Phenotype prediction using biologically interpretable neural networks on multi-cohort multi-omics data
npj Systems Biology and Applications, vol. 10, pp. 81
Abstract
Abstract Integrating multi-omics data into predictive models has the potential to enhance accuracy, which is essential for precision medicine. In this study, we developed interpretable predictive models for multi-omics data by employing neural networks informed by prior biological knowledge, referred to as visible networks. These neural networks offer insights into the decision-making process and can unveil novel perspectives on the underlying biological mechanisms associated with traits and complex diseases. We tested the performance, interpretability and generalizability for inferring smoking status, subject age and LDL levels using genome-wide RNA expression and CpG methylation data from the blood of the BIOS consortium (four population cohorts, N total = 2940). In a cohort-wise cross-validation setting, the consistency of the diagnostic performance and interpretation was assessed. Performance was consistently high for predicting smoking status with an overall mean AUC of 0.95 (95% CI: 0.90–1.00) and interpretation revealed the involvement of well-replicated genes such as AHRR , GPR15 and LRRN3 . LDL-level predictions were only generalized in a single cohort with an R 2 of 0.07 (95% CI: 0.05–0.08). Age was inferred with a mean error of 5.16 (95% CI: 3.97–6.35) years with the genes COL11A2, AFAP1 , OTUD7A , PTPRN2 , ADARB2 and CD34 consistently predictive. For both regression tasks, we found that using multi-omics networks improved performance, stability and generalizability compared to interpretable single omic networks. We believe that visible neural networks have great potential for multi-omics analysis; they combine multi-omic data elegantly, are interpretable, and generalize well to data from different cohorts.
Authors 52
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Arno van Hilten corresponding
Affiliation as printed
Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands. a.vanhilten@erasmusmc.nl
Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
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Affiliation as printed
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
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Affiliation as printed
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
Department of Orthopaedics and Sports Medicine, Erasmus MC, Rotterdam, The Netherlands
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Amsterdam Neuroscience · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
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Amsterdam Neuroscience · Vrije Universiteit Amsterdam
Affiliation as printed
Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands
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Amsterdam Neuroscience · Vrije Universiteit Amsterdam
Affiliation as printed
Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands
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Amsterdam Neuroscience · Vrije Universiteit Amsterdam
Affiliation as printed
Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands
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Amsterdam Neuroscience · Vrije Universiteit Amsterdam
Affiliation as printed
Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands
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Maastricht University Medical Centre · Maastricht University
Affiliation as printed
Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands
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Maastricht University Medical Centre · Maastricht University
Affiliation as printed
Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands
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Maastricht University Medical Centre · Maastricht University
Affiliation as printed
Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands
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Maastricht University Medical Centre · Maastricht University
Affiliation as printed
Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
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University Medical Center Utrecht
Affiliation as printed
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
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Affiliation as printed
Department of Genetic Epidemiology, Erasmus MC, Rotterdam, The Netherlands
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Affiliation as printed
Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
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Affiliation as printed
Department of Genetic Epidemiology, Erasmus MC, Rotterdam, The Netherlands
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Affiliation as printed
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
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Affiliation as printed
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
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Affiliation as printed
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
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Affiliation as printed
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Sequence Analysis Support Core, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
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Affiliation as printed
SURFsara, Amsterdam, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Sequence Analysis Support Core, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
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Affiliation as printed
SURFsara, Amsterdam, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Sequence Analysis Support Core, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
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Leiden University · Leiden University Medical Center
Affiliation as printed
Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
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Leiden University · Leiden University Medical Center
Affiliation as printed
Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
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Leiden University · Leiden University Medical Center
Affiliation as printed
Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
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Delft University of Technology
Affiliation as printed
Department of Imaging Physics, Delft University of Technology, Delft, The Netherlands
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Erasmus MC · Delft University of Technology
Affiliation as printed
Department of Imaging Physics, Delft University of Technology, Delft, The Netherlands
Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
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Affiliation as printed
Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
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