title: Distribution based nearest neighbor imputation for truncated high dimensional data with applications to pre-clinical and clinical metabolomics studies.
abstract: BACKGROUND
  High throughput metabolomics makes it possible to measure the relative abundances of numerous metabolites in biological samples, which is useful to many areas of biomedical research. However, missing values (MVs) in metabolomics datasets are common and can arise due to both technical and biological reasons. Typically, such MVs are substituted by a minimum value, which may lead to different results in downstream analyses.
  
  
  RESULTS
  Here we present a modified version of the K-nearest neighbor (KNN) approach which accounts for truncation at the minimum value, i.e., KNN truncation (KNN-TN). We compare imputation results based on KNN-TN with results from other KNN approaches such as KNN based on correlation (KNN-CR) and KNN based on Euclidean distance (KNN-EU). Our approach assumes that the data follow a truncated normal distribution with the truncation point at the detection limit (LOD). The effectiveness of each approach was analyzed by the root mean square error (RMSE) measure as well as the metabolite list concordance index (MLCI) for influence on downstream statistical testing. Through extensive simulation studies and application to three real data sets, we show that KNN-TN has lower RMSE values compared to the other two KNN procedures as well as simpler imputation methods based on substituting missing values with the metabolite mean, zero values, or the LOD. MLCI values between KNN-TN and KNN-EU were roughly equivalent, and superior to the other four methods in most cases.
  
  
  CONCLUSIONS
  Our findings demonstrate that KNN-TN generally has improved performance in imputing the missing values of the different datasets compared to KNN-CR and KNN-EU when there is missingness due to missing at random combined with an LOD. The results shown in this study are in the field of metabolomics but this method could be applicable with any high throughput technology which has missing due to LOD.
authors.affiliation: Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY, 40202, USA. jasmit.shah@louisville.edu.|Department of Medicine, Division of Cardiovascular Medicine, Diabetes and Obesity Center, University of Louisville, Louisville, KY, 40202, USA. jasmit.shah@louisville.edu.
authors.forename: Jasmit S
authors.initials: JS
authors.lastname: Shah
authors.affiliation: Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY, 40202, USA.
authors.forename: Shesh N
authors.initials: SN
authors.lastname: Rai
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Diabetes and Obesity Center, University of Louisville, Louisville, KY, 40202, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: DeFilippis
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Diabetes and Obesity Center, University of Louisville, Louisville, KY, 40202, USA.
authors.forename: Bradford G
authors.initials: BG
authors.lastname: Hill
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Diabetes and Obesity Center, University of Louisville, Louisville, KY, 40202, USA.
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.affiliation: Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY, 40202, USA. Guy.Brock@osumc.edu.|Present Affiliation: Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA. Guy.Brock@osumc.edu.
authors.forename: Guy N
authors.initials: GN
authors.lastname: Brock
mesh_terms: D000465:Algorithms; D035843:Biomedical Research; D019295:Computational Biology; D006801:Humans; D055432:Metabolomics
keywords: High dimensional data; Imputation; K-nearest neighbors; Metabolomics; Missing value; Truncated normal