</edition><keywords><keyword>DNA, Complementary/*genetics</keyword><keyword>Gene Expression Profiling/*methods</keyword><keyword>Genetic Association Studies/*methods</keyword><keyword>Genomics/*methods</keyword><keyword>Sequence Analysis, DNA/*methods</keyword><keyword>*Software</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1750-2799 (Electronic)&#xD;1750-2799 (Linking)</isbn><accession-num>22383036</accession-num><urls><related-urls><url> [pii]&#xD;10.1038/nprot.2012.016</electronic-resource-num><language>eng</language></record></Cite></EndNote>(130) quantificationCufflinks ADDIN EN.CITE <EndNote><Cite><Author>Trapnell</Author><Year>2012</Year><RecNum>1861</RecNum><DisplayText>(130)</DisplayText><record><rec-number>1861</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="0">1861</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Trapnell, C.</author><author>Roberts, A.</author><author>Goff, L.</author><author>Pertea, G.</author><author>Kim, D.</author><author>Kelley, D. 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ADDIN EN.CITE.DATA (136) expression DEGseq ADDIN EN.CITE <EndNote><Cite><Author>Wang</Author><Year>2010</Year><RecNum>5310</RecNum><DisplayText>(137)</DisplayText><record><rec-number>5310</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1524157907">5310</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wang, L.</author><author>Feng, Z.</author><author>Wang, X.</author><author>Wang, X.</author><author>Zhang, X.</author></authors></contributors><auth-address>MOE Key Laboratory of Bioinformatics and Bioinformatics Division, TNLIST/Department of Automation, Tsinghua, University, Beijing 100084, China.</auth-address><titles><title>DEGseq: an R package for identifying differentially expressed genes from RNA-seq data</title><secondary-title>Bioinformatics</secondary-title></titles><periodical><full-title>Bioinformatics</full-title></periodical><pages>136-8</pages><volume>26</volume><number>1</number><keywords><keyword>*Algorithms</keyword><keyword>Base Sequence</keyword><keyword>Gene Expression Profiling/*methods</keyword><keyword>Molecular Sequence Data</keyword><keyword>Oligonucleotide Array Sequence Analysis/*methods</keyword><keyword>*Programming Languages</keyword><keyword>RNA/*genetics</keyword><keyword>Sequence Analysis, RNA/*methods</keyword><keyword>*Software</keyword></keywords><dates><year>2010</year><pub-dates><date>Jan 1</date></pub-dates></dates><isbn>1367-4811 (Electronic)&#xD;1367-4803 (Linking)</isbn><accession-num>19855105</accession-num><urls><related-urls><url>;(137)DESeq2 ADDIN EN.CITE <EndNote><Cite><Author>Love</Author><Year>2014</Year><RecNum>4980</RecNum><DisplayText>(138)</DisplayText><record><rec-number>4980</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1452522614">4980</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Love, M. 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D.</author><author>McCarthy, D. J.</author><author>Smyth, G. K.</author></authors></contributors><auth-address>Cancer Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia. mrobinson@wehi.edu.au</auth-address><titles><title>edgeR: a Bioconductor package for differential expression analysis of digital gene expression data</title><secondary-title>Bioinformatics</secondary-title></titles><periodical><full-title>Bioinformatics</full-title></periodical><pages>139-40</pages><volume>26</volume><number>1</number><keywords><keyword>*Algorithms</keyword><keyword>Gene Expression Profiling/*methods</keyword><keyword>Oligonucleotide Array Sequence Analysis/*methods</keyword><keyword>*Programming Languages</keyword><keyword>*Signal Processing, Computer-Assisted</keyword><keyword>*Software</keyword></keywords><dates><year>2010</year><pub-dates><date>Jan 1</date></pub-dates></dates><isbn>1367-4811 (Electronic)&#xD;1367-4803 (Linking)</isbn><accession-num>19910308</accession-num><urls><related-urls><url>;(139)limma/voom ADDIN EN.CITE <EndNote><Cite><Author>Law</Author><Year>2014</Year><RecNum>5245</RecNum><DisplayText>(140)</DisplayText><record><rec-number>5245</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1516377225">5245</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Law, C. W.</author><author>Chen, Y.</author><author>Shi, W.</author><author>Smyth, G. K.</author></authors></contributors><titles><title>voom: Precision weights unlock linear model analysis tools for RNA-seq read counts</title><secondary-title>Genome Biol</secondary-title></titles><periodical><full-title>Genome Biol</full-title></periodical><pages>R29</pages><volume>15</volume><number>2</number><keywords><keyword>*Algorithms</keyword><keyword>Base Sequence</keyword><keyword>Bayes Theorem</keyword><keyword>Computer Simulation</keyword><keyword>Gene Expression Profiling</keyword><keyword>High-Throughput Nucleotide Sequencing/*methods</keyword><keyword>*Linear Models</keyword><keyword>RNA/*genetics</keyword><keyword>Sequence Analysis, RNA</keyword></keywords><dates><year>2014</year><pub-dates><date>Feb 3</date></pub-dates></dates><isbn>1474-760X (Electronic)&#xD;1474-7596 (Linking)</isbn><accession-num>24485249</accession-num><urls><related-urls><url>;(140)PoissonSeq ADDIN EN.CITE <EndNote><Cite><Author>Burden</Author><Year>2014</Year><RecNum>5312</RecNum><DisplayText>(141)</DisplayText><record><rec-number>5312</rec-number><foreign-keys><key app="EN" db-id="awesrdpfqpvff3esrdqxd5vnp0d9wevsxxfz" timestamp="1524158115">5312</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Burden, C. 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C.</author><author>Cleland, J.</author><author>Kim, R.</author><author>Wong, W. C.</author><author>Weinstein, J. 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Article published online before print in May 2002</electronic-resource-num><language>eng</language></record></Cite></EndNote>(124) 6: Selected examples of omics integration and using omics for functional validation studies.TechniqueExampleContext-dependent eQTLs Li and coworkers showed that cytokine production by peripheral blood mononuclear cells upon stimulation depends on six specific SNPs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaTwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051

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ADDIN EN.CITE.DATA (153). One inducible cytokine QTL at the NAA35-GOLM1 locus markedly modulated interleukin (IL)-6 production in response to multiple pathogens and also showed association with susceptibility to candidemia.Imputed gene expression (PrediXcan)Ferreira et al tested for associations between asthma and 17,190 genes found to have cis- and/or trans-eQTLs across 12 cell types relevant to asthma PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GZXJyZWlyYTwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+

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ADDIN EN.CITE.DATA (154). They confirmed 37 genes where the association was driven by eQTLs located in established risk loci for allergic disease, and discovered 11 novel genetic associations.Gene knockdownDixit et al investigated the effect of gene knockdown by CRISPR/Cas9 on RNA-seq expression in human LPS stimulated bone marrow dendritic cells, a method they called Perturb-seq PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaXhpdDwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (155). By analyzing the transcriptional consequences of perturbations of transcription factors in these cells, they were able to interpret the functional consequences of these transcription factors, as well as their interaction, uncovering their molecular mechanisms.Figure 1:Figure 2: 00Formulation of study aimsConsideration of ethical aspects and health disparitiesSubject consent and phenotypingSample collectionStudy designEnrollmentNucleic acid isolationLibrary constructionNext-gen sequencingSequencingSequence readsGenome alignmentData analysisQuality controlVariant callingAssociation analysisQuality controlQuantificationDifferential expressionDownstream analysesReplication studiesData integrationFunctional validationManuscriptShared datasetsResearch productsRNADNAFormulation of study aimsConsideration of ethical aspects and health disparitiesSubject consent and phenotypingSample collectionStudy designEnrollmentNucleic acid isolationLibrary constructionNext-gen sequencingSequencingSequence readsGenome alignmentData analysisQuality controlVariant callingAssociation analysisQuality controlQuantificationDifferential expressionDownstream analysesReplication studiesData integrationFunctional validationManuscriptShared datasetsResearch productsRNADNAReferences ADDIN EN.REFLIST 1. 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