title: Plasma Anti-Glycan Antibody Profiles Associated with Nickel level in Urine.
abstract: Nickel (Ni) compounds are widely used in industrial and commercial products including household and cooking utensils, jewelry, dental appliances and implants. Occupational exposure to nickel is associated with an increased risk for lung and nasal cancers, is the most common cause of contact dermatitis and has an extensive effect on the immune system. The purpose of this study was two-fold: (i) to evaluate immune response to the occupational exposure to nickel measured by the presence of anti-glycan antibodies (AGA) using a new biomarker-discovery platform based on printed glycan arrays (PGA), and (ii) to evaluate and compile a sequence of bioinformatics and statistical methods which are specifically relevant to PGA-derived information and to identification of putative "Ni toxicity signature". The PGAs are similar to DNA microarrays, but contain deposits of various carbohydrates (glycans) instead of spotted DNAs. The study uses data derived from a set of 89 plasma specimens and their corresponding demographic information. The study population includes three subgroups: subjects directly exposed to Nickel that work in a refinery, subjects environmentally exposed to Nickel that live in a city where the refinery is located and subjects that live in a remote location. The paper describes the following sequence of nine data processing and analysis steps: (1) Analysis of inter-array reproducibility based on benchmark sera; (2) Analysis of intra-array reproducibility; (3) Screening of data - rejecting glycans which result in low intra-class correlation coefficient (ICC), high coefficient of variation and low fluorescent intensity; (4) Analysis of inter-slide bias and choice of data normalization technique; (5) Determination of discriminatory subsamples based on multiple bootstrap tests; (6) Determination of the optimal signature size (cardinality of selected feature set) based on multiple cross-validation tests; (7) Identification of the top discriminatory glycans and their individual performance based on nonparametric univariate feature selection; (8) Determination of multivariate performance of combined glycans; (9) Establishing the statistical significance of multivariate performance of combined glycan signature. The above analysis steps have delivered the following results: inter-array reproducibilityρ=0.920 ± 0.030; intra-array reproducibilityρ=0.929 ± 0.025; 249 out of 380 glycans passed the screening at ICC>80%, glycans in selected signature have ICC ≥ 88.7%; optimal signature size (after quantile normalization)=3; individual significance for the signature glycansp=0.00015 to 0.00164, individual AUC values 0.870 to 0.815; observed combined performance for three glycansAUC=0.966,p=0.005,CI=[0.757, 0947];specifity=94.4%,sensitivity=88.9%; predictive (cross-validated) AUC value 0.836.
authors.affiliation: Department of Computer Science, San Diego State University, San Diego, 92182 CA, USA.
authors.forename: Marko
authors.initials: M
authors.lastname: Vuskovic
authors.affiliation: Department of Cardiothoracic Surgery, NYU School of Medicine, New York, 10016 NY, USA.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Barbuti
authors.affiliation: Department of Cardiothoracic Surgery, NYU School of Medicine, New York, 10016 NY, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Goldsmith-Rooney
authors.affiliation: Department of Cardiothoracic Surgery, NYU School of Medicine, New York, 10016 NY, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Glassman
authors.affiliation: Shemyakin Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Bovin
authors.affiliation: Department of Cardiothoracic Surgery, NYU School of Medicine, New York, 10016 NY, USA.
authors.forename: Harvey
authors.initials: H
authors.lastname: Pass
authors.affiliation: Department of Environmental Medicine, NYU School of Medicine, New York, 10016 NY, USA.
authors.forename: Kam-Meng
authors.initials: KM
authors.lastname: Tchou-Wong
authors.affiliation: Lanzhou University School of Public Health, Lanzhou, Gansu 730000, China.
authors.forename: Meichi
authors.initials: M
authors.lastname: Chen
authors.affiliation: Lanzhou University School of Public Health, Lanzhou, Gansu 730000, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
authors.affiliation: Lanzhou University School of Public Health, Lanzhou, Gansu 730000, China.
authors.forename: Jingping
authors.initials: J
authors.lastname: Niu
authors.affiliation: Department of Environmental Medicine, NYU School of Medicine, New York, 10016 NY, USA.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Qu
authors.affiliation: Department of Environmental Medicine, NYU School of Medicine, New York, 10016 NY, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Costa
authors.affiliation: Department of Cardiothoracic Surgery, NYU School of Medicine, New York, 10016 NY, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Huflejt
keywords: Discriminatory signatures; Immune response to occupational exposure to Nickel; Immunoprofiling; Immunoruler; Plasma anti-glycan antibodies; Printed glycan arrays; Quality analysis of printed glycan arrays
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