ABSTRACT
While pediatric COVID-19 is rarely severe, a small fraction of children infected with SARS-CoV-2 go on to develop multisystem inflammatory syndrome (MIS-C), with substantial morbidity. An objective method with high specificity and high sensitivity to identify current or imminent MIS-C in children infected with SARS-CoV-2 is highly desirable. The aim was to learn about an interpretable novel cytokine/chemokine assay panel providing such an objective classification. This retrospective study was conducted on four groups of pediatric patients seen at multiple sites of Texas Children's Hospital, Houston, TX who consented to provide blood samples to our COVID-19 Biorepository. Standard laboratory markers of inflammation and a novel cytokine/chemokine array were measured in blood samples of all patients. Group 1 consisted of 72 COVID-19, 70 MIS-C and 63 uninfected control patients seen between May 2020 and January 2021 and predominantly infected with pre-alpha variants. Group 2 consisted of 29 COVID-19 and 43 MIS-C patients seen between January and May 2021 infected predominantly with the alpha variant. Group 3 consisted of 30 COVID-19 and 32 MIS-C patients seen between August and October 2021 infected with alpha and/or delta variants. Group 4 consisted of 20 COVID-19 and 46 MIS-C patients seen between October 2021 andJanuary 2022 infected with delta and/or omicron variants. Group 1 was used to train an L1-regularized logistic regression model which was tested using five-fold cross validation, and then separately validated against the remaining naïve groups. The area under receiver operating curve (AUROC) and F1-score were used to quantify the performance of the cytokine/chemokine assay-based classifier. Standard laboratory markers predict MIS-C with a five-fold cross-validated AUROC of 0.86 ± 0.05 and an F1 score of 0.78 ± 0.07, while the cytokine/chemokine panel predicted MIS-C with a five-fold cross-validated AUROC of 0.95 ± 0.02 and an F1 score of 0.91 ± 0.04, with only sixteen of the forty-five cytokines/chemokines sufficient to achieve this performance. Tested on Group 2 the cytokine/chemokine panel yielded AUROC = 0.98 and F1 = 0.93, on Group 3 it yielded AUROC = 0.89 and F1 = 0.89, and on Group 4 AUROC = 0.99 and F1 = 0.97. Adding standard laboratory markers to the cytokine/chemokine panel did not improve performance. A top-10 subset of these 16 cytokines achieves equivalent performance on the validation data sets. Our findings demonstrate that a sixteen-cytokine/chemokine panel as well as the top ten subset provides a highly sensitive, and specific method to identify MIS-C in patients infected with SARS-CoV-2 of all the major variants identified to date.
ABSTRACT
An objective method to identify imminent or current Multi-Inflammatory Syndrome in Children (MIS-C) infected with SARS-CoV-2 is highly desirable. The aims was to define an algorithmically interpreted novel cytokine/chemokine assay panel providing such an objective classification. This study was conducted on 4 groups of patients seen at multiple sites of Texas Children's Hospital, Houston, TX who consented to provide blood samples to our COVID-19 Biorepository. Standard laboratory markers of inflammation and a novel cytokine/chemokine array were measured in blood samples of all patients. Group 1 consisted of 72 COVID-19, 66 MIS-C and 63 uninfected control patients seen between May 2020 and January 2021 and predominantly infected with pre-alpha variants. Group 2 consisted of 29 COVID-19 and 43 MIS-C patients seen between January-May 2021 infected predominantly with the alpha variant. Group 3 consisted of 30 COVID-19 and 32 MIS-C patients seen between August-October 2021 infected with alpha and/or delta variants. Group 4 consisted of 20 COVID-19 and 46 MIS-C patients seen between October 2021-January 2022 infected with delta and/or omicron variants. Group 1 was used to train a L1-regularized logistic regression model which was validated using 5-fold cross validation, and then separately validated against the remaining naïve groups. The area under receiver operating curve (AUROC) and F1-score were used to quantify the performance of the algorithmically interpreted cytokine/chemokine assay panel. Standard laboratory markers predict MIS-C with a 5-fold cross-validated AUROC of 0.86 ± 0.05 and an F1 score of 0.78 ± 0.07, while the cytokine/chemokine panel predicted MIS-C with a 5-fold cross-validated AUROC of 0.95 ± 0.02 and an F1 score of 0.91 ± 0.04, with only sixteen of the forty-five cytokines/chemokines sufficient to achieve this performance. Tested on Group 2 the cytokine/chemokine panel yielded AUROC =0.98, F1=0.93, on Group 3 it yielded AUROC=0.89, F1 = 0.89, and on Group 4 AUROC= 0.99, F1= 0.97). Adding standard laboratory markers to the cytokine/chemokine panel did not improve performance. A top-10 subset of these 16 cytokines achieves equivalent performance on the validation data sets. Our findings demonstrate that a sixteen-cytokine/chemokine panel as well as the top ten subset provides a sensitive, specific method to identify MIS-C in patients infected with SARS-CoV-2 of all the major variants identified to date.
ABSTRACT
In schizophrenia and related disorders, a deeper mechanistic understanding of neocortical dysfunction will be essential to developing new diagnostic and therapeutic techniques. To this end, combined transcranial magnetic stimulation and electroencephalography (TMS/EEG) provides a non-invasive tool to simultaneously perturb and measure neurophysiological correlates of cortical function, including oscillatory activity, cortical inhibition, connectivity, and synchronization. In this review, we summarize the findings from a variety of studies that apply TMS/EEG to understand the fundamental features of cortical dysfunction in schizophrenia. These results lend to future applications of TMS/EEG in understanding the pathophysiological mechanisms underlying cognitive deficits in schizophrenia.
