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Batch effects introduce significant variability into high-dimensional data, complicating accurate analysis and leading to potentially misleading conclusions if not adequately addressed. Despite technological and algorithmic advancements in biomedical research, effectively managing batch effects remains a complex challenge requiring comprehensive considerations. This paper underscores the necessity of a flexible and holistic approach for selecting batch effect correction algorithms (BECAs), advocating for proper BECA evaluations and consideration of artificial intelligence-based strategies. We also discuss key challenges in batch effect correction, including the importance of uncovering hidden batch factors and understanding the impact of design imbalance, missing values, and aggressive correction. Our aim is to provide researchers with a robust framework for effective batch effects management and enhancing the reliability of high-dimensional data analyses., (© The Author(s) 2024. Published by Oxford University Press.)

This article summarizes the PROTREC method and investigates the impact that the different hyper-parameters have on the task of missing protein prediction using PROTREC. We evaluate missing protein recovery rates using different PROTREC score selection approaches (MAX, MIN, MEDIAN, and MEAN), different PROTREC score thresholds, as well as different complex size thresholds. In addition, we included two additional cancer datasets in our analysis and introduced a new validation method to check both the robustness of the PROTREC method as well as the correctness of our analysis. Our analysis showed that the missing protein recovery rate can be improved by adopting PROTREC score selection operations of MIN, MEDIAN, and MEAN instead of the default MAX. However, this may come at a cost of reduced numbers of proteins predicted and validated. The users should therefore choose their hyper-parameters carefully to find a balance in the accuracy-quantity trade-off. We also explored the possibility of combining PROTREC with a p-value-based method (FCS) and demonstrated that PROTREC is able to perform well independently without any help from a p-value-based method. Furthermore, we conducted a downstream enrichment analysis to understand the biological pathways and protein networks within the cancerous tissues using the recovered proteins. Missing protein recovery rate using PROTREC can be improved by selecting a different PROTREC score selection method. Different PROTREC score selection methods and other hyper-parameters such as PROTREC score threshold and complex size threshold introduce accuracy-quantity trade-off. PROTREC is able to perform well independently of any filtering using a p-value-based method. Verification of the PROTREC method on additional cancer datasets. Downstream Enrichment Analysis to understand the biological pathways and protein networks in cancerous tissues., (© 2023 Wiley-VCH GmbH.)

Missing values (MVs) can adversely impact data analysis and machine-learning model development. We propose a novel mixed-model method for missing value imputation (MVI). This method, ProJect (short for Protein inJection), is a powerful and meaningful improvement over existing MVI methods such as Bayesian principal component analysis (PCA), probabilistic PCA, local least squares and quantile regression imputation of left-censored data. We rigorously tested ProJect on various high-throughput data types, including genomics and mass spectrometry (MS)-based proteomics. Specifically, we utilized renal cancer (RC) data acquired using DIA-SWATH, ovarian cancer (OC) data acquired using DIA-MS, bladder (BladderBatch) and glioblastoma (GBM) microarray gene expression dataset. Our results demonstrate that ProJect consistently performs better than other referenced MVI methods. It achieves the lowest normalized root mean square error (on average, scoring 45.92% less error in RC_C, 27.37% in RC_full, 29.22% in OC, 23.65% in BladderBatch and 20.20% in GBM relative to the closest competing method) and the Procrustes sum of squared error (Procrustes SS) (exhibits 79.71% less error in RC_C, 38.36% in RC full, 18.13% in OC, 74.74% in BladderBatch and 30.79% in GBM compared to the next best method). ProJect also leads with the highest correlation coefficient among all types of MV combinations (0.64% higher in RC_C, 0.24% in RC full, 0.55% in OC, 0.39% in BladderBatch and 0.27% in GBM versus the second-best performing method). ProJect's key strength is its ability to handle different types of MVs commonly found in real-world data. Unlike most MVI methods that are designed to handle only one type of MV, ProJect employs a decision-making algorithm that first determines if an MV is missing at random or missing not at random. It then employs targeted imputation strategies for each MV type, resulting in more accurate and reliable imputation outcomes. An R implementation of ProJect is available at https://github.com/miaomiao6606/ProJect., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In mass spectrometry (MS)-based proteomics, protein inference from identified peptides (protein fragments) is a critical step. We present ProInfer (Protein Inference), a novel protein assembly method that takes advantage of information in biological networks. ProInfer assists recovery of proteins supported only by ambiguous peptides (a peptide which maps to more than one candidate protein) and enhances the statistical confidence for proteins supported by both unique and ambiguous peptides. Consequently, ProInfer rescues weakly supported proteins thereby improving proteome coverage. Evaluated across THP1 cell line, lung cancer and RAW267.4 datasets, ProInfer always infers the most numbers of true positives, in comparison to mainstream protein inference tools Fido, EPIFANY and PIA. ProInfer is also adept at retrieving differentially expressed proteins, signifying its usefulness for functional analysis and phenotype profiling. Source codes of ProInfer are available at https://github.com/PennHui2016/ProInfer., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Peng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Data analysis is complex due to a myriad of technical problems. Amongst these, missing values and batch effects are endemic. Although many methods have been developed for missing value imputation (MVI) and batch correction respectively, no study has directly considered the confounding impact of MVI on downstream batch correction. This is surprising as missing values are imputed during early pre-processing while batch effects are mitigated during late pre-processing, prior to functional analysis. Unless actively managed, MVI approaches generally ignore the batch covariate, with unknown consequences. We examine this problem by modelling three simple imputation strategies: global (M1), self-batch (M2) and cross-batch (M3) first via simulations, and then corroborated on real proteomics and genomics data. We report that explicit consideration of batch covariates (M2) is important for good outcomes, resulting in enhanced batch correction and lower statistical errors. However, M1 and M3 are error-generating: global and cross-batch averaging may result in batch-effect dilution, with concomitant and irreversible increase in intra-sample noise. This noise is unremovable via batch correction algorithms and produces false positives and negatives. Hence, careless imputation in the presence of non-negligible covariates such as batch effects should be avoided., (© 2023. The Author(s).)

Proteomics data are often plagued with missingness issues. These missing values (MVs) threaten the integrity of subsequent statistical analyses by reduction of statistical power, introduction of bias, and failure to represent the true sample. Over the years, several categories of missing value imputation (MVI) methods have been developed and adapted for proteomics data. These MVI methods perform their tasks based on different prior assumptions (e.g., data is normally or independently distributed) and operating principles (e.g., the algorithm is built to address random missingness only), resulting in varying levels of performance even when dealing with the same dataset. Thus, to achieve a satisfactory outcome, a suitable MVI method must be selected. To guide decision making on suitable MVI method, we provide a decision chart which facilitates strategic considerations on datasets presenting different characteristics. We also bring attention to other issues that can impact proper MVI such as the presence of confounders (e.g., batch effects) which can influence MVI performance. Thus, these too, should be considered during or before MVI., (© 2022 Wiley-VCH GmbH.)

Effective integration and analysis of new high-throughput data, especially gene-expression and proteomic-profiling data, are expected to deliver novel clinical insights and therapeutic options. Unfortunately, technical heterogeneity or batch effects (different experiment times, handlers, reagent lots, etc.) have proven challenging. Although batch effect-correction algorithms (BECAs) exist, we know little about effective batch-effect mitigation: even now, new batch effect-associated problems are emerging. These include false effects due to misapplying BECAs and positive bias during model evaluations. Depending on the choice of algorithm and experimental set-up, biological heterogeneity can be mistaken for batch effects and wrongfully removed. Here, we examine these emerging batch effect-associated problems, propose a series of best practices, and discuss some of the challenges that lie ahead., (Copyright © 2017 Elsevier Ltd. All rights reserved.)