SwCAM: Estimation of subtype-specific expressions in individual samples with unsupervised sample-wise deconvolution

Lulu Chen, Chiung Ting Wu, Chia Hsiang Lin, Rujia Dai, Chunyu Liu, Robert Clarke, Guoqiang Yu, Jennifer E. Van Eyk, David M. Herrington, Yue Wang

研究成果: Article同行評審

1 引文 斯高帕斯(Scopus)

摘要

Motivation: Complex biological tissues are often a heterogeneous mixture of several molecularly distinct cell subtypes. Both subtype compositions and subtype-specific (STS) expressions can vary across biological conditions. Computational deconvolution aims to dissect patterns of bulk tissue data into subtype compositions and STS expressions. Existing deconvolution methods can only estimate averaged STS expressions in a population, while many downstream analyses such as inferring co-expression networks in particular subtypes require subtype expression estimates in individual samples. However, individual-level deconvolution is a mathematically underdetermined problem because there are more variables than observations. Results: We report a sample-wise Convex Analysis of Mixtures (swCAM) method that can estimate subtype proportions and STS expressions in individual samples from bulk tissue transcriptomes. We extend our previous CAM framework to include a new term accounting for between-sample variations and formulate swCAM as a nuclearnorm and ℓ2,1-norm regularized matrix factorization problem. We determine hyperparameter values using crossvalidation with random entry exclusion and obtain a swCAM solution using an efficient alternating direction method of multipliers. Experimental results on realistic simulation data show that swCAM can accurately estimate STS expressions in individual samples and successfully extract co-expression networks in particular subtypes that are otherwise unobtainable using bulk data. In two real-world applications, swCAM analysis of bulk RNASeq data from brain tissue of cases and controls with bipolar disorder or Alzheimer's disease identified significant changes in cell proportion, expression pattern and co-expression module in patient neurons. Comparative evaluation of swCAM versus peer methods is also provided.

原文English
頁(從 - 到)1403-1410
頁數8
期刊Bioinformatics
38
發行號5
DOIs
出版狀態Published - 2022 3月 1

All Science Journal Classification (ASJC) codes

  • 統計與概率
  • 生物化學
  • 分子生物學
  • 電腦科學應用
  • 計算機理論與數學
  • 計算數學

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