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Derivation and Validation of a Serum Biomarker Panel to Identify Infants With Acute Intracranial Hemorrhage
Rachel Pardes Berger1, Brian J Pak2, Mariya D Kolesnikova2
1Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania2Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Insights
A new model accurately identifies acute intracranial hemorrhage in infants at risk for abusive head trauma. This biomarker-based score can help reduce infant mortality and morbidity from physical abuse.
Area of Science:
- Pediatric Emergency Medicine
- Biomarker Discovery
- Infant Trauma
Background:
- Abusive head trauma is a leading cause of death in physically abused children.
- Delayed diagnosis of abusive head trauma, especially mild cases, increases morbidity and mortality.
- Serum biomarkers show promise for point-of-care screening of intracranial hemorrhage.
Purpose of the Study:
- To identify and validate serum biomarkers for a multivariable model.
- To develop a model for detecting intracranial hemorrhage in well-appearing infants.
- To utilize the Ziplex System for multiplex biomarker analysis.
Main Methods:
- Developed a multivariable model using logistic regression.
- Included 3 serum biomarkers (MMP-9, NSE, VCAM-1) and total hemoglobin.
- Prospectively validated the model in 599 infants across 3 pediatric trauma centers.
Main Results:
- The Biomarkers for Infant Brain Injury Score demonstrated 89.3% sensitivity and 48.0% specificity for acute intracranial hemorrhage.
- Positive and negative predictive values were 21.3% and 95.6%, respectively.
- The model was not effective for atraumatic brain abnormalities, skull fractures, or chronic hemorrhage.
Conclusions:
- The Biomarkers for Infant Brain Injury Score effectively identifies acute intracranial hemorrhage in at-risk infants.
- Timely diagnosis through this model can decrease abusive head trauma-related morbidity and mortality.
- This biomarker-based approach offers potential for improved infant safety and care.
Importance:
Abusive head trauma is the leading cause of death from physical abuse. Missing the diagnosis of abusive head trauma, particularly in its mild form, is common and contributes to increased morbidity and mortality. Serum biomarkers may have potential as quantitative point-of-care screening tools to alert physicians to the possibility of intracranial hemorrhage.
Objective:
To identify and validate a set of biomarkers that could be the basis of a multivariable model to identify intracranial hemorrhage in well-appearing infants using the Ziplex System.
Design, Setting, And Participants:
Binary logistic regression was used to develop a multivariable model incorporating 3 serum biomarkers (matrix metallopeptidase-9, neuron-specific enolase, and vascular cellular adhesion molecule-1) and 1 clinical variable (total hemoglobin). The model was then prospectively validated. Multiplex biomarker measurements were performed using Flow-Thru microarray technology on the Ziplex System, which has potential as a point-of-care system. The model was tested at 3 pediatric emergency departments in level I pediatric trauma centers (Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Primary Children's Hospital, Salt Lake City, Utah; and Lurie Children's Hospital, Chicago, Illinois) among well-appearing infants who presented for care owing to symptoms that placed them at increased risk of abusive head trauma. The study took place from November 2006 to April 2014 at Children's Hospital of Pittsburgh, June 2010 to August 2013 at Primary Children's Hospital, and January 2011 to August 2013 at Lurie Children's Hospital.
Main Outcomes And Measures:
A mathematical model that can predict acute intracranial hemorrhage in infants at increased risk of abusive head trauma.
Results:
The multivariable model, Biomarkers for Infant Brain Injury Score, was applied prospectively to 599 patients. The mean (SD) age was 4.7 (3.1) months. Fifty-two percent were boys, 78% were white, and 8% were Hispanic. At a cutoff of 0.182, the model was 89.3% sensitive (95% CI, 87.7-90.4) and 48.0% specific (95% CI, 47.3-48.9) for acute intracranial hemorrhage. Positive and negative predictive values were 21.3% and 95.6%, respectively. The model was neither sensitive nor specific for atraumatic brain abnormalities, isolated skull fractures, or chronic intracranial hemorrhage.
Conclusion And Relevance:
The Biomarkers for Infant Brain Injury Score, a multivariable model using 3 serum biomarker concentrations and serum hemoglobin, can identify infants with acute intracranial hemorrhage. Accurate and timely identification of intracranial hemorrhage in infants without a history of trauma in whom trauma may not be part of the differential diagnosis has the potential to decrease morbidity and mortality from abusive head trauma.
