bioRxiv Science⌕ Search

bioRxiv · 10.1101/2022.05.03.490388

A real data-based simulation procedure to select an imputation strategy for mixed-type trait data

Abstract

Missing observations in trait datasets pose an obstacle for analyses in myriad biological disciplines. Considering the mixed results of imputation, the wide variety of available methods, and the varied structure of real trait datasets, a framework for selecting a suitable imputation method is advantageous. We invoked a real data-driven simulation strategy to select an imputation method for a given mixed-type (categorical, count, continuous) target dataset. Candidate methods included mean/mode imputation, k-nearest neighbour, random forests, and multivariate imputation by chained equations (MICE). Using a trait dataset of squamates (lizards and amphisbaenians; order: Squamata) as a target dataset, a complete-case dataset consisting of species with nearly complete information was formed for the imputation method selection. Missing data were induced by removing values from this dataset under different missingness mechanisms: missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR). For each method, combinations with and without phylogenetic information from single gene (nuclear and mitochondrial) or multigene trees were used to impute the missing values for five numerical and two categorical traits. The performances of the methods were evaluated under each missing mechanism by determining the mean squared error and proportion falsely classified rates for numerical and categorical traits, respectively. A random forest method supplemented with a nuclear-derived phylogeny resulted in the lowest error rates for the majority of traits, and this method was used to impute missing values in the original dataset. Data with imputed values better reflected the characteristics and distributions of the original data compared to complete-case data. However, caution should be taken when imputing trait data as phylogeny did not always improve performance for every trait and in every scenario. Ultimately, these results support the use of a real data-driven simulation strategy for selecting a suitable imputation method for a given mixed-type trait dataset. Author summaryThe issue of missing data is problematic in trait datasets as the missingness pattern may not be entirely random. Whether data are missing may depend on other known observations in the dataset, or on the value of the missing data points themselves. When only complete cases are used in an analysis, derived results may be biased. Imputation is an alternative to complete-case analysis and entails filling in the missing values using information provided by other trait values present in the dataset. Including phylogenetic information in the imputation process can improve the accuracy of imputed values, though results are dependent on the amount and pattern of missingness. Most previous evaluations of imputation methods for trait datasets are limited to numerical simulated data, with categorical traits not considered. Given a particular dataset, we propose the use of a real data-driven simulation strategy to select an imputation method. We evaluated the accuracies of four different imputation methods, with and without phylogeny information, and under different simulated missingness patterns using an example reptile trait dataset. Results indicated that data imputed using the best-performing method better reflected the original dataset characteristics compared to complete-case data. As imputation performance varies depending on the properties of a given dataset, a real data-driven simulation strategy can be used to provide guidance on best imputation practices.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

May, J. A., Feng, Z. A., Adamowicz, S. J.. 2022-05-04. A real data-based simulation procedure to select an imputation strategy for mixed-type trait data. https://doi.org/10.1101/2022.05.03.490388

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

Accelerating discovery and integration from RNA to Protein with R2T2P

Integrating transcriptomics and proteomics data remains an unmet challenge in the post-genomics era, discouraging researchers from pursuing integrative approaches to molecular biology research. Leveraging the power of translation profiling, we present RNA to Translation to Protein (R2T2P), a computational platform integrating genome-guided transcriptome assembly with identification of translation and proteins, including a tailored differential analysis framework and support for multiple reference transcriptomes. We applied R2T2P to investigate a cellular model of facioscapulohumeral muscular dystrophy (FSHD), where ectopic expression of the DUX4 retrogene in skeletal muscle triggers significant alterations in transcription and RNA metabolism. We uncovered hundreds of uncharacterized, highly overexpressed RNAs, including antisense and alternative transcripts, and quantified their contribution to translatome and proteome. Re-analysis of expression datasets from patient-derived myotubes and muscle biopsies validated this alternative transcriptome in FSHD patients, adding a reservoir of bona-fide novel molecular actors in a rare disease. Available at https://github.com/nfdata-omics/R2T2P/, R2T2P is a flexible and powerful workflow in modern integrative biology.

bioinformatics↗

MorphoANOVA: Dissecting Histology-Gene Expression Relationships in Spatial Transcriptomics

Spatial transcriptomics (ST) measures the expression of hundreds to thousands of genes within tissue architecture, often accompanied by histology images. However, it remains challenging to systematically characterize which genes exhibit associations with tissue morphology, whether these associations vary spatially, and which genes show additional spatial expression patterns beyond those captured by morphology. Here we introduce MorphoANOVA, a gene-wise statistical framework for characterizing morphology--expression relationships across genes measured by ST. Using nested spatially varying coefficient models and sequential ANOVA, MorphoANOVA assesses slide-wide associations with an H\&E-derived morphology feature, location-specific changes in these associations, and additional spatial variation after accounting for the selected feature. The resulting statistics enable gene prioritization and pathway enrichment analysis, while spatial component maps support the interpretation of individual genes. Simulations demonstrate MorphoANOVA's ability to distinguish the modeled components and recover their spatial patterns. Applications to human cortex and breast cancer identify biological programs associated with different morphology--expression patterns and reveal distinct relationships with cell composition. Across three HER2-positive breast cancer patients, invasive-cancer marker genes consistently exhibit stronger evidence of location-specific morphology associations. MorphoANOVA thus provides a framework for systematically interpreting spatial gene-expression patterns in relation to tissue morphology.

bioinformatics↗

Evaluation effects can rival reported concordance gains in cross-cancer survival prediction

Studies of cross-cancer learning for survival prediction from tumour omics have reported concordance gains of 0.020 and 0.045, but how such gains compare with evaluation effects remains unclear. We examined these effects across 13 TCGA cancers (5,761 patients, 1,526 disease-specific deaths), using five repeats of five-fold cross-validation and paired bootstrap intervals. When model selection did not use test data, our borrowing model gained 0.009 (95% interval 0.001 to 0.016) over its target-fitted reference when cancers received equal weight (post hoc). Random-effects pooling gave a gain of 0.002 (-0.002 to 0.006), with most weight assigned to cancers where the model made little use of the pretrained score. Choosing the fusion weight on test splits raised the apparent equal-weight gain to 0.017. We reimplemented a published method, VAECox, which showed no pretraining gain over random initialisation at the last or validation-selected training step. Choosing each network's best test step, as the published code does, raised concordance by 0.03 to 0.05 across the 13-cancer and ten-cancer overall-survival settings, but barely changed the difference between networks. In a constructed post hoc experiment, choosing the best test step only for the pretrained network changed the equal-weight mean difference from -0.004 to +0.045 (+0.035 to +0.054). Across seven multi-omics comparisons, estimates from single five-fold runs differed from their cancer's five-run mean by at least 0.02 in 11% to 42% of runs. Concordance was about 0.02 lower at held-out tissue source sites. Interpreting a reported gain therefore requires each model's selection rule, variation across repeated partitions, the weighting of cancers and the evaluation population.

bioinformatics↗