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Abstract Details

Machine learning-driven Interferon Signaling Gene Expression Score predicts Aicardi Goutières Syndrome
Autoimmune Neurology
P10 - Poster Session 10 (8:00 AM-9:00 AM)
6-019
Interferon Signaling Genes (ISG) scores have evolved as an important surrogate metric of interferon signaling, used in clinical trials and to measure disease activity in genetic interferonopathies. Recently, multiplexed approaches for gene expression have increased the need for standardization of ISG calculation from interferon response gene expression panels. 
To define the biomarkers in Aicardi Goutieres Syndrome (AGS).
We measure interferon response gene expression using NanoString nCounter® Analysis System in 997 individual samples, of which 334 were from AGS affected subjects, and randomized samples into training and validation data sets. The training data set was used to develop several machine learning models. These models were assessed on the validation dataset along with the original 6 gene AGS score. 
The random forest was the best performing model, achieving accuracy of 91.1% and area under the curve (AUC) of .962. This performance was better than the existing standard, 6 gene ISG AGS 6 gene score, which has an accuracy of 73.3% and AUC of .896. All classification methods evaluated perform worse in the AGS samples from patients with an RNASEH2 complex mutation. In addition, the longitudinal stability was lower for RNASEH2 complex mutation samples than for non- RNASEH2 related samples. 

This study validates a machine learning-driven ISG score as candidate diagnostic biomarker of AGS. Further study will be necessary to assess whether this score is useful in other genetic interferonpathies and whether there is any correlation with disease severity or therapeutic response.

Authors/Disclosures
Adeline Vanderver, MD, FAAN (Children'S Hospital of Philadelphia)
PRESENTER
An immediate family member of Dr. Vanderver has received personal compensation for serving as an employee of Maryland Physician Care. The institution of Dr. Vanderver has received research support from Takeda. The institution of Dr. Vanderver has received research support from Passage Bio. The institution of Dr. Vanderver has received research support from Homology. The institution of Dr. Vanderver has received research support from Eli Lilly. The institution of Dr. Vanderver has received research support from Myrtelle. The institution of Dr. Vanderver has received research support from SynaptixBio. The institution of Dr. Vanderver has received research support from PMD Foundation. The institution of Dr. Vanderver has received research support from Ionis. The institution of Dr. Vanderver has received research support from ISD . The institution of Dr. Vanderver has received research support from Boehringer-Ingelheim. The institution of Dr. Vanderver has received research support from Biogen. The institution of Dr. Vanderver has received research support from Sana. The institution of Dr. Vanderver has received research support from Affinia. The institution of Dr. Vanderver has received research support from BridgeBio. The institution of Dr. Vanderver has received research support from Orchard. The institution of Dr. Vanderver has received research support from Minoryx. The institution of Dr. Vanderver has received research support from Forge Biologics. The institution of Dr. Vanderver has received research support from Vigil. Dr. Vanderver has received intellectual property interests from a discovery or technology relating to health care. Dr. Vanderver has received intellectual property interests from a discovery or technology relating to health care.
Russell D'Aiello, Other (Children's Hospital of Philadelphia) The institution of Mr. D'Aiello has received research support from Takeda Pharmaceuticals. The institution of Mr. D'Aiello has received research support from Orchard Therapeutics.
Asako Takanohashi, PhD, DVM (Children's Hospital of Philadelphia) Dr. Takanohashi has nothing to disclose.
Francesco Gavazzi, MD (Children'S Hospital of Philadelphia) Dr. Gavazzi has nothing to disclose.
Justine Shults Justine Shults has nothing to disclose.
Sarah Woidill Sarah Woidill has nothing to disclose.
Laura Ann Adang, MD Dr. Adang has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda Development Center Americas, Inc.. Dr. Adang has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Middle East Genetics and Metabolic Academy (MEGMA).