Use of biclustering for missing value imputation in gene expression data

(1) Background: Gene-expression data usually contain missing values (MVs). Numerous methods focused on how to estimate MVs have been proposed in the past few years. Recent studies show that those imputation algorithms made little difference in classification. Thus, some scholars believe that how to select the informative genes for downstream classification is more important than how to impute MVs. However, most feature-selection (FS) algorithms need beforehand imputation, and the impact of beforehand MV imputation on downstream FS performance is seldom considered. (2) Method: A modified chi-square test-based FS is introduced for gene-expression data. To deal with the challenge of a small sample size of gene-expression data, a heuristic method called recursive element aggregation is proposed in this study. Our approach can directly handle incomplete data without any imputation methods or missing-data assumptions. The most informative genes can be selected through a threshold. After that, the best-first search strategy is utilized to find optimal feature subsets for classification. (3) Results: We compare our method with several FS algorithms. Evaluation is performed on twelve original incomplete cancer gene-expression datasets. We demonstrate that MV imputation on an incomplete dataset impacts subsequent FS in terms of classification tasks. Through directly conducting FS on incomplete data, our method can avoid potential disturbances on subsequent FS procedures caused by MV imputation. An experiment on small, round blue cell tumor (SRBCT) dataset showed that our method found additional genes besides many common genes with the two compared existing methods.

Most of the gene expression data analysis algorithms require the entire gene expression matrix without any missing values. Hence, it is necessary to devise methods which would impute missing data values accurately. There exist a number of imputation algorithms to estimate those missing values. This work starts with a microarray dataset containing multiple missing values. We first apply the modified version of the fuzzy theory based existing method LRFDVImpute to impute multiple missing values of time series gene expression data and then validate the result of imputation by genetic algorithm (GA) based gene ranking methodology along with some regular statistical validation techniques, like RMSE method. Gene ranking, as far as our knowledge, has not been used yet to validate the result of missing value estimation. Firstly, the proposed method has been tested on the very popular Spellman dataset and results show that error margins have been drastically reduced compared to some previous works, which indirectly validates the statistical significance of the proposed method. Then it has been applied on four other 2-class benchmark datasets, like Colorectal Cancer tumours dataset (GDS4382), Breast Cancer dataset (GSE349-350), Prostate Cancer dataset, and DLBCL-FL (Leukaemia) for both missing value estimation and ranking the genes, and the results show that the proposed method can reach 100% classification accuracy with very few dominant genes, which indirectly validates the biological significance of the proposed method.

Background . Properly constructed decision support systems (DSS) for modelling and forecasting behaviour of dynamic systems provide a possibility for taking into consideration uncertainties of probabilistic, statistical and structural types what results in higher quality of developed models and estimated forecasts. Objective . To consider general reasons for loosing (missing) data in statistical data analysis; to provide categorization of missing data into several groups, and identify the reasons for missing measurements; to provide stepwise system methodology for uncertainty analysis and selection of data imputation techniques; to give an insight into some popular missing values imputation techniques regarding their possible applications. Methods . To solve the problems mentioned the following methods have been used: data categorization approach from business or practical point of view that is necessary for discovering the reasons for availability of systemic and/or random missing values; the modern systemic methodology was hired for analysis of uncertainty causes and missing values imputation; the decision tree based imputation procedures; EM algorithm and regression model approach to forecasting missing data using forecasting functions. Results . The main results of the study are in categorization of the missing data into groups; development of systemic methodology for analysis of uncertainty causes and missing values imputation; providing an analysis for possibilities of missing values imputation with decision trees, EM algorithm and regression models; development of multistep forecasting functions on the basis of autoregression models; illustration of application of some selected perspective methods for missing data imputation. Conclusions . We proposed the six steps system methodology for data imputation which stresses that selection of correct method for imputation is tightly connected with the step-by-step analysis of the gaps causes and finding an appropriate technique for their imputation. The results of imputation sometimes are rather far from the existing data and should be smoothed or even broken from the sample due to their incorrectness. For such cases it should be proposed a new probabilistic-regression method which allows define parameters of the probability interval for the regression aiming missing data imputation. A series of computing experiments performed with EM algorithm, forecast regression based imputation technique and some other approaches shows that it is possible to reach high quality results regarding correct processing of data with missing values.

Gene expression data often contain missing expression values. Effective missing value estimation methods are needed since many algorithms for gene expression data analysis require a complete matrix of gene array values. In this paper, imputation methods based on the least squares formulation are proposed to estimate missing values in the gene expression data, which exploit local similarity structures in the data as well as least squares optimization process. The proposed local least squares imputation method (LLSimpute) represents a target gene that has missing values as a linear combination of similar genes. The similar genes are chosen by k-nearest neighbors or k coherent genes that have large absolute values of Pearson correlation coefficients. Non-parametric missing values estimation method of LLSimpute are designed by introducing an automatic k-value estimator. In our experiments, the proposed LLSimpute method shows competitive results when compared with other imputation methods for missing value estimation on various datasets and percentages of missing values in the data. The software is available at http://www.cs.umn.edu/~hskim/tools.html hpark@cs.umn.edu

High-throughput biotechnologies, such as gene expression microarrays or mass-spectrometry-based proteomic assays, suffer from frequent missing values due to various experimental reasons. Since the missing data points can hinder downstream analyses, there exists a wide variety of ways in which to deal with missing values in large-scale data sets. Nowadays, it has become routine to estimate (or impute) the missing values prior to the actual data analysis. After nearly a decade since the publication of the first missing value imputation methods for gene expression microarray data, new imputation approaches are still being developed at an increasing rate. However, what is lagging behind is a systematic and objective evaluation of the strengths and weaknesses of the different approaches when faced with different types of data sets and experimental questions. In this review, the present strategies for missing value imputation and the measures for evaluating their performance are described. The imputation methods are first reviewed in the context of gene expression microarray data, since most of the methods have been developed for estimating gene expression levels; then, we turn to other large-scale data sets that also suffer from the problems posed by missing values, together with pointers to possible imputation approaches in these settings. Along with a description of the basic principles behind the different imputation approaches, the review tries to provide practical guidance for the users of high-throughput technologies on how to choose the imputation tool for their data and questions, and some additional research directions for the developers of imputation methodologies.

 Electrocardiogram signal analysis is very difficult to classify cardiac arrhythmia using machine learning methods. The ECG datasets normally come with multiple missing values. The reason for the missing values is the faults or distortion. When performing data mining, missing value imputation is the biggest task for data preprocessing. This problem could arise due to incomplete medical datasets if the incomplete missing values and cases were removed from the original database. To produce a good quality dataset for better analyzing the clinical trials, the suitable missing value imputation method is used. In this paper, we explore the different machine-learning techniques for the computed missing value in the electrocardiogram dataset. To estimate the missing imputation values, the collected data contains feature dimensions with their attributes. The experiments to compute the missing values in the dataset are carried out by using the four feature selection methods and imputation methods. The implemented results are shown by combined features using IG (information gain), GA (genetic algorithm) and the different machine learning classifiers such as NB (naïve bayes), KNN (K-nearest neighbor), MLP (Multilayer perception), and RF (Random forest). The GA (genetic algorithm) and IG (information gain) are the best suitable methods for obtaining the results on lower dimensional datasets with RMSE (Root mean square error. It efficiently calculates the best results for missing values. These four classifiers are used to analyze the impact of imputation methods. The best results for missing rate 10% to 40% are obtained by NB that is 0.657, 0.6541, 0.66, 0.657, and 0.657, as computed by RMSE (Root mean Square error). It means that error will efficiently reduced by naïve bayes classifier.

Fuzzy neuron modeling of incomplete data for missing value imputation

BackgroundMissing data are a common problem in prospective studies with a long follow-up, and the volume, pattern and reasons for missing data may be relevant when estimating the cost of illness. We aimed to evaluate the effects of different methods for dealing with missing longitudinal cost data and for costing caregiver time on total societal costs in Alzheimer’s disease (AD).MethodsGERAS is an 18-month observational study of costs associated with AD. Total societal costs included patient health and social care costs, and caregiver health and informal care costs. Missing data were classified as missing completely at random (MCAR), missing at random (MAR) or missing not at random (MNAR). Simulation datasets were generated from baseline data with 10–40 % missing total cost data for each missing data mechanism. Datasets were also simulated to reflect the missing cost data pattern at 18 months using MAR and MNAR assumptions. Naïve and multiple imputation (MI) methods were applied to each dataset and results compared with complete GERAS 18-month cost data. Opportunity and replacement cost approaches were used for caregiver time, which was costed with and without supervision included and with time for working caregivers only being costed.ResultsTotal costs were available for 99.4 % of 1497 patients at baseline. For MCAR datasets, naïve methods performed as well as MI methods. For MAR, MI methods performed better than naïve methods. All imputation approaches were poor for MNAR data. For all approaches, percentage bias increased with missing data volume. For datasets reflecting 18-month patterns, a combination of imputation methods provided more accurate cost estimates (e.g. bias: −1 % vs −6 % for single MI method), although different approaches to costing caregiver time had a greater impact on estimated costs (29–43 % increase over base case estimate).ConclusionsMethods used to impute missing cost data in AD will impact on accuracy of cost estimates although varying approaches to costing informal caregiver time has the greatest impact on total costs. Tailoring imputation methods to the reason for missing data will further our understanding of the best analytical approach for studies involving cost outcomes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12874-016-0188-1) contains supplementary material, which is available to authorized users.

BackgroundExtracellular vesicle-derived (EV)-miRNAs have potential to serve as biomarkers for the diagnosis of various diseases. miRNA microarrays are widely used to quantify circulating EV-miRNA levels, and the preprocessing of miRNA microarray data is critical for analytical accuracy and reliability. Thus, although microarray data have been used in various studies, the effects of preprocessing have not been studied for Toray’s 3D-Gene chip, a widely used measurement method. We aimed to evaluate batch effect, missing value imputation accuracy, and the influence of preprocessing on measured values in 18 different preprocessing pipelines for EV-miRNA microarray data from two cohorts with amyotrophic lateral sclerosis using 3D-Gene technology.ResultsEighteen different pipelines with different types and orders of missing value completion and normalization were used to preprocess the 3D-Gene microarray EV-miRNA data. Notable results were suppressed in the batch effects in all pipelines using the batch effect correction method ComBat. Furthermore, pipelines utilizing missForest for missing value imputation showed high agreement with measured values. In contrast, imputation using constant values for missing data exhibited low agreement.ConclusionsThis study highlights the importance of selecting the appropriate preprocessing strategy for EV-miRNA microarray data when using 3D-Gene technology. These findings emphasize the importance of validating preprocessing approaches, particularly in the context of batch effect correction and missing value imputation, for reliably analyzing data in biomarker discovery and disease research.

BackgroundIn modern biomedical research of complex diseases, a large number of demographic and clinical variables, herein called phenomic data, are often collected and missing values (MVs) are inevitable in the data collection process. Since many downstream statistical and bioinformatics methods require complete data matrix, imputation is a common and practical solution. In high-throughput experiments such as microarray experiments, continuous intensities are measured and many mature missing value imputation methods have been developed and widely applied. Numerous methods for missing data imputation of microarray data have been developed. Large phenomic data, however, contain continuous, nominal, binary and ordinal data types, which void application of most methods. Though several methods have been developed in the past few years, not a single complete guideline is proposed with respect to phenomic missing data imputation.ResultsIn this paper, we investigated existing imputation methods for phenomic data, proposed a self-training selection (STS) scheme to select the best imputation method and provide a practical guideline for general applications. We introduced a novel concept of “imputability measure” (IM) to identify missing values that are fundamentally inadequate to impute. In addition, we also developed four variations of K-nearest-neighbor (KNN) methods and compared with two existing methods, multivariate imputation by chained equations (MICE) and missForest. The four variations are imputation by variables (KNN-V), by subjects (KNN-S), their weighted hybrid (KNN-H) and an adaptively weighted hybrid (KNN-A). We performed simulations and applied different imputation methods and the STS scheme to three lung disease phenomic datasets to evaluate the methods. An R package “phenomeImpute” is made publicly available.ConclusionsSimulations and applications to real datasets showed that MICE often did not perform well; KNN-A, KNN-H and random forest were among the top performers although no method universally performed the best. Imputation of missing values with low imputability measures increased imputation errors greatly and could potentially deteriorate downstream analyses. The STS scheme was accurate in selecting the optimal method by evaluating methods in a second layer of missingness simulation. All source files for the simulation and the real data analyses are available on the author’s publication website.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-014-0346-6) contains supplementary material, which is available to authorized users.

Currently, many databases contain missing values, especially in medical data. Statistical and data mining approaches often require complete data conditions, where these two approaches will not provide adequate performance if the data contains missing values. Several techniques have been made to overcome missing values, one of which is by deleting data containing missing values. However, this approach will omit a lot of information if the data found includes many missing values. This study used an imputation approach (filling in the missing attributes) with a clustering approach. One of the most common clustering approaches is K-Means Clustering. In K-means clustering, the value of the centroid gets from the closest observed value. In this study, we propose updating the centroid value based on the harmonic average of the distance across all observations per centroid. This method is known as K-Harmonic Means Clustering (KHM). We proposed a new program approach for a mixed dataset on three scenarios for missing values of 10%, 20%, and 30%. From the experiments conducted on experimental data sets containing missing values, we get a small proportion of missing values (10%) with a small number of clusters or K, which gives a smaller RMSE value compared to other scenarios.

A massive amount of data is emerging continuously in the era of big data; the missing value is a common yet challenging problem. Missing data or missing value can be described as the data whose values in any given dataset are unknown. It is a recurrent phenomenon and can give biased results from the data to be observed and affect the value of the learning process. Therefore, it is mandatory to use missing value imputation techniques. Missing value imputation provides (MVI) optimal solutions for missing values in a dataset. There are diverse missing value imputation techniques such as statistical method and machine learning methods proposed till date, each having their own significances and flaws. Reasonably, good imputation results may be produced by machine learning MVI approaches but they take greater imputation times than statistical approaches usually. In this paper, we have reviewed some of the missing value imputation approaches proposed. In order to show the efficiency of their proposed approaches, they had compared their proposed methods with some baseline imputation algorithms like mode/median, k-nearest neighbor, Naive Bayes, support vector machine. The outcome of each proposed method is analyzed and their extension scopes from the perspectives of research focus. The main idea of this literature is to give a general review of missing value imputation approaches.

Many datasets include missing values in their attributes. Data mining techniques are not applicable in the presence of missing values. So an important step in preprocessing of a data mining task is missing value management. One of the most important categories in missing value management techniques is missing value imputation. This paper presents a new imputation technique. The proposed imputation technique is based on statistical measurements. The suggested imputation technique employs an ensemble of the estimators built to estimate the missing values based on positive and negative correlated observed attributes separately. Each estimator guesses a value for a missed value based on the average and variance of that feature. The average and variance of the feature are estimated from the non-missed values of that feature. The final consensus value for a missed value is the weighted aggregation of the values estimated by different estimators. The chief weight is attribute correlation, and the slight weight is dependent to kernel function such as kurtosis, skewness, number of involved samples and composition of them. The missing values are deliberately produced randomly at different levels. The experimentations indicate that the suggested technique has a good accuracy in comparison with the classical methods.

A two-phase learning strategy for rule induction from incomplete data is proposed, and a new form of rules is introduced so that a user can easily identify attributes with or without missing values in a rule. Two levels of measurement are assigned to a rule. An algorithm for two-phase rule induction is presented. Instead of filling in missing attribute values before or during the process of rule induction, we divide rule induction into two phases. In the first phase, rules and partial rules are induced based on non-missing values. In the second phase, partial rules are modified and refined by the imputation of some missing values. Such rules truthfully reflect the knowledge embedded in the incomplete data. The study not only presents a new view of rule induction from incomplete data, but also provides a practical solution. Experiments validate the effectiveness of the proposed method.

Despite considerable advances in high throughput technology over the last decade, new challenges have emerged related to the analysis, interpretation, and integration of high-dimensional data. The arrival of omics datasets has contributed to the rapid improvement of systems biology, which seeks the understanding of complex biological systems. Metabolomics is an emerging omics field, where mass spectrometry technologies generate high dimensional datasets. As advances in this area are progressing, the need for better analysis methods to provide correct and adequate results are required. While in other omics sectors such as genomics or proteomics there has and continues to be critical understanding and concern in developing appropriate methods to handle missing values, handling of missing values in metabolomics has been an undervalued step. Missing data are a common issue in all types of medical research and handling missing data has always been a challenge. Since many downstream analyses such as classification methods, clustering methods, and dimension reduction methods require complete datasets, imputation of missing data is a critical and crucial step. The standard approach used is to remove features with one or more missing values or to substitute them with a value such as mean or half minimum substitution. One of the major issues from the missing data in metabolomics is due to a limit of detection, and thus sophisticated methods are needed to incorporate different origins of missingness. This dissertation contributes to the knowledge of missing value imputation methods with three separate but related research projects. The first project consists of a novel missing value imputation method based on a modification of the k nearest neighbor method which accounts for truncation at the minimum value/limit of detection. The approach assumes that the data follows a truncated normal distribution with the truncation point at the detection limit. The aim of the second project arises from the limitation in the first project. While the novel approach is useful, estimation of the truncated mean and standard deviation is problematic in small sample sizes (N < 10). In this project, we develop a Bayesian model for imputing missing values with small sample sizes. The Bayesian paradigm has generally been utilized in the omics field as it exploits the data accessible from related components to acquire data to stabilize parameter estimation. The third project is based on the motivation to determine the impact of missing value imputation on down-stream analyses and whether ranking of imputation methods