Proteomic Analysis of Plasma from California Sea Lions (Zalophus californianus) Reveals Apolipoprotein E as a Candidate Biomarker of Chronic Domoic Acid Toxicosis.
Domoic acid toxicosis (DAT) in California sea lions (Zalophus californianus) is caused by exposure to the marine biotoxin domoic acid and has been linked to massive stranding events and mortality. Diagnosis is based on clinical signs in addition to the presence of domoic acid in body fluids. Chronic DAT further is characterized by reoccurring seizures progressing to status epilepticus. Diagnosis of chronic DAT is often slow and problematic, and minimally invasive tests for DAT have been the focus of numerous recent biomarker studies. The goal of this study was to retrospectively profile plasma proteins in a population of sea lions with chronic DAT and those without DAT using two dimensional gel electrophoresis to discover whether individual, multiple, or combinations of protein and clinical data could be utilized to identify sea lions with DAT. Using a training set of 32 sea lion sera, 20 proteins and their isoforms were identified that were significantly different between the two groups (p<0.05). Interestingly, 11 apolipoprotein E (ApoE) charge forms were decreased in DAT samples, indicating that ApoE charge form distributions may be important in the progression of DAT. In order to develop a classifier of chronic DAT, an independent blinded test set of 20 sea lions, seven with chronic DAT, was used to validate models utilizing ApoE charge forms and eosinophil counts. The resulting support vector machine had high sensitivity (85.7% with 92.3% negative predictive value) and high specificity (92.3% with 85.7% positive predictive value). These results suggest that ApoE and eosinophil counts along with machine learning can perform as a robust and accurate tool to diagnose chronic DAT. Although this analysis is specifically focused on blood biomarkers and routine clinical data, the results demonstrate promise for future studies combining additional variables in multidimensional space to create robust classifiers.
Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, United States of America.
Benjamin A
BA
Neely
Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, United States of America; Grice Marine Laboratory, College of Charleston, Charleston, SC, United States of America.
Jason A
JA
Ferrante
Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, United States of America.
J Mauro
JM
Chaves
The Marine Mammal Center, Sausalito, CA, United States of America.
Jennifer L
JL
Soper
Department of Biomedical Informatics, Stony Brook University, Long Island, NY, United States of America.
Jonas S
JS
Almeida
Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, United States of America; Research Service, Ralph H. Johnson VA Medical Center, Charleston, SC, United States of America.
John M
JM
Arthur
The Marine Mammal Center, Sausalito, CA, United States of America.
Frances M D
FM
Gulland
Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC, United States of America; Grice Marine Laboratory, College of Charleston, Charleston, SC, United States of America; Research Service, Ralph H. Johnson VA Medical Center, Charleston, SC, United States of America.
Michael G
MG
Janech
D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D004804:Eosinophils / Q000378:metabolism; D005260:Female; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D000069550:Machine Learning; D008297:Male; D009467:Neuromuscular Depolarizing Agents / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000175:diagnosis / Q000662:veterinary; D040901:Proteomics / Q000379:methods*; D012189:Retrospective Studies; D046070:Sea Lions / Q000097:blood*; D060388:Support Vector Machine
D001057:Apolipoproteins E; D009467:Neuromuscular Depolarizing Agents; C012301:domoic acid; D007608:Kainic Acid