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Original Investigation
June 5, 2017

Derivation and Validation of a Serum Biomarker Panel to Identify Infants With Acute Intracranial Hemorrhage

Author Affiliations
  • 1Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  • 2Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  • 3Axela Inc, Toronto, Ontario, Canada
  • 4Department of Pediatrics, University of Utah, Primary Children’s Hospital, Salt Lake City, Utah
  • 5Department of Pediatrics, Ann and Robert H. Lurie Children’s Hospital, Chicago, Illinois
  • 6Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
JAMA Pediatr. 2017;171(6):e170429. doi:10.1001/jamapediatrics.2017.0429
Key Points

Question  Is it possible to develop a panel of serum biomarkers that can be used to identify infants who are at increased risk of having an acute intracranial hemorrhage and/or abusive head trauma?

Findings  This study used a retrospective cohort of 99 patients followed by a prospective cohort of 599 patients to derive and validate the Biomarkers of Infant Brain Injury Score. The Biomarkers of Infant Brain Injury Score predicted intracranial hemorrhage with a higher sensitivity than clinical judgement, the current criterion standard.

Meaning  The Biomarkers of Infant Brain Injury Score may be useful in clinical practice to identify infants who should undergo neuroimaging to identify abusive head trauma.


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.