title: Biomarkers in Ocular Chronic Graft Versus Host Disease: Tear Cytokine- and Chemokine-Based Predictive Model.
abstract: OBJECTIVE
  To develop a tear molecule level-based predictive model based on a panel of tear cytokines and their correlation with clinical features in ocular chronic graft versus host disease (cGVHD).
  
  
  METHODS
  Twenty-two ocular cGVHD patients and 21 healthy subjects were evaluated in a controlled environmental research laboratory (CERLab). Clinical parameters were recorded, and tears were collected. Levels of 15 molecules (epidermal growth factor [EGF], IL receptor antagonist [IL-1Ra], IL-1β, IL-2, IL-6, IL-8/CXCL8, IL-10, IL-12p70, IL-17A, interferon inducible protein [IP]-10/CXCL10, IFN-γ, VEGF, TNF-α, eotaxin 1, and regulated on activation normal T cell expressed and secreted [RANTES]) were measured by multiplex-bead assay and correlated with clinical parameters. Logistic regression was used to develop a predictive model. Leave-one-out cross-validation was applied. Classification capacity was evaluated in a cohort of individuals with dry eye (DE) of other etiologies different from GVHD.
  
  
  RESULTS
  Epidermal growth factor and IP-10/CXCL10 levels were significantly decreased in ocular cGVHD, positively correlating with tear production and stability and negatively correlating with symptoms, hyperemia, and vital staining. Interleukin-1Ra, IL-8/CXCL8, and IL-10 were significantly increased in ocular cGVHD, and the first two correlated positively with symptoms, hyperemia, and ocular surface integrity while negatively correlating with tear production and stability. Predictive models were generated, and the best panel was based on IL-8/CXCL8 and IP-10/CXCL10 tear levels along with age and sex, with an area under the receiving operating curve of 0.9004, sensitivity of 86.36%, and specificity of 95.24%.
  
  
  CONCLUSIONS
  A predictive model based on tear levels of IL-8/CXCL8 and IP-10/CXCL10 resulted in optimal sensitivity and specificity. These results add further knowledge to the search for potential biomarkers in this devastating ocular inflammatory disease.
authors.affiliation: Institute of Applied OphthalmoBiology (IOBA), University of Valladolid, Valladolid, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Cocho
authors.affiliation: Institute of Applied OphthalmoBiology (IOBA), University of Valladolid, Valladolid, Spain 2Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Valladolid, Spain.
authors.forename: Itziar
authors.initials: I
authors.lastname: Fernández
authors.affiliation: Institute of Applied OphthalmoBiology (IOBA), University of Valladolid, Valladolid, Spain 2Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Valladolid, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Calonge
authors.affiliation: Institute of Applied OphthalmoBiology (IOBA), University of Valladolid, Valladolid, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Martínez
authors.affiliation: Institute of Applied OphthalmoBiology (IOBA), University of Valladolid, Valladolid, Spain 2Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Valladolid, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: González-García
authors.affiliation: Hematology Service, University Hospital, Instituto de Investigación Biomédica de Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Caballero
authors.affiliation: Hematology Service, University Hospital, Instituto de Investigación Biomédica de Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: López-Corral
authors.affiliation: Institute of Applied OphthalmoBiology (IOBA), University of Valladolid, Valladolid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: García-Vázquez
authors.affiliation: Hematology Service, University Hospital, Instituto de Investigación Biomédica de Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Vázquez
authors.affiliation: Allergan, Inc., Irvine, California, United States.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Stern
authors.affiliation: Institute of Applied OphthalmoBiology (IOBA), University of Valladolid, Valladolid, Spain 2Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Valladolid, Spain.
authors.forename: Amalia
authors.initials: A
authors.lastname: Enríquez-de-Salamanca
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D054413:Chemokine CCL11 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism*; D015352:Dry Eye Syndromes / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D005128:Eye Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006086:Graft vs Host Disease / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011237:Predictive Value of Tests; D013666:Tears / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015415:Biomarkers; C515456:CCL11 protein, human; D054413:Chemokine CCL11; D018925:Chemokines; D016207:Cytokines; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor; D007371:Interferon-gamma