ResearchIn-Press PreviewInflammationNeuroscience Open Access | 10.1172/jci.insight.178456
1Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, United States of America
3Division of Rheumatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Allergy Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadephia, United States of America
5Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America
6AGS Clinical Trials, Work Group, Philadelphia, United States of America
7Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America
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1Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, United States of America
3Division of Rheumatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Allergy Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadephia, United States of America
5Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America
6AGS Clinical Trials, Work Group, Philadelphia, United States of America
7Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America
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1Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, United States of America
3Division of Rheumatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Allergy Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadephia, United States of America
5Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America
6AGS Clinical Trials, Work Group, Philadelphia, United States of America
7Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America
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1Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, United States of America
3Division of Rheumatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Allergy Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadephia, United States of America
5Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America
6AGS Clinical Trials, Work Group, Philadelphia, United States of America
7Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America
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1Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, United States of America
3Division of Rheumatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Allergy Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadephia, United States of America
5Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America
6AGS Clinical Trials, Work Group, Philadelphia, United States of America
7Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America
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1Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, United States of America
3Division of Rheumatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Allergy Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadephia, United States of America
5Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America
6AGS Clinical Trials, Work Group, Philadelphia, United States of America
7Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America
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1Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, United States of America
3Division of Rheumatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Allergy Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadephia, United States of America
5Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America
6AGS Clinical Trials, Work Group, Philadelphia, United States of America
7Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America
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1Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, United States of America
3Division of Rheumatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Allergy Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadephia, United States of America
5Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America
6AGS Clinical Trials, Work Group, Philadelphia, United States of America
7Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America
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1Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, United States of America
3Division of Rheumatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Allergy Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadephia, United States of America
5Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America
6AGS Clinical Trials, Work Group, Philadelphia, United States of America
7Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America
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1Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, United States of America
3Division of Rheumatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Allergy Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadephia, United States of America
5Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America
6AGS Clinical Trials, Work Group, Philadelphia, United States of America
7Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America
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1Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, United States of America
3Division of Rheumatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Allergy Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadephia, United States of America
5Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America
6AGS Clinical Trials, Work Group, Philadelphia, United States of America
7Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America
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1Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
2Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, United States of America
3Division of Rheumatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, United States of America
4Department of Allergy Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadephia, United States of America
5Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America
6AGS Clinical Trials, Work Group, Philadelphia, United States of America
7Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America
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Published June 17, 2024 - More info
Interferon signaling gene (ISG) expression scores are potential markers of inflammation with significance from cancer to genetic syndromes. In Aicardi Goutières Syndrome (AGS), a disorder of abnormal DNA and RNA metabolism, this score has potential as a diagnostic biomarker, although the approach to ISG calculation has not been standardized or validated. To optimize ISG calculation and validate ISG as a diagnostic biomarker, mRNA levels of 36 type I interferon response genes were quantified from 997 samples (including 334 AGS), and samples were randomized into training and test datasets. An independent validation cohort (n = 122) was also collected. ISGs were calculated using all potential combinations up to 6 genes. A 4-gene approach (IFI44L, IFI27, USP18, IFI6) was the best-performing model [area under the curve (AUC) of 0.8872 (training dataset), 0.9245 (test dataset)]. The majority of top performing gene combinations included IFI44L. Performance of IFI44L-alone was 0.8762 (training dataset) and 0.9580 (test dataset) by AUC. The top approaches were able to discriminate cases of genetic interferonopathy from control samples. This study validates the context of use for the ISG score as a diagnostic biomarker and underscores the importance of IFI44L in diagnosis of genetic interferonopathies.